I II
Great auricular n. III
Ant. cut. n. of neck Supraclavicular n’s.
Axillary n. (circumflex)
Ant. cut.
Lower lat.cut. n. of arm (from radial n.)
Lat. rami cut.
of thor.
Lat. cut. of forearm (from musculocut. n.)
rami Ilioinguinal n. Femoral branch of genitofemoral n. (lumbo-inguinal n.)
Lat. cut. n. of thigh Intermed. & med. cut. n’s. of thigh (from femoral n.)
n’s.
T2 3 4 5 6 7 8 9 10 11 12
Med. cut. n. of arm & intercostobrachial n.
Med. cut. n. of forearm Iliohypogastric n. Genital branch of genitofem. n.
Radial n. Median n.
Ulnar n. Dorsal n. of penis Scrotal branch of perineal n. Obturator n.
Saphenous n. (from femoral n.)
Lat.cut. n. of calf (from common peroneal n.)
Greater Lesser n.
} occipital nerves
Great auricular n. Deep peroneal n. (from common peroneal n.) Med. & lat. plantar n’s. (from posttibial n.)
Superficial peroneal n. (from common peroneal n.) Sural n. (from tibial n.)
Figure 9-1. The cutaneous fields of peripheral nerves. (Reproduced by permission from Haymaker W, Woodhall B: Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.)
Ant. cut. n. of neck C5 C6
Axillary n. (circumflex) Post cut. n. of arm (from radial n.) Lower Lat. cut. of arm (from radial n.) Iliohypogastric n. Inf. med. cluneal n.
T2 3 4 5 6 7 8 9 10 11 12
T1
Supraclavicular n’s.
Post. cut. rami Lat. of cut. thor. rami n’s.
Med. cut. n. of arm & intercostobrachial n.
Post. cut. n. of forearm (from radial n.)
L1
S1 Post. rami of lumbar sacral & coccygeal n’s.
Lat. cut. n. of forearm (from musculocut n.)
Med. cut. n. of forearm
Radial n.
Ulnar n. Inf. lat. cluneal n’s. Median n.
Inf. med. n. of thigh Obturator n.
Post cut. n. of thigh
Lat. cut. n.of calf (from common femoral n.)
Med. cut. n. of thigh (from femoral n.)
Lat. plantar n.
Saphenous n. (from femoral n.)
Med. plantar n.
Superficial peroneal n. (from common peroneal n.) Sural n. (from tibial n.) Calcanean branches of sural & tibial n’s.
Figure 9-1. (Continued)
Saphenous n. Calcanean branches of tibial & sural n’s.
Lat. plantar n. Superficial peroneal n.
Sural n.
C3 C5 C6 T1
C3 C4
T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L L3 2 S1 S2
T2 C5
T3 T4 T5 T6 T7 T8 T9 T10 T11 T12
T1 C6
L1 C7
C4
C5 T2
C6 C8
C8 S5 S4
S3
L2
S2 L3 L3
L4
L5
L4
L5
S1
S1 L5
Figure 9-2. Distribution of the sensory spinal roots on the surface of the body (dermatomes). (Reproduced by permission from Sinclair.)
Adams and Victor’s
PRINCIPLES OF
NEUROLOGY
NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.
Adams and Victor’s
PRINCIPLES OF
NEUROLOGY NINT H ED ITION
Allan H. Ropper, MD Professor of Neurology Harvard Medical School Executive Vice Chair of Neurology Brigham and Women’s Hospital Boston, Massachusetts
Martin A. Samuels, MD, FAAN, MACP, DSc (Hon) Chairman Department of Neurology Brigham and Women’s Hospital Professor of Neurology Harvard Medical School Boston, Massachusetts
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Contents International Advisory Board, vii Preface, ix
PART 1: THE CLINICAL METHOD OF NEUROLOGY, 1 1 Approach to the Patient with Neurologic Disease, 3 2 Special Techniques for Neurologic Diagnosis, 13
PART 2: CARDINAL MANIFESTATIONS
OF NEUROLOGIC DISEASE, 39 SECTION 1
20 Delirium and Other Acute Confusional States, 398 21 Dementia and the Amnesic (Korsakoff) Syndrome with Comments on the Neurology of Intelligence and Memory, 410 22 Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum, 430 23 Disorders of Speech and Language, 461
Disorders of Motility, 41
3 Motor Paralysis, 43 4 Abnormalities of Movement and Posture Caused by Disease of the Basal Ganglia, 61 5 Incoordination and Other Disorders of Cerebellar Function, 78 6 Tremor, Myoclonus, Focal Dystonias, and Tics, 89 7 Disorders of Stance and Gait, 111 SECTION 2
Pain and Other Disorders of Somatic Sensation, Headache, and Backache, 123 8 9 10 11
SECTION 5 Derangements of Intellect, Behavior, and Language Caused by Diffuse and Focal Cerebral Disease, 397
Pain, 124 Other Somatic Sensation, 145 Headache and Other Craniofacial Pains, 162 Pain in the Back, Neck, and Extremities, 189
SECTION 3
Disorders of the Special Senses, 215 12 Disorders of Smell and Taste, 216 13 Disturbances of Vision, 225 14 Disorders of Ocular Movement and Pupillary Function, 248 15 Deafness, Dizziness, and Disorders of Equilibrium, 276 SECTION 4
Epilepsy and Disorders of Consciousness, 303 16 Epilepsy and Other Seizure Disorders, 304 17 Coma and Related Disorders of Consciousness, 339 18 Faintness and Syncope, 362 19 Sleep and Its Abnormalities, 374
SECTION 6 Disorders of Energy, Mood, and Autonomic and Endocrine Functions, 481
24 Fatigue, Asthenia, Anxiety, and Depressive Reactions, 482 25 The Limbic Lobes and the Neurology of Emotion, 493 26 Disorders of the Autonomic Nervous System, Respiration, and Swallowing, 505 27 The Hypothalamus and Neuroendocrine Disorders, 536
PART 3: GROWTH AND DEVELOPMENT
OF THE NERVOUS SYSTEM AND THE NEUROLOGY OF AGING, 549 28 Normal Development and Deviations in Development of the Nervous System, 551 29 The Neurology of Aging, 580
PART 4: MAJOR CATEGORIES OF
NEUROLOGIC DISEASE, 589 30 Disturbances of Cerebrospinal Fluid and Its Circulation, Including Hydrocephalus, Pseudotumor Cerebri, and Low-Pressure Syndromes, 591 31 Intracranial Neoplasms and Paraneoplastic Disorders, 612 32 Infections of the Nervous System (Bacterial, Fungal, Spirochetal, Parasitic) and Sarcoidosis, 667 33 Viral Infections of the Nervous System, Chronic Meningitis, and Prion Diseases, 711 34 Cerebrovascular Diseases, 746 35 Craniocerebral Trauma, 846 v
vi
Contents
36 Multiple Sclerosis and Allied Demyelinating Diseases, 874 37 Inherited Metabolic Diseases of the Nervous System, 904 38 Developmental Diseases of the Nervous System, 960 39 Degenerative Diseases of the Nervous System, 1011 40 The Acquired Metabolic Disorders of the Nervous System, 1081 41 Diseases of the Nervous System Caused by Nutritional Deficiency, 1108 42 Alcohol and Alcoholism, 1131 43 Disorders of the Nervous System Caused by Drugs, Toxins, and Other Chemical Agents, 1145
PART 5: DISEASES OF SPINAL CORD,
PERIPHERAL NERVE, AND MUSCLE, 1179 44 Diseases of the Spinal Cord, 1181 45 Electrophysiologic and Laboratory Aids in the Diagnosis of Neuromuscular Disease, 1231 46 Diseases of the Peripheral Nerves, 1251 47 Diseases of the Cranial Nerves, 1326
48 Principles of Clinical Myology: Diagnosis and Classification of Diseases of Muscle and Neuromuscular Junction, 1341 49 The Infectious and Inflammatory Myopathies, 1353 50 The Muscular Dystrophies, 1366 51 The Metabolic and Toxic Myopathies, 1384 52 The Congenital Neuromuscular Disorders, 1398 53 Myasthenia Gravis and Related Disorders of the Neuromuscular Junction, 1405 54 Ion Channel Disorders: The Periodic Paralyses and Hereditary Nondystrophic Myotonias (Channelopathies), 1422 55 Disorders of Muscle Characterized by Cramp, Spasm, Pain, and Localized Masses, 1434
PART 6: PSYCHIATRIC DISORDERS, 1445 56 The Anxiety Neuroses, Hysteria, and Personality Disorders, 1447 57 Depression and Bipolar Disease, 1466 58 The Schizophrenias and Paranoid States, 1478 Index, 1495
International Advisory Board Lisa DeAngelis
James Lance
United States
Australia
Roland Eastman
Elio Lugaresi
South Africa
Italy
Werner Hacke
Bihm Singhal
Germany
India
Jun Kimura
Jaime Toro
Japan
Columbia
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Preface Neurology is the broad field of clinical study of the nervous system. As a profession, it is a highly enjoyable endeavor that is a constant source of professional and personal enrichment. Through Principles of Neurology we have the privilege of continuing a tradition established 35 years ago by our esteemed teachers Dr. Raymond D. Adams and Dr. Maurice Victor. Our friend and colleague, Dr. Robert Brown, ably participated in the eighth edition, adding his expertise in the neurosciences, much to our benefit and that of the book. Principles of Neurology originated from the chapters on neurological diseases in the first several editions of Harrison’s Principles of Internal Medicine. The continued expansion of these sections by Adams and Victor, despite repeated commitments to shortening them, led an exasperated Tinsley Harrison to exclaim to Dr. Adams “…. we’ll have to change the name of the book to Principles of Internal Medicine and Details of Neurology.” Ray Adams wrote the entire first edition of the book in longhand during his summer vacation of 1975 in Lausanne and asked his highly regarded young colleague Maurice Victor to round out the manuscript over the following year. Adams and Victor attracted considerable attention by initiating a new style of pedagogy that emphasized the basic principles of neurology before introducing the disease entities. While the enormous advances in imaging, genetics, molecular biology, and pharmacology have improved our capacity to diagnose and treat disorders of the nervous system, they have not reduced the necessity to understand certain basic principles of anatomy and physiology, to obtain the correct history, perform a capable neurological examination and to cohere them based on a body of clinical knowledge and experience. We continue the original structure of the book, re-affirming that comprehensive knowledge of clinical neurology is required to meet the challenge of this sophisticated specialty. We have also maintained personal authorship with the hope that a single voice will allow the reader to enjoy the experience of learning the field from two longtime practitioners in a manner similar to the way we learned it from the original authors and their colleagues. In taking the responsibility of revising this book, we acknowledge that pedagogy in medicine has changed enormously to accommodate technical advances, particularly those in imaging. However, certain principles seem immutable and they derive from the traditional principles, virtues, and logic of medicine that dominate neurological thinking. Clinical neurology, being an applied science, depends on a set of heuristics that direct the clinician to the best diagnosis and therapeutic plan. This book provides an exposition of clinical material in an order that should allow the reader to obtain a comprehensive view of the field and at the same time appreciate the full breadth and depth of each disease of the nervous tissue.
At the same time we have written the chapters on major diseases in a manner that allows the book to be used as a reference in depth. Certainly, advances in neuroscience inform one’s perspective on the nature of disease and produce a fuller appreciation of the manifestations in each patient. A case in point is the large number of previously inexplicable degenerative diseases that have yielded to scientific understanding on the levels of pathology, genetics, subcellular mechanisms, and neurochemistry. At the same time, therapeutic advances often precede basic understanding of disease and the neurologist has the duty to provide the best possible treatment at the time, even if science has not provided a full explanation or mechanism. Examples abound; we have an incomplete understanding of epilepsy, Parkinson disease and multiple sclerosis but many reasonably effective treatments have been devised. While the neurosciences are the instruments of advance in understanding disease, the work of clinical neurology is more pragmatic, yet it retains its own form of scholarship. Neurology is not simply a trade in relation to the sciences. Difficulty in mastering neurology derives from a need to combine considerable knowledge and personal experience with special skills of observation and disciplined thinking. Our goal is to present an assemblage of clinical knowledge, and we hope wisdom, rather than disembodied facts. The book contains information that should be the property of the well-educated physician at all levels, including the medical student, resident, practitioner and academic physician. The neurologist stands at the nexus of the study of the nervous system and includes many aspects of general medicine, psychiatry, neurosurgery, pain management, rehabilitation, ophthalmology, otolaryngology, anesthesiology, critical care and emergency medicine and Neurology serves as Medicine’s spokesperson to society on matters such as mental capability, learning and teaching, aging and the brain, death, and disability. Therefore the breadth of Neurology has directed the liberal inclusion of material in the book. Neurology, like internal medicine, has become increasingly subspecialized. Modern departments of neurology include divisions of stroke, epilepsy, movement disorders, sleep, neuromuscular disease, multiple sclerosis, pain and headache, otoneurology, neuro-ophthalmology, cognitive and behavioral neurology, critical care neurology, spinal disorders, neuro-infectious diseases, cancer neurology, and pediatric neurology. Yet, there is a need for all clinicians, including the subspecialist, to maintain a comprehensive understanding of the major categories of neurological diseases. We respect and commend the community practitioner who by necessity maintains a broad gauge view of the field and we write with them in mind. We thank our many colleagues who reviewed chapters and suggested alterations or additions. Several readers
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Preface
made invaluable contributions: Roland Eastman, Anthony Amato, Edward Bromfield, James Lance, Marc Dinkin, Jun Kimura, Jaime Toro, Elio Lugaresi, and Werner Hacke. We are indebted to Susan Pioli for her superb editorial skills, Desi Allevato of Silverchair for her compositing efforts, and Kim Davis of McGraw-Hill for her efficient work as our developmental editor. We thank Anne Sydor of McGrawHill for her publishing expertise and for promoting the goals of the book. This ninth edition introduces as an author a consummate neurologic clinician and teacher, Dr. Martin A. Samuels. Marty brings intelligence, style and accessibility to Neurology and particularly to its interface with Internal Medicine. His thoughtfulness and clinical experience extends to all aspects of clinical material, and his exceptional teaching skills have been used to full extent in updating the text. It has been a pleasure for us to challenge each other in considering the needs of our clinician colleagues during the process of rewriting the text. We are, of course, products of our exposure to influential if not charismatic teachers. Raymond D. Adams was the progenitor of several generations of influential neurologists. He inculcated a method for approaching complicated neurological problems in a manageable way. Observing his analysis of a patient’s problem gave students the impres-
sion of remarkable ease and fluidity reminiscent of watching a gifted artist or musician. Dr. Adams knew the field so well and thought so critically, based in large part on his experience with neuropathology, that he allowed all of his residents to believe that they too, could and should aspire to excellence. His encouragement and cultivation of enormously talented colleagues such as C. Miller Fisher and E.P. Richardson, among many others of that time, reflected an unpretentious self-confidence, flexibility of mind, and mastery that derived enjoyment from the brightness around him. He read widely in neurology, medicine, and literature (in several languages; he often reminded us by providing articles that were beyond our personal reach) and was always ready to incorporate the modern advances in science into his thinking. His hundreds of residents wished to model themselves after him not because of personal suasion or celebrity but because of a genuine admiration for his intellect and intensely cultivated clinical skills. In tribute to Dr. Adams this ninth edition, published soon after his death, serves as recognition of his lasting accomplishments from his grateful students.
Raymond D. Adams 1911–2008
Allan H. Ropper, MD Martin A. Samuels, MD Boston, March 2009
PA R T THE CLINICAL METHOD OF NEUROLOGY
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1 Approach to the Patient with Neurologic Disease
Neurology is regarded by many as one of the most difficult and exacting medical specialties. Students and residents who come to a neurology service for the first time may be easily discouraged, and may already be intimidated by the complexity of the nervous system through their brief contact with neuroanatomy, neurophysiology, neuropathology, neurogenetics, and cell biology. The ritual they then witness of putting the patient through a series of maneuvers designed to evoke certain mysterious signs is hardly reassuring; in fact, the procedure often appears to conceal the intellectual processes by which neurologic diagnosis is made. Moreover, the students have had little or no experience with the many special tests used in neurologic diagnosis—such as lumbar puncture, EMG (electromyography), electroencephalography, CT, MRI, and other imaging procedures—nor do they know how to interpret the results of such tests. Neurology textbooks only confirm their fears as they read the detailed accounts of the many rare diseases of the nervous system. The authors believe that many of the difficulties in comprehending neurology can be overcome by adhering to the basic principles of clinical medicine. First and foremost, it is necessary to learn and acquire facility in the use of the clinical method. Without a full appreciation of this method, the student is virtually as helpless with a new clinical problem as a botanist or chemist who would undertake a research problem without understanding the steps in the scientific method. Even the experienced neurologist faced with a complex clinical problem depends on this basic approach. The importance of the clinical method stands out more clearly in the study of neurologic disease than in certain other fields of medicine. In most cases, the clinical method consists of an orderly series of steps, as follows: 1. The symptoms and signs are secured by history and physical examination. 2. The symptoms and physical signs considered relevant to the problem at hand are interpreted in terms of physiology and anatomy—that is, one identifies the disorder(s) of function and the anatomic structure(s) that are implicated. 3. These analyses permit the physician to localize the disease process, i.e., to name the part or parts of the nervous system involved. This step is called anatomic,
or topographic, diagnosis. Often one recognizes a characteristic clustering of symptoms and signs, constituting a syndrome of anatomic, physiologic, or temporal type. The formulation and aggregation of symptoms and signs in cohesive terms is particularly helpful in ascertaining the locus and nature of the disease. This step is called syndromic diagnosis and is often conducted in parallel with anatomic diagnosis. 4. From the anatomic diagnosis and other medical data— particularly the mode and speed of onset, evolution, and course of the illness, the involvement of nonneurologic organ systems, the relevant past and family histories, and the laboratory findings—one deduces the pathologic diagnosis and, when the mechanism and causation of the disease can be determined, the etiologic diagnosis. This may include the rapidly increasing number of molecular and genetic etiologies if they have been determined for a particular process. Expert diagnosticians often make successively more accurate estimates of the likely diagnosis, utilizing pieces of the history and findings on the examination to either further refine or exclude specific diseases. Flexibility of thought must be practiced so as to avoid the common pitfall of retaining an initially incorrect impression and selectively ignoring data that would bring it into question. It is perhaps not surprising that the method of successive estimations works well in that evidence from neuroscience reveals that this is the mechanism that the nervous system uses to process information. 5. Finally, the physician should assess the degree of disability and determine whether it is temporary or permanent ( functional diagnosis); this is important in managing the patient’s illness and judging the potential for restoration of function. All of these steps are undertaken in the service of effective treatment, an ever-increasing prospect in neurology. As is emphasized repeatedly in later sections, there is always a premium in the diagnostic process on the discovery of treatable diseases, but even when specific treatment is not available, accurate diagnosis may, in its own right, function as a therapy, as uncertainty about the cause of a neurologic illness may be more troubling to the patient than the disease itself. Figure 1-1, a procedural diagram by which the clinical problem is solved in a series of sequential finite steps,
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THE CLINICAL METHOD OF NEUROLOGY
Syndromic diagnosis
By history Elicitation of clinical facts By neurologic examination
Interpretation of symptoms and signs in terms of physiology and anatomy
Mode of onset and course Syndromic formulation and localization of the lesion
Other medical and demographic data Appropriate lab tests Pathologic or etiologic diagnosis
Figure 1-1. Steps in the diagnosis of neurologic disease. The clinician proceeds from left to right in order to make a diagnosis.
summarizes the foregoing approach to the diagnosis of neurologic disease. This systematic approach, allowing the confident localization and often precise diagnosis of disease, is one of the intellectual attractions of neurology. Of course, the solution to a clinical problem need not always be schematized in this way. The clinical method offers a much wider choice in the order and manner by which information is collected and interpreted. In fact, in some cases, adherence to a formal scheme is not necessary at all. In relation to the aforementioned syndromic diagnosis, the clinical picture of Parkinson disease, for example, is usually so characteristic that the nature of the illness is at once apparent. In other cases it is not necessary to carry the clinical analysis beyond the stage of the anatomic diagnosis, which, in itself, may virtually indicate the cause of a disease. For example, when vertigo, cerebellar ataxia, a unilateral Horner syndrome, paralysis of a vocal cord, and analgesia of the face of acute onset are combined with loss of pain and temperature sensation in the opposite arm, trunk, and leg, the cause is an occlusion of the vertebral artery, because all the involved structures lie in the lateral medulla, within the territory of this artery. Thus, the anatomic diagnosis determines and limits the etiologic possibilities. If the signs point to disease of the peripheral nerves, it is usually not necessary to consider the causes of disease of the spinal cord. Some signs themselves are almost specific—e.g., opsoclonus for paraneoplastic cerebellar degeneration and Argyll Robertson pupils for neurosyphilitic or diabetic oculomotor neuropathy. Nonetheless, one is cautious in calling any single sign pathognomonic as exceptions are found regularly. The experienced clinician acquires the habit of attempting to categorize every case in terms of a characteristic feature, or a syndrome. One must always keep in mind that syndromes are not disease entities but rather abstractions set up by clinicians to facilitate diagnosis. For example, the symptom complex of right–left confusion and inability to write, calculate, and identify individual fingers constitutes the so-called Gerstmann syndrome, recognition of which determines the anatomic locus of the disease (region of the left angular gyrus) and at the same time narrows the range of possible etiologic factors. In the initial analysis of a neurologic disorder, anatomic localization takes precedence over etiologic diagnosis. To
seek the cause of a disease of the nervous system without first ascertaining the parts or structures that are affected would be analogous in internal medicine to attempting an etiologic diagnosis without knowing whether the disease involved the lungs, stomach, or kidneys. Ascertaining the cause of a clinical syndrome (etiologic diagnosis) requires knowledge of an entirely different order. Here one must be conversant with the clinical details, including the mode of onset, course, and natural history of a multiplicity of diseases. Many of these facts are well known and form the substance of later chapters. When confronted with a constellation of clinical features that do not lend themselves to a simple or sequential analysis, one resorts to considering the broad classical division of diseases in all branches of medicine, as summarized in Table 1-1. Irrespective of the intellectual process that one utilizes in solving a particular clinical problem, the fundamental steps in diagnosis always involve the accurate elicitation of symptoms and signs and their correct interpretation in terms of disordered function of the nervous system. Most often when there is uncertainty or disagreement as to diagnosis, it is found later that the symptoms or signs were incorrectly interpreted in the first place. Thus, if a complaint of dizziness is identified as vertigo instead of light-headedness or if partial continuous epilepsy is mistaken for an extrapyramidal movement disorder such as tremor or choreoathetosis, then the clinical method is
Table 1-1 THE MAJOR CATEGORIES OF NEUROLOGIC DISEASE Infectious Genetic–congenital Traumatic Degenerative Vascular Toxic Metabolic Inherited Acquired Neoplastic Inflammatory–immune Psychogenic Iatrogenic
CHAPTER 1
derailed from the beginning. Repeated examinations may be necessary to establish the fundamental clinical findings beyond doubt. Hence the aphorism: A second examination is the most helpful diagnostic test in a difficult neurologic case.
PREVALENCE AND INCIDENCE OF NEUROLOGIC DISEASE To offer the physician the broadest perspective on the relative frequency of neurologic diseases, our estimates of their approximate prevalence in the United States, taken from several sources, including the NIH, are given in Table 1-2. Donaghy and colleagues have provided a similar but more extensive listing of the incidence of various neurologic diseases that are likely to be seen by a general physician practicing in the United Kingdom. They note stroke as far and away the most commonly encountered condition; those that follow in frequency are listed in Table 1-3. More focused surveys, such as the one conducted by Hirtz and colleagues, give similar rates of prevalence, with migraine, epilepsy, and multiple sclerosis being the most common neurologic disease in the general population (121, 7.1, and 0.9 per 1,000 persons in a year); stroke, traumatic brain injury, and spinal injury occurring in 183, 101, and 4.5 per 100,000 per year; and Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (ALS) among older individuals at rates of 67, 9.5, and 1.6 per 100,000 yearly. Data such as these assist in guiding societal resources to the cure of various conditions, but Table 1-2 RELATIVE PREVALENCE OF THE MAJOR NEUROLOGIC DISORDERS IN THE UNITED STATES APPROXIMATE PREVALENCE
Degenerative diseases Amyotrophic lateral sclerosis Huntington disease Parkinson disease Alzheimer disease Macular degeneration Autoimmune neurologic diseases Multiple sclerosis Stroke, all types Central nervous system trauma Head Spinal cord Metabolic Diabetic retinopathy Headache Epilepsy Back pain Peripheral neuropathy Total Inherited Diabetic neuropathy Mental retardation Severe Moderate Schizophrenia Manic depressive illness
5 × 104 5 × 104 5 × 106 5 × 106 5 × 107 4 × 105 5 × 106 2 × 106 2.5 × 105 2 × 106 3 × 107 3 × 106 5 × 107 2.5 × 107 104 2 × 106 106 107 3 × 106 3 × 106
Approach to the Patient with Neurologic Disease
5
Table 1-3 APPROXIMATE ORDER OF INCIDENCE AND PREVALENCE OF NEUROLOGIC CONDITIONS IN A GENERAL PRACTICE IN THE UNITED KINGDOM INCIDENCE IN GENERAL PRACTICE
PREVALENCE IN THE COMMUNITY
Stroke (all types) Carpal tunnel syndrome Epilepsy Bell’s palsy Essential tremor Parkinson disease Brain tumor Multiple sclerosis (especially in Scotland) Giant cell arteritis Migraine Unexplained motor symptoms Trigeminal neuralgia
Migraine Chronic tension headache Stroke Alzheimer disease Epilepsy Essential tremor Multiple sclerosis Chronic fatigue syndrome Parkinson disease Unexplained motor symptoms Neurofibromatosis Myasthenia gravis
Source: Adapted from Donaghy and colleagues: Brain’s Diseases of the Nervous System.
they are somewhat less helpful in leading the physician to the correct diagnosis except insofar as they emphasize the oft-stated dictum that “common conditions occur commonly” and therefore should be considered a priori to be more likely diagnoses (see discussion, further on under “Shortcomings of the Clinical Method”).
TAKING THE HISTORY In neurology, more than any other specialty, the physician is dependent upon the cooperation of the patient for a reliable history, especially for a description of those symptoms that are unaccompanied by observable signs of disease. If the symptoms are in the sensory sphere, only the patient can tell what he* sees, hears, or feels. The first step in the clinical encounter is to enlist the patient’s trust and cooperation and make him realize the importance of the history and examination procedure. The practice of making notes at the bedside or in the office is particularly recommended. Immediate recording of the history assures maximal reliability. Of course, no matter how reliable the history appears to be, verification of the patient’s account by a knowledgeable and objective informant is always desirable. The following points about taking the neurologic history deserve further comment: 1. Special care must be taken to avoid suggesting to the patient the symptoms that one seeks. Errors and inconsistencies in the recorded history are as often the fault of the physician as of the patient. The patient should be discouraged from framing his symptom(s) in terms of a diagnosis that he may have heard; rather, *Throughout this text we follow the traditional English practice of using the pronoun he, his, or him in the generic sense whenever it is not intended to designate the sex of a specific individual.
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he should be urged to give as accurate a description of the symptom as possible—being asked, for example, to choose a single word that best describes his pain and to describe precisely what he means by a particular term, such as dizziness, imbalance, or vertigo. The patient who is given to highly circumstantial and rambling accounts can be kept on the subject of his illness by directive questions that draw out essential points. 2. The setting in which the illness occurred, its mode of onset and evolution, and its course are of paramount importance. One must attempt to learn precisely how each symptom began and progressed. Often the nature of the disease process can be decided from these data alone. If such information cannot be supplied by the patient or his family, it may be necessary to judge the course of the illness by what the patient was able to do at different times (e.g., how far he could walk, when he could no longer negotiate stairs or carry on his usual work) or by changes in the clinical findings between successive examinations. 3. As neurologic diseases often impair mental function, it is necessary in every patient who might have cerebral disease, for the physician to decide whether the patient is competent to give a history of the illness. If the patient’s powers of attention, memory, and coherence of thinking are inadequate, the history must be obtained from a spouse, relative, friend, or employer. Also, illnesses that are characterized by seizures or other forms of episodic confusion abolish or impair the patient’s memory of events occurring during these episodes. In general, one tends to be careless in estimating the mental capacities of patients. Attempts are sometimes made to take histories from patients who are cognitively impaired or so confused that they have no idea why they are in a doctor’s office or a hospital.
THE NEUROLOGIC EXAMINATION The neurologic examination begins with observations of the patient while the history is being obtained. The manner in which the patient tells the story of his illness may betray confusion or incoherence in thinking, impairment of memory or judgment, or difficulty in comprehending or expressing ideas. The physician should learn to obtain this type of information without embarrassment to the patient. A common error is to pass lightly over inconsistencies in history and inaccuracies about dates and symptoms, only to discover later that these flaws in memory were the essential features of the illness. Asking the patient to give his own interpretation of the possible meaning of symptoms may sometimes expose unnatural concern, anxiety, suspiciousness, or even delusional thinking. Young physicians and students also have a natural tendency to “normalize” the patient, often collaborating with a hopeful family in the misperception that no real problem exists. This attempt at sympathy does not serve the patient and may delay the diagnosis of a potentially treatable disease.
One then generally proceeds from an examination of the cranial nerves, neck, and trunk to the testing of motor, reflex, and sensory functions of the upper and lower limbs. This is followed by an assessment of the function of sphincters and the autonomic nervous system and testing for meningeal irritation by examining the suppleness of the neck and spine. Gait and station (standing position) should be observed before or after the rest of the examination. When an abnormal finding is detected, whether cognitive, motor, or sensory, it becomes necessary to analyze the problem in a more elaborate fashion. Details of these more extensive examinations are to be found in appropriate chapters of the book (motor: Chaps. 3, 4, and 5; sensory: Chaps. 8 and 9; and cognitive and language disorders: Chaps. 22 and 23). The neurologic examination is ideally performed and recorded in a relatively uniform manner in order to avoid omissions and facilitate the subsequent analysis of case records. Some variation in the precise order of examination from physician to physician is understandable, but each examiner should establish an accustomed pattern. Even when it is impractical to perform the examination in the customary way, as in patients who are unable to cooperate because of age or cognitive deficiency, it is good practice to record the findings in an orderly fashion. If certain portions are not performed (e.g., olfactory testing in a completely uncooperative patient), this omission should be stated so that those reading the description at a later time are not left wondering whether an abnormality was not previously detected. The thoroughness of the neurologic examination of necessity must be governed by the type of clinical problem presented by the patient. To spend a half hour or more testing cerebral, cerebellar, cranial nerve, and sensorimotor function in a patient seeking treatment for a simple compression palsy of an ulnar nerve is pointless and uneconomical. The examination must also be modified according to the condition of the patient. Obviously, many parts of the examination cannot be carried out in a comatose patient; also, infants and small children, as well as patients with psychiatric disease, must be examined in special ways. Certain portions of the general physical examination that may be particularly informative in the patient with neurologic disease should be included. For example, examination of the heart rate and blood pressure, as well as carotid and cardiac auscultation, are essential in a patient with stroke. Likewise, the skin can reveal a number of conditions that pertain to congenital, metabolic, and infectious causes of neurologic disease.
EXAMINING PATIENTS WHO PRESENT WITH NEUROLOGIC SYMPTOMS Numerous guides to the examination of the nervous system are available (see the references at the end of this chapter). For a full account of these methods, the reader is referred to several of the many monographs on the subject, including those of Bickerstaff and Spillane, Campbell (DeJong’s Neurological Examination), and
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of the staff members of the Mayo Clinic, each of which approaches the subject from a somewhat different point of view. An inordinately large number of tests of neurologic function have been devised, and it is not proposed to review all of them here. Some are described in subsequent chapters dealing with disorders of mentation, cranial nerves, and motor, sensory, and autonomic functions. Many tests are of doubtful value or are repetitions of simpler tests and thus should not be taught to students of neurology. Merely to perform all of them on one patient would require several hours and, in most instances, would not make the examiner any the wiser. The danger with all clinical tests is to regard them as indisputable indicators of disease rather than as ways of uncovering disordered functioning of the nervous system. The following approaches are relatively simple and provide the most useful information.
Testing of Higher Cortical Functions These functions are tested in detail if the patient’s history or behavior during the general examination has provided a reason to suspect some defect. Broadly speaking, the mental status examination has two main components, although the separation is somewhat artificial: the psychiatric aspects, which incorporate affect, mood, and normality of thought processes and content, and the neurologic aspects, which include the level of consciousness, awareness (attention), language, memory, and visuospatial abilities. Questions are first directed toward determining the patient’s orientation in time and place and insight into his current medical problem. Attention, speed of response, ability to give relevant answers to simple questions, and the capacity for sustained and coherent mental effort all lend themselves to straightforward observation. There are many useful bedside tests of attention, concentration, memory, and clarity of thinking include the repetition of a series of digits in forward and reverse order and serial subtraction of 3s or 7s from 100, and recall of three items of information or a short story after an interval of 3 min. More detailed examination procedures appear in Chaps. 20 through 23. The patient’s account of his recent illness, dates of hospitalization, and his day-to-day recollection of recent incidents are excellent tests of memory; the narration of the illness and the patient’s choice of words (vocabulary) provide information about his language ability and coherence of thinking. If there is any suggestion of a speech or language disorder, the nature of the patient’s spontaneous speech should be noted. In addition, the accuracy of reading, writing, and spelling, executing spoken commands, repeating words and phrases spoken by the examiner, naming objects and parts of objects, and solving simple arithmetical problems should be assessed. The ability to carry out commanded tasks (praxis) has great salience in the evaluation of several aspects of cortical function. Bisecting a line, drawing a clock or the floor plan of one’s home or a map of one’s country, and copying figures are useful tests of visuospatial perception and are indicated in cases of suspected cerebral dis-
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ease. The testing of language, cognition, and other aspects of higher cerebral function are considered in Chaps. 21, 22, and 23.
Testing of Cranial Nerves The function of the cranial nerves must generally be investigated more fully in patients who have neurologic symptoms than in those who do not. If one suspects a lesion in the anterior fossa, the sense of smell should be tested in each nostril; then it should be determined whether odors can be discriminated. Visual fields should be outlined by confrontation testing, in some cases by testing each eye separately. If any abnormality is suspected, it should be checked on a perimeter and scotomas sought on the tangent screen or, more accurately, by computerized perimetry. Pupil size and reactivity to light, direct, consensual, and during convergence, the position of the eyelids, and the range of ocular movements should next be observed. Details of these test procedures and their interpretation are given in Chaps. 12, 13, and 14. Sensation over the face is tested with a pin and wisp of cotton. Also, the presence or absence of the corneal reflexes, direct and consensually, may be determined. Facial movements should be observed as the patient speaks and smiles, for a slight weakness may be more evident in these circumstances than on movements to command. The auditory meati and tympanic membranes should be inspected with an otoscope. A high-frequency (512 Hz) tuning fork held next to the ear and on the mastoid discloses hearing loss and distinguishes middle-ear (conductive) from neural deafness. Audiograms and other special tests of auditory and vestibular function are needed if there is any suspicion of disease of the eighth nerve or the cochlear and labyrinthine end organs (see Chap. 15). The vocal cords must be inspected with special instruments in cases of suspected medullary or vagus nerve disease, especially when there is hoarseness. Voluntary pharyngeal elevation and elicited reflexes are meaningful if there is a difference on the two sides; bilateral absence of the gag reflex is seldom significant. Inspection of the tongue, both protruded and at rest, is helpful; atrophy and fasciculations may be seen and weakness detected. Slight deviation of the protruded tongue as a solitary finding can usually be disregarded, but a major deviation represents underaction of the hypoglossal nerve and muscle on that side. The pronunciation of words should be noted. The jaw jerk and the snout, buccal, and sucking reflexes should be sought, particularly if there is a question of dysphagia, dysarthria, or dysphonia.
Testing of Motor Function In the assessment of motor function, it should be kept in mind that observations of the speed and strength of movements and of muscle bulk, tone, and coordination are most informative and are considered in the context of the state of tendon reflexes. The maintenance of the supinated arms against gravity is a useful test; the weak arm, tiring first, soon begins to sag, or, in the case of a corticospinal
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lesion, to resume the more natural pronated position (“pronator drift”). The strength of the legs can be similarly tested with the patient prone and the legs flexed at hips and knees and observing downward drift of the weakened leg. In the supine position at rest, weakness due to an upper motor neuron lesion causes external rotation of the hip. It is essential to have the limbs exposed and to inspect them for atrophy and fasciculations. Abnormalities of movement and posture as well as tremors may be exposed by observing the limbs at rest and in motion (see Chaps. 4, 5, and 6). This is accomplished by watching the patient maintain the arms outstretched in the prone and supine positions; perform simple tasks, such as alternately touching his nose and the examiner’s finger; make rapid alternating movements that necessitate sudden acceleration and deceleration and changes in direction, such as tapping one hand on the other while alternating pronation and supination of the forearm; rapidly touch the thumb to each fingertip; and accomplish simple tasks such as buttoning clothes, opening a safety pin, or handling common tools. Estimates of the strength of leg muscles with the patient in bed are often unreliable; there may seem to be little or no weakness even though the patient cannot arise from a chair or from a kneeling position without help. Running the heel down the front of the shin, alternately touching the examiner’s finger with the toe and the opposite knee with the heel, and rhythmically tapping the heel on the shin are the only tests of coordination that need be carried out in bed.
Testing of Reflexes Testing of the biceps, triceps, supinator-brachioradialis, patellar, Achilles, and cutaneous abdominal and plantar reflexes permits an adequate sampling of reflex activity of the spinal cord. Elicitation of tendon reflexes requires that the involved muscles be relaxed; underactive or barely elicitable reflexes can be facilitated by voluntary contraction of other muscles (Jendrassik maneuver). The plantar response poses some difficulty because several different reflex responses besides the Babinski response can be evoked by stimulating the sole of the foot along its outer border from heel to toes. These are (1) the normal quick, high-level avoidance response that causes the foot and leg to withdraw; (2) the pathologic slower, spinal flexor nocifensive (protective) reflex (flexion of knee and hip and dorsiflexion of toes and foot, “triple flexion”). Dorsiflexion of the large toe and fanning of the other toes as part of this reflex is the well-known Babinski sign (see Chap. 3); (3) plantar grasp reflexes; and (4) support reactions in infants. Avoidance and withdrawal responses interfere with the interpretation of the Babinski sign and can sometimes be overcome by utilizing the several alternative stimuli (e.g., squeezing the calf or Achilles tendon, flicking the fourth toe, downward scraping of the shin, lifting the straight leg, and others) or by having the patient scrape his own sole. An absence of the superficial cutaneous reflexes of the abdominal, cremasteric, and other muscles are useful ancillary tests for detecting corticospinal lesions particularly when unilateral.
Testing of Sensory Function Because this part of the examination is attainable only through the subjective responses of the patient, it requires great patient cooperation. For the same reason, it is subject to overinterpretation and suggestibility. Usually, sensory testing is reserved for the end of the examination and, if the findings are to be reliable, should not be prolonged for more than a few minutes. Each test should be explained briefly; too much discussion of these tests with a meticulous, introspective patient might encourage the reporting of meaningless minor variations of stimulus intensity. It is not necessary to examine all areas of the skin surface. A quick survey of the face, neck, arms, trunk, and legs with a pin takes only a few seconds. Usually one is seeking differences between the two sides of the body (it is better to ask whether stimuli on opposite sides of the body feel the same than to ask if they feel different), a level below which sensation is lost, or a zone of relative or absolute analgesia (loss of pain sensibility) or anesthesia (loss of touch sensibility). Regions of sensory deficit can then be tested more carefully and mapped out. Moving the stimulus from an area of diminished sensation into a normal area is recommended because it enhances the perception of a difference. The sense of vibration may be tested by comparing the thresholds at which the patient and examiner lose perception at comparable bony prominences. We suggest recording the number of seconds for which the examiner appreciates vibration at the malleolus, toe, or finger after the patient reports that the fork has stopped buzzing. The finding of a zone of heightened sensation (“hyperesthesia”) calls attention to a disturbance of superficial sensation. Variations in sensory findings from one examination to another reflect differences in technique of examination as well as inconsistencies in the responses of the patient. Sensory testing is considered in greater detail in Chaps. 8 and 9.
Testing of Gait and Stance The examination is completed by observing the patient stand and walk. An abnormality of stance or gait may be the most prominent or only neurologic abnormality, as in certain cases of cerebellar or frontal lobe disorder; and an impairment of posture and highly automatic adaptive movements in walking may provide the most definite diagnostic clues in the early stages of diseases such as Parkinson disease. Having the patient walk tandem or on the sides of the soles may bring out a lack of balance or dystonic postures in the hands and trunk. Hopping or standing on one foot may also betray a lack of balance or weakness, and standing with feet together and eyes closed will bring out a disequilibrium that is due to deep sensory loss (Romberg test). Disorders of gait are discussed in Chap. 7.
TESTING THE PATIENT WITHOUT NEUROLOGIC SYMPTOMS In this situation, brevity is desirable but any test that is undertaken should be done carefully and recorded accurately and legibly. As indicated in Table 1-4, the patient’s
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Table 1-4 BRIEF NEUROLOGIC EXAMINATION IN THE GENERAL MEDICAL OR SURGICAL PATIENT (PERFORMED IN 5 MIN OR LESS) 1. Orientation, insight into illness, language assessed during taking of the history 2. Size of pupils, reaction to light, visual and auditory acuity 3. Movement of eyes, face, tongue 4. Examination of the outstretched hands for atrophy, pronating or downward drift, tremor, power of grip, and wrist dorsiflexion 5. Biceps, supinator, and triceps tendon reflexes 6. Inspection of the legs during active flexion and extension of the hips, knees, and feet 7. Patellar, Achilles, and plantar (Babinski) reflexes 8. Vibration sensibility in the fingers and toes 9. Finger-to-nose and heel-to-shin testing of coordination 10. Gait
orientation, insight, judgment, and the integrity of language function are readily assessed in the course of taking the history. With respect to the cranial nerves, the size of the pupils and their reaction to light, ocular movements, visual and auditory acuity, and movements of the face, palate, and tongue should be tested. Observing the bare outstretched arms for atrophy, weakness (“pronator drift”), tremor, or abnormal movements; checking the strength of hand grip and dorsiflexion at the wrist; inquiring about sensory disturbances; and eliciting the biceps, and triceps reflexes are usually sufficient for the upper limbs. Inspection of the legs while the feet, toes, knees, and hips are actively flexed and extended; elicitation of the patellar, Achilles, and plantar reflexes; testing of vibration and position sense in the fingers and toes; and assessment of coordination by having the patient alternately touch his nose and the examiner’s finger and run his heel up and down the front of the opposite leg, and observation of walking complete the essential parts of the neurologic examination. This entire procedure does not add more than a few minutes to the physical examination but the routine performance of these few simple tests provides clues to the presence of disease of which the patient is not aware. For example, the finding of absent Achilles reflexes and diminished vibratory sense in the feet and legs alerts the physician to the possibility of diabetic or alcoholic-nutritional neuropathy even when the patient has no symptoms referable to these disorders. Carotid auscultation has been adopted as a component of the screening examination by many neurologists and recording of the heart rate and rhythm, blood pressure, and heart auscultation is included in the examination in stroke patients. Accurate recording of negative data may be useful in relation to some future illness that requires examination.
THE COMATOSE PATIENT Although subject to obvious limitations, careful examination of the stuporous or comatose patient yields considerable information concerning the function of the nervous system. It is remarkable that, with the exception of cogni-
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tive function, almost all parts of the nervous system, including the cranial nerves, can be evaluated in the comatose patient. The demonstration of signs of focal cerebral or brainstem disease or of meningeal irritation is particularly useful in the differential diagnosis of diseases that cause stupor and coma. The adaptation of the neurologic examination to the comatose patient is described in Chap. 17.
THE PSYCHIATRIC PATIENT One is compelled in the examination of psychiatric patients to rely less on the cooperation of the patient and to be unusually critical of their statements and opinions. The depressed patient, for example, may perceive impaired memory or weakness when actually there is neither amnesia nor diminution in muscular power, or the sociopath or hysteric may feign paralysis. The opposite is sometimes true: Psychotic patients may make accurate observations of their symptoms, only to have them ignored because of their mental state. If the patient will speak and cooperate even to a slight degree, much may be learned about the functional integrity of different parts of the nervous system. By the manner in which the patient expresses ideas and responds to spoken or written requests, it is possible to determine whether there are hallucinations or delusions, defective memory, or other recognizable symptoms of brain disease merely by watching and listening to the patient. Ocular movements and visual fields can be tested with fair accuracy by observing the patient’s response to a moving stimulus or threat in the visual fields. Cranial nerve, motor, and reflex functions are tested in the usual manner, but it must be remembered that the neurologic examination is never complete unless the patient will speak and cooperate in testing. On occasion, mute and resistive patients judged to be psychotic prove to have some widespread cerebral disease such as hypoxic or hypoglycemic encephalopathy, a brain tumor, a vascular lesion, or extensive demyelinative lesions.
INFANTS AND SMALL CHILDREN The reader is referred to the special methods of examination described by Gesell and Amatruda, Andrè-Thomas and colleagues, Paine and Oppe, and the staff members of the Mayo Clinic, which are listed in the references and described in Chap. 28. Many of these volumes address the developmental aspects of the child’s nervous system, and although some signs may be difficult to obtain because of the age of the patient, they still stand as the best explications of the child’s neurologic examination.
THE GENERAL MEDICAL EXAMINATION The findings on general medical examination very often disclose evidence of an underlying systemic disease that has secondarily affected the nervous system. In fact, many of the most serious neurologic problems are of this
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type. Two common examples will suffice: adenopathy or a lung infiltrate implicate neoplasia or sarcoidosis as the cause of multiple cranial nerve palsies, and the presence of low-grade fever, anemia, a heart murmur, and splenomegaly in a patient with unexplained stroke points to a diagnosis of bacterial endocarditis with embolic occlusion of brain arteries. Certainly no examination of a patient with stroke is complete without a search for hypertension, carotid bruits, heart murmurs, and irregular heart rhythm.
IMPORTANCE OF A WORKING KNOWLEDGE OF NEUROANATOMY, NEUROPHYSIOLOGY, MOLECULAR GENETICS, AND NEUROPATHOLOGY Once the technique of obtaining reliable clinical data is mastered, students and residents may find themselves handicapped in the interpretation of the findings by a lack of knowledge of the basic sciences of neurology. For this reason, each of the later chapters dealing with the motor system, sensation, special senses, consciousness, and language is introduced by a review of the anatomic and physiologic facts that are necessary for an understanding of the associated clinical disorders. At a minimum, physicians should know the anatomy of the corticospinal tract; motor unit (anterior horn cell, nerve, and muscle); basal ganglionic and cerebellar motor connections; main sensory pathways; cranial nerves; hypothalamus and pituitary; reticular formation of brainstem and thalamus; limbic system; areas of cerebral cortex and their major connections; visual, auditory, and autonomic systems; and cerebrospinal fluid pathways. A working knowledge of neurophysiology should include an understanding of the nerve impulse, neuromuscular transmission, and contractile process of muscle; spinal reflex activity; central neurotransmission; processes of neuronal excitation, inhibition, and release; and cortical activation and seizure production. The genetics and molecular biology of neurologic disease have assumed increasing importance in the past few decades. The practitioner should, at minimum, be familiar with the terminology of mendelian and mitochondrial genetics and the main aberrations in the genetic code that give rise to neurologic disease. From a practical diagnostic and therapeutic point of view, we believe the neurologist is helped most by a knowledge of pathologic anatomy—i.e., the neuropathologic changes that are produced by disease processes such as infarction, hemorrhage, demyelination, physical trauma, compression, inflammation, neoplasm, and infection, to name the more common ones. Experience with the gross and microscopic appearances of these disease processes greatly enhances one’s ability to explain their clinical effects. The ability to visualize the abnormalities of disease on nerve and muscle, brain and spinal cord, muscle, meninges, and blood vessels gives one a strong sense of which clinical features to expect of a particular disease and which features are untenable or inconsistent with a particular diagnosis. An additional advantage of being exposed to neuropathology is, of course,
that the clinician is better able to evaluate pathologic changes and reports of material obtained by biopsy.
LABORATORY DIAGNOSIS From the foregoing description of the clinical method, it is evident that the use of laboratory aids in the diagnosis of diseases of the nervous system is ideally preceded by rigorous clinical examination. As in all of medicine, laboratory study can be planned intelligently only on the basis of clinical information. To reverse this process is wasteful of medical resources and prone to the discovery of irrelevant information. In the prevention of neurologic disease, however, the clinical method in itself is inadequate; thus, of necessity, one resorts to two other approaches, namely, the use of genetic information and laboratory screening tests. Biochemical screening tests are applicable to an entire population and permit the identification of neurologic diseases in individuals, mainly infants and children, who have yet to show their first symptom; in some diseases, treatment can be instituted before the nervous system has suffered damage. Similarly in adults, screening for atherosclerosis and its underlying metabolic causes is profitable in certain populations as a way of preventing stroke. Genetic information enables the neurologist to arrive at the diagnosis of certain illnesses and to identify patients and relatives at risk of developing certain diseases. The laboratory methods that are available for neurologic diagnosis are discussed in the next chapter and in Chap. 45, on clinical electrophysiology. The relevant principles of genetic and laboratory screening methods for the prediction of disease are presented in the discussion of the disease to which they are applicable.
SHORTCOMINGS OF THE CLINICAL METHOD If one adheres faithfully to the clinical method, neurologic diagnosis is greatly simplified. In most cases one can reach an anatomic diagnosis but discovering the cause of the disease may prove more elusive and usually entails the selective employment of the laboratory procedures described in the next chapter. However, even after the most assiduous application of the clinical method and laboratory procedures, there are numerous patients whose diseases elude diagnosis. In such circumstances we have often been aided by the following rules of thumb: 1. As mentioned earlier, when the main sign has been misinterpreted—if a tremor has been taken for ataxia or fatigue for weakness—the clinical method is derailed from the start. Focus the clinical analysis on the principal symptom and signs and avoid being distracted by minor signs and uncertain clinical data. 2. Avoid early closure of diagnosis. Often this is the result of premature fixation on some item in the history or examination, closing the mind to alternative diagnostic considerations. The first diagnostic formu-
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lation should be regarded as only a testable hypothesis, subject to modification when new items of information are secured. Should the disease be in a stage of transition, time will allow the full picture to emerge and the diagnosis to be clarified. 3. When several of the main features of a disease in its typical form are lacking, an alternative diagnosis should always be entertained. In general, however, one is more likely to encounter rare manifestations of common diseases than the typical manifestations of rare diseases (a paraphrasing of the Bayes theorem). 4. It is preferable to base diagnosis on clinical experience with the dominant symptoms and signs and not on statistical analyses of the frequency of clinical phenomena. For the most part, the methods of probability-based decision analysis have proved to be disappointing in relation to neurologic disease because of the impossibility of weighing the importance of each clinical datum. Nonetheless, implicit in all diagnostic methods is an assessment of the likely causes of a sign or syndrome in the context of the patient’s broad demographic characteristics including their sex, age, race, ethnicity, and the geographical circumstances. For example, the neurologist in the United States considers it unlikely a case of chronic meningitis would be caused by Behçet disease, whereas a colleague in Turkey might find this to be a very likely diagnosis. Moreover, as mentioned earlier, neurologists place a premium on finding treatable illnesses, even if the odds do not favor its presence. As pointed out by Chimowitz, students tend to err in failing to recognize a disease they have not seen, and experienced clinicians may fail to appreciate a rare variant of a common disease. There is no doubt that some clinicians are more adept than others at solving difficult clinical problems. Their talent is not intuitive, as sometimes is presumed, but is attributable to having paid close attention to the details of their experience with many diseases and having catalogued them for future reference. The unusual case is recorded in memory and can be resurrected when another one like it is encountered.
THERAPEUTICS IN NEUROLOGY Among medical specialties, neurology has traditionally occupied a somewhat anomalous position, being thought of by many as little more than an intellectual exercise concerned with making diagnoses of untreatable diseases. This view of our profession is not at all valid. There are a growing number of diseases, some medical and others surgical, for which specific therapy is now available; through advances in neuroscience, their number is steadily increasing. Matters pertaining to these therapies and to the dosages, timing, and manner of administration of particular
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drugs are considered in later chapters in relation to the description of individual diseases. There are, in addition, many diseases in which neurologic function can be restored to a varying degree by appropriate rehabilitation measures or by the judicious use of therapeutic agents that have not been fully validated. Claims for the effectiveness of a particular therapy based on statistical analysis of large-scale clinical studies must be treated circumspectly. Was the study well conceived as reflected in a clearly stated hypothesis and outcome criteria; was there adherence to the plans for randomization and admission of cases into the study; were the statistical methods appropriate; and were the controls truly comparable? It has been our experience that the original claims must always be accepted with caution and it is prudent to wait until further studies confirm the benefits that have been claimed. While supportive of the recent emphasis on evidence-based medicine, we are in agreement with Caplan’s point that much of this “evidence” is not applicable to difficult individual therapeutic decisions. This is in part true because small albeit statistically significant effects may be of little consequence when applied to an individual patient. It goes without saying that data derived from trials must be used in the context of a patient’s overall physical and mental condition and age. Furthermore, for many neurologic conditions there is, at the moment, inadequate evidence on which to base treatment. Here, the patient requires a skilled physician to make judgments based on partial or insufficient data. Even as science moves forward, wise clinicians must treat patients in the present by prudent use of properly catalogued personal experience coupled with the best current data. Even when no effective treatment is possible, neurologic diagnosis is more than an intellectual pastime. The first step in the scientific study of a disease process is its identification in the living patient. The clinical method of neurology thus serves both the physician in the practical matters of diagnosis, prognosis, and treatment, and the clinical scientist, in the search for the mechanism and cause of disease. In closing this introductory chapter, a comment regarding the extraordinary burden of diseases of the nervous system throughout the world and in the United States is appropriate. It is not just that conditions such as brain and spinal cord trauma, stroke, epilepsy, mental retardation, mental diseases, and dementia are ubiquitous and account for the majority of illness, second only in some parts of the world to infectious disease, but that these are highly disabling and often chronic in nature, altering in a fundamental way the lives of the affected individuals. Furthermore, more so than in other fields, the promise of cure or amelioration by new techniques such as molecular biology, genetic therapy, and brain–computer interfaces has excited vast interest, for which reason aspects of the current scientific insights are included in appropriate sections.
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References Andrè-Thomas, Chesni Y, Dargassies St-Anne S: The Neurological Examination of the Infant. London, National Spastics Society, 1960. Campbell WW: DeJong’s The Neurological Examination, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2005. Caplan LR: Evidence-based medicine: Concerns of a clinical neurologist. J Neurol Neurosurg Psychiatry 71:569, 2001. [PMID: 11606661] Chimowitz MI, Logigian EL, Caplan LP: The accuracy of bedside neurological diagnoses. Ann Neurol 28:78, 1990. [PMID: 2375637] DeMyer WE: Technique of the Neurologic Examination: A Programmed Text, 4th ed. New York, McGraw-Hill, 1994. Donaghy M, Compston A, Rossor M, Warlow C: Clinical diagnosis, in Brain’s Diseases of the Nervous System, 11th ed. Oxford, UK, Oxford University Press, 2001, pp 11–60.
Gesell A, Amatruda CS, in Knoblock H, Pasamanick B (eds): Gesell and Amatruda’s Developmental Diagnosis, 3rd ed. New York, Harper, 1974. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al: How common are the “common” neurologic disorders? Neurology 68:326, 2007. [PMID: 17261678] Holmes G: Introduction to Clinical Neurology, 3rd ed. Revised by Bryan Matthews. Baltimore, Williams & Wilkins, 1968. Mayo Clinic Examinations in Neurology, 7th ed. St. Louis, Mosby-Year Book, 1998. Paine RS, Oppe TE: Neurological Examination of Children . London, Spastics Society Medical Education and Information Unit, 1966. Spillane JA: Bickerstaff’s Neurological Examination in Clinical Practice, 6th ed. Oxford, Blackwell Scientific, 1996.
2 Special Techniques for Neurologic Diagnosis
The analysis and interpretation of data elicited by a careful history and examination may prove to be adequate for diagnosis. Special laboratory examinations then do no more than corroborate the clinical impression. However, it happens more often that the nature of the disease is not discerned by “case study” alone; the diagnostic possibilities may be reduced to two or three, but the correct one is uncertain. Under these circumstances, one resorts to ancillary examinations. The aim of the neurologist is to arrive at a final diagnosis by artful analysis of the clinical data aided by the least number of laboratory procedures. Only a few decades ago, the only laboratory procedures available to the neurologist were examination of a sample of cerebrospinal fluid, conventional radiology of the skull and spinal column, contrast myelography, pneumoencephalography, and electroencephalography. Now, through formidable advances in scientific technology, the physician’s armamentarium has been expanded to include a multitude of neuroimaging, biochemical, and genetic methods. Some of these new methods are so impressive that there is a temptation to substitute them for a careful, detailed history and physical examination. Use of the laboratory in this way should be avoided. Reflecting this limitation, in a carefully examined series of 86 consecutively hospitalized neurologic patients, laboratory findings (including MRI) clarified the clinical diagnosis in 40 patients but failed to do so in the remaining 46 (Chimowitz et al). Moreover, it is quite common in modern practice for ancillary testing to reveal abnormalities that are of no significance to the problem at hand. Consequently, the physician should always judge the relevance and significance of laboratory data only in the context of clinical findings. Hence the neurologist must be familiar with all laboratory procedures relevant to neurologic disease, their reliability, and their hazards. What follows is a description of laboratory procedures that have application to a diversity of neurologic diseases. Procedures that are pertinent to a particular symptom complex or category of disease—e.g., audiography to study deafness; electronystagmography (ENG) in cases of vertigo; electromyography (EMG) and nerve conduction studies, as well as nerve and muscle biopsy, where there is neuromuscular disease—are presented in the chapters devoted to these disorders.
LUMBAR PUNCTURE AND EXAMINATION OF CEREBROSPINAL FLUID The information yielded by examination of the cerebrospinal fluid (CSF) is crucial in the diagnosis of certain neurologic diseases, particularly infectious and inflammatory conditions, subarachnoid hemorrhage, and diseases that alter intracranial pressure. Certain combinations of findings, or formulas, in the CSF generally denote particular classes of disease; these are summarized in Table 2-1.
Indications for Lumbar Puncture 1. To obtain pressure measurements and procure a sample of the CSF for cellular, cytologic, chemical, and bacteriologic examination. 2. To aid in therapy by the administration of spinal anesthetics and occasionally, antibiotics or antitumor agents, or by reduction of CSF pressure. 3. To inject a radiopaque substance, as in myelography, or a radioactive agent, as in radionuclide cisternography. Lumbar puncture (LP) carries certain risks if the CSF pressure is very high (evidenced mainly by headache and papilledema), for it increases the possibility of a fatal cerebellar or transtentorial herniation. The risk is considerable when papilledema is the result of an intracranial mass, but it is much lower in patients with subarachnoid hemorrhage, in hydrocephalus with communication between all the ventricles, or with pseudotumor cerebri, conditions in which repeated LPs have actually been employed as a therapeutic measure. In patients with purulent meningitis, there is also a small risk of herniation, but this is far outweighed by the need for a definitive diagnosis and the institution of appropriate treatment at the earliest moment. With this last exception, LP should generally be preceded by CT or MRI whenever an elevation of intracranial pressure is suspected. If radiologic procedures do disclose a mass lesion that is causing displacement of brain tissue toward the tentorial opening or the foramen magnum (the presence of a mass alone is of less concern) and if it is considered absolutely essential to have the information yielded by CSF examination, the LP may be performed— with certain precautions. A fine-bore (no. 22 or 24) needle should be used, and if the pressure proves to be very
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Table 2-1 CHARACTERISTIC CSF FORMULAS CONDITION
CELLS 3
PROTEIN
GLUCOSE
Bacterial infection
WBC >50/mm , often greatly increased
100–250 mg%
20–50 mg%; usually lower than half of blood glucose level Normal or slightly reduced
Viral, fungal, spirochetal infection
WBC 10–100/mm3
50–200 mg%
Tuberculous infection
WBC >25/mm3
100–1,000 mg%
500/mm3; slight increase in WBC
60–150 mg%
Normal
Cerebral hemorrhage, trauma
50–150 mg%
Normal
Ischemic stroke
RBC 50–200/mm3; higher if ventricular rupture of blood Normal or few WBC
Normal
Normal
Multiple sclerosis
Normal or few WBC
Normal
Meningeal cancer
WBC 10–100/mm3
Normal or slightly increased Usually elevated
Normal or depressed
OTHER FEATURES
Gram stain shows organisms; pressure increased Special culture techniques required; pressure normal or slightly increased Special culture techniques and PCR may be needed to detect organisms Must be distinguished from traumatic lumbar puncture by presence of xanthochromia of spun sample; greatly increased pressure Pressure may be elevated Normal pressure unless brain swelling Increased IgG fraction and oligoclonal bands Neoplastic cells in CSF; elevation of certain protein markers (e.g., β2microglobulin)
IgG, immunoglobulin G; PCR, polymerase chain reaction; RBC, red blood cells; WBC, white blood cells.
high—over 400 mm H2O—one should obtain the smallest necessary sample of fluid and then, according to the suspected disease and patient’s condition, administer mannitol and observe a fall in pressure on the manometer. Dexamethasone or an equivalent corticosteroid may also be given in an initial intravenous dose of 10 mg, followed by doses of 4 to 6 mg every 6 h in order to produce a sustained reduction in intracranial pressure. Corticosteroids are particularly useful in situations in which the increased intracranial pressure is caused by vasogenic cerebral edema (e.g., tumor-associated edema). Cisternal puncture and lateral cervical subarachnoid puncture, although safe in the hands of an expert, are too hazardous to entrust to those without experience and do not circumvent the problem of increased intracranial pressure. LP is preferred except in obvious instances of spinal block requiring a sample of cisternal fluid or for myelography above the lesion.
Technique of Lumbar Puncture Experience teaches the importance of meticulous technique. LP should be done under locally sterile conditions. Xylocaine is injected in and beneath the skin, which should render the procedure almost painless. Warming of the analgesic by rolling the vial between the palms seems to diminish the burning sensation that accompanies cutaneous infiltration. The patient is positioned on his side, preferably on the left side for righthanded physicians, with hips and knees flexed, and the head as close to the knees as comfort permits. The patient’s hips should be vertical, the back aligned near
the edge of the bed, and a pillow placed under the ear. The puncture is easiest to perform at the L3-L4 interspace, which corresponds to the axial plane of the iliac crests, or at the interspace above or below. In infants and young children, in whom the spinal cord may extend to the level of the L3-L4 interspace, lower levels should be used. Experienced anesthesiologists have suggested that the smallest possible needle be used and that the bevel be oriented in the longitudinal plane of the dural fibers (see below regarding atraumatic needles). It is usually possible to appreciate a palpable “give” as the needle transgresses the dura, followed by a subtle “pop” on puncturing the arachnoid membrane. At this point, the trocar should be removed slowly from the needle to avoid sucking a nerve rootlet into the lumen and causing radicular pain. Sciatic pain during the insertion of the needle indicates that it is placed too far laterally. If the flow of CSF slows, the patient’s head can be elevated slowly. Occasionally, one resorts to gentle aspiration with a small-bore syringe to overcome the resistance of proteinaceous and viscous CSF. Failure to enter the lumbar subarachnoid space after two or three trials usually can be overcome by performing the puncture with the patient in the sitting position and then helping him to lie on one side for pressure measurements and fluid removal. The “dry tap” is more often the result of an improperly placed needle than of obliteration of the subarachnoid space by a compressive lesion of the cauda equina or by adhesive arachnoiditis. LP has few serious complications. The most common is headache, estimated to occur in one-third of patients, but in severe form in far fewer. The pain is presumably the
CHAPTER 2
result of a reduction of CSF pressure and tugging on cerebral and dural vessels as the patient assumes the erect posture. Although neither recumbency nor oral fluid administration after LP has been shown to prevent headache, they are often implemented nonetheless. Strupp and colleagues found that the use of an atraumatic needle almost halved the incidence of headache. Curiously, headaches are twice as frequent after diagnostic LP as they are after spinal anesthesia. Patients who are prone to frequent headaches before LP reportedly have higher rates of headache afterwards, which accords with our experience. Severe headache can be associated with vomiting and mild neck stiffness. Unilateral or bilateral sixth nerve or other cranial nerve palsies (VII, VIII) occur rarely after lumbar puncture, even at times without headache. The syndrome of low CSF pressure, its treatment by “blood patch,” and other complications of lumbar puncture are considered further in Chap. 30. Bleeding into the spinal meningeal or epidural spaces can occur in patients who are taking anticoagulants (generally with an international normalized ratio [INR] >1.7), have low platelet counts (75 mm/h) but elevation of the C-reactive protein (CRP) level is a more sensitive indicator of this inflammatory condition and is particularly helpful when the sedimentation rate is normal or only mildly elevated. A few patients have a neutrophilic leukocytosis. As many as 50 percent of patients have generalized aching of proximal limb muscles, reflecting the presence of polymyalgia rheumatica (see Chap. 55, “Polymyalgia Rheumatica”). The importance of early diagnosis relates to the threat of blindness from thrombosis of the ophthalmic or posterior ciliary arteries. This may be preceded by several episodes of amaurosis fugax (transient monocular blindness, hemispheric transient ischemic attacks [carotid artery territory]). Ophthalmoplegia may also occur but is less frequent, and its cause, whether neural or muscular, is not settled. Masticatory claudication is a specific but not particularly sensitive symptom of cranial arteritis. The large intracranial vessels are occasionally affected, thereby causing stroke. Once vision is lost, it is seldom recoverable. For this reason, the earliest suspicion of cranial arteritis should lead to the immediate administration of corticosteroids and then to biopsy of the appropriate scalp artery. Microscopic examination discloses an intense granulomatous or “giant cell” arteritis. If biopsy on one side fails to clarify the situation and there are sound clinical reasons for suspecting the diagnosis, the other side should be sampled. Arteriography of the external carotid artery branches is probably the most sensitive test but is seldom used, because of its relatively high risk. Ultrasonographic examination of the temporal arteries may display a dark halo and irregularly thickened vessel walls. This technique has not yet been incorporated into the routine evaluation because its sensitivity has not been established; our own experience suggests that it may miss cases, but it may find use in choosing the site for biopsy of the temporal artery.
Treatment The administration of prednisone, 45 to 60 mg/d in single or divided doses over a period of several weeks, is indicated in all cases, with gradual reduction to 10 to 20 mg/d and maintenance at this dosage for several months or years, if necessary, to prevent relapse. The headache can be expected to improve within a day or two of beginning treatment; failure to do so brings the diagnosis into question. When the sedimentation rate or CRP is elevated, its return to normal, usually over months, is a reliable index of therapeutic response.
Headaches of Pseudotumor Cerebri (Benign or Idiopathic Intracranial Hypertension) The headache of pseudotumor cerebri assumes a variety of forms. Most typical is a feeling of occipital pressure that is greatly worsened by lying down, but many patients have—in addition or only—headaches of migraine or ten-
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sion type. Indeed, some of them respond to medications such as propranolol and ergot compounds. None of the proposed mechanisms for pain in pseudotumor cerebri seems to be adequate as an explanation, particularly the idea that cerebral vessels are displaced or compressed, as neither has been demonstrated. It is worth noting that facial pain may also be a feature of the illness, albeit rare. Chapter 30 has a more complete description of the clinical features and treatment.
SPECIAL VARIETIES OF HEADACHE Low-Pressure and Spinal Puncture Headache These are commonly known to neurologists, as noted earlier in this chapter, and the latter type is an unavoidable part of lumbar punctures in approximately 5 percent of cases. The headache is associated with the greatly reduced pressure of the CSF compartment and probably caused by vertical traction or cranial blood vessels. Assuming the supine position almost immediately relieves the cranial pain and eliminates vomiting, but a blood-patch procedure may be required in persistent cases. In a limited number of cases, success has been obtained by the use of intravenous caffeine injections. The condition and its treatment are discussed in Chap. 30 “Lumbar Puncture Headache” and “Spontaneous Intracranial Hypotension.”
Menstrual (Catamenial) Migraine and Other Headaches Linked to the Hormonal Cycle The relation of headache to a drop in estradiol levels during the late luteal phase was mentioned in “Migraine” above. There it was also indicated that the mechanism is probably more complex than can be explained simply by a drop in hormone levels. In practice, factors such as sleep deprivation are at least as important in triggering perimenstrual headaches. Premenstrual headache, taking the form of migraine or a combined tension-migraine headache, usually responds to the administration of an NSAID begun 3 days before the anticipated onset of the menstrual period; oral sumatriptan (25 to 50 mg qid) and zolmitriptan (2.5 to 5 mg bid) are equally effective. Manipulation of the hormonal cycle with danazol (a testosterone derivative) or estradiol has also been effective but is rarely necessary. The management of migraine during pregnancy poses special problems because one wants to restrict exposure of the fetus to medications. It can be stated that beta-adrenergic compounds and tricyclic antidepressants may be used safely in the small proportion of women whose headaches persist or intensify during pregnancy. From a limited registry of patients who were given sumatriptan during pregnancy, and from several small trials summarized by Fox and colleagues, no teratogenic effects or adverse effects on pregnancy arose, but serotonin agonist drugs should perhaps be used advisedly until their safety is confirmed. For those women who use antiepileptic drugs as a means of headache prevention, it is recommended that the drugs be stopped prior to pregnancy or as soon as it is known that pregnancy has begun.
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Cough and Exertional Headache A patient may complain of very severe, transient cranial pain on coughing, sneezing, laughing heartily, lifting heavy objects, stooping, and straining at stool. Pain is usually felt in the front of the head, sometimes occipitally, and may be unilateral or bilateral. As a rule, it follows the initiating action within a second or two and lasts a few seconds to a few minutes. The pain is often described as having a bursting quality and may be of such severity as to cause the patient to cradle his head in his hands, thereby simulating the headache of acute subarachnoid hemorrhage. Most often this syndrome is a benign idiopathic state that recurs over a period of several months to a year or two and then disappears. Many decades ago, Symonds emphasized the benignity of the condition. In a report of 103 patients followed for 3 years or longer, Rooke found that additional symptoms of neurologic disease developed in only 10. The cause and mechanism have not been determined. During the headache, the CSF pressure is normal. Bilateral jugular compression may induce an attack, possibly because of traction on the walls of large veins and dural sinuses. In a few instances, we have observed this type of headache after lumbar puncture or after a hemorrhage from an arteriovenous malformation. Aside from a rare instance of subarachnoid hemorrhage, patients with cough or strain headache may occasionally be found to have serious intracranial disease; most often it has been traced to lesions of the posterior fossa and foramen magnum, arteriovenous malformation, subdural hematoma, Chiari malformation, basilar impression, or tumor. It may be necessary, therefore, to supplement the neurologic examination by appropriate CT and MRI. Far more common, of course, are the temporal and maxillary pains that are caused by dental or sinus disease, which may also be worsened by coughing. All manner of headache has been attributed to Chiari type 1 malformation (with tonsils descended at least 3 mm below the lip of the foramen magnum) with little justification, but exertional and Valsalva-induced suboccipital pain can be attributed to this disease. A few patients have reported radiating pain across the base of the neck and shoulders with straining and headache. In the survey by Pascual and colleagues of 50 patients with Chiari type 1 malformations, the incidence of migraine and tension-type headache was found to be appropriate to the population at large and only the degree of tonsillar descent correlated with the presence of exertional headache. It follows that suboccipital decompressive operations should be undertaken selectively. Chiari malformation is discussed further in Chap. 38. A special variant of exertional headache is “weightlifter’s headache.” It occurs either as a single event or repeatedly over a period of several months, but each episode of headache may last many hours or days, again raising the suspicion of subarachnoid hemorrhage. The pain begins immediately or within minutes of heavy lifting. If the pain resolves in an hour or less and there is no meningismus or sign of bleeding on the CT, we have foregone lumbar puncture and angiography but have suggested that weight lifting not be resumed for several weeks. Athletes and runners in general seem to suffer exertional
headaches quite often in our experience, and the episodes usually have migrainous features. Indomethacin may be quite effective in controlling exertional headaches; this has been confirmed in controlled trials. Useful alternatives are NSAIDs, ergot preparations, and propranolol. In a few of our patients, lumbar puncture appeared to resolve the problem in some inexplicable way.
Headaches Related to Sexual Activity Lance (1976) has described 21 cases of this type of headache, 16 in males and 5 in females. The headache took one of two forms: one in which headache of the tension type developed as sexual excitement increased and another in which a severe, throbbing, “explosive” headache occurred at the time of orgasm and persisted for several minutes or hours. The latter headaches were of such abruptness and severity as to suggest a ruptured aneurysm, but the neurologic examination was negative in every instance, as was arteriography in 7 patients who were subjected to this procedure. In 18 patients who were followed for a period of 2 to 7 years, no other neurologic symptoms developed. Characteristically, the headache occurred on several consecutive occasions and then inexplicably disappeared. In cases of repeated coital headache, indomethacin has been effective. Of course, so-called orgasmic headache is not always benign; a hypertensive hemorrhage, rupture of an aneurysm or vascular malformation, or myocardial infarction may occur during the exertion of sexual intercourse.
Thunderclap Headache The headache of subarachnoid hemorrhage caused by rupture of a berry aneurysm is among the most abrupt and dramatic of cranial pains (see Chap. 34). There are several reports regarding such pains as a “warning leak” of rupture and even reports suggesting that such headaches occur as a consequence of unruptured aneurysms (although subsequent studies suggest that this is infrequent). It was in relation to a case of this nature that the term thunderclap was introduced by Day and Raskin. Patients in our services have offered colorful descriptions, such as “being kicked in the back of the head.” Thunderclap headache, as pointed out by Dodick, has also been at times a symptom of pituitary apoplexy, cerebral venous thrombosis, cervical arterial dissection, or hypertensive crisis (Table 10-2). To this list we would Table 10-2 PROCESSES THAT HAVE BEEN ASSOCIATED WITH “THUNDERCLAP HEADACHE” Migraine variant Subarachnoid hemorrhage Cerebral venous thrombosis Diffuse cerebral vasculopathy (Call-Fleming syndrome) Subdural hematoma Accelerated hypertension Pituitary apoplexy Cervical arterial dissection Cocaine Serotoninergic drugs Perimesencephalic hemorrhage
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add diffuse idiopathic arterial spasm (Call-Fleming syndrome; see “Diffuse and Focal Cerebral Vasospasm” in Chap. 34) and cerebral vasospasm as the result of the administration of sympathomimetic or serotonergic drugs, including cocaine and the triptan group of medications for the treatment of migraine. Recurrent thunderclap pain may be particularly indicative of multifocal or diffuse vasospasm, as pointed out by Chen and colleagues, who found this vasculopathy in 39 percent of their patients with recurrent thunderclap pain. However, in a large proportion of patients with thunderclap headache the pain is indistinguishable from that caused by subarachnoid hemorrhage, even to the extent of being accompanied by vomiting and acute hypertension in a few cases. The diagnosis is clarified when, after lumbar puncture and cerebral imaging exclude bleeding and aneurysm, the pain resolves in hours or less and is found to have no discernible cause. Wijdicks and colleagues confirmed that thunderclap headache is usually a benign condition; among 71 patients followed for more than 3 years they found no serious cerebrovascular lesions. For this reason, these idiopathic thunderclap headaches have been presumed to be a form of migraine (“crash migraine”). This opinion is based in part on a history of preceding or of subsequent headaches and migrainous episodes in affected individuals; however, in our experience not all of such patients have had migraine in the past. There is a notable tendency for thunderclap headaches to recur.
Erythrocyanotic Headache On rare occasions, an intense, generalized, throbbing headache may occur in conjunction with flushing of the face and hands and numbness of the fingers (erythromelalgia). Episodes tend to be present on awakening from sound sleep. This condition has been reported in a number of unusual settings: (1) in mastocytosis (infiltration of tissues by mast cells, which elaborate histamine, heparin, and serotonin); (2) with carcinoid tumors; (3) with serotonin-secreting tumors; (4) with some tumors of the pancreatic islets; and (5) with pheochromocytoma. Seventy-five percent of patients with pheochromocytoma reportedly have vascular-type headaches coincident with paroxysms of hypertension and release of catecholamines (Lance and Hinterberger).
Headache Related to Medical Diseases Severe headache may occur with a number of infectious illnesses caused by banal viral upper respiratory infections, by organisms such as Mycoplasma or Coxiella (Q fever), and particularly by influenza. The suspicion of meningitis is raised, even subarachnoid hemorrhage, but there is no reaction in the CSF (“meningism”). The mild aseptic meningitis that accompanies HIV seroconversion may be accompanied by headache. Approximately 50 percent of patients with hypertension complain of headache, but the relationship of one to the other is not clear. Minor elevations of blood pressure may be a result rather than the cause of tension headaches. Severe (malignant) hypertension, with diastolic pressures
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of more than 120 mm Hg, is regularly associated with headache, and measures that reduce the blood pressure relieve it. In preeclampsia, the headaches occur at lower levels of blood pressure. Abrupt elevations of blood pressure, as occur in patients who take monoamine oxidase inhibitors and then ingest tyramine-containing food, can cause headaches that are abrupt and severe enough to simulate subarachnoid hemorrhage. However, it is the individual with moderately severe hypertension and frequent severe headaches who causes the most concern. In some of these patients the headaches are of the common migrainous or tension type, but in others, they defy classification. According to Wolff, the mechanism of the hypertensive headache is similar to that of migraine, i.e., increased vascular pulsations. The headaches, however, bear no clear relation to modest peaks in blood pressure. The acute headache of pheochromocytoma correlates with the rate of increase of blood pressure rather than its absolute value. Curiously, headaches that occur toward the end of renal dialysis or soon after its completion are associated with a fall in blood pressure (as well as a decrease in blood sodium levels and osmolality). The latter type of headache is bifrontal and throbbing and is sometimes accompanied by nausea and vomiting. The mechanism of occipital pain that may awaken the hypertensive patient and wear off during the day is not understood. Headaches frequently follow a seizure, having been recorded in half of one large series of epileptic patients analyzed in a Great Britain study. In migraineurs, the postictal headache may reproduce a typical migraine attack. Rarely, in patients with a vascular malformation, a migraine-like attack precedes a seizure. Experienced physicians are aware of many other conditions in which headache may be a principal symptom. These include fevers of any cause, carbon monoxide exposure, chronic lung disease with hypercapnia (headaches often nocturnal or early morning), sleep apnea, hypothyroidism, Cushing disease, withdrawal from corticosteroid medication, hypoglycemia, mountain (altitude) sickness, chronic exposure to nitrates, occasionally adrenal insufficiency, use of an oral contraceptive medication, and development of acute anemia with hemoglobin below 10 g. No attempt is made here to discuss the symptomatic treatment of headache that may accompany these many medical conditions. Obviously, the guiding principle is to address the underlying disease.
Headache Related to Diseases of the Cervical Spine Headaches that accompany diseases of the upper cervical spine are well recognized, but their mechanism is obscure and their frequency possibly overrated. Recent writings have focused on a wide range of causative lesions, such as zygapophyseal (facet) arthropathy, C2 dorsal root entrapment, calcified ligamentum flavum, hypertrophied posterior longitudinal ligament, and rheumatoid arthritis of the atlantoaxial region. CT and MRI have divulged a number of these abnormalities. They are discussed below, under “‘Third Occipital Nerve’ Headache,” and further in Chap. 11.
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OTHER CRANIOFACIAL PAINS (See Table 10-3 and Chap. 47.)
Trigeminal Neuralgia (Tic Douloureux) This is a common disorder of middle age and later life, consisting of paroxysms of intense, stabbing pain in the distribution of the mandibular and maxillary divisions (rarely
the ophthalmic division) of the fifth cranial nerve. The pain seldom lasts more than a few seconds or a minute or two, but it may be so intense that the patient winces involuntarily; hence the term tic. It is uncertain whether the tic is reflexive or quasivoluntary. The paroxysms recur frequently, both day and night, for several weeks at a time. Another characteristic feature is the initiation of a jab or a series of jabs of pain by stimulation of certain areas of the
Table 10-3 TYPES OF FACIAL PAIN
TYPE
SITE
Trigeminal neuralgia (tic douloureux)
Second and third divisions of trigeminal nerve, unilateral
Postzoster neuralgia
Unilateral Usually ophthalmic division of fifth nerve
Costen syndrome (temporomandibular joint syndrome)
Unilateral, behind or front of ear, temple, face
Tolosa-Hunt syndrome (see Chap. 47)
Unilateral, mainly retroorbital
Raeder paratrigeminal syndrome
Unilateral, frontotemporal and maxilla
“Migrainous neuralgia” (migraine cluster crossover)
Orbitofrontal, temple, upper jaw, angle of nose and cheek Unilateral face, ear, jaws, teeth, upper neck
Carotidynia, lowerhalf headache, sphenopalatine neuralgia, etc. Atypical facial neuralgia (facial pain of indeterminate cause)
Unilateral or bilateral; cheek or angle of cheek and nose; deep in nose
CLINICAL CHARACTERISTICS
AGGRAVATING/ RELIEVING FACTORS
ASSOCIATED DISEASES
TREATMENT
Men:women = 1:3 Older than age 50 years Paroxysms (10–30 s) of stabbing, burning pain; persistent for weeks or longer Trigger points No sensory or motor paralysis History of zoster Aching, burning pain; jabs of pain Paresthesia, slight sensory loss Dermal scars Severe aching pain, intensified by chewing Tenderness over temporomandibular joints Malocclusion, missing molars Intense sharp, aching pain, associated with ophthalmoplegias and sensory loss over forehead; pupil usually spared Intense sharp or aching pain, ptosis, miosis, preserved sweating See cluster headache, Table 10-1
Touching trigger points, chewing, smiling, talking, blowing nose, yawning
Idiopathic If in young adults, multiple sclerosis Vascular anomaly Tumor of fifth cranial nerve
Carbamazepine, phenytoin, gabapentin, alcohol injection, coagulation, or surgical (vascular) decompression of root
Contact, movement
Herpes zoster
Carbamazepine, antidepressants, and sedatives
Chewing, pressure over temporomandibular joints
Loss of teeth, rheumatoid arthritis
Correction of bite Surgery in some
None
Granulomatous lesion of cavernous sinus or superior orbital fissure
Corticosteroids
None
Parasellar tumors, granulomatous lesions, trauma, idiopathic
Depends on type of lesion
Both sexes, constant dull ache 2–4 h
Compression of common carotid at or below bifurcation reproduces pain in some None
Predominantly female 30–50 years of age Continuous intolerable pain Mainly maxillary areas
Alcohol in some
Occasionally with cranial arteritis, carotid tumor, migraine and cluster headache Depressive and anxiety states Idiopathic
Indomethacin, triptan, or ergotamine before anticipated attack Corticosteroid acutely; triptans Calcium channel blockers Antidepressant and antianxiety medication
CHAPTER 10
face, lips, or gums, as in shaving or brushing the teeth, or by movement of these parts in chewing, talking, or yawning, or even by a breeze—the so-called trigger factors. Sensory or motor loss in the distribution of the fifth nerve cannot be demonstrated, though there are minor exceptions to this rule. In addition to the paroxysmal pain, some patients complain of a more or less continuous discomfort, itching, or sensitivity of restricted areas of the face, features regarded as atypical even though not infrequent. In studying the relationship between stimuli applied to the trigger zones and the paroxysms of pain, the latter are found to be induced by touch and possibly tickle rather than by a painful or thermal stimulus. Usually a spatial and temporal summation of impulses is necessary to trigger a paroxysm of pain, which is followed by a refractory period of up to 2 or 3 min. The diagnosis of tic douloureux must rest on the strict clinical criteria enumerated above, and the condition must be distinguished from other forms of facial and cephalic neuralgia and pain arising from diseases of the jaw, teeth, or sinuses. Most cases of trigeminal neuralgia are without obvious assignable cause (idiopathic), in contrast to symptomatic trigeminal neuralgia, in which paroxysmal facial pain is because of involvement of the fifth nerve by some other disease: multiple sclerosis (may be bilateral), aneurysm of the basilar artery, or tumor (acoustic or trigeminal schwannoma, meningioma, epidermoid) in the cerebellopontine angle. It has become apparent, however, that a proportion of ostensibly idiopathic cases are caused by compression of the trigeminal roots by a small tortuous branch of the basilar artery, as originally pointed out by Dandy and brought to greater attention by Jannetta, who has observed it frequently and has relieved the pain by surgical decompression of the trigeminal root. In this procedure, the offending small vessel is removed from contact with the proximal portion of the nerve (see below). Others have declared a vascular compressive causation to be less frequent, but modern imaging has increasingly revealed a putative association. Each of the forms of symptomatic trigeminal neuralgia may give rise only to pain in the distribution of the fifth nerve, or it may produce a loss of sensation as well. This and other disorders of the fifth nerve, some of which give rise to facial pain, are discussed in Chap. 47.
Treatment Antiepileptic drugs such as phenytoin (300 to 400 mg/d), valproic acid (800 to 1,200 mg/d), clonazepam (2 to 6 mg/ d), gabapentin (300 to 900 mg/d or more), pregabalin (150 to 300 mg/d), and carbamazepine (600 to 1,200 mg/d), alone or in combination, suppress or shorten the duration and severity of the attacks. Carbamazepine is effective in 70 to 80 percent of patients, but half become tolerant over a period of several years. Baclofen may be useful in patients who cannot tolerate carbamazepine or gabapentin, but it is most effective as an adjunct to one of the anticonvulsant drugs. Capsaicin applied locally to the trigger zones or the topical instillation in the eye of an anesthetic (proparacaine 0.5 percent) has been helpful in some patients. By temporizing and using these drugs, one may permit a spontaneous remission to occur in perhaps 1 in 5 patients.
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Most of the patients with intractable pain, however, come to surgery or an equivalent form of root destruction. The procedure of vascular decompression, popularized by Jannetta, which requires a posterior fossa craniotomy but leaves no sensory loss, has been the most popular. Barker and colleagues reported that 70 percent of 1,185 patients were relieved of pain by repositioning a small branch of the basilar artery that was found to compress the fifth nerve, and this benefit persisted with a recurrence rate of less than 1 percent annually for 10 years. It is not clear if arteriography is useful in identifying an aberrant blood vessel prior to surgery and many neurosurgeons obtain these studies before committing a patient to surgery. A procedure used more in the past, was stereotactically controlled thermocoagulation of the trigeminal roots (Sweet and Wepsic). The therapeutic efficacy of the two surgical approaches is roughly equivalent; in recent years, there has been a preference for microvascular decompression on the basis of its sparing of sensation, especially late in the course of the illness (Fields). Gamma Knife and other forms of focused radiation are emerging as less intrusive alternatives to destroying the ganglion, but its full effect is not evident for months. In practice, an antiepileptic medication is often required for some period of time after any of these procedures, and it must be reinstituted when symptoms reoccur, as they often do in our experience.
Glossopharyngeal Neuralgia This syndrome is much less common than trigeminal neuralgia but resembles the latter in many respects. The pain is intense and paroxysmal; it originates in the throat, approximately in the tonsillar fossa, and is provoked most commonly by swallowing but also by talking, chewing, yawning, laughing, etc. The pain may be localized in the ear or radiate from the throat to the ear, implicating the auricular branch of the vagus nerve. For this reason, White and Sweet suggested the term vagoglossopharyngeal neuralgia. This is the main craniofacial neuralgia that may be accompanied by bradycardia and even by syncope, presumably because of the triggering of cardioinhibitory reflexes by afferent vagal pain impulses. There is no demonstrable sensory or motor deficit. Rarely, carcinoma or epithelioma of the oropharyngeal-infracranial region or peritonsillar abscess may give rise to pain that is clinically indistinguishable from glossopharyngeal neuralgia. For idiopathic glossopharyngeal neuralgia, a trial of carbamazepine, gabapentin, pregabalin, or baclofen may be useful. If these are unsuccessful, the conventional surgical procedure had been to interrupt the glossopharyngeal nerve and upper rootlets of the vagus nerve near the medulla but recent observations suggest that a vascular decompression procedure similar to the one used for tic and directed to a small vascular loop under the ninth nerve relieves the pain in a proportion of patients.
Acute Zoster and Postherpetic Neuralgia Neuralgia associated with a vesicular eruption caused by the herpes zoster virus may affect cranial as well as peripheral nerves. In the region of the cranial nerves, two
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syndromes are frequent: herpes zoster auricularis and herpes zoster ophthalmicus. Both may be exceedingly painful in the acute phase of the infection. In the auricular form, herpes of the external auditory meatus and pinna and sometimes of the palate and occipital region—with or without deafness, tinnitus, and vertigo—is combined with facial paralysis. This syndrome, since its original description by Ramsay Hunt, has been known as geniculate herpes, a notion supported by the postmortem study of Denny-Brown and R.D. Adams (see also Chap. 47). The more common pain and herpetic eruption caused by herpes zoster infection of the gasserian ganglion are practically always limited to the first division (herpes zoster ophthalmicus). Ordinarily, the rash appears within 4 to 5 days or less after the onset of the pain, thereby making the clinical diagnosis difficult; however, treatment should be instituted (see below) based on the clinical likelihood of zoster infection. If the eruption does not appear, some cause other than herpes zoster will almost invariably declare itself; nevertheless, a few cases have been reported in which the characteristic location of pain with serologic evidence of herpes zoster infection was not accompanied by skin lesions. The acute discomfort associated with the herpetic eruption usually subsides after several days or weeks, or it may linger for several months. Treatment with acyclovir, along the lines indicated in Chap. 33, will shorten the period of eruption and pain, but the drug does not prevent its persistence as a chronic pain. It is mostly in the elderly that the pain becomes chronic and intractable. Usually it is described as a constant burning, with superimposed waves of stabbing pain, and the skin in the territory of the preceding eruption is exquisitely sensitive to the slightest tactile stimuli, even though the threshold of pain and thermal perception is elevated. This unremitting postherpetic neuralgia of long duration represents one of the most difficult pain problems with which the physician must deal. Some relief may be provided by application of capsaicin cream, use of a mechanical or electrical stimulator, or administration of one of the antiepileptic drugs. Antidepressants such as amitriptyline and fluoxetine are helpful in some patients, and Bowsher has suggested, on the basis of a small placebo-controlled trial, that treatment with amitriptyline during the early acute phase may prevent persistent pain. The use of preemptive measures, such as gabapentin or pregabalin administered at the outset, may be effective but a properly performed clinical trial is lacking. The addition of amitriptyline 75 mg at bedtime has proved to be a useful measure. Probably equivalent results are obtained by a combination of valproic acid and an antidepressant, as reported by Raftery. King has reported that two 325-mg aspirin tablets crushed and mixed with cold cream or chloroform (15 mL) and spread over the painful zone on the face or trunk relieved the pain for several hours in most patients with postzoster neuralgia. Ketamine cream has been suggested as an alternative. Extensive trigeminal rhizotomy or other destructive procedures should be avoided, as these surgical measures are not universally successful and may superimpose a diffuse refractory dysesthetic component on the neuralgia (anesthesia dolorosa).
Trochlear Headache Under the heading of “primary trochlear headache,” Yanguela and colleagues have described a periorbital pain that emanates from the superomedial orbit in the region of the trochlea (the pulley of the superior oblique muscle). Most of their patients were women. The pain was worsened by adduction and elevation of the globe on the affected side, in the direction of action of the superior oblique muscle. The authors describe a diagnostic method of examination that begins by having the patient look downward so that the trochlea can be palpated and compressed; the patient then looks upward, eliciting or exaggerating the pain, while the examiner continues compression. Injection of the trochlea with corticosteroids relieved the pain in almost all of these patients. The authors make a distinction between primary trochlear headache and “trochleitis,” which seems to us ambiguous. There is no limitation of ocular movement or autonomic change and imaging of the orbit is normal. This syndrome, with which we have no experience, brings to mind the entity of the Brown syndrome of trochlear entrapment with diplopia and pain (Chap. 13). The above authors are of the opinion that the trochlea may be a trigger point for migraine.
Otalgia Pain localized in and around one ear is occasionally a primary complaint. It is commonly the incipient symptom of Bell’s palsy but there are a number of different causes and mechanisms. During neurosurgical operations in awake patients, stimulation of cranial nerves V, VII, IX, and X causes ear pain, yet interruption of these nerves usually causes no or limited demonstrable loss of sensation in the ear canal or the ear itself (superficial sensation in this region is supplied by the great auricular nerve, which is derived from the C2 and C3 roots). The neurosurgical literature cites examples of otalgia that were relieved by section of the nervus intermedius (sensory part of VII) or of nerves IX and X. In otalgic cases, one is prompted to search for a nasopharyngeal tumor, vertebral artery aneurysm or to anticipate an outbreak of zoster. Formerly, lateral sinus thrombosis was a common cause in children. When these possibilities are eliminated by appropriate studies, there always remain examples of primary idiopathic otalgia, lower cluster headache, and glossopharyngeal neuralgia. Some patients with common migraine have pain centered in the ear region and occiput, but we have never observed a trigeminal neuralgia in which the ear was the predominant site of pain.
Occipital Neuralgia Paroxysmal pain may occasionally occur in the distribution of the greater or lesser occipital nerves (suboccipital, occipital, and posterior parietal areas). While tenderness may be localized to the region where these nerves cross the superior nuchal line, there is only questionable evidence of an occipital nerve lesion at this site. The finding of hypesthesia in the distribution of the occipital nerves makes the possibility of an entrapment neuropathy more convincing. Carbamazepine or gabapentin may provide
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some relief. Blocking the nerves with lidocaine may abolish the pain and encourage attempts to section one or more occipital nerves or the second or third cervical dorsal root, but the results have rarely been successful, and several such patients who had these procedures were later referred to us with disabling anesthesia dolorosa. We have advised repeated injections of local anesthetic agents and the use of steroids, traction, local heat, and analgesic and antiinflammatory drugs. The pain at times may be difficult to distinguish from that arising in the upper three cervical facet joints, one type of which is discussed below.
“Third Occipital Nerve” Headache This condition, a unilateral occipital and suboccipital ache, may be a prominent symptom in patients with neck pain, particularly after neck injuries (a prevalence of 27 percent, according to Lord et al). Bogduk and Marsland attribute it to a degenerative or traumatic arthropathy involving the C2 and C3 apophysial joints with impingement on the “third occipital nerve” (a branch of the C3 dorsal ramus that crosses the dorsolateral aspect of the apophysial joint). Ablation of the neck pain and headache by percutaneous blocking of the third occipital nerve under fluoroscopic control is diagnostic and temporarily therapeutic. More sustained relief (weeks to months) has been obtained by radiofrequency coagulation of the nerve or steroid injections of the joint. NSAIDs also provide some relief.
Carotidynia and Extracranial Artery Dissection Carotidynia was coined by Temple Fay in 1927 to designate a special type of cervicofacial pain that could be elicited by pressure on the common carotid arteries of patients with atypical facial neuralgia. Compression of the artery in these patients, or mild electrical stimulation at or near the bifurcation, produced a dull ache that was referred to the ipsilateral face, ear, jaws, and teeth or down the neck. This type of carotid sensitivity occurs rarely as part of cranial (giant cell) arteritis and of the rare condition known as Takayasu arteritis (Chap. 34), and during attacks of migraine or cluster headache. It has also been described with displacement of the carotid artery by tumor and dissecting aneurysm of its wall; among these causes, the last is of greatest concern. The idiopathic variety may have to do with a swelling or inflammation of the tissue surrounding the carotid bifurcation, a change that has been demonstrated on MRI by Burton and colleagues but the problem has been seen most frequently in migraineurs. Roseman has described a variant of carotidynia that has a predilection for young adults. This syndrome takes the form of recurrent, self-limited attacks of pain and tenderness at the carotid bifurcation lasting a week or two. During the attack, aggravation of the pain by head movement, chewing, and swallowing is characteristic. This condition is treated with simple analgesics. Yet another possible variety of carotidynia appears at any stage of adult life and recurs in attacks lasting minutes to hours in association with throbbing headaches indistinguishable from common migraine (Raskin and Prusiner). This form
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responds favorably to the administration of ergotamine, methysergide, and other drugs that are effective in the treatment of migraine. Although most pain of carotid or vertebral artery dissection is localized to the site of injury in the anterior or posterior neck, Arnold and colleagues have emphasized the frequency with which headache, and not neck pain, was the sole feature. Some had a paroxysmal (“thunderclap”) onset but most had throbbing and progressive pain over days, sometimes bilaterally. The combination of focal neck pain and localized headache over an eye is particularly suggestive and, of course, if there are corresponding symptoms of fluctuating or static regional brain ischemia, or Horner syndrome, the diagnosis is likely.
Temporomandibular Joint Pain (Costen Syndrome) This is a form of craniofacial pain consequent on dysfunction of one temporomandibular joint. Malocclusion because of illfitting dentures or loss of molar teeth on one side, with alteration of the normal bite, may lead to distortion of and ultimately degenerative changes in the joint and to pain in front of the ear, with radiation to the temple and over the face (see Guralnick et al). The diagnosis is supported by the findings of tenderness over the joint, crepitus on opening the mouth, and limitation of jaw opening. The favored diagnostic maneuver involves palpating the joint from its posterior aspect by placing a finger in the external auditory meatus and pressing forward. The diagnosis can be made with some confidence only if this entirely reproduces the patient’s pain. CT and plain films are rarely helpful, but effusions have been shown in the joints by MRI. Management consists of careful adjustment of the bite by a dental specialist and should be undertaken only when the patient meets the strict diagnostic criteria for this condition. Small doses of amitriptyline at bedtime may be helpful. In our experience, most of the putative diagnoses of Costen syndrome that reach the neurologist have been erroneous and the number of headaches and facial pains that are attributed to “temporomandibular joint dysfunction” is excessive, especially if judged by the response to treatment. The temporomandibular joint may also be the source of pain when involved with rheumatoid arthritis and other connective tissue diseases.
Facial Pain of Dental or Sinus Origin Maxillary and mandibular discomfort is a common effect of nerve irritation from deep caries, dental pulp degeneration, or periodontal abscess. The pain of dental nerve origin is most severe at night, slightly pulsating, and often associated with local tenderness at the root of the tooth in response to heat, cold, or pressure. The diagnosis can be confirmed by infiltrating the base of the tooth with lidocaine and the pain is eradicated by proper dental management. Trigeminal neuritis following dental extractions or oral surgery is another vexing problem. There may be sensory loss in the tongue or lower lip and weakness of the masseter or pterygoid muscle. Sometimes the onset of “atypical facial pain” (see below) can be dated to a dental procedure such as tooth
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extraction, and, as usually happens, neither the dentist nor the neurologist is able to find a source for the pain or any malfunction of the trigeminal nerve. Roberts and coworkers, as well as Ratner and associates, have pointed out that residual microabscesses and subacute bone infection account for some of these cases. They isolated the affected region by local anesthetic blocks, curetted the bone, and administered antibiotics, following which the pain resolved. The removed bone fragments showed vascular and inflammatory changes and infection with oral bacterial flora.
Facial Pain of Uncertain Origin (Idiopathic, “Atypical” Facial Pain) There remains—after all the aforementioned pain syndromes and all the possible intracranial and local sources of pain from throat, mouth, sinuses, orbit, and carotid vessels have been excluded—a fair number of patients with pain in the face for which no cause can be found. These patients are most often young women, who describe the pain as constant and unbearably severe, deep in the face, or at the angle of cheek and nose and unresponsive to all varieties of analgesic medication. Because of the failure to identify an organic basis for the pain, one is tempted to attribute it to psychologic or emotional factors. Depression of varying severity is found in many. Some such patients, with or without depression, respond to tricyclic antidepressants and monoamine oxidase inhibitors. Differentiated from this group is the condition of trigeminal neuropathy, described in Chap. 47. Facial pain of the “atypical type,” like other chronic pain of indeterminate cause, requires close observation of the patient, looking for lesions such as nasopharyngeal carcinoma or apical lung carcinoma to declare themselves. The pain should be managed by the conservative methods outlined in the preceding chapter and not by destructive surgery. Antidepressants may be helpful, especially if the patient displays obsessive characteristics in relation to the pain; some European neurologists favor clomipramine for various facial and scalp pains.
References Anderson CD, Frank RD: Migraine and tension headache: Is there a physiological difference? Headache 21:63, 1981. [PMID: 7239903] Arnold M, Cumurcivc R, Stapf C, et al: Pain as the only symptom of cervical artery dissection. J Neurol Neurosurg Psychiatry 77:1021, 2006. Ashina M, Lassin LH, Bendsten L, et al: Effect of inhibition of nitric oxide synthetase on chronic tension type headache: A randomised crossover trial. Lancet 353:287, 1999. [PMID: 9929022] Barker FG, Jannetta PJ, Bissonette DJ, et al: The long-term outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med 334:1077, 1996. [PMID: 8598865] Bartsch T, Pirsker MO, Rasche D, et al: Hypothalamic deep brain stimulation for cluster headache: experience from a new multicentre series. Cephalalgia 28:285, 2008. [PMID:18254897]
Other Rare Types of Facial Pain Neuralgia may arise in the terminal branches of the trigeminal, ciliary, nasociliary, and supraorbital nerves, some of which have already been mentioned. Some of these are vague entities at best and merely descriptive terms given to pains localized around the eye and nose (see “Cluster Headache” above; also Table 10-2). The Tolosa-Hunt syndrome of pain behind the eye and granulomatous involvement of some combination of cranial nerves III, IV, VI, and ophthalmic V, responsive to steroids, is discussed in Chap. 47. A kind of reflex sympathetic dystrophy of the face is postulated as another rare form of persistent facial pain that may follow dental surgery or penetrating injuries to the face. It is characterized by severe burning pain and hyperpathia in response to all types of stimuli. Sudomotor, vasomotor, and trophic changes are lacking, unlike causalgia that affects the limbs. Nevertheless, this form of facial pain is said to respond to repeated blockade or resection of the stellate ganglion. Under the title of neck–tongue syndrome, Lance and Anthony have described the occurrence of a sharp pain and tingling in the upper neck or occiput on sudden rotation of the neck associated with numbness of the ipsilateral half of the tongue. They attribute the syndrome to stretching of the C2 ventral ramus, which contains proprioceptive fibers from the tongue; these fibers run from the lingual nerve to the hypoglossal nerve and thence to the second cervical root. A problem that has gone by the self-evident name burning mouth syndrome (stomatodynia) occurs mainly in middle-aged and older women, as commented in Chap. 12. The tongue or other oral sites may be most affected or the entire oral mucosa may burn. A few patients are found to have diabetes, vitamin B12 deficiency, or Sjögren syndrome as possible causes. A hint to the last diagnosis is the inability to feel food in the mouth. The oral mucosa is normal when inspected, and no one treatment has been consistently effective, but gabapentin combined with antidepressants or clonazepam may be tried (see the review by Grushka et al). One of our patients with a limited form of this condition, which affected only the upper palate and gums, benefited from dental nerve blocks with lidocaine.
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Rooke ED: Benign exertional headache. Med Clin North Am 52:801, 1968. [PMID: 5742064] Roseman DM: Carotidynia. Arch Otolaryngol 85:103, 1967. [PMID: 6016255] Sakai F, Ebihara S, Akiyama M, Horikawa M: Pericranial muscle hardness in tension-type headache: A non-invasive measurement method and its clinical application. Brain 118:523, 1995. [PMID: 7735892] Singhal AB, Caviness VS, Begleiter MD, et al: Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 58:130, 2002. [PMID: 11781419] Sjaastad O, Dale I: A new (?) clinical headache entity “chronic paroxysmal hemicrania.” Acta Neurol Scand 54:140, 1976. [PMID: 782140] Somerville BW: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972. [PMID: 5062827] Stewart WF, Lipton RB, Liberman J: Variation in migraine prevalence by race. Neurology 47:52, 1996. [PMID: 8710124] Subcutaneous Sumatriptan International Study Group: Treatment of migraine attacks with sumatriptan. N Engl J Med 325:316, 1991. Sweet WH: The treatment of trigeminal neuralgia (tic douloureux). N Engl J Med 315:174, 1986. [PMID: 3523243] Sweet WH, Wepsic JG: Controlled thermocoagulation of trigeminal ganglion and rootlets for differential destruction of pain fibers. J Neurosurg 40:143, 1974. [PMID: 4587949] Symonds CP: Cough headache. Brain 79:557, 1956. [PMID: 13396063] Taimi C, Navez M, Perrin A-M, Laurent B: Cephales induites par abus des traitments symptomatique antalgiques et antimigraineux. Rev Neurol 157:1221, 2001. [PMID: 11885515] Watson P, Steele JC: Paroxysmal dysequilibrium in the migraine syndrome of childhood. Arch Otolaryngol 99:177, 1974. [PMID: 4853539] Welch KMA: Migraine: A behavioral disorder. Arch Neurol 44:323, 1987. [PMID: 3827684] White JC, Sweet WH: Pain and the Neurosurgeon. Springfield, IL, Charles C Thomas, 1969, p 265. Wijdicks EF, Kerkhoff H, Van Gijn J: Long-term follow up of 71 patients with thunderclap headache mimicking subarachnoid hemorrhage. Lancet 2:68, 1988. [PMID: 2898698] Wolff HG: Headache and Other Head Pain, 2nd ed. New York, Oxford University Press, 1963. Woods RP, Iacoboni M, Mazziotta JC: Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 331:1690, 1994. [PMID: 7969360] Yanguela J, Sanchez-del-Rio M, Bueno A, et al: Primary trochlear headache. A new cephalgia generated and modulated on the trochlear region. Neurology 62:1134, 2004. [PMID: 15079013] Ziegler DK, Hurwitz A, Hassanein RS, et al: Migraine prophylaxis: A comparison of propranolol and amitriptyline. Arch Neurol 44:486, 1987. [PMID: 3579659]
11 Pain in the Back, Neck, and Extremities
We include an extensive chapter on this subject in recognition of the fact that back pain is among the most frequent of medical complaints. Up to 80 percent of adults have low back pain at some time in their lives and, according to Kelsey and White, an even larger percentage will be found at autopsy to have degenerative disc disease. The diagnosis of pain in these parts of the body often requires the assistance of a neurologist. One task is to determine whether a disease of the spine has compressed the spinal cord or the spinal roots. To do this effectively, a clear understanding of the structures involved and some knowledge of orthopedics and rheumatology is necessary. As pains in the lower part of the spine and legs are caused by different types of disease than those in the neck, shoulder, and arms, they are considered separately.
PAIN IN THE LOWER BACK AND LIMBS The lower parts of the spine and pelvis, with their massive muscular attachments, are relatively inaccessible to palpation and inspection. Although some physical signs and imaging studies are helpful, diagnosis often depends on the patient’s description of the pain and his behavior during the execution of certain maneuvers. Seasoned clinicians appreciate the need for a systematic inquiry and method of examination, the descriptions of which are preceded here by a brief consideration of the anatomy and physiology of the spine.
Anatomy and Physiology of the Lower Part of the Back The bony spine is a complex structure, roughly divisible into an anterior and a posterior part. The anterior component consists of cylindric vertebral bodies, articulated by the intervertebral discs and held together by the anterior and posterior longitudinal ligaments. The posterior elements are more delicate and extend from the bodies as pedicles and laminae, which form the spinal canal by joining with the posterior aspects of the vertebral bodies and ligaments. Large transverse and spinous processes project laterally and posteriorly, respectively, and serve as the origins and insertions of the muscles that support and protect the
spinal column. The bony processes are also held together by sturdy ligaments, the most important being the ligamentum flavum, which runs along the ventral surfaces of the posterior elements and is applied to the inner surface of the laminae. The posterior longitudinal ligament lies opposite it on the dorsal surfaces of the vertebral bodies. These two ligaments bound the posterior and anterior structures of the spinal canal, respectively. The posterior parts of the vertebrae articulate with one another at the diarthrodial facet joints (also called apophysial or zygapophysial joints), each of which is composed of the inferior facet of the vertebra above and the superior facet of the one below. Figures 11-1 and 11-2 illustrate these anatomic features. The facet and sacroiliac joints, which are covered by synovia, the compressible intervertebral discs, and the collagenous and elastic ligaments, permit a limited degree of flexion, extension, rotation, and lateral motion of the spine. The stability of the spine depends on the integrity of the vertebral bodies and intervertebral discs and on two types of supporting structures, ligamentous (passive) and muscular (active). Although the ligamentous structures are quite strong, neither they nor the vertebral body–disc complexes have sufficient integral strength to resist the enormous forces that may act on the spinal column. Consequently, the stability of the lower back is largely dependent on the voluntary and reflex activity of the sacrospinalis, abdominal, gluteus maximus, and hamstring muscles, and on the integrity of the ligamentum flavum and posterior longitudinal ligament. The vertebral and paravertebral structures derive their innervation from the meningeal branches of the spinal nerves (also known as recurrent meningeal or sinuvertebral nerves). These meningeal branches spring from the posterior divisions of the spinal nerves just distal to the dorsal root ganglia, reenter the spinal canal through the intervertebral foramina, and supply pain fibers to the intraspinal ligaments, periosteum of bone, outer layers of the annulus fibrosus (which enclose the disc), and capsule of the articular facets. Coppes and associates have found A-δ and C pain fibers extending into the inner layers of the annulus, and even into the nucleus pulposus. Although the spinal cord itself is insensitive, many of the conditions that affect it produce pain by involving these adjacent structures. For example, the sensory fibers from the lumbosacral and sacroiliac joints enter the spinal cord via the fifth lumbar
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Spine
Superior articular process Mamillary process Transverse process Inferior articular process Mamillary process
Lamina
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Figure 11-1. The fifth lumbar vertebra viewed from above (A) and from the side (B).
and first sacral roots. Motor fibers exit through the corresponding anterior roots and form the efferent limb of segmental reflexes. The spinal roots in the lumbar region, after exiting from the spinal cord, course downward in the spinal canal and are gradually displaced laterally until they angulate and exit at the intervertebral foramina. Prior to entering the short foraminal canal, the spinal root lies in a shallow furrow along the inner surface of the pedicle, the lateral recess. This is a common site of root entrapment by disc fragments and bony overgrowth. The parts of the back that possess the greatest freedom of movement, and hence are most frequently subject to injury, are the lumbar, lumbosacral, and cervical. In addition to bending, twisting, and other voluntary movements, many actions of the spine are reflexive in nature and are the basis of erect posture.
cent by the fiftieth year of life. Jensen and colleagues recorded similar abnormalities in asymptomatic men and women (see further on). The problem of degenerative spinal disease has been conceptualized as having its genesis in shrinkage of the disc that subsequently alters the alignment of the articular facets and vertebral bodies, leading to facet arthropathy and bony spur formation. These ostensibly reactive changes contribute to stenosis of the spinal canal and directly compromise the lateral recesses of the canal and the intervertebral foramina, where they impinge on nerve roots. Osteoporosis, especially in older women, is a further important cause of vertebral flattening or collapse, additionally narrowing the spinal canal.
General Clinical Features of Low Back Pain Types of Low Back Pain
Aging Changes in Spinal Structures Degeneration in the intervertebral discs and ligaments is a consequence of aging and the succession of inevitable minor traumas to the spine. Deposition of collagen and elastin and alterations of glycosaminoglycans combine to decrease the water content of the nucleus pulposus; concomitantly, the cartilaginous endplate becomes less vascular (Hassler). The dehydrated disc thins out and becomes more fragile. Similar changes occur in the annulus of the disc, which frays to an increasing degree with the passage of time, permitting the nucleus pulposus to bulge and, sometimes with injury, to extrude. This process can be observed by MRI, which shows a gradual reduction in the high signal of the nucleus pulposus with the passage of time. In women who had MRI for gynecologic reasons, Powell and coworkers found an increasing frequency of lumbar disc degeneration and bulging, approaching 70 per-
Of the several symptoms of spinal disease (pain, stiffness, limitation of movement, and deformity), pain is of foremost importance. Four types of pain may be distinguished: local, referred, radicular, and that arising from secondary muscular spasm. These several types of pain can often be discerned from the patient’s description; reliance is placed mainly on the character of the pain, its location, and conditions that modify it. Local pain is caused by any pathologic process that impinges on structures containing sensory endings, including the periosteum of the vertebral body, capsule of apophysial joints, annulus fibrosus, and ligaments. Destruction of the nucleus pulposus alone produces little or no pain but the annulus is innervated with small nerve fibers and, when subject to disruption, may produce considerable pain. Local pain is steady and aching, but it may be intermittent and sharp, and, although not well circumscribed, is
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Figure 11-2. The main ligamentous structures of the spine. A. Buckling of the yellow ligament (ligamentum flavum) may compress the nerve root or the spinal nerve at its origin in the intervertebral foramen, particularly if the foramen is narrowed by osteophytic overgrowth. B. Posterior aspect of the vertebral bodies. Fibers of the posterior longitudinal ligament merge with the posteromedial portion of the annulus fibrosus, leaving the posterolateral portion of the annulus relatively unsupported. (Reproduced by permission from Finneson.)
felt in or near the affected part of the spine. Pathologic change arising in spinal structures may also evoke discomfort in regions that share common innervation and thereby vaguely simulate the pain of radicular disease. These areas of projection may be considered similarly to the referred pain of the “sclerotomes” discussed in Chap. 8 and just below. Referred pain in reference to the spine is of two types: one that is projected from the spine to viscera and other structures lying within the territory of the lumbar and upper sacral dermatomes, and another that is projected from pelvic and abdominal viscera to the spine. Pain caused by
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disease of the upper part of the lumbar spine may be referred to the medial flank, lateral hip, groin, and anterior thigh (sclerotomes; see Chap. 8). This has been attributed to irritation of the superior cluneal nerves, which are derived from the posterior divisions of the first three lumbar spinal nerves and innervate the superior portions of the buttocks. Pain from the lower part of the lumbar spine is usually referred to the lower buttocks and posterior thighs and is a result of irritation of lower spinal nerves, which activate the same pool of intraspinal neurons as the nerves that innervate the posterior thighs. Pain of this type is usually diffuse and has a deep, aching quality, but it tends at times to be more superficially projected. In general, the intensity of the referred pain parallels that of the local pain. Maneuvers that alter local pain have a similar effect on referred pain. McCall and colleagues and Kellgren have verified these areas of reference by the injection of hypertonic saline into the facet joints and the “sclerotomes” they determined are discussed in Chap. 8. But, as Sinclair and coworkers have pointed out, the sites of reference are inexact and cannot be relied on for precise anatomic localization. Pain from visceral diseases is usually felt within the abdomen, flanks, or lumbar region and may be modified by the state of activity of the viscera and sometimes by assuming an upright or supine posture. Its character and temporal relationships have little relationship to movement of the back. Radicular or “root” pain has some of the characteristics of referred pain but differs in its greater intensity, distal radiation, circumscription to the territory of a root, and factors that excite it. The mechanism is stretching, irritation, or compression of a spinal root within or central to the intervertebral foramen. The pain is sharp, often intense, and usually superimposed on the dull ache of referred pain; it nearly always radiates from a paracentral position near the spine to some part of the lower limb. Coughing, sneezing, and straining characteristically evoke this sharp radiating pain, although each of these actions may also jar or move the spine and enhance local pain. Any maneuver that stretches the nerve root—e.g., “straight-leg raising” in cases of sciatica—evokes radicular pain. The patterns of radicular pain because of involvement of particular roots are described in the sections on prolapsed discs further on in the chapter, and the distribution of cutaneous innervation of the spinal roots is shown in Figs. 9-2 and 9-3. The most common pattern is sciatica, pain that originates in the buttock and is projected along the posterior or posterolateral thigh. It results from irritation of the L5 or S1 nerve root. Paresthesia or superficial sensory loss, soreness of the skin, and tenderness in certain regions along the nerve usually accompany radicular pain. If the anterior roots are involved as well, there is weakness, atrophy, or muscular twitching. In patients with severe circumferential constriction of the cauda equina because of spondylosis (lumbar stenosis), sensorimotor impairment and referred pain are elicited by standing and walking. The symptoms are projected to the calves and the backs of the thighs thereby simulating the exercise-induced symptoms of ileofemoral vascular insufficiency—hence the term spinal claudication has been
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applied to the activity-induced symptoms of lumbar stenosis (see “Lumbar Stenosis and Spondylotic Caudal Radiculopathy” later in this chapter). Referred pain from structures of the lower back (sometimes called pseudoradicular) does not, as a rule, project below the knees and is not accompanied by neurologic changes other than sometimes a vague numbness without demonstrable sensory impairment. This is quite in contrast to the pain of root compression. Pain resulting from muscular spasm usually occurs in relation to local spinal irritation and may be thought of as a nocifensive reflex for the protection of the diseased parts against injurious motion. Chronic muscular contraction may give rise to a dull, sometimes cramping ache. One can sometimes feel the tautness of the sacrospinalis and gluteal muscles and demonstrate by palpation that the pain is localized to them. However, except for the most severe degrees of acute injuries of the back, the spasms are difficult to detect and their contribution to back pain has appeared to us to be relatively small. In addition to assessing the character and location of the pain, one should determine the factors that aggravate and relieve it, its constancy, and its relationship to activity and to rest, posture, forward bending, coughing, sneezing, and straining. Frequently, the most important lead comes from knowledge of the mode of onset and the circumstances that initiated the pain. Inasmuch as many painful conditions of the back are the result of injuries incurred during work or in automobile accidents, the possibility of exaggeration or prolongation of pain for purposes of compensation must always be kept in mind.
Examination of the Lower Back The main goals of the examination of the back are to differentiate pain that is caused by nerve root compression from musculoskeletal strains, metastatic spinal tumor, and infectious and inflammatory diseases of the spine and hips. Some information may be gained by inspection of the back, buttocks, and lower limbs in various positions. The normal spine shows a thoracic kyphosis and lumbar lordosis in the sagittal plane, which in some individuals may be exaggerated. In the coronal plane, the spine is normally straight or shows a slight curvature, particularly in women. One should observe the spine for excessive curvature, a list, flattening of the normal lumbar lordosis, presence of a gibbus (a sharp, kyphotic angulation usually indicative of a fracture), pelvic tilt or obliquity (Trendelenburg sign), and asymmetry of the paravertebral or gluteal musculature. A sagging gluteal fold suggests involvement of the S1 root. In sciatica one may observe a flexed posture of the affected leg, presumably to reduce tension on the irritated nerve. Or, patients in whom a free fragment of lumbar disc material has migrated posterolaterally may be unable to lie down and extend the spine. The next step in the examination is observation of the spine, hips, and legs during certain motions. No advantage accrues from determining how much pain the patient can tolerate. More important is to determine when and under what conditions the pain begins or worsens. Observation of the
patient’s gait may disclose a subtle limp, a pelvic tilt, a shortening of step, or a stiffness of bearing—indicative of a disinclination to bear weight on a painful leg. One looks for limitation of motion while the patient is standing, sitting, and reclining. When standing, the motion of forward bending normally produces flattening and reversal of the lumbar lordotic curve and exaggeration of the thoracic curve. With lesions of the lumbosacral region that involve the posterior ligaments, articular facets, or sacrospinalis muscles and with ruptured lumbar discs, protective reflexes prevent flexion, which stretches these structures (“splinting”). As a consequence, the sacrospinalis muscles remain taut and prevent motion in the lumbar part of the spine. Forward bending then occurs at the hips and at the thoracolumbar junction; also, the patient bends in such a way as to avoid tensing the hamstring muscles and putting undue leverage on the pelvis. In the presence of degenerative disc disease, straightening up from a flexed position is performed only with difficulty. Lateral bending is usually less instructive than forward bending but, in unilateral ligamentous or muscular strain, bending to the opposite side aggravates the pain by stretching the damaged tissues. With unilateral sciatica, the patient lists to one side and strongly resists bending to the opposite side, and the preferred posture in standing is with the leg slightly flexed at the hip and knee. When the herniated disc lies lateral to the nerve root and displaces it medially, tension on the root is reduced and pain is relieved by bending the trunk to the side opposite the lesion; with herniation medial to the root, tension is reduced by inclining the trunk to the side of the lesion. In the sitting position, flexion of the spine can be performed more easily, even to the point of bringing the knees in contact with the chest. The reason for this is that knee flexion relaxes tightened hamstring muscles and relieves the stretch on the sciatic nerve. Examination with the patient in the reclining position yields much the same information as in the standing and sitting positions. With lumbosacral disc lesions and sciatica, passive lumbar flexion causes little pain and is not limited as long as the hamstrings are relaxed and there is no stretching of the sciatic nerve. Thus, with the knees flexed to 90 degrees, sitting up from the reclining position is unimpeded and not painful; with knees extended, there is pain and limited motion (Kraus-Weber test). With vertebral disease, passive flexion of the hips is free, whereas flexion of the lumbar spine may be impeded and painful. Among the most helpful signs in detecting nerve root compression is passive straight-leg raising (possible up to almost 90 degrees in normal individuals) with the patient supine. This places the sciatic nerve and its roots under tension, thereby producing radicular, radiating pain from the buttock through the posterior thigh. This maneuver is the usual way in which compression of the L5 or S1 nerve root is detected (Lasègue sign), however, it may also cause an anterior rotation of the pelvis around a transverse axis, increasing stress on the lumbosacral joint and causing milder radiating pain if this joint is arthritic or otherwise diseased. Straight raising of the opposite leg (“crossed straight-leg raising,” Fajersztajn sign) may also cause pain on the affected side and is a more specific sign of pro-
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lapsed disc than is the Lasègue sign. Several of the many derivatives of the straight-leg raising sign are discussed in the section on lumbar disc disease. Asking the seated patient to extend the leg so that the sole of the foot can be inspected is a way of checking for a feigned Lasègue sign. A patient with lumbosacral strain or disc disease (except in the acute phase or if the disc fragment has migrated laterally) can usually extend or hyperextend the spine with little or no aggravation of pain. If there is an active inflammatory process or fracture of the vertebral body or posterior elements, hyperextension may be markedly limited. In disease of the upper lumbar roots, hyperextension of the leg with the patient prone is the motion that is most limited and reproduces pain; however, in some cases of lower lumbar disc disease with thickening of the ligamentum flavum, this movement is also painful. Maneuvers in the lateral decubitus position yield less information but are useful in eliciting joint disease. In cases of sacroiliac joint disease, abduction of the upside leg against resistance reproduces pain in the sacroiliac region, sometimes with radiation of the pain to the buttock, posterior thigh, and symphysis pubis. Hyperextension of the upside leg with the downside leg flexed is another test for sacroiliac disease. Rotation and abduction of the leg evoke pain in a diseased hip joint and with trochanteric bursitis. A helpful indicator of hip disease is the Patrick test: With the patient supine, the heel of the offending leg is placed on the opposite knee and pain is evoked by depressing the flexed leg and externally rotating the hip. Gentle palpation and percussion of the spine are the last steps in the examination. It is preferable to first palpate the regions that are the least likely to evoke pain. At all times the examiner should know what structures are being palpated (Fig. 11-3). Localized tenderness is seldom pronounced in disease of the spine because the involved structures are so deep. Nevertheless, tenderness over a spinous process or jarring by gentle percussion may indicate the presence of local spinal inflammation (as in disc space infection), pathologic fracture, metastasis, epidural abscess, or a disc lesion. Tenderness over the interspinous ligaments or over the region of the articular facets between the fifth lumbar and first sacral vertebrae is consistent with lumbosacral disc disease (Fig. 11-3, sites 2 and 3). Tenderness in this region and in the sacroiliac joints is also a frequent manifestation of ankylosing spondylitis. Arthritic changes at a facet may cause the same tenderness. Tenderness over the costovertebral angle often indicates genitourinary disease, adrenal disease, or an injury to the transverse process of the first or second lumbar vertebra (Fig. 11-3, site 1). Tenderness on palpation of the paraspinal muscles may signify a strain of muscle attachments or injury to the underlying transverse processes of the lumbar vertebrae. Focal pain in the same parasagittal line along the thoracic spine points to inflammation of the costotransverse articulation between spine and rib (costotransversitis). Other sites of tenderness and the structures implicated by disease are shown in the figure. In palpating the spinous processes, it is important to note any deviation in the lateral plane (this may be indica-
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1
5 6
3 4
7 8 9
10
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Figure 11-3. (1) Costovertebral angle. (2) Spinous process and interspinous ligament. (3) Region of articular facet (fifth lumbar to first sacral). (4) Dorsum of sacrum. (5) Region of iliac crest. (6) Iliolumbar angle. (7) Spinous processes of fifth lumbar and first sacral vertebrae (tenderness = faulty posture or occasionally spina bifida occulta). (8) Region between posterior superior and posteroinferior spines. Sacroiliac ligaments (tenderness = sacroiliac sprain, often tender, with fifth lumbar or first sacral disc). (9) Sacrococcygeal junction (tenderness = sacrococcygeal injury; i.e., sprain or fracture). (10) Region of sacrosciatic notch (tenderness = fourth or fifth lumbar disc rupture and sacroiliac sprain). (11) Sciatic nerve trunk (tenderness = ruptured lumbar disc or sciatic nerve lesion).
tive of fracture or arthritis) or in the anteroposterior plane. A “step-off” forward displacement of the spinous process and exaggerated lordosis are important clues to the presence of spondylolisthesis (see further on). Abdominal, rectal, and pelvic examinations may lead to the discovery of neoplastic or inflammatory diseases in these body parts that are referred to the lower part of the spine. On completion of the examination of the back and legs, one turns to a search for motor, reflex, and sensory changes in the lower extremities (see “Herniation of Lumbar Intervertebral Discs,” further on in this chapter).
Diagnostic Procedures Depending on the circumstances, these may include a blood count and erythrocyte sedimentation rate (especially helpful in screening for spinal osteomyelitis, epidural abscess, or myeloma). The C-reactive protein is at times a more sensitive measure of inflammation and may be especially useful when the erythrocyte sedimentation rate
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is normal. Other useful blood tests are calcium, alkaline phosphatase, and prostate-specific antigen (if one suspects metastatic carcinoma of the prostate); a serum protein immunoelectrophoresis (myeloma proteins); in special cases, a tuberculin test or serologic test for Brucella; a test for rheumatoid factor; and human leukocyte antigen (HLA) typing (for ankylosing spondylitis). Radiographs of the lumbar spine (preferably with the patient standing) in the anteroposterior, lateral, and oblique planes may still be useful in the routine evaluation of low back pain and sciatica. Readily demonstrable in plain films are narrowing of the intervertebral disc spaces, bony facetal or vertebral overgrowth, displacement of vertebral bodies (spondylolisthesis), and an unsuspected infiltration of bone by cancer. However, in cases of suspected disc herniation or tumor infiltration of the spinal canal, one generally proceeds directly to MRI. Administration of gadolinium at the time of MRI enhances regions of inflammation and tumor but is not particularly helpful in cases of degenerative and disc disease of the spine. The current generation of MRI scanners has replaced conventional myelography for the examination of spinal disease but the latter examination, when combined with CT, provides detailed information about the dural sleeves that surround the spinal roots, disclosing subtle truncations caused by laterally situated disc herniations and at times revealing surface abnormalities of the spinal cord, such as arteriovenous malformations. When metallic devices such as a pacemaker preclude the performance of MRI, CT with or without myelography remains very useful for diagnosis. Nerve conduction studies and electromyography (EMG) are particularly helpful in suspected root and nerve diseases as indicated further on in the discussion of lumbar disc disease. However, as for all the aforementioned tests, they must be interpreted in the context of the history and clinical examination; otherwise they are subject to overuse and overinterpretation.
Conditions Giving Rise to Pain in the Lower Back Congenital Anomalies of the Lumbar Spine Anatomic variations of the spine are frequent and, though rarely themselves the source of pain and functional derangement, they may predispose an individual to discogenic and spondylotic complications by virtue of altering the mechanics and alignment of the vertebrae or size of the spinal canal. A common anomaly is fusion of the fifth lumbar vertebral body to the sacrum (“sacralization”) or, conversely, separation of the first sacral segment, giving rise to 6, rather than the usual 5 lumbar vertebrae (“lumbarization”). However, neither of these is consistently associated with any type of back derangement. Another less-common finding is a lack of fusion of the laminae of one or several of the lumbar vertebrae or of the sacrum (spina bifida). Occasionally, a subcutaneous mass, hypertrichosis, or hyperpigmentation in the sacral area betrays the condition, but in most patients it remains occult until it is disclosed radiologically. The anomaly may be accompanied by malformation of verte-
bral joints and usually induces pain only when aggravated by injury. The neurologic aspects of defective fusion of the spine (dysraphism) are discussed in Chap. 38, with other developmental abnormalities of the nervous system. Many other congenital anomalies affect the lower lumbar vertebrae: asymmetrical facet joints, abnormalities of the transverse processes, are seen occasionally in patients with low back symptoms, but apparently with no greater frequency than in asymptomatic individuals. Spondylolysis consists of a congenital and probably genetic bony defect in the pars interarticularis (the segment at the junction of pedicle and lamina) of the lower lumbar vertebrae. It is remarkably common, affecting approximately 5 percent of the North American population and mainly a disease of children (peak incidence between 5 and 7 years of age). The defect assumes importance in that it predisposes to subtle fracture of the pars articularis, sometimes precipitated by slight trauma but often in the absence of an appreciated injury. In some young individuals it is unilateral and may cause unilateral lumbar aching back pain that is accentuated by hyperextension and twisting. In the usual bilateral form, small fractures at the pars interarticularis allow the vertebral body, pedicles, and superior articular facets to move anteriorly, leaving the posterior elements behind. This leads to an anterior displacement of one vertebral body in relation to the adjacent spondylolisthesis. (The main cause of spondylolisthesis in older adults is degenerative arthritic disease of the spine as discussed further on.) Patients with progressive vertebral displacement and neurologic deficits require surgery. Reduction of displaced vertebral bodies before fusion and direct repair of pars defects are possible in special cases. Back pain is relieved in the majority of cases.
Traumatic Disorders of the Low Back These constitute by far the most frequent causes of low back pain. In severe acute injuries from direct impact the examiner must be careful to avoid further damage and movements should be kept to a minimum until an approximate diagnosis has been made. If the patient complains of pain in the back and cannot move the legs, the spine may have been fractured and the cord or cauda equina compressed or crushed. The neck should not be manipulated, and the patient should not be allowed to sit up. (See Chap. 44 for further discussion of spinal cord injury.) Lesser degrees of injury, such as sprains and strains, are ubiquitous and can be handled with less caution because they do not involve compression of neural structures. Acute Sprains and Strains The terms lumbosacral strain, sprain, and derangement are used loosely and it is probably not possible to differentiate them. Furthermore, what was formerly referred to as “sacroiliac strain” or “sprain” is now known to be caused by, in some instances, disc disease. The term acute low back strain is preferable for minor, self-limiting injuries that are usually associated with lifting heavy loads when the back is in a mechanically disadvantaged position, or there may have been a fall, prolonged uncomfortable postures such as in air travel or car rides, or sudden unexpected motion, as may occur in an auto accident.
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Nonetheless, the discomfort of acute low back strain can be severe, and the patient may assume unusual postures related to spasm of the lower lumbar and sacrospinalis muscles. The pain is usually confined to the lower part of the back, in the midline, across the posterior waist, or just to one side of the spine. The diagnosis of lumbosacral strain is dependent on the biomechanics of the injury or activity that precipitated the pain. The injured structures are identified by the localization of the pain, the finding of localized tenderness, augmentation of pain by postural changes—e.g., bending forward, twisting, or standing up from a sitting position, and by the absence of signs of radicular involvement. In more than 80 percent of cases of acute low back strain of this type, the pain resolves in a matter of several days or a week, even with no specific treatment. Sacroiliac joint and ligamentous strain is the most likely diagnosis when there is tenderness over the sacroiliac joint and pain radiating to the buttock and posterior thigh, but this always needs to be distinguished from the sciatica of a ruptured intervertebral disc (see further on). Strain is characteristically worsened by abduction of the thigh against resistance and may produce pain that is also felt in the symphysis pubis or groin. It, too, responds within days or a week or two to conservative management. Treatment of Acute Low Back Strain The pain of muscular and ligamentous strains is usually self-limiting, responding to simple measures in a relatively short period of time. The basic principle of therapy in both disorders is to avoid reinjury and reduce the discomfort of painful muscles. As a result of several studies that have failed to demonstrate a benefit of bed rest, the recent practice has been to mobilize patients as soon as they are able and to prescribe corrective exercises designed to stretch and strengthen trunk (especially abdominal) muscles, overcome faulty posture, and increase the mobility of the spinal joints. Despite this modern approach, the authors can affirm from personal experience that some injuries produce such discomfort that arising from a bed or chair is simply not possible in the early days after injury (see Vroomen et al). Lying on the side with knees and hips flexed or supine with a pillow under the knees favor relief of pain. With strains of the sacrospinalis muscles and sacroiliac ligaments, the optimal position is hyperextension, which is effected by having the patient lie with a small pillow under the lumbar portion of the spine or by lying prone. Local physical measures—such as application of ice in the acute phase and, later, heat diathermy and massage—often relieve pain temporarily. Nonsteroidal antiinflammatory drugs (NSAIDs) may be given liberally during the first few days. Muscle relaxants (e.g., cyclobenzaprine, carisoprodol, metaxalone, and the diazepams) serve mainly to make bed rest more tolerable. Traction, formerly a popular treatment, is no longer used. When weight bearing is resumed, discomfort may be diminished by a light lumbosacral support, but many orthopedists refrain from prescribing this aid. The use of spinal manipulation—practiced by chiropractors, osteopaths, and others—has always been a contentious matter partly because of unrealistic therapeutic claims made in treating diseases other than low back
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derangements. A type of slow muscle stretching and joint distraction (axial traction on a joint) administered by physiatrists and physical therapists is quite similar. It must be recognized that many patients seek chiropractic manipulation on their own for back complaints, often before seeing a physician and may not disclose this information to the physician. When the supporting elements of the spine (pedicles, facets, and ligaments) are not disrupted, chiropractic manipulation of the lumbar spine has undoubtedly provided acute relief to a number of our patients with low back strain or facet pain. At issue is the durability of the effect, particularly the need for repeated spinal adjustments. One randomized British trial has shown manipulation to be superior to analgesics and bed rest in returning patients to work after minor back injury (Meade et al). Some other trials have corroborated this finding (Hadler et al), whereas others have not, or, often, the results have been ambiguous. In the study by Cherkin and colleagues comparing chiropractic, physical therapy (McKenzie method), and simple instruction to the patient from a booklet, manipulation yielded a slightly better outcome at the end of a month. Despite several hypotheses offered by practitioners of spinal manipulation, the mechanism of pain relief is not known. The cracking sound created by rapid and forceful distraction of the facet joints (and attributed to gas coming out of solution in the joint fluid) seems not to be necessary for pain relief. It seems unlikely that mundane low back pain represents minor subluxation, as claimed by chiropractors. In the authors’ clinical experience, chronic low back pain, discussed below, has been less successfully treated by manipulative procedures, but there are some patients who testify to improvement in their clinical state and admittedly the medical profession has little to offer in most cases and the rate of spontaneous improvement is high. The results for acute and chronic back pain with another popular approach, acupuncture, have been even more uncertain, most studies showing it to be no more effective than a sham treatment (Tudler et al). It should be emphasized, however, the use of NSAIDs or narcotic analgesics for many months is hazardous and should be avoided. Chronic and Recurrent Low Back Syndrome Often the symptoms of low back strain are recurrent and more chronic in nature, being regularly exacerbated by bending or lifting, suggesting that postural, muscular, and arthritic factors play a role. This is the most common syndrome seen in spine clinics, more often in men than in women. Insidiously, or after some unusual activity, raising the question of trauma, especially if it happens in the workplace, the patient develops aching pain in the low back, increased by certain movements and attended by stiffness. The pain may additionally have a restricted radiation into the buttocks and posterior thigh, thereby simulating root compression. There are no motor, sensory, or reflex abnormalities. Radiographs and imaging procedures usually reveal some combination of osteoarthropathy, changes in vertebral discs, osteoarthritic changes in apophysial joints, and sometimes osteoporosis or slight spondylosis, or they may be entirely normal. Treatment with short-duration bed rest, analgesics, and
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physiotherapy, as outlined for acute strains, helps to relieve the symptoms, and the majority of patients recover within a few weeks, only to have a recurrence of similar pains in the future. Recurrent attacks are typical of degenerative spine disease that affects the vertebrae and facet joints. Chiropractic manipulation has the same uncertain effect as for acute low back symptoms. Usually the origin of the pain cannot be assigned with certainty to spinal, joint, or muscular injury, but direct percussion tenderness of one vertebral segment always raises concern of metastatic disease as noted above. Quite often, changing the firmness of the mattress (in either direction) is helpful. Compensation relating to injuries at work or to an accident and related legal matters often add to the disability, but there are, of course, many legitimate injuries that occur in these circumstances. Vertebral Fractures Fractures of lumbar vertebral bodies are usually the result of flexion injuries. Such trauma may occur in a fall or jump from a height (if the patient lands on his feet, the calcanei may also be fractured) or as a result of an auto accident or other violent injury. If the injury is severe, it may cause a fracture dislocation, a “burst” fracture of one or more vertebral bodies, or an asymmetrical fracture of a pedicle, lamina, or spinous process; most often, however, there is asymmetrical loss of height of a vertebral body (compression fracture), which may be extremely painful at the onset. When compression or other fractures occur with minimal trauma (or spontaneously), the bone has presumably been weakened by some pathologic process. Most of the time, particularly in older individuals, osteoporosis is the cause of such an event, but there are many other causes, including osteomalacia, hyperparathyroidism, prolonged use of corticosteroids, myeloma, metastatic carcinoma, and a number of other conditions that are destructive of bone. Spasm of the lower lumbar muscles, limitation of all movements of the lumbar section of the spine, and the radiographic appearance of the damaged lumbar portion (with or without neurologic abnormalities) are the basis of clinical diagnosis. The pain is usually immediate, although occasionally it may be delayed for days. A fractured transverse process, which is almost always associated with high-impact rotary injury of the spine and causes tearing of the paravertebral muscles and a local hematoma, produces deep tenderness at the site of the injury and limitation of all movements that stretch the lumbar muscles. The imaging findings, particularly MRI, confirm the diagnosis. In some circumstances, tears of the paravertebral musculature may be associated with extensive bleeding into the retroperitoneal space; this produces paraspinal or groin pain and proximal leg weakness with loss of the patellar reflex on the affected side. There may be a delayed subcutaneous hematoma in the flanks (GreyTurner sign). A problem not easily classified but having a distinctive clinical profile that should be known to neurologists is that of an osteoid osteoma. These benign tumors characteristically cause severe nocturnal pain located in one region of the parasagittal spine that awakens the patient from a peaceful sleep; also typical is complete relief after aspirin or small doses of other NSAIDs. MRI or CT is
required to detect the lesion, as it may not be evident on plain radiographs of the spine.
Herniation of Lumbar Intervertebral Discs (Table 11-1) This condition is a major cause of severe and chronic or recurrent low back and leg pain. It occurs mainly during the third and fourth decades of life when the nucleus pulposus is still gelatinous. The disc between the fifth lumbar or first sacral vertebrae (L5-S1) is most often involved, and, with decreasing frequency, that between the fourth and fifth (L4-L5), third and fourth (L3-L4), second and third (L2L3), and—quite infrequently—the first and second (L1-L2) lumbar vertebrae. Relatively rare but well described in the thoracic portion of the spine, disc disease is again frequent in the cervical spine at the fifth and sixth and the sixth and seventh cervical vertebrae (see further on). The likely cause of a herniated lumbar disc is a flexion injury, but a considerable proportion of patients do not recall a traumatic episode. Degeneration of the nucleus pulposus, the posterior longitudinal ligaments, and the annulus fibrosus may have taken place silently or have been manifest by mild, recurrent lumbar ache. A sneeze, lurch, or other trivial movement may then cause the nucleus pulposus to prolapse, pushing the frayed and weakened annulus posteriorly. Fragments of the nucleus pulposus protrude through rents in the annulus, usually to one side or the other (sometimes in the midline), where they impinge on a root or roots and cause the most characteristic sciatic or other radicular pains and neurologic signs. In more severe cases of disc disease, a small piece of the nucleus may be entirely extruded as a “free fragment” and be mobile enough to affect a root at an adjacent level or to give rise to unusual precipitating features of radicular pain. Large protrusions cause pain by compressing the adjacent root against the articular apophysis or lamina. The protruded material may become reduced in size, presumably from desiccation, but often there is continued chronic irritation of the root or a discarthrosis with posterior osteophyte formation. The Clinical Syndrome of Lumbar Disc Herniation The fully developed syndrome of the common prolapsed intervertebral lower lumbar disc consists of (1) pain in the sacroiliac region, radiating into the buttock, thigh, and the calf, a symptom broadly termed sciatica; (2) a stiff or unnatural spinal posture; and often (3) some combination of paresthesia, weakness, and reflex impairment. The pain of herniated intervertebral disc varies in severity from a mild aching discomfort to severe knife-like stabs that radiate the length of the leg and are superimposed on a constant intense ache. Sciatic pain is perceived by the patient as originating deep in the buttock and radiating to the posterolateral thigh; it may progress to the calf and ankle—to the medial malleolus (L4), lateral malleolus (L5), or heel (S1). Distal radiation to the foot is infrequent and should raise concern of an alternative process. Abortive forms of sciatica may produce aching discomfort only in the lower buttock or proximal thigh and occasionally only in the lower hamstring or upper calf. With the most severe pain, the patient is forced to stay in bed, avoiding the slightest movement; a cough, sneeze, or strain is intolerable. The
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Table 11-1 FEATURES OF THE MAIN ROOT-COMPRESSIVE SYNDROMES DUE TO CERVICAL AND LUMBAR DISC HERNIATION a INTERVERTEBRAL DISC SPACE
ROOT AFFECTED
PAIN REFERRAL
C4-C5
C5
Shoulder, trapezius
C5-C6
C6
C6-C7
C7
Trapezius ridge and tip of shoulder, radiation to anterior upper arm, thumb, and index finger Shoulder, axilla, posterolateral arm, elbow, and middle finger
C7-T1
C8
L2-L3
L3
L3-L4
L4
L4-L5
L5
L5-S1
S1
aFor
WEAKNESS
REFLEX CHANGE
Supra- and infraspinatus deltoid, slight biceps weakness Biceps, brachioradialis, extensor carpi radialis
Slightly diminished biceps jerk
Triceps, wrist extensors
Diminished or absent triceps jerk
Medial forearm
Intrinsic hand muscles
Anterior thigh, over knee Anterolateral thigh, medial foreleg
Thigh adductor, quadriceps Anterior tibial, sometimes with partial foot drop Extensor hallucis longus and extensor digitorum brevis; some weakness of anterior tibialis, sometimes with foot drop Plantar-flexor and hamstring weakness
Slight or no decrease in triceps jerk Absent or diminished knee jerk Diminished or normal knee jerk
Posterolateral gluteal sciatica; lateral thigh, anterolateral foreleg, dorsal foot, lateral malleolus and great or second and third toe Midgluteal sciatica; posterior thigh, posterolateral leg, lateral foot, heel, or lateral toes
Diminished biceps and supinator jerk
ADDITIONAL FEATURES
Tenderness over spine or scapula and suprascapular region; paresthesias in thumb and index finger Tenderness over medial scapula and supraclavicular region or triceps. May complain of paresthesias in most of the fingers Mimics ulnar palsy
Unaffected (except posterior tibial)
Pain with straight-leg raising and variant tests; tenderness over fourth lumbar lateral process and lateral gluteal region
Absent or diminished ankle jerk
Pain with straight-leg raising and variant tests; tenderness over lumbosacral (L5-S1) joint and sciatic notch; discomfort walking on heels
pattern of sensory loss, see dermatomal diagram in Figs. 9-2 and 9-3.
most comfortable position is lying on the back with legs flexed at the knees and hips and the shoulders raised on pillows to obliterate the lumbar lordosis. For some patients, a lateral decubitus position is more comfortable. Free fragments of disc that find their way to a lateral and posterior position in the spinal canal may produce the opposite situation, one whereby the patient is unable to extend the spine and lie supine. Sitting and standing up from a sitting position are particularly painful. It is surprising to patients that a lumbar disc protrusion may cause little or no back pain. As a corollary, the presence of lumbar disc disease, even frank rupture, bears an inconsistent relationship to low back pain, as already emphasized. In cases of root compression, pain is also characteristically provoked by pressure along the course of the sciatic nerve at the classic points of Valleix (sciatic notch, retrotrochanteric gutter, posterior surface of thigh, and head of fibula). Pressure at one point may cause radiation of pain and tingling down the leg. Elongation of the nerve root by straight-leg raising or by flexing the leg at the hip and extending it at the knee (Lasègue maneuver as discussed earlier) is the most consistent of all pain-provoking signs, as discussed earlier. During
straight-leg raising, the patient can distinguish between the discomfort of ordinary tautness of the hamstring and the sharper, less-familiar root pain, particularly when asked to compare the experience with that on the normal side. Many variations of the Lasègue maneuver have been described (with numerous eponyms), the most useful of which is accentuation of the pain by dorsiflexion of the foot (Bragard sign) or of the great toe (Sicard sign). The Lasègue maneuver with the healthy leg may evoke sciatic pain on the contralateral side), but usually of lesser degree (Fajersztajn sign). However, the presence of the “crossed straight-leg-raising sign” is highly indicative of a ruptured disc as the cause of sciatica (56 of 58 cases in the series of Hudgkins). With the patient standing, forward bending of the trunk will cause flexion of the knee on the affected side (Neri sign). Sciatica may be provoked by forced flexion of the head and neck, coughing, or pressure on both jugular veins, all of which increase the intraspinal pressure (Naffziger sign). Marked inconsistencies in response to these tests raise the suspicion of psychologic factors or of referred muscular pain. An antalgic posture, referred to as sciatic scoliosis, is maintained by reflex contraction of the paraspinal muscles, which can be both seen and palpated. In walking, the
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knee is slightly flexed, and weight bearing on the painful leg is brief and cautious on the ball of the foot, giving a limp. It is particularly painful for the patient to go up and down stairs. The signs of more severe spinal root compression are impairment of sensation, loss or diminution of tendon reflexes, and muscle weakness, as summarized in Table 11-1. Generally, disc herniation compresses the root on one side, at the level just below the herniation (see below). Hypotonia may be evident on inspection and palpation of the buttock and calf. In only a few patients is a foot drop (L5 root) or weakness of plantar flexion (S1 root) the main feature of disc protrusion, but it is notable that some of these patients have little associated pain. The reflex changes noted below have little relationship to the severity of the pain or sensory loss. Furthermore, compression of the fourth, or sometimes fifth, lumbar root may occur without any change in the tendon reflexes. Bilaterality of symptoms and signs is rare, as is sphincteric paralysis, but they occur with large central protrusions that compress the cauda equina. The cerebrospinal fluid (CSF) protein is then predictably elevated, usually in the range of 55 to 85 mg/dL, sometimes higher. As emphasized earlier, herniations of the intervertebral lumbar discs occur most often between the fifth lumbar and first sacral vertebrae (compressing the S1 root; Fig. 11-4) and between the fourth and fifth lumbar vertebrae (compressing the L5 root). Lesions of the fifth lumbar root (L5) produce pain in the region of the hip and posterolateral thigh (i.e., sciatica) and, in more than half such cases, lateral calf (to the lateral
4th Lumbar Vertebra
L4 Root
Protruded Discs
5th Lumbar Vertebra
L5 Root
S1 Root
S2 Root
Figure 11-4. Mechanisms of compression of the fifth lumbar and first sacral roots. A lateral disc protrusion at the L4-L5 level usually involves the fifth lumbar root and spares the fourth; a protrusion at L5-S1 involves the first sacral root and spares the fifth lumbar root. Note that a more medially placed disc protrusion at the L4-L5 level (cross-hatched) may involve the fifth lumbar root as well as the first (or second and third) sacral root.
malleolus), and less often, the dorsal surface of the foot and the first or second and third toes. Pain is elicited by the straight-leg raising test or one of its variants, and protective nocifensive reflexes come into play, limiting further elevation of the leg. Paresthesia may be felt in the entire territory or only in its distal parts. The tenderness is in the lateral gluteal region and near the head of the femur. Weakness, if present, involves the extensors of the big toe and foot and the foot invertors (a distinguishing feature of foot drop originating in peroneal nerve damage). The ankle jerk may be diminished (more often it is normal), but the knee jerk is hardly ever altered. With lesions of the first sacral root (S1), the pain is felt in the midgluteal region, mid-posterior part of the thigh, posterior region of the calf to the heel, outer plantar surface of the foot, and fourth and fifth toes. Tenderness is most pronounced over the midgluteal region. Paresthesia and sensory loss are mainly in the lower part of the leg and outer toes, and weakness, if present, involves the plantar flexor muscles of the foot and toes, abductors of the toes, and hamstring muscles. The Achilles reflex is diminished or absent in the majority of cases. In fact, loss of the Achilles reflex may be the only objective sign. Walking on the toes is more difficult and uncomfortable than walking on the heels because of weakness of the plantar flexors. The less-frequent lesions of the third (L3) and fourth (L4) lumbar roots give rise to pain in the anterior part of the thigh and knee and anteromedial part of the leg (fourth lumbar), with corresponding sensory impairment in these dermatomal distributions. The knee jerk is diminished or abolished. Third lumbar (L3) motor root lesions may weaken the quadriceps, thigh adductor, and iliopsoas; L4 root lesions weaken the anterior tibial innervated muscles, sometimes with a mild foot drop. First lumbar (L1) root pain is projected to the groin, and L2, to the lateral hip. Much has been made of a distinctive syndrome associated with extreme lateral disc protrusions, particularly those situated within the proximal portion of the intervertebral spinal foramina. Unremitting radicular pain without back pain and a tendency to worsen with extension of the back and torsion toward the side of the herniation are characteristic. Also, in rare instances of lumbar intradural disc rupture, there may not be sciatic pain because the free fragment in the subarachnoid space does not impinge on the roots of the cauda equina. Both of these configurations may confound clinical and radiologic diagnosis and make surgery more difficult. Rarer still, and often clinically obscure, are protrusions of thoracic intervertebral discs (0.5 percent of all surgically verified disc protrusions, according to Love and Schorn). The four lowermost thoracic interspaces are the most frequently involved. Trauma, particularly hard falls on the heels or buttocks, is an important causative factor. Deep boring spine pain; root pain circling the body or projected to the abdomen or thorax (sometimes simulating visceral disease); paresthesia below the level of the lesion; loss of sensation; both deep and superficial; and paraparesis or paraplegia are the usual clinical manifestations. A herniated lumbar disc at one interspace may compress more than one root (Fig. 11-4), and it follows that the symp-
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toms will then reflect this. Furthermore, the above descriptions of single root compression refer mainly to signs and symptoms of atypical posterolateral disc protrusion. Very large central disc protrusions may compress the entire cauda equina with a dramatic syndrome that includes intense low back and bilateral sciatic pain, incomplete paraparesis, loss of both ankle jerks, and, most characteristic, varying degrees of urinary retention and incontinence. This circumstance demands surgical attention. Anomalies of the lumbosacral roots may lead to errors in localization (see descriptions by Postacchini et al). The combined rupture of two or more discs occurs occasionally and complicates the clinical picture. When both the L5 and S1 roots are compressed by a large herniated disc, the signs of the S1 lesion usually predominate. Herniation may occur into the adjacent vertebral body, giving rise to a Schmorl nodule. In such cases there are no signs of nerve root involvement although back pain may be present, sometimes recurrent and referred to the thigh. Most often, these circular radiographic densities adjacent to the endplate of the vertebral body are found incidentally on CT or MRI. Diagnosis When all components of the lumbar disc syndrome are present, diagnosis is virtually assured. With persistent symptoms, many neurologists prefer to corroborate their clinical impression with MRI of the spine from L3 to S1. This, of course, is not necessary if the pain is manageable and surgery is not contemplated (see further on). MRI is favored over CT because of the advantages of the sagittal image and the clarity of the anatomic relationships between discs and nerve roots. MRI also excludes herniations at other sites or an unsuspected tumor (Fig.
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11-5). As indicated earlier, in cases in which MRI is not possible or it has been unrevealing, we often turn to CT or CT with myelography for a refined definition of the root sleeves and use the EMG to corroborate subtle findings. At the lumbosacral junction there is a wide gap between the posterior margins of the vertebrae and the dural sac, so that a lateral or central protrusion of the L5-S1 disc may fail to distort the dural margin and remain undetected on myelography. The needle EMG study is abnormal, showing fibrillation potentials in denervated muscles after 1 or 2 weeks in more than 90 percent of cases according to Leyshon and colleagues. Loss or marked asymmetry of the H reflex is another useful indication of S1 radiculopathy, but this finding simply corroborates the loss of an Achilles reflex. The finding of denervation potentials in the paraspinal muscles (indicating root rather than peripheral nerve lesions) and in muscles that conform to a root distribution is also helpful, but at least 2 or 3 weeks must have elapsed from the onset of root pain for these findings to be present. We emphasize that, while useful information is to be gained from EMG, it is required in only a fraction of cases and often provides mainly corroborating data. Many disc abnormalities observed on MRI and loosely referred to as “herniation” are incidental findings, unrelated to the patient’s symptoms. Jensen and colleagues, in an MRI study of the lumbar spine in 98 asymptomatic adults, found that in more than half there was a symmetrical extension of a disc (or discs) beyond the margins of the interspace (bulging). In 27 percent, there was a focal or asymmetrical extension of the disc beyond the margin of the interspace (protrusion), and in only 1 percent was there
Figure 11-5. Lumbar disc herniation on T1-weighted MRI. A. Sagittal view of large L5-S1 herniated nucleus pulposus (arrow). The extruded material has the same signal characteristics as the normal adjacent disc. B. Axial view showing the paracentral mass that obliterates the epidural fat signal and compresses the left S1 nerve root.
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more extreme extension of the disc (extrusion). These findings emphasize the importance of using precise terms in describing the imaging abnormalities and evaluating them strictly in the context of the patient’s symptoms.
Treatment of Ruptured Lumbar Disc In the treatment of an acute or chronic rupture of a lumbar disc, we have advised avoidance of physical activities and positions that cause pain, and suggested bed rest if it appears to be helpful to the patient. But even this timehonored tenet has been strongly questioned by the results of several randomized studies (Vroomen et al). It would appear that the main benefit is simply that time has passed and the expected resolution of pain has taken its course in many patients. Traction is of little or no value in lumbar disc disease. The patient may suffer minor recurrence of pain but should be able to continue some of his usual activities. Analgesic medications, either NSAIDs or opioids, may be required for a few days. In a few patients with severe sciatica we have been impressed with the temporary relief afforded by administration of oral dexamethasone (4 mg every 8 h) for several days, although this approach has not been studied systematically. The treatment of nerve root compression with repeated epidural injections of corticosteroids has enjoyed periods of popularity, but controlled studies have failed to confirm a sustained efficacy (White et al; Cuckler et al), and it is not without complications. As with many similar studies, Carette and colleagues (1997) found only short-term improvement with epidural steroid injection and the ultimate need for surgery was not altered. Nevertheless, we and many other neurologists and pain clinics have not discarded this form of treatment in view of notable success in selected patients, even if short-lived. Surgical Relief of Lumbar Disc Disease The only indication for emergency surgery is an acute compression of the cauda equina by massive disc extrusion, causing bilateral sensorimotor loss and sphincteric paralysis. Although not the recommended course, it should be pointed out that there are instances where even a dramatic syndrome of cauda equina compression has resolved after several weeks of bed rest. If the pain and neurologic findings do not subside in response to conservative management or the patient suffers frequent disabling acute episodes, surgical treatment must be considered. Useful information regarding surgery and its timing can be ascertained from a recent randomized Dutch trial conducted by Peul and colleagues and from the Spine Patients Outcomes Research Trial (SPORT) conducted by Weinstein and coworkers (2006). In the first trial, a large proportion of patients assigned to treatment with physical therapy and pain medications nonetheless had enough pain that they required surgery after several months. Patients assigned initially to surgery by microdiscectomy also had considerably faster relief of back and sciatic pain, but at the end of a year, both groups had minimal disability and similar degrees of minor pain. The implications of this study are that avoiding surgery initially does not have adverse consequences but if rapid pain relief and mobilization is the aim, surgery is prefera-
ble. In the second cited study there was even greater crossover between conservative and surgically assigned groups but there was a slightly more favorable outcome in those who underwent early surgery. The surgical procedure most often indicated for lumbar disc disease is one of the variants of a hemilaminectomy with excision of the disc fragment. Questions relating to the relative merits of very limited (“microscopic”) excision of the lamina are often raised by patients and no clear answer can be given except that individual surgeons excel at one or another technique and the outcomes are similar. Eighty-five to 90 percent of cases with sciatic pain because of L4-L5 or L5-S1 disc ruptures are relieved by operation, are home in days or less, and are resuming activities within weeks. Rerupture occurs in approximately 5 percent or fewer operated cases according to Shannon and Paul. Arthrodesis (spinal fusion) of the involved segments is indicated only in cases in which there is extraordinary instability, usually related to extensive or prior surgery or to an anatomic abnormality (such as spondylolysis). In our experience and that of our neurosurgical colleagues, the features that are predictive of better outcome from decompressive surgery are the presence of radicular leg pain, younger age, a clear precipitating event for the back and sciatic pain, clinical features that are restricted to compression of a single nerve root, and the absence of chronic or frequently recurrent back pain.
Other Causes of Sciatica and Low Back Pain An increasing experience with lumbar back pain and sciatica has impressed the authors with the large number of such cases that have no clear cause. At one time all these cases were classified as sciatic neuritis or “sacroiliac strain.” After Mixter and Barr popularized the concept of prolapsed disc, all sciatica and lumbar pains were ascribed to this condition. Operations became widely practiced, not only for frank disc protrusion but also for “hard discs” (unruptured) and related pathologies of the spine. In large referral centers the surgical results became decreasingly satisfactory until recently, as many patients were being seen with unrelieved postlaminectomy pain as with unoperated ruptured discs. To explain these cases of chronic sciatic pain, a number of pathologic entities have been described. Entrapment of lumbar roots may be the consequence not only of disc rupture but also of spondylotic spurs with stenosis of the lateral recess, cysts of the synovium derived from degenerative disease of the facet joint, hypertrophy of facets, and, rarely, arachnoiditis. Lateral recess stenosis in particular may be a cause of sciatica not relieved by disc surgery (see below, under “Lumbar Stenosis [Spondylotic Caudal Radiculopathy; Verbiest Syndrome]”). Synovial cysts arising from a facet joint are not uncommon, and even very small ones may be situated in the proximal portion of the foramen, thereby causing sciatica. If pain is intractable, surgical removal of the cyst is indicated. Another surprising finding in the course of imaging the spinal canal is a cyst-like dilatation of the perineurial sheath (Tarlov cysts). One or more sacral roots may be involved at points where they penetrate the dura and may be associated with radicular symptoms.
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There are reports of relief from opening the cysts and freeing the roots, but the results seem more uncertain to us. Sciatica that is temporally linked to the premenstrual period is almost always a result of endometriosis involving the nerve at the sciatic notch (“catamenial sciatica”). We have also observed cases of sciatica that occurred with each pregnancy, presumably from uterine traction on the nerve. Over the years the notion of a pyriformis (piriformis) syndrome, so named by Kopell and Thompson, has arisen as a cause of otherwise unexplained buttock pain or vague sciatica. The muscle overlies or, in a small proportion, embeds the peroneal trunk of the sciatic nerve. Hypertrophy, spasm, or simply the anatomic variation in which the nerve is entrapped in the tendinous origin of the muscle have all putatively caused local and some degree of sciatic pain. Pain in these cases is ostensibly elicited by stretching the muscle through flexion, adduction, and internal rotation of the hip. The validity of this syndrome is uncertain and it has been the subject of polemical discussions in the literature. EMG data are ambiguous but reportedly show distal denervation, sparing more proximally innervated muscles. Our practice would be to avoid surgery in such cases, but to endorse innocuous physical therapy at the patient’s request. Compression of the cauda equina by epidural tumor, as described further on, most often begins with back pain or sciatica, as a result of deposits of prostatic or breast cancer or myeloma. The sciatic nerve or the plexus from which it originates may be implicated in tumor growths (lymphoma, neurofibrosarcoma). Several inflammatory diseases of the cauda equina produce back pain and bilateral sciatica and may be mistaken for the more usual types of cauda equina compression; cytomegalovirus infection in AIDS patients, Lyme disease (Bannwarth syndrome), herpetic infection, and neoplastic meningitis at times behave in this fashion. In all of these, the CSF shows a pleocytosis. The Guillain-Barré syndrome may also produce misleading back and radicular pain before weakness is apparent. The caudal roots in these diseases usually enhance with gadolinium on MRI. An unusual lumbosacral plexus neuritis (Wartenberg plexitis) is a unilateral (occasionally bilateral) disorder akin to brachial neuritis, which may cause sciatica, as does occasionally nerve infarction or damage from diabetes, herpes zoster, or a retroperitoneal mass (see Chap. 46). Again, if one sees enough of these cases, the cause of a number of them, particularly those with bilateral burning along the sciatic nerve, cannot be settled.
Lumbar Stenosis (Spondylotic Caudal Radiculopathy; Verbiest Syndrome) In the lumbar region, osteoarthritic and related degenerative changes, which together are called spondylotic, lead to compression of one or more lumbar and sacral roots. The problem is more likely to occur if there is a congenitally narrow lumbar canal. The roots are typically compressed between the posterior surface of the vertebral body anteriorly, the facet joint laterally, and the ligamentum flavum posteriorly. Lateral recess stenosis, which is a common feature of spondylotic change (as mentioned
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above in relation to disc disease), also contributes to root compression and may be the main cause of root compression in some patients. The typical features are of fluctuating aching and sharp pain in the low back, buttock and sciatic distribution, occasionally including femoral areas, and generally elicited by prolonged sitting, standing, or walking and relieved by rest. Some patients have virtually constant pain in these areas but still have relief with rest in one or another body position. In the distinctive syndrome of lumbar stenosis of “neurogenic claudication” standing or walking causes a gradual onset of numbness and weakness of the legs, usually with asymmetrical sciatic, calf, or buttock discomfort that forces the patient to sit down. When the condition is more severe, the patient gains relief by squatting or lying with the legs flexed at the hips and knees. Often the numbness begins in one leg, spreads to the other, and ascends as standing or walking continues. The ankle tendon reflexes may disappear after walking a distance, only to return on flexing the spine. Pain in the low back and glutei is variable. Disturbances of micturition and impotence are infrequent unless there has been an additional more acute disc herniation. In some patients with lumbar stenosis, neurologic symptoms persist without relation to body position. The process is distinguished from vascular claudication of the legs by its appearance in the standing position, the prominence of numbness in some cases, and, of course, by the preservation of distal leg pulses and loss of ankle reflexes. This “claudication of the cauda equina” was described by van Gelderen in 1948, and it was shown by Verbiest to not be caused by ischemia but by encroachment on the cauda by hypertrophied joints, thickened ligaments, and protrusions of disc material on a developmentally shallow canal. A slight subluxation at L3-L4 or at L4-L5 may contribute to the stenosis in the anteroposterior dimension. Later, the canal is also narrowed from side to side (reduced interpedicular distance). A prominent feature of many cases of the degenerative spinal disorder is spondylolisthesis. The displacement and malalignment of one vertebral body in relation to the adjacent one may cause little difficulty at first but eventually the patient complains of limitation of motion and pain in the low back radiating into the thighs. In the extreme case examination discloses tenderness near the segment that has “slipped” forward (most often L5, occasionally L4 in middle-aged women) or a palpable “step” of the spinous process forward and shortening of the trunk with protrusion of the lower abdomen (forward shift of L5 on S1, spondyloptosis). Compression of the corresponding spinal roots by the displaced vertebrae causes paresthesia and sensory loss, muscle weakness, and reflex impairment. These neurologic features, however, tend not to be severe. When spondylolisthesis is unstable, new symptoms may appear abruptly in the form of a new foot drop, urinary retention, or overflow incontinence. The instability is evidenced on conventional radiographs by a change in the diameter of the spinal canal as the patient moves between the flexed and extended position of the back. A striking syndrome that has been attached to lumbar stenosis consists of painful legs–moving toes, described by
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Spillane. There is burning leg pain and continuous and complex rhythmic movements of the toes, as the name implies. Symptoms may begin on one side but become bilateral. Lumbar nerve root compression, most often from lumbar stenosis, or other types of peripheral damage underlie most cases. Treatment of Lumbar Stenosis Decompression of the spinal canal relieves the symptoms of lumbar stenosis in a considerable proportion of cases, but the results have been inconsistent. Patients must be chosen carefully for surgery, and success is likely if the clinical features conform to the typical syndrome, mainly pain that altered in various positions and at least partially relieved by rest, with definite evidence of root compression by imaging. In perhaps the most careful trial comparing surgery to conservative treatment for lumbar spinal stenosis, pain and overall function at 2 years were severalfold better in those who had operations (Weinstein et al, 2008). However, interpretation was hampered by a large number of patients who crossed over between arms of the study. Issues pertaining to the methodology of operation, the need for fusion of the lumbar spine to limit mobility, and various forms of “instrumentation” are of great interest, but are best discussed in textbooks of neurosurgery and orthopedics. Insofar as lumbar stenosis is a cauda equina syndrome, its differential diagnosis is also considered in Chap. 44.
Degenerative Osteoarthritis or Osteoarthropathy Independent of stenosis of the lumbar canal is chronic and recurring back pain caused by degenerative arthritic disease. It occurs in later life and may involve all or any part of the spine but is most prevalent in the cervical and lumbar regions. The pain is described as a stiffness that is centered in the affected part of the spine. It is increased initially by movement and is associated with limitation of motion but is often worse on arising in the morning. In contrast to the spinal claudicatory syndrome, warming up and progressive mobilization make the pain better. There is a notable absence of systemic symptoms such as fatigue, malaise, or fever, and, more importantly, there are no features of radicular compression. Some patients complain of vague and intermittent pains in the upper or posterior legs, but sciatica is not a component and the straight-leg raising tests do not elicit pain. The sitting position is usually comfortable, although stiffness and discomfort are accentuated when the erect posture is resumed. The severity of the symptoms often bears little relation to the radiologic changes; pain may be present despite minimal radiographic findings; conversely, marked osteophytic overgrowth with spur formation, ridging, bridging of vertebrae, narrowing of disc spaces, subluxation of posterior joints on flexion, and air in the disc spaces can be seen in both symptomatic and asymptomatic persons.
Facet Syndrome This syndrome has been somewhat clarified in recent years but its definition and nature remain imprecise. In the more common syndrome, osteoarthritic degeneration of the facet joint gives rise to a focal parasagittal lumbar back pain, with variable tenderness over the joint but without signs of
root compression. The pain can be severe, worse at night, and prevent sleep if no comfortable position can be found. Nonsteroidal drugs are helpful. The diagnosis is confirmed when the pain is relieved for a variable period by injection of the joint with local anesthetic. Often one is uncertain whether it was the analgesic effect on the joint or the infiltration of the region around the nerve root that relieved the pain. Two controlled studies have provided evidence of the inefficacy, both in the short and long term, of corticosteroid injections into the facet joints (Carette et al, 1991; Lilius et al). Notwithstanding these reports, we have found the injection of analgesics and steroids in and around the facet to be a useful temporizing measure in some patients. (Epidural injections of steroids have no role in the treatment of this problem.) In any case, this group of patients does not require operation. Some patients have discovered that they may obtain temporary relief from facet pain by forcefully twisting or stretching the back and creating an audible pop at the affected joint, comparable to chiropractic manipulation. Over time, they acquire a laxity of the supporting structures of the joint, which may actually perpetuate the problem. If the diagnosis is established by local injection, most pain centers offer radiofrequency ablation of the small recurrent sensory nerves that innervate the joint as a means of permanent relief. This has met with some success, but has not been studied systematically. Some writers have used the term facet syndrome to describe a painful state from facetal hypertrophy that gives rise to a lumbar monoradiculopathy indistinguishable from that caused by a ruptured disc or spondylotic disease. Reynolds, Weinstein, et al have documented such cases. At operation, the spinal root is compressed against the floor of the intervertebral canal by overgrowth of an inferior or superior facet. Foraminotomy and facetectomy, after exploration of the root from the dural sac to the pedicle, have relieved the pain in many operated cases.
Lumbar Adhesive Arachnoiditis This is a somewhat vague entity in which the arachnoid membrane is thickened and opaque in the vicinity of the cauda equina. The term is also applied to thickening of the arachnoidal sheaths around roots (normal roots have essentially no epineurium). According to one review, lumbar arachnoiditis is rare, having been seen in only 80 of 7,600 myelograms, and it should virtually vanish as the use of MRI and water-soluble dyes for myelography take precedence. The usual clinical features are intractable lowback and leg pain and paresthesia, all positionally sensitive, in combination with neurologic abnormalities referable to lumbar spinal roots. In our few patients, multiple previous myelograms (a problem of the past), disc rupture, operative procedures, infections, and subarachnoid bleeding have been causal. Some cases have followed spinal anesthesia and even epidural anesthesia by a period of months or years. The presumption is that the dura had been breached and often there were clinical signs of aseptic meningitis soon after the procedure. In the absence of such an acute reaction, the later diagnosis of arachnoiditis rests on less-certain grounds.
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The MRI shows eccentrically thickened meninges in the spinal canal with arachnoid adhesions and collections of CSF that displace nerve roots (Fig. 11-6). Abnormalities are even more striking on CT myelographic studies in which the contrast is broken up and fails to outline the roots. Treatment is unsatisfactory. Lysis of adhesions under an operating microscope and administration of intrathecal steroids have been of little value, although some experienced surgeons claim otherwise. Epidural injection of steroids is occasionally helpful according to some of our orthopedic surgeon colleagues.
Ankylosing Spondylitis This disorder, referred to in the past as rheumatoid spondylitis and as von Bechterew or Marie-Strümpell arthritis, affects young adult males predominantly. Approximately 95 per-
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cent of patients with ankylosing spondylitis are marked by the histocompatibility antigen HLA-B27 (which is present in only 7 percent of nonaffected persons of European extraction). Pain, usually centered in the low back, is the main early complaint. Often it radiates to the back of the thighs and groin. At first, the symptoms are vague (tired back, “catches” up and down the back, sore back), and the diagnosis may be overlooked for many years. Although the pain is recurrent, limitation of movement is constant and progressive and comes to dominate the clinical picture. Early in the course of disease there is only “morning stiffness” or an increase in stiffness after periods of inactivity similar to lumbar osteoarthritis but unusual for the affected age group. In advanced stages, a cauda equina compression syndrome may complicate ankylosing spondylitis, the result apparently of an inflammatory reaction and proliferation of connective tissue (Matthews). Limitation of chest expansion, tenderness over the sternum, decreased motion and tendency to progressive flexion of the hips, and the characteristic immobility and flexion deformity of the spine (“poker spine”) may be present early in the course of the disease. The radiologic hallmarks are destruction and subsequent obliteration of the sacroiliac joints, followed by bony bridging of the vertebral bodies to produce the characteristic “bamboo spine.” When this change becomes apparent, the pain usually subsides, but the patient by then has little motion of the back and neck. An unusual additional feature, almost unique to this condition, is an extreme dilatation of the lumbar thecal sac. Ankylosing spondylitis may also be accompanied by the Reiter syndrome, psoriasis, and inflammatory diseases of the intestine (see also Chap. 44). The great risk in this disease is fracture dislocation of the spine from relatively minor trauma, particularly flexion– extension injuries. Occasionally ankylosing spondylitis is complicated by destructive vertebral lesions. This complication should be suspected whenever the pain returns after a period of quiescence or becomes localized. The cause of these lesions is not known, but they may represent a response to nonunion of fractures, taking the form of an excessive production of fibrous inflammatory tissue. When it is severe, ankylosing spondylitis may involve both hips, greatly accentuating the back deformity and disability. Rheumatoid arthritis of the spine may be confined to the cervical region and creates risk of fracture–dislocation; it is considered further on in this chapter.
Neoplastic and Infectious Diseases of the Spine (See also Chap. 44)
Figure 11-6. Severe lumbar arachnoiditis causing back pain, sciatica, and paresthesia years after spinal analgesia. Lumbar MRI performed with infusion of gadolinium showing thickened arachnoid and displacement of cauda equina roots (arrow) by acquired arachnoid cysts.
Metastatic carcinoma (breast, bronchus, prostate, thyroid, kidney, stomach, uterus), multiple myeloma, and lymphoma are the common malignant tumors that involve the spine. The primary lesion may be small and asymptomatic, and the first manifestation of the tumor may be pain in the back caused by metastatic deposits. The pain is constant and dull; it is often unrelieved by rest and is generally worse at night, interrupting sleep. Radicular pain may be added if the metastasis extends laterally. A fracture of a vertebral body in an otherwise healthy young or middle-aged person should alert the physician to the possibility of an underlying metas-
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tasis. At the time of onset of the back pain, there may be no radiographic changes on plain radiographs; when such changes do appear, they usually take the form of destructive lesions in one or several vertebral bodies with little or no involvement of the disc space, even in the face of a compression fracture. However, the changes are evident on CT and MRI or radioactive isotope scan that detects areas of osteoblastic activity caused by neoplastic or inflammatory disease. Infection of the vertebral column, osteomyelitis, is usually caused by staphylococci and less often by coliforms and mycobacteria. The patient complains of subacute or chronic pain in the back, which is exacerbated by movement but not materially relieved by rest. Motion becomes limited, and there is percussion-induced tenderness over the spine in the involved segments and pain with jarring of the spine, as occurs when the heels strike the floor. Often these patients are afebrile and do not have a leukocytosis. The erythrocyte sedimentation rate and C-reactive protein are elevated as a rule. Highly characteristic is the demonstration by CT scanning and MRI of involvement of both the vertebral body and the adjacent intervertebral disc, and the finding of a breached disc space with involvement of two adjacent vertebral bodies is one of the features that differentiates infectious from neoplastic diseases of the spine. A paravertebral mass is often found, indicating an abscess, which may, in the case of tuberculosis, drain spontaneously at sites quite remote from the vertebral column. We have also encountered a number of patients with subacute bacterial endocarditis who complained of severe midline thoracic and lumbar back pain but had no evident infection of the spine. Tuberculous spinal infection and the resultant kyphotic deformity (Pott disease) represent a special condition that is common in developing countries (see Chaps. 32 and 44). Special emphasis is placed on spinal epidural abscess, which usually necessitates urgent surgical treatment. Failure to properly identify this lesion has led to cases of paraplegia or death from sepsis. Most often this is caused by staphylococcal infection, which is carried in the bloodstream from a septic focus (e.g., furuncle) or is introduced into the epidural space from an osteomyelitic lesion. Another important avenue of infection is the intravenous self-administration of drugs and use of contaminated needles. Rarely, the infection is introduced in the course of a lumbar puncture, epidural injection, or laminectomy for disc excision. In some instances, the source of an epidural abscess cannot be ascertained. The main symptoms are low-grade fever, leukocytosis, and persistent and severe localized pain that is intensified by percussion and pressure over the vertebral spines. Additionally the pain may acquire radicular radiation. These symptoms mandate immediate investigation by MRI or CT myelography and surgical intervention, preferably before the signs of paraplegia, sphincter dysfunction, and sensory loss become manifest. Small abscesses and granulomas that are the residua of previous and partially treated abscesses can be sometimes treated successfully with antibiotics alone as discussed further on.
Intraspinal Hemorrhage (See Chap. 44) Sudden, excruciating midline back pain (le coup de poignard or “the strike of the dagger”)—often with rapidly evolving
paraparesis, urinary retention, and numbness of the legs— may announce the occurrence of subarachnoid, subdural, or epidural bleeding. The most common causes of such an event are a coagulopathy (mainly from warfarin) and a spinal arteriovenous malformation (AVM), as discussed in Chap. 44. Spinal arterial aneurysms are much-less-common underlying lesions. It should be mentioned that focal back pain of comparable intensity may mark the onset of acute myelitis, spinal cord infarction, compression fracture, and, occasionally, Guillain-Barré syndrome.
Back Pain from Visceral Disease Peptic ulcer disease and carcinoma of the stomach and pancreas most typically induce pain in the epigastrium. However, if the posterior stomach wall is involved, particularly if there is retroperitoneal extension, the pain may be felt in the thoracic spine, centrally or to one side, or in both locations. If intense, it may seem to encircle the body. The back pain tends to reflect the temporal characteristics of the pain from the affected organ; e.g., if caused by peptic ulceration, it appears about 2 h after a meal and is relieved by food and antacids. Diseases of the pancreas are apt to cause pain in the back, being more to the right of the spine if the head of the pancreas is involved and to the left if the body and tail are implicated. Retroperitoneal neoplasms—e.g., lymphomas, renal cell tumors, sarcomas, and other malignancies—may evoke pain in the lower thoracic or lumbar spine with a tendency to radiate to the lower part of the abdomen, groins, anterior thighs, or flank. A tumor in the iliopsoas region often produces a unilateral lumbar ache with radiation toward the groin and labia or testicle; there may also be signs of involvement of the upper lumbar spinal roots. An aneurysm of the abdominal aorta may induce pain localized to an analogous region of the spine. The sudden appearance of lumbar pain in a patient receiving anticoagulants should arouse suspicion of retroperitoneal bleeding; this pain may also be referred to the groin. Inflammatory diseases and neoplasms of the colon cause pain that may be felt in the lower abdomen, the midlumbar region, or both. As with intense pain higher in the spine, it may have a belt-like distribution. Pain from a lesion in the transverse colon or first part of the descending colon may be central or left-sided; its level of reference is to the second and third lumbar vertebrae. If the sigmoid colon is implicated, the pain is lower in the upper sacral spine and anteriorly in the suprapubic region or left lower quadrant of the abdomen. Retroperitoneal appendicitis may have an odd referral of pain to the low flank and back. Gynecologic disorders often manifest themselves by back pain, and their diagnosis may prove difficult. Thorough abdominal palpation, as well as vaginal and rectal examination by an experienced physician, supplemented by ultrasonography and CT scanning or MRI, usually discloses the source of pain. The uterosacral ligaments are the most important pelvic source of chronic back pain. Endometriosis or carcinoma of the uterus (body or cervix) may invade these structures, causing pain localized to the sacrum either centrally or more to one side. In endometriosis, the pain begins premenstrually and often merges with menstrual
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pain, which also may be felt in the sacral region. Rarely, cyclic engorgement of ectopic endometrial tissue may give rise to sciatica and other radicular pain. Changes in posture may also evoke pain here when a fibroma of the uterus pulls on the uterosacral ligaments. Low back pain with radiation into one or both thighs is a common phenomenon during the last weeks of pregnancy. Pain because of neoplastic infiltration of pelvic nerve plexuses may be projected to the low back and is continuous, becoming progressively more severe; it tends to be more intense at night and may have a burning quality. The primary lesion can be inconspicuous and may be overlooked on pelvic examination.
Atherosclerosis of the Distal Aorta (Vascular Claudication) Atherosclerosis of large and medium-sized arteries, the most common vascular disease of humans, often leads to symptoms that are induced by exercise (intermittent claudication) but may also occur at rest (ischemic rest pain). The diabetic patient is especially susceptible. The muscle pain that is brought on by exercise and promptly relieved by rest most frequently involves the calf and thigh muscles. If the atherosclerotic narrowing or occlusion implicates the aorta and iliac arteries, it may also cause hip and buttock claudication and impotence in the male (Leriche syndrome). Ischemic rest pain—and sometimes attendant ulceration and gangrene—is usually localized to the foot and toes; it is the consequence of multiple sites of vascular occlusion. Pain at rest is characteristically worse at night and totally or partially relieved by dependency. The examination of such patients will reveal a loss of one or more peripheral pulses, trophic changes in the skin and nails (in advanced cases), and the presence of bruits over or distal to sites of narrowing. The ankle reflexes are often diminished. The similarities to a claudicatory syndrome of lumbar spine stenosis have already been mentioned.
Coccydynia This is the name applied to pain localized to the “tail piece,” the three or four small vestigial bones at the lowermost part of the sacrum. The trauma of childbirth, a fall on the buttocks, avascular necrosis, a neurofibroma or glomus tumor, or one of a variety of other rare tumors and anal disorders, and, of course, pilonidal cyst, can sometimes be established as the cause of pain in this region. Far more often, the source remains obscure. In the past, patients in this latter group were indiscriminately subjected to coccygectomy, but more recent studies have demonstrated that most cases respond favorably to injections of local anesthetic and methylprednisolone or to manipulation of the coccyx under anesthesia (Wray et al).
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examination, there remains a sizable group of patients in whom no basis for the back pain can be found. Two categories can be recognized: one with postural back pain and pain after injury, and another with aggravating psychiatric illness, but there are always cases where the diagnosis remains obscure. Low back pain may be a major symptom in patients with hysteria, malingering, anxiety, depression, and hypochondriasis as well as in many persons whose symptoms do not conform to any of these psychiatric illnesses. It is good practice to assume that pain in the back in such patients may signify disease of the spine or adjacent structures, and this should always be carefully sought. However, even when some organic factors are found, the pain may be exaggerated, prolonged, or woven into a pattern of invalidism because of coexistent primary or secondary factors. This is especially true when there is the possibility of secondary gain (notably workers’ compensation or settlement of personal injury claims). Patients seeking compensation for protracted low back pain without obvious structural disease tend, after a time, to become suspicious, uncooperative, and hostile toward their physicians or anyone who might question the authenticity of their illness. One notes in them a tendency to describe their pain vaguely and a preference to discuss the degree of their disability and their mistreatment at the hands of the medical profession. The description of the pain may vary considerably from one examination to another. Often also, the region(s) in which pain is experienced and its radiation are nonphysiologic, and the condition fails to respond to rest and inactivity. These features and a negative examination of the back should lead one to suspect a psychologic factor. A few patients, usually frank malingerers, adopt bizarre gaits and attitudes, such as walking with the trunk flexed at almost a right angle (camptocormia), and are unable to straighten up. Or the patient may be unable to bend forward even a few degrees, despite the absence of muscle spasm, and may wince at the slightest pressure, even over the sacrum, which is seldom a site of tenderness unless there is pelvic disease. The depressed and anxious patient with back pain represents a troublesome problem. The disability seems excessive for the degree of spinal malfunction. Anxiety and depression may become important components of the back syndrome and the patient may ruminate about an undiagnosed cancer or other serious illness. In these circumstances, common and minor back ailments—e.g., those caused by osteoarthritis and postural ache—are enhanced and rendered intolerable. Such patients are still subjected to unnecessary surgical procedures. It is not clear if one can depend on the diagnostic features of a response to drugs that alleviate depression (see Chap. 57).
Failed Back Syndrome Obscure Types of Low Back Pain and the Question of Psychiatric Disease It is a safe clinical rule that most patients who complain of low back pain have some type of primary or secondary disease of the spine and its supporting structures or of the abdominal or pelvic viscera. However, even after careful
Surely among the most difficult patients to manage are those with chronic low back pain who have already had one or more laminectomies and sometimes a fusion without substantial relief. In one perhaps dated but large series of patients operated on for proven disc prolapse, 25 percent were left with troublesome symptoms and 10 percent
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required further surgery (Weir and Jacobs). In such patients our practice has been to repeat the MRI or CT myelography. In a small number it will be found that the disc has reruptured, or that there is unaddressed lateral recess stenosis, or that a disc has ruptured at another level. It may happen that the surgeon did not remove all the herniated disc tissue, in which case another operation to remove the remainder will usually be successful. EMG and nerve conduction studies, searching for evidence of a radiculopathy, are also helpful. If there is evidence of a radiculopathy but no disc material, or only scar tissue is seen on MRI, one cannot know whether the pain is because of injury from the initial rupture or is the aftermath of surgery. Various explanations are then invoked—radiculitis, lateral recess syndrome, facet syndrome, unstable spine, and lumbar arachnoiditis, each described earlier in this chapter (see reviews by Quiles et al and by Long). One would suppose that these patients with chronic pain could be subdivided into a group with continued radicular pain and another with referred pain from disease of the spine. However, once the pain becomes chronic, the separation is not easy. Pressure over the spine, buttock, or thigh may cause pain to be projected into the leg. Lidocaine blocks of nerve roots have yielded inconsistent results. Transcutaneous stimulators, posterior column stimulators, intrathecal injections of analgesics, and epidural steroid injections have seldom helped for long in our experience, but we have seen striking exceptions, especially with epidural pumps that administer analgesics. At present, the best that can be offered the patient is weight reduction (in appropriate individuals), stretching and progressive exercise to strengthen abdominal and back muscles, as well as mild nonnarcotic analgesics and antidepressant drugs. A trial of massage and other types of physiotherapy or a limited course of spinal chiropractic manipulation is reasonable.
PAIN IN THE NECK, SHOULDER, AND ARM General Considerations It is useful to distinguish three major categories of painful disease of the neck and arms—that originating in the cervical spine, in the brachial plexus, and in the shoulder. Although the distribution of pain from each of these sources may overlap, the patient can usually indicate its site of origin. Pain arising from the cervical part of the spine is felt in the neck or back of the head and is projected to the shoulder and upper arm; it is evoked or enhanced by certain movements or positions of the neck and is accompanied by limitation of motion of the neck and by tenderness to palpation over the cervical spine. Pain of brachial plexus origin is experienced in the supraclavicular region, or in the axilla and around the shoulder; it may be worsened by certain maneuvers and positions of the arm and neck (extreme rotation). A palpable abnormality above the clavicle may disclose the cause of the plexopathy (aneurysm of the subclavian artery, tumor, cervical rib). The combination of circulatory abnormalities and signs referable to the medial cord of the brachial plexus is characteristic of the thoracic outlet syndrome, described further on.
Pain localized to the shoulder region, worsened by motion, and associated with tenderness and limitation of movement, especially internal and external rotation and abduction, points to a tendonitis, subacromial bursitis, or tear of the rotator cuff, which is made up of the tendons of the muscles surrounding the shoulder joint. The term bursitis is often used loosely to designate these disorders. Shoulder pain, like spine and plexus pain, may radiate vaguely into the arm and rarely into the hand, but sensorimotor and reflex changes—which always indicate disease of nerve roots, plexus, or nerves—are absent. Shoulder pain of this type is very common in middle and late adult life. It may arise spontaneously or after unusual or vigorous use of the arm. Local tenderness over the greater tuberosity of the humerus is characteristic. Plain radiographs of the shoulder may be normal or show a calcium deposit in the supraspinatus tendon or subacromial bursa. MRI is able to demonstrate more subtle abnormalities, such as muscle and tendon tears of the rotator cuff or a labral tear of the joint capsule. In most patients the pain subsides gradually with immobilization and analgesics followed by a program of increasing shoulder mobilization. If it does not, the injection of small amounts of corticosteroids into the bursa, or the site of major pain indicated by passive shoulder movement in the case of rotator cuff injuries, is often temporarily effective and allows the patient to mobilize the shoulder. The problem of the “frozen shoulder” is addressed further on. Osteoarthritis and osteophytic spur formation of the cervical spine may cause pain that radiates into the back of the head, shoulders, and arm on one or both sides. Coincident compression of nerve roots is manifest by paresthesia, sensory loss, weakness and atrophy, and tendon reflex changes in the arms and hands. Should bony ridges form in the spinal canal, as described in detail in Chap. 44, the spinal cord may be compressed, with resulting spastic weakness, ataxia, and loss of vibratory and position sense in the legs (cervical spondylosis). The bony changes are evident on plain films but are better seen by CT and MRI. There may be difficulty in distinguishing cervical spondylosis with root and spinal cord compression from a disc (see further on) or from a primary neurologic disease (syringomyelia, amyotrophic lateral sclerosis, or tumor) with an unrelated cervical osteoarthritis. Here the MRI is of particular value in revealing compression of the spinal cord, but this study is prone to overinterpretation when a bony ridge barely comes into contact with the cord but does not deform it (see “Cervical Spondylosis with Myelopathy” in Chap. 44). Spinal rheumatoid arthritis may be restricted to the cervical apophysial (facet) joints and the atlantoaxial articulation. The usual manifestations are pain, stiffness, and limitation of motion in the neck and pain in the back of the head. In contrast to ankylosing spondylitis, rheumatoid arthritis is rarely confined to the spine. Because of evident disease of other joints, the diagnosis is relatively easy to make, but significant involvement of the cervical spine may be overlooked. In the advanced stages, one or several of the vertebrae may become displaced anteriorly, or a synovitis of the atlantoaxial joint may damage the transverse ligament of the atlas, resulting in forward displacement of the atlas on the axis, i.e., atlantoaxial subluxation.
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In either instance, serious and even life-threatening compression of the spinal cord may occur gradually or suddenly. Cautiously performed lateral radiographs in flexion and extension are useful in visualizing atlantoaxial dislocation or subluxation of the lower segments. Occipital headache and neck pain related to degenerative changes in the upper cervical facets is discussed with other cranial pains in “‘Third Occipital Nerve’ Headache” (so-called third occipital nerve pain) in Chap. 10. Traumatic and Whiplash Injury Injury to ligaments and muscles as a result of forcible extension and flexion of the neck can create a number of difficult clinical problems. The injury ranges from a minor sprain of muscles and ligaments to severe tearing of these structures, to avulsion of muscle and tendon from vertebral body, and even to vertebral and intervertebral disc damage. The latter lesions can be seen with MRI and, if severe, can result in root or spinal cord compression or, occasionally, in cartilaginous embolization of the spinal cord (see “Fibrocartilaginous Embolism” in Chap. 44). If there is preexisting cervical osteoarthritis, there may be considerable pain, and in extreme cases, cord compression. However, the more ubiquitous and milder degrees of whiplash injury without the above described structural injuries are so often complicated by psychologic and compensation factors leading to prolonged disability that the syndrome has become a vexing problem without clear medical definition and occupies a disproportionate amount of time on the part of physicians, compensation boards, and courts (see LaRocca for a review and the book by Malleson for an interesting discussion of the sociology and psychology of this subject). We have no doubt that authentic traumatic neck injuries exist, even at times from minor trauma, but we are in accord with the above-mentioned authors that the high frequency of this putative injury is sustained by societal and legal structures.
Cervical Disc Herniation (See Table 11-1) A common cause of neck, shoulder, and arm pain is disc herniation in the lower cervical region; the process is comparable to disc herniation in the lumbar region but gives rise, of course, to a different set of symptoms (Table 11-1). The problem appears most often without a clear and immediate cause, but it may develop after trauma, which may be major or minor (from sudden hyperextension of the neck, falls, diving accidents, forceful manipulations). The roots most commonly involved are the seventh (in 70 percent of cases) and the sixth (in 20 percent of cases); fifth- and eighth-root compression makes up the remaining 10 percent (Yoss et al). When the protruded disc lies between the sixth and seventh vertebrae, there is involvement of the seventh cervical root as outlined in Table 11-1. The pain is then in the region of the shoulder blade, or spine of the scapula, and posterolateral upper arm; it may project to the elbow and dorsal forearm, index and middle fingers, or all the fingers. Occasionally discomfort is felt in the pectoral or axillary region. Tenderness is most pronounced over the medial aspect of the shoulder blade opposite the third to fourth thoracic spinous processes and in the supraclavicular area and tri-
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ceps region. Paresthesia and sensory loss are most evident in the index and middle fingers. Weakness involves the extensors of the forearm and sometimes of the wrist; occasionally the handgrip is weak as well; the triceps may be weak and the triceps reflex is usually diminished or absent; the biceps and supinator reflexes are preserved. With a laterally situated disc herniation between the fifth and sixth cervical vertebrae, the symptoms and signs are referred to the sixth cervical root. The full syndrome is characterized by pain at the trapezius ridge and tip of the shoulder, with radiation into the anterior-upper part of the arm, radial forearm, often the thumb, and sometimes the index finger as well. There may also be paresthesia and sensory impairment in the same regions; tenderness in the area above the spine of the scapula and in the supraclavicular and biceps regions; weakness in flexion of the forearm (biceps) and in contraction of the deltoid when sustaining arm abduction; and diminished or absent biceps and supinator reflexes (the triceps reflex is retained or sometimes has the appearance of being slightly exaggerated because of flaccidity of the biceps). The fifth cervical root syndrome, produced by disc herniation between the fourth and fifth vertebral bodies, is characterized by pain in the shoulder and trapezius region and by supra- and infraspinatus weakness, manifest by an inability to abduct the arm and rotate it externally with the shoulder adducted (weakness of the supra- and infraspinatus muscles). There may be a slight degree of weakness of the biceps and a corresponding reduction in the reflex, but these are inconsistent findings. A small patch of diminished sensation commonly overlies the deltoid muscle. Compression of the eighth cervical root at (C7-T1 disc) may mimic an ulnar nerve palsy. The pain is along the medial side of the forearm and the sensory loss is in the distribution of the medial cutaneous nerve of the forearm and of the ulnar nerve in the hand. The weakness largely involves the intrinsic muscles supplied by the ulnar nerve (see “Ulnar Nerve” in Chap. 46). The reflexes may be unaffected but the triceps jerk is often slightly reduced. These syndromes are usually incomplete in that only one or several of the typical findings are present. Particularly noteworthy is the occurrence, in laterally placed cervical disc rupture, of isolated weakness without pain, especially with discs at the fifth and sixth levels. Friis and coworkers have described the distribution of pain in 250 cases of herniated disc or spondylotic nerve root compression in the cervical region. Virtually every patient, irrespective of the particular root(s) involved, showed a limitation in the range of motion of the neck and aggravation of pain with movement (particularly hyperextension). Coughing, sneezing, and downward pressure on the head in the hyperextended position usually exacerbated the pain, and traction (even manual) tended to relieve it. Nerve conduction studies, F responses, and EMG are helpful in confirming the level of root compression and distinguishing pain of radicular origin from that originating in the brachial plexus or in individual nerves of the arm (see “Brachial Neuritis” in Chap. 46). Unlike herniated lumbar discs, cervical ones, if large and centrally situated, result in compression of the spinal cord (Fig. 11-7). The centrally situated disc is often painless, and the cord syndrome may simulate multiple sclerosis or a
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Figure 11-7. Cervical disc herniation. MRI in sagittal (A) and axial (B) views of a disc extrusion at C5-C6 (arrow) that caused myelopathy and left sided radicular pain.
degenerative neurologic disease. Bilateral hand numbness, paresthesia, or similar altered sensation is common. Failure to consider a protruded cervical disc in patients with obscure symptoms in the legs, including stiffness and falling, is a common error. A vague sensory change can often be detected on the thorax, the rostral margin of which is several dermatomes below the level of compression. The diagnosis and the level of disc protrusion can be confirmed by MRI or by CT myelography (Fig. 11-7).
Management of Herniated Cervical Disc Conservative measures should be instituted before turning to surgical removal of the disc unless there are signs of a rapidly or subacutely progressing myelopathy (i.e., leg and arm weakness, hyperreflexia in the legs, gait ataxia, sphincteric dysfunction). Treatment In the case of cervical disc with radicular pain, a close-fitting foam collar is sometimes beneficial. The collar should be fitted so that minimal flexion and extension of the neck are allowed, but it must remain comfortable enough to encourage consistent use. The patient is advised to wear the collar at all times during the day, especially while riding in a car, unless this becomes completely impractical. Although of uncertain value, traction with a halter around the occiput and chin may be of some benefit in cervical disc syndromes. Analgesic medication may be required for a few days. In most instances the radicular pain subsides over a few weeks or less. Intractable cases may require surgery, especially if there is substantial weakness in the muscles corresponding to the affected root. Mild weakness alone is not recognized as an indication for surgery, and in those few cases where weakness alone has occurred, without pain, the same conservative measures outlined above should be implemented. Most often the surgeon tackles this problem
through an anterior approach (transdiscally), which leaves the posterior elements intact and allows for remaining stability of the spine.
Cervical Spondylosis (See also Chap. 44) This is basically a chronic degenerative disease of the midand lower cervical spine that narrows the spinal canal and intervertebral foramina, causing compressive injury of the spinal cord and roots. The problem of central disc protrusion, discussed above, often contributes as one component of the narrowing of the canal. Because the main effects of cervical spondylosis are on the cord, this process is discussed in detail in Chap. 44, but cervical spondylosis is also a common cause of neck and arm pain, as described earlier. If minor signs of spinal cord and root involvement are present, a collar to limit movement of the head and neck may halt the progression and lead to improvement. Decompressive laminectomy or anterior excision of single spondylotic spurs and fusion are reserved for instances of the disease with advancing neurologic symptoms or intractable pain as discussed in Chap. 44. As with lumbar stenosis, success is not assured with surgery, but almost invariably, progression of symptoms is prevented.
Thoracic Outlet Syndromes (Superior Thoracic Aperture Syndrome) A number of anatomic anomalies occur in the lateral cervical region. These may, under certain circumstances, compress the brachial plexus, the subclavian artery, and the subclavian vein, causing muscle weakness and wasting, pain, and vascular abnormalities in the hand and arm. The condition is undoubtedly diagnosed more often than is justified, and the term has been applied ambiguously to a number of conditions, some of which are almost cer-
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tainly nonexistent, comparable to the pyriformis syndrome in the buttock. The most frequent of the abnormalities that cause neural compression and are encompassed by the term thoracic outlet syndrome are an anomalous incomplete cervical rib, with a sharp fascial band passing from its tip to the first rib; a taut fibrous band passing from an elongated and down-curving transverse process of C7 to the first rib; less often, a complete cervical rib, which articulates with the first rib; and anomalies of the position and insertion of the anterior and medial scalene muscles. Thus, the sites of potential neurovascular compression extend all the way from the intervertebral foramina and superior mediastinum to the axilla. Depending on the postulated abnormality and mechanism of symptom production, the terms cervical rib, anterior scalene, costoclavicular, and neurovascular compression have been applied. In addition, a droopy shoulder syndrome has been identified that purportedly stretches the brachial plexus and gives rise to similar symptoms; a majority of the patients have been young women with asthenic body habitus. Variations in regional anatomy could explain these several postulated mechanisms, but to this day there is not full agreement about the validity of anterior scalene and costoclavicular syndromes. An anomalous cervical rib, which arises from the seventh cervical vertebra and extends laterally between the anterior and medial scalene muscles and then under the brachial plexus and subclavian artery to attach to the first rib, obviously disturbs the anatomic relationships of these structures and may compress them (Fig. 11-8). However, as an estimated 1 percent of the population has cervical ribs, usually on both sides, and only about 10 percent of these persons have neurologic or vascular symptoms (almost always one-sided), other factors must be operative. The anterior and middle scalene muscles, which flex and rotate the neck, are both inserted into the first rib so that the subclavian artery and vein and the brachial plexus must pass between them. Hence abnormalities of insertion and hypertrophy of these muscles were once thought to be causes of the syndrome but sectioning them (scalenectomy) has so rarely altered the symptoms that this mechanism is no longer given credence. Three neurovascular syndromes are associated with a rudimentary cervical rib (rarely with a complete cervical rib) and related abnormalities at the thoracic outlet: subclavian venous or arterial compression and a brachial plexopathy. In all three forms, shoulder and arm pain is prominent. The discomfort is of the aching type and is felt in the posterior hemithorax, pectoral region, and upper arm. These syndromes sometimes coexist, but more often each occurs independently. Compression or spontaneous thrombosis of the subclavian vein is a rare occurrence causing a dusky discoloration, venous distention, and edema of the arm. The vein may become thrombosed after prolonged exercise (PagetSchrötter syndrome) or in cases of a clotting diathesis in cancer patients. Compression of the subclavian artery, which results in ischemia of the limb, may be complicated by digital gangrene and retrograde embolization, also is a rare entity. A
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unilateral Raynaud phenomenon, brittle nails, and ulceration of the fingertips are important diagnostic findings. A supraclavicular bruit is suggestive but not in itself diagnostic of subclavian artery compression. The conventional tests for vascular compression—obliteration of the pulse when the patient, seated and with the arm extended, takes and holds a full breath, tilts the head back, and turns it to the affected side (Adson test) or abducts and externally rotates the arm and braces the shoulders and turns the head to either side (Wright maneuver)—are not entirely reliable. Sometimes these maneuvers fail to obliterate the radial pulse in cases of proved compression; contrariwise, these tests may be positive in normal persons. Nevertheless, a positive test only on the symptomatic side (with reproduction of the patient’s symptoms) is suggestive of the diagnosis of arterial compression and, by implication, some form of thoracic outlet syndrome. Plethysmographic recording of the radial pulse and ultrasound of the vessel add greatly to the accuracy of these positional tests. A primarily neurologic problem may characterize the thoracic outlet syndrome. There is slight wasting and weakness of the hypothenar, interosseous, adductor pollicis, and deep flexor muscles of the fourth and fifth fingers (i.e., the muscles innervated by the lower trunk of the brachial plexus and ulnar nerve). Weakness of the flexor muscles of the forearm may be present in advanced cases. Tendon reflexes are usually preserved. In addition, most patients complain of an intermittent aching of the arm, particularly of the ulnar side, and about half of them complain also of numbness and tingling along the ulnar border of the forearm and hand. A loss of superficial sensation in these areas is variable. It may be possible to reproduce the sensory symptoms by firm pressure just above the clavicle or by traction on the arm. Vascular features are often absent or minimal in patients with the neurologic form of the syndrome. In patients with neurologic signs, nerve conduction studies disclose reduced amplitude of the ulnar sensory potentials. There may be decreased amplitude of the median motor evoked potentials as well, a mild but uniform slowing of the median motor conduction velocity, and a prolongation of the F-wave latency. Concentric needle examination of affected hand muscles reveals largeamplitude motor units, suggesting collateral reinnervation. Somatosensory evoked potentials may be a useful adjunct to the conventional nerve conduction and EMG studies (Yiannikas and Walsh). Brachial artery MR angiography is usually reserved for patients with a suspected arterial occlusion, an aneurysm, or an obvious cervical rib. The place of venography in the diagnostic workup is uncertain, for a number of otherwise normal individuals can occlude the subclavian vein by fully abducting the arm. In the authors’ experience, unambiguous instances of thoracic outlet syndrome are not common. This has also been the experience of Wilbourn, whose review of this subject is recommended. One should be skeptical of the diagnosis unless the clinical and EMG features enumerated above are present. Common mistakes are to confuse the thoracic outlet syndrome with carpal tunnel syndrome, ulnar neuropathy or entrapment at the elbow, or cervical radiculopathy caused by arthritis or disc disease.
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anterior Scalene muscles
middle posterior
Brachial plexus
Clavicle
Subclavian artery Subclavian vein First rib
Subclavian vein
Figure 11-8. Course of the brachial plexus and subclavian artery between the anterior scalene and middle scalene muscles. Dilatation of the subclavian artery just distal to the anterior scalene muscle is illustrated. Immediately distal to the anterior and middle scalene muscles is another potential area of constriction, between the clavicle and the first rib. With extension of the neck and turning of the chin to the affected side (Adson maneuver), the tension on the anterior scalene muscle is increased and the subclavian artery compressed, resulting in a supraclavicular bruit and obliteration of the radial pulse.
Brachial neuritis may have a similar presentation. Imaging studies and careful nerve conduction and EMG studies may be necessary to exclude all of these disorders.
Treatment of the Thoracic Outlet Syndrome A conservative approach is advisable. If the main symptoms are pain and paresthesia, Leffert suggests the use of local heat, analgesics, muscle relaxants, and an assiduous program of special exercises to strengthen the shoulder muscles. A full range of neck motions is then practiced. On such a regimen, some patients experience a relief of
symptoms after 2 to 3 weeks. Instruction by a qualified physical therapist is invaluable. Only if pain is severe and persistent and is clearly associated with the vascular or neurogenic features of the syndrome is surgery indicated. The usual approach is through the supraclavicular space, with cutting of fibrous bands and excision of the rudimentary rib. In cases of venous or minor arterial forms of the syndrome, some thoracic surgeons favor the excision of a segment of the first rib through the axilla. Pain is often dramatically relieved, but the sensorimotor defects improve only slightly. Sectioning of the scalenus muscle is not endorsed
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because, as already noted, the role of muscle in causing thoracic outlet syndrome has been questioned.
Other Painful Conditions Originating in the Neck, Brachial Plexus, and Shoulder The brachial plexus is an important source of shoulder and arm pain. The main disorders are brachial neuritis and metastatic infiltration and radiation damage to the plexus. Chapter 46 discusses these disorders in detail. Metastases to the cervical region of the spine are less common than to other parts of the vertebral column. They are, however, frequently painful and may cause root compression. Posterior extension of the tumor from the vertebral bodies or compression fractures may lead to the rapid development of quadriplegia. The Pancoast tumor, usually a squamous cell carcinoma in the superior sulcus of the lung, may implicate the lower cervical and upper thoracic (T1 and T2) spinal nerves as they exit the spine. In these cases, a Horner syndrome, numbness of the inner side of the arm and hand, and weakness of all muscles of the hand and of the triceps muscle are combined with pain beneath the upper scapula and in the arm. The neurologic abnormalities may occur long before the tumor becomes visible radiographically. Shoulder injuries (rotator cuff), subacromial or subdeltoid bursitis, periarthritis or capsulitis (frozen shoulder), tendonitis, and arthritis may develop in patients who are otherwise well, but these conditions also occur as complications of hemiplegia. The pain tends to be severe and extends toward the neck and down the arm into the hand. The dorsum of the hand may tingle without other signs of nerve involvement. Immobility of an arm following myocardial infarction may be associated with pain in the shoulder and arm and with vasomotor changes and secondary arthropathy of the hand joints (shoulder–hand syndrome); after a time, osteoporosis and atrophy of cutaneous and subcutaneous structures occur (Sudeck atrophy or SudeckLeriche syndrome). Similar changes may occur in the foot and leg, or all articular structures on the side of a hemiplegia, or in association with the painful lesions described in the first part of this chapter. The neurologist should know that these complications can be prevented by proper exercises and relieved by cooling of the affected limb. Vasomotor, sudomotor, and trophic changes in the skin, with atrophy of the soft tissues and decalcification of bone, may follow the prolonged immobilization and disuse of an arm (i.e., frozen shoulder syndrome) or leg for whatever reason. Medial and lateral epicondylitis (tennis elbow) are readily diagnosed by demonstrating tenderness over the affected parts and an aggravation of pain on certain movements of the wrist. We have observed entrapment of the ulnar nerve in some cases of medial epicondylitis. The pain of the carpal tunnel syndrome often extends into the forearm and sometimes into the anterior biceps region and may be mistaken for disease of the shoulder or neck. Similarly, involvement of the ulnar, radial, or median nerves may be mistaken for brachial plexus or root lesions. EMG and nerve conduction studies are helpful in these circumstances (this common disorder is discussed in Chap. 46).
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Polymyalgia Rheumatica (See also Chaps. 10 and 34) This syndrome is observed in middle-aged and elderly persons and is characterized by severe pain, aching, and stiffness in the proximal muscles of the limbs and a markedly elevated erythrocyte sedimentation rate. The shoulders are most affected, but half of these patients have hip or neck pain as well. Constitutional symptoms (loss of weight, fever, and anemia) and articular swelling are less consistent manifestations. Many physicians have drawn attention to the high incidence of depression, but as is typical of chronic disease, it is difficult to know whether this is a cause or an effect. A few patients have pitting edema of the hands or feet, as illustrated in the review by Salvarini and colleagues; others have knee or wrist arthritis or carpal tunnel syndrome. Arthroscopy and MRI suggest that the pain originates in a synovitis or, sometimes more accurately, a bursitis, and in an inflammation of periarticular structures. The fundamental cause is not known. Activity of the disease correlates with elevation of the sedimentation rate, almost always above 40 mm/h and typically higher than 70 mm/h (and corresponding elevation of C-reactive protein); unlike the case in polymyositis, with which it is confused, creatine kinase levels are normal. In many patients, polymyalgia rheumatica is associated with giant cell (temporal, or cranial) arteritis. The precise concordance of these two allied conditions is not known but there is not a high frequency of overlap. The arteritis may affect one or both optic nerves; blindness is the main risk of the disease, as discussed in detail in Chap. 13. Treatment This disorder is self-limiting, lasting 6 months to 2 years, and responds dramatically to corticosteroid therapy, although this may have to be continued in low dosage for several months or a year or longer. We begin treatment with 20 mg of prednisone if there is no evidence of temporal arteritis (which requires higher doses). The absence of improvement in a day or two should bring the diagnosis into question. The degree of hip and shoulder pain is the best guide to the duration of steroid therapy and the rate at which the drug is withdrawn, usually in very small increments every 2 weeks. The sedimentation rate or C-reactive protein can be used as a guide, but neither alone is adequate to alter the medication schedule.
Raynaud Phenomenon Painful blanching of the fingers with emotional stress or exposure to cold is the main feature. In many cases, no cause can be discerned. Other so-called secondary cases are a result of partial obstruction of the brachial circulation, as occurs with some of the forms of the thoracic outlet syndrome; with repeated trauma to the hands, as in sculling or with use of a jackhammer; or with cryoglobulinemia, osteosclerotic myeloma, and autoimmune diseases, particularly scleroderma.
Reflex Sympathetic Dystrophy and Causalgia (See Chap. 8) This painful response to injury of the shoulder, arm, or leg, is usually the result of an incomplete nerve injury. It consists of protracted pain, characteristically described as
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“burning,” together with cyanosis or pallor, swelling, coldness, pain on passive motion, osteoporosis, and marked sensitivity of the affected part to tactile stimulation. The condition has been variously described under such terms as Sudeck atrophy, posttraumatic osteoporosis (in which case the bone scan may show increased local uptake of radioactive nuclide), and the related shoulder–hand syndrome. The current term is complex regional pain syndrome. When the pain syndrome occurs in isolation, it is referred to as causalgia. Pharmacologic or surgical sympathectomy appears to relieve the symptoms in some patients. In others with a hypersensitivity of both C-fiber receptors and postganglionic sympathetic fibers, it is not helpful. Chapter 8 discusses this subject further.
Neuroma Formation after Nerve Injury Persistent and often incapacitating pain and dysesthesias may follow any type of injury that leads to partial or complete interruption of a nerve, with subsequent neuroma formation or intraneural scarring—fracture, contusion of the limbs, compression from lying on the arm while intoxicated, severing of sensory nerves in the course of surgical operations or biopsy of nerve, or incomplete regeneration after nerve suture. It is stated that the nerves in these cases contain a preponderance of unmyelinated C fibers and a reduced number of A-δ fibers; this imbalance is presumably related to the genesis of painful dysesthesias. These cases are best managed by complete excision of the neuromas with end-to-end suture of healthy nerve, but not all cases lend themselves to this procedure. Another special type of neuroma is the one that forms at the end of a nerve severed at amputation (stump neuroma). Pain from this source is occasionally abolished by relatively simple procedures such as injection of lidocaine, resection of the distal neuroma, proximal neurotomy, or resection of the regional sympathetic ganglia. More common in clinical practice is the mundane, but painful, Morton neuroma, usually found on the plantar nerve between the third and fourth metatarsal bones. Pain on compression of the forefoot is the characteristic Mulder sign.
Erythromelalgia This rare disorder of the microvasculature produces a burning pain and bright red color change, usually in the toes and forefoot and sometimes in the hands, precipitated by changes in ambient temperature. Since its first description by Weir Mitchell in 1878, many articles have been written about it, and recently the cause of a primary familial form was traced to a mutation in a sodium channel protein. Each patient has a temperature threshold above which symptoms appear and the feet become bright red, warm, and painful. The afflicted patient rarely wears stockings or regular shoes because these tend to bring out the symptoms. The pain is relieved by walking on a cold surface or soaking the feet in ice water and by rest and elevation of the legs. The peripheral pulses are intact, and there are no motor, sensory, or reflex changes. The review by Layzer is recommended. Most cases are idiopathic, some familial and inherited as a dominant trait. There are secondary forms of the dis-
ease, the most important one being that associated with essential thrombocythemia (up to 25 percent of patients may have erythromelalgia as the first symptom) but also with other myeloproliferative disorders such as polycythemia vera and with collagen vascular diseases, including thrombotic thrombocytopenic purpura (TTP), during the use of calcium channel blockers and certain dopaminergic agonists such as pergolide and bromocriptine, and with occlusive vascular diseases. Some instances arise as a result of a painful polyneuropathy that predominantly affects the small sensory fibers; more often in these latter conditions, the redness and warmth are constant and the result of damage to sympathetic nerve fibers; see Chap. 46. These symptomatic forms have led some experts to question whether erythromelalgia is a type of neuropathy (Davis et al). The familial form of erythromelalgia has been traced to a mutation in a sodium channel (NaV 1.7) that is selectively expressed in dorsal root ganglia nociceptive neurons. In addition to its inherent value in explaining the manifestations of this disease, the discovery of this channelopathy has evinced interest in novel ways to treat pain by manipulating sodium channels. Treatment According to Abbott and to Mitts and others, aspirin is useful in the treatment of paroxysms of secondary erythromelalgia and of some primary cases as well; others had recommended methysergide, which has fallen out of use because of retroperitoneal and cardiac valvular fibrosis. Even small doses of aspirin provide relief within an hour, lasting for several days, a feature that is diagnostic. Sano and colleagues report that cyclosporine was of great benefit in a case of familial erythromelalgia that had not responded to other medications. A similar condition, restricted in topography to the region of an acquired single nerve or skin injury, has been described by Ochoa under the term ABC syndrome (angry, backfiring C-nociceptors). Episodes of pain and cutaneous vasodilatation were induced by mechanical or thermal stimulation and relieved by cooling. There may be persistent hyperalgesia over the affected area. Lance has suggested that a similar mechanism is operative in the “red ear syndrome” as a result of irritation of the third cervical root.
Myofascial Pain Syndrome and Fibromyalgia A confusing problem in the differential diagnosis of neck and limb pain is posed by the patient with pains that are clearly musculoskeletal in origin but are not attributable to a disease of the spine, articular structures, or nerves. The pain is localized to certain vague points in skeletal muscles, particularly the large muscles of the neck and shoulder girdle, arms, and thighs. We have been unable to corroborate the ill-defined tender nodules or cords (trigger points) that have been reported as an essential element of this illness. Excision of such nodules has not revealed any sign of inflammation or other disease process. The currently fashionable terms myofascial pain syndrome, fibromyalgia, and fibrositis have been attached to the syndrome, depending on the particular interest or personal bias of the physician. Many of the patients are middle-aged women, who also have the equally vague chronic fatigue
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syndrome (myalgic encephalopathy). Some relief is afforded by local anesthetic injections, administration of local coolants, stretching of underlying muscles (“spray
and stretch”), massage, etc., but the results in any given individual are unpredictable and the status of the disorder is not settled.
References
LaRocca H: Acceleration injuries of the neck. Clin Neurosurg 25:209, 1978. [PMID: 101328] Layzer RB: Hot feet: Erythromelalgia and related disorders. J Child Neurol 16:199, 2001. [PMID: 11305688] Leffert RD: Thoracic outlet syndrome, in Omer G, Springer M (eds): Management of Peripheral Nerve Injuries. Philadelphia, Saunders, 1980. Leyshon A, Kirwan EO, Parry CB: Electrical studies in the diagnosis of compression of the lumbar root. J Bone Joint Surg Br 63B:71, 1981. [PMID: 7204478] Lilius G, Laasonen EM, Myllynen P, et al: Lumbar facet joint syndrome: A randomized clinical trial. J Bone Joint Surg Br 71:681, 1989. [PMID: 2527856] Long DM: Low-back pain, in Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Disease, 5th ed. St. Louis, Mosby, 1997, pp 71–76. Lord SM, Barnsley L, Wallis BJ, et al: Percutaneous radio-frequency neurotomy for chronic cervical zygoapophyseal joint pain. N Engl J Med 335:1721, 1996. [PMID: 8929263] Love JG, Schorn VG: Thoracic-disc protrusions. JAMA 191:627, 1965. [PMID: 14242418] Matthews WB: The neurological complications of ankylosing spondylitis. J Neurol Sci 6:561, 1968. [PMID: 4303835] Malleson A: Whiplash and Other Useful Illnesses. Montreal, McGillQueen’s University Press, 2002. McCall IW, Park WM, O’Brian JP: Induced pain referral from posterior lumbar elements in normal subjects. Spine 4:441, 1979. [PMID: 161074] Meade TW, Dyer S, Browne W, et al: Low back pain of mechanical origin: Randomised comparison of chiropractic and hospital outpatient treatment. BMJ 300:1431, 1990. [PMID: 2143092] Michiels JJ, Van Joost TH, Vuzevski VD: Idiopathic erythromelalgia: A congenital disorder. J Am Acad Dermatol 21:1128, 1989. [PMID: 2808845] Mikhael MA, Ciric I, Tarkington JA, et al: Neurologic evaluation of lateral recess syndrome. Radiology 140:97, 1981. [PMID: 7244248] Mixter WJ, Barr JS: Rupture of the intervertebral disc with involvement of the spinal canal. N Engl J Med 211:210, 1934. Ochoa JL: Pain mechanisms and neuropathy. Curr Opin Neurol 7:407, 1994. [PMID: 7804461] Peul WC, van Houweilingen HC, van den Hout WB, et al: Surgery versus prolonged conservative treatment for sciatica. N Engl J Med 356:356, 2007. [PMID: 17538084] Postacchini F, Urso S, Ferro L: Lumbosacral nerve-root anomalies. J Bone Joint Surg Am 64A:721, 1982. [PMID: 7085697] Powell MC, Szypryt P, Wilson M, et al: Prevalence of lumbar disc degeneration observed by magnetic resonance in symptomless women. Lancet 2:1366, 1986. [PMID: 2878228] Quiles M, Marchisello PJ, Tsairis R: Lumbar adhesive arachnoiditis: Etiologic and pathologic aspects. Spine 3:45, 1978. [PMID: 644392] Reynolds AF, Weinstein PR, Wachter RD: Lumbar monoradiculopathy due to unilateral facet hypertrophy. Neurosurgery 10:480, 1982. [PMID: 7099396] Salvarini C, Cantini F, Boiardi L, Hunder GG: Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 347: 261, 2002. [PMID: 12140303] Sano S, Itami S, Yoshikawa K: Treatment of primary erythromelalgia with cyclosporine. N Engl J Med 349:816, 2003. [PMID: 12930941]
Abbott KH, Mitts MG: Reflex neurovascular syndromes, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, vol 8. Amsterdam, North-Holland, 1970, pp 321–356. Carette S, Leclaire R, Marcoux S, et al: Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Engl J Med 336:1634, 1997. [PMID: 9171065] Carette S, Marcoux S, Truchon R, et al: A controlled trial of corticosteroid injections into facet joints for chronic low back pain. N Engl J Med 325:1002, 1991. [PMID: 1832209] Cherkin DC, Devo RA, Battiè M: A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain. N Engl J Med 339:1021, 1998. [PMID: 9761803] Collier B: Treatment for lumbar sciatic pain in posterior articular lumbar joint syndrome. Anaesthesia 34:202, 1979. [PMID: 443519] Coppes MH, Marani E, Thomeer RTWM: Innervation of annulus fibrosus in low back pain. Lancet 1:189, 1990. [PMID: 1973516] Cuckler JM, Bernini PA, Wiesel SW, et al: The use of epidural steroids in the treatment of lumbar radicular pain. J Bone Joint Surg Am 67:63, 1985. [PMID: 3155742] Davis MD, Sandroni P, Rooke TW, Law PA: Erythromelalgia: Vasculopathy, neuropathy, or both. Arch Dermatol 139:1337, 2003. [PMID: 14568838] Epstein NE, Epstein JA, Carras R, Hyman RA: Far lateral lumbar disc herniations and associated structural abnormalities: An evaluation in 60 patients of the comparative value of CT, MRI and myelo-CT in diagnosis and management. Spine 15:534, 1990. [PMID: 2402692] Evans BA, Stevens JC, Dyck PJ: Lumbosacral plexus neuropathy. Neurology 31:1327, 1981. [PMID: 6287351] Finneson BE: Low Back Pain, 2nd ed. Philadelphia, Lippincott, 1981. Friis ML, Bulliksen GC, Rasmussen P: Distribution of pain with nerve root compression. Acta Neurochir (Wien) 39:241, 1977. [PMID: 602854] Hadler NM, Curtis P, Gillings DB: A benefit of spinal manipulation as adjunctive therapy for acute low-back pain: A stratified controlled trial. Spine 12:703, 1987. [PMID: 2961085] Hagen KD, Hilde G, Jamtveldt G, Winnem MF: The Cochrane review of bed rest for acute low back pain. Spine 25:2932, 2000. [PMID: 11074682] Hassler O: The human intervertebral disc: A micro-angiographical study on its vascular supply at various ages. Acta Orthop Scand 40:765, 1970. [PMID: 5394000] Hudgkins WR: The crossed straight leg raising sign (of Fajersztajn). N Engl J Med 297:1127, 1977. Jensen MC, Brant-Zawadzki MN, Obuchowski N, et al: Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 331:69, 1994. [PMID: 8208267] Kellgren JH: On the distribution of pain arising from deep somatic structures with charts of segmental pain areas. Clin Sci 4:35, 1939. Kelsey JL, White AA: Epidemiology and impact of low back pain. Spine 5:133, 1980. [PMID: 6446158] Kopell HP, Thompson WA: Peripheral Entrapment Neuropathies. Baltimore, Williams & Wilkins, 1963. Kristoff FV, Odom GL: Ruptured intervertebral disc in the cervical region. Arch Surg 54:287, 1947. Lance JW: The red ear syndrome. Neurology 47:617,1996. [PMID: 8797453]
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Shannon N, Paul EA: L4/5, L5/S1 disc protrusions: Analysis of 323 cases operated on over 12 years. J Neurol Neurosurg Psychiatry 42:804, 1979. [PMID: 501380] Sinclair DC, Feindel WH, Weddell G, et al: The intervertebral ligaments as a source of segmental pain. J Bone Joint Surg 30B:515, 1948. Tarlov IM: Perineurial cysts of the spinal nerve roots. Arch Neurol Psychiatry 40:1067, 1938. Tudler MW, Cherkin DC, Berman B, et al: Acupuncture for low back pain. Cochrane Database Syst Rev 2:CD001351, 2000. [PMID: 10796434] van Gelderen C: Ein orthotisches (lordotisches) Kaudasyndrom. Acta Psychiatr Neurol Scand 23:57, 1948. Verbiest H: A radicular syndrome from developmental narrowing of the lumbar vertebral canal. J Bone Joint Surg Br 36B:230, 1954. [PMID: 13163105] Vroomen P, DeKrom M, Wilmink JT, et al: Lack of effectiveness of bed rest for sciatica. N Engl J Med 340:418, 1999. [PMID: 9971865] Weinstein JN, Tosteson TD, Lurie JD, et al: Surgical versus nonsurgical treatment for lumbar spinal stenosis. N Engl J Med 358:794, 2008. [PMID: 18287602]
Weinstein JN, Tosteson TD, Lurie JD, et al: Surgical vs nonoperative treatment for lumbar disk herniation. The spine patients outcomes research trial (SPORT): a randomized trial. JAMA 296:2441, 2006. [PMID: 17119140] Weir BKA, Jacobs GA: Reoperation rate following lumbar discectomy. Spine 5:366, 1980. [PMID: 7455766] White AH, Derby R, Wynne G: Epidural injections for the diagnosis and treatment of low-back pain. Spine 5:78, 1980. [PMID: 6444766] Wilbourn AJ: The thoracic outlet syndrome is overdiagnosed. Arch Neurol 47:328, 1990. [PMID: 2310317] Wilbourn AJ: Thoracic outlet syndromes: Plea for conservatism. Neurosurg Clin N Am 2:235, 1991. [PMID: 1821733] Wray CC, Easom S, Hoskinson J: Coccydynia: Aetiology and treatment. J Bone Joint Surg Br 73B:335, 1991. [PMID: 2005168] Yiannikas C, Walsh JC: Somatosensory evoked responses in the diagnosis of the thoracic outlet syndrome. J Neurol Neurosurg Psychiatry 46:234, 1983. [PMID: 6842231] Yoss RE, Corbin KB, MacCarty CS, Love JG: Significance of symptoms and signs in localization of involved root in cervical disc protrusion. Neurology 7:673, 1957. [PMID: 13477342]
CHAPTER 12 CHAPTER 13 CHAPTER 14 CHAPTER 15
Disorders of Smell and Taste Disturbances of Vision Disorders of Ocular Movement and Pupillary Function Deafness, Dizziness, and Disorders of Equilibrium
The four chapters in this section are concerned with the clinical aspects of the highly specialized functions of taste and smell, vision, hearing, and the sense of balance. These special senses and the cranial nerves that subserve them represent the most finely developed parts of the sensory nervous system. Dysfunction of the eye and ear are, of course, the domain of the ophthalmologist and otologist, but they also are of great interest to the neurologist. Some defects in the special sensory apparatus reflect the presence of systemic disease and others represent the initial or leading manifestation of neurologic disease. It is from both these points of view that they are considered here. In keeping with the general scheme of this text, the disorders of the special senses and of ocular movement are discussed in a particular sequence: first, certain facts of anatomic and physiologic importance, followed by cardinal clinical manifestations of disease, and then a consideration of the syndromes of which these manifestations are a part.
SECTION 3
Disorders of the Special Senses
12 Disorders of Smell and Taste
The sensations of smell (olfaction) and taste (gustation) are suitably considered together. Physiologically, these modalities share the singular attribute of responding primarily to chemical stimuli; i.e., the end organs that mediate olfaction and gustation are chemoreceptors. Also, taste and smell are interdependent clinically as the appreciation of the flavor of food and drink depends to a large extent on their aroma, and an abnormality of one of these senses is frequently misinterpreted as an abnormality of the other. In comparison to sight and hearing, taste and smell play a less-evident role in the life of the individual. However, the role of chemical stimuli in communication between humans is probably very important for some functions and has not been fully explored. Pheromones (pherein, “to carry”; hormon, “exciting”), that is, odorants exuded from the body as well as perfumes, play a part in sexual attraction; noxious body odors repel. Agosta has provided an extensive review of this aspect of the subject. In certain vertebrates the olfactory system is remarkably well developed, rivaling the sensitivity of the visual system, but it has been stated that even humans, in whom the sense of smell is relatively weak, have the capacity to discriminate between as many as 10,000 different odorants (Reed). Clinically, disorders of taste and smell can be persistently unpleasant, but only rarely is the loss of either of these modalities a serious handicap. Nevertheless, as all foods and inhalants pass through the mouth and nose, these two senses serve to detect noxious odors (e.g., smoke) and to avoid tainted food and potential poisons. The loss of these senses could then have serious consequences. Also, because a loss of taste and smell may signify a number of intracranial, neurodegenerative, and systemic disorders, they assume clinical importance.
OLFACTORY SENSE Anatomic and Physiologic Considerations Nerve fibers subserving the sense of smell have their cells of origin in the mucous membrane of the upper and posterior parts of the nasal cavity (superior turbinates and nasal septum). The entire olfactory mucosa covers an area of about 2.5 cm2 and contains three cell types: the olfactory or receptor cells, which number between 6 and 10 million
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in each nasal cavity; sustentacular or supporting cells, which maintain the electrolyte (particularly K) levels in the extracellular milieu; and basal cells, which are stem cells and the source of both the olfactory and sustentacular cells during regeneration. The olfactory cells are actually bipolar neurons. Each of these cells has a peripheral process (the olfactory rod) from which project 10 to 30 fine hairs, or cilia. These hair-like processes, which lack motility, are the sites of olfactory receptors. The central processes of these cells, or olfactory fila, are very fine (0.2 mm in diameter) unmyelinated fibers that converge to form small fascicles enwrapped by Schwann cells that pass through openings in the cribriform plate of the ethmoid bone into the olfactory bulb (Fig. 12-1). Collectively, the central processes of the olfactory receptor cells constitute the first cranial (olfactory nerve). Notably, this is the only site in the body where neurons are in direct contact with the external environment. The epithelial surface is covered by a layer of mucus, which is secreted by tubuloalveolar cells (Bowman glands) and within which there are immunoglobulins A and M, lactoferrin, and lysoenzyme as well as odorant-binding proteins. These molecules are thought to prevent the intracranial entry of pathogens via the olfactory pathway (Kimmelman). In the olfactory bulb, the receptor-cell axons synapse with granule cells and mitral cells (so-called because they are triangular, like a bishop’s miter), the dendrites of which form brush-like terminals or olfactory glomeruli (Fig. 12-1). Smaller “tufted” cells in the olfactory bulb also contribute dendrites to the glomerulus. Approximately 15,000 olfactory-cell axons converge on a single glomerulus. This high degree of convergence is thought to account for an integration of afferent information. The mitral and tufted cells are excitatory; the granule cells—along with centrifugal fibers from the olfactory nuclei, locus ceruleus, and piriform cortex—inhibit mitral cell activity. Presumably, interaction between these excitatory and inhibitory neurons provides the basis for the special physiologic aspects of olfaction. The axons of the mitral and tufted cells form the olfactory tract, which courses along the olfactory groove of the cribriform plate to the cerebrum. Lying caudal to the olfactory bulbs are groups of cells that constitute the anterior olfactory nucleus (Fig. 12-1). Dendrites of these cells synapse with fibers of the olfactory tract, while their axons
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Amygdaloid nucleus Anterior olfactory nucleus Interior granule cell Anterior perforated space
Olfactory bipolar cell
Anterior commissure
Septal area
Medial olfactory stria Cell of anterior olfactory nucleus
Intermediate olfactory striae
Internal granule cell Mitral cell
Olfactory glomerulus Olfactory neuron
Nasal mucous Gyrus rectus membrane Anterior commissure Diagonal band Lamina terminalis
Olfactory bulb Olfactory tract
Lateral olfactory stria
Medial olfactory stria Lateral olfactory stria Anterior perforated substance
Primary olfactory cortex
Figure 12-1. Diagram illustrating the relationships between the olfactory receptors in the nasal mucosa and neurons in the olfactory bulb and tract. Cells of the anterior olfactory nucleus are found in scattered groups caudal to the olfactory bulb. Cells of the anterior olfactory nucleus make immediate connections with the olfactory tract. They project centrally via the medial olfactory stria and to contralateral olfactory structures via the anterior commissure. Inset: diagram of the olfactory structures on the inferior surface of the brain (see text for details).
project to the olfactory nucleus and bulb of the opposite side; these neurons are thought to function as a reinforcing mechanism for olfactory impulses. Posteriorly, the olfactory tract divides into medial and lateral olfactory striae. The medial stria contains fibers from the anterior olfactory nucleus; these pass to the opposite side via the anterior commissure. Fibers in the lateral stria originate in the olfactory bulb, give off collaterals to the anterior perforated substance, and terminate in the medial and cortical nuclei of the amygdaloid complex and the prepiriform area (also referred to as the lateral olfactory gyrus). The latter represents the primary olfactory cortex, which in humans occupies a restricted area on the anterior end of the parahippocampal gyrus and uncus (area 34 of Brodmann; see Figs. 22-1 and 22-2). Thus olfactory impulses reach the cerebral cortex without relay through the thalamus; in this respect also, olfaction is unique among sensory systems. From the prepiriform cortex, fibers project to the neighboring entorhinal cortex (area 28 of Brodmann) and the medial dorsal nucleus of the thalamus; the amygdaloid nuclei connect with the hypothalamus and septal nuclei. The role of these latter structures in olfaction is not well understood, but presumably they subserve reflexes related to eating and sexual
function. As with all sensory systems, feedback regulation occurs at every point in the afferent olfactory pathway. In quiet breathing, little of the air entering the nostril reaches the olfactory mucosa; sniffing carries the air into the olfactory crypt. To be perceived as an odor, an inhaled substance must be volatile—i.e., spread in the air as very small particles—and soluble in water. Molecules provoking the same odor seem to be related by their shape than by their chemical quality. When a jet of scented vapor is directed to the sensory epithelium, as by sniffing, a slow negative potential shift called the electroolfactogram (EOG) can be recorded from an electrode placed on the mucosa. The conductance changes that underlie this receptor potential are induced by molecules of odorous material dissolved in the mucus overlying the receptor. The transduction of odorant stimuli to electrical signals is mediated in part by a guanosine triphosphate (GTP)dependent adenylyl cyclase (“G protein”). Like other cyclic adenosine monophosphate (AMP) pathways, this one utilizes an intracellular second messenger; but in the case of olfaction, the responsible molecule has not been identified. There follow conformational changes in transmembrane receptor proteins and a series of intracellular biochemical events that generate axon potentials.
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Intensity of olfactory sensation is determined by the frequency of firing of afferent neurons. The quality of the odor is thought to be provided by “cross-fiber” activation and integration, as described earlier, because the individual receptor cells are responsive to a wide variety of odorants and exhibit different types of responses to stimulants— excitatory, inhibitory, and on–off responses have been obtained. The olfactory potential can be eliminated by destroying the olfactory receptor surface or the olfactory filaments. The loss of EOG occurs 8 to 16 days after severance of the nerve; the receptor cells disappear, but the sustentacular (Sertoli) cells are not altered. As a result of division of the basal cells of the olfactory epithelium, the olfactory receptor cells are constantly dying and being replaced by new ones. In this respect the chemoreceptors, both for smell and for taste, constitute one of the few examples of neuronal regeneration in humans. The trigeminal system also participates in chemesthesis through undifferentiated receptors in the nasal mucosa. These receptors have little discriminatory ability but a great sensitivity to all irritant stimuli. The trigeminal afferents also release neuropeptides that result in hypersecretion of mucus, local edema, and sneezing. Finally, stimulation of the olfactory pathway at cortical sites of the temporal lobe may also induce olfactory experiences. The olfactory system adapts quickly to a sensory stimulus, and for sensation to be sustained, there must be repeated stimulation. The olfactory sense differs from other senses in yet another way. It is common experience that an aroma can restore long-forgotten memories of complex experiences. That olfactory and emotional stimuli are strongly linked is not surprising in view of their common roots in the limbic system. Yet, paradoxically, the ability to recall an odor is negligible in comparison with the ability to recall sounds and sights. As Vladimir Nabokov has remarked: “Memory can restore to life everything except smells.” It is also interesting that dreams do not embody olfactory experiences. The remarkable evolutionary role of these receptors can be appreciated by the fact that about 2 percent of the human genome exists to express unique odorant receptors (over 500 distinct genes). The wide diversity of these transmembrane proteins permits subtle differentiation of thousands of different odorant molecules, as outlined by Young and Trask. This specificity for molecules is encoded neuroanatomically. Different odorant molecules activate specific olfactory receptors. Each olfactory neuron expresses only one allele of one receptor gene. Moreover, each olfactory glomerulus receives inputs from neurons expressing only one type of odorant receptor. In this way, each of the glomeruli is attuned to a distinct type of odorant stimulus. Presumably, this encoding is preserved in the olfactory cortex. Something is to be learned from olfaction in lower vertebrates, which have a second, physically distinct olfactory system (the vomeronasal olfactory system or organ of Jacobson), in which the repertoire of olfactory receptors is much more limited than in their main olfactory system. This functionally and anatomically distinct olfactory tissue is attuned to, among other odorants, pheromones and thereby importantly influences menstrual, reproductive,
ingestive, and defensive behavior (see review of Wysocki and Meredith). The vomeronasal receptors employ different signaling mechanisms than other olfactory receptors and project to the hypothalamus and amygdala via a distinct accessory olfactory bulb.
Clinical Manifestations of Olfactory Lesions Disturbances of olfaction may be subdivided into four groups, as follows: 1. Quantitative abnormalities: loss or reduction of the sense of smell (anosmia, hyposmia) or, rarely, increased olfactory acuity (hyperosmia) 2. Qualitative abnormalities: distortions or illusions of smell (dysosmia or parosmia) 3. Olfactory hallucinations and delusions caused by temporal lobe disorders or psychiatric disease 4. Higher-order loss of olfactory discrimination (olfactory agnosia)
Anosmia or Loss of the Sense of Smell (Table 12-1) This is the most frequent clinical abnormality and, if unilateral, usually is not recognized by the patient. Unilateral anosmia can sometimes be demonstrated in the hysterical patient on the side of anesthesia, blindness, or deafness. Bilateral anosmia is a common complaint, and the patient is usually convinced that the sense of taste has been lost as well (ageusia). This calls attention to the fact that taste depends largely on the volatile particles in foods and beverages, which reach the olfactory receptors through the nasopharynx, and that the perception of flavor is a combination of smell, taste, and tactile sensation. This can be proved by demonstrating that patients with anosmia but without a complaint of ageusia are able to distinguish the elementary taste sensations on the tongue (sweet, sour, bitter, and salty). The olfactory defect can be verified readily enough by presenting a series of nonirritating olfactory stimuli (vanilla, peanut butter, coffee, tobacco, etc.), first in Table 12-1 MAIN CAUSES OF ANOSMIA Nasal Smoking Chronic rhinitis (allergic, atrophic, cocaine, infectious—herpes, influenza) Overuse of nasal vasoconstrictors Olfactory epithelium Head injury with tearing of olfactory filaments Cranial surgery Subarachnoid hemorrhage, meningitis Toxic (organic solvents, certain antibiotics-aminoglycosides, tetracyclines, corticosteroids, methotrexate, opiates, L-dopa) Metabolic (thiamine deficiency, adrenal and thyroid deficiency, cirrhosis, renal failure, menses) Wegener granulomatosis Compressive and infiltrative lesions (craniopharyngioma, meningioma, aneurysm, meningoencephalocele) Central Degenerative diseases (Parkinson, Alzheimer, Huntington) Temporal lobe epilepsy Malingering and hysteria
CHAPTER 12
one nostril, then in the other, and asking the patient to sniff once and identify them. If the odors can be detected and described, even if they cannot be named, it may be assumed that the olfactory nerves are relatively intact (humans can distinguish many more odors than they can identify by name). If they cannot be detected, there is an olfactory defect. Ammonia and similar pungent substances are unsuitable stimuli because they do not test the sense of smell but have a primary irritating effect on the mucosal free nerve endings of the trigeminal nerves. The value of testing smell in one nostril at a time has been questioned, for example by Welge-Luessen and colleagues, who studied olfactory groove meningiomas. They found, contrary to expectations, that this test was not sensitive to the presence of a unilateral lesion ostensibly because of mixing of air in the nasopharynx. Nonetheless, other experience suggests that rapidly sniffing through one nostril does briefly allow segregation of each side of the nasal cavities and can detect unilateral lesions. A more elaborate scratch-and-sniff test has been developed and standardized by Doty and colleagues (University of Pennsylvania Smell Identification Test). In this test the patient attempts to identify 40 microencapsulated odorants and his olfactory performance is compared with that of ageand sex-matched normal individuals. Unique features of this test are a means for detecting malingering and amenability to self-administration. Air-dilution olfactory detection is a more refined way of determining thresholds of sensation and of demonstrating normal olfactory perception in the absence of odor identification. The use of olfactory evoked potentials is being investigated in some electrophysiology laboratories, but their reliability is uncertain. These refined techniques are essentially research tools and are not used in neurologic practice. The loss of smell usually falls into one of three categories: nasal (in which odorants do not reach the olfactory receptors), olfactory neuroepithelial (caused by destruction of receptors or their axon filaments), and central (olfactory pathway lesions). In an analysis of 4,000 cases of anosmia from specialized clinics, Hendriks found that three categories of pathology—viral infection of the upper respiratory tracts (the largest group), nasal or paranasal sinus disease, and head injury—accounted for most of the cases. Regarding the nasal diseases responsible for bilateral hyposmia or anosmia, the most frequent are those in which hypertrophy and hyperemia of the nasal mucosa prevent olfactory stimuli from reaching the receptor cells. Heavy smoking is probably the most frequent cause of hyposmia in clinical practice. Chronic atrophic rhinitis; sinusitis of allergic, vasomotor, or infective types; nasal polyposis; and overuse of topical vasoconstrictors are other common causes. Biopsies of the olfactory mucosa in cases of allergic rhinitis have shown that the sensory epithelial cells are still present, but their cilia are deformed and shortened, and are buried under other mucosal cells. Influenza, herpes simplex, and hepatitis virus infections may be followed by hyposmia or anosmia caused by destruction of receptor cells; if the basal cells are also destroyed, this may be permanent. These cells may also be affected as a result of atrophic rhinitis and local radiation therapy or by a rare type of tumor (esthesioneuroblastoma) that originates in the
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olfactory epithelium. There is also a group of uncommon diseases in which the primary receptor neurons are congenitally absent or hypoplastic and lack cilia. One of these is the Kallmann syndrome of congenital anosmia and hypogonadotropic hypogonadism. A similar disorder occurs in Turner syndrome and in albinos because of an ill-defined congenital structural defect. Anosmia that follows head injury is most often a result of tearing of the delicate filaments of the receptor cells as they pass through the cribriform plate, especially if the injury is severe enough to cause fracture. The damage may be unilateral or bilateral. With closed head injury, complete anosmia is relatively infrequent (6 percent of Sumner’s series of 584 cases) but lesser degrees are common in our experience. Some recovery of olfaction occurs in about one-third of cases over a period of several days to months. Beyond 6 to 12 months, recovery is negligible. Cranial surgery, subarachnoid hemorrhage, and chronic meningeal inflammation may have similar effects. In some of the cases of traumatic anosmia, there is also a loss of taste (ageusia). Ferrier, who first described traumatic ageusia in 1876, noted that there was always anosmia as well—an observation subsequently corroborated by Sumner. Often the ageusia clears within a few weeks. A bilateral lesion near the frontal operculum and paralimbic region, where olfactory and gustatory receptive zones are in close proximity, would best explain this concurrence, but this has not been proven. As stated earlier, the interruption of olfactory filaments alone would explain a reduction in the ability to perceive the subtleties of specific tastes, but not ageusia. In women, olfactory acuity varies throughout the menstrual cycle and may be disordered during pregnancy. Nutritional and metabolic diseases such as thiamine deficiency (Wernicke disease), vitamin A deficiency, adrenal and perhaps thyroid insufficiency, cirrhosis, and chronic renal failure may give rise to transient anosmia, all as a result of sensorineural dysfunction. A large number of toxic agents— the more common ones being organic solvents (benzene), metals, dusts, cocaine, corticosteroids, methotrexate, aminoglycoside antibiotics, tetracyclines, opiates, and L-dopa— can damage the olfactory epithelium (Doty et al). Hyman and colleagues have remarked on the early neuronal degeneration in the region of the hippocampus in cases of Alzheimer disease. Moreover a large proportion of patients with other degenerative diseases of the brain have anosmia or hyposmia. Included in this group are Parkinson, Huntington, and Pick diseases and the Parkinson-dementia syndrome of Guam. A number of theories have been proposed to explain the loss of smell, the most relevant of which is based on the finding that the earliest neuropathologic changes of many neurodegenerative processes begin in olfactory structures and then spread to neighboring structures, only later reaching the parts of the brain that produces the characteristic neurologic features of these diseases. The studies relating to olfaction in Parkinson disease have been reviewed by Doty and by Braak and colleagues. The reverse, however, is not the case; i.e., the majority of individuals with hyposmia do not have a generalized neurodegenerative disease. It has been known for some time that alcoholics with Korsakoff psychosis have a defect in odor discrimination
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(Mair et al). In this disorder, anosmia is presumably caused by degeneration of neurons in the higher-order olfactory systems involving the medial thalamic nuclei. Anosmia has been found in some patients with temporal lobe epilepsy and particularly in such patients who had been subjected to anterior temporal lobectomy. In these conditions, Andy and coworkers have found an impairment in discriminating the quality of odors and in matching odors with test objects seen or felt. As with other sensory modalities, olfaction (and taste) is diminished with aging (presbyosmia). The receptor cell population is depleted, and if the loss is regional, neuroepithelium is slowly replaced with respiratory epithelium (which is normally present in the nasal cavity and serves to filter, humidify, and warm incoming air). Neurons of the olfactory bulb may also be reduced as part of the aging process. Bilateral anosmia has been a manifestation of malingering, now that it has been recognized as a compensable disability. The fact that true anosmics will complain inordinately of a loss of taste (but show normal taste sensation) may help to separate them from malingerers. If it were to be perfected, testing of olfactory evoked potentials would be of use here. The nasal epithelium or the olfactory nerves themselves may be affected in Wegener granulomatosis and by craniopharyngioma respectively. A meningioma of the olfactory groove may implicate the olfactory bulb and tract and may extend posteriorly to involve the optic nerve, sometimes with optic atrophy; if combined with papilledema on the opposite side, these abnormalities are known as the Foster Kennedy syndrome (see Chap. 13). A large aneurysm of the anterior cerebral or anterior communicating artery may produce a similar constellation. With tumors confined to one side, the anosmia may be strictly unilateral, in which case it will not be reported by the patient but will be found on examination. The limitations of testing each side of the nose separately have been mentioned earlier. These defects in the sense of smell are attributable to lesions of either the receptor cells and their axons or the olfactory bulbs, and current test methods do not distinguish between lesions in these two localities. In some cases of increased intracranial pressure, olfactory sense has been impaired without evidence of lesions in the olfactory bulbs. The term specific anosmia has been applied to an unusual olfactory phenomenon in which a person with normal olfactory acuity for most substances encounters a particular compound or class of compounds that is odorless to him, although obvious to others. In a sense, this is a condition of “smell blindness,” analogous to color blindness. The basis of this disorder is unclear, although there is evidence that specific anosmia for musky and uriniferous odors is inherited as an autosomal recessive trait (see Amoore). Whether a true hyperosmia exists is a matter of conjecture. Anxious highly introspective individuals may complain of being unduly sensitive to odors, but there is no proof of an actual change in their threshold of perception of odors. During migraine attacks and in some cases of aseptic meningitis, the patient may be unusually sensitive
not only to light and sound but sometimes to odors as well.
Dysosmia or Parosmia These terms refer to distortions of odor perception where an odor is present. Parosmia may occur with local nasopharyngeal conditions such as empyema of the nasal sinuses and upper respiratory infections. In some instances the abnormal tissue itself may be the source of unpleasant odors; in others, where partial injuries of the olfactory bulbs have occurred, parosmia is in the nature of an olfactory illusion. Parosmia may also be a troublesome symptom in middle-aged and elderly persons with a depressive illness, who may report that every article of food has an extremely unpleasant odor (cacosmia). Sensations of disagreeable taste are often associated (cacogeusia). Nothing is known of the basis of this state; there is usually no loss of discriminative sensation. The treatment of parosmia is difficult. The use of neuroleptic or antiepileptic drugs has given unpredictable results. Claims for the efficacy of zinc and vitamins have not been verified (and there is a risk that zinc administration may interfere with the absorption of copper). Some reports indicate that repeated anesthetization of the nasal mucosa reduces or abolishes the parosmic disturbance. In many cases the disorder subsides spontaneously. Minor degrees of parosmia are not necessarily abnormal, for unpleasant odors have a way of lingering for several hours and of being reawakened by other olfactory stimuli (phantosmia), as every pathologist knows.
Olfactory Hallucinations These are always of central origin. The patient perceives an odor that no one else can detect (phantosmia). Most often this is because of temporal lobe seizures (“uncinate fits”), in which circumstances the olfactory hallucinations are brief and accompanied by an alteration of consciousness and other manifestations of epilepsy (see Chap. 16 on epilepsy). If the patient is convinced of the presence of what is in fact a hallucination and also gives it personal origin, the symptom assumes the status of a delusion. The combination of olfactory hallucinations and delusions of this type signifies a psychiatric illness. Zilstorff wrote informatively on this subject. There is often a complaint of a large array of odors, most of them noxious and seemingly emanating from the patient (intrinsic hallucinations); in others, they are attributed to an external source (extrinsic hallucinations). Both types vary in intensity and are remarkable with respect to their persistence. They may be combined with gustatory hallucinations. According to Pryse-Phillips, who took note of the psychiatric illness in a series of 137 patients with olfactory hallucinations, most were associated with endogenous depression and schizophrenia. In schizophrenia, the olfactory stimulus is usually interpreted as arising externally and as being induced by someone for the purpose of upsetting the patient. In depression, the perception is of the stimulus being intrinsic. The patient may go to great lengths to rid himself of the perceived stench, the usual ones being excessive wash-
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ing and use of deodorants; the condition may lead to social withdrawal. There is reason to believe that the amygdaloid group of nuclei is the source of the hallucinations, as stereotactic lesions here have reportedly abolished both the olfactory hallucinations and the psychiatric disorder (see Chitanondh). Olfactory hallucinations and delusions may occur in conjunction with Alzheimer dementia but one should also consider the possibility of an associated late-life depression.
Loss of Olfactory Discrimination (Olfactory Agnosia) Finally, one must consider a disorder in which the primary perceptual aspects of olfaction (detection of odors, adaptation to odors, and recognition of different intensities of the same odor) are intact but the capacity to distinguish between odors and their recognition by quality is impaired or lost. In the writings on this subject, this deficit is usually referred to as a disorder of olfactory discrimination. In dealing with other sense modalities, however, the inability to identify and name a perceived sensation would be called an agnosia. To recognize this deficit requires special testing, such as matching to sample, the identification and naming of a variety of scents, and determining whether two odors are identical or different. Such an alteration of olfactory function has been shown to characterize patients with the alcoholic form of Korsakoff psychosis; this impairment is not attributable to impaired olfactory acuity or to failure of learning and memory (Mair et al). As indicated above, the olfactory disorder in the alcoholic Korsakoff patient is most likely caused by lesions in the medial dorsal nucleus of the thalamus; several observations in animals indicate that this nucleus and its connections with the orbitofrontal cortex give rise to deficits in odor discrimination (Mair et al; Slotnick and Kaneko). Eichenbaum and associates demonstrated a similar impairment of olfactory capacities in a patient who had undergone extensive bilateral medial temporal lobe resections. The operation was believed to have eliminated a substantial portion of the olfactory afferents to the frontal cortex and thalamus, although there was no anatomic verification of this. In patients with stereotactic or surgical amygdalotomies, Andy and coworkers noted a similar reduction in odor discrimination. Thus it appears that both portions of the higher olfactory pathways (medial temporal lobes and medial dorsal nuclei) are necessary for the discrimination and identification of odors.
GUSTATORY SENSE Anatomic and Physiologic Considerations The sensory receptors for taste (taste buds) are distributed over the surface of the tongue and, in smaller numbers, over the soft palate, pharynx, larynx, and esophagus. Mainly they are located in the epithelium along the lateral surfaces of the circumvallate and foliate papillae and to a lesser extent on the surface of the fungiform papillae. The taste buds are round or oval structures, each composed of up to 200 vertically oriented receptor cells arranged like
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the staves of a barrel. The superficial portion of the bud is marked by a small opening, the taste pore or pit, which opens onto the mucosal surface. The tips of the sensory cells project through the pore as a number of filiform microvilli (“taste hairs”). Fine, unmyelinated sensory fibers penetrate the base of the taste bud and synapse directly with the sensory taste cells, which have no axons. The taste receptors are activated by chemical substances in solution and transmit their activity along the sensory nerves to the brainstem. There are four primary and readily tested taste sensations that have been long known: salty, sweet, bitter, and sour; recently a fifth, umani—the taste of glutamate, aspartate, and certain ribonucleotides—has been added. The full range of taste sensations is much broader, consisting of combinations of these elementary gustatory sensations. Older notions of a “tongue map,” which implied the existence of specific areas subserving one or another taste, are incorrect. Any one taste bud is capable of responding to a number of sapid substances, but it is always preferentially sensitive to one type of stimulus. In other words, the receptors are only relatively specific. The sensitivity of these receptors is remarkable: as little as 0.05 mg/dL of quinine sulfate will arouse a bitter taste when applied to the base of the tongue. In recent years, a G-protein transduction system (gustducin), similar to the one for olfaction, has been found to be operative in signaling taste sensations in the tongue receptors. A discussion of this system can be found in the commentary by Brand. The receptor cells of the taste buds have a brief life cycle (about 10 days), being replaced constantly by mitotic division of adjacent basal epithelial cells. The number of taste buds, not large to begin with, is gradually reduced with age; also, changes occur in the taste cell membranes, with impaired function of ion channels and receptors (Mistretta). Gustatory (and olfactory) acuity diminishes with age (everything begins to taste and smell the same). According to Schiffman, taste thresholds for salt, sweeteners, and amino acids are 2 to 2.5 times higher in the elderly than in the young. The reduction in the acuity of taste and smell with aging may lead to a distortion of food habits (e.g., excessive use of salt and other condiments) and contribute to the anorexia and weight loss of elderly persons. Richter has explored the biologic role of taste in normal nutrition. Animals made deficient in sodium, calcium, certain vitamins, proteins, etc., will automatically select the correct foods, on the basis of their taste, to compensate for their deficiency. Interesting genetic polymorphisms in the receptor for sweet substances in rats have been found to underlie differences in the proclivity to ingest sweet substances, and a similar system has been proposed in humans (Chaudhari and Kinnamon).
Neural Innervation of Tongue Regions Sensory impulses for taste arise from several sites in the oropharynx and are transmitted to the medulla via several cranial nerves (V, VII, IX, and X). The main pathway arises on the anterior two-thirds of the tongue; these taste fibers first run in the lingual nerve (a major branch of the mandibular-trigeminal [V] cranial nerve). After coursing
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within the lingual nerve for a short distance, the taste fibers diverge to enter the chorda tympani (a branch of the seventh nerve); thence they pass through the pars intermedia and geniculate ganglion of the seventh nerve to the rostral part of the nucleus of the tractus solitarius in the medulla, where all taste afferents converge (see below and Fig. 47-3). From the posterior third of the tongue, soft palate, and palatal arches, the sensory taste fibers are conveyed via the glossopharyngeal (IX) nerve and ganglion nodosum to the nucleus of the tractus solitarius. Taste fibers from the extreme dorsal part of the tongue and the few that arise from taste buds on the pharynx and larynx run in the vagus nerve. The gustatory nucleus is situated in the rostral and lateral parts of the nucleus tractus solitarius, which receive the special afferent (taste) fibers from the facial and glossopharyngeal nerves. Probably both sides of the tongue are represented in this nucleus. Fibers from the palatal taste buds pass through the pterygopalatine ganglion and greater superficial petrosal nerve, join the facial nerve at the level of the geniculate ganglion, and proceed to the nucleus of the solitary tract (see Fig. 47-3). Possibly, some taste fibers from the tongue may also reach the brainstem via the mandibular division of the trigeminal nerve. The presence of this alternative pathway probably accounts for reported instances of unilateral taste loss that have followed section of the root of the trigeminal nerve and instances in which no loss of taste has occurred with section of the chorda tympani. The second sensory neuron for taste has been difficult to track. Neurons from the gustatory segment of the nucleus solitarius project to adjacent nuclei (e.g., dorsal motor nucleus of the vagus, ambiguus, salivatorius superior and inferior, trigeminal, and facial nerves), which serve viscerovisceral and viscerosomatic reflex functions, but those concerned with the conscious recognition of taste are currently considered to form an ascending pathway to a pontine parabrachial nucleus. From the latter, two ascending pathways have been traced (in animals). One is the solitariothalamic lemniscus to the ventroposteromedial nucleus of the thalamus. A second passes to the ventral parts of the forebrain, to parts of the hypothalamus (which probably influences autonomic function), and to other basal forebrain limbic areas in or near the uncus of the temporal lobe. Other ascending fibers lie near the medial lemniscus and are both crossed and uncrossed. Experiments in animals indicate that taste impulses from the thalamus project to the tongue–face area of the postrolandic sensory cortex. This is probably the end station of gustatory projections in humans as well, insofar as gustatory hallucinations have been produced by electrical stimulation of the parietal and/or rolandic opercula (Hausser-Hauw and Bancaud). Penfield and Faulk evoked distinct taste sensations by stimulating the anterior insula.
Clinical Manifestations Testing of Taste Sensation Unilateral gustatory impairment can be identified by withdrawing the tongue with a gauze sponge and using a moistened applicator to place a few crystals of salt, sugar, lemon (sour), and quinine (bitter)
on discrete parts of the tongue; the tongue is then wiped clean and the subject is asked to report what he had sensed. One use of such testing is to corroborate the existence of a complete but mundane Bell’s palsy by comparing taste sensation on each side of the anterior tongue (Chap. 47). A stimulus that has been used as a surrogate for sour sensation is a low-voltage direct current, the electrodes of which can be accurately placed on the tongue surface. If the taste loss is bilateral, mouthwashes with a dilute solution of sucrose, sodium chloride, citric acid, and quinine may be used. After swishing, the test fluid is spit out and the mouth rinsed with water. The patient indicates whether he had tasted a substance and is asked to identify it. Special types of apparatus (electrogustometers) have been devised for the measurement of taste intensity and for determining the detection and recognition thresholds of taste and olfactory stimuli (Krarup; Henkin et al), but these are beyond the scope of the usual clinical examination.
Causes of Loss of Taste Apart from the loss of taste sensation that accompanies normal aging (see above), smoking is probably the most common cause of impairment of taste sensation. Extreme drying of the tongue from any cause may lead to temporary loss or reduction of the sense of taste (ageusia or hypogeusia), as saliva is essential for normal taste function. Saliva acts as a solvent for chemical substances in food and for conveying them to taste receptors. Dryness of the mouth (xerostomia) from inadequate saliva, as occurs in Sjögren syndrome; hyperviscosity of saliva, as in cystic fibrosis; irradiation of head and neck; and pandysautonomia all interfere with taste. Also, in familial dysautonomia (Riley-Day syndrome), the number of circumvallate and fungiform papillae is reduced, accounting for a diminished ability to taste sweet and salty foods. If unilateral, ageusia is seldom the source of complaint. Taste is frequently lost over the anterior two-thirds of one side of the tongue in cases of mundane Bell’s palsy, as indicated above and in Chap. 47. A permanent decrease in the acuity of taste and smell (hypogeusia and hyposmia), sometimes associated with perversions of these sensory functions (dysgeusia and dysosmia), may follow influenza-like illnesses. These abnormalities have been associated with pathologic changes in the taste buds as well as in the nasal mucous membranes. In a group of 143 patients who presented with hypogeusia and hyposmia, 87 were of this postinfluenzal type, as determined by Henkin and colleagues; the remainder developed their symptoms in association with scleroderma, acute hepatitis, viral encephalitis, myxedema, adrenal insufficiency, malignancy, deficiency of vitamins B and A, and the administration of a wide variety of drugs. Also, according to Schiffman, more than 250 drugs have been implicated in the alteration of taste sensation. Lipid-lowering drugs, antihistamines, antimicrobials, antineoplastics, bronchodilators, antidepressants, and anticonvulsants are the main offenders, but little is known about the mechanisms by which drugs induce these effects. More obvious is altered taste because of nasally and orally administered inhalant drugs, including the “triptans” for migraine and a variety of antiallergy and antiasthmatic medications.
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Distortions of taste and loss of taste are sources of complaint in patients with certain local malignant tumors. Oropharyngeal tumors may, of course, abolish taste by invading the chorda tympani or lingual nerves. Malnutrition because of neoplasm or radiation therapy may also cause ageusia. Some patients with certain carcinomas remark on a reduced perception for bitter foods, and some who have been radiated for breast cancer or sublingual or oropharyngeal tumors find sour foods intolerable. The loss of taste from radiation of the oropharynx is usually recovered within a few weeks or months; the reduced turnover of taste buds caused by radiation therapy usually recovers. An interesting syndrome of idiopathic hypogeusia—in which decreased taste acuity is associated with dysgeusia, hyposmia, and dysosmia—has been described by Henkin, Schechter, et al. Food has an unpleasant taste and aroma, to the point of being revolting (cacogeusia and cacosmia); the persistence of these symptoms may lead to a loss of weight, anxiety, and depression. Zinc supplements are contained in over-the-counter and complementary medical products aimed at improving smell and appetite and for the treatment of incipient colds. We have had no opportunity to confirm the often-cited benefits of zinc on any of these conditions, but the supporting evidence is sparse. Another poorly defined disorder is the burning mouth syndrome, which occurs mainly in postmenopausal women and is characterized by persistent, severe intraoral pain (particularly of the tongue). We have seen what we believe to be fragmentary forms of the syndrome in which pain and burning are isolated to the alveolar ridge or gingival mucosa. The oral mucosa appears normal and some patients may report a diminution of taste sensation. A small number of such patients prove to have diabetes,
Sjögren syndrome, or vitamin B12 deficiency (causing glossitis), but in most no systemic illness or local abnormality can be found. The few such patients that we have encountered appeared to have a depressive illness, but they responded variably to administration of antidepressants. A few patients have this complaint as a component of a small fiber neuropathy or ganglionopathy (Chap. 46). Clonazepam may be useful and capsaicin has been tried with uncertain results. This disorder is commented on in Chap. 10. Unilateral lesions of the medulla oblongata have not been reported to cause ageusia, perhaps because the nucleus of the tractus solitarius is usually outside the zone of infarction or because there is representation from both sides of the tongue in each nucleus. Unilateral thalamic and parietal lobe lesions, however, have both been associated with contralateral impairment of taste sensation in rare cases. As indicated above, a gustatory aura occasionally marks the beginning of a seizure originating in the frontoparietal (suprasylvian) cortex or in the uncal region. Gustatory hallucinations are much less frequent than olfactory ones. Nevertheless, gustatory sensations were reported in 30 of 718 cases of intractable epilepsy (Hausser-Hauw and Bancaud). During surgery, these investigators produced an aura of disagreeable taste by electrical stimulation of the parietal and frontal opercula and also by stimulation of the hippocampus and amygdala (uncinate seizures). In their view, the low-threshold seizure focus for taste in the temporal lobe is secondary to functional disorganization of the opercular gustatory cortex by the seizure. Gustatory hallucinations were more frequent with right-hemisphere lesions, and in half of the cases, the gustatory aura was followed by a convulsion.
References
Taste in Health and Disease. New York, Raven Press, 1991, pp 735– 751. Doty RL, Shaman P, Applebaum SL: Smell identification ability: Changes with age. Science 226:1441, 1984. [PMID: 6505700] Doty RL, Shaman P, Dann M: Development of University of Pennsylvania Smell Identification Test. Physiol Behav 32:489, 1984. [PMID: 6463130] Eichenbaum H, Morton TH, Potter H, Corkin S: Selective olfactory deficits in case H.M. Brain 106:459, 1983. [PMID: 6850278] Getchell TV, Bartoshuk LM, Doty RL, Snow JB Jr (eds): Smell and Taste in Health and Disease. New York, Raven Press, 1991. Hausser-Hauw C, Bancaud J: Gustatory hallucinations in epileptic seizures. Brain 110:339, 1987. [PMID: 3105808] Hendriks AP: Olfactory dysfunction. Rhinology 4:229, 1988. [PMID: 3070710] Henkin RI, Gill JR Jr, Bartter FC: Studies on taste thresholds in normal man and in patients with adrenal cortical insufficiency: The effect of adrenocorticosteroids. J Clin Invest 42:727, 1963. [PMID: 16695903] Henkin RI, Larson AL, Powell RD: Hypogeusia, dysgeusia, hyposmia and dysosmia following influenza-like infection. Ann Otol Rhinol Laryngol 84:672, 1975. [PMID: 1190677] Henkin RI, Schechter PJ, Hoye R, Mattern CFT: Idiopathic hypogeusia with dysgeusia, hyposmia, and dysosmia: A new syndrome. JAMA 217:434, 1971. [PMID: 5109029]
Agosta WC: Chemical Communication: The Language of Pheromones. New York, Scientific American Library, Freeman, 1992. Amoore JE: Specific anosmias, in Getchell TV, Bartoshuk LM, Doty RL, Snow JB (eds): Smell and Taste in Health and Disease. New York, Raven Press, 1991, pp 655–664. Andy OJ, Jurko MF, Hughes JR: The amygdala in relation to olfaction. Confin Neurol 37:215, 1975. [PMID: 1132230] Brand JG: Within reach of an end to unnecessary bitterness. Lancet 356:1371, 2000. [PMID: 11052575] Buck LB: Smell and taste: The chemical senses, in Kandel ER, Schwartz JH, Jessel TM (eds): Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000, pp 625–647. Braak H, Ghebremedhin E, Rub U, et al: Stages of development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121, 2004. [PMID: 15338272] Chitanondh H: Stereotaxic amygdalotomy in the treatment of olfactory seizures and psychiatric disorders with olfactory hallucinations. Confin Neurol 27:181, 1966. [PMID: 5334010] Chaudhari N, Kinnamon SC: Molecular basis of the sweet tooth? Lancet 358:210, 2001. [PMID: 11784621] Doty RL: Olfactory dysfunction in neurodegenerative disorders, in Getchell TV, Bartoshuk LM, Doty RL, Snow JB (eds): Smell and
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Hyman BT, van Hoesen GW, Damasio AR: Alzheimer disease: Cell specific pathology isolates the hippocampal formation. Science 225:1168, 1984. [PMID: 6474172] Kimmelman CP: Clinical review of olfaction. Am J Otolaryngol 14:227, 1993. [PMID: 8214314] Krarup B: Electrogustometry: A method for clinical taste examinations. Acta Otolaryngol 69:294, 1958. [PMID: 13570949] Mair R, Capra C, McEntee WJ, Engen T: Odor discrimination and memory in Korsakoff’s psychosis. J Exp Psychol 6:445, 1980. [PMID: 6447759] Mistretta CM: Aging effects on anatomy and neurophysiology of taste and smell. Gerontology 3:131, 1984. [PMID: 6595203] Penfield W, Faulk ME: The insula: Further observations on its function. Brain 78:445, 1955. [PMID: 13293263] Pryse-Phillips W: Disturbances in the sense of smell in psychiatric patients. Proc R Soc Med 68:26, 1975. [PMID: 1202481] Quinn NP, Rossor MN, Marsden CD: Olfactory threshold in Parkinson’s disease. J Neurol Neurosurg Psychiatry 50:88, 1987. [PMID: 3819760] Reed RR: The molecular basis of sensitivity and specificity in olfaction. Semin Cell Biol 5:33, 1994. [PMID: 8186395] Richter CP: Total self-regulatory functions in animals and human beings. Harvey Lect 38:63, 1942–1943.
Schiffman SS: Drugs influencing taste and smell perception, in Getchell TV, Bartoshuk LM, Doty RL, Snow RL (eds): Smell and Taste in Health and Disease. New York, Raven Press, 1991, pp 845–850. Schiffman SS: Taste and smell losses in normal aging and disease. JAMA 276:1357, 1997. [PMID: 9343468] Slotnick BM, Kaneko N: Role of mediodorsal thalamic nucleus in olfactory discrimination learning in rats. Science 214:91, 1981. [PMID: 7280684] Sumner D: Disturbances of the senses of smell and taste after head injuries, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 24. Amsterdam, North-Holland, 1975, pp 1–25. Sumner D: Post-traumatic ageusia. Brain 90:187, 1967. [PMID: 6023073] Welge-Luessen A, Temmel A, Quint C, et al: Olfactory function in patients with olfactory groove meningiomas. J Neurol Neurosurg Psychiatry 70:218, 2001. [PMID: 11160471] Wysocki CJ, Meredith H: The vomeronasal system, in Finger TE, Silver WL (eds): Neurobiology of Taste and Smell. New York, Wiley, 1987, pp 125–150. Young JM, Trask BJ. The sense of smell: Genomics of vertebrate odorant receptors. Hum Mol Genet 11:1153, 2002. [PMID: 12015274] Zilstorff W: Parosmia. J Laryngol Otol 80:1102, 1966. [PMID: 5927746]
13 Disturbances of Vision
The importance of the visual system is attested to by the magnitude of its representation in the central nervous system (CNS). A large part of the cerebrum is committed to vision, including the visual control of movement and the perception of printed words and the form and color of objects. The optic nerve, which is a CNS structure, contains more than a million fibers (compared to 50,000 in the auditory nerve). The visual system also has special significance in that study of this system has greatly advanced our knowledge of both the organization of all sensory neuronal systems and the relation of perception to cognition. Indeed, we know more about vision than about any other sensory function. The eyes, because of their diverse composition of epithelial, vascular, neural, and pigmentary tissues, are virtually a medical microcosm, susceptible to many diseases, and its tissues are available for inspection through a transparent medium. Because the eye is the sole organ of vision, impairment of visual function, expressed as defects in acuity and alterations of visual fields, obviously stands as the most frequent and important symptoms of eye disease. A number of terms are commonly used to describe visual loss. Amaurosis is a general term that refers to partial or complete loss of sight. Amblyopia refers to any monocular deficit in vision that occurs in the presence of normal ocular structures. A major cause of amblyopia is the suppression of vision from one eye during early childhood mainly caused by either strabismus, but also to anisometropia (a significant difference in refractive error), or by media opacities. Nyctalopia is the term for poor twilight or night vision and is associated with extreme myopia, cataracts, vitamin A deficiency, retinitis pigmentosa, and, often, color blindness. There are also a number of positive visual symptoms (phosphenes, visual illusions, and hallucinations), but they are generally less significant than symptoms of visual loss. Irritation, redness, photophobia, pain, diplopia and strabismus, changes in pupillary size, and drooping or closure of the eyelids are another group of major ocular symptoms and signs. The impairment of vision may be unilateral or bilateral, sudden or gradual, episodic or enduring. The common causes of failing eyesight vary with age. In infancy, congenital defects, retinopathy of prematurity, severe myopia, hypoplasia of the optic nerve, optic pits, and coloboma are the main causes. In childhood and ado-
lescence, nearsightedness or myopia, and amblyopia as a result of strabismus are the usual causes (see Chap. 14), although a pigmentary retinopathy or a retinal, optic nerve, or suprasellar tumor may begin at this age. In middle age, usually beginning in the fifth decade, a progressive loss of accommodation (presbyopia) is almost invariable (at this age, half or more of the amplitude of accommodative power is lost and must be replaced by plus lenses). Still later in life, cataracts, glaucoma, retinal vascular occlusion and detachments, macular degeneration, and tumor, unilateral or bilateral, are the most frequent causes of visual impairment. As a rule, episodic visual loss in early adult life, often hemianopic, is a result of migraine. The other important cause of transient (weeks) monocular visual loss in this age period is optic neuritis, often a harbinger of multiple sclerosis. Later in life, transient monocular blindness, or amaurosis fugax, lasting minutes to hours is more common; it is caused by vascular disease, particularly stenosis of the ipsilateral carotid artery. Amaurosis in the child or young adult may also be caused by systemic lupus erythematosus and the related antiphospholipid syndrome, or there may be no discernible cause. Table 13-1 lists the causes of episodic visual loss. Of course, at any age, diseases of the retina and of other components of the ocular apparatus are important causes of progressive visual loss, and the problem may at first be transient.
APPROACH TO THE PROBLEM OF VISUAL LOSS In the investigation of a disturbance of vision, one inquires as to what the patient means when he claims not to see properly, for the disturbance in question may vary from near- or farsightedness to diplopia, partial syncope, dizziness, or a hemianopia. Fortunately the patient’s statement can be checked by the measurement of visual acuity, which is the single most important part of the ocular examination. Inspection of the refractive media and the optic fundi—especially the macular region—the testing of pupillary reflexes, color vision, and the plotting of visual fields complete this part of the examination. Examination of the eye movements is also essential, particularly if
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Table 13-1 CAUSES OF EPISODIC VISUAL LOSS Adolescence and young adulthood Migraine Optic neuritis Papilledema Antiphospholipid antibody syndrome and systemic lupus erythematosus Early tumor compression of the optic nerve Takayasu aortic arteritis Viral neuroretinitis Idiopathic Adulthood Carotid stenosis or dissection Embolism to the retina Intrinsic central retinal artery atherosclerotic disease Temporal arteritis (generally over age 55) Glaucoma Papilledema
amblyopia predicated on an early life strabismus is suspected, as discussed in Chap. 14. In the measurement of distance visual acuity the Snellen chart, which contains letters (or numbers or pictures) arranged in rows of decreasing size, is used. Each eye is tested separately and, if glasses are required, glasses for distance, not reading glasses, should be worn. The letter at the top of the chart subtends 5 min of an arc at a distance of 200 ft (or roughly 60 m). The patient follows rows of letters that can normally be read at lesser distances. Acuity is reported as a nonmathematical fraction that represents the patient’s ability compared to that of a person with normal distance vision. Thus, if the patient can read only the top letter at 20 rather than the normal 200 ft, the acuity is expressed as 20/200, or if the distance is measured in meters rather than feet, as 6/60. If the patient’s eyesight is normal, the visual acuity will equal 20/20, or 6/6. Many persons, especially during youth, can read at 20 ft the line that can normally be read at 15 ft from the chart (20/15) and hence have better than “normal” vision. For bedside testing, a “near card” or newsprint held 14 in from the eyes can be used and the results expressed in a distance equivalent as if a distance chart had been used. Here, the Jaeger system is sometimes used (J1 is “normal” vision, corresponding to the line 20/25, J5 to 20/50, J10 to 20/100, J16 to 20/200, and so on). In young children, acuity can be estimated by having them mimic the examiner’s finger movements at varying distances or having them recognize and pick up objects of different sizes from varying distances. The Teller acuity cards test a child’s preference (and hence ability) to view cards with increasingly fine stripes. In most jurisdictions, a corrected acuity of 20/40 or better in one eye is required to obtain and retain a driver’s license. If the visual acuity (with glasses) is less than 20/20, either the refractive error has not been properly corrected or there is some other reason for the diminished acuity. The possibility of a nonrefractive error can usually be ruled out if the patient can read the 20/20 line (not the near card) through a pinhole in a cardboard held in front of the eye. The pinhole permits a narrow shaft of light to fall on the fovea (the area of greatest visual acuity) with-
out distortion by the curvature of the lens; this eliminates the eye’s optical system, thereby testing the macula alone, and should give an acuity of 20/20 if the structures of the ocular media (cornea, lens, aqueous and vitreous humors) are clear. Minor degrees of visual impairment may be disclosed by alternately stimulating each eye with a bright white or colored object, enabling the patient to compare the intensity of vision in the two eyes. Objects look less bright and colors less saturated when viewed by the faulty eye. Light entering the eye is focused by the biconvex lens onto the outer layer of the retina. Consequently, the cornea, fluid of the anterior chamber, lens, vitreous, and retina itself must be transparent. The clarity of these media can be determined ophthalmoscopically, and a complete examination requires that the pupil be dilated to at least 6 mm in diameter. This is accomplished by instilling two drops of 2.5 phenylephrine (Neo-Synephrine) and/or 0.5 to 1.0 percent tropicamide (Mydriacyl) in each eye after the visual acuity has been measured, the pupillary response recorded, and the intraocular pressure estimated. In elderly persons, lower concentrations of these mydriatics should be used. The mydriatic action of phenylephrine lasts for 3 to 6 h. Rarely, an attack of angle-closure glaucoma (manifesting itself by diminished vision, ocular pain, nausea, and vomiting) may be precipitated by pharmacologic pupillary dilatation; this requires the immediate attention of an ophthalmologist. By looking through a high-plus lens of the ophthalmoscope from a distance of 6 to 12 in, the examiner can visualize opacities in the refractive media; by adjusting the lenses from a high-plus to a zero or minus setting, it is possible to “depth-focus” from the cornea to the retina. Depending on the refractive error of the examiner, lenticular opacities are best seen within the range of +20 to +12. The retina comes into focus with +1 to +1 lenses. The illuminated pupil appears as a red circular structure (red reflex), the color being provided by blood in the capillaries of the choroid layer. If all the refractile media are clear, reduced vision that is uncorrectable by glasses is caused by a defect in the macula, the optic nerve, or parts of the brain with which they are connected. The main limit of direct ophthalmoscopy is its inability to visualize lesions in the retina that lie anterior to the equator of the globe; these are seen only by the indirect method.
NONNEUROLOGIC CAUSES OF REDUCED VISION It is hardly possible within the confines of this chapter to describe all the causes of opacification of the refractive media. Those with the most important medical or neurologic implications are briefly commented upon. Although changes in the refractive media do not involve neural tissue primarily, certain ones assume importance because they are often associated with neurologic disease and provide clues to its presence. In the cornea, the most common abnormality that reduces vision is scarring caused by trauma and infection. Ulceration and subsequent fibrosis may occur following recur-
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rent herpes simplex, herpes zoster, and trachomatous infections of the cornea, or with certain mucocutaneous-ocular syndromes (Stevens-Johnson, Reiter). Hypercalcemia secondary to sarcoidosis, hyperparathyroidism, and vitamin D intoxication or milk-alkali syndrome may give rise to precipitates of calcium phosphate and carbonate beneath the corneal epithelium, primarily in a plane corresponding to the interpalpebral fissure—so-called band keratopathy. Other causes include chronic uveitis, interstitial keratitis, corneal edema, lattice corneal dystrophy (amyloid deposition), and long-standing glaucoma. Polysaccharides are deposited in the corneas in some of the mucopolysaccharidoses (Chap. 37), and copper is deposited in the Descemet membrane in hepatolenticular degeneration (Kayser-Fleischer ring). Crystal deposits may be observed in multiple myeloma and cryoglobulinemia. The corneas are also diffusely clouded in certain lysosomal storage diseases (Chap. 37). Arcus senilis occurring at an early age (because of hyperlipidemia), sometimes combined with yellow lipid deposits in the eyelids and periorbital skin (xanthelasma), serves as a marker of atheromatous vascular disease. In the anterior chamber of the eye, a common problem is impediment to the outflow of aqueous fluid, associated with excavation of the optic disc and visual loss, i.e., glaucoma. In more than 90 percent of cases (of the open-angle type), the cause of this syndrome is unknown and a genetic factor is suspected. The drainage channels in this type appear normal. In approximately 5 percent of cases, the angle between iris and the peripheral cornea is narrow and blocked when the pupil is dilated (angle-closure glaucoma). In the remaining cases, the condition is a result of some disease process that blocks outflow channels— inflammatory debris of uveitis, red blood cells from hemorrhage in the anterior chamber (hyphema), new formation of vessels and connective tissue on the surface of the iris (rubeosis iridis), a relatively infrequent complication of ocular ischemia secondary to diabetes mellitus, retinal vein occlusion, or carotid artery occlusion. The visual loss is gradual in open-angle glaucoma and the eye looks normal, unlike the red, painful eye of angle-closure glaucoma. However, some cases of open-angle glaucoma may progress to rapid loss of vision. Intraocular pressures that are persistently above 20 mm Hg may damage the optic nerve over time. This may be manifest first as an arcuate defect in the upper or lower nasal field or as a paracentral field defect, which, if untreated, may proceed to blindness. The classic finding in glaucoma, termed the Bjerrum field defect, consists of an arcuate scotoma extending from the blind spot and sweeping around the macula to end in a horizontal line at the nasal equator. Other characteristic glaucomatous field patterns are winged extensions from the blind spot (Seidel scotoma) and a narrowing of the superior nasal quadrant that may progress to a horizontal edge, corresponding to the horizontal raphe of the retina (nasal step). The damage is at the optic nerve head, the optic disc appearing excavated and any pallor that is present extends only to the rim of the disc and not beyond, thus distinguishing it from other optic neuropathies. Elongation of the optic cup in the vertical axis is typical. It is now appreciated that elevated intraocular pressure is only a concurrent finding
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and a risk factor for glaucoma and that optic damage may be seen in patients with normal pressure. In the lens, cataract formation is the most common and mundane abnormality. The cause of the common type in the elderly is unknown. The “sugar cataract” of diabetes mellitus is the result of sustained high levels of blood glucose, which is changed in the lens to sorbitol, the accumulation of which leads to a high osmotic gradient with swelling and disruption of the lens fibers. Galactosemia is a much rarer cause, but the mechanism of cataract formation is similar, i.e., the accumulation of dulcitol in the lens. In hypoparathyroidism, lowering of the concentration of calcium in the aqueous humor is in some way responsible for the opacification of newly forming superficial lens fibers. Prolonged high doses of chlorpromazine and corticosteroids, as well as radiation therapy, induce lenticular opacities in some patients. Down syndrome and oculocerebrorenal syndrome (Chap. 38), spinocerebellar ataxia with oligophrenia (Chap. 39), and certain dermatologic syndromes (atopic dermatitis, congenital ichthyosis, incontinentia pigmenti) are also accompanied by lenticular opacities. Myotonic dystrophy (Chap. 50) and, rarely, Wilson disease (Chap. 37) are associated with special types of cataract. Subluxation of the lens, the result of weakening of its zonular ligaments, occurs in syphilis, Marfan syndrome (upward displacement), and homocystinuria (downward displacement). In the vitreous humor, hemorrhage may occur from rupture of a ciliary or retinal vessel. On ophthalmoscopic examination, the hemorrhage appears as a diffuse haziness of part or all of the vitreous or, if the blood is between the retina and the vitreous and displaces the latter rather than mixing with it, takes the form of a sharply defined clot. The common cause is rupture of newly formed vessels of proliferative retinopathy in patients with diabetes mellitus, but there are many others including orbital or cranial trauma, rupture of an intracranial aneurysm or arteriovenous malformation with high intracranial pressure, retinal vein occlusion, sickle cell disease, age-related macular degeneration, and retinal tears, in which the hemorrhage breaks through the internal limiting membrane of the retina. The most common vitreous opacities are benign “floaters” caused by the condensation of vitreous collagen fibers, which appear as darting gray flecks or threads with changes in the position of the eyes; they may be annoying or even alarming until the person stops looking for them. A sudden burst of flashing lights associated with an increase in floaters may mark the onset of retinal detachment. Patients complaining of bright flashes and spots in vision should be examined with the indirect ophthalmoscope to rule out tears, holes, or detachments. Another common occurrence with advancing age is shrinkage of the vitreous humor and retraction from the retina, causing persistent streaks of light, usually in the periphery of the visual field. These phosphenes, also known as Moore lightning streaks, had been thought to be quite benign, but they may indicate incipient retinal or vitreous tears or detachment, and their first appearance requires prompt evaluation by an ophthalmologist. They are most prominent on movement of the globe, on closure of the eyelids, at the moment of accommodation, with saccadic eye movements, and with sudden exposure to dark. The vitreous may also be infil-
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trated by lymphoma originating in the brain; biopsy by planar vitrectomy may be used to establish the diagnosis in those rare instances where the lymphoma is restricted to the eye; its presence can be inferred when there is vitreous cellular infiltration and also a brain lymphoma. The term uveitis refers to an infective or noninfective inflammatory disease that affects any of the uveal structures (iris, ciliary body, and choroid). According to Bienfang and colleagues, uveitis accounts for 10 percent of all cases of legal blindness in the United States. Infective causes of posterior uveitis (choroidal) are toxoplasmal and cytomegalic inclusion disease, occurring mainly in patients with AIDS and other forms of reduced immune function. Noninfective autoimmune types are also common in the adult. The inflammation may be in the anterior part of the eye or in the posterior part, behind the iris and extending to the retina and choroid. Anterior uveitis is sometimes linked to ankylosing spondylitis and the human leukocyte antigen (HLA) B-27 marker, sarcoidosis, and recurrent meningitis (Vogt-Koyanagi-Harada disease); the posterior forms are associated with sarcoidosis, Behçet disease, multiple sclerosis, and lymphoma. Retinal diseases, particularly age-related macular degeneration and diabetic retinopathy, are a more common cause of blindness than are neurologic diseases, as discussed further on, under “Other Diseases of the Retina.”
NEUROLOGIC CAUSES OF REDUCED VISION Certain anatomic and physiologic facts are requisite for an interpretation of the neurologic lesions that affect vision. Visual stimuli entering the eye traverse the inner layers of the retina to reach its outer (posterior) layer, which contains two classes of photoreceptor cells: the flask-shaped cones and the slender rods. The photoreceptors rest on a single layer of pigmented epithelial cells, which form the outermost surface of the retina. The rods and cones and pigmentary epithelium receive their blood supply from the capillaries of the choroid and, to a smaller extent, from the retinal arterioles. The rod cells contain rhodopsin, a conjugated protein in which the chromophore group is a carotenoid akin to vitamin A. The rods function in the perception of visual stimuli in subdued light (twilight or scotopic vision), and the cones are responsible for color discrimination and the perception of stimuli in bright light (photopic vision). Most of the cones are concentrated in the macular region, particularly in its central part, the fovea, and are responsible for the highest level of visual acuity. Traquair described the rapid falloff of acuity as the distance from the fovea increases as “an island of vision in a sea of blindness.” Specialized pigments in the rods and cones absorb light energy and transform it into electrical signals, which are transmitted to the bipolar cells of the retina and then, in turn, to the superficially (anteriorly) placed neurons, or ganglion cells (Fig. 13-1). There are no ganglion cells in the fovea. The axons of the retinal ganglion cells, as they stream across the inner surface of the retina, pursue an arcuate course. Being unmyelinated, they are not visible, although
fluorescein retinography shows a trace of their outlines; an experienced examiner, using a bright light and deep green filter, can visualize them through direct ophthalmoscopy. The axons of ganglion cells are collected in the optic discs and then pass uninterruptedly through the optic nerves, optic chiasm, and optic tracts to synapse in the lateral geniculate nuclei, the superior colliculi, the midbrain pretectum and the suprachiasmatic nucleus of the hypothalamus (Figs. 13-1 and 13-2). The fibers derived from macular cells form a discrete bundle that first occupies the temporal side of the disc and optic nerve and then assumes a more central position within the nerve (papillomacular bundle). These fibers are of smaller caliber than the peripheral optic nerve fibers and appear to be especially sensitive to toxic and metabolic injury. Damage to the papillomacular bundle produces the “cecocentral” scotoma (extending from fixation to the blind spot). It is important to keep in mind that the retinal ganglion cells and their axonic extensions are, properly speaking, an exteriorized part of the brain and that their pathologic reactions are the same as in other parts of the CNS. In the optic chiasm, the fibers derived from the nasal half of each retina decussate and continue in the optic tract with uncrossed temporal fibers of the other eye (Figs. 13-2 and 13-3). Thus interruption of the left optic tract causes a right hemianopic defect in each eye, i.e., a homonymous (left nasal and right temporal) field defect (Fig. 13-2D). In partial tract lesions, the visual defects in the two eyes may not be exactly congruent, as the tract fibers are not evenly admixed. Lesions at the junction of the optic nerve and chiasm, generally compressive in nature, may cause a small contralateral superotemporal quadrantic defect in addition to the expected central scotoma in the ipsilateral eye (“junctional scotoma,” Fig. 13-2B). The finding is explained by the compression of the tract and the nerve on the same side. It had been thought for many decades to result from compression of the Wilbrand knee, a bundle of fibers that turn back into the contralateral optic nerve before crossing in the chiasm, but it has since been related by Horton that the very existence of the bundle is merely an artifact of fixation in experimental material. The optic chiasm lies just above the pituitary gland and also forms part of the anterior wall of the third ventricle; hence the crossing fibers may be compressed from below by a pituitary tumor, a meningioma of the tuberculum sellae, or an aneurysm, and from above by a dilated third ventricle or craniopharyngioma. The resulting field defect is bitemporal (“bitemporal hemianopia”; Fig. 13-2C); if the lesion has an anterior extension, one optic nerve is also implicated, and there is a loss of full-field vision in that eye. Optic tract lesions, in comparison with chiasmatic and optic nerve lesions, are relatively rare. In albinism, there is an abnormality of chiasmatic decussation, in which a majority of the fibers cross to the other side. How this relates to the global albinic defect in pigmented epithelium is not known. Approximately 80 percent of the fibers of the optic tract terminate in the lateral geniculate body and synapse with the six laminae of its neurons. Three of these laminae (1, 4, 6), which constitute the large dorsal nucleus, receive crossed (nasal) fibers from the contralateral eye, and three (2, 3, 5) receive uncrossed (temporal) fibers from the ipsi-
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Light
Internal limiting membrane
Anterior
Nerve fiber layer Ganglion cell layer Inner plexiform layer Amacrine cell Müller cell Bipolar cells Horizontal cell
Inner nuclear layer Outer plexiform layer Figure 13-1. Diagram of the cellular elements of the retina. Light entering the eye anteriorly passes through the full thickness of the retina to reach the rods and cones (first system of retinal neurons). Impulses arising in these cells are transmitted by the bipolar cells (second system of retinal neurons) to the ganglion cell layer. The third system of visual neurons consists of the ganglion cells and their axons, which run uninterruptedly through the optic nerve, chiasm, and optic tracts, synapsing with cells in the lateral geniculate body. (Courtesy of Dr. E.M. Chester.)
Outer nuclear layer External limiting membrane Layer of rods and cones
lateral eye. Selective occlusion of both components of the dual blood supply to the lateral geniculate is a rarity (anterior or posterior choroidal arteries) but produces a characteristic wedge-shaped “sectoral field defect.” The geniculate cells project to the visual (striate) cortex of the occipital lobe, also called area 17 (Brodmann classification) or V1 (Fig. 13-4). Other optic tract fibers terminate in the pretectum and innervate both Edinger-Westphal nuclei, which subserve pupillary constriction and accommodation (see Fig. 14-7). A small group of fibers terminate in the suprachiasmatic nuclei in animals and presumably also in humans. These anatomic details explain several useful clinical signs. If there is a lesion in one optic nerve, a light stimulus to the affected eye will have no effect on the pupil of either eye, although the ipsilateral pupil will still constrict consensually, i.e., in response to a light stimulus from the normal eye. This is termed an afferent pupillary defect. In their course through the temporal lobes, the fibers from the lower and upper quadrants of each retina diverge. The lower ones arch around the anterior pole of the temporal horn of the lateral ventricle before turning posteriorly; the upper ones follow a more direct path through the white matter of the uppermost part of the temporal lobe (Fig. 13-2) and probably of the adjacent interior parietal lobe. Both groups of fibers merge posteriorly at the internal sagittal stratum. For these reasons, incomplete lesions of the genic-
Pigmented layer Posterior
ulocalcarine pathways (optic radiations) cause visual field defects that are partial and often not fully congruent (Fig. 13-2E and F). It is in Brodmann area 17, embedded in the medial lip of the occipital pole, that cortical processing of the retinogeniculate projections occurs. The receptive neurons are arranged in columns, some of which are activated by edges and forms and others by moving stimuli or by color. The neurons for each eye are grouped together and have concentric, center-surround receptive fields. The deep neurons of area 17 project to the secondary and tertiary visual areas of the occipitotemporal cortex of the same and opposite cerebral hemispheres and also to other multisensory parietal and temporal cortices. Several of these extrastriate connections are just now being identified. Separate visual systems are utilized in the perception of motion, color, stereopsis, contour, and depth perception. Conceptually, the flow of secondary visual processing can be divided into a ventral stream, which carries predominantly spatial information to the parietal lobe (“the where”) and a dorsal stream, which carries shape and color information to the temporal lobe (“the what”) as articulated by Levine and colleagues. The classic studies of Hubel and Wiesel have elucidated much of this visual cortical anatomy and physiology and their papers should be consulted for a fuller appreciation of the organization of the visual cortex.
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Temporal
Nasal
Nasal
Temporal
A
B A C B
C
D
D
E F
E
F
G
G H H
Figure 13-2. Diagram showing the effects on the fields of vision produced by lesions at various points along the optic pathway. A. Complete blindness in left eye from an optic nerve lesion. B. The usual effect is a left-junction scotoma in association with a right upper quadrantanopia. A left nasal hemianopia could occur from a lesion at this point but is rare. C. Chiasmatic lesion causing bitemporal hemianopia. D. Right homonymous hemianopia from optic tract lesion. E and F. Right superior and inferior quadrant hemianopia from interruption of visual radiations. G. Right homonymous hemianopia caused by lesion of occipital striate cortex. H. Hemianopia with macular sparing.
The normal development of the connections described above requires that the visual system be activated at each of several critical periods of development. The early deprivation of vision in one eye causes a failure of development of the geniculate and cortical receptive fields of that eye. Moreover, the cortical receptive fields of the seeing eye become abnormally large and usurp the monocular dominance columns of the blind eye (Hubel and Wiesel).
In children with a congenital cataract, the eye will remain amblyopic if the opacity is removed after a critical period of development. A severe strabismus in early life, especially an esotropia, will have the same effect (amblyopia ex anopsia). In regard to the vascular supply of the eye, the ophthalmic branch of the internal carotid artery supplies the retina, posterior (uveal) coats of the eye, and optic nerve head. This
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Lat. geniculate body Lateral ventricle Optic radiation Optic tract Calcarine area
Chiasm Optic nerve Temporal horn (Meyer’s loop) Temporal detour
Figure 13-3. The geniculocalcarine projection, showing the detour of lower fibers around the temporal horn. Note that a very small proportion of the pathway traverses the parietal lobe.
artery gives origin to the posterior ciliary arteries; the latter form a rich circumferential plexus of vessels (arterial circle of Zinn-Haller) located deep to the lamina cribrosa. This arterial circle supplies the optic disc and adjacent part of the distal optic nerve, the choroid, and the ciliary body; it anastomoses with the pial arterial plexus that surrounds the optic nerve. The other major branch of the ophthalmic artery is the central retinal artery. It supplies the inner retinal layers and issues from the optic disc, where it divides into four branches, each of which supplies a quadrant of the retina; it is these vessels and their branches that are visible by ophthalmoscopy. A short distance from the disc, these vessels lose their internal elastic lamina and the media (muscularis) becomes thin; they are properly classed as arterioles. The inner layers of the retina, including the ganglion and bipolar cells, receive their blood supply from these arterioles and their capillaries, whereas the deeper photoreceptor elements and the fovea are nourished by the underlying choroidal vascular bed, by diffusion through the retinal pigmented cells and the semipermeable Bruch membrane upon which they rest. In up to a third of the population, a small cilioretinal artery may arise from either the choroidal circulation or from the circle of Zinn-Haller and supply the macula. In the case of a central retinal artery occlusion, the presence of this vessel leads to the preservation of central acuity.
disc and provides for 95 percent of visual acuity) and to search the periphery of the retina through a dilated pupil. There are variations in the appearance of the normal macula and optic disc, and these may prove troublesome. A normal macula may be called abnormal because of a slight aberration of the retinal pigment epithelium, a few drusen, or a deep optic cup (see further on). With experience, the examiner can visualize the unmyelinated nerve
Nasal half of left retina
Temporal half of right retina
Right lateral geniculate nucleus
Visual area of right hemisphere
Abnormalities of the Retina As indicated above, the thin (100- to 350-mm) retinal sheet and the optic nerve head, into which all visual information flows, are exteriorized parts of the CNS and the only part of the nervous system that can be inspected directly. Common deficiencies in the funduscopic examination in cases of visual loss are failure to carefully inspect the macular zone (which is located 3 to 4 mm lateral to the optic
Figure 13-4. Diagrammatic depiction of the retinal projections, showing the disproportionately large representation of the macula in the lateral geniculate nucleus and visual (striate) cortex. (Redrawn by permission from Barr ML, Kiernan J: The Human Nervous System, 4th ed. Philadelphia, Lippincott, 1983.)
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fiber layer of the retina by using bright-green (red-free) illumination. This is most often helpful in detecting demyelinative lesions of the optic nerve, which produce a loss of discrete bundles of the radially arranged and arching bundles of retinal fibers as they converge to the disc. The normal optic disc varies in color, being paler in infants and in blond individuals, and the prominence of the lamina cribrosa (a sieve-like structure in the central and nasal part of the disc through which run the fascicles of unmyelinated axons of the retinal ganglion cells) differs from one individual to another. The absence of receptive elements in the optic disc accounts for the normal blind spot. The ganglion-cell axons normally acquire their myelin sheaths after penetration of the lamina cribrosa, but they sometimes do so in their intraretinal course, as they approach the disc. These myelinated fibers adjacent to the disc appear as white patches with fine-feathered edges and are a normal variant, not to be confused with exudates. In evaluating changes in the retinal vessels, one must remember that these are arterioles and not arteries. Since the walls of retinal arterioles are transparent, what is observed with the ophthalmoscope is a column of blood within them. The central light streak of many normal arterioles is thought to represent the reflection of light as it strikes the interface of the column of blood and the concave vascular wall. In arteriolosclerosis (usually coexistent with hypertension), the lumina of the vessels are segmentally narrowed because of fibrous tissue replacement of the media and thickening of the basement membrane. Straightening of the arterioles and venous compression by arterioles are other signs of hypertension and arteriolosclerosis. In this circumstance the vein is compressed by the thickened arteriole within the adventitial envelope shared by both vessels at the site of crossing. Progressive arteriolar disease, to the point of occlusion of the lumen, results in a narrow, white (“silver-wire”) vessel with no visible blood column. This change is associated most often with severe hypertension but may follow other types of occlusion of the central retinal artery or its branches (see descriptions and retinal illustrations further on). Sheathing of the venules, probably representing focal leakage of cells from the vessels, is reportedly observed in up to 25 percent of patients with the optic neuritis of multiple sclerosis, but we have only rarely been able to detect it. Arterial and venule sheathing are also seen in leukemia, sarcoid, Behçet disease, and other forms of vasculitis. In malignant hypertension there are, in addition to swelling of the optic nerve head and the retinal arteriolar changes noted above, a number of extravascular lesions: the so-called soft exudates or cotton-wool patches, sharply marginated and glistening “hard” exudates, and retinal hemorrhages. In many patients who show these retinal changes, analogous lesions are found in the brain (necrotizing arteriolitis and microinfarcts) and underlie hypertensive encephalopathy. The ophthalmoscopic appearance of retinal hemorrhage is determined by the structure of the particular tissue in which it occurs. In the superficial layer of the retina, they are linear or flame-shaped (“splinter” hemorrhages) because of their confinement by the horizontally coursing nerve fibers in that layer. These hemorrhages usually overlie and obscure
the retinal vessels. Round or oval (“dot-and-blot”) hemorrhages lie behind the vessels, in the outer plexiform layer of the retina (synaptic layer between bipolar cells and nuclei of rods and cones—Fig. 13-1); in this layer, blood accumulates in the form of a cylinder between vertically oriented nerve fibers and appears round or oval when viewed end-on with the ophthalmoscope. Rupture of arterioles on the inner surface of the retina—as occurs with ruptured intracranial saccular aneurysms, arteriovenous malformations, and other conditions causing sudden severe elevation of intracranial pressure—permits the accumulation of a sharply outlined lake of blood between the internal limiting membrane of the retina and the vitreous or hyaloid membrane (the condensed gel at the periphery of the vitreous body); this is the subhyaloid or preretinal hemorrhage, also termed Terson syndrome. Either the small superficial or deep retinal hemorrhage may show a central or eccentric pale (Roth) spot, which is caused by an accumulation of white blood cells, fibrin, histiocytes, or amorphous material between the vessel and the hemorrhage. This lesion is said to be characteristic of bacterial endocarditis, but it is also seen in leukemia and occasionally in embolic retinopathy caused by carotid disease. Cotton-wool patches, or soft exudates, like splinter hemorrhages, overlie and tend to obscure the retinal blood vessels. These patches, even large ones, rarely cause serious disturbances of vision unless they involve the macula. Soft exudates are in reality infarcts of the nerve fiber layer, caused by occlusion of precapillary arterioles; they are composed of clusters of ovoid structures called cytoid bodies, representing the terminal swellings of interrupted axons. Hard exudates appear as punctate white or yellow bodies; they lie in the outer plexiform layer, behind the retinal vessels, like the punctate hemorrhages. If present in the macular region, they are arranged in lines radiating toward the fovea (macular star). Hard exudates consist of lipid and other serum precipitants as a result of abnormal vascular permeability of a type that is not completely understood. They are observed most often in cases of diabetes mellitus and chronic hypertension. Drusen in the retina (colloid bodies) appear ophthalmoscopically as pale yellow spots and are difficult to distinguish from hard exudates except when they occur alone; as a rule, hard exudates are accompanied by other funduscopic abnormalities. Although retinal drusen may be a benign finding, in many cases they reflect an age-related macular degeneration and their accumulation in the macula eventually leads to significant visual loss. The source of retinal drusen is uncertain, but they may result from chronic inflammation generated by degeneration of the retinal pigment epithelium. Hyaline bodies, located on or near the optic disc, are also referred to as drusen but must be distinguished from those occurring peripherally. Drusen of the optic discs are probably mineralized residues of dead axons and can be seen on CT in some cases. Their main significance for neurologists is that they are often associated with anomalous elevation of the disc that can be mistaken for papilledema (Table 13-2) but they are for the most part, benign. Microaneurysms of retinal vessels appear as small, discrete red dots and are located in largest number in the paracentral region. They are most often a sign of diabetes
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Table 13-2 CAUSES OF OPTIC DISC SWELLING OPHTHALMIC ABNORMALITY
UNDERLYING CAUSE
Papilledema
Increased intracranial pressure
Anterior ischemic optic neuropathy
Infarction of disc and intraorbital optic nerve due to atherosclerosis or temporal arteritis Inflammatory changes in disc and intraorbital part of optic nerve— usually due to MS, sometimes to ADEM Congenital, familial
Optic neuritisa (“papillitis”)
Hyaline bodiesb (drusen)
VISUAL LOSS
ASSOCIATED SYMPTOMS
PUPILS
None or transient blurring; constriction of visual fields and enlargement of blind spot; findings almost always binocular Acute visual loss, monocular (usually); may be an altitudinal defect
Headache; signs of intracranial mass
Normal unless succeeded by optic atrophy
Headache with temporal arteritis
Afferent pupillary defect
Rapidly progressive visual loss; usually monocular
Tender globe, pain on ocular movement
Afferent pupillary defect
Usually none but may be slowly progressive Enlargement of blind spot or arcuate inferior nasal defect
Usually none; rarely transient visual obscurations
Normal
MS, multiple sclerosis; ADEM, acute disseminated encephalomyelitis. Optic neuritis affecting the retrobulbar portion of the nerve shows no funduscopic changes. b May be mistaken for papilledema (pseudopapilledema). a
mellitus, sometimes appearing before the usual clinical manifestations of that disease. The use of the red-free (green) light on the ophthalmoscope helps to pick out microaneurysms from the background. Microscopically, the aneurysms take the form of small (20- to 90-mm) saccular outpouchings from the walls of capillaries, venules, or arterioles. The vessels of origin of the aneurysms are invariably abnormal, being either acellular branches of occluded vessels or themselves occluded by fat or fibrin. The periphery of the retina may harbor a hemangioblastoma, which may appear during adolescence, before the more characteristic cerebellar lesion. A large retinal artery may be seen leading to it and there may be a large draining vein. Occasionally, retinal examination discloses the presence of a vascular malformation that may be coextensive with a much larger malformation of the optic nerve and basilar portions of the brain.
Ischemic Lesions of the Retina Transient ischemic attacks of visual loss, involving all or part of the field of vision of one eye, are referred to as amaurosis fugax or transient monocular blindness (TMB). They are common manifestations of atherosclerotic carotid stenosis but have other causes. Fortuitous inspection of the retina during an attack may show stagnation of arterial blood flow, which returns within seconds or minutes as vision is restored (Fisher). One or as many as 100 attacks may precede infarction of a cerebral hemisphere, or they may abate without adverse consequence. In one series of 80 such patients followed by Marshall and Meadows for 4 years, in an era prior to modern treatment of this condition, 16 percent developed permanent unilateral blindness, a completed hemispheral stroke, or both. Chapter 34 discusses this subject further. Occlusion of the internal carotid artery usually causes no disturbance of vision whatsoever provided that there are
adequate anastomotic branches from the external carotid artery in the orbit. Rarely, carotid occlusion with inadequate collateralization is associated with a chronic ischemic oculopathy, which may predominantly affect the anterior or posterior segment or both. In this case, insufficient circulation to the anterior segment is manifest by scleral vascular congestion, cloudiness of the cornea, anterior chamber flare, and low intraocular pressure, or sometimes high intraocular pressure if rubeosis iridis (neovascularization of the iris) occurs and compromises the outflow of aqueous humor. Ischemia of the posterior segment is manifest by circulatory changes in the retina and optic nerve and by venous stasis. Other neurologic signs of carotid disease may be present, for example, a local bruit. More often, ischemia of the retina can be traced to occlusion of the central retinal artery or its branches by thrombi or emboli—central retinal artery occlusion (often abbreviated CRAO). Occlusion of the main artery is attended by sudden blindness. The retina becomes opaque and has a gray-yellow appearance, the arterioles are narrowed, with segmentation of columns of blood and a cherry-red appearance of the fovea (Fig. 13-5). With occlusions of smaller branches of the central retinal artery by emboli, one may be able to see the occluding material. Most frequently observed are so-called Hollenhorst plaques—glistening, white-yellow atheromatous particles (Fig. 13-6) seen in 40 of 70 cases of retinal embolism in the series of Arruga and Sanders but are often an asymptomatic manifestation of carotid or aortic atherosclerosis. The remainder are white calcium particles from calcified aortic or mitral valves or atheroma of the great vessels, and red or white fibrin-platelet emboli from a number of sources, mostly undefined and perhaps from the heart or its valves. Emboli to retinal artery branches may be asymptomatic or associated with transient blindness and may be difficult to see without fluorescein retinography; most of these emboli soon disappear. Because central retinal artery occlu-
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Figure 13-5. Appearance of the fundus in central retinal artery occlusion. In addition to the paucity of blood flow in retinal vessels, the retina has a creamy gray appearance and there is a “cherry-red spot” at the fovea.
sion occurs as a consequence of giant cell arteritis, patients who are in their 50s or older should be screened for symptoms and signs of this condition. It has become routine in some centers to treat acute central retinal artery occlusion in an urgent manner with a number of methods in the hope that the embolus or thrombus will be propelled into more distal vessels. These treatments are generally aimed at lowering intraocular pressure (acetazolamide, carbon dioxide; paracentesis of the anterior chamber) or dilating or reestablishing flow in the retinal vessels. We can only offer the impression that these procedures have often not been successful, but some case series have suggested that local thrombolysis with intraarterial agents may be useful. A multicenter trial of thrombolysis is ongoing in Europe (the Eagle Study). Because the central retinal artery and vein share a common adventitial sheath, atheromatous plaques in the artery
Figure 13-6. Glistening “Hollenhorst plaque” occlusion of a superior retinal artery branch (arrow). These occlusions represent atheromatous particles or, less often, platelet-fibrin emboli. Some are asymptomatic and others are associated with segmental visual loss or are seen after central retinal artery occlusion.
Figure 13-7. Occlusion of the central retinal vein with suffusion of the veins, swelling of the disc, and florid retinal hemorrhages.
are said to be associated in some instances with thrombosis of the retinal vein. This results in a spectacular display of retinal lesions that differs from the picture of central retinal artery occlusion. The veins are engorged and tortuous, and there are multiple diffuse “dot-and-blot” and streaky linear retinal hemorrhages (Fig. 13-7). Retinal vein thrombosis is observed most frequently with diabetes mellitus, hypertension, and leukemia; less frequently with sickle cell disease; and rarely with multiple myeloma and macroglobulinemia in relation to the hyperviscosity that these two diseases cause. Sometimes no associated systemic disease can be identified, in which case the possibility of an orbital mass (e.g., optic nerve glioma) should always be considered. In retinal vein thrombosis, visual loss is variable and there may be recovery of useful vision. In cases where macular edema ensues, recovery may be enhanced by laser photocoagulation. Transitory retinal ischemia is observed occasionally as a manifestation of migraine; it has also occurred in polycythemia, hyperglobulinemia, antiphospholipid syndrome, hyperviscosity of any type, and sickle cell anemia. In younger persons, transient monocular blindness is relatively uncommon and the cause is often not immediately apparent. Ischemia related to the antiphospholipid antibody or “retinal migraine” is presumed to be responsible for many cases. Rarely, vasospasm of the central retinal artery may be implicated as a cause of transient monocular blindness, in which case the episodes may cease with the introduction of a calcium channel blocker, as reported by Winterkorn and colleagues. A common and critical cause of sudden monocular blindness, especially in elderly persons, is anterior ischemic optic neuropathy (AION). It is caused by disease of ciliary vessels that supply the optic nerve and is considered further on, in the discussion of diseases of the optic nerve. The retinal vessels in this condition usually have a normal appearance. In summary, sudden, painless, monocular loss of vision should always raise the question of either retinal ischemia, caused by occlusive disease of the central retinal artery or vein, or of ischemic optic neuropathy from disease of the
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ciliary vessels. Detachment of the retina and macular and vitreous hemorrhages are less common but relatively obvious causes.
Other Diseases of the Retina Aside from vascular lesions, tears and detachments of the retina may impair vision acutely. The most common form of detachment is an intraretinal one caused by separation of the pigment epithelium layer from the sensory retina with fluid accumulation through a tear or hole in the retina. In so-called traction detachment—observed in cases of premature birth or proliferative retinopathy secondary to diabetes or other vascular disease—contracting fibrous tissue pulls the retina from the choroid. Serous retinopathy, a cause of monocular visual disturbance in young or middle-aged males, may be associated with the use of corticosteroids. The entire perimacular zone is elevated by edema fluid. The condition may arise acutely or slowly. Metamorphopsia (distortion of vision) in one eye is a common presentation but acuity is not much impaired. The optic disc remains normal. The retinal change (leakage of vascular fluid into the subretinal space) causes a loss of visualization of the detail of the choroid and is demonstrated by fluorescein angiography or by optical coherence tomography. The condition tends to resolve over several months and is treated by laser to seal the sites of leakage. Chorioretinitis, generally the result of an infectious process, may cause difficulty in diagnosis. In a many patients the initial diagnosis had been retrobulbar neuritis. One cannot depend upon the appearance of a macular star (see above) for diagnosis. A large number of patients with AIDS develop retinal lesions of various types. Infarcts of the nerve-fiber layer (cotton-wool patches), hemorrhages, and perivascular sheathing are the usual findings. Toxoplasmosis is the most common infective lesion, followed in frequency by cytomegalovirus (CMV), but histoplasmosis, Pneumocystis carinii, herpes zoster, syphilis, and tuberculosis are well documented. CMV may cause a particularly severe necrotizing retinitis and permanent impairment of vision. Both the retina and choroid may be involved by these diseases, in which case the ophthalmoscopic picture is characteristic, showing the destruction of the “punched-out” lesions that exposes the whitish sclera, and deposits of black pigment. The choroid may also be the site of viral and noninfective inflammatory reactions, often in association with painful recurrent iridocyclitis and lacrimal inflammation. Degenerations of the retina are an important cause of chronic progressive visual loss. These assume several forms and may be associated with other neurologic abnormalities. The most frequent in youth and middle age is retinitis pigmentosa, a hereditary disease of the outer photoreceptor layer and subjacent pigment epithelium. The retina is thin, and there are fine deposits of black pigment in the shape of bone corpuscles, more in the periphery; later the optic discs become pale. The disorder is marked by constriction of the visual fields with relative sparing of central vision (“gunbarrel” vision), metamorphopsia (distorted vision), delayed recovery from glare, and nyctalopia (reduced twilight
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vision). The causes of retinitis pigmentosa and related retinal degenerations are diverse, too numerous to list here. Furthermore, these degenerations have been linked to deficits in more than 75 different genes. In one form of isolated retinitis pigmentosa, which follows an autosomal dominant pattern of inheritance, the gene for rhodopsin (a combination of vitamin A and the rod-cell protein opsin) produces a defective opsin, resulting in a diminution of rhodopsin, diminished response to light, and eventual degeneration of the rod cells (Dryja et al). Retinitis pigmentosa is associated with the Laurence-Moon-Biedl syndrome, with certain mitochondrial diseases (Kearns-Sayre syndrome, Chap. 38) and with a number of degenerative and metabolic diseases (e.g., Refsum disease) of the nervous system. Another early life hereditary retinal degeneration, characterized by massive central retinal lesions, is the autosomal recessive Stargardt form of juvenile tapetoretinal degeneration. Like retinitis pigmentosa, Stargardt disease may be accompanied by progressive spastic paraparesis or ataxia. Nonpigmentary retinal degeneration is a familiar feature of a number of rare syndromes and diseases, such as neuronal ceroid lipofuscinosis, Bassen-Kornzweig disease, Batten-Mayou disease, and others (see Chap. 37). Medications have emerged as a cause of retinal damage. Phenothiazine derivatives may conjugate with the melanin of the pigment layer, resulting in degeneration of the outer layers of the retina and a characteristic “bull’s-eye retinopathy” by fluorescein angiography. If these drugs are administered in high dosages for protracted periods, the patient should be tested frequently for defects in visual fields and color vision. Among drugs used to treat neurologic disease, vigabatrin is notable for causing retinal degeneration and a concentric restriction of the visual fields in almost half of exposed patients. Elevated levels of gamma-aminobutyric acid (GABA) in the retina are presumably the cause of toxicity. High-dose tamoxifen has caused toxicity in the retina, characterized by the deposition of refractile opacities and in more severe cases, by macular edema. A cancer-associated retinopathy (CAR) has been described in patients with an oat-cell carcinoma of the lung as a paraneoplastic illness (see Chap. 31). The typical presentation is of positive visual phenomenon and rapid bilateral visual loss. Antibodies against the recoverin protein, which modulates rhodopsin kinase, have been demonstrated in the serum of affected patients (Grunwald et al; Kornguth et al; Jacobson et al). More recently, a melanoma-associated retinopathy (MAR) that affects only rods has been described. These processes are further described in Chap. 31. Certain lysosomal diseases of infancy and early childhood are characterized by an abnormal accumulation of undegraded proteins, polysaccharides, and lipids in cerebral neurons, as well as in the macula and other parts of the retina (hence the terms storage diseases and cerebromacular degenerations). Corneal clouding, cherry-red spot and graying of the retina, and later optic atrophy are the observed ocular abnormalities. Chapter 37 discusses these diseases. In some of these retinal diseases, minimal changes in the pigment epithelium or other layers of the retina that reduce visual acuity may not be readily detected by oph-
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thalmoscopy. A test to expose such subtle retinal changes is to estimate the time required for recovery of visual acuity following light stimulation (macular photostress test). The test is conducted by shining a strong light through the pupil of an affected eye for 10 s and measuring the time necessary for the acuity to return to the pretest level (normally 50 s or less). With macular lesions, recovery time is prolonged, but with lesions of the optic nerve, it is not affected. This phenomenon may also be observed in the eye on the side of a carotid occlusion, in essence an ischemic retinopathy. Retinal diseases reduce or abolish the electrical activity generated by the outer layers of the retina, and this can be measured by the electroretinogram (ERG). Fluorescein retinography and various new imaging tests are now essential for proper diagnosis of retinal disease. Optical coherence tomography (OCT) uses reflected light to construct a high-resolution two-dimensional image of the retinal layers; it is able to demonstrate with remarkable resolution retinal edema, tears, macular holes, and the thinning of the retinal nerve fiber layer that follows optic neuropathy. Age-Related Macular Degeneration This is perhaps the most important cause of visual loss in the elderly. As agerelated macular degeneration (ARMD) begins to disturb vision, the straight lines on the Amsler grid are observed by the patient to be distorted. Examination discloses a central scotomata and an alteration of the retina around the macula. Central vision is at first distorted, then gradually diminishes, impairing reading, but these patients can still get about because of retained peripheral vision. The two most common types of macular degeneration are an atrophic “dry” type, which is a true pigmentary degeneration associated with retinal drusen, of unknown cause but with a genetic component, and an exudative “wet” type, which is the result of choroidal neovascularization that results in secondary macular damage. The wet form is amenable to laser treatment and to the injection into the orbit of ranibizumab, an antiangiogenic monoclonal antibody against vascular endothelial growth factor. Progression of the dry form may be slightly reduced by the use of antioxidants and zinc. The pathophysiology and treatment of ARMD have been more thoroughly reviewed by DeJong. Diabetic Retinopathy Although not strictly speaking a problem taken up by neurologists, this is such an important cause of reduced vision and blindness that the basic facts should be known to all physicians. The earliest changes are of microaneurysms and tiny intraretinal hemorrhages; these are present in almost all diabetics who have had type 1 disease for more than 20 years. Cottonwool spots and small hemorrhages appear as the retina becomes ischemic. Subsequently, there is a more threatening proliferative retinopathy that consists of the formation of new blood vessels and consequent leakage of proteins and blood. The proliferative feature occurs in half of type 1 diabetics and 10 percent of those who have had type 2 disease for 15 to 20 years. The new vessels can grow into the vitreous and hemorrhages from them may cause traction on the retina, which results in detachment. Serous visual loss may also be the result of macular edema. Reabsorption of the edema leads to the deposition of lipid
“hard exudates.” The maintenance of glucose control reduces the frequency and severity of retinopathy but does not prevent it. Elevated levels of vascular endothelial growth factor have been shown to be the involved in the pathophysiology of diabetic retinal neovascularization and recent studies show that improvement in neovascular leakage can be obtained, at least in the short term, with intravitreal injections of the antivascular endothelial growth factor (anti-VEGF) antibody, bevacizumab. The review of the subject by Frank is recommended.
Papilledema and Raised Intracranial Pressure Of the various abnormalities of the optic disc, papilledema or optic disc swelling has the greatest neurologic implication, for it signifies the presence of increased intracranial pressure. It must be made clear, however, that an ophthalmoscopic appearance identical to that of papilledema can be produced by infarction of the optic nerve head (the “papillopathy” of anterior ischemic optic neuropathy) and by inflammatory changes in the intraorbital portion of the optic nerve (“papillitis” or optic neuritis). Certain clinical and funduscopic findings, listed in Table 13-2 and described below, assist in distinguishing between these processes, although all share the basic feature of conspicuous optic disc swelling. In its mildest form, papilledema takes the form of only slight elevation of the disc and blurring of the disc margins, especially of the superior and inferior aspects, and a mild fullness of the veins in the disc. Subtle disc elevation is also indicated by a loss of definition of the vessels overlying the disc as they approach the disc margin from the periphery; this appearance is produced by edema in the adjacent retina. Because many normal individuals, especially those with hypermetropia, have ill-defined disc margins, the early stage of papilledema may be difficult to detect (Fig. 13-8). Pulsations of the retinal veins, best seen where the veins turn to enter the disc, will have disappeared by the time intracranial pressure is raised, but this finding is not
Figure 13-8. Mild papilledema with hyperemia of the disc and slight blurring of the disc margins.
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specific, as venous pulsations are not present in a proportion of normal individuals in the seated position. On the other hand, the presence of spontaneous venous pulsations is a reliable indicator of an intracranial pressure below 200 mm H2O and thus usually excludes papilledema (Levin). Fluorescein angiography, red-free fundus photos (which highlight the retinal nerve fibers), and newer imaging techniques alluded to above also may be helpful in detecting early edema of the optic discs. More severe degrees of papilledema appear as further elevation, or a “mushrooming” of the entire disc and surrounding retina. There is subtle or overt edema and obscuration of vessels at the disc margins and, in some instances, peripapillary hemorrhages (Fig. 13-9). When advanced as a result of raised intracranial pressure, papilledema is almost always bilateral, although it may be more pronounced on the side of an intracranial tumor. A purely unilateral edema of the optic disc is indicative of a perioptic meningioma or other tumor involving the optic nerve, but it can sometimes occur at an early stage of increased intracranial pressure. As the papilledema becomes chronic, elevation of the disc margin becomes less prominent and pallor of the optic nerve head, representing a dropout of nerve fibers (atrophy), becomes more evident (Fig. 13-10). Varying degrees of secondary optic atrophy remain in the wake of papilledema that has persisted for more than several days or weeks, leaving the disc pale, gliotic, and shrunken. Constriction in one quadrant of the nasal portion of the visual field is an early sign of the loss of nerve fibers from optic atrophy. Acute papilledema, while it may enlarge the blind spot slightly, does not greatly affect visual acuity (except tran-
Figure 13-9. Fully developed papilledema. The main characteristics are marked swelling and enlargement of the disc, vascular engorgement, obscuration of small vessels at the disc margin as a result of nerve fiber edema, and white “cotton-wool spots” that represent superficial infarcts of the nerve fiber layer.
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Figure 13-10. Chronic papilledema with beginning optic atrophy, in which the disc stands out like a champagne cork. The hemorrhages and exudates have been absorbed, leaving a glistening residue around the disc.
siently during spontaneous waves of increased intracranial pressure). Therefore, optic disc swelling in a patient with severely reduced vision cannot be attributed to papilledema; instead, intraorbital optic neuritis (papillitis) or infarction of the nerve head (ischemic optic neuropathy) must be present. The examiner is aided by the fact that papilledema because of raised intracranial pressure is generally bilateral, although, as mentioned earlier, the degree of disc swelling may not be symmetrical. In contrast, papillitis and infarction of the nerve head affect one eye, but there are exceptions to both of these statements. Also, the pupillary reaction to light is muted only with infarction and optic neuritis, not with acute papilledema (once secondary optic atrophy supervenes, the loss of afferent light reaction is indeed observed). The occurrence of papilledema on one side and optic atrophy on the other is referred to as the Foster Kennedy syndrome; it is typically caused by a frontal lobe tumor or an olfactory meningioma on the side of the atrophic disc. In its complete form, which is seen only rarely, there is also anosmia on the side of the optic atrophy. A more common cause of the same funduscopic appearance is the “pseudo-Foster Kennedy syndrome,” which occurs when papillitis in one eye occurs years after an optic neuropathy of the opposite one. Papilledema caused by infarction of the nerve head is characterized by extension of the swelling beyond the nerve head, as described below, whereas the papilledema of increased pressure is associated with peripapillary hemorrhages. Often these distinctions cannot be made on the basis of the funduscopic appearance alone, in which case the most reliable distinguishing feature is again the presence or absence of visual loss (Table 13-2). Papilledema caused by increased intracranial pressure must also be distinguished from combined edema of the optic nerve and retina, which typifies both malignant hypertension and posterior uveitis. Chronic papilledema, as occurs in pseudotumor cerebri (see Chap. 31), presents a special problem in diagnosis and represents a risk for permanent reduction in visual acuity from
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optic atrophy. In addition to testing visual acuity at regular intervals, our colleagues advise serial evaluation of the visual fields; a constriction of the nasal field, detectable by automated perimetry and tangent screen testing, is an early and ominous optic atrophy. The essential element in the pathogenesis of papilledema is an increase in pressure in the sheaths of the optic nerve, which communicate directly with the subarachnoid space of the brain. This was demonstrated convincingly by Hayreh (1964), who produced bilateral chronic papilledema in monkeys by inflating balloons in the subarachnoid space and then opening the sheath of one optic nerve; the papilledema promptly subsided on the operated side but not on the opposite side. The appearance of the swollen disc, however, has been ascribed to a blockage of axoplasmic flow in the optic nerve fibers (Minckler et al; Tso and Hayreh). It was found that compression of the optic nerve by elevated cerebrospinal fluid (CSF) pressure resulted in swelling of axons behind the optic nerve head and leakage of their contents into the extracellular spaces of the disc. In our opinion, the block in axonic flow alone could not account for the marked congestion of vessels and hemorrhages that accompany papilledema and a component of vascular congestion is likely. The mechanism of papilledema that on rare occasions accompanies spinal tumors, particularly oligodendrogliomas, and the Guillain-Barré syndrome is not entirely clear. Usually the CSF protein is more than 1,000 mg/100 mL, but this cannot be the entire or only explanation, as instances occur in which the protein concentration is only slightly elevated (also the concentration of protein in the ventricular and cerebral subarachnoid spaces is considerably lower than in the lumbar sac, where it is usually sampled; see Chap. 30). In other diseases that at times give rise to papilledema—e.g., chronic lung disease with hypercarbia, cancer with meningeal infiltration, or dural arteriovenous malformation—the mechanism is most often one of a generalized increase of intracranial pressure. Other causes of papilledema are cyanotic congenital heart disease and other forms of polycythemia, hypocalcemia though an obscure mechanism, and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; see Chap. 46).
Diseases of the Optic Nerves The optic nerves, which constitute the axonic projections of the retinal ganglion cells to the lateral geniculate bodies and superior colliculi can be inspected in the optic nerve head. Observable changes in the optic disc are therefore of particular importance. They may reflect the presence of raised intracranial pressure as already described; optic neuritis (“papillitis”); infarction of the optic nerve head; congenital defects of the optic nerves (optic pits and colobomas); hypoplasia and atrophy of the optic nerves; and glaucoma. Illustrations of these and other abnormalities of the disc and ocular fundus can be found in the atlas by E.M. Chester and in the text by Glaser. In general, optic neuropathies are distinguished from other causes of visual loss by a predominance of loss of color vision and by the presence of an afferent pupillary defect.
Table 13-2 lists the main causes of optic neuropathy, which are discussed in the following portions of this chapter.
Optic Neuritis (Papillitis; Retrobulbar Neuritis) (See Chap. 36) This inflammatory process causes acute impairment of vision in one or both eyes, either simultaneously or successively. It develops in a number of clinical settings, particularly allied with multiple sclerosis. The most common situation is one in which an adolescent or young adult has a rapid diminution of vision in one eye as though a veil had covered the eye, sometimes progressing within hours or days to complete blindness. The optic disc and retina may appear normal, in which case the condition is of the more common retrobulbar variety, but if the inflammation is near the nerve head, there is swelling of the disc, i.e., papillitis (Fig. 13-11). The disc margins are then seen to be elevated, blurred, and, rarely, surrounded by hemorrhages. As indicated above, papillitis is associated with marked impairment of vision and a scotoma, thus distinguishing it from the papilledema of increased intracranial pressure. Pain on movement and tenderness on pressure of the globe and a difference between the two eyes in the perception of brightness of light are other common but not invariable findings (Table 13-2). The pupil on the affected side has a muted response to direct light. In the following days and weeks, the patient may report an increase in blurring of vision with exertion or with exposure to heat (Uhthoff phenomenon). In papillitis, but not retrobulbar neuritis, examination may disclose haziness of the vitreous that causes difficulty in visualizing the retina. Inflammatory sheathing of the retinal veins, as described by Rucker, is known to occur but has been uncommon in our patients. In extreme cases, edema may suffuse from the disc to cause a rippling in the adjacent retina. However, as just noted, most cases of optic neuritis are retrobulbar and little is seen when examining the optic nerve head. In approximately 10 percent of cases, both eyes are involved, either simultaneously or in rapid succession. Sometimes, no cause can be found for optic neuropathy, but a first bout of multiple sclerosis is always suspected, as discussed in Chap. 36. After several weeks to months there is spontaneous recovery; vision returns to normal in more than two-thirds of cases. Regression of symptoms may occur spontaneously or may be hastened by the intravenous administration of high doses of corticosteroids, but in one study the oral administration of the same drugs increased the frequency of a relapse of optic neuritis (see “Treatment of Optic Neuritis” in Chap. 36). Occasionally, diminution of brightness, dyschromatopsia, or a scotoma remains; rarely, the patient is left blind. As time progresses, more than half of adults with optic neuritis will develop other symptoms and signs of multiple sclerosis, usually within 5 years, and probably even more do so when they are observed for longer periods. And in approximately 15 percent of patients with multiple sclerosis, the history discloses that retrobulbar neuritis was the first symptom. Postinfectious demyelinative disease is a possible cause in some of those cases that do not later show signs of multiple sclerosis. Less is known about children with retrobulbar neuropathy, in whom the disor-
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teria (cat scratch fever, formerly called Bartonella henselae). Papillitis is accompanied by macular edema and exudates situated radially in the Henle layer, producing a “macular star” appearance. Also mentioned here, for lack of a better placement, is a type of chronic relapsing optic neuritis that has been described by Kidd and colleagues. They did not view it as a variant of multiple sclerosis but instead related it to an idiopathic granulomatous disease of the optic nerve that is known to occur as an isolated illness or with sarcoidosis.
Anterior Ischemic Optic Neuropathy
Figure 13-11. Acute optic neuritis in a patient with multiple sclerosis. The disc is swollen from an inflammatory process near the nerve head (papillitis) and the patient is virtually blind in the affected eye.
der is more often bilateral and frequently related to a preceding viral infection (“neuroretinitis,” see below). Their prognosis is better than that of adults. Formerly, optic neuritis was often blamed on paranasal sinus disease, but this condition rarely affects vision and with a few exceptions, the association is tenuous, as discussed further on. Optic neuritis is a main component of neuromyelitis optica (Devic disease; see Chap. 36); the prognosis for recovery is generally poorer than for optic neuritis in multiple sclerosis but there are many exceptions, in part reflecting the ambiguity of the relationship between these two demyelinating diseases. Despite the return of visual acuity in the majority of patients with optic neuritis, a degree of optic atrophy almost always remains. The disc then appears shrunken and pale, particularly in its temporal half (temporal pallor) and the pallor extends beyond the margins of the disc into the peripapillary retinal nerve fibers. The patternshift visual evoked potential becomes delayed as a result; this test is a highly sensitive indicator of previous, even asymptomatic, episodes of optic neuritis. The treatment of optic neuritis is taken up with multiple sclerosis in Chap. 36. Leber hereditary optic neuropathy, a maternally inherited mitochondrial disorder, is an important cause of blindness in children and younger adults that may simulate the more common inflammatory optic neuropathies, even at times causing a relatively abrupt onset of visual loss followed by some degree of recovery (see “Hereditary Optic Atrophy of Leber” in Chap. 37). The visual field defect typically takes the form of a cecocentral scotoma. Certain nutritional and toxic states may do the same, as well as sarcoidosis and the other causes of optic neuropathy discussed further on. Neuroretinitis is a rare post- or parainfectious process seen mostly in children and young adults, sometimes in association with exposure to the Rochalimaea henselae bac-
In persons older than 50 years of age, ischemic infarction of the optic nerve head is the most common cause of a persistent monocular loss of vision (Fig. 13-12). The onset is abrupt and painless, but on occasion the visual loss is progressive for several days. The field defect is often altitudinal and involves the area of central fixation, accounting for a severe loss of acuity. Swelling of the optic disc, extending for a short distance beyond the disc margin, and associated small, flame-shaped hemorrhages, is typical; less often, if the infarction is situated behind the optic nerve head, the disc appears entirely normal. The retina and retinal vessels are not affected, as they are in cases of embolic occlusion of the central retinal artery. AION may also complicate intraocular surgery. As the disc edema subsides, optic atrophy becomes evident. The second eye may be similarly affected at a later date, particularly in those patients with hypertension and diabetes mellitus. Usually there are no premonitory symptoms or episodes of transient visual loss. Despite these distinctive features, ischemic optic neuropathy can sometimes be difficult to differentiate from optic neuritis, as pointed out by Rizzo and Lessell. This proves particularly problematic only when visual loss evolves over days, the disc is swollen, and pain accompanies the ischemic condition. However, the age of the patient and nature of the field defect (central in optic neuritis in contrast to altitudinal in ischemic neuropathy) further serve to clarify the situation.
Figure 13-12. Anterior ischemic optic neuropathy (AION) related to hypertension and diabetes. There is diffuse disc swelling from infarction that extends into the retina as a milky edema. The veins are engorged. “Cotton-wool” infarcts can be seen to the left of the disc and a “flame” hemorrhage extends from the right disc margin.
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As to the pathogenesis of ischemic optic neuropathy, the usual (anterior) form has been attributed by Hayreh to ischemia in the posterior ciliary artery circulation and more specifically to occlusion of the branches of the peripapillary choroidal arterial system. A small cup-to-disc ratio is reportedly a risk factor. Infarction of the posterior portions of the optic nerve(s) is uncommon. Most cases of either type occur on a background of hypertensive vascular disease and diabetes, but not necessarily in relation to carotid artery atherosclerotic stenosis, which in our experience has accounted for only a few cases, or in the setting of giant cell arteritis (see below). A putative and plausible relationship has been suggested between ischemic optic neuropathy and the use of nitric oxide inhibitors, such as sildenafil, for erectile dysfunction. The visual loss has occurred within 24 h of taking the drug and is usually unilateral. According to Pomeranz and colleagues, all affected patients have risk factors for vascular disease such as hypertension, diabetes, or hyperlipidemia, but there have been exceptions and the risk factors are likely to be present in older men who are likely to use the drug. There may be complete recovery or persistent blindness. Massive blood loss or intraoperative hypotension, particularly in association with the use of cardiac surgery with a bypass pump, may also produce visual loss and ischemic infarction of the retina and optic nerve. A remarkable bilateral optic neuropathy, which we have observed and which is also, presumably, ischemic in nature, occurs after prolonged laminectomy operations that are performed with the patient in the prone position. Obese individuals and those with small optic cups are seemingly at risk for this complication. Some recovery is possible after many weeks but most patients remain blind from infarction of the optic nerve heads. Blood loss of greater than 1 L and surgery longer than 6 h seem to be common to most cases. The reported cases have been summarized from a registry by Lee and coworkers. Temporal, or giant cell, arteritis is another important cause of AION (see also Chap. 10 on the related headache and Chap. 34 for a discussion of cerebrovascular disease in association with giant cell arteritis). Fleeting premonitory symptoms of visual loss (amaurosis fugax) may precede infarction of the nerve. Infarction caused by cranial arteritis may affect both optic nerves in close succession and, less often, ocular motor function. Temporal arteritis less often presents with the picture of central retinal artery occlusion or posterior ischemic optic neuropathy (in which ischemic injury to the optic nerve is not accompanied by acute changes in the appearance of the disc). Systemic lupus erythematosus, diabetes, sarcoidosis, neurosyphilis, and AIDS rarely give rise to optic neuropathies.
Optic Neuropathy Caused by Acute Cavernous and Paranasal Sinus Disease A number of disease processes adjacent to the orbit and optic nerve can cause blindness, usually with signs of compression or infarction of the optic and oculomotor nerves. They are seen far less frequently than are ischemic optic neuropathy and optic neuritis. Septic cavernous sinus thrombosis (see “Cavernous Sinus Thrombosis” in Chap. 34) may be accompanied by blindness of one eye or both
eyes asymmetrically. In our experience with 4 such patients, the visual loss appeared days after the characteristic chemosis and oculomotor palsies of the venous sinus occlusion. The mechanism of visual loss, sometimes without swelling of the optic nerve head, is unclear but most likely relates to retrobulbar ischemia of the nerve. Similarly, optic and oculomotor disorders may rarely complicate ethmoid or sphenoid sinus infections. Severe diabetes with mucormycosis or other invasive fungal or bacterial infection is the usual setting for these complications. Although the formerly held notion that uncomplicated sinus disease is a common cause of optic neuropathy is no longer tenable, there are still a few instances in which such an association occurs but the nature of the visual loss nonetheless remains unclear. Slavin and Glaser described a case of loss of vision from a sphenoethmoidal sinusitis with cellulitis at the orbital apex. Visual symptoms in these exceptional circumstances can occur prior to overt signs of local inflammation. An otherwise benign sphenoidal mucocele may cause a compressive optic neuropathy, usually with accompanying ophthalmoparesis and slight proptosis.
Toxic and Nutritional Optic Neuropathies (Table 13-3) Simultaneous impairment of vision in the two eyes, with central or centrocecal scotomas, is often caused not by a demyelinative process but also by toxic or nutritional processes. The latter condition is observed most often in the chronically alcoholic or malnourished patient. Impairment of visual acuity evolves over several days or a week or two, and examination discloses bilateral, roughly symmetrical central or centrocecal scotomas, the peripheral fields being intact. With appropriate treatment (nutritious diet and B vitamins) instituted soon after the onset of amblyopia, complete recovery is possible. If treatment is delayed, patients are left with varying degrees of permanent defect in central vision and pallor of the temporal portions of the optic discs. This disorder has been referred to as “tobacco-alcohol amblyopia,” the implication being that it is caused by the toxic effects of tobacco or alcohol or both. In fact, the problem is one of nutritional deficiency and is more properly designated as deficiency amblyopia or nutritional optic neuropathy (Chap. 41). The same disorder may be seen under conditions of severe dietary deprivation (see Chap. 41) and in patients with vitamin B12 deficiency. A subacute optic neuropathy of possible toxic origin has been described in Jamaican natives. It is characterized by bilaterally symmetrical central visual loss and may have additional features of nerve deafness, ataxia, and spasticity. A similar condition is described periodically in other Caribbean countries, most recently in Cuba, where an optic neuropathy of epidemic proportions was associated with a sensory polyneuropathy. A nutritional etiology, rather than tobacco use (putatively cigars in the Cuban epidemic), is likely in these outbreaks but has not been proven (see Sadun et al and The Cuba Neuropathy Field Investigation Team report). Impairment of vision because of methyl alcohol intoxication (methanol) is abrupt in onset and characterized by large symmetrical central scotomas as well as symptoms
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of acidosis. Treatment is directed mainly to correction of the acidosis. The subacute development of central field defects is attributable to other toxins and to the chronic administration of certain therapeutic agents, notably halogenated hydroxyquinolines (clioquinol), chloramphenicol, ethambutol, linezolid, isoniazid, streptomycin, chlorpropamide (Diabinese), infliximab, and various ergot preparations. The main drugs reported to have a toxic effect on the optic nerves are listed in Table 13-3 and have been catalogued more extensively by Grant.
Developmental Abnormalities of the Optic Nerve Congenital cavitary defects because of defective closure of the optic fissure may be a cause of impaired vision because of failure of development of the papillomacular bundle. Usually the optic pit or a larger coloboma is unilateral and unassociated with developmental abnormalities of the brain (optic disc dysplasia and dysplastic coloboma). A Table 13-3 CAUSES OF UNILATERAL AND BILATERAL OPTIC NEUROPATHY I. Demyelinative (optic neuritis) Multiple sclerosis Postinfectious and viral neuroretinitis II. Ischemic Arteriosclerotic (usually in-situ occlusion; occasionally carotid artery disease) Granulomatous (giant cell) arteritis Syphilitic arteritis III. Parainfectious Cavernous sinus thrombosis Paranasal sinus infection IV. Toxins and drugs Methanol Ethambutol Chloroquine Streptomycin Chlorpropamide Chloramphenicol Tiagabine Linezolid Infliximab Sildenafil Ergot compounds, etc. V. Deficiency states Vitamin B12 Thiamine or possibly several B vitamins (“tobacco-alcohol” amblyopia) Epidemic nutritional types (Cuban, Jamaican) VI. Heredofamilial and developmental Dominant juvenile optic atrophy Leber optic atrophy Developmental failure of disc or papillomacular bundle Progressive hyaline body encroachment VII. Compressive and infiltrative Meningioma of sphenoid wing or olfactory groove Metastasis to optic nerve or chiasm Glioma of optic nerve (neurofibromatosis type I) Optic atrophy following long-standing papilledema Pituitary tumor and apoplexy Thyroid ophthalmopathy Sarcoidosis Giant aneurysms Lymphoma Wegener granulomatosis VIII. Radiation-induced optic neuropathy
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hereditary form is known (Brown and Tasman). Vision may also be impaired as a result of a developmental anomaly in which the discs are of small diameter (hypoplasia of the optic disc or micropapilla).
Other Optic Neuropathies Optic nerve and chiasmal compression and infiltration by gliomas, meningiomas, craniopharyngiomas, and metastatic tumors may cause scotomas and optic atrophy (Chap. 31). Pituitary tumors characteristically cause bitemporal hemianopia, but very large adenomas, in particular if there is pituitary apoplexy, can cause blindness in one or both eyes (see “Pituitary Apoplexy” in Chap. 31). Infiltration of an optic nerve may occur in sarcoidosis (Fig. 32-4, bottom panel), Wegener granulomatosis, and with certain neoplasms, notably leukemia and lymphoma. Of particular importance is the optic nerve glioma that occurs in 15 percent of patients with type I von Recklinghausen neurofibromatosis. Usually it develops in children, often before the fourth year, causing a mass within the orbit and progressive loss of vision. If the eye is blind, the recommended therapy is surgical removal to prevent extension into the optic chiasm and hypothalamus. If vision is retained, radiation and chemotherapy are the recommended forms of treatment. Although most such gliomas are of low grade, a malignant form (glioblastoma multiforme) has been described in adults. Thyroid ophthalmopathy with orbital edema, exophthalmos, and usually a swelling of extraocular muscles is an occasional cause of optic nerve compression. Radiation-induced damage of the optic nerves and chiasm has been well documented. In a series of 219 patients at the M.D. Anderson Cancer Center who received radiotherapy for carcinomas of the nasal or paranasal region, retinopathy occurred in 7, optic neuropathy with blindness in 8, and chiasmatic damage with bilateral visual impairment in 1. These complications followed the use of more than 50 Gy (5,000 rad) of radiation (see Jiang et al). Radiation-induced optic neuropathy is typically delayed, occurring at an average of 18 months after radiation exposure, and is often accompanied by enhancement of the nerve on MRI. In the case of pseudotumor cerebri, the visual loss may be unexpectedly abrupt, appearing in a day or less and even sequentially in both eyes. This seems to happen most often in patients with constitutionally small optic nerves, no optic cup of the nerve head, and, presumably, a small aperture of the lamina cribrosa. Such explosive visual loss in pseudotumor cerebri may respond to urgent optic nerve fenestration, but this approach is controversial as discussed in “Pseudotumor Cerebri” in Chap. 30.
NEUROLOGY OF THE CENTRAL VISUAL PATHWAYS From the retina there is a point-to-point projection to the lateral geniculate ganglion and from there, to the calcarine cortex of the occipital lobe. Thus the visual cortex receives a
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spatial pattern of stimulation that corresponds with the retinal image of the visual field. Visual impairments caused by lesions of the central pathways usually involve only a part of the fields, and a plotting of the fields provides fairly specific information as to the site of the lesion. For purposes of description of the visual fields, each retina and macula are divided into a temporal and nasal half by a vertical line passing through the fovea. A horizontal line represented roughly by the junction of the superior and inferior retinal vascular arcades also passes through the fovea and divides each half of the retina and macula into upper and lower quadrants. Visual field defects are always described in terms of the field defect from the patient’s view (nasal, temporal, superior, inferior) rather than the retinal defect or the examiner’s perspective. The retinal image of an object in the visual field is inverted and reversed from right to left, like the image on the film of a camera. Thus the left visual field of each eye is represented in the opposite half of each retina, with the upper part of the field represented in the lower part of the retina (see Fig. 13-2). Figure 13-4 illustrates the retinal projections to the geniculate nuclei and occipital cortex.
Testing for Abnormalities of the Visual Fields Figure 13-2 illustrates the visual field defects caused by lesions of the retina, optic nerve and tract, lateral geniculate body, geniculocalcarine pathway, and striate cortex of the occipital lobe. In the alert, cooperative patient, the visual fields can be plotted accurately at the bedside. With one of the patient’s eyes covered and the other fixed on the corresponding eye of the examiner (patient’s right with examiner’s left), a target—such as a moving finger, a cotton pledget, or a white disc mounted on a stick—is brought from the periphery toward the center of the visual field (confrontational testing). With the target at an equal distance between the eye of the examiner and that of the patient, the fields of the patient and examiner are then compared. Similarly, the patient’s blind spot can be aligned with the examiner’s and its size determined by moving the target outward from the blind spot until it is seen. Central and paracentral defects in the field can be outlined the same way. For reasons not known, red-green test objects are more sensitive than white ones in detecting defects of the visual pathways. It should be emphasized that movement of the visual target provides the coarsest stimulus to the retina, so that a perception of its motion may be preserved while a stationary target of the same size may not be seen. In other words, moving targets are less useful than static ones in confrontational testing of visual fields. Finger counting and comparison of color intensity of a red object or the clarity of the examiner’s hand from quadrant to quadrant are simple confrontation tests that will disclose most field defects. Glaser recommends presenting the examiner’s hands simultaneously, one on each side of the vertical meridian; the hand in the hemianopic field appears blurred or darker than the other. Similarly, a scotoma may be defined by asking the patient to report changes in color or brightness of a red test object as it is moved toward or away from the point of fixation. Similarly, a central scotoma may be identified by hav-
ing the patient fix with one eye on the examiner’s nose, on which the examiner places the index finger of one hand or a white-headed pin and has the patient compare it for brightness, clarity, and color with a finger or pin held in the periphery. We continue to teach that these confrontation techniques are reasonably sensitive for routine clinical work if performed carefully, but we are chastened by the article from Pandit and colleagues, who found false-negative findings in 42 percent of patients tested with quadrant finger counting, using static automated perimetry as a standard. If any defect is found or suspected by confrontational testing, the fields should be charted and scotomas outlined on a tangent screen or perimeter. Accurate computer-assisted perimetry is now available in most ophthalmology clinics. Although the commonly used automated techniques encompass only the central visual field, this is more than adequate to detect most clinically important defects. The method of testing by double simultaneous stimulation may elicit defects in the central processing of vision that are undetected by conventional perimetry. Movement of one finger in all parts of each temporal field may disclose no abnormality, but if movement is simultaneous in analogous parts of both temporal fields, the patient with a parietal lobe lesion, especially on the right, may see only the one in the normal right hemifield. In young children or uncooperative patients, the integrity of the fields may be roughly estimated by observing whether the patient is attracted to objects in the peripheral field or blinks in response to sudden threatening gestures in half of the visual field. A common abnormality disclosed by visual field examination is concentric constriction. This may be a result of severe papilledema, in which case it is usually accompanied by an enlargement of the blind spot. A progressive constriction of the visual fields, at first unilateral and later bilateral, associated with pallor of the optic discs (optic atrophy), should suggest a chronic meningeal process involving the optic nerves (syphilis, cryptococcosis, sarcoidosis, lymphoma). Long-standing, untreated glaucoma and retinitis pigmentosa are other causes of concentric constriction. Marked constriction of the visual fields of unvarying degree, regardless of the distance of the visual stimulus from the eye (“gun-barrel” or “tunnel” vision), is a sign of hysteria. With organic disease, the constricted visual field naturally enlarges as the distance between the patient and the test object increases. A regional constriction of the field, especially in a nasal quadrant, usually signifies early optic atrophy, as mentioned earlier; it is the first sign that chronic papilledema is threatening the patient’s vision.
Prechiasmal Lesions Lesions of the macula, retina, or optic nerve cause a scotoma (an island of impaired vision surrounded by normal vision) rather than a defect that extends to the periphery of one visual field (“field cut”). Scotomas are named according to their position (central, cecocentral) or their shape (ring, arcuate). A small scotoma that is situated in the macular part of the visual field may seriously impair visual acuity.
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Scotomas are the main features of optic neuropathy, the main causes of which were discussed earlier and are listed in Table 13-3. Demyelinatng disease (optic neuritis), Leber hereditary optic atrophy, toxins and nutritional deficiencies, and vascular disease (ischemic optic neuropathy or occlusion of a branch of the retinal artery) are the main ones. Orbital or retroorbital tumors and infectious or granulomatous processes (e.g., sarcoidosis, retinal toxoplasmosis in AIDS) are other common causes. In the elderly, there may be compression of the optic nerve by a dolichoectatic aneurysm of the carotid, ophthalmic, or basilar arteries, resulting most often in a nasal field loss, according to Purvin and colleagues, but sometimes a bitemporal defect. As discussed earlier, certain toxic and malnutritional states are characterized by more or less symmetrical bilateral central scotomas (involving the fixation point) or cecocentral ones (involving both the fixation point and the blind spot). The cecocentral scotoma, which tends to have an arcuate border, represents a lesion that is predominantly in the distribution of the papillomacular bundle. However, the presence of this visual field abnormality does not establish whether the primary defect is in the cells of the origin of the bundle, i.e., the retinal ganglion cells, or in their fibers. Demyelinating disease is characterized by unilateral or asymmetrical bilateral scotomas. Vascular lesions that take the form of retinal hemorrhages or infarctions of the nerve-fiber layer (cotton-wool patches) give rise to unilateral scotomas; occlusion of the central retinal artery or its branches causes infarction of the retina and, as a rule, a loss of central vision, while occlusion of a branch of the retinal artery may cause an altitudinal defect. As pointed out earlier, anterior ischemic optic neuropathy causes sudden monocular blindness or an altitudinal field defect. Since the optic nerve also contains the afferent fibers for the pupillary light reflex, extensive lesions of the nerve will cause a so-called afferent pupillary defect, which was mentioned earlier and is considered further in Chap. 14. With most diseases of the optic nerve, as alluded to above, the optic disc will eventually become pale (atrophic). This usually requires 4 to 6 weeks to develop. If the optic nerve degenerates (e.g., in multiple sclerosis, Leber hereditary optic atrophy, traumatic transection, tumor of nerve, or syphilitic optic atrophy), the disc becomes chalk-white, with sharp, clean margins. If the atrophy is secondary to papillitis or papilledema, the disc margins are indistinct and irregular; the disc has a pallid, yellow-gray appearance, like candle tallow; the vessels are partially obscured; and the adjacent retina is altered because of the outfall of fibers. As in the case of optic neuritis, visual evoked potentials from the stimulation of one eye may be slowed even if the optic disc appears normal and there is no perimetric abnormality. As mentioned above, OCT has become a very sensitive way of displaying thinning of the retinal nerve fiber layer in a number of optic neuropathies.
Lesions of the Chiasm, Optic Tract, and Geniculocalcarine Pathway Hemianopia (hemianopsia) means blindness in half of the visual field. Bitemporal hemianopia indicates a lesion of the decussating fibers of the optic chiasm and is caused most often by the suprasellar extension of a tumor of the pitu-
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itary gland (Fig. 13-2C). It may also be the result, at this same site, of a craniopharyngioma, a saccular aneurysm or dolichoectatic artery of the anterior circle of Willis, and a meningioma of the tuberculum sellae; less often, it may be a result of sarcoidosis, metastatic carcinoma, ectopic pinealoma or dysgerminoma, Hand-Schüller-Christian disease, or hydrocephalus with dilatation and downward herniation of the posterior part of the third ventricle (Corbett). In some instances a tumor pushing upward presses the medial parts of the optic nerves, just anterior to the chiasm, against the anterior cerebral arteries. Chiasmal syndromes from causes other than pituitary adenoma are usually associated with unilateral optic disc atrophy, a relative afferent pupillary defect and a greater defect in the inferior field. Heteronymous field defects, i.e., scotomas or field defects that differ in the two eyes, are a sign of involvement of the optic chiasm or the adjoining optic nerves or tracts; they are caused by craniopharyngiomas or other suprasellar tumors and rarely by mucoceles, angiomas, giant carotid aneurysms, and opticochiasmic arachnoiditis. The visual field pattern created by a lesion in the optic nerve as it joins the chiasm typically includes a scotomatous defect on the affected side coupled with a contralateral superior quadrantanopia (“junctional field defect”). As noted previously, the latter is caused by interruption of nasal retinal fibers from the contralateral optic nerve. This was originally attributed to fibers projecting into the base of the affected optic nerve but there is now evidence against the existence of this structure as mentioned earlier and discussed in the reference by Horton. Variations in the pattern of visual loss from chiasmatic are frequent, in part accounted for by the location of the chiasm in an individual patient—a prefixed chiasm making unilateral eye findings more common. Homonymous hemianopia (a loss of vision in corresponding halves of the visual fields) signifies a lesion of the visual pathway behind the chiasm and, if complete, gives no more information than that. Incomplete homonymous hemianopia has more localizing value. As a rule, if the field defects in the two eyes are identical (congruous), the lesion is likely to be in the calcarine cortex and subcortical white matter of the occipital lobe; if they are incongruous, the visual fibers in the optic tract or in the parietal or temporal lobe are more likely to be implicated. Absolute congruity of field defects is actually infrequent, even with occipital lesions. The lower fibers of the geniculocalcarine pathway (from the inferior retinas) swing in a wide arc over the temporal horn of the lateral ventricle and then proceed posteriorly to join the upper fibers of the pathway on their way to the calcarine cortex (Fig. 13-2). This arc of fibers is known variously as the Flechsig, Meyer, or Archambault loop, and a lesion that interrupts these fibers will produce a superior homonymous quadrantanopia (contralateral upper temporal and ipsilateral upper nasal quadrants; Fig. 13-2E), or in incomplete cases, a homonymous superior wedge defect respecting the vertical meridian. This clinical effect was first described by Harvey Cushing, so that his name also was in the past applied to the loop of temporal visual fibers. Parietal lobe lesions are said to affect the inferior
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quadrants of the visual fields more than the superior ones, but this is difficult to document; with a lesion of the right parietal lobe, the patient ignores the left half of space; with a left parietal lesion, the patient is often aphasic. As to the localizing value of quadrantic defects, the report of Jacobson is of interest; he found, in reviewing the imaging studies of 41 patients with inferior quadrantanopia and 30 with superior quadrantanopia, that in 76 percent of the former and 83 percent of the latter the lesions were confined to the occipital lobe. If the entire optic tract or calcarine cortex on one side is destroyed, the homonymous hemianopia is complete. But often that part of the field subserved by the macula is spared, i.e., there is a 5- to 10-degree island of vision around the fixation point on the side of the hemianopia (sparing of fixation, or macular sparing). With infarction of the occipital lobe as a result of occlusion of the posterior cerebral artery, the macular region, represented in the most posterior part of the striate cortex, may be spared by virtue of collateral circulation from branches of the middle cerebral artery. Incomplete lesions of the optic tract and radiation also usually spare central (macular) vision. We have nevertheless observed a lesion of the tip of one occipital lobe that produced central homonymous hemianopic scotomata, bisecting the maculae. Lesions of both occipital poles (as in embolization of the posterior cerebral arteries) result in bilateral central scotomas; if all the calcarine cortex or all the subcortical geniculocalcarine fibers on both sides are completely destroyed, the bilateral hemianopias cause cerebral, or “cortical,” blindness (see below and Chap. 22). An altitudinal defect is one that is confined by a horizontal border and crosses the vertical meridian. Homonymous altitudinal hemianopia is usually caused by lesions of both occipital lobes below or above the calcarine sulcus and rarely to a lesion of the optic chiasm or nerves. The most common cause is occlusion of both posterior cerebral arteries at their origin at the termination of the basilar artery. Herniation of the occipital lobe over the tentorial margin can produce a homonymous superior altitudinal defect by selectively compressing the inferior branches of the posterior cerebral arteries. A monocular altitudinal hemianopia, by contrast, is almost invariably an ischemic optic neuropathy that arises from occlusion of the posterior ciliary vessels. In certain instances of homonymous hemianopia, the patient is capable of some visual perception in the hemianopic fields, a circumstance that permits the study of the vulnerability of different visual functions. Colored targets may be detected in the hemianopic fields, whereas achromatic ones cannot. But even in seemingly complete hemianopic defects, in which the patient admits to being blind, it has been shown that he may still react to visual stimuli when forced-choice techniques are used. Blythe and coworkers found that 20 percent of their patients with no ability to discriminate patterns in the hemianopic field nonetheless could still reach accurately and look at a moving light in the “blind” field. This type of residual visual function has been called “blindsight” by Weiskrantz and colleagues. These residual visual functions are generally attributed to the preserved function of retinocollicular or geniculoprestriate cortical connections, but in some cases
they may be a result of sparing of small islands of calcarine neurons. In yet other instances of complete homonymous hemianopia, the patient may be little disabled by visual field loss (Benton et al; Meienberg). This is because of preservation of vision in a small monocular part of the visual field known as the temporal crescent. The latter is a peripheral unpaired portion of the visual field, between 60 and 100 degrees from the fixation point, and is represented in the most anterior part of the visual striate cortex. In particular, the temporal crescent is sensitive to moving stimuli, allowing the patient to avoid collisions with people and objects. The tendency for patients with occipital lesions to have greater sensitivity for kinetic stimuli than for static ones was described by Riddoch in 1917.
Blindness in the Hysterical or Malingering Patient Hysterical, or psychogenic blindness, is described in Chap. 56, along with other features of hysteria, but a few comments are in order here. Feigned or hysterical visual loss is usually detected by attending to the patient’s activities when he thinks he is unobserved and it can be confirmed by a number of simple tests. Complete feigned blindness is exposed by observing the normal ocular jerk movements in response to a rotating optokinetic drum or strip or by noting that the patient’s eyes follow their own image in a mirror that is moved in front of them. The hysterical nature of total monocular blindness is apparent from the presence of a normal direct pupillary response to light. An optokinetic response in the nonseeing eye (with the good eye covered) is an even more convincing test; also, the visual evoked potential from the allegedly blind eye is normal. Hysterical monocular loss may also be revealed by the use of red-green glasses and an acuity chart with red and green letters, where each eye can only see letters with the color of its lens. The patient cannot tell which letters should be visible to them and the intact acuity in the involved eye is soon exposed. Hysterical homonymous hemianopia is rare and is displayed mostly by practiced malingerers; all manner of field defects are common in this population (Keane). The uniformly constricted tubular field defect of hysteria has already been mentioned. Starand spiral-shaped visual fields are also indicative of psychogenic visual loss.
Cerebral Forms of Blindness and Visual Agnosia (See also Chap. 22) The ability to recognize visually presented objects and words depends on the integrity not only of the visual pathways and primary visual area of the cerebral cortex (area 17 of Brodmann) but also of those cortical areas that lie just anterior to area 17 (areas 18 and 19 of the occipital lobe and area 39—the angular gyrus of the dominant hemisphere). Blindness that is the result of destruction of both visual and adjacent regions of the occipital lobes is termed cortical or cerebral blindness. Another remarkable condition exists in which the patient denies or is oblivious to blindness despite overt manifestations of the defect (Anton syndrome).
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In distinction to these forms of blindness, there is a lesscommon category of visual impairment in which the patient cannot understand the meaning of what he sees, i.e., visual agnosia. Primary visual perception is more or less intact, and the patient may accurately describe the shape, color, and size of objects and draw copies of them. Despite this, he cannot identify the objects unless he hears, smells, tastes, or palpates them. The failure of visual recognition of words alone is called visual verbal agnosia, or alexia. Visual-object agnosia rarely occurs as an isolated finding: as a rule, it is combined with visual verbal agnosia, homonymous hemianopia, or both. These abnormalities arise from lesions of the dominant occipital cortex and adjacent temporal and parietal cortex (angular gyrus) or from a lesion of the left calcarine cortex combined with one that interrupts the fibers crossing from the right occipital lobe (see Fig. 22-6). In the latter case, fibers responsible for writing are spared and the patient remains with a syndrome of alexia without agraphia. Failure to understand the meaning of an entire picture even though some of its parts are recognized is referred to as simultanagnosia, and is found in bilateral lesions of the occipital–parietal junction. When combined with deficits in visual control of eye and hand movements (optic ataxia and ocular apraxia), the resulting condition is referred to as Balint syndrome. A failure to recognize familiar faces is called prosopagnosia and typically results from occipital–temporal lesions. These and other variants of visual agnosia (including visual neglect) and their pathologic bases are dealt with more fully in Chap. 22. Other cerebral disturbances of vision include various types of distortion in which images seem to recede into the distance (teleopsia), appear too small (micropsia), or, less frequently, seem too large (macropsia). If such distortions are perceived with only one eye, a local retinal lesion should be suspected. If perceived with both eyes, they usually signify disease of the temporal lobes, in which case the visual disturbances tend to occur in attacks and are accompanied by other manifestations of temporal lobe seizures (Chap. 16). Palinopsia, a persistence of repetitive afterimages, similar to the appearance of a celluloid movie strip, occurs with right parietooccipital lesions; it has been a consequence of seizures in the cases we have encountered, but instances associated with static disorders (tumor, infarction) have been described as well. Patients describe the images as “trailing” or “echoing.” With parietal lobe lesions, objects may appear to be askew or even turned upside down. More often, lesions of the vestibular nucleus or its immediate connections produce the illusion that objects are tilted or turned upside down (tortopsia) or that straight lines are curved. Presumably this is the result of a mismatch between the visual image and the otolithic or vestibular input to the visual system.
Abnormalities of Color Vision Normal color vision depends on the integrity of cone cells, which are most numerous in the macular region. When activated, they convey information to special columns of cells in the striate cortex. Three different cone pigments with optimal sensitivities to blue, green, and orange-yellow wavelengths are said to characterize these cells; presumably each cone possesses only one of these pigments. Transmission to
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higher centers for the perception of color is effected by neurons and axons that encode at least two pairs of complementary colors: red-green in one system and yellow-blue in the other. In the optic nerves and tracts, the fibers for color are of small caliber and seem to be preferentially sensitive to certain noxious agents and to pressure. The geniculostriate fibers for color are separate from fibers that convey information about form and brightness but course alongside them; hence there may be a homonymous color hemianopia (hemiachromatopsia). The visual fields for blue-yellow are smaller than those for white light, and the red and green fields are smaller than those for blue-yellow. Diseases may affect color vision by abolishing it completely (achromatopsia) or partially by quantitatively reducing one or more of the three attributes of color—brightness, hue, and saturation. Or, only one of the complementary pairs of colors may be lost, usually red-green. The disorder may be congenital and hereditary or acquired. The most common form, and the one to which the term color blindness is usually applied, is a male sex-linked inability to see red and green while normal visual acuity is retained. The main problem arises in relation to traffic lights, but patients learn to use the position of the light as a guide. Several other genetic abnormalities of cone pigments and their phototransduction have been identified as causes of achromatopsia. The defect cannot be seen by inspecting the retina. A failure of the cones to develop or a degeneration of cones may cause a loss of color vision, but in these conditions visual acuity is often diminished, a central scotoma may be present, and, although the macula also appears to be normal ophthalmoscopically, fluorescein angiography shows the pigment epithelium to be defective. Whereas congenital color vision defects are usually protan (red) or detan (green), leaving yellow-blue color vision intact, most acquired lesions affect all colors, at times disparately. Lesions of the optic nerves usually affect redgreen more than blue-yellow; the opposite is true of retinal lesions. An exception is a rare, dominantly inherited, optic atrophy, in which the scotoma mapped by a large blue target is larger than that for red. Damasio has drawn attention to a group of acquired deficits of color perception with preservation of form vision, the result of focal damage (usually infarction) of the visual association cortex and subjacent white matter. Color vision may be lost in a quadrant, half of the visual field, or the entire field. The latter, or full-field achromatopsia, is the result of bilateral occipitotemporal lesions involving the fusiform and lingual gyri, a localization that accounts for its frequent association with visual agnosia (especially prosopagnosia) and some degree of visual field defect. A lesion restricted to the inferior part of the right occipitotemporal region, sparing both the optic radiations and striate cortex, causes the purest form of achromatopsia (left hemiachromatopsia). With a similar left-sided lesion, alexia may be associated with the right hemiachromatopsia.
Other Visual Disorders In addition to the losses of perception of form, movement, and color, lesions of the visual system may also give rise to a variety of positive sensory visual experiences. The simplest of these are called phosphenes, i.e., flashes of light and col-
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ored spots in the absence of luminous stimuli. Mechanical pressure on the normal eyeball may induce them at the retinal level, as every child discovers. Or they may occur with disease of the visual system at many different sites. As mentioned earlier, elderly patients commonly complain of flashes of light in the peripheral field of one eye, most evident in the dark (Moore lightning streaks); these are related to vitreous tags that rest on the retinal equator and may be quite benign or may be residual evidence of retinal detachment. Cancer associated retinopathy is frequently associated with photopsias prior to visual loss. Retinal toxicity from digitalis causes a chromatopsia with a characteristic “yellowish vision” and may also cause photopsias. In patients with migraine, ischemia (or perhaps activation) of nerve cells in the occipital lobe gives rise to the bright zigzag lines of a fortification spectrum. Stimulation of the cortical terminations of the visual pathways accounts for the simple or unformed visual hallucinations in epilepsy. Formed or complex visual hallucinations (of people, animals, landscapes) are observed in a variety of conditions, notably in old age when vision fails (Bonnet syndrome, discussed in “Visual Hallucinations” in Chap. 22), in the withdrawal state following chronic intoxication with alcohol and other sedative-hypnotic drugs (Chaps. 42 and 43), in Alzheimer disease, and in infarcts of the occipitoparietal or occipitotemporal regions (release hallucinations) or the diencephalon (“peduncular hallucinosis”). These disorders are discussed in Chap. 22. Occasionally, patients in whom a hemianopia is evident only when tested by double simultaneous stimulation (“attention hemianopia”) may displace an image to the nonaffected half of the field of vision (visual allesthesia), or a visual image may persist for minutes to hours or reappear episodically, after the exciting stimulus has been removed (palinopsia or paliopsia mentioned earlier); the latter disorder also occurs in defective but not blind homonymous fields of vision. Polyopia, the perception of multiple images when a single stimulus is presented, is said to be associated predominantly with right occipital lesions and can occur with either eye. Usually there is one primary and a number of secondary images, and their relationships may be constant or changing. Bender and Krieger, who described several such patients, attributed the polyopia to unstable fixation. When this is monocular, there is either a defect in the lens or, more often, hysteria. Oscillopsia, or illusory movement of the environment, is a perception caused by nystagmus and occurs mainly with lesions of the labyrinthine-vestibular apparatus; it is described with disor-
References Arruga J, Sanders M: Ophthalmologic findings in 70 patients with evidence of retinal embolism. Ophthalmology 89:1336, 1982. [PMID: 7162779] Bender MB, Krieger HP: Visual function in perimetric blind fields. Arch Neurol Psychiatry 65:72, 1951. [PMID: 14782771] Benton S, Levy I, Swash M: Vision in the temporal crescent in occipital infarction. Brain 103:83, 1980. [PMID: 7363060] Bienfang DC, Kelly LD, Nicholson DH, et al: Ophthalmology. N Engl J Med 323:956, 1990. [PMID: 2205800]
ders of ocular movement. A rare idiopathic myokymia of one superior oblique muscle may produce a monocular oscillopsia (see “Fourth Nerve Palsy” in Chap. 14). Chapter 22 discusses the clinical effects and syndromes that result from occipital lobe lesions further.
Amblyopia Because of Early Life Strabismus (Amblyopia Ex Anopia) As noted in the introductory part of this chapter, the generic term “amblyopia” has been adopted for a special circumstance in which a normal eye fails to acquire its potential visual acuity because images are not properly projected onto the fovea during a formative period of cerebral development. It is a disorder, as quipped by van Noorden and Campos, “in which the patient sees nothing and the doctor sees nothing.” The period of risk is during the first 7 years but it is of greater consequence in the earlier part of this epoch, and the visual loss may still be rectifiable beyond the time. The degradation of vision and disuse of the fovea may be the result of a number of processes, most often misaligned ocular axes (strabismus) but also including unequal refractive errors (anisometropia; discussed in Chap. 14). These conditions are the most common sources of visual disturbance in children. The condition has remained uncorrected in a large enough group that it affects an estimated 3 percent of adults and is the main cause of monocular visual loss. By convention, the diagnosis of amblyopia requires that a loss of 2 lines or more between eyes be observed on the Snellen chart. The developmental deficiency in the occipital cortex that gives rise to amblyopia has been extensively studied in animals and humans; a discussion of the subject can be found in numerous texts including the one by van Noorden and Campos. Neurologists should be aware that screening children for the disorder is highly valuable even if treatment is not always successful. The correction of refractive errors, cataract, and other correctible ocular problems are attended to first. Attempts are then made to force the utilization of the disadvantaged eye in preference to the normal one; patching and atropine drops are the typical methods to accomplish this. Other techniques of management and a summary of clinical trials of each can be found in the review by Holmes and Clarke. Chapter 14 discusses the problem of strabismus and the latent phorias that create confusion in the neurologic examination.
Blythe IM, Kennard C, Ruddock KH: Residual vision in patients with retrogeniculate lesions of the visual pathways. Brain 110:887, 1987. [PMID: 3651800] Brown GC, Tasman WS: Congenital Anomalies of the Optic Disc. New York, Grune & Stratton, 1983. Chester EM: The Ocular Fundus in Systemic Disease. Chicago, Year Book, 1973. Corbett JJ: Neuro-ophthalmologic complications of hydrocephalus and shunting procedures. Semin Neurol 6:111, 1986. [PMID: 3332415] Damasio AR: Disorder of complex visual processing: Agnosia, achromatopsia, Balint’s syndrome and related difficulties of orientation
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and construction, in Mesulam M-M (ed): Principles of Behavioral Neurology. Philadelphia, Davis, 1985, pp 259– 288. D’Amico DJ: Disease of the retina. N Engl J Med 331:95, 1994. [PMID: 16041823] DeJong PT: Age-related macular degeneration. N Engl J Med 355:1474, 2006. [PMID: 17021323] Digre KB, Kurcan FJ, Branch DW, et al: Amaurosis fugax associated with antiphospholipid antibodies. Ann Neurol 25:228, 1989. [PMID: 2729913] Dryja TP, McGee TL, Reichel E, et al: A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343:364, 1990. [PMID: 2137202] Fisher CM: Observations on the fundus in transient monocular blindness. Neurology 9:333, 1959. [PMID: 13657292] Frank RN: Diabetic retinopathy. N Engl J Med 350:48, 2004. [PMID: 14702427] Glaser JS (ed.): Neuro-ophthalmology, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 1999. Grant WM: Toxicology of the Eye. Springfield, IL, Charles C Thomas, 1986. Grunwald GB, Klein R, Simmonds MA, Kornguth SE: Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma. Lancet 1:658, 1985. [PMID: 2858616] Hayreh SS: Anterior ischemic optic neuropathy. Arch Neurol 38:675, 1981. [PMID: 7305693] Hayreh SS: Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic disc. Br J Ophthalmol 53:721, 1969. [PMID: 4982590] Hayreh SS: Pathogenesis of oedema of the optic disc (papillo-edema). Br J Ophthalmol 48:522, 1964. [PMID: 14221776] Holmes JM, Clarke MP: Amblyopia. Lancet 367:1343, 2006. [PMID: 16631913] Horton JC: Wilbrand’s knee of the primate optic chiasm is an artefact of monocular enucleation. Trans Am Ophthalmol Soc 95:579, 1997. [PMID: 9440188] Hubel DH, Wiesel TN: Functional architecture of macaque monkey visual cortex. Proc R Soc Lond B Biol Sci 198:1, 1977. [PMID: 20635] Jacobson DM: The localizing value of a quadrantanopia. Arch Neurol 54:401, 1997. [PMID: 9109741] Jacobson DM, Thurkill CE, Tipping SJ: A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 28:162, 1990. [PMID: 2171418] Jiang GL, Tucker SL, Guttenberger R, et al: Radiation-induced injury to the visual pathway. Radiother Oncol 30:17, 1994. [PMID: 8153376] Keane JR: Patterns of hysterical hemianopia. Neurology 51:1230, 1998. [PMID: 9781576] Kidd D, Burton B, Plant GT, et al: Chronic relapsing inflammatory optic neuropathy (CRION). Brain 126:276, 2003. [PMID: 12538397] Kornguth SE, Klein R, Appen R, Choate J: The occurrence of anti-retinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 50:1289, 1982. [PMID: 6286090] Lee LA, Roth S, Cheney FW, et al: The American Society of Anesthesiologists Postoperative Visual Loss Registry: Analysis of 93 spine surgery cases with postoperative visual loss. Anesthesiology 105:652, 2006. [PMID: 17006060] Leibold JE: Drugs having a toxic effect on the optic nerve. Int Ophthalmol Clin 11:137, 1971. [PMID: 4338111] Levin BE: The clinical significance of spontaneous pulsations of the retinal vein. Arch Neurol 35:37, 1978. [PMID: 619871] Levine DN, Warach J, Farrah M: Two visual systems in mental imagery: Dissociation of “what” and “where” in imagery disorders due to bilateral posterior cerebral lesions. Neurology 35:1010, 1985. [PMID: 4010939]
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Marshall J, Meadows S: The natural history of amaurosis fugax. Brain 91:419, 1968. [PMID: 5723016] Meienberg O: Sparing of the temporal crescent in homonymous hemianopia and its significance for visual orientation. Neuroophthalmology 2:129, 1981. Minckler DS, Tso MOM, Zimmerman LE: A light microscopic autoradiographic study of axoplasmic transport in the optic nerve head during ocular hypotony, increased intraocular pressure, and papilledema. Am J Ophthalmol 82:741, 1976. [PMID: 63246] Newman NJ: Optic neuropathy. Neurology 46:315, 1996. [PMID: 8614487] Pandit RJ, Gales K, Griffiths PG: Effectiveness of testing of visual fields by confrontation. Lancet 358:1339, 2001. [PMID: 11684217] Pearlman AJ: Visual system, in Pearlman AL, Collins RC (eds): Neurobiology of Disease. New York, Oxford University Press, 1990, pp 124–148. Pomeranz HD, Smith KH, Hart WM, Egan RA: Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven cases. J Neuroophthalmol 25:9, 2005. [PMID: 15756125] Purvin V, Kawasaki A, Zeldes S: Dolichoectatic arterial compression of the anterior visual pathways: neuron-ophthalmic features and clinical course. J Neurol Neurosurg Psychiatry 75:27, 2004. [PMID: 14707301] Rizzo JF, Lessell S: Optic neuritis and ischemic optic neuropathy. Arch Ophthalmol 109:1668, 1999. [PMID: 1841572] Rucker CW: Sheathing of retinal venus in multiple sclerosis. Mayo Clin Proc 47:335, 1972. [PMID: 4555346] Sadun RA, Martone JF, Muci-Mendoza R, et al: Epidemic optic neuropathy in Cuba: Eye findings. Arch Ophthalmol 112:691, 1994. [PMID: 8185530] Savino PJ, Paris M, Schatz NJ, et al: Optic tract syndrome. Arch Ophthalmol 96:656, 1978. [PMID: 646693] Slavin M, Glaser JS: Acute severe irreversible visual loss with sphenoethmoiditis-posterior orbital cellulitis. Arch Ophthalmol 105:345, 1987. [PMID: 3827709] Smith JL, Hoyt WP, Susac JO: Optic fundus in acute Leber’s optic atrophy. Arch Ophthalmol 90:349, 1973. [PMID: 4746084] The Cuba Neuropathy Field Investigation Team: Epidemic optic neuropathy in Cuba—clinical characteristics and risk factors. N Engl J Med 333:1176, 1995. [PMID: 7565972] Traquair HM. An Introduction to Clinical Perimetry. St. Louis, CV Mosby, 1948. Tso MOM, Hayreh SS: Optic disc edema in raised intracranial pressure: III. A pathologic study of experimental papilledema. Arch Ophthalmol 95:1448, 1977; IV: Axoplasmic transport in experimental papilledema, Arch Ophthalmol 95:1458, 1977. [PMID: 70201] Van Noorden GK, Campos E: Binocular Vision and Ocular Motility, 6th ed. St. Louis, Mosby, 2002. Weiskrantz L, Warrington EK, Sanders MD, Marshall J: Visual capacity in the hemianopic field following a restricted occipital ablation. Brain 97:709, 1974. [PMID: 4434190] Winterkorn J, Kupersmith MJ, Wirtschafter JD, Forman S: Treatment of vasospastic amaurosis fugax with calcium-channel blockers. N Engl J Med 329:396, 1993. [PMID: 8326973] Wray SH: Neuro-ophthalmologic diseases, in Rosenberg RN (ed): Comprehensive Neurology, 2nd ed. New York, Wiley-Liss, 1998, pp 561–594. Wray SH: Visual aspects of extracranial carotid artery disease, in Bernstein EF (ed): Amaurosis Fugax. New York, Springer-Verlag, 1988, pp 72–80. Young LHY, Appen RE: Ischemic oculopathy. Arch Neurol 38:358, 1981. [PMID: 7236064]
14 Disorders of Ocular Movement and Pupillary Function
Ocular movement and vision are virtually inseparable. A moving object evokes movement of the eyes and almost simultaneously arouses attention and initiates the perceptive process. To look searchingly, i.e., to peer, requires stable fixation of the visual image on the center of the two retinas. One might say that the ocular muscles are at the service of vision. Abnormalities of ocular movement are of three basic types. One category can be traced to a lesion of the extraocular muscles themselves, the neuromuscular junction, or to the cranial nerves that supply them (nuclear or infranuclear palsy). The second type is a derangement in the highly specialized neural mechanisms that enable the eyes to move together (supranuclear and internuclear palsies). This distinction, in keeping with the general concept of upper and lower motor neuron paralysis, hardly portrays the complexity of the neural mechanisms governing ocular motility; nevertheless, it constitutes an essential step in the approach to the patient with defective eye movements. A knowledge of the anatomic basis of normal movement is essential to an understanding of abnormal movement. Perhaps more common but not primarily neurologic is a third group, strabismus, in which there is a congenital imbalance of the yoked muscles of extraocular movement that leads to a developmental reduction in monocular vision, as discussed at the end of the previous chapter.
SUPRANUCLEAR CONTROL OF EYE MOVEMENT Anatomic and Physiologic Considerations In no aspect of human anatomy and physiology is the sensory guidance of muscle activity more instructively revealed than in the neural control of coordinated ocular movement. Moreover, the entirely predictable and “hardwired” nature of the central and peripheral oculomotor apparatus allows for a very precise localization of lesions within these pathways. To focus the eyes voluntarily, to stabilize objects for scrutiny when one is moving, to bring into sharp focus near and far objects—all require the perfect coordination of six sets of extraocular muscles and three sets of intrinsic muscles (ciliary muscles, sphincters, and dilators of the iris). The neural mechanisms that gov-
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ern these functions reside mainly in the midbrain and pons but are greatly influenced by centers in the medulla, cerebellum, basal ganglia, and the frontal, parietal, and occipital lobes of the brain. Most of the nuclear structures and pathways concerned with fixation and stable ocular movements are now known, and much has been learned of their physiology both from clinical-pathologic correlations in humans and from experiments in monkeys. Different diseases give rise to particular defects in ocular movement and pupillary function, and these are of diagnostic importance. Accurate binocular vision is actually achieved by the associated action of all the ocular muscles. The symmetrical and synchronous movement of the eyes is termed conjugate movement or gaze (conjugate meaning yoked or joined together). The simultaneous movement of the eyes in different directions, as in convergence, is termed dysconjugate or disjunctive. These two forms of normal ocular movement are also referred to as versional and vergence, respectively. Vergence movements have two components—fusional and accommodative. The fusional movements are convergence and divergence, which maintain binocular single vision and depth perception (stereopsis); they are necessary at all times to ensure that visual images fall on corresponding parts of the retinas. Convergent movements are brought into action when one looks at a near object. The eyes turn inward and at the same time the pupils constrict and the ciliary muscles relax to thicken the lens and allow near vision (the accommodative-near reflex, or triad). Divergence, albeit slight, is required for distant vision. Rapid voluntary conjugate movements of the eyes to the opposite side are initiated in area 8 of the frontal lobe (see Fig. 22-1) and relayed to the pons. These quick movements are termed saccadic (peak velocity may exceed 700 degrees per second). Their purpose is to rapidly change ocular fixation and bring images of new objects of interest onto the foveae. Saccades are so rapid that there is no subjective awareness of movement during the change in eye position, essentially, a momentary blindness. Saccadic movements can be elicited by instructing an individual to look to the right or left (commanded saccades) or to move the eyes to a target (refixation saccades). These two movements are often differently affected in neurologic disease. Saccades may also be elicited reflexively, as when a sudden sound or the appearance of an object in the peripheral field of vision
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attracts attention and triggers an automatic movement of the eyes in the direction of the stimulus. Saccadic latency, the interval between the appearance of a target and the initiation of a saccade, is approximately 200 ms. The neurophysiologic pattern of pontine neurons that produces a saccade has been characterized as “pulse-step” in type. This refers to the sudden increase in neuronal firing (the pulse) that is necessary to overcome the inertia and viscous drag of the eyes and move them into their new position; it is followed by a return to a new baseline firing level (the step), which maintains the eyes in their new position by tonic contraction of the extraocular muscles ( gaze holding). Saccades are distinguished from the slower and smoother, largely involuntary pursuit or following movements, for which the major stimulus is a moving target. The function of pursuit movements is to stabilize the image of a moving object on the foveae and thus to maintain a continuous clear image of the object as the object changes position (“smooth tracking”). Unlike saccades, pursuit movements to each side are generated in the ipsilateral parietooccipital cortex, with modulation by the ipsilateral cerebellum, especially the vestibulocerebellum (flocculus and nodulus). Another portion of the cerebellum, the posterior vermis, also influences saccadic movements (see further on). When following a moving target, as the visual image slips off the foveae, the firing rate of the governing motor neurons increases in proportion to the speed of the target, so that eye velocity matches target velocity. If the eyes fall behind the target, supplementary catch-up saccades are required for refixation. The pursuit movement is then not smooth but becomes jerky (“saccadic” pursuit). A lesion of one cerebral hemisphere may cause pursuit movements to that side to break up into saccades. Diseases of the basal ganglia are also a common cause of a disruption of normally smooth pursuit into a ratchet-like saccadic pursuit in all directions. If a series of visual targets enters the visual field, as when one is watching trees from a moving car or the stripes on a rotating drum, involuntary repeated quick saccades refocus the eyes centrally; the resulting cycles of pursuit and refixation are termed optokinetic nystagmus. This phenomenon is used as a bedside test, the main value of which is in revealing a lesion of the ipsilateral posterior parietal lobe. It may also be found that a frontal lobe lesion eliminates the quick nystagmoid refixation phase away from the side of the lesion, thereby causing the eyes to continue to follow the target until it is out of view. This optokinetic phenomenon is described more fully further on, in the section on nystagmus. Vestibular influences are of particular importance in stabilizing images on the retina during head and body movement. By means of the vestibuloocular reflex (VOR), a prompt short latency movement of the eyes is produced that is equal and opposite to movement of the head. During sustained rotation of the head, the VOR is supplemented by the optokinetic system, which enables one to maintain compensatory eye movements for a more prolonged period. If the VOR is lost, as occurs with disease of the vestibular apparatus or eighth nerve, the slightest movements of the head, especially those occurring during locomotion, cause a movement of images across the retina large enough to impair vision. When objects are tracked using both eye and
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head movements, the VOR must be suppressed, otherwise the eyes would remain fixed in space; to accomplish this, the smooth pursuit signals cancel the unwanted vestibular ones (Leigh and Zee). It follows that the inability to suppress the VOR while viewing a target while the patient is rotated is indicative of a defect of supranuclear pursuit.
Horizontal Gaze Saccades As already mentioned, the signals for volitional horizontal gaze saccades originate in the eye field of the opposite frontal lobe (area 8 of Brodmann, see Fig. 22-1) and are modulated by the adjacent supplementary motor eye field and by the posterior visual cortical areas. Leichnetz traced the corticalto-pontine pathways for saccadic horizontal gaze in the monkey. These fibers traverse the internal capsule and separate at the level of the rostral diencephalon into two bundles, the first being a primary ventral “capsular–peduncular” bundle, which descends through the most medial part of the cerebral peduncle. This more ventral pathway undergoes a partial decussation in the low midbrain, at the level of the trochlear nucleus, and terminates mainly in the vaguely defined paramedian pontine reticular formation (PPRF) of the opposite side, neurons of which, in turn, project to the adjacent sixth nerve nucleus (Fig. 14-1). A second, more dorsal “transthalamic” bundle is predominantly uncrossed and courses through the internal medullary lamina and paralaminar parts of the thalamus to terminate diffusely in the pretectum, superior colliculus, and periaqueductal gray matter. An offshoot of these fibers (the prefrontal oculomotor bundle) projects to the rostral part of the oculomotor nucleus and to the ipsilateral rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and to the interstitial nucleus of Cajal (INC), which are involved in vertical eye movements, as discussed in the next section.
Pursuit The pathways for smooth pursuit movements are less well defined. One probably originates in the posterior parietal cortex and the adjacent temporal and anterior occipital cortex (area MT of the monkey) and descends to the ipsilateral dorsolateral pontine nuclei. Also contributing to smooth pursuit movements are projections from the frontal eye fields to the ipsilateral dorsolateral pontine nuclei. The latter, in turn, project to the flocculus and dorsal vermis of the cerebellum, which provide stability for the pursuit movements. However, for the purposes of clinical work, lesions of the posterior parietal cortex are the ones known to impair pursuit toward the damaged side. Part of the frontal eye fields have been shown experimentally to participate in pursuit eye movements, but the influence of this area on pursuit is far less than that of the parietal lobes and is insignificant clinically.
Brainstem (Internuclear) Pathways and Oculomotor Nuclei Ultimately, all the pathways mediating saccadic and pursuit movements in the horizontal plane, as well as for ves-
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RIGHT FRONTAL
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tibular and optokinetic movements, converge on the pontine tegmental center for horizontal gaze, the PPRF. Also required for horizontal versional movements are the nuclei prepositus hypoglossi and their commissure, the abducens and medial vestibular nuclei, and pathways in the pontine and tegmentum of the brainstem that interconnect the oculomotor nuclei (Fig. 14-1). Conventionally, the term ocular motor nuclei refers to the nuclei of the third, fourth, and sixth cranial nerves; the term oculomotor nucleus refers to the third nerve nucleus alone. The fiber bundle connecting the third and sixth nerve nuclei and connecting both these nuclei with the vestibular nuclei lies in the medial tegmentum of the brainstem; this pathway is the medial longitudinal fasciculus (MLF). The PPRF and the prepositus and medial vestibular nuclei are conceptualized as a “neural integrator” and relay station for horizontal saccade pathways. However, it is understood from animal experiments that the neural signals that encode smooth pursuit and vestibular and optokinetic movements bypass the PPRF and project independently to the abducens nuclei (Hanson et al).
Figure 14-1. The supranuclear pathways subserving saccadic horizontal gaze to the left. The pathway originates in the right frontal cortex, descends in the internal capsule, decussates at the level of the rostral pons, and descends to synapse in the left pontine paramedian reticular formation (PPRF). Further connections with the ipsilateral sixth nerve nucleus and contralateral medial longitudinal fasciculus are also indicated. Cranial nerve nuclei III and IV are labeled on left; nucleus of VI and vestibular nuclei (VN) are labeled on right. LR, lateral rectus; MLF, medial longitudinal fasciculus; MR, medial rectus.
The abducens nucleus contains two groups of neurons, each with distinctive morphologic and physiologic properties: (1) the intranuclear abducens motor neurons, which innervate the ipsilateral lateral rectus muscle, and (2) abducens internuclear neurons, which project via the contralateral MLF to the medial rectus neurons of the opposite oculomotor nucleus. Conjugate lateral gaze is accomplished by the simultaneous activation of the ipsilateral, lateral rectus, and the contralateral medial rectus, again, the latter through fibers that run in the medial portion of the MLF. Interruption of the MLF results in a discrete impairment or loss of adduction of the eye ipsilateral to the MLF lesion, a sign referred to as internuclear ophthalmoplegia, the details of which are discussed further on (see Fig. 14-1). Two other ascending pathways between the pontine centers and the mesencephalic reticular formation have been traced: one traverses the central tegmental tract and terminates in the pretectum, in the nucleus of the posterior commissure; the other is a bundle separate from the MLF that passes around the nuclei of Cajal and Darkschewitsch to the riMLF. These nuclei are involved more in vertical
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gaze and are described below. In addition, each vestibular nucleus projects onto the abducens nucleus and the MLF of the opposite side. This pathway is considered to generate the slow phase of the VOR. Although direct projections from the frontal eye fields to the oculomotor nuclei, as described above, undoubtedly exist, indirect projections are more important in the voluntary control of conjugate eye movements. According to Leigh and Zee, a more accurate view of these various voluntary influences is one of a hierarchy of cell stations and parallel pathways that do not project directly to oculomotor nuclei but to adjacent premotor or burst neurons, which discharge at high frequencies immediately preceding a saccade. The premotor or burst neurons for horizontal saccades lie within the PPRF and those for vertical saccades in the riMLF (see below). Yet a third class of neurons (omnipause cells), lying in the midline of the pons, is involved in the inhibition of unwanted saccadic discharges. Nonetheless, in clinical work, the circuit that comprises in sequence (1) frontal lobe eye fields, (2) contralateral pontine PPRF, (3) abducens nucleus, (4) MLF, and (5) opposite oculomotor nucleus is exposed by a number of highly characteristic defects of horizontal ocular motion, as detailed in the remainder of the chapter.
Vertical Gaze In contrast to horizontal gaze, which is generated by unilateral aggregates of cerebral and pontine neurons, vertical eye movements, with few exceptions, are under bilateral control of the cerebral cortex and upper brainstem. The groups of nerve cells and fibers that govern upward and downward gaze as well as torsional saccades are situated in the pretectal areas of the midbrain and involve three integrated structures—the riMLF, the INC, and the nucleus and fibers of the posterior commissure (Fig. 14-2). The riMLF lies at the junction of the midbrain and thalamus, at the rostral end of the medial longitudinal fasciculus, just dorsomedial to the rostral pole of the red nucleus. The riMLF functions as the “premotor” nucleus with “burst cells” for the production of fast (saccadic) vertical versional and torsional movements. Input to the riMLF arises both from the PPRF and the vestibular nuclei. Each riMLF projects mainly ipsilaterally to the oculomotor and trochlear nuclei, but each riMLF is connected to its counterpart by fibers that traverse the posterior commissure. Bilateral lesions of the riMLF or of their interconnections in the posterior commissure are more common than unilateral ones and cause a loss either of downward saccades or of all vertical saccades. The INC is a small collection of cells that lies just caudal to the riMLF on each side. Each nucleus projects to the motor neurons of the opposite elevator muscles (superior rectus and inferior oblique) by fibers that cross through the posterior commissure, and it projects ipsilaterally to the depressor muscles (inferior rectus and superior oblique). The functional role of the INC appears to be in holding eccentric vertical gaze, especially after a saccade; it is also integral to the vestibuloocular reflex. Lesions of the INC produce a vertical gaze-evoked and torsional nystagmus and an ocular tilt reaction and probably slow all conjugate eye movements, mainly vertical ones.
Posterior Commissure riMLF
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CN III
CN III Vestibular Nucleus
Figure 14-2. Pathways for the control of vertical eye movements. The main structures are the interstitial nucleus of Cajal (INC), the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), and the subnuclei of the third nerve, all located in the dorsal midbrain. Voluntary vertical movements are initiated by the simultaneous activity of both frontal cortical eye fields. The riMLF serves as the generator of vertical saccades and the INC acts tonically to hold eccentric vertical gaze. The INC and riMLF connect with their contralateral nuclei via the posterior commissure, where fibers are subject to damage. Projections for upgaze cross through the commissure before descending to innervate the third nerve nucleus, while those for downgaze may travel directly to the third nerve, thus accounting for the frequency of selective upgaze palsies (see text). The MLF carries signals from the vestibular nuclei, mainly ipsilaterally, to stabilize the eyes in the vertical plane (VOR) and maintain tonic vertical position.
Lesions of the posterior commissure are common; they interrupt signals crossing to and from the INC and the riMLF. A lesion here characteristically produces a paralysis of upward gaze and of convergence, often associated with mild mydriasis accommodative loss, convergence nystagmus, lid retraction (Collier “tucked lid” sign), and, less commonly, ptosis. In some instances, only a restricted combination of these signs is seen. This constellation is the Parinaud syndrome, also referred to as the pretectal, dorsal midbrain, or sylvian aqueduct syndrome (see “Vertical Gaze Palsy” further on). The same syndrome may be produced by unilateral lesions of the posterior commissure, presumably by interrupting bidirectional connections from the riMLF and INC. With acute lesions of the commissure, there is a tonic downward deviation of the eyes and lid retraction (“setting-sun sign”). The MLF is the main conduit of vertical gaze signals from the vestibular nuclei in the medulla to the midbrain centers. For this reason, with internuclear ophthalmoplegia along with the characteristic adductor paresis on the
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affected side, vertical pursuit and the VOR are impaired. This is most evident when these are bilateral internuclear ophthalmoplegias. Vertical deviation of the ipsilateral eye (skew) may be seen in cases of unilateral internuclear ophthalmoplegia, as discussed further on.
Vestibulocerebellar Influences on Eye Movements There are important vestibulocerebellar influences on both smooth pursuit and saccadic movements (see also Chap. 5). The flocculus and posterior vermis of the cerebellum receive abundant sensory projections from proprioceptors of the cervical musculature (responsive to head velocity), the retinas (sensitive to target velocity), proprioceptors of eye muscles (eye position and eye velocity), auditory and tactile receptors, and the superior colliculi and PPRF. Cerebellar efferents concerned with ocular movement project onto the vestibular nuclei, and the latter, in turn, influence gaze mechanisms through several projection systems: one, for horizontal movements, consists of direct projections from the vestibular nuclei to the contralateral sixth nerve nucleus; another, for vertical movements, projects via the contralateral MLF to third and fourth nerve nuclei (Figs. 14-1 and 14-2). Lesions of the flocculus and posterior vermis are consistently associated with deficits in smooth pursuit movements and an inability to suppress the vestibuloocular reflex by fixation (Baloh et al). Floccular lesions are also an important cause of downbeat nystagmus. As indicated in Chap. 5, patients with cerebellar (floccular) lesions are unable to hold eccentric positions of gaze and must make repeated saccades to look at a target that is away from the neutral position (gaze-paretic nystagmus, a term also applied to nystagmus arising from a lesion in the PPRF). This phenomenon is explained by the fact that with acute, one-sided lesions of the vestibulocerebellum, the inhibitory discharges of the Purkinje cells onto the ipsilateral medial vestibular nucleus are removed and the eyes deviate away from the lesion. When gaze to the side of the lesion is attempted, the eyes drift back to the midline and fixation can be corrected only by a saccadic jerk. The head and neck may also turn away from the lesion (the occiput toward the lesion and the face away). In addition, the vestibuloocular reflexes, which coordinate eye movements with head movements, are improperly adjusted (Thach and Montgomery). The interested reader can find further details concerning cerebellar influences on ocular movements in the monograph by Leigh and Zee and the review by Lewis and Zee.
Testing of Conjugate Gaze It is apparent from the foregoing remarks that there is considerable clinical information to be obtained from an analysis of ocular movements. To fully examine the eye movements, the patient should be asked to look quickly to each side as well as up and down (saccades) and to follow a moving target (pursuit of a light, the examiner’s finger, or an optokinetic drum). A patient with stupor and coma can be examined by passively turning the head or by irrigating the external auditory canals; these are vestibular stimuli to reflex eye movement as discussed in Chap. 17.
Most individuals make accurate saccades to a target. Alterations of saccadic movements, particularly overshooting of the eyes (hypermetria), are characteristic of a cerebellar lesion. Slowness of saccadic movements is mainly the result of disease of the basal ganglia such as Huntington and Wilson diseases, ataxia-telangiectasia, progressive supranuclear palsy, olivopontocerebellar degeneration, and certain lipid storage diseases. Lesions involving the PPRF may also be accompanied by slow saccadic movements to the affected side. Hypometric, slow saccades occurring only in the adducting eye indicate an incomplete internuclear ophthalmoparesis caused by a lesion of the ipsilateral MLF. When the earliest sign of a progressive eye movement disorder is slow saccades in the vertical plane, the likely diagnosis is progressive supranuclear palsy, but the same sign may occur in Parkinson disease and several less common processes that affect the basal ganglia, as discussed further on under “Vertical Gaze Palsy.” Slow up-and-down saccades are also found in Niemann-Pick disease type C. Yet another saccadic disorder takes the form of an inability to initiate voluntary movements, either vertically or horizontally. This abnormality may be congenital in nature, as in the ocular “apraxia” of childhood (Cogan syndrome, see below) and in ataxia-telangiectasia; an acquired difficulty in the initiation of saccadic movements may be seen in patients with Huntington disease or with a lesion of the contralateral frontal lobe or ipsilateral pontine tegmentum. We have observed it as a sign of hysteria. In addition to abnormalities of the saccades themselves, saccadic latency or reaction time (the interval between the impulse to move and movement) is prolonged in Huntington chorea and Parkinson disease. Saccadic latency is also increased in corticobasal ganglionic degeneration (see Chap. 39), in which case it seems to correspond to the degree of motor apraxia. Fragmentation of smooth pursuit movement, a frequent neuroophthalmic finding, is a jerky irregularity of tracking. Drug intoxication—with phenytoin, barbiturates, diazepam, and other sedative drugs—is probably the most common cause. As a manifestation of structural disease, it points to a lesion of the vestibulocerebellum. A similar-appearing but distinct phenomenon occurs in certain extrapyramidal diseases, as mentioned earlier, such as Parkinson disease, Huntington disease, and progressive supranuclear palsy. In these diseases there is often a ratchet-like impairment of smooth pursuit movements in association with slow, hypometric saccades (“saccadic pursuit”). Indeed, according to Vidailhet and colleagues, smooth pursuit movements are found to be impaired in all types of basal ganglionic degenerations. Asymmetrical impairment of smooth pursuit movements is indicative of a parietal or a frontal lobe lesion. Pursuit is impaired toward the side of a parietal lesion and away from a frontal lesion, as described earlier. The evaluation of visual pursuit by optokinetic testing is explained further on. Vestibuloocular Reflex Testing Evaluation of the VOR can provide considerable information and may be simply performed in the cooperative patient by rapidly turning the head to one side by 5 to 10 degrees and requesting that the patient fixate on a distant target (passive head turning; see “Tests of Labyrinthine Function” in Chap. 15). Slippage
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of fixation (impaired VOR) is appreciated by observing a small corrective saccade in the direction opposite head turning. An alternative is to rotate the patient in a chair while he fixates on the thumb of his outstretched hand. There should be no loss of fixation at moderate rotational speeds. Zee has described yet another means of testing the VOR in which the examiner observes the optic nerve head while the patient rotates the head back and forth at a rate of one to two cycles per second. If the VOR is impaired, the optic nerve head appears to oscillate. Normally, movement of the head at this rate does not cause blurring of vision because of the rapidity with which the VOR accomplishes compensatory eye movements. By contrast, with the head in a fixed position, to-and-fro movement of the environment will cause blurring of vision because normal tracking movements are too slow to fixate the object in space. As a result of inability to suppress the VOR, the patient with impairment of smooth pursuit movements experiences a feeling of instability. Testing the Near Response (Accommodative Triad) Combined convergence and accommodative movements are tested by asking the patient to look at his thumbnail, the examiner’s finger, or object as it is brought toward the eyes. However, these fusional movements are frequently impaired in the elderly and in confused or inattentive patients and should not be interpreted as the result of disease in the ocular motor pathways. Otherwise, the absence or impairment of these movements should suggest a lesion in the rostral midbrain. Convergence spasms and retraction nystagmus may accompany paralysis of vertical gaze from a dorsal midbrain lesion. But when such convergent spasms occur alone, they are characteristic of hysteria, in which full horizontal movement can usually be obtained if each eye is tested separately. Also, cycloplegic eye drops will abolish the accommodation and pupillary miosis.
alous phenomenon is not established, but interference with descending oculomotor tracts in the midbrain has been postulated by Tijssen. It should be emphasized that cerebral gaze paralysis is not attended by strabismus or diplopia, i.e., the eyes always move conjugately. The usual causes of gaze paresis are vascular occlusion with infarction, hemorrhage, and abscess or tumor of the frontal lobe. A seizure originating in the frontal lobe may also drive the eyes to the opposite side and simulate a gaze palsy. Gaze Palsies of Brainstem Origin A unilateral lesion in the rostral midbrain tegmentum, by interrupting the cerebral pathways for horizontal conjugate gaze before their decussation, will cause a gaze palsy to the opposite side. Far more common is a lesion in the pontine horizontal gaze complex (PPRF; also involving the abducens nucleus), which causes ipsilateral gaze palsy and deviation of the eyes to the opposite side. As a rule, the horizontal gaze palsies of cerebral and pontine origin are readily distinguished by the side of an accompanying hemiparesis. When there is a tonic deviation of the eyes from a cerebral lesion, this relationship is expressed as “the eyes look toward the brain lesion and away from the hemiparesis.” The opposite pertains to brainstem gaze palsies, that is, gaze is impaired toward the side opposite the lesion, and if there is gaze deviation, the eyes are turned toward a hemiparesis. Palsies of pontine origin need not have an accompanying hemiparesis but are associated with other signs of pontine disease, particularly peripheral facial palsies and internuclear ophthalmoplegia on the same side as the paralysis of gaze. Pontine gaze palsies tend to be longer lasting than those of cerebral origin. Also, in the case of a cerebral lesion (but not a pontine lesion), the eyes can be turned to the paralyzed side if they are fixated on the target and the head is rotated passively to the opposite side (i.e., by utilizing the VOR).
Paralysis of Conjugate Gaze
Vertical Gaze Palsy
Horizontal Gaze Palsy Cerebral Origin An acute lesion of one frontal lobe, such as an infarct, usually causes impersistence or paresis of contralateral gaze, and the eyes may for a limited time turn involuntarily toward the side of the cerebral lesion. In most cases of acute frontal lobe damage, the gaze palsy is incomplete and temporary, lasting for a week or less. Almost invariably, it is accompanied by hemiparesis. Forced closure of the eyelids may cause the eyes to move paradoxically to the side of the hemiparesis rather than upward (Bell phenomenon), as would be expected. During sleep, the eyes may also deviate conjugately from the side of the lesion to the side of the hemiplegia. Also as indicated above, pursuit movements away from the side of the lesion tend to be fragmented or lost. Posterior parietal lesions reduce pursuit movements but do not cause a gaze palsy. With bilateral frontal lesions, the patient may be unable to turn his eyes voluntarily in any direction but retains fixation and following movements. Occasionally, a deep cerebral lesion, particularly a thalamic hemorrhage extending into the midbrain, will cause the eyes to deviate conjugately to the side opposite the lesion (“wrong-way” gaze); the basis for this anom-
Midbrain lesions affecting the pretectum and the region of the posterior commissure interfere with conjugate movements in the vertical plane. Paralysis of vertical gaze is a prominent feature of the Parinaud or dorsal midbrain syndrome described earlier. Upward gaze in general is affected far more frequently than downward gaze because, as already explained, some of the fibers subserving upgaze cross rostrally and posteriorly between the riMLF and INC and are subject to interruption before descending to the oculomotor nuclei, whereas the pathways for downgaze apparently project directly downward to oculomotor nuclei from the two controlling centers. Optokinetic nystagmus in the vertical plane is usually lost in association with any interruption of vertical gaze. The range of upward gaze is frequently restricted by a number of extraneous factors, such as drowsiness, increased intracranial pressure, and, particularly, aging. In a patient who cannot elevate the eyes voluntarily, the presence of reflex upward deviation of the eyes in response to flexion of the head (“doll’s-head maneuver”) or to voluntary forceful closure of the eyelids (Bell phenomenon) indicates that the nuclear and infranuclear mechanisms for upward gaze are intact and that the defect is supranuclear.
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However useful this rule may be, in some instances of disease of the peripheral neuromuscular apparatus—such as Guillain-Barré syndrome and myasthenia gravis—in which voluntary upgaze may be limited, the strong stimulus of eye closure may cause upward deviation, whereas voluntary attempts at upgaze are unsuccessful, thereby spuriously suggesting a lesion of the upper brainstem. In addition, approximately 15 percent of normal adults do not show a Bell phenomenon; in others, deviation of the eyes is paradoxically downward. In patients who during life had shown an isolated palsy of downward gaze, autopsy has disclosed bilateral lesions of the rostral midbrain tegmentum (just medial and dorsal to the red nuclei). An unusual case, described by Bogousslavsky and colleagues, suggests that a paralysis of vertical gaze may follow a strictly unilateral infarction that comprises the posterior commissure, riMLF, and INC. Hommel and Bogousslavsky summarized the location of strokes that cause monocular and binocular vertical gaze palsies. Several degenerative and related processes exhibit selective or prominent upgaze or vertical gaze palsies, as mentioned earlier (Table 14-1). In progressive supranuclear palsy, a highly characteristic feature is a selective paralysis of vertical gaze, with the more specific feature being downward paralysis, beginning with impairment of saccades and later restriction of all vertical movements. Parkinson and Lewy-body diseases (Chap. 39), corticobasal ganglionic degeneration (Chap. 39), and Whipple disease of the brain (Chap. 40) may also produce vertical gaze palsies as these diseases progress.
or downward. Recurrent attacks, sometimes associated with spasms of the neck, mouth, and tongue muscles and lasting from a few seconds to an hour or two, were pathognomonic of postencephalitic parkinsonism in the past. Now this phenomenon is observed as an acute reaction in patients being given phenothiazine and related neuroleptic drugs and in Niemann-Pick disease. The pathogenesis of these ocular spasms is not known. In the drug-induced form, upward deviation of the eyes is often associated with a report by the patient of peculiar obsessional thoughts; the entire syndrome can be terminated by the administration of an anticholinergic medication such as benztropine. Congenital oculomotor “apraxia” (Cogan syndrome) is a congential disorder characterized by abnormal eye and head movements during attempts to change the position of the eyes. The patient is unable to make normal voluntary horizontal saccades when the head is stationary. If the head is free to move and the patient is asked to look at an object to either side, the head is thrust to one side and the eyes turn in the opposite direction; the head overshoots the target, and the eyes, as they return to the central position, fixate on the target. Both voluntary saccades and the quick phase of vestibular nystagmus are defective. The pathologic anatomy is not understood. This same phenomenon is also seen in ataxia-telangiectasia (Louis-Bar disease, Chap. 37) and with agenesis of the corpus callosum, in which both horizontal and vertical saccades may be affected.
NUCLEAR AND INFRANUCLEAR DISORDERS OF EYE MOVEMENT
Other Supranuclear Disorders of Gaze The ocular tilt reaction, in which skew deviation (discussed further on) is combined with ocular torsion and head tilt, is attributed to an imbalance of otolithic-ocular and otolithic-colic reflexes. In unilateral lesions involving the vestibular nuclei, as occurs in lateral medullary infarction, the eye is lower on the side of the lesion. With lesions of the MLF or INC, which can also cause an ocular tilt reaction, the eye is higher on the side of the lesion. Another unusual disturbance of gaze is the oculogyric crisis, or spasm, which consists of a tonic spasm of conjugate deviation of the eyes, usually upward and less frequently laterally
Table 14-1 DISEASES EXHIBITING UPGAZE OR VERTICAL GAZE PALSY Midbrain infarction and hemorrhage Tumor in the region of the dorsal midbrain (e.g., pinealoma) Advanced hydrocephalus with enlargement of third ventricle Progressive supranuclear palsy Parkinson disease Lewy body disease Cortical basal ganglionic degeneration Whipple disease Metabolic diseases of childhood (Niemann-Pick type C, Gaucher, Tay-Sachs) Any cause of bilateral internuclear ophthalmoplegia (e.g., multiple sclerosis)
Anatomic Considerations The third (oculomotor), fourth (trochlear), and sixth (abducens) cranial nerves innervate the extrinsic muscles of the eye. Because their actions are closely integrated and many diseases involve all of them at once, they are suitably considered together. The oculomotor (third-nerve) nuclei consist of several paired groups of motor nerve cells adjacent to the midline and ventral to the aqueduct of Sylvius at the level of the superior colliculi. A centrally located group of cells that innervate the pupillary sphincters and ciliary bodies (muscles of accommodation) is situated dorsally in the Edinger-Westphal nucleus; this is the parasympathetic portion of the oculomotor nucleus. Ventral to this nuclear group are cells that mediate the actions of the levator of the eyelid, superior and inferior recti, inferior oblique, and medial rectus, in this dorsal–ventral order. This functional arrangement has been determined in cats and monkeys by extirpating individual extrinsic ocular muscles and observing the retrograde cellular changes (Warwick). Subsequent studies using radioactive tracer techniques have shown that medial rectus neurons occupy three disparate locations within the oculomotor nucleus rather than being confined to its ventral tip (Büttner-Ennever and Akert). These experiments also indicated that the medial and inferior recti and the inferior oblique are innervated strictly homolaterally from the oculomotor nuclei, whereas the superior rectus receives only crossed fibers and the levator
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palpebrae superioris has bilateral innervation. Whether this precise arrangement is reproduced in humans is not known. Vergence movements are under the control of medial rectus neurons and not, as was once supposed, by an unpaired medial group of cells (nucleus of Perlia). The fibers of the third-nerve nucleus course ventrally in the midbrain, crossing the medial longitudinal fasciculus, red nucleus, substantia nigra, and medial part of the cerebral peduncle successively. Lesions involving these structures therefore interrupt oculomotor fibers in their intramedullary course and give rise to crossed syndromes of hemiplegia and ocular palsy. The sixth nerve (abducens) arises at the level of the lower pons from a paired group of cells in the floor of the fourth ventricle, adjacent to the midline. The intrapontine portion of the facial nerve loops around the sixth-nerve nucleus before it turns anterolaterally to make its exit; a lesion in this locality therefore causes a homolateral paralysis of the lateral rectus and facial muscles. It is important to note that the efferent fibers of the oculomotor and abducens nuclei have a considerable intramedullary extent, termed their fascicular portions (Fig. 14-3A and B).
Cerebral aqueduct Oculomotor nucleus (III N.) III N.fibers Red nucleus Corticospinal tract Substantia nigra
III Nerve
A
4th ventricle Facial nucleus VII N.
Nodulus
Superior vestibular nucleus Inferior cerebellar peduncle Abducens nucleus (VI N.) VI N.fibers
VII N.fibers Corticospinal tract
B Figure 14-3. A. Midbrain in horizontal section, indicating the effects of lesions at different points along the intramedullary course of the third-nerve fibers. A lesion at the level of oculomotor nucleus results in homolateral third-nerve paralysis and homolateral anesthesia of the cornea. A lesion at the level of red nucleus results in homolateral third-nerve paralysis and contralateral ataxic tremor (Benedikt and Claude syndromes). A lesion near the point of exit of third-nerve fibers results in homolateral third-nerve paralysis and crossed corticospinal tract signs (Weber syndrome; see Table 47-2). B. Brainstem at the level of the sixth-nerve nuclei, indicating effects of lesions at different loci. A lesion at the level of the nucleus results in homolateral sixth- and seventh-nerve paralyses with varying degrees of nystagmus and weakness of conjugate gaze to the homolateral side. A lesion at the level of corticospinal tract results in homolateral sixthnerve paralysis and crossed hemiplegia (Millard-Gubler syndrome).
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The cells of origin of the trochlear nerves are just caudal to those of the oculomotor nerves in the lower midbrain. Unlike the third and sixth nerves, the fourth nerve emerges from the dorsal surface of the lower midbrain and then courses posteriorly (dorsally) and decussates a short distance from its origin, just caudal to the inferior colliculi. The nerves proceed circumferentially and ventrally around the midbrain toward its entry into the posterior cavernous sinus. Each nucleus therefore innervates the contralateral superior oblique muscle. The long extraaxial course and the position of the nerves adjacent to the brainstem is a putative explanation for the common complication of fourthnerve palsy in head injury (see Chap. 35). The superior oblique muscle forms a tendon that passes through a pulley structure (the trochlea) and attaches to the upper aspect of the globe. When the eye is adducted, the muscle exerts an upward pull, but being attached to the globe behind the axis of rotation, it causes depression and intorsion of the eye; in abduction, it pulls the ocular meridian toward the nose, thereby causing intorsion (i.e., clockwise in the right eye and counterclockwise in the left from the examiner’s perspective). The oculomotor nerve, soon after it emerges from the brainstem, passes between the superior cerebellar and posterior cerebral arteries. The nerve (and sometimes the posterior cerebral artery) may be compressed at this point by herniation of the uncal gyrus of the temporal lobe through the tentorial opening (see Chap. 17). The sixth nerve, after leaving the brainstem, sweeps upward along the clivus and then runs alongside the third and fourth cranial nerves; together they course anteriorly, pierce the dura just lateral to the posterior clinoid process, and run in the lateral wall of the cavernous sinus, where they are closely applied to the internal carotid artery and first and second divisions of the fifth nerve (Fig. 14-4 and Fig. 34-32, “Cavernous Sinus Thrombosis” in Chap. 34). When infraclinoid retrocavernous compressive lesions, such as aneurysms and tumors, affect the oculomotor nerve, they tend to also involve all three divisions of the trigeminal nerve. In the posterior portion of the cavernous sinus, the first and second trigeminal divisions are involved along with the oculomotor nerves; in the anterior portion, only the ophthalmic division of the trigeminal nerve is affected. Just posterior and superior to the cavernous sinus, the oculomotor nerve crosses the terminal portion of the internal carotid artery at its junction with the posterior communicating artery. An aneurysm at this site frequently damages the third nerve; this serves to localize the site of compression or bleeding. Together with the first division of the fifth nerve, the third, fourth, and sixth nerves enter the orbit through the superior orbital fissure. The oculomotor nerve, as it enters the orbit, divides into superior and inferior branches, although a functional separation of nerve bundles occurs well before this anatomic bifurcation. The superior branch supplies the superior rectus and the voluntary (striated) part of the levator palpebrae (the involuntary part is under the control of sympathetic fibers of Müller); the inferior branch supplies the pupillary and ciliary muscles and all the other extrinsic ocular muscles except, of course, two—the superior oblique and the external rectus
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Pituitary stalk Internal carotid artery N. III N. IV V1 V2 V3
Cavernous sinus
Optic chiasm
Trigeminal ganglion
Internal carotid artery
N. VI N. VII N. VIII N. IX N. X N. XII
Oculomotor N. Trochlear N.
Hypophysis
Ophthalmic N. (V1) Abducens N. Maxillary N. (V2)
Transverse sinus
Vein of Galen
A
Sphenoid sinus
Nasopharynx
B
Figure 14-4. (See also Fig. 34-29.) The cavernous sinus and its relation to the cranial nerves. A. Base of the skull; the cavernous sinus has been removed on the right. B. The cavernous sinus and its contents viewed in the coronal plane.
which are innervated by the trochlear and abducens nerves, respectively. Superior branch lesions of the oculomotor nerve caused by an aneurysm or more commonly by diabetes result in ptosis and uniocular upgaze paresis. Under normal conditions, all the extraocular muscles participate in every movement of the eyes; for proper movement, the contraction of any muscle requires relaxation of its antagonist. Clinically, however, an eye movement can be thought of in terms of the one muscle that is predominantly responsible for an agonist movement in that direction; e.g., outward movement of the eye requires the action of the lateral rectus; inward movement, action of the medial rectus. The action of the superior and inferior recti and the oblique muscles varies according to the position of the eye. When the eye is turned outward, the elevator is the superior rectus and the depressor is the inferior rectus. When the eye is turned inward, the elevator and depressor are the inferior and superior oblique muscles, respectively. The actions of the ocular muscles in different positions of gaze are illustrated in Fig. 14-5 and Table 14-2. The clinical implications of deficiencies of each of these muscle actions are discussed below.
This tendency is referred to as a phoria and is normally overcome by the fusion mechanisms. A misalignment that is manifest during binocular viewing of a target and cannot be overcome, even when the patient is forced to fixate with the deviant eye, is called a tropia. The ocular misalignment is then apparent by viewing the position of the patient’s eyes while they fixate on a distant target. The prefixes esoand exo- indicate that the phoria or tropia is directed inward or outward, respectively, and the prefixes hyper- and hypo-, that the deviation is upward or downward. Paralytic strabismus is primarily a neurologic problem; nonparalytic strabismus (referred to as comitant strabismus if the angle between the visual axes is the same in all fields of gaze) is managed by ophthalmologists, although it is associated with a number of congenital cerebral diseases and forms of mental retardation.
SUP. RECT.
INF. OBL.
Diplopia and Strabismus The term diplopia refers to binocular double vision caused by a misalignment of the visual axes of the two eyes. With very few exceptions, in order to experience diplopia there must be some vision in both eyes. Put another way, covering one eye usually obliterates double vision. Strabismus, strictly speaking, refers to a muscle imbalance of any type that results in misalignment of the visual axes but the term is used most often by neurologists to describe a congenital variety of misalignment. Strabismus may be caused by weakness of an individual eye muscle (paralytic strabismus) or by an imbalance of muscular tone, presumably because of a faulty “central” mechanism that normally maintains a proper angle between the two visual axes (nonparalytic or pediatric strabismus, see below). Almost everyone has a slight tendency to strabismus, i.e., to misalign the visual axes when a target is viewed preferentially with one eye.
INF. RECT.
SUP. OBL. INF. OBL.
SUP. RECT.
SUP. OBL.
INF. RECT.
Figure 14-5. Muscles chiefly responsible for vertical movements of the eyes in different positions of gaze. (Adapted by permission from Cogan DG: Neurology of the Ocular Muscles, 2nd ed. Springfield, IL, Charles C Thomas, 1956.)
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Table 14-2 ACTIONS OF THE EXTRAOCULAR MUSCLES MUSCLE
Medial rectus Lateral rectus Superior rectus Inferior rectus Superior oblique Inferior oblique
PRIMARY ACTION
SECONDARY ACTION
OCULOMOTOR NERVE
Adduction Abduction Elevation Depression Intorsion
— — Intorsion Extorsion Depression
III VI III III IV
Extorsion
Elevation
III
(See also Fig. 14-5.)
Pediatric Nonparalytic Strabismus It is in this sense that the unqualified term strabismus is often used. The normal slight exotropia of neonates corrects by about 3 months of age. Large malalignments (greater than 15 degrees) are considered abnormal, even at birth. Most children with developmental esotropic strabismus present between ages 2 and 3 years, whereas those with exotropia show the condition in a broader range of preschool years. Esodeviations are initially intermittent and then become persistent; exodeviations are commonly intermittent. In both cases, eye movements are full and the child initially alternates fixation. Esotropia is typically an acquired problem as a result of congenital farsightedness and the overengagement of the near response in order to see clearly, thereby driving the eyes to cross. Treatment with glasses within 6 months of the onset of the strabismus therefore restores vision and usually leads to realignment of the axes. Large degrees of esotropia that are not the result of hypermetropia (farsightedness) are best treated by surgical realignment. In contrast, persistent exotropic strabismus in a child is usually associated with a developmental delay, often as a component of a recognizable mental retardation syndrome, as detailed in Chap. 38, or with ocular pathology. It does, however, occur in neurologically normal children. If mild, intermittent exotropia is initially treated by one of a number of nonsurgical means such as patching and visual exercises to stimulate convergence; surgical correction is reserved for unresponsive cases. See Donohue for a recent review of the subject. Once binocular fusion is established, usually by 6 months of age, any type of ocular muscle imbalance will cause diplopia, as images then fall on disparate or noncorresponding parts of the two functionally active retinas. After a time, however, the child eliminates the diplopia by suppressing the image from one eye. After a variable period, the suppression becomes permanent, and the individual grows up with a diminished visual acuity in that eye, the result of prolonged disuse (amblyopia ex anopsia) as described in the last portion of Chap. 13. Nonparalytic strabismus may create misleading ocular findings in the neurologic examination. Sometimes a slight misalignment of the eyes is first noticed after a head injury or a febrile infection, or it may be exposed by any other neurologic disorder or drug intoxication that impairs fusional mechanisms (vergence). In a cooperative patient, nonparalytic strabismus may be demonstrated by showing that each eye moves fully when the other eye is covered. Tropias and
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phorias can also readily be detected by means of the simple “cover” and “cover–uncover” tests. When fusion is disrupted by covering one eye, the occluded eye will deviate; uncovering that eye results in a quick corrective movement designed to reestablish the fusion mechanism.
Clinical Effects of Lesions of the Third, Fourth, and Sixth Ocular Nerves Third (Oculomotor) Nerve A complete third nerve lesion causes ptosis, or drooping of the upper eyelid (as the levator palpebrae is supplied mainly by this nerve), and an inability to rotate the eye upward, downward, or inward. This corresponds to the weaknesses of the medial, superior, and inferior recti and the inferior oblique muscles. The remaining actions of the fourth and sixth nerves give rise to a position of the eye described by the mnemonic “down and out.” In addition, one finds a dilated, light-nonreactive pupil (iridoplegia) and paralysis of accommodation (cycloplegia) because of interruption of the parasympathetic fibers in the third nerve. However, the extrinsic and intrinsic (papillary) eye muscles may be affected separately in certain diseases. For example, infarction of the central portion of the oculomotor nerve, as occurs in diabetic ophthalmoplegia, typically spares the pupil, as the parasympathetic preganglionic pupilloconstrictor fibers lie near the surface. Conversely, compressive lesions of the nerve usually dilate the pupil as an early manifestation. After injury, regeneration of the thirdnerve fibers may be aberrant, in which case some of the fibers that originally moved the eye in a particular direction now reach another muscle or the iris; in the latter instance the pupil, which is unreactive to light, may constrict when the eye is turned up and in. Fourth (Trochlear) Nerve A lesion of the fourth nerve, which innervates the superior oblique muscle, is the most common cause of isolated symptomatic vertical diplopia. Although oculomotor palsy was a more common cause of vertical diplopia in Keane’s 1975 series, as stated earlier, in instances where this is the sole complaint, trochlear palsy (and brainstem lesions) have predominated in our material. Paralysis of the superior oblique muscle results in weakness of downward movement of the affected eye, most marked when the eye is turned inward (Fig. 14-6E), so that the patient complains of special difficulty in reading or going down stairs. The affected eye tends to deviate slightly upward when the patient looks straight ahead. This defect may be overlooked in the presence of a third-nerve palsy if the examiner fails to note the absence of an expected intorsion as the patient tries to move the paretic eye downward. Head tilting to the opposite shoulder (Bielschowsky sign) is especially characteristic of fourth-nerve lesions; this maneuver causes a compensatory intorsion of the unaffected eye and ameliorates the double vision. Bilateral trochlear palsies, as may occur after head trauma, give a characteristic alternating hyperdeviation depending on the direction of gaze (unilateral traumatic trochlear paresis is still the more common finding with head injury). A useful review of the approach to vertical diplopia is given by Palla and Straumann. Sixth (Abducens) Nerve Lesions of the sixth nerve result in a paralysis of the abducens muscle and a resultant weakness of lateral or outward movement leading to a crossing of
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the visual axes. The affected eye deviates medially, i.e., in the direction of the opposing muscle. With incomplete sixthnerve palsies, turning the head toward the side of the paretic muscle overcomes the diplopia. The main causes of individual oculomotor palsies and of combined palsies are listed in Table 14-3 and are illustrated in Fig. 14-6 and below.
The Analysis of Diplopia Almost all instances of diplopia (i.e., seeing a single object as double) are the result of an acquired paralysis or paresis of one or more extraocular muscles. The signs of the oculomotor palsies, as described above, are manifest in various degrees of completeness. With complete palsies, the affected muscle can often be surmised from the resting dysconjugate positions of the globes. With incomplete paresis, noting the relative positions of the corneal light
reflections and having the patient perform common versional movements will usually disclose the faulty muscle(s) as the eyes are turned into the field of action of the paretic muscle. The muscle weakness may be so slight, however, that no strabismus or defect in ocular movement is obvious, yet the patient experiences diplopia. It is then necessary to use the patient’s report of the relative positions of the images of the two eyes. Two rules are applied sequentially to identify the affected ocular muscle in the analysis of diplopia: 1. The direction in which the images are maximally separated indicates the action of a pair of muscles at fault. For example, if the greatest horizontal separation is in looking to the right, either the right abductor (lateral rectus) or the left adductor (medial rectus) muscle is weak; if maximal gazing to the left, the left lateral rectus and right medial rectus are implicated (Fig. 14-6A and B). As a
Table 14-3 MAIN CAUSES OF INDIVIDUAL AND COMBINED OCULOMOTOR PALSIES Lesions of the third (oculomotor) nerve Nuclear and intramedullary (fascicular) Infarction (midbrain stroke) Demyelination Tumor Trauma Wernicke disease Radicular (subarachnoid space and tentorial edge) Aneurysm (posterior communicating or basilar) Meningitis (infectious, neoplastic, granulomatous) Diabetic infarction Tumor Raised intracranial pressure (shift and herniation of medial temporal lobe, hydrocephalus, pseudotumor cerebri) Cavernous sinus and superior orbital fissure Diabetic infarction of nerve Aneurysm of internal carotid artery Carotid-cavernous fistula Cavernous thrombosis (septic and bland) Tumor (pituitary, meningioma, nasopharyngeal carcinoma, metastasis) Pituitary apoplexy Sphenoid sinusitis and mucocele Herpes zoster Tolosa-Hunt syndrome Orbit Trauma Fungal infection (mucormycosis, etc.) Tumor and granuloma Orbital pseudotumor Uncertain localization Migraine Postinfectious cranial mono- and polyneuropathy Lesions of the fourth (trochlear) nerve Nuclear and intramedullary (fascicular) Midbrain hemorrhage and infarction Tumor Arteriovenous malformation Demyelination Radicular (subarachnoid space) Traumatic Tumor (pineal, meningioma, metastasis, etc.) Hydrocephalus Pseudotumor cerebri and other causes of increased intracranial pressure Meningitis (infectious, neoplastic, granulomatous) Source: Adapted by permission from Leigh and Zee.
Cavernous sinus and superior orbital fissure Tumor Tolosa-Hunt syndrome Internal carotid aneurysm Herpes zoster Diabetic infarction Orbit Trauma Tumor and granuloma Lesions of the sixth (abducens) nerve Nuclear (characterized by gaze palsy) and intramedullary (fascicular) Möbius syndrome Wernicke syndrome Infarction (pontine stroke) Demyelination Tumor Lupus Radicular (subarachnoid) Aneurysm Trauma Meningitis Tumor (clivus, fifth- and eighth-nerve schwannoma, meningioma) Petrous Infection of mastoid and petrous bone Thrombosis of inferior petrosal vein Trauma Cavernous sinus and superior orbital fissure Carotid aneurysm Cavernous sinus thrombosis Tumor (pituitary, nasopharyngeal, meningioma) Tolosa-Hunt syndrome Diabetic or arteritic infarction Herpes zoster Orbit Tumor and granulomas Uncertain localization Migraine Viral and postviral Transient in newborns
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corollary, if the separation is mainly horizontal, the paresis will be found in one of the horizontally acting recti (a small vertical disparity should be disregarded); if the separation is mainly vertical, the paresis will be found in the remaining vertically acting muscles, and a small horizontal deviation should be disregarded. 2. The second step in analysis identifies which of the two implicated muscles is responsible for the diplopia. The image projected farther from the center is attributable to eye with the paretic muscle. Rt. lat. rectus
Rt. med. rectus
A
B
Rt. inf. rectus
Rt. sup. rectus
C
D
Rt. sup. obl.
Rt. inf. obl.
E
F
Figure 14-6. Diplopia fields with individual muscle paralysis. The red glass is in front of the right eye, and the fields are projected as the patient sees the images (see text). A. Paralysis of right lateral rectus. Characteristic: right eye does not move to the right. Field: horizontal homonymous diplopia increasing on looking to the right. B. Paralysis of right medial rectus. Characteristic: right eye does not move to the left. Field: horizontal crossed diplopia increasing on looking to the left. C. Paralysis of right inferior rectus. Characteristic: right eye does not move downward when eyes are turned to the right. Field: vertical diplopia (image of right eye lowermost) increasing on looking to the right and down. D. Paralysis of right superior rectus. Characteristic: right eye does not move upward when eyes are turned to the right. Field: vertical diplopia (image of right eye uppermost) increasing on looking to the right and up. E. Paralysis of right superior oblique. Characteristic: right eye does not move downward when eyes are turned to the left. Field: vertical diplopia (image of right eye lowermost) increasing on looking to left and down. F. Paralysis of right inferior oblique. Characteristic: right eye does not move upward when eyes are turned to the left. Field: vertical diplopia (image of right eye uppermost) increasing on looking to left and up. (Adapted by permission from Cogan DG: Neurology of the Ocular Muscles, 2nd ed. Springfield, IL, Charles C Thomas, 1956.)
The simplest maneuver for the analysis of diplopia consists of asking the patient to follow an object or light into the six cardinal positions of gaze. When the position of maximal separation of images is identified, one eye is covered and the patient is asked to identify which image disappears. The red-glass test is an enhancement of this technique. A red glass is placed in front of the patient’s right eye (the choice of the right eye is arbitrary, but if the test is always done in the same way, interpretation is simplified). The patient is then asked to look at a flashlight (held at a distance of 1 m), to turn the eyes sequentially to the six cardinal points in the visual fields, and to indicate the positions of the red and white images and the relative distances between them. The positions of the two images are plotted as the patient indicates them to the examiner (i.e., from the patient’s perspective; Fig. 14-6). This allows the identification of both the field of maximal separation and the eye responsible for the eccentric image. If the white image on right lateral gaze is to the right of the red (i.e., the image from the left eye is projected outward), then the left medial rectus muscle is weak. If the maximum vertical separation of images occurs on looking downward and to the left and the white image is projected farther down than the red, the paretic muscle is the left inferior rectus; if the red image (from the right eye) is lower than the white, the paretic muscle is the right superior oblique. As already mentioned, correction of vertical diplopia by a tilting of the head implicates the superior oblique muscle of the opposite side. Separation of images on looking up and to the right or left will similarly distinguish paresis of the inferior oblique and superior rectus muscles. Most patients are attentive enough to open and close each eye and determine the source of the image thrown most outward in the field of maximal separation. In the classic diagram analyzing diplopia that is widely reproduced from Cogan’s 1956 book, we have noted the curiosity that the fields are shown from the perspective of the examiner rather than of the patient, as is the convention. We have taken the liberty of repairing this reversal and showing the fields from the patient’s perspective. The eyes are still shown from the examiner’s perspective. There are several alternative methods for studying the relative positions of the images of the two eyes. One, a refinement of the red-glass test, is the Maddox rod, in which the occluder consists of a transparent red lens with series of parallel cylindrical bars that transform a point source of light into a red line perpendicular to the cylinder axes. The position of the red line is easily compared by the patient with the position of a white point source of light seen with the other eye. Another technique, the alternate cover test, requires less cooperation than the red-glass test and is, therefore, a passive
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maneuver that is more useful in the examination of children and inattentive patients. It does, however, require sufficient visual function to permit central fixation with each eye. The test consists of rapidly alternating an occluder or the examiner’s hand from one eye to another and observing the deviations from and return to the point of fixation, as described earlier in the chapter in the discussion of tropias and phorias. Measuring the prismatic correction in each field of gaze with a prism bar allows the quantification of deviation and provides a method to follow diplopia over time. The more sophisticated Lancaster test uses red/green glasses and a red and green bar of laser light projected on a screen to accomplish essentially the same result but has the advantage of reflecting the actual position and torsion of each eye. Detailed descriptions of the Maddox rod and alternate cover tests, which are the ones favored by neuroophthalmologists, can be found in the monographs of Leigh and Zee and of Glaser. In all these tests the examiner is aided by committing to memory the cardinal actions of the ocular muscles shown in Fig. 14-5 and Table 14-2. Other Forms of Diplopia The red-glass and other similar tests are most useful when a single muscle is responsible for the diplopia. If testing suggests that more than one muscle is involved, myasthenia gravis and thyroid ophthalmopathy are likely causes as they affect several muscles of ocular motility. Monocular diplopia occurs most commonly in relation to diseases of the cornea and lens rather than the retina; usually the images are overlapping or superimposed rather than discrete. In most cases, monocular diplopia can be traced to a lenticular distortion or displacement but in some, no abnormality can be found. Monocular diplopia has been reported in association with cerebral disease (Safran et al), but this must be a very rare occurrence. Occasionally patients with homonymous scotomas caused by a lesion of the occipital lobe will see multiple images (polyopia) in the defective field of vision, particularly when the target is moving. Rarely, the acute onset of convergence paralysis gives rise to diplopia and blurred vision at all near points; most cases are a result of head injury, some to encephalitis or multiple sclerosis. Many instances of convergence paralysis do not have a demonstrable neurologic basis; they are caused by hysteria or remain unexplained. The ill-defined entity of divergence paralysis causes diplopia at a distance because of crossing of the visual axes; in such patients images fuse only at a near position. This disorder, the basis of which is unknown and for which there is no common lesion, is difficult to distinguish from mild bilateral sixth-nerve palsies and from convergence spasm, which is common in malingerers and hysterics. A special type of divergence paralysis is seen regularly with strokes in the rostral midbrain; these display an asymmetrical incompleteness of ocular abduction on both sides (pseudosixth palsy). Based on scant clinical data, a center for active divergence has been postulated to reside in the rostral midbrain tegmentum.
Causes of Third-, Fourth-, and Sixth-Nerve Palsies (Table 14-3) Ocular palsies may have a central cause—i.e., a lesion of the nucleus or the intramedullary (fascicular) portion of the
cranial nerve—but more often they are peripheral. Weakness of ocular muscles because of a lesion in the brainstem is usually accompanied by involvement of other cranial nerves and by signs referable to the “crossed” brainstem syndromes of a cranial nerve palsy on one side and a hemiparesis on the opposite side (see Table 34-3 and Chap. 47). Peripheral lesions, which may or may not be solitary, have a great variety of causes. Rucker (1958, 1966), who analyzed 2,000 cases of paralysis of the oculomotor nerves, found that the most common were tumors at the base of the brain or skull (primary, metastatic, meningeal carcinomatosis), head trauma, ischemic infarction of a nerve (generally associated with diabetes), and aneurysms of the circle of Willis, in that order. The sixth nerve was affected in about half of the cases; third-nerve palsies were about half as common; and the fourth nerve was involved in less than 10 percent of cases. In 1,000 unselected cases reported subsequently by Rush and Younge, trauma was a more frequent cause than neoplasm and the frequency of aneurysm-related cases was fewer than in the aforementioned series; otherwise the findings were similar. Less-common causes of paralysis of the oculomotor nerves, but nonetheless seen by most practitioners, include variants of Guillain-Barré syndrome, herpes zoster, giant cell arteritis, ophthalmoplegic migraine, carcinomatous or lymphomatous meningitis, and the granulomatous disease sarcoidosis and Tolosa-Hunt syndrome, as well as fungal, tuberculous, syphilitic, and other chronic forms of meningitis. Myasthenia gravis, discussed in Chap. 53, must always be considered in cases of ocular muscle palsy, particularly if several muscles are involved and if fluctuating ptosis is a prominent feature. Thyroid ophthalmopathy, discussed further on, presents in a similar fashion but without ptosis and is less common than myasthenia. Actually, in the single largest group (20 to 30 percent) contained in each of the above mentioned series, no cause could be assigned, although more cases are now being resolved with MRI. Sixth-Nerve Palsy Infarction of the sixth nerve is a common cause of sixth-nerve palsy in diabetics, in which case there is usually pain near the outer canthus of the eye at the onset. An idiopathic form that occurs in the absence of diabetes—possibly atherosclerotic—is also well known. Isolated sixth nerve palsy with global headache, and more specifically when the sign is bilateral, sometimes proves to be caused by raised intracranial pressure from an intracranial neoplasm. In children, the most common tumor involving the sixth nerve is a pontine glioma; in adults, it is tumor arising from the nasopharynx. As the abducens nerve passes near the apex of the petrous bone it is in close relation to the trigeminal nerve. Both may be implicated by petrositis, manifest by facial pain and diplopia (Gradenigo syndrome). Fractures at the base of the skull and petrous-clivus tumors may have a similar effect, and sometimes head injury alone is the only assignable cause, even in the absence of a fracture, fourth-nerve palsy is a more common complication of closed cranial injury (as noted below). As mentioned, unilateral or bilateral abducens weakness may be a nonspecific sign of increased intracranial pressure from any source—including brain tumor, meningitis, and pseudotumor cerebri; rarely, it may appear after
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lumbar puncture, epidural injections, or insertion of a ventricular shunt. The type of bilateral weakness of ocular abduction that arises with infarction of the rostral midbrain (pseudosixth) was described above. Occasionally, the nerve is compressed by a congenitally persistent trigeminal artery. A congenital form of bilateral abducens palsy is associated with bilateral facial paralysis (Mobius syndrome) as discussed in Chap. 38. Patients with retraction syndrome (absent sixth nerve) usually do not have diplopia and are aware of the retraction problem but an examiner may note a defect in unilateral abduction (this entity is discussed again further on). Fourth-Nerve Palsy The fourth nerve is particularly vulnerable to head trauma (this was the cause in 43 percent of 323 cases of trochlear nerve lesions collected by Wray from the literature). The reason for this vulnerability has been speculated to be the long, crossed course of the nerves. A fair number of cases remain idiopathic even after careful investigation. The fourth and sixth nerves are practically never involved by aneurysm. This reflects the relative infrequency of carotid artery aneurysms in the infraclinoid portion of the cavernous sinus, where they could impinge on the sixth nerve. (In contrast, supraclinoid aneurysms commonly involve the third nerve.) Herpes zoster ophthalmicus may affect any of the oculomotor nerves but particularly the trochlear, which shares a common sheath with the ophthalmic division of the trigeminal nerve. Diabetic infarction of the fourth nerve occurs, but far less frequently than infarction of the third or sixth nerves. Trochlear-nerve palsy may also be a false localizing sign in cases of increased intracranial pressure, but again, not nearly as often as abducens palsy. Entrapment of the superior oblique tendon is a rare cause (Brown syndrome) in which, in addition to diplopia, there is focal pain at the corner of the orbit; hence it may be mistaken for the Tolosa-Hunt syndrome, discussed further on. Trochlear-nerve palsies have been described in patients with lupus erythematosus and with Sjögren syndrome, but their basic pathology is not known. Many cases of fourthnerve palsy are idiopathic and most of these resolve. Superior oblique myokymia is an unusual but easily identifiable condition, characterized by recurrent episodes of vertical diplopia, monocular blurring of vision, and a tremulous sensation in the affected eye. The globe is observed to make small arrhythmic torsional movements, especially when viewed with an ophthalmoscope. The problem is usually benign and responds to carbamazepine but rare instances presage pontine glioma or demyelinating disease. Compression of the fourth nerve by a small looped branch of the basilar artery has been suggested as the cause of the idiopathic variety, analogous to several other better documented vascular compression syndromes affecting cranial nerves. This notion is supported by findings on MRI reported by Yousry and colleagues. Third-Nerve Palsy The third nerve is commonly compressed by aneurysm, tumor, or temporal lobe herniation. In a series of 206 cases of third-nerve palsy collected by Wray and Taylor, neoplastic diseases accounted for 25 percent and aneurysms for 18 percent. Of the neoplasms, 25 percent were parasellar meningiomas and 4 percent were pituitary adenomas. The palsy is usually chronic, progressive, and painless. As emphasized earlier, enlargement of
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the pupil is a sign of extramedullary third nerve compression because of the peripheral location in the nerve of the pupilloconstrictor fibers. By contrast, infarction of the nerve in diabetics usually spares the pupil, as the damage is situated in the central portion of the nerve. The oculomotor palsy that complicates diabetes (the cause in 11 percent in the Wray and Taylor series) develops over a few hours and is accompanied by pain, usually severe, in the forehead and around the eye. The prognosis for recovery (as in other nonprogressive lesions of the oculomotor nerves) is usually good because of the potential of the nerve to regenerate. Infarction of the third nerve occurs in nondiabetics as well. In chronic compressive lesions of the third nerve (distal carotid, basilar, or, most commonly, posterior communicating artery aneurysm; pituitary tumor, meningioma, cholesteatoma) the pupil is almost always affected by way of dilatation or reduced light response. However, the chronicity of the lesion may permit aberrant nerve regeneration. This is manifest by pupillary constriction on adduction of the eye or by retraction of the upper lid on downward gaze or adduction. Rarely, children or young adults have one or more attacks of ocular palsy in conjunction with an otherwise typical migraine (ophthalmoplegic migraine). The muscles (both extrinsic and intrinsic) innervated by the oculomotor or less commonly, by the abducens nerve, are affected. Presumably, intense spasm of the vessels supplying these nerves or compression by edematous arteries causes a transitory ischemic paralysis but these are speculations. Arteriograms done after the onset of the palsy usually disclose no abnormality. The oculomotor palsy of migraine tends to recover; after repeated attacks, however, there may be permanent partial paresis.
Painful Ophthalmoplegia, Tolosa-Hunt Syndrome, and Cavernous Sinus Syndrome (Table 14-4) Some of the diseases discussed above are associated with a degree of pain, often over the site of an affected nerve or muscle or in the immediately surrounding area. But the development over days or longer of a painful unilateral ophthalmoplegia constitutes a special syndrome that is usually traceable to an aneurysm, tumor, or inflammatory and granulomatous process in the anterior portion of the cavernous sinus or the adjacent superior orbital fissure. The idiopathic granulomatous painful condition has been termed Tolosa-Hunt syndrome; a similar but more extensive process is known as orbital pseudotumor. Although there is little pathologic material on which to base an understanding of these two diseases, they appear to be related orbital inflammations. Orbital pseudotumor causes an inflammatory enlargement of the extraocular muscles, which often also encompasses the globe and other orbital contents accompanied by injection of the conjunctiva and lid and slight proptosis (Fig. 14-7). The Tolosa-Hunt syndrome lacks these features but is occasionally associated with additional signs of cavernous sinus disease, particularly sensory loss in the periorbital branches of the trigeminal nerve. In pseudotumor of the orbit, a single muscle or sev-
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Table 14-4 CAUSES OF PAINFUL OPHTHALMOPLEGIA Vascular Intracavernous carotid artery aneurysm Posterior communicating or posterior cerebral artery aneurysm Cavernous sinus thrombosis (septic and aseptic) Carotid-cavernous fistula Diabetic oculomotor mononeuroapthy Temporal arteritis Ophthalmoplegic migraine Neoplastic Pituitary adenoma Pituitary apoplexy Pericavernous meningioma Metastatic nodules to dura of cavernous sinus Giant-cell tumor of orbital bone Nasopharyngeal tumor invading cavernous sinus or orbit Inflammatory and infectious Tolosa-Hunt syndrome Orbital pseudotumor Sinusitis Mucocele Herpes zoster Mucormycosis Sarcoidosis
eral may be involved and there is a tendency to relapse and later to involve the opposite globe. Visual loss from compression of the optic nerve is a rare complication of either condition. Associations with connective tissue disease have been reported in orbital pseudotumor but most cases in our experience have occurred in isolation. Ultrasonography examination or CT scans of the orbit show enlargement of the orbital contents in pseudotumor, mainly the muscles, similar to the findings in thyroid ophthalmopathy (which is not, however, painful unless there is secondary corneal ulceration). The inflammatory changes of Tolosa-Hunt syndrome are limited to the superior orbital fissure and can sometimes be detected by MRI; coronal views taken after gadolinium infusion show the lesion to best advantage. It should be noted, however, that sarcoidosis, lymphomatous infiltration, and a small meningioma may produce
similar radiographic findings and granulomatous (temporal) arteritis rarely causes ophthalmoplegia. The sedimentation rate in our patients has varied but it has been moderately elevated in reported cases, sometimes accompanied by a leukocytosis at the onset of symptoms. Sarcoidosis also can infiltrate the posterior orbit or cavernous sinus and cause a single or multiple unilateral nerve ophthalmoparesis as discussed in Chap. 47. Treatment Both the Tolosa-Hunt syndrome and orbital pseudotumor are treated with corticosteroids. A marked response with reduction in pain and improved ophthalmoplegia in 1 or 2 d is confirmatory of the diagnosis; however, as pointed out in the review by Kline and Hoyt, tumors of the parasellar region that cause ophthalmoplegia may also respond, albeit not to the same extent. In both diseases, we have generally given prednisone 60 mg and tapered the medication slowly; although there are no data to guide the proper treatment, corticosteroids should be continued for several weeks or longer. In the cavernous sinus syndrome, involvement of the oculomotor nerve on one or both sides is accompanied by periorbital pain and chemosis (Fig. 14-4B). In a series of 151 such cases reported by Keane, the third nerve (typically with pupillary abnormalities) and sixth nerve were affected in almost all and the fourth nerve in one-third; complete ophthalmoplegia, usually unilateral, was present in 28 percent. Sensory loss in the distribution of the ophthalmic division of the trigeminal nerve was often added, a finding that is helpful in the differentiation of cavernous sinus disease from other causes of orbital edema and ocular muscle weakness. Trauma and neoplastic invasion are the most frequent causes of the cavernous sinus syndrome, whereas conditions that in the past were commonly responsible (thrombophlebitis, intracavernous carotid aneurysm or fistula, fungal infection, meningioma) now account for a small proportion (see “Septic Cavernous Sinus Thrombophlebitis” and “Cavernous Sinus Thrombosis” in Chap. 34). A dural arteriovenous fistula is another rare cause. Chapter 34 discusses this process more fully with other disorders of the cerebral venous sinuses; the optic neuropathy that sometimes accompanies the syndrome is noted in Chap. 13. The other important considerations in older patients with painful ophthalmoplegia are temporal arteritis (see Chap. 10) and thyroid ophthalmopathy (although pain tends not to be prominent in the latter), which are discussed further on. When only the superior oblique muscle is involved and there is focal pain over the upper outer canthus, the Brown syndrome, mentioned earlier, must be considered.
Acute Ophthalmoplegia (Table 14-5)
Figure 14-7. MRI of orbital pseudotumor showing swelling of the extraocular muscles and adjacent orbital contents. This patient was responsive to corticosteroids.
When a total or nearly complete loss of eye movements of both eyes evolves within a day or days, it raises a limited number of diagnostic possibilities. Keane, who analyzed 60 such cases, found the responsible lesion to lie within the brainstem in 18 (usually infarction and less often Wernicke disease), in the cranial nerves in 26 (Guillain-Barré syndrome or tuberculous meningitis), within the cavernous sinus in 8 (tumors or infection), and at the myoneural junction in 8 (myasthenia gravis and botulism). Our experience has tended toward the Guillain-Barré syndrome, as
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Table 14-5 CAUSES OF COMPLETE OPHTHALMOPLEGIA (ACUTE SYNDROMES ARE NOTED BY AN ASTERISK) Brainstem lesions Wernicke disease* Pontine infarction* Infiltrating glioma Acute disseminated encephalomyelitis and multiple sclerosis Cranial nerve lesions Guillain-Barré syndrome* Neoplastic meningitis Granulomatous meningitis (tuberculous, sarcoid) Cavernous sinus thrombosis Tolosa-Hunt syndrome Orbital pseudotumor* Neuromuscular junction syndromes Myasthenia gravis* Thyroid ophthalmopathy Lambert-Eaton syndrome Botulism* Congenital myasthenic syndromes (“slow-channel” disease) Muscle disease Progressive external ophthalmoplegia (mitochondrial and dystrophic types) Oculopharyngeal dystrophy Congenital polymyopathies (myotubular, nemaline rod, central core)
did Keane’s later series (2007), and, somewhat less frequently in our material, myasthenia. The ophthalmoplegic form of Guillain-Barré syndrome is almost always associated with circulating antibodies to GQ1b ganglioside (see Chap. 46). There may be an accompanying paralysis of the dilator and constrictor of the pupil (“internal ophthalmoplegia”) that is not seen in myasthenia. Unilateral complete ophthalmoplegia has an even more limited list of causes, largely related to local disease in the orbit and cavernous sinus, mainly infectious, neoplastic, or thrombotic and most of which have already been mentioned.
Chronic and Progressive Bilateral Ophthalmoplegia This is most often caused by an ocular myopathy (the mitochondrial disorder known as progressive external ophthalmoplegia), a restricted muscular dystrophy, thyroid ophthalmopathy (see below and Chap. 51), and, sometimes, myasthenia gravis or Lambert-Eaton syndrome. We have encountered instances of the LambertEaton myasthenic syndrome that caused an almost complete ophthalmoplegia (but not as an initial sign, as it may be in myasthenia) and a patient with paraneoplastic brainstem encephalitis similar to the case reported by Crino and colleagues, but both of these are certainly rare as causes of complete loss of eye movements. Among the group of congenital myopathies, most of which are named for the morphologic characteristic of the affected limb musculature. A few of these—such as the central core, myotubular, and nemaline types, as well as the slow channel congenital myasthenic syndrome—may cause a generalized ophthalmoparesis (see Chaps. 52 and 53). The Duane retraction syndrome (so-called because of the retraction of the globe and narrowing of the palpebral fis-
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sure that are elicited by attempted adduction) occurs when the lateral rectus branches are aberrantly innervated by the third nerve. Cocontraction of the medial and lateral recti results in retraction of the globe in all directions of ocular movement. Thyroid ophthalmopathy is discussed below.
Mechanical-Restrictive Ophthalmoparesis Several causes of a pseudoparalysis of ocular muscles are distinguished from the neuromuscular and brainstem diseases discussed above. In thyroid disease, a swollen and tight inferior or superior rectus muscle may limit upward and downward gaze; less frequently, involvement of the medial rectus limits abduction. The frequency of involvement of the ocular muscles is given by Wiersinga and colleagues as inferior rectus 60 percent; medical rectus 50 percent; and superior rectus 40 percent. The extraocular muscle enlargement can be demonstrated by CT scans and ultrasonography. Their inelasticity is confirmed by forced duction tests in which the insertions of the extraocular muscles are anesthetized and grasped by toothed forceps and attempts to move the globe are palpably restricted. In most instances of thyroid ophthalmopathy, diagnosis is clear as there is an associated proptosis, but in the absence of the latter sign, and particularly if the ocular muscles are affected on one side predominantly, there may be difficulty. This disorder is discussed further in Chap. 51. In a significant number of cases, 10 percent according to Bahn and Heufelder, there are no signs of hyperthyroidism. However, most of these patients have laboratory evidence of thyroid autoimmune disease.
Mixed Gaze and Ocular Muscle Paralysis We have already considered two types of neural paralysis of the extraocular muscles: paralysis of conjugate movements (gaze) and paralysis of individual ocular muscles. Here we discuss a third, more complex one—namely, mixed gaze and ocular muscle paralysis. The mixed type is always a sign of an intrapontine or mesencephalic lesion that may be caused by a wide variety of pathologic changes.
Internuclear Ophthalmoplegia and Other Pontine Gaze Palsies These abnormalities have already been mentioned previously because they are components of numerous tegmental brainstem syndromes affecting both horizontal and vertical gaze. A lesion of the lower pons in or near the sixth-nerve nucleus causes an ipsilateral paralysis of the lateral rectus muscle and a failure of adduction of the opposite eye, which is manifest simply as a gaze palsy to the side of the lesion. As already indicated, a presumed pontine center accomplishes horizontal conjugate gaze by simultaneously innervating the ipsilateral lateral rectus (via the abducens neurons) and the contralateral medial rectus via fibers that originate in the internuclear neurons of the abducens nucleus and cross at the level of the nucleus to traverse the MLF of the opposite side (Fig. 14-1). With a complete lesion of the left MLF, the left ipsilateral eye fails to adduct when the patient looks to the right; this condition is referred to as internuclear ophthalmoplegia (INO; reciprocally, with a lesion of the right MLF, the right eye
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fails to adduct when the patient looks to the left—namely, right internuclear ophthalmoplegia). Quite often, rather than a complete paralysis of adduction, there are only slowed adducting saccades in the affected eye while its opposite quickly arrives at its fully abducted position This can be brought out by having the patient make large side-to-side refixation movements between two targets or by observing the slowed corrective saccades induced by optokinetic stimulation. Typically, the affected eye at rest does not lie in an abducted position, but there are exceptions and in most cases this finding most dependably differentiates INO from a partial third-nerve palsy with weakness of the medial rectus muscle. The two medial longitudinal fasciculi lie close together, each being situated adjacent to the midline, so that they are frequently affected together, yielding a bilateral internuclear ophthalmoplegia; this condition should be suspected when the predominant ocular finding is bilateral paresis of adduction. A second component of INO is a nystagmus that is limited to or most prominent in the opposite (abducting) eye. The intensity of nystagmus varies greatly from case to case. Several explanations have been offered to account for this dissociated nystagmus, all of them speculative. The favored one invokes the Hering law in which activated pairs of yoked muscles receive equal and simultaneous innervation; because of an adaptive increase in innervation of the weak adductor there is a commensurate increase in innervation to the strong abductor (manifest as nystagmus). Whatever the afferent stimulus for this overdrive, it is probably proprioceptive, because occlusion of the affected eye does not suppress the nystagmus. The MLF also contains axons that originate in the vestibular nuclei and govern vertical eye position, for which reason an INO may also cause a skew (vertical deviation of one eye) or monocular vertical nystagmus with impairment of vertical fixation and pursuit (bilaterally with bilateral INO). Lesions involving the MLF in the high midbrain cause a loss of convergence (“anterior” internuclear ophthalmoplegia); more commonly the MLF is involved by a lesion in the pons and convergence is spared, but there is then sometimes an additional slight degree of horizontal gaze or sixth-nerve palsy as a result of disturbance of adjacent horizontal gaze centers (“posterior” internuclear ophthalmoplegia). The main cause of unilateral INO is a small paramedian pontine infarction. Other common lesions are lateral medullary infarction (where skew deviation is often a component), a demyelinating plaque of multiple sclerosis (more common as a cause of bilateral INO, as noted below), lupus erythematosus, and infiltrative tumors of the brainstem and fourth ventricular region. Occasionally, an INO is an unexplained finding after mild head injury or with subdural hematoma or hydrocephalus. Some of the more unusual causes are given personal experience by Keane (2005). Bilateral INO is most often the result of a demyelinating lesion (multiple sclerosis) in the posterior part of the midpontine tegmentum. Pontine myelinolysis, pontine infarction from basilar artery occlusion, Wernicke disease, or infiltrating tumors are other causes. Brainstem damage
following compression by a large cerebral mass has on occasion produced the syndrome. An ipsilateral gaze palsy is the simplest oculomotor disturbance that results from a lesion in the paramedian tegmentum. The palsy is, of course, on the side of the lesion and the eyes are deviated contrawise. Another common pontine disorder of ocular movement combines an internuclear ophthalmoplegia and a horizontal gaze palsy on the same side. As a result, one eye lies fixed in the midline for all horizontal movements; the other eye makes only abducting movements and may be engaged in horizontal nystagmus in the direction of abduction (“one-and-a-half syndrome” of Fisher; see also Wall and Wray). Unlike the situation of an INO alone, the mobile eye rests abducted because of the gaze palsy, a sign that has been termed “paralytic pontine exotropia.” In some cases the patient is able to adduct the eye (“nonparalytic exotropia,” a condition which has other causes). The lesion in the one-and-ahalf syndrome involves the pontine center for gaze plus the adjacent ipsilateral MLF on one side; it is usually of vascular or, less often, demyelinative cause. A related condition is “wall-eyed bilateral internuclear ophthalmoplegia” (WEBINO), which probably represents a bilateral form of the one-and-a-half syndrome. Caplan has summarized the features of mixed oculomotor defects that occur with thrombotic occlusion of the upper part of the basilar artery (“top of the basilar” syndromes). These include upgaze or complete vertical gaze palsy and so-called pseudoabducens palsy, mentioned earlier. The latter is characterized by bilateral incomplete esotropia that simulates bilateral sixth nerve paresis but appears to be a type of sustained convergence or a paresis of divergence; it can be overcome by vestibular stimulation. Among the most unusual of the complex ocular disturbances is a subjective tilting of the entire visual field that may produce any angle of divergence but most often creates an illusion of environmental tilting of 45 to 90 degrees (tortopia) or of 180-degree vision (upside-down vision). Objects normally on the floor, such as chairs and tables, are perceived to be on the wall or ceiling. Although this symptom may arise as a result of a lesion of the parietal lobe or in the otolithic (utricular) apparatus, it has most often been associated in our experience with an internuclear ophthalmoplegia and slight skew deviation. Presumably the vestibular-otolithic nucleus or its connections in the MLF that maintain the vertical position of the ipsilateral eye are impaired. Lateral medullary infarction has been a common cause; other cases may be migrainous (Ropper, 1983). Ocular lateropulsion, in which the eyes are driven to one side and the patient feels pushed or pulled in the same direction, is another component in some cases of lateral medullary infarction. Skew Deviation Skew deviation is a disorder in which there is vertical deviation of one eye above the other that is caused by an imbalance of the vestibular inputs to the oculomotor system. The patient may complain of similar degrees of diplopia in all fields of gaze (comitant), or diplopia may vary with different directions of gaze. In either case, the patient complains of vertical diplopia. A noncomitant vertical deviation of the eyes, most pronounced when the affected eye is adducted and turned down, is characteristic of fourth-nerve palsy, described further on. Skew deviation
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does not have precise localizing value and is associated with a variety of lesions of the cerebellum and the brainstem, particularly those involving the MLF. With skew deviation due to cerebellar disease, the eye on the side of the lesion usually rests lower (in a ratio of 2:1 in Keane’s series), but sometimes it is higher than the other eye. The corresponding image, of course, rests higher in the first instance and lower with the latter, which is most often a component of an INO. The hypertropic eye has been known to alternate with the direction of gaze (“alternating skew”) and has also been seen with the condition known as periodic alternating nystagmus. A cerebellar or other posterior fossa lesion is the usual cause. A mechanism for this sign has been proposed based on otolithic influences on cerebellar centers. Ford and coworkers have described a rare form of skew deviation caused by a monocular palsy of elevation stemming from a lesion immediately rostral to the ipsilateral oculomotor nucleus; a lesion of upgaze efferents from the ipsilateral riMLF was postulated but an abnormality of the vertical gaze holding mechanism related to the function of the INC is an alternative explanation.
Nystagmus Nystagmus refers to involuntary rhythmic movements of the eyes and is of two general types. In the more common jerk nystagmus, the movements alternate between a slow component and a fast corrective component, or jerk, in the opposite direction. In pendular nystagmus, the oscillations are roughly equal in rate in both directions, although on lateral gaze the pendular type may be converted to the jerk type with the fast component to the side of gaze. Nystagmus reflects an imbalance in one or more of the systems that maintain stability of gaze. The causes may therefore be viewed as originating in (1) structures that maintain steadiness of gaze in the primary position; (2) the system for holding eccentric gaze—the so-called neural integrator; or (3) the VOR system, which maintains foveal fixation of images as the head moves. Abadi reviews these theoretical aspects of nystagmus. For the purposes of clinical work, however, certain types of nystagmus are identified as corresponding to lesions in specific structures within each of these systems, and it is this approach that we take in the following pages. It follows that nystagmus can be classified as the result of a disturbance in the vestibular apparatus or its brainstem nuclei, the cerebellum, or a number of specific regions of the brainstem such as the MLF. In testing for nystagmus, the eyes should be examined first in the central position and then during upward, downward, and lateral movements. Jerk nystagmus is the more common type. It may be horizontal or vertical and is elicited particularly on ocular movement in these planes, or it may be rotatory and, rarely, refractory or vergent. By custom the direction of the nystagmus is designated according to the direction of the fast component. There are several varieties of jerk nystagmus. Some occur spontaneously; others are readily induced in normal persons by drugs or by labyrinthine or visual stimulation. Drug intoxication is certainly the most frequent cause of nystagmus. Alcohol, barbiturates, other sedative-hypnotic drugs, phenytoin, and other antiepileptic drugs are the
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common ones. This form of nystagmus is most prominent on deviation of the eyes in the horizontal plane, but occasionally it also may appear in the vertical plane. For no known reason, it may occasionally be asymmetrical in the two eyes. Oscillopsia is the illusory movement of the environment in which stationary objects seem to move back and forth, up and down, or from side to side. It may be associated with ocular flutter (a cerebellar sign as discussed later) or with coarse nystagmus of any type. With lesions of the labyrinths (as in aminoglycoside toxicity), the symptom of oscillopsia is only provoked by motion—e.g., walking or riding in an automobile—and indicates an impaired ability of the vestibular system to stabilize ocular fixation during body movement (i.e., impaired VOR function). In these circumstances cursory examination of the eyes may disclose no abnormalities; however, if the patient’s head is rotated slowly from side to side or moved rapidly in one direction while attempting to fixate a target, impairment of smooth eye movements and their replacement by saccadic movements is evoked (see Chap. 15 for further discussion of these tests). If episodic and involving only one eye, oscillopsia is usually caused by myokymia of an ocular muscle (usually the superior oblique).
Nystagmus of Labyrinthine Origin (See also Chap. 15) This is predominantly a horizontal or vertical unidirectional jerk nystagmus, often with a slight torsional component, that is evident when the eyes are close to the central position and does not change with the direction of gaze. It is more prominent when visual fixation is eliminated (conversely, it is suppressed by fixation). The observation of suppression with visual fixation is facilitated by the use of Frenzel lenses, but most instances are evident without elaborate apparatus. Vestibular nystagmus of peripheral (labyrinthine) origin beats in most cases away from the side of the lesion and increases as the eyes are turned in the direction of the quick phase (the Alexander law). In contrast, as noted below, nystagmus of brainstem and cerebellar origin is most apparent when the patient fixates upon and follows a moving target and the direction of nystagmus changes with the direction of gaze. Labyrinthine-vestibular nystagmus is horizontal, vertical, or oblique, and that of purely labyrinthine origin characteristically has an additional torsional component. Tinnitus and hearing loss are often associated with disease of the peripheral labyrinthine mechanism; also, vertigo, nausea, vomiting, and staggering may accompany disease of any part of the labyrinthine-vestibular apparatus or its central connections. These points are elaborated in Chap. 15. As a characteristic example, the intense nystagmus of benign positional vertigo (described fully in Chap. 15) is evoked by moving from the sitting to the supine position, with the head turned to one side. In this condition, nystagmus of vertical-torsional type and vertigo develop a few seconds after changing head position and persist for another 10 to 15 s. When the patient sits up, the nystagmus changes to beat in the opposite direction. In many normal individuals, a few irregular jerks are observed when the eyes are moved far to one side (“nys-
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tagmoid” jerks), but the movements cease once lateral fixation is attained. A fine rhythmic nystagmus may also occur normally in extreme lateral gaze, beyond the range of binocular vision; but it is bilateral and disappears as the eyes move a few degrees toward the midline. These latter movements are probably analogous to the tremulousness of skeletal muscles when maximally contracted.
Nystagmus Caused by Brainstem and Cerebellar Disease Brainstem lesions often cause a coarse, unidirectional, gazedependent nystagmus, which may be horizontal or vertical, meaning that the nystagmus is exaggerated when the eyes sustain an eccentric position of gaze; vertical nystagmus, for example, is brought out usually on upward gaze, less often downward. Unlike the vestibular nystagmus discussed above, the central type usually changes direction depending on the direction of gaze. The presence of bidirectional vertical nystagmus usually indicates disease in the pontomedullary or mesencephalic tegmentum. Vertigo is less common or less intense than with labyrinthine nystagmus, but signs of disease of other nuclear structures and tracts in the brainstem are frequent. Upbeat nystagmus is observed frequently in patients with demyelinating or vascular disease, tumors, or Wernicke disease. There is still uncertainty about the anatomic basis of coarse upbeat nystagmus. According to some authors, it has been associated with lesions of the anterior cerebellar vermis, but we have not observed such cases. Kato and associates cite cases with a lesion at the pontomedullary junction involving the nucleus prepositus hypoglossi, which receives vestibular connections and projects to all brainstem and cerebellar regions concerned with oculomotor functions. Bilateral internuclear ophthalmoplegia is also a cause. Downbeat nystagmus, which is always of central origin, is characteristic of lesions in the medullary–cervical region such as syringobulbia, Chiari malformation, basilar invagination, and demyelinating plaques. It has also been seen with Wernicke disease and may be an initial sign of either paraneoplastic brainstem encephalitis or cerebellar degeneration with opsoclonus. Downbeat nystagmus, usually in association with oscillopsia, has also been observed in patients with lithium intoxication or with profound magnesium depletion (Saul and Selhorst). Halmagyi and coworkers, who studied 62 patients with downbeat nystagmus, found that half were associated with the Chiari malformation and various forms of cerebellar degeneration; in most of the remainder, the cause could not be determined. A case associated with antibodies against glutamic acid decarboxylase (GAD), a substance that has a documented relationship to the stiff man syndrome has been reported by Antonini and colleagues. Whether this antibody explains the idiopathic cases is not known. Nystagmus of several types—including gaze-evoked nystagmus, downbeat nystagmus, and “rebound nystagmus” (gaze-evoked nystagmus that changes direction with refixation to the primary position)—occurs with cerebellar disease, particularly with lesions of the vestibulocerebellum or with brainstem lesions that involve the nucleus prepositus hypoglossi and the medial vestibular nucleus.
Characteristic of cerebellar disease are several closely related disorders of saccadic movement that appear as nystagmus (opsoclonus, flutter, dysmetria) described below. Tumors situated in the cerebellopontine angle may cause a coarse bilateral horizontal nystagmus that is higher amplitude to the side of the lesion. Nystagmus that occurs only in the abducting eye is referred to as dissociated nystagmus and is a common sign of internuclear ophthalmoplegia, as discussed above.
Infantile (Congenital, Pendular) Nystagmus This is found in a variety of conditions in which central vision is lost early in life, such as albinism and various other diseases of the retina and refractive media. Occasionally it is observed as a congenital abnormality, even without poor vision. The defect is postulated to be an instability of smooth pursuit or gaze-holding mechanisms. The nystagmus is always binocular and in one plane; i.e., it will remain horizontal even during vertical movement. It is mainly pendular (sinusoidal) except in extremes of gaze, when it comes to resemble jerk nystagmus. Head oscillation may accompany the nystagmus and is probably compensatory. With eye movement recordings it displays a feature unique among nystagmus, an exponentially increasing velocity of the slow phase. Indications as to the congenital nature of nystagmus are that it remains horizontal in all directions of gaze; it is suppressed during convergence and may be associated with odd head positions or with head oscillations and with strabismus. Also characteristic is a paradoxical response to optokinetic testing (see below), in which the quick phase is in the same direction as the drum rotation. The related condition of latent nystagmus is the result of a lack of normal development of stereoscopic vision and may be detected by noting that the nystagmus changes direction when the eyes are alternately covered. In addition, severe visual loss or blindness of acquired type that eliminates the ability to accurately direct gaze, even in adulthood, produces nystagmus of pendular or jerk variety. Both horizontal and vertical components are evident and the characteristic feature is a fluctuation over several seconds of observation in the dominant direction of beating. The formerly common syndrome of “miner’s nystagmus” is an associated condition that occurs in patients who have worked for many years in comparative darkness. The oscillations of the eyes are usually very rapid, increase on upward gaze, and may be associated with compensatory oscillations of the head and intolerance of light. Spasmus nutans, a specific type of pendular nystagmus of infancy, is accompanied by head nodding, and occasionally by wry positions of the neck. Most cases begin between the fourth and twelfth months of life, never after the third year. The nystagmus may be horizontal, vertical, or rotatory; it is usually more pronounced in one eye than the other (or limited to one eye) and can be intensified by immobilizing or straightening the head. Most infants recover within a few months or years. Most cases are idiopathic, but symptoms like those of spasmus nutans betray the presence of a perichiasmal or third ventricular tumor
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(see also seesaw nystagmus below in “Other Types of Nystagmus”); rare cases accompany childhood retinal diseases. Although there is no direct connection, the rare condition of bobble-head doll syndrome, consisting of rhythmic head movements, is also caused by lesions in or adjacent to the third ventricle as described in Chap 30. Acquired forms of pendular nystagmus may occur with adult leukodystrophies (Chap. 37), multiple sclerosis (Chap. 36), toluene intoxication, and in the oculomasticatory myorhythmia of Whipple disease, in which the nystagmus is conjoined to rhythmic jaw movements (Chap. 32).
Optokinetic Nystagmus When one is watching a moving object (e.g., the passing landscape from a train window, a rotating drum with vertical stripes, or a strip of cloth with similar stripes), a rhythmic jerk nystagmus, optokinetic nystagmus (OKN), normally appears. This phenomenon is explained by a slow component of nystagmus that represents an involuntary pursuit movement to the limit of comfortable conjugate gaze followed by a quick saccadic movement in the opposite direction in order to fixate the next new target that is entering the visual field. With unilateral lesions of the parietal region, the slow pursuit phase of the OKN may be lost or diminished when the stimulus—e.g., the striped OKN drum—is moving toward the side of the lesion, whereas rotation of the drum to the opposite side elicits a normal response. (A prominent neurologist of our acquaintance in past days correctly made the diagnosis of parietal lobe abscess on the basis of fever and absent pursuit to the side of the lesion.) It is remarkable that patients with hemianopia caused by an occipital lobe lesion show a normal optokinetic response. The loss of the pursuit phase with a parietal lesion is presumably because of interruption of efferent pathways from the parietal cortex to the brainstem centers for conjugate gaze. On the other hand, frontal lobe lesions allow the eyes to tonically follow in the direction of the target but with little or no fast-phase correction in the direction opposite the lesion. In recent years, however, it has been suggested from primate experiments that there is a subcortical relay station for OKN in the geniculate nucleus of the optic tract contralateral to the slow phase of nystagmus. An important additional fact about OKN is that the ability to evoke it in all directions proves that the patient is not blind. Each eye can be tested separately to exclude monocular blindness. Thus the test is of particular value in the examination of hysterical patients and malingerers who claim that they cannot see, and of neonates and infants (a nascent OKN is established within hours after birth and becomes more easily elicitable over the first few months of life). Labyrinthine stimulation—e.g., irrigation of the external auditory canal with warm or cold water, or “caloric testing”—produces a marked nystagmus. Cold water induces a slow tonic deviation of the eyes toward the irrigated ear and a compensatory nystagmus in the opposite direction; warm water does the reverse. Thus the acronym taught to generations of medical students: COWS, or “cold opposite, warm same,” to refer to the direction of the fast phase of the induced nystagmus. The slow tonic component
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reflects impulses originating in the semicircular canals, and the fast component is a corrective movement. Chapter 15 discusses the production of nystagmus by labyrinthine stimulation and other features of vestibular nystagmus.
Other Types of Nystagmus Convergence nystagmus has already been alluded to in several contexts—it refers to a rhythmic oscillation in which a slow abduction of both eyes is followed by a quick movement of adduction, usually accompanied by quick rhythmic retraction movements of the eyes (nystagmus retractorius, retraction nystagmus) and by one or more features of the Parinaud–dorsal midbrain syndrome discussed earlier in the chapter. There may also be rhythmic movements of the eyelids or a maintained spasm of convergence, best brought out on attempted elevation of the eyes on command or downward rotation of an OKN drum. These unusual phenomena all point to a lesion of the upper midbrain tegmentum and are usually manifestations of vascular disease, traumatic damage, or tumor, notably pinealoma that compresses this region. Seesaw nystagmus is a torsional-vertical oscillation in which the intorting eye moves up and the opposite (extorting) eye moves down, then both move in the reverse direction. It is occasionally observed in conjunction with chiasmatic bitemporal hemianopia caused by sellar or parasellar masses. Spasmus nutans has some similarities, as mentioned above, and alternating skew may be a related phenomenon. Periodic alternating nystagmus is a remarkable horizontal jerking that periodically (every 90 seconds or so) changes direction, interposed with a brief neutral period during which the eyes show no nystagmus, or jerk downward. Alternating nystagmus is seen with lesions in the lower brainstem but has also been reported with CreutzfeldtJakob disease, hepatic encephalopathy, lesions of the cerebellar nodulus, carcinomatous meningitis, anti-GAD antibodies, and varied other processes. A congenital form is associated with albinism. It differs from ping-pong gaze, which is a saccadic variant with a more rapid alternating of gaze from side to side and usually the result of bilateral cerebral strokes. So-called palatal nystagmus, which is really a tremor, is caused by a lesion of the central tegmental tract and may be accompanied by a convergence–retraction nystagmus that has the same beat as the palatal and pharyngeal muscles, as discussed in Chap. 4.
Other Spontaneous Ocular Movements Roving conjugate eye movements are characteristic of light coma. Slow horizontal ocular deviations that shift every few seconds from side to side (ping-pong gaze) is a form of roving eye movement that occurs with bihemispheric infarctions or sometimes with posterior fossa lesions. C.M. Fisher has noted a similar slower, side-toside pendular oscillation of the eyes (“windshield-wiper eyes”). This phenomenon has been associated with bilateral hemispheric lesions that have presumably released a brainstem pacemaker. Ocular bobbing is a term coined by Fisher to describe a distinctive spontaneous fast downward jerk of the eyes
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followed by a slow upward drift to the midposition. It is observed in comatose patients in whom horizontal eye movements have been obliterated by large destructive lesions of the pons, less often of the cerebellum. The movements may be disconjugate in the vertical plane, especially if there is an associated third-nerve palsy on one side. Other spontaneous vertical eye movements have been given a variety of confusing names: atypical bobbing, inverse bobbing, reverse bobbing, and ocular dipping. For the most part, they are observed in coma of metabolic or anoxic origin and in the context of preserved horizontal eye movements (in distinction to ocular bobbing). Ocular dipping is the term we have used to describe an arrhythmic slow conjugate downward movement followed in several seconds by a more rapid upward movement; it occurs spontaneously but may at times be elicited by moving the limbs or neck. Anoxic encephalopathy has been the most common cause, but a few cases have followed drug overdose (Ropper, 1981). Oculogyric crisis, formerly associated with postencephalitic parkinsonism, is now most often caused by phenothiazine drugs, as discussed earlier. Saccadic Intrusions (Opsoclonus and Ocular Dysmetria) This group of phasic or repetitive eye movements is distinguished from nystagmus in that the first movement is a fast saccade, in contrast to jerk nystagmus, where by definition the movement starts with a slow phase. Opsoclonus is the term applied to rapid, conjugate oscillations of the eyes in horizontal, rotatory, and vertical directions, made worse by voluntary movement or the need to fixate the eyes. These movements are continuous and chaotic, without an intersaccadic pause (hence the colorful term saccadomania), and are almost unique among disorders of ocular movement in that they persist in sleep. As indicated in Chap. 6, they are sometimes part of a widespread myoclonus associated with parainfectious disease, occasionally with AIDS, poststreptococcal infection, West Nile virus encephalitis, and rickettsial infections, but most characteristically as a paraneoplastic manifestation with severe ataxia (“Paraneoplastic Cerebellar Degeneration” discussed in Chap. 31). Opsoclonus may also be observed in patients who are intoxicated with antidepressants, anticonvulsants, organophosphates, cocaine, lithium, thallium, and haloperidol; in the nonketotic hyperosmolar state; and in cerebral Whipple disease, where the eye movements are coupled with rhythmic jaw movements (oculomasticatory myorhythmia). A childhood form, associated with limb ataxia and myoclonus that is responsive to adrenocorticotropic hormone (ACTH), may persist for years without explanation, as in the “dancing eyes” of children (Kinsbourne syndrome). However, a distant (paraneoplastic) effect of neuroblastoma remains the main consideration in children with this ocular disorder. There is also a self-limited benign form in neonates. Similar movements have been produced in monkeys by creating bilateral lesions in the pretectum. Ocular dysmetria, the analogue of limb dysmetria, consists of an overshoot of the eyes on attempted fixation followed by several cycles of oscillation of diminishing amplitude until fixation is attained. The overshoot may
occur on eccentric fixation or on refixation to the primary position of gaze. It probably reflects dysfunction of the anterosuperior vermis and underlying deep cerebellar nuclei. Ocular flutter refers to occasional bursts of very rapid horizontal oscillations around the point of fixation; this abnormality is also associated with cerebellar disease. Flutter at the end of a saccade, called flutter dysmetria (“fish-tail nystagmus”) has the appearance of dysmetria, but careful analysis indicates that it is probably a different phenomenon. Whereas the inaccurate saccades of ataxia are separated by normal brief pause (intersaccadic interval), flutter dysmetria consists of consecutive saccades without an intersaccadic interval (Zee and Robinson). Nonetheless, all those movements have the same implication of cerebellar cortical disease. Opsoclonus, ocular dysmetria, and flutter-like oscillations may occur together, or a patient may show only one or two of these ocular tremors, either simultaneously or in sequence. One hypothesis relates opsoclonus and ocular flutter to a disorder of the saccadic “pause neurons” (see above), but their exact anatomic basis has not been elucidated. Some normal individuals can voluntarily induce flutter. An eye movement difficult to classify is ocular neuromyotonia that is found after radiation that includes the field of the ocular motor nerves (and less characteristically from vascular or tumor compression). There is intermittent contraction of one or more ocular muscles that may cause paroxysmal diplopia. Superior oblique myokymia was discussed in an earlier section of the chapter.
Disorders of the Eyelids and Blinking A consideration of oculomotor disorders would be incomplete without reference to the eyelids and blinking. In the normal individual, the eyelids on both sides are at the same level with respect to the limbus of the cornea and there is a variable prominence of the eyes, depending on the width of the palpebral fissure. The function of the lids is to protect the delicate corneal surfaces against injury and the retinae against glare; this is done by blinking and lacrimation. Eyelid movement is normally coordinated with ocular movement—the upper lids elevate when looking up and descend when looking down. Turning the eyes quickly to the side is usually attended by a single blink, which is necessarily brief so as not to interfere with vision. When the blink duration is prolonged, it is indicative of an abnormally intense effort required to initiate the saccade; usually this is because of frontal lobe or basal ganglionic disease. Closure and opening of the eyelids is accomplished through the reciprocal action of the levator palpebrae and orbicularis oculi muscles. Relaxation of the levator and contraction of the orbicularis effect closure; the reverse action of these muscles effects opening of the closed eyelids. Opening of the lids is aided by the tonic sympathetic innervation of Müller’s muscles, which is innervated by sympathetic fibers. The levator is innervated by the oculomotor nerve, and the orbicularis by the facial nerve. The trigeminal nerves provide sensation to the eyelids and are also the afferent limbs of corneal and palpebral reflexes.
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Central mechanisms for the control of blinking, in addition to the reflexive brainstem connections between the third-, fifth-, and seventh-nerve nuclei, include slower and polysynaptic circuits of the cerebrum, basal ganglia, and hypothalamus. Voluntary lid closure is initiated through frontobasal ganglionic connections. The eyelids are kept open by the tonic contraction of the levator muscles, which overcomes the elastic properties of the periorbital muscles. The eyelids close during sleep and certain altered states of consciousness as a result of relaxation of the levator muscles. Facial paralysis causes the closure to be incomplete. Blinking occurs irregularly at a rate of 12 to 20 times a minute, the frequency varying with the state of concentration and with emotion. The natural stimuli for the blink reflex (blinking is always bilateral) are corneal contact (corneal reflex), a tap on the brow or around the eye, visual threat, an unexpected loud sound, and, as indicated above, turning of the eyes to one side. There is normally a rapid adaptation of blink to visual and auditory stimuli but not to corneal stimulation. Electromyography of the orbicularis oculi reveals two components of the blink response, an early and late one, features that are readily corroborated by clinical observation. The early response consists of only a slight movement of the upper lids; the immediately following response is more forceful and approximates the upper and lower lids. Whereas the early part of the blink reflex is beyond volitional control, the second part can be inhibited voluntarily. Blepharospasm, an excessive and forceful closure of the lids, is a common disorder that is seen in isolation or as part of a number of dyskinesias and drug-induced movement disorders. Extremes of this condition may result in functional blindness. Increased blink frequency is a subtle part of the same condition but also occurs with corneal irritation. The opposite sign, reduced frequency of blinking (65
Years
or multifocal cortical discharges; however, as is the case with most EEG changes in neonates, these are poorly formed and less distinct than seizure discharges in later life. Presumably the immaturity of the cerebrum prevents the development of a fully organized seizure pattern. The EEG is nonetheless helpful in diagnosis. Periods of EEG suppression may alternate with sharp or slow waves, or there may be discontinuous theta activity. Electrical seizure activity in the neonate may be unattended by clinical manifestations. According to Aicardi, an early onset of myoclonic jerks, either fragmentary or massive, with an EEG pattern of alternating suppression and complex bursts of activity is particularly ominous. Ohtahara described another malignant form of neonatal seizure evolving in infancy into infantile spasms (West syndrome) and Lennox-Gastaut syndrome and leaving in its wake severe brain damage. Most of the reported patients were left mentally retarded (Brett). Neonatal seizures occurring within 24 to 48 h of a difficult birth are usually indicative of severe cerebral damage, usually anoxic, either antenatal or parturitional. Such infants often succumb, and about half of the survivors are seriously handicapped. Seizures having their onset several days or weeks after birth are more often an expression of acquired or hereditary metabolic disease. In the latter group, hypoglycemia is the most frequent cause; another, hypocalcemia with tetany, has become infrequent. A hereditary form of pyridoxine deficiency is a rare cause, sometimes also inducing seizures in utero and characteristically responding promptly to massive doses (100 mg) of vitamin B6 given intravenously. Biotinidase deficiency is another rare but correctable cause. Nonketotic hyperglycemia, maple syrup urine disease, as well as other metabolic disorders may lead to seizures in the first week or two of life and are expressive of a more diffuse encephalopathy. Benign forms of neonatal seizures have also been identified. Plouin described a form of benign neonatal clonic convulsions beginning on days 2 and 3, up to day 7, in which there were no specific EEG changes. The seizures then remitted. The inheritance was autosomal dominant. There are other nonfamilial cases with onset on days 4 to 6, wherein the partial seizures may even increase to status epilepticus; the EEG consists of discontinuous theta activity. In both these groups, the outlook for normal development is good and seizures seldom recur later in life. There are also benign forms of polymyoclonus without seizures or EEG abnormality in this age period. Some occur only with slow-wave sleep or feeding. They disappear after a few
Figure 16-3. Distribution of the main causes of seizures at different ages. Evident is the prevalence of congenital causes in childhood and the emergence of cerebrovascular disease in older patients. (Adapted from several sources including Hauser and Annegers and the texts of Engel and of Pedley.)
months and require no treatment. A form of benign nocturnal myoclonus in the neonate has also been documented.
Infantile Seizures (Occurring in the First Months, up to 2 Years) Neonatal seizures may continue into the infantile period, or seizures may begin in an infant who seemed to be normal up to the time of the first convulsive attack. The most characteristic pattern at this age is the massive sudden myoclonic jerk of head and arms leading to flexion or, less often, to extension of the body (infantile spasms, salaam spasms). This form, known as the West syndrome, as described earlier, is the most threatening of all infantile seizures. The same seizure type in infants with tuberous sclerosis (diagnosed in infancy by dermal white spots), phenylketonuria, or Sturge-Weber angiomatosis, but most often it is associated with other diseases beginning in this age period. West syndrome is probably a metabolic encephalopathy of unknown type or, in some cases, a cortical dysgenesis (Jellinger) and is identified by an EEG picture of large bilateral slow waves and multifocal spikes (hypsarrhythmia). Again, there is a benign form of infantile myoclonic epilepsy in which repetitive myoclonic jerking occurs in otherwise normal infants whose EEGs show only spike waves in early sleep. In contrast, when the myoclonus begins in infancy with fever and unilateral or bilateral clonic seizures or with partial seizures followed by focal neurologic abnormalities, there is a likelihood of developmental delay. The latter types are sometimes referred to as complicated febrile seizures, but, as indicated above, they must be distinguished from the benign familial febrile seizure syndrome discussed earlier in the chapter. Infantile spasms cease by the end of the second year and are replaced by partial and generalized grand mal seizures. They do not respond well to the usual anticonvulsant medications. While myoclonic activity with seizures in this age group raises concern of a grave condition, there is a common benign form that has a heritable component and does not lead to developmental delay.
Seizures Presenting in Early Childhood (Onset during the First 5 to 6 Years) The convulsive state in this age group may present around the age of 4 years as a focal myoclonus with or without astatic seizures, atypical absence, or generalized tonic-clonic seizures. The EEG, repeated if initially nor-
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mal, is most helpful in diagnosis; it reveals a paroxysmal 2- to 2.5-per-second spike-and-wave pattern on a background of predominant 4- to 7-Hz slow waves. Many of these cases qualify as the Lennox-Gastaut syndrome, are difficult to treat, and are likely to be associated with developmental retardation. At this age, perhaps more than any other, the first burst of seizures may take the form of status epilepticus and, if not successfully controlled, may end fatally. In contrast to the Lennox-Gastaut group, the more typical absence, with its regularly recurring 3-per-second spike-and-wave EEG abnormality, also begins in this age period (rarely before age 4 years) and carries a good prognosis. This seizure disorder responds well to medications, as indicated further on. Its features are fully described in “Absence Variants.” A number of partial epilepsies may appear for the first time during this age period and carry a good prognosis, i.e., the neurologic and intellectual capacities remain relatively unimpaired and seizures may cease in adolescence. These disorders begin between 3 and 13 years of age and there is often a familial predisposition. Most are marked by distinctive focal spike activity that is accentuated by sleep (see above, in reference to benign childhood epilepsy with centrotemporal or occipital spikes). In one form, unilateral tonic or clonic contractions of the face and limbs recur repeatedly with or without paresthesia; anarthria may follow the seizure. There are central and temporal spikes in the EEG interictally. According to Gastaut, the focus may involve an occipital lobe with EEG spiking on eye closure. An acquired aphasia was noted by Landau and Kleffner to mark the beginning of an illness in which there are partial or generalized motor seizures and multifocal spike or spike-and-wave discharges in the EEG and deterioration of language function. Tumor and arteriovenous malformation are rare causes in this age group. Rasmussen Encephalitis In other rare cases, a lesion, usually identified by MRI and confirmed by biopsy, and in some cases by special autoantibodies, takes the form of a chronic focal encephalitis. In 1958, Rasmussen described three children in whom the clinical problem consisted of intractable focal epilepsy in association with a progressive hemiparesis. The cerebral cortex disclosed a mild meningeal infiltration of inflammatory cells and an encephalitic process marked by neuronal destruction, gliosis, neuronophagia, some degree of tissue necrosis, and perivascular cuffing. Many additional cases were soon uncovered, and by 1991, in a publication devoted to this subject (edited by Andermann), Rasmussen was able to summarize the natural history of 48 personally observed patients. An expanded view of the syndrome has added several interesting features. All the patients were children ages 3 to 15 years, more girls than boys. Half of them had epilepsia partialis continua. The progression of the disease led to hemiplegia or other deficits and focal brain atrophy in most cases. The neuropathology of five fully examined cases revealed extensive destruction of the cortex and white matter with intense gliosis and lingering inflammatory reactions. The CSF in this disease shows a pleocytosis and sometimes oligoclonal bands but these are not uniform find-
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ings. Focal cortical and subcortical lesions are usually visualized by MRI and are bilateral in some cases. The finding of antibodies to glutamate receptors (GluR3) in a proportion of patients with Rasmussen encephalitis has raised interest in an immune causation (see review by Antel and Rasmussen). An autoimmune hypothesis has been supported by the findings of Twyman and colleagues that these antibodies cause seizures in rabbits and lead to the release of the neurotoxin kainate in cell cultures. However, Wendl’s group and others have found these antibodies in many types of focal epilepsy and have questioned their specificity. The unrelenting course of the disease had in the past defied medical therapy. In some patients the process has eventually burned out, but in those with continuous focal epilepsy the seizures continued despite all antiepileptic drugs. The use of high doses of corticosteroids, when started within the first year of the disease, proved beneficial in 5 of the 8 patients treated by Chinchilla and colleagues. Repeated plasma exchanges and immune globulin have also been tried, but the results are difficult to interpret. When the disease is extensive and unilateral, neurosurgeons in the past have resorted to partial hemispherectomy. The authors have cared for a number of such patients with the same discouraging results.
Seizures in Later Childhood and Adolescence These represent the most common epileptic problem in general practice. Here, we face two different issues: one relates to the nature and management of the first seizure in an otherwise normal young person and the other to the management of a patient who has had one or more seizures at some time in the past. With respect to the first, a search for a cause by MRI, CSF examination, and EEG rarely discloses a tumor, infection, or a vascular malformation and the epilepsy is then classed as idiopathic. The type of seizure that first brings the child or adolescent to medical attention is most likely to be a generalized tonicclonic convulsion and often marks the beginning of a juvenile myoclonic epilepsy, as described in the section on “Juvenile Myoclonic Epilepsy.” In the second type of case, in which there had been some type of seizure at an earlier period, one should suspect a developmental disorder, parturitional hypoxicischemic encephalopathy (birth injury), or one of the hereditary metabolic diseases. Several groups of patients fall between these two distinct types. Development may have been slightly delayed, but reportedly no seizures had occurred earlier in life. Closer investigation may disclose a history compatible with absence seizures, not always recognized as such by parents or teachers, and a typical absence EEG, which points more directly to a genetic factor and to a more favorable prognosis. When the seizures are an expression of a long-standing epileptic focus or foci that is associated with mental retardation, scholastic failure, or inadequacy of social adjustment, the diagnostic and therapeutic problem becomes much more demanding. Poor observations by the family, muddled thinking or bizarre ideation on the part of the
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patient, as well as poor compliance with therapy, may pose problems as difficult as the seizures themselves. Some patients of this group will eventually fall into the category of epilepsy with complex partial seizures. In adulthood, the seizures may interfere with work, marriage, and family relationships. In the interictal periods, the patients may exhibit bursts of bad temper, wide mood swings of sadness and anger or elation. As indicated earlier, paranoid ideation or a frank hallucinatory-delusional psychosis sometimes appears and lasts for weeks after a single seizure, without any specific EEG changes. In the large group of younger individuals with intractable seizures in early life, nearly half end up in the group identified as temporal lobe epilepsies. Huttenlocher and Hapke, in a follow-up study of 145 infants and children with intractable epilepsy, found that the majority had borderline or subnormal intelligence. This group stands in contrast to the group of otherwise normal adolescents with a first seizure whose scholastic progress and social and emotional adjustment are affected little if at all. Juvenile myoclonic epilepsy also has its onset during this age period. As described earlier, it is identified by intermittent myoclonic jerks when the patient is tired or after the ingestion of alcohol. Seizures are usually grand mal or absence, and are infrequent. The EEG shows a characteristic polyspike pattern, and treatment with certain anticonvulsants is very successful at suppressing seizures and myoclonus (see further on under “Antiepileptic Drugs—General Principles”). Finally, a first generalized seizure may bring to attention an adolescent who is abusing alcohol or another drug. Usually it is difficult from the clinical information alone to determine the type and quantity of the drug(s) and the setting in which the seizure occurred—whether in relation to overdose or withdrawal. Although steps must be taken to exclude an infection of the nervous system, vascular occlusion, or trauma, the more important issue is generally not the seizure, but the drug use and potential addiction. Opinion is divided on whether treatment is required for the older child or adolescent who comes to medical attention because of a first seizure. When such cases have been left untreated, such as in the series reported by Hesdorfer and colleagues, the risk of another seizure over 10 years was 13 percent unless the first episode was status epilepticus, in which case the risk was 41 percent. Age, sex, and the circumstances of the seizure (withdrawal from drugs or alcohol, myoclonic episodes, family history, etc.) all figured into the risk.
Seizures with Onset in Adult Life Secondary to Medical Disease Several primary diseases of the brain announce themselves by an acute convulsion, particularly primary and metastatic brain tumors; these are discussed further on in the section “Focal or Generalized Seizures in Late Adult Life.” Here we focus on generalized medical disorders as causes of single and repeated seizures. Withdrawal Seizures The possibility of abstinence seizures in patients who abuse alcohol, barbiturates, or benzodiazepine and related sedative drugs must be considered when seizures occur for the first time in adult life (or even
in adolescence). Suspicion is raised by the stigmata of alcohol abuse or a history of prolonged nervousness and depression requiring sedative drugs. Also, sleep disturbance, tremulousness, disorientation, illusions, and hallucinations are often associated with the convulsive phase of the illness. Seizures in this setting may occur singly, but as often, in a brief flurry, the entire convulsive period lasting for several hours and rarely for a day or longer, during which time the patient may display twitchiness or myoclonus and be unduly sensitive to photic stimulation. Chapter 42 discusses alcohol and other drug-related seizures in detail. Infections An outburst of seizures is also a prominent feature of all varieties of bacterial meningitis, more so in children than in adults. Fever, headache, and stiff neck provide the clues to diagnosis, and lumbar puncture yields the salient data. Myoclonic jerking and seizures appear early in acute herpes simplex encephalitis and other forms of viral, treponemal, and parasitic encephalitis, including those derived from HIV infection, both directly and indirectly such as toxoplasmosis and brain lymphoma; and in subacute sclerosing panencephalitis. In tropical countries, cysticercosis and tuberculous granulomas of the brain are very common causes of epilepsy. Seizure(s) without fever or stiff neck may be the initial manifestation of syphilitic meningitis, a fact worth noting as this process reemerges in AIDS patients. Seizures in Metabolic Encephalopathy Uremia has a strong convulsive tendency. Of interest is the relation of seizures to the development of acute anuric renal failure, generally from acute tubular necrosis but occasionally due to glomerular disease. Total anuria may be tolerated for several days without the appearance of neurologic signs, and then there is an abrupt onset of twitching, trembling, myoclonic jerks, and brief generalized motor seizures; acute hypertension probably plays a role. The entire motor constellation, one of the most dramatic in medicine, lasts several days until the patient sinks into terminal coma or recovers by dialysis. When this twitch-convulsive syndrome accompanies lupus erythematosus, seizures of undetermined cause, or generalized neoplasia, one should suspect its basis in renal failure. Other acute metabolic illnesses and electrolytic disorders complicated by generalized and multifocal motor seizures are hyponatremia and its opposite, the hypernatremic hyperosmolar state, thyrotoxic storm, porphyria, hypoglycemia, hyperglycemia, hypomagnesemia, and hypocalcemia. In all these cases rapidly evolving electrolyte abnormalities are more likely to cause seizures than those occurring gradually. For this reason it is not possible to assign absolute levels of sodium, blood urea nitrogen (BUN), or glucose concentrations above or below which seizures are likely to occur. Lead (in children) and mercury (in children and adults) are the most frequent of the metallic poisons that cause convulsions. The presence of these heavy metals in culturally based homeopathic treatments should not be overlooked. In most cases of seizures caused by metabolic and withdrawal states, treatment with antiepileptic drugs is not necessary as long as the underlying disturbance is rectified. Indeed, anticonvulsants are usually ineffective in halting the seizures if the metabolic disorder persists.
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Generalized seizures, with or without twitching, occur in the advanced stages of many other illnesses, such as hypertensive encephalopathy, sepsis—especially gram-negative septicemia with shock—hepatic stupor, and intractable congestive heart failure. Usually, seizures in these circumstances can be traced to an associated metabolic abnormality and are revealed by appropriate studies of the blood. Seizures are a central feature of the eclamptic syndrome as discussed in a separate section below. Medications as a Cause of Seizures A large number of medications are capable of causing seizures, usually when toxic blood levels are attained. The antibiotic imipenem and excessive doses of other penicillin congeners and linezolid may be responsible, particularly if renal failure leads to drug accumulation. Cefepime, a fourth-generation cephalosporin, widely used for the treatment of gram-negative sepsis, can result in status epilepticus, if given in excessive dosage (Dixit et al). The tricyclic antidepressants, bupropion, and lithium may cause seizures, particularly in the presence of a structural brain lesion. Lidocaine and aminophylline are known to induce an unheralded single convulsion if administered too quickly or in excessive doses. The use of the analgesic tramadol has also been associated with seizures. Curiously, the anesthetic propofol, which is discussed further on as a potent anticonvulsant in the treatment of status epilepticus, has caused marked myoclonic phenomena in some patients and, rarely, seizures. These may occur during induction or emergence from anesthesia or as a delayed effect (Walder et al). The list of medications that at one time or another have been associated with a convulsion is long, and if no other explanation for a single seizure is evident, the physician is advised to look up in standard references the side effects of the drugs being administered to the patient for a variety of indications. In a few of our otherwise healthy adult patients, extreme sleep deprivation coupled with ingestion of large doses of antibiotics or adrenergic medications or other remedies that are used indiscriminately for the symptomatic relief of colds has been the only plausible explanation for a single or doublet seizure. Global Arrest of Circulation and Cerebrovascular Diseases Cardiac arrest, suffocation or respiratory failure, carbon monoxide poisoning, or other causes of hypoxic encephalopathy tend to induce diffuse myoclonic jerking and generalized seizures as cardiac function resumes. The myoclonic-convulsive phase of this condition may last only a few hours or days, in association with coma, stupor, and confusion; or it may persist indefinitely as an intention myoclonus state (Lance-Adams syndrome). Convulsive seizures are quite uncommon in the acute or evolving phases of an arterial stroke. The ischemic convulsive phenomena of a “limb-shaking TIA” and a burst of generalized clonic motor activity during basilar artery occlusion have been mentioned earlier, but are uncommon. Only exceptionally will acute embolic infarction of the brain cause a focal seizure at the onset. With these exceptions, a new seizure should not be attributed to an acute arterial occlusion in the cerebrum. However, embolic infarcts involving the cortex become epileptogenic in
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fewer than 10 percent of cases but only after an interval of months or longer. It has been stated in texts that thrombotic infarcts involving the cortex are almost never convulsive at their onset but any distinction in seizure frequency between stroke types seems to us to be based on limited data. Lacunar infarction, being deep and not involving the cortical surface, of course, does not produce convulsions. In great contrast, cortical venous thrombosis with underlying ischemia and infarction acts as a highly epileptogenic lesion. The same is true for hypertensive encephalopathy (including reversible posterior encephalopathy and eclampsia) and thrombotic thrombocytopenic purpura (TTP), which has a strong tendency to cause nonconvulsive status epilepticus. The rupture of a saccular aneurysm is sometimes marked by one or two generalized convulsions. Deep cerebral hemorrhages, spontaneous or traumatic, also occasionally become sources of recurrent focal seizures. The use of anticonvulsants as prophylaxis for seizures after a typical cortical stroke of embolic or thrombotic type or cerebral hemorrhage is not necessary. The rate of such seizures has been estimated to be 3 percent or less in the first year. This subject is addressed further in Chap. 34 and by Grisar and colleagues. Seizures with Acute Head Injury It is not uncommon for severe concussion to be attended by a brief convulsive movement (see Chap. 35). The appearance is in most cases of clonic twitching but may include a momentary tonic phase. Rarely, a prolonged clonic convulsion occurs. The nature of this event, whether originating in the reticular formation as a component of concussion or from some disruption of cortical activity, is not clear. Almost invariably in our experience, the EEG recorded hours or a day later is normal, and imaging studies are likewise normal or show a small contusion. There is little to guide one in treatment of these patients; we tend to give a course of anticonvulsant medications for several months but it is not established if this is the correct approach. Aside from penetrating brain trauma, the risk of delayed seizures is low and generally does not require prophylactic anticonvulsant treatment. Further details on this subject can be found in Chap. 35.
Seizures during Pregnancy Here one contends with two problems: one, the woman with epilepsy who becomes pregnant; the other, the woman who has her first seizure during pregnancy. According to the extensive EURAP study, about twothirds of epileptic women who become pregnant have no change in seizure frequency or severity (the majority remain seizure free); the remainder are evenly split between those in whom the frequency increases and in an equal number, it lessens. In a large cohort of such women, there was a slight increase in the number of stillbirths and a doubling in the expected incidence of mental retardation and nonfebrile seizures in their offspring. Issues regarding a coagulopathy in the fetus exposed to phenobarbital (now infrequently used for adult seizure disorders) and certain of the other drugs are well known to
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obstetricians and pediatric specialists and are treated with the oral administration of vitamin K 20 mg/d during the eighth month or 10 mg IV 4 h before birth and 1 mg IM to the neonate. The conventional anticonvulsants also seem to be safe for the baby during breast-feeding in that only small amounts are excreted in lactated milk. For example, carbamazepine in human milk is found to be 40 percent of the mother’s serum concentration, which results in a neonatal blood level that is below the conventionally detectable amount. Phenytoin is excreted at 15 percent of maternal serum concentration, and valproate, being highly protein bound, is virtually absent in breast milk. No adverse effects have been attributed to these small amounts of drug. The special issue of the teratogenicity of antiepileptic drugs is addressed further on. Seizures with Eclampsia (See also Chap. 34.) This syndrome appears during the last trimester of pregnancy or soon after delivery and may announce itself by hypertension and convulsions; the latter are generalized and tend to occur in clusters. The standard practice is to induce labor or perform a cesarean section and manage the seizures as one would manage those of hypertensive encephalopathy (of which this is one type). The administration of magnesium sulfate continues to be the favored treatment by obstetricians for the prevention of eclamptic seizures; two randomized trials have reestablished its value in preventing seizures in preeclamptic women (Lucas et al) and in avoiding a second convulsion once one had occurred (Eclampsia Trial Collaborative Group). Magnesium sulfate, 10 g IM, followed by 5 g every 4 h, proved comparable to standard doses of phenytoin as prophylaxis for seizures. Our colleagues use a regimen of 4 g IV over 5 to 10 min followed by a maintenance dose of 5 g every 4 h IM or 1 to 2 g/h IV. Whether magnesium is as effective in the management of active convulsions of eclampsia remains uncertain. In nontoxic gestational epilepsy, approximately 25 percent of patients are found to have some disease (neoplastic, vascular, or traumatic) that will persist.
Focal or Generalized Seizures in Late Adult Life Hauser and Kurland reported a marked increase in the incidence of seizures as the population ages—from 11.9 per 100,000 in the 40- to 60-year-old age group to 82 per 100,000 in those 60 years of age or older. A person in the latter age group who begins to have seizures of either partial or generalized type is always to be suspected of harboring a primary or secondary tumor or a past cerebral infarct that had not declared itself clinically. Recent published series suggesting that the majority of seizures in this age group are caused by infarction and a small number by tumor are not in accord with our experience. For example, according to Sung and Chu, previous infarcts are by far the most common lesions underlying status epilepticus in late adult life, but our experience has been that old trauma is considerably more common. Probably the nature of the population in a given clinic determines the relative frequency of underlying causes. In any case, cerebral imaging settles the issue. Cortical and subcortical encephalomalacia, the result of previous traumatic contusions, is a particularly important cause of seizures among alcoholics; the lesions are revealed
by brain imaging and are typically located in the anterior frontal and temporal lobes. Brain abscess and other inflammatory and infectious illnesses remain common causes of adult seizures in tropical regions. In the elderly, seizures as a result of Alzheimer and other degenerative diseases occur in up to 10 percent of cases, but are not a source of diagnostic challenge; nonetheless, these patients are subject to falls, subdural hematoma, and all other illnesses of old age, such as cancer, that affect the brain. In the common case of an adult with a first unexplained seizure, it has been our practice to administer an antiepileptic medication and to reevaluate the situation in 6 to 12 months, with the goal of eventually discontinuing the drug. Usually, a second MRI and EEG are performed to exclude focal abnormalities that were not appreciated during the initial evaluation, but often these studies are again unrevealing. This approach has been prompted by data such as those of Hauser and colleagues, who found that about onethird of patients with a single unprovoked seizure will have another seizure within 5 years; the risk is even greater if there is a history of seizures in a sibling, a complex febrile convulsion in childhood, or a spike-and-wave abnormality in the EEG. Moreover, the risk of recurrence is greatest in the first 24 months. In patients with two or three unexplained seizures, a far higher proportion, about 75 percent, have further seizures in the subsequent 4 years.
TREATMENT OF EPILEPSY The treatment of epilepsy of all types can be divided into four parts: the use of antiepileptic drugs, the surgical excision of epileptic foci and other surgical measures, the removal of causative and precipitating factors, and the regulation of physical and mental activity.
Antiepileptic Drugs—General Principles The use of antiepileptic drugs is the most important facet of treatment. In approximately 70 percent of all patients with epilepsy, the seizures are controlled completely or almost completely by medications; in an additional 20 to 25 percent, the attacks are significantly reduced in number and severity. Table 16-5 lists the most commonly used drugs along with their dosages, effective blood levels, and serum half-lives. Because of the long half-lives of phenytoin, phenobarbital, and ethosuximide, these drugs need be taken only once daily, preferably at bedtime. Valproate and carbamazepine have shorter half-lives, and their administration should be spaced during the day. It is useful to be familiar with the serum protein-binding characteristics of antiepileptic drugs and the interactions among these drugs, and between antiepileptic and other drugs. Certain drugs are somewhat more effective in one type of seizure than in another, and it is necessary to use the proper drugs in optimum dosages for different circumstances. Initially, only one drug should be used and the dosage increased until sustained therapeutic levels have been attained. If the first drug does not control seizures, a different one should be tried, but frequent shifting of drugs is not
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Table 16-5 COMMON ANTIEPILEPTIC DRUGS USUAL DOSAGE GENERIC NAME
TRADE NAME
CHILDREN, MG/KG
Major anticonvulsants used as monotherapy Valproic acid Depakote 30–60
1,000–3,000
Phenytoin
Dilantin
4–7
300–400
Carbamazepine
Tegretol
20–30
600–1,200b
Oxcarbazepine Phenobarbital
Trileptal Luminal
10–40 3–5 (8 for infants) Lamotrigine Lamictal 0.5 Levetiracetam Keppra 20–60 Adjuvant and special-use anticonvulsants Topiramate Topamax —
Tiagabine
Gabitril
PRINCIPAL THERAPEUTIC INDICATIONS
ADULTS, MG/D
900–2,400 90–200 300–500 500–3,000b 400
—
30–60
Gabapentin
Neurontin
30–60
900–1,800b
Primidone
Mysoline
10–25
750–1,500b
Ethosuximide Methsuximide ACTH
Zarontin Celontin —
Generalized tonicclonic, partial, absence, myoclonic Generalized tonicclonic, partial, absence, myoclonic Generalized tonicclonic, partial Partial Generalized tonicclonic, partial Generalized, partial Partial, myoclonic Generalized tonicclonic, atypical absence, myoclonic, partial Partial and secondary generalized Partial and secondary generalized Generalized tonicclonic, partial Absence Absence Infantile spasms
SERUM HALF-LIFE, H
EFFECTIVE BLOOD LEVEL,a μG/ML
6–15
50–100
12–36
10–20
14–25
4–12
1–5 40–120
— 15–40
15–60 6–8
2–7 —
20–30
—
7–9
—
5–7
—
6–18
5–12
20–40 750–1,500 20–60 50–100 10–20 500–1,000 28–50 40–100 40–60 Units — — — daily Clonazepam Klonopin 0.01–0.2 2–10 Absence, myoclonus 18–50 0.01–0.07 Anticonvulsants for status epilepticus (initial loading or continuous infusion doses shown)c—phenytoin and phenobarbital used in doses higher than shown above Diazepam Valium 0.15–2 2–20 Status epilepticus — — Lorazepam Ativan 0.03–0.22 2–20 Status epilepticus — — Midazolam Versed — 0.1–0.4 mg/ Status epilepticus — — kg/h Propofol Diprivan 2.5–3.5 2–8 mg/kg/h Status epilepticus — — Fosphenytoin Cerebyx 30–50 mg 1,000–1,500 Status epilepticus — 10–20 aAverage
trough values. require slow dose escalation. Administered intravenously.
bMay c
advisable; each should be given an adequate trial before another is substituted. A general approach to the choice of drug in certain common forms of epilepsy is given in Tables 16-6 for adults and 16-7 for children, but it must be noted that there are a number of drugs that may be appropriate in each circumstance. A guide to various combinations of drugs that are helpful in refractory cases is given in Table 16-8. In changing medication, the dosage of the new drug should be increased gradually to an optimum level while the dosage of the old drug is gradually decreased; the sudden withdrawal of a drug may lead to an increase in seizure frequency or status epilepticus, even though a new antiepileptic medicine has been substituted. If seizures are still not controlled, a second drug can then be added. Seldom if ever are more than two drugs necessary. To reiterate, the physician should make an effort to succeed with one drug and with no more than
Table 16-6 CHOICES OF ANTIEPILEPTIC DRUGS BY TYPE OF ADULT SEIZURE DISORDER SEIZURE TYPE
Tonic-clonic Myoclonic
INITIAL CHOICE
Carbamazepine, valproate, phenytoin Valproate
Partial
Carbamazepine, phenytoin
Absence Unclassifiable
Valproate Valproate
SECOND LINE
Lamotrigine, oxcarbazepine Topiramate, levetiracetam, zonisamide Valporate, lamotrigine, oxcarbazine, levetiracetam Ethosuximide, lamotrigine Lamotrigine
Source: Adapted by permission from Brodie MJ, Schachter SC. Epilepsy, 2nd ed. Oxford, England, Health Press, 2001.
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Table 16-7 CHOICES OF ANTIEPILEPTIC DRUGS IN CHILDHOOD SEIZURE DISORDERS SEIZURE TYPE
INITIAL CHOICE
Tonicclonic Myoclonic
Valproate, carbamazepine Valproate
Lamotrigine, oxcarbazine Lamotrigine
Absence
Valproate
Partial
Carbamazepine, phenytoin
Infantle spasms LennoxGastaut
Vigabatrin, corticosteroids Valproate
Topiramate, levetiracetam, ethosuximide Valproate, levetiracetam, gabapentin, oxcarbazine Valproate
SECOND
Topiramate, lamotrigine
THIRD
Phenytoin Phenobarbital, clobazam Lamotrigine Lamotrigine, vigabatrin, topiramate Lamotrigine Felbamate
Source: Adapted by permission from Brodie MJ, Schachter SC. Epilepsy, 2nd ed. Oxford, England, Health Press, 2001.
two, given in adequate dosages. Once an anticonvulsant or a combination of anticonvulsants is found to be effective, their use in most cases should be maintained for a period of years, or indefinitely if circumstances and the causative lesion or disease justify their long-term use. The therapeutic dose for any given patient must be determined, to some extent by trial and error and by measurement of serum levels, as described below. Not uncommonly, a drug is discarded as being ineffective when a slight increase in dosage would have led to suppression of attacks. It is, however, also an error to administer a drug to the point where the patient is so dull and stupefied that the toxic effects are more incapacitating than the seizures. Patients can be reassured that it is doubtful that prolonged administration of antiepileptic medication is a factor in the development of the mental deterioration that occurs in a small percentage of patients with convulsive seizures. In fact, improvement in mentation more often occurs following control of the seizures. The management of seizures is facilitated by having patients chart their daily medication and the number, time, and circumstances of each episode. Some patients find it helpful to use a dispenser that is filled with medications on
Table 16-8 COMBINATION ANTIEPILEPTIC REGIMENS FOR REFRACTORY SEIZURES COMBINATION
INDICATION
Valproate and lamotrigine or levetiracetam Valproate and ethosuximide Carbamazepine and valproate Levetiracetam and lamotrigine or tiagabine Topiramate and lamotrigine or levetiracetam
Partial or generalized seizures Generalized absence Complex partial seizures Partial seizures Numerous types
Source: Adapted by permission from Brodie MJ, Schachter SC. Epilepsy, 2nd ed. Oxford, England, Health Press, 2001.
Sunday, for example, with sufficient pills to last the week. This indicates to the patient whether a dose had been missed and whether the supply of medications is running low. Furthermore, the proper use of anticonvulsant drugs is enhanced by the measurement of their serum levels. The concentrations of almost all the commonly used drugs can be measured on a single specimen by immunoassay or by the older gas-liquid chromatography method. These measurements are helpful in regulating dosage, detecting irregular drug intake, identifying the toxic agent in patients taking more than one drug, and ensuring patient compliance. Blood for serum levels is ideally drawn in the morning before breakfast, before the first ingestion of anticonvulsants (“trough levels”), a practice that introduces consistency in measurement. There is no uniform prescription for the frequency with which serum concentrations should be determined; this is determined by the difficulty in controlling seizures. Table 16-5 indicates the effective serum levels for each of the commonly used antiepileptic drugs. The upper and lower levels of the therapeutic range are not to be regarded as immutable limits. In some patients, seizures are controlled at levels below the therapeutic range; in others, seizures continue despite serum values within this range. In the latter group, control may sometimes be achieved by raising levels above the therapeutic range but not to the point of producing toxicity. In general, higher serum concentrations of drugs are necessary for the control of simple or complex partial seizures than for the control of tonic-clonic seizures. The usual blood level assay is of the total concentration of the drug; this is not a precise reflection of the amount of drug entering the brain, because—in the case of the most widely used anticonvulsants—the large proportion of drug is bound to albumin and does not penetrate nervous tissue. Also, in patients who are malnourished or chronically ill or who have a constitutional reduction in proteins, there may be intoxication at low total serum levels. Certain anticonvulsants also have active metabolites that are not measured by methods ordinarily used to determine serum concentrations but nonetheless produce toxicity. This is particularly true for the epoxide of carbamazepine. The situation may be further complicated by interactions between one anticonvulsant and the metabolites of another, as, for example, the inhibition of epoxide hydrolase by valproic acid, leading to toxicity through the buildup of carbamazepine epoxide. In circumstances of unexplained toxicity in the face of conventionally obtained serum levels that are normal, measurement may be undertaken of the levels of free drug and the concentration of active metabolites by chromatographic techniques. Drugs in common use for which tests of serum levels are not easily available include levetiracetam, topiramate, tiagabine, gabapentin, and others; this requires an empiric dosing schedule based on recommended amounts and dose escalations for each age group. Deterioration of control after the introduction of a second anticonvulsant is often the result of an induced reduction in the serum levels of the first concomitantly administered agent (see below). Rarely, worsening of seizures that occurs upon introduction of a first antiepileptic is caused by the induction of porphyria.
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Finally, the pharmacokinetics of each drug plays a role in toxicity and the serum level that is achieved with each alteration in the dose. This is particularly true of phenytoin, which, as the result of saturation of liver enzymatic capacity, has nonlinear kinetics once serum concentration exceeds 10 mg/mL. For this reason, a typical increase in dose from 300 to 400 mg daily results in a disproportionate elevation of the serum level and toxic side effects. Elevations in drug concentrations are also accompanied by prolongation of the serum half-life, which increases the time to reach a steadystate concentration of phenytoin after dosage adjustments. Contrariwise, carbamazepine is known to induce its own metabolism, so that doses adequate to control seizures at the outset of therapy are no longer effective several weeks later.
Antiepileptic Drug Interactions Antiepileptic drugs have manifold interactions with each other and with a wide variety of other drugs. Although many such interactions are known, only a few are of clinical significance and most pertain to older generations of medications, requiring adjustment of drug dosages (Kutt). Among interactions between anticonvulsant drugs, valproate often leads to accumulation of active phenytoin and of phenobarbital by displacing them from serum proteins, as well as slightly elevating serum total levels. Agents that alter the concentrations of antiepileptic medications are chloramphenicol, which causes the accumulation of phenytoin and phenobarbital, and erythromycin, which causes the accumulation of carbamazepine. Antacids reduce the blood phenytoin concentration, whereas histamine blockers used to reduce gastric acid output do the opposite. Salicylates reduce the total plasma levels of anticonvulsant drugs but elevate the free fraction by displacing the drug from its protein carrier. More importantly, warfarin levels are decreased by the addition of phenobarbital or carbamazepine and may be increased by phenytoin although, with this last drug there may be unexpected alterations of the international normalized ratio (INR) in either direction. Enzyme-inducing drugs such as phenytoin, carbamazepine, and barbiturates can greatly increase the chance of breakthrough menstrual bleeding in women taking oral contraceptives and may lead to failure of contraceptive medications, and adjustments in the amount of estradiol must be made. These interactions are emphasized further below under the discussions of each agent. Hepatic function greatly affects antiepileptic drug concentrations, since most of these drugs are metabolized in the liver. Serum levels must be checked more frequently than usual if there is liver failure, and with hypoalbuminemia it is advisable to obtain free drug levels for reasons just mentioned. Renal function has an indirect effect on the concentrations of the commonly used anticonvulsants, but some newer agents, such as levetiracetam, vigabatrin, gabapentin, and pregabalin, are excreted through the kidneys and require dosage adjustment in cases of renal failure. The main renal effects have to do with alterations in protein binding that are induced by uremia. In end-stage renal failure, serum levels are not an accurate guide to therapy and the goal should be to attain adequate free concentrations of, for example, 1 to 2 mg/mL. In addition, uremia causes the accumulation of
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phenytoin metabolites, which are measured with the parent drug by enzyme-multiplied immunoassay techniques. In patients who are being dialyzed, total blood levels of phenytoin tend to be low because of decreased protein binding; in this situation it is also necessary to track free (unbound) phenytoin levels. Because dialysis removes phenobarbital and ethosuximide, dosage of these drugs may have to be increased. Decreased phenytoin levels are also known to occur during viral illnesses, and supplementary doses are occasionally necessary.
Teratogenic Effects of Antiepileptic Medications Because it is essential to prevent convulsions in the pregnant epileptic woman, anticonvulsant medication should not be discontinued or arbitrarily reduced, particularly if there have been recent convulsions. The conventional drugs (phenytoin, carbamazepine, phenobarbital, valproate, lamotrigine) are all tolerated in pregnancy. Plasma levels of most of these drugs, both the free and proteinbound fractions, fall slightly in pregnancy and are cleared more rapidly from the blood. The main practical issue pertains to the potential teratogenicity of most of the drugs with valproate perhaps having slightly more risk than the others. The most common teratogenic effects have been cleft lip and cleft palate, but infrequently also a subtle facial dysmorphism (“fetal anticonvulsant syndrome”), similar to the fetal alcohol syndrome. In general, the risk of major congenital defects is low; it increases to 4 to 5 percent in women taking anticonvulsant drugs during pregnancy, in comparison to 2 to 3 percent in the overall population of pregnant women. These statistics are essentially confirmed in the large study by Holmes and colleagues, conducted among several Boston hospitals. When all types of malformations were included, both major and minor, 20 percent of infants born to mothers who took anticonvulsants during pregnancy showed abnormalities, compared to 9 percent of mothers who had not taken medications. However, similar to other large surveys, major malformations appeared in only 5 percent of infants exposed to anticonvulsants, in contrast to 2 percent in the nonexposed. These authors identified “midface hypoplasia” (shortened nose, philtrum, or inner canthal distance) and finger hypoplasia as characteristic of anticonvulsant exposure; these changes were found in 13 and 8 percent of exposed infants, respectively. The infants born of a group of women with epilepsy who had not taken anticonvulsants during pregnancy showed an overall rate of dysmorphic features comparable to that in control infants, but there was still a 2 to 3 percent rate of facial and finger hypoplasia. This risk is shared more or less equally by all the major anticonvulsants again, with concern that valproate is associated with a higher rate of various malformations. The risk of neural tube defects is also slightly increased by anticonvulsants during pregnancy, and greatest is for the use of valproate. It can be reduced by giving folate before pregnancy has begun (it is not clear if this is true for valproate), but some epilepsy experts prefer to avoid the use of valproate during pregnancy altogether. Also, these risks are greater in women taking more than one anticon-
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vulsant, so that monotherapy is a desirable goal. Furthermore, the risk is disproportionately increased in families with a history of these defects. Some of the newer anticonvulsants should probably be used cautiously until greater experience has been obtained. As each new anticonvulsant has been introduced over the years, there is usually a tentative claim of reduced teratogenic effects, often proven later to be incorrect. Claims have been made of safety in this regard for lamotrigine, causing many specialists to change from the more conventional drugs to this one in women who anticipate becoming pregnant, but lamotrigine levels tend to fall precipitously during pregnancy. A report by Cunningham and colleagues using registry information suggests that the incidence of major birth defects in the fetuses exposed to lamotrigine during the first trimester is just under 3 percent, similar to risk estimates for the general population but also close to the 3 to 4 percent risk derived from most registries of women on anticonvulsants. Polytherapy with lamotrigine and valproate raised the risk estimate to 12 percent. If a woman with seizure disorder has been off epilepsy medications for a time before getting pregnant and seizes during the pregnancy, the best choice of medications is probably phenytoin. Exposure of the fetus late in gestation poses few teratogenic risks. The special case of eclamptic seizures is managed by infusion of magnesium. It should be mentioned again that most of the last generation of antiepileptics induce the activity of hepatic enzymes, and this may result in the failure of contraceptive pills as a consequence of the accelerated metabolism of steroids. Epileptic women of childbearing age should be advised that higher doses of the estradiol component are required.
Skin Eruptions from Antiepileptic Drugs As mentioned in the discussion above, rashes are the most frequent idiosyncratic reactions to the drugs used to treat epilepsy. The aromatic compounds (phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine) are the ones most often responsible. Furthermore, there is a high degree of cross-reactivity within this group, particularly between phenytoin, carbamazepine, and phenobarbital, and, possibly, lamotrigine. The problem arises most often in the first month of use. The typical eruption is maculopapular, mainly on the trunk; it usually resolves within days of discontinuing the medication. More severe rashes may develop, sometimes taking the form of erythema multiforme and Stevens-Johnson syndrome, or even toxic epidermal necrolysis. Certain polymorphisms in HLA genes have been associated with an increased risk of these types of severe skin reactions but it does not seem reasonable at this time to screen all patients for such an infrequent complication. Another rare systemic hypersensitivity syndrome associated with the use of antiepileptic medications is one of high fever, rash, lymphadenopathy, and pharyngitis. Eosinophilia and hepatitis (or nephritis) may follow. If any of these reactions require that one of the aromatic drugs be replaced, valproate, gabapentin, topiramate, or levetiracetam are reasonable substitutes, depending, of course, on the nature of the seizures.
Discontinuation of Anticonvulsants Withdrawal of anticonvulsant drugs may be undertaken in patients who have been free of seizures for a prolonged period. There are few firm rules to guide the physician in this decision. One component of a safe plan, applicable to most forms of epilepsy, is to obtain an EEG whenever withdrawal of medication is contemplated. We have taken the approach that if the tracing is abnormal by way of showing paroxysmal activity, it is generally better to continue treatment. A prospective study by Callaghan and colleagues showed that in patients who had been seizurefree during 2 years of treatment with a single drug, onethird relapsed after discontinuation of the drug, and this relapse rate was much the same in adults and children and whether the drug was reduced over a period of weeks or months. The relapse rate was lower in patients with absence and generalized-onset seizures than in patients with complex partial seizures and secondary generalization. Another study by Specchio and colleagues gave results similar to those of the large Medical Research Council Antiepileptic Drug Withdrawal Study—namely, that after 2 years on a single anticonvulsant during which no seizures had occurred, the rate of relapse was 40 percent 2.5 years later and 50 percent at 5 years after discontinuation; this compared to a seizure recurrence rate of 20 percent for patients remaining on medication. Other epileptologists have suggested that a longer seizure-free period is associated with a lesser rate of relapse (see reviews of Todt and of Pedley, and comments above under “Focal or Generalized Seizures in Late Adult Life”). Patients with juvenile myoclonic epilepsy, even those with long seizure-free periods, should probably continue medication lifelong, but there have been no thorough studies to support this dictum. The appropriate duration of treatment for postinfarction epilepsy has not been studied, and most neurologists continue to use one drug indefinitely. Interestingly, epilepsy caused by military brain wounds tends to wane in frequency or to disappear in 20 to 30 years, thereafter no longer requiring treatment (Caveness). A curious and unexplained lesion in the splenium of the corpus callosum has been detected in patients who have had their antiepileptic drug(s) withdrawn in the previous few days. A review of 16 patients by Gürtler and colleagues did not find a clinical correlate for this change. A broad range of drugs was implicated and the lesion was most prominent on T2 and FLAIR sequences.
Specific Drugs in the Treatment of Seizures General Comments Phenytoin, carbamazepine, and valproate are representative of antiepileptic drugs and are more or less equally effective in the treatment of both generalized and partial seizures (see Table 16-5 for typical initial dosages). Valproate is probably less effective in the treatment of complex partial seizures. The first two of these drugs putatively act by blocking sodium channels, thus preventing abnormal neuronal firing and seizure spread. Lamotrigine is emerging as a popular alternative for partial seizures with a different side effect profile from the other three.
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Because carbamazepine (or the related oxcarbazepine) has somewhat fewer side effects, it is preferred as the initial drug by many neurologists, but phenytoin and valproate have very similar therapeutic and side-effect profiles. Carbamazepine and valproate are probably preferable to phenytoin for epileptic children because they do not coarsen facial features and do not produce gum hypertrophy or breast enlargement. In many cases, phenytoin or carbamazepine alone will control the seizures. If not, the use of valproate (which facilitates GABA activity) alone, or the combined use of phenytoin and carbamazepine, produces better control. In others, the addition of valproate to carbamazepine may prove effective. Because of the high incidence of myoclonic epilepsy in adolescence, it has been our practice to use valproate as the first drug in this age group. Weight gain, menstrual irregularities (see below) during the period of initiation of valproate, and its teratogenic effects may also figure into the decision regarding the choice of initial drug for otherwise uncomplicated seizures in young women. Finally, it should be said that most of the commonly used antiepileptic drugs cause, to varying degrees, a decrease in bone density and an increased risk of fracture from osteoporosis in older patients, particularly in women. Several mechanisms are probably active, among them, induction of the cytochrome P450 system, which enzymatically degrades vitamin D. No specific recommendations have been offered to counteract this effect of bone loss, but we have advised patients to take calcium supplements or one of the bisphosphonates, if there is no contraindication, or to check bone density at regular intervals. Phenytoin Oral, intramuscular, and intravenous forms are available. Rash, fever, lymphadenopathy, eosinophilia and other blood dyscrasias, and polyarteritis are manifestations of idiosyncratic phenytoin hypersensitivity; their occurrence calls for discontinuation of the medication. Overdose with phenytoin causes ataxia, diplopia, and stupor. The prolonged use of phenytoin often leads to hirsutism (mainly in young girls), hypertrophy of gums, and coarsening of facial features in children. Chronic phenytoin use over several decades may occasionally be associated with peripheral neuropathy and probably with a form of cerebellar degeneration (Lindvall and Nilsson); it is not clear if these are strictly dose-related effects or idiosyncratic reactions. An antifolate effect on blood and interference with vitamin K metabolism have also been reported, for which reason pregnant women taking phenytoin (and in fact most other antiepileptic drugs) should be given folate supplementation and vitamin K before delivery and the newborn infant also should receive vitamin K to prevent bleeding. Phenytoin should not be used together with disulfiram (Antabuse), chloramphenicol, sulfamethizole, phenylbutazone, or cyclophosphamide, and the use of either phenobarbital or phenytoin is not advisable in patients receiving warfarin (Coumadin) because of the undesirable interactions already described. Choreoathetosis is a rare idiosyncratic side effect. Fosphenytoin for intramuscular and intravenous administration allows somewhat faster attainment of serum levels and may have minor advantages in special circumstances,
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especially the availability of the IM route. Intravenous phenytoin and fosphenytoin are discussed further in the section on status epilepticus. Carbamazepine This drug causes many of the same side effects as phenytoin, but to a slightly lesser degree. Mild leukopenia is common, and there have been rare instances of pancytopenia, hyponatremia (inappropriate antidiuretic hormone [ADH]), and, rarely, diabetes insipidus as idiosyncratic reactions. It is essential therefore, that a complete blood count be done before treatment is instituted and that the white cell counts are checked regularly. Oxcarbazepine, a more recently introduced analogue of carbamazepine, has fewer of these side effects than the parent drug, especially marrow toxicity, but its long-term therapeutic value is not yet established. Hyponatremia has been reported in 3 percent of patients taking oxcarbazepine. Should drowsiness or increased seizure frequency occur, this complication should be suspected. Valproate All preparations of this drug are occasionally hepatotoxic, an adverse effect that is usually (but not invariably) limited to children 2 years of age and younger. The use of valproate with hepatic enzyme-inducing drugs increases the risk of liver toxicity. However, mild elevations of serum ammonia and mild impairments of liver function tests in an adult do not require discontinuation of the drug. An increasingly emphasized problem with valproate has been weight gain during the first months of therapy. In one study there was an average addition of 5.8 kg, and even more in those disposed to obesity. In addition, menstrual irregularities and polycystic ovarian syndrome may appear in young women taking the drug, perhaps as a consequence of the aforementioned weight gain. Pancreatitis is a rare but important complication of valproate. An intravenous form of valproate is available. The maximum recommended rate of administration is 3 mg/kg per min. Phenobarbital Introduced as an antiepileptic drug in 1912, phenobarbital is still highly effective, but because of its toxic effects—drowsiness and mental dullness, nystagmus, and staggering, as well as the availability of better alternatives—it is seldom used in adults. The adverse effects of primidone are much the same. Both drugs may provoke behavioral problems in retarded children. It is still used to advantage as an adjunctive anticonvulsant and as primary therapy in infantile seizures. Lamotrigine Lamotrigine closely resembles phenytoin in its antiseizure activity but has different features relating to toxicity. It functions by selectively blocking the slow sodium channel, thereby preventing the release of the excitatory transmitters glutamate and aspartate. It is effective as a first-line and adjunctive drug for generalized and focal seizures, and may be an alternative to valproate in young women because it does not provoke weight gain and ovarian problems. The main limitation to its use has been a serious rash in approximately 1 percent of patients, requiring discontinuation of the drug, and lesser dermatologic eruptions in 12 percent. It should be pointed out that some registries have reported lower rates of these complications. The slow introduction of the medication may reduce the incidence of drug eruptions (see below). Rare cases of reversible chorea have been reported, especially
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with the concurrent use of phenytoin. Combined use with valproate greatly increases the serum level of lamotrigine. Levetiracetam This is a novel drug with uncertain mechanism that has been useful in the treatment of partial and generalized seizures, mainly but not only as an adjunct. The agent affects the SV2A synaptic vesicle protein, but how this relates to its antiepileptic properties is still being investigated. It is well tolerated if initiated slowly, but produces considerable sleepiness and dizziness otherwise and if used at high doses. A major advantage is that there are no important interactions with other antiepileptic drugs. Other Antiepileptic Drugs Felbamate, a drug similar to meprobamate, showed promise as an adjunctive form of treatment of generalized seizures, complex partial seizures, and Lennox-Gastaut syndrome, but its use has been greatly limited because of the rare occurrence of bone marrow suppression and liver failure. Two other drugs, gabapentin and vigabatrin, were synthesized specifically to enhance the intrinsic inhibitory system of GABA in the brain. Gabapentin is chemically similar to GABA, but its anticonvulsant mechanism is not known; it has an apparent effect on calcium channels. It is moderately effective in partial and secondary generalized seizures and has the advantage of not being metabolized by the liver. Vigabatrin inhibits GABA transaminase. Tiagabine is considered to be an inhibitor of GABA reuptake. Both are effective in the treatment of partial seizures and, to a lesser extent, primary generalized seizures. They have the advantage of few toxic effects and few known adverse drug interactions. Topiramate, another new antiepileptic agent, has much the same mode of action and probably a broader effectiveness as tiagabine. It rarely causes serious dermatologic side effects, especially if used with valproate, and appears to induce renal stones in 1.5 percent of patients. Angle-closure glaucoma has also been reported as a complication. A minor problem has been the development of hyperchloremic metabolic acidosis. Ethosuximide and valproate are equally effective for the treatment of absence seizures, the latter one being used mainly in children older than 4 years of age. It is good practice, so as to avoid excessive sleepiness, to begin with a single dose of 250 mg of ethosuximide per day and to increase it every week until the optimum therapeutic effect is achieved. Methsuximide (Celontin) is useful in individual cases where ethosuximide and valproate have failed. In patients with benign absence attacks that are associated with photosensitivity, myoclonus, and clonictonic-clonic seizures (including juvenile myoclonic epilepsy), valproate is the drug of choice. Valproate is particularly useful in children who have both absence and grand mal attacks, as the use of this drug alone often permits the control of both types of seizures. The concurrent use of valproate and clonazepam has been known to produce absence status.
Treatment of Seizures in the Neonate and Young Child This specialized area is discussed by Fenichel and by Volpe. In general, phenobarbital has been preferred for seizure control in infancy. Probably the form of epilepsy that is
most difficult to treat is the childhood Lennox-Gastaut syndrome. Some of these patients have as many as 50 or more seizures per day, and there may be no effective combination of anticonvulsant medications. Valproic acid (900 to 2,400 mg/d) will reduce the frequency of spells in approximately half the cases. The newer drugs—lamotrigine, topiramate, vigabatrin—are each effective in approximately 25 percent of cases. Clonazepam also has had limited success. In the treatment of infantile spasms, ACTH or adrenal corticosteroids had been used, but vigabatrin is now found to be as effective, including in patients with underlying tuberous sclerosis (see Elterman et al).
Status Epilepticus Recurrent generalized convulsions at a frequency that precludes regaining of consciousness in the interval between seizures (grand mal status) constitute the most serious therapeutic problem, with an overall mortality of 20 to 30 percent, according to Towne and colleagues, but probably lower in recent years. Most patients who die of epilepsy do so because of uncontrolled seizures of this type, complicated by the effects of the underlying illness or an injury sustained as a result of a convulsion. Rising temperature, acidosis, hypotension, and renal failure from myoglobinuria is a sequence of life-threatening events that may be encountered in cases of status epilepticus. Prolonged convulsive status (for longer than 30 min) also carries a risk of serious neurologic sequelae (“epileptic encephalopathy”). The MRI during and for days after a bout of status epilepticus may show signal abnormalities in the region of a focal seizure or in the hippocampi, most often reversible, but we have had several such patients who awakened and were left in a permanent amnesic state. The MRI changes are most evident in FLAIR sequences. With regard to acute medical complications, from time to time a case of neurogenic pulmonary edema is encountered during or just after the convulsions, and some patients may become extremely hypertensive, making it difficult to distinguish the syndrome from hypertensive encephalopathy. The etiologies of status epilepticus vary between age groups but all the fundamental causes of seizures are able to produce the syndrome. The most recalcitrant cases we have encountered in adults were associated with viral or paraneoplastic encephalitis, old traumatic injury, and epilepsy with idiopathic mental retardation. Stroke and brain tumor have, in contrast, been infrequent. Treatment of Status Epilepticus (Table 16-9) The many regimens that have been proposed for the treatment of status epilepticus attest to the fact that no one of them is altogether satisfactory and none is clearly superior (Treiman et al). We have had the most success with the following program: When the patient is first seen, an initial assessment of cardiorespiratory function is made and an oral airway established. A large-bore intravenous line is inserted; blood is drawn for glucose, BUN, electrolytes, and a metabolic and drug screen. A normal saline infusion is begun and a bolus of glucose is given (with thiamine if malnutrition and alcoholism are potential factors). To rapidly suppress the seizures, we have used diazepam intravenously at a rate of about 2 mg/min until the seizures stop or a
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Table 16-9 APPROACH TO THE TREATMENT OF STATUS EPILEPTICUS IN ADULTS Initial assessment Ensure adequate ventilation, oxygenation, blood pressure Intubate if necessary, based on low oxygen saturation and labored breathing Insert intravenous line Administer glucose and thiamine in appropriate cirumstances Send toxic screen Assess quickly for cranial and cervical injury if onset of seizures is unwitnessed Immediate suppression of convulsions Lorazepam or diazepam, 2 to 4 mg/min IV to a total dose of 10 to 15 mg with blood pressure monitoring when higher rates or doses are used Initiation or reloading with anticonvulsants Phenytoin 15–20 mg/kg IV at 25–50 mg/min in normal saline or fosphenytoin at 50 to 75 mg/min General anesthetic doses of medication for persistent status epilepticus Midazolam 0.2 mg/kg loading dose followed by infusion at 0.1 to 0.4 mg/kg/h or propofol 2 mg/kg/h Further treatment if convulsions or electrographic seizures persist after several hours May add valproate or phenobarbital 10 mg/min to total dose of 20 mg/kg as additional anticonvulsants intravenously, or carbamazepine or levetiracetam by nasogastric tube if there is gastric and bowel activity Consider neuromuscular paralysis with EEG monitoring if convulsions persist Pentobarbital 10 mg/kg/h Inhalational anesthetics (isoflurane)
total of 20 mg has been given; alternatively, lorazepam, 0.1 mg/kg given by intravenous push at a rate not to exceed 2 mg/min, may be administered, being marginally more effective than diazepam because of its putatively longer duration of action in the CNS (see Table 16-9). Immediately thereafter, a loading dose (20 mg/kg) of phenytoin is administered by vein at a rate of less than 50 mg/min. More rapid administration risks hypotension and heart block; consequently, it is recommended that the blood pressure and electrocardiogram be monitored during the infusion. Phenytoin must be given through a freely running line with normal saline (it precipitates in other fluids) and should not be injected intramuscularly. A study by Treiman and colleagues has demonstrated the superiority of using lorazepam instead of phenytoin as the first drug to control status, but this is not surprising considering the longer latency of onset of phenytoin. Alldredge and colleagues showed that diazepines can be administered by paramedical workers in nursing homes with good effect in status epilepticus, terminating the seizures in about half of cases. Nonetheless, a long-acting anticonvulsant such as phenytoin must be given immediately after a diazepine has controlled the initial seizures. An alternative is the water-soluble drug fosphenytoin, which is administered in the same dose equivalents as phenytoin but can be injected at twice the maximum rate. Moreover, it can be given intramuscularly in cases where venous access is difficult. However, the delay in hepatic conversion of fosphenytoin to active phenytoin makes the latency of clinical effect approximately the same for both drugs.
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In an epileptic patient known to be taking anticonvulsants chronically but in whom the serum level of drug is unknown, it is probably best to administer the full-recommended dose of phenytoin. If it can be established that the serum phenytoin is above 10 mg/mL, a lower loading dose may be advisable. If seizures continue, an additional 5 mg/kg is indicated. If this fails to suppress the seizures and status has persisted for 20 to 30 min, an endotracheal tube should be inserted and O2 administered. Several approaches have been suggested to control status epilepticus that persists after these efforts. At this stage we have resorted to the approach suggested by Kumar and Bleck of giving high doses of midazolam (0.2 mg/kg loading dose followed by an infusion of 0.1 to 0.4 mg/kg/ h as determined by clinical and EEG monitoring). If seizures continue, the dose can be raised as blood pressure permits. We have had occasion to use in excess of 20 mg/h because of a diminishing effect over days. This regimen of midazolam and phenytoin may be maintained for several days without major ill effect in previously healthy patients. Propofol given in a bolus of 2 mg/kg and then as an intravenous drip of 2 to 8 mg/kg/h is also an effective alternative to midazolam, but after 24 h the drug behaves like a high dose of barbiturate and there may be difficulty because of hypotension. Another dependable approach is infusion of either pentobarbital, starting with 5 mg/kg, or phenobarbital, at a rate of 100 mg/min until the seizures stop or a total dose of 20 mg/kg is reached; a long period of stupor must be anticipated after. Hypotension often limits the continued use of the barbiturates, but Parviainen and colleagues were able to manage this problem by fluid infusions, dopamine, and neosynephrine. If none of these measures controls the seizures, a more aggressive approach taken to subdue all brain electrical activity by the use of general anesthesia. The preferred medications for this purpose have been pentobarbital or propofol, which, despite their moderate efficacy as primary anticonvulsants, are easier to manage than the alternative inhalational anesthetic agents. An initial intravenous dose of 5 mg/kg pentobarbital or 2 mg/kg propofol is given slowly to induce an EEG burst-suppression pattern, which is then maintained by the administration of pentobarbital, 0.5 to 2 mg/kg/h, or propofol, up to 10 mg/kg/h. Every 12 to 24 h, the rate of infusion is slowed to determine whether the seizures have stopped. The experience of Lowenstein and colleagues, like our own, is that most instances of status epilepticus that cannot be controlled with the combination of standard anticonvulsants and midazolam will respond to high doses of barbiturates or to propofol, but that these infusions cause hypotension and cannot be carried out for long periods. Should the seizures continue, either clinically or electrographically, despite all these medications, one is justified in the assumption that the convulsive tendency is so strong that it cannot be checked by reasonable quantities of medications. A few patients in this predicament have survived and awakened, even at times with minimal neurologic damage. The volatile anesthetic agent isoflurane has also been used in these circumstances with good effect, as we have reported (Ropper et al), but the continuous administration
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of inhalational anesthetic agents is impractical in most critical care units. Halothane has been relatively ineffective as an anticonvulsant, but ether, although impractical, has in the past been effective in some cases. In the end, in these patients with truly intractable status, one usually depends on phenytoin, phenobarbital (smaller doses in infants and children, as shown in Tables 16-9), and on measures that safeguard the patient’s vital functions. Valproate and levetiracetam are available as intravenous preparations, making them suitable for administration in status, but their role in this circumstance has not been extensively studied. A word is added here concerning neuromuscular paralysis and continuous EEG monitoring in status epilepticus. With failure of aggressive anticonvulsant and anesthetic treatment, there may be a temptation to paralyze all muscular activity, an effect easily attained with drugs such as pancuronium, while neglecting the underlying seizures for which reason the use of neuromuscular blocking drugs without a concomitant attempt to suppress seizure activity is inadvisable. If such measures are undertaken, continuous or frequent intermittent EEG monitoring is essential; this may also be also helpful in the early stages of status epilepticus in that it guides the dosages of anticonvulsants required to suppress the seizures. In the related but less-serious condition of acute repetitive seizures, in which the patient awakens between fits, a diazepam gel, which is well absorbed if given rectally, is available and has been found useful in institutional and home care of epileptic patients, although it is quite expensive. A similar effect has been attained by the nasal or buccal (transmucosal) administration of midazolam, which is absorbed from these sites (5 mg/mL, 0.2 mg/kg nasally; 2 mL to 10 mg buccally). Midazolam may be preferred among the diazepines for transmucaosal use because it produces somewhat less respiratory depression than the others in the class and has been more effective at controlling seizures, according to a study by McIntyre and colleagues. Still, only half were controlled. These approaches have found their main use in children with frequent seizures who live in supervised environments, where a nurse or parent is available to administer the medication. Petit mal status should be managed by intravenous lorazepam, valproic acid, or both, followed by ethosuximide. Nonconvulsive status is treated along the lines of grand mal status, usually stopping short of using anesthetic agents.
Surgical Treatment of Epilepsy The surgical excision of epileptic foci in simple and complex partial epilepsies that have not responded to intensive and prolonged medical therapy is being used with increasing effectiveness in a growing number of specialized epilepsy units. At these centers, it has been estimated that approximately 25 percent of all patients with epilepsy are candidates for surgical therapy and more than half of these may benefit from surgery. With increasing experience and standardized approaches, especially in patients with temporal lobe epilepsy, it has been suggested that many patients are waiting too long before the surgical option. A perspective that may promote surgery in even more patients is the
observation that approximately 60 percent of patients with partial seizures will respond to a conventional anticonvulsant, but that among the remainder, few will respond to the addition of a second or third drug. To locate the discharging focus requires a careful analysis of clinical and EEG findings, often including those obtained by long-term video/EEG monitoring and, sometimes, intracranial EEG recording by means of intraparenchymal depth electrodes, subdural strip electrodes, and subdural grids. Recently, functional imaging and specialized EEG analysis have been introduced to supplement these methods. The most favorable candidates for surgery are those with complex partial seizures and a unilateral temporal lobe focus, in whom rates of cure and significant improvement approach 90 percent in some series, but, overall, are probably closer to 50 percent after 5 years. A randomized trial conducted by Wiebe and colleagues gave representative results after temporal lobectomy of 58 percent of 40 carefully studied patients remaining seizure-free after 1 year, in contrast to 8 percent on medication alone. Furthermore, as reported by Yoon and colleagues, among those patients who remain free of seizures for 1 year after surgery, more than half are still free of seizures after 10 years and most of the remainder had one or fewer episodes per year. It should be emphasized that most of the patients who underwent surgery in all these studies still required some anticonvulsant medication. Excision of cortical tissue outside of the temporal lobe accomplishes complete seizure-free states in approximately 50 percent. Taking all seizure types together, only approximately 10 percent of patients obtain no improvement at all and less than 5 percent are worse. The matter of resection of areas of focal cortical dysplasias in children is a highly specialized area. It has been indicated that the histologic features of the dysplasia are important determinants of the success of surgery (Fauser et al). Other surgical procedures of value in selected cases are sectioning of the corpus callosum and hemispherectomy. The most encouraging results with callosotomy have been obtained in the control of intractable partial and secondarily generalized seizures, particularly when atonic drop attacks are the most disabling seizure type. Removal of the entire cortex of one hemisphere, in addition to the amygdala and hippocampus, has been of value in children, as well as in some adults with severe and extensive unilateral cerebral disease and intractable contralateral motor seizures and hemiplegia. Rasmussen encephalitis, Sturge-Weber disease, and large porencephalic cysts at times fall into this category. Surgical, focused radiation, or endovascular reduction of arteriovenous malformations may reduce the frequency of seizures, but the results in this regard are somewhat unpredictable (see Chap. 34).
Vagal Nerve Stimulation This technique has found favor in cases of intractable partial and secondarily generalizing seizures. A pacemakerlike device is implanted in the anterior chest wall and stimulating electrodes are connected to the vagus at the left carotid bifurcation. The procedure is well tolerated
CHAPTER 16
except for hoarseness in some cases. Several trials have demonstrated an average of 25 percent reduction in seizure frequency among patients who were resistant to all manner of anticonvulsant drugs (see Chadwick for a discussion of recent trials). The mechanism by which vagal stimulation produces its effects is unclear, and its role in the management of seizures is still being defined. Stimulation of the cerebellum and of other sites in the brain has also been used in the control of seizures, with no clear evidence of success. They must currently be considered to be experimental. Driving and Epilepsy Only a few states in the United States and most provinces of Canada mandate that physicians report patients with seizures under their care to the state motor vehicle bureau. Nonetheless, physicians should counsel such a patient regarding the obvious danger to himself and others if a seizure should occur while driving (the same holds for the risks of swimming unattended). What few data are available suggest that accidents caused directly by a seizure are rare and, in any case, 15 percent have been the result of a first episode of seizure that could not have been anticipated. In some states where a driver’s license has been suspended on the occurrence of a seizure, there is usually some provision for its reinstatement—such as a physician’s declaration that the patient is under medical care and has been seizure-free for some period of time (usually 6 months or 1 to 2 years). The Epilepsy Foundation website can be consulted for updated information regarding restrictions on driving, and this serves as an excellent general resource for patients and their families (http://www.efa.org).
Ketogenic Diet Since the 1920s, interest in this form of seizure control has varied, being revived periodically in centers caring for many children with intractable epilepsy. Despite the absence of controlled studies showing its efficacy or an agreed upon hypothesis for its mechanism, several trials in the first half of the twentieth century, and again more recently, demonstrated a reduction in seizures in half of the patients, including handicapped children with severe and sometimes intractable fits. The diet is used mainly in children between the ages of 1 and 10 years. The regimen is initiated during hospitalization by starvation for a day or two in order to induce ketosis, followed by a diet in which 80 to 90 percent of the calories are derived from fat (Vining). The
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difficulties in making such a diet palatable leads to its abandonment by about one-third of children and their families. A summary of experience from the numerous trials of the ketogenic diet can be found in the review by Lefevre and Aronson and in the report of its use in 58 children by Kinsman and colleagues. They both concluded that the diet is effective in refractory cases of epilepsy in childhood, reducing seizure frequency in two-thirds of children and allowing a reduction in the amount of anticonvulsant medication in many. It has also been commented that some benefit persists even after the diet has been stopped. Nephrolithiasis is a complication in somewhat less than 10 percent of children, and this risk is particularly high if topiramate is being used.
Regulation of Physical and Mental Activity The most important factors in seizure breakthrough, next to the abandonment of medication or a natural reduction of serum levels of medication, are loss of sleep and abuse of alcohol or other drugs. The need for moderation in the use of alcohol must be stressed, as well as the need to maintain regular hours of sleep. These seemingly anachronistic suggestions in an age of many available anticonvulsants are still valid. A moderate amount of physical exercise is allowable, if not desirable. With proper safeguards, even potentially more dangerous sports, such as swimming, may be permitted. However, a person with incompletely controlled epilepsy should not be allowed to drive an automobile, operate unguarded machinery, climb ladders, or take tub baths behind locked doors; such a person should swim only in the company of a good swimmer and wear a life preserver when boating. Psychosocial difficulties must be identified and addressed early. Simple advice and reassurance will frequently help to prevent or overcome the feelings of inferiority and self-consciousness of many patients with epilepsy. Patients and their families may benefit from more extensive counseling, and proper family attitudes should be cultivated. It is important that the patient be allowed to live as normal a life as possible. Every effort should be made to keep children in school, and adults should be encouraged to work. Many communities have vocational rehabilitation centers and special social agencies for epileptics, and advantage should be taken of such facilities.
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17 Coma and Related Disorders of Consciousness
In hospital and emergency neurology, the clinical analysis of unresponsive and comatose patients becomes a practical necessity. There is always urgency about such medical problems—a need to determine the underlying disease and the direction in which it is evolving in order to protect the brain against more serious or irreversible damage. When called upon, the physician must therefore be prepared to implement a rapid, systematic investigation of the comatose patient and prompt therapeutic and diagnostic action that allows no time for deliberate, leisurely investigation. Some idea of the dimensions of the problem of coma can be obtained from published statistics. Eighty years ago, in two large municipal hospitals, it was estimated that 3 percent of all admissions to the emergency wards were for diseases that had caused coma. Alcoholism, cerebral trauma, and cerebrovascular diseases were the most common, accounting for 82 percent of the comatose patients admitted to the Boston City Hospital (Solomon and Aring). Epilepsy, drug intoxication, diabetes, and severe infections were the other major causes for admission. It is perhaps surprising to learn that recent figures from municipal hospitals are much the same; they emphasize that the common conditions underlying coma are relatively invariant in general medical practice. In university hospitals, which tend to attract patients with more obscure diseases, the statistics are somewhat different. For example, in the series collected by Plum and Posner (Table 17-1), only 25 percent proved to have cerebrovascular disease, and in only 6 percent was coma the consequence of trauma. Indeed, all obvious “mass lesions”—such as tumors, abscesses, hemorrhages, and infarcts—made up less than one-third of the coma-producing diseases. A majority was the result of exogenous (drug overdose) and endogenous (metabolic) intoxications and hypoxia. Subarachnoid hemorrhage, meningitis, and encephalitis accounted for another 5 percent of the total. Thus the order is, relatively speaking, reversed, but still intoxication, stroke, and cranial trauma stand as the “big three” of coma-producing conditions. Equally common in some series, albeit obvious and usually transient, is the coma that follows seizures or resuscitation from cardiac arrest. The terms consciousness, confusion, stupor, unconsciousness, and coma have been endowed with so many different meanings that it is almost impossible to avoid ambiguity in their usage. They are not strictly medical terms but are also
literary, philosophic, and psychologic terms. The word consciousness is the most difficult of all. William James once remarked that everyone knows what consciousness is until he attempts to define it. To the psychologist, consciousness denotes a state of continuous awareness of one’s self and environment. Knowledge of self includes all “feelings, attitudes and emotions, impulses, volitions, and the active or striving aspects of conduct”; in short, a near continuous self-awareness of a person’s mental functioning, particularly of cognitive processes and their relation to past memories and experience. These can be judged only by the individual’s verbal account of his introspections and, indirectly, by his actions. Physicians, being more practical and objective for the most part, give greater credence to the patient’s behavior and reactions to overt stimuli than to what the patient says. For this reason they usually use the term consciousness in its most common and simplest operational meaning—namely, the state of awareness of self and environment and responsiveness to external stimulation and inner need. This narrow definition has an advantage in that unconsciousness has the opposite meaning: a state of unawareness of self and environment or a suspension of those mental activities by which people are made aware of themselves and their environment, coupled always with a diminished responsiveness to environmental stimuli. A clear distinction is also made in medicine between the level of consciousness—meaning the state of arousal or the degree of variation from normal alertness as judged by the appearance of facial muscles, fixity of gaze, and body posture—and the content of consciousness, i.e., the quality and coherence of thought and behavior. For clinical purposes, the loss of normal arousal is by far the more important and dramatic aspect of disordered consciousness and the one identified by laypersons and physicians as being the central feature of coma. Much more could be said about the history of our ideas concerning consciousness and the theoretical problems with regard to its definition. Furthermore, there has been an ongoing polemic among philosophers of mind as to whether it will ever be possible to understand mind and consciousness in terms of reductionist physical entities, such as cellular and molecular neural systems. Although it serves little practical purpose to review these subjects in detail here, we note that contemporary investigations indicate that one constructive approach is to define the
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Table 17-1 FINAL DIAGNOSIS IN 500 PATIENTS ADMITTED TO HOSPITAL WITH “COMA OF UNKNOWN ETIOLOGY” Metabolic and other diffuse disorders Drug poisoning Anoxia or ischemia Hepatic encephalopathy Encephalomyelitis and encephalitis Subarachnoid hemorrhage Endocrine disorders (including diabetes) Acid–base disorders Temperature regulation Uremic encephalopathy Pulmonary disease Nutritional Nonspecific metabolic coma Supratentorial mass lesions Intracerebral hematoma Subdural hematoma Cerebral infarct Brain tumor Brain abscess Epidural hematoma Thalamic infarct Pituitary apoplexy Closed head injury Subtentorial lesions Brainstem infarct Pontine hemorrhage Cerebellar hemorrhage Cerebellar tumor Cerebellar infarct Brainstem demyelination Cerebellar abscess Posterior fossa subdural hemorrhage Basilar migraine Psychiatric disorders
326 (65%) 149 87 17 14 13 12 12 9 8 3 1 1 101 (20%) 44 26 9 7 6 4 2 2 1 65 (13%) 40 11 5 3 2 1 1 1 1 8 (2%)
Note: Listed here are only those patients in whom the initial diagnosis was uncertain and a final diagnosis was established. Thus, obvious poisonings and closed head injuries are underrepresented. Source: Data adapted from Plum and Posner.
neurobiologic correlates of those elements of consciousness that are subject to observation by behavioral, electrical, or imaging methods. Importantly, these controversies are greatly informed in neurology by analyses of unusual neurologic disorders, such as those that disturb perception and consciousness of perception (phantom limb, “blindsight,” etc.). The interested reader is referred to the discussions of consciousness by Crick and Koch, Plum and Posner, Young, and Zeman listed in the references.
States of Normal and Impaired Consciousness The following definitions, although probably not acceptable to all psychologists, are of service to clinicians and provide a convenient terminology for describing the states of awareness and responsiveness of our patients.
Normal Consciousness This is the condition of the normal person when awake. In this state the individual is fully responsive to a thought or perception and indicates by his behavior and speech the same awareness of self and environment as that of the
examiner. This normal state may fluctuate during the day from one of keen alertness or deep concentration with a marked constriction of the field of attention to one of mild general inattentiveness, but even in the latter circumstances, the normal individual can be brought immediately to a state of full alertness and function.
Confusion The term confusion lacks precision, but in general it denotes an inability to think with customary speed, clarity, and coherence. Almost all states of confusion are marked by some degree of inattentiveness and disorientation. In this condition the patient does not take into account all elements of his immediate environment. This state also implies a degree of imperceptiveness and distractibility, referred to traditionally as “clouding of the sensorium.” Here, one difficulty is to define thinking, a term that refers variably to problem solving or to coherence of ideas. Confusion results most often from a process that influences the brain globally, such as a toxic or metabolic disturbance or a dementia. In addition, any condition that causes drowsiness or stupor, including the natural state that comes from sleep deprivation, results in some degradation of mental performance and inattentiveness. A confusional state can also accompany focal cerebral disease in various locations, particularly in the right hemisphere, or result from disorders that disturb mainly language, memory, or visuospatial orientation, but these are distinguished from the global confusional state and represent special states that are analyzed differently. These matters are discussed further in Chaps. 20 and 23. The mildest degree of confusion may be so slight that it can be overlooked unless the examiner searches for deviations from the patient’s normal behavior and liveliness of conversation. The patient may even be roughly oriented as to time and place, with only occasional irrelevant remarks betraying an incoherence of thinking. Even moderately confused persons can carry on a simple conversation for short periods of time, but their thinking is slow and incoherent, their responses are inconsistent, attention span is reduced, and they are unable to stay on one topic and to inhibit inappropriate responses. Usually they are disoriented and distractible at the mercy of every stimulus. Periods of irritability and excitability may alternate with drowsiness and diminished vigilance. Movements are often tremulous, jerky, and ineffectual. Sequences of movement also reveal impersistence. Severely confused and inattentive persons are usually unable to do more than carry out the simplest commands, and these only inconsistently and in brief sequence. Few if any thought processes are in operation. Their speech is usually limited to a few words or phrases; infrequently the opposite pertains—namely, some confused individuals are voluble. They are unaware of much that goes on around them, are disoriented in time and place, do not grasp their immediate situation, and may misidentify people or objects. These illusions may lead to fear or agitation. Occasionally, hallucinatory or delusional experiences impart a psychotic cast to the clinical picture, obscuring the deficit in attention.
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The degree of confusion often varies from one time of day to another. It tends to be least pronounced in the morning and increases as the day wears on, peaking in the early evening hours (“sundowning”) when the patient is fatigued and environmental cues are less apparent. Many events that involve the confused patient leave no trace in memory; in fact, the capacity to recall events of the past hours or days is one of the most delicate tests of mental clarity. Another is the use of so-called working memory, which requires the temporary storage of the solution of one task for use in the next. This deficit, which is such a common feature of the confusional states, can be demonstrated by tests of serial subtraction and the spelling of words (or repeating a phone number) forward and then backward. Careful analysis will show these defects to be tied to inattention and impaired perception or registration of information rather than a fault in retentive memory. This phenomenon of inattention is the central feature of most confusional states, but the observed behavior of a confused person transcends inattention alone. It often incorporates elements of clouded interpretation of internal and external experience and an inability to integrate and attach symbolic meaning to experience (apperception). In some medical writings, particularly in the psychiatric literature, the terms delirium and confusion are used interchangeably, the former connoting nothing more than a nondescript confusional state. However, in the syndrome of delirium tremens (observed most often but not exclusively in alcoholics), the vivid hallucinations; extreme agitation; trembling, startling easily, and convulsion; and the signs of overactivity of the autonomic nervous system suggest to us that the term delirium should be reserved for this type of highly distinctive confusional syndrome (elaborated in Chap. 20). These distinctions may be semantic in that “quiet delirium” qualifies as the typical form of confusion and “agitated delirium” as our concept of delirium. A relationship between the level of consciousness and disordered thinking is evident as patients pass through states of inattention, drowsiness, confusion, stupor, and coma as they become comatose or emerge from coma. The authors have not observed such a relationship between coma and delirium except possibly in patients suffering from bacterial meningitis, certain drug intoxications, or hepatic stupor and coma, which in some few instances may be preceded by a brief period of delirium.
Drowsiness and Stupor In these states, mental, speech, and physical activity are reduced. Drowsiness denotes an inability to sustain a wakeful state without the application of external stimuli. Inattentiveness and mild confusion are the rule, both improving with arousal. The patient shifts positions somewhat naturally and without prompting in the bed or chair. The lids droop without closing completely; there may be snoring, the jaw and limb muscles are slack, and the limbs are relaxed. This state is indistinguishable from light sleep, with slow arousal elicited by speaking to the patient or applying a tactile stimulus. Stupor describes a state in which the patient can be roused only by vigorous and repeated stimuli but the state of arousal cannot be sustained without repeated external
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stimulation. Responses to spoken commands are either absent or slow and inadequate. Restless or stereotyped motor activity is common and there is a reduction or elimination of the natural shifting of body positions. When left unstimulated, these patients quickly drift back into a sleep-like state. The eyes move outward and upward, a feature that is shared with sleep (see further on). Tendon and plantar reflexes and the breathing pattern may or may not be altered, depending on how the underlying disease has affected the nervous system. In psychiatry, the term stupor has been used in a second sense—to denote an uncommon condition in which the perception of sensory stimuli is presumably normal but activity is suspended and motor activity is profoundly diminished (catatonia, or catatonic stupor).
Coma The patient who appears to be asleep and is at the same time incapable of being aroused by external stimuli or inner need is in a state of coma. There are variations in the degree of coma; in its deepest stages, no reaction of any kind is obtainable: corneal, pupillary, pharyngeal, tendon, and plantar reflexes are in abeyance, and tone in the limb muscles is diminished. With lesser degrees of coma, pupillary reactions, reflex ocular movements, and corneal and other brainstem reflexes are preserved in varying degree, and muscle tone in the limbs may be increased. Respiration may be slow or rapid, periodic, or deranged in other ways (see further on). In still lighter stages, sometimes referred to by the ambiguous and unhelpful terms semicoma or obtundation, most of the above reflexes can be elicited, and the plantar reflexes may be either flexor or extensor (Babinski sign). These physical signs vary somewhat depending on the cause of coma. For example, patients with alcoholic coma may be areflexic and unresponsive to noxious stimuli, even when respiration and other vital functions are not threatened. The depth of coma and stupor is gauged by the response to externally applied stimuli and is most useful in assessing the direction in which the disease is evolving, particularly when compared in serial examinations. Relationship of Sleep to Coma Persons in sleep give little evidence of being aware of themselves or their environment; in this respect, they are unconscious. Sleep shares a number of other features with the pathologic states of drowsiness, stupor, and coma. These include yawning, closure of the eyelids, cessation of blinking and swallowing, upward deviation or divergence or roving movements of the eyes, loss of muscular tone, decrease or loss of tendon reflexes, and even the presence of Babinski signs and irregular respirations, sometimes CheyneStokes in type. Upon being awakened from deep sleep, a normal person may be confused for a few moments, as every physician knows from personal experience. Nevertheless, sleeping persons may still respond to unaccustomed stimuli and are capable of some mental activity in the form of dreams that leave traces of memory, thus differing from persons in stupor or coma. The most important difference, of course, is that persons in sleep, when stimulated, can be roused to normal and persistent con-
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sciousness. There are important physiologic differences as well. Cerebral oxygen uptake does not decrease during sleep, as it usually does in coma. Recordable electrical activity—electroencephalographic (EEG) and cerebral evoked responses—and spontaneous motor activity differ in the two states, as indicated later in this chapter and in Chap. 19. The anatomic and physiologic bases for these differences are only partly known.
The Persistent Vegetative and Minimally Conscious States, Locked-in Syndrome, and Akinetic Mutism Vegetative State With increasing refinements in the treatment of severe systemic diseases and cerebral injury, increasing numbers of patients who formerly would have died have survived for indefinite periods without regaining any meaningful mental function. For the first week or two after the cerebral injury, these patients are in a state of deep coma. Then they begin to open their eyes, at first in response to painful stimuli and later spontaneously and for increasingly prolonged periods. The patient may blink in response to threat or to light and intermittently the eyes move from side to side, seemingly following objects or fixating momentarily on the physician or a family member and giving the erroneous impression of recognition. Respiration may quicken in response to stimulation, and certain automatisms—such as swallowing, bruxism, grimacing, grunting, and moaning—may be observed (Zeman). However, the patient remains totally inattentive, does not speak, and shows no signs of awareness of the environment or inner need; responsiveness is limited to primitive postural and reflex movements of the limbs. There is loss of sphincter control. There may be arousal or wakefulness in alternating cycles as reflected in partial eye opening, but the patient regains neither awareness nor purposeful behavior of any kind. One sign of the vegetative state is a lack of consistent visual following of objects; again, brief observation of ocular movements are easily subject to misinterpretation and repeated periods of examination are required. However, this state is characterized by one of a number of EEG abnormalities. There may be predominantly low-amplitude delta-frequency background activity, burst suppression, widespread alpha and theta activity, an alpha coma pattern, and sleep spindles, all of which have been described in this syndrome, as summarized by Hansotia (see Chap. 2). One important feature is a lack of— or minimal change in—the background EEG activity during and after stimulating the patient. In the initial days and weeks this syndrome of unconscious awakening has been referred to as the vegetative state and, if lasting 3 months after nontraumatic and 12 months after traumatic injury, the syndrome has been termed the persistent vegetative state (PVS; Jennett and Plum). These terms have gained wide acceptance and apply to this clinical appearance whatever the underlying cause. The most common pathologic bases of this state are diffuse cerebral injury as a result of closed head trauma, widespread necrosis of the cortex after cardiac arrest, and thalamic necrosis from a number of causes. Most often,
and contrary to the notion held by most neurologists, the most prominent pathologic changes are usually in the thalamic and subthalamic nuclei, as in the celebrated Quinlan case (Kinney et al) rather than solely in the cortex; this holds for postanoxic as well as traumatic cases. A review by J.H. Adams and colleagues found these thalamic changes, but attributed them to secondary degeneration from white matter and cortical lesions. However, in several of our cases the thalamic damage stood almost alone as the cause of persistent “awake coma.” In traumatic cases, the pathologic findings are of diffuse subcortical white matter degeneration (described as diffuse axonal injury), prominent thalamic degeneration, and ischemic damage in the cortex. Taken together, these anatomic findings suggest the concept that PVS is a state in which the cortex is either diffusely injured or effectively disconnected and isolated from the thalamus, or the thalamic nuclei are destroyed. In either the traumatic or anoxic types of PVS, atrophy of the cerebral white matter may lead to ventricular enlargement and thinning of the corpus callosum. The vegetative state or the minimally conscious state described further on, may be the terminal phase of progressive cortical degenerative processes such as Alzheimer and Creutzfeldt-Jakob disease (where the pathologic changes may include the thalamus). In all these clinical states, the profound and widespread dysfunction of the cerebrum is reflected by extreme reductions in cerebral blood flow and metabolism, measured with positron emission tomography (PET) and other techniques. On the basis of PET studies in a patient with carbon monoxide poisoning, Laureys and colleagues observed that the main difference between the vegetative state and the recovered state was the degree of hypometabolism in the parietal lobe association areas. Anatomic changes in this same cortical region have been implicated in the transition from minimally conscious to a more awake state. The finding in this PET study that noxious somatosensory stimulation fails to activate the association cortices is consistent with the concept that large regions of cortex are isolated from thalamic input. Of practical value is the observation that the CT and MRI scans show progressive and profound cerebral atrophy in cases of vegetative state. In the absence of this atrophy after several months or more, it may be unwise to offer a pessimistic prognosis. One case with clinical features of the traumatic vegetative state but lacking cerebral atrophy on imaging studies regained normal cognitive ability after a year, although he remained paralyzed (R. Cranford, personal communication). These observations notwithstanding, there is little doubt that the neuroanatomic and neurophysiologic basis of the vegetative state will prove to be complex or at least separable into categories defined by the locus of brain damage. In particular, a striking experiment was conducted by Owen and colleagues in a 23-year-old woman who had been vegetative for 5 months after a head injury (thus not strictly speaking a “persistent” vegetative state). They observed localized cortical activity in the middle and superior temporal gyri in response to the presentation of spoken sentences that was comparable to the brain activity in control individuals. Even more impressive was activation of the supple-
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mentary motor areas when the patient was asked to imagine walking through her house or playing tennis. Di and colleagues have reproduced a brain activation response only to the patient’s own name and not to other names in 7 vegetative patients. These data suggest that processing can go on during an ostensible vegetative state but it is not clear if this situation is representative or almost unique. Furthermore, it does not provide information about self-awareness, a requisite for consciousness. An additional observation of some consequence is the finding of purported axonal growth over time in a patient with traumatic brain injury who had been in a minimally conscious state (see below) for 19 years and then began to speak and comprehend, while remaining virtually quadriplegic. Voss and colleagues, using sophisticated MRI tensor imaging, have shown axonal sprouting in the posterior parietal and midline cerebellar regions. They compared the results of tensor imaging to a patient who had been in a minimally conscious state for 6 years without improvement and to 20 normal individuals. Their findings are subject to several interpretations, but they do offer a potential explanation for the few instances in which recovery from severe injury does occur. When combined with the findings of Laureys and colleagues, a further case can be made for the posterior parietal regions as necessary for full consciousness. They further raise the possibility that these states are forms of disconnection syndrome and that certain islands of limited awareness may be dissociated from global brain function. Additional terms that have been used to describe this syndrome of preserved autonomic and respiratory function without cognition include apallic syndrome and neocortical death. A position paper has codified the features of the PVS and suggests dropping a number of related ambiguous terms, although some, such as akinetic mutism, discussed further on, have a more specific neurologic meaning and still find use (see Multi-Society Task Force on PVS). It is difficult to predict which comatose patients will later fall permanently into the PVS minimally conscious categories (see Chap. 40). Plum and Posner reported that of 45 patients with signs of the vegetative state at 1 week after onset, 13 had awakened and 5 of these had satisfactory outcomes. After being vegetative for close to 2 weeks, only 1 recovered to a level of moderate disability; after 2 weeks, the prognosis was uniformly poor. Larger studies by Higashi and colleagues have given similar results. As a rough guide to prognosis specifically in head injury, Braakman and colleagues found that among a large group of comatose patients, 59 percent regained consciousness within 6 h, but of those in a vegetative state at 3 months, none became independent. At no time was it possible to distinguish patients who would remain in a vegetative state from those who would die. A study by the MultiSociety Task Force on PVS concluded that the outcome from a vegetative state is better in traumatic as compared to nontraumatic cases. J.H. Adams and coworkers have proposed that this reflects differences in the state of thalamic neurons in the two situations. They propose that after acute hypoxia, neurons subjected to ischemic necrosis are liable to be permanently lost; by contrast, in trauma, the loss of thalamic neurons is more frequently
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secondary to transsynaptic degeneration following diffuse axonal injury, allowing a greater potential for recovery if there is improvement of early axonal injury. We find many of these ideas speculative. If one allows the term vegetative state to be applied soon after the onset of coma, rather than requiring coma to persist for several months, then fewer cases would be “persistent.” For this reason and because of the anxiety created for families by such a final diagnosis, it has been suggested that the term be abandoned (Kennard and Illingworth); a more meaningful goal would be to insist on careful examination and strict adherence to the clinical diagnostic criteria. Minimally Conscious State The condition of PVS blends into a less severe but still profound dementia that has been termed the “minimally conscious state,” wherein the patient is capable of some rudimentary behavior such as following a simple command, gesturing, or producing single words or brief phrases, always in an inconsistent way from one examination to another (see Giacino et al). Here there is preservation of the ability to carry out basic motor behaviors that demonstrate a degree of alertness, at least at some times. The minimally conscious state is found as either a transitional or permanent condition and is sometimes difficult to separate from akinetic mutism discussed further on. Any notion of such a patient’s selfawareness is purely conjectural but there may be an impressive array of behaviors and activation of associative cortex that suggest at least some relationship to processing of external information beyond a rudimentary level (see discussion by Bernat). The causes and pathologic changes underlying the minimally conscious state are identical to those of the vegetative state, including the frequent finding of thalamic and multiple cerebral lesions, and the distinction between them is one of degree. It is useful to maintain a critical view of news reports of remarkable recuperation after months or years of prolonged coma or the vegetative state. When the details of such cases become known, it is evident that recovery might reasonably have been expected. There are, however, numerous reported instances of partial recovery in patients—particularly children and young adults—who display vegetative features for several weeks or, as Andrews and Childs and Mercer describe, even several months after injury. Such observations cast doubt on unqualified claims of success with certain therapies, such as sensory stimulation. Nevertheless, the occurrence of rare instances of very late recovery in adults must be acknowledged (see Andrews; Higashi et al; and Rosenberg et al, 1977). Prognosis in coma is discussed in a later part of this chapter. Cases of improvement from the “minimally conscious state” are more plausible, including with the institution of thalamic stimulation as discussed below. Among the most interesting recent observations has come from Schiff and colleagues, who were able to improve function by stimulating the medial (interlaminar) thalamic nuclei through implanted electrodes in a patient who had been initially vegetative and made a transition to a minimally conscious state after traumatic brain injury. Longer periods of eye opening and increased responses to execute commands, such as bringing a cup to his mouth,
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were observed, including, for the first time since his injury, intelligible verbalization. The authors point out that this individual had preserved language cortex and connections between thalamus and cortex. Whether this remarkable result is generalizable is not known. Locked-in Syndrome The states of coma described above and the PVS must be clearly distinguished from a clinical state in which there is little or no disturbance of awareness (consciousness) but only an inability of the patient to respond adequately. The latter is referred to as the locked-in syndrome or the deefferented state. The term pseudocoma as a synonym for this state is best avoided, because it is used by some physicians to connote the feigned unconsciousness of the hysteric or malingerer. The locked-in syndrome is most often caused by a lesion of the ventral pons (basis pontis) as a result of basilar artery occlusion. Such an infarction spares both the somatosensory pathways and the ascending neuronal systems responsible for arousal and wakefulness, as well as certain midbrain elements that allow the eyelids to be raised and give the appearance of wakefulness; the lesion essentially interrupts the corticobulbar and corticospinal pathways, depriving the patient of speech and the capacity to respond in any way except by vertical gaze and blinking. Severe motor neuropathy (e.g., Guillain-Barré syndrome), pontine myelinolysis, or periodic paralysis may have a similar effect. One could logically refer to the locked-in state as akinetic mutism insofar as the patient is akinetic (motionless) and mute, but this is not the sense in which the term was originally used by Cairns and colleagues, who described a patient who appeared to be awake but was unresponsive (actually their patient was able to answer in whispered monosyllables). Following each of several drainings of a third ventricular cyst, the patient would become aware and responsive but would have no memory for any of the events that had taken place when she was in the akinetic mute state. This state of apparent vigilance in an imperceptive and unresponsive patient has been referred to by French authors as coma vigile, but the same term has been applied to the vegetative state. Akinetic Mutism The term akinetic mutism has been applied to yet another group of patients who are silent and inert as a result of bilateral lesions usually of the anterior parts of the frontal lobes, leaving intact the motor and sensory pathways; the patient is profoundly apathetic, lacking to an extreme degree the psychic drive or impulse to action (abulia). However, the abulic patient, unlike Cairns’ patient, registers most of what is happening about him and intensely stimulated, may speak normally, relating events observed in the recent and distant past. Catatonia The patient with catatonia appears unresponsive, in a state that simulates stupor, light coma, or akinetic mutism. There are no signs of structural brain disease, such as pupillary or reflex abnormalities. Oculocephalic responses are preserved, as in the awake state—i.e., the eyes move concurrently as the head is turned. There is usually resistance to eye opening, and some patients display a waxy flexibility of passive limb movement that gives the examiner a feeling of bending a wax rod (flexibilitas cerea); there is also the retention for a long period of seemingly uncomfortable limb postures (catalepsy). Peculiar motor mannerisms or repetitive motions,
seen in a number of these patients, may give the impression of seizures; choreiform jerking has also been reported, but the latter sign should also suggest the possibility of seizure activity. The EEG shows normal posterior alpha activity that is attenuated by stimulation. Catatonia is discussed further in Chaps. 20 and 57. Because there is considerable imprecision in the use of terms by which various states of reduced consciousness are designated, the physician would be better advised to supplement designations such as coma and akinetic mutism by simple descriptions indicating whether the patient appears awake or asleep, drowsy or alert, aware or unaware of his surroundings, and responsive or unresponsive to a variety of stimuli. This requires that the patient be observed more frequently or over a longer period than the several minutes usually devoted to this portion of the neurologic examination.
Brain Death In the late 1950s, European neurologists called attention to a state of coma in which the brain was irreversibly damaged and had ceased to function but pulmonary and cardiac function could still be maintained by artificial means. Mollaret and Goulon referred to this condition as coma dépassé (a state beyond coma). A Harvard Medical School committee, in 1968, called it brain death and established a set of clinical criteria by which it could be recognized (Beecher et al). R.D. Adams, who was a member of the committee, defined the state as one of complete unresponsiveness to all modes of stimulation, arrest of respiration, and absence of all EEG activity for 24 h. The concept that a person is dead if the brain is dead and that death of the brain may precede the cessation of cardiac function has posed a number of important ethical, legal, and social problems, as well as medical ones. All aspects of brain death have since been the subject of close study by several professional committees, which for the most part have confirmed the 1968 guidelines for determining that the brain is dead. The monograph by our colleague Wijdicks is a thorough modern source on the subject of brain death and also addresses the subject from an international perspective. The central considerations in the diagnosis of brain death are (1) absence of all cerebral functions; (2) absence of all brainstem functions, including spontaneous respiration; and (3) irreversibility of the state. Following from the last of these criteria, it is necessary to demonstrate an irrefutable cause of the underlying catastrophic brain damage (e.g., trauma, cardiac arrest, cerebral hemorrhage) and to exclude reversible causes such as drug overdose. In the diagnosis of brain death, the absence of cerebral function is demonstrated by the presence of deep coma and total lack of spontaneous movement and of motor and vocal responses to all visual, auditory, and cutaneous stimulation. Spinal reflexes may persist, and the toes often flex slowly in response to plantar stimulation; but a welldeveloped Babinski sign is unusual in our experience (although its presence does not exclude the diagnosis of brain death). Extensor or flexor posturing is seen from time to time as a transitional phenomenon just after brain
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death becomes evident and the status of these movements in the diagnosis is ambiguous, but the physician should proceed cautiously in declaring a patient dead in their presence and should consider conducting the examination again at a later time. The absence of brainstem function is judged by the loss of spontaneous eye movements, midposition of the eyes, and lack of response to oculocephalic and caloric (oculovestibular) testing; the presence of dilated or midposition fixed pupils (not smaller than 3 mm); paralysis of bulbar musculature (no facial movement or gag, cough, corneal, or sucking reflexes); an absence of motor and autonomic responses to noxious stimuli; and absence of respiratory movements. The clinical findings should show complete absence of brain function, not an approximation that might be reflected, for example, by small or poorly reactive pupils, slight eye deviation with oculovestibular stimulation, posturing of the limbs, and the like. As a final demonstration of destruction of the medulla, it has become customary to perform an “apnea test” to demonstrate unresponsiveness of the medullary centers to a high carbon dioxide tension. This test is conducted by first employing preoxygenation for several minutes with high inspired oxygen tension, the purpose of which is to displace nitrogen from the alveoli and create a reservoir of oxygen that will diffuse down a gradient into the pulmonary blood. The patient can then be disconnected from the respirator for several minutes (during which time 100 percent oxygen is being delivered by cannula or ventilator that has its pumping mechanism turned off; this allows the arterial PCO2 to rise to 50 to 60 mm Hg (typically, CO 2 rises approximately 2.5 mm Hg per minute at normal body temperature—slower if the patient is hypothermic). The hypercarbia serves both as a stimulus to breathing and a confirmation that spontaneous ventilation has failed. If no breathing is observed and examination of the blood gases shows that an adequate level of PCO2 has been attained, the presence of this component of brain death is corroborated. Several sets of formal criteria have chosen a level of CO 2 of 60 mm Hg (7.98 kPa [kilopascals]) as adequate to stimulate the medulla, even under circumstances in which it has been badly damaged. In our experience, patients who have a severely damaged brainstem but nonetheless breathe, have done so at a PCO2 below 50 mm Hg, but there are exceptions in which higher levels were required. The risks of apnea testing are minimal, but hypotension, hypoxemia, cardiac arrhythmias, and barotrauma may occasionally occur. In patients who cannot tolerate the test for more than a brief period, initially raising the CO 2 rapidly by insufflation of this gas has been suggested, but this approach has not been studied extensively. Delivering oxygen during the test with a low tidal volume and a ventilator rate of 1 to 2 breaths per minute or by continuous positive airway pressure may ameliorate hypoxia and resultant hypotension to allow apnea to continue for a period long enough to reach the target PCO2 but this technique has also not been adequately studied. Most but not all brain-dead patients have diabetes insipidus. Its absence reflects the imprecision of clinical signs in detecting a total loss of brain function. Other ancillary
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bedside tests may be conducted. Among the ones we use from time to time is an absence of tachycardic response to the injection of atropine; this reflects the loss of innervation of the heart by medullary vagal neurons. The authors have observed a number of dramatic spontaneous movements when hypoxic levels are attained during apnea testing or upon terminal disconnection from the ventilator for several minutes. These include opisthotonos with chest expansion that simulates a breath, elevation of the arms and crossing them in front of the chest or neck (termed the Lazarus sign by Ropper, 1984), head-turning, shoulder-shrugging, and variants of these posturing-like movements (Ropper, 1984). For this reason it is advisable that the family not be in attendance immediately after mechanical ventilation has been discontinued. The EEG provides confirmation of cerebral death, and many institutions prefer corroboration of the clinical features by the demonstration of electrocerebral silence (“flat” or, more accurately, isoelectric EEG, shown first by Schwab). Electrocerebral silence is considered to be present if there is no electrical potential of more than 2 mV during a 30-min recording (except for artifacts created by the ventilator, electrocardiograph [ECG], or surrounding electrical devices; the absence of these artifacts suggests a technical problem with the recording). There are cases on record in which a patient with an isoelectric EEG has had preserved brainstem reflexes. It must also be emphasized that cerebral unresponsiveness and a flat EEG do not necessarily signify brain death; both may occur and may be reversible in states of profound hypothermia or intoxication with sedative-hypnotic drugs and immediately following cardiac arrest. For this reason, it has been recommended that the diagnosis of brain death not be entertained until several hours have passed from the time of initial observation. If the examination is performed at least approximately 6 h after the ictus and there is prima facie evidence of overwhelming brain injury from trauma, or massive cerebral hemorrhage (the most common conditions causing brain death), there is no need for serial testing. If cardiac arrest was the antecedent event, or the cause of neurologic damage is unclear, or drug or alcohol intoxication could reasonably have played a role in suppressing the brainstem reflexes, it is advisable to wait about 24 h before pronouncing the patient dead. Toxicologic screening of the serum or urine is requisite in the latter circumstances. Because evoked potentials show variable abnormalities in brain-dead patients, they are not of primary value in the diagnosis. Some centers use nuclide brain scanning or cerebral angiography to demonstrate an absence of blood flow to the brain, equating this with brain death; but there are technical pitfalls in the use of these methods, and it is preferable to keep the diagnosis of death primarily clinical. Others take the view that demonstrating failed blood flow equates with brain death. False-negative tests are possible if a small amount of filling of the intracranial vertebral arteries is revealed. The same can be said for transcranial Doppler sonography, which in brain death shows a to-and-fro pendelfluss blood-flow pattern in the basal vessels. In our experience, the main difficulties that arise in relation to brain death are not the technical ones but those
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involving the sensitive conversations with the family of the patient and, to some extent, with other medical professionals. These tasks often fall to the neurologist. It is best not to embark on clinical or EEG testing for brain death unless there is a clear intention on the part of the physician to remove the ventilator or request organ donation at the end of the process. The nature of testing for brain death and its intended outcome should be explained to the family in plain language. The family’s desires regarding organ transplantation should be sought after adequate time has passed for them to absorb the shock of the circumstances. Neurologists must, of course, resist pressures from diverse sources that might lead them to the premature designation of a declaration of brain death. To avoid the appearance of conflict of motivations, many centers have a separate team to address the issues of organ transplantation after brain death has been established. The complex matter of a family’s desire to maintain ventilation in a brain-dead relative is best addressed with kind consideration and counseling by clergy, ethics (“optimal care”) committees, and hospital staff so as to avoid confrontation. Time often allows such situations to be defused. At the same time, it should be clarified that while brain death is an operational state that allows transplantation to proceed and mandates withdrawal of ventilation and blood pressure support, patients with overwhelming brain injuries need not fulfill these absolute criteria in order for medical support to be withdrawn. A task force for the determination of brain death in children has recommended the adoption of essentially the same criteria as for adults. However, the great difficulty in evaluating the status of nervous function in relation to perinatal insults, has led them to suggest that the determination not be made before the seventh postnatal day and that the period of observation should be extended to 48 h. As with adults, the possibility of reversible brain dysfunction from toxins, drugs, hypothermia, and hypotension must always be considered. The ethical and moral dimensions of brain death are complex and subject to differing interpretations in various societies, religions, and cultures. One justification for equating brain death with somatic death is the general inevitability of cardiorespiratory failure in patients who fulfill the standard criteria. This tenet has exceptions, the most striking of which is a well-studied case of 20-year survival in a boy who had meningitis reported by Reptinger and colleagues, but others have been described with varying degrees of documentation. These have been collected by Shewmon who makes the further point that the arguments equating brain death with death on the basis of the brain’s role in creating “somatic unity” are weakened by the existence of such cases as well as by delivery of live babies from brain-dead mothers. In the end, these philosophical concerns matter as much as medical ones and the operational state called brain death serves both patients and society well and is compatible with most of the world’s religions.
The Electroencephalogram and Disturbances of Consciousness The EEG provides one of the most delicate confirmations of the fact that states of impaired consciousness are
expressions of neurophysiologic changes in the cerebrum. Some change of brain waves occurs in all disturbances of consciousness except for the milder degrees of confusion, delirium tremens, and in catatonia. These alterations usually consist of a disorganization of the EEG background pattern, including disappearance of the normal alpha rhythm and replacement by random slow waves of low to moderate voltage in the initial stages of confusion and drowsiness; a more regular pattern of slow, 2- to 3-per-second waves of high voltage occurs in stupor; slow lowvoltage waves or intermittent suppression of organized electrical activity in the deep coma of hypoxia and ischemia; and, ultimately, a complete absence of electrical activity in brain death. In some deeply comatose patients, the EEG may transiently show diffuse and variable alpha (8- to 12-Hz) activity, which may be mistaken for the physiologic alpha rhythm. However, this pattern (so-called alpha coma) is not limited to the posterior cerebral regions, is not monorhythmic like normal alpha activity, and displays no reactivity to sensory stimuli. Alpha coma is usually associated with pontine or diffuse cortical lesions and has a poor prognosis (see Iragui and McCutchen). A rarer EEG abnormality is “spindle coma,” in which sleep spindles dominate the record (see “Disorders of Sleep Related to Neurologic Disease” in Chap. 19). The EEG accurately reflects the depth of certain metabolic comas, particularly those caused by hepatic or renal failure. In these conditions, the slow waves become higher in amplitude as coma deepens, ultimately assuming a highvoltage rhythmic delta pattern and a triphasic configuration. Not all cerebral disorders that cause confusion, stupor, and coma have the same effects on the EEG. In cases of intoxication with sedatives, exemplified by barbiturates and diazepines, fast (beta) activity initially replaces normal rhythms. Coma in which myoclonus or twitching is a major clinical feature may show frequent sharp waves or a sharpness of the background slowing of the EEG. The differences in EEG changes among metabolic derangements probably represent biologic distinctions at the neuronal level that have not yet been elucidated (see also Chap. 2).
The Anatomy and Neurophysiology of Alertness and Coma Our current understanding of the anatomy and physiology of alertness comes largely from the elegant experiments of Bremer and of Moruzzi and Magoun in the 1930s and 1940s. Observing cats in whom he had sectioned the brainstem between the pons and midbrain and at the level of the lower medulla, Bremer found that the rostral section caused a sleep-like state and “synchronized” EEG rhythms that were characteristic of sleep; animals with the lower section remained awake with appropriate “desynchronized” EEG rhythms. He interpreted this to mean, in large part correctly, that a constant stream of sensory stimuli, provided by trigeminal and other cranial sources, was required to maintain the awake state. More recently, a system of “nonspecific” projections from the thalamus to all cortical regions, independent of any specific sensory nucleus has been demonstrated. A critical refinement of this concept
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resulted from the observation by Moruzzi and Magoun that electrical stimulation of the medial midbrain tegmentum and adjacent areas just above this level caused a lightly anesthetized animal to become suddenly alert and its EEG to change correspondingly, i.e., to become “desynchronized,” in a manner identical to normal arousal by sensory stimuli. The sites at which stimulation led to arousal consisted of a series of points extending from the nonspecific medial thalamic nuclei down through the caudal midbrain. These loci are situated along the loosely organized core of neurons that anatomists had referred to as the reticular system or formation. The anatomic studies of the Scheibels have described widespread innervation of the reticular formation by multiple bifurcating and collateral axons of the ascending sensory systems, implying that this area was maintained in a tonically active state by ascending sensory stimulation. Because this region, especially the medial thalamus, projects widely to the cerebral hemispheres, the concept arose of a reticular activating system (RAS) that maintained the alert state and the inactivation of which led to an unarousable state. In this way, despite a number of experimental inconsistencies (see Steriade), the paramedian upper brainstem tegmentum and lower diencephalon came to be conceived as the locus of the alerting system of the brain. The anatomic boundaries of the upper brainstem RAS are somewhat indistinct. This system is interspersed throughout the paramedian regions of the upper (rostral) pontine and midbrain tegmentum; at the thalamic level, it includes the functionally related posterior paramedian, parafascicular, and medial portions of the centromedian and adjacent intralaminar nuclei. In the brainstem, nuclei of the reticular formation receive collaterals from the spinothalamic and trigeminal–thalamic pathways and project not just to the sensory cortex of the parietal lobe, as do the thalamic relay nuclei for somatic sensation, but to the whole of the cerebral cortex. Thus, it would seem that sensory stimulation has a double effect—it conveys information to the brain from somatic structures and the environment and also activates those parts of the nervous system on which the maintenance of consciousness depends. The cerebral cortex not only receives impulses from the ascending RAS but also modulates this incoming information via corticofugal projections to the reticular formation. Although the physiology of the RAS is far more complicated than this simple formulation would suggest, it nevertheless, as a working idea, retains a great deal of clinical credibility and makes comprehensible some of the neuropathologic observations noted further on, and effects of the deep brain stimulation to improve function in minimally conscious patients (see further on). The presence of alpha rhythm with the eyes closed is a marker for wakefulness but its representation at the cortical surface is not required for wakefulness as it is obliterated in cases of bilateral occipital infarction. It is, of course, possible that deep nuclei are still projecting the rhythm to other parts of the cerebrum to maintain wakefulness. Although for many years it has been taught that arousal causes a desynchronization of brainwave activity (in distinction to the synchronized activity of sleep), it has become apparent that during wakefulness, there is a wide-
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spread low-voltage fast rhythm (a gamma rhythm that has a frequency of 30 to 60 Hz). This activity, coordinated by the thalamus, has been theorized to synchronize widespread cortical activity and to account perhaps for the unification of modular aspects of experience (color, shape, motion) that are processed in different cortical regions. In this way, the rhythm is said to “bind” various aspects of a sensory experience or memory. This fast and widespread electrographic activity is not appreciated with the usual EEG surface recordings, but it can be extracted by sophisticated mathematical tools. Using such electrophysiologic methods, Meador and colleagues have shown that the gamma rhythm can be detected over the primary somatosensory cortex after an electrical stimulus on the contralateral hand is perceived, but not if the patient fails to perceive it. The clinical relevance of the rhythm is uncertain, but it has elicited interest because it may give insight into several intriguing questions about consciousness.
Metabolic Mechanisms That Disturb Consciousness In a number of diseases that disturb consciousness, there is direct interference with the metabolic activities of the nerve cells in the cerebral cortex and the central nuclei of the brain. Hypoxia, global ischemia, hypoglycemia, hyper- and hypoosmolar states, acidosis, alkalosis, hypokalemia, hyperammonemia, hypercalcemia, hypercarbia, drug intoxication, and severe vitamin deficiencies are well-known examples (see Chap. 40 and Table 40-1). In general, the loss of consciousness in these conditions parallels the reduction in cerebral metabolism. For example, in the case of global ischemia, in which oxygen and glucose are removed from the brain, an acute drop in cerebral blood flow (CBF) to 25 mL/min/100 g brain tissue from its normal 55 mL/min/100 g causes slowing of the EEG and syncope or impaired consciousness; a drop in CBF below 12 to 15 mL/min/100 g causes electrocerebral silence, coma, and cessation of most neuronal metabolic and synaptic functions. Lower levels of ischemia are tolerated if acquired more slowly, but neurons cannot survive when flow is reduced below 8 to 10 mL/min/100 g. Oxygen consumption of 2 mg/min/100 g (approximately half of normal) is incompatible with an alert state. In other types of metabolic encephalopathy, or with widespread anatomic damage to the hemispheres, blood flow may stay near normal while metabolism is greatly reduced. An exception to these statements is the coma that arises from seizures, in which metabolism and blood flow are greatly increased. Extremes of body temperature (above 41°C [105.8°F] or below 30°C [86F°]) also induce coma through a nonspecific effect on the metabolic activity of neurons. Some of these metabolic changes are probably epiphenomena reflecting, in each particular encephalopathy, a specific type of dysfunction in neurons and their supporting cells. The endogenous metabolic toxin(s) that are responsible for coma cannot always be identified. In diabetes, acetone bodies (acetoacetic acid, β-hydroxybutyric acid, and acetone) are present in high concentration; in uremia, there is probably an accumulation of dialyzable small molecular toxins, notably phenolic derivatives of the aromatic amino acids. In hepatic coma, elevation of blood NH3 (ammonia)
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to 5 to 6 times normal levels corresponds roughly to the level of coma. Lactic acidosis may affect the brain by lowering arterial blood pH to less than 7.0. The impairment of consciousness that accompanies pulmonary insufficiency is related mainly to hypercapnia. This is not to say that the toxic effects of these molecules has been confirmed or is well understood, as noted below. In acute hyponatremia (Na 173 cm ≥6 s Height >159 cm ≥6 s 3. Grip strength (lbs) BMI ≤24 ≤29 BMI ≤23 ≤17 BMI 24.1–26 ≤30 BMI 23.1–26 ≤17.3 BMI 26.1–28 ≤30 BMI 26.1–29 ≤18 BMI >28 ≤32 BMI >29 ≤21 4. Physical activity 50 y Immunocompromised state Basilar skull fracture Head trauma; neurosurgery CSF shunt
ANTIMICROBIAL THERAPYa
Cefotaxime plus ampicillin Third-generation cephalosporin plus ampicillin (plus dexamethasone) Third-generation cephalosporin plus vancomycin (± ampicillin) Third-generation cephalosporin plus vancomycin ((± ampicillin) Third-generation cephalosporin plus vancomycin plus ampicillin Vancomycin plus ampicillin and ceftazidime Third-generation cephalosporin plus vancomycin Vancomycin plus ceftazidime Vancomycin plus ceftazidime
aFor all ages from 3 months onward, an alternative treatment is meropenem
plus vancomycin (does not provide coverage for Listeria). For severe penicillin allergy, consider vancomycin and chloramphenicol (for meningococcus) and trimethoprim-sulfamethoxazole (for Listeria). A high failure rate has been reported with chloramphenicol in patients with drug-resistant pneumococcus.
a
TOTAL DAILY DOSE
DOSING INTERVAL, HOURS
15 mg/kg 12 g 4–6 g 12 g 6g 4g 6g 800–1,200 mg 5 mg/kg 1,200 mg 3–6 g 9–12 g 9–12 g 24 million units 22.5 mg/kg 600 mg 5 mg/kg 20 mg/kg
8 4 8–12 4–6 8 12–24 6 12 8 12 8 4 4 4 8 24 8 6–12
2–4 g
6–12
Unless indicated, therapy is administered intravenously. Aminoglycosides are not used as sole treatment for meningitis. Peak and trough serum concentrations should be monitored. c Higher dose recommended for pneumococcal meningitis. d Risk of seizures with meropenem. e Oral administration. f Dosage based on trimethoprim component. g CSF concentrations may have to be monitored in severely ill patients. Newer drugs are available for methicillin-resistant staphyloccocal infections but are not well studied for staphylococcal meningitis: linezolid, quinupristin-dalfopristin, and daptomycin. b
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Table 32-4 SPECIFIC ANTIMICROBIAL THERAPY FOR ACUTE MENINGITIS MICROORGANISM
Haemophilus influenzae Beta-lactamase–negative Beta-lactamase–positive Neisseria meningitidis Streptococcus pneumoniae Penicillin MIC 2,000 >10,000
Diffusion-weighted image (DWI) Susceptibility sequence Short tau inversion recovery (STIR)
Edema, inflammation Acute infarcts Hemorrhages, calcification Spine and orbit studies (eliminates fat signals)
BRIGHT
CSF, bone, edema, deoxyhemoglobin mineralization CSF, liquids, edema “Most pathology” Edema, inflammation, gliosis
DARK
Solids, calcium Fat, water, acute blood CSF; otherwise like T2 Blood after several days Blood
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Figure 34-17. Left carotid stenosis with border zone infarction demonstrated by MRI. Conventional angiography (right) shows severe stenosis of the left internal carotid artery. The patient was a 72-year-old woman with acute onset of right hemiplegia.
course of stroke. A mild paralysis may become a disastrous hemiplegia or the patient’s condition may worsen only temporarily. In cases of basilar artery occlusion, dizziness and dysphagia may progress in a few days to total paralysis and deep coma. Anticoagulation and thrombolytic therapy may alter the course as discussed further on, but cerebral thrombosis is so often progressive that a cautious attitude on the part of the physician in what first appears to be a mild stroke is usually justified, at least for the first day. During the period 1970–1974 in Rochester, Minnesota, 94 percent of patients with ischemic strokes survived for 5 days and 84 percent for 1 month (Garraway et al, 1983a and b). The survival rate was 54 percent at 3 years and 40 percent at 7 years. These were significantly greater than had been the case during the period 1965–1969. These figures, which were gathered retrospectively, are comparable to more recent ones reported by Bamford and colleagues. The mortality rate following cerebral infarcts (no separation being made between thrombotic and embolic types) at the end of 1 month was 19 percent and at the end of 1 year, 23 percent. Of the survivors, 65 percent were capable of an independent existence. In every series, among long-term survivors, heart disease is a more frequent cause of death than additional strokes. It has been repeatedly pointed out that pneumonia as a result of faulty swallowing is a major determinant of survival; further discussion regarding aspiration problems following stroke are found in later sections of the chapter. As indicated above, progression of the stroke is most often because of increasing stenosis and occlusion of the involved artery by mural thrombus. In some instances, extension of the thrombus along the vessel may block side branches and hinder anastomotic flow. In the basilar artery, thrombus may gradually build up along its entire length. In the carotid system, thrombus at times propagates distally from the site of origin in the neck to the
supraclinoid portion or even into the anterior cerebral artery, preventing collateral flow from the opposite side. Several other circumstances influence the early prognosis in cerebral thrombosis. In the case of very large infarcts in the middle cerebral artery territory, swelling of the infarcted tissue may occur, followed by displacement of central structures, transtentorial herniation, and death of the patient after several days (Fig. 34-18). This can at times be anticipated by the sheer volume of the infarct and is usually evident on the CT or MRI scan within a day of the stroke. Smaller infarcts of the inferior surface of the cerebellum may also cause a fatal herniation into the foramen magnum. Milder degrees of swelling and increased intracranial pressure in both of the above cited cases may progress slightly for 2 to 3 days but do not prove fatal. (See further on under “Treatment of Infarctive Cerebral Edema and Raised Intracranial Pressure.”) In extensive brainstem infarction associated with deep coma caused by basilar artery occlusion, the early mortality rate approaches 40 percent. In any type of stroke, if coma or stupor is present from the beginning, survival is largely determined by success in keeping the airway clear, controlling brain swelling, preventing aspiration pneumonia, and maintaining fluid and electrolyte balance, as described further on. With smaller thrombotic infarcts, the mortality is 3 to 6 percent, much of it from myocardial infarction and aspiration pneumonia. As for the eventual prognosis of the neurologic deficits, some improvement is the rule if the patient survives. The patient with a lacunar infarct usually fares well but may take months to improve to the maximum extent. With other small infarcts, recovery may start within a day or two, and restoration may be complete or nearly complete within a week. In cases of severe deficit, there may be little significant recovery; after months of assiduous efforts at rehabilitation,
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Figure 34-18. Massive ischemic infarct of left cerebral hemisphere mainly in the distribution of the superior division of the middle cerebral artery. CT scans taken 24 h (left) and 72 h (right) following the onset of neurologic symptoms. The second scan demonstrates marked swelling of the infarcted tissue and displacement of central structures.
the patient may remain bereft of speech and understanding, with the upper extremity still useless and the lower extremity serving only as an uncertain prop during attempts to walk. Between these two extremes there is every gradation of recovery. Measurement of central motor conduction by magnetic stimulation has been predictive of recovery but is not widely used for clinical work. If clinical recovery does not begin in 1 or 2 weeks, the outlook is poor for both motor and language functions. Constructional apraxia, uninhibited anger (with left and rarely with right temporal lesions), nonsensical logorrhea and placidity, unawareness of the paralysis and neglect (with nondominant parietal lesions), and confusion and delirium (with nondominant temporal lesions) all tend to diminish and may disappear within a few weeks. A hemianopia that has not cleared in a few weeks will usually be permanent, although reading and color discrimination may continue to improve. In lateral medullary infarction, difficulty in swallowing may be protracted, lasting 4 to 8 weeks or longer, yet relatively normal function is finally restored in nearly every instance. Aphasia, dysarthria, cerebellar ataxia, and walking may improve for a year or longer, but for all practical purposes it may be said that whatever motor and language deficits remain after 5 to 6 months will be permanent. Characteristically, the paralyzed muscles are flaccid in the first days or weeks following a stroke; the tendon reflexes are usually unchanged but may be slightly increased or decreased. Gradually spasticity develops, and the tendon reflexes become brisker. The arm tends to assume a flexed adducted posture and the leg an extended one. Function is rarely if ever restored after the slow evolution of spasticity; however, the use of botulinum toxin may help considerably in relieving the spasticity. Conversely, the early development of spasticity in the arm or the early appearance of a
grasp reflex may presage a favorable outcome. In some patients with extensive temporoparietal lesions, the hemiplegia remains flaccid; the arm dangles and the slack leg must be braced to stand. The physiologic explanation of this remains obscure. If the internal capsule is not interrupted completely in a stroke that involves the lenticular nucleus or thalamus, the paralysis may give way to hemichoreoathetosis, hemitremor, or hemiataxia, depending on the particular anatomy of the lesion. Bowel and bladder control usually returns; sphincteric disorders persist in only a few cases. Physical therapy should be initiated early in order to prevent pseudocontracture of muscles and periarthritis at the shoulder, elbow, wrist, knuckles, knee, and ankle. These are frequent complications and often the source of pain and added disability, particularly of the shoulder. Occasionally, atrophy of bone and pain in the hand may accompany the shoulder pain (shoulder–hand syndrome). An annoying dizziness and unsteadiness often persists after damage to the vestibular system in brainstem infarcts. Seizures are a relatively uncommon sequel of thrombotic strokes in comparison to embolic cortical infarcts, which are followed by seizures in up to 10 percent of patients. Most often in our experience, the EEG in these cases had never normalized and showed sharp activity over the region of the infarct even many months after the stroke (see further on for advice on the treatment of seizures after stroke). Many patients complain of fatigability and are depressed, possibly more so after strokes that involve the left frontal lobe (Starkstein et al). The explanation of these symptoms is uncertain; some are certainly expressions of a reactive depression. Several small series have suggested that prophylactic treatment with antidepressants reduce the incidence of depression as described in the review by Chen and colleagues, but the routine administration of these medications
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has not found its way into general practice. Only a few patients develop serious behavior problems or are psychotic after a stroke, but paranoid trends, confusion, stubbornness, and peevishness may appear, or an apathetic state ensues. Large lesions affect concentration as well as synthetic and executive mental functions in rough proportion to their size; these mental changes are independent of any disturbances in language function. When multiple infarcts occur over a period of months or years, special types of dementia may develop. In some, the major lesions involve the white matter and spare, relatively, the cortex and basal ganglia; the lesions may be lacunar or larger infarctions. This disorder, referred to as arteriosclerosis dementia and Binswanger subcortical leukoencephalopathy, probably represents the accumulation of multiple white matter infarcts and lacunes (see further on and the papers by Mohr and Mast and by Babikian and Ropper). The white matter that is destroyed tends to lie in the border zones between the penetrating cortical and basal ganglionic arteries. Large patches of subcortical myelin loss and gliosis, in combination with small cortical and subcortical infarcts, are evident with brain imaging. This process and the histologically similar but biologically unique inherited condition of white matter termed CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy) are discussed further on.
Transient Ischemic Attacks As has already been emphasized, when brief transient ischemic attacks precede a stroke, they almost always stamp the underlying process as atherothrombotic involving a large or small blood vessel. Although there is little doubt that TIAs are caused by transient focal ischemia, their mechanism is not fully understood. Current opinion holds that TIAs are brief, reversible episodes of focal ischemic brain disturbance without evidence of cerebral infarction. The consensus had been that their duration should be less than 24 h, an idea introduced 40 years ago by a committee assigned to study the problem. It is more useful to separate attacks that last only a few minutes (up to 1 h) and leave no permanent signs, from those of longer duration, which are almost invariably a result of embolism, that have evidence of infarction on imaging studies and therefore carry an entirely different connotation than briefer TIAs. In the clinical analysis of TIAs, it is also important to separate a single transient episode from repeated ones that are all of uniform type. The latter are more a warning of impending vascular occlusion, particularly of the internal carotid artery, whereas the former, especially when prolonged, are again often caused by an embolus that leaves no lasting clinical effect. It should also be pointed out that blood diseases that cause excessive viscosity or sludging of blood (polycythemia vera, sickle cell disease, thrombocytosis, leukemia, and hyperglobulinemic states) may also cause TIAs prior to a stroke. In a prospective study of 390 patients with focal TIAs caused by atherosclerotic vascular disease, the 5-year cumulative rate of fatal or nonfatal cerebral infarction was 23 percent (Heyman et al). Interestingly, the rate of myocardial infarction in this group of patients, particularly in those with carotid lesions, was almost as high (21 percent), and in
other series it has exceeded the risk of stroke. Thus the occurrence of carotid TIAs is a predictor not only of cerebral infarction but also of myocardial infarction. About twothirds of all patients with TIAs are men with hypertension, reflecting the higher incidence of atherosclerosis in this group. Occasionally, in younger adults, TIAs may occur as relatively benign phenomena, without recognizable features of atherosclerosis or risk factors for it. Migraine is suspect in such patients (see further on); other such instances are a result of special hematologic disorders such as the antiphospholipid antibody discussed later in the chapter.
Clinical Syndrome Transient ischemic attacks can reflect the involvement of virtually any cerebral artery: common or internal carotid; middle, posterior, or anterior cerebral; ophthalmic; vertebral, basilar, or cerebellar; or a penetrating branch to the internal capsule, thalamus, or brainstem (lacunar TIAs). TIAs may precede, accompany, or infrequently follow the development of a stroke, or they can occur by themselves without leading to a stroke—a fact that makes any form of therapy difficult to evaluate. As just noted, TIAs that presage stroke may last a few seconds or up to an hour, longer ones almost certainly being the result of embolic infarction. Most last 2 to 15 min. There may be only a few attacks or several hundred. Between attacks, the neurologic examination discloses no abnormalities. A stroke may occur after the first or second episode or only after numerous attacks have occurred over a period of weeks or months. Not infrequently the attacks gradually cease and no important paralysis occurs. Many attacks which appear over a long period of time tend to be less likely to lead to thrombosis. Prolonged, fluctuating TIAs are the most ominous. Approximately 20 percent of infarcts that follow TIAs occur within a month after the first attack, and approximately 50 percent within a year (Whisnant et al). In an attempt to provide a predictive tool, various scales have been devised, among them the “ABCD” system devised by Rothwell and colleagues and derivatives of this scale. Blood pressure, unilateral weakness, speech disturbance, and the duration of symptoms (all less than 1 hour) are added to produce a predictive score for stroke within 1 week. Studies subsequent to the original one have given variable sensitivities, for which reason this interesting approach must be considered in clinical context. In the original study, unilateral weakness and duration lasting over an hour were most predictive of stroke. The problem with identifying a TIA with prolonged episodes has been alluded to—many of these cases are a result of emboli.
Hemispheric Transient Ischemic Attacks (Carotid Artery, Anterior Circulation Territory) In the carotid system, TIAs indicate involvement of one cerebral hemisphere or eye. The visual disturbance is ipsilateral; the sensorimotor disturbance is contralateral. Individual attacks tend to involve either the eye or the brain; only rarely are the two involved simultaneously or even sequentially. In the hemispheric attacks, ischemia occurs mainly in the distal territory of the middle cerebral artery or in an adjacent border zone, producing weakness or numbness of the opposite hand and arm. However, many
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different combinations may be seen: face and lips, lips and fingers, fingers alone, hand and foot. Rather than being paralyzed or weak, the arm may on occasion shake irregularly, simulating a seizure (“limb-shaking TIA”) or rarely display other transient movement disorders (Yanagihara et al). Less-common manifestations include confusion, aphasia and difficulty in calculation (when the dominant hemisphere is involved), apractagnosia (nondominant hemisphere), and other temporoparietal disturbances. Headache is not a feature of TIAs. In ocular attacks, transient monocular blindness (also called amaurosis fugax or TMR) is the usual symptom. Most of the visual episodes evolve swiftly, over 5 to 30 s, and are described as a horizontal shade falling (or rising) smoothly over the visual field until the eye is completely but painlessly blind. The attack clears slowly and uniformly. Sometimes the attack takes the form of a wedge of visual loss, sudden generalized blurring, or, a gray or bright light obscuring vision. Transient attacks of monocular blindness are usually more stereotyped with repeated episodes than are hemispheric attacks. TIAs consisting of a homonymous hemianopia should suggest a stenosis of the posterior cerebral artery but it is often difficult for the patient to make the distinction from monocular blindness. The implications of amaurosis fugax have been evaluated by several investigators and found not to be quite as ominous as those of hemispheral TIAs, particularly in younger patients. Poole and Ross Russell observed a group of 110 patients for periods of 6 to 19 years following an episode of amaurosis fugax (exclusive of the type caused by cholesterol emboli). At the end of 6 years, the mortality rate (mainly because of heart disease) was 21 percent, but the incidence of stroke was 13 percent (compared to expected figures of 15 and 3, respectively, percent in an age-matched population). Of the patients who were alive at the end of the observation period, 43 percent had had no further attacks of amaurosis fugax following the initial episode. Noteworthy also was the finding that among patients with normal carotid arteriograms, only 1 of 35 had had a stroke during the followup period, whereas stroke had occurred in 8 of 21 patients in whom the internal carotid artery was occluded or stenotic. As pointed out by Benavente and colleagues, the risk of stroke over the 3 years following an attack is as low as 2 percent if there are no other issues such as diabetes, but it may be as high as 24 percent in older patients with risk factors for atherosclerosis. Tippin and coworkers reviewed the records of 83 patients with onset of amaurosis fugax before the age of 45 years and found evidence of stroke in none; moreover, 42 of these patients were examined after a mean period of 5.8 years during which no stroke had occurred. It is evident that in this younger group a mechanism other than atherosclerosis was operative, such as migraine or an antiphospholipid antibody (discussed further on).
Brainstem Transient Ischemic Attacks (Vertebrobasilar, Posterior Circulation Territory) TIAs referable to vertebrobasilar disease tend to be less stereotyped and more prolonged than those related to the
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carotid circulation. They are also more likely to culminate in a stroke. The clinical picture of TIAs in the vertebrobasilar territory is diverse, because this circulation sustains such a varied sensorimotor traffic. Vertigo, diplopia (vertical or horizontal), dysarthria, bifacial numbness, ataxia, and weakness or numbness of part or all of one or both sides of the body (i.e., a disturbance of the long motor or sensory tracts bilaterally) are the hallmarks of vertebrobasilar involvement. Transient vertigo, diplopia, or headache occurring as solitary symptoms should not be interpreted as a TIA. The issue of the uncertainty regarding vertigo alone as a manifestation of a TIA referable to the basilar or vertebral artery was addressed in Chap. 15. There are occasional cases in which multiple brief episodes of vertigo, lasting perhaps a minute or less and fluctuating in intensity, may be interspersed with additional signs of brainstem ischemia. Careful questioning of the patient usually settles the question but imaging may be necessary in cases where uncertainty remains. Even then, more instances of vertigo than are justified are attributed to atherosclerotic disease in the posterior vessels. In some patients, the complaint of “dizziness” will prove, however infrequently, to be part of a carotid TIA; hence this symptom, in our experience and that of Ueda and associates, is not a totally reliable indicator of the vascular territory involved. Other manifestations of vertebrobasilar TIAs, in approximate order of frequency, include staggering, veering to one side, a feeling of cross-eyedness, dark vision, blurred vision, tunnel vision, partial or complete blindness, pupillary change, ptosis, paralysis of gaze, dysarthria, and dysphagia. Less-common symptoms include hemiplegia, noise or pounding in the ear or in the head, pain in the head or face or other peculiar head sensations, vomiting, hiccups, sense of tilting, lapse of memory, confused behavior, drowsiness, transient unconsciousness (rare), impaired hearing, deafness, hemiballismus, hallucinosis, and forced deviation of the eyes. According to Ross Russell, so-called drop attacks (see Chap. 7) have been recorded in 10 to 15 percent of patients with vertebrobasilar insufficiency but we have never observed such attacks as a recurrent ischemic phenomenon or a manifestation of other forms of cerebrovascular disease and the syndrome has usually been due to syncope, seizure, or has been of obscure origin. Vertebrobasilar TIAs may be identical from one episode to another, or more typically they vary in detail while maintaining the same basic pattern. For example, weakness or numbness may involve the fingers and face in some episodes and only the fingers in others; or dizziness and ataxia may occur in some attacks, while in others diplopia is added to the picture. In atherothrombotic basilar artery disease, each side of the body may be affected alternately. All the involved parts may be affected simultaneously, or a march or spread from one region to another may occur over a period of 10 s to a minute or a few minutes—much slower than the spread of a seizure. The individual attack may cease abruptly or fade gradually. The wide variety of manifestations invites a broad differential diagnosis as detailed further on but any constellation of these features occurring in episodes is strongly supportive of the diagnosis of vertebrobasilar TIA.
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Lacunar Transient Ischemic Attacks It has been recognized that strokes caused by occlusion of small penetrating vessels of the brain have a propensity to be intermittent (“stuttering”) at their onset and occasionally to allow virtually complete restitution of function between discrete episodes. Whether this constitutes a “lacunar TIA” has been debated, but it seems to us that the more important problem is our inability to distinguish a transitory occlusion of a small vessel from that of a larger vessel. Donnan and colleagues (1993) speak of a “capsular warning syndrome,” which we have seen a number of times, consisting of escalating episodes of weakness in the face, arm, and leg and culminating in a capsular lacunar stroke. We conclude that lacunar symptoms at their onset may stutter or remit for hours or days, and there is no doubt that one or many of them may precede a lacunar stroke. Nevertheless, the basic pattern of a small deep stroke remains identifiable in mild form; partial syndromes that simulate cortical TIA are less common.
Mechanism of Transient Ischemic Attacks The question here, so far not satisfactorily answered, is whether reduced blood flow or embolic particles are responsible for TIAs. Whatever the cause of the attacks, they are in most cases intimately related to vascular stenosis and, usually, to ulceration as a result of atherosclerosis and thrombus formation. Embolization of fibrin-platelet material from atherosclerotic sites indeed may be the cause of attacks in some cases, but it is difficult to understand how attacks of identical pattern could be caused by successive emboli from a distance that enter the same arterial branch each time. Moreover, one would expect the involved cerebral tissue to be at least partially damaged by embolism, leaving some residual signs. When a single transient episode has occurred, particularly if prolonged, the factor of recurrence does not enter into the diagnosis, and cerebral embolism must, of course, then be considered. In some cases of documented embolism, the neurologic state fluctuates from normal to abnormal repeatedly for as long as 36 h, giving the appearance of TIAs (“accelerated TIAs”); in others, a deficit of several hours’ duration occurs, fulfilling the traditional (now largely discarded) criterion for TIAs. As already noted, the same sequence of events can precede lacunar infarction and seem far more likely to be the result of locally reduced blood flow than to recurrent emboli. Restated, a single transitory episode, especially if it lasts longer than 1 h, and multiple episodes of different pattern, suggest embolism and must be distinguished from brief (2- to 10-min) recurrent attacks of the same clinical pattern, which suggest TIAs from atherosclerosis and thrombosis in a large vessel. Ophthalmoscopic observations of the retinal vessels made during episodes of transient monocular blindness show either an arrest of blood flow in the retinal arteries and breaking up of the venous columns to form a “boxcar” pattern or scattered bits of white material temporarily blocking the retinal arteries. These observations indicate that in some cases of ischemic attacks involving the retinal vessels, a temporary, complete, or relatively complete cessation of blood flow occurs locally. Whether this is a result of
platelet or fibrin emboli or of platelet aggregation in situ because of decreased perfusion pressure remains unsettled. In the past, TIAs have been attributed to cerebral vasospasm or to transient episodes of systemic arterial hypotension with resulting compromise of the intracranial circulation, but neither of these mechanisms is likely in the typical case. The attacks do not bear a strict relation to position or activity, although they are likely to occur when the patient is up and around rather than lying down. Nevertheless, a small proportion of patients with carotid or basilar artery stenosis clearly relate the onset of their attacks to standing up after lying or sitting. Transient symptoms present on awakening from sleep usually indicate that a stroke is impending. Rarely, TIAs are experienced in relation to exercise, outbursts of anger or joy, and bouts of coughing. On the other hand, exercise and postural TIAs, when they do occur, are particularly suggestive of stenosis of aortic branches, as occurs in Takayasu disease (see further on) and in dissection of the aortic arch and, occasionally, in a fixed atherosclerotic carotid stenosis. TIAs induced by hyperventilation are said to be characteristic of moyamoya disease, a progressive stenosis of intracranial vessels discussed in a later section. In states of anemia, polycythemia, thrombocythemia, extreme hyperlipidemia, hyperviscosity from macroglobulinemia, sickle cell anemia, and extreme hyper- or hypoglycemia, there may be transient neurologic deficits related to rheologic or other changes in blood, as already mentioned. In some of these cases, the metabolic or rheologic change appears to have brought out symptoms of stenosis in a large or small vessel, but just as often the vasculature is normal. Patients with antiphospholipid antibodies may have TIAs, the mechanism of which is undefined. In some instances the TIAs begin after the artery has already been occluded by thrombus. As shown by Barnett, emboli may arise from the distal end of the thrombus or enter the upper part of the occluded vessel through a collateral artery. However, almost one-fifth of “carotid TIAs” in the series of Pessin and colleagues (1977), and a somewhat larger proportion of cases reported by Ueda and coworkers, had neither stenosis nor ulceration of the carotid arteries. In most of the cases with normal carotids, the ischemic attacks exceeded 1 h in duration, suggesting embolism from the heart or great vessels including the aortic arch; but there were also a small number of brief ischemic attacks that were unexplained even after arteriography. In general, hemodynamic changes in the retinal or cerebral circulation make their appearance when the lumen of the internal carotid artery is reduced to 1.5 mm or less (normal diameter, 7.0 mm; range, 5 to 10 mm, lower part of this range in women). This corresponds to a reduction in cross-sectional area of the vessel of more than 95 percent. The exact degree of stenosis that may cause TIAs and the risk of stroke with mild and moderate degrees of stenosis is controversial and is addressed further on.
Differential Diagnosis of Transient Ischemic Attacks Transient focal neurologic symptoms are ubiquitous in neurologic practice. They may be a result of seizures, migraine,
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or other conditions such as transient global amnesia (Chap. 21), and they occur occasionally in patients with multiple sclerosis. The clinical setting in which they occur almost always makes clear the nature of the attack. Furthermore, transient and reversible episodes of focal cerebral symptoms, indistinguishable from TIAs, are known to occur in patients with meningioma, glioblastoma, metastatic brain tumors situated in or near the cortex, and even with subdural hematoma. Although infrequent, these attacks are important mainly because the use of anticoagulants is relatively contraindicated in some of these circumstances. We have seen these episodes mainly with meningiomas and subdural hematomas; they have consisted of transient aphasia or speech arrest lasting from 2 min to several hours, but sensory symptoms with or without spread over the body, arm weakness, and hemiparesis have also been reported. Some remarkable cases of meningioma have involved repeated transient attacks for decades. Seizures are always suspected in these cases but cannot be proved. It has been speculated that a local vascular disturbance of some kind is operative, but the mechanism is not understood. As far as we can determine, mass lesions have not caused episodes that simulate posterior circulation TIAs.
Treatment of Atherothrombotic Infarction and Transient Ischemic Attacks The main objective in these forms of cerebrovascular disease is the amelioration of the existing deficit and the prevention of future stroke. Ideally this should be accomplished by finding patients in the asymptomatic stages of atherosclerosis. In addition to reduction of known risk factors such as hypertension, smoking, and glucose control in diabetics, the widespread use of cholesterol-lowering statin medications has been shown in some studies to reduce the primary incidence of stroke and of recurrent stroke. The treatment of atherothrombotic stroke may be divided into four parts: (1) management in the acute phase, (2) measures to restore the circulation and arrest the pathologic process, (3) physical therapy and rehabilitation, and (4) measures to prevent further strokes and progression of vascular disease.
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coronary syndromes. Patients with impaired consciousness require special care of skin, eyes, mouth, bladder, and bowel. These measures are best provided in a unit with trained clinical staff and the technology to monitor blood pressure, pulmonary function, blood gases, and, when appropriate, intracranial pressure as discussed in Chap. 17.
Measures to Restore the Circulation and Arrest the Pathologic Process Efforts are directed at establishing a diagnosis of thrombotic stroke at the earliest possible stage and circumventing the full deficit by all means available without risking the safety of the patient. Even when the symptoms and signs have become static, some of the affected tissue may not be irreversibly damaged and will survive if perfusion can be reestablished (the penumbra). If the patient is under care within 3 h of onset of the first symptom and this time can be established with confidence, thrombolytic therapy with tissue plasminogen activator (tPA) is usually indicated. The contraindications and implementation of thrombolytic therapy is given in detail in the next section. On the assumption that cerebral perfusion might be diminished by assuming the upright position, it is probably advisable for patients with a major stroke to remain nearly horizontal in bed for the first day. When sitting and walking begin, special attention should be given to maintenance of normal blood pressure. Several studies have confirmed the high prevalence of new or enhanced levels of hypertension immediately following an ischemic stroke and its tendency to decline over subsequent days even without medications. The treatment of previously unappreciated hypertension is preferably deferred until the neurologic deficit has stabilized. As suggested by Britton and colleagues, more were of the opinion that it is prudent to avoid antihypertensive drugs in the first few days unless there is active myocardial ischemia or the blood pressure is high enough to pose a risk to other organs, particularly the kidneys, or there is a special risk of cerebral hemorrhage as a result of the use of thrombolytic drugs.
Thrombolytic Agents Management in the Acute Phase The relative advantages of placing the seriously ill acute stroke patient in a neurologic special care or “stroke” unit have been the subject of much study. The outcome in these patients in terms of morbidity and mortality is improved, although the differences have been small and difficult to document (for details, see Ropper and also Brott and Reed). Like the well-organized coronary care unit, stroke units have the capability of expediting evaluation and early rehabilitation and monitoring patients for complications of thrombolytic treatment. Protocols to prevent excessive hypertension after thrombolytic treatment are best instituted in units that have staffing patterns that create familiarity with these and other protocols. As already emphasized, the prevention of aspiration and pneumonia is paramount by identifying those patients at risk also benefits from systematic application of protocols. Also deserving attention is the prevention of venous thrombosis in the legs, pulmonary embolism, and
Tissue plasminogen activators (recombinant tPA and formerly, streptokinase) convert plasminogen to plasmin, the latter being a proteolytic enzyme capable of hydrolyzing fibrin, fibrinogen, and other clotting proteins. These drugs are effective in the treatment of coronary artery occlusion (but are associated with a 1 percent risk of cerebral hemorrhage) and have a reasonably clear role in the treatment of stroke. The current benchmark study organized by the National Institute of Neurological and Communicative Disorders and Stroke (see the NINCDS and Stroke rtPA Stroke Study Group in the references) has provided evidence of benefit from intravenous tPA. Treatment within 3 h of the onset of symptoms led to a 30 percent increase in the number of patients who remained with little or no neurologic deficit when re-examined 3 months after the stroke; this benefit persisted when assessed 1 year later in the study by Kwiatkowski and associates. It is not easy to comprehend why
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the benefits apparently extended to all types of ischemic strokes, including those caused by occlusion of small vessels (lacunes) and why improvement was not apparent in the days immediately following treatment, only at later times. The tPA was administered in a dose of 0.9 mg/kg, 10 percent of which was given as an initial bolus, followed by an infusion of the remainder over 1 h. A dose of 90 mg was not exceeded, this being lower than the dose used for myocardial infarction. The relative improvement in neurologic state came at the expense of a 6 percent risk of symptomatic cerebral hemorrhage, i.e., a far lower rate than in most previous studies and twice the expected rate without thrombolysis (some of the hemorrhages were into the area of infarction and did not cause symptomatic worsening). Patients were excluded from the study if they had massive infarcts (encompassing more than two-thirds of the territory of the middle cerebral artery), had high scores on a clinical stroke scale devised for the National Institutes of Health (NIH) study, had uncontrolled hypertension, were more than 80 years of age, or had recently received anticoagulants (except aspirin). Further analysis of the NINCDS trial revealed that patients who were treated earliest within the 3-h time frame had more benefit than those treated later; indeed, the administration of tPA in the time period between 2.5 and 3 h after the stroke was of less value. Attempts to establish that patients with a longer duration of ischemic symptoms benefit from tPA have varied in success but favor an effect up to 4.5 h as noted below. Data from the randomized European Cooperative Acute Stroke Study (ECASS; see Hacke et al), identified two situations in which tPA administered intravenously within 6 h at a slightly higher dose than in the above trial (1.1 mg/kg, to a maximum of 100 mg) led to an improved neurologic outcome, but the overall results of this trial were considered to be unfavorable because of a high rate of cerebral hemorrhage. In a second trial (ECASS II) in 800 patients, up to 6 h after the stroke, no benefit could be confirmed and the rate of symptomatic hemorrhage was 8.8 percent (compared with 3.4 percent in untreated patients). Yet a subgroup of patients with carotid– middle cerebral artery strokes of moderate severity—specifically those with moderate-sized infarcts from occlusion of vessels distal to the carotid artery and adequate collateral circulation through surface vessels—did appear to benefit. In some patients with basilar artery occlusion and coma of brief duration and those without extensive thrombosis, prompt tPA treatment also resulted in an overall improvement in neurologic function, but there were numerous exceptions. In two trials conducted by the European MAST-I groups (see the Multicentre Acute Stroke Trial in References) using streptokinase within 6 h of stroke, there was actually an adverse outcome—the treated group having an excess of early deaths; this trial had a 21 percent incidence of symptomatic cerebral hemorrhage and an 18 percent incidence of hemorrhagic infarctions. However, in a recent randomized trial of over 800 patients receiving tPA between 3 and 4.5 h after the onset of symptoms, 10% more achieved a good outcome if given the drug and, although more had cerebral hemorrhage, the overall mortality was the same in the treated and untreated groups (Hacke et al, 2008). This study will probably alter practice to extend the acceptable interval for
drug administration to 4.5 h if proper care is taken to select low risk patients and prevent excessive blood pressure after tPA is given. At the present time, the use of intravenous tPA therapy is advocated in patients who arrive in the emergency department and can be evaluated and treated within 4.5 h of the onset of a stroke, preferably sooner (thus excluding those who awaken from a night’s sleep with symptoms), and have no hemorrhage on the CT scan. Generally also excluded are those in whom the deficit is either very small (e.g., hand affected only, dysarthria alone, minor aphasia) or, more importantly, is so large as to implicate the entire territory of the middle cerebral artery. Many centers have expanded their practices beyond the confines of the NIH study, treating patients older than age 80 years and some with large strokes. Attempts are currently being made to identify patients in whom there is a mismatch between regional cerebral perfusion and colocalized preservation of brain tissue (typically shown by the absence of restricted water diffusion on MRI), but it is not yet clear if this will improve outcome. Also ambiguous is the treatment of patients with acute stroke in whom the referable cerebral vessels are entirely patent. Although a valid approach to acute stroke, the use of acute thrombolytic therapy depends on the very early identification of a restricted group of patients; therefore this therapy is applicable to only a limited proportion of patients who present to the emergency department soon after the first symptoms (approximately 10 percent) or those who have strokes while under observation in the hospital. It is noteworthy that attempts to reproduce the beneficial effects of tPA in a community setting have been disappointing largely because of deviations from treatment guidelines and an excess number of hemorrhages (Katzan et al). Nonetheless, acute intravenous thrombolysis that is managed closely by experienced individuals using validated protocols is an appropriate treatment for acute ischemic stroke. Public health education should increase the numbers of stroke patients who seek early attention and thus raise the proportion who are eligible for tPA treatment. Thrombolytics injected intraarterially or mechanical lysis for disruption or removal of an intravascular clot can in some instances restore blood flow of the middle cerebral and basilar arteries and, if administered within hours, may reduce the neurologic deficit. There is a high incidence of reocclusion of the treated vessel unless anticoagulants and stenting are also used. The most recent and popular alternatives involve a number of devices that retrieve clots from the intravascular lumen. The results of intravascular mechanical methods are somewhat better than for thrombolysis alone and have come into increasing use in the time period up to 6 h after the stroke onset. Basilar artery thrombosis without cerebellar infarctions but with large neurologic deficits are at times reversed. Treatment even several hours after the first symptoms may stop progression, but the lack of a systematic study of this approach makes it difficult to routinely endorse this approach until further data are collected. An apparently effective ancillary technique has been to supplement intravenously administered tPA with 2 h of continuously applied transcranial ultrasound aimed at the occluded vessel. According to Alexandrov and colleagues, complete recanalization of the middle cerebral artery or
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clinical recovery occurred within 2 h but the outcome at 3 months did not differ from those who did not receive ultrasound in part because other similar trials were terminated prematurely as a result of high rates of cerebral hemorrhage.
Acute Surgical Revascularization In past decades, there had been limited experience with immediate surgical removal of a clot from the carotid artery or the performance of a bypass to restore function. Ojemann and colleagues (1995) operated on 55 such patients as an emergency procedure; 26 of these had stenotic vessels and 29 acutely thrombosed vessels. Of the latter, circulation was restored in 21, with an excellent or good clinical result in 16. In 26 patients with stenotic carotid arteries, an excellent or good result was obtained in 19. Usually several hours will have elapsed before the diagnosis is established. If the interval is longer than 12 h, opening the occluded vessel is usually of little value and may present additional dangers. In any case, this approach has been largely supplanted by the above described endovascular techniques. Reoperation after carotid endarterectomy is a special circumstance in which rapid removal of a clot is performed more or less routinely.
Treatment of Infarctive Cerebral Edema and Raised Intracranial Pressure In the first few days following massive cerebral infarction, brain edema of the necrotic tissue may threaten life. Most often this occurs with a complete infarction in the territory of the middle cerebral artery, i.e., encompassing the deep and distal vascular territory. Some degree of mass effect may be evident on a CT scan in the first 24 h. Additional infarction in the territory of the anterior cerebral artery (total carotid occlusion) worsens the situation. Clinical deterioration occurs usually on the third to fifth day, sometimes later, but may rarely evolve as quickly as several hours after the onset (see Fig. 34-18). The clinical indicators of worsening—drowsiness, a fixed (but not necessarily enlarged) pupil, a Babinski sign on the side of the infarction (on the preserved side of the body), and changes in breathing pattern, as well as characteristic imaging signs—are all a result of secondary tissue shifts, as described in Chaps. 17 and 30 and detailed in the studies of Hacke and colleagues (1996) and Ropper and Shafran. Frank has shown that clinical deterioration is not always associated with an initial elevation of intracranial pressure. It may therefore be advisable, in selected cases, to measure the intracranial pressure (ICP) directly before embarking on an aggressive medical regimen to lower the pressure. Intravenous mannitol in doses of 1 g/kg, then 50 g every 2 or 3 h, may forestall further deterioration, but most of these patients, once comatose, are likely to die unless drastic measures are taken. In such instances, controlled hyperventilation may be useful as a temporizing maneuver. Corticosteroids are probably of little value; several trials have failed to demonstrate their efficacy. In the past several years there has been renewed interest in hemicraniectomy as a means of reducing the mass effect and intracranial pressure in these extreme circumstances. Our success in salvaging several patients even after a period of coma—similar to several reported nonrandom-
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ized series such as the one by Rieke and colleagues and randomized studies such as the one reported by Jüttler and colleagues. A different approach has been to perform hemicraniectomy fairly early in the course of brain swelling, generally in the first 2 or 3 days, well before coma supervenes. A pooled analysis of these randomized trials based on this premise has been given by Vahedi and colleagues. Excluding patients older than age 60 years, a total of 93 patients who were not fully alert could be analyzed. An advantage in survival and disability were found favoring the group operated within 48 h. Nonetheless, our recent practice has been to wait for signs of deterioration, generally leading to operation on fewer than half of patients with large MCA territory strokes and, generally having operations from the third through eighth days. Hemicraniectomy combined with an overlying duraplasty is then undertaken if the patient is progressing from a stuporous state to coma and imaging studies show increasing mass effect. Whether anterior temporal lobectomy is of added benefit is not known, but it is now infrequently included. The value of surgical decompression has not been limited to patients with right-hemispheric strokes; those with initially limited degrees of aphasia may also be appropriate candidates, but the family must understand the risks involved and the likelihood that the stroke deficits will persist. After a protracted period of coma with bilaterally enlarged pupils or with evidence that the midbrain has been irrevocably damaged, the procedure may be futile. In the special case of large cerebellar infarctions, usually from occlusion of a vertebral artery, swelling may compress the lower brainstem within hours or days. This complication carries the risk of sudden respiratory arrest. Cerebellar swelling may occur with or without an associated lateral medullary stroke and the situation is comparable to medullary compression caused by cerebellar hemorrhage. Hydrocephalus usually develops as a prelude to deterioration and is manifest as drowsiness and stupor, increased tone in the legs, and Babinski signs; other sentinel signs of compression of the brainstem are gaze paresis, sixth nerve palsy, or hemiparesis ipsilateral to the ataxia (Kanis and Ropper). It is at times difficult to differentiate the effects of increasing hydrocephalus from those of brainstem infarction from thrombus propagation in the basilar artery (Lehrich et al). Surgical decompression of the infarcted and swollen tissue should be undertaken almost as soon as cerebellar edema becomes clinically apparent by the emergence of hydrocephalus or brainstem signs, as further swelling can be anticipated. A brief period of observation before committing to surgery is not unreasonable if the fourth ventricle and peribrainstem cisterns are open and the patient is awake. Mannitol may be used to prepare the patient for surgery or if a period of observation is anticipated but its value is not clear. As in the case of cerebellar hemorrhage, ventricular drainage alone is usually inadequate and, in any case, is unnecessary if the pressure is relieved by hemicraniectomy and resection of infarcted tissue.
Anticoagulation Several considerations weigh in any discussion of the use of anticoagulant treatment of stroke. First is the distinction
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between anticoagulation to prevent the progression of an acute stroke and the prophylactic use of anticoagulation for the prevention of future strokes after the occurrence of TIAs or an initial infarction. In the latter instance, the pivotal issue is whether the stroke or TIA is atherothrombotic or cardioembolic. As discussed further on, several studies point conclusively to a role for anticoagulation in certain cardioembolic cases, while the indications in atherothrombotic disease are less certain. Warfarin and heparin had been used extensively to prevent TIAs and reduce the chances of an impending stroke. These anticoagulants may halt the advance of a progressive thrombotic stroke, but they are clearly not effective in all cases and numerous recent studies and position papers have questioned their value altogether (see, for example, the Report of the Joint Stroke Guideline Development Committee authored by Coull et al). In deciding whether to use anticoagulants, one faces the question of where in the course of the stroke the patient stands when first examined. One fact seems definite—that the administration of anticoagulants is not of great value once the stroke is fully developed, whether in a patient with a lacunar infarct or one with a massive infarction and hemiplegia. It is as yet uncertain whether the long-term use of anticoagulants prevents the recurrence of a thrombotic stroke; in these cases, the incidence of complicating hemorrhage probably outweighs the value of anticoagulants (atrial fibrillation is an exception as noted further on). The two situations in which the immediate administration of heparin has drawn the most support from our own clinical practice are in fluctuating basilar artery thrombosis and in impending carotid artery occlusion from thrombosis or dissection. In these situations, the administration of heparin may be initiated while the nature of the illness is being clarified; the drug is then discontinued if contraindicated by new findings. It must be acknowledged that satisfactory clinical studies in support of this approach of acute anticoagulation have not been carried out. The issue of heparin in cases of recent cardioembolic cerebral infarction is addressed further on in this chapter, under “Embolic Infarction.” In anticipation of that discussion it can be stated that there is little evidence in support of heparin use in most strokes. In the event heparin is given, if tPA has not been used in the preceding 24 h, the heparin may be given intravenously, beginning with a bolus of 100 U/kg followed by a continuous drip (1,000 U/h) and adjusted according to the partial thromboplastin time (PTT). Bleeding into any organ may occur when the PTT is greater than 3 times the pretreatment level. When the PTT exceeds 100 s, it is preferable to discontinue the infusion, check the blood clotting values, and then reinstitute the infusion at a lower rate based on the test results (rather than simply lower the infusion rate). In circumstances of fluctuating basilar artery ischemia, it is our practice to permit higher values of PTT. The use of low-molecular-weight heparin (anti–factor Xa enoxaparin or nadroparin) given subcutaneously within the first 48 h of the onset of symptoms have uncertain benefit but may improve outcome from stroke. In a limited randomized trial, there was no increase in the fre-
quency of hemorrhagic transformation of the ischemic region when compared to placebo treatment (Kay et al). Because the outcome measures in this study were coarse (death or dependence 6 months after stroke), further investigations of this approach need to be carried out. We can only infer that the use of low-molecular-weight heparin (approximately 4,000 U subcutaneously, tid) appears to be safe and is possibly beneficial. Whether anticoagulant therapy is effective in preventing strokes in patients with TIAs or recent stroke is a question that has never been answered satisfactorily. Swanson reviewed several trials evaluating heparin (including the International Stroke Trial and the TOAST study) and suggested that there was no net benefit from heparin in acute stroke because of an excess of cerebral hemorrhages. However, in these series there was a low incidence, estimated as 2 percent, of recurrent stroke in the first weeks after a cerebral infarction in the untreated groups. An early recurrent stroke rate this low almost precludes demonstrating a benefit from the use of heparin or heparinoid drugs except in a study with very large groups of patients. The long-term use of warfarin following atherothrombotic stroke is also still under critical analysis. To date it seems to be of some slight value in the prevention of further thrombosis and embolism. There are data to suggest that it is of greatest use in the first 2 to 4 months following the onset of ischemic attack(s); after that time the risk of intracranial hemorrhage may exceed the benefits of anticoagulant therapy (Sandok et al). However, in comparison to aspirin, discussed below, there is no reason to favor warfarin in cases of atherothrombotic stroke. This was amply shown in the Warfarin-Aspirin Recurrent Stroke Study (WARSS; not including cardioembolic stroke) published by Mohr and colleagues (2001); over 2 years the recurrent stroke rate was about 16 percent in both groups, and, surprisingly, the rate of cerebral hemorrhage was similar (near 2 percent). Similarly, for the special case of TIA or stroke that is shown to be because of intracranial atherosclerosis, Chimowitz and colleagues in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial have suggested that warfarin provided no benefit over aspirin in preventing subsequent cerebrovascular events but warfarin had more risk as commented below. The WASID trial exposed not so much the deficiency of Warfarin in prevention of stroke as much as the difficulties in its use, as pointed out by Koroshetz. In contrast to the situation with atherothrombotic disease, warfarin has been found to be superior for prevention of a second stroke in cardioembolic disease, as discussed further on. Of course, the use of anticoagulant drugs makes an accurate diagnosis imperative. Intracranial hemorrhage must be excluded by CT or MRI. A determination of prothrombin and partial thromboplastin activity is needed before therapy is started, but if this is not feasible, the initial doses of anticoagulant drugs can usually be given safely if there is no clinical evidence of bleeding anywhere in the body and there has been no recent surgery. Warfarin therapy, beginning with a dose of 5 to 10 mg daily, is relatively safe provided that the international normalized ratio (INR) is brought to 2 to 3 (formerly measured as a prothrombin time between 16 and 19 s)
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and the level is determined regularly (an approximate plan is once a day for the first 5 days, then 2 or 3 times a week for 1 to 2 weeks, and finally once every several weeks). Because there is no reliable evidence that complications are more frequent in the presence of mild to moderate hypertension if the INR is not allowed to exceed 2 to 3 times normal, we have not withheld anticoagulant therapy in these patients. However, when the blood pressure is greater than 220/ 120 mm Hg, an attempt is made to lower it gradually at the same time. Numerous drugs may alter the anticoagulant effects of the coumarins or add to the risk of bleeding—aspirin, cholestyramine, alcohol, barbiturates, carbamazepine, cephalosporin and quinolone antibiotics, sulfa drugs, and high-dosage penicillin being the most important ones. Hemorrhagic skin necrosis is a rare but dangerous complication. It is the result of a paradoxical microthrombosis of skin vessels and is liable to occur in patients with unsuspected deficiencies of endogenous clotting proteins (S and C). Although the disseminated form of skin necrosis occurs within days of initiating warfarin therapy, we have seen one patient with a form of this lesion following local skin injury after months on treatment. Any type of serious bleeding with warfarin, even if not a result of overdosage, justifies immediate administration of fresh-frozen plasma and large doses of vitamin K. An INR above 5 in a patient who must remain anticoagulated—for example, one with a prosthetic heart valve— may be corrected with small doses of vitamin K (0.5 to 2 mg), preferably given intravenously. The problem that continues to plague all attempts to use long-term anticoagulants, as already noted in the discussion regarding heparin in the acute situation, is the risk of hemorrhage estimated by Whisnant and colleagues to be 5 percent overall and considerably higher in elderly patients who have been treated for more than 1 year. Thus, it would appear that with long-term administration of anticoagulants, except in certain circumstances—such as a severely stenotic cerebral vessel, atrial fibrillation, prosthetic heart valve, and certain blood disorders—the risk of hemorrhage outweighs the benefit from prevention of stroke.
Antiplatelet Drugs Aspirin (325 mg daily) has proved to be perhaps the most consistently useful drug in the prevention of thrombotic and possibly in embolic strokes. One currently favored approach, based in part on the above-mentioned WARSS trial, is to simply administer aspirin in all cases of acute stroke (except perhaps if tPA has been used). This approach is further endorsed by the WASID trial comparing aspirin (1,300 mg/d) to warfarin for treatment of intracranial arterial stenosis on the basis that warfarin was no better at preventing strokes while aspirin was associated with fewer gastrointestinal hemorrhages and a lower overall death rate. Confirmation of this approach was given by the IST and CAST trials that established a modest reduction in mortality and stroke recurrence if aspirin was given within 48 h of stroke. The acetyl moiety of aspirin combines with the platelet membrane and inhibits platelet cyclooxygenase, thus preventing the production of thromboxane A2, a vasoconstrict-
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ing prostaglandin, and also prostacyclin, a vasodilating prostaglandin. In patients who cannot tolerate aspirin, the platelet aggregate inhibitor clopidogrel or a similar drug (such as ticlopidine or dipyridamole) can be substituted (see below). A number of controlled studies have attested to the therapeutic value of aspirin and ticlopidine, clopidogrel, or dipyridamole in long-term stroke prevention (not acute treatment as discussed above), but it is important not to exaggerate the magnitude of their effects. With few exceptions, it can be concluded that aspirin is beneficial in preventing stroke; whether low doses (50 to 100 mg) and high doses (1,000 to 1,500 mg) provide equivalent protection is still uncertain. From a review of several studies, it appears that both dosages are effective and that the addition of dipyridamole further reduces the risk of stroke by a small amount. Ticlopidine and clopidogrel are considered, on the basis of clinical trials, to be equivalent to or marginally more effective than aspirin for the prevention of stroke but they are more expensive. Furthermore, both drugs are potentially toxic; ticlopidine may produce neutropenia and clopidogrel may cause thrombotic thrombocytopenic purpura. Dipyridamole in high doses has not been as well tolerated by many of our patients because of dizziness induced by peripheral vasodilatation. The combined use of these drugs with aspirin has generally been superior to aspirin alone in secondary stroke prevention, but with increased risk of cerebral hemorrhage in some studies. In most large trials, the incremental benefits of adding one of these drugs to aspirin has been of the order of 1 to 3 percent (see the ESPRIT study and Bhatt et al). In trials comparing aspirin to anticoagulation for stroke prevention in atrial fibrillation, anticoagulation has still been superior (see ACTIVE Writing Group). These studies notwithstanding, the therapeutic effectiveness of aspirin is still rather slight. Moreover, in each of the trials, a significant number of subsequent ischemic strokes occurred in patients while they were receiving aspirin. The best course of treatment for patients who have lacunar or atherothrombotic strokes while already receiving antiplatelet medications is not clear. Switching to warfarin from antiplatelet agents is sensible in some circumstances but should be done with caution. Control of blood pressure and the administration of a lipid-lowering drug are advisable, even if lipid levels are normal. In the most comprehensive study of statins to date, the institution of high doses of drug reduced the incidence of subsequent stroke after a TIA or first stroke by 2 percent over 5 years (see Stroke Prevention by Aggressive Reduction in Cholesterol Investigators [SPARCL trial]). This was at the expense of a slight increase in the other large studies that have not shown this effect with lower doses of statin drugs. Whether this is adequate to adapt into routine practice is unclear to us.
Other Forms of Medical Treatment In the past, treatment by hemodilution was popularized by the studies of Wood and Fleischer, who showed a high incidence of short-term improvement when the hematocrit was reduced to approximately 33 percent. That lowering blood viscosity improves regional blood flow in the heart had been
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known for some time, and a similar effect on the brain has been demonstrated by CBF studies. Earlier observations had shown a reduction in the overall neurologic deficit, but almost all larger randomized trials—which included patients in many settings who were treated at various times up to 48 h after stroke—failed to confirm any such benefit, and the use of this treatment has been virtually abandoned. While this treatment cannot be recommended as a routine approach, it may have some merit in selected situations, such as fluctuating stroke. Therapies aimed at improving blood flow by enhancing cardiac output (aminophylline, pressor agents), by improving the microcirculation (mannitol, glycerol, dextran), or by use of a large number of vasodilating drugs (see below) have failed to show consistent benefits, but several are still under study. Hyperbaric oxygen may reduce ischemic deficits temporarily but has no sustained effect. Induced hypothermia limits the size of ischemic stroke, but it is technically difficult to administer and often has serious side effects. Calcium channel blockers of the types administered for cardiac disease have also been found to increase CBF and to reduce lactic acidosis in stroke patients. However, several multicenter clinical trials that compared calcium channel blockers with placebo did not establish a difference in outcome in the two groups. There has also been interest, as noted earlier in this chapter, in drugs that inhibit excitatory amino acid transmitters and free-radical scavengers such as dimethyl sulfoxide (DMSO) and growth factors, but so far none of these has been successfully applied to humans. Despite some experimental evidence that certain vasodilators, such as CO2 and papaverine, increase CBF, none has proved beneficial in carefully studied human stroke cases at the stage of TIAs, thrombosis in evolution, or established stroke. Vasodilators may actually be harmful, at least on theoretical grounds, because by lowering the systemic blood pressure or dilating vessels in normal brain tissue (the autoregulatory mechanisms are lost in vessels within the infarct), they may reduce the intracranial anastomotic flow. Moreover, the vessels in the margin of the infarct (border zone) are already maximally dilated. New discoveries regarding the role of nitric oxide in vascular control will probably give rise to new pharmacologic agents that will require evaluation. The metabolic stresses of ischemia and the production of destructive oxygen free radicals were referred to earlier. Among the numerous “brain-sparing” agents that have been tried in an attempt to reduce the size of infarction, certain ones have had erratic results in large randomized trials. Two recent trials, for example, gave initially promising results and later proved ineffective (Shuaib et al). These agents are of interest because they can be administered up to several hours after the stroke (continuing for 72 h).
Physical Therapy and Rehabilitation In all but the most seriously ill patients, beginning within a few days of the stroke the paralyzed limbs ideally should be carried through a full range of passive movement several times a day. The purpose is to avoid contracture (and periarthritis), especially at the shoulder, elbow, hip, and ankle. Soreness and aching in the paralyzed limbs should
not be allowed to interfere with exercises to the extent possible. Patients should be moved from bed to chair as soon as the stroke is completed and blood pressure is stable. Prophylaxis for deep venous thrombosis with compression boots or anticoagulation is appropriate if the patient cannot be mobilized. An assessment for swallowing difficulty should be made early during recovery and dietary adjustments on the insertion of a nasogastric tube made if there is a risk of aspiration. Nearly all hemiplegic patients regain the ability to walk to some extent, usually within a 3- to 6month period, and this should be a primary aim in rehabilitation. The presence of deep sensory loss or anosognosia in addition to hemiplegia are the main limiting factors. A short or long leg brace is often required. By teaching patients with cerebellar ataxia new strategies, balance and gait disorders can be made less disabling. As motor function improves and if mentality is preserved, instruction in the activities of daily living and the use of various special devices can help the patient to become at least partly independent in the home. What little research is available on the effectiveness of stroke rehabilitation suggests that a greater intensity of physical therapy does indeed achieve better scores on some measures of walking ability and dexterity. In a randomized trial, Kwakkel and colleagues achieved these results by applying an additional 30 min per day beyond conventional physical therapy of focused treatments to the leg or arm, 5 d per week, for 20 weeks. Other studies have demonstrated clearly the undesirable effects of immobilizing a limb in a splint after a stroke. Experimental work in monkeys and limited data from patients suggest that improvement can be obtained by restraining the normal limb and forcing use of the sound limb. In a randomized trial, Wolf and colleagues (2006) were able to demonstrate a benefit from this form of “constraint” therapy by forcing the patient to wear a mitt on the good hand while engaging in persistent exercises with the hemiplegic limb for more than 90 percent of their waking time through 2 weeks. This may reflect functional expansion of the cortical motor representation into adjacent undamaged cortical areas, indicating the potential for some degree of reorganization that corresponds to clinical recovery. The neural substrates of improvement after stroke are just beginning to be studied. Considerable clinical experience and physiologic data such as those reported by Luft and colleagues have demonstrated that the injured brain has some degree of plasticity; remodeling of brain tissue and reorganization of neural function may occur with training even months after large strokes. Speech and language therapy is particularly valuable in identifying the risk of aspiration as noted above. Specific therapy should be given in appropriate cases and certainly improves the morale of the patient and family. Further comments on the value of such treatments can be found in Chap. 23.
Preventive Measures Because the primary objective in the treatment of atherothrombotic disease is prevention, efforts to control the risk factors must continue after stroke. The carotid vessels, being readily accessible, may be examined for the pres-
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ence of a bruit; the latter often indicates a stenosis, although not all stenoses cause a bruit and some bruits heard are transmitted sounds from a stenotic aortic valve. Ultrasonography, CT, or MRA examination of the cervical and intracranial vessels is justified in almost all patients with TIAs and ischemic stroke. The management of patients with asymptomatic carotid bruits has been considered above. For patients who have had a stroke from atherothrombotic disease and are functional, preventive measures include the following: (1) aspirin, which reduces the risk of second stroke slightly, but its effect, as already noted, should not be overestimated (see earlier under “Antiplatelet Drugs”); (2) administration of any required antihypertensive agents but with caution in the first days after ischemic stroke; (3) administration of cholesterol-lowering drugs unless the cholesterol level is already very low or there is a contraindication as commented below; (4) smoking cessation, which is mandatory and the patient should be supported in such efforts; and (5) maintenance of the systemic blood pressure, oxygenation, and intracranial blood flow during future general surgical procedures, especially in elderly patients. There may be additional but modest value in administering high doses of statin drugs even in patients with normal cholesterol levels who have had an atherothrombotic stroke. A large study, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, has shown that secondary stroke prevention is possible in patients with TIA or stroke in the prior 6 months with the use of high-dose atorvastatin (80 mg) but the magnitude of benefit was small (approximately 3 percent). The trial included mainly patients whose LDL cholesterol levels were modestly elevated. The clinician should be mindful of the risk of a statin-induced myopathy, and it is not known if lower doses of medication have the same preventative effect. Consistent with some other trials using statins, there was a slight increase in the number of hemorrhages in the treated group compared to the placebo group. The outcome results in this study contrast with at least one other large secondary prevention trial (the Heart Protection Collaborative Study) that used simvastatin at lower doses. The solution of the problems of ischemic infarction and TIAs lies in more fundamental fields—namely, the prevention or alleviation of hypertension and atherosclerosis.
Carotid Stenosis Symptomatic Carotid Stenosis Comments have already been made concerning the opening of an occluded carotid artery soon after a stroke. Here we discuss the patient who has had TIAs or who has passed the acute period of stroke, when surgery is considered to be safer. The region that most often lends itself to such therapy is the carotid sinus (the bulbous expansion of the internal carotid artery just above its origin from the common carotid). Other sites suitable for surgical management include the common carotid, innominate, and subclavian arteries. Operation on the vertebral artery at its
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origin has proved successful only in exceptional circumstances. In recent years, balloon angioplasty and stenting of the carotid artery have become increasingly popular as an alternative to surgery (see below). Surgery and angioplasty, in our opinion, are as yet applicable mainly to the group of patients with symptomatic carotid artery stenosis (the asymptomatic ones are discussed below) who have substantial extracranial stenosis but not complete occlusion, and, in special instances, in those with nonstenotic ulcerated plaques. Those with stenosis constitute less than 20 percent of all patients with TIAs (Marshall); but from the perspective of surgical therapy, the term symptomatic encompasses both TIAs and small strokes ipsilateral to the stenosis that may be evident only with cerebral imaging. There is evidence that well-executed surgery in appropriately chosen cases arrests the TIAs and diminishes the risk of future strokes. These views have received strong affirmation from two often-cited randomized studies—the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST). The conclusion reached in each of these studies was that carotid endarterectomy for symptomatic lesions causing degrees of stenosis greater than 70 to 80 percent in diameter reduces the incidence of ipsilateral hemispheral strokes and shows greater benefit with increasing degrees of stenosis. These two trials differed in the method of estimating the degree of stenosis, but when adjustments are made, the results are comparable (Donnan et al, 1998). Further analysis of the North American trial by Gasecki and colleagues indicated that the risk of cerebral infarction on the side of the symptomatic stenosis is increased if there is a contralateral carotid stenosis but that operated patients (on the side of symptomatic stenosis) still had fewer strokes than those treated with medication alone. In those with bilateral carotid disease, the risk of stroke after 2 years was 69 percent, and if operated, 22 percent. In the final analysis, the relative benefits of surgery or medical treatment (anticoagulation or aspirin) depend mainly on the actual surgical risk—i.e., on the record of an individual surgeon. If there is an established operative complication rate of less than 3 percent, then surgery can be recommended in symptomatic patients with carotid stenosis greater than 70 percent. This benefit extends to elderly patients and, indeed, it has been shown on a statistical basis to be most evident in patients older than age 75 (see the post hoc analysis of NASCET data by Alamowitch et al). Before operation or angioplasty, the existence of the carotid lesion and its extent must be determined. Conventional arteriography, the procedure that yields the best images and most accurate measurements of the residual lumen, carries a small risk of worsening the stroke or producing new focal signs though this notion has never been documented systematically. CTA has emerged as a surrogate that well demonstrates the carotid bulb and carries only the risk of renal damage from dye infusion. Severe stenosis is also indirectly reflected in angiography by the filling of the distal branches of the external carotid artery before the branches of the middle cerebral artery are opacified—a reversal of the usual filling pattern. Increasingly the diagnosis of carotid stenosis is being initially
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made by less invasive methods, but with ultrasonography and magnetic resonance arteriography there is some difficulty in quantifying severe stenosis and, often, in separating it from complete carotid artery occlusion. If the patient is in good medical condition, has normal vessels on the contralateral side, and has normal cardiac function (no heart failure, uncontrolled angina, or recent infarction), symptomatic lesions can usually be dealt with safely by endarterectomy. The procedure may be followed by a new hemiplegia or aphasia that becomes evident soon after endarterectomy, usually by the time the patient arrives in the recovery room. In these cases, surgeons prefer to return the patient to the operating room and open the artery, as discussed earlier on. An intimal flap at the distal end of the endarterectomy and varying amounts of fresh clot proximal to it are usually encountered; but after removal and repair of the vessel, the effects of the stroke, if one has occurred, are not usually improved. Carotid angioplasty and stenting were mentioned earlier. The role of this approach in clinical practice in comparison to endarterectomy is still being determined but it offers an alternative for the patient who is too ill to undergo surgery. Direct comparisons have been made in several organized studies. In one randomized trial reported by the CAVATAS investigators (Carotid and Vertebral Artery Transluminal Angioplasty Study), the incidence of minor (nonstroke) complications was lower in patients who had angioplasty and stenting. This has not been our experience, where sizable groin hematomas have been common. Also, a higher proportion of patients undergoing angioplasty had restenosis. Otherwise, the recurrent stroke rates were similar, 10 percent for both groups. A useful comparison between angioplasty and surgical endarterectomy has been made in the trial reported by Mas and associates (2006) and in the “SPACE” trial. While the first of these favored a surgical approach for severe symptomatic stenosis, the second gave equivalent results of approximately 6 percent combined stroke and death rates with both procedures. Additional trials are ongoing, including those comparing stenting, endarterectomy, and statin (with other contemporary medical) treatment, but it bears repeating that the critical factor in comparing these techniques is the complication rate that can be attained. The postoperative care of carotid endarterectomy focuses on reversing reflex hypotension that is induced by exposing the carotid wall to high perfusion pressure. This phenomenon can be reduced by infiltrating the carotid sinus with anesthetic prior to the operation. An uncommon but rather striking hyperperfusion syndrome develops several days to a week after carotid endarterectomy. The features are headache, focal deficits, seizures, brain edema, or cerebral hemorrhage. These are thought to reflect autoregulatory failure of the cerebral vasculature in the face of abrupt restoration of normal blood pressure and perfusion. After a long period of autoregulatory compensation for a stenotic carotid artery, then a normal cerebral perfusion pressure may result in endothelial incompetence with leakage of water across the blood–brain barrier. Unilateral severe headache is the most common symptom and may be the only manifestation. On occasion cerebral edema is so mas-
sive as to lead to death (Breen et al). Treatment is by control of hypertension; it is unclear whether anticonvulsant medications are required if there has been a seizure as a component of the syndrome. We mention here that an identical syndrome of focal cerebral deficits and brain edema, perhaps with the exception of seizures, has been seen, rarely and with no explanation, in migraineurs, including two cases with which we are familiar. For intracranial internal carotid occlusion that extends into the siphon and distally, a transcranial (superficial temporal–middle cerebral) anastomosis had been employed in the past. Although this operation is technically feasible, its therapeutic value has been questioned by the multicenter study of Barnett and collaborators (1985), who found that it did not produce a reduction in TIAs, strokes, or deaths. That study was criticized for having a skewed patient selection and several smaller and uncontrolled trials have suggested that the procedure may benefit some patients. There may be particular circumstances that justify its use; for example, when there are ongoing TIAs in relation to upright posture or with episodes of mild hypotension. Bypass procedures and their derivatives such as temporal synangiosis may be useful in reestablishing flow to a hemisphere when there has been progressive intracranial carotid stenosis. Testament to the success of the bypass procedure is the regression of symptoms and of the network of collateral vessels in moyamoya disease (see further on).
Asymptomatic Carotid Stenosis Finally, there is the problem of the asymptomatic carotid bruit or incidentally discovered stenosis. The population study by Heyman and associates has shed some light on this. They found, not surprisingly, that cervical bruits in men constituted a risk for death from ischemic heart disease, and that the presence of asymptomatic bruits in men (but not in women) carried a slightly increased risk of stroke. Notably, the subsequent stroke often did not usually coincide in its angioanatomic locus and laterality with the cervical bruit so that asymptomatic stenosis is in the short term a general marker for atherosclerosis more so than for a proximate stroke. Other investigators have reported similar findings. On the other hand, Wiebers and colleagues (1990) found that patients with asymptomatic carotid bruits who were followed for 5 years were approximately 3 times more likely to have ischemic strokes than an age- and sex-matched population sample without carotid bruits. While a self-audible bruit occasionally indicates carotid stenosis, dissection, or fibromuscular dysplasia, it is usually benign and in some instances associated with an enlarged and superiorly located jugular bulb—a benign anatomic variant that can be discerned on CT scan (Adler and Ropper). In an attempt to clarify the role of treating asymptomatic carotid stenosis, the Asymptomatic Carotid Atherosclerotic Study (ACAS), as reported by its Executive Committee, found that the frequency of strokes could be reduced from 11 percent to 5 percent over 5 years by removing the plaque if there was a stenosis greater than 60 percent (in diameter). These conclusions have been tempered by a reanalysis of the ACAS data, in which almost half of the strokes were of
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lacunar or cardioembolic (Inzitari et al). Data from a European trial, encompassing 3,120 patients (MRC Asymptomatic Carotid Surgery Trial [ACST] Collaborative Group), have indicated that asymptomatic carotid stenosis of more than 70 percent carries a 2 percent annual risk of stroke over a 5-year period and that the risk is reduced to 1 percent with endarterectomy. It was concluded that endarterectomy may be justified for asymptomatic carotid stenosis of this degree but that an audited surgical risk below 3 percent was required to obtain favorable results (just as for symptomatic carotid stenosis). From these and other trials it can also be inferred that endarterectomy does not reduce the incidence of strokes in patients who have asymptomatic carotid stenosis with luminal narrowing that is less than 70 percent of normal diameter. For those with greater degrees of stenosis, the benefits are slight and it is not clear if the presence of an ulcerated plaque or heavy calcification alters this view. These comments probably also apply to patients with asymptomatic carotid stenosis who are about to undergo major surgery such as cardiac bypass grafting, but adequate studies in this circumstance have not been performed. As already noted, any advice should be tempered by the surgical risk in a particular institution. Our usual practice with asymptomatic cases has been to reevaluate the lumen of the internal carotid artery (using ultrasonography) at 6- to 12-month intervals. If the stenosis is advancing and becomes narrowed to 1.5 mm or less, or if there is an event that could be construed as a TIA referable to the stenotic side, then surgery or angioplasty with stenting is considered. In the case of an asymptomatic but progressive stenosis, statin agents, accompanied by smoking cessation and glucose control where applicable, are a reasonable alternative approach. These comments reflect the guidelines for carotid endarterectomy set forth by the American Heart Association as reported by Moore and colleagues but there must be a careful evaluation of the circumstances in each patient and a recognition that residual lumen diameters and percent stenoses are measured in different ways by varying techniques, both in the above described studies and in clinical practice.
Embolic Infarction This is the most common cause of stroke. Its characteristic feature is an abrupt neurologic deficit referable to one restricted section of the brain. In most cases, the embolic material consists of a fragment that has broken away from a thrombus within the heart (“cardioembolic”). Certain circumstances such as atrial fibrillation predispose to this type of stroke. Somewhat less frequently, the source is intraarterial from the distal end of a thrombus within the lumen of an occluded or severely stenotic carotid or vertebral artery, or a clot that originates in the nervous system and passes through an aperture in the heart walls, or from large atheromatous plaques in the aorta. Thrombotic or infected material (endocarditis) that adheres to the aortic or mitral heart valves and break free are also well-appreciated sources of embolism, as are clots originating on prosthetic heart valves. Embolism caused by fat, tumor cells (atrial myxoma), fibrocartilage, amniotic fluid, or air sel-
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dom enters into the differential diagnosis of stroke except in special circumstances. The embolus usually becomes arrested at a bifurcation or other site of natural narrowing of the lumen of an intracranial vessel and ischemic infarction follows. The infarction is pale, hemorrhagic, or mixed; hemorrhagic infarction nearly always indicates embolism (venous occlusion can do the same). Any region of the brain may be affected, the territories of the middle cerebral artery, particularly the superior division, being most frequently involved. The two cerebral hemispheres are approximately equally affected. Large embolic clots can block large vessels (e.g., the carotids in the neck or at their termination intracranially), while tiny fragments may reach vessels as small as 0.2 mm in diameter, usually with inconsequential effects. The embolic material may remain arrested and plug the lumen solidly, but more often it breaks into fragments that enter smaller vessels so that even careful pathologic examination fails to reveal their final location. In this instance, the clinical effects may clear in hours. Because of the rapidity with which embolic occlusion develops, useful collateral influx does not become established. Thus, sparing of the brain territory distal to the site of occlusion is usually not as evident as in thrombosis that develops more slowly. However, the vascular anatomy and ischemia-modifying factors described earlier are still operative and influence the magnitude and configuration of the infarct. Brain embolism is predominantly a manifestation of heart disease, and fully 75 percent of cardiogenic clinically recognizable emboli lodge in the brain. The most common identifiable cause is chronic or recent atrial fibrillation, the source of the embolus being a mural thrombus within the atrial appendage (Table 34-7). According to the Framing-
Table 34-7 CAUSES OF CEREBRAL EMBOLISM 1. Cardiac origin a. Atrial fibrillation and other arrhythmias (with rheumatic, atherosclerotic, hypertensive, congenital, or syphilitic heart disease) b. Myocardial infarction with mural thrombus c. Acute and subacute bacterial endocarditis d. Heart disease without arrhythmia or mural thrombus (mitral stenosis, myocarditis, etc.) e. Complications of cardiac surgery f. Valve prostheses g. Nonbacterial thrombotic (marantic) endocardial vegetations h. Prolapsed mitral valve i. Paradoxical embolism with congenital heart disease (e.g., patent foramen ovale) j. Myxoma 2. Noncardiac origin a. Atherosclerosis of aorta and carotid arteries (mural thrombus, atheromatous material) b. From sites of dissection and/or fibromuscular dysplasia of carotid and vertebrobasilar arteries c. Thrombus in pulmonary veins d. Fat, tumor, or air e. Complications of neck and thoracic surgery f. Pelvic and lower extremity venous thrombosis in presence of right-to-left cardiac shunt 3. Undetermined origin
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ham Heart Study, patients with chronic atrial fibrillation are approximately 6 times more liable to stroke than an agematched population with normal cardiac rhythm (Wolf et al, 1983) and the risk is considerably higher if there is also rheumatic valvular disease, now less prevalent than in the past. Furthermore, the risk for stroke conferred by the presence of atrial fibrillation varies with age, being 1 percent per year in persons younger than age 65 years, and as high as 8 percent per year in those older than age 75 years with additional risk factors. These levels of risk are of prime importance in determining the benefit of chronic anticoagulation, as discussed below. Embolism may also occur in cases of paroxysmal atrial fibrillation or flutter. Mural thrombus deposited on the damaged endocardium overlying a myocardial infarct in the left ventricle, particularly if there is an aneurysmal sac, is an important source of cerebral emboli, as is a thrombus associated with severe mitral stenosis without atrial fibrillation. Emboli tend to occur in the first few weeks after an acute myocardial infarction but Loh and colleagues found that a lesser degree of risk persists for up to 5 years. Cardiac catheterization or surgery, especially valvuloplasty, may disseminate fragments from a thrombus or a calcified valve. Mitral and aortic valve prostheses are, as mentioned, additional important sources of embolism. Another source of embolism is the carotid or vertebral artery, where clot forming on an ulcerated atheromatous plaque may be detached and carried to an intracranial branch (artery-to-artery embolism). A similar phenomenon occurs with arterial dissections and sometimes with fibromuscular disease of the carotid or vertebral arteries. Atheromatous plaques in the ascending aorta have been recognized in the last decades to be a more frequent source of embolism than had been previously appreciated. Amarenco and colleagues reported that as many as 38 percent of a group of patients with no discernible cause for embolic stroke had echogenic atherosclerotic plaques in the aortic arch that were greater than 4 mm in thickness, a size found to be associated on a statistical basis with strokes. Disseminated cholesterol emboli from the aorta are known to occur in the cerebral circulation and may be dispersed to other organs as well; rarely, this is sufficiently severe to cause an encephalopathy and pleocytosis in the spinal fluid. Paradoxic embolism occurs when an abnormal communication exists between the right and left sides of the heart (particularly a patent foramen ovale [PFO]) or when both ventricles communicate with the aorta. Embolic material arising in the veins of the lower extremities or pelvis or elsewhere in the systemic venous circulation bypasses the pulmonary circulation and reaches the cerebral vessels. Pulmonary hypertension (often from previous pulmonary embolism) favors the occurrence of paradoxic embolism, but these strokes occur even in the absence of pulmonary hypertension. Several studies indicate that the presence of a small atrial septal aneurysm adjacent to the patient foramen increases the likelihood of stroke. In the series reported by Mas and colleagues (2001), patients ages 18 to 55 years who had a stroke were followed for 4 years; the risk of second stroke was 2 percent in those with a PFO alone and 15 percent among those with both a PFO and an atrial septal aneurysm (curiously, the risk among those with neither congenital abnormality was 4 percent—higher than for
those with a PFO alone). This mechanism comes into play mainly in considering the causes of stroke in the younger patient, but Handke and colleagues published a series in which there was a slightly increased risk of stroke in patients who were older than age 55 who had PFO. It must be emphasized, however, that about one-third of patients in all age groups will be found to have a PFO and anticoagulation or repair of these lesions in older patients with embolic stroke has not been established. Subendocardial fibroelastosis, idiopathic myocardial hypertrophy, cardiac myxomas, and myocardial lesions of trichinosis are additional rare causes of embolism from a cardiac source. The vegetations of bacterial endocarditis give rise to several different lesions in the brain as described in Chap. 32. Mycotic aneurysm is a rare complication of septic embolism and may be a source of intracerebral or subarachnoid hemorrhage. Marantic or nonbacterial thrombotic endocarditis is a frequently overlooked cause of cerebral embolism; at times it produces a baffling clinical picture but its strong association with cancer, cachexia from any cause, or lupus erythematosus should raise suspicion in these circumstances. This subject is discussed further on. Mitral valve prolapse may be a source of emboli, especially in young patients, but its importance has probably been highly overestimated. The initial impetus for considering this abnormality as a source of embolus came from the study of Barnett and colleagues (1980) of a group of 60 patients who had TIAs or small strokes and were younger than 45 years of age; mitral prolapse was detected (by echocardiography and a characteristic midsystolic click) in 24 patients, but in only 5 of 60 age-matched controls. However, several subsequent large studies (Sandok and Giuliani; Jones et al) found that only a very small proportion of strokes in young patients could be attributed to prolapse; even then, the connection was inferred by the exclusion of other causes of stroke. Indeed, in a recent study using stringent criteria for the echocardiographic diagnosis of prolapse, Gilon and colleagues were unable to establish a relation to stroke. Of interest, Rice and colleagues described a family with premature stroke in association with valve prolapse and a similar relationship has been reported in twins; the same may occur in EhlersDanlos disease. The pulmonary veins are a potential if infrequent source of cerebral emboli, as reflected by the occurrence of cerebral abscesses in association with pulmonary infectious disease (and by the high incidence of cerebral deposits secondary to pulmonary carcinoma). In Osler-Weber-Rendu disease, pulmonary shunts serve as a conduit for emboli. A rare type of embolism follows thyroidectomy, where thrombosis in the stump of the superior thyroid artery extends proximally until a section of the clot, protruding into the lumen of the carotid artery, is carried into the cerebral circulation. During cerebral arteriography, emboli may arise from the tip of the catheter, or manipulation of the catheter may dislodge atheromatous material from the aorta or carotid or vertebral arteries and account for some of the strokes during this procedure. Monitoring of the cerebral arteries by transcranial Doppler insonation has suggested that small emboli frequently arise during angiographic procedures. For example, a study by Bendszus and colleagues
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found that 23 of 100 consecutive patients had new cortical lesions shown on diffusion-weighted MRI just after cerebral arteriography. However, none of these patients was symptomatic, and with good technique, emboli from vascular catheters are infrequent. Cerebral embolism of special type must always have occurred when secondary tumor is deposited in the brain but a mass of tumor cells is seldom large enough to occlude a cerebral artery and produce the picture of a stroke. Nevertheless, tumor embolism with stroke is known from cardiac myxoma and occasionally with other tumors. The above syndrome must be distinguished from embolism caused by nonbacterial endocarditis that complicates malignant neoplasms (nonbacterial thrombotic endocarditis is discussed further on). This special source of cerebral embolism is a component of a hypercoagulable state that accompanies especially adenocarcinoma and cachexia. Diffuse cerebral fat embolism is related to severe bone trauma. As a rule, the emboli are minute and widely dispersed, giving rise first to pulmonary symptoms and then to multiple dermal (anterior axillary fold and elsewhere) and cerebral petechial hemorrhages. Accordingly, the clinical picture is more of an encephalopathy and not strictly focal as it is in a stroke, although in some instances there may be focal features. Cerebral air embolism is a rare complication of abortion, scuba diving, or cranial, cervical, or thoracic operations involving large venous structures or venous catheter insertion; it was formerly encountered as a complication of pneumothorax therapy. Clinically, cerebral air embolism may be difficult to separate from the deficits following hypotension or hypoxia with which it frequently coexists. Hyperbaric treatment might be effective if instituted early. Despite the large number of established sources of emboli, the point of origin cannot be determined in approximately 30 percent of presumed embolic strokes. In such cases, emboli likely have originated from thrombi in the cardiac chambers but have left behind no residual clot and may be undetectable even by sophisticated methods, such as transesophageal echocardiography and newer MR techniques. Other cases may be a result of atheromatous material arising from the aorta or paradoxical embolism. If extensive evaluation fails to disclose the origin, the odds still favor a source in the left heart. Often, the diagnosis of cerebral embolism is made at autopsy without finding a source. In these cases, one presumes that the search for a thrombotic nidus may not have been sufficiently thorough and small thrombi in the atrial appendage, endocardium (between the papillary muscles of the heart), the aorta and its branches, or pulmonary veins may have been overlooked. Nevertheless, the source of embolic material is not revealed in a number of cases.
Clinical Syndrome of Embolic Stroke Of all ischemic strokes, those caused by cerebral embolism develop most rapidly, “like a bolt out of the blue.” As a rule, the full-blown picture evolves within seconds, exemplifying most perfectly the idealized temporal profile of a stroke. With rare exceptions, there are no warning episodes. The embolus strikes at any time of the day or night. Only occasionally and for unclear reasons the neurologic problem unfolds more gradually, over many hours, with
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some fluctuation of symptoms. Possibly, in these cases the embolus initiates a propagating thrombotic process in the occluded vessel. The stroke syndrome will depend on the artery involved and the site of obstruction in the vessel. The clinical findings related to each angioanatomic territory are those outlined earlier in this chapter. A large embolus may plug the distal internal carotid artery or the stem of the middle cerebral artery, thereby producing the full-blown syndromes that follow occlusion of these arteries. More often the embolus passes into one of the branches of the middle cerebral artery, resulting in a strikingly focal disorder such as a motor or a sensory aphasia, a monoplegia, or a brachiofacial weakness with dysarthria. Any fragment of the middle cerebral syndrome or the complete picture may occur. The same is true for the anterior (leg weakness) and posterior cerebral arteries (hemianopia), which are affected at a somewhat lower frequency than the middle cerebral because of their lower rates of blood flow. Embolic material entering the vertebrobasilar system occasionally stops in the vertebral artery just below its union with the basilar artery; more often it traverses the vertebral and the entire length of the basilar artery, which is larger than the vertebral, and it reaches the upper basilar bifurcation where it produces either the abrupt onset of coma or one of the related “top of the basilar” syndromes described earlier in the chapter or it enters one or both posterior cerebral arteries and causes unilateral or bilateral homonymous hemianopias. The medial temporal lobe or thalamus and subthalamus may be affected as a consequence of occlusion of one of the temporal branches of small penetrating vessels that arise from the posterior cerebral artery; these produce a number of complex disorders of memory, sensation, and movement. Embolic infarction of the undersurface of the cerebellum is not infrequent from occlusion of the posterior inferior cerebellar artery (Figs. 34-2 and 34-19); in addition to ataxia, there are often subtle signs of lateral medullary ischemia. Embolic material rarely enters the penetrating branches of the pons. It is important to note again that an embolus may produce a severe neurologic deficit that is only temporary; symptoms abate as the embolus fragments. In other words, embolism is a common cause of a single evanescent stroke that may reasonably be called a prolonged TIA. Also, as already pointed out, several sequential emboli can give rise to multiple scattered infarcts or two or three transient attacks of differing pattern or, rarely, of almost identical pattern. It is doubtful that a “shower” of emboli with multiple simultaneous focal infarctions is a common occurrence without some easily explanatory cause such as crossclamping of the aorta during thoracic surgery. Also of interest are the symptoms caused by an embolus as it traverses a large vessel. This migrating or traveling embolus syndrome is most evident in cases of posterior cerebral artery occlusion, either from a cardiogenic source or from a thrombus in the proximal vertebral artery (“arteryto-artery” embolism; see Koroshetz and Ropper). Minutes or more before the hemianopia develops, the patient reports fleeting dizziness or vertigo, diplopia, or dysarthria, the result of transient occlusion of the origins of penetrating vessels as the clot material traverses the basilar
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Figure 34-19. Early inferior cerebellar cortical infarction (arrow). T2weighted MRI showing the lesion which encompasses the surface of the cerebellum and the immediately underlying tissue, typical of an embolic stroke, in the territory of the right posterior inferior cerebellar artery. There is a small infarction on the undersurface of the left cerebellum as well, further indicative of embolism.
artery. Small residual areas of infarction within the brainstem or cerebellum can be seen on MRI or found at autopsy, and some of the signs of brainstem infarction may persist. Although the abruptness with which the stroke develops and the lack of prodromal symptoms point strongly to embolism, the diagnosis is based on the total clinical circumstances. As already emphasized, the presence of atrial fibrillation, a history of recent myocardial infarction, cardiac valvular disease or a prosthetic valve, signs of endocarditis, or the occurrence of embolism to other vascular territories of the brain or to other regions of the body all support the diagnosis. Embolism always merits careful consideration in young persons, in whom atherosclerosis is unlikely.
Laboratory Findings The first sign of an arrhythmia or a myocardial infarction is often the occurrence of cerebral embolism; consequently, it is advisable that an electrocardiogram (ECG) and echocardiogram be obtained in all patients with stroke of uncertain origin. If the ECG does not yield relevant information, more prolonged study of heart rhythm in the hospital or with Holter monitoring should be undertaken. It is advisable in the elderly or in patients with severe atherosclerosis to image the aortic arch with ultrasonography or MRA, looking for plaques greater than approximately 4 mm in thickness (Amarenco et al). Transesophageal echocardiography, which has a higher sensitivity than transthoracic echocardiography, is an
important test in the evaluation of stroke, particularly in younger patients in whom a patent foramen may be a mechanism for paradoxical embolism, and in older patients with arteriopathy in whom an atrial clot or an aortic plaque may be responsible. In a study of 824 patients at the Cleveland Clinic (Leung et al), transesophageal echocardiography detected a potential source of embolism in 50 percent, an atrial clot in 7 percent, and a complex aortic atheroma in 13 percent of those with normal transthoracic studies. The precise indications for this test, however, have not been clearly determined and several studies give widely varying estimates of its usefulness in detecting a cardiac thrombus. In some 30 percent of cases, cerebral embolism produces some degree of hemorrhagic infarction. CT scanning or MRI may be helpful in showing the more intense hemorrhagic strokes, particularly if the scan is repeated on the second or third day. As mentioned previously, lumbar puncture is no longer a part of the standard evaluation of stroke but it is noteworthy that in only a minority of ischemic strokes do red cells enter the CSF—rarely as many as 10,000/mm3; a slight xanthochromia may appear after a few days. Septic embolism resulting from subacute bacterial endocarditis may cause white blood cells (WBCs) to appear in the CSF, up to 200/mm3 but occasionally higher; the proportion of lymphocytes and polymorphonuclear cells varies with the acuteness of the inflammatory reaction. There may also be an equal number of red blood cells and faint xanthochromia. The protein content is elevated but the glucose content is normal, however, no bacteria are seen or obtained from culture. By contrast, the CSF formula in septic embolism from acute bacterial endocarditis may be that of purulent meningitis (many polymorphonuclear cells, reduced glucose and bacteria on the Gram stain).
Course and Prognosis The remarks concerning the immediate prognosis of atherothrombotic infarction apply also to embolic infarction. Most patients survive the initial event and in many, the neurologic deficit may recede relatively rapidly, as indicated above. Progressive brain swelling occurs in a small proportion, less than 5 percent, and mainly in patients with embolic occlusion of the distal carotid or the stem of the middle cerebral artery and in a proportion of sizable cerebellar infarcts. The eventual prognosis is determined by the occurrence of further emboli and the gravity of the underlying illness—cardiac failure, myocardial infarction, bacterial endocarditis, malignancy, and so on. In a small number of cases, the first episode of cerebral embolism will be followed by another, frequently with severe consequences if the second stroke affects the opposite hemisphere. There is no certain way of predicting when the second embolus will strike. However, the frequency of this second event, once thought to be as high as 20 percent, has been revised downward, to perhaps 2 percent, based on several large trials that were designed to test the effects of anticoagulation (see the review of Swan-
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son). This has a bearing on the choice of early treatment after embolic stroke.
Treatment and Prevention Three phases of therapy—(1) measures directed to restoring the circulation, (2) measures instituted to prevent a recurrent embolus; and (3) physical therapy and rehabilitation—are much the same as described earlier, under “Atherothrombotic Infarction.” Issues pertaining to the prevention of recurrent embolism are discussed below. Thrombolysis has been successful to the extent indicated previously and may be attempted by intravenous injection of tPA when practical and within 4.5 h of the first stroke symptoms. There is no evidence that the risk of symptomatic hemorrhage from this treatment is any higher than in other types of strokes. Embolectomy or thrombolysis at the bifurcation of the middle cerebral artery or common carotid artery by endovascular techniques is being studied by several means, mainly as a method of restoring circulation in the period from 4 to 6 h, a time beyond the opportunity for intravenous thrombolysis. Of prime importance is the prevention of cerebral embolism; this applies both to patients who have had an episode of embolism and to those who are at risk of doing so. The long-term use of anticoagulants has proved to be effective in the prevention of embolism in cases of atrial fibrillation, myocardial infarction, and valve prosthesis, as noted below. The roles of aspirin and warfarin depend on the specific circumstances and presumed origin of the embolus. The most convincing evidence favoring the efficacy of anticoagulants in the prevention of embolism comes from the Boston Area Anticoagulant Trial for Atrial Fibrillation. A group of patients at risk for stroke from chronic atrial fibrillation was randomized to be maintained for 2 years on warfarin (INR of 1.5 to 2) or no anticoagulation; there were 212 anticoagulated patients and 208 controls. Recurrent strokes were reduced by 86 percent in the warfarin group and the death rate was lower. One fatal hemorrhage occurred in each group; minor hemorrhages occurred in 38 of the warfarin-treated group and in 21 of the control group. In a similar study from Copenhagen, the incidence of stroke in a group receiving warfarin was calculated to be 2 percent per year in comparison to 5.5 percent per year in an untreated group. Several subsequent trials have attested to the efficacy of warfarin in the prevention of stroke in patients with nonrheumatic atrial fibrillation (see Singer). Subsequent studies suggest that an INR between 2 and 3 confers better protection than levels below 2. It should be pointed out, however, that patients younger than 65 years of age in these trials did not clearly benefit from long-term prophylactic anticoagulation unless there were additional cerebrovascular risk factors such as diabetes, hypertension, congestive heart failure, or cardiac valvular disease. Those younger than 65 years old and without such additional features (lone fibrillators), constituting about one-third of adults with atrial fibrillation, have a low risk of stroke. Aspirin does not appear to afford the same degree of protective benefit as does anticoagulation, but some studies suggest a slightly better
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outcome than with no treatment; it has been used in the younger group of patients and in those unable to take warfarin. For patients with atrial fibrillation of recent onset, an attempt should be made to restore normal sinus rhythm by the use of electrical cardioversion or a trial of antiarrhythmic drugs. If these fail, prophylactic anticoagulant therapy is recommended. Before attempting cardioversion of more long-standing atrial fibrillation, anticoagulation for several days or longer is advisable to reduce emboli. When the stroke is of unknown origin but presumed to be embolic, the data regarding aspirin treatment are uncertain. Most large trials comparing aspirin to warfarin have studied patients in whom cardiogenic embolus is not implicated (such as in the earlier-mentioned WARSS study) but there are probably many cases that have a cardiac source nonetheless (see earlier discussion of treatment for thrombotic stroke). Opinions vary about the use and precise timing of instituting anticoagulation with warfarin after an embolic stroke, in part because the risk of recurrent stroke in the first days is low. On the basis of the aforementioned trials of acute anticoagulation that show a 2 percent frequency of early recurrent stroke, many clinicians prefer to start warfarin and await its effects over several days rather than using heparin immediately. Nonetheless, once a firm diagnosis of embolic occlusion has been made, and particularly if there has been a recent myocardial infarction, atrial fibrillation, or a demonstrated cardiac thrombus on the echocardiogram our customary practice has been to begin heparin on the same or the next day, coincident with the institution of warfarin on the same or the following days. However, many of our colleagues no longer use heparin in this setting, and others even forgo the use of warfarin unless a definite source of embolism is detected by echocardiography. Whether the newer low-molecularweight heparinoid drugs yield an advantage over conventional heparin treatment is unknown. They offer the ease of subcutaneous administration and offer the possibility of discharge to home or a rehabilitation facility. In patients with very large cerebral infarcts that have a component of deep (basal ganglionic) tissue damage, especially in those patients who are also markedly hypertensive, there may be a risk of anticoagulant-related hemorrhage into the acute infarct (Shields et al). In these patients, anticoagulation therapy perhaps should be delayed for several days but this is uncertain. A frequent clinical problem arises in an elderly patient with atrial fibrillation who is at risk of falling from any of a number of causes including the stroke itself. In a review of selected administrative database records, Gage and colleagues concluded that the overall risk of inducing cerebral hemorrhage in older patients with atrial fibrillation treated with warfarin was lower than the risk of recurrent stroke. In those patients who had hemorrhages while receiving warfarin, they were, however, more likely to be fatal. Of course, decisions about anticoagulation must be tailored to the conditions of the individual patient. Alternatives to warfarin in patients with atrial fibrillation have been explored, such as the thrombin inhibitor ximelagatran, which has the advantage of not requiring monitoring
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by blood tests (see the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation [SPORTIF] trial). Anticoagulant therapy may also be desirable for at least several weeks in patients with acute myocardial infarction, especially if the left side of the heart is involved. No guidelines have been established in these circumstances the new common use of one or more platelet aggregation inhibitor drugs after myocardial infarction may preclude the concurrent use of warfarin. In cerebral embolism associated with bacterial endocarditis, anticoagulant therapy should be used cautiously because of the danger of intracranial bleeding, and one proceeds instead with antibiotics. Generally, we have not anticoagulated these patients. The advisability of surgical or endovascular closure of a patent foramen ovale or of treatment with aspirin or warfarin if no other source of cerebral embolism is found is currently uncertain and several trials are under way to address the problem. The added risk of an associated atrial septal aneurysm has already been mentioned. If there is a well-defined concurrent venous thrombosis that represents a likely source of stroke, we have endorsed several months of anticoagulation. If a stroke occurs while warfarin is being administered, or if there is a valid reason not to employ anticoagulation, surgical closure is reasonable. Kizer and Devereux have summarized the subject. Valvuloplasty, removal of verrucous lesions in endocarditis, and amputation of the atrial appendage had in the past apparently reduced the incidence of embolism in the now infrequent case of rheumatic heart disease. The need for special care in preventing emboli that arise from the cardiac chambers or the aortic arch from entering the carotid arteries during the performance of valvuloplasty is acutely appreciated by cardiothoracic surgeons.
GENERALIZED BRAIN ISCHEMIA AND HYPOXIA (See Chap. 40) This constitutes a special type of infarction that follows cardiac arrest and other forms of prolonged hypotension or hypoxia. In the case of reduced blood flow to the cerebral hemispheres, there is a tendency for regional infarctions to occur in the areas of lowest blood flow that lie between the major surface arteries, referred to metaphorically as a watershed infarction. An important distinction is drawn between the concept of end-arterial distribution, the site of distal embolization, and the area of lowest flow between two or more end territories, which is compromised in any form of globally returned blood flow. In extreme cases of hypotension, there is global infarction of the brain accompanied by the clinical syndrome of brain death. Pure hypoxia-anoxia without hypotension produces another type of damage in areas susceptible to reduced oxygen delivery, mainly affecting the hippocampi; a Korsakoff syndrome results. Most often, ischemic and hypoxic states coexist and produce complex patterns of cerebral damage. This topic is discussed fully in Chap. 40. The special problem of cerebral ischemia during cardiac surgery with the use of a bypass pump is discussed further on in the section on “Stroke with Cardiac Surgery.”
LESS-COMMON CAUSES OF ISCHEMIC CEREBROVASCULAR DISEASE Fibromuscular Dysplasia (See also “Inflammatory Diseases of Brain Arteries” further on) This is a segmental, nonatheromatous, noninflammatory arterial disease of unknown etiology, almost exclusively in women. It is uncommon (0.5 percent of 61,000 arteriograms in the series of So et al) but it is being reported with increasing frequency because of improved arteriographic techniques. In our experience, it has often been an incidental finding in asymptomatic individuals undergoing vascular imaging for other reasons. First described in the renal artery by Leadbetter and Burkland in 1938, fibromuscular dysplasia is now known to affect other vessels including cervicocerebral ones. The internal carotid artery is involved most frequently, followed by the vertebral and cerebral arteries. The radiologic picture is of a series of transverse constrictions, giving the appearance of an irregular string of beads or a tubular narrowing; it is observed bilaterally in 75 percent of cases. Usually only the extracranial part of the artery is involved. A single transverse web that occupies a portion of the carotid lumen is probably a variant of the fibromuscular condition or could conceivably represent an entirely different static congenital process. In the series of Houser and colleagues 42 of 44 patients were women and 75 percent were older than 50 years of age. All of the patients reported by So and coworkers were women, ranging in age from 41 to 70 years. Cerebral ischemia may be associated with the process but the rate of this complication has not been established; our impression is that it is low. In the study by Corrin and colleagues, among 79 untreated asymptomatic patients followed for an average of 5 years, 3 had a cerebral infarct 4 to 18 years after the initial diagnosis. Also, between 7 and 20 percent of affected individuals are found to have intracranial saccular aneurysms (rarely a giant aneurysm), which may be sources of subarachnoid hemorrhage, and up to 12 percent develop arterial dissections, as described below. The narrowed arterial segments show degeneration of elastic tissue and irregular arrays of fibrous and smooth muscle tissue in a mucous ground substance. Interspersed dilatations are a result of atrophy of the coat of the vessel wall. There is atherosclerosis in some and small degrees of arterial dissection in others. Usually vascular occlusion is not present, though there may be marked stenosis. Schievink and colleagues have summarized the pathology of this disease. In some instances the mechanism of the cerebral ischemic lesion is unexplained, but is presumed to be from thrombi in the pouches or in relation to intraluminal septa. So and colleagues have recommended excision of the affected segments of the carotid artery if ischemic neurologic symptoms are related to them, and conservative therapy if the fibromuscular dysplasia is an incidental and asymptomatic arteriographic finding. It is now possible to
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dilate the affected vessel by means of endovascular techniques and several case reports have suggested that benefit is achieved at lower risk than with surgical excision. Intracranial saccular aneurysms should be sought by arteriography, CT, or MRA and obliterated if their size warrants. It is not known if anticoagulation or antiplatelet therapy confer protection from stroke.
Dissection of the Cervical and Intracranial Arteries Internal Carotid Artery Dissection It has long been appreciated that the process formerly known as Erdheim’s medionecrosis aortica cystica, the main cause of aortic dissection, may independently involve or extend into the common carotid arteries, occluding them and causing massive infarction of the cerebral hemispheres. Examples of such occurrences were cited by Weisman and Adams in 1944 in their study of the neurology of dissecting aneurysms of the aorta, and Chase and colleagues gave the clinicopathologic details of 16 cases they studied. The principal neurologic features in both series were syncope, hemiparesis, or coma. The frequency of cerebral stroke with aortic dissection has varied from 10 to 50 percent and that of spinal stroke has been approximately 10 percent (see Chap. 44). In more recent years, attention has been drawn to the occurrence of both spontaneous and traumatic dissection of the internal carotid artery and the fact that it is an important cause of nonatherosclerotic stroke in young adults. Many large series of such cases have been reported in separate studies by Ojemann and colleagues (1972) and by Mokri and coworkers (1986). Spontaneous dissection should be suspected in women, typically in their late thirties or early forties, who seem especially susceptible to the condition, either as a spontaneous event or in relation to a whiplash injury, bouts of violent coughing, or direct trauma to the head or neck, which need not be severe— e.g., being struck in the neck by a golf or tennis ball. We have encountered cases that occurred during pregnancy and immediately after delivery. Indeed, it is questionable if most cervical arterial dissections are truly “spontaneous,” as many can be connected to some strenuous event. Three of our patients over the years had a carotid dissection that was manifest as a hemiplegia days after blunt head injury. Only small numbers of patients have fibromuscular disease as discussed above. The Ehlers-Danlos and Marfan syndromes, osteogenesis imperfecta, LoeysDietz syndrome (transforming growth factor [TGF]-β receptor mutation), and alpha1-antitrypsin deficiency are also associated with an increased risk of vascular dissection. One of these conditions should be suspected if multiple extracranial vessels are involved in spontaneous dissections or if there is joint and skin laxity or widespread vascular tortuosity (neck and thoracic trauma or aortic arch dissection are more common causes of multiple extracranial dissection). It is of interest that a few patients with carotid dissection have had preceding unilateral cranial or facial pain lasting days, followed by stroke in the territory of the internal carotid artery. The pain is aching, may fluctuate in severity,
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and is centered most often in and around the eye; less often, it is in the frontal or temporal regions, angle of the mandible, or high anterior neck over the carotid artery. Rapid and marked relief of the pain after the administration of corticosteroids in a young person is virtually a diagnostic feature (see below). Neck pain over a site of dissection is usually present as well; it may be absent, particularly if the dissection originates nearer the base of the skull. The ischemic manifestations consist of transient attacks in the territory of the internal carotid, followed frequently by the signs of hemispheral stroke, which may be abrupt or evolve smoothly over a period of minutes to hours or over several days in a fluctuating or stepwise fashion. A unilateral Horner syndrome is often present. A cervical bruit, sometimes audible to the patient, amaurosis fugax, faintness and syncope, and facial numbness are less common symptoms. Most of the patients described by Mokri and coworkers (1986) presented with one of two distinct syndromes: (1) unilateral headache associated with an ipsilateral Horner syndrome or (2) unilateral headache and delayed focal cerebral ischemic symptoms. Some patients have evidence of involvement of one or more of the vagi, spinal accessory, or hypoglossal nerve on one side; these nerves lie in close proximity to the carotid artery and are nourished by small branches from it. In most cases, dissection of the internal carotid artery can be detected by ultrasonography and confirmed by MRI and CTA, which show a double lumen. A double lumen is often apparent within the vessel on axial MRI sections. Arteriography by any of these methods or by CT or conventional angiography reveals an elongated, irregular narrow column of dye, usually beginning 1.5 to 3 cm above the carotid bifurcation and extending to the base of the skull, a picture that Fisher has called the string sign. There may be a characteristic tapered occlusion or an outpouching at the upper end of the string. It is the site and the shape of the occlusion that are helpful in identifying dissection. Less often the dissection is confined to the midcervical region, and occasionally it extends into the middle cerebral artery or involves the opposite carotid artery or the vertebral and basilar arteries. Purely intracranial dissections also occur, mainly of the middle cerebral artery but we have had experience with 2 cases involving the basilar artery, one after cocaine ingestion and both with disastrous outcomes. The study by Mokri and colleagues (1988) reported a complete or excellent recovery in 85 percent of patients with the angiographic signs of cervical artery dissection; mainly, these were patients who had fluctuating ischemic symptoms but without stroke. The outcome in cases complicated by stroke is far less benign. Approximately 25 percent of such patients succumb and most others remain seriously impaired. If early recanalization of the occluded artery is observed (as determined by ultrasonography), there may also be good functional recovery. Local pseudoaneurysms form in a small proportion of patients and generally do not require surgical repair; they also do not preclude cautious anticoagulation. Subarachnoid hemorrhage from transmural rupture is mostly a complication of vertebral artery dissection discussed below. The pathogenesis of spontaneous carotid dissection is at present uncertain. In most reported cases, cystic medial necrosis has not been found on microscopic examination
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of the involved artery. In some, there has been disorganization of the media and internal elastic lamina, but the specificity of these changes is in doubt, as Ojemann and colleagues (1972) noted similar changes in some of their control cases. In a small proportion of cases there are the changes of fibromuscular dysplasia, as noted earlier. Several groups have found structural collagen abnormalities in the skin biopsies of patients with dissection. A more thorough study of these vessels is needed.
Vertebral Artery Dissection Dissection of these arteries may originate in the neck and extend into the intracranial portion of the vessel or remain isolated to either of these segments as noted below. In both instances there is a tendency to form pseudoaneurysms, mostly with the intracranial type, and in the latter there is a risk of rupture through the adventitia leading to a subarachnoid hemorrhage. Rapid and extreme rotational movement of the neck is the most common identifiable cause of vertebral artery dissection, as in turning the head to back up a car or with chiropractic manipulation. Extending the neck to have one’s hair washed, swinging a golf club, and direct neck trauma have also been precipitants. Forceful coughing may also cause dissection, as it may in the carotid vessels. There is no female predominance (in contrast to carotid dissection) but the previously cited intrinsic weaknesses of the vascular wall from Ehlers-Danlos disease and fibromuscular dysplasia are risk factors. The dissection most commonly originates in the C1-C2 segment of the vessel, where it is mobile but tethered as it leaves the transverse foramen of the axis and turns sharply to enter the cranium. The symptoms, mainly vertigo, are fragments of the lateral medullary syndrome, often with additional features referable to the pons or midbrain, particularly diplopia and dysarthria. The clinical manifestations in our experience have fluctuated over minutes and hours, quite unlike the usual vertebrobasilar TIA. Less-common strokes include artery-to-artery embolism to the posterior cerebral territory or, a syndrome that has come to our attention several times in the past few years, a centrally placed infarction of the cervical spinal cord with bibrachial weakness, presumably from occlusion of the anterior spinal arteries. The diagnosis of vertebral dissection should be suspected if persistent occipitonuchal pain and vertigo or related medullary symptoms arise following one of the known precipitants—such as chiropractic manipulation of the neck, head trauma, or Valsalva straining or coughing activities— but it may otherwise escape detection until the full-blown medullary or cerebellar stroke is established. The stroke may follow the inciting event by several days or weeks or even longer, obscuring the relationship. Axial MRI images, particularly the T1-weighted sequences, show a double lumen in the dissected vessel, and skillful ultrasound investigation documents the same. Some patients will be found to have evidence of spontaneous or traumatic dissection of multiple extracranial vessels; this also occurs as a consequence of dissection of the aortic arch from chest trauma. No generally agreed upon method has been devised to detect the infrequent instance of subarachnoid hemor-
rhage from dissection. Lumbar puncture is not routinely performed. CT is probably adequate for this purpose but it must be acknowledged that it, too, is not often obtained, except in cases of strong suspicion that the dissection has extended into the subarachnoid space, as evidenced by lower cranial nerve palsies. Treatment The treatment of arterial dissection has usually been anticoagulation if there has not been subarachnoid hemorrhage in order to prevent embolism—using first heparin, then warfarin—but it must be acknowledged that this approach has not been demonstrated to be more successful than careful observation without medical or surgical intervention. Once a stroke has occurred, even though embolic in most cases, prompt reopening of the artery can at times prove beneficial; this is currently performed by endovascular techniques. Most neurologists take the approach that warfarin, if used, may be discontinued after several months or a year, when angiography or MRA shows the lumen of the carotid artery to be patent, or at least reduced to no more than 50 percent of the normal diameter, and smooth walled. Despite numerous publications demonstrating the ability of skilled operators to reopen a dissection by endovascular methods, acute intervention has not been studied in a way that allows a judgment regarding its value. Of both therapeutic and diagnostic value is the relief of pain afforded by corticosteroids in cervical and intracranial dissections, as mentioned above. Pseudoaneurysms in the cervical portions of the vessels generally do not require specific treatment; the series of 38 cases collected by Benninger and colleagues is instructive in that none of the aneurysms ruptured during several years of followup and one had a delayed ischemic strokes.
Intracranial Arterial Dissection Dissections of intracranial arteries are less common than extracranial ones and they present in several unusual ways. A number of times we have misinterpreted the arteriographic appearance of a short segment of narrowing of the basilar or proximal middle cerebral arteries, assuming these changes to represent embolism or arteritis when in fact they proved to be dissections of the vessel wall. In the case of purely intracranial dissection of the middle cerebral or basilar arteries, there is usually no preceding trauma, but a few patients have had minor head injuries, extreme coughing, or other recently Valsalva-producing events (e.g., after childbirth)—or they had used cocaine. The typical picture is of fluctuating symptoms referable to the affected circulation and severe cranial pain on the side of the occlusion—retroorbital in the case of middle cerebral dissection, occipital in the case of basilar dissection, occipital combined with supraorbital in the case of vertebral dissection (see above). A few patients have had sudden strokes that suggested embolic infarction, and a small number present with subarachnoid hemorrhage.
Treatment of Arterial Dissection This is primarily with anticoagulation and followup arteriography. It is again notable that corticosteroids have relieved the cranial and retroorbital pain in our cases, and dramatic
CHAPTER 34
relief of pain within an hour is virtually diagnostic. Endovascular revascularization has been attempted with mixed results, the main problem being catastrophic and usually fatal vessel rupture during angioplasty.
Moyamoya Disease Moyamoya is a Japanese word for a “haze”; it has been used to refer to an extensive basal cerebral rete mirabile—a network of small anastomotic vessels at the base of the brain around and distal to the circle of Willis, seen in carotid arteriograms, associated with segmental stenosis or occlusion of the terminal intracranial parts of both internal carotid arteries. Nishimoto and Takeuchi reported on 111 cases that were selected on the basis of these two radiologic criteria. The condition was observed mainly in infants, children, and adolescents (more than half the patients were younger than 10 years of age, and only 4 were older than age 40 years). All of their patients were Japanese, in whom the disease seems disproportionately prevalent; both males and females were affected, and 8 were siblings. The symptom that led to medical examination was usually a sudden weakness of an arm, leg, or both on one side. The symptoms tended to clear rapidly but recurred in some instances. Headache, convulsions, impaired mental clarity, visual disturbance, and nystagmus were less frequent. In older patients, subarachnoid hemorrhage was the most common initial manifestation. Other symptoms and signs were speech disturbance, sensory impairment, involuntary movements, and unsteady gait. Characteristics noted in other series have included prolonged TIAs (this accords with our experience), characteristically induced by hyperventilation or hyperthermia, parenchymal rather than subarachnoid hemorrhages (most situated in the basal ganglia or thalamus), and an unusual “rebuildup” EEG phenomenon in which high-voltage slow waves reappear 5 min after the end of hyperventilation. Postmortem examinations of cases of moyamoya have yielded a reasonably clear picture of the intracranial distal carotid lesion. The adventitia, media, and internal elastic laminae of the stenotic or occluded arteries were normal, but the intima was greatly thickened by fibrous tissue. No inflammatory cells or atheromata were seen. In a few cases, hypoplasia of the vessel with absent muscularis has been described. The profuse rete mirabile consists of a fine network of vessels over the basal surface of the brain (in the pia-arachnoid), which, according to Yamashita and coworkers, reveals microaneurysm formation because of weakness of the internal elastic lamina and thinness of the vessel wall. The latter lesion is the source of subarachnoid hemorrhage. Thus one part of the symptomatology is traced to the distal carotid stenosis and another to the rupture of the vascular network. Opinion is divided as to whether the basal rete mirabile represents a congenital vascular malformation (i.e., a persistence of the embryonal network) or a rich collateral vascularization secondary to a congenital hypoplasia, acquired stenosis, or occlusion of the internal carotid arteries early in life. This form of cerebrovascular disease is not limited to the Japanese. The authors have periodically observed
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such patients, as have others, in the United States, Western Europe, and Australia. Certain hemoglobinopathies, particularly sickle cell anemia, may cause a condition equivalent to moyamoya disease, possibly because of sickling of red blood cells in the vasa vasorum of the supraclinoid carotid artery. An association between moyamoya, Down syndrome, and certain human leukocyte antigen (HLA) types favors a hereditary basis (Kitahara et al). Treatment The treatment of moyamoya is far from satisfactory. Certain surgical measures have been employed, including transplantation of a vascular muscle flap, omentum, or pedicle containing the superficial temporal artery to the pial surface of the frontal lobe temporal pial synangiosis with the idea of creating neovascularization of the cortical convexity. These measures have reportedly reduced the number of ischemic attacks, but whether they alter the natural history of the illness cannot be stated. Anticoagulation is considered risky in view of the possibility of cerebral hemorrhage, but there have not been systematic studies.
Binswanger Disease This entity was mentioned briefly in the discussion of the course and prognosis of atherothrombotic infarction and as a cause of dementia in Chaps. 21 and 39. The term has come to denote a widespread degeneration of cerebral white matter having a vascular causation and observed in the context of hypertension, atherosclerosis of the small blood vessels, and multiple strokes. Hemiparesis, dysarthria, TIAs, and typical lacunar or cortical strokes are admixed in many cases. The process has been associated with a particular radiologic appearance that reflects confluent areas of white matter signal change. The term leukoaraiosis, meant to describe the lessintense appearance of periventricular tissues in imaging studies, complicates the matter because this condition is also assumed to have a vascular basis and the term has been used indiscriminately as equivalent to Binswanger disease. Whether multiple discrete lacunes in the deep white matter constitute Binswanger disease may be a semantic issue, but we adhere to the notion that the former is characterized by a more widespread ischemic and gliotic change in the deep white matter. Dementia, a pseudobulbar state, and a gait disorder, alone or in combination, are the main features of Binswanger cases. They have been attributed to the cumulative effects of the ischemic changes and specifically to the white matter degeneration. However, the pathologic basis of such a clinical entity has not been well delineated. More importantly, the gliosis that is found in white matter has been assumed to represent a special type of ischemic change, but the vessels in these regions have never been adequately studied. Yet another problem is to distinguish such a state from deficits produced by the cumulative effect of numerous larger lacunes, which have for a century been known to cause the aforementioned syndromes of dementia, gait disturbance, and a pseudobulbar syndrome. From time to time, imaging studies of the brain disclose large regions of white matter change or the occurrence of multiple infarctions in the absence of hypertension, and it is not clear how such cases should be classified. Some prove to be areas of demyelination or metabolic dysmyelination; others are mitochondrial
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disorders, and perhaps some are related to the familial CADASIL syndrome discussed below. Fabry disease also enters into the differential diagnosis of multiple small infarctions in the cerebrum that may coalesce into areas of white matter damage. Readers may consult the reviews on the subject by Babikian and Ropper, by Caplan (1995), and by Mohr and Mast.
Familial Subcortical Infarction (CADASIL and CARASIL) A process with a radiologic appearance similar to Binswanger leukoencephalopathy, but without hypertension, has been identified as an autosomal dominant familial trait linked in several families to a missense mutation on chromosome 19. In the past, it had been described under a number of names, including hereditary multiinfarct dementia. The acronym CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is now applied. In these patients recurrent small strokes beginning in early adulthood culminate in a subcortical dementia (see Chap. 21). Migraine headaches, often with neurologic accompaniments, may precede the strokes by several years, as may numerous and varied TIAs that are attributed, probably incorrectly, to the migraine. On the other hand, some individuals display few clinical changes while yet others are demented or have strokes that simulate lacunes. We are unable to comment on the encephalopathy and coma accompanied by fever described by Schon and colleagues that has been attributed to this condition. The familial nature of the process may not be appreciated because genetic penetrance is not complete until after 60 years of age. On MRI scans, clinically unaffected family members may show substantial changes in the white matter well before strokes or dementia arises. A syndrome of early alopecia and lumbar spondylosis with the white matter changes typical of CADASIL has been identified as a recessively inherited disease (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy [CARASIL]) and is discussed separately below. The MRI and CT appearance is of multiple confluent white matter lesions of various sizes, many quite small and concentrated around the basal ganglia and periventricular areas. Lesions anterior to the temporal horns of the lateral ventricles are particularly characteristic of the entity. When the affected regions are asymmetrical and periventricular, they are difficult to distinguish from the lesions of multiple sclerosis. In the autopsy cases studied by Jung and colleagues, numerous partially cavitated infarctions were found in the white matter and basal ganglia. Small vessels in the regions of these infarctions, 100- to 200-mm diameters, contained basophilic granular deposits in the media with degeneration of smooth muscle fibers. Attribution of the white matter lesions to these vascular changes presents the same problems as in Binswanger disease, particularly in view of patency of most of the many small vessels in the examined material. Nevertheless, CADASIL is probably the main cause of sporadic instances of what otherwise passes for Binswanger disease but without the obligate hypertension of the latter. Also, migraine headaches are not a component of Binswanger disease.
The responsible mutation is a missense change on chromosome 19 of the NOTCH 3 gene, in the same locus as the gene for familial hemiplegic migraine, and has been characterized by Joutel and colleagues; this provides a diagnostic test that can be performed on the blood or skin. The diagnosis can also be confirmed by finding eosinophilic inclusions in the arterioles of a skin biopsy (osmophilic with electron microscopy). An entirely different vasculopathy with widespread white matter signal change has been reported in Japan. Migraine is not a component of the syndrome, and the NOTCH gene, implicated in CADASIL, is normal. Inheritance is as a recessive trait from a mutation in the HTAR1 gene. The result is fragmentation and duplication of the internal elastic lamina of cerebral vessels with narrowing of their lumens. As intriguing from this mutation is an associated osteoid growth that causes lumbar stenosis and alopecia. An interesting mutation of the COL4A1 gene for type 4 collagen leads to familial small vessel disease and intracerebral hemorrhage in mice and humans (Gould et al). More often, as in the cases described by Verreault and colleagues, there are simply numerous white matter infarctions that are not explained by hypertension and similar lesions may be found in family members by MRI. Under the terms HERNS (hereditary endotheliopathy, retinopathy, nephropathy and strokes) and CRV (cerebroretinal vasculopathy), additional rare dominantly inherited conditions have been described that cause subcortical white matter degeneration, presumably on a microvascular occlusive basis. Ocular symptoms and retinopathy are the main features and the neurologic aspects. Awareness of these vascular forms of white matter degenerations adds to the list of inherited leukoencephalopathies discussed in Chap. 38 and the action of the genes reveals novel mechanisms of damage to small cerebral vessels.
Cerebral Amyloid Angiopathy This process is discussed again further on in relation to lobar cerebral hemorrhages in the elderly, but it also pertains to ischemic strokes. The angiopathy consists of the deposition of amyloid in the media and adventitia of small vessels, predominantly in the meninges, cortex, and cortical penetrating vessels. The incidence at autopsy of vascular amyloid deposition in the brain is related to the age of the population studied; rates of 12 percent are cited in patients older than 85 years of age (the same changes are present in more than 25 percent of individuals with Alzheimer disease, but the nature of the amyloid is different in the two conditions). Over the last few years, our colleague S.M. Greenberg has emphasized certain clinical features associated with cerebrovascular amyloidosis (see Kinnecom et al). A strong association has been found with the homozygous APOE e4/e4 genotype. The MRI appearance is of large subcortical patches of T2 signal change suggestive of cerebral edema. Included in the clinical picture are encephalopathy, seizures, and focal cerebral symptoms such as aphasia. Other reports, not necessarily of the inflammatory type of amyloid, have been associated with multiple TIAs,
CHAPTER 34
some with migrainous features such as spreading sensory symptoms, and in some cases, fairly rapid progression to dementia. Telltale signs of multiple small and larger hemorrhages are often present in these cases; they are seen to advantage with gradient-echo sequences on the MRI. The frequency of this interesting condition in the elderly is unclear. There is a separate familial amyloidotic condition of diffuse white matter degeneration with dementia, associated in some families with calcification in the occipital lobes, and the aforementioned mutations in the COL4A gene cause a disruption of the small vessel wall that can cause small cerebral hemorrhages that are similar to those of cerebrovascular amyloid.
Strokes in Children and Young Adults As indicated in Table 34-2, it is probable that ischemic necrosis of cerebral tissue can occur in utero. The resulting stroke is usually referred to as congenital hemiplegia. However, very little is known about the underlying vascular lesions, or at least there are heterogeneous causes, so that little further can be said about them here. Acute hemiplegia in infants and children is a rare but well-recognized phenomenon. In a series of 555 consecutive postmortem examinations at the Children’s Medical Center in Boston, there were 48 cases (8.7 percent) of occlusive vascular disease of the brain (Banker). The occlusions were both embolic (mainly associated with congenital heart disease) and thrombotic, and the latter were actually more common in veins than in arteries. Similarly, stroke is not an uncommon event in young adults (ages 15 to 45 years), accounting for an estimated 3 percent of cerebral infarctions in many series. In terms of causation, this group is remarkably heterogeneous. Among 144 such patients, more than 40 possible etiologies were identified by H.P. Adams and colleagues. Nevertheless, most of the strokes could be accounted for by three categories, more or less equal in size: atherosclerotic thrombotic infarction (usually with a recognized risk factor); cardiogenic embolism (particularly in the past association with rheumatic heart disease, bacterial and verrucous endocarditis, paradoxic embolism through patent foramen ovale, and prosthetic heart valves); and one of several nonatherosclerotic vasculopathies (arterial trauma, dissection of the carotid artery, moyamoya, lupus erythematosus, druginduced vasculitis). Hematologically related disorders— use of oral contraceptives (discussed further on), the postpartum state, and other hypercoagulable states—were the probable causes in 15 percent of the 144 patients. The presence of antiphospholipid or anticardiolipin antibodies (lupus anticoagulant) explains some of these cases and is discussed further in the section on “Stroke as a Complication of Hematologic Disease”; the majority of these patients are women in their thirties without manifest systemic lupus erythematosus. Despite the attention they have received recently as a cause of strokes in the juvenile and young adult period, the frequency of inherited deficiencies of naturally occurring anticoagulant factors as a cause of stroke is low. Table 34-8 summarizes the main inherited prothrombotic clotting defects. They predispose primarily to cerebral venous
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clotting. Most arise from partial protein deficiencies as a result of heterozygous mutations in the genes encoding proteins in the clotting cascade (antithrombin III, proteins S and C) and from those that disturb clotting balance (resistance to activated protein C, or factor V Leiden mutation, and prothrombin mutations as well as excess factor VIII) (see discussion by Brown and Bevan). When homozygous, these mutations may be associated with devastating neonatal hemorrhagic conditions. In some series that report cases of strokes in youth, such as the one reported by Becker and colleagues, up to half of stroke cases had one of these disorders, the most common being the factor V Leiden mutation, but others have found this mutation to be much less frequent, which is more consonant with our experience. Nevertheless, in children with unexplained stroke, particularly venous ones, and especially if there has been a previous thrombosis or if the strokes are recurrent, it is advisable to carry out an extensive hematologic investigation, including testing for antiphospholipid antibody (an acquired defect), as described in the later section on “Antiphospholipid Antibody Syndrome.” Establishing a diagnosis of a prothrombotic clotting gene variant has further significance because strokes are prone to occur in the setting of additional risks, such as the use of oral contraceptives and smoking. In adults, the evaluation for inherited clotting defects is far less fruitful. Furthermore, it should be kept in mind that the levels of proteins C and S and of antithrombin are temporarily depressed after stroke, so that any detected abnormalities must be confirmed months later and in the absence of anticoagulation. Persistent cerebral ischemia and infarction may occasionally complicate migraine in young persons. The combination of migraine and oral contraception is particularly hazardous, as detailed below. Despite the common occurrence of mitral valve prolapse in young adults, it is probably only rarely a cause of stroke (see previous comments). Stroke because of either arterial or venous occlusion occurs occasionally in association with ulcerative colitis and to a lesser extent with regional enteritis. Evidence points to a hypercoagulable state during exacerbations of inflammatory bowel disease, but a precise defect in coagulation has not been identified. Meningovascular syphilis and fungal and tuberculous meningitis and other forms of chronic basal meningitis are also considerations in this age group; the strokes are usually of the lacunar type, resulting from inflammatory occlusion of small basal vessels. Sickle cell anemia is a rare but important cause of stroke in children of African ancestry; acute hemiplegia is the most common manifestation but all types of focal cerebral disorders have been observed. The pathologic findings are those of infarction, large and small; their basis is assumed to be vascular obstruction associated with the sickling process. The association of sickle cell anemia with the moyamoya syndrome was mentioned earlier. Intracranial bleeding (subdural, subarachnoid, and intracerebral) and cerebral venous thrombosis may also complicate sickle cell anemia, and—probably because of autosplenectomy—there is an increased incidence of pneumococcal meningitis. Treatment of the cerebral circulatory disorder, based presumably on sludging of red blood cells, is with intravenous hydration
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Table 34-8 STROKE ASSOCIATED WITH GENETIC DISORDERS
GENE
Causes of arterial or venous infarction Activated protein C Leiden factor V mutation resistance Prothrombin 20210 Prothrombin Protein C deficiency Protein C gene Protein S deficiency Protein S gene Increased Factor VIII von Willebrand factor deficiency Antithrombin III deficiency Antithrombin III Plasminogen deficiency Plasminogen activator-1 Lipoprotein (a) Apolipoprotein (a) Marfan syndrome Fibrillin 1 Fabry disease Alpha-galactosidase Sickle cell syndrome Globin genes Heparin cofactor II Heparin cofactor II Platelet collagen receptor Platelet collagen receptor Factor XII Factor XII Phosphodiesterase 4D Phosphodiesterase 4D CADASIL Notch 3 Hyperhomocysteinemia Methylene tetrahydrofolate reductase Homocysteinemia Cystathione beta-synthase Homocysteinemia Homocysteine methyl transferase Ehlers Danlos disease MELAS (mitochondrial) mtDNA Causes of cerebral hemorrhage associated with congenital diseases von Hippel-Lindau (Chap. 31) pVHL Cavernous malformations Cerebral cavernous malformations (CCM1) Cerebral amyloidosis Apolipoprotein E4 Cerebral hemorrhage with amyloidosis Dutch type Amyloid precursor protein Icelandic type Cystatin C Hereditary hemorrhagic Endoglin telangiectasia Hereditary hemorrhagic Activin receptor-like kinase telangiectasia (ALK-1) Polycystic kidney disease Polycystin 1, 2
WITH CEREBRAL THROMBOSIS (%)
INHERITANCE
STRUCTURES AFFECTED
GENERAL POPULATION (%)
AR
v
2–15
5–20
AR AR AR AR AR AR AR
0.1 0.2–0.4 0.03–0.13 10 Rare
1–5 3–6 1–5 25 3–8
AR AR AR Complex AD AR
v v v v v v v v,h,ao v v,a v v v a a a
AR AR
a a
AR
0.03 Rare
?5
Rare
20 in young
a Maternal AD AD
hemorrhage "
Complex
" "
AD AD AD
" " "
AD
"
AD
"
a, arterial; AD, autosomal dominant; ao, aorta; AR, autosomal recessive; h, heart; v, venous.
and transfusion. Cerebral venous sinus thrombosis in young children and neonates represents a special problem, difficult to diagnose, and with a poor prognosis (see deVeber et al). Certain hereditary metabolic diseases (homocystinuria and Fabry angiokeratosis) and the mitochondrial disorder MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) may give rise to strokes in children or young adults; investigation of these causes is undertaken if the aforementioned clotting disorders have been excluded or if there is a family history. Overall, in children and young adults with ischemic stroke, the main diagnoses to be considered are carotid and vertebral dissection, drug abuse (mainly cocaine), thrombosis induced by birth control pills (see below), antiphospholipid antibody syndrome, and patent foramen ovale (PFO). Migraine might be added to this list, but it is a diagnosis by exclusion in these circumstances and CADASIL, albeit rare,
should also be considered if migraine headaches and TIAs precede a stroke. Inherited prothrombotic states—such as those caused by the various clotting factor deficiencies discussed above, Fabry disease, moyamoya, and Takayasu arteritis—arise in the younger age group and require exploration if clinical circumstances suggest one of these processes on the basis of unusual TIAs (orthostatic, hyperventilation, or fever induced), Down syndrome, or strong family history of strokes in youth. Oral Contraceptives, Estrogen, and Cerebral Infarction The early studies of Longstreth and Swanson and of Vessey and associates indicated that women who take oral contraceptives in the childbearing years—particularly if they are older than 35 years of age and also smoke, are hypertensive, or have migraine—are at increased risk of cerebral infarction. Stroke in these cases is usually a result of arterial occlusion, occurring in both the carotid–middle cerebral and vertebrobasilar territories and sometimes to
CHAPTER 34
occlusion of cerebral veins. In most of the reported fatal cases, the thrombosed vessel has been free of atheroma or other disease. The vascular lesion underlying cerebral thrombosis in women taking oral contraceptives was studied by Irey and colleagues. It consists of nodular intimal hyperplasia of eccentric distribution with increased acid mucopolysaccharides and replication of the internal elastic lamina. Similar changes have been found in pregnancy and in humans and animals receiving exogenous steroids, including estrogens. These observations, coupled with evidence that estrogen alters the coagulability of the blood, suggest that a state of hypercoagulability is the important factor in the genesis of contraceptive-associated infarction. Mainly at increased risk of stroke are women taking high-dose (0.50-mg) estrogen pills; in recent years, lowering the estrogen content has substantially reduced, but not eliminated, this risk. The use of progestin-only pills or of subcutaneously implanted capsules of progestin has not been associated with stroke as far as can be currently determined (Petitti et al). It has also become clear that mutations of the prothrombin gene are more frequent than in the general population in patients who have cerebral venous thrombosis while on oral contraceptive pills. Martinelli and associates propose that these genetic abnormalities account for 35 percent of idiopathic cases of cerebral vein thrombosis; and they contend that contraceptives increase this risk 20-fold.
Stroke in Pregnancy and the Postpartum Period In addition to the eclamptic-hypertensive state, there is an increased incidence of cerebrovascular events during pregnancy and the postpartum period. The risk of both cerebral infarction and intracerebral hemorrhage appears to be mainly in the 6-week period after delivery rather than during the pregnancy itself (Kittner et al). Fisher (1971) reviewed the literature and analyzed 12 postpartum, 9 puerperal, and 14 contraceptive cases, as well as 9 patients receiving estrogen therapy; arterial thrombosis was demonstrated in half of these cases. Most of the focal vascular lesions during pregnancy were a result of arterial occlusion in the second and third trimesters and in the first week after delivery. Venous occlusion tended to occur 1 to 4 weeks postpartum. In Rochester, New York, the incidence rate of stroke during pregnancy was 6.2 per 100,000, but it doubled with each advance in age from 25 to 29, 30 to 39, and 40 to 49 years. Included in most past series are cases with cardiac disease, particularly valve-related embolism. It is perhaps surprising that subarachnoid hemorrhage is not more frequent during the Valsalva activity of childbirth. Carotid artery dissection may also be encountered late in pregnancy or soon after delivery. The occurrence of paradoxical embolus is always a consideration in pregnancy because of a tendency to form clots in the pelvic and leg veins, coupled with increased right heart pressures. Amniotic fluid embolus may rarely cause stroke in this manner and should be suspected in multiparous women who have had uterine tears; there are almost invariably signs of acute pulmonary disease from
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simultaneous occlusion of lung vessels. A rare peripartum cardiomyopathy is yet another source of embolic stroke.
Stroke with Cardiac Surgery Incident to cardiac arrest and bypass surgery there is risk of both generalized and focal ischemia of the brain. Improved operative techniques have lessened the frequency of these complications but they are still distressingly frequent. Fortunately, most are transient. Atherosclerotic plaques may be dislodged during cross-clamping of the proximal aorta and are an important source of cerebral emboli. In the last decade the incidence of stroke related to cardiac surgery has dropped to between 2 and 3 percent in large series numbering thousands of patients (Libman et al; Ahlgren and Arén). Advanced age, congestive heart failure, and more complex surgeries have been listed as risk factors for stroke from various reports. Representative is a retrospective study by Dashe and colleagues, in which 2 percent had strokes; most minor, but the risk was greatly increased on the side of a carotid stenosis. Curiously, almost one-fifth of postoperative strokes in some series have been of lacunar type. In one prospective study of 2,108 patients who underwent coronary operations in several institutions, 3 percent had strokes or TIAs; the adverse effects mostly occurred in older patients and were transient (Roach et al). Mohr and coworkers (1978) examined 100 consecutive cases pre- and postoperatively and observed two types of stroke-like complications—one occurring immediately after the operation and the other after an interval of days or weeks. The immediate neurologic disorder consisted of a delay in awakening from the anesthesia; subsequently there was slowness in thinking, disorientation, agitation, combativeness, visual hallucinations, and poor registration and recall of what was happening. These symptoms, in the form of a confusional state sometimes verging on delirium or acute psychosis, usually cleared within 5 to 7 days, although some patients were not entirely normal mentally some weeks later. As the confusion cleared, about half of the patients were found to have small visual field defects, dyscalculia, Balint syndrome (Chap. 22), alexia, or defects of perception suggestive of lesions in the parietooccipital regions. The immediate effects were attributed to hypotension and various types of embolisms (atherosclerotic, air, silicon, fat, platelets). The delayed effects were more clearly embolic and were especially frequent in patients having prosthetic valve replacements or other valve repairs. In addition to overt and covert strokes detected only by imaging, a degree of cognitive decline and depression is to be expected in a proportion of patients undergoing coronary artery bypass grafting. The frequency of these changes is reported to be between 40 and 70 percent (see Chap. 20). It is our impression that many of these neurologic complications, both small strokes and cognitive abnormalities, pass unnoticed in many cardiac surgical units. This was emphasized in the study by McKhann and colleagues, who tested several neuropsychologic functions and found that only 12 percent of patients escaped some type of early cognitive problem. However, his group and others, for example, Mülges and colleagues, have shown that only a small proportion (13 percent in the latter series) retained perma-
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nent effects 5 years after operation. Others have reported higher rates, but it is clear that the cognitive problems improve over time in the majority of patients. The use of Doppler insonation of the middle cerebral arteries is being studied to detect transient signals called HITs (high-intensity transients) as a manifestation of small emboli during surgery but, as for the transients frequently noted during cerebral arteriography, the clinical importance of these emboli is not known. In an attempt to avoid neurologic complication related to extracorporeal circulation, off-pump coronary artery bypass has been popularized in many centers. Unfortunately, most studies have found no fewer cognitive complications as compared to conventional coronary artery bypass surgery. This is contrary to the notion that the extracorporeal apparatus is the cause of the problem. The issue of the neurologic complications of cardiac surgery may be summarized as follows: Stroke originating from the aorta is the cause of cognitive failure. The clinical syndromes seem to fall on a continuum. A few strokes (less than 3 percent) are gross and singular producing an obvious deficit (e.g., hemiplegia), but most of the emboli are multiple. When there are numerous small emboli, an acute encephalopathy ensues. When the burden of emboli is lower, no deficit is recognized in the acute period. In patients with premorbid presymptomatic Alzheimer disease, confusion and dementia are made manifest by the stress of cardiac surgery and the surgery is erroneously blamed for the emergence of an ostensibly new problem. The other special stroke problems relating to prosthetic heart valves—mainly infective endocarditis causing embolic strokes and anticoagulant-related cerebral hemorrhage—are described in later sections of this chapter.
INTRACRANIAL HEMORRHAGE This is the third most frequent cause of stroke. Although more than a dozen causes of nontraumatic intracranial hemorrhage are listed in Table 34-9, primary or hypertenTable 34-9 CAUSES OF INTRACRANIAL HEMORRHAGE (INCLUDING INTRACEREBRAL, SUBARACHNOID, VENTRICULAR, AND SUBDURAL BLEEDING) 1. Primary (hypertensive) intracerebral hemorrhage 2. Ruptured saccular aneurysm 3. Ruptured arteriovenous malformation; less often, venous and dural vascular malformations 4. Cavernous angioma 5. Trauma including posttraumatic delayed apoplexy 6. Hemorrhagic disorders: leukemia, aplastic anemia, thrombocytopenic purpura, liver disease, complication of anticoagulant or thrombolytic therapy, hypofibrinogenemia, hemophilia, Christmas disease, etc. 7. Hemorrhage into primary and secondary brain tumors 8. Septic embolism, mycotic aneurysm 9. With hemorrhagic infarction, arterial or venous 10. With inflammatory and infectious disease of the arteries and veins 11. With arterial amyloidosis 12. Miscellaneous rare types: vasopressor drugs, cocaine, moyamoya, herpes simplex encephalitis, vertebral artery dissection, acute necrotizing hemorrhagic encephalitis (Hurst disease), tularemia, anthrax, etc.
sive (“spontaneous”) intracerebral hemorrhage, ruptured saccular aneurysm and vascular malformation, and hemorrhage associated with the use of anticoagulants or thrombolytic agents account for the majority. Cerebrovascular amyloidosis and acquired or congenital bleeding disorders account for a smaller number. The small brainstem hemorrhages secondary to temporal lobe herniation and brainstem compression (Duret hemorrhages), hypertensive encephalopathy, and brain purpura might be included in this group, but they do not simulate a stroke.
Primary (Hypertensive) Intracerebral Hemorrhage This is the mundane but often devastating “spontaneous” brain hemorrhage. It is predominantly a result of chronic hypertension and degenerative changes in cerebral arteries. In recent decades, with increased awareness of the need to control blood pressure, the proportion of hemorrhages attributable to causes other than hypertension has greatly increased so that more than half such hemorrhages on our services now occur in normotensive individuals, and the hemorrhages more often than previously arise in locations that are not typical for hypertension. Nevertheless, the hypertensive cerebral hemorrhage serves as a model for understanding and managing other cerebral hemorrhages. In order of frequency, the most common sites of a cerebral hemorrhage are (1) the putamen and adjacent internal capsule (50 percent); (2) the central white matter of the temporal, parietal, or frontal lobes (lobar hemorrhages, not strictly associated with hypertension); (3) the thalamus; (4) one or the other cerebellar hemisphere; and (5) the pons. The vessel involved is usually a small penetrating artery that originates from a larger trunk vessel. Approximately 2 percent of primary hemorrhages are multiple. Multiple nearly simultaneous intracerebral hemorrhages raise the possibility of amyloid angiopathy or a bleeding diathesis (see further on) but may occur when one conventional hypertensive intracerebral hemorrhage causes hypertension, which in turn leads to one or more additional hemorrhages. The extravasation of blood into the substance of the brain forms a roughly circular or oval mass that disrupts the tissue and can grow in volume if the bleeding continues (Fig. 34-20). Adjacent brain tissue is distorted and compressed. If the hemorrhage is large, midline structures are displaced to the opposite side of the cranium and the reticular activating and respiratory centers are compromised, leading to coma and death in the manner described in Chap. 17. It has been long known that both the size and the location of the clot determine the degree of secondary brainstem compression and this was confirmed by Andrew and associates. Rupture or seepage of blood into the ventricular system or rarely to the surface subarachnoid space may occur, and the CSF becomes bloody in these cases. When the hemorrhage is small and located at a distance from the ventricles, the CSF may remain clear even on repeated examinations. In the first hours and days following the hemorrhage, varying degrees of edema accumulates around the clot and adds to the mass effect. Hydrocephalus may occur as a result of bleeding into the ventricular system or from compression of the third ventricle.
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Figure 34-20. An unenhanced CT scan showing the typical picture of a massive primary (hypertensive) hemorrhage in the basal ganglia. The third ventricle and ipsilateral lateral ventricle are compressed and displaced by the expanding mass (12 h after onset of stroke).
The extravasated blood undergoes a predictable series of changes. At first fluid, the collection becomes a clot within hours. Before the clot forms, red cells settle in the dependent part of the hematoma and forms a meniscus with the plasma above; this is particularly prone to occur in cases of anticoagulant-induced hemorrhage. The resultant fluid–fluid level can be observed on CT scan and MRI (“hematocrit effect”). Hematomas, when examined in autopsy material, contain only masses of red blood cells and proteins; rarely one sees a few remnants of destroyed brain tissue. The hematoma is often surrounded by petechial hemorrhages from torn arterioles and venules. Within a few days, hemoglobin products, mainly hemosiderin and hematoidin, begin to appear. The hemosiderin forms within histiocytes that have phagocytized red blood cells (RBCs) and takes the form of ferritin granules that stain positively for iron. As oxyhemoglobin is liberated from the RBCs and becomes deoxygenated, methemoglobin appears. This begins within a few days and imparts a brownish hue to the periphery of the clot. Phagocytosis of red cells begins within 24 h, and hemosiderin is first observed around the margins of the clot in 5 to 6 days. The clot changes color gradually over a few weeks from dark red to pale red, and the border of golden-brown hemosiderin widens. The edema disappears over many days or weeks. In 2 to 3 months, larger clots are filled with a chrome-colored thick fluid, which is slowly absorbed, leaving a smooth-walled cavity or a yellow-brown scar. The iron pigment (hematin) becomes dispersed and studs
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adjacent astrocytes and neurons and may persist well beyond the border of the hemorrhage for years. Imaging techniques demonstrate a predictable sequence of changes. In CT scans, fresh blood is visualized as a white mass as soon as it is shed. The mass effect and the surrounding extruded serum and edema are hypodense. After 2 to 3 weeks, the surrounding edema begins to recede and the density of the hematoma decreases, first at the periphery. Gradually the clot becomes isodense with brain. There may be a ring of enhancement from the hemosiderin-filled macrophages and the reacting cells that form a capsule for the hemorrhage. At one point several weeks after the bleed, the appearance may transiently simulate a tumor or abscess. By MRI, either in conventional T1- or T2-weighted images, the hemorrhage is not easily visible in the 2 or 3 days after bleeding, as oxyhemoglobin is diamagnetic or, at most, is slightly hypointense, so that only the mass effect is evident. MR gradient-echo images that display areas of magnetic susceptibility will show hemorrhages earlier and detect remnants of deposited hemosiderin even years afterwards. After several days the surrounding edema is hyperintense in T2-weighted images. As deoxyhemoglobin and methemoglobin form, the hematoma signal becomes bright on T1weighted images and dark on T2. As the hematoma becomes subacute, the dark images gradually brighten. When methemoglobin disappears and only hemosiderin remains, the entire remaining mass is hypodense on T2-weighted images, as are the surrounding deposits of iron. The sizes of cerebral hemorrhages vary widely. Massive refers to hemorrhages several centimeters in diameter; small applies to those 1 to 2 cm in diameter and less than 20 mL in volume. The volume and location relate to outcome and the nature of the initial neurologic deficit.
Pathogenesis The hypertensive vascular lesion that leads to arterial rupture in most cases appears to arise from an arterial wall altered by the effects of hypertension, i.e., the change referred to in a preceding section as segmental lipohyalinosis and the false aneurysm (microaneurysm) named for Charcot and Bouchard. Ross Russell’s work has affirmed the relationship of these microaneurysms to hypertension and hypertensive hemorrhage and their frequent localization on penetrating small arteries and arterioles of the basal ganglia, thalamus, pons, and subcortical white matter. However, in the few hemorrhages examined in serial sections by our colleague C.M. Fisher, the bleeding could not be traced to Charcot-Bouchard aneurysms. Takebayashi and coworkers, in an electron microscope study, found breaks in the elastic lamina at multiple sites, almost always at bifurcations of the small vessels. Possibly these represent sites of secondary rupture from tearing of small vessels by the expanding hematoma. Amyloid impregnation of vessel walls represents a different mechanism for vessel rupture, as discussed further on.
Clinical Picture Of all the cerebrovascular diseases, brain hemorrhage is the most dramatic and from ancient times has been given its own name, “apoplexy.” The prototype is an obese, ple-
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thoric, hypertensive male who falls senseless to the ground—impervious to shouts, shaking, and pinching— breathes stertorously, and dies in a few hours. A massive blood clot escapes from the brain as it is removed postmortem. With smaller hemorrhages, the clinical picture conforms more closely to the usual temporal profile of a stroke, i.e., an abrupt onset of symptoms that evolve gradually and steadily over minutes or hours, depending on the size of the ruptured artery and the speed and expansion of bleeding. Several general features of intracerebral hemorrhage should be emphasized. Acute reactive hypertension, far exceeding the patient’s chronic hypertensive level, is a feature that, in the context of a stroke, suggests hemorrhage; it is seen particularly with moderate and large clots situated in deep regions. Vomiting at the onset of intracerebral hemorrhage occurs much more frequently than with infarction and likewise suggests bleeding as the cause of an acute hemiparesis. Severe headache is generally considered to be an accompaniment of intracerebral hemorrhage and in many cases it is, but in almost half of our cases it has been absent or mild. Nuchal rigidity is infrequent. If there is stiffness of the neck, it characteristically disappears as coma deepens. The patient is often alert and responding accurately when first seen. This can be true even when the CSF is grossly bloody; thus the adage that hemorrhage into the ventricular system always precipitates coma is quite incorrect. Only if bleeding into the ventricles is massive or there is substantial distortion of the midbrain does coma result. Seizures, usually focal, occur in the first few days in only 10 percent of cases of supratentorial hemorrhage, rarely at the time of the ictus and more commonly as a delayed event, months or years after the hemorrhage. In the selected population of patients with cerebral hemorrhage who are continuously monitored by EEG in an intensive care unit, the frequency may be higher, up to one-third of which half are purely electrographic, according to Claassen and associates. This finding is interesting but does not seem to us to justify routine EEG monitoring. The fundi often show hypertensive changes in the arterioles. Rarely, white-centered retinal hemorrhages (Roth spots) or fresh preretinal (subhyaloid) hemorrhages occur; the latter are much more common with ruptured aneurysm, arteriovenous malformation, or severe cranial trauma. Therefore, headache, acute hypertension, and vomiting with a focal neurologic deficit are the cardinal features and serve most dependably to distinguish hemorrhage from ischemic stroke. Small hemorrhages in “silent” regions of the brain may escape clinical detection. Hemorrhages that complicate the administration of anticoagulants, like those from some vascular malformations, may evolve at a slower pace. Usually there are no warnings or prodromal symptoms; headache, dizziness, epistaxis, or other symptoms do not occur with any consistency. There is no age predilection except that the average age of occurrence is lower than in thrombotic infarction and neither sex is more disposed. The incidence of hypertensive cerebral hemorrhage is higher in African Americans than in whites and seems recently to have been reported with increasing frequency in people of Japanese descent. In the majority of cases, the
hemorrhage has its onset while the patient is up and active; onset during sleep is rare. There has long been a notion that acute hypertension can precipitate the hemorrhage. This is based on the known occurrence of cerebral hemorrhage at moments of extreme fright or anger or intense excitement, presumably as the blood pressure rises abruptly beyond its chronically elevated level. Similarly, hemorrhages have been described in relation to taking sympathomimetic medications such as phenylpropanolamine (Kernan et al), ephedra, or cocaine, and to numerous other hypertensive circumstances. However, in fully 90 percent of instances, the hemorrhage occurs when the patient is calm and unstressed, according to Caplan (1993). The level of blood pressure rises early in the course of the hemorrhage but the preceding chronic hypertension is usually of the “essential” type. Nonetheless, causes of hypertension must always be considered—renal disease, renal artery stenosis, eclampsia, pheochromocytoma, hyperaldosteronism, adrenocorticotropic hormone or corticosteroid excess and, of course, sympathetically active drugs as mentioned. There is ordinarily only one episode of hypertensive hemorrhage; recurrent bleeding from the same site, as happens with saccular aneurysm and arteriovenous malformation, is infrequent. However, it has been recognized by serial CT scanning that in many instances, there is slight enlargement of the hematoma. In the series reported by Brott and colleagues, 25 percent were found to have enlarged in the first hour and another 12 percent in the first day. Contrast extravasation into the adjacent brain after CTA was associated in a retrospective study with expansion of a hematoma (Goldstein et al), but there are no other clear predictive factors. Blood in cerebral tissue is absorbed slowly over months during which time symptoms and signs recede. Hence the neurologic deficit is never transitory in intracerebral hemorrhage, as it so often is in embolism. The main types and locations of cerebral hemorrhage are described below. Chronic hypertension is associated with bleeding into the putamen, thalamus, pons, and cerebellum. Lobar hemorrhages have numerous causes.
Putaminal Hemorrhage The most common syndrome is the one caused by putaminal hemorrhage with extension to the adjacent internal capsule (see Fig. 34-20). Neurologic symptoms and signs vary slightly with the precise site and size of the extravasation, but hemiplegia from interruption of the capsule is a consistent feature of medium-sized and large clots. Vomiting occurs in about half the patients. Headache is frequent but not invariable. With large hemorrhages, patients lapse almost immediately into a stupor with hemiplegia and their condition visibly deteriorates as the hours pass. More often there is headache or some other abnormal cephalic sensation. Within a few minutes or less the face sags on one side, speech becomes slurred or aphasic, the arm and leg weaken and are flaccid, and the eyes tend to deviate away from the side of the paretic limbs. These events, occurring gradually over a period of several minutes or more, are strongly suggestive of intracerebral bleeding. More advanced stages are
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characterized by signs of upper brainstem compression (coma); bilateral Babinski signs; irregular or intermittent respiration; dilated, fixed pupils, first on the side of the clot; and decerebrate rigidity. The widespread use of CT scanning has disclosed the frequent occurrence of many smaller putaminal hemorrhages, which in former years would have been misdiagnosed as embolic or thrombotic strokes (especially if the CSF was clear). With hemorrhages confined to the anterior segment of the putamen, the hemiplegia and hyperreflexia tend to be less severe and to clear more rapidly according to Caplan (1993). There is also prominent abulia, motor impersistence, temporary unilateral neglect, and with left-sided lesions, nonfluent aphasia, and dysgraphia. With small posterior lesions, weakness is also mild and is attended by sensory loss, hemianopia, impaired visual pursuit to the opposite side, Wernicke-type aphasia (left-sided lesions), and anosognosia (right-sided). The effects of relatively pure caudate hematoma have been difficult to define. Those extending laterally and posteriorly into the internal capsule behave much like large putaminal hemorrhages. Those extending medially into the lateral ventricle give rise to drowsiness, stupor, and either confusion and underactivity or restlessness and agitation.
Thalamic Hemorrhage The central feature here is severe multimodal sensory loss on the entire contralateral body. If large or moderate in size, thalamic hemorrhage also produces a hemiplegia or hemiparesis by compression or destruction of the adjacent internal capsule (Fig. 34-21). The sensory deficit involves all of the opposite side including the trunk and may exceed the motor weakness. A fluent aphasia or anemia may be present with lesions of the dominant side and amorphosynthesis and contralateral neglect, with lesions of the nondominant side. A homonymous field defect, if present, usually clears in a few days. Thalamic hemorrhage, by virtue of its extension into the subthalamus and high midbrain, may also cause a series of ocular disturbances—pseudoabducens palsies with one or both eyes turned asymmetrically inward and slightly downward, palsies of vertical and lateral gaze, forced deviation of the eyes downward, inequality of pupils with absence of light reaction, skew deviation with the eye ipsilateral to the hemorrhage assuming a higher position than the contralateral eye, ipsilateral ptosis and miosis (Horner syndrome), absence of convergence, retraction nystagmus, and tucking in (retraction) of the upper eyelids. Extension of the neck may be observed. Compression of the adjacent third ventricle leads to enlargement of the lateral ventricles that may require temporary drainage. Small and moderatesized hemorrhages that rupture into the third ventricle have been associated with fewer neurologic deficits and better outcomes, but early hydrocephalus is common.
Pontine Hemorrhage Hemorrhage into the pons is almost invariably associated with deep coma within a few minutes; the remainder of the clinical picture is dominated by total paralysis with bilateral Babinski signs, decerebrate rigidity, and small (1-mm) pupils that react to light. Lateral eye movements, evoked by
Figure 34-21. CT scan of a left thalamic hemorrhage that caused hemiplegia and hemisensory loss in a hypertensive patient. A small amount of blood is seen in the adjacent posterior third ventricle.
head turning or caloric testing, are impaired or absent. Death usually occurs within a few hours, but there are exceptions in which consciousness is retained and the clinical manifestations indicate a smaller lesion in the tegmentum of the pons (disturbances of lateral ocular movements, crossed sensory or motor disturbances, small pupils, and cranial nerve palsies) in addition to signs of bilateral corticospinal tract involvement. A number of our patients with limited tegmental hemorrhages and blood in the CSF have survived with good functional recovery. In a series of 60 patients with pontine hemorrhage reviewed by Nakajima, 19 survived (8 of whom had remained alert). Similarly, Wijdicks and St. Louis reported that 21 percent made a good recovery—mostly those who were awake on admission.
Cerebellar Hemorrhage This usually develops over a period of 1 or more hours, and loss of consciousness at the onset is unusual. Repeated vomiting is a prominent feature, with occipital headache, vertigo, and inability to sit, stand, or walk. Often these are the only abnormalities, making it imperative to have the patient attempt to ambulate; otherwise the examination may erroneously seem to be normal. In the early phase of the illness other clinical signs of cerebellar disease are usually minimal or lacking; only a minority of cases show nystagmus or cerebellar ataxia of the limbs, although these signs must always be sought. A mild ipsilateral facial weakness and a diminished corneal reflex are common. Dysarthria and dysphagia may be prominent in some cases but usually are also absent. Contralateral hemiplegia and ipsilateral facial weakness do not occur
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unless there is displacement and compression of the medulla against the clivus. There is often paresis of conjugate lateral gaze to the side of the hemorrhage, forced deviation of the eyes to the opposite side, or an ipsilateral sixth-nerve weakness. Vertical eye movements are retained. Other infrequent ocular signs include blepharospasm, involuntary closure of one eye, skew deviation, “ocular bobbing,” and small, often unequal pupils that continue to react until very late in the illness. Occasionally at the onset there is a spastic paraparesis or a quadriparesis with preservation of consciousness. The plantar reflexes are flexor in the early stages but extensor later. When these signs occur, hydrocephalus is usually found and may require drainage. In the series collected by St. Louis and colleagues, patients with vermian clots and hydrocephalus were at the highest risk for rapid deterioration. As the hours pass, and occasionally with unanticipated suddenness, the patient becomes stuporous and then comatose or suddenly apneic as a result of brainstem compression, at which point reversal of the syndrome, even by surgical therapy, is seldom successful. As discussed further on, cerebellar hemorrhage is the most amenable to surgical evacuation with good results.
Lobar Hemorrhage Bleeding in areas other than those listed above, specifically in the subcortical white matter of one of the lobes of the cerebral hemisphere, is not associated strictly with hypertension. Any number of other causes are usually responsible, the main ones being anticoagulation or thrombolytic therapy, acquired coagulopathies, cranial trauma, arteriovenous malformation (discussed further on), trauma, and, in the elderly, amyloidosis of the cerebral vessels. Most lobar hemorrhages are spherical or ovoid, but a few follow the contour of the subcortical white matter tracts and take the form of a slit (subcortical slit hemorrhage). It is our impression that many of these are the result of a bleeding diathesis, such as thrombocytopenia. In a consecutive series of 26 cases of lobar hemorrhage, we found 11 to lie within the occipital lobe, causing pain around the ipsilateral eye and a dense homonymous hemianopia; 7 in the temporal lobe that produced pain in or anterior to the ear, partial hemianopia, and fluent aphasia; 4 in the frontal lobe, with frontal headache and contralateral hemiplegia, mainly of the arm; and 3 in the parietal lobe that presented with anterior temporal headache and hemisensory deficit contralaterally (Ropper and Davis). The smaller hematomas simulate an embolic stroke in the same territory. The occurrence of a progressively worsening headache, vomiting, or drowsiness in conjunction with any one of these syndromes is virtually diagnostic, and, of course, the presence of a lobar hemorrhage is readily corroborated by an unenhanced CT scan. Of our 26 patients, 14 had normal blood pressure, and in several of the fatal cases there was amyloidosis of the affected vessels; 2 patients were receiving anticoagulants, 2 had an arteriovenous malformation, and 1 had a metastatic tumor. Similarly, in the series of 22 patients with lobar clots reported by Kase and colleagues, 55 percent were normotensive; metastatic tumors, arteriovenous malformations, and blood dyscrasias were found in 14, 9, and 5 percent of the patients, respec-
tively. The role of amyloid angiopathy in lobar hemorrhage in the elderly patient is discussed further on. In the localization of an intracerebral hemorrhage, ocular signs may be particularly useful. In putaminal hemorrhage, the eyes are deviated to the side opposite the paralysis; in thalamic hemorrhage, the most common ocular abnormality is downward deviation of the eyes and the pupils may be unreactive; in pontine hemorrhage, the eyeballs are fixed and the pupils are tiny but reactive; and in large cerebellar hemorrhage, the eyes may be deviated laterally to the side opposite the lesion and ocular bobbing may occur (as often in cerebellar hemorrhage in awake patients there are no eye signs).
Laboratory Findings For the rapid diagnosis of intracerebral hemorrhage, the CT scan occupies the foremost position. It is totally reliable in the detection of hemorrhages that are 1.0 cm or more in diameter. Smaller pontine hemorrhages may be missed because of the artifact produced by adjacent bone. At the same time, coexisting hydrocephalus, tumor, cerebral swelling, and displacement of the intracranial contents are readily appreciated. MRI is particularly useful for demonstrating brainstem hemorrhages and residual hemorrhages, which remain visible long after they are no longer visible on the CT scan (after 4 to 5 weeks). Hemosiderin and iron pigment have characteristic appearances, as described earlier and in Chap. 2. In general, lumbar puncture is ill advised, for it may precipitate or aggravate an impending shift of central structures and herniation. The white cell count in the peripheral blood may rise transiently to 15,000/mm3, a higher figure than in thrombosis, but it is most often normal. The sedimentation rate may be mildly elevated in some patients. Determination of the INR, partial thromboplastin time and platelet count is advisable.
Course and Prognosis The immediate prognosis for large and medium-sized cerebral clots is grave; some 30 to 35 percent of patients die in 1 to 30 days. In these cases, either the hemorrhage has extended into the ventricular system or intracranial pressure becomes elevated to levels that preclude normal perfusion of the brain. Or the hemorrhage seeps into vital centers such as the hypothalamus or midbrain. A formula that predicts outcome of hemorrhage based on clot size was devised by Broderick and coworkers; it is mainly applicable to putaminal and thalamic clots. A volume of 30 mL or less, calculated by various methods from the CT scan predicted a generally favorable outcome; only 1 of their 71 patients with clots larger than 30 mL had regained independent function by 1 month. By contrast, in patients with clots of 60 mL or larger and an initial Glasgow Coma Scale score of 8 or less, the mortality was 90 percent (this scale is detailed in Table 35-1). As remarked earlier, it is the location of the hematoma, not simply its size that determines the clinical effects. A clot 60 mL in volume is almost uniformly fatal if situated in the basal ganglia but may allow reasonably good outcome if located in the frontal or occipital lobe. From the studies of Diringer and colleagues (1998), hydrocephalus is also an important predictor of poor outcome, and this accords with our experi-
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ence. Prompt drainage of the ventricles can markedly improve the clinical state. In patients who survive, there can be a surprising degree of restoration of function, because, in contrast to infarction, the hemorrhage has to some extent pushed brain tissue aside rather than destroyed it. Function returns very slowly, however, because extravasated blood takes time to be removed from the tissues. Healed scars impinging on the cortex are liable to be epileptogenic; the frequency of seizures after each type of hemorrhage has not been established, but it is lower than for ischemic strokes. There is no need to administer anticonvulsive medication unless a seizure has occurred. The poor prognosis of all but the smallest pontine hemorrhages has already been mentioned. Cerebellar hemorrhages present special problems that are discussed below.
Treatment The management of patients with large intracerebral hemorrhages and coma includes the maintenance of adequate ventilation, selective acute use of controlled hyperventilation to a PCO2 of 25 to 30 mm Hg, monitoring of intracranial pressure in some cases and its control by the use of tissue-dehydrating agents such as mannitol (osmolality kept at 295 to 305 mOsm/L and Na at 145 to 150 mEq), and limiting intravenous infusions to normal saline. Qureshi’s group offered data suggesting that aggressive measures to reduce intracranial pressure may be lifesaving and result in good outcome even in patients who have signs of transtentorial herniation. In our experience, this type of recovery is exceptional, but medical treatment of raised intracranial pressure may be justified in patients whose medical condition allows it. As mentioned, virtually all patients with intracerebral hemorrhage are hypertensive immediately after the stroke because of a generalized sympathoadrenal response. The natural trend is for the blood pressure to diminish over several days; therefore active treatment in the acute stages has been a matter of controversy. Rapid reduction of moderately elevated blood pressure (between 140 and 160 mm Hg systolic), in the hope of reducing further bleeding, is not recommended, because it risks compromising cerebral perfusion in cases of raised intracranial pressure. On the other hand, sustained mean blood pressures of greater than 110 mm Hg (generally above 160 mm Hg systolic) may exaggerate cerebral edema and perhaps enhance the risk extension of the clot. It is at approximately this level of acute hypertension that the use of beta-blocking drugs (esmolol, labetalol) or angiotensin-converting enzyme (ACE) inhibitors is recommended. The major calcium channel-blocking drugs are used less often for this purpose because of reports of adverse effects on intracranial pressure, although this information derives mainly from patients with brain tumors. Hayashi and associates have shown that although blood pressure is lowered with nifedipine after cerebral hemorrhage, intracranial pressure is raised, resulting in an unfavorable net reduction in cerebral perfusion pressure. Nevertheless, we have used all classes of medication in patients with small- and medium-sized clots without adverse effects. Diuretics are helpful in combination with any of the antihypertensive medications. More rapidly acting and titratable agents such as nitroprusside may be used
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in extreme situations, recognizing that they may further raise intracranial pressure. Although it would appear intuitively that evacuation of a hematoma might be beneficial, surgical results have not been superior to those with medical measures alone (Waga and Yamamoto; Batjer et al; Juvela et al; Rabinstein et al). A large, multicenter, randomized study involving 1,033 patients with supratentorial hemorrhage, under the auspices of the Surgical Trial in Intracerebral Haemorrhage (STICH) study reported by Mendelow and colleagues, has failed to show a benefit from early surgery on survival or neurologic functioning at 6 months. This negative result extended to almost all levels of neurologic deficit and all age groups. In a post hoc analysis, clots that were small and close to the surface of the brain may have benefited from evacuation. As a result, this approach has been virtually abandoned, but we acknowledge that in a few instances with ongoing deterioration in young patients with hematomas that were easily accessible from the cortical surface, we asked our neurosurgical colleagues to undertake evacuation of the clot. Mayer and coworkers studied the promising approach of administering clotting factor VII within 4 h of hemorrhage. In a preliminary study, survival was improved and there was a reduction in enlargement of the hematoma, but their subsequent series has failed to confirm the benefit on survival so that infusion of factor VII is not currently part of routine practice. If acute hydrocephalus has resulted from a centrally placed hemorrhage or rupture into the ventricular system, a drain is needed. It has been appreciated for some time that intraventricular extension of cerebral hemorrhage generally denotes a poor outcome. An exception may be small thalamic hemorrhages. An ongoing study of the reduction of intraventricular hemorrhage size by the use of infused tissue plasminogen activator through a ventricular catheter. Preliminary results suggest that this approach may reduce mortality, and similar practices have been adopted for some time on many neurosurgical services. Once the patient with a supratentorial hemorrhage becomes deeply comatose with dilated fixed pupils, the chance of recovery is negligible. Even in retrospective studies in which clinical worsening was the reason for surgery, such as the one by Rabinstein and colleagues, only 25 percent of patients attained a state of functional independence and all of their patients who lost their brainstem reflexes and had extensor posturing died despite surgery; there have been a few exceptions to this observation. In comatose patients with large hemorrhages, the placement of a device for monitoring of intracranial pressure enables the clinician to use medical measures with greater precision, as outlined in Chap. 17, but there is no evidence that outcome is significantly improved (Ropper and King). Whether hemicraniectomy is of value, as it is with large hemispheral strokes, is not known but it seems unlikely. Surgical Evacuation of Cerebellar Hematoma In contrast, the surgical evacuation of cerebellar hematomas is a generally accepted treatment and is a more urgent matter because of the proximity of the mass to the brainstem and the risk of abrupt progression to coma and respiratory failure. Also, hydrocephalus from compression of the fourth ventricle more often complicates the clinical picture
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and further raises intracranial pressure (St. Louis et al). As a rule, a cerebellar hematoma less than 2 cm in diameter leaves most patients awake and infrequently leads to deterioration, therefore generally not requiring surgery. Hematomas that are 4 cm or more in largest diameter, especially if located in the vermis, pose the greatest risk, and some surgeons have recommended evacuation of lesions of this size no matter what the clinical status of the patient. In determining the need for surgical evacuation, we have been guided by the patient’s state of consciousness, the mass effect caused by the clot as visualized on CT scan (particularly the degree of compression of the quadrigeminal cistern, as pointed out by Taneda and colleagues), and the presence or absence of hydrocephalus. Assessment may require daily or even more frequent CT scans. The patient who is stuporous or displays arrhythmic breathing is best intubated and brought to the operating room within hours or sooner. Once coma and pupillary changes supervene, few patients survive, even with surgery; however, rapid medical intervention with mannitol and hyperventilation, followed by surgical evacuation of the clot and drainage of the ventricles within hours of the onset of coma has been successful in a few cases. Patients who are drowsy and those with hematomas of 2 to 4 cm in diameter in the cerebellar hemisphere pose the greatest difficulty in determining if, and when surgery is advisable. If the level of consciousness is fluctuating or if there is obliteration of the perimesencephalic cisterns, particularly if coupled with hydrocephalus, we believe that the risk of surgery is less than that of a sudden deterioration. In only a very limited number of patients have we found it practical to perform only drainage of the enlarged ventricles, although some groups still favor this procedure and eschew a posterior fossa operation. Evacuation of the clot in our experience has been more important than reduction of the hydrocephalus.
SPONTANEOUS SUBARACHNOID HEMORRHAGE (RUPTURED SACCULAR ANEURYSM) This is the fourth most frequent cerebrovascular disorder—following atherothrombosis, embolism, and primary intracerebral hemorrhage, but one that is often disastrous. Saccular aneurysms also have been called “berry” aneurysms. They take the form of small, thin-walled blisters protruding from arteries of the circle of Willis or its major branches. Their rupture causes a flooding of the subarachnoid space with blood under high pressure. As a rule, the aneurysms are located at vessel bifurcations and branchings (Fig. 34-22) and are generally presumed to result from developmental defects in the media and elastica of the arteries. An alternate theory holds that the aneurysmal process is initiated by focal destruction of the internal elastic membrane, which is produced by hemodynamic forces at the apices of bifurcations (Ferguson). As a result of the local weakness in the vessel wall, the intima bulges outward, covered only by adventitia; the sac then gradually enlarges and may finally rupture. Cerebral aneurysms vary in size from 2 mm to 2 or 3 cm in diameter, averaging 7.5 mm (Wiebers et al, 1981 and 1987). Those that rupture usually have a diameter of 10 mm or more, but rupture also occurs, albeit less often, in those of smaller size. Aneurysms vary greatly in form. Some are round and connected to the parent artery by a narrow stalk; others are broad-based without a stalk; and still others take the form of narrow cylinders. The site of rupture is usually at the dome of the aneurysm, which may have one or more secondary sacculations. A review of the subject by Schievink gives further details of this extensively studied subject. The incidence of unruptured aneurysms in routine autopsies is almost 2 percent—excluding minor vessel outpouch-
Ant. communicating A Ophthalmic A Ant. cerebral artery Middle cerebral stem
Int. carotid A
Post. communicating A 3rd cranial nerve
Post. cerebral A
Sup. cerebellar A
Basilar A
Post. inf. cerebellar A Vertebral A
Figure 34-22. Diagram of the circle of Willis showing the principal sites of saccular aneurysms. Approximately 90 percent of aneurysms are on the anterior half of the circle. The sizes of the aneurysms depicted correspond roughly to the frequency of occurrence at those sites.
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ings of 3 mm or less. Moreover, aneurysms are multiple in 20 percent of patients. In the past, it was estimated that 400,000 Americans harbored unruptured aneurysms and that there were 26,000 aneurysmal subarachnoid hemorrhages per year (Sahs et al, 1981 and 1984). Rupture of saccular aneurysms in childhood is rare, and they are seldom found at routine postmortem examination in this age group; beyond childhood, they gradually increase in frequency to reach their peak incidence between ages 35 and 65 years. Therefore aneurysms cannot be regarded as fully formed congenital anomalies; rather, they appear to develop over the years on the basis of either a developmental or acquired arterial defect. There is an increased incidence of congenital polycystic kidneys, fibromuscular dysplasia of the extracranial arteries, moyamoya, arteriovenous malformations of the brain, and coarctation of the aorta among persons with saccular aneurysms and vice versa. An accompanying saccular aneurysm occurs in approximately 5 percent of cases of cerebral arteriovenous malformation, usually on the main feeding artery of the malformation. Numerous reports have documented a familial occurrence of saccular aneurysms, lending support to the idea that genetic factors play a role in their development. The number of first-degree relatives found to harbor an unsuspected aneurysm has been approximately 4 percent in most series. This low rate, the finding that half of the discovered aneurysms are small, and the complications of surgery make routine screening of siblings, children, and parents of patients with ruptured aneurysms impractical, according to the Magnetic Resonance Angiography in Relatives of Patients with Subarachnoid Hemorrhage Study Group. However, because aneurysms of the familial variety tend to be larger at the time of rupture and more numerous than in patients who have sporadic ones, there are exceptions to this statement (Ruigrok et al), and there is little question that, in practice, the close relatives of patients with ruptured aneurysms ask for, and are accommodated, screening for aneurysms. From a survey in Scotland, the lifetime risk of hemorrhage was only 4.7 percent for a first-degree relative and 1.9 percent for a second-degree relative (Teasdale et al). From several series, it is apparent that the risk is highest for individuals with two or more first-degree relatives and negligible for one seconddegree relative. Although hypertension is more frequently present than in the general population, aneurysms most often occur in persons with normal blood pressure. Pregnancy does not appear to be associated with an increased incidence of aneurysmal rupture, although there is always concern about the possibility of inducing bleeding during the straining of natural delivery. Atherosclerosis, although present in the walls of some saccular aneurysms, probably plays no part in their formation or enlargement. Approximately 90 to 95 percent of saccular aneurysms lie on the anterior part of the circle of Willis (see Fig. 34-22). The four most common sites are (1) the proximal portions of the anterior communicating artery, (2) at the origin of the posterior communicating artery from the stem of the internal carotid, (3) at the first major bifurcation of the middle cerebral artery, and (4) at the bifurcation of the internal carotid into middle and anterior cerebral arteries. Other sites include the internal carotid artery in
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the cavernous sinus, at the origin of the ophthalmic artery, the junction of the posterior communicating and posterior cerebral arteries, the bifurcation of the basilar artery, and the origins of the cerebellar arteries. Aneurysms of the carotid artery that rupture in the cavernous sinus give rise to an arteriovenous fistula (see further on). There are several types of aneurysms other than saccular, e.g., mycotic, fusiform, diffuse, and globular. The mycotic aneurysm is caused by a septic embolus that weakens the wall of the vessel in which it lodges, almost always at a site in a distal cerebral vessel, well beyond the circle of Willis. These lesions are discussed separately in a later section of this chapter. The others are named for their predominant morphologic characteristics and consist of enlargement or dilatation of the entire circumference of the involved vessels, usually the internal carotid, vertebral, or basilar arteries. Fusiform deformities are also referred to as arteriosclerotic aneurysms, as they frequently show atheromatous deposition in their walls, but it is likely that they are at least partly developmental in nature. Some are very large (so-called giant aneurysms) and press on neighboring structures or become occluded by thrombus but they rupture only infrequently (as discussed further on).
Clinical Syndrome With rupture of the aneurysm, blood under high pressure is forced into the subarachnoid space and the resulting clinical events assume one of three patterns: (1) the patient is stricken with an excruciating generalized headache and vomiting and falls unconscious almost immediately; (2) severe generalized headache develops in the same instantaneous manner but the patient remains relatively lucid with varying degrees of stiff neck—the most common syndrome; (3) rarely, consciousness is lost so quickly that there is no preceding complaint. If the hemorrhage is massive, death may ensue in a matter of minutes or hours, so that ruptured aneurysm must be considered in the differential diagnosis of sudden death. A considerable proportion of such patients probably never reach a hospital. Decerebrate rigidity and brief clonic jerking of the limbs may occur at the onset of the hemorrhage, always in association with unconsciousness. Persistent deep coma is accompanied by irregular respirations, attacks of extensor rigidity, and finally respiratory arrest and circulatory collapse. In these rapidly evolving cases, the subarachnoid blood has greatly increased the intracranial pressure to a level that approaches arterial pressure and caused a marked reduction in cerebral perfusion. In some instances, the hemorrhage has dissected intracerebrally and entered the brain or ventricular system. Rupture of the aneurysm usually occurs while the patient is active rather than during sleep, and in a few instances during sexual intercourse, straining at stool, lifting heavy objects, or other sustained exertion (see “Headaches Related to Sexual Activity” in Chap. 10). A momentary Valsalva maneuver, as in coughing or sneezing, has generally not caused aneurysmal rupture (it may cause arterial dissection). In patients who survive the initial rupture, the most feared complication is rerupture, an event that may occur at any time from minutes up to 2 or 3 weeks.
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In less-severe cases, consciousness, if lost, may be regained within minutes or hours, but a residuum of drowsiness, confusion, and amnesia accompanied by severe headache and stiff neck persists for at least several days. Because the hemorrhage in most cases is confined to the subarachnoid space, there are few if any focal neurologic signs. That is to say, hemiparesis, hemianopia, and aphasia are absent. On occasion, a jet of blood emanating from an aneurysm ruptures into the adjacent brain or insular cistern and produces a hemiparesis or other focal syndrome. This may be more common when the aneurysm has bled in the past, after which it adheres to the brain, thus predisposing to intracerebral hemorrhage at the time of subsequent rupture. There is, however, a transient focal acute syndrome that occasionally occurs in the territory of the aneurysm-bearing artery. The pathogenesis of such manifestations is not fully understood, but a transitory fall in pressure in the circulation distal to the aneurysm or some form of acute transient vasospasm has been postulated. An entirely separate problem of delayed vasospasm is responsible for focal signs that emerge after several days as discussed below. Transient deficits when they do occur constitute reliable indicators of the site of the ruptured aneurysm (see below). Convulsive seizures, usually brief and generalized, occur in 10 to 25 percent of cases according to Hart and associates (but far less often in our experience) in relation to acute bleeding or rebleeding. These early seizures do not correlate with the location of the aneurysm and do not appear to alter the prognosis. Prior to rupture, saccular aneurysms are usually asymptomatic. Exceptionally, if large enough to compress painsensitive structures, they may cause localized cranial pain. With a cavernous or anterolaterally situated aneurysm on the first part of the middle cerebral artery, the pain may be projected to the orbit. An aneurysm on the posteroinferior or anteroinferior cerebellar artery may cause unilateral occipital or cervical pain. The presence of a partial oculomotor palsy with dilated pupil may be indicative of an aneurysm of the posterior communicating–internal carotid junction or at the posterior communicating–posterior cerebral junction. Occasionally, large aneurysms just anterior to the cavernous sinus compress the optic nerves or chiasm, third nerve, hypothalamus, or pituitary gland. A monocular visual field defect may also develop with a supraclinoid aneurysm near the anterior and middle cerebral bifurcation or the ophthalmic–carotid bifurcation. In the cavernous sinus, they may compress the third, fourth, or sixth nerve, or the ophthalmic division of the fifth nerve. Whether a small leak of blood from an aneurysm may serve as a warning sign of a subsequent more catastrophic rupture (“warning leak”) has been disputed. An entity known as “sentinel headache” has been used in an imprecise way to refer to both a headache that precedes subarachnoid hemorrhage and to a small leakage prior to a major rupture. The former in our view has little validity, as headaches are so ubiquitous that many, even severe ones, are coincidental in relation to subarachnoid hemorrhage. The frequency of true warming leaks is unknown but is not likely to be high. We have seen several cases where an acute and severe exertional or spontaneous headache was found to be associated with a small subarachnoid hemorrhage that was discovered by
lumbar puncture; more often the headache is unrelated to hemorrhage and is attributable to migraine. This type of “thunderclap headache,” which may be a variant of migraine, or less often, cerebral venous thrombosis, diffuse vasospasm (the Call-Fleming syndrome), or even less often, pituitary apoplexy, hypertensive encephalopathy, intracranial hypotension, and intracranial or extracranial arterial dissection The details of the CSF examination assume great importance in the diagnosis of subarachnoid hemorrhage and the exclusion of the disorders mentioned above. Vasospasm Delayed hemiplegia and other deficits because of focal vasospasm usually appear 3 to 10 days after rupture and rarely before or after this period. Fisher and coworkers (1980) have shown that the most severe vasospasm occurs in arteries that are surrounded by collections of clotted subarachnoid blood after 24 hours. These same authors devised a widely used scale that rates the extent and location of remaining clot. The reduction in the caliber of blood vessels (vasospasm) appears to be a direct effect of some blood product on the adventitia of the adjacent artery. Areas of ischemic infarction in the territory of the vessel bearing the aneurysm, without thrombosis or other intraluminal changes in the vessel, is the usual finding in such cases. The mechanism is presumed to be purely a reduction in blood flow distal to the area of vasospasm but therefore influenced by systemic blood pressure and by collateral circulation in the cortex. The ischemic lesions are often multiple and had in the past occurred with great frequency, according to Hijdra and associates. After a few days, arteries in chronic spasm undergo a series of morphologic changes. The smooth muscle cells of the media become necrotic, and the adventitia is infiltrated with neutrophilic leukocytes, mast cells, and red blood corpuscles, some of which have migrated to a subendothelial position. The current notion is that these changes are caused by products of hemolyzed blood seeping inward from the pia-arachnoid into the muscularis of the artery. The clinical features of delayed cerebral vasospasm depend on the affected blood vessel but typically include a fluctuating hemiparesis or aphasia and increasing confusion that must be distinguished from the effects of hydrocephalus (see below). In the past, an arteriogram was required to verify the diagnosis, although it is not often performed now because of the slight associated risk of worsening vascular spasm and the ease with which the condition can be recognized by its clinical presentation. Severe vasospasm is also visualized with MRA and CT techniques. Transcranial Doppler ultrasonography measurements provide an indirect way of following, by observations of blood flow velocity, the caliber of the main vessels at the base of the brain but they are somewhat imprecise for this purpose. Almost all patients have a greatly increased velocity of blood flow in the affected vessel that can be detected by ultrasound in the days after hemorrhage. However, progressive elevation of flow velocity in any one vessel (especially if over 175 cm/s) suggests that focal vasospasm is occurring. There is a reasonable correlation between these findings and the radiographic appearance of vasospasm, but the clinical manifestations of ischemia depend on additional factors such as collateral blood supply and the cerebral perfusion pressure.
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Hydrocephalus If a large amount of blood ruptures into the ventricular system or floods the basal subarachnoid space, it may find its way into the ventricles through the foramina of Luschka and Magendie. The patient then becomes confused or unconscious as a result of acute hydrocephalus. The clinical signs are reversed by draining the ventricles, either by external ventriculostomy or, in selected cases, by lumbar puncture, but the routine use of ventricular drainage after subarachnoid hemorrhage is not uniformly agreed upon. Delayed and subacute hydrocephalus as a result of blockage of the CSF pathways by blood may appear after 2 to 4 weeks and is managed similarly. Many of these latter cases improve. There are further instances of long-delayed hydrocephalus that present as normal-pressure hydrocephalus (NPH) months or years after subarachnoid hemorrhage, as described in Chap. 30.
Anatomic–Clinical Correlations of Aneurysms In most patients, the neurologic manifestations do not point to the exact site of the aneurysm, but it can often be inferred from the location of the main clot on CT scan. A collection of blood in the anterior interhemispheric fissure indicates rupture of an anterior communicating artery aneurysm; in the sylvian fissure, a middle cerebral artery aneurysm; in the anterior perimesencephalic cistern, a posterior communicating or distal basilar artery aneurysm. In other instances clinical signs provide clues to its localization, as follows: (1) third-nerve palsy (ptosis, diplopia, dilatation of pupil, and divergent strabismus), indicates an aneurysm at the junction of the posterior communicating artery and the internal carotid artery—the third nerve passes immediately lateral to this point or at the posterior cerebral-posterior communicating artery junction; (2) transient paresis of one or both of the lower limbs at the onset of the hemorrhage suggests an anterior communicating aneurysm that has interfered with the circulation in the anterior cerebral arteries; (3) hemiparesis or aphasia points to an aneurysm at the first major bifurcation of the middle cerebral artery; (4) unilateral blindness indicates an aneurysm lying anteromedially in the circle of Willis (usually at the origin of the ophthalmic artery or at the bifurcation of the internal carotid artery); (5) a state of retained consciousness with akinetic mutism or abulia favors a location on the anterior communicating artery; (6) the side on which the aneurysm lies may be indicated by a unilateral preponderance of headache or by unilateral preretinal (subhyaloid) hemorrhage (Terson syndrome), the occurrence of monocular pain, or, rarely, lateralization of an intracranial sound heard at the time of rupture of the aneurysm. Sixth-nerve palsy, unilateral or bilateral, is usually attributable to raised intracranial pressure and is less often of localizing value. In summary, the clinical sequence of sudden severe headache, vomiting, collapse, relative preservation of consciousness with few or no lateralizing signs, and neck stiffness is diagnostic of subarachnoid hemorrhage caused by a ruptured saccular aneurysm. Other clinical data may be of assistance in reaching a correct diagnosis. Levels of blood pressure of 200 mm Hg systolic are seen occasionally just after rupture, but usually the pressure is elevated only moderately and fluctuates with the
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degree of head pain. Nuchal rigidity is usually present but occasionally absent, and the main complaint of pain may be referable to the interscapular region or even the low back rather than to the head. Examination of the fundi frequently reveals smooth-surfaced, sharply outlined collections of blood that cover the retinal vessels—preretinal or subhyaloid hemorrhages (Terson syndrome); Roth spots are seen occasionally. Bilateral Babinski signs are found in the first few days following rupture if there is hydrocephalus. Fever up to 39°C (102.2°F) may be seen in the first week, but most patients are afebrile. Rarely, escaping blood enters the subdural space and produces a hematoma, evacuation of which may be lifesaving.
Laboratory Findings A CT scan will detect blood locally or diffusely in the subarachnoid spaces or within the brain or ventricular system in more than 90 percent of cases and in practically all cases in which the hemorrhage has been severe enough to cause momentary or persistent loss of consciousness (Fig. 34-23). Therefore, this should be the initial investigative procedure. Because the blood may appear as a subtle shadow along the tentorium or in the sylvian or adjacent fissures, it is more easily appreciated in the noncontrast study. A large localized collection of subarachnoid blood or a hematoma in brain tissue or within the sylvian fissure indicates the adjacent location of the aneurysm and the likely region of subsequent vasospasm, as already noted. When two or more aneurysms are visualized, the CT scan can identify the one that had ruptured by the clot that surrounds it. Also, coexistent hydrocephalus will be demonstrable. If the CT scan documents subarachnoid blood with certainty, a spinal tap is not necessary. MRI can also detect blood in the protondensity sequence; after a day has passed, this is also appreciated with the FLAIR technique. In all other cases where subarachnoid hemorrhage is suspected but not apparent on imaging studies, a lumbar puncture should be undertaken. Usually the CSF becomes grossly bloody within 30 min or sooner of the hemorrhage, with RBC counts up to 1 million/mm3 or even higher. Blood may not be easily apparent in a lumbar puncture minutes after the hemorrhage. With a relatively mild hemorrhage, there may be only a few thousand cells, a severe headache syndrome from subarachnoid hemorrhage is associated with at least several hundred cells. It is also probably not possible for an aneurysm to rupture entirely into brain tissue without some leakage of blood into the subarachnoid fluid. In other words, the diagnosis of ruptured saccular aneurysm is essentially excluded if blood is not present in the CSF, provided the spinal fluid is examined more than 30 min after the event. Xanthochromia is found after centrifugation if several hours or more have elapsed from the moment of the ictus. In a patient who reports a headache that was consistent with subarachnoid hemorrhage but that had occurred several days earlier, the CT scan may be normal and xanthochromia is the only diagnostic finding. To determine whether xanthochromia is present, fresh CSF must be centrifuged in a tube with a conical bottom and the supernatant compared to clear water in good light or examined by spectrophotometric techniques. It has been our experience that most hospital laboratories can-
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Figure 34-23. Subarachnoid hemorrhage as a result of rupture of a basilar artery aneurysm. Left: Axial CT scan image at the level of the lateral ventricles showing widespread blood in the subarachnoid spaces and layering within the ventricles with resultant hydrocephalus. There is a blood–CSF level in the posterior horns of the lateral ventricles, typical of recent bleeding. Right: At the level of the basal cisterns, blood can be seen surrounding the brainstem, in the anterior sylvian fissures and the anterior interhemispheric fissure. The temporal horns of the lateral ventricles are again enlarged, reflecting acute hydrocephalus.
not be depended on to give accurate results for this test. Also helpful after several days is the MRI taken with the FLAIR sequence as mentioned, which will demonstrate blood (the proton-density sequence is more sensitive to blood in the first day). The problem of a “traumatic tap” often clouds the early diagnosis and several aids to detecting this misleading laboratory result are discussed in Chap. 2. Here it is reiterated that in addition to the absence of xanthochromia, the most important features indicating that blood has been spuriously introduced by entering small veins in the epidural space with the lumbar puncture needle are the clearing of blood as one continues to collect fluid and a marked reduction in the number of RBCs in serial tubes of spinal fluid. A normal opening pressure also suggests puncture of a local vessel rather than a ruptured aneurysm. The combination of subarachnoid hemorrhage and a traumatic tap generally requires that vascular imaging procedures be performed to resolve the issue. The CSF in the first days is under increased pressure, as high as 500 mm H2O—but usually closer to 250 mm H2O—an important finding in differentiating spontaneous subarachnoid hemorrhage from a traumatic tap. In both a traumatic puncture and early in subarachnoid hemorrhage, the proportion of WBCs to RBCs in the CSF is usually the same as in the circulating blood (approximately 1:700), but in some patients with genuine hemorrhage a brisk CSF leukocytosis appears within 48 h, sometimes reaching more than 1,000 cells/mm3. The protein is slightly or moderately elevated and in some instances glucose is reduced sometimes dramatically so.
Bilateral carotid and vertebral (“four-vessel”) angiography is the most dependable means of demonstrating an aneurysm and does so in essentially all patients who harbor an aneurysm, but in addition to other causes of subarachnoid hemorrhage, approximately 5 to 10 percent of patients with aneurysmal rupture will not have an aneurysm evident. Some of these instances are a result of the obliteration of the lesion in the process of rupture. Others are because of somewhat more benign lesions. Patients with the typical clinical picture of spontaneous subarachnoid hemorrhage in whom an aneurysm or arteriovenous malformation cannot be demonstrated angiographically have a distinctly better prognosis than those in whom the lesion is visualized (Nishioka et al). For example, in a series of 323 angiographically negative cases followed for an average of 10 years, there was rebleeding in only 12 (Hawkins et al). After 22 years, 69 percent of these patients had survived. If the first study does not reveal an aneurysm, it is customary in most centers to repeat an arteriogram in several weeks because it has been observed that vascular spasm may have earlier obscured the aneurysm. Even when there is no vasospasm visualized, it is sometimes the case that a second study shows the lesion. It is advantageous to obtain images from several different angles in order to expose those views that may be obscured by adjacent overlying vessels. If the first study involves all cerebral vessels and uses several views of the basal circulation, it has been our experience that the second arteriogram is infrequently revealing, but we follow general practice and repeat it nonetheless. Another clinical circumstance with a favorable outcome is a limited perimesencephalic hemorrhage as described by van
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Figure 34-24. Berry aneurysm of the anterior communicating aneurysm. A. MRA; B. CTA showing the aneurysm in relation to the adjacent bony and vascular structures.
Gijn and colleagues. The cisterns surrounding the midbrain and upper pons are symmetrically filled with blood, the headache is mild, and signs of vasospasm do not develop. No aneurysm is found at the expected site for blood in this region, i.e., at the top of the basilar artery. The patient usually does well and a second arteriogram is probably not required. It has been speculated that the bleeding has a venous rather than an aneurysmal source. MRI detects most aneurysms of the basal vessels and of their first branches but may not yet be of sufficient sensitivity to replace CT or conventional angiography in cases where an aneurysm is strongly suspected but too small to be detected by MRA. Even when MRA demonstrates the aneurysm, the surgeon usually requires the kind of anatomic definition that can be obtained only by conventional angiography. CT technology scanning with contrast infusion has certainly begun to equal the detail provided by conventional angiography and has additional advantages of showing the lesion in relation to the adjacent brain and skull in multiple views (Fig. 34-24).
Systemic Changes Associated with Subarachnoid Hemorrhage Acute subarachnoid hemorrhage is associated with several characteristic responses in the systemic circulation, water balance, and cardiac function. The ECG changes include symmetrically large peaked T waves (“cerebral T waves”) and other alterations, suggesting subendocardial or myocardial ischemia. There may be a minor elevation of troponin and the myocardial band (MB) of creatine phosphokinase (CPK). In some patients, the cardiac dysfunction is severe enough to seriously reduce the ejection fraction and cause heart failure. There is a tendency to develop hyponatremia; this abnormality and its relationship to intravascular volume depletion play a key role in treatment, as discussed further on. Albuminuria and glycosuria may be present for a few days. Rarely, diabetes insipidus occurs in the acute stages, but water retention or a natriuresis is more frequent. There may
be a leukocytosis of 15,000 to 18,000 cells/mm3, but the sedimentation rate and C-reactive protein are usually normal, or any elevation is attributable to another cause.
Rebleeding and Prognosis The outstanding characteristic of this condition, mentioned earlier, is the tendency for the hemorrhage to recur from the same site in more than one-third of patients, often catastrophically. This threat colors all prognostications and dominates modern treatment strategies. There does not appear to be a way of determining reliably which patients will bleed again. The cause of recurrent bleeding is not understood but is related to naturally occurring mechanisms of clot lysis at the site of initial rupture, usually at the dome of the aneurysm. As regards prognosis of aneurysmal hemorrhage, McKissock and colleagues decades ago found that the patient’s state of consciousness at the time of arteriography was the single best index of outcome, and this remains largely true today. Their data, representative of the status of aneurysm management in the 1950s and consonant with the natural history before the advent of modern surgical and intensive care techniques, indicated that of every 100 patients reaching a hospital and coming to arteriography, 17 were stuporous or comatose and 83 appeared to be recovering from the ictus. At the end of 6 months, 8 of every 100 patients had died of the original hemorrhage and 59 had had a recurrence (with 40 deaths), making a total of 48 deaths and 52 survivors. In regard to recurrence of bleeding, it was found that of 50 patients seen on the first day of the illness, 5 rebled in the first week (all fatal), 8 in the second week (5 fatal), 6 in the third and fourth weeks (4 fatal), and 2 in the next 4 weeks (2 fatal), making a total of 21 recurrences (16 fatal) in 8 weeks. The most comprehensive long-term analysis of the natural history of the disease, outdated but still instructive, is contained in the report of the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage (Sahs et al,
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1984). The study was based on long-term observations of 568 patients who sustained an aneurysmal bleed between 1958 and 1965 and were managed only by a conservative medical program. A followup search in 1981 and 1982 disclosed that 378, or two-thirds of the patients, had died; 40 percent of the deaths had occurred within 6 months of the original hemorrhage. For the patients who survived the original hemorrhage for 6 months, the chances of survival during the next 2 decades were significantly worse than those of a matched normal population. Rebleeding occurred at a rate of 2.2 percent per year during the first decade and 0.86 percent per year during the second, and these were fatal in 78 percent of cases. Although these statistics reflect the outcome prior to the modern era of microsurgery and neurologic intensive care management, current figures are only modestly better. In a prospective clinical trial conducted by the International Cooperative Study in 1990 and based on observations of 3,521 patients (surgery performed in 83 percent), it was found at the 6-month evaluation that 26 percent had died and 58 percent had made a good recovery (Kassell et al). Vasospasm and rebleeding were the leading causes of morbidity and mortality in those who survived the initial hemorrhage. In respect to rebleeding, all series indicate that the risk is greatest in the first day but extends for weeks. The observations of Aoyagi and Hayakawa are representative of other series; they found that rebleeding occurred within 2 weeks in 20 percent of patients, with a peak incidence in the 24 h after the initial episode. Surgical treatment is largely oriented towards reducing this complication.
Treatment This is influenced by the neurologic and general medical state of the patient as well as by the location and morphology of the aneurysm. Ideally, all patients should have the aneurysmal sac obliterated, but the mortality is high if the patient is stuporous or comatose. Before deciding on a course of action, it has been useful to assess the patient with reference to the widely employed scale introduced by Botterell and refined by Hunt and Hess, as follows: Grade I. Asymptomatic or with slight headache and stiff neck Grade II. Moderate to severe headache and nuchal rigidity but no focal or lateralizing neurologic signs Grade III. Drowsiness, confusion, and mild focal deficit Grade IV. Persistent stupor or semicoma, early decerebrate rigidity and vegetative disturbances Grade V. Deep coma and decerebrate rigidity The general medical management in the acute stage includes the following, all or in part: bed rest, fluid administration to maintain above-normal circulating blood volume and central venous pressure; use of elastic stockings and stool softeners; administration of calcium channel blockers to reduce infarction from vasospasm (see below); additional beta-adrenergic blockers, intravenous nitroprusside, or other medication to reduce greatly elevated blood pressure and then maintain systolic blood pressure at 150 mm Hg or less; and pain-relieving medication for headache (this alone will often reduce the hypertension). The prevention of systemic venous thrombosis is critical; it usually is accomplished by the use of cyclically inflated whole-leg compression boots.
The use of antiepileptic drugs is controversial; many neurosurgeons administer them early, with a view of preventing a seizure-induced risk of rebleeding. Several small studies suggest they may be detrimental and we have generally avoided them unless a seizure has occurred. Calcium channel blockers are used to reduce the incidence of stroke from vasospasm. Nimodipine 60 mg administered orally every 4 h is currently favored. Although calcium channel blockers do not alter the incidence of angiographically demonstrated vasospasm, they have reduced the number of strokes in each of five randomized studies, beginning with the one conducted by Allen and colleagues. Several groups use angioplasty techniques to dilate vasospastic vessels and report symptomatic improvement, but there are as yet insufficient controlled data to judge the merits and safety of this procedure. The most notable advances in this disease have been in the techniques for the early obliteration of aneurysms, particularly the operating microscope and endovascular approaches, and in the management of circulatory volume. In the majority of patients intravascular volume is depleted in the days after subarachnoid hemorrhage. This, in turn, greatly increases the chances of ischemic infarction from vasospasm. In part, this volume contraction can be attributed to bed rest, but sodium loss, probably resulting from the release of atrial natriuretic factor (ANF), a potent oligopeptide stimulator of sodium loss in renal tubules, may also be a factor. Hyponatremia develops in the first week after hemorrhage, but it is unclear whether this also results from the natriuretic effects of ANF or is an effect of antidiuretic hormone, causing water retention. The work of Diringer and coworkers (1988) suggests that both mechanisms are operative but it is the volume depletion, not hyponatremia per se, that is of the greatest clinical consequence. Both the risk of rerupture of the aneurysm and some of the secondary problems that arise because of blood in the subarachnoid space can be obviated by early obliteration of the aneurysm. Because of the changes in water balance and the risk of delayed stroke from vasospasm, there has been an emphasis on early volume expansion and sodium repletion by the intravenous infusion of crystalloids. As Solomon and Fink point out, this can be accomplished without fear of aneurysmal rupture if blood pressure is allowed to rise only minimally. Of course, fluid replacement and a modest elevation of blood pressure become completely safe if the aneurysm has been surgically occluded. Thus the current approach is to operate or eliminate the aneurysm by endovascular means early, within 24 h if possible, for patients in grades I and II, and then to increase intravascular volume and maintain normal or above-normal blood pressures. This precludes rebleeding, with its high mortality, and ameliorates the second cause of morbidity, stroke from vasospasm. The timing of surgery or endovascular treatment for grade III patients is still controversial but if their medical condition allows, they, too, probably benefit from the same early and aggressive approach. In grade IV patients, the outcome is generally dismal, no matter what course is taken, but we have usually counseled against early operation; some neurosurgeons disagree. The insertion of ventricular drains into both frontal horns has occasionally raised a patient with severe hydrocephalus to a better grade and facilitated early opera-
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tion. In the hands of experienced anesthesiologists and cerebrovascular surgeons, the operative mortality, even in grades III and IV patients, has now been reduced to 2 to 3 percent. For a detailed account of the operative approach to each of the major classes of saccular aneurysm, the reader is referred to the monograph by Ojemann and colleagues (1995). Several alternative therapeutic measures are in common use but are still being studied. Among these, endovascular obliteration of the lumen of the aneurysm holds the most promise. This has become the preferred approach for aneurysms that are surgically inaccessible—for example, those in the cavernous sinus—and for patients whose medical state precludes an operation. Among several trials that have compared surgery with endovascular placement of coils in the aneurysm, most have shown equivalence or a slight superiority of the latter. For example, the International Subarachnoid Aneurysm Trial Group randomly assigned more than 2,000 patients to surgery or coil deployment; the overall rate of death or dependence at 1 year was 24 percent in the endovascular group and 31 percent in the operated group, a difference that was sustained at 2 years of followup (Molyneux et al). Doubtless, further studies will continue to clarify the relative benefits of the treatment. It is self-evident that the skill of the surgeon and the quality of postoperative care are major determinants of outcome; perhaps the simplicity of endovascular treatment and the improvements in the training of interventional specialists will prove its advantage over time. Because of the current approach of ablating the aneurysm early, the previously popular use of antifibrinolytic agents as a means of impeding lysis of the clot at the site of aneurysmal rupture has been generally abandoned. Repeated drainage of the CSF by lumbar puncture is also no longer practiced as a routine. One lumbar puncture is generally carried out for diagnostic purposes if the CT scan is inconclusive; thereafter, spinal fluid drainage is performed only for the relief of intractable headache or to detect recurrence of bleeding. As mentioned earlier, patients with stupor or coma who have massive hydrocephalus often benefit from decompression of the ventricular system. This is accomplished initially by external drainage and may require permanent shunting if the hydrocephalus returns. The common practice of draining milder degrees of hydrocephalus has not been proven to be helpful. Some risk may attend rapid removal of CSF by this method or lumbar puncture. The risk of infection of the external shunt tubing is high if it is left in place for much more than 3 days. Replacement with a new drainage tube, preferably at another site, reduces this risk.
Unruptured Intracranial Aneurysms Quite often in clinical practice, cerebral angiography, MRI, MRA, or CT scanning performed for an unrelated reason discloses the presence of an unruptured saccular aneurysm. Or, a second or third aneurysm is found during the angiogram to assess a ruptured one. There is now a reasonably sound body of information about the natural history of these lesions. Wiebers and colleagues (1987) observed 65 patients with one or more unruptured aneurysms for 5 years or longer after their detection. The only feature of significance relative to rupture was aneurysmal size. Of the 44 aneurysms
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smaller than 10 mm in diameter, none had ruptured, whereas 8 of 29 aneurysms 1 cm or larger eventually did so, with a fatal outcome in 7 cases. Two large studies have attempted to refine these statistical data. In the older Cooperative Study of Intracranial Aneurysms, none of the aneurysms less than 7 mm diameter “had further trouble.” A more recent and sizable cooperative study that included 4,060 patients and gathered data prospectively for 5 years, conducted by the International Study of Unruptured Intracranial Aneurysms Investigators, found an extremely low rate of rupture, approximately 0.1 percent yearly, for aneurysms smaller than 7 mm in diameter, an annual risk of 0.5 percent for aneurysms between 7 and 10 mm, and a risk ranging from 0.6 to 3.5 percent for lesions between 13 and 24 mm (depending on location). The risk ranged up to 10 percent for aneurysms greater than 25 mm diameter. The yearly rates for rupture were higher in all categories if there had been prior bleeding from another site. The location of the lesion also had great bearing on the risk of rupture, as did increasing age; notably, vertebrobasilar and posterior cerebral aneurysms bled at a rate many times higher than the others. The importance of such data aids in comparison to the risk of surgery and endovascular treatment, which, for example, exceed the risk of bleeding within 5 years for small aneurysms located in the carotid circulation. In almost all other circumstances, there is overall benefit to obliterating the unruptured aneurysm. A special problem pertains to clots within an aneurysm that cause transient ischemic attacks or small strokes in the vascular territory distal to the site. The frequency of this complication is not clear and it occurs at times without evident intraluminal clot on an angiogram.
Giant Cerebral Aneurysms These are believed to be congenital anomalies even when there is considerable atherosclerosis in their walls. They may become enormous in size, by definition greater than 2.5 cm in diameter, but sometimes twice or more as large. Most are located on a carotid, basilar, anterior, or middle cerebral artery, but also are found on the vertebral artery (Fig. 34-25). They grow slowly by accretion of blood clot within their lumens or by the organization of surface blood clots from small leaks. At a certain point they may compress adjacent structures, e.g., those in the cavernous sinus, optic nerve, or lower cranial nerves. The giant fusiform aneurysm of the midbasilar artery, with signs of brainstem ischemia and lower cranial nerve palsies, is a relatively common form. Clotting within the aneurysm may cause ischemic infarction in its territory of supply, as mentioned in the case of berry aneurysms. Giant aneurysms may also rupture and cause subarachnoid hemorrhage, but not nearly as often as saccular aneurysms. These clinical observations were confirmed by the International Study, referred to above. Treatment of saccular aneurysms is surgical if the lesion is symptomatic and it is accessible; endovascular techniques have been employed if the lesion is in the vertebral or midbasilar artery. Obliteration of the lumen, coupled with vascular bypass procedures, has been successful in the hands of cerebrovascular neurosurgeons, but the morbidity is high. Some giant aneurysms can be ligated at
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Figure 34-25. Giant aneurysm of the anterior cerebral artery. A. T1-weighted MRI without gadolinium infusion. The white signal is clot within the sac of the aneurysm that is typical of this lesion; there is some blood flow within the lesion evidenced by the darker signal. B. Cerebral angiogram showing the residual flow in the proximal portion of the aneurysm.
their necks, others by trapping or by the use of an intravascular detachable balloon. Drake summarized his surgical experience in the treatment of 174 such cases. Some fusiform aneurysms have been wrapped in muslin or similar material with mixed results. We have followed one such patient who had been operated on by T. Sundt more than 35 years ago. Recent attempts at stabilizing the expansion of the aneurysm by deploying an intravascular stent are under study. The term mycotic aneurysm designates an aneurysm caused by a localized bacterial or fungal inflammation of an artery. (Osler introduced the term mycotic to describe endocarditis, but its proper current use is to describe fungal infection.) With the introduction of antibiotics, mycotic aneurysms have become less frequent, but they are still being seen in patients with bacterial endocarditis and in intravenous drug abusers. Peripheral arteries are involved more often than intracranial ones; about two-thirds of the latter are associated with subacute bacterial endocarditis caused by streptococcal infections. In recent years, the number of mycotic aneurysms caused by staphylococcal infections and acute endocarditis appears to us to have increased. The usual pathogenic sequence is an embolic occlusion of a small artery, which may announce itself clinically by an ischemic stroke with white blood cells in the CSF. Later, or sometimes as the first manifestation, the weakened vessel wall ruptures and causes a subarachnoid or brain hemorrhage. The mycotic aneurysm may appear on only one artery or several arteries, and the hemorrhage may recur. A consensus regarding the treatment of mycotic aneurysm has not been reached. The underlying endocarditis or septicemia mandates appropriate antibiotic therapy and, in at least 30 percent of cases, healing of the aneurysm can be observed in successive arteriograms with this approach alone. Treatment is usually continued for at least 6 weeks. Some neurosurgeons favor excising an accessible aneurysm if it is solitary and the systemic infection is under control. Many mycotic aneurysms do not bleed, and in our view medical therapy takes precedence over surgical therapy.
ARTERIOVENOUS MALFORMATIONS OF THE BRAIN An arteriovenous malformation (AVM) consists of a tangle of dilated vessels that form an abnormal communication between the arterial and venous systems. These developmental abnormalities represent persistence of an embryonic pattern of blood vessels and not a neoplasm, but the constituent vessels may proliferate and enlarge with the passage of time. Venous malformations, consisting purely of distended veins deep in the white matter, are a separate entity; they may be the cause of seizures and headaches but seldom of hemorrhage. When a small hemorrhage occurs, it is usually the result of an associated malformation of the so-called cavernous type; these are small hamartomatous lesions of multiple juxtaposed endothelium-lined cavities without interposed neural tissue. These are discussed further on. True vascular malformations vary in size from a small blemish a few millimeters in diameter lying in the cortex or white matter to a huge mass of tortuous channels constituting an atrioventricular (AV) shunt of sufficient magnitude to raise cardiac output. Hypertrophic dilated arterial feeders can be seen approaching the main lesion and to break up into a network of thin-walled blood vessels that connect directly with draining veins. The latter often form greatly dilated, pulsating channels, carrying away arterial blood. The tangled blood vessels interposed between arteries and veins are abnormally thin and do not have the structure of normal arteries or veins. AVMs occur in all parts of the cerebrum, brainstem, and cerebellum (and spinal cord), but the larger ones are more frequently found in the central part of a cerebral hemisphere, commonly forming a wedge-shaped lesion extending from the cortex to the ventricle. Some lie on the dural surface of the brain or spinal cord, but these more often turn out to be direct arteriovenous fistulas, as discussed further on. When hemorrhage occurs from an AVM, blood may enter the subarachnoid space, producing a picture almost identical to that of a ruptured saccular aneurysm, but gen-
CHAPTER 34
erally less severe. Because most AVMs lie within cerebral tissue, bleeding is more than likely to be intracerebral as well, or to be solely intracerebral, causing a hemiparesis, hemiplegia, and so forth, or even death. AVMs are about one-tenth as common as saccular aneurysms and about equally frequent in males and females. The two lesions—AVM and saccular aneurysm (on the main feeding artery of the AVM)—are associated in approximately 5 percent of cases; the conjunction increases with the size of the AVM and the age of the patient (Miyasaka et al). AVMs rarely occur in more than one member of a family in the same generation or successive ones. For a review of the embryologic theories of formation of AVMs, the reader is directed to the article by Fleetwood and Steinberg.
Clinical Features Bleeding or seizures are the main modes of presentation. Most AVMs are clinically silent for a long time. Although the lesion is present from birth, onset of symptoms is most common between 10 and 30 years of age; occasionally it is delayed to age 50 or even beyond. In almost half of patients, the first clinical manifestation is a cerebral subarachnoid hemorrhage; in 30 percent, a seizure is the first and only manifestation; and in 20 percent, the only symptom is headache. Progressive hemiparesis or other focal neurologic deficit is present in approximately 10 percent of patients. The first hemorrhage may be fatal, but in more than 90 percent of cases the bleeding stops and the patient survives. Most often there are no symptoms before rupture. Chronic, recurrent headache may be a complaint; usually it is of a nondescript type but a classic migraine with or without neurologic accompaniment occurs in approximately 10 percent of patients—probably with greater frequency than it does in the general population. Most of the malformations associated with migraine-like headaches lie in the parietooccipital region of one cerebral hemisphere, and about two-thirds of such patients have a family history of migraine. Huge AVMs may produce a slowly progressive neurologic deficit because of compression of neighboring structures by the enlarging mass of vessels and by shunting of blood through greatly dilated vascular channels. It has also been proposed that an “intracerebral steal” can result in hypoperfusion of the surrounding brain (Homan et al). When the vein of Galen is enlarged as a result of drainage from an adjacent AVM, hydrocephalus may result, particularly in children. With moderate size and large lesions, one or both carotid arteries frequently pulsate unusually forcefully in the neck. A systolic bruit heard over the carotid in the neck or over the mastoid process or the eyeballs in a young adult is almost pathognomonic of an AVM. However, such bruits have been heard in fewer than 25 percent of our patients. Exercise such as repeated squatting that increases the pulse pressure may bring out a bruit if none is present at rest. There is no relation of the existence of an AVM, or its rupture, to chronic hypertension (the same pertains to cerebral aneurysms). Inspection of the eye grounds rarely discloses a retinal vascular malformation that is coextensive with a similar lesion of the optic nerve and basal portions of the brain. Cutaneous, orbital, and nasopharyngeal AVMs may occasionally be
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found in relation to a cerebral lesion. Skull films rarely show crescentic linear calcifications in the larger malformations. The natural history of AVMs has been studied by Ondra and colleagues, who have presented data on a large and comprehensive series of untreated malformations in Finland over a 30-year period, and another similar series has been reported by Crawford and coworkers in Great Britain. The rate of rebleeding in most series has been 2 to 4 percent per year over decades but may be as high as 6 to 9 percent in the year after a first hemorrhage. In the latter study, comprising 343 patients, 217 were managed without surgery and observed for many years (mean: 10.4 years). Hemorrhage occurred in 42 percent and seizures in 18 percent. By 20 years after diagnosis, 29 percent had died and 27 percent of the survivors had a neurologic handicap. In a series of 1,000 patients referred mainly for proton-beam radiation of an AVM and studied by our colleague R.D. Adams, 464 had a hemorrhage as the first manifestation and 218 had a seizure (mainly with frontal and frontoparietal lesions). In those few AVMs that came to attention as a result of a progressive neurologic deficit, most were situated in the posterior fossa or axially in the cerebrum. The combination of a prolonged history of headaches, seizures, and a progressive deficit in Adams’ series almost always indicated a large malformation. The matter of an increased risk of AVM rupture during pregnancy has been disputed. The weight of evidence suggests that the risk is not raised by pregnancy alone. Fully 90 percent of AVMs are disclosed by CT scans if performed with contrast infusion, and an even larger number by MRI (Fig. 34-26). Magnetic-susceptibility MRI shows small areas of previous bleeding around AVMs. Arteriography is usually necessary to establish the diagnosis with certainty and will demonstrate AVMs larger than 5 mm in diameter (Fig. 34-27); MRI may fail to reveal smaller lesions. Even at autopsy, a careful search under the dissecting microscope may be necessary to find the malformation. The decision regarding imaging to detect an AVM in cases of mundane cerebral hemorrhage is based on factors such as early age (childhood and adolescence onset is particularly suggestive), preceding unilateral headaches, a focal seizure disorder, the absence of other apparent cause (e.g., coagulopathy, chronic hypertension, metastatic tumor), but most of all, recurrent bleeding in one location of the brain.
Treatment The preferred approach in most centers is surgical excision. Some 20 to 40 percent of AVMs are amenable to block dissection, with an operative mortality rate of 2 to 5 percent and a morbidity of 5 to 10 percent (see Fleetwood and Steinberg for a summary of reported surgical results up to 2002). For inaccessible lesions, attempts have been made to obliterate the malformed vessels by ligation of feeding arteries or by the use of endovascular embolization with liquid adhesives or particulate material that is injected via a balloon catheter that has been navigated into a feeding vessel. Complete obliteration of large AVMs is usually not possible by these methods but they are highly effective in reducing the size of the AVM prior to surgery. Kjellberg and Chapman pioneered the treatment of AVMs using a single dose of subnecrotizing stereotactically
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Figure 34-26. A. Left temporal AVM, demonstrated by MRI. The patient was a 59-year-old woman with long-standing complaints of headache. B. Arteriogram showing large feeding and draining vessels and the characteristic vascular blush of the malformation.
directed proton radiation. The technique of radiosurgery has been adopted by others using photon radiation sources, such as a linear accelerator, gamma Knife, and other modes of focused x-ray radiation as accepted alternatives to operative treatment of lesions situated in deep regions, including the brainstem, the thalamus, or in “eloquent” areas of the cortex. Generally, malformations smaller than 3 cm diameter are treatable in this way. The main drawback to “radiosurgery” is that obliteration of AVMs occurs in a delayed manner, usually with a latency of at least 18 to 24 months after treatment, during which the patient is unprotected from rebleeding. The likelihood of successful radiotherapy treatment and the nature of the risks depend on the location and size of the AVM and the radiation dose delivered. After 2 years, 75 to 80 percent of AVMs smaller than 2.5 cm in diameter have been obliterated. Even for those AVMs that have not been totally eliminated, the radiation effect appears to confer some long-term protection from bleeding. Of the larger ones, a majority are shrunken or appear less dense. The rest show no change at this low-dose level, but even in this group, the morbidity and mortality are lower than in the untreated group. A proportion of larger AVMs that are initially obliterated will later recanalize, and many of these will subsequently bleed. Among more than 250 patients whose AVMs disappeared following proton-beam therapy, there has been no recurrence of hemorrhage for up to 10 years. The results of treatment with focused gamma radiation and the newer cyber knife have been about the same. In one study, the risk of hemorrhage was reduced by 54 percent between
the time of radiation and obliteration of the malformation and by 88 percent thereafter (Maruyama et al). Two types of complications of radiation occur at a combined rate of approximately 2 to 4 percent. The first is delayed radiation necrosis, which is predictable based on the radiation dose, and the second is venous congestion that occurs several weeks or months after treatment. The latter is indicative of the desired effect of thrombosis of the malformation. Both may cause local symptoms for weeks or months. Radiation necrosis may be reduced by the administration of corticosteroids but the vascular problem generally is not helped. The treatment of AVMs by endovascular techniques is increasingly popular but is only recently being fully evaluated. Nearly every AVM has several feeding arteries, some not reachable by a catheter, and some part of the AVM may remain after treatment. In most series, 25 percent or more of AVMs, mostly of small and medium size, have been completely obliterated, with a mortality rate below 3 percent and morbidity of 5 to 7 percent, both of which compare favorably with surgical outcomes. These techniques are also particularly suited to lesions of a combined AVM and an aneurysm on the feeding vessel. In the past several years, combined therapy that begins with endovascular reduction of the lesion and is followed by either surgery or radiation has been viewed favorably. Using this approach, more than 90 percent of lesions can be obliterated with a very low rebleeding rate over several years. It is clear that the plan for each patient must be individualized based on the size, location, nature of feeding vessels, the
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Figure 34-28. Cerebral angiogram of a cerebral dural arteriovenous malformation. The nidus is located at the cerebral convexity (arrow). There is rapid filing of the cerebral venous system after injection of dye into one internal carotid artery. Figure 34-27. Top: Angiogram of a large parietooccipital AVM prior to treatment showing the malformation and greatly enlarged draining veins. Bottom: Obliteration of the malformation 2 years after proton beam treatment.
presence of other vascular lesions (aneurysm or additional AVM), and the age of the patient. Even then, there will be differences of opinion based on local resources and experience. Finally, if the primary problem is recurrent seizure, eliminating the malformation achieves reduction or cessation of seizures in a very high proportion of cases. In the interval, antiepileptic drugs are required and may be needed for a period of years after obliteration.
Dural Arteriovenous Fistula These curious vascular abnormalities, occurring in both the cranial and spinal dura, have different presentations at each site. The spinal form, more common in our experience, is discussed with other diseases of the spinal cord in Chap. 46. The cranial type is being detected with increasing frequency as refinements continue to be made in imaging of the cerebral vessels, but its incidence and pathogenesis are not fully known. The defining features are radiologic—a nidus of abnormal arteries and veins with arteriovenous shunting contained entirely within the leaflets of the dura. The lesion is usually fed by dural arterial vessels derived from the internal cranial circulation and often, more prolifically, from the external cranial circulation (external carotid artery and muscular branches of the vertebral artery). Venous drainage of these lesions is often complex and is largely directed to the dural venous sinuses (Fig. 34-28). The rapid transit of injected angiographic dye through dural fistulas accounts for the early opacification of the draining venous structures. In the case of high-flow connections, this may not be seen unless images are taken almost immediately after the injection. A number of potential feeding vessels must be individually opacified to
demonstrate all the conduits into the lesion. On CT scanning and MRI, the fistula is sometimes detected as a thickening or enhancement of a region of dura, generally close to a large dural venous sinus. In other cases, the dilated draining vessels may be seen only with the injection of dye or gadolinium. Probably, many are not detected by either of these techniques. The origin of these vascular lesions has not been settled— several mechanisms may be involved. Most evidence suggests that at least some of them, unlike conventional cerebral AVMs and aneurysms, are not developmental in origin. The best-defined examples of acquired fistulas are those that arise adjacent to a venous sinus thrombosis or in association with a vascular atresia, most often of the transverse sigmoid sinus or adjacent to the cavernous sinus. However, it is not always clear whether the abnormality of the venous sinus is the cause or the result of the dural fistula. In a number of cases, a dural fistula has appeared after a forceful head injury, often in a region remote from the site of impact. Another small group is associated with the Klippel-Trenaunay or Osler-Weber-Rendu syndromes, diseases in which a conjunction with AVMs is well known. (In the first of these they may also be associated with enlargement of the affected limb.) Usually, all of these causes can be excluded and the largest group remains idiopathic. A major obstacle to understanding of dural fistula is the varied ways in which this lesion presents itself clinically. Subdural hemorrhage is an infrequent but dramatic mode of presentation, sometimes creating a large and fatal clot; another syndrome is a cerebral–subarachnoid hemorrhage, although this occurs with not nearly the frequency or severity as bleeding from brain AVMs. Indeed, the risk of bleeding from dural fistulas and the evolution of these lesions is far less precise than it is for cerebral AVMs. It appears that the dural lesions most at risk of bleeding are those located in the anterior cranial fossa and those at the tentorial incisura. Seizures are distinctly uncommon. Yet another special syndrome linked to dural AVMs, although it may occur also
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with high-flow cerebral malformations, is of headache, vomiting, and papilledema—namely, pseudotumor cerebri (Chap. 30). Whether the increased intracranial pressure is the cause or the result of the fistula is unsettled but relief of venous insufficiency may result in regression of fistulae. A cranial bruit, audible to either the examiner or patient, is infrequent with fistula. In small children, the high-flow lesions may shunt so much blood as to cause congestive heart failure, similar to arteriovenous malformations of the vein of Galen. Treatment is by surgical extirpation or endovascular embolization, at times a painstaking procedure because of the multitude of potential feeding vessels. Surgery seems preferable for the smaller lesions and embolization for larger and inaccessible ones. The issue of anticoagulation when there is slowed flow in a venous sinus draining a malformation that risks thrombosis is unsettled.
Cavernous Malformations Vascular malformations composed mainly of clusters of thinwalled veins without important arterial feeders and with little or no intervening nervous tissue make up a significant group, some 7 to 8 percent of AVMs. Conventional subdivisions of this group into cavernous, venous, and telangiectatic types have not proven useful. We have roughly designated them all as cavernous. Several attributes set them apart. Their tendency to bleed is probably no less than that of the more common AVMs, but far more often the hemorrhages are small and clinically silent. The incidence of bleeding is uncertain but is estimated to be less than 1 percent per year per lesion but quite often they are multiple lesions so that the cumulative risk in any one patient is higher. The diagnosis is based on clinical manifestations and MRI, which discloses a cluster of vessels surrounded by a zone of hypodense ferritin in the T1-weighted images (Fig. 34-29), the product of previous small episodes of bleeding. A small but uncertain number are associated with adjacent deep venous anomaly visualized by imaging studies. About one-half of all cavernous angiomas lie in the brainstem, and in the past (before the availability of MRI), many of them were misdiagnosed as multiple sclerosis because of the stepwise accumulation of neurologic deficits with each hemorrhage. A large series of cavernous malformations of the brainstem, most in the pons, has been described by Porter and colleagues. They describe a higher rate of bleeding than had been reported for similar malformations in the cerebral hemispheres, frequent adjacent venous anomalies (all in the case of one of the coworkers), and good results from surgical ablation. They estimated the rate of bleeding to be 5 percent per year and the rate of rebleeding close to 30 percent per year. As mentioned, approximately 10 percent of these lesions are multiple and 5 percent are familial. In one family we have followed, there were 29 affected members in 3 generations; the inheritance followed an autosomal dominant pattern. Marchuk and coworkers have localized an abnormal gene in other kindreds to the long arm of chromosome 7. One interesting characteristic of this group, as pointed out by Labauge and colleagues, is the appearance over time of new lesions in one-third of patients. The followup of some of our patients has affirmed this.
Figure 34-29. Large cavernous vascular malformation. MRI in the sagittal (above) and axial (below) planes demonstrates a medial left frontal lesion with a prominent rim of hemosiderin-laden macrophages and no associated edema. Most cavernous angiomas are much smaller and sometimes multiple but have the same signal characteristics.
Treatment Cavernous angiomas on the surface of the brain, within reach of the neurosurgeon, even those in the brainstem, can be plucked out like blackberries, with low morbidity and mortality. Kjellberg and colleagues treated 89 deeply situated cavernous angiomas with low-dose proton radiation, but our impression is that these vascular malformations, like hemangioblastomas, respond poorly to radiation and are not amenable to treatment by endovascular techniques. Lesions that cause recurrent bleeding and are surgically accessible with little risk are often removed but incidentally discovered angiomas, even if they have caused a small hemorrhage, and those that are inaccessible may be left alone.
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Although this conservative approach is usually taken, there are not adequate data on the rate and risk of bleeding to determine the proper course of action.
Other Causes of Intracranial Bleeding and Multiple Cerebral Hemorrhages Next to hypertension, anticoagulant therapy is currently the most common cause of cerebral hemorrhage. The hemorrhages that develop, although sometimes situated in the sites of predilection of hypertensive hemorrhage, are more likely to occur elsewhere, mainly in the lobes of the brain. When the bleeding is precipitated by warfarin therapy, treatment with fresh-frozen plasma and vitamin K is recommended; when bleeding is associated with aspirin therapy or other agents that affect platelet function, fresh platelet infusion, often in massive amounts, may be required to control the hemorrhage. The use of thrombolytic drugs in the treatment of stroke is complicated by intracranial hemorrhage in 6 to 20 percent of cases, depending on the dose and timing of drug administration in relation to the onset of symptoms, as discussed in the section earlier on “Thrombolytic Agents.” In the elderly, amyloid angiopathy appears to be a major cause of lobar bleeding, especially if hemorrhages appear in succession or are multiple. Several of our patients who later proved to have amyloid angiopathy had minor head injuries in the weeks before hemorrhage. In our own material, only severe impregnation of vessels with amyloid and fibrinoid change in the vessel wall were associated with hemorrhage (Vonsattel et al). Greenberg and colleagues found that apolipoprotein E4, the same marker that is overrepresented in Alzheimer disease, is associated with severe amyloid angiopathy and a risk of intracerebral hemorrhage, but others have found an association with the E2 allele. Contrary to previous pronouncements, there is probably no greater risk in evacuating these clots surgically than in the case of other cerebral hemorrhages, but most of them are of a size that allows conservative management and evidence is lacking that surgery improves outcome as discussed earlier. Several primary hematologic disorders are also complicated by hemorrhage into the brain. The most frequent of these are leukemia, aplastic anemia, and thrombocytopenia of various causes. Often they give rise to multiple intracranial hemorrhages, some in the subdural and subarachnoid spaces. As a rule, this complication signals a fatal outcome. Other, less-common causes of intracerebral bleeding are advanced liver disease, uremia being treated with dialysis, and lymphoma. Usually several factors are operative in these hematologic cases: reduction in prothrombin or other clotting elements (fibrinogen, factor V), bone marrow suppression by antineoplastic drugs, and disseminated intravascular coagulation. Any part of the brain may be involved, and the hemorrhagic lesions are usually multiple. Frequently there is also evidence of abnormal bleeding elsewhere (skin, mucous membranes, kidney) by the time cerebral hemorrhage occurs. Plasma exchange, used in the treatment of myasthenia gravis and Guillain-Barré disease, lowers the serum fibrinogen to a marked degree, but we have not observed a single instance of intracerebral hemorrhage in more than 500 patients treated in this way.
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Occasionally the origin of intracranial hemorrhage cannot be determined clinically or pathologically. In some postmortem cases, a careful microscopic search discloses a small arteriovenous malformation; this is the basis for suspecting that an overlooked lesion of this type may be the cause of cerebral hemorrhage in other cases. Primary intraventricular hemorrhage, a rare event in adults, can sometimes be traced to a vascular malformation or neoplasm of the choroid plexus or one of the choroidal arteries; more often, such a hemorrhage is the result of periventricular bleeding often from a medial thalamic hemorrhage, in which blood enters the ventricle without producing a large parenchymal clot. Hemorrhage into primary and secondary brain tumors is not rare. When this is the first clinical manifestation of the neoplasm, diagnosis may be difficult. Choriocarcinoma, melanoma, renal cell and bronchogenic carcinoma, pituitary adenoma, thyroid cancer, glioblastoma multiforme, intravascular lymphoma, carcinoid, and medulloblastoma may present in this way, but bleeding is most characteristic of the first three types. Careful inquiry will usually disclose that neurologic symptoms compatible with intracranial tumor growth had preceded the onset of hemorrhage or the primary neoplasm had been revealed previously. Needless to say, a thorough search should be made in these circumstances for evidence of intracranial tumor or of secondary tumor deposits in other organs, particularly the lungs. A number of disparate circumstances may result in a multitude of simultaneous or at least temporally clustered cerebral hemorrhages. Among the most common causes are those related to hematologic and clotting disease, particularly ones that progress rapidly, such as leukemia, but almost any coagulopathy, including those brought on by the administration of medications, at one time or another have caused this state. The most overwhelming examples in our experience have occurred in the hours after injecting tPA for acute stroke. Amyloid angiopathy, discussed earlier, is associated with this state, sometimes after cerebral trauma. Serious cranial injury itself may produce a passel of scattered contusions, some of which have the appearance of ball hemorrhages, but most are recognized to be along force lines (Chap. 35). Occlusion of cerebral veins, particularly of the superior sagittal sinus, causes several biparietal hemorrhages. Multiple small hemorrhages, brain “microbleeds,” are associated with chronic hypertension (Fig. 34-30) and with an associated ostensible microvascular disease, according to Cordonnier and colleagues, but we have been unable to confirm this from our own material. Often, these dozens of small areas of residual blood products or acute hemorrhages do not cause symptoms and are revealed on MRI that is performed for other reasons with gradient-echo and other susceptibility sequences. Certainly, other forms of cerebrovascular disease are found disproportionately in these patients and several series suggest that they represent a risk for future bleeding or ischemic stroke, including lacunes. Multiple cavernous angiomas, the above-described amyloid angiopathy, CADASIL, bacterial endocarditis, moyamoya, and mutations that affect blood vessel integrity may also be implicated but the cause in any individual case often remains uncertain. The pathologic entity called brain purpura (pericapillary encephalorrhagia), incorrectly referred to as “hemorrhagic
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Figure 34-30. MRI gradient-echo sequence of multiple small hemorrhages in a 68-year-old woman with hypertension and seizures. No vascular malformation, amyloidosis, or genetic defect could be found.
encephalitis,” consists of multiple petechial hemorrhages scattered throughout the white matter of the brain. The clinical picture is that of a diffuse encephalopathy, but diagnosis is essentially a pathologic one. Blood does not appear in the CSF, and the condition should not be confused with a stroke. It is virtually impossible to establish the diagnosis during life, but the pathologic appearance is unique and highly characteristic. The lesions in brain purpura are small, 0.1 to 2.0 mm in diameter, and are confined to the white matter, particularly the corpus callosum, centrum ovale, and middle cerebellar peduncles. Each lesion is situated around a small blood vessel, usually a capillary. In this para-adventitial area, both the myelin and axis cylinders are destroyed, and the lesion is usually though not always hemorrhagic. Fibrin exudation, perivascular and meningeal infiltrates of inflammatory cells, and widespread necrosis of tissue are not observed. In these respects brain purpura differs fundamentally from acute necrotizing hemorrhagic leukoencephalitis. Usually the patient becomes stuporous and comatose without focal neurologic signs, and the CSF is normal. The etiology of brain purpura is quite obscure and there may be several causes. It may complicate viral pneumonia, uremia, arsenical intoxication, and, rarely, metabolic encephalopathy and sepsis, or there may be no associated disease. Amyloid angiopathy and an uncharacterized cerebral small vessel disease also have caused this picture of a multiplicity of small hemorrhages. Primary or secondary thrombotic thrombocytopenic purpura (TTP) may be the final common pattern for this entity. A degree of brain hemorrhage is to be expected in acute hemorrhagic leukoencephalitis (Hurst type), which represents an extreme form of acute disseminated encephalomyelitis (Chap. 36), and in herpes encephalitis (Chap. 33).
Inflammatory diseases of arteries and veins, especially polyarteritis nodosa, lupus erythematosus, and moyamoya disease, are occasionally associated with cerebral hemorrhage. Rupture of a vessel in these circumstances may be on the basis of hypertension or local vascular disease, and bleeding nearly always occurs into brain tissue rather than into the subarachnoid space. As mentioned earlier, intracranial dissection of an artery (usually the vertebral) may allow some blood to escape into the subarachnoid space. The other rare types of hemorrhages, listed in Table 34-9, are self-explanatory. Hemorrhages of intraspinal origin, all of them rare, may be the result of trauma, AVM (the usual cause of nontraumatic hematomyelia), anterior spinal artery aneurysms, or bleeding into tumors. Spinal subarachnoid hemorrhage from an AVM may simulate an intracranial subarachnoid hemorrhage, causing a stiff neck, headache, and even subhyaloid hemorrhages. Subarachnoid hemorrhage in which interscapular or neck pain predominates should raise the suspicion of an aneurysm of the anterior spinal artery or of a spinal AVM or cavernous angioma. Angiographic study of the radicular spinal vessels and the origins of the anterior spinal arteries from the vertebral arteries may disclose the source of bleeding. Extradural and subdural spinal extravasations may be spontaneous (sometimes in relation to rheumatoid arthritis) but are far more often a result of trauma, anticoagulants, or both. Extradural spinal hemorrhage causes the rapid evolution of paraplegia or quadriplegia; diagnosis must be prompt if function is to be salvaged by surgical drainage of the hematoma. These entities are discussed further in Chap. 44.
HYPERTENSIVE ENCEPHALOPATHY AND DIFFUSE VASOSPASM Clinical Features Hypertensive encephalopathy is the term applied to a relatively rapidly evolving syndrome of severe hypertension in association with headache, nausea and vomiting, visual disturbances, confusion, and—in advanced cases—stupor and coma. Multiple seizures are frequent and may be more marked on one side of the body. Diffuse cerebral disturbance may be accompanied by focal or lateralizing neurologic signs, either transitory or lasting, which should suggest cerebral hemorrhage or infarction, i.e., the more common cerebrovascular complications of severe chronic hypertension. A clustering of multiple microinfarcts and petechial hemorrhages (the basic neuropathologic changes in hypertensive encephalopathy) in one region may occasionally result in a mild hemiparesis, aphasic disorder, or rapid failure of vision. The last of these is particularly characteristic of accelerated hypertension and has special characteristics of signal changes in the occipital white matter; the terms reversible posterior leukoencephalopathy (RPLE) and posterior or reversible leukoencephalopathy syndrome (PRES) have been applied to this condition, as noted below and shown in Fig. 34-31. By the time the neurologic manifestations appear, the hypertension has usually reached the malignant stage, with diastolic pressures above 125 mm Hg, retinal hemorrhages,
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Figure 34-31. Hypertensive encephalopathy in a 55-year-old woman with headache and a single seizure. The characteristic changes of excess water in large regions of the white matter are seen on the CT scan (left panel) and in a T2-weighted MRI (right panel). The areas of signal change are associated with little mass effect and tend to be concentrated in the posterior regions of the brain. Other small cortical and subcortical lesions are common in watershed areas. There may be associated heterogeneous infarctions in the cerebral cortex, as shown in the following figure. The same changes in the occipital white matter may occur in eclampsia and from other numerous other causes of “posterior leukoencephalopathy” (see also Chap. 43).
exudates, papilledema, and evidence of renal and cardiac disease. However, instances of encephalopathy at lower pressures are common, especially if the hypertension has been abrupt in onset (see below). The term hypertensive encephalopathy should be reserved for the above syndrome and should not be used to refer to chronic recurrent headaches, dizziness, epileptic seizures, TIAs, or strokes, which may occur in association with high blood pressure. Encephalopathy may complicate extreme hypertension from any cause (chronic renal disease, renal artery stenosis, acute glomerulonephritis, acute toxemia, pheochromocytoma, Cushing syndrome), cocaine, or administration of drugs such as aminophylline or phenylephrine, but it occurs most often in patients with rapidly worsening “essential” hypertension. In eclampsia, which from a neurologic perspective may be considered a special form of hypertensive encephalopathy, and in acute renal disease, particularly in children, encephalopathic symptoms may develop at blood pressure levels considerably lower than those of hypertensive encephalopathy of “essential” type. Eclamptic retinal and cerebral lesions are the same as those that complicate malignant nephrosclerosis; in both there is also failure of autoregulation of the cerebral arterioles. In the pathogenesis of preeclampsia, rising levels of the antiangiogenic proteins endoglin and placental growth factor has been postulated appear to play a role (Levine et al, 2006). Nonetheless, we have been impressed that the distribution of lesions on the MRI differs between eclamptic and older hypertensive patients, suggesting some difference in pathophysiology, or perhaps simply that chronic hypertension in the latter group predisposes to the occipital lesions.
A discussion of eclamptic seizures can be found in the section on eclampsia in Chap. 16.
Laboratory Features Hypertensive encephalopathy is marked by already alluded to changes on CT scanning and MRI. The findings are often misinterpreted as large areas of infarction or demyelination, but their tendency to normalize over several weeks is remarkable. As summarized by Hauser and coworkers, the main feature is a bilateral increase in T2 signal intensity in the white matter on MRI and a corresponding reduced density (representing edema) on CT, usually concentrated in the posterior part of the hemispheres (see Fig. 34-31). Thus this condition is one of the causes of reversible posterior leukoencephalopathy. These imaging characteristics are a result of an accumulation of fluid, but—unlike the edema in trauma, neoplasm, or stroke—there is little or no mass effect and the water does not tend to course along white matter tracts such as the corpus callosum. In addition, scattered cortical lesions may occur in a watershed vascular distribution and probably correspond to small infarctions. These same findings in the white matter and cortex occur in eclampsia (Fig. 34-32) and have been seen in cases of diffuse vasospasm caused by sympathomimetic and serotonergic drugs, discussed further on. Hypertensive encephalopathy and eclampsia may cause subarachnoid hemorrhage. Most such cases are not caused by the rupture of an intracranial aneurysm and are not as overwhelming as in the latter case; indeed, the headache associated with this form of hemorrhage tends to be much milder than with aneurysmal rupture and it may even be absent. The bleeding is mainly a feature of the radiologic or
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be responsible for the necrosis of the vessel wall (see reviews of Auer and of Chester et al). The brain edema is the result of active exocytosis of water rather than simply a passive leak from vessels subjected to high pressures. A few eclamptic women will develop hemolysis, hepatic failure, and thrombocytopenia—hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome—an illness that has similarities to TTP and the hemolytic uremic syndrome (HUS). The interplay between eclampsia and HELLP syndrome in relation to cerebral lesions is complex and not fully understood.
Treatment
Figure 34-32. MRI T2 signal changes in eclampsia. Most of the vascular changes and edema are situated in the cortical watershed distributions between the middle and an anterior cerebral arteries. These imaging findings were transient, as was mild signal change in the occipital subcortical regions, the latter being typical of hypertensive encephalopathy, as in Fig. 34-31.
MRI examination of the brain, as described by Shah. The mechanism is obscure. In many, but not all, cases, the CSF pressure and protein values are elevated; the latter to more than 100 mg/dL in some instances, but there is no cellular reaction.
Pathophysiology Neuropathologic examination reveals a rather normal-looking brain, but in some cases cerebral swelling, hemorrhages of various sizes, or both will be found. In extreme instances, a cerebellar pressure cone reflects an increased volume of tissue and increased pressure in the posterior fossa; lumbar puncture appears to have only rarely precipitated fatalities. Microscopically there are widespread minute infarcts in the brain (with a predilection for the basis pontis), the result of fibrinoid necrosis of the walls of arterioles and capillaries and occlusion of their lumens by fibrin thrombi (Chester et al). This is often associated with zones of cerebral edema. Similar vascular changes are found in other organs, particularly in the retinae and kidneys. Volhard originally attributed the symptoms of hypertensive encephalopathy to vasospasm. This notion was reinforced by Byrom, who demonstrated, in rats, a segmental constriction and dilatation of cerebral and retinal arterioles in response to severe hypertension. However, the observations of Byrom and of others indicate that over-distention of the arterioles (which have lost their adaptive capacity), rather than excessive constriction, may
In the past, when effective treatment was not available, the outcome was often fatal. Lowering of the blood pressure with antihypertensive drugs may reverse the picture in a day or two. The same can be accomplished by administering magnesium sulfate in the eclamptic woman. However, antihypertensive drugs must be used cautiously; a safe target is a pressure of 150/100 mm Hg. One may use intravenous sodium nitroprusside, 0.5 to 0.8 mg/kg/min; a calcium channel blocker such as nifedipine, 10 to 20 mg sublingually; or intravenous beta-adrenergic blockers (labetalol, 20 to 40 mg intravenously followed by an infusion at 2 mg/min, or esmolol are favored). Longer-acting antihypertensive agents, such as ACE inhibitors and calcium channel blockers, must follow these. If there is already evidence of brain edema and increased intracranial pressure, dexamethasone, 4 to 6 mg every 6 h, is sometimes added, but its effect, and the use of hyperosmolar therapy, have not been studied systematically; our clinical impression is that they have little effect.
Diffuse Cerebral Vasospasm, Call-Fleming Syndrome, Postpartum Cerebral Vasculopathy A focal reduction in the caliber of the basal vessels and their proximal branches is a well-known complication of subarachnoid hemorrhage as described in earlier. Vasospasm has also been implicated in migraine and migrainous stroke and as an explanation for TIAs, but with little supportive evidence. Some degree of attenuation of large cerebral vessels is observed in hypertensive encephalopathy, in eclampsia, and with adrenergic drug use (e.g., phenylpropanolamine, cocaine, “triptan” drugs used for the treatment of migraine) but the role of the vascular changes in causing strokes has never been clear. In the most extreme forms, the narrowing of vessels is very diffuse, involving virtually all vessels distal to the circle of Willis. Segmental attenuation of the vascular caliber of many vessels is also a feature of cerebral vasculitis. In addition to these disorders of known causation, Call and colleagues have described a striking idiopathic widespread segmental vasospasm of cerebral vessels that is characterized clinically by severe headache (often of the “thunderclap” variety, as described in Chap. 10) and fluctuating TIA-like episodes (all cases drawn from our hospital services; termed Call-Fleming syndrome in some publications). The middle cerebral artery and its branches are mainly affected; the angiographic appearance may be mistaken for arteritis. The patients we have seen with this process, after several weeks of dramatically fluctuating
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focal neurologic symptoms and disabling headache, have recovered completely or nearly so, but several have had small strokes. There may be an associated posterior leukoencephalopathy that is similar to the imaging appearance in hypertensive encephalopathy. Sometimes the headache is minimal and the attenuation of vessels is found in imaging performed for other reasons. The spinal fluid, except perhaps for elevated pressure, is normal. The nature of this condition is unknown. A relationship to hypertensive encephalopathy or to delayed postpartum eclampsia has been suggested because of the aforementioned white matter changes and the observation of widespread vasospasm in eclamptic women. Two of our patients have been in the postpartum period and other such patients have been described in the first three weeks after delivery. In all likelihood, several disorders cause this type of vasculopathy (Table 34-10). Singhal and colleagues and others have brought to attention that serotonergic drugs may produce a similar syndrome of reversible multifocal vasospasm, severe headache, and stroke. One of their patients was using the antimigraine medicine sumatriptan; others were using serotonin reuptake inhibitor antidepressants and, in addition, had taken overthe-counter cold remedies that included pseudoephedrine and dextromethorphan; we are aware of other similar cases. These authors proposed that in these cases a “serotonin syndrome” had occurred, similar to what has been seen with overdoses of this class of antidepressants. The same type of vasculopathy is produced by sympathomimetic drugs alone, such as ephedra in health food supplements, phenylpropanolamine, pseudoephedrine, and cocaine, but there are few well-studied cases, as also discussed just below. In all cases, including those noted above, the treatment is cessation of the offending drugs; calcium channel blockers, corticosteroids, nitroglycerin, nitroprusside, and beta-adrenergic or papaverine infusions have been tried with uncertain effect. We have generally prescribed calcium channel-blocking drugs orally.
INFLAMMATORY DISEASES OF BRAIN ARTERIES Infectious Vasculitis Inflammatory diseases of the blood vessels that are of infectious origin and their effects upon the nervous system are considered in detail in Chap. 32. There it was pointed out that meningovascular syphilis, tuberculous meningitis, fungal meningitis, and the subacute (untreated or partially treated) forms of bacterial meningitis may be accompanied by inflammatory changes and occlusion of the cerebral arteries or veins. Occasionally, a small deep stroke is the first clinical sign of chronic basilar meningitis, but more often it develops well after the meningeal symptoms are established. The nature of the cerebral vasculitis that may rarely accompany AIDS is unclear. Typhus, schistosomiasis, mucormycosis, malaria, and trichinosis are rare causes of inflammatory arterial disease, which, unlike the above-mentioned infections, are not secondary to meningeal infections. In typhus and other rickettsial diseases,
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Table 34-10 CONDITIONS THAT HAVE BEEN ASSOCIATED WITH DIFFUSE OR WIDESPREAD CEREBRAL VASOSPASM Idiopathic Postpartum state Eclampsia Hypertensive encephalopathy Massive subarachnoid hemorrhage Ergot, sympathomimetic, and serotoninergic drugs including “triptans” and cocaine “Thunderclap headache” (see Chap. 10) Head trauma Post-carotid endarterectomy Acute porphyria Hypercalcemia Migraine?
capillary and arteriolar changes and perivascular inflammatory cells are found in the brain; presumably they are responsible for the seizures, acute psychoses, cerebellar syndromes, and coma characterizing the neurologic disorder in these diseases. The internal carotid artery may be occluded in diabetic patients as part of the orbital and cavernous sinus infections with mucormycosis. In trichinosis, the cause of the cerebral symptoms has not been clearly established. Parasites have been found in the brain; in one of our patients the cerebral lesions were produced by bland emboli arising in the heart and related to a severe myocarditis. In cerebral malaria, convulsions, coma, and, sometimes, focal symptoms appear to be due to the blockage of capillaries and precapillaries by masses of parasitized red blood corpuscles. Schistosomiasis may implicate cerebral or spinal arteries. These diseases are discussed further in Chap. 32.
Noninfectious Inflammatory Diseases of Cranial Arteries Included under this heading is a diverse group of arteritides that have little in common except their tendency to involve the cerebral vasculature. One group includes the giant cell arteritides—extracranial (temporal) arteritis; granulomatous arteritis of the brain; and aortic branch arteritis, one form of which is known as Takayasu disease. A second group includes polyarteritis nodosa, the Churg-Strauss type of arteritis, Wegener granulomatosis, systemic lupus erythematosus, Behçet disease, postzoster arteritis, and AIDS-related arteritis. Immunologic studies show that in most of these processes there is an abnormal deposit of complement-fixing immune complex on the endothelium, leading to inflammation, vascular occlusion, or rupture with small hemorrhage. The initial inflammatory event is thought in some cases to be evoked by a virus, bacterium, or drug, but these are rarely proven in any one case. It is postulated by some immunologists that in the granulomatous arteritides, a different mechanism is operative—that an exogenous antigen induces antibodies that attach to the primary target (the vessel wall) as immune complexes, damage it, and attract lymphocytes and mononuclear cells. The giant cells form around remnants of the vessel wall. Wegener granulomatosis may fit this model. An acute necrotizing cerebral angiitis some-
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times complicates ulcerative colitis and responds to treatment with prednisone and cyclophosphamide; it may also belong in this category. The special case of intravascular lymphoma, which closely simulates a cerebral vasculitis, is discussed in Chap. 31.
Temporal Arteritis (Giant Cell Arteritis, Cranial Arteritis) (See also Chap. 10) In this disease, which is common among elderly persons, arteries of the external carotid system, particularly the temporal branches, are the sites of a subacute granulomatous inflammatory exudate consisting of lymphocytes and other mononuclear cells, neutrophilic leukocytes, and giant cells. The most severely affected parts of the artery usually become thrombosed. The sedimentation rate is characteristically elevated above 80 mm/h and sometimes exceeds 120 mm/h, but a small number of cases occur with values below 50 mm/h. Regional or bilateral headache or head pain is the chief complaint, and there may be severe pain, aching, and stiffness in the proximal muscles of the limbs associated with the markedly elevated sedimentation rate. Thus the clinical picture overlaps that of polymyalgia rheumatica as discussed in Chap. 10. Other less-frequent systemic manifestations include fever, anorexia and loss of weight, malaise, anemia, and a mild leukocytosis. Instances of dementia, depression, and other neurologic illnesses that have been described in the literature in patients with temporal arteritis are difficult to understand and seem to us coincidental, but not all our colleagues agree. Occlusion of branches of the ophthalmic artery, resulting in blindness in one or both eyes, is the most feared complication, occurring in approximately 25 percent of patients, often unpredictably. In the most extreme form, the optic nerve head becomes infarcted with consequent severe visual loss. This is one of the main forms of anterior ischemic optic neuropathy discussed in Chap. 10. In a few cases, blindness is preceded by transient visual loss, thereby simulating a TIA (transient monocular blindness). Occasionally the arteries of the oculomotor nerves are also involved, causing various ophthalmoplegias. Rarely, an arteritis of the aorta and its major branches—including the carotid, subclavian, coronary, and femoral arteries—is found at postmortem examination. Significant inflammatory involvement of intracranial arteries from temporal arteritis is uncommon, perhaps because of a relative lack of elastic tissue, but in a few cases strokes have occurred on the basis of occlusion of the internal carotid or vertebral arteries. We are unable to comment on reported cases of dementia or encephalopathy without overt cerebral infarction in temporal arteritis. These cases are notable for apparent improvement with the administration of corticosteroids. The diagnosis should be suspected in elderly patients who develop severe, persistent headache and elevation of the sedimentation rate. In instances where the sedimentation rate is marginally elevated, measurement of C-reactive protein (CRP) may be helpful. The diagnosis can be established by finding a tender, thrombosed, or thickened cranial artery and demonstration of the lesion in a biopsy. The procedure is relatively innocuous and the diagnosis may require that both
sides be sampled because of the patchy distribution of granulomatous lesions. Schmidt and colleagues have reported that the diagnosis can also be made with duplex ultrasonography. A dark halo, probably reflecting edema, surrounded the affected temporal artery and there were no false-positive tests according to these authors. A considerable length of the temporal artery can be insonated by this technique, a particularly useful feature in a process that affects the vessel segmentally. From our limited experience, these findings have proven difficult to detect. The arteritic changes may also be revealed by conventional arteriography of the external carotid arteries. The administration of prednisone, 50 to 75 mg/d, provides striking relief of the headache and polymyalgic symptoms within days and sometimes within hours, and also prevents blindness. The medication must be given in very gradually diminishing doses for at least several months or longer, guided by the symptoms and the sedimentation rate. The latter begins to drop within days but seldom falls below 25 mm/ h. These issues are discussed in greater detail in Chap. 10.
Intracranial Granulomatous Arteritis Scattered examples of a small-vessel giant cell arteritis of undetermined etiology in which only brain vessels are affected have come to medical attention over the years. The clinical aspects have taken diverse forms, sometimes presenting as low-grade, nonfebrile meningitis with sterile CSF followed by infarction of one or several parts of the cerebrum or cerebellum. In other cases it has evolved over a period of weeks, with strokes or an unusual dementia. Headaches (variable in our experience but sometimes severe), focal cerebral or cerebellar signs of gradual (occasionally stroke-like) evolution, confusion with memory loss, pleocytosis and elevated CSF protein, and papilledema as a result of increased intracranial pressure (in about half of reported cases but far fewer in our experience) constitute the most frequently encountered syndromes. The symptoms usually persist for several months. In contrast to temporal arteritis, the sedimentation rate is generally normal or only slightly elevated. In about half the patients can the diagnosis be made by angiography, which demonstrates an irregular narrowing and in some cases blunt ending of small cerebral arteries (Fig. 34-33). CT scanning and MRI show multiple irregular white matter and cortical changes and small cortical lesions; sometimes these cannot be differentiated from a tumor or demyelinative or infectious process. If the white matter abnormalities become confluent, the radiologic appearance simulates Binswanger disease or hypertensive encephalopathy. The diagnosis is made most often by a brain biopsy, which includes a sample of the meninges with vessels, but even with tissue sampling, about half of suspected cases show the typical histopathologic changes. It is not unusual, however, for patients with normal angiograms to have the typical arteritic findings on biopsy. As pointed out by Alrawi and colleagues, many patients prove to have an alternative condition, mainly an infectious encephalitis and brain or intravascular lymphoma, abscess, or Creutzfeldt-Jakob disease. Tissue excised during an operation (or brain biopsy) for a suspected brain
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phamide therapy (Moore, 1994), and we have used this combined approach from the time the diagnosis is established. The severity and configurations of the process are so variable that judging the effects of treatment is difficult, but our untreated patients have uniformly deteriorated or died without treatment.
Takayasu Disease (Aortic Branch Disease)
Figure 34-33. Granulomatous angiitis of the brain. Carotid angiogram, lateral projection, demonstrating numerous areas of irregular narrowing (arrows) and, in some areas, contiguous slight dilatation (“beading”), particularly in the anterior cerebral artery.
tumor, lymphoma, or white matter disease has revealed the characteristic vasculitis in some of our patients; in others, the diagnosis has been made only at autopsy, the findings coming as a distinct surprise. The affected vessels are mainly in the 100- to 500-mm diameter arteries and arterioles and are surrounded and infiltrated by lymphocytes, plasma cells, and other mononuclear cells; giant cells are distributed in small numbers in the media, adventitia, or perivascular connective tissue. Infarction of brain tissue can be traced to widespread thrombosis in these vessels. The meninges are variably infiltrated with inflammatory cells. Sometimes only a part of the brain has been clinically affected—in one of our cases the cerebellum, in another, one frontal lobe and the opposite parietal lobe. Among the most important considerations in this disease is the cerebral arteritis caused by varicella zoster virus of the ophthalmic division of the trigeminal nerve; it simulates in radiographic appearance granulomatous arteritis and giant cell arteritis. On occasion, intravascular lymphoma may present a similar picture and sympathomimetic agents, as mentioned earlier, cause a vasculopathy with segmental narrowing of cerebral vessels that has many similarities. The clinical and radiologic appearance of brain arteritis also raises the question of sarcoidosis, which is sometimes limited to the nervous system, of CADASIL, multiple sclerosis, or of the polyarteritis (allergic granulomatous angiitis) described by Churg and Strauss. Unlike some of these diseases, however, the lungs and other organs are spared; there is no systemic eosinophilia, increase in sedimentation rate or antineutrophil cytoplasmic antibodies (ANCA), or anemia. Some patients with isolated angiitis of nervous system presenting as an aseptic meningitis and multiple cerebral infarcts have responded to corticosteroid and cyclophos-
This is a nonspecific chronic arteritis involving mainly the aorta and the large arteries arising from its arch. It is similar in some ways to giant cell arteritis except for its propensity to involve the proximal rather than the distal branches of the aorta. Most of the patients have been young Asian women, but there are now numerous reports of similar cases from the United States, Latin America, and Europe. The etiology has never been ascertained but an autoimmune mechanism is suspected. Constitutional symptoms such as malaise, fever, anorexia, weight loss, and night sweats usually introduce the disease. The erythrocyte sedimentation rate is elevated in the early and active stages. Later there is evidence of occlusion of the innominate, subclavian, carotid, vertebral, and other arteries that may be asymptomatic or cause neurologic ischemic symptoms. The affected arteries no longer pulsate, hence the descriptive term pulseless disease. When renal arteries are involved, hypertension results, and there may be coronary occlusion, which may be fatal. Involvement of the pulmonary artery may lead to pulmonary hypertension. Coolness of the hands and weak radial pulses are common indicators of the disease and headaches are frequent. Blurring of vision, especially upon physical activity or fever, dizziness, and hemiparetic and hemisensory syndromes are the usual neurologic manifestations (Lupi-Herrera et al). The frequency of posturally induced neurologic symptoms has been emphasized, as well as the relative infrequency of major strokes despite multiple TIA-like spells. The inflamed vessels in the thorax are revealed by in radionuclide scans using gallium. Pathologic studies disclose a periarteritis of the large vessels, often with giant cells and reparative fibrosis. Many of the patients die in 3 to 5 years. According to Ishikawa and colleagues, the administration of corticosteroids in the acute inflammatory stage of the disease improves the prognosis. Reconstructive vascular surgery has helped some of the patients in the later stages of the disease.
Polyarteritis Nodosa of Cerebral Vessels The inflammatory necrosis of arteries and arterioles throughout the body in this disease rarely affects the central (in contrast to frequent involvement of the peripheral) nervous system. The lungs are usually spared, which is the basis of distinguishing this form of vasculitis from the Churg-Strauss granulomatous angiitis, mentioned above. It has been estimated that the brain is involved in fewer than 5 percent of cases and takes the form of one or more microinfarcts; macroscopic infarction is a rarity. The clinical manifestations vary and have included headache, confusion and fluctuating cognitive disorders, convulsions,
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hemiplegia, and brainstem signs. We have also observed one instance of acute spinal cord lesions. Brain hemorrhage is rare and usually occurs in a setting of extreme renal hypertension.
Wegener Granulomatosis This is a rare disease of unknown cause, affecting adults as a rule and favoring males slightly. A subacutely evolving vasculitis with necrotizing granulomas of the upper and lower respiratory tracts followed by necrotizing glomerulonephritis are its main features. Neurologic complications come later in one-third to one-half of cases and take two forms: (1) a peripheral neuropathy either in a pattern of polyneuropathy or, far more frequently, in a pattern of mononeuropathy multiplex (see discussion in Chap. 44), and (2) multiple cranial neuropathies as a result of direct extension of the nasal and sinus granulomas into adjacent upper cranial nerves and from adjacent to pharyngeal lesions to the lower cranial nerves (see Chap. 47). We have seen this disease produce the syndrome of episodic hemicrania, with periorbital ecchymosis. The basilar parts of the skull may be eroded, with spread of granuloma to the cranial cavity and more remote parts. A description is included here because cerebrovascular events, seizures, and cerebritis are less common but well described neurologic complications. Spastic paraparesis, temporal arteritis, Horner syndrome, and papilledema have been observed but are rare (see Nishino et al). The orbits are involved in 20 percent of patients and lesions here simulate the clinical and radiologic appearance of orbital pseudotumor, cellulitis, or lymphoma. Pulmonary granulomas, usually asymptomatic but evident on a chest CT, are also common. The vasculitis implicates both small arteries and veins. There is a fibrinoid necrosis of their walls and an infiltration by neutrophils and histiocytes. The sedimentation rate is elevated, as are the rheumatoid and antiglobulin factors. The presence in the blood of cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) has been found to be relatively specific and sensitive for Wegener disease but it may also be present in intravascular lymphoma. A degree of therapeutic success in this formerly fatal disease has been achieved by the use of cyclophosphamide, chlorambucil, rituximab, or azathioprine. Cyclophosphamide in oral doses of 1 to 2 mg/kg per day has cured 90 to 95 percent of the cases. In acute cases, rapidly acting steroids—prednisone, 50 to 75 mg/d—should be given in conjunction with the immunosuppressant drug(s).
Systemic Lupus Erythematosus Involvement of the nervous system is an important aspect of this disease. In the pathologic and clinical series reported by Johnson and Richardson, the central nervous system (CNS) was affected in 75 percent of cases, but our recent experience has suggested a far lower frequency of clinical manifestations. Disturbances of mental function— including alteration of consciousness, seizures, and signs referable to cranial nerves—are the usual neurologic manifestations; most often they develop in the late stages of the disease, but they may occur early and may be mild
and transient. Hemiparesis, paraparesis, aphasia, homonymous hemianopia, movement disorders (chorea), and derangements of hypothalamic function occur but have been infrequent in our experience. Larger infarcts are usually traceable to emboli from Libman-Sacks (nonbacterial thrombotic, marantic) endocarditis. In some instances the CNS manifestations resemble multiple sclerosis, especially when there is an optic neuritis and myelopathy. The presence of serum antinuclear antibodies is of help in the differentiation of lupus erythematosus but in itself does not establish the diagnosis. The CSF is entirely normal or shows only a mild lymphocytic pleocytosis and increase in protein content, although in some patients—primarily those with peripheral neuropathy and myelopathy—the protein content may be greatly increased. Most of the neurologic manifestations can be accounted for by widespread microinfarcts in the cerebral cortex and brainstem; these, in turn, are related to destructive and proliferative changes in arterioles and capillaries. The acute lesion is subtle; it is not a typical fibrinoid necrosis of the vessel wall, like that in hypertensive encephalopathy, and there is no cellular infiltration. Attachment of immune complexes to the endothelium is the postulated mechanism of vascular injury. Thus, the changes do not represent a vasculitis in the strict sense of the word. Other neurologic manifestations are related to hypertension, which frequently accompanies the disease and may precipitate cerebral hemorrhage; to endocarditis, which may give rise to cerebral embolism; to thrombotic thrombocytopenic purpura, which commonly complicates the terminal phase of the disease (Devinsky et al); and to treatment with corticosteroids, which may precipitate or accentuate muscle weakness, seizures, and psychosis. In other cases, steroids appear to improve these neurologic manifestations. A similar set of neurologic problems arises in relation to the antiphospholipid antibody syndrome, which may be a feature of lupus or arise independently (see “Antiphospholipid Antibody Syndrome”). It is not been entirely clear to us what proportion of the cerebrovascular features of lupus might be explained on the basis of the coagulation disorder.
Arteritis Symptomatic of Underlying Systemic Disease and Sympathomimetic Drug Reactions Both AIDS and drug abuse (mainly cocaine) are associated with a cerebral vasculitis that is similar to polyarteritis nodosa. With respect to the former, if deep infarctions have occurred, basal meningitis because of tuberculosis, cryptococcosis, or syphilis with occlusion of penetrating vessels must always be entertained. Drug-induced vasculitis is difficult to distinguish from a more common state of focal vasospasm that may also be induced by these same agents, as discussed earlier under “Diffuse and Focal Cerebral Vasospasm, Call-Fleming Syndrome, Postpartum Cerebral Vasculopathy.” Finally, a true cerebral or spinal cord vasculitis can rarely be found in association with systemic lymphoma, particularly with Hodgkin disease. The nature of this process is indeterminate but may be related to the deposition of circulating immune complexes in the walls of cerebral vessels. The cerebrovascular problems consequent to cocaine use are quite varied. Seizures and death may occur as a result of
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a syndrome of delirium and extreme hyperthermia. More interesting are the strokes that arise during and just after cocaine use. Here, as emphasized by Levine and colleagues (1991), a clear distinction should be made between the complications of cocaine hydrochloride (the usual form of ingestible cocaine) and the alkaloid form, or “crack cocaine.” The former, when injected intravenously more so than when used intranasally, is prone to cause cerebral hemorrhage as a result of acute hypertension, similar to the bleeding that may be precipitated by other sympathomimetic drugs such as amphetamine and phenylpropanolamine. Both subarachnoid and intracerebral hemorrhage may result. Or, the features of hypertensive encephalopathy are precipitated, including changes in the posterior white matter of the cerebral hemispheres that are so striking on imaging studies. The strokes with crack cocaine, however, are more often ischemic, typically involving the territory of a large vessel. Some ambiguity attends the vasculopathy induced by crack cocaine, less often by cocaine hydrochloride, and by the amphetamines. There are undoubted instances of a true cerebral inflammatory vasculitis, perhaps of a hypersensitivity type such as those reported with biopsy verification by Krendel and colleagues, by Merkel and associates, and by others. What is confusing about these cases is the normal angiographic appearance in many instances and large-vessel occlusions in others, in contrast to the pathologic changes, which are concentrated in small cortical vessels. Furthermore, many cases seem to be of an entirely different type, displaying long segments of vascular attenuation in the angiogram and no evidence of an inflammatory process in biopsy or autopsy material. The correct treatment, aside from lowering the blood pressure, is uncertain. Whether there is an increased incidence of arteriovenous malformation and cerebral aneurysm in patients who have cerebral hemorrhages after ingestion of cocaine, as suggested in several articles, is uncertain but seems possibly the result of selection bias in collecting series of affected patients. Crack cocaine may also cause a choreiform disorder (“crack dancing”), not unlike that associated with antiphospholipid antibody but generalized rather than focal (see further on); usually there are small infarctions in the basal ganglia, but an immune mechanism has also been suggested. Another type of small vessel arteritis occurs as a hypersensitivity phenomenon. Often it is associated with an allergic skin lesion (Stevens-Johnson vasculopathy or a leukocytoclastic vasculitis). The clinical picture does not resemble that of polyarteritis nodosa, but the central or peripheral nervous system is affected in rare instances. The response to corticosteroids is excellent. Susac Syndrome This is yet another ill-defined form of vasculitis, consisting of a microangiopathy affecting mainly the brain and retina. Psychiatric symptoms, dementia, sensorineural deafness, and impairments of vision are the clinical manifestations. Funduscopy (multiple retinal artery branch occlusions) and arteriography manifest evidence of the vasculopathy. The patients seem to respond to steroid therapy. Only biopsy material has been examined. Mixed essential cryoglobulinemia, a vasculitic disorder that more often affects the peripheral than the central nervous system, may nonetheless produce an encephalopathy.
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Behçet Disease This disorder may suitably be considered here because it is essentially a chronic, recurrent vasculitis, involving small vessels, with prominent neurologic manifestations. It is most common in Turkey, where it was first described, in other Mediterranean countries, and in Japan, but it occurs throughout Europe and North America, affecting men more often than women. The disease was originally distinguished by the triad of relapsing iridocyclitis and recurrent oral and genital ulcers, but it is now recognized to be a systemic disease with a much wider range of symptoms, including erythema nodosum, thrombophlebitis, polyarthritis, ulcerative colitis, and a number of neurologic manifestations, some of them encephalitic or meningitic in nature. The most reliable diagnostic criteria, according to the International Study Group that assembled data on 914 cases from 12 medical centers in 7 countries, were recurrent aphthous or herpetiform oral ulceration, recurrent genital ulceration, anterior or posterior uveitis, cells in the vitreous or retinal vasculitis, and erythema nodosum or papulopustular lesions. The nervous system is affected in approximately 30 percent of patients with Behçet disease (Chajek and Fainaru); the manifestations are recurrent meningoencephalitis, cranial nerve (particularly abducens) palsies, cerebellar ataxia, corticospinal tract signs, and venous occlusion disease. There may be episodes of diencephalic and brainstem dysfunction resembling minor strokes. A few postmortem examinations have related these small foci of necrosis to a vasculitis, including perivascular and meningeal infiltration of lymphocytes. There may also be cerebral venous thrombosis. The neurologic symptoms usually have an abrupt onset and are accompanied by a brisk spinal fluid pleocytosis (lymphocytes or neutrophils may predominate), along with elevated protein but normal glucose values (in one of our patients, 3,000 neutrophils per cubic millimeter were found at the onset of an acute meningitis). As a rule, neurologic symptoms clear completely in several weeks, but they have a tendency to recur, and some patients are left with persistent neurologic deficits. Rarely, the clinical picture is that of a progressive confusional state or dementia (see the reviews of Alema and of Lehner and Barnes for detailed accounts). The cause of Behçet disease is unknown. We have been unable to detect virus particles in the margins of an ulcerative mouth lesion. A pathergy skin test—the formation of a sterile pustule at the site of a needle prick—is listed as an important diagnostic test by the International Study Group, but on the basis of admittedly limited U.S. experience, we and our colleagues have found it to be of questionable value. Administration of corticosteroids has been the usual treatment, on the assumption of an autoimmune etiology. Because the episodes of disease naturally subside and recur, evaluation of treatment is difficult.
THROMBOSIS OF CEREBRAL VEINS AND VENOUS SINUSES Thrombosis of the cerebral venous sinuses, particularly of the superior sagittal or lateral sinus and the tributary cortical and
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deep veins, gives rise to a number of important neurologic syndromes. Cerebral vein thrombosis may develop in relation to infections of the adjacent ear and paranasal sinuses or to bacterial meningitis, as described in Chap. 32. More common is noninfectious venous occlusion resulting from one of the many hypercoagulable states discussed below. Occlusion of cortical veins that are the tributaries of the dural sinuses takes the form of a venous infarctive stroke. The diagnosis is difficult except in certain clinical settings known to favor the occurrence of venous thrombosis, such as the taking of birth control pills or postpartum and postoperative states, which are often characterized by thrombocytosis and hyperfibrinogenemia. Hypercoagulable conditions also occur in cancer (particularly of the pancreas and other abdominal organs), cyanotic congenital heart disease; cachexia in infants; sickle cell disease; antiphospholipid antibody syndrome, the aforementioned Behçet disease, factor V Leiden mutation, protein S or C deficiency, antithrombin III deficiency, resistance to activated protein C; primary or secondary polycythemia and thrombocythemia; and paroxysmal nocturnal hemoglobinuria. The administration of drugs such as tamoxifen and erythropoietin, and even the hypercoagulable reaction to heparin that is associated with thrombocytopenia have all been cited as risks for cerebral venous thrombosis. The study by Martinelli and colleagues, mentioned earlier in the chapter, attributed 35 percent of cases of cerebral vein thrombosis to a mutation in the factor V or the prothrombin gene. Averback, who reported 7 cases of venous thrombosis in young adults, has emphasized the diversity of the clinical causes. Two of his patients had carcinoma of the breast and one had ulcerative colitis. A few cases will follow head injury or remain unexplained. A stroke in a patient suffering from any one of these systemic conditions should suggest venous thrombosis, although in some instances—e.g., postpartum strokes— arteries are occluded as often as veins. The slower evolution of the clinical stroke syndrome, the presence of multiple cerebral lesions not in arterial territories, and an epileptic and hemorrhagic tendency favor venous over arterial thrombosis. The reasons for these clinical features and their variability as well as the differences from ischemic brain damage caused by arterial occlusion become apparent in the discussions below. Stam has undertaken a review of this subject.
Superficial Thrombosis of Cortical Veins Certain syndromes occur with sufficient regularity that they suggest thrombosis of a particular vein or sinus. The signature features of isolated thrombosis of superficial cortical veins are the presence of large superficial (cortex and subjacent white matter) hemorrhagic infarctions and a marked tendency to partial seizures. Hemiparesis, incomplete hemianopia, and aphasia, any of which may fluctuate over days, are also characteristic, according to Jacobs and colleagues. These variable syndromes reflect the inconstant location of the main surface veins. Thrombosis of the vein of Labbé causes infarction of the underlying superior temporal lobe, and occlusion of the vein of Trolard implicates the parietal cortex. Quite often, in our experience, the focal deficit worsens immedi-
ately after a partial seizure. The intracranial pressure is not elevated, as it is when the dural venous sinuses are occluded. The diagnosis is now made by careful examination of the MRV or by the venous phase of the conventional angiogram. Cortical vein thrombosis should be suspected in the situation of multiple hemorrhagic infarctions in one hemisphere without a source of embolism or atherothrombosis.
Dural Sinus Thrombosis Sagittal and Lateral Sinus Thrombosis In the case of sagittal sinus thrombosis, intracranial hypertension with headache, vomiting, and papilledema may constitute the entire syndrome (this is the main consideration in the differential diagnosis of pseudotumor cerebri, Chap. 30) or it may be conjoined with hemorrhagic infarction. Paraparesis, hemiparesis, fluctuating unilateral or bilateral sensory symptoms, or aphasia result only if the thrombosis propagates to surface veins. Focal or odd sensory or motor seizures occur on the same basis but are not as common as with cortical vein thrombosis. The common radiologic picture that results from occlusion of the superior sagittal sinus is of bilateral superficial paramedian parietal or frontal hemorrhagic infarction or edematous venous congestion. In the case of CT scan with contrast infusion, a lack of dye opacification in the posterior sagittal sinus can be observed with careful adjustment of the viewing window (“empty delta sign”). The spinal fluid pressure is increased, and the fluid may be slightly sanguinous. Lateral sinus thrombosis causes hemorrhagic infarction of the temporal lobe convexity, usually with considerable vasogenic edema. The enhanced CT scan, arteriography (venous phase), and MRV greatly facilitate diagnosis by directly visualizing the venous occlusion. Once a venous thrombosis becomes established, the tributary surface veins take on a “corkscrew” appearance that is appreciated on the venous phase of an angiogram. Cavernous Sinus Thrombosis As pointed out in Chaps. 13 and 14, in cases of anterior cavernous sinus thrombosis there is marked chemosis and proptosis—with disordered function of cranial nerves III, IV, VI, and the ophthalmic division of V (Fig. 34-34). Posterior cavernous sinus thrombosis, spreading to the inferior petrosal sinus, may cause palsies of cranial nerves VI, IX, X, and XI without proptosis, and involvement of the superior petrosal sinus may be accompanied by a fifth nerve palsy. Increased intracranial pressure without ventricular dilatation occurs with thrombosis of the superior sagittal sinus, the main jugular vein, and the lateral sinus or the confluence of the sinuses. Thrombosis of the venous sinuses in neonates presents special problems in diagnosis. In the series reported by deVeber and colleagues, various perinatal complications, including systemic illness such as severe dehydration or infection were common precedents; the outcome was poor. In young children the risk factors differed, in that connective tissue and prothrombotic disorders and head and neck infections were more common.
Deep Cerebral Vein Thrombosis Occlusion of the vein of Galen and of the internal cerebral veins is the least common and clinically most obscure of the venous syndromes.
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1 2 3 4 5 6 7 Figure 34-34. Diagram of the cavernous sinus: (1) optic chiasm; (2) oculomotor nerve; (3) cavernous sinus; (4) trochlear nerve; (5) internal carotid artery; (6) ophthalmic nerve; (7) abducens nerve; (8) maxillary nerve. (Reproduced by permission from Krayenbühl and Yasargil.)
From the few cases that have been studied, a picture of bithalamic infarction emerges, sometimes reversible, and consisting mainly of inattention, spatial neglect, and amnesia in the case reported by Benabdeljili and colleagues, and of akinetic mutism and apathy in the case of Gladstone and associates. The case series of van den Bergh and colleagues emphasizes the difficulty in diagnosis of partial syndromes of this nature. In most reports of this condition, it is the neuropsychological aspects that are emphasized. Other cases have manifested coma and pupillary changes referable to the ischemic diencephalon and rostral midbrain. Perhaps most striking is the MRI, with a large bilobular region of signal change that encompasses the thalami. Much of the signal change probably represents reversible edema and venous congestion, because substantial clinical improvement may occur. Angiography is needed to confirm the diagnosis, most often a magnetic resonance venogram.
Treatment of Cerebral Venous Thrombosis Anticoagulant therapy beginning with heparin for several days, followed by warfarin, and combined with antibiotics if the venous occlusion is infectious (it rarely is in recent times) has been lifesaving in some cases. Nonetheless, the overall mortality rate remains high, with large hemorrhagic venous infarctions found in 10 to 20 percent of cases. The clinical trial conducted by Einhaupl and colleagues generally settled the question of therapy in favor of aggressive anticoagulation, but this could not be confirmed by de Bruijn and coworkers, who found a minimal difference between patients who were treated with lowmolecular-weight heparin followed by oral anticoagulation. The combination of local infusion of tPA has been encouraging, but not subjected to the same randomized testing. Thrombolytic therapy by local venous or systemic infusion has also been successful in small series of cases, such as the 5 patients treated with urokinase and heparin by DiRocco and colleagues. However, this approach has not been subjected to a systematic study. We have reserved thrombolysis for extreme cases of dural sinus thrombosis with stupor or coma and greatly raised CSF
8
pressure. This subject was reviewed by Benamer and Bone, who concluded that warfarin anticoagulation should be reserved for patients who deteriorate despite treatment with heparin. Most treated patients do well, but it may take weeks for the headaches to remit. Coma and multiple cerebral hemorrhages, on the other hand, are usually fatal.
STROKE DUE TO HYPERCOAGULABLE STATES Nonbacterial Thrombotic (Marantic) Endocarditis and Cerebral Embolism Sterile vegetations, referred to also as nonbacterial thrombotic endocarditis, consist of fibrin and platelets and are loosely attached to the mitral and aortic valves and contiguous endocardium. They are a common source of cerebral embolism (almost 10 percent of all instances of cerebral embolism according to Barron et al, but lower in the experience of others). In almost half the patients, the vegetations are associated with a malignant neoplasm; the remainder occurs in patients debilitated by other diseases (Biller et al). Except for the setting in which it occurs, marantic embolism has no distinctive clinical features that permit differentiation from cerebral embolism of other types other than that it is often the cause of sequential strokes over days or weeks. The apoplectic nature of marantic embolism distinguishes it from the usual forms of tumor metastases. The hazards of using anticoagulants in gravely ill patients with widespread malignant disease probably outweigh the benefits from this treatment, but drugs that prevent platelet aggregation, while possibly helpful, have not been studied systematically for this condition.
Stroke as a Complication of Hematologic Disease The brain is involved in the course of many hematologic disorders, some of which have already been mentioned. A
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number of the better-characterized ones are discussed here.
Antiphospholipid Antibody Syndrome This condition, in which TIAs, or stroke, migraine, and thrombocytopenia in various combinations, occur in young adults, has already been mentioned under “Strokes in Children and Young Adults.” The related term lupus anticoagulant is not ideal, as most patients with the anticoagulant do not have lupus and the antibody is a procoagulant, not an anticoagulant. Nonetheless, the main laboratory feature of the illness is a prolonged partial thromboplastin time. Further testing for antiphospholipid antibody consists of detection of both lupus anticoagulant and anticardiolipin antibody; there is a partial overlap between these—80 percent of patients with lupus anticoagulant have anticardiolipin antibody but fewer than 50 percent of those with anticardiolipin antibody have lupus anticoagulant. The principal antigen involved is in fact not phospholipid but β2-glycoprotein 1, a protein that binds to phospholipid. The titer of antibody correlates with the risk of thrombosis and smoking; pregnancy and the use of oral contraceptives raise the risk further. There may be an increased incidence of migraine but this has been disputed. The most frequent neurologic abnormality is a TIA, usually taking the form of amaurosis fugax (transient monocular blindness), with or without retinal arteriolar or venous occlusion (Digre et al). Stroke-like phenomena are more frequent in patients who also have migraine, hyperlipidemia, and antinuclear antibodies, and in those who smoke or take birth control pills. Almost one-third of the 48 patients reported by Levine and associates (1990) had thrombocytopenia and 23 percent had a false-positive Venereal Disease Research Laboratory (VDRL) test. Some of the phospholipids with which the antibodies react are shared with clotting factors, particularly prothrombin and annexin, as well as with the “lupus anticoagulant” (a cardiolipin-glycoprotein complex). These antibodies are circulating serum polyclonal immunoglobulins (immunoglobulin [Ig] G, IgM, IgA). The vascular lesions are mainly in the cerebral white matter and are infarcts, seen well with MRI. Angiography reveals occlusions of arteries at unusual sites (Brey et al). The mechanism of stroke is not entirely clear and may derive from emboli originating on mitral valve leaflets similar to nonbacterial thrombotic endocarditis; alternatively, and more likely in our view, there is a noninflammatory in situ thrombosis of medium-sized cerebral vessels, as suggested by the limited pathologic material studied by Briley and colleagues. These circulating antibodies may also cause a syndrome of transient bilateral chorea or hemichorea; some patients have an additional slight hemiparesis or other subtle focal signs. Almost all of the affected patients we have seen have been women with thrombocytopenia, some of whom probably had systemic lupus, at least on the grounds of laboratory studies. A direct connection of the choreic syndrome to the antibodies comparable to what is proposed in Sydenham chorea may be valid, but at the moment is unproven. Some cases display microinfarctions in the basal ganglia, perhaps on the basis of valvular vegetations. The syndrome may be precipitated in these patients
by the introduction of estrogen-containing birth control pills and is improved, usually promptly, by corticosteroids or antiplatelet agents. The Sneddon syndrome consists of deep blue-red lesions of livedo reticularis and livedo racemosa in association with multiple strokes; 126 cases had been reported up to 1992. Most, but not all, patients have high titers of antiphospholipid antibodies. Although the skin lesions show a noninflammatory vasculopathy with intimal thickening, the pathology of the occlusive disease has not been adequately studied. In a report of 17 such patients by Stockhammer and coworkers, 8 had strokes and MRI showed lesions in 16 patients. The age of patients with strokes was 30 to 35 years; hence this condition is considered in young adults with cerebrovascular disease. Many of the lesions on MRI were small, deep, and multiple. Although there is a tendency for strokes to recur, many of the patients have remained well for years after a single stroke. Skin biopsy aids in diagnosis. There are instances in which the radiologic changes caused by recurrent small infarctions are difficult to distinguish from multiple sclerosis, as discussed in several parts of Chap. 36, on demyelinative diseases. Associations of the antiphospholipid syndrome with transverse myelitis (see Chap. 44), Guillain-Barré syndrome, hearing loss, and a number of other processes have been suspected but not proven. Treatment Warfarin has been used with some benefit in the above conditions. Khamashta and colleagues have found that the INR must be maintained close to 3 for effective prevention of stroke. According to the study conducted by Crowther and colleagues, an INR of 2 to 3 conferred the same degree of protection from thrombosis as did higher levels, but the number of thrombotic events was low in both groups and there was only 1 stroke in 114 patients over a period of about 3 years. Patients with severe thrombocytopenia and with other intrinsic coagulopathies should be treated with warfarin very cautiously. Although the INR is used as a gauge of the level of anticoagulation, it may be altered by the antibodies; no ideal method for monitoring treatment has been devised. Aspirin, on uncertain grounds, is thought not to confer protection for stroke, but in only a few small series has its effect been analyzed. In “catastrophic” cases, intravenous immunoglobulin and plasma exchange have been used with some effect. It is important to eliminate smoking and estrogen-containing compounds, as these greatly raise the risk of stroke in this syndrome. Aspirin and heparin are favored in women with recurrent fetal loss related to antiphospholipid antibody (Lockshin and Sammaritano).
Thrombotic Thrombocytopenic Purpura (Moschcowitz Syndrome) and Hemolytic Uremic Syndrome These are serious diseases of the small blood vessels combined with microangiopathic hemolytic anemia characterized by widespread occlusions of arterioles and capillaries involving practically all organs of the body, including the brain. It was described by Adams and colleagues (1948) and named thrombocytic acroangiothrombosis. Fibrin compo-
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nents have been identified by immunofluorescent techniques; some investigators have demonstrated disseminated intravascular platelet aggregation rather than fibrin thrombi. Sporadic TTP is caused by an acquired circulating IgG inhibitor of the von Willebrand factor-cleaving protease (termed “a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 [ADAMTS13]”). A rarer familial form (The Upshaw-Shulman syndrome) is caused by a inherited deficiency of ADAMTS13. Clinically, the main features of this disease are fever, anemia, symptoms of renal and hepatic disease, and thrombocytopenia—the latter giving rise to the common hemorrhagic manifestations (petechiae and ecchymoses of the skin, retinal hemorrhages, hematuria, gastrointestinal bleeding, etc.). Neurologic symptoms are practically always present and are the initial manifestation of the disease in about half the cases. Confusion, delirium, seizures, and hemiparesis—sometimes remittent or fluctuating in nature—are the usual manifestations of the nervous system disorder and are readily explained by the widespread microscopic ischemic lesions in the brain. Garrett and colleagues have emphasized the presentation of nonconvulsive status epilepticus in TTP, and we have encountered two such cases. Gross infarction was not observed. In most patients who survive, recovery of the focal neurologic deficits can be expected unless there is an identifiable infarction on CT or MRI. The CSF is normal except for elevated protein in some cases. To our knowledge, a mononeuritis multiplex does not occur. The diagnosis is made by finding a microangiopathic hemolytic anemia in the context of the characteristic clinical picture. An assay for ADAMTS13 activity is available using an enzyme-linked immunosorbent assay but the initiation of treatment usually cannot await confirmation of the diagnosis. There is an important overlap among TTP, HUS, toxemia of pregnancy, the hemolytic anemia with elevated liver function tests and platelet count (HELLP syndrome), hypertensive encephalopathy, and other causes of the posterior reversible leukoencephalopathy syndrome. In all of them, the central nervous system problem is mediated by endothelial dysfunction with breakdown of the blood– brain barrier. The recommended treatment for TTP is plasma exchange or plasma infusion. Further details can be found in Harrison’s Principles of Internal Medicine.
Polycythemia Vera, Thrombocytosis, and Thrombocythemia Polycythemia vera is a myeloproliferative disorder of unknown cause, characterized by a marked increase in RBC mass and in blood volume and often by an increase in WBCs and platelets. The condition must be distinguished from the many secondary or symptomatic forms of polycythemia (erythrocytosis), in which the platelets and white cells remain normal. The slightly increased incidence of thrombosis in primary polycythemia is attributed to the high blood viscosity, engorgement of vessels, and reduced rate of blood flow. The majority of patients with cerebrovascular manifestations have TIAs and small strokes, but we have seen one case of sagittal sinus thrombosis. With very high hematocrit, sludging of red cells
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may be seen in the retinal vessels. The cause of cerebral hemorrhage in this disease is less clear, although a number of abnormalities of platelet function and of coagulation have been described (see Davies-Jones et al). Instances of platelet counts above 800,000/mm3 are considered to be a form of myeloproliferative disease allied with polycythemia vera. In some patients there is an enlarged spleen, polycythemia, chronic myelogenous leukemia, or myelosclerosis. In several of our patients, no explanation of the thrombocytosis was found. They presented with recurrent cerebral and systemic thrombotic episodes, often of minor degree and transient. Cytapheresis, to reduce the platelets, and antiplatelet drugs (hydroxyurea anagrelide) to suppress megakaryocyte formation, are helpful in ameliorating the neurologic symptoms. In one of the cases we have followed, several small lesions, presumably infarctions, were situated in the white matter and simulated multiple sclerosis. Another patient with essential thrombocytosis developed dramatic new migraine with aura when her platelet counts exceeded 1,000,000/mm3. A wide variety of bleeding disorders—such as leukemia, aplastic anemia, thrombocytopenic purpura, and hemophilia— may also give rise to cerebral hemorrhage. Many rare forms of bleeding disease may be complicated by hemorrhagic manifestations; these are reviewed by Davies-Jones and colleagues.
Sickle Cell Disease This inherited disease is related to the presence of the abnormal hemoglobin S in the red corpuscles. Clinical abnormalities occur mainly in patients with sickle cell disease—i.e., with the homozygous state, and not in those with the sickle cell trait, which represents the heterozygous state. We have seen neurologic symptoms in patients with a heterozygous mixed hemoglobinopathy, such as sickle-thalassemia, sickle-S, and sickle-D, but all are less severe and less frequent than in sickle cell anemia. The disease, which is practically limited to persons of central African and certain Mediterranean origins, begins early in life and is characterized by “crises” of infection (particularly pneumococcal meningitis), pain in the limbs and abdomen, chronic leg ulcers, and infarctions of bones and visceral organs. Ischemic lesions of the brain, both large and small, are the most common neurologic complications, but cerebral, subarachnoid, and subdural hemorrhage may also occur, and the vascular occlusions may be either arterial or venous. Patients with sickle cell anemia may develop progressive stenosis of the supraclinoid intracranial carotid artery with consequent collateral formation, producing a syndrome akin to the moyamoya disease. These fragile collateral vessels may rupture causing intracranial hemorrhage. Lee and colleagues demonstrated that exchange transfusions with monitoring of the velocities of flow in the middle cerebral artery by transcranial Doppler examination reduces the risk of this important neurologic complication. In the stroke prevention trial of sickle cell anemia, the risk of first stroke was reduced by 90 percent in 63 children who received periodic transfusions as compared to 67 children who received only supportive care.
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Disseminated Intravascular Coagulation This is perhaps the most common and most serious disorder of coagulation affecting the nervous system. The basic process depends on the release of thromboplastic substances from damaged tissue, resulting in the activation of the coagulation process and the formation of fibrin, in the course of which clotting factors and platelets are consumed. Virtually any mechanism that produces tissue damage can result in the release of tissue thromboplastins into the circulation. Thus, disseminated intravascular coagulation (DIC) complicates a wide variety of clinical conditions—overwhelming sepsis, massive trauma, cardiothoracic surgery, heat stroke, burns, incompatible blood transfusions and other immune complex disorders, diabetic ketoacidosis, leukemia, obstetric complications, cyanotic congenital heart disease, and shock from many causes. The essential pathologic change in DIC is the occurrence of widespread fibrin thrombi in small vessels, resulting in numerous small infarctions of many organs, including the brain. Sometimes DIC is manifest by a hemorrhagic diathesis in which petechial hemorrhages are situated around small penetrating vessels. In some cases, cerebral hemorrhage is quite extensive, similar to a primary hypertensive hemorrhage. The main reason for the hemorrhage is the consumption of platelets and various clotting factors that occurs during fibrin formation; in addition, fibrin degradation products have anticoagulant properties of their own. The diffuse nature of the neurologic damage may suggest a metabolic rather than a vascular disorder of the brain. In the absence of a clear metabolic, infective, or neoplastic cause of an encephalopathy, the onset of acute and fluctuating focal neurologic abnormalities or a generalized and sometimes terminal neurologic deterioration during the course of a severe illness should arouse suspicion of DIC, and coagulation factors and fibrin split products should be measured. Platelet counts are invariably depressed and there is evidence of consumption of fibrinogen and other clotting factors, indicated by prolonged prothrombin and partial thromboplastin times. In the related illness abbreviated as HELLP mentioned previously, women with eclampsia develop liver failure and thrombocytopenia; the contribution of this limited form of DIC to the eclamptic effects on the nervous system have not been established (see earlier discussion of eclampsia).
DIFFERENTIATION OF VASCULAR DISEASE FROM OTHER NEUROLOGIC ILLNESSES The diagnosis of a vascular lesion rests essentially on recognition of the stroke syndrome; without evidence of this, the diagnosis must always be in doubt. The three criteria by which the stroke is identified should be reemphasized: (1) the temporal profile of the clinical syndrome, (2) evidence of focal brain disease, and (3) the clinical setting. Definition of the temporal profile requires a clear history of the premonitory phenomena, the mode of onset, and the evolution of the neurologic disturbance in relation to the patient’s medical status. Here, an inadequate history is
the most frequent cause of diagnostic error. If these data are lacking, the stroke profile may still be determined by extending the period of observation for a few days or weeks, thus invoking the clinical rule that the physician’s best diagnostic tool is a second and third examination. There are few categories of neurologic disease whose temporal profile mimics that of the cerebrovascular disorders. Migraine may do so, but the history usually provides the diagnosis. A seizure may be followed by a prolonged focal deficit (Todd paralysis) but is rarely the initial event in a stroke; the setting in which these symptoms occur and their subsequent course clarify the clinical situation. Strokelike episodes appear in the course of certain hereditary metabolic disorders (Fabry disease, homocystinuria, mitochondrial disease). Differentiation is not difficult because of the associated myopathic and neurologic signs and characteristic metabolic defects. Tumor, infection, inflammation, degeneration, and nutritional deficiency are unlikely to manifest themselves precipitously, although rarely a brain metastasis produces a focal deficit of abrupt onset (see below). Trauma, of course, occurs abruptly but usually offers no problem in diagnosis. In multiple sclerosis and other demyelinative diseases, there may be an abrupt onset or exacerbation of symptoms, but for the most part they occur in a different age group and clinical setting. Conversely, a stroke-like onset of cerebral symptoms in a young adult should always raise a suspicion of demyelinative disease. A stroke developing over a period of several days usually progresses in a stepwise fashion, increments of deficit being added abruptly from time to time. A slow, gradual, downhill course over a period of 2 weeks or more indicates that the lesion is probably not vascular but rather neoplastic, demyelinative, infectious (abscess) or granulomatous, or a subdural hematoma. In regard to the focal neurologic deficits of cerebrovascular disease, many of the nonvascular diseases may produce symptoms that are much the same, and the diagnosis cannot rest solely on this aspect of the clinical picture. Nonetheless, certain combinations of neurologic signs, if they conform to a neurovascular pattern—e.g., the lateral medullary syndrome—mark the disease as vascular-occlusive in nature. Many thrombotic strokes are preceded by TIAs, which, if recognized, are diagnostic of this form of vascular disease. It is essential that TIAs be differentiated from seizures, syncope, panic attacks, neurologic migraine, and attacks of labyrinthine vertigo, because a failure to do so may result in unnecessary arteriographic studies and even a surgical operation. With very few exceptions, the presence of blood in the CSF points to a cerebrovascular (rarely, spinal vascular) lesion, provided that trauma and a traumatic tap can be excluded. Headache is common in cerebrovascular disease; it occurs not only with hemorrhage but also with thrombosis, arterial dissections, and, rarely, with embolism. Seizures are almost never the premonitory, first, or only manifestation of a stroke but can rarely occur in the first few hours after infarction or intracranial bleeding. Brief unconsciousness (5 to 10 min) is rare in stroke, being seen only with basilar artery insufficiency and as an initial event in ruptured aneurysm or primary intracerebral hemorrhage. In the latter case, a depression in the state of consciousness soon
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reasserts itself and is then progressive. Certain neurologic disturbances are hardly ever attributable to stroke—e.g., diabetes insipidus, fever, bitemporal hemianopia, parkinsonism, generalized myoclonus, repeated falls, and isolated cranial nerve palsies—and their presence may be of help in excluding vascular disease. Finally, the diagnosis of cerebrovascular disease should always be made on positive data, not by exclusion. A few conditions are so often confused with cerebrovascular diseases that they merit further consideration. When a history of trauma is absent, the headache, drowsiness, mild confusion, and hemiparesis of subdural hematoma may be ascribed to a “small stroke,” and the patient may fail to receive immediate surgical therapy. In subdural hematoma, the symptoms and signs usually develop gradually over a period of days or weeks. The degree of headache, obtundation, and confusion is disproportionately greater than the focal neurologic deficit, which tends to be indefinite and variable until late in the evolution of the hematoma. If the patient has fallen and injured his head at the onset of the stroke, it may be impossible to rule out a complicating subdural hematoma on clinical grounds alone, in which case CT scanning and MRI are usually diagnostic. The reverse diagnostic error will not be made if one remembers that patients with subdural hematoma rarely exhibit a total hemiplegia, monoplegia, hemianesthesia, homonymous hemianopia, or aphasia. If such focal signs are present and particularly if they developed suddenly, subdural hematoma is not likely to be the explanation. A brain tumor, especially a rapidly growing glioblastoma or lymphoma, may produce a severe hemiplegia within a week or two. Also, the neurologic deficit caused by carcinoma metastatic to the cerebrum may evolve rapidly, almost at a stroke-like pace. Moreover, in rare cases, the hemiplegia may be preceded by transitory episodes of neurologic deficit, indistinguishable from TIAs. However, in both conditions, a detailed history will indicate that the evolution of symptoms was gradual; if it was saltatory, seizures will usually have occurred. The chest film frequently discloses a primary or secondary tumor, and an increased blood sedimentation rate suggests that a concealed systemic disease process is at hand. A lack of detailed history may also be responsible for the opposite diagnostic error, i.e., mistaking a relatively slowly evolving stroke (usually caused by internal carotid artery or basilar occlusion) for a tumor. Again, CT scanning and MRI usually settles the problem. A brain abscess or inflammatory necrotic lesion—e.g., herpes encephalitis or toxoplasmosis— may also develop rapidly. Dementia of the Alzheimer type is often ascribed, on insufficient and conceptually incorrect grounds, to the occurrence of multiple small strokes. If vascular lesions are responsible, evidence of an apoplectic episode or episodes and of focal neurologic deficit to account for at least part of the syndrome will almost invariably be disclosed by history and examination. In the absence of a history of episodic development or of focal neurologic signs, it is unwarranted to attribute senile dementia to cerebrovascular disease—in particular to small strokes in silent areas. Cerebral arteriosclerosis is another term that has often been used carelessly to explain such mental changes, the implication (incorrect) being that arteriosclerosis itself causes
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ischemic damage to the nervous system, producing loss of intellectual function but no other neurologic deficit. If cerebral arteriosclerosis (atherosclerosis) is actually responsible, there should be evidence of it in the form of strokes at some time in the course of the illness and often in the heart (myocardial infarction, angina pectoris) or legs (intermittent claudication, loss of pulses). Frequently, the lesions of both vascular and Alzheimer disease are present, in which case there may be difficulty in determining to what extent each of them is responsible for the neurologic deficit. Several studies have shown an increased incidence or an acceleration of Alzheimer dementia if there are concurrent vascular lesions, but further studies are needed to confirm this notion. Recurrent seizures as the result of a previous stroke occur in up to 10 percent of cases (postinfarction epilepsy; see “Seizures Following Stroke” later on). When evidence, by history or examination, of the original stroke is lacking, as it often is, or if the seizures are not observed or leave behind a temporary increase in the neurologic deficit (Todd paralysis), the diagnosis of another stroke or a tumor may be made in error. Miscellaneous conditions occasionally taken to be a stroke are Bell’s palsy; Stokes-Adams attacks; a severe attack of labyrinthine vertigo; diabetic ophthalmoplegia; acute ulnar, radial, or peroneal palsy; embolism to a limb; and temporal arteritis associated with blindness. Contrariwise, certain manifestations of stroke may be incorrectly interpreted as evidence of some other neurologic disorder. In lateral medullary infarction, dysphagia may be the outstanding feature; if the syndrome is not kept in mind, a fruitless radiologic search for a local esophageal or pharyngeal cause may be undertaken. Similarly, facial pain or a burning sensation because of involvement of the trigeminal spinal nucleus in lateral medullary stroke may be misattributed to sinus disease. Headache, at times severe, often occurs as a prodrome of a thrombotic stroke or subarachnoid hemorrhage; unless this is appreciated, a diagnosis of migraine may be made. Dizzy spells, vertigo, vomiting, or brief intermittent lapses of equilibrium as a result of vascular disease of the brainstem may be ascribed to vestibular neuronitis, Ménière disease, StokesAdams syncope, or gastroenteritis. A detailed account of the attack will usually avert this error. A strikingly focal monoplegia of cerebral origin, causing only weakness of the hand or arm or foot-drop, is not infrequently misdiagnosed as a peripheral neuropathy. In the presence of coma, the differentiation of vascular from other neurologic diseases offers special problems. If the patient is comatose when first seen and an adequate history is not available, cerebrovascular lesions must be differentiated from all the other causes of coma described in Chap. 17 and commented on below.
COMMON CLINICAL PROBLEMS IN CEREBROVASCULAR DISEASE Inevitably, most patients are seen first by clinicians who may not be expert in all the fine points of cerebrovascular
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disease. Situations arise in which critical decisions must be made regarding anticoagulation, further laboratory investigation, and the advice and prognosis to be given to the family. The following are some of the situations encountered by the authors that may be of value to students and residents and to nonspecialists in the field.
The Patient with a History of an Ischemic Attack or Small Stroke in the Past The patient may be functioning normally when examined, but it has been ascertained by the history or radiologic procedures that a stroke or TIA occurred in the past. The problem is what measures should be taken to reduce the risk of further strokes. This is particularly problematic if a surgical procedure is planned. A brief focal TIA, several minutes or less in duration, or many stereotyped spells usually represent severe stenosis of the internal carotid artery on the side of the affected cerebral hemisphere. If the symptoms have occurred recently, these may be forerunners of complete occlusion. If the TIA was far in the past—more than several weeks previously—the immediate risks of occlusion are reduced. The initial approach is to establish the patency of the carotid arteries by ultrasonography or MRA. If there is a reduction in diameter of greater than 70 percent when compared with an adjacent normal segment of vessel, and probably if there is a severely ulcerated but not critically stenotic plaque, carotid surgery (or angioplasty) is advisable. If a single TIA lasted more than an hour or the neurologic examination discloses minor signs referable to the region of the hemisphere affected by the TIA, a search for a source of embolus is indicated. Appropriate diagnostic studies include ECG, a transesophageal echocardiogram, monitoring for cardiac arrhythmia, ultrasonography of the carotid arteries, and a CT scan or MRI if it has not already been performed. Preventive anticoagulation (warfarin) is instituted if a source of clot within the cardiac chambers is found or if there is atrial fibrillation. Aspirin is appropriate but not imperative if no abnormality is found. Control of elevated blood pressure and addressing high cholesterol levels are ancillary steps. The mistake is to ignore the potential significance of a small stroke or TIA.
The Patient with Atrial Fibrillation In patients with this arrhythmia who are older than age 65 years and in those of any age with valvular disease, anticoagulation with warfarin is virtually mandated unless there is excessive risk because of falling or hematologic disease. Patients below approximately age 65 who are “lone fibrillators” (have no other cardiac or systemic disease) need not receive anticoagulation unless there has been a previous embolism. Whether younger patients who have additional vascular risk factors, such as diabetes or hypertension, benefit from anticoagulation is not known. If warfarin is to be discontinued for a necessary surgical procedure, it should be reinstated as soon as the surgeon deems it safe, as this is a time of increased stroke vulnerability. It has been the sense of many cardiologists that intermittent atrial fibrillation and fibrillation-flutter
tachycardias also represent a risk of cerebral embolism, but there are no adequate studies to confirm this.
The Patient with a Recent Stroke That May Not Be Complete Here the basic problem is whether a thrombotic infarction (venous or arterial) will spread and involve more brain tissue; or if embolic, whether the ischemic tissue will become hemorrhagic or another embolus will occur; or if there is an arterial dissection, whether it will give rise to emboli. Therapies are controversial in most of these circumstances. In some centers, it is the practice to try to prevent propagation of a thrombus by administering heparin (or low-molecular-weight heparin) followed by warfarin, as discussed earlier. Thrombolytic agents are an alternative if the stroke has occurred within the previous 2 or 3 h and is not too large. Except perhaps in cases of recent myocardial infarction, atrial fibrillation, or carotid disease, it is not imperative to begin heparin immediately while awaiting the effects of warfarin.
The Inevident or Misconstrued Syndromes of Cerebrovascular Disease Although hemiplegia is the classic type of stroke, cerebrovascular disease may manifest itself by signs that spare the motor pathways but have the same serious diagnostic and therapeutic implications. The following stroke syndromes tend to be overlooked. Sometimes disregarded is a leaking aneurysm presenting as a sudden and intense generalized headache lasting hours or days and unlike any headache in the past. Examination may disclose no abnormality except for a slightly stiff neck and raised blood pressure. Failure to investigate such a case by imaging procedures and examination of the CSF may permit the occurrence of a later massive subarachnoid hemorrhage. Small cerebral hemorrhages, subdural hematomas, and brain tumors figure into the differential diagnosis, which is usually settled by a CT scan or MRI. A second nonobvious stroke is one caused by occlusion of the posterior cerebral artery, usually embolic. This may not be recognized unless the visual fields are routinely tested at the bedside. The patient himself may not be aware of the difficulty or will complain only of blurring of vision or the need for new glasses. Accompanying deficits are inability to name colors or recognize manipulable objects or faces, difficulty in reading, etc. MRI or CT scanning usually corroborates the clinical diagnosis, and therapy is directed against further emboli or extension of the thrombosis. Another inapparent or confounding stroke that may be mistaken for psychiatric disease is an attack of paraphasic speech from embolic occlusion of a branch of the left middle cerebral artery. The patient talks in nonsensical phrases, appears confused, and does not fully comprehend what is said to him. He may perform satisfactorily at a superficial level and offer socially appropriate greetings and gestures. Only scrutiny of language function and behavior will lead to the correct diagnosis. Infarction (or trauma) of the dominant or nondominant temporal lobe
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and rarely of the caudate may produce an agitated delirium with few focal findings. This may be mistaken for a toxic or withdrawal state. Parietal infarctions on either side (usually nondominant hemisphere) are often missed because the patient is entirely unaware of the problem or the symptoms create only a subtle confusional state, drowsiness, or only subtle problems with calculation, dialing a phone, reaching accurately for objects, or loss of ability to write. Extinction of bilaterally presented visual or tactile stimuli gives a clue; marked asymmetry of the optokinetic nystagmus response is sometimes the only definite sign. A cerebellar hemorrhage may at first be difficult to recognize as a stroke. An occipital headache and complaint of dizziness with vomiting may be interpreted as a labyrinthine disorder, gastroenteritis, or myocardial infarction. A slight ataxia of the limbs, inability to sit or stand, and mild gaze paresis may not have been properly tested or have been overlooked. Early intervention by surgery may be lifesaving; but once the syndrome has progressed to the point of coma with pupillary abnormalities with bilateral Babinski signs, surgery is usually useless. Periventricular white matter changes (leukoaraiosis) correlate poorly with cerebrovascular disease and may be misinterpreted. We prefer to ignore them unless they are extensive and obscure a new lacunar stroke.
The Comatose Stroke Patient The most common causes of vascular coma are intracranial hemorrhage—usually deep in the hemisphere, less often in the cerebellum or brainstem, extensive subarachnoid hemorrhage, and basilar artery occlusion. After several days, brain edema surrounding a large infarction in the territory of the middle cerebral artery or adjacent to a hemorrhage may compress the midbrain and produce the same effect. Certain remedial surgical measures are still available in these circumstances: drainage of blood from
References ACTIVE Writing Group, The: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with Irbesartan for prevention of vascular events (ACTIVE W)—a randomized trial. Lancet 367:1903, 2006. [PMID: 16765759] Adams HP Jr, Butler MJ, Biller J, Toffol GN: Nonhemorrhagic cerebral infarction in young adults. Arch Neurol 43:793, 1986. [PMID: 3729759] Adams RD: Mechanisms of apoplexy as determined by clinical and pathological correlation. J Neuropathol Exp Neurol 13:1, 1954. [PMID: 13118371] Adams RD, Cammermeyer J, Fitzgerald PJ: The neuropathological aspects of thrombotic acroangiothrombosis. J Neurol Neurosurg Psychiatry 11:1, 1948. [PMID: 18907040] Adams RD, Torvik A, Fisher CM: Progressing stroke: Pathogenesis, in Siekert RG, Whisnant JP (eds): Cerebral Vascular Diseases, Third Conference. New York, Grune & Stratton, 1961, pp 133–150. Adams RD, Vander Eecken HM: Vascular disease of the brain. Annu Rev Med 4:213, 1953. [PMID: 13105274]
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the ventricles, shunting of the ventricles in cases of secondary hydrocephalus due to obstruction of the third ventricle or aqueduct, evacuation of a cerebral hemorrhage in cases of recent decline into stupor and coma, and hemicraniectomy in the case of massive stroke edema. Also, thrombolytic therapy and anticoagulants are sometimes successful in reversing the progression of basilar artery thrombosis. These procedures are best carried out in centers with experience in cerebrovascular intensive care. If coma persists or is deep and sudden, only supportive treatment is possible.
Seizures following Stroke With the exception of infarction caused by cerebral venous occlusion, epileptic seizures following stroke are not a great problem. As mentioned earlier and in other chapters of the book, seizures are quite infrequent as the initial manifestation of an ischemic stroke, and when they do occur in this fashion, an embolus is usually the causative mechanism. In the data presented by Lamy and colleagues (who were studying stroke in young patients with patent foramen ovale), when seizures occurred not at the outset but within the first week after stroke, as they did in 2 to 4 percent of their cases, about half had another seizure, usually single, during the next several years. However, the same was true for those with a first seizure after 1 week. No satisfactory study has been conducted to determine if these patients benefit from anticonvulsant therapy to prevent the second or subsequent seizures. Following the practice of most other neurologists, we prescribe phenytoin or an equivalent drug only if there has been a seizure and continue it for about 18 months. If the EEG continues to show focal sharp waves or other epileptic activity at that time, we continue the drug; if not, we may discontinue the medication. It is also clear that prophylactic anticonvulsant treatment of all stroke patients is not necessary.
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CHAPTER 34
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35 Craniocerebral Trauma
Among the vast array of neurologic diseases, cerebral trauma ranks high in order of frequency and gravity. In the United States, traum854a is the leading cause of death in persons younger than 45 years of age and more than half of these deaths are a result of head injuries. According to the American Trauma Society, an estimated 500,000 Americans are admitted to hospitals yearly following cerebral trauma; of these, 75,000 to 90,000 die and even larger numbers, most of them young and otherwise healthy, are left permanently disabled. The basic problem in craniocerebral trauma is at once both simple and complex: simple because there is usually no difficulty in determining causation, namely, a blow to the head, and complex because of a number of delayed effects that may complicate the injury. As for the trauma itself, nothing medical can be done, for it is finished before the physician arrives on the scene. At most there can be an assessment of the full extent of the immediate cerebral injury, an evaluation of factors conducive to complications and further lesions, and the institution of measures to avoid such additional problems. But of the disastrous intracranial phenomena that can be initiated by head injury, several fall within the purview of the neurologist and offer possibilities of treatment. New techniques of cellular biology are exposing phenomena that are set in motion by traumatic injury of nerve cells and glia. Some of these changes may be reversible, but at the moment, such knowledge is limited. It is a common misconception that craniocerebral injuries are matters that concern only the neurosurgeon and not the general physician or neurologist. Actually, some 80 percent of head injuries are first seen by a general physician in an emergency department, and probably fewer than 20 percent ever require neurosurgical intervention of any kind, even this number is decreasing. The neurologist must be familiar with the clinical manifestations and the natural course of primary brain injury and its complications and have a sound grasp of the underlying physiologic mechanisms. Such knowledge must be up-to-date and immediately applicable, particularly as it relates to the interpretation of CT and MRI, both of which have greatly enhanced our ability to deal with head trauma. The present chapter reviews the salient facts concerning craniocerebral injuries and outlines a clinical approach that the authors have found useful over the years. Matters
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pertaining to spinal injuries, often coexistent with head trauma, are considered in Chap. 44.
DEFINITIONS AND MECHANISMS The very language that one uses to discuss certain types of head injuries divulges a number of misconceptions inherited from previous generations of physicians. Certain terms have crept into the medical vocabulary and have been retained long after the ideas for which they stood have been refuted, attesting to the disadvantage of premature adoption of explanatory terms rather than descriptive ones. The word concussion, for example, implies a violent shaking or jarring of the brain and a resulting transient functional impairment. Yet despite numerous postulates of physical changes within nerve cells, axons, or myelin sheaths (vibration effects, formation of intracellular vacuoles), confirmation of their existence has proven difficult in humans and experimental animals. Similarly the word contusion, meaning a bruising of cerebral tissue without interruption of its architecture, is applied rather indiscriminately to a variety of entities, some of which could not depend on a pathologic change of this type, e.g., “minor contusion state, or syndrome,” an expression introduced by Wilfred Trotter, who was himself critical of words that “embalm a fallacious theory.” In all attempts to analyze the mechanisms of closed, or blunt (nonpenetrating), head injury, one fact is preeminent: there must be the sudden application of a physical force of considerable magnitude to the head. Unless the head is struck, the brain suffers no injury except in the rare instances of violent flexion–extension (whiplash) of the neck and in explosion-blast injury with a sudden extreme increase of atmospheric pressure. In military medical practice, blast injuries assume great importance and in theory, challenge many concepts of loss of consciousness in closed head injury; i.e., there is no sudden acceleration or deceleration of the cranium as discussed further on. The mechanical factors of importance in brain injury are the differential mobility of the head and brain on the neck, the tethering of the upper brainstem that allows movement of the cerebral hemispheres, and the relationship of injured parts of the brain to dural septa and bony promi-
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nences. As to concussive injuries, it is useful to point out that all concussions involve a physical force that imparts motion to the stationary head or, more commonly, a hard surface that arrests the motion of a moving head, i.e., concussion does not occur if the head is stationary. This sudden deceleration or acceleration of the cranium is the mechanism of most civilian head injuries, and they are notable in two respects: they frequently induce at least a temporary loss of consciousness, and the brain may suffer gross damage even though the skull is not penetrated, i.e., contusion, laceration, hemorrhage, and swelling. A theory that would bring into coherent form all of these physical and gross neuropathologic changes and their relation to transient loss of consciousness (concussion) and prolonged coma has only been tentatively formulated. In contrast to closed head injury, high-velocity missiles penetrate the skull and cranial cavity, or, rarely, the skull may be compressed between two converging forces that crush the brain without causing significant displacement of the head or the brain. In these circumstances, the patient may suffer severe and even fatal injury without immediate loss of consciousness. Hemorrhage, destruction of brain tissue, and, if the patient survives for a time, meningitis or abscess are the principal pathologic changes created by injuries of these types. They offer little difficulty to our understanding. Figure 35-1 illustrates these various types of head injuries. The relation of skull fracture to brain injury has been viewed in changing perspective throughout the history of
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this subject. In the first half of the last century, fractures dominated the thinking of the medical profession, and cerebral lesions were regarded as secondary. Later, it became clear that the skull, although rigid, is still flexible enough to yield to a blow that injures the brain without causing fracture. Therefore the presence of a fracture, although a rough measure of the force to which the brain has been exposed, is not an infallible index of the presence of cerebral injury (see further on in discussion of predictive features for imaging abnormalities with concussion). Even in fatal head injuries, autopsy reveals an intact skull in 20 to 30 percent of cases. Of course, many patients suffer skull fractures without serious or prolonged disorder of cerebral function, largely because the energy of a blow is dissipated in the fracture. Indeed, this diffusion of the impact might be expected to reduce underlying brain damage. The modern trend is to be concerned primarily with the presence or absence of brain injury rather than with the fracture of the skull itself. Nevertheless, fractures cannot be dismissed without further comment for several reasons. Overall, brain injury is estimated to be 5 to 10 times more frequent with skull fractures than without them and perhaps 20 times more frequent with severe and multiple fractures. Fractures assume further importance in providing an explanation for cranial nerve palsies, and in creating potential pathways for the ingress of bacteria and air or the egress of cerebrospinal fluid (CSF leak). In these respects, fractures through the base of the skull are of special significance, and are considered below.
A B
E
Figure 35-1. Mechanisms of craniocerebral injury. A. Cranium distorted by forceps (birth injury). B. Gunshot wound of the brain. C. Falls (also traffic accidents). D. Blows on the chin (“punch-drunk”). E. Injury to skull and brain by falling objects. (Reproduced by permission from Courville.)
C
D
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Basal Skull Fractures and Cranial Nerve Injuries Figure 35-2 illustrates some of the major sites and directions of basilar skull fractures. One can readily perceive the possibilities of injury to cranial nerves in relation to such fractures. Fractures of the base are difficult to detect in plain skull films and may be missed by other imaging techniques, but their presence should always be suspected if any one of a number of characteristic clinical signs is in evidence. Fracture of the petrous pyramid often deforms the external auditory canal or tears the tympanic membrane, with resultant leakage of CSF (otorrhea); or, blood may collect behind an intact tympanic membrane and discolor it. If the fracture extends more posteriorly, damaging the sigmoid sinus, the tissue behind the ear and over the mastoid process becomes boggy and discolored (Battle sign). Basal fracture of the anterior skull may also cause blood to leak into the periorbital tissues, imparting a characteristic “raccoon” or “panda bear” appearance. The
Figure 35-2. The course of fracture lines through the base of the skull. Arrows indicate point of application and direction of force. (Reproduced by permission from Courville.)
presence of any of these signs calls for CT scanning of the skull base using bone window settings to detect a fracture. The existence of a basal fracture is also indicated by signs of cranial nerve damage. The olfactory, facial, and auditory nerves are the ones most liable to injury, but any one, including the twelfth, may be damaged. Anosmia and an apparent loss of taste (actually a loss of perception of aromatic flavors as the elementary modalities of taste are unimpaired) are frequent sequelae of head injury, especially with falls on the back of the head. In the majority of cases the anosmia is permanent. If unilateral, it will not be noticed by the patient. However, mechanism of these disturbances is thought to be a displacement of the brain and tearing of the olfactory nerve filaments in or near the cribriform plate, through which they course, rather than necessarily to a fracture. A fracture in or near the sella may tear the stalk of the pituitary gland with resulting diabetes insipidus. Rarely, such a fracture may cause bleeding from a preexisting pituitary adenoma and produce the syndrome of pituitary apoplexy (see Chap. 31). A fracture of the sphenoid bone may lacerate the optic nerve, with blindness from the beginning. The pupil is unreactive to a direct light stimulus but still reacts to a light stimulus to the opposite eye (consensual reflex). The optic disc becomes pale, i.e., atrophic, after an interval of several weeks. Partial injuries of the optic nerve result in scotomas and a troublesome blurring of vision. Complete oculomotor nerve injury is characterized by ptosis and diplopia, a divergence of the globes with the affected eye resting in an abducted and slightly depressed position, loss of medial and most of the vertical movements of the eye, and a fixed, dilated pupil, as described in Chap. 13. Diplopia that is worse on looking down and compensatory tilting of the head suggest trochlear nerve injury. In a series of 60 patients with head injury, Lepore confirmed the common experience that fourth-nerve palsy was the most common cause of diplopia, occurring unilaterally twice as often as bilaterally, followed in frequency by damage to one or both third nerves, then, least often, a unilateral or bilateral sixth-nerve palsy. Five of his patients had palsies that reflected damage to more than one nerve and 7 had supranuclear disorders of convergence. The long subarachnoid course of the fourth nerve is usually given as the explanation for its frequent injury, but this mechanism has never been validated. These optic and ocular motor nerve disorders must be distinguished from those caused by displacement of the globe as a result of direct injury to the orbit and the oculomotor muscles. Injury to the ophthalmic and maxillary divisions of the trigeminal nerve may be the result of either a basal fracture across the middle cranial fossa or a direct extracranial injury to the branches of the nerves. Numbness and paresthesia of the skin supplied by the nerve branch or a neuralgia can be troublesome sequelae of these injuries. The facial nerve may be involved in one of two ways. In the first type of injury, associated with transverse fractures through the petrous bone, there is an immediate facial palsy, probably caused by contusion or transection of the nerve. Surgical anastomosis has sometimes been successful in this circumstance. The second, more common type, is associated with longitudinal fractures of the petrous
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bone, the facial palsy then often being delayed for several days, a sequence that may be misinterpreted as progression of the intracranial traumatic lesion. This latter type is usually transitory, and its mechanism is not known. Injury to the eighth cranial nerve because of petrous fractures results in a loss of hearing or in postural vertigo and nystagmus coming on immediately after the trauma. Deafness as a result of nerve injury must be distinguished from the high-tone hearing loss because of cochlear injury and from deafness caused by bleeding into the middle ear and disruption of the ossicular chain (conduction deafness). Also, vertigo must be distinguished from the very common symptom of posttraumatic dizziness discussed in a later section. A rare fracture through the hypoglossal canal causes weakness of one side of the tongue. It should be kept in mind that blows to the upper neck may also cause lower cranial nerve palsies, either by direct injury to their peripheral extensions or as a result of carotid artery dissection, either in the cervical or intracranial segment of the artery.
Carotid–Cavernous Fistula A basal fracture through the sphenoid bone may lacerate the internal carotid artery or one of its intracavernous branches where it lies in the cavernous sinus. Within hours or a day or two, a disfiguring pulsating exophthalmos develops as arterial blood enters the sinus and distends the superior and inferior ophthalmic veins that empty into the sinus. The orbit feels tight and painful, and the eye may become partially or completely immobile because of pressure on the ocular nerves traversing the sinus (see Fig. 14-4). The sixth nerve is affected most often, and the third and fourth nerves less often. Also, there may be a loss of vision as a result of ischemia of the optic nerve and retina; congestion of the retinal veins and glaucoma are additional factors in the visual failure. Some 5 to 10 percent of fistulas resolve spontaneously, but the remainder must be obliterated by interventional radiologic means (by a detachable balloon inserted into the carotid artery via a transfemoral catheter) or by a direct surgical repair of the fistula (see Stern). Not all carotid–cavernous fistulas are traumatic. They may occasionally occur with rupture of an intracavernous saccular aneurysm or in Ehlers-Danlos disease, where the connective tissue is defective; or the cause may be unexplained.
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sorbed by pledgets placed in the nasal cavity. Most cases of acute CSF rhinorrhea heal by themselves. An indwelling lumbar drain for a few days may aid the process. If the condition is persistent or is complicated by an episode of meningitis, repair of the torn dura mater is indicated. The prophylactic use of antibiotics to prevent meningitis in cases of nasal CSF leak is controversial, but many neurosurgeons continue this practice, particularly in children. A collection of air in the cranial cavity (aerocele) is a common occurrence following skull fracture or any extended neurosurgical procedure. The pocket of air is apparent by CT scan in the epidural or subdural space over the cerebral convexities or between the hemispheres, and serves only to warn of a potential route for the entry of bacteria into the cranium. Small collections of air are usually absorbed without incident, but a large volume may act as a mass and cause clinical deterioration after injury (tension pneumocranium; Fig. 35-3). Inhalation of 100 percent oxygen has a salutary effect, but needle aspiration of the air is required if the collection is causing clinical signs. Depressed (“derby hat”) fractures are of significance only if the underlying dura is lacerated or the brain is compressed by indentation of bone. They then are surgically repaired, preferably within the first 24 to 48 h.
Cerebral Concussion Much has been written about the mechanisms of concussion and transient coma in closed head injury. Certain facts concerning these conditions stand out. Concussion,
Pneumocephalus, Aerocele, and Rhinorrhea (Cerebrospinal Fluid Leak) If the skin over a skull fracture is lacerated and the underlying meninges are torn, or if the fracture passes through the inner wall of a paranasal sinus, bacteria may enter the cranial cavity, with resulting meningitis or abscess formation. Also, CSF that leaks into the sinus presents as a watery discharge from the nose (CSF rhinorrhea). The nasal discharge can be identified as CSF by testing it for glucose with diabetic test tape (mucus has no glucose) or by the presence of fluorescein or radionuclide-labeled dye that is injected into the lumbar subarachnoid space and then ab-
Figure 35-3. CT of postoperative tension pneumocranium (aerocele) that caused progressive drowsiness and required removal by aspiration. The air is apparent as a very-low-density collection that compresses the frontal lobes.
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meaning a reversible traumatic paralysis of nervous function, is always immediate (not delayed even by seconds). The effects of concussion on brain function may last for a variable time (seconds, minutes, hours, or longer). To set arbitrary limits on the duration of loss of consciousness, i.e., to consider a brief loss as indicative of concussion and a prolonged loss as indicative of contusion or other traumatic cerebral lesion, as proposed in some older medical writings, is illogical and unsound physiologically. As pointed out by Symonds, any such difference is quantitative, not qualitative (see Ropper and Gorson). Nonetheless, in the more prolonged states of stupor or coma, there is a far greater chance of finding hemorrhage and contusion, which undoubtedly contribute to the persistence of coma and the likelihood of irreversible change. Finally, the optimal condition for the production of concussion, demonstrated originally by Denny-Brown and Russell, is a sudden change in the momentum of the head; i.e., either movement is imparted to the stationary head by a blow or movement of the head is arrested by a hard, unyielding surface. These two types of blunt (nonpenetrating) head injuries are called accelerative and decelerative, respectively. The mechanism of concussive “cerebral paralysis” has been interpreted in various ways throughout medical history in light of the state of knowledge at a particular period of time. The favored hypotheses for the better part of a century were “vasoparalysis” (suggested by Fischer in 1870) or an arrest of circulation by an instantaneous rise in intracranial pressure (proposed by Strohmeyer in 1864 and popularized by Trotter in 1932). Jefferson, in his essay on the nature of concussion (1944), convincingly refuted these vascular hypotheses. Later, Shatsky and coworkers, by the use of high-speed cineangiography, showed displacement of vessels but no arrest of circulation immediately after impact. Beginning with the work of Denny-Brown and Russell in 1941, the physical factors involved in head and brain injuries were subjected to careful analysis. These investigators demonstrated, in the monkey and cat that concussion resulted when the freely moving head was struck by a heavy mass. If the head was prevented from moving at the moment of impact, the same degree of force invariably failed to produce concussion. The importance of head motion was verified by Gennarelli and colleagues, who were able to induce concussion in primates by rapid acceleration of the freely moving head without impact, a condition that rarely occurs in humans. Holbourn, a Cambridge physicist, from a study of gelatin models under conditions simulating head trauma, deduced that when the head is struck, movement of the partly tethered but suspended brain always lags (because of inertia), but inevitably the brain moves also, and when it does it must rotate in an arc because of attachment to the neck. Ommaya and Gennarelli (1974) proved the correctness of this assumption by photographing the brain through a transparent calvarium at the moment of impact. The brain was thus subjected to stresses set up by rotational forces mainly in the sagittal plane, centered at its point of tethering in the high midbrain. The torque at the level of the upper reticular formation would explain the immediate loss of consciousness, as described below. An
extensive and scholarly review of the pathophysiology of concussion was done by Shaw (although we do not agree with his view of a seizure-concussive mechanism). Not well explained by any of these mechanisms are concussions after blast injuries, a serious problem in military medicine. As mentioned in the introductory remarks, this syndrome possibly resurrects the notion that a shock wave travels through the brain and disrupts neural function without displacement of the cerebral hemispheres and an impact on the reticular formation of the midbrain. These rotational movements of the brain provide a reasonable explanation for the occurrence of surface injuries in specific locations, i.e., where the swirling brain comes into contact with bony prominences on the inner surface of the skull (petrous and orbital ridges, sphenoid wings), and of injuries to the corpus callosum, which is flung against the falx. These views on the site and mechanism of concussion are not fully accepted but have been supported by a number of additional physiologic observations. Foltz and Schmidt, in 1956, suggested that the reticular formation of the upper brainstem was the anatomic site of concussive injury. They showed that in the concussed monkey, lemniscal sensory transmission through the brainstem was unaltered, but its effect in activating the reticular formation was blocked and that the electrical activity of the medial reticular formation was depressed for a longer time and more severely than that of the cerebral cortex. Furthermore, Strich (1961) described the neuropathologic findings in patients who died months after severe closed head injuries that had caused immediate and protracted coma. In all of her cases, in which there were no signs of skull fracture, raised intracranial pressure or gross subarachnoid hemorrhage, she also observed an uneven but diffuse degeneration of the cerebral white matter that has become the basis of the notion of diffuse axonal shearing. In cases of shorter survival (up to 6 weeks), she observed ballooning and interruption of axis cylinders. These findings were subsequently confirmed and expanded by Nevin, by Adams and colleagues (1982), and by Gennarelli and coworkers, the last of these groups also working with monkeys. It is noteworthy that in most of these cases, and in those reported by Jellinger and Seitelberger, there were additional lesions in the region of the reticular activating system and small hemorrhagic softenings in the corpus callosum, superior cerebellar peduncles, and dorsolateral tegmentum of the midbrain. Strich (1956) interpreted the extensive white matter lesions, both in the hemispheres and in the upper brainstem, to represent a degeneration of nerve fibers that had been stretched or torn by the shear stresses set up during rotational acceleration of the head, as had been postulated earlier by Holbourn. She suggested that if nerve fibers are stretched rather than torn, the lesions may be reversible and may play a part in the mechanism of concussion. Symonds elaborated on this view and saw in the shearing stresses, which are maximal at the point where the cerebral hemispheres rotate on the relatively fixed brainstem, the explanation of concussion. The extension of Strich’s concept, namely that diffuse axonal injury throughout the cerebral white matter is the main cause of persistent unconsciousness, has been widely adopted. However, even
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the proponents of diffuse axonal injury as an important immediate effect of severe brain damage have found that thalamic lesions are almost always present in cases of prolonged coma or the persistent vegetative state (Adams et al, 2000).
Clinical Manifestations of Concussion In its fullest form, the characteristic clinical signs of concussive brain injury are the immediate abolition of consciousness, suppression of reflexes (falling to the ground if standing), transient arrest of respiration, a brief period of bradycardia, and fall in blood pressure following a momentary rise at the time of impact. Rarely, if these abnormalities are sufficiently intense, death may occur at the moment of impact, presumably from respiratory arrest. In its mildest form, there is no apparent loss of consciousness or collapse, only a brief period of stunned disorientation and amnesia during which the individual appears outwardly normal. The vital signs usually return to normal and stabilize within a few seconds while the patient remains unconscious. Brief tonic extension of the limbs, clonic convulsive movements lasting up to approximately 20 seconds and other peculiar movements may occur immediately after the loss of consciousness (see McCrory et al). These “concussive convulsions” are probably of little significance and have not been shown to confer an increased risk of future seizures. McCrory and colleagues noted an association between motor and convulsive movements and facial impact, and we have seen this feature twice in teenagers who collided while both were pursuing a ball. The plantar reflexes are transiently extensor. After a variable period of time, the patient begins to stir and opens his eyes. Corneal, pharyngeal, and cutaneous reflexes, originally depressed, return, and the limbs withdraw from painful stimuli. Gradually, contact is made with the environment and the patient begins to obey simple commands and respond slowly to simple questions. Memories are not formed during this period; the patient may even carry on a conversation, which he cannot later recall. Finally, there is full neurologic recovery corresponding to the time when the patient can form consecutive memories of current experiences. The time required for the patient to pass through these stages of recovery may be only a few seconds or minutes, several hours, or possibly days; but again, between these extremes there seem to be only quantitative differences. To the observer, such patients are comatose only from the moment of injury until they open their eyes and begin to speak; however, for the patient, the period of unconsciousness in one limited perspective extends from a point before the injury occurred (retrograde amnesia) until the time when he is able to form consecutive memories at the end of the period of anterograde amnesia. The duration of the amnesic period, particularly of anterograde amnesia, is one index of the severity of the concussive injury. Although the notion that momentary “stunning” represents the mildest degree of concussion seems valid, it is not known at the moment if it shares the same mechanism as more overt concussion with loss of consciousness.
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Pathologic Changes Associated with Severe Head Injury In contrast to concussion, in fatal cases of head injury the brain is usually bruised, swollen, or lacerated, and there are hemorrhages, either meningeal or intracerebral, as well as hypoxic-ischemic lesions. The prominence of these pathologic findings was responsible for the formerly held view that cerebral injuries are largely a matter of contusions, hemorrhages, and the need for urgent operations. That this can hardly be the case is indicated by the fact that some patients survive and make an excellent recovery from head injuries that are clinically as severe or almost as severe as the fatal ones. One can only conclude, therefore, that most of the immediate symptoms of severe head injury depend at least in part on histologically invisible and highly reversible functional changes. The effects of contusions, lacerations, hemorrhages, localized swellings, white matter necroses, and herniations of tissue should not be minimized, because they are probably responsible for or contribute to most of the fatalities after the injury. A majority of patients who remain in a coma for more than 24 h after a head injury are found to have intracerebral hematomas. Of these lesions, the most important are contusions of the surface of the brain beneath the point of impact (coup lesion) and the sometimes more extensive lacerations and contusions on the side opposite the site of impact (contrecoup lesion), as shown in Fig. 35-4. Blows to the front of the head may produce mainly coup lesions, whereas blows to the back of the head may cause mainly contrecoup lesions. Blows to the side of the head produce either coup or contrecoup lesions, or both. Irrespective of the site of the impact, the common sites of cerebral contusions are in the frontal and temporal lobes, as illustrated in Figs. 35-4 and 35-5. The inertia of the malleable brain— which causes it to be flung against the side of the skull that is struck, to be pulled away from the contralateral side, and to be impelled against bony promontories within the cranial cavity, explains these coup–contrecoup patterns. Relative sparing of the occipital lobes in coup–contrecoup injury has been explained by the smooth inner surface of the occipital bones and subadjacent tentorium as pointed out by Courville. The contused cortex is diffusely swollen and hemorrhagic, most of the blood being found around parenchymal vessels. On CT scanning, the lesions appear as edematous regions of cortex and subcortical white matter admixed with areas of increased density representing leaked blood (Fig. 35-6). The bleeding points may coalesce and give the appearance of a unitary clot in the cortex and immediately adjacent white matter. The predilection of these lesions for the crowns of convolutions attests to their traumatic origin (being thrown against the overlying skull) and distinguishes them from cerebrovascular and other types of cerebral lesions. In nearly all cases of severe head injury, there is damage to the corpus callosum by impact with the falx; necrosis and hemorrhage are sometimes visible by CT scanning and can be seen to spread bilaterally to adjacent white matter (Fig. 35-7). There may also be scattered hemorrhages in the white matter along lines of force from the
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B
A
E
D
Figure 35-4. Mechanisms of cerebral contusion. Arrows indicate point of application and direction of force; dark blue areas indicate location of contusion. A. Frontotemporal contusion consequent to frontal injury. B. Frontotemporal contusion following occipital injury. C. Contusion of temporal lobe because of contralateral injury. D. Frontotemporal contusion as a result of injury to opposite temporooccipital region. E. Diffuse mesial temporooccipital contusion caused by a blow on the vertex. (Reproduced by permission from Courville.)
point of impact to the contralateral side. Areas of white matter degeneration of the type described by Strich (1961) may accompany injury of this degree. The degeneration of white matter can be remarkably diffuse, with no apparent relationship to focal destructive lesions although differentiating it from secondary wallerian change can be difficult.
Investigations using MRI, such as the series by Kampfl and colleagues, suggest that diffuse axonal injury may be the substrate of the persistent vegetative state. However, in almost all of our cases of severe cranial injury and protracted coma, there were major sites of injury adjacent to zones of ischemia and old hemorrhages in the midbrain
C
A
C B
Figure 35-5. Distribution of contusions emphasizing the frontal and frontotemporal distribution in 40 consecutive autopsy cases collected by Courville. (Reproduced by permission from Courville.)
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Figure 35-6. CT scan without contrast infusion showing areas of hemorrhagic contusion adjacent to bony prominences. There is also slight subarachnoid blood along the tentorium and in the insular cisterns, both typical of traumatic bleeding.
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and subthalamus, i.e., in the zones subjected to the greatest torque, and we continue to favor these latter lesions as the critical ones in most cases of persistent coma and vegetative state (Ropper and Miller). This was true also of the cases of persistent coma described by Jellinger and Seitelberger. Notable was that these deep lesions coincided with the postulated locus of reversible concussive paralysis. In other words, the attribution of persistent coma and the vegetative state to diffuse axonal injury remains uncertain in our view. Primary brainstem hemorrhages are distinguished from the secondary hemorrhages that are a result of the effects of downward displacement of the brainstem. Duret originally emphasized the medullary location of these secondary hemorrhages, but the term Duret hemorrhage has come to signify all brainstem hemorrhages when there is mass effect that distorts the brainstem. In addition to contusions and extradural, subdural, subarachnoid, and intracerebral hemorrhages, closed head injury induces variable degrees of vasogenic edema that increases during the first 24 to 48 h, and sometimes small zones of infarction as a result of vascular spasm caused by subarachnoid blood surrounding basal vessels. The frequency and importance of cerebral infarction have been debated. A retrospective imaging study by Marino and colleagues found that 17 of 89 patients had strokes after moderate or severe head injury. Most were in the distribution of a major branch or penetrating cerebral vessel or in a watershed territory. The presence of intracranial hypertension was asso-
Figure 35-7. CT scan (left) and MRI (right) from a patient with diffuse axonal injury. There are multiple small hemorrhagic areas (one of which is shown by the dark arrow) in the cerebral white matter. The MRI highlights the small amount of blood in these lesions. Also shown are a contusion in the anterior temporal lobe ( white arrow), which often accompanies the deep type of axonal injury, and blood in the ventricle.
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ciated with a higher incidence of infection. Marmarou and colleagues demonstrated that brain swelling after head injury is essentially the result of edema and not of an increase in cerebral blood volume, as has long been postulated. In children, and in some cases in adults, the cerebral edema may be massive and lead to secondary brainstem compression.
APPROACH TO THE PATIENT WITH HEAD INJURY The physician first called on to attend a patient who has had a closed head injury will generally find the patient in one of three clinical conditions, each of which is dealt with differently. It is usually possible to categorize the patient by assessing his mental and neurologic status when first seen and at intervals after the accident. The Glasgow Coma Scale is used as a rapid reference to accomplish this purpose (Table 35-1). It registers three aspects of neurologic function: eye opening, verbal response, and motor response to various stimuli. The scale uses a summed score with a maximum of 15; a score of 7 or less is considered to reflect severe trauma and a poor clinical state, 8 to 12, moderate injury, and higher scores, mild injury. The scores provided by this scale correspond roughly with the outcome of the head injury as discussed further on, but its main utility is in recording sequential changes in the patient’s clinical state with an easily learned and reproducible tool.
Patients Who Are Conscious or Are Rapidly Regaining Consciousness (Concussion and Minor Head Injury) This is the most frequently encountered clinical situation. Roughly, two degrees of disturbed function can be recogTable 35-1 GLASGOW COMA SCALE (TOTAL SCORE IS USED FOR SERIAL ASSESSMENT AND PROGNOSIS) EYES OPEN
Never To pain To verbal stimuli Spontaneously
1 2 3 4 BEST VERBAL RESPONSE
No response Incomprehensible sounds Inappropriate words Disoriented and converses Oriented and converses
1 2 3 4 5
BEST MOTOR RESPONSE
No response Extension (decerebrate rigidity) Flexion abnormal (decorticate rigidity) Flexion withdrawal Localizes pain Obeys
1 2 3 4 5 6
Total
3–15
nized within this category. In one, the patient was not unconscious at all but only stunned momentarily, “saw stars,” or was briefly disoriented. This injury is insignificant when judged in terms of life or death and brain damage, although, as we point out further on, there is still the small possibility of a skull fracture or the later development of an epidural or subdural hematoma. Moreover, the patient may be liable to a troublesome posttraumatic syndrome consisting of headache, giddiness, fatigability, insomnia, and nervousness that can appear soon after or within a few days of the injury. This problem is discussed in a later section. In the instance of consciousness that was temporarily abolished for a few seconds or minutes, recovery may already be complete, or the patient may be in one of the stages of partial recovery described earlier. Even though mentally clear, there is amnesia for events immediately preceding and following the injury. In most cases of this type, a brief assessment for mental clarity, weakness, ocular abnormalities, and Babinski signs is appropriate, but there is little need of extensive neurologic consultation and hospitalization is not required, provided that a responsible family member is available to report any change in the clinical state. In only a small group of these patients, mainly in those who are slow in regaining consciousness or who have severe headache, vomiting, or a skull fracture, is there significant risk of intracerebral hemorrhage or other delayed complications. Whether to obtain imaging of the head routinely in such patients is an unresolved problem. In our litigious society, the physician is inclined to obtain some form of imaging and CT has supplanted skull radiography. If there is no fracture and the patient is mentally clear, Jennett estimated that there was only a 1 in 1,000 chance of developing an intracranial (extradural) hemorrhage. He stated that this increased to 1 in 30 in patients with a fracture; but most studies, such as the one by Lloyd and colleagues, have found that the presence of a skull fracture in children proves to be a relatively poor indicator of intracranial injury. With a modern focus on cost-effective use of ancillary studies, there has been considerable examination of the criteria that justify obtaining a cranial CT following minor forms of head trauma. We have generally advised a CT in cases of head injury associated with prolonged loss of consciousness (more than 1 min), severe and persisting headache, nausea and vomiting, a confusional state, and any new, objective neurologic signs, but these are admittedly arbitrary criteria. The CT scan may be particularly important in elderly patients with minor head trauma, in whom the presence of an intracranial lesion (mainly subdural hematoma) may not be predicted by clinical signs. However, in children, it may be advisable to perform the scans more liberally. This is underscored by the results of a study of 215 children with minor head trauma conducted by Simon and colleagues: 34 children with no known loss of consciousness and a Glasgow Coma Scale score of 15 nonetheless displayed intracranial lesions, although only 3 required surgery. Several studies in adults have given some broad guidance in choosing which patients to scan (“New Orleans Criteria” and “Canadian CT Head Rule”; see Table 35-2). They include features that are sensitive but not specific for intracranial injury, such as older than age 60 years, intoxication, more than 30 min of retrograde amnesia, suspected skull fracture,
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Table 35-2 THE NEW ORLEANS AND CANADIAN CLINICAL DECISION RULES FOR CT AFTER CONCUSSION New Orleans Criteriaa—Glasgow Coma Scale Score of 15 Headache Vomiting Age >60 y Drug or alcohol intoxication Persistent anterograde amnesia (deficits in short-term memory) Evidence of traumatic soft-tissue or bone injury above clavicles Seizure Canadian CT Head Ruleb—Glasgow Coma Scale Score of 13–15 For patients age 16 y and older High risk of neurosurgical intervention Glasgow Coma Scale score 54 y Moderate risk of brain injury detected by CT Retrograde amnesia for ≥30 min Dangerous mechanism a b
Adapted from Haydel et al. Adapted from Stiell et al.
seizure, anticoagulation, and dangerous mechanism of injury, most of which are self-evident reasons for imaging (see Smits et al and Stiell et al). Two validated schemes for assisting in the determination of need for CT scanning in the emergency department are included for the reader’s reference but they should be viewed as broad guidelines with fairly high sensitivity for important lesions on the CT, but low sensitivity. These and related issues are addressed in a review by Ropper and Gorson. The special issue of athletic concussion is discussed in a later section. Minor and seemingly trivial head injuries may sometimes be followed by a number of puzzling and worrisome clinical phenomena, some insignificant, others serious and indicative of a pathologic process other than concussion. The latter are described below. When they occur, a neurologic or neurosurgical evaluation is indicated. Delayed Fainting after Head Injury Following an accident, the injured person, after walking about and seeming to be normal, may turn pale and have a syncopal spell. Recovery occurs within a few seconds or minutes. This is a vasodepressor phenomenon, possibly related to pain and emotional upset, and differs in no way from the fainting that follows pain and fright without injury. Such syncopal attacks also occur with injuries that spare the head, but with head injury they become more difficult to interpret. Denny-Brown described a more severe type of delayed posttraumatic collapse that we have not seen. Again, the patient appears to be recovering from a blow to the head, which may simply have dazed him or caused a brief period of unconsciousness when suddenly, after a period of several minutes or hours, he collapses and becomes unresponsive for a brief time. The most disquieting feature of this clinical state as described was marked bradycardia. What is unexplained is that the disorder fails to develop further and, following a brief period of restlessness, vomiting and headache, the patient recovers over several days. DennyBrown, in an era well before brain imaging was possible,
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suggested that the syndrome was caused by a contusion of the medulla but how this explains the sequence of clinical events is not clear. A similar syndrome was described by Snoek and colleagues in 4 percent of children with minor head injury but also they acknowledge that an explanation is lacking. The authors believe it possibly to be a severe form of vasodepressor syncope. The more serious form of delayed collapse after head injury is described further on, under “Concussion Followed by a Lucid Interval and Serious Cerebral Damage.” Drowsiness, Headache, and Confusion This syndrome occurs most often in children, who, minutes or hours after a concussive or nonconcussive head injury, seem not to be themselves. They lie down, are drowsy, complain of headache, and may vomit—symptoms that suggest the presence of an epidural or subdural hemorrhage. Mild focal edema near the point of impact may be seen on MRI. There is usually no skull fracture but, as Nee and colleagues point out, vomiting is associated with an increase in the incidence of skull fracture and the New Orleans and Canadian CT rules find vomiting to be a risk for intracranial bleeding (see Table 35-2). The symptoms subside after a few hours, attesting to the benign nature of the condition in most cases but some form of cerebral imaging is none the less required. Transient Paraplegia, Blindness, and Migrainous Phenomena With falls or blows on top of the head, both legs may become temporarily weak and numb, with wavering bilateral Babinski signs and sometimes with sphincteric incontinence. Impact over the occiput may cause temporary blindness. The symptoms disappear after a few hours. When they first occur, a cortical contusion is considered. It seems unlikely that these transient symptoms represent a direct localized concussive effect, caused either by indentation of the skull or by impact on these parts of the brain against the inner table of the skull, but this mechanism cannot be excluded. The blindness and paraplegia are usually followed by a throbbing, vascular type of headache. Transient migrainous visual phenomena, aphasia, or hemiparesis, followed by a headache, are observed sometimes after minimal concussion in athletes who participate in competitive contact sports. Possibly all of these phenomena are the result of an attack of migraine or migraine equivalent induced by a blow to the head. These focal syndromes can be perplexing for a few hours, especially if it is the first such attack of migraine in a child. A possibility to be remembered, particularly in cases of acute quadriplegia, is cartilaginous embolism of the cervical cord (see “Fibrocartilaginous Embolism” in Chap. 44). A concussion of the cervical portion of the spinal cord is another suggested but improbable mechanism of transient paraplegia. Episodes of transient global amnesia after minor head injury are known, as mentioned in Chap. 21 and described by Haas and Ross. The problem in interpreting these spells is their similarity to simply prolonged posttraumatic amnesia. A duration of 2 to 24 h and the feature of repetitive querying were pointed out by Haas and Ross as differentiating the two but the separation is not compelling. More interesting is the similarity of the two syndromes. Delayed Hemiplegia The main causes of delayed hemiplegia are a late evolving epidural or subdural hematoma and, in more severe injuries, an intracerebral hemorrhage.
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Most of these are associated with a diminution in the level of consciousness from the outset but there are exceptions. Dissection of the internal carotid artery should always be considered in cases of delayed hemiplegia. The dissection may occur in the extracranial or the intracranial portion of the carotid artery and should be sought by MR angiography or arteriography if the hemiparesis has no other explanation. In yet other instances, the hemiplegia has no explanation other than the blow to the head, perhaps the result of the migraine phenomenon described earlier. Cerebral Fat Embolism With fractures of large bones, after 24 to 72 h there may be an acute onset of pulmonary symptoms (dyspnea and hyperpnea) followed by coma with or without focal signs or seizures. This sequence is a result of systemic fat embolism, first of the lungs and then of the brain. Cranial trauma is not required. In some cases the onset of pulmonary symptoms is associated with a petechial rash over the thorax, and one in three cases is said to show fat globules in the urine. Respiratory distress is the most important and often the only feature of the fat embolism syndrome, evident in the chest film as fluffy infiltrates in both lungs. In the brain, the multiple small fat emboli cause widespread petechial hemorrhages, involving both white and gray matter and a few larger infarcts. Most patients with fat embolism recover spontaneously in 3 or 4 days, although a mortality rate of up to 10 percent is quoted, usually related to the underlying systemic and bony injuries. Treatment, aside from respiratory support, is uncertain. Heparin, which had been used in the past, is not considered effective.
Concussion Followed by a Lucid Interval and Serious Cerebral Damage This group is smaller than the other two but is of importance because it includes a disproportionate number of patients who are in urgent need of surgical treatment. The less-serious circumstance of vasodepressor syncope after head trauma was discussed earlier. The initial coma may have lasted only a few minutes or, exceptionally, there may have been no period of unresponsiveness at all, in which instance one might wrongly conclude that because there was no concussion, there is no possibility of traumatic hemorrhage or other type of brain injury. Patients who display this sequence of events, formerly referred to as “talk and die” by Marshall and associates (1983) deteriorate because of the delayed expansion of a small subdural hematoma, worsening brain edema around a contusion, or the late appearance of an epidural clot. Among 34 such patients in the Traumatic Coma Data Bank who had a lucid interval, the majority show substantial degrees of midline shift on the initial CT scan, reflecting the presence of early brain edema and contusion (Marshall et al, 1983). A similar condition of delayed intracerebral hematoma, discussed further on (spät apoplexie), is a feature of a more severe initial head injury that engenders coma from the onset. Delayed but transient deterioration in children and adults has already been mentioned.
Athletic Concussion This is a topic of current interest and various guidelines regarding return to play abound. Many useful observa-
tions have emerged from study of amateur and professional athletes. First, athletes who have had concussion are more likely than other players to have another concussion in the same playing season; whether this is a reflection of incoordination or the person’s style of play, or another factor is not known. Second, most prospective studies show a decline in reaction time and some other neuropsychological tests after concussion that returns to baseline only after days or weeks. Third, there is an indication from several series of concussions in National Collegiate Athletic Association and National Football League players that the number of recollected concussions is proportional to the degree of impairment on neuropsychologic tests (McCrea et al). Similar results have been found in other pursuits such as jockeying (Wall et al), but there are few adequate prospective studies. Despite the earlier noted demential pugilistica and several outstanding examples of an Alzheimer-like dementia after repeated athletic concussion, the frequency and relationship of the two are quite obscure; the same is true for a putative late-life depression from multiple concussions. The effect of “microconcussion,” as imputed from heading the ball in soccer, has not been carefully studied but seems to be negligible. The appropriate duration of removal from play has been the subject of numerous arbitrary systems. The basis of most rules has been an appropriate conservatism and the absence of cerebral symptoms both at rest and under physical stress testing such as running or repetitive squatting. The duration of loss of consciousness and of amnesia was formerly a major component of the decision about return to play. More up-to-date guidelines focus instead on slowness in answering questions, uncertainty about plays or game assignments, and clumsiness, even without loss of consciousness or amnesia. All such players are removed from the game. After medical evaluation, which may include imaging and neuropsychologic testing, a program of physical and cognitive “rest” is followed by graduated physical and mental activity under observation and a return to a lower level if symptoms occur (McCrory et al). Specifically, light aerobic exercise is followed by sport-specific training and noncontact, then contact, drills.
Patients Who Have Been Comatose from the Time of Head Injury Here, the central problem, set forth by Symonds, is the relationship between concussion and contusion and other forms of persisting structural brain damage. Because consciousness is abolished at the moment of injury, one can hardly doubt the existence of concussion in such cases; but when hours and days pass without consciousness being regained, the second half of the usual definition of concussion—that the paralysis of cerebral function be transitory— is not satisfied. Pathologic examination of such cases usually discloses evidence of increased intracranial pressure and of cerebral contusions, subarachnoid hemorrhage, zones of infarction, and scattered intracerebral hemorrhages both at the point of injury (coup) and on the oppo-
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site side (contrecoup), in the corpus callosum, and between these points, along the line of force of the impact. In some patients, the diffuse axonal type of injury is a prominent abnormality; most often in cases of coma, there are separate but strategically placed ischemic and hemorrhagic lesions in the upper midbrain and lower thalamic region, as already mentioned. Varying amounts of blood in the subarachnoid and subdural spaces are present. Displacement of the thalamus and midbrain is frequently present, with compression of the opposite cerebral peduncle against the free margin of the tentorium as well as secondary midbrain hemorrhages and zones of necrosis; in some cases, there is frank transtentorial herniation. Severe head injury is often associated with an immediate arrest of respiration and sometimes with bradyarrhythmia and cardiac arrest. The immediate effects on the brain of these systemic changes may in themselves be sufficiently profound to cause coma. Also, head injury often complicates alcohol and drug ingestion, so the possibility of a toxic or metabolic encephalopathy as the cause (or a contributing cause) of stupor must always be considered. Intracranial pressure is almost always elevated and imaging of the brain shows various degrees of brain swelling, ventricular compression, and displacement of midline structure. In all of these patients, following the initial period of stabilization, the matter of interest is the clinical and radiologic assessment, with the purpose of uncovering a surgically remediable lesion, namely a subdural or epidural hematoma or a treatable intraparenchymal hematoma. In most cases, the discovery of such a mass lesion mandates surgical removal. But unless it is the only lesion, the procedure often proves to be insufficient and coma is likely to persist because of the associated cerebral damage. The recognition and management of these hematomas are described further on. In the Traumatic Coma Data Bank, which includes 1,030 gravely injured patients with Glasgow Coma Scale scores of 8 or less, 21 percent had subdural hematomas, 11 percent had intracerebral clots, and 5 percent had epidural hematomas. Notable, however, half the patients had no mass lesions on the CT scan. On this basis, these patients were thought to have diffuse axonal injury. However, in 50 consecutive autopsies of severely injured patients, summarized in an earlier era by Rowbotham, all but 2 showed macroscopic changes, suggesting the relative unreliability of CT analysis. The lesions in these cases consisted of surface contusions (48 percent), lacerations of the cerebral cortex (28 percent), subarachnoid hemorrhage (72 percent), subdural hematoma (15 percent), extradural hemorrhage (20 percent), and skull fractures (72 percent). As these figures indicate, several pathologic entities were found in the same patient. Among patients who survived and remained vegetative until death, Adams and colleagues (2000) found that 80 percent had thalamic damage and 71 percent had findings of diffuse axonal injury. Moreover, trauma of extracranial organs and tissues is frequent and obviously contributes to the fatal outcome. This leaves in somewhat ambiguous status the proximate cause of the persistent vegetative state after blunt head injury, but it does emphasize the frequency of bilateral thalamic–midbrain damage in cases of the vegetative state from all causes.
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There is that relatively small, distressing group of severely brain-injured patients in whom the vital signs become normal but who never regain full consciousness. As the weeks pass, the prospects become bleaker. Such a patient, especially if a child, may still emerge from coma after 6 to 12 weeks and make a surprisingly good, although usually incomplete, recovery. Some of those who survive for long periods open their eyes and move their heads and eyes from side to side but betray no evidence of seeing or recognizing even the closest members of their families. They do not speak and are capable of only primitive postural or reflex withdrawal movements. Jennett and Plum referred to this as the “persistent vegetative state” (see Chap. 17 for a full discussion of this subject). Fourteen percent of the patients in the Traumatic Coma Data Bank remain in this state. Hemiplegia or quadriplegia with varying degrees of decerebrate or decorticate posturing are usually present. Life is mercifully terminated after several months or years by some medical complication but some of our patients have survived for decades. Our colleague R.D. Adams has examined the brains of 14 patients who remained in coma and in vegetative states from 1 to 14 years. All showed extensive zones of necrosis and hemorrhage in the upper brainstem. In generalizing about this category of head injury, the effects of contusion, hemorrhage, and brain swelling often become evident within 18 to 36 h after the injury and then may progress for several days. If a patient survives this period, his chances of dying from complications of these effects are greatly reduced. The mortality rate of those who reach the hospital in coma is approximately 20 percent, and most of the deaths occur in the first 12 to 24 h as a result of direct injury to the brain in combination with other nonneurologic injuries. Of those alive at 24 h, the overall mortality falls to 7 to 8 percent; after 48 h, only 1 to 2 percent of patients succumb. There is some evidence that transfer of such patients to an intensive care unit, where personnel experienced in the handling of head injury can monitor them, improves the chances for survival (see further on). In respect to patients with relatively less severe and seldom fatal head injuries, all gradations in timing and degree of recovery can be observed. In the least severely injured of this group, recovery of consciousness begins in a few hours, although there may be a decline within the first day or two as a result of swelling of contused brain tissue, enlargement or emergence of a subdural hematoma, brain hemorrhage, or infarction, the last possibly provoked by arterial spasm in relation to subarachnoid hemorrhage. The CSF is usually bloody and intracranial pressure is usually slightly to moderately elevated. Eventually, recovery may be nearly complete, but the period of traumatic amnesia covers a span of several days or weeks. It is during the period of recovery of consciousness that focal neurologic signs (hemiparesis, aphasia, abulia, etc.) become more obvious. In our experience, a fairly dependable sign that presages reasonable recovery has been restless and natural movements in all the limbs without posturing. Once the patient improves to the point of being able to converse, he is demonstrably slow in thinking, with few mental associations, unstable in emotional reactions and faulty in judgment.
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SPECIFIC TRAUMATIC CRANIAL LESIONS (Table 35-3) The following lesions are considered in all cases of serious initial injury. They each have characteristic clinical and imaging features but they may be admixed and the contribution of each to the clinical state must be assessed before deciding on a course of action.
Acute Epidural Hemorrhage As a rule, epidural hematoma arises with a temporal or parietal fracture and laceration of the middle meningeal artery or vein. Less often, there is a tear in a dural venous sinus. The injury, even when it fractures the skull, may not have produced coma initially, or it may be part of a devastating craniocerebral injury. A typical example is that of a child who has fallen from a bicycle or swing or has suffered some other hard blow to the head and was unconscious only momentarily. A few hours later (exceptionally, with venous bleeding the interval may be several days or a week), headache of increasing severity develops, with vomiting, drowsiness, confusion, aphasia, seizures (which may be one-sided), hemiparesis with slightly increased tendon reflexes, and a Babinski sign. As coma develops, the hemiparesis may give way to bilateral spasticity of the limbs and Babinski signs. The pulse is often slow (below 60 beats/min) and bounding, with a concomitant rise in systolic blood pressure (Cushing effect). The pupil may dilate on the side of the hematoma. Physicians need not be reminded that lumbar puncture is contraindicated in this setting, particularly now that CT and MRI are available. Death, which is almost invariable if an expanding clot is not removed surgically, comes at the end of a comatose period and is a result of respiratory arrest. The visualization of a fracture line across the groove of the middle meningeal artery and knowledge of which side of the head was struck (the clot is on that side) are of aid in diagnosis and lateralization of the lesion. However, meningeal vessels may occasionally be torn without fracture. The CT scan is definitive and reveals a lens-shaped clot with a smooth inner margin (Fig. 35-8). The surgical procedure consists of placement of burr holes in an emergency situation or, preferably, a craniotomy, drainage of the hematoma, and identification and ligation of the bleeding vessel. The operative results are excellent except in cases with extended fractures and laceration of the dural venous sinuses, in which the epidural hematoma may be bilateral rather than unilateral. If coma, bilateral Babinski signs, spasticity, or decerebrate rigidity supervene before operation, it usually means that displacement of central structures and compression of the midbrain have already occurred; prognosis is then poor, but a few patients do well if surgery is not greatly delayed. Small epidural hemorrhages can be followed by serial CT scanning and will be seen to enlarge gradually for a week or two and then be absorbed. There is controversy about the benefit of removing these smaller clots in a patient who has no symptoms; with careful clinical and imaging surveillance, most can be left alone.
Acute and Chronic Subdural Hematomas The problems created by acute and chronic subdural hematomas are so different that they must be considered separately. In acute subdural hematoma, which may be unilateral or bilateral, there may be a brief lucid interval between the blow to the head and the advent of coma. More often, the patient is comatose from the time of the injury and the coma deepens progressively. Acute subdural hematoma may be combined with epidural hemorrhage, cerebral contusion, or laceration. The clinical effects of these several lesions are difficult to distinguish and there are a few patients in whom it is impossible to state before operation whether the clot is epidural or subdural in location. Subdural clots more than a few mm in thickness can be accurately visualized by the CT scan in more than 90 percent of cases, but the window settings must be appropriate to avoid obscuring of the clot by adjacent bone (Fig. 35-9). A large acute clot causes a shift of midline structure as well as marked compression of one lateral ventricle; but if there are bilateral clots, there may be no shift and the ventricles may appear symmetrically compressed. Rapidly evolving subdural hematomas are usually a result of tearing of bridging veins, and symptoms are caused by compression of the adjacent brain and of deep structures. Unlike epidural arterial hemorrhage, which is steadily progressive, the rising intracranial pressure usually arrests venous bleeding. Exceptionally, the subdural hematoma forms in the posterior fossa and gives rise to headache, vomiting, pupillary inequality, dysphagia, cranial nerve palsies, and, rarely, stiff neck, and ataxia of the trunk and gait if the patient is well enough to be tested for these functions. Because of their apposition to bone or an axial orientation along the tentorial dura, posterior fossa clots are likely to be overlooked in CT scans. In chronic subdural hematoma, the traumatic etiology is often less clear. The head injury, especially in elderly persons and in those taking anticoagulant drugs, may have been trivial and forgotten. A period of weeks then follows when headaches (not invariable), light-headedness, slowness in thinking, apathy and drowsiness, unsteady gait, and occasionally a seizure are the main symptoms. The initial impression may be that the patient has a vascular lesion or brain tumor or is suffering from drug intoxication, a depressive illness, or Alzheimer disease. Gradual expansion of the hematoma by one of several mechanisms discussed further on is believed to cause the progression of symptoms. As with acute subdural hematoma, the disturbances of mentation and consciousness (drowsiness, inattentiveness, and confusion) are more prominent than focal or lateralizing signs, and they may fluctuate. Focal signs, when present, consist of mild hemiparesis and, rarely, an aphasic disturbance. Homonymous hemianopia is seldom observed, probably because the geniculocalcarine pathway is deep and not easily compressed; similarly, hemiplegia, i.e., complete paralysis of one arm and leg, is usually indicative of a lesion within the cerebral hemisphere rather than a compressive lesion on its surface. Hemiparesis from subdural hematoma may sometimes be ipsilateral to the clot, the result of compression of the contralateral cerebral
Table 35-3 CLINICAL AND RADIOGRAPHIC CHARACTERISTICS OF THE MAIN TRAUMATIC BRAIN LESIONS EPIDURAL HEMATOMA
ACUTE SUBDURAL HEMATOMA
CHRONIC SUBDURAL HEMATOMA
CONTUSION/ PARENCHYMAL HEMORRHAGE
INTRAVENTRICULAR HEMATOMA
Trauma (may be absent or minimal) Risk factors: coagulopathy and severe brain atrophy Lateral cerebral convexities, may be bilateral
Shearing of parenchymal vessels. Risk factors: coagulopathy and amyloid vasculopathy
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SUBARACHNOID HEMORRHAGE
SUBDURAL HYGROMA
DIFFUSE AXONAL INJURY
Shearing of parenchymal vessels; rule out vascular defects
Exclude underlying aneurysmal rupture
Arachnoid tear, following meningitis
Deceleration or rotational forces
Inferior frontal and temporal lobes
Lateral and third ventricles blood filled
Basilar cisterns
Lateral cerebral convexities
Expand over 12– 48 h Stupor → coma, dilated pupil, progressive hemiplegia, spasticity
Rapid
Minutes to hours
Days to weeks
Progressive signs of hydrocephalus
Headache, meningismus, delayed manifestations, vasospasm
Mimics chronic subdural hematoma
Deep white matter, corpus callosum, dorsolateral pons From time of injury Coma, posturing, normal intracranial pressure
Infants, children, adults Focal, CSF density, fluid collection
Any
Aspiration of fluid
None
Causative factor
Laceration of middle cerebral artery or dural sinus
Tearing of bridging pial veins and arteries
Typical location
Lateral cerebral convexities
Lateral cerebral convexities
Evolution
Hours
Many hours
Days to weeks
Clinical profile
Classically, lucid interval then coma, but more variable; pupillary dilatation with contralateral then bilateral limb weakness; slowly evolving stupor then coma Children, young adults Acute bulging epidural clot bounded by cranial sutures; lenticular in shape
Drowsiness, coma; pupillary dilatation with contralateral then bilateral limb weakness; progressive stupor then coma
Headache, progressive alteration in mental status ± focal neurologic signs
Any
Elderly
Any
Any
Any
Acute blood rimming broad region of cerebral convexity
Hyper- or isodense, unilateral or bilateral
Focal, acute blood within ventricles; may layer with gravity
Acute blood lining cortex in subarachnoid space
Urgent evacuation
Urgent evacuation if large enough to cause symptoms
Evacuation in some circumstances
Multiple, confluent regions of edema intermixed with focal, acute blood Evacuate if large
Shunting
May cause secondary vasospasm or late hydrocephalus
Age at risk Radiologic features
Surgical intervention
CT may be normal; MRI shows evolving small deep contusions
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Figure 35-8. Acute epidural hematoma. Unenhanced CT scan showing a typical lens-shaped frontal epidural clot.
peduncle against the free edge of the tentorium (KernohanWoltman sign; see “Pathoanatomy of Brain Displacement and Herniations” in Chap. 17). If the condition progresses, the patient becomes stuporous or comatose but this course is often interrupted by striking fluctuations of awareness. With both large acute and chronic hematomas, dilatation of the ipsilateral pupil is a fairly reliable indicator of the side of the hematoma, although this sign may be misleading, occurring on the opposite side in 10 percent of cases, according to Pevehouse and coworkers. Convulsions are seen occasionally, most often in alcoholics or in patients with cerebral contusions, but they cannot be regarded as a cardinal sign of subdural hematoma. Rare cases of internuclear ophthalmoplegia and of chorea have been reported but have not occurred in our material. Presumably they are a result of distortion of deep structures. Also, brief and self-limited disturbances of neurologic function simulating transient ischemic attacks (TIAs) may occur with chronic hematomas; their mechanism is uncertain, but they do not appear to represent seizures. In infants and children, enlargement of the head, vomiting, and convulsions are prominent manifestations of subdural hematoma. CT scanning with contrast infusion and MRI are the most reliable diagnostic procedures. On CT scans, the acute clot is initially hyperdense but becomes slowly more isodense after a period of 1 or more weeks (Fig. 35-10). At that stage it may be difficult to detect except by the tissue shifts it causes. The fluid collection then becomes progressively hypodense (with respect to the cortex) over 2 to 6 weeks. The evolution of signal changes in the MRI is similar to the sequential imaging changes found with parenchymal hematomas. The acute clot is hypointense on T2-weighted images, reflecting the presence of deoxyhemoglobin. Over the subsequent weeks, all image sequences show it as hyperintense as a result of methemoglobin formation. Eventually the chronic clot again
Figure 35-9. Acute subdural hematoma over the right convexity, with substantial mass effect (displacement) of brain tissue but little edema.
becomes hypointense on the T1-weighted images. With contrast infusion, both imaging procedures usually reveal the vascular and reactive border surrounding the clot. Usually, by the fourth week, sometimes later, the hematoma becomes hypodense, giving rise to a chronic subdural hygroma that is indistinguishable from idiopathic ones that are presumably caused by a rent in the arachnoid that allows CSF to escape to the subdural compartment, as discussed further on. In an arteriogram, the cortical branches of the middle cerebral artery are separated from the inner surface of the skull, and the anterior cerebral artery may be displaced contralaterally. The CSF may be clear and acellular but more often is bloody or xanthochromic depending on the presence or absence of recent or old contusions and subarachnoid hemorrhage; the pressure may be elevated or normal. Xanthochromic fluid with relatively low protein content should always raise the suspicion of chronic subdural hematoma. The chronic subdural hematoma becomes gradually encysted by fibrous membranes (pseudomembranes) that grow from the dura. Some hematomas, probably those in which the initial bleeding was slight (see below), resorb spontaneously. Others expand slowly and act as spaceoccupying masses (Fig. 35-11). Gardner, in 1932, first postulated that the gradual enlargement of the hematoma was a result of the accession of fluid, particularly CSF, which was drawn into the hemorrhagic cyst by its increasing osmotic tension as red blood cells (RBCs) hemolyzed and protein was liberated. This hypothesis, which came to be widely accepted, is not supported by the available data. Rabe and colleagues demonstrated that the breakdown of RBCs contributes little, if at all, to the accumulation of fluid in the subdural space. According to the latter authors, the most important factor in the accumulation of subdural fluid is a pathologic permeability of the developing capillaries in the outer pseudomembrane of the hematoma. The CSF plays
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Figure 35-10. Subacute subdural hematoma on the left (reader’s right). CT scans after administration of intravenous contrast material. The lesion is isodense to the adjacent brain tissue, but its margin can be appreciated with contrast enhancement. Note displacement of cerebral structures.
Figure 35-11. Chronic subdural hematomas over both cerebral hemispheres without shift of the ventricular system. Chronicity results in hypodense appearance of the clots. Some old blood can still be seen on the right side. The bilaterally balanced masses result in an absence of horizontal displacement, but they may compress the upper brainstem.
no discernible role in this process, contrary to the original view of Munro and Merritt. The experimental observations of Labadie and Glover suggest that the volume of the original clot is a critical factor: The larger its initial size, the more likely it will be to enlarge. An inflammatory reaction, triggered by the breakdown products of blood elements in the clot, appears to be an additional stimulus for growth as well as for neomembrane formation and its vascularization. In any event, as the hematoma enlarges, the compressive effects increase gradually. Treatment of Subdural Hematoma In most cases of acute hematoma it is sufficient to place burr holes and evacuate the clot before coma has developed. Treatment of larger hematomas, particularly after several hours have passed and the blood has clotted, consists of wide craniotomy to permit control of the bleeding and removal of the clot. As one would expect, the interval between loss of consciousness and the surgical drainage of the clot is perhaps the most important determinant of outcome in serious cases. Thin, crescentic clots can be observed and followed over several weeks and surgery undertaken only if focal signs or indications of increasing intracranial pressure arise (headache, vomiting, and bradycardia). Small subdural hematomas causing no symptoms and followed by CT scans will self-absorb, leaving only a deep yellow, sometimes calcified membrane attached to the inner dural surface. If the acute clot is too small to explain the coma or other symptoms, there is probably extensive contusion of the cerebrum or another lesion. To remove the more chronic hematomas a craniotomy must be performed and an attempt made to strip the membranes that surround the clot. This diminishes the likeli-
hood of reaccumulation of fluid but it is not always successful. Other causes of operative failure are postoperative swelling of the compressed hemisphere or failure of the hemisphere to expand after removal of a large clot. The difficulty of managing these patients surgically should not be underestimated. Elderly patients may be slow to recover after removal of the chronic hematoma or may have a prolonged period of confusion. Postoperative expansion of the brain can be followed by serial CT scans and may take weeks. Small, asymptomatic chronic collections are usually left alone and followed serially by clinical and CT examination, first at several week and then longer intervals. Although no longer a common practice, the administration of corticosteroids is an alternative to surgical removal of subacute and chronic subdural hematomas in patients with minor symptoms or with contraindications to surgery. This approach, reviewed by Bender and Christoff several decades ago, has not been studied systematically but has been ostensibly successful in a few of our patients (of course, they may have improved independent of the steroids). Headache and other symptoms, such as gait difficulty or limb clumsiness, may resolve satisfactorily after several weeks of medication and may remain abated when the steroids are slowly reduced.
Subdural Hygroma This is an encapsulated collection of clear or slightly xanthochromic fluid in the subdural space; such collections form after an injury, as well as after meningitis (in an infant or young child). As often, subdural hygromas appear without precipitant, presumably because of a ball-valve effect of an
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arachnoidal tear that allows cerebrospinal fluid to collect in the space between the arachnoid and the dura; brain atrophy is conducive to this process. Occasionally a hygroma originates from a tear in an arachnoidal cyst. It may be difficult to differentiate a long-standing subdural hematoma from hygroma, and some chronic subdural hematomas are probably the result of repeated small hemorrhages that arise from the membranes of hygromas. Shrinkage of the hydrocephalic brain after ventriculoperitoneal shunting is also conducive to the formation of a subdural hematoma or hygroma, in which case drowsiness, confusion, irritability, and low-grade fever are relieved when the subdural fluid is aspirated or drained. In adults, hygromas are usually asymptomatic and do not require treatment; they are infrequently the cause of seizures.
Cerebral Contusion Severe closed head injury is almost universally accompanied by cortical contusions and surrounding edema. The mass effect of contusional swelling, if sufficiently large, becomes a major factor in the genesis of tissue shifts and raised intracranial pressure. The CT appearance of contusion was already described (see Figs. 35-4 and 35-5). In the first few hours after injury, the bleeding points in the contused area may appear small and innocuous. The main concern, however, is the tendency for a contused area to swell or to develop into a hematoma during the first several days after injury. This may give rise to delayed clinical deterioration, sometimes abrupt in onset and concurrent with the appearance of swelling of the damaged region on the CT scan. It has been claimed, on uncertain grounds, that the swelling in the region of an acute contusion is precipitated by excessive administration of intravenous fluids (fluid management is considered further on in this chapter). Craniotomy and decompression of the swollen brain may be of benefit in selected cases with elevated intracranial pressure but it has no effect on the focal neurologic deficit.
cranial pressure monitoring and of CT scans at intervals after the injury facilitates diagnosis. Boto and colleagues found that basal ganglia hemorrhages were prone to enlarge in the day or two after closed head injury and that those greater than 25 mL in volume were fatal in 9 of 10 cases. It should be mentioned again that subarachnoid blood of some degree is very common after serious head injury. A problem that sometimes arises in cases that display both contusions and substantial subarachnoid blood is the possibility that a ruptured aneurysm was the initial event and that a resultant fall caused the contusions. In cases where the subarachnoid blood is concentrated around one of the major vessels of the circle of Willis, an angiogram is justified to exclude the latter possibility. Also in elderly patients, it has been difficult to determine whether a fall had been the cause or the result of an intracerebral hemorrhage. These subjects are addressed further in Chap. 34.
Acute Brain Swelling in Children This condition is seen in the first hours after injury and may prove rapidly fatal. The CT scan shows enlargement of both hemispheres and compression of the basal cisterns and ventricles. There is usually no papilledema in the early stages, during which the child hyperventilates, vomits, and shows extensor posturing. The assumption has been that this represents a loss of regulation of cerebral blood flow and a massive increase in the blood volume of the brain. The administration of excessive water in intravenous fluids may contribute to the problem and should be avoided. Inappropriate secretion of antidiuretic hormone (ADH) also exaggerates the swelling in some children. We have not observed this complication in adults. Fear of massive brain swelling from a minor second impact after a concussion has often been raised as a rationale for keeping youngsters from returning to athletic activity, but there is little evidence for the existence of this entity.
“Shaken Baby” Syndrome Traumatic Intracerebral Hemorrhage One or several intracerebral hemorrhages may be apparent immediately after head injury, or hemorrhage may be infrequently delayed in its development by several days (the earlier mentioned spät apoplexie). The bleeding is in the subcortical white matter of one lobe of the brain or in deeper structures such as the basal ganglia or thalamus. The injury had nearly always been severe; blood vessels as well as cortical tissue are torn. The clinical picture of traumatic intracerebral hemorrhage is similar to that of hypertensive brain hemorrhage with deepening coma with hemiplegia, a dilating pupil, bilateral Babinski signs, and stertorous and irregular respirations. The additional mass may be manifest by an abrupt rise in blood pressure and in intracranial pressure. Craniotomy with evacuation of an acute or delayed clot has given a successful result in some cases but the advisability of surgery is governed by several factors including the level of consciousness, the time from the initial injury, and the associated damage (contusions, subdural and epidural bleeding) shown by imaging studies. Application of intra-
This form of craniocerebral trauma in infants is well known in large emergency practices but can be missed if not specifically considered. As the name implies, the inciting trauma is typically violent shaking of the body or head of an infant, resulting in rapid acceleration and deceleration of the cranium. The presence of this type of injury must often be inferred from the combination of lesions on imaging studies or autopsy examination, but precision in examination is paramount because of its forensic and legal implications. The diagnosis is suspected from the combination of subdural hematomas and retinal hemorrhages, as summarized by Bonnier and colleagues. Sometimes there are occult skull fractures, but more often, there is little or no direct cranial trauma. Additional lesions may be evident on diffusionweighted MRI, particularly in the white matter of the corpus callosum and the temporo-occipito-parietal region. This syndrome confers a high risk for slowing of development; there may be acquired microcephaly reflecting brain atrophy consequent to both contusions and infarctions. A low initial Glasgow Coma Scale score, severe retinal hemorrhages, and skull fractures are associated with poor out-
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comes. Old and recent fractures in other parts of the body should arouse suspicion of this syndrome.
Penetrating Wounds and Blast Injuries Missiles and Fragments The descriptions in the preceding pages apply to blunt, nonpenetrating injuries of the skull and their effects on the brain. In the past, the care of penetrating craniocerebral injuries was mainly the preoccupation of the military surgeon, but—with the persistence of violent crime in society—such cases have also become commonplace on the emergency wards of general hospitals. In civilian life, missile injuries are essentially caused by bullets fired from rifles or handguns at high velocities. Air is compressed in front of the bullet so that it has an explosive effect on entering tissue and causes damage for a considerable distance around the missile track. Missile fragments, or shrapnel, from exploding shells, mines, grenades, or bombs are the usual causes of penetrating cranial injuries in wartime. The cranial wounds that result from missiles and shrapnel have been classified by Purvis as tangential, with scalp lacerations, depressed skull fractures, and meningeal and cerebral lacerations; penetrating, with in-driven metal particles, hair, skin, and bone fragments; and through-and-through wounds. In most penetrating injuries from high-velocity missiles, the object (such as a bullet) causes a high-temperature coagulative lesion that is sterile and does not require surgery if the projectile exits the skull. In these instances, the main considerations are the development of infection or CSF leaks or, in the long-term, epilepsy or aneurysms in distal blood vessels. The latter are considered to be the result of disruption of the vessel wall by the local high-energy shock wave. If the brain is penetrated at the lower levels of the brainstem, death is instantaneous because of respiratory and cardiac arrest. Even through-and-through wounds at higher levels, as a result of energy dissipated in the brain tissue, may damage vital centers sufficiently to cause death immediately or within a few minutes. Once the initial complications are dealt with, the surgical problems, as outlined by Meirowsky, are reduced to three: prevention of infection by debridement accompanied by the administration of broad-spectrum antibiotics; control of increased intracranial pressure and shift of midline structures by removal of clots of blood and the administration of mannitol or other dehydrating agents, and the prevention of life-threatening systemic complications. When first seen, the majority of patients with penetrating cerebral lesions are comatose. A small metal fragment may have penetrated the skull without causing concussion, but this is usually not true of high-velocity missiles. In a series of 132 patients analyzed by Frazier and Ingham, consciousness was lost initially in 120. The depth and duration of coma seemed to depend on the degree of cerebral necrosis, edema, and hemorrhage. In the series of the Traumatic Coma Data Bank, the mortality rate in 163 patients who were initially comatose from a cranial gunshot wound is 88 percent—more than twice the rate from severe blunt head injury. On emerging from coma, the patient passes through
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states of stupor, confusion, and amnesia, not unlike those following severe closed head injuries. Focal or focal and generalized seizures occur in the early phase of the injury in some 15 to 20 percent of cases. Recovery may take many months. Frazier and Ingham comment on the “loss of memory, slow cerebration, indifference, mild depression, inability to concentrate, sense of fatigue, irritability, vasomotor, and cardiac instability, frequent seizures, headaches, and giddiness, all reminiscent of the residual symptoms from severe closed head injury with contusions.” Every possible combination of focal cerebral symptoms may be caused by such lesions. The excellent older articles by Feiring and Davidoff, by Russell, and by Teuber are still very useful references on this subject. Epilepsy is the most troublesome sequela and is described further on. Ascroft and also Caviness, in reviewing World War II cases, found that approximately half of all patients with bullet or shrapnel wounds that had penetrated the dura eventually developed seizures, most focal in nature; the figures reported by Caveness for Korean War veterans are about the same. CSF rhinorrhea, discussed earlier and in Chap. 30, may occur as an acute manifestation of a penetrating injury that produces a fracture through the frontal, ethmoid, or sphenoid bones. Cairns listed these acute cases as a separate group in his classification of CSF rhinorrheas, the others being (1) a delayed form after craniocerebral injury, (2) a form that follows sinus and cranial surgery, and (3) a spontaneous variety. Pneumoencephalocele (aerocele)—i.e., air entering the cerebral subarachnoid space or ventricles spontaneously or as a result of sneezing or blowing the nose—is evidence of an opening from the paranasal sinus through the dura, as mentioned earlier in relation to skull fracture (see Fig. 35-3).
Blast Injuries The shock wave of an explosive device such as bomb can propel objects into the cranium but there is a direct form of organ damage from the dissipation of energy at the interfaces of tissues of different densities. This form of barotrauma invariably ruptures the tympanic membranes, a sign that is a dependable marker of blast injury. Deafness, tinnitus, and vertigo are common accompaniments from cochlear concussion. The lung is next most often affected. Rupture of the tympanic membranes is a sensitive indicator of blast injury (Xydakis et al). Loss of consciousness may occur but there is little understanding of the mechanism aside from the more conventional flinging of the skull from the pressure wave. Acute gas embolism of the brain has also been reported in the military medical literature. DePalma and colleagues have thoroughly reviewed blast injuries but the neurologic literature is quite deficient and does not settle whether the percussion wave can produce unconsciousness by direct “concussion” of brain tissue, in the original meaning of the term.
Birth Injuries These involve a unique combination of physical forces and circulatory-oxygenation factors and are discussed separately in Chap. 38.
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SEQUELAE OF HEAD INJURY Posttraumatic Epilepsy (See also Chap. 16) Seizures are the most common delayed sequela of craniocerebral trauma, with an overall incidence of approximately 5 percent in patients with closed head injuries and 50 percent in those who had sustained a compound skull fracture and direct wounds of the brain. The basis is nearly always a contusion or laceration of the cortex. As one might expect, the risk of developing posttraumatic epilepsy is also related to the overall severity of the closed head injury. In a civilian cohort of 2,747 head-injured patients described by Annegers and colleagues (1980), the risk of seizures after severe head injury (defined by loss of consciousness or amnesia for more than 24 h, including subdural hematoma and brain contusion) was 7 percent within 1 year and 11.5 percent in 5 years. If the injury was only moderate (unconsciousness or amnesia for 30 min to 24 h or causing only a skull fracture), the risk fell to 0.7 and 1.6 percent, respectively. After mild injury (loss of consciousness or amnesia of less than 30 min), the incidence of seizures was not significantly greater than in the general population. In a subsequent study, Annegers and colleagues (1998) expanded the original cohort to include 4,541 children and adults with cerebral trauma. The results were much the same as those of the first study except that in patients with mild closed head injuries, there was only a slight excess risk of developing seizures—a risk that remained elevated only until the fifth year after injury. The likelihood of epilepsy is said to be greater in parietal and posterior frontal lesions, but it may arise from lesions in any area of the cerebral cortex. Also, the frequency of seizures is considerably higher after penetrating cranial injury, as cited above. The interval between the head injury and the first seizure varies greatly. A small number of patients have a generalized seizure within moments of the injury (immediate epilepsy). Usually this amounts to a brief tonic extension of the limbs, with slight shaking movements immediately after concussion, followed by awakening in a mild confusional state. Whether this represents a true epileptic phenomenon or, as appears more likely, is the result of arrest of cerebral blood flow or a transient brainstem dysfunction is unclear. Some 4 to 5 percent of hospitalized head-injured individuals are said to have one or more seizures within the first week of their injury (early epilepsy). The immediate seizures have a good prognosis and we tend not to treat them as if they represented epilepsy; on the other hand, late seizures are significantly more frequent in patients who had experienced epilepsy in the first week after injury (not including the convulsions of the immediate injury; Jennett). Seizures occurring minutes or hours after the injury in an otherwise fully awake patient, have sometimes turned out to be factitious in our experience. In medical writings, the term posttraumatic epilepsy usually refers to late epilepsy, i.e., to seizures that develop several weeks or months after closed head injury (1 to 3 months in most cases). Approximately 6 months after injury, half the patients who will develop epilepsy have had their first epi-
sode; by the end of 2 years, the figure rises to 80 percent (Walker). Data derived from a 15-year study of military personnel with severe (penetrating) brain wounds indicate that patients who escape seizures for 1 year after injury can be 75 percent certain of remaining seizure-free; patients without seizures for 2 years can be 90 percent certain; and for 3 years, 95 percent certain. For the less-severely injured (mainly closed head injuries), the corresponding times are 2 to 6 months, 12 to 17 months, and 21 to 25 months (Weiss et al). Despite this, there is no doubt that seizures in adulthood occur for which there is no other explanation than a scarred cortical contusion that had been acquired decades before. The interval between head injury and development of seizures is said to be longer in children. Posttraumatic seizures (both focal and generalized) tend to decrease in frequency as the years pass, and a significant number of patients (10 to 30 percent, according to Caviness) eventually stop having them. Status epilepticus is uncommon. Individuals who have early attacks (within a week of injury) are more likely to have a complete remission of their seizures than those whose attacks begin a year or so after injury. A low frequency of attacks is another favorable prognostic sign. Alcoholism is considered to have an adverse effect on this seizure state, but there are no systematic studies of this subject. Our colleague, M. Victor, observed some 25 patients with posttraumatic epilepsy in whom seizures had ceased altogether for several years, only to recur in relation to drinking. In these patients the seizures were precipitated by a weekend or even one evening of heavy drinking and occurred, as a rule, not when the patient was intoxicated but in the withdrawal period. The nature of the epileptogenic lesion has been a cortical scar in most instances, but in some cases, particularly in alcoholics, it has been elusive. From the examination of old cortical contusions (plaques jaunes), one cannot, on morphologic grounds, determine whether a lesion had or had not been epileptogenic. Electrocorticograms of the brain in regions adjacent to old traumatic foci reveal a number of spontaneously electrically active zones adjacent to the scars. Treatment and Prophylaxis Usually the seizures can be controlled by a single antiepileptic medication, and relatively few are recalcitrant to the point of requiring excision of the epileptic focus. In this small group, the surgical results vary according to the methods of patient selection and techniques of operation. Under the neurosurgical conditions 3 decades ago, with careful selection of cases, Rasmussen (also Penfield and Jasper) was able to eradicate seizures in 50 to 75 percent of cases by excision of the focus; the results currently are somewhat better. The use of antiepileptic drugs to prevent the first seizure and subsequent epilepsy after closed or penetrating cranial injury has its proponents and opponents. In one study, patients receiving phenytoin developed fewer seizures at the end of the first year than a placebo group, but a year after medication was discontinued, the incidence was the same (and quite low) in the two groups. One extensive randomized study by Temkin and colleagues demonstrated that when administered within a day of injury and continuing for 2 years, phenytoin reduced the incidence of seizures in the first week, but not thereafter.
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Also, in a study of a large number of patients with penetrating head injuries, the prophylactic use of anticonvulsants was ineffective in preventing early seizures (Rish and Caveness), and this has guided our own approach.
Autonomic Dysfunction Syndrome in Traumatic Coma A troublesome consequence of severe head injury, that is observed in comatose patients and those in the persistent vegetative state, is a syndrome of violent extensor posturing, profuse diaphoresis, hypertension, and tachycardia lasting minutes to an hour. A slight fever may accompany the spells. Families and staff are greatly disturbed by the display, particularly when the patient’s grimacing suggests suffering. These spells of excessive sympathetic activity and posturing may be precipitated by painful stimuli or by distention of a viscus, but often they arise spontaneously. The syndrome is often mistakenly identified as a seizure and in many texts is still referred to as “diencephalic epilepsy” but it is more likely the result of the removal of suppressive cortical influences on autonomic structures, allowing the hypothalamus to function independently of normal inhibitory mechanisms. A survey of 35 such patients by Baugley and colleagues identified diffuse axonal injury and a period of hypoxia as being the main associated injuries, and this has been our experience as well. Narcotics and diazepines have a slightly beneficial effect but bromocriptine, which may be used in combination with sedatives or with small doses of morphine, has been most effective according to Rossitch and Bullard.
Extrapyramidal and Cerebellar Disorders following Trauma The question of a causative relationship between cerebral trauma and the development of Parkinson disease has been a controversial issue for many years—usually with the conclusion that the condition does not exist and that any apparent relationship, particularly in relation to a single brain injury, is coincidental. Most such patients probably had early symptoms of Parkinson disease brought to light by the head injury. There are, however, cases such as the one reported by Doder and colleagues, in which traumatic necrosis of the lenticular and caudate nuclei was followed after a period of 6 weeks by the onset of predominantly contralateral parkinsonian signs, including tremor, which progressed slowly and were unresponsive to L-dopa. There are also undoubted instances of parkinsonism following severe closed head injury and the vegetative state (Matsuda et al). An exception to these statements may be a parkinsonian syndrome in ex-boxers, as a manifestation of the “punch-drunk” syndrome (see below). Whether several athletic concussions in past years can cause Parkinson disease seems unlikely to us. Cerebellar ataxia is another rare consequence of cranial trauma unless the latter was complicated by cerebral anoxia (causing ataxia with myoclonus) or a by a hemorrhage strategically placed in the deep midbrain or cerebellum. When cerebellar ataxia is caused by the trauma itself, it is frequently unilateral and the result of injury to the superior cerebellar peduncle. We have experience with a
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severely ataxic patient who had only small lesions in the cerebellar after bilateral acute subdural hematomas from an assault with head trauma. An “apraxia” of gait may also reflect the presence of a communicating hydrocephalus (see below and Chap. 30).
“Punch-Drunk” Encephalopathy (Dementia Pugilistica) The cumulative effects of repeated cerebral injuries, observed in boxers who had engaged in many bouts over a long period of time, constitute a type of head injury that is difficult to classify. What is referred to is the development, after many years in the ring (sometimes toward the end of the boxer’s career, more often within a few years of retirement), of dysarthric speech and a state of forgetfulness, slowness in thinking, and other signs of dementia. Movements are slow, stiff, and uncertain, especially those involving the legs, and there is a shuffling, wide-based gait. In other words, a parkinsonian and dementing syndrome emerges and sometimes a moderately disabling ataxia, but there is no mistaking these for idiopathic Parkinson or Alzheimer disease. The plantar reflexes may be extensor on one or both sides. The clinical syndrome was reanalyzed by Roberts and colleagues, who found it present to some degree in 37 of the 224 professional boxers they examined. More recent studies show that in about one-half of all professional boxers, both active and retired, the CT scan discloses ventricular dilatation and/or sulcal widening and a cavum septi pellucidi (why the latter, which is ostensibly a developmental anomaly, would be overrepresented in boxers is unclear). These anatomic abnormalities had been demonstrated many years before by pneumoencephalography and were found to be related to the number of bouts (Ross et al; Casson et al). Whether repeated concussions in football players can lead to dementia of a type related to dementia pugilistica is a matter of dispute. A thorough pathologic study of this disorder has been made by Corsellis and associates. They examined the brains of 15 retired boxers who had shown the punchdrunk syndrome and identified a group of cerebral changes that appear to explain the clinical findings. Mild to moderate enlargement of the lateral ventricles and thinning of the corpus callosum were present in all cases. Also, as mentioned, practically all of them showed a greatly widened cavum septi pellucidi and fenestration of the septal leaves. Readily identified areas of glial scarring were situated on the inferior surface of the cerebellar cortex. In these areas, and well beyond them, Purkinje cells were lost and the granule cell layer was somewhat thinned. Surprisingly, cerebral cortical contusions were found in only a few cases. Notably absent also was evidence of previous hemorrhage. Of the 15 cases, 11 showed varying degrees of loss of pigmented cells of the substantia nigra and locus ceruleus, and many of the remaining cells showed Alzheimer neurofibrillary change; Lewy bodies were not observed. Neurofibrillary changes were scattered diffusely through the cerebral cortex and brainstem but were most prominent in the mediotemporal gray matter. Noteworthy was the absence of discrete amyloid plaques in this material by the usual staining methods;
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however, all cases showed extensive immunoreactive deposits of beta-amyloid (“diffuse plaques”). In 3 boxers who developed a parkinsonian syndrome, Davie and colleagues found a reduction of N-acetylaspartate in the putamen and pallidum by protein magnetic resonance spectroscopy. This probably reflected a loss of neurons in these regions and was said by these authors to differentiate it from idiopathic Parkinson disease. The pathogenesis of the punch-drunk state, therefore, remains unclear.
Posttraumatic Hydrocephalus This is probably an uncommon complication but one that is frequently imputed to severe head injury. It conforms to the category of normal pressure hydrocephalus, as discussed in Chap. 30. Intermittent headaches, vomiting, confusion, and drowsiness are the initial manifestations. Later on, mental dullness, apathy, and psychomotor retardation are seen; by this time the CSF pressure may have fallen to a normal level (normal-pressure hydrocephalus). Postmortem examinations have demonstrated an adhesive basilar arachnoiditis. Early subarachnoid hemorrhage may be involved in the mechanisms. The response to ventriculoperitoneal shunt may be dramatic. Zander and Foroglou have had extensive experience with this condition and have written informatively about it.
Postconcussion Syndrome This troublesome and frequent problem has been mentioned above, as well as in Chap. 10. When the syndrome is protracted, neurologists are vexed by the condition—a problem intensified by worried patients and family. It has numerous similarities to the posttraumatic stress disorder, and has also been termed posttraumatic nervous instability syndrome and traumatic neurasthenia (Symonds, among many other names). Headache and lack of mental clarity are the central symptoms. The pain is either generalized or localized to the part that had been struck and variously described as aching, throbbing, pounding, stabbing, pressing, or band-like; it is remarkable for its variability in an individual patient. The intensification of the headache and other symptoms by mental and physical effort, straining, stooping, and emotional excitement has been mentioned earlier; rest and quiet tend to relieve it. Such headaches may present a major obstacle to convalescence. Dizziness, another prominent symptom, is usually not a true vertigo but a giddiness or light-headedness. The patient may feel unsteady, dazed, weak, or faint. However, a certain number of patients describe symptoms that are at least consonant with labyrinthine disorder; objects in the environment move momentarily, and looking upward or to the side may cause a sense of unbalance. Labyrinthine tests may show hyporeactivity but far more often they disclose no abnormalities. McHugh found a high incidence of minor abnormalities by electronystagmography, both in concussed patients and in those suffering from whiplash injuries of the neck; but we find much of the data difficult to interpret. Exceptionally, vertigo is accompanied by diminished excitability of both the labyrinth and the cochlea (deafness), and one may assume the existence of direct injury to the eighth nerve or end organ.
These physical symptoms clear up in several weeks in the majority of patients. When the symptoms persist, the patient becomes intolerant of noise, emotional excitement, and crowds. Tenseness, restlessness, fragmentation of sleep, inability to concentrate, feelings of nervousness, fatigue, worry, apprehension, and an inability to tolerate the usual amount of alcohol complete the clinical picture. The resemblance of these symptoms to those of anxiety and depression and to other forms of “posttraumatic stress disorder” is quite apparent. In contrast to this multiplicity of subjective symptoms, memory and other intellectual functions after a single concussion usually show little or no impairment, although this statement has been strongly disputed. A further discussion of cognitive sequelae is found below. The postconcussion syndrome complicates all types of head injury, mild and severe. Once established, it may persist for months or even years, and it tends to resist all varieties of treatment. Eventually, the symptoms lessen. Strangely, this syndrome is almost unknown in children. Characteristic also is the augmentation of both the duration and intensity of this syndrome by problems with compensation and litigation, suggesting a psychologic factor. In countries where these matters are a less-prominent part of the social fabric, the occurrence of posttraumatic syndrome is far less frequent. Environmental stress assumes importance as well, for if too much is demanded of the patient soon after injury, irritability, insomnia, and anxiety are enhanced. In this connection, an interesting experiment was conducted by Mittenberg and colleagues (1992). A group of subjects with no personal experience or knowledge of head injury were asked to select from a list those symptoms that they would expect after a concussive head injury. They chose a cluster of symptoms virtually identical to that of the postconcussion syndrome. The high background rates of various components of the postconcussion syndrome make it appear to be more prevalent than it truly is. The prospective study by Meares and coworkers found that, when compared to a group of patients who had noncranial trauma, the rates of the features of the syndrome were the same and that the strongest predictor of its occurrence was a previous anxiety disorder. An approach to treating such patients is given further on, It has also been reported that military personnel who experience head injuries of any degree have a higher incidence of posttraumatic stress disorder (PTSD) than those with other somatic injuries. The same disorder can be detected in civilians after injury and it then blends clearly into the above-described postconcussion syndrome.
Posttraumatic Cognitive and Psychiatric Disorders In all patients with cerebral concussive injury, there remains a gap in memory (traumatic amnesia) spanning a variable period from before the accident to some point following it. This gap is permanent and is filled in only by what the patient is told. In addition, as stated in the introduction to this section, some degree of impairment of higher cortical function may persist for weeks (or be permanent) after
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moderate to severe head injuries, even after the patient has reached the stage of forming continuous memories. During the period of deranged mentation, the memory disorder is the most prominent feature; in that respect, the state resembles the alcoholic form of the Korsakoff amnesic state and has some resemblance to the state of transient global amnesia (Chap. 21). It has been repeatedly asserted that this amnesic state is a constant feature of every prolonged traumatic mental disorder, but to the authors it reflects in part the ease with which memory can be tested. With more careful testing, other cognitive disorders are usually evident. Concussed patients, during the period of posttraumatic amnesia, rarely confabulate. Apart from disorientation in place and time, the head-injured patient also shows defects in attention, as well as showing distractibility, perseveration, and an inability to synthesize perceptual data. Judgment and executive function may be mildly impaired, rarely severely, during the amnestic epoch. A perseverative tendency interferes with both action and thought. Leininger and associates, for example, found that most of their 53 patients who suffered minor head injury in traffic accidents performed less well than controls on psychologic tests (category test, auditory verbal learning, copying of complex figures). The fact that those who were merely dazed did as poorly as those who were concussed and that litigation was involved in some cases would lead one to question these results. Perhaps most affected, and most evident to highfunctional individuals is a problem with overall planning and coherence that is attributable to a defect in frontal lobe “executive functioning.” As a general rule, the lower the score on the Glasgow Coma Scale immediately after injury (see Table 35-1) and the longer the posttraumatic gap in the formation of new memories (anterograde amnesia), the more likely the patient is to suffer some permanent cognitive and personality changes. According to Jennett and Bond, patients with good recovery achieved their maximum degree of improvement within 6 months. Others have found that detailed and repeated psychologic testing over a prolonged period, even in patients with relatively minor cerebral injuries, discloses measurable improvement for as long as 12 to 18 months. There are other mental and behavioral abnormalities of a more subtle type that remain as sequelae to serious cerebral injury. As the stage of posttraumatic dementia recedes, the patient may find it impossible to work or to adjust to his family situation. Such patients are often abnormally abrupt, argumentative, and suspicious. Unlike the postconcussion syndrome described above, in which there is a certain uniformity, these traits vary with the patient’s age, past experience, and environmental stresses. Extremes of age have been particularly important in our experience. The most prominent behavioral abnormality in children, described by Bowman and colleagues, is a change in character. They become impulsive, heedless of the consequences of their actions, and lacking in social norms—much like those who in the past had recovered from encephalitis lethargica. Some adolescents or young adults show the general lack of inhibition and impulsivity that one associates with frontal lobe disease. In the older person, it is the impairment of intellectual functions that
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assumes greater prominence. In most instances, these more serious behavioral changes can be traced to contusions in the frontal and temporal lobes. In cases without obvious structural brain damage, cognitive deficiency after trauma has been widely attributed to diffuse axonal injury. Attempts to validate this by modern techniques such as diffusion tensor imaging have met with some success, such as the series described by Kraus and colleagues, but require further study. The tendency is for all such symptoms to subside slowly although not always completely, even in those in whom an accident has provoked a frank outburst of psychosis (as may happen to a person who is bipolar or a paranoid schizophrenic). These forms of what had colorfully in the past been called “traumatic insanity” were carefully analyzed for the first time by Adolf Meyer. Hysterical symptoms that develop after head injury, both cognitive and somatic, appear to be more common than those following injury to other parts of the body. These symptoms are discussed in Chap. 56. They may be immediate or delayed and vary from stuttering to blindness, paralysis, inability to stand, and even to catatonia.
TREATMENT OF HEAD INJURY Patients with Only Transient Unconsciousness Patients with an uncomplicated concussive injury who have already regained consciousness by the time they are seen in a hospital and have a normal neurologic examination pose few difficulties in management. They should not be discharged until the appropriate examinations (CT scans, skull films, if necessary) have been obtained and the results prove to be negative. Also, the patient should not be released until the capacity for consecutive memories has been regained and arrangements have been made for observation by the family of signs of possible, although unlikely, delayed complications (subdural and epidural hemorrhage, intracerebral bleeding, and edema). A program instituted by Mittenberg and colleagues (2001) has shown that reassurance and explanation of the concussive injury and anticipated aftereffects reduces the incidence of postconcussive symptoms at 6 months. Most such patients become mentally clear, have mild or no headache, and are found to have a normal neurologic examination. They do not require hospitalization or special testing, but in the current litigious climate of the United States, some form of brain imaging is nonetheless often performed. Acetaminophen may be prescribed for headache. Any increase in headache, vomiting, or difficulty arousing the patient should prompt a return to the emergency department. A written instruction sheet with symptoms to be expected and clear advice about returning for examination is very helpful. The patients with persistent complaints of headache, dizziness, and nervousness, the syndrome that we have designated as posttraumatic nervous instability, are the most difficult to manage, as discussed above. A treatment program must be planned in accordance with the basic problem. If there is mainly an anxious depression, antidepressant medications—
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such as fluoxetine, paroxetine, or a tricyclic—may be useful, but their effects are often disappointing. Simple analgesics, such as acetaminophen or nonsteroidal antiinflammatory drugs, should be prescribed for the headache. Litigation should be settled as soon as possible. To delay settlement usually works to the disadvantage of the patient. Long periods of observation, repetition of a multitude of tests, and waiting only reinforce the patient’s worries and fears and reduce the motivation to return to work. Neuropsychologic tests may be useful in the group with persistent cognitive difficulty, but the results should be interpreted with caution, as depression and poor motivation will degrade performance.
Patients with Severe Head Injury If the physician arrives at the scene of an accident and finds an unconscious patient, a rapid examination should be made before the patient is moved. First it must be determined whether the patient is breathing and has a clear airway and obtainable pulse and blood pressure, and whether there is dangerous hemorrhage from a scalp laceration or injured viscera. Severe head injuries that arrest respiration are soon followed by cessation of cardiac function. Injuries of this magnitude are often fatal; if resuscitative measures do not restore and sustain cardiopulmonary function within 4 to 5 min, the brain is usually irreparably damaged. Oxygen should be administered. Bleeding from the scalp can usually be controlled by a pressure bandage unless an artery is divided; then a suture becomes necessary. Resuscitative measures (artificial respiration and cardiac compression) should be continued until they are taken over by ambulance personnel. The likelihood of a cervical fracture–dislocation, which may be associated with any severe head injury, is the reason for taking precautions in immobilizing the neck and moving the patient. In the awake patient, neck pain calls attention to this complication. It should be recalled that even in the absence of a spinal fracture, the spinal cord may be threatened by the instability resulting from ligamentous injuries (posing the risk of subluxation). In the study of 292 patients with traumatic cervical injuries by Demetriades and colleagues, 31 (11 percent) showed subluxations without fracture and 11 (4 percent) had cord injuries with neither fracture nor subluxation. The combined use of standard cervical spine films and cervical CT scanning detected all cervical injuries. After severe head or neck injury, it is therefore advisable also to obtain standard anteroposterior, lateral, and oblique neck films, with additional gentle flexion (20 degrees) and extension (30 degrees) views of the neck and a neck CT scan. If these are normal and there is little or no neck pain, the cervical collar is no longer required. If these studies cannot be obtained, or if there is significant persistent pain or other neurologic findings induced by head movement, a cervical MRI is advisable. In the hospital, the first step is to clear the airway and ensure adequate ventilation by endotracheal intubation if necessary. A search for other injuries must be made, particularly of the abdomen, chest, spine, and long bones. Chestnut et al, in analyzing the data from the Traumatic Coma Data Bank, found that sustained early hypotension (systolic blood pressure 0.18 mM) and urine is diagnostic. The disease is caused by a gene defect on chromosome 15 that codes for the enzyme fumarylacetoacetate hydrolase, a deficiency of which results in the accumulation of tyrosine and its metabolites. A low-tyrosine and low-PA diet, optimized to allow growth and development, has resulted in rapid amelioration of symptoms but must be started early. Retinoids given orally improve the skin lesions. Neonatal tyrosinemia can cause liver failure and early death. This disease can be distinguished from the Cross syndrome (albinism with mental retardation, growth impairment, spastic weakness, and alkalosis) and from the Waardenburg ocular albinism syndrome (white forelock, hypertelorism, deafness). For a detailed discussion of the albinism syndromes, see the article by Oetting and King.
Tyrosine Hydroxylase Deficiency This disease causes a progressive infantile encephalopathy; it is of special interest because tyrosine is the precursor of Ldopa and the other catecholamines. Levels of these chemical substances in the brain are greatly reduced. As a result, the encephalopathy takes the form mainly of fluctuating extrapyramidal signs in combination with ocular and vegetative symptoms. L-Dopa causes some improvement in the motor symptoms (see Hoffmann et al). This disease has similarities to juvenile dopa-responsive dystonia, which is exquisitely sensitive to L-dopa treatment (as discussed in Chap. 39) and to the deficiency of L-amino decarboxylase, described above, which also causes low levels of catecholamines and a movement disorder.
Hartnup Disease This amino acid disorder, named after the family in which it was first observed, is probably transmitted in an autosomal recessive pattern. The causative gene, SLC6A19, is located on chromosome 5. The babies are normal at birth. The onset of symptoms is in late infancy or early childhood. The clinical features consist of an intermittent red, scaly rash over the face, neck, hands, and legs, resembling that of pellagra. It is often combined with an episodic personality disorder in the form of emotional lability, uncontrolled temper, and confusional-hallucinatory psychosis; episodic cerebellar ataxia (unsteady gait, intention tremor, and dysarthria); and, occasionally, spasticity, vertigo, nystagmus, ptosis, and diplopia. Attacks of disease are triggered by exposure to sunlight, emotional stress, and sulfonamide drugs and last for about 2 weeks, followed by variable periods of relative normalcy. The frequency of attacks diminishes with maturation, but some children suffer retarded growth and development with a mild persistent mental retardation. The metabolic faults are the result of a transport error of neutral amino acids across renal tubules, with excretion of
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greatly increased amounts of these amino acids in the urine and feces. In particular, there is the excretion of large amounts of indicans, mainly indoxyl sulfate, particularly after oral L-tryptophan loading, and an abnormally high excretion of nonhydroxylated indole metabolites. Impaired intestinal transport of tryptophan and loss in the urine reduce its availability for the synthesis of niacin and accounts for the pellagrous skin changes. The pathologic basis of the disease is undetermined. It must be differentiated from the large number of intermittent and progressive cerebellar ataxias of childhood, described below. Treatment consists of avoiding exposure to sunlight and to sulfonamide drugs. Because of the similarities between pellagra and Hartnup disease, the usual practice is to give nicotinamide in doses of 50 to 300 mg daily. The skin lesions disappear and there are reports of subsidence of ataxia and psychotic behavior. However, the results of treatment are inconsistent. Possibly a better response is obtained by the administration of L-tryptophan ethyl ester in doses of 20 mg/kg tid.
Other Metabolic Diseases with Episodic or Persistent Ataxia, Seizures, and Mental Retardation In addition to Hartnup disease, a number of other metabolic diseases give rise to intermittent episodes of ataxia during early childhood. These are (1) mild forms of maple syrup urine disease and the congenital hyperammonemias (type II hyperammonemia, citrullinemia, argininosuccinic aciduria, hyperornithinemia), described in an earlier part of the chapter; (2) subacute necrotizing encephalomyelopathy (Leigh disease), described further on; (3) hyperalaninemia and hyperpyruvic acidemia (Lonsdale et al; Blass et al); and (4) autosomal dominant, acetazolamide-responsive ataxia that may have its onset in childhood but usually appears later; and (5) familial hypobetalipoproteinemia—Bassen Kornzweig disease. In all of these conditions, the ataxia, which is of cerebellar type, is variable from time to time and may follow a burst of seizures (such as occur in argininosuccinic aciduria). The seizures are treated with antiepileptic drugs, which may at first be held responsible for the ataxia. In time, however, it becomes apparent that the ataxia lasts a week or two and bears no relation to the anticonvulsant therapy. Indeed, seizures and ataxia are both a result of the common biochemical abnormality. Between attacks, in all the intermittent ataxias, the patient’s movements are relatively normal, but most of the affected children have learning disabilities to a varying degree.
Progressive Cerebellar Ataxia of Early Childhood The differentiation among the childhood ataxias is difficult. The problem is twofold—first, to be certain that ataxia exists and, second, to differentiate cerebellar ataxia from the sensory ataxia of peripheral nerve disease and from generalized tremor and polymyoclonus. Because cerebellar ataxia is more a disorder of voluntary than of postural movements, its presence usually cannot be determined
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with certainty until intentional (projected) movements become part of the child’s repertoire of motor activity. As indicated in Chap. 28, the earliest signs become manifest in the arms when the infant reaches for an object and brings it to his mouth or transfers it from hand to hand. A jerky, wavering, tremulous movement then appears; in sitting, titubation of the head and a tremor of the trunk may be apparent. Once walking begins, apart from the usual clumsiness of the toddler, there is a similar incoordination of movement. Sensory ataxia is always difficult to distinguish but is rare at this age and usually accompanied by weakness and absence of tendon reflexes. By the fourth or fifth year, when more detailed sensory testing becomes possible, the presence or absence of a proprioceptive disturbance and a Romberg sign can be demonstrated. The group of persistent and progressive cerebellar ataxias is heterogeneous and of varied etiology; some of them merge with Friedreich ataxia, Levy-Roussy neuropathy, and other adolescent–adult degenerative hereditary ataxias. These disorders are discussed in Chap. 39. There are many other childhood ataxias that probably belong in the category of degenerative disease, some in which cerebellar ataxia is the most prominent disorder and in which other neurologic abnormalities are more prominent. To describe each in detail would be impractical in a book on the principles of neurology; consequently, the non-Friedreich ataxias are only tabulated here. 1. Cerebellar ataxia with diplegia, hypotonia, and mental retardation (also called atonic diplegia of Foerster); this is a form of cerebral palsy. 2. Agenesis of the cerebellum: early cerebellar ataxia (with or without mental retardation) and episodic hyperventilation; this group included the selective agenesis of the vermis—Joubert syndrome. 3. Cerebellar ataxia with cataracts and oligophrenia: onset from childhood (mainly) to as late as adult years (Marinesco-Sjögren disease). 4. Familial cerebellar ataxia and retinal degeneration (Behr disease). 5. Familial cerebellar ataxia with cataracts and ophthalmoplegia or with cataracts and mental as well as physical retardation. 6. Familial cerebellar ataxia with mydriasis. 7. Familial cerebellar ataxia with deafness and blindness and a similar combination, called retinocochleodentate degeneration, involving the loss of neurons in these three structures. 8. Familial cerebellar ataxia with choreoathetosis, corticospinal tract signs, and mental and motor retardation. In none of the syndromes mentioned above has a biochemical abnormality been established, so their metabolic nature is a matter of speculation. However, disorders of the electron transport chain can, on occasion, present as the Marinesco-Sjögren phenotype, mentioned above. The persistent cerebellar ataxias of childhood in which a metabolic fault or gene defect has been demonstrated are as follows: 1. Refsum disease 2. Abetalipoproteinemia (Bassen-Kornzweig syndrome) 3. Ataxia-telangiectasia
4. Galactosemia 5. Friedreich ataxia Bassen-Kornzweig syndrome (onset more often in late than in early childhood) is described in the following section of this chapter. Ataxia-telangiectasia is described below. Generally, it is not difficult to differentiate these diseases from the acquired postinfectious variety that occurs predominantly in children (Chap. 36).
Ataxia-Telangiectasia This disease, also referred to as the Louis-Bar syndrome, was first described by Sylaba and Henner in 1926, long before Louis-Bar’s report in 1941. It combines a progressive ataxia with humoral immune deficiency and telangiectasias. Like xeroderma pigmentosum and the Cockayne syndrome, ataxia-telangiectasia has been attributed to defective repair of DNA. The inheritance pattern is autosomal recessive. The disorder first presents as an ataxic-dyskinetic syndrome in children who appear to have been normal in the first few years of life. The onset of the disease coincides more or less with the acquisition of walking, which is awkward and unsteady. Later, by the age of 4 to 5 years, the limbs become ataxic, and choreoathetosis, grimacing, and dysarthric speech are added. The eye movements become jerky, with slow and long-latency saccades, and there is also apraxia for voluntary gaze (the patient turns the head but not the eyes on attempting to look to the side). Optokinetic nystagmus is lost. By the age of 9 to 10 years, slight intellectual decline sets in and signs of mild polyneuropathy are evident. Muscle power is reduced little if at all until late in the illness, but tendon reflexes may disappear. The characteristic telangiectatic lesions, which are mainly transversely oriented subpapillary venous plexuses, appear at 3 to 5 years of age or later and are most apparent in the outer parts of the bulbar conjunctivae (Fig. 37-5), over the ears, on exposed parts of the neck, on the bridge of the nose and cheeks in a butterfly pattern, and in the flexor creases of the forearms. Vitiligo, café-aulait spots, loss of subcutaneous fat, and premature graying of hair are observed in some older patients. Many of the patients have endocrine alterations (absence of secondary sexual development, glucose intolerance). The disease is progressive, and death usually occurs in the second decade from intercurrent bronchopulmonary infection or neoplasia—usually lymphoma, less often glioma (Boder and Sedgwick). The significant abnormalities in the CNS are severe degeneration in the cerebellar cortex (visible in MRI scans); loss of myelinated fibers in the posterior columns, spinocerebellar tracts, and peripheral nerves; degenerative changes in the posterior roots and cells of the sympathetic ganglia; and loss of anterior horn cells at all levels of the spinal cord. In a few cases, vascular abnormalities, like the mucocutaneous ones, have been found scattered diffusely in the white matter of the brain and spinal cord, but they are of questionable significance. Also, there may be a loss of pigmented cells in the substantia nigra and locus ceruleus (a feature shared with PKU), and cytoplasmic
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Figure 37-5. Ocular appearance of ataxia-telangiectasia. (Reproduced by permission from Lyon et al.)
inclusions (Lewy bodies) in the cells that remain (Agamanolis and Greenstein). During early development there are abnormalities of Purkinje cell migration and variations in nuclear size. Intranuclear inclusions and bizarre nuclear formations have also been found in the satellite cells (amphicytes) of dorsal root ganglion neurons (Strich). There is an absence or decrease in several immunoglobulins—IgA, IgE and isotypes, IgG2, IgG4—in practically every patient. These deficiencies, shown by McFarlin and associates to be a result of decreased synthesis, are associated with hypoplasia of the thymus, loss of follicles in lymph nodes, failure of delayed hypersensitivity reactions, and lymphopenia. This immunodeficient state accounts for the striking susceptibility of these patients to recurrent pulmonary infections and bronchiectasis. Transplantation of normal thymus tissue into the patient and administration of thymus extracts have been of no therapeutic value. The defective gene (designated ATM) is a kinase that mediates DNA repair by halting the cell cycle after DNA damage. For this reason, there is faulty repair of DNA after radiation and a greatly increased risk of lymphomas, leukemias, and other tumors. The only therapy centers on the control of infections. Free radical scavengers such as vitamin E have been recommended without proof of their effectiveness. Because of radiation sensitivity, even conventional diagnostic tests (dental, chest radiography) should be avoided unless there is a compelling reason for them.
Metachromatic Leukodystrophy (MLD, Arylsulfatase Deficiency) This is another of the lysosomal (sphingolipid) storage diseases (see Tables 37-3 and 37-6). The abnormality is the
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mutation of the gene for enzyme arylsulfatase A, which prevents the conversion of sulfatide to cerebroside (a major component of myelin) and results in an accumulation of the former. The disease is transmitted as an autosomal recessive trait and usually becomes manifest between the first and fourth years of life (variants have their onset in the congenital period, in late childhood, and even in adult life). Variability of gene mutation accounts for the different forms. The so-called O-type mutation causes a lack of active gene product and of the corresponding enzyme; the R-type mutation results in low levels. The infantile form is associated with two copies of the O gene, the juvenile form, with either O or R, and the adult form is usually from two copies of R. Another genetic classification system denominates I and A alleles and differentiates the types of diseases by age of onset and residual enzyme activity. The disease in this age group is characterized clinically by progressive impairment of motor function (gait disorder, spasticity) in combination with reduced output of speech and mental regression. At first the tendon reflexes are usually brisk, but later, as the peripheral nerves become more involved, the tendon reflexes are decreased and eventually lost. Or, there may be variable hypotonia and areflexia from the beginning, or spasticity may be present throughout the illness, but with hyporeflexia and slowed conduction velocities. Signs of mental regression may be apparent from the onset or appear after the motor disorder has become established. Later there is impairment of vision, sometimes with squint and nystagmus; intention tremor in the arms and dysarthria; dysphagia and drooling; and optic atrophy (one-third of patients), sometimes with grayish degeneration around the maculae. Seizures are rare, and there are no somatic abnormalities. The head size is usually normal, but rarely there is macrocephaly. Progression to a bedridden quadriplegic state without speech or comprehension occurs over a 1- to 3year period, somewhat more slowly in late-onset types. The CSF protein is elevated. There is widespread degeneration of myelinated fibers in the cerebrum (Fig. 37-6), cerebellum, spinal cord, and peripheral nerves. The presence of metachromatic granules in glia cells and engorged macrophages is characteristic and enables the diagnosis to be made from a biopsy of a peripheral nerve. The stored material, sulfatide, stains brown-orange rather than purple with aniline dyes. Sulfatides are also PAS-positive in frozen sections. The diagnostic laboratory findings, in addition to the MRI and histologic changes, are the elevated CSF protein (75 to 250 mg/dL) and a marked increase in sulfatide in urine and an absence of arylsulfatase A in white blood cells, in serum, and in cultured fibroblasts. Assays of arylsulfatase A activity in cultured fibroblasts and amniocytes permit the identification of carriers and prenatal diagnosis of the disease but a pseudodeficiency of the enzyme is known (the Pd allelic variant). In this condition, measured enzyme activity is 10 percent of normal, but no clinical manifestations result. Treatment with enzyme replacement or bone marrow transplantation is being tried. Marrow transplant appears to be of less benefit once the patient becomes sympto-
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Forms of metachromatic leukodystrophy developing in adult years are discussed further on.
Neuroaxonal Dystrophy (Degeneration)
Figure 37-6. Metachromatic leukodystrophy. T2-weighted axial MRI of a 3-year-old boy. Abnormal high signal intensity involves the entire centrum ovale but spares the subcortical arcuate fibers. (Reproduced by permission from Lee SH, Rao K, Zimmerman RA: Cranial MRI and CT, 3rd ed. New York, McGraw-Hill, 1992.)
matic, but it may be useful early in the disease and in the treatment of an asymptomatic sibling of an index case. The differential diagnosis of this leukodystrophy includes neuroaxonal dystrophy (see below), cases of early onset inherited polyneuropathy, late-onset Krabbe disease, and childhood forms of Gaucher disease and Niemann-Pick disease. A variant of metachromatic leukoencephalopathy, caused by a deficiency of the isoenzymes of arylsulfatase A, B, and C, was described by Austin in 1973 and called multiple sulfatase deficiency. The neurologic manifestations resemble those of metachromatic leukodystrophy but, in addition, there are facial and skeletal changes similar to those of a mucopolysaccharidosis. Deafness, hepatic enlargement, ichthyosis, and beaking of lumbar vertebrae are additional findings in some cases. Metachromatic material is found in the urinary sediment. Pathologically, in addition to metachromasia of degenerating white matter in cerebrum and peripheral nerve, there may be storage material (sulfated glycolipids), like that found in the gangliosidoses in neurons as well as in liver, gallbladder, and kidney. Granules are demonstrable in neutrophilic leukocytes. There has also been described a state of “arylsulfatase pseudodeficiency,” which exists as a polymorphism in approximately 7 percent of Europeans and makes the point that low enzyme levels alone are insufficient to be expressed as a phenotype of metachromatic leukodystrophy.
This is a rare disease, inherited as an autosomal recessive trait. In the largest group of cases (77 collected by Aicardi and Castelein), the onset was near the beginning of the second year in 50 patients and before the third year in all instances. The clinical constellation comprised psychomotor deterioration (loss of ability to sit, stand, and speak), marked hypotonia but brisk reflexes and Babinski signs, and progressive blindness with optic atrophy but normal retinae. Seizures, myoclonus, and extrapyramidal signs were rare. Loss of sensation was found later in some cases. Terminally, bulbar signs, spasticity, and decerebrate rigidity often supervened. The course was relentlessly progressive, with fatal issue in a decorticate state in 3 to 8 years. There were no abnormalities of the liver and spleen and no facial or skeletal changes. Pathologic examination reveals eosinophilic spheroids of swollen axoplasm in the posterior columns and nuclei of Goll and Burdach and in the Clarke column, substantia nigra, subthalamic nuclei, central nuclei of brainstem, and cerebral cortex. There is cerebellar atrophy, affecting the granule cell layer predominantly, and increased iron-containing pigment in the basal ganglia (like that observed in Hallervorden-Spatz disease). The CT scans and CSF are normal, and there are no biochemical or blood cell abnormalities. After the age of 2 years, however, the EEG shows characteristic high-amplitude fast rhythms (16 to 22 Hz). Evoked responses may be abnormal. Nerve conduction velocities are normal despite EMG evidence of denervation. The diagnosis can be reliably established during life by electron microscopic examination of skin and conjunctival nerves, which show the characteristic spheroids within axons. There is a later-onset form of the disease in which the course is more protracted and the neurologic manifestations (rigidity and spasticity, cerebellar ataxia, and myoclonus) are more pronounced. In these cases the mental regression is slow. Vision may be retained but retinal degeneration has been documented. Some of the late-onset cases are indistinguishable from Hallervorden-Spatz disease. The primary mutation in most cases is unknown. In early infantile forms there is a mutation in a lysosomal hydrolase.
Late Infantile and Early Childhood Gaucher Disease As stated earlier, Gaucher disease usually develops in early infancy, but some cases, so-called Gaucher disease type III, may begin in childhood, between 3 and 8 years of age. The clinical picture is variable and combines features of infantile Gaucher disease—such as abducens palsies, dysphagia, trismus, rigidity of the limbs, and dementia— with features of the late childhood–early adult form, such as palsies of horizontal gaze, diffuse myoclonus, generalized seizures, and a chronic course. The diagnosis is established by the finding of splenomegaly, Gaucher cells,
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glucocerebroside storage, and deficient activity of glucocerebrosidase in leukocytes or cultured fibroblasts.
Late Infantile–Early Childhood Niemann-Pick Disease Niemann-Pick disease is a subacute or chronic neurovisceral storage disease with early signs of hepatosplenomegaly and later signs (2 to 4 years) of neurologic involvement. These later onset types have been termed C and D, and formerly, III and IV, to differentiate them from infantile forms discussed earlier. The neurologic disorder consists of progressive dementia, dysarthria, ataxia, rarely extrapyramidal signs (choreoathetosis), and paralysis of horizontal and vertical gaze, the latter being a distinguishing feature of the later onset types. On attempting to look to the side, some of the patients make head-thrusting movements of the same type that one observes in ataxia-telangiectasia and the oculomotor apraxia of Cogan. Lateral eye movements are full on passive movement of the head (oculocephalic maneuver). Convergence is also deficient. A subtype called juvenile dystonic lipidosis is characterized by extrapyramidal symptoms and paralysis of vertical eye movements. The syndrome of the “sea-blue histiocyte” (liver, spleen, and bone marrow contain histiocytes with sea-blue granules)—in which there is retardation in mental and motor development, grayish macular degeneration, and, in rare cases, posterior column and pyramidal degeneration—may be another variant. The diagnosis is made by bone marrow biopsy, which discloses vacuolated macrophages and sea-blue histiocytes, and by measuring the defect in cholesterol esterification in cultured fibroblasts.
Late Infantile–Childhood GM1 Gangliosidosis In type 2 or so-called juvenile GM1 gangliosidosis, the onset is between 12 and 24 months, with survival for 3 to 10 years. The first sign is usually difficulty in walking, with frequent falls, followed by awkwardness of arm movements, loss of speech, severe mental regression, gradual development of spastic quadriparesis and pseudobulbar palsy (dysarthria, dysphagia, drooling), and seizures. Retinal changes are variable—usually they are absent—but macular red spots may be seen at the age of 10 to 12 years; vision is usually retained, but squints (comitant) are common. There is a facial dysmorphism resembling that of the Hurler syndrome, and the liver and spleen are enlarged. Important laboratory findings are hypoplasia of the thoracolumbar vertebral bodies, mild hypoplasia of the acetabula, and the presence in the bone marrow of histiocytes with clear vacuoles or wrinkled cytoplasm. As noted in the discussion of Tay-Sachs Disease, leukocytes and cultured skin fibroblasts show a deficiency or absence of beta-galactosidase activity. GM1 ganglioside accumulates in the cerebral neurons.
The Neuronal Ceroid Lipofuscinoses (Batten Disease) Four types of lipofuscinoses have been identified, defined largely by the age of onset: Santavuori-Haltia Finnish infantile type, Jansky-Bielschowsky early childhood type,
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Vogt-Spielmeyer juvenile type, and Kufs adult type. All except a few adult cases are autosomal recessive. The storage material in neuronal cytoplasm consists of two pigmented lipids, presumably ceroid and lipofuscin, which are cross-linked polymers of polyunsaturated fatty acids and have the property of autofluorescence. Mole has published a useful review of the genetics of these diseases and points out that at least 8 gene loci are implicated, for 6 of which the mutation has been identified. All the infantile forms and 1 juvenile form of the disease are because of mutations affecting the lysosomal enzyme palmitoyl–protein thioesterase. Other lysosomal enzymes are abnormal in the remaining juvenile and in the adult forms. In the Santavuori-Haltia form of the disease, infants from 3 to 18 months of age, after a normal period of development, undergo psychomotor regression with ataxia, hypotonia, and widespread myoclonus. There are retinal changes with extinction of the electroretinogram, slowing of the EEG with spike and slow-wave discharges, and eventually an isoelectric record. Within a few years these patients become blind, develop spastic quadriplegia and microcephaly, and succumb. In the Jansky-Bielschowsky type, the onset of symptoms is between 2 and 4 years, after normal or slightly slow earlier development, with survival to 4 to 8 years of age. Usually the first neurologic manifestations are seizures (petit mal or grand mal) and myoclonic jerks evoked by proprioceptive and other sensory stimuli, including voluntary movement and emotional excitement. Incoordination, tremor, ataxia, and spastic weakness with lively tendon reflexes and Babinski signs, deterioration of mental faculties, and dysarthria proceed to dementia and eventually to mutism. In patients with relatively late onset, a progressive dementia is the cardinal manifestation. Visual failure may occur early in some cases because of retinal degeneration (of rods and cones) with pigmentary deposits, but in others vision is normal. The electroretinogram becomes isoelectric if vision is affected. Abnormal inclusions (translucent vacuoles) are seen in 10 to 30 percent of circulating lymphocytes, and azurophilic granules in neutrophils. High-voltage EEG spikes are induced by photic stimuli. Only in early onset cases is there microcephaly. Pathologic examination shows neuronal loss in the cerebral and cerebellar cortices (granule and Purkinje cells), and curvilinear storage particles and osmophilic granules are visible in the remaining neurons. Inclusions are also observed in cutaneous nerve twigs and endothelial cells of blood vessels, findings that permit diagnosis during life by electron microscopy of skin, conjunctival, or rectal mucosal biopsies. In many patients with lipofuscinoses, diagnosis can be confirmed by demonstrating the presence of one of several recently identified gene mutations. There are no definite markers for the group in blood or urine, but in some patients a structural component of mitochondria is excreted in excess (the so-called C-fragment). In the differential diagnosis, one must consider late infantile GM1 gangliosidosis, idiopathic epilepsy, Alpers disease, and other forms of neuronal ceroid-lipofuscinosis. The lipofuscinoses of later onset—the Vogt-Spielmeyer (juvenile) type and the Kufs (adult) type—are discussed
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further on. There is no treatment for the basic disease process but approaches involving gene therapy are being explored.
Mucopolysaccharidoses (Table 37-7) This is a group of diseases in which the storage of lipid in neurons is combined with that of polysaccharides in connective tissues. As a consequence there is a conjunction of neurologic and skeletal abnormalities that is virtually unique. The nervous system may also be involved secondarily as a result of skeletal deformities and thickening and hyperplasia of connective tissue at the base of the brain, leading to obliteration of the subarachnoid space and obstructive hydrocephalus or compression of the cervical cord. The prevalence of mucopolysaccharides as a whole is approximately 1 per 8,000 births, according to Meikle and colleagues. Depending on the degree of visceral-skeletal and neurologic changes, at least 7 distinct clinical subtypes are recognized (see Table 37-7). The basic abnormality is an enzymatic defect that prevents the degradation of acid mucopolysaccharides (now called glycosaminoglycans). The latter can be measured and are increased in serum, leukocytes, or cultured fibroblasts. The storage is, again, within lysosomes in the brain, spinal cord, heart, viscera, bone, and connective tissue. All forms of the disease except the Hunter syndrome, which is sex-linked, are inherited in an autosomal recessive pattern. The studies of Neufeld and Muenzer indicate that each type of mucopolysaccharidosis is caused by a defect in a different enzyme.
gargoyle facies; large head with synostosis of longitudinal suture; kyphosis; broad hands with short, stubby fingers; flexion contractures at knees and elbows). Conductive deafness and corticospinal signs are usually present. Protuberant abdomen, hernias, enlarged liver and spleen, valvular heart disease, chronic rhinitis, recurrent respiratory infections, and corneal opacities complete the picture. The biochemical abnormalities consist of the accumulation of dermatan and heparan sulfate (glycosaminoglycans) in the tissues and their excretion in the urine, probably as a consequence of absence of activity of α-L-iduronidase. Also, there is an increase in the ganglioside content in nerve cells of the brains of these patients. In the milder Scheie (MPS V) variant of Hurler disease, intelligence and life span are normal. Treatment Enzyme replacement therapy (laronidase) is now available. The enzymes are produced with recombinant technology and are successful where previous attempts with enzymes delivered by white cell or other infusions had been ineffective. Hematopoietic stem cell bone marrow transplantation (cord blood from unrelated donors) has also been used (see Staba et al). To be effective, treatment must commence before the accumulation of glycosaminoglycans and neurologic decline. The eye and bone deterioration associated with Hurler disease is not improved. In children with the milder Scheie form and those with CNS involvement, bone marrow transplantation is not helpful and enzyme replacement is recommended. Enzyme treatment is also being tried concurrently with bone marrow transplantation in early cases. These approaches have not been effective in the Hunter or the Sanfilippo diseases, discussed below.
Hurler Disease This, the classic form, also known as MPS I, begins clinically toward the end of the first year. Mental retardation is severe, and skeletal abnormalities are prominent (dwarfism;
Hunter Disease Unlike the Hurler and other types, the Hunter form (MPS II) is transmitted as an X-linked trait. The Hurler and
Table 37-7 CLASSIFICATION OF THE MUCOPOLYSACCHARIDOSES NUMBER
EPONYM
Ia
Hurler
MPS II
Hunter
MPS III
Sanfilippo
MPS IV
Morquio
MPS V MPS VI
No longer used Maroteaux-Lamy
MPS VII
Sly
MPS
CLINICAL MANIFESTATIONS
ENZYME DEFICIENCY
GLYCOSAMINOGLYCAN
Corneal clouding, severe skeletal changes and MR, organomegaly, heart disease Dysostosis, normal corneas, MR, joint stiffness, hydrocephalus, short stature, organomegaly MR, mild or absent somatic changes, hyperactivity, hepatosplenomegaly Distinctive skeletal abnormalities, slight corneal clouding, odontoid hypoplasia, normal intelligence, hepatomegaly
α-L-Iduronidase
Dermatan sulfate, heparan sulfate
Iduronate sulfatase
Dermatan sulfate, heparan sulfate
Heparan N-sulfatase
Heparan sulfate
Galactose 6-sulfatase
Keratan sulfate, chondroitin 6-sulfate
Dysostosis, corneal clouding, normal intelligence, spinal cord compression, organomegaly Dysostosis, hepatosplenomegaly, wide range of severity, corneal clouding
N-acetylgalactosamine, 4-sulfatase (arylsulfatase B) β-Glucuronidase
Dermatan sulfate
a Less-severe phenotypes are known as Scheie or Hurler-Scheie syndromes. MR, mental retardation. Source: Modified by permission from Neufeld and Muenzer.
Dermatan sulfate, heparan sulfate, chondroitin 4sulfate
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Hunter syndromes are clinically alike except that the Hunter form is milder: mental retardation is less severe than in the Hurler type, deafness is less common, and corneal clouding is usually absent. Probably there are two forms of the syndrome—a more severe one, in which the patients do not survive beyond their midteens, and a less severe form with relatively normal intelligence and survival to middle age. Excessive amounts of dermatan and heparan sulfate are excreted in the urine. The basic abnormality is a deficiency of iduronate sulfatase.
Sanfilippo Disease This form, or MPS III, expresses itself clinically between 2 and 3 years of age, with progressive intellectual deterioration. The patients are of short stature, but in other respects the physical changes are fewer and less severe than in the Hunter and Hurler syndromes. Three and possibly four types of Sanfilippo disease, designated A, B, C, and D, are distinguished on the basis of their enzymatic defects (Neufeld and Muenzer). All subtypes are phenotypically similar, and all of them may excrete excessive amounts of heparan sulfate in the urine.
Morquio Disease This form of the disease, MPS IV, is characterized by marked dwarfism and osteoporosis. Skeletal deformity and compression of the spinal cord and medulla are constant threats because of hypoplasia of the odontoid process and atlantoaxial dislocation and thickening of the dura around the cervical cord and inferior surface of the cerebellum. Intelligence is affected only slightly or not at all. Corneal opacities may be present. Patients excrete large amounts of keratan sulfate in the urine; two types of enzymatic deficiencies have been identified (Neufeld and Muenzer).
Maroteaux-Lamy Disease This syndrome, MPS VI, includes severe skeletal deformities (short stature, anteriorly beaked vertebrae) but normal intelligence. Several patients observed by our colleagues have had a cervical pachymeningitis with spinal cord compression and hydrocephalus during adult life. Spinal cord function improved with cervical decompression and the hydrocephalus with ventriculoatrial shunting (Young et al). Hepatosplenomegaly is often present. Large amounts of dermatan sulfate are excreted in the urine, as a result of an arylsulfatase B deficiency.
β-Glucuronidase Deficiency (Sly Disease) This (MPS VII) is a rare type of mucopolysaccharidosis, the clinical features of which have yet to be sharply delineated. Short stature, progressive thoracolumbar gibbus, hepatosplenomegaly, and the bony changes of dysostosis multiplex (as in the Hurler type) are the main clinical features. There is excessive excretion of dermatan and heparan sulfate, the result of a deficiency of β-glucuronidase. Attempts to treat the mucopolysaccharidoses by enzyme replacement therapy, bone marrow transplantation, and gene transfer are in progress. None of these is far enough along to determine its efficacy.
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Mucolipidoses and Other Diseases of Complex Carbohydrates (Sialidoses; Oligosaccharidoses) (See Table 37-3) Several diseases have been described in which there is an abnormal accumulation of mucopolysaccharides, sphingolipids, and glycolipids in visceral, mesenchymal, and neural tissues, because of an α-N-acetylneuraminidase defect. In some types there is an additional deficiency of betagalactosidase. All are autosomal recessive diseases that manifest many of the clinical features of Hurler disease, but—in contrast to the mucopolysaccharidoses—normal amounts of mucopolysaccharides are excreted in the urine. Frequently, GM1 gangliosidosis, described above, is also classified with the mucolipidoses. The other members of this category are synopsized below and in Table 37-3.
Mucolipidoses At least three and possibly four closely related forms have been described. In mucolipidosis I (lipomucopolysaccharidosis), the morphologic features are those of gargoylism, with slowly progressive mental retardation. Cherry-red spots in the maculae, corneal opacities, and ataxia have been noted in some patients. Vacuolation of lymphocytes, marrow cells, hepatocytes, and Kupffer cells in the liver and metachromatic changes in the sural nerve have been described. In mucolipidosis II (I-cell disease), the most common of the mucolipidoses, there is usually an early onset of psychomotor retardation, but in some cases this does not appear until the second or third decade of life. Abnormal facies and periosteal thickening (dysostosis multiplex, like that of GM1 gangliosidosis and Hurler disease) are characteristic. Gingival hyperplasia is prominent, and the liver and spleen are enlarged; but deafness is not found and corneal opacities are slower to develop. Tonic-clonic seizures are frequent in older patients. In most cases, death from heart failure occurs by the third to eighth year. There is a typical vacuolation of lymphocytes, Kupffer cells, and cells of the renal glomeruli. Bone marrow cells are also vacuolated and contain refractile cytoplasmic granules (hence the designation inclusion-cell, or I-cell, disease). A deficiency of several lysosomal enzymes required for the catabolism of mucopolysaccharides, glycolipids, and glycoproteins have been found. In mucolipidosis III (pseudo-Hurler polydystrophy), the biochemical abnormalities are like those of I-cell disease, but there are clinical differences. In the pseudo-Hurler type, symptoms do not appear until 2 years of age or later and are relatively mild. Retardation of growth, fine corneal opacities, and valvular heart disease are the major manifestations. Yet another variant, mucolipidosis IV, has been described (see Tellez-Nagel et al). Here, clouding of the corneas is noticed soon after birth, and profound developmental retardation is evident by 1 year of age. Skeletal deformities, enlargement of liver and spleen, seizures, or other neurologic abnormalities are notably lacking. Ultrastructural examination of conjunctival and skin fibroblasts has demonstrated lysosomal inclusions of material similar to lipids and mucopolysaccharides that remain to be further characterized.
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Mannosidosis
Cockayne Syndrome
This is another rare hereditary disorder with poorly differentiated symptomatology but with dysmorphic features of broad nose, depressed bridge, thick lips, and protruding tongue. The onset is in the first 2 years, with Hurler-like facial and skeletal deformities, mental retardation, and slight motor disability. Corticospinal signs, loss of hearing, variable degrees of gingival hyperplasia, and spoke-like opacities of the lens (but no diffuse corneal clouding) may be present. The liver and spleen are enlarged in some cases. Radiographs show beaking of the vertebral bodies and poor trabeculation of long bones. Vacuolated lymphocytes and granulated leukocytes are present and aid in diagnosis. The urinary mucopolysaccharides are normal. Mannosiduria is diagnostic, caused by a defect in α-mannosidase. Mannose-containing oligosaccharides accumulate in nerve cells, spleen, liver, and leukocytes (see Kistler et al).
This disorder is probably inherited as an autosomal recessive trait. The onset is in late infancy, after apparently normal earlier development. The main clinical findings are stunting of growth, evident by the second and third years; photosensitivity of the skin; microcephaly; retinitis pigmentosa, cataracts, blindness, and pendular nystagmus; nerve deafness; delayed psychomotor and speech development; spastic weakness and ataxia of limbs and gait; occasionally athetosis; amyotrophy with abolished reflexes and reduced nerve conduction velocities; wizened face, sunken eyes, prominent nose, prognathism, anhidrosis, and poor lacrimation (resembling progeria and bird-headed dwarfism). Some cases show calcification of the basal ganglia. The CSF is normal, and there are no diagnostic biochemical findings. Pathologic examination reveals a small brain, striatal and cerebellar calcifications, leukodystrophy like that of Pelizaeus-Merzbacher disease, and a severe cerebellar cortical atrophy. The peripheral nerve changes are those of a primary segmental demyelination. It is now apparent that Cockayne syndrome, like ataxiatelangiectasia, is a consequence of mutations in genes that mediate DNA repair. At least three different forms of Cockayne syndrome have been identified, each with a different underlying gene defect.
Fucosidosis This also is a rare autosomal recessive disorder, with neurologic deterioration beginning usually at 12 to 15 months and progressing to spastic quadriplegia, decerebrate rigidity, severe psychomotor regression, and death within 4 to 6 years. Hepatomegaly, splenomegaly, enlarged salivary glands, thickened skin, excessive sweating, normal or typical gargoyle facies, beaking of the vertebral bodies, and vacuolated lymphocytes are the main features. A variant of this disease has been described with slower progression and survival into late childhood and adolescence and even into adult life (Ikeda et al). The latter type is characterized by mental and motor retardation, along with the corneal opacities, coarse facial features, skeletal deformities of gargoylism, and dermatologic changes of Fabry disease (angiokeratoma corporis diffusum), but no hepatosplenomegaly. The basic abnormality in both types is a lack of lysosomal L-fucosidase, resulting in accumulation of fucose-rich sphingolipids, glycoproteins, and oligosaccharides in cells of the skin, conjunctivae, and rectal mucosa.
Aspartylglycosaminuria This disease is characterized by the early onset of psychomotor regression; delayed, inadequate speech; severe behavioral abnormalities (bouts of hyperactivity mixed with apathy and hypoactivity or psychotic manifestations); progressive dementia; clumsy movements; corticospinal signs; corneal clouding (rare); retinal abnormalities and cataracts; coarse facies including low bridge of the nose, epicanthi, thickening of the lips and skin; enlarged liver; and abdominal hernias in some. Radiographs show minimal beaking of the vertebral bodies, and the blood lymphocytes are vacuolated. The pattern of inheritance in this entire group of diseases, as already stated, is probably autosomal recessive. Diagnostic methods applicable to amniotic fluid and cells are being developed so that prenatal diagnosis will be possible, prompted often by the occurrence of the disease in an earlier child. Neurons are vacuolated rather than stuffed with granules, much like the lymphocytes and liver cells. The specific biochemical abnormalities, as far as they are known, are listed in Table 37-3.
Other Metabolic Diseases of Late Infancy and Early Childhood Globoid cell leukodystrophy (Krabbe), subacute necrotizing encephalomyelopathy (Leigh), and Gaucher disease may also begin in late infancy or early childhood. They are described in the preceding section of this chapter. Familial striatocerebellar calcification (Fahr disease) and Lesch-Nyhan disease may also become manifest in this age period, but they usually have a later onset and are therefore described with the diseases of later childhood in the section that follows. This group of metabolic disorders presents many of the same diagnostic problems as those of early infancy. The flow chart in Fig. 37-4, which divides these disorders into dysmorphic, visceromegalic, and purely neurologic groups, is equally useful in the differential diagnosis of both age groups. As with the early infantile diseases, certain clusters of neurologic, skeletal, dermal, ophthalmic, and laboratory findings are highly distinctive and often permit the identification of a particular disease. These signs are listed below: 1. Evidence of involvement of peripheral nerves (weakness, hypotonia, areflexia, sensory loss, reduced conduction velocities) in conjunction with lesions of the CNS—metachromatic leukodystrophy, Krabbe leukodystrophy, neuroaxonal dystrophy, and Leigh disease (rare) 2. Ophthalmic signs a. Corneal clouding—several of the mucopolysaccharidoses (Hurler, Scheie, Morquio, MaroteauxLamy), mucolipidoses, tyrosinemia, aspartylglycosaminuria (rare) b. Cherry-red macular spot—GM2 gangliosidosis, GM1 gangliosidosis (half the cases), lipomucopolysaccharidosis, occasionally Niemann-Pick disease
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4.
5. 6. 7.
8. 9. 10. 11. 12.
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c. Retinal degeneration with pigmentary deposits— Jansky-Bielschowsky lipid storage disease, GM1 gangliosidosis, syndrome of sea-blue histiocytes d. Optic atrophy and blindness—metachromatic leukodystrophy, neuroaxonal dystrophy e. Cataracts—Marinesco-Sjögren syndrome, Fabry disease, mannosidosis f. Ocular apraxia—ataxia-telangiectasia, NiemannPick disease g. Impairment of vertical eye movements—late infantile Niemann-Pick disease, juvenile dystonic lipidosis, sea-blue histiocyte syndrome, Wilson disease h. Jerky eye movements, limited abduction—late infantile Gaucher disease Extrapyramidal signs—late-onset Niemann-Pick disease (rigidity, abnormal postures), juvenile dystonic lipidosis (dystonia, choreoathetosis), Rett, ataxia-telangiectasia (athetosis), Sanfilippo mucopolysaccharidosis, type I glutaric acidemia, Wilson disease, Segawa dopa-responsive dystonia Facial dysmorphism—Hurler, Scheie, Morquio, and Maroteaux-Lamy forms of mucopolysaccharidosis, aspartylglycosaminuria, mucolipidoses, GM1 gangliosidosis, mannosidosis, fucosidosis (some cases), multisulfatase deficiencies (Austin), some mitochondrial disorders Dwarfism, spine deformities, arthropathies—Hurler, Morquio, and other mucopolysaccharidoses, Cockayne syndrome Enlarged liver and spleen—Niemann-Pick disease, Gaucher disease, all mucopolysaccharidoses, fucosidosis, mucolipidoses, GM1 gangliosidosis Alterations of skin—photosensitivity (Cockayne syndrome and one form of porphyria); papular nevi and angiokeratoma (Fabry disease, fucosidosis); telangiectasia of ears, conjunctiva, chest (ataxiatelangiectasia); ichthyosis (Sjögren-Larsen disease, caused by fatty alcohol dehydrogenase deficiency); plaque-like lesions in Hunter syndrome Beaked thoracolumbar vertebrae—all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis; aspartylglycosaminuria, multiple sulfatase deficiencies Deafness—mucopolysaccharidoses, mannosidosis, Cockayne syndrome Hypertrophied gums—mucolipidoses, mannosidosis Vacuolated lymphocytes—all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis Granules in neutrophils—all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis, multiple sulfatase deficiencies
One of the most difficult diagnostic problems in this age period is distinguishing neuroaxonal dystrophy, metachromatic leukodystrophy, subacute necrotizing encephalomyelopathy (Leigh disease), some cases of lipofuscinosis, and the late form of GM1 gangliosidosis. In none of these diseases is the clinical picture entirely stereotyped. The clinician is aided in identifying neuroaxonal dystrophy by noting an onset, at 1 to 2 years of age, of severe hypotonia with retained reflexes and Babinski signs, early visual
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involvement without retinal changes, lack of seizures, normal CSF, physiologic evidence of denervation of muscles, fast-frequency EEG, normal CT scan, and N-acetylgalactosaminidase deficiency in cultured fibroblasts. Metachromatic leukodystrophy can be excluded if the CSF protein is normal and if nerve conduction velocities and enzymatic studies of leukocytes and fibroblasts are normal. Similar criteria enable one to rule out GM1 gangliosidosis. Mitochondrial disorders (Leigh disease) may begin at the same age; in many cases lactic acidosis and pyruvate decarboxylase defect will corroborate the diagnosis. Sequencing tests of the mitochondrial genome allow definitive diagnosis in most cases, as described in a later section. Also in Leigh disease, imaging of the brain may disclose hypodense lesions in the basal ganglia and brainstem, in contrast to the normal CT scan in neuroaxonal dystrophy. In metachromatic leukodystrophy, the cerebral white matter shows a diffusely decreased attenuation and the MR images are striking (see Fig. 37-6). Lipofuscinosis cannot always be diagnosed accurately; curvilinear bodies in nerve twigs and in the endothelial cells in skin biopsies and the recently discovered gene mutations are the most informative laboratory tests.
INHERITED METABOLIC ENCEPHALOPATHIES OF LATE CHILDHOOD AND ADOLESCENCE Unavoidably, one must refer here to certain inherited metabolic diseases already described that permit survival into late childhood and adolescence, as well as to diseases that begin in adolescence or adult life after a normal childhood. There is a tendency for them to be less severe and less rapidly progressive, an attribute shared by many diseases with a dominant mode of inheritance. Nonetheless, there are diseases, such as Wilson disease, in which the onset of neurologic symptoms occurs after the tenth year and in rare instances after the thirtieth year, and the mode of inheritance is recessive in type. However, in the latter instance, the basic abnormality has existed since early childhood in the form of a ceruloplasmin deficiency with early cirrhosis and splenomegaly; only the neurologic disorder is of late onset. This brings us to another principle: The pathogenesis of the cerebral lesion may involve a factor or factors once removed from the underlying biologic abnormality. Genetic heterogeneity poses another problem with respect to both the clinical and biochemical findings. It is well established that a single clinical phenotype, such as the one seen in Hurler disease, can be the expression of a number of different alleles of a given gene mutation. Conversely, a number of different clinical phenotypes may be based on different degrees of the same enzyme deficiency. One must, therefore, not rely solely on clinical appearances for diagnosis but always combine them with biochemical tests and molecular genetic studies for confirmation. No one of these lines of data, including genomics, is sufficient for classification of disease. The diseases in this category are probably of greater interest to neurologists than the preceding ones, for they
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more consistently cause familiar neurologic abnormalities such as epilepsy, polymyoclonus, dementia, cerebellar ataxia, choreoathetosis, dystonia, tremor, spastic-ataxic paraparesis, blindness, deafness, and stroke. These manifestations appear much the same in late childhood and adolescence as they do in adult life, and the neurologist whose experience has been mainly with adult patients feels quite comfortable with them. Diseases in this age period have a diversity of manifestations, yet each disease tends to have a certain characteristic pattern of neurologic expression, as though the pathogenetic mechanism were acting more selectively on particular systems of neurons. Such affinities between the disease process and certain anatomic structures raise the question of pathoclisis, i.e., specific vulnerability of particular neuronal systems to certain morbid agents. Stated another way, for each disease there is a common and relatively stereotyped clinical syndrome and a small number of variants; conversely, certain other symptoms and syndromes are rarely observed with a given disease. At the same time, however, it is clear that more than one disease may cause the same syndrome. In deference to these principles, the diseases in this section are grouped according to their most common mode of clinical expression, as follows: 1. The progressive cerebellar ataxias of childhood and adolescence 2. The familial polymyoclonias and epilepsies 3. Extrapyramidal syndromes of parkinsonian type 4. The syndrome of dystonia and generalized choreoathetosis 5. The syndrome of bilateral hemiplegia, cerebral blindness and deafness, and other manifestations of focal cerebral disorder 6. Strokes in association with inherited metabolic diseases 7. Metabolic polyneuropathies 8. Personality changes and behavioral disturbances as manifestations of inherited metabolic diseases It is advantageous to be familiar with these groupings. Like the age of onset and the distinctions between gray and white matter diseases of earlier onset, this scheme facilitates clinical diagnosis. One word of caution: It is a mistake to assume that the diseases in these categories affect one and only one particular part of the nervous system or to assume that they are exclusively neurologic. Once the biochemical abnormality is discovered, it is usually found to implicate cells of certain nonneurologic tissues as well; whether or not the effects of such involvement become symptomatic is often a quantitative matter. Also, one encounters mixed neurologic syndromes in which tremor, myoclonus, cerebellar ataxia, seizures, and choreoathetosis are present in various combinations; it is then difficult to decide whether a movement disorder is of one type or another.
The Progressive Cerebellar Ataxias of Late Childhood and Adolescence In the preceding section it was pointed out that there is a large group of diseases, some with a known metabolic
basis, in which an acute, episodic, or chronic cerebellar ataxia becomes manifest in early childhood. Here the discussion of the cerebellar ataxias is continued, with reference to those forms that begin in late childhood and adolescence. In these later age periods, the number of ataxias of proven metabolic type diminishes markedly. Most of them, of chronic progressive type, are part of the late-onset lipid storage diseases. Of the other cerebellar ataxias of late childhood and adolescence, only the Bassen-Kornzweig acanthocytosis, late-onset GM2 gangliosidosis, Refsum disease, ataxia telangiectasia and a genetic fault in vitamin E metabolism fall into the category of truly metabolic disease. Refsum disease is so clearly a polyneuropathy (cerebellar features only in exceptional cases) that it is presented in Chap. 46. Ataxia-telangiectasia is usually encountered in late childhood, but the ataxia may begin as early as the second year of life; therefore it has been described in the preceding section with the ataxias of early childhood. There are many other conditions of metabolic type in which cerebellar ataxia figures in the clinical picture. Some of these are associated with polymyoclonus and cherry-red macular spots (mainly sialidosis or α-neuraminidase deficiency; see below). Cerebellar ataxia is a prominent feature of Unverricht-Lundborg (Baltic) disease and Lafora-body disease (Chap. 16). The Cockayne syndrome and Marinesco-Sjögren disease persist into later childhood and adolescence or may even have their onset in this later period. In cerebrotendinous xanthomatosis (see further on), spastic weakness and pseudobulbar palsy are combined with cerebellar ataxia. Prader-Willi children have a broad-based gait and are clumsy in addition to being obese, genitally deficient, and diabetic. Several diseases associated with hyperuricemia implicate defective purine and pyrimidine metabolism and fit into this category; the enzymatic defect of Lesch-Nyhan disease is not present, however. Marsden and coworkers (1982) have observed cerebellar ataxia beginning in late childhood as an expression of adrenoleukodystrophy (see below). The familial syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) caused by a mitochondrial genome mutation that impairs ATP synthase can cause ataxia and closely mimic the Marinesco-Sjögren syndrome. Doubtless, many of the progressive forms of cerebellar ataxia now classified as degenerative and described in Chap. 39 will be proved to have an underlying biochemical or similar subcellular pathogenesis and will logically fall in place here, with the metabolic diseases. At present, when faced with a progressive ataxia of cerebellar type, even in a young adult, the reader should consult both this chapter and Chap. 39. The acute forms of cerebellar ataxia that occur in late childhood and adolescence are essentially nonmetabolic, being traceable to postinfectious encephalomyelitis (see Chap. 36) or to postanoxic, postmeningitic, or posthyperthermic states and certain drug intoxications. With relatively pure cerebellar ataxias of this age period, postinfectious cerebellitis, cerebellar tumors (medulloblastomas, astrocytomas, hemangioblastomas, and ganglioneuromas of LhermitteDuclos) should be considered in the differential diagnosis. MRI establishes the correct diagnosis.
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Bassen-Kornzweig Acanthocytosis (Abetalipoproteinemia) Bassen and Kornzweig, in 1950, first described this rare metabolic disease of lipoproteins that causes ataxia, sensory neuropathy, and acanthocytic deformity of red cells. It excited great interest, for it gave promise of a breakthrough into a hitherto obscure group of “degenerative” disorders. The inheritance is autosomal recessive. The initial symptoms, occurring between 6 and 12 years (range: 2 to 20 years), are weakness of the limbs with areflexia and ataxia of sensory (tabetic) type, to which a cerebellar component is added later (the first two aspects relating to a peripheral neuropathy are discussed in Chap. 46). Steatorrhea, raising the suspicion of celiac disease (sprue), often precedes the appearance of a weak and unsteady gait. Later, in more than half the patients, vision may fail because of retinal degeneration (similar to retinitis pigmentosa). Kyphoscoliosis, pes cavus, and Babinski signs are other elements in the clinical picture. The neurologic disorder is relatively slowly progressive—by the second to third decade, the patient is usually bedridden. The diagnostic laboratory findings are spiky or thorny red blood cells (acanthocytes), low sedimentation rate, and a marked reduction in the serum of low-density lipoproteins (LDL cholesterol, phospholipid, and β-lipoprotein levels are all subnormal). Pathologic study has revealed the presence of foamy, vacuolated epithelial cells in the intestinal mucosa (causing absorption block); diminished numbers of myelinated nerve fibers in sural nerve biopsies, depletion of Purkinje and granule cells in all parts of the cerebellum; loss of fibers in the posterior columns and spinocerebellar tracts; loss of anterior horn and retinal ganglion cells and of muscle fibers and fibrosis of the myocardium. It has been proposed that the basic defect is an inability of the body to synthesize the proteins of cell membranes because of the impaired absorption of fat through the mucosa of the small intestine. Vitamin E deficiency may be a pathogenic factor, because the administration of a low-fat diet and high doses of vitamins A and E may prevent progression of the neurologic disorder, according to Illingworth and colleagues, but the pathophysiology appears to be more complex. Often mentioned in the context of acanthocytosis is a related rare condition, McLeod syndrome, in which progressive muscular atrophy, seizures, involuntary movements and elevated serum creatine kinase (CK) are combined in various configurations. The acanthocytosis in this disease is the result of an abnormality of the red cell surface Kell antigen (Kx, coding for the protein XK).
Familial Hypobetalipoproteinemia This is another rare but well-defined disease resembling abetalipoproteinemia, in which there is hypocholesterolemia, acanthocytosis of red blood corpuscles, retinitis pigmentosa, and a pallidal atrophy (HARP syndrome). Inheritance is autosomal dominant, and heterozygotes may exhibit some part of the syndrome. Many cases are caused by mutations in the gene encoding β-lipoprotein B. Fat droplets may be seen in the jejunal mucosa, indicating malabsorption. Cases have been reported from Europe,
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Asia, and the United States. Treatment consists of restriction of dietary fat and supplements of vitamin E. An adult form of acanthocytosis unrelated to the above several diseases is associated with hereditary chorea and dystonia but evidence of lipid malabsorption is lacking. This disease is described in Chap. 39.
The Familial Polymyoclonias As stated in Chap. 6, the term myoclonus is applied to many conditions that are not at all alike but share a single clinical feature—a multitude of exceedingly brief, random, arrhythmic twitches of parts of muscles, entire muscles, or groups of muscles. Myoclonic jerks differ from chorea by virtue of their brevity (15 to 50 ms). Notably, both phenomena are considered to be symptomatic of “gray matter” diseases (“polioencephalopathies”). Myoclonus or polymyoclonus may, in certain conditions, stand alone as a relatively pure syndrome. In most other cases, it is mixed with epilepsy or athetosis and dystonia, discussed further on. Most often, myoclonus is associated with cerebellar ataxia; thus it is being considered here, with the progressive cerebellar ataxias. The many acquired forms of polymyoclonus, such as subacute sclerosing panencephalitis, were mentioned in Chap. 6. This chapter is concerned only with those of known or presumed metabolic origin.
Myoclonic Encephalopathy of Infants (Infantile Opsoclonus-Myoclonus Syndrome) Under this title, Kinsbourne originally described a form of widespread, continuous myoclonus (except during deep sleep) affecting male and female infants whose development had been normal until the onset of the disease at the age of 9 to 20 months. The myoclonus evolves over a week or less, affects all the muscles of the body, and interferes seriously with all the natural muscular activities of the child. The eyes are notably affected by rapid (up to 8/s), irregular conjugate movements (“dancing eyes” of an opsoclonic type). The child is irritable and speech may cease. All laboratory tests are normal. Treatment Dexamethasone in doses of 1.5 to 4.0 mg/d suppresses the myoclonus and permits developmental progress. Some patients have recovered from the myoclonus but have been left mentally slow and mildly ataxic. Others have required corticosteroid therapy for 5 to 10 years, with relapse whenever it was discontinued. Ordinary anticonvulsants seem to have no effect. The pathology has not been determined. A similar syndrome has been observed in conjunction with neuroblastoma in children and as a transient illness of unknown cause (probably viral or postinfectious) in young adults (Baringer et al; see Chap. 33). A similar condition is also known in adults as a paraneoplastic disease with ovarian, breast, gastric, and bronchogenic carcinomas and with other occult tumors. In a broader survey of the pediatric opsoclonus-myoclonus syndrome, Pranzatelli and associates reported their experience with 27 cases, some with neural crest tumors, others with viral infections or hypoxic injury (intention
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myoclonus). In nearly all of their patients there was cerebellar ataxia and mental disorder, and 10 percent had seizures. The CSF was normal. The investigators have emphasized the pathogenetic heterogeneity and defined a rare serotoninergic type (low levels of 5-hydroxytryptophan and homovanillic acid in the CSF) that responds to 5-hydroxyindole acetic acid.
Familial Progressive Myoclonus Five major categories of familial polymyoclonus of late childhood and adolescence have been delineated: (1) Lafora- or amyloid-body type, (2) juvenile cerebroretinal degeneration, (3) cherry-red spot myoclonus (sialidosis or α-neuraminidase deficiency), (4) mitochondrial encephalopathy, and (5) a more benign degenerative disease (dyssynergia cerebellaris myoclonica of Hunt). Familial myoclonus may also be a prominent feature of two other diseases—GM2 gangliosidosis and Gaucher disease—which occasionally have their onset in this age period. Lafora-Body Polymyoclonus with Epilepsy This disease, which is inherited as an autosomal recessive trait, was first identified by Lafora in 1911 on the basis of the large basophilic cytoplasmic bodies that were found in the dentate, brainstem, and thalamic neurons. These inclusions have been shown by Yokoi and colleagues to be composed of a glucose polymer (polyglucosan) that is chemically but not structurally related to glycogen. Possibly some of the cases of familial myoclonus epilepsy reported by Unverricht and by Lundborg were of this type, but because these authors provided no pathologic data, one cannot be sure. Beginning in late childhood and adolescence (11 to 18 years) in a previously normal individual, the disease announces itself by a seizure, a burst of myoclonic jerks, or both. In about half the cases there are focal (often occipital) seizures. The illness may at first be mistaken for ordinary epilepsy, but within a few months it becomes evident that something far more serious is occurring. The myoclonus becomes widespread and can be evoked as a startle by noise, an unexpected tactile stimulus (even the tap of a reflex hammer), and also by excitement, or certain sustained motor activities. An evoked train of myoclonic jerks may progress to a generalized seizure with loss of consciousness. As the disease advances, the myoclonus interferes increasingly with the patient’s motor activities until voluntary function is seriously impaired. Speech may be marred, much as it is in chorea. Close examination may also reveal an alteration in muscle tone and a slight degree of cerebellar ataxia. At this time, or even before the onset of myoclonus and seizures, the patient may experience visual hallucinations or exhibit irritability, odd traits of character, uninhibited or impulsive behavior, and, ultimately, progressive failure in all cognitive functions. Deafness has been an early sign in a few cases. Rigidity or hypotonia, impaired tendon reflexes, acrocyanosis, and rarely corticospinal tract signs are late findings. Finally the patient becomes cachectic and bedfast and succumbs to intercurrent infection. Most do not survive beyond their twenty-fifth birthday. Nonetheless there are isolated reports of Lafora-body disease in which symptoms began as late as age 40 years, with death as late as age 50 years. These late cases may constitute a separate genetic type.
No abnormalities of the blood, urine, or CSF have been detected. The EEG shows diffuse slow waves and spikes as well as bursts of focal or multifocal discharges. Altered hepatocytes with homogeneous PAS-positive bodies that displace the nuclei have been observed in both the presymptomatic and symptomatic stages of the disease. These inclusions have been seen in skin and liver biopsies, even though liver function tests were normal. Neuropathologic examinations have shown a slight loss of granule and Purkinje cells and loss of neurons in the dentate nuclei, inner segment of globus pallidus, and cerebral cortex in addition to the Lafora bodies. The latter may also be seen in the retina, cerebral cortex, myocardium, and striated muscles. Anticonvulsant drugs, especially methsuximide and valproic acid, help in the control of the seizures but have no effect on the basic process. Juvenile Ceroid Lipofuscinosis (Cerebroretinal Degeneration; Batten Disease) As stated earlier, this is one of the most variable forms of the lipidoses. The salient clinical features of the later-onset types are severe myoclonus, seizures, and visual loss. In the juvenile type, the first lesions are seen in the maculae; they appear as yellow-gray areas of degeneration and stand in contrast to the cherry-red spot and the encircling white ring of Tay-Sachs disease. At first, the particles of retinal pigment are fine and dust-like; later they aggregate to resemble more the bone-corpuscular shapes of retinitis pigmentosa. The liver and spleen are not enlarged and there are no osseous changes. The usual development of these and other manifestations of the disease were outlined by Sjögren, who studied a large number of the late infantile and juvenile types of cases in Sweden. He divided the illness into stages, the first of which was visual impairment, followed approximately sequentially by generalized seizures and myoclonus, often with irritability, poor control of emotions, and stuttering, jerky speech at 2 years, then gradual intellectual deterioration to which were added cerebellar ataxia and intention tremor, in this respect coming to resemble Wilson disease. Finally, the patient lies curled up in bed, blind and speechless, with strong extensor plantar reflexes, occasionally adopting dystonic postures. Life usually ends in 10 to 15 years. In the early stages, the EEG pattern of random, high-voltage, triphasic waves is diagnostic; later, as the seizures and myoclonic jerks become less frequent and finally cease, only delta waves remain. The electroretinographic waveforms are lost once the retina is affected. The lateral ventricles are slightly dilated in CT scans and on MRI. The CSF is normal. Diagnosis can be confirmed by the appearance of inclusions of a curvilinear “fingerprint” pattern in electron microscopic study of biopsy material, particularly of the eccrine sweat glands of the skin. A defective membrane protein has been identified that forms the inclusion material in the most common, or classic, juvenile phenotype. The genetics of the lipofuscinoses have been reviewed by Mole.
Late Juvenile and Adult Ceroid Lipofuscinosis (Kufs-Parry or Kufs Disease) The type of ceroid lipofuscinosis that develops later (15 to 25 years of age or older) is often unattended by visual or retinal changes and is even slower in its evolution. It is pre-
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sented here for ease of exposition, but it becomes relevant mostly in relation to dementing illness in young adulthood. Personality change or dementia is one constellation, the other being myoclonic seizures with subsequent dementia and even later pyramidal and extrapyramidal signs. As the disease progresses, cerebellar ataxia, spasticity, rigidity or athetosis, or mixtures thereof, are combined with dementia. As a reflection of the variability of the clinical presentation, a recent patient of ours had vague visual difficulties at age 51 years and evolved a spastic quadriparesis with disinhibited behavior over 5 years. Additional comments regarding the unusual presentations of this disease can be found further on, under “Adult Forms of Inherited Metabolic Disease.” van Bogaert pointed out to our colleague R.D. Adams that relatives of these patients may have retinal changes without neurologic accompaniments. The genetic defect for the adult form has been analyzed (see below). Of all the lipidoses, these cerebroretinal degenerations had for decades defied unifying biochemical definition. Our understanding of these diseases is difficult because they embody both enzymatic defects and structural protein dysfunctions. In a few of the early childhood types, mutations of one of several lysosomal enzymes have been identified as summarized by Mole and by Wisniewski and colleagues. As mentioned earlier, Zeman and coworkers have shown that the cytoplasmic inclusions are autofluorescent and give a positive histochemical reaction for both ceroid and lipofuscin, but this material is not different biochemically from the lipid substance that accumulates in aging cells. In addition to the presence of curvilinear bodies in the cytoplasm of neurons and other tissues, some in a fingerprint pattern, there is a reduction in type II synapses in the distal parts of the axon. All these changes precede nerve cell loss. The genetic defects have been tentatively determined for some of the subtypes of neuronal ceroid lipofuscinosis (see Wisniewski et al). These genes have been designated CLN 1 through 9 and they embody over 100 different mutations. Childhood or Juvenile GM2 Gangliosidosis Instances of the recessive type of GM2 gangliosidosis rarely have their onset at the typical age period. Twenty-four such cases (from 20 kindreds) were collected from the medical literature by Meek and coworkers. Ataxia and dysarthria were frequently the presenting symptoms, followed by dementia, dysphagia, spasticity, dystonia, seizures, and myoclonus. Degeneration of anterior horn cells with progressive muscular atrophy may be a feature, although this is more characteristic of the adult-onset variety (see further on). Atypical cherry-red spots are observed in some patients. The biochemical abnormality, i.e., a deficiency of hexosaminidase A, is the same as in Tay-Sachs disease, but not as severe or as extensive. Progression of the disease is slow, over a period of many years. Late Gaucher Disease with Polymyoclonus A type of Gaucher disease is occasionally encountered in which seizures, severe diffuse myoclonus, supranuclear gaze disorders (slow saccades, saccadic and pursuit horizontal gaze palsies), and cerebellar ataxia begin in late childhood, adolescence, or adult life. The course is slowly progressive. The intellect is relatively spared. The spleen is enlarged.
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The pathologic and biochemical abnormalities are the same as those of Gaucher disease of earlier onset . Cherry-Red Spot-Myoclonus Syndrome (Sialidosis Type 1, α-Neuraminidase Deficiency) This is a genetically distinct class of disease characterized by the storage in nervous tissue of sialylated glycopeptides. It is caused by a neuraminidase deficiency. In some of the patients, the onset was in late childhood or adolescence, and in others, even later. In addition to the patients initially reported by Rapin and coworkers, 24 similar cases have appeared in the medical literature. In the cases described by Rapin and colleagues the first findings were visual impairment with cherry-red macular spots, similar to those seen in Tay-Sachs disease and less consistently in GM1 gangliosidosis, Niemann-Pick disease, and metachromatic leukodystrophy. In one case, there was severe episodic pain in the hands, legs, and feet during hot weather, reminiscent of Fabry disease. Polymyoclonus followed within a few years and, together with cerebellar ataxia, disabled the patients. Mental function remained relatively normal. Liver and spleen were not enlarged, but storage material was found in the Kupffer cells, neurons of the myenteric plexus, and cerebral neurons, and presumably in cerebellar and retinal neurons. The cases of Thomas and colleagues were young adults, all members of one generation, who had developed dysarthria, intention myoclonus, cerebellar ataxia, and cherryred macular lesions. Like the cases of Rapin and coworkers, the heredity was autosomal recessive. There was urinary excretion of sialylated oligosaccharides and a sialidase deficiency in cultured fibroblasts. The two patients described by Tsuji and associates (1982) are noteworthy in that they were age 50 and 30 years. In addition to the macular lesions, polymyoclonia, and cerebellar ataxia, there were gargoyle-like facial features, corneal opacities, and vertebral dysplasia. These patients also had a neuraminidase (partial beta-galactosidase) deficiency. Dentatorubral Cerebellar Atrophy with Polymyoclonus This progressive degeneration of the cerebellar-dental efferent system was originally described by Ramsay Hunt under the title of dyssynergia cerebellaris myoclonica. The onset is in late childhood; both sexes are vulnerable, and it probably has more than one cause. In Hunt’s case, a progressive ataxia was accompanied by a striking degree of action myoclonus. Seizures are infrequent, and the intellect is relatively preserved. The neurons of the dentate nuclei and their ascending and descending brainstem axons gradually disappear. Berkovic and associates studied 84 cases of polymyoclonus, 13 of which conformed to the Hunt syndrome. Of these, 9 proved to have a mitochondrial encephalomyopathy. However, there are other reports (Tassinari et al) in which muscle biopsies showed no mitochondrial abnormalities. In the series of 30 cases reported by Marsden and coworkers (1990) the onset was usually before the age of 21 years. Cortical electrographic discharges were found to precede each myoclonic twitch (cortical myoclonus). A biochemically supported diagnosis could not be made in nearly half of their cases. Extremely chronic forms of rhythmic myoclonus involving only the facial and bulbar muscles also occur. Although this benign familial polymyoclonia has not been
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associated with any biochemical abnormality, its association with cellular mitochondrial abnormalities in some cases justifies its inclusion in this chapter rather than with the degenerative diseases. Another mitochondrial disorder, the myoclonic epilepsy ragged red fiber (MERRF) disease, begins in the second decade or later with myoclonus and ataxia and enters into the differential diagnosis of this group of diseases. The mitochondrial diseases as a group are considered in the last part of this chapter.
Epilepsies of Hereditary Metabolic Disease (See Chap. 16) Convulsive seizures may complicate nearly all hereditary metabolic diseases. The seizures may occur at all ages but more frequently in the neonate, infant, or young child than in the older child or adolescent. The seizures take many forms, as discussed in Chap. 16. Most often they are generalized grand mal or partial types; typical petit mal probably does not occur. Some diseases may cause focal seizures, simple or complex partial, before becoming generalized. The combination of series of polymyoclonic jerks progressing to a generalized motor seizure is always highly suggestive of one of the hereditary metabolic diseases. Another highly significant form of presentation is with sensory evoked seizures. The subject of epilepsy and the hereditary metabolic diseases was reviewed by Sansaricq and colleagues.
EXTRAPYRAMIDAL SYNDROMES WITH HEREDITARY METABOLIC DISEASE Parkinsonian Syndromes In the typical parkinsonian syndrome, with features of rigidity, tremor, and bradykinesia, strength remains relatively intact and corticospinal signs are absent, but effectiveness of movement is nonetheless impaired by the patient’s disinclination to use the affected parts (hypo- or akinesia), by slowness (bradykinesia), and by rigidity and tremor (see Chap. 4). Other clinical syndromes in this category include choreoathetosis, dystonia, and spasms of gaze. When the parkinsonian syndrome or some component thereof has its onset in middle or late adult life, it usually indicates idiopathic Parkinson disease or related multisystem forms. The development of such an extrapyramidal motor disorder in late childhood and adolescence instead suggests Wilson disease, juvenile Huntington disease, Hallervorden-Spatz disease, and the Segawa type of Ldopa–responsive dystonia as well as other so-called Parkin mutations (see Chap. 39).
Hepatolenticular Degeneration (Wilson Disease, Westphal-Strümpell Pseudosclerosis) Wilson’s description of “Progressive Lenticular Degeneration: A Familial Nervous Disease Associated with Cirrhosis of the Liver” appeared in 1912. A similar neurologic disorder had been described previously by Gowers (1906)
under the title of “tetanoid chorea” and by Westphal (1883) and Strümpell (1898), as “pseudosclerosis.” None of these authors, however, recognized the association with cirrhosis. The clinical studies of Hall (1921) and the histopathologic studies of Spielmeyer (1920), who reexamined sections from the liver and brain of Westphal’s and Strümpell’s cases, clearly established that the pseudosclerosis described by these authors was the same disease as the one that had been described by Wilson. Interestingly, none of these authors, including Wilson, noticed the golden-brown (Kayser-Fleischer) corneal ring, the one pathognomonic sign of the disease. Rumpell had demonstrated the greatly increased copper content of the liver and brain as early as 1913, but this discovery was generally ignored until Mandelbrote (1948) found, quite by chance, that the urinary excretion of copper was greatly increased in patients with Wilson disease and that it was increased even more after the intramuscular administration of the chelating agent British anti-Lewisite (BAL). In 1952, Scheinberg and Gitlin discovered that ceruloplasmin, the serum protein that binds copper, is reduced in this disease (see reviews by Scheinberg and Sternlieb for a full historical account and references). Denny-Brown demonstrated a recession of symptoms after prolonged treatment with BAL. The prevalence of the disease cannot be stated exactly, but is on the order of 1 per 50,000 to 1 per 100,000 of the general population. The disease is transmitted as an autosomal recessive trait. The gene, called ATP7B (homologous with the ATP7A gene, which is defective in Menkes disease), codes for a membrane-bound, copper-binding ATPase. One of the curious aspects of the genetics of the disease is the multitude of mutations within this gene that give rise to the disease and no one mutation accounts for more than 30 percent of cases. Inadequate functioning of the ATPase enzyme in some way reduces excretion of copper in the bile. As noted further on, liver transplantation halts progression of the disease, indicating that the primary biochemical effect of the mutation is in the liver rather than the nervous system. The mutation gives rise to two fundamental disturbances of copper metabolism: (1) a reduced rate of incorporation of copper into ceruloplasmin and (2) a reduction in biliary excretion of copper. The deposition of copper in tissues is the cause of virtually all the manifestations of the disease—cirrhosis, hemolytic anemia, renal tubular changes, Kayser-Fleischer rings, and, in all likelihood, the cerebral damage—as discussed below. Clinical Features The onset of neurologic symptoms is usually in the second, and less often in the third, decade, but rarely beyond that time. Half of patients are symptomatic by age 15 years, but exceptional cases, including two under our care, had their first clinical manifestations as late as their midfifties. In all instances the initial event is a deposition of copper in the liver, leading to an acute or chronic hepatopathy and eventually to multilobular cirrhosis and splenomegaly (Scheinberg and Sternlieb). In childhood, the liver disorder often takes the form of attacks of jaundice, unexplained hepatosplenomegaly, or hypersplenism with thrombocytopenia and bleeding. Rarely is there clear evidence of cirrhosis alone. The
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hepatic abnormalities may be asymptomatic (except for elevated serum transaminases), in which case the initial clinical presentation is neurologic. In some instances, a hemolytic anemia or, less often, renal tubular acidosis may first draw attention to the disease. The first neurologic manifestations are most often extrapyramidal with a proclivity to affect the oropharyngeal musculature. The typical presentations are tremor of a limb or of the head and generalized slowness of movement (i.e., a parkinsonian syndrome); or slowness of movement of the tongue, lips, pharynx, larynx, and jaws, resulting in dysarthria, dysphagia, and hoarseness; or there may be slowness of finger movement and occasionally choreic movements or dystonic postures of the limbs. Often the mouth is held slightly open in the early stage of the disease. Exceptionally, an abnormality of behavior (argumentativeness, impulsiveness, excessive emotionality, depression, delusions) or a gradual impairment of intellectual faculties precedes other neurologic signs by a year or more (see Starosta-Rubinstein et al). As the disease progresses, the “classic syndrome” evolves: dysphagia and drooling, rigidity and slowness of movements of the limbs; flexed limb postures; fixity of facial muscles with mouth constantly agape, giving an appearance of grinning or a “vacuous smile”; dysarthria or virtual anarthria (bulbar extrapyramidal syndrome); and a tremor in repose that increases when the limbs are outstretched to a coarse, “wing-beating” movement. Slowed saccadic eye movements and limitation of upgaze are also characteristic. A notable feature is the tendency for the motor disorders to be concentrated in the bulbar musculature and to spread caudally. Thus, the syndrome differs from classic parkinsonism. Usually elements of cerebellar ataxia and intention tremor of variable degree are added at some stage of the disease. Approximately 6 percent of patients develop seizures (Dening et al). Gradually the disability increases because of increasing rigidity and tremor. The patient becomes mute, immobile, extremely rigid, dystonic, and slowed mentally, the latter usually being a late and variable effect. With progression of the neurologic disease, the KayserFleischer rings become more evident (Fig. 37-7). They take
Figure 37-7. Kayser-Fleischer corneal ring (arrow) in Wilson disease. (Reproduced by permission from Lyon et al.)
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the form of a crescentic rusty-brown discoloration of the deepest layer of the cornea (Descemet membrane). In the purely hepatic stage of the disease, the rings may not be evident (in 25 percent of cases), but they are virtually always present (if properly sought) once the neurologic signs become manifest. A slit-lamp examination may be necessary for their early detection, particularly in brown-eyed patients, but in the majority of patients with neurologic signs the rings can be visualized with the naked eye or with the aid of an indirect ophthalmoscope focused on the limbus. The diagnosis is virtually certain when there is a similar syndrome in a sibling or when an extrapyramidal motor disorder of this type is conjoined with liver disease and the corneal rings. Variants of the above syndrome that the authors have seen are an early choreoathetosis (like Sydenham chorea); prominent dystonic postures; a cerebellar ataxia with minimal rigidity; a syndrome of coarse action or action and intention tremor resembling that of dentatorubral degeneration; an immobile mute state with profound rigidity; and a dementia, character change, or psychosis with relatively few extrapyramidal signs. Action myoclonus as a prominent early manifestation has also been described. The parkinsonian features do not respond to L-dopa treatment. Laboratory Findings In both the typical and variant forms of the disease, the finding of a low serum ceruloplasmin level (less than 20 mg/dL in 80 to 90 percent of patients), low serum copper (3 to 10 mM/L; normal 11 to 24 mM/L), and increased urinary copper excretion (more than 100 mg Cu/24 h) corroborate the diagnosis. Because 90 percent of copper is carried by ceruloplasmin and the latter is generally reduced in Wilson disease, serum copper values alone may be misleadingly normal. Early in the course of the illness, the most reliable diagnostic findings are a high copper content in a biopsy of liver tissue (more than 200 μg Cu/g dry weight) and a failure to incorporate labeled 64Cu into ceruloplasmin. The latter test, however, fails to dependably differentiate asymptomatic carriers from affected individuals. Measurement of increased cupruresis after the administration of penicillamine has not been shown to be more sensitive than an unenhanced 24-h urine collection for copper. Persistent aminoaciduria, reflecting a renal tubular abnormality, is present in most but not all patients. Liver function tests are usually abnormal; some patients are jaundiced and other signs of liver failure may appear late in the illness. In these patients, the serum ammonia may be elevated and the symptomatology may worsen with increases in dietary protein. The cirrhosis is not always evident in a liver biopsy (some regenerative nodules are large, and the biopsy may be taken from one of them). On the other hand, the diagnosis in children may be revealed when a liver biopsy is taken for the evaluation of cirrhosis. As mentioned earlier, the large number of mutations that give rise to the disease makes it impractical to use genetic analysis for diagnosis, but once the gene abnormality has been established in a given family, linkage studies may be used to identify other affected sibs. It has been established that copper deposition in the liver is the initial disturbance; over time it leads to cirrhosis, so that, as already mentioned, the hepatic stage of the disease
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precedes neurologic involvement. Cranial CT scans are abnormal even in the hepatic stage and are invariably so when the neurologic disorder supervenes. The lateral ventricles and often the third ventricle are slightly enlarged, the cerebral and cerebellar sulci are widened, the brainstem appears shrunken, and the posterior parts of the lenticular nuclei, red nuclei, and dentate nuclei become hypodense (Ropper et al). With treatment, these radiologic changes become less marked (Williams and Walshe). MRI is an even more sensitive means of visualizing the structural changes, particularly those in the subcortical white matter, midbrain, pons, and cerebellum (Starosta-Rubinstein et al). In the MRI survey by Saatci and colleagues, the putamen was involved most frequently (although not invariably), showing a symmetrical T2 signal change in a laminar pattern; there was also an increase in T1 signal throughout the basal ganglia, particularly in the pallidum. Signal changes are almost universally found in the claustrum and also in the midbrain (pars compacta of the substantia nigra), dentate nucleus of the cerebellum, pons, and thalami. We have been impressed with a glassy diffuse and confluent signal abnormality on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the hemispheral white matter in some cases—findings that were mistaken for multiple sclerosis. Neuropathologic Changes These vary with the rate of progress of the disease. Exceptionally, in the rapidly advancing and fatal form, there is frank cavitation in the lenticular (putaminal and pallidal) nuclei, as observed in Wilson’s original cases. In the more chronic form, there is only shrinkage and a light-brown discoloration of these structures. Nerve cell loss and some degree of degeneration of myelinated fibers in lenticular nuclei, substantia nigra, and dentate nuclei are usually apparent. Subcortical myelin degeneration is found in some cases. More striking, however, is a marked hyperplasia of protoplasmic astrocytes (Alzheimer type II cells) in the cerebral cortex, basal ganglia, brainstem nuclei, and cerebellum, almost certainly a reaction to liver failure and hyperammonemia. Treatment Ideally, treatment should be started before the appearance of neurologic signs; if this can be implemented, neurologic deterioration can be prevented to a large extent. Treatment consists of (1) reduction of dietary copper to less than 1 mg/d, which can usually be accomplished by avoidance of copper-rich foods (liver, mushrooms, cocoa, chocolate, nuts, and shellfish), and (2) administration of the copper chelating agent D-penicillamine (1 to 3 g/d) by mouth, in divided doses. Pyridoxine 25 mg/d should be added in order to prevent anemia. The use of D-penicillamine is associated with a number of problems. Sensitivity reactions to the drug (rash, arthralgia, fever, leukopenia) develop in 20 percent of patients and require a temporary reduction of dosage or a course of prednisone to bring them under control. Reinstitution of drug therapy should then be undertaken, using low dosages (250 mg daily) and, later, small, widely spaced increases. If the patient is still sensitive to D-penicillamine or if severe reactions (lupus-like or nephrotic syndromes or myasthenia gravis) occur, the drug should be discontinued and another chelating agent, triethylene tetramine (trientine) or ammonium tetrathiomolybdate may be substituted. Zinc, which blocks the intestinal absorption of copper, is also a suitable treatment, but ineffective alone. It is given as zinc
acetate, 100 to 150 mg daily in 3 to 4 divided doses at least 1 h before meals (Hoogenraad et al). The appropriate drug must then be continued for the patient’s lifetime. Some women report improvement in neurologic symptoms during pregnancy, although there is no apparent change in copper metabolism during this time. In most patients, neurologic signs improve in response to decoppering agents. The Kayser-Fleischer rings disappear and liver function tests may return to normal, although the abnormalities of copper metabolism remain unchanged. In moderately severe and advanced cases, clinical improvement may not begin for several months despite full doses of D-penicillamine, and it is important to resist discontinuing the drug during this latent period. It is also well known that the institution of treatment with penicillamine may induce an abrupt worsening of neurologic signs, and we have witnessed several such instances, including one that culminated fatally from a cardiac arrhythmia. Furthermore, in many of these patients, the lost function is never retrieved. Presumably this deterioration is a result of the rapid mobilization of copper from the liver and its redistribution to the brain. The slow introduction of penicillamine may avoid this complication. The additional use of zinc or one of the newer agents mentioned above should be instituted as soon as neurologic deterioration becomes evident. In at least one reported case, new lesions of Wilson disease (shown by MRI) developed while the patient was receiving full doses of D-penicillamine and excellent decoppering of the liver had occurred (Brewer et al). In the few patients who develop seizures, they may become apparent soon after therapy is begun. Many wilsonian patients with advanced liver disease have been subjected to liver transplantation, which is curative for the underlying metabolic defect. The degree of neurologic improvement varies; in some it has been remarkable and sustained, confirming that the hepatic defect is primary and that the brain is involved secondarily. According to Schilsky and coworkers, the main indication for transplantation is severe and progressive liver damage, but the operation has been used successfully in some patients with intractable neurologic deterioration and only mild signs of liver disease. An important aspect of treatment is the screening of potentially affected relatives for abnormalities of serum copper and ceruloplasmin; if any relative is found to have the disease, penicillamine should be given indefinitely to prevent the emergence of neurologic symptoms. A full explanation of the dangers of ceasing the medication must be given, and compliance may have to be monitored.
Hereditary Deficiency of Ceruloplasmin (Aceruloplasminemia) This is a rare illness, similar to Wilson disease, occurring in patients with a recessively inherited deficiency of ceruloplasmin; it is not simply a heterozygous form of Wilson disease (the mutation involves a different gene). Cirrhosis and Kayser-Fleischer rings are not features of the disease but diabetes is common and extrapyramidal signs may or may not arise. Rather than copper, iron is deposited in the brain and liver (see discussion by Logan). Those few cases that
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have been well studied, mainly Japanese, show mainly an ataxic disorder (Miyajima et al).
Hyprocupric Myeloneuropathy Noted briefly here and discussed more extensively in Chap. 44, is an idiopathic progressive posterior and lateral column myelopathy that closely simulates subacute combined degeneration of B12 deficiency. It is associated with low serum copper levels, usually idiopathic but sometimes caused by malabsorption or the intake of zinc as an overthe-counter supplement to prevent colds or to improve the senses of smell and taste; zinc inhibits absorption of copper from the gut.
Neurodegeneration with Brain Iron Accumulation (Hallervorden-Spatz Disease) This disease, recently renamed because of ignoble associations of the eponymous Hallervorden and Spatz, is also known as pigmentary degeneration of the globus pallidus. It is inherited as an autosomal recessive trait and is caused by, in all classic cases, a defect in the gene encoding pantothenate kinase 2 (PANK2), usually in the form of a missense mutation. The onset of symptoms is in late childhood or early adolescence with slow progression over a period of 10 or more years. The early signs are highly variable but are predominantly motor, both corticospinal (spasticity, hyperreflexia, Babinski signs) and extrapyramidal (rigidity, dystonia, and choreoathetosis). General deterioration of intellect is conjoined. In individual cases, ataxia and myoclonus have appeared at some phase of the illness. The spasticity and rigidity are most prominent in the legs, but in some instances they begin in the bulbar muscles, interfering with speech and swallowing, as happens in Wilson disease. We have observed patients who, over a period of years, exhibited only dystonia of the tongue, blepharospasm, or arching of the back. The relationship of this restricted form to the complete syndrome remains unsettled. Eventually, the patient becomes almost completely inarticulate and unable to walk or use his or her arms. Hayflick and colleagues found that only one-third of patients with atypical forms of the disease have mutations of the PANK2 gene. Moreover, variant cases tended not to show the characteristic changes on MRI described below. Reduced levels of PANK2 in the blood corroborate the diagnosis but this test is available only in research laboratories with an interest in the disease. The characteristic deposits of iron in the basal ganglia have not been associated with a demonstrable abnormality of serum iron or of iron metabolism. It has, however, been reported that there is increased uptake of radioactive iron in the region of the basal ganglia following intravenous injection of labeled ferrous citrate (Vakili et al; Szanto and Gallyas). CT scanning reveals hypodense zones in the lenticular nuclei, resembling those of hepatolenticular degeneration (also of sulfite oxidase deficiency, glutaric acidemia and Leigh disease), although high-density lesions have been described in one autopsy-proven case of this disease (Tennison et al). The MRI findings are striking (Fig. 37-8). In T2-weighted images, the rim of the pallidum appears intensely black (iron deposition), with a small white area in its medial part (“eye-of-the-tiger” sign; see also Savoiardo et al).
Figure 37-8. Hallervorden-Spatz disease. T2-weighted MRI showing areas of decreased signal intensity of the pallidum bilaterally (corresponding to iron deposition) and a central high signal area because of necrosis (“eye-of-the-tiger” sign). (Reproduced by permission from Lyon et al. Courtesy of Dr. C. Gillain.)
The neuropathologic features prove to be the most distinctive attributes of the disease. There is an intense brown pigmentation of the globus pallidus, substantia nigra (especially the anteromedial parts), and red nucleus. Granules and larger amorphous deposits of iron mixed with calcium stud the walls of small blood vessels or lie free in the tissue. A loss of neurons and medullated fibers occurs in the most affected regions. Another unique feature is the presence of swollen axon fragments, which resemble those of neuroaxonal dystrophy. The significance of iron deposition is difficult to judge. To some extent, there is an increase of iron in the basal ganglia in other degenerative diseases. In Parkinson disease and striatonigral degeneration, for example, the deposition of iron is two to three times normal, presumably the result of degeneration of those tissues that are known to be rich in iron. No treatment is known to be effective. Some of our patients responded temporarily to L-dopa, but the effect was slight. The use of chelating agents to reduce iron storage has not helped.
Syndromes of Dystonia and Generalized Chorea and Athetosis As indicated in Chap. 4, the differences between dystonia and choreoathetosis are not fundamental. If one examines many patients with these involuntary movements, every gradation between the two is seen, and often the quicker, unpatterned involuntary movements of mild ballismus
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are added. Even tremor and myoclonus may complicate the composite movement disorder. With reference to muscular tone in patients with athetosis and dystonia, there are unpredictable associations of hypertonia and hypotonia. A number of inherited metabolic diseases, all of them rare, express themselves by this syndrome of chorea, athetosis, and dystonia.
Lesch-Nyhan Syndrome This rare metabolic disease is inherited as an X-linked recessive trait. Although it carries the names of Lesch and Nyhan, the occurrence of uricemia in association with spasticity and choreoathetosis in early childhood had been described earlier by Cateland Schmidt. Essentially, it is a hereditary choreoathetosis with self-mutilation and hyperuricemia. The affected children appear normal at birth and usually develop on schedule up to 3 to 6 months of age. Maturational delay then sets in, initially with hypotonia that later gives way to hypertonia. Also, the patient’s behavior becomes abnormal, with aggressiveness and compulsive actions. The uncontrollable self-mutilation, mainly of the lips, occurs early (during the second and third year), and spasticity, choreoathetosis, and tremor come later. Most of the children learn to walk. Speech is delayed, and once attained, it is dysarthric and remains so throughout life. Mental retardation is moderately severe. In patients more than 10 years of age, gouty tophi appear on the ears, and there is increasing risk from gouty nephropathy. The serum levels of uric acid are in the range of 7 to 10 mg/dL. A deficiency of the enzyme hypoxanthine-guanine-phosphoribosyl transferase (HPRT) has been found in all typical cases of this disease. The HPRT gene lies on the X chromosome (Xq 26-q 27), and accurate diagnosis of affected males and carriers can be made by DNA analysis. As a result of this deficiency, hypoxanthine is either excreted or catabolized to xanthine and uric acid. The details of the biochemical abnormality responsible for CNS dysfunction are unclear. In the differential diagnosis, one must consider nonspecific mental retardation or autism with hand biting and other self-mutilations, athetosis from birth trauma, and encephalopathies with chronic renal disease. Hyperuricemia has also been reported in a family with spinocerebellar ataxia and deafness and in another with autism and mental retardation, neither of them with the enzymatic defect of Lesch-Nyhan disease. As mentioned earlier, there are several other disorders of purine and pyrimidine metabolism, some of them with hyperuricemia, that present with a neurologic syndrome like that of LeschNyhan. Treatment This is with the xanthine oxidase inhibitor allopurinol, which blocks the last steps of uric acid synthesis, reduces the uric acid in Lesch-Nyhan disease, and prevents the uricosuric nephropathy, but it seems to have no effect on CNS symptoms. Guanosine 5-monophosphate and inosine 5-monophosphate, both of which are deficient in Lesch-Nyhan disease, have been replaced without benefit to the patient. Transitory success has also been achieved by the administration of 5-hydroxytryptophan in combination with L-dopa. Fluphenazine (Prolixin) is reported to have suppressed the self-mutilation after halo-
peridol (Haldol) had failed to do so. Behavior modification programs may be of some value.
Calcification of Vessels in Basal Ganglia and Cerebellum Ferrugination and calcification of vessels in the basal ganglia occur to a slight degree in many elderly persons (and in other mammals) who are otherwise normal. The widespread use of CT scans and MRI has brought the condition to light with increasing frequency (Fig. 37-9). Usually it may be dismissed as an aging phenomenon of no clinical significance. When it occurs early in life and is of such degree as to be visible in plain films of the skull, it must always be regarded as abnormal. Fahr Disease An adult case of this type was described by Fahr, so that his name is sometimes attached to this disorder. This is an idiopathic form of calcification of the basal ganglia and cerebellum in which choreoathetosis and rigidity are prominent acquired features. The clinical state may also take the form of a parkinsonian syndrome or bilateral athetosis. In two of our patients there was unilateral choreoathetosis, which was replaced gradually by a parkinsonian syndrome, and in another of our sporadic cases, the initial abnormality was a unilateral dystonia responsive to L-dopa. Some patients have been mentally retarded but most are intellectually intact. The serum calcium levels in the aforementioned diseases are usually normal and there is no explanation of the calcification. Hypoparathyroidism In hypoparathyroidism (idiopathic or acquired) and pseudohypoparathyroidism (a rare familial disease, caused by end-organ insensitivity to parathyroid hormone with distinctive skeletal and developmental abnormalities), the diminution in ionized serum calcium
Figure 37-9. Idiopathic basal ganglionic and cerebellar calcification discovered 5 years after the onset of a slowly progressive rigid Parkinson syndrome in a 54-year-old woman.
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induces not only tetany and seizures but also choreoathetosis. This last symptom is presumably a result of calcification of the basal ganglia, which occurs in about one-half of the patients but of unknown mechanism. Also, in some instances there are signs of a cerebellar lesion. Pseudopseudohypoparathyroidism is a disorder that imitates the bony abnormalities seen in pseudohypoparathyroidism but in which calcium metabolism is normal and there are no neurologic features.
Osteopetrosis Sly and colleagues described the familial occurrence (21 cases in 12 families) of calcification in the caudate and lenticular nuclei, thalami, and frontal lobe white matter in association with osteopetrosis (“marble bones”) and renal tubular acidosis. Clinically, there were multiple cranial nerve palsies—including optic atrophy as well as psychomotor delay and learning disabilities—but no extrapyramidal signs. The cranial nerve palsies, which are a result of bony encroachment in neural foramina, were much less severe than in the lethal form of osteopetrosis. The pattern of inheritance of this disease is autosomal recessive, and the basic abnormality was found to be a deficiency in carbonic anhydrase II in red blood corpuscles and probably in kidney and brain.
Other Metabolic Disorders Associated with Choreoathetosis and Dystonia We emphasize that acquired extrapyramidal disorders are much more common than metabolic ones. For example, athetosis may follow hypoxic encephalopathy of birth or follow kernicterus caused by Rh and ABO blood incompatibilities and erythroblastosis fetalis. The same is true of the Crigler-Najjar form of hereditary hyperbilirubinemia, in which kernicterus (with ataxia or athetosis) may rarely appear as late as childhood or adolescence, the defect being one of glucuronide-bilirubin conjugation. Later in life, the more common causes are medications, illicit drug use, focal cerebral lesions, hyperosmolar nonketotic state, antiphospholipid antibody syndrome, among many others discussed in Chap. 6. Furthermore, a number of other rare diseases, which can only be classified as heredofamilial degenerations, also figure in the differential diagnosis of choreoathetotic or dystonic syndromes and are discussed in Chap. 39. Torsion dystonia is the best-known example. With regard to rarer metabolic causes, ceroid-lipofuscinosis of the Kufs type, GM1 gangliosidosis, late-onset metachromatic leukodystrophy, Niemann-Pick disease (type C), Hallervorden-Spatz disease, and Wilson disease may present with a syndrome of which dystonia or athetosis is an important component. Usually, there are other elements in the clinical picture as well, so that the correct diagnosis is seldom in doubt for long. dal Canto and colleagues have described a variant of neuronal ceroid-lipofuscinosis in which a boy and girl of unrelated non-Jewish parents developed severe choreoathetosis and dystonia at 6 to 7 years of age. Intellectual deterioration, gait abnormality, and seizures were added clinical features. Cerebral biopsy showed intraneuronal inclusions consisting of curvilinear bodies. These observations support the notion of nosologic heterogeneity among the nonglycolipid neuronal storage disorders.
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Glutaric acidemia (type I) is another rare metabolic disorder, in which progressive choreoathetosis and dystonia are combined with intermittent acidemia. In some cases, ataxia of movement and a variable degree of mental retardation are also present. Glutaric acid is present in the urine, as are its metabolites 3-hydroxyglutarate and glutamate. The basic defect is in glutaryl CoA dehydrogenase, which has been found in leukocytes, hepatocytes, and fibroblasts. Neuropathologically, there is loss of neurons in the caudate, putamen, and pallidum, with gliosis. A spongy change is said to affect the white matter. Infants with glutaric acidemia are often subject to sudden episodes of acidosis, coma, and flaccidity. There are signal changes on MRI, corresponding to the acute necrosis of nerve cells in the basal ganglia. These crises can be prevented and the infants can develop normally if the diagnosis is made before the development of neurologic signs, for example, in the sibling of an older affected child, and treatment is undertaken with a diet low in protein, particularly in tryptophan and lysine (Cho et al).
SYNDROMES OF BILATERAL HEMIPLEGIA, BLINDNESS, AND OTHER MANIFESTATIONS OF DECEREBRATION (THE LEUKODYSTROPHIES) Categorized here are late life manifestations of familial leukodystrophies. Of the several varieties of late-onset leukodystrophy, some are of unquestionable metabolic origin. The terms metachromatic, sudanophilic, orthochromic, etc., refer to the distinctive products of myelin degeneration and staining characteristics (or lack thereof) of the white matter in the individual leukodystrophies. As emphasized earlier, these are distinguished from the cerebral gray matter diseases (poliodystrophies), which have a different mode of presentation—seizures, myoclonus, chorea, choreoathetosis, and tremor being prominent. Instead, recognition of the entire group of leukodystrophies is based on symptoms and signs attributable to the interruption of tracts (corticospinal, corticobulbar, cerebellar peduncular, sensory) and visual pathways (optic nerve, optic tract, geniculocalcarine) and the infrequency or absence of seizures, myoclonus, and spike-and-wave abnormalities in the EEG. However, this distinction is not infallible, particularly in the later stages of the disease. The syndrome of progressive spasticity and rigidity with spastic dysarthria and pseudobulbar palsy poses a difficult diagnostic problem. One’s first impulse is to assume the presence of a corticospinal disorder, especially if tendon reflexes are brisk, but frequently the plantar reflexes are flexor and the facial reflexes are not enhanced (“pseudo-pseudobulbar palsy,” a term we attribute to Marsden). In addition, unusual postures and a more plastic type of rigidity may occur, consistent with an extrapyramidal condition. Adrenomyeloneuropathy is another syndrome that combines reduced or absent tendon reflexes and Babinski signs, signifies a combination of corticospinal and peripheral nerve lesions, and is highly characteristic of metachromatic leukoencephalopathy.
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The leukodystrophies that become apparent only in later life pose yet another problem: the clinical and radiologic differentiation from cerebral forms of multiple sclerosis. In identifying the metabolic diseases of myelin, one is helped by the relative symmetry and steady progression of the clinical signs; the early onset of cognitive impairment (which is uncharacteristic of multiple sclerosis); and the symmetrical and massive degeneration of the cerebral white matter (in distinction to the asymmetrical and often multiple lesions of demyelinative disease). At various times in life, particularly in young individuals, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) enters into the differential diagnosis (see Chap. 34); late in life, distinguishing a metabolic disorder of myelin from the subcortical multiple infarctions of Binswanger disease and from the ubiquitous rarefaction of the periventricular regions of the cerebrum may be a problem. Differentiation from cerebral gliomatosis, brain lymphoma, toxic forms of leukodystrophy, and progressive multifocal leukoencephalopathy, all affecting deep cerebral or white matter structures, offers less difficulty.
Adrenoleukodystrophy (Sudanophilic Leukodystrophy) This combination of leukodystrophy and Addison disease, originally included under the rubric of Schilder disease, is now set apart as an independent metabolic encephalopathy. It is transmitted as an X-linked recessive trait with an incidence of 1 in 20,000 male births. The fundamental defect is impairment in peroxisomal oxidation of very-long-chain fatty acids (VLCFAs), leading to their accumulation in the brain and adrenal glands (see the publications of H.W. Moser and of Igarashi and associates). The deficient membrane protein, encoded by a gene that maps to chromosome X28, is a peroxisomal membrane transporter (ABCD1). The gene is located close to the gene for color vision. In the typical X-linked adrenoleukodystrophy (ALD), there is an inability to metabolize VLCFAs, but it came as a surprise that the disease was not caused by an enzyme deficiency. The modern classification of the disease categorizes it as a disorder of peroxisomes, subcellular organelles containing numerous enzymes, each of which is unaffected. This peroxisomal assignation connects adrenoleukodystrophy with Zellweger and Refsum disease. The onset is usually between 4 and 8 years, sometimes later; in the most common form of this disorder, only males are affected with the entire syndrome (women carriers may display a special myelopathy discussed further on). The signs of either the adrenal insufficiency or the cerebral lesion may be the first to appear. In the case described by Siemerling and Creutzfeldt, the first recorded example of this disorder, bronzing of the skin of the hands appeared at 4 years of age; quadriparesis, with dysarthria and dysphagia (i.e., pseudobulbar palsy), became evident at 7 years; a single seizure occurred at 8 years; and by 9 years, shortly before death, the patient was decerebrate and unresponsive. In personally observed cases, the first abnormalities appeared at 9 to 10 years and took the form of episodic vomiting, decline in scholastic performance and change in personality with inappropriate giggling and crying. After a time, severe vomiting
and an episode of circulatory collapse occurred, following which the gait became unsteady and arms ataxic with an intention tremor. Only then did the addisonian increase of pigmentation of the oral mucosa and the skin around nipples and over elbows, knees, and scrotum become evident. Cortical blindness follows in some instances. The late stages are marked by bilateral hemiplegia (at first asymmetrical), pseudobulbar paralysis, blindness, deafness, and impairment of all higher cerebral functions. The severity of the disease varies. We are caring for two adult men in whom the cerebral symptoms have been mild, allowing for high-level cognitive achievement, albeit with peculiarities of personality, and with mild spastic gait, urinary difficulty, testicular insufficiency, and baldness. In each family there was a male sibling who died in childhood, ostensibly of adrenal insufficiency. Griffin and coworkers have described a spinal-neuropathic form of the disease (adrenomyeloneuropathy [AMN]). In their patients, evidence of adrenal insufficiency had been present since early childhood, but only in the third decade of life did a progressive spastic paraparesis and a relatively mild polyneuropathy develop. It should be noted that the spasticity is occasionally asymmetrical, and the gait may have an ataxic component. This neurologic picture, in mild form and without adrenal insufficiency, is also the manner in which the disease may present in female carriers of the gene abnormality (see below). Like adrenoleukodystrophy, adrenomyeloneuropathy is typically inherited as an X-linked, male-specific trait. However, we have encountered a large family with adrenomyeloneuropathy in which males and females are both affected in a pattern that suggests dominant inheritance. The VLCFAs are modestly elevated in affected individuals, and there is no evidence of cerebral involvement. Moser and colleagues (1980), using clinical and biochemical criteria, have identified the following subtypes of ALD: 1. A progressive degeneration of cerebral white matter in young males, often with cortical blindness—the classic type, accounting for half of all cases (Fig. 37-10) 2. An intermediate form in juvenile or young adult males with cerebral and spinal involvement (5 percent of cases) 3. A progressive spinal cord tract degeneration in adult males (25 percent of cases) 4. A chronic mild, nonprogressive spastic paraparesis in heterozygous female carriers (10 percent of cases) 5. Familial instances of Addison disease without neurologic involvement in males (10 percent of cases) 6. Possibly, in male infants, a form originating at birth (e.g., Zellweger disease) Illustrating the variability in presentation among kindreds, Marsden and colleagues (1982) and, subsequently, Kobayashi and coworkers described a familial spinocerebellar syndrome, and Ohno and associates reported a sporadic instance of adrenoleukodystrophy presenting as olivopontocerebellar atrophy. Moser found cerebral forms alone in 30 percent, adrenomyeloneuropathy alone in 20 percent, and combined childhood cerebral and myelopathic forms in the remaining half.
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Figure 37-10. Adrenal leukodystrophy in a 7-year-old male. Confluent areas of increased signal involving the frontal, occipital, and parietal white matter (thick arrows) and of the anterior and posterior portions of the corpus callosum (long-stemmed arrows). (Reproduced by permission from Bisese JH: Cranial MRI. New York, McGraw-Hill, 1991.)
Female Heterozygotes Neurologic manifestations develop in up to 50 percent of female carriers but in our experience with siblings of affected patients, the figure has been lower. The onset of a spastic paraparesis tends to occur later in life, usually in the third or fourth decade, and progression tends to be slow, but an explosive onset has been reported (see Chap. 44). As already mentioned, multiple sclerosis is the main consideration in differential diagnosis, particularly as 20 percent of heterozygotes have white matter changes on cerebral MRI. Overt adrenal insufficiency is rare in female carriers, but scalp hair may be scant as a subtle manifestation of adrenal hypofunction. Pathologically in classic instances, massive degeneration of the myelin occurs, often asymmetrically in various parts of the cerebrum, brainstem, optic nerves, and sometimes spinal cord (see Fig. 37-10). Degradation products of myelin are visible in macrophages in recent lesions, namely, sudanophilic demyelination. There is extensive astrocytic gliosis. Axons are damaged, but to a lesser degree. The cortex of the adrenal glands is atrophic, and the cells and invading histiocytes contain an abnormal lipid material. The testes show marked interstitial fibrosis and atrophy of the seminiferous tubules. Electron microscopically, the macrophages of the brain and adrenals and the Leydig cells of the testes contain characteristic lamellar cytoplasmic inclusions. Laboratory Diagnosis The specific laboratory marker of the disease is an excess of VLCFAs, in particular three measurements are of value: the absolute level of hexacosanoic acid (C26), the ratio of C26 to C22 (docosahexanoic acid; C26:C22), and of C24 (tetracosanoic acid) to docosahexanoic acid (C24:C22) in plasma, erythrocytes, leukocytes, or cultured fibroblasts as detailed by A.B. Moser and colleagues
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(1999). This reflects the basic biochemical fault in this disease, namely defective fatty acid oxidation within the peroxisomes. If skin fibroblasts and plasma testing are both performed, 93 percent of female carriers will show the abnormal VLCFA. MRI of the brain is abnormal in the majority of patients with cerebral symptoms and in a proportion of others. Other laboratory findings are low serum sodium and chloride levels and elevated potassium levels reflecting the atrophy of the adrenal glands. The latter results in reduced excretion of corticosteroids, low serum cortisol levels, and lack of rise in 17-hydroxyketosteroids after adrenocorticotropic hormone (ACTH) stimulation. The CSF protein may be elevated. As a research tool, Öz and colleagues have shown that magnetic resonance spectroscopy that measures the concentrations of several metabolites can be used as a guide to the progression of the disease and to gauge the effects of new therapies as they are introduced. Treatment Adrenal replacement therapy prolongs life and occasionally effects a partial neurologic remission. A diet enriched with monounsaturated fatty acids and devoid of long-chain fatty acids has been said to slow the progress of the disease when administered before the age of 6 years. Bone marrow transplantation, to date performed in more than 50 children, has been the only treatment shown to stabilize the disease and reverse some of the MRI changes. The reviews by van Geel and colleagues, and the ones by Moser (1997 and 1999) the leading worker in the field, summarizing diagnosis and treatment, are recommended.
Juvenile and Adult Metachromatic Leukodystrophy This form of leukodystrophy was described in relation to the inherited metabolic disorders of late infancy and early childhood in an earlier section. We mention it here to emphasize that the disease may have its onset at almost any age. Juvenile forms may begin between 4 and 12 years of age and adult forms between the midteens and the seventh decade of life. The mutations giving rise to these various forms are described in the earlier section on metachromatic leukodystrophy (MLD). Some of the sporadic cases reported in the adult probably were examples of cerebral multiple sclerosis, but we have seen, as have others, cases of MLD appearing as late as middle adult life. In almost all cases, the clinical picture, like those described by Turpin and Baumann, was one of slowly evolving intellectual decline or behavioral abnormality, followed by spastic weakness, hyperreflexia, Babinski signs, and stiff, short-stepped gait, with or without a polyneuropathy. Without manifest neurologic signs, misdiagnosis of psychiatric disease is common. As the disease progresses over a period of 3 to 5 years there may be a loss of vision and speech, then of hearing, and finally a state of virtual decerebration. In some of these cases it is impossible to distinguish the white matter disease from that of Pelizaeus-Merzbacher and of Cockayne, described in the preceding section.
Orthochromatic Leukodystrophies This refers to a heterogeneous group of disorders, also called nonmetachromatic leukodystrophy, in which no enzyme defect or special staining characteristic of degen-
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erated white matter has been identified. Furthermore, most of them have been sporadic, obscuring the nosology of the process. One type is associated with cerebellar ataxia and dementia; other adult cases have been described in which epilepsy was associated with a frontal lobe type of dementia. A surprising feature, such as in the cases of Letournel and colleagues, has been normal MRI, even with the more sensitive FLAIR sequences.
Cerebrotendinous Xanthomatosis This rare disease is probably transmitted by an autosomal recessive gene. It usually begins in late childhood, with cataracts and xanthomas of tendon sheaths and lungs. As it progresses, difficulty in learning, impairment of retentive memory, and deficits in attention and visuospatial perception (the earliest neurologic manifestations) give way to dementia, ataxic or ataxic-spastic gait, dysarthria and dysphagia, and polyneuropathy. In the late stages (after 5 to 15 years), the patient becomes bedfast and helpless; death occurs at 20 to 30 years of age. In other cases, the clinical course is much more benign. Neuropathologic examination shows masses of crystalline cholesterol in the brainstem and cerebellum and sometimes in the spinal cord, with symmetrical destruction of myelin in the involved areas. The white matter lesions are visible by CT scanning and MRI. The basic defect is in the synthesis of primary bile acids, leading to an increased hepatic production of cholesterol and cholestanol, which accumulate in brain and tendons. The serum cholesterol levels are normal in most cases but may be as high as 450 mg/dL in others. The tendon xanthomas contain cholesterol, of which 4 to 9 percent is cholestanol (dihydrocholesterol) according to the studies of Moser and colleagues (1984). Cholestanol levels in the serum and red cells are increased. The same elevated levels are found in heterozygotes. Treatment In response to long-term treatment with chenodeoxycholic acid, 750 mg daily, the corticospinal and cerebellar signs and dementia receded in 10 of 17 patients treated and followed by Berginer and coworkers. This drug corrects the defective synthesis of bile acids and restores the low level of chenodeoxycholic acid. Ideally, treatment should begin before the neurologic symptoms appear (Meiner et al).
STROKES IN ASSOCIATION WITH INHERITED METABOLIC DISEASES In Chap. 34 it was remarked that strokes occur from time to time in children and young adults, often as a result of inherited disorders of the clotting system typified by protein C deficiency, but also of a number of other metabolic derangements, including the mitochondrial disorder MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). Among the many causes, three metabolic diseases must always be considered in the diagnosis of such cases: homocystinuria, Fabry disease, and sulfite oxidase deficiency. Other less-common ones are Tangier disease and familial hypercholesterolemia.
Stroke in young persons is also a central feature of the mitochondrial disorder MELAS, discussed further on in this chapter, and of the genetically determined microvasculopathy CADASIL (“Familial Subcortical Infarction” discussed in Chap. 34).
Homocystinuria This aminoaciduria is inherited as an autosomal recessive trait and simulates Marfan disease. Tall, slender habitus; great length of limbs, sometimes scoliosis and arachnodactyly (long, spidery fingers and toes); thin and rather weak muscles; knock-knees; highly arched feet; and kyphosis are the typical skeletal features. Sparse, blond, brittle hair; malar flush; and livedo reticularis are common dermal manifestations, and a dislocation of one or both lenses (usually downward) may occur, imparting a tremulous appearance to the irides (iridodonesis). The only neurologic abnormality is mental retardation, usually of mild degree, which sets this syndrome apart from Marfan disease, in which intellect is unimpaired. Blood vessel changes of thickening and fibrosis of the coronary, cerebral, and renal arteries tend to appear later in the illness. An abnormality of platelets favoring clot formation and thrombosis of cerebral arteries has been observed. Some patients have died of coronary occlusions during adolescence, and a myocardial lesion may be the source of emboli to cerebral arteries. Homocysteine is elevated in the blood and CSF, and homocystine in the urine. This is because of an inherited cystathionine synthase deficiency that results in an inadequacy of cystathionine formation, a substance essential to many tissues including the brain. This may be the explanation of the mental retardation. Plasma methionine levels are also elevated. The infarcts in the brain are clearly related to thrombotic and embolic arterial occlusions. The administration of large doses (50 to 500 mg) of pyridoxine (a cystathionine synthase coenzyme), folate 5 mg daily and cobalamin (vitamin B12) 1,000 μg daily, reduces the excretion of homocystine. If vascular lesions have occurred, anticoagulants probably prevent further occlusions. Homocysteinemia and homocystinuria may also be expressions of 5,10-methylenetetrahydrofolate reductase deficiency. Again, the clinical manifestations consist of multiple cerebrovascular lesions, dementia, epilepsy, and polyneuropathy. The last is believed to be caused by a coincidental folic acid deficiency, but in some cases it may have been caused by chronic phenytoin administration (Nishimura et al). Much milder elevations of serum homocystine have been recognized as contributing to the risk of coronary disease and stroke in otherwise normal individuals.
Fabry Disease (Anderson-Fabry Disease) (See also Chaps. 34 and 46) This disease, also known as angiokeratoma corporis diffusum, is inherited as an X-linked recessive trait. It occurs in complete form in males and in incomplete form in female carriers. The primary deficit is in the enzyme alpha-galactosidase A, the result of which is the accumulation of ceramide trihexoside in endothelial, perithelial, and smooth muscle cells
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of blood vessels as well as in renal tubular and glomerular cells and other viscera and in nerve cells in many parts of the nervous system (hypothalamic and amygdaloid nuclei, substantia nigra, reticular and other nuclei of the brainstem, anterior and intermediolateral horns of the spinal cord, sympathetic and dorsal root ganglia). The disease becomes manifest clinically in childhood or adolescence, with intermittent lancinating pains and dysesthesias of the extremities. A notable feature of these pains is their evocation by fever, hot weather, and vigorous exercise. Usually there is no sensory loss, but autonomic disturbances have been recorded in a series of our cases. Many years later there is a diffuse vascular involvement that leads to hypertension, renal damage, cardiomegaly, and myocardial ischemia. Thrombotic infarctions occur in the brain during early adult years. Occasional cases are discovered in adulthood with confluent cerebral white matter changes on MRI and progressive problems such as dysarthria. The characteristic angiokeratomas tend to be most prominent periumbilically and resemble small angiomas that obliterate slightly with pressure. Desnick and colleagues have reviewed the neurologic, neuropathologic, and biochemical findings in this disease, and Cable and colleagues have written informatively on the autonomic aspects. Treatment Enzyme replacement, given by infusion, is now available. The two main trials of this treatment, summarized in an editorial by Pastores and Thadhani, were each conducted quite differently. Both showed an improvement in kidney and other organ function but only one demonstrated a reduction in neuropathic pain, and neither studied the risk of stroke. Like enzyme replacement therapy for Gaucher disease, prolonged treatment is expensive; but some evidence from the trials cited above indicates that certain aspects of the disease are reversible. The painful neuropathic features that have brought several cases to our attention are discussed with the polyneuropathies, in Chap. 46.
Sulfite Oxidase Deficiency This disorder was discussed briefly with the neonatal metabolic disorders. The occurrence of stroke as a complication of this disorder was placed on record by our colleagues Shih et al (1977). A child 4.5 years of age, whose development had been retarded since birth (seizures and opisthotonos had been present), became hemiplegic. Another unrelated child, supposedly normal until 2 years of age, entered the hospital with fever, confusion, generalized seizures, right hemiplegia, and aphasia (infantile hemiplegia); subluxation of the lenses (upward) was discovered later. There was an increased level of sulfite and thiosulfate and an abnormal amino acid, S-sulfocysteine, in the blood. One child appeared to respond to a low-sulfur–amino-acid diet.
CHANGES IN BEHAVIOR AND INTELLECT AS MANIFESTATIONS OF INHERITED METABOLIC DISEASE Certain metabolic diseases may be the cause of serious disturbances of cognitive function and behavior, even in
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the adolescent and early adult period. The diagnosis and management of these metabolic diseases are so unusual that some special remarks are appropriate. When they present later in adolescence and adult life they evolve more slowly than childhood forms. The most obvious and easily detectable of these derangements are in the cognitive sphere, i.e., memory, calculation, problem solving, and verbal skills. Impulsivity, loss of self-control, and antisocial behavior are the most troubling behavioral abnormalities. Each of these phenomena has its own cerebral anatomy, as pointed out in Chap. 22, and the state of dementia comprises various degrees and combinations of these abnormalities. Intellectual functions are difficult to accurately assess in early childhood. Slowness in learning and in acquiring language functions become manifest in school and may then be interpreted loosely as mental retardation. Up until school age, these intellectual functions have not developed sufficiently to allow recognition of their regressive course. Only in late childhood do mental retardation and dementia become clearly distinguishable and measurable by standardized tests. Far less tangible are subtle changes in personality and behavior. A useful principle in recognizing those adolescents with a metabolic brain disease is that sooner or later, such a condition will cause a regression in cognitive and intellectual functions. Bipolar disease, sociopathies, and character disorders do not result in the loss of neurologic function. The recognition of a metabolic cause of mental deterioration depends on the demonstration of failing memory, impaired thinking, inability to learn, and loss of verbal and arithmetic abilities, many of which are measured quantitatively by intelligence tests. The appearance of pyramidal signs, aphasia, apraxia, ataxia, or areflexia further sets them apart. If one reviews all the diseases described in this chapter and selects those that may demonstrate regression of cognitive function in association with personality change and alteration of behavior in an adult—diseases that may for a time be unaccompanied by other neurologic abnormalities— the following metabolic disorders merit special consideration in approximate relative order of importance: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Wilson disease Adrenoleukodystrophy Metachromatic leukodystrophy Hallervorden-Spatz pigmentary degeneration Late-onset neuronal ceroid-lipofuscinosis (Kufs form) Juvenile and adult Gaucher disease (type III) Some of the mucopolysaccharidoses Adult GM2 gangliosidosis Mucolipidosis I (type I sialidosis) Lafora-body myoclonic epilepsy Nonwilsonian copper disorder (hereditary ceruloplasmin deficiency)
In each of these diseases, dementia and personality disorder may gradually develop and exist for many months, even a year or two, before other neurologic signs appear. One must look carefully for the earliest signs of movement disorders and other neurologic abnormalities, which greatly clarify the diagnostic problem. The common use of
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neuroleptic drugs, causing tardive dyskinesia and parkinsonian signs, is an obstacle to determining if there are neurologic features in these ostensibly psychiatric conditions.
ADULT FORMS OF INHERITED METABOLIC DISEASES The increasing range and precision of biochemical and cytologic tests have brought to light a number of inherited metabolic diseases that sometimes have their onset in adult life. Such disorders, while uncommon, nevertheless are important because they must be considered in the differential diagnosis of degenerative diseases. Also to be considered in the differential diagnosis is an array of mitochondrial disorders, to be discussed further on in this chapter. In the last three decades, the authors have personally observed or have otherwise come to know of examples of the following metabolic diseases, the onset of which was in adult life: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Metachromatic leukoencephalopathy Adrenoleukodystrophy Globoid body leukodystrophy (Krabbe disease) Kufs form of neuronal ceroid lipofuscinosis GM2 gangliosidosis Wilson disease Gaucher disease Niemann-Pick disease Carnitine palmityl transferase deficiency Mucopolysaccharide encephalopathy Mucolipidosis type I Polyneuropathies (Andrade disease, Fabry disease, porphyria, Refsum disease) 13. Mitochondrial diseases, particularly progressive external ophthalmoplegia and Leigh disease In the encephalopathic forms of the metabolic and mitochondrial diseases, the diagnosis is usually made only after symptoms have been present for months or years, the disease having been mistaken for some other condition, particularly depression or a degenerative dementia. Even a manifest psychosis may have occurred in relation to some of these disorders, but such occurrences are admittedly rare. For example, one of our patients with metachromatic leukodystrophy, a 30-year-old man, began failing in college years and was later unsuccessful in holding a job because of carelessness and mistakes in his work and indifference to criticism, irritability, and stubbornness (clearly traceable to a mild dementia). Only when Babinski signs and loss of tendon reflexes in the legs were detected was the correct diagnosis entertained for the first time. By then he had been ill for nearly 10 years. Bosch and Hart described a patient with the onset of dementia at 62 years of age and drew attention to 27 other similar cases of adult-onset metachromatic leukoencephalopathy (see also the 7 cases of Turpin and Baumann). Overt signs of neuropathy are usually lacking in these adult-onset cases, but EMG and sural nerve biopsy will disclose the characteristic abnormalities. One of our adult patients with Wilson disease had been committed to a psychiatric hospital because of his paranoid tendencies and fighting with his family; the presence
of a tremor and mild rigidity of the limbs had been attributed at first to phenothiazine drugs. In some of Griffin’s cases of adrenomyeloneuropathy, a spastic weakness of the legs and sensory ataxia progressing over several years were the main clinical manifestations; a spinocerebellar degeneration was suspected. One of our patients with Kufs lipid storage disease began to deteriorate mentally in early adult life and only much later showed an increasing rigidity, with athetotic posturing of limbs and difficulty in walking; he succumbed to his disease after more than a decade of symptoms. Another recent patient with Kufs disease presented at age 51 with vague visual difficulty, which was followed by spasticity of the legs, behavioral disinhibition, and dementia spanning 6 years. Josephs and colleagues describe 2 of 5 patients with adult-onset type C Niemann-Pick disease who had a psychosis beginning at ages 61 and 27, respectively. We have observed cerebellar ataxia, polymyoclonus, and progressive blindness in adolescents and adults with a variant of GM2 gangliosidosis; cherry-red macular spots provided the clue to diagnosis. Several such cases have been reported in the last decade, particularly among the Japanese (Miyatake et al). Nine cases of a spinocerebellar ataxia with dementia or psychosis of adult onset were described by Wilner and colleagues. Also in our service were 2 adult patients with progressive spinal muscular atrophy who proved to have this same GM2 hexosaminidase deficiency; the process was clinically almost indistinguishable from a very slowly progressive lower motor neuron form of motor neuron disease but they had no macular changes and displayed the additional features of ataxia and an intermittent and atypical psychosis. An asymmetrical corticospinal syndrome with areflexia had advanced so slowly in one of our cases of Krabbe disease that she became disabled only in her sixties. Another of our patients, an adolescent with severe diffuse myoclonus and seizures and slight intellectual deterioration, was found after several years to have one of the rare variants of Gaucher disease. Another with dementia, rigidity, choreoathetosis, slight cerebellar ataxia, and Babinski signs had a variant of Niemann-Pick disease. Rarely, Gaucher disease may be associated with an early and severe parkinsonian syndrome. Cases of familial adult onset Leigh disease have been described by Kalimo and colleagues. Adrenoleukodystrophy presenting in adult life as a spinocerebellar or olivopontocerebellar syndrome has already been mentioned. These rare forms of inherited metabolic disease are notable for their chronicity and for the early prominence of a particular neurologic symptom or syndrome. Once the disease is established, however, there is nearly always evidence of involvement of multiple neuronal systems, reflected in a subtle or overt dementia, character disorder, or signs referable to corticospinal, cerebellar, extrapyramidal, visual, and peripheral nerve structures. This multiplicity of neuronal system involvement is much more a feature of heritable metabolic disease than of degenerative disease and the finding of such involvement should provoke a search for an inherited metabolic disorder. Viewed from another perspective, certain outstanding clinical symptoms that are more often attributable to com-
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mon diseases of the adult nervous system, such as multiple sclerosis and atherosclerosis, are sometimes the result of an inborn error of metabolism. These infrequent instances are categorized by their main features in Table 37-8, which is adopted from Grey et al. To reiterate, the aforementioned dictum that tract involvement (corticospinal, cerebellar, peduncular, sensory, optic nerve) indicates a leukodystrophy and that “gray matter” signs (seizures, myoclonus, dementia, retinal lesions) indicate a poliodystrophy is useful mainly in the early stages of a disease. Some of the lysosomal storage diseases affect both galactolipids (galactocerebrosides and sulfatides) and gangliosides; hence both white and gray matter are involved. The paper by Turpin and Baumann is of interest when this group of diseases is viewed from the strictly psychiatric point of view. In concluding this discussion, which classifies the inherited monogenetic metabolic diseases in accordance with their clinical characteristics, the reader will appreciate its artificiality. Nearly every one of the diseases of each category may present some neurologic abnormality other than the ones we have emphasized, so that the potential number of variations is almost limitless. However, the plan presented here of thinking of these diseases in reference to age periods and syndromes, is of heuristic value and facilitates clinical study of this extremely difficult segment of neurologic medicine.
Table 37-8 MAJOR SYNDROMES ADULT-ONSET INHERITED METABOLIC DISEASES Dementia and psychosis Kufs disease Niemann-Pick disease type C Wilson disease Adrenoleukodystrophy Metachromatic leukodystrophy Aceruloplasminemia Motor neuron disease GM2 gangliosidosis Polyglycosan disease Choreoathetosis Wilson disease GM2 gangliosidosis Niemann-Pick disease type C Ataxia Aceruloplasminemia Abetalipoproteinemia GM2 gangliosidosis Hartnup disease Sialidosis Niemann-Pick disease type C Leukodystrophy Krabbe disease Metachromatic leukodystrophy Adrenoleukodystrophy Orthochromatic leukodystrophy Strokes Fabry disease Homocystinuria MELAS MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
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MITOCHONDRIAL DISORDERS As with the metabolic disorders of the nervous system, the diseases included under this heading are so varied and may involve so many parts of the nervous system that the clinical entities by which they are identified cannot be easily addressed in any one part of this book. In their overlapping relationships, however, these diseases are unlike the more discrete clinical entities caused by nuclear genetic mutations. Their diversity is evident not only in the details of their clinical presentations but also in the age at which symptoms first become apparent and, what is most intriguing, sometimes in the abrupt onset of their neurologic manifestations. Most of this variability in presentation is understandable from the principles of mitochondrial genetics outlined in the introductory section of this chapter. Of particular importance is the mosaicism of the mitochondria within cells and from cell to cell and the crucial role the organelles play in the oxidative energy metabolism that supports the function of cells in all organs. Fortunately for the clinician, the most important of these diseases are expressed in several recognizable core syndromes and in a few variants thereof. A number of acronyms derived from the initial letters of the main clinical features are used to designate the major mitochondrial syndromes: MERRF, MELAS, PEO, NARP, etc., as summarized in Table 37-9. The addition of certain subtle dysmorphic features including short stature; endocrinopathies, particularly diabetes; and a number of other systemic abnormalities such as lactic acidosis (discussed further on) aids in diagnosis of this class of disorder. These diseases are the result of mutations in the mitochondrial genome, a ringed DNA of 16,569 base pairs and 37 genes contained within the organelle, or of mutations in a few nuclear genes that code for a component of the mitochondrion. To date, more than 100 point mutations and 200 deletions, insertions, and rearrangements have been identified. It is estimated that two-thirds of the point mutations affect the transfer RNA of the mitochondrion, one-third affect polypeptide units of the respiratory chain, and a small number affect mitochondrial ribosomal RNA. This corresponds approximately to the proportion of genes devoted to each of these functions. DiMauro and Schon wrote a thorough review of mitochondrial genomics and the most relevant diseases, which may be consulted by interested readers. The first described and best-characterized member of this group of diseases is a symmetrical proximal myopathy that occurs as an isolated illness or in combination with any of the major mitochondrial syndromes. In 1966, Shy and coworkers described the histochemical and electron-microscopic abnormalities of the muscle mitochondria in a childhood myopathy, which they called megaconial (meaning marked enlargement of the mitochondria) or pleoconial (referring to an excessive number of mitochondria). Later this change came to be known as “ragged red fibers,” so named because of the subsarcolemmal and intermyofibrillar collections of membranous (mitochondrial) material in the type 1 (red) muscle fibers as visualized by the Gomori trichrome stain in sections of frozen muscle. This morpho-
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Table 37-9 THE MAJOR CATEGORIES OF MITOCHONDRIAL DISORDERS COMMON MITOCHONDRIAL GENE MUTATION
SYNDROME
Ragged red fiber polymyopathy Progressive external ophthalmoplegia (PEO) and KearnsSayre variants Leigh syndrome, fatal lactic acidosis, and neuropathy with proximal weakness, ataxia, and retinitis pigmentosa (NARP) Myoclonic-epilepsy and ragged red fibers in muscle (MERRF) Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Leber optic neuropathy Myoneural-gastrointestinal encephalopathy
RAGGED RED FIBERS
LACTIC ACIDOSIS
–
Point mutation at 3250 Heteroplasmic deletions or point mutation at 3243 Point mutation at 8993
+ –
–
–
+
Point mutation at 8344
+ (usually)
±
Point mutation at 3243
+
+
Point mutation at 3460, 4160, or 11778 Unknown (maternal inheritance)
– +
– –
+ = present; – = absent.
logic change may be an asymptomatic accompaniment of the mitochondrial disorders or, conversely, a mitochondrial disease of the CNS may exist without histologic or ultrastructural abnormalities in the muscle. A second unifying feature of these diseases is an elevation of lactate concentration or of the lactate-to-pyruvate ratio in the blood and CSF; this is the result of the respiratory chain abnormalities. These elevations are most prominent after exercise, infection, fever, or alcohol ingestion and in some conditions are capable of inducing recurrent ketoacidotic coma, which may be the presenting manifestation of a mitochondrial disease. Leigh syndrome and MELAS particularly have a tendency to exhibit elevations of lactate; however, the diagnosis of either cannot be excluded in the presence of normal levels of this substance, even after provocation by exercise (see further on for a description of testing for elevated lactate). Using phosphorus MRI scans, one can compare levels of inorganic phosphate to phosphocreatine levels in muscle; in genetic muscle diseases of several types, this ratio increases, but it is highest in those of mitochondrial origin. Although the mitochondrial diseases are considered here as a group, individual ones are of necessity mentioned in other chapters because of their outstanding characteristics. Thus the syndrome that combines epilepsy, deafness, and developmental delay with ragged red muscle fibers (myoclonic epilepsy with ragged red fibers, or MERRF) was discussed in Chap. 16, on epilepsy. The syndrome of progressive external ophthalmoplegia (PEO) has been included with other abnormalities of eye movements (Chap. 50); lactic acidosis and stroke-like episodes (MELAS) were considered in Chap. 34, with the cerebrovascular diseases; and Leber hereditary optic neuropathy, with other causes of visual loss (Chaps. 13 and 39). Leigh syndrome, a symmetrical subacute necrotizing encephalomyelopathy, usually with lactic acidosis, also has a number of complex presentations and is mentioned in the differential diagnosis of several diseases. For each of the aforementioned processes, wide clinical experience will bring to light an individual or a family in whom some odd syndrome has been linked to a mitochondrial disorder. Furthermore, two major syndromes may coexist in one individual and fragmentary
subsyndromes are known to occur, having an onset any time from childhood to early adult life. Consequently, it serves little purpose to catalogue all of these associations. Only the best-characterized entities, listed in Table 37-9, are described here. The most common combinations of mitochondrial syndromes have been of Kearns-Sayre syndrome with MELAS or with MERRF, progressive ophthalmoplegia with MERRF, and MERRF with MELAS. We prefer to avoid the issue of what defines a “mitochondrial disorder”—its genetic defect, the biochemical disorder, or the clinical syndrome. The clinician assigns this term to the combination of a mutation of mitochondrial DNA and certain clinical features that constitute a recognizable syndrome; the biochemical changes are taken as markers of the disordered energy-producing mechanisms of the mitochondrial machinery. Mitochondrial failure has also become a focus of interest in various degenerative neurologic conditions, such as Alzheimer and Parkinson diseases but none of the currently understood mutations of the mitochondrial genome is clearly implicated in these conditions.
Mitochondrial Myopathies The mildest form of muscle disorder caused by mitochondrial disease is a benign and relatively static proximal weakness that tends to be more severe in the arms. Exercise intolerance alone is reported by more than half of these patients. There are adult-onset cases, but careful questioning usually reveals lifelong symptoms (weakness, poor endurance, discomfort, exertional dyspnea, and tachycardia), which may be so slight and slowly progressive that the patient leads a relatively normal life for decades. Less-frequent patterns of muscle disease include a fascioscapulohumeral or limb-girdle pattern of weakness as well as occasional episodes of exertional myoglobinuria. Some patients develop PEO several years after the limb weakness becomes evident. Several mutations are associated with a pure or predominant myopathic syndrome, the most common one being located at position 3250 of the mitochondrial genome. Rare variants, such as combined skeletal weakness and cardiomyopathy, are referable to other loci.
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At the opposite end of the spectrum is an infantile myopathy in which weakness and lactic acidosis become evident in the first week of life and are fatal by 1 year. Many of these patients and some members of their families have a history of renal dysfunction combined with weakness of early onset. The muscle tissue shows numerous ragged red fibers, and cytochrome oxidase activity is virtually absent. DiMauro (1983) and others have described a remarkable partly reversible form, which, early on, requires ventilatory support and gastric feeding but improves clinically as the child ages; the lactic acidosis disappears by age 2 or 3 years. In these severe childhood cases, the deficiencies in cytochrome oxidase suggest a defect in mitochondrial genes, but the site has not been found. As mentioned above, the histologic feature that unites mitochondrial myopathies is the presence of ragged red fibers. This finding points to the diagnosis of a mitochondrial disorder in any case where weakness is coupled with exercise intolerance and elevated serum lactate, particularly if there is a family history of similar problems. Also, the presence of ragged red fibers differentiates the mitochondrial myopathies from the glycogenoses but it bears emphasizing that ragged red fibers are rare in infants and young children, even in those with confirmed mitochondrial disease.
Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome (See also Chap. 50) The combination of progressive ptosis and symmetrical ophthalmoplegia is a common manifestation of mitochondrial disease. Usually there is no diplopia or strabismus or at most only transient diplopia, despite slightly dysconjugate gaze. Mitochondrial abnormalities are found in the extraocular muscles of these patients. We have been impressed at how long the illness can exist before it brings the patient to a physician. To be differentiated is myasthenia gravis, which is characterized by fatigable weakness and responsiveness to cholinergic medications, neither of which is a feature of mitochondrial disorders. In our experience, nearly all cases of PEO are because of mitochondrial disorders, but rarely the condition may be simulated by one of several genetically determined muscular dystrophies, including oculopharyngeal dystrophy and a type in which there are no other associated weaknesses but is, however, linked to facioscapulohumeral dystrophy (FSH; Chap. 50). PEO bears a close relationship to the Kearns-Sayre syndrome of retinitis pigmentosa (onset before age 20 years), ataxia, heart block and other conduction defects, and elevated CSF protein; sensorineural deafness, seizures, or pyramidal signs may be added (see Chap. 50 for clinical description). The CNS syndromes of MELAS or MERRF (see further on) may also be combined with PEO.
Subacute Necrotizing Encephalomyelopathy (Leigh Disease) This is a familial or sporadically occurring mitochondrial disorder with a wide range of clinical manifestations.
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Only some of the cases display a maternal pattern of inheritance. The onset of neurologic difficulty in more than half of these patients is in the first year of life, mostly before the sixth month; but late-onset forms, with great heterogeneity of presentation as late as early adulthood, are also known. Neurologic symptoms often appear subacutely or abruptly, sometimes precipitated by a febrile illness or a surgical operation. It has seemed to us that this rapid onset is more characteristic of Leigh disease than it is of the other mitochondrial disorders and the disease could reasonably be designated as “acute necrotizing encephalomyelopathy” (ANE), a term applied to a similar entity in Japan and China. In infants, loss of head control and other recent motor acquisitions, hypotonia, poor sucking, anorexia and vomiting, irritability and continuous crying, generalized seizures, and myoclonic jerks constitute the usual clinical picture. If the onset is in the second year, there is delay in walking, ataxia, dysarthria, psychomotor regression, tonic spasms, characteristic respiratory disturbances (episodic hyperventilation, especially during infections, and periods of apnea, gasping, and quiet sobbing), external ophthalmoplegia, nystagmus, and disorders of gaze (like those of Wernicke disease), paralysis of deglutition, and abnormal movements of the limbs (particularly dystonia but also jerky and choreiform movements). Mild cases, showing mainly developmental delay, have been mistaken for cerebral palsy. Peripheral nerves are involved in some cases (areflexia, weakness, atrophy, and slowed conduction velocities of peripheral nerves); in a few, autonomic failure is the most prominent feature. In some children the disease is episodic; in others it is intermittently progressive and quite protracted, with exacerbation of neurologic symptoms in association with nonspecific infections. The CSF is usually normal but the protein content may be increased. The pathologic changes take the form of bilaterally symmetrical foci of spongy necrosis with myelin degeneration, vascular proliferation, and gliosis in the thalami, midbrain, pons, medulla, and spinal cord. In cases of acute onset there may be minor hemorrhagic change. The basal ganglia are characteristically but not invariably affected. Also, there may be a demyelinative type of peripheral neuropathy. In their distribution and histologic appearance, the CNS lesions resemble those of Wernicke disease (caused by a deficiency of thiamine) except that the lesions of Leigh disease are more extensive—sometimes involving the striatum—and they spare the mammillary bodies. The lesions, particularly those of the lenticular nuclei and brainstem, may be seen in CT scans and are strikingly demonstrated by MRI. The histochemical appearance of muscle is normal, although electron microscopy may show an increased number of mitochondria. The clinical boundaries of Leigh disease have not been defined precisely. A familial disorder of infancy and early childhood, referred to as bilateral striatal necrosis and associated with dystonia, visual failure, and other neurologic defects, is probably a variant. The same may be true of an obscure adult-onset syndrome of progressive dementia, caused by thalamic lesions, in the form of necrosis, vascular proliferation, and gliosis. A resemblance to what has recently been termed acute necrotizing encephalomyelopathy, arising in children after an infectious illness, was alluded to earlier.
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The mitochondrial 8993 mutation associated with Leigh disease that explains 20 percent of cases is also discussed below in relation to the NARP syndrome. The close relationship between the two processes reemphasizes the point that several mitochondrial mutations rise to the clinical and pathologic picture of a necrotizing encephalopathy. However, it has been recently pointed out that many cases of Leigh disease are associated with nuclear mutations, including in RANBP2 that codes for a component of the nuclear pore.
Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome (NARP) As just indicated, Leigh syndrome exemplifies to a remarkable degree the heterogeneity of abnormalities that may be associated with cytochrome oxidase deficiency caused by a single mitochondrial gene mutation. A minor transversion error, the substitution of one nucleotide in the mitochondrial DNA at position 8993, the same site implicated in Leigh syndrome, also gives rise to a maternally inherited syndrome of sensory NARP. The mutation creates a defective ATPase-6 of complex V of the mitochondrial respiratory chain. Included in some cases of NARP are developmental delay, seizures, and proximal muscle weakness. The severity of the NARP syndrome corresponds to the amount of aberrant DNA in the mitochondrial genome; mutations involving more than 90 percent of mitochondrial DNA produce the more severe phenotype of the necrotizing encephalopathy. Santorelli and colleagues found that 12 of 50 patients with Leigh syndrome from 10 families displayed the 8993 point mutation. Within one kindred, the mitochondrial aberration may vary from a mild developmental delay, to NARP, to the full-blown Leigh syndrome, or early death with lactic acidosis. These differences in severity are thought to result from the mosaicism of mitochondrial genetics and specifically to the protective effect of even small amounts of the normal mitochondrial genome. The first manifestations of disease may not appear until adulthood, although it only rarely begins after age 20 years. Further confounding the clinical classification of this disease complex is the observation that many patients with the Leigh syndrome have a pyruvate dehydrogenase (usually Xlinked) or pyruvate decarboxylase deficiency or a cytochrome oxidase deficiency. These are common to many mitochondrial disorders and inherited usually as an autosomal recessive trait. However, patients with Leigh syndrome and the 8993 mutation tend not to have these enzymatic deficiencies. Bridging these complex cases to the typical ones are instances with cytochrome oxidase deficiency with psychomotor retardation, slowed growth, and lactic acidosis, many without the striatal or brainstem spinal necroses of Leigh syndrome.
Congenital Lactic Acidosis and Recurrent Ketoacidosis Certain types of organic acidemia occurring in early infancy and of unproved genetic etiology have already been mentioned. Here reference is made to those few cases
that are associated with deletions of mitochondrial DNA. The syndrome consists of psychomotor regression and episodic hyperventilation, hypotonia, and convulsions with intervening periods of normalcy. Choreoathetosis or progressive ophthalmoplegia have been added in a few cases. Probably most cases of this type are caused by disorders of the mitochondrial respiratory chain, particularly of the pyruvate-decarboxylase complex. Some children are dysmorphic, with a broad nasal bridge, micrognathia, posteriorly rotated ears, short arms and fingers, and other similar but mild dysmorphic features. De Vivo and colleagues have written a synopsis of this disease. Death usually occurs before the third year. The important laboratory findings are acidosis with high lactate levels and hyperalaninemia. The few cases that have been examined postmortem are found to have necrosis and cavitation of the globus pallidus and cerebral white matter, as in subacute necrotizing encephalomyelopathy (SNE). The diagnosis can be made by the finding of ragged red fibers in muscle or by measurement of enzyme activity. The process must be distinguished from the several diseases of infancy that are complicated by lactic acidosis.
Myoclonic Epilepsy with Ragged Red Fibers (MERRF) This disease presents as progressive myoclonic epilepsy or myoclonic ataxia. As was noted in Chap. 6, these cases must be differentiated from several similar clinical entities, such as juvenile myoclonic epilepsy, UnverrichtLundborg disease, Lafora-body disease, Baltic myoclonus, and neuronal ceroid-lipofuscinosis, discussed earlier in this chapter. Tsairis and colleagues were the first to describe the connection between familial myoclonic epilepsy and mitochondrial changes in muscle, and numerous variants have been identified since their report. Myoclonus in a child or young adult is the most typical feature and is elicited by startle or by voluntary movement of the limbs. The nature of the seizures varies but includes drop attacks, focal epilepsy, or tonic-clonic types, some of which are photosensitive. The ataxia tends to worsen progressively, replacing the myoclonus and seizures in some instances and remaining a minor feature in others. The myopathy usually produces inapparent or mild weakness, but the presence of mitochondrial muscle abnormalities is necessary for clinical diagnosis. To this constellation may be added any of the other elements of the mitochondrial diseases that have already been denoted, including deafness (present in our cases), mental decline, optic atrophy, ophthalmoplegia, cervical lipomas, short stature, or neuropathy. Most cases are familial and display maternal inheritance, but the age of onset may vary and affected individuals have been reported with symptoms beginning as late as the sixth decade. Almost always the patients with later onset have the mildest disease, with only myoclonic epilepsy. Conversely, those with onset in the first decade tend to be more severely affected and die before the third decade. As with the other mitochondrial processes, the quantitative burden of mutant DNA bears some relationship to the time of onset and severity of the disease.
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Eighty percent of patients with MERRF have a point mutation of the mitochondrial genome at locus 8344, which codes for a transfer RNA and, conversely, most patients with this mutation will ultimately manifest some or all the clinical features of MERRF, including those with crossover features of the Leigh syndrome.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Patients with this syndrome have normal early development followed by poor growth, focal or generalized seizures, and recurrent acute episodes that resemble strokes or prolonged transient ischemic attacks. The stroke deficits often improve but in some cases lead to a progressive encephalopathy. Some have hemicranial headaches that cannot be distinguished from migraine, and others suffer repetitive vomiting or episodic lactic acidosis. If there is a characteristic feature it is the unusual clinical pattern of focal seizures, sometimes prolonged, which herald a stroke and produce an unusual radiographic pattern of infarction involving the cortex and immediate subcortical white matter. The CT scan may also show numerous low-density regions that have no clinical correlates. Most patients have ragged red fibers in muscle but only rarely is there weakness or exercise intolerance. Approximately 80 percent of MELAS cases are related to a mitochondrial mutation occurring at the 3243 site of the mitochondrial gene or, in a few instances, at an alternative locus that also codes for a segment of transfer RNA. Maternal inheritance is common but sporadic cases are well known. In the survey conducted by Hammans and coworkers, only half of the cases of the 3243 mutation were associated with the MELAS syndrome. The finding of an abnormal mitochondrial genome in the endothelium and smooth muscle of cerebral vessels has been suggested as a basis for the strokes and migraine headaches.
The Diagnosis of Mitochondrial Disorders The characteristic neurologic signs of a mitochondrial disorder fall into certain broad groups: (1) combinations of ataxia, seizures, and myoclonus, typified by the MERRF syndrome; (2) migraine-like headaches, recurrent small strokes, and preceding seizures, represented by the MELAS syndrome; (3) combinations of ophthalmoplegia (progressive external ophthalmoplegia), retinitis pigmentosa, polyneuropathy, or deafness (Kearns-Sayre syndrome); (4) optic atrophy (Leber type); and (5) a myopathy that is slowly progressive or fluctuating in severity. These may be combined with dementia, lactic acidosis, short stature, diabetes, ptosis, and cardiac conduction defects as well as with multiple symmetrical lipomas. Peripheral nerve involvement, although common in these disorders, is usually asymptomatic; autonomic failure may be a rare manifestation. A panoply of visceral dysfunctions are at times associated with the neurologic features including bone marrow changes of sideroblastic anemia, renal tubular defects, endocrinopathies (mainly diabetes mellitus,
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but also hypothyroidism or deficiency of growth hormone), hepatopathy, cardiomyopathy, and recurrent vomiting with intestinal pseudoobstruction. Diabetes has been a marker in several of the early onset MELAS and MERRF cases that we have seen, but less often when the first manifestations appeared in adulthood. The investigation of a suspected case of mitochondrial disease begins with an exploration of the family history for unusual childhood diseases including neonatal death, unexplained seizure disorders, and progressive neurologic deficits of the types already described. Unexplained deafness or diabetes in family members might also raise the level of suspicion of a mitochondrial disorder. The diagnosis should be suspected when a disorder with these characteristics occurs in a pattern that indicates maternal inheritance. However, one encounters families with mendelian patterns of inheritance due to nuclear gene defects as described in the introductory section of this chapter. Commercial tests are available for the more frequent mitochondrial point mutation sites (3243, 8993, and 8344) in leukocytes. Detection of deletions requires analysis of muscle tissue. They are useful for diagnosis but reveal abnormalities in only a modest number, estimated to be approximately 15 percent of cases that have the index aspect of this group of diseases, ragged red muscle fibers; the frequency is higher in cases with identifiable phenotypes such as MERRF and MELAS. Resting and postexercise lactate and pyruvate determinations are helpful, but this test of aerobic capacity has limitations. The more recent work of Taivassalo and colleagues, although showing a wide range of values, suggests that measurement of the partial pressure of oxygen in venous blood from the forearm after ischemic exercise (ischemic forearm test) may still be useful in distinguishing patients with mitochondrial disease from normal subjects. In the former there is a paradoxical rise in PO2 from an average of 27 to 38 mm Hg, whereas normals show a decline in this value. A muscle biopsy will disclose several basic abnormalities; ragged red fibers can be recognized by use of the modified Gomori stain on frozen material, and the absence of succinate dehydrogenase and cytochrome oxidase by appropriate histochemical staining. In cases of suspected Leigh syndrome or MELAS, the CT or MRI may show some of the characteristic cerebral lesions; in the other mitochondrial disorders, there are often focal nondescript hyperintensities on T2-weighted MRI as well as atrophy, lucencies, or calcification. Sampling of chorionic villi for prenatal diagnosis may reveal mutant mitochondrial DNA, but this information is not entirely dependable. It should be evident from the foregoing discussion that normal findings in any of these tests, including the muscle biopsy, do not exclude mitochondrial disease. In the final analysis, it is the clinical syndrome, family history, and corroborating evidence of a mitochondrial disorder or its genetic representation that is diagnostic. Jackson and coworkers suggest that isolated phenomena, such as dementia, muscle weakness, epilepsy, nerve deafness, migraine with strokes, small stature, myoclonic epilepsy, and cardiomyopathy, should prompt consideration of a mitochondrial disorder when no other explanation is evident.
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Thomas PK, Abrams JD, Swallow D, Stewart G: Sialidosis type I: Cherryred spot-myoclonus syndrome with sialidase deficiency and altered electrophoretic mobilities of some enzymes known to be glycoproteins. J Neurol Neurosurg Psychiatry 42:873, 1979. [PMID: 512662] Trobe JD, Sharpe JA, Hirsch DK, Gebarski SS: Nystagmus of Pelizaeus-Merzbacher disease: A magnetic search-coil study. Arch Neurol 48:87, 1991. [PMID: 1986731] Tsairis P, Engel WK, Kark P: Familial myoclonic epilepsy syndrome associated with skeletal muscle abnormalities. Neurology 23:408, 1973. Tsuji S, Choudary PV, Martin BM, et al: A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher’s disease. N Engl J Med 316:570, 1987. [PMID: 2880291] Tsuji S, Yamada T, Tsutsumi A, Miyatake T: Neuraminidase deficiency and accumulation of sialic acid in lymphocytes in adult type sialidosis with partial β-galactosidase deficiency. Ann Neurol 11:541, 1982. [PMID: 6808893] Turpin JC, Baumann N: Manfiestations psychiatriques ou cognitves inaugurales dans les neurolipidoses de l’adulte. Rev Neurol 159:637, 2003. [PMID: 12910071] Vakili S, Drew AL, von Schuching S, et al: Hallervorden-Spatz syndrome. Arch Neurol 34:729, 1977. [PMID: 201232] van Bogaert L: Contribution clinique et anatomique a l’etude de la paralysie agitante juvenile primitive. Rev Neurol 2:315, 1930. van Bogaert L: Le cadre des xanthomatoses et leurs differents types: Xanthomatoses secondaires. Rev Med (Paris) 17:433, 1962. van Bogaert L, Bertrand I: Sur une idiotie famaliale avec dégénérescence spongieuse du neuraxe. Acta Neurol Belg 49:572, 1949. [PMID: 13924474] van Geel MB, Assies J, Wanders RJ, Barth P’G: X linked adrenoleukodystrophy: Clinical presentation, diagnosis and therapy. J Neurol Neurosurg Psychiatry 63:4, 1997. [PMID: 9221959] Vogt C, Vogt O: Zur Lehre der Erkrankungen des striaren Systems. J Psychol Neurol 25:627, 1920. Walsh PJ: Adrenoleukodystrophy. Arch Neurol 37:448, 1980. [PMID: 6248004] Williams FJB, Walshe JM: Wilson’s disease: An analysis of the cranial computerized tomographic experiences found in 60 patients and the changes in response to treatment with chelating agents. Brain 104:735, 1981. [PMID: 7326565] Williams RS, Marshall PC, Lott IT, et al: The cellular pathology of Menkes steely hair syndrome. Neurology 28:575, 1978. [PMID: 565889] Willvonseder R, Goldstein NP, McCall JT, et al: A hereditary disorder with dementia, spastic dysarthria, vertical eye movement paresis, gait disturbance, splenomegaly, and abnormal copper metabolism. Neurology 23:1039, 1973. [PMID: 4795418] Wilner JP, Grabowski GA, Gordon RF, et al: Chronic GM2 gangliosidosis masquerading as atypical Friedreich’s ataxia: Clinical, morphologic, and biochemical studies of nine cases. Neurology 31:787, 1981. [PMID: 6454083] Wilson SAK: Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 34:295, 1912. Wisniewski KE, Zhong N, Phillipart M: Pheno/genotypic correlations of neuronal ceroid lipofuscinosis. Neurology 57:576, 2001. [PMID: 11548735] Yokoi S, Nakayama H, Negeshi T: Biochemical studies on tissues from a patient with Lafora disease. Clin Chim Acta 62:415, 1975. [PMID: 170019] Young RR, Kleinman G, Ojemann RG, et al: Compressive myelopathy in Maroteaux-Lamy syndrome: Clinical and pathological findings. Ann Neurol 8:336, 1980. [PMID: 6776877] Zeman W, Donahue S, Dyken P, Green J: The neuronal ceroid-lipofuscinoses (Batten-Vogt syndrome), in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 10. Amsterdam, North-Holland, 1970, pp 588–679.
38 Developmental Diseases of the Nervous System
This broad heading subsumes a wide diversity of both developmental malformations and diseases acquired during the intrauterine or early neonatal periods of life. They number in the hundreds according to the tabulation of Dyken and Krawiecki although many, if not most, are rare. Taxonomically, they make up two broad categories. The first includes unrelated genetic pathologic processes, some of which originate in germ line abnormalities, including triplication, deletion, and translocations of chromosomes, and probably some are inherited on a polygenic basis. A remarkable accomplishment has been the identification in the past several years of specific gene defects that give rise to a number of these brain malformations. The second category comprises a variety of noxious and infectious agents acting at different times on the immature nervous system during the embryonal, fetal, and perinatal periods of life. It would be intellectually satisfying if all the states that originate in the intrauterine period could be separated strictly into genetic or nongenetic forms, but in most instances the biologic information and the pathologic changes in the brain at this early age do not allow such a division. For example, among the many diseases in which the neural tube fails to close (rachischisis), more than one member of a family may be affected but it cannot be stated whether a genetic factor is operative or an exogenous factor, such as folic acid deficiency, has acted on several members during a succession of pregnancies of one mother. Even what appears to be an outright malformation of the brain may be no more than a reflection of the timing of an exogenous process that has affected the nervous system early in the embryonal period, derailing later processes of development. Teratology, the scientific study of malformations, is replete with such examples. Several points should be noted regarding the frequency of developmental disorders; Smith (see Jones) has pointed out that a single malformation, usually of no clinical significance, occurs in 14 percent of newborns. Two malformations appear in 0.8 percent of newborns, and in this group, a major defect is 5 times more frequent than in the normal population. Three or more malformations are found in 0.5 percent of newborns, and in this latter group, more than 90 percent have one or more major abnormalities that seriously interfere with viability or physical wellbeing. The figures for major congenital malformations compiled by Kalter and Warkany are comparable but
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somewhat higher. What is most important for the neurologist is the fact that the nervous system is involved in most of infants with major malformations. Indeed, approximately 40 percent of deaths during the first postnatal year are in some manner related to prenatal malformations of the central nervous system. Certain principles are applicable to the entire group of developmental brain disorders. First, as just noted, the abnormality of the nervous system is frequently accompanied by an abnormality of some other structure or organ (eye, nose, cranium, spine, ear, and heart), which relates them chronologically to a certain period of embryogenesis. Conversely, the presence of these malformations of nonnervous tissues suggests that an associated abnormality of the nervous system is developmental in nature. The conjunction of cardiac, limb, gut, and bladder abnormalities with neurologic disorder indicates the time at which the insult takes place: cardiac abnormalities occur between the fifth and sixth week; extroversion of the bladder at less than 30 days; duodenal atresia, before 30 days; syndactyly, before 6 weeks; meningomyelocele, before 28 days; anencephaly, before 28 days; cleft lip, before 36 days; syndactyly, cyclopia, and holoprosencephaly, before 23 days. Each is discussed in this chapter. This principle is not inviolable; in certain maldevelopments of the brain that must have originated in the embryonal period, all other organs are normal. One can only assume that the brain was more vulnerable than any other organ to prenatal as well as natal influences. Perhaps this occurs because the nervous system, of all organ systems, requires the longest time for its development and maturation, during which it is susceptible to disease. Second, a maldevelopment of whatever cause should be present at birth and remain stable thereafter, i.e., be nonprogressive, in contrast to the majority of metabolic diseases of infancy discussed in the preceding chapter. Again, this principle requires qualification: The abnormality may have affected parts of the brain that are not functional at birth, so that an interval of time must elapse postnatally before the defect can express itself. Third, for an abnormality to be characterized as truly developmental, birth should have been nontraumatic and the pregnancy uncomplicated by infection or other injurious event. Furthermore, the occurrence of a traumatic birth is not proof of a causative relationship between the injury (or infection) and the abnormality because a defective nervous sys-
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tem may itself interfere with the birth or the gestational process. Fourth, if the congenital abnormality has occurred in other members of the family of the same or previous generations, it is usually genetic, although, as noted above, this does not exclude the possible adverse effects of exogenous agents. Fifth, many of the teratologic conditions that cause birth defects pass unrecognized because they end in spontaneous abortions. For example, defects caused by chromosomal abnormalities occur in approximately 0.6 percent of live births, but such defects are found in more than 5 percent of spontaneous abortuses at 5 to 12 weeks gestational age. Finally, low birth weight and gestational age, indicative of premature birth, increase the risk of mental subnormality, seizures, cerebral palsy, and death. Regarding etiology, which is really the crux of the problem of birth defects, some semblance of order and a general classification have emerged. Malformations may be subdivided into four groups: (1) one in which a single mutant gene is responsible (2.25 per 1,000 live births); (2) those in which birth defects are associated with chromosomal aberrations (duplication, breakage); (3) a group comprising defects attributable solely to exogenous factors such as a virus or other infectious agent, irradiation, or toxin; and (4) the largest group of all, at least half of cases, in which no cause can be identified. It has been stated that true malformations are caused by fundamental endogenous disturbances of cytogenesis and histogenesis occurring in the first half of gestation and that exogenous factors, which destroy brain tissue but do not cause malformations, operate in the second half. The fallacy of this division is obvious. An exogenous lesion
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occurring during the embryonal period may not only destroy tissue but also derail the neuronal migrations of normal development. A textbook on principles of neurology cannot catalog all the hereditary and congenital developmental abnormalities that affect the nervous system. For such details, the interested reader should refer to several excellent monographs. Three that the authors consult are Brett’s Pediatric Neurology, Berg’s Principles of Child Neurology, and Lyon and Evrard’s Neuropediatrie. These are supplemented by special atlases of congenital malformations mentioned further on. In this chapter, we sketch only the major groups and discuss in detail a few of the more common entities. The classification in Table 38-1 adheres to a grouping in accordance with the main presenting abnormality. Represented here are the common problems that lead families to seek consultation with the pediatric neurologist: (1) structural defects of the cranium, spine, and limbs, and of eyes, nose, ears, jaws, and skin; (2) disturbed motor function, taking the form of retarded development or abnormal movements; (3) epilepsy; and (4) mental retardation. The following discussion focuses on each of these clinical states.
NEUROLOGIC DISORDERS ASSOCIATED WITH CRANIOSPINAL DEFORMITIES A majority of the disorders in this group are to the result of a genetic error, including those with a specific chromosomal abnormality. One has only to walk through an insti-
Table 38-1 CLASSIFICATION OF CONGENITAL NEUROLOGIC DISORDERS I. Neurologic disorders associated with craniospinal deformities A. Enlarged head (see also Table 38-2) 1. Hydrocephalus 2. Hydranencephaly 3. Macrocephaly B. Craniostenoses 1. Turricephaly 2. Scaphocephaly 3. Brachycephaly C. Disturbances of neuronal formation and migration 1. Anencephaly 2. Lissencephaly, holoprosencephaly, and gyral malformations D. Microcephaly 1. Primary (vera) 2. Secondary to cerebral disease E. Combinations of cerebral, cranial, and other anomalies 1. Syndactylic craniocerebral anomalies 2. Other craniofacial anomalies 3. Oculoencephalic defects 4. Oculoauriculocephalic anomalies 5. Dwarfism 6. Dermatocephalic anomalies F. Rachischisis 1. Cephalic and spinal meningocele, meningoencephalocele, Dandy-Walker syndrome, meningomyelocele 2. Chiari malformation 3. Platybasia and cervical-spinal anomalies (Chap. 45) G. Chromosomal abnormalities
II. The phakomatoses (see Table 38-4) A. Tuberous sclerosis B. Neurofibromatosis C. Cutaneous angiomatosis with central nervous system abnormalities III. Restricted developmental abnormalities of the nervous system A. Focal cortical dysgenesis B. Möbius syndrome C. Congenital apraxia of gaze D. Other restricted congenital abnormalities (Horner syndrome, unilateral ptosis, anisocoria, etc.) IV. Congenital abnormalities of motor function (cerebral palsy) A. Subependymal (matrix) hemorrhage B. Cerebral spastic diplegia C. Infantile hemiplegia, double hemiplegia, and quadriplegia D. Congenital extrapyramidal disorders (double athetosis; erythroblastosis fetalis and kernicterus) E. Congenital ataxias F. The flaccid paralyses V. Prenatal and paranatal infections A. Rubella B. Cytomegalic inclusion disease C. Congenital neurosyphilis D. HIV infection and AIDS E. Toxoplasmosis F. Other viral and bacterial infections VI. Epilepsies of infancy and childhood VII. Mental retardation
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tution for the mentally retarded to appreciate the remarkable number and diversity of dysmorphisms that attend abnormalities of the nervous system. Smith, in the third edition of his monograph on the patterns of human malformations, listed 345 distinctive syndromes; in the fourth edition (edited by K.L. Jones [1988]), many new ones were added. Indeed, a normal-appearing and severely retarded individual stands out in such a crowd and will frequently be found to have an inherited metabolic defect or birth injury. The intimate relationship between the growth and development of the cranium and that of the brain is likely responsible for many of the associations in maldevelopment. In embryonic life the most rapidly growing parts of the neural tube induce unique changes in, and at the same time are influenced by, the overlying mesoderm (a process termed induction); hence abnormalities in the formation of skull, orbits, nose, and spine are regularly associated with anomalies of the brain and spinal cord. During early fetal life the cranial bones and vertebral arches enclose and protect the developing brain and spinal cord. Throughout the period of rapid brain growth, as pressure is exerted on the inner table of the skull, the latter accommodates to the increasing size of the brain. This adaptation is facilitated by the membranous fontanels, which remain open until maximal brain growth has been attained; only then do they ossify (close). In addition, stature is apparently controlled by the nervous system, as shown by the fact that a majority of mentally retarded individuals are also stunted physically to a varying degree. Thus disorders of craniovertebral development assume importance not merely because of the physical disfigurement but also because they often reflect an abnormality of the underlying brain and spinal cord, whereby they become the main diagnostic signs of the maldevelopment.
Cranial Malformations at Birth and in Early Infancy Certain alterations in size and shape of the head in the infant, child, or even the adult, always signify a pathologic process that affected the brain before birth or in early infancy. Because the size of the cranium reflects the size of the brain, the tape measure is one of the most useful tools in pediatric neurology—no examination in a neurologically affected child is complete without a measurement of the circumference of the head. Graphs of head circumference in males and females from birth to 18 years of age were compiled by Nellhaus and are commonly used by pediatricians. A newborn whose head circumference is below the third percentile for age and sex and whose fontanels are closed may be judged to have a developmental abnormality of the brain. A head that is normal in size at term but fails to keep pace with body length (microcephaly) reflects a later failure of growth and maturation of the cerebral hemispheres (microencephaly).
Enlargement of the Head (Macrocephaly) This can be caused by factors extrinsic to the brain tissue, such as hydrocephalus and hydrancephaly (as defined below), or excessive brain growth (megalo- or macroenceph-
aly; Table 38-2). The hydrocephalic head is distinguished by several features: frontal protuberance, or bossing; a tendency for the eyes to turn down so that the sclerae are visible between the upper eyelids and iris (sunset sign); thinning of the scalp and prominence of scalp veins; separation of the cranial sutures; and a “cracked pot” sound on percussion of the skull. Infantile hydrocephalus usually comes to medical attention because of an expanding cranium that exceeds normal dimensions for age. The usual causes are type II Chiari malformation, hereditary aqueductal stenosis, and prenatal infections, e.g., toxoplasmosis. These disorders are discussed further on. Hydranencephaly, defined as hydrocephalus and destruction or failure of development of parts of the cerebrum, is often associated with enlargement of the skull. When the cranium is transilluminated with a strong flashlight in a darkened room, the fluid-filled region of the cranium glows like a jack-o’-lantern. It can be caused by cerebral infarction from intrauterine vascular occlusion or by diseases such as toxoplasmosis and cytomegalovirus (CMV) disease, which destroy parts of each cerebral hemisphere. The lack of brain tissue reduces resistance to intraventricular pressure, permitting great enlargement of both lateral ventricles; it is especially marked if there is an added hydrocephalic state because of interference with cerebrospinal fluid circulation. This type of destruction of the cerebral mantle in the embryonal period may lead to the formation of huge brain defects with apposition of ventricular and pial surfaces (porencephaly) and subsequent failure of development of that part of the brain. Yakovlev and Wadsworth referred to the localized failure of evagination as schizencephaly and postulated that it was the result of a focal developmental defect in the wall of the cerebral mantle. They based their interpretation on the finding of malformed cortex in the margins of the defect but this might indicate only that the lesion preceded neuronal migration. Levine and coworkers attributed it to a destructive, possibly ischemic, lesion occurring in the first few weeks of gestation, at a time when neuronal migration was incomplete. However, at least some forms have been traced to genetic defects as detailed further on. The macrocephalic head (a large head with normal or only slightly enlarged ventricles) may be indicative of an advancing metabolic disease that enlarges the brain, as in Alexander disease, Canavan spongy degeneration of infancy, and later phases of Tay-Sachs disease, all of which are described in Chap. 37. Agenesis of the corpus callosum, a common congeni-
Table 38-2 CAUSES OF MACROCEPHALY 1. Hydrocephalus 2. Hydranencephaly 3. Macroencephaly (enlarged brain) a. Alexander disease b. Canavan disease c. Tay-Sachs disease 4. Agenesis of corpus callosum 5. Subdural hematoma 6. Constitutional (familial) macrocephaly 7. Hemimegalencephaly
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tal defect, may be associated with macrocephaly and varying degrees of mental impairment, optic defects, and seizures. In a series of 56 patients with agenesis of the corpus callosum, Taylor and David reported the presence of epilepsy in 32 and varying degrees of mental retardation in 28; only 9 had no recognizable neurologic defects. Also noted was a high incidence of psychiatric disturbances in these patients. In such cases, CT and MRI reveal the characteristic “bat-wing” deformity of the ventricles. There is also asynchrony of electrical activity of the two cerebral hemispheres on the electroencephalogram (EEG). In a few of these patients, an autosomal dominant inheritance was found (Lynn et al). Agenesis of the corpus callosum is also part of the Aicardi syndrome (see further on) and the Andermann syndrome, and it has been noted, without explanation, in some cases of nonketotic hyperglycinemia. Subdural hematomas also enlarge the child’s head and cause bulging of the fontanels and separation of the sutures. The infant is usually irritable and listless, taking nourishment poorly. Infants and children with neurofibromatosis, osteogenesis imperfecta, and achondroplasia also have enlarged heads; in the last of these, some degree of hydrocephalus appears to be responsible. Ultrasonography, which can be performed in the prenatal and neonatal periods, is usually diagnostic in all these cranial enlargements. Also MRI and CT scanning will disclose the size of the ventricles and the presence of subdural blood or fluid (hygroma). Apart from patients with these pathologic states, there are individuals whose heads and brains are enlarged but who are normal in all other respects. Many of them come from families with large heads. Schreier and colleagues, who traced this condition through three generations of several families, declared it to be an autosomal dominant trait. This group represented 20 percent of 557 children referred to a clinic because of cranial enlargement, according to Lorber and Priestley. Hemimegalencephaly This term refers to a marked enlargement of one cerebral hemisphere as a result of a developmental abnormality. The cortical gray matter and sometimes the basal ganglia are greatly increased in volume and weight. The cerebellum, brainstem, and spinal cord retain their normal dimensions. The cranium may be misshapen or enlarged but is normal in size in some cases. Rarely, the face and body are enlarged on the side of the enlarged hemisphere. The cortex of the giant hemisphere is thick and disorganized. Neurons are in disarray and some are enlarged; in some places the natural lamination of the cortex is effaced. Nothing is known about causation, but clearly embryogenesis has been deranged at the stage of neuroblast formation. Clinically, these individuals are mentally retarded and some have epilepsy. A degree of hemiparesis may be present but severe hemispheral neurologic deficits are generally not reported. However, hemimegalencephaly has been discovered at autopsy in a few individuals who had no mental or neurologic deficits.
Craniostenoses Some of the most startling cranial deformities are caused by premature closure of the cranial sutures (membranous junc-
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tions between bones of the skull). Such conditions are estimated to occur in 1 of every 1,000 births, with predominance in males (Lyon and Evrard). The growth of the cranium is inhibited in a direction perpendicular to the involved suture(s), creating a compensatory enlargement in other dimensions as allowed by the patent sutures. For example, when the lambdoid and coronal sutures are both affected, the thrust of the growing brain enlarges the head in a vertical direction (tower skull, or oxycephaly, also referred to as turricephaly and acrocephaly). The orbits are shallow, the eyes bulge, and skull films show islands of bone thinning (lückenschädel). When only the sagittal suture is involved, the head is long and narrow (scaphocephalic) and the closed suture projects, keel-like, in the midline. With premature closure of the coronal suture, the head is excessively wide and short (brachycephalic). The nervous system is usually normal in these restricted craniostenoses. If this condition is recognized before 3 months of age, the surgeon can make artificial sutures that may permit the shape of the head to become more normal (Shillito and Matson). Once brain growth has been completed, little can be done aside from complex reconstructive surgery. When several sutures (usually coronal and sagittal) are closed, so as to diminish the cranial capacity, intracranial pressure may increase, causing headache, vomiting, and papilledema. An operation is then needed to increase the capacity of the skull. In acrocephalosyndactyly, or Apert syndrome, craniostenoses are combined with syndactyly (fused, or webbed, fingers or toes). There are often added complications: mental retardation, deafness, convulsions, and loss of sight secondary to papilledema. The so-called clover-shaped skull is the most severe and lethal of the craniostenoses because of the associated developmental anomalies of the brain (see further on). Approximately one-quarter of affected children with craniostenoses will be found to have a single gene or chromosomal adnormality, most commonly in the FGFR3 gene. When, for any reason, an infant lies with the head turned constantly to one side (because of a shortened sternomastoid muscle or hemianopia, for example), the occiput on that side, over time, becomes flattened, as does the opposite frontal bone. The other occipital and frontal bones bulge, so that the maximum length of the skull is not in the sagittal but in the diagonal plane. This condition is called plagiocephaly, or wry head. Craniostenosis of one-half of a coronal suture may also distort the skull in this way.
Disturbances of Neuronal Migration and Cortical Development Neuroembryologic studies have identified several milestones of neuroblast formation, migration, cortical organization, neuron differentiation, and connectivity. Certain developmental anomalies can be traced to one of these stages of cytogenesis and histogenesis in the first trimester of gestation and to the growth and differentiation that take place in the second and third trimesters. During the first trimester, postmitotic neurons that will ultimately reside in the cortex arise in the ventricular zone adjacent to the ventricles. They migrate along the scaffold of radial glia to form the multilayered cortex. It is interesting that
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neurons moving up the scaffold must pass through neurons that are already in position in the cortex, leading to an “inside-out” lamination in which the most recently born and arrived neurons reside on the outermost surface of the forming cortex. Originally there is an excess of neurons, many of which degenerate during development—a process properly called apoptosis. There are recorded instances in which the full complement of neuroblasts and neurons fails to be generated. In the extreme, the emergence of two separate cerebral hemispheres may not occur (holoprosencephaly), or the bihemispheric brain may remain small (microcephaly). In other described instances, a diminished number of neurons is less obvious than their failure to migrate to the cortical surface; they remain scattered through the mantle zone in sheets and heterotopic aggregates. One type of focal band-shaped subcortical heterotopia is termed “double cortex.” Micropolygyria refers to an excessive number of abnormally small gyri. It is expressed by a syndrome of mental retardation, seizures, delayed speech, and motor abnormalities. The cortex may fail to become sulcated—i.e., it is lissencephalic or may be defectively convoluted, forming microgyric and pachygyric (broad gyral) patterns. In yet other brains, neuronal migration is normal for the most part, but small groups of neurons in particular regions may lag or present in regional heterotopias (focal dysgeneses; Fig. 38-1). These migrational disorders, particularly heterotopias, are now being recognized more often by MRI and are found to have a functional significance in epilepsy but also possibly in such states as mental retardation, and dyslexia. Finally, the cortex may be normally formed and structured but there is a failure of differentiation of intra- and intercortical and interhemispheral connections, the most obvious one being agenesis of the corpus callosum. The timing of embryogenesis of the main visceral organs and of the coincident stages of neural tube closure were given in the introduction. With these elementary facts of neuroembryology in mind, the bases of the following clinical states are readily conceptualized: anencephaly, lissencephaly, holoprosencephaly, polymicrogyria and pachygyria, microcephaly, and special combinations of cranial and somatic abnormalities. Each is described below. In regard to disorders of brain development, there are also special types of tumors that are the consequence of abnormal neuronal or glial development. These are variously termed gangliomas, or gangliocytomas, dysembryoplastic neuroepitheliomas (DNETs), and low-grade astrocytomas. Sometimes they become manifest in the first year of life or even before birth. Their relatively slow growth and benign character suggest that some of them represent hamartomas rather than true neoplasms (see Chap. 31). Among the ones we have encountered in adults is the Lhermitte-Duclos type of cerebellar gangliocytoma that is characterized by a “tigroid” appearance on MRI (see Fig. 31-15). Genetics of Cerebral Disorders of Neuronal Migration (Table 38-3) Because each phase of cerebral development is under genetic control, it comes as no surprise that aberrant development might have a genetic basis. A singular advance in this field has been the identification in recent years of large numbers of genetic defects that underlie disorders of neuronal migration. These mutations, and what are known of their effects on the developing nervous system, were reviewed
Figure 38-1. MRI in the coronal plane in an infant with seizures. Deep in the white matter, adjacent to the lateral ventricle, is a large heterotopic aggregate of gray matter. Also, there appears to be an increased infolding of the cerebral cortex (polymicrogyria).
extensively by Mochida and Walsh, by Kato and Dobyn, and by Barkovich and colleagues; a summary is given in Table 38-3. The reader will notice that several quite different mutations may give rise to the same type of maldevelopment and that any given gene can cause malformations of varying severity but in most cases, the affected gene is active at a stage in brain development that makes the nature of the malformation understandable. It should at the same time be noted that metabolic disturbances may also give rise to malformations of cerebral development. For example, in their review of the inborn errors of metabolism that are linked to cerebral dysgeneses. Nissenkorn and colleagues point out that disorders such as Zellweger syndrome and disorders of fatty oxidation, phenylketonuria (PKU), hyperglycinemia, and pyruvate dehydrogenase deficiency cause aberrant neuronal migration and dysgenesis of the corpus callosum.
Anencephaly This is one of the most frequent and also most appalling congenital malformations of the brain. Its incidence is 0.1 to 0.7 per all 1,000 births and females predominate in ratios ranging between 3:1 and 7:1 in different series. The concordance rate is low, both in identical and fraternal twins, but the incidence of the malformation is, nonetheless, several times the expected rate if one child in the sibship has been affected. Anencephaly has also been more frequent in certain geographic areas, e.g., Ireland, for which various explanations of population genetics or environmental exposure have been postulated. Missing in cases of anencephaly are large portions of scalp, cranial bones, and brain, including both cerebral cortex and white matter. All that remains is a hemorrhagic nubbin of nerve, glial, and connective tissue. Brainstem, cerebellum, and spinal cord are present but often, they too
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Table 38-3 MUTATIONS ASSOCIATED WITH DISORDERS OF NEURONAL MIGRATION AND CORTICAL MALDEVELOPMENT DISEASE
Lissencephaly Lissencephaly with cerebellar hypoplasia Lissencephaly (Miller-Dieker) or isolated lissencephaly X-linked lissencephaly with hypogonadism (Partington syndrome) Muscle-eye-brain disease Walker-Warburg Holoprosencephaly Double cortex Double-cortex or X-linked lissencephaly Heterotopias Periventricular nodular heterotopia Tuberous sclerosis Tuberous sclerosis Fukuyama muscular dystrophy Schizencephaly Schizencephaly Microcephaly Microcephaly Microcephaly
are malformed, as are the heart and other organs (15 to 40 percent of cases). In anencephalics who survive for a few days (65 percent die in utero and almost 100 percent before the end of the first postnatal week), startle reactions may be observed, as well as movements of limbs, spontaneous respirations, pupillary light reactions, ocular movements, and corneal reflexes. In a few, avoidance reactions, crying, and feeding reflexes can be elicited, indicating that only the rudimentary brain structures are required for these functions. This condition, or a related one, can be anticipated if the mother’s serum levels of alpha-fetoprotein and acetylcholine esterase are elevated—even more reliably anticipated if they are elevated in the amniotic fluid. Positive tests should lead to ultrasonograph imaging of the fetus. Hydramnios is common. The causes of anencephaly are multiple and include chromosomal abnormalities, maternal hyperthermia, and, apparently, deficiencies of folate, zinc, and copper (see Medical Task Force on Anencephaly). Of these, there is fairly secure evidence that supplemental intake of folic acid during the first trimester of pregnancy (i.e., from the time of conception) reduces the incidence of anencephaly and of myelomeningocele. Additional comments on anencephaly are given further on in this chapter in the section on “Dysraphism, or Rachischisis” (lack of fusion of the neural tube).
Lissencephaly (Agyria), Holoprosencephaly, and Gyral Malformations Included under this heading are several forms of defects of cerebral sulcation. In the lissencephalies, cortical convolutions may be absent altogether and there is morphologic evidence of several types of neuroblast deficiency. Such cases are of particular interest to neonatologists because of their associated physical abnormalities. The degree of impairment of neurologic function seldom allows longevity, so that relatively few affected individuals are found in
GENE
GENE FUNCTION
RELN (reelin) LIS1 ARX (aristaless) POMGNT1 POMT1 SHH (sonic hedgehog)
Extracellular matrix protein Microtubule regulator Transcription factor Glycosyltransferase Glycosyltransferase Transcription factor
DCX (doublecortin)
Microtubule-associated protein
FLNA (filamin A) TSC1 (hamartin) TSC2 (tuberin) FCMD (fukutin)
Actin-binding protein Tumor suppressor Tumor suppressor Possible glycosyltransferase
EMX2
Transcription factor
MCPH1 (microcephalin) MCPH5 ASPM
? DNA repair Mitotic/meiotic spindle
institutions for the mentally retarded. Seizures, poor temperature regulation, failure to accept nourishment, and apneic attacks combine to shorten life. The failures of sulcation vary in severity. Neurons may fail to form or to migrate along glial projections to reach the more superficial layers of the cortex (a condition called in the past, Bielschowsky type); or the cortex, meninges, and eyes may fail to differentiate normally except for the dentate gyrus and hippocampus (Walker-Warburg type); or there may be other more minor focal derangements of cortical migrations and laminations with heterotopias of neurons in the white matter. In the complete lissencephalies, the lateral and third ventricles enlarge because of a lack of the normal quantities of surrounding cerebral tissue (i.e., the aforementioned hydranencephaly). The cerebellar cortex is also abnormal. In some lissencephalic brains, there is slight sulcation presenting as abnormally broad or narrow convolutions, with thick, poorly laminated cortex; these are called pachygyrias or microgyrias, respectively, but the fundamental migratory abnormality is basically the same. The cerebellum is also abnormal, usually showing hypoplasia or aplasia involving the vermis or neocerebellum. In the severe defects, the cranium is small at birth. In one type, which is inherited as an autosomal recessive trait, there are subtle craniofacial features (short nose, small mandible, ear abnormalities) as well as congenital heart disease. In another group, there is an associated familial congenital muscular dystrophy, placing the case between the Fukuyama and Walker-Warburg syndromes (see “Congenital Muscular Dystrophy” in Chapter 50). Alobar and lobar holoprosencephalies are other examples of sulcation defects with craniofacial abnormalities in which development has gone awry in the fifth and sixth weeks of gestation (see Volpe, 1995). In these subtypes, the two cerebral hemispheres, either totally or only in part, form as a single telencephalic mass. In nearly all cases the cerebral defect is reflected by a single eye (cyclopia) and
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the absence of the nose, imparting an astonishing and diagnostic appearance. Most of the severe disorders are sporadic, and the infants seldom survive for long. In a few of the malformations, a congenital infection with CMV or rubella has been implicated (Hayward et al). The Dandy-Walker syndrome represents a more restricted form of migration and neural tube defect. There is vermian hypoplasia with or without hydrocephalus and, in some cases, an added agenesis of the corpus callosum with cerebral cortical dysgeneses (Landrieu). This defect, which is identified by the cystic enlargement of the fourth ventricle, is discussed further on, with the dysraphic neural tube defects. That some instances of lissencephaly have a genetic basis has already been mentioned (see Table 38-3). Two genes that modify microtubular function have been identified: LIS1 and “doublecortin” or DCX. Large chromosomal deletions that span LIS1 cause Miller-Dieker syndrome, in which lissencephaly is associated with distinctive facial abnormalities; small defects in the same gene cause only lissencephaly. Lissencephaly with cerebellar hypoplasia is caused by mutations in the human “reelin” gene (RELN), the analogue of the defective gene in reelin mice (which have a reeling gait and abnormal cortical neuronal lamination). Defects in the transcription factor ARX are associated with X-linked lissencephaly, agenesis of the corpus callosum, and hypogonadism. Periventricular nodular heterotopia is caused by another gene defect, filamin A gene on the X chromosome. Some cases of holoprosencephaly have been traced to mutations in the sonic hedgehog gene.
Microcephaly In most of the above-described cerebral dysplasias, the cranium and brain are small, but there is also a primary form of hereditary microcephaly, called microcephaly vera, in which the head is astonishingly reduced in size (circumference less than 45 cm in adult life—i.e., 5 standard deviations below the mean). In contrast, the face is of normal size, the forehead is narrow and recedes sharply, and the occiput is flat. The brain often weighs less than 300 g (normal adult range: 1,100 to 1,500 g) and shows only a few primary and secondary sulci. The cerebral cortex is thick and unlaminated and grossly deficient in neurons. A few cases have an associated cerebellar hypoplasia or an infantile muscular atrophy. Stature is usually moderately reduced. Such individuals can be recognized at birth by their anthropoid appearance and later by their lumbering gait, extremely low intelligence, and lack of communicative speech. Vision, hearing, and cutaneous sensation are spared. In one of the cases studied by our colleagues, laborious effort using operant conditioning made it possible to teach the patient the shapes of simple figures. (His sister’s brain, examined by R.D. Adams, was malformed and weighed only 280 g.) Skull films show that the cranial sutures are present, as are convolutional markings on the inner table. Lesser degrees of microencephaly have been associated with progressive motor neuron disease and degeneration of the substantia nigra (Halperin et al). Evrard and associates have described another rare type of microcephaly, which they call “radial microbrain.” The sulcal pattern is normal, and neuronal arrangements in the cerebral cortex are nor-
mal as well. The defect appears to be in the small number of neurons that are generated, not in their migration.
Disorders of the Pial Surface This category of maldevelopment is characterized by inappropriate migration of neurons to the pial surface, leading to a nodularity of the surface described as a cobblestone appearance. In the three disorders with this pathologic finding, the clinical picture is one of mental retardation conjoined with congenital muscular dystrophy. Three identified gene defects are thought to alter the glycosylation of critical proteins in the brain and in skeletal muscle. These genes include the gene fukutin in Fukuyama muscular dystrophy (see “Congenital Muscular Dystrophy” in Chap. 50), the POMGNT1 gene in muscle-eye-brain disease, and the POMT1 gene in Walker-Warburg syndrome, as summarized in Table 38-3.
Combined Cerebral, Cranial, and Somatic Abnormalities There are so many cerebrosomatic anomalies that one can hardly retain visual images of them, much less recall all the physicians’ names by which they are known. There is great advantage in grouping these anomalies according to whether the extremities, face, eyes, ears, and skin are associated with a cerebral defect. The sheer number and variety of these anomalies permit only an enumeration of the more common ones and their most obvious physical characteristics. Unfortunately, apart from certain genetic linkages, no useful leads as to their origin have been forthcoming. Of necessity, one turns to atlases, one of the most thorough of which was compiled by Holmes and colleagues and is based on clinical material drawn in large part from the Fernald School and Eunice K. Shriver Center in Massachusetts. The reader may also turn to the texts by Gorlin and colleagues and by Jones for specific information. The older Ford’s Diseases of the Nervous System in Infancy, Childhood, and Adolescence is still a valuable reference, as is Jablonski’s Dictionary of Syndromes and Eponymic Diseases.
The Syndactylic–Craniocerebral Anomalies (Acrocephalosyndactyly) Fusion of two fingers or two toes or the presence of a tab of skin representing an extra digit may be seen at birth in an otherwise normal individual. However, when syndactylism is more severe and is accompanied by premature closure of cranial sutures, the nervous system usually proves to be abnormal as well. The general term acrocephalosyndactyly is used to describe the several combinations of craniostenotic and facial deformities and fusion of digits. Several of these disorders are a consequence of mutations in genes encoding one of two fibroblast growth factors or proteins related to them. The following descriptions include only the major features; most have, in addition, distinctive malformations of the orbits, ears, and palate. 1. Acrocephalosyndactyly types I and II (typical and atypical Apert syndrome). Turribrachycephalic skull, syndactyly of hands and feet (“mitten hands,” “sock feet”), moderate to severe mental retardation.
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2. Acrocephalosyndactyly III (Saethre-Chotzen syndrome). Various types of craniostenoses, proximally fused and shortened digits, moderate degree of mental retardation. Transmission as an autosomal dominant trait. 3. Acrocephalosyndactyly IV (Pfeiffer syndrome). Turribrachycephaly; broad, enlarged thumbs and great toes; partially flexed elbows (radiohumeral or radioulnar synostoses); mild and variable mental retardation; autosomal dominant inheritance. 4. Acrocephalopolysyndactyly V (Carpenter syndrome). Premature fusion of all cranial sutures with acrocephaly, flat bridge of nose, medial canthi displaced laterally, excess digits and syndactyly, subnormal intelligence. 5. Acrocephalosyndactyly with absent digits. High, bitemporally flattened head; absent toes and syndactylic fingers; moderate mental retardation. 6. Acrocephaly with cleft lip and palate, radial aplasia, and absent digits. Microbrachycephaly because of craniostenosis, cleft lip and palate, absent radial bones, severe mental retardation. 7. Dyschondroplasia, facial anomalies, and polysyndactyly. Keel-shaped skull and ridge through center of forehead (metopic suture), short arms and legs, postaxial polydactyly and short digits, moderate mental retardation. In all the foregoing types of syndactylism and cranial abnormalities, which may be regarded as variants of a common syndrome, the diagnosis can be made at a glance because of the deformed head, protuberant eyes, and abnormal hands and feet. The degree of mental retardation proves to be variable, usually moderate to severe, but occasionally intelligence is normal or nearly so. The brain has been examined in only a few instances and not in a fashion to display fully the type and extent of this developmental abnormality.
Other Craniocephalic–Skeletal Anomalies Members of this group have distinctive anomalies of the cranium, face, and other parts, but craniostenosis is not a consistent feature. 1. Craniofacial dysostosis (Crouzon syndrome). Variable degrees of craniosynostosis; broad forehead with prominence in the region of the anterior fontanel region; shallow orbits with proptosis; midline facial hypoplasia and short upper lip; malformed auditory canals and ears; high, narrow palate; moderate mental retardation. As noted above, a genetic defect in one of the fibroblast growth factor receptors is responsible for about one-third of cases that are not associated with other deformities (Moloney et al). Autosomal dominant inheritance is seen in most cases. 2. Median cleft facial syndrome (frontonasal dysplasia; hypertelorism of Greig). Widely spaced eyes, broad nasal root, cleft nose and premaxilla, V-shaped frontal hairline, heterotypic anterior frontal fontanel (midline cranial defect); mild to severe mental retardation. 3. Chondrodystrophia calcificans congenita (chondrodysplasia punctata, Conradi-Hünermann syndrome). Prominent forehead; flat nose; widely separated eyes; short neck and trunk with kyphoscoliosis; dry, scaly, atrophic skin; cicatricial alopecia; irregularly deformed verte-
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bral bodies; mental retardation infrequent. Severe shortening of limbs is seen in some cases. 4. Orofaciodigital syndrome. All the patients are female; they have pseudoclefts involving the mandible, tongue, maxilla, and palate; hypertrophied buccal frenula; hamartomas of tongue; sparse scalp hair; subnormal intelligence in one-half of cases. 5. Pyknodysostosis. Large head and frontal-occipital bossing, underdeveloped facial bones, micrognathia, unerupted and deformed teeth, dense and defective long bones with shortened limbs, short and broad terminal digits of fingers and toes, mental retardation in one-quarter of the cases. 6. Craniotubular bone dysplasias and hyperostoses. Included under this title are several different genetic disorders of bone, characterized by modeling errors of tubular and cranial bones. Frontal and occipital hyperostosis, overgrowth of facial bones, and widening of long bones occur in various combinations. Hypertelorism, broad nasal root, nasal obstruction, seizures, visual failure, deafness, prognathism, and retardation of growth are the major features.
Oculoencephalic (Cranio-Ocular) Defects In this category of anomalies, there is simultaneous failure or imperfect development of eye and brain. One member of this group, the oculocerebrorenal syndrome of Lowe, has already been mentioned and, of course, many of the mucopolysaccharidoses are characterized by corneal opacities, skeletal changes, and psychomotor regression as considered separately in Chap. 37. Also, congenital syphilis, rubella, toxoplasmosis, and CMV inclusion disease may affect retina and brain; hypoxia at birth requiring treatment with oxygen may injure the brain and lead to retrolental fibrodysplasia. The true developmental defects in this group are as follows: 1. Anophthalmia with mental retardation. Sex-linked recessive. Absent eyes; orbits and maxillae remain underdeveloped, but adnexal tissues of eyes (lids) are intact; subnormal intelligence. Some cases of anophthalmia have been ascribed to genes encoding transcription factors that play a role in the development of the neuraxis (SOX2, RAX, RAX6). 2. Norrie disease. Also sex-linked recessive; some sight may be present at birth; later, eyes become shrunken and recessed (phthisis bulbi); some have short digits, outbursts of anger, hallucinations, and possibly regression of psychomotor function. A novel gene, norrin, on the X chromosome has been implicated. 3. Oculocerebral syndrome with hypopigmentation. Autosomal recessive with absence of pigment of hair and skin; small, cloudy, vascularized corneas and small globes (microphthalmia); marked mental retardation; athetotic movements of limbs. 4. Microphthalmia with corneal opacities, eccentric pupils, spasticity, and severe mental retardation. 5. Aicardi syndrome with ocular abnormality. Chorioretinopathy, retinal lacunae, staphyloma, coloboma of optic nerve, microphthalmos, mental retardation, infantile spasms and other forms of epilepsy, agenesis of corpus callosum, and cortical heterotopias. The “batwing”
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deformity of the third and lateral ventricles on MR images and asynchronous burst-suppression discharges and sleep spindles are diagnostic. The condition is found only in females. 6. Lissencephaly of the Walker-Warburg type. This anomaly has already been mentioned, as has its association with congenital muscular dystrophy. Inheritance is autosomal recessive. Ocular lesions are a regular feature but of variable type (retinal dysplasia, microphthalmia, coloboma, cataracts, corneal opacities). There may be hydrocephalus, and CT scans and MRI disclose the lack of cerebral sulci (lissencephaly). The abnormal eyes and orbits and absence of cerebellar vermis are diagnostic (see Table 38-3). 7. Congenital tapetoretinal degeneration (Leber amaurosis). Visual loss from birth, moderate to severe mental retardation, and microcephaly. Early onset of blindness and absent electrical potentials on the electroretinogram (ERG) distinguish it from later-onset Leber optic atrophy, which is a mitochondrial disorder (Chaps. 13 and 37). 8. Septooptic dysplasia (de Morsier syndrome). Diminished visual acuity, small optic discs, absence of septum pellucidum, and precocious puberty. Varying degrees of pituitary insufficiency may be present, requiring endocrine replacement.
2.
3.
Oculoauriculocephalic Anomalies These are less important from the neurologic standpoint, and mental retardation is present only in some cases.
4.
1. Mandibulofacial dysostosis (Treacher-Collins syndrome, Franceschetti-Zwahlen-Klein syndrome) 2. Oculoauriculovertebral dysplasia (Goldenhar syndrome) 3. Oculomandibulodyscephaly with hypotrichosis (Hallermann-Streiff syndrome)
Dwarfism Midgets are abnormally small but perfectly formed people of normal intelligence; they differ from dwarfs, who are not only very small but whose bodily proportions are markedly abnormal and who may or may not be mentally normal. It should be commented that a majority of mentally retarded patients fall below average for height and weight, but there is a small group whose fully attained height is well below 135 cm (4.5 ft) and who stand apart by this quality alone (see Jones for Smith’s classification of dwarfs). The main types of dwarfism are as follows: 1. Nanocephalic dwarfism (Seckel bird-headed dwarfism). The uncomplimentary term bird head has been applied to individuals with a small head, large-appearing eyeballs, beaked nose, and underdeveloped chin. Such a physiognomy is not unique to any disease, but when combined with dwarfism it includes a few more or less specific syndromes. Up to 1976, approximately 25 cases had been reported, some with other skeletal and urogenital abnormalities, such as medial curvature of middle digits; occasional syndactyly of toes; dislocations of elbow, hip, and knee; premature closure of cranial sutures; and clubfoot deformity. These individuals are short at birth and remain so, living until adolescence or
5.
6.
adulthood. Retardation is severe. A recessive autosomal type of inheritance is probable. At autopsy the brain is found to have a simplified convolutional pattern; one of our patients had a type of myelin degeneration similar to that of Pelizaeus-Merzbacher disease. Russell-Silver syndrome. Possibly an autosomal dominant pattern of inheritance, with short stature of prenatal onset, craniofacial dysostosis, short arms, congenital hemihypertrophy (arm and leg on one side larger and longer), pseudohydrocephalic head (normal-sized cranium with small facial bones), abnormalities of genital development in one-third of cases, delay in closure of fontanels and in epiphyseal maturation, elevation of urinary gonadotropins. Some cases appear to be caused by a nonmutational modification of genes, which are nonetheless inherited (imprinting). Smith-Lemli-Opitz syndrome. Autosomal recessive inheritance with microcephaly, broad nasal tip and anteverted nares, wide-set eyes, epicanthal folds, ptosis, small chin, low-set ears, enlarged alveolar maxillary ridge, cutaneous syndactyly, hypospadias in boys, short stature, subnormal neonatal activity, and normal amino acids and serum immunoglobulins. Older survivors are bereft of language and are paraparetic, with increased reflexes and Babinski signs. The hips are usually dislocated. The karyotype is normal. The brain is small but has not been fully examined. Two of our patients are sibling girls. Rubinstein-Taybi syndrome. Microcephaly but no craniostenosis, downward palpebral slant, heavy eyebrows, beaked nose with nasal septum extending below alae nasi, mild retrognathia, “grimacing smile,” strabismus, cataracts, obstruction of nasolacrimal canals, broad thumbs and toes, clinodactyly, overlapping digits, excessive hair growth, hypotonia, lax ligaments, stiff gait, seizures, hyperactive tendon reflexes, absence of corpus callosum, mental retardation, and short stature. This dominantly inherited disease is a result of disruption of so-called CREB-binding protein, a nuclear protein necessary for gene expression that is modulated by cyclic adenosine monophosphate (cAMP). Pierre Robin syndrome. Possible autosomal recessive pattern of inheritance with microcephaly but no craniostenosis, small and symmetrically receded chin, glossoptosis (tongue falls back into pharynx), cleft palate, flat bridge of nose, low-set ears, mental deficiency, and congenital heart disease in half the cases. Camptomelia (bent bones) and diastrophic dwarfism (short limbs) are common. DeLange syndrome (Cornelia DeLange syndrome). This phenotype shows some degree of variability but the essential diagnostic features are intrauterine growth retardation and stature falling below the third percentile at all ages, microbrachycephaly, generalized hirsutism and synophrys (eyebrows that meet across the midline), anteverted nostrils, long upper lip, and skeletal abnormalities (flexion of elbows, webbing of second and third toes, clinodactyly of fifth fingers, transverse palmar crease). All are moderately or, more often, severely retarded mentally, which, with the above craniofacial abnormalities, is diagnostic. It has been said, and it has been our experience, that many
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of these patients are prone to have a bad disposition, manifested by biting and spitting. There are no chromosomal abnormalities. A polygenic inheritance has been postulated, but most cases are sporadic. 7. Smith-Magenis syndrome. This is caused by deletions on chromosome 17, in which there is learning disability, severe behavioral problems (violence and self-injury), hyperactivity, deafness, and ocular abnormalities.
Neurocutaneous Anomalies with Mental Retardation It is not surprising that skin and nervous system should share in pathologic states that impair development, as both have a common ectodermal derivation. Nevertheless, it is difficult to find a common theme in the diseases that affect both organs. In some instances, it is clear that ectoderm has been malformed from early intrauterine life; in others, a number of nondevelopmental acquired diseases of skin may have been superimposed. For reasons to be discussed later in this chapter, neurofibromatosis, tuberous sclerosis, and Sturge-Weber encephalofacial angiomatosis must be set apart in a special category of disease termed phakomatoses. Hemangiomas of the skin are without doubt the most frequent cutaneous abnormalities present at birth, and usually they are entirely innocent. Many recede in the first months of life. However, an extensive vascular nevus located in the territory of the trigeminal nerve—and sometimes in other parts of the body as well—causes permanent disfigurement and usually portends an associated and topographically underlying cerebral lesion (SturgeWeber syndrome). Other neurocutaneous diseases are summarized below. A more complete review of these diseases will be found in the article by Short and Adams in Fitzpatrick’s Dermatology and the 1987 monograph by Gomez. The importance of recognizing the cutaneous abnormalities relates to the fact that the nervous system is usually abnormal, and often the skin lesion appears before the neurologic symptoms are detectable. Thus the skin lesion becomes a predictor of potential neurologic involvement. Basal-cell nevus syndrome. This condition is transmitted as an autosomal dominant trait and is characterized by superficial pits in the palms and soles; multiple solid or cystic tumors over the head, face, and neck appearing in infancy or early childhood; mental retardation in some cases; frontoparietal bossing; hypertelorism; and kyphoscoliosis. Congenital ichthyosis, hypogonadism, and mental retardation. This disorder is inherited as a sex-linked recessive trait. Aside from the characteristic triad of anomalies, there are no special features. Xeroderma pigmentosum. The genetic pattern of inheritance is autosomal recessive. Skin lesions appear in infancy, taking the form of erythema, blistering, scaling, scarring, and pigmentation on exposure to sunlight; old lesions are telangiectatic and parchment-like, covered with fine scales; skin cancer may develop later; loss of eyelashes, dry bulbar conjunctivae; microcephaly, hypogonadism, and mental retardation (50 percent of cases). Kanda and associates classify this disease with what in the
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past had been called DeSanctis-Cacchione syndrome of “xerodermic idiocy” and believe the basic mechanism to be a faulty repair of DNA. They described two young adults with low intelligence, evidence of spinal cord degeneration, and peripheral neuropathy. The peripheral nerve lesions resembled those of amyloidosis, Riley-Day syndrome, and Fabry disease in that there was a predominant loss of small fibers. Other variants are described. Sjögren-Larsson syndrome. Autosomal recessive with congenital ichthyosiform erythroderma, normal or thin scalp hair, sometimes defective dental enamel, pigmentary degeneration of retinae, spastic legs, and mental retardation. Poikiloderma congenitale (Rothmund-Thompson syndrome). Autosomal recessive heredity; appearance of skin changes from the third to sixth months of life; diffuse pink coloration of cheeks spreading to ears and buttocks, later replaced by macular and reticular pattern of skin atrophy mixed with striae, telangiectasia, and pigmentation; sparse hair in half of the cases; cataracts; small genitalia; abnormal hands and feet; short stature; and mental retardation. Linear sebaceous nevus syndrome. Here there is a linear nevus of one side of face and trunk, lipodermoids on bulbar conjunctivae, vascularization of corneas, mental retardation, focal seizures, and spike and slow waves in the EEG. Genetics uncertain. Incontinentia pigmenti (Bloch-Sulzberger syndrome). Only females are affected; appearance of dermal lesions in first weeks of life; vesicles and bullae followed by hyperkeratoses and streaks of pigmentation, scarring of scalp, and alopecia; abnormalities of dentition; hemiparesis; quadriparesis; seizures; mental retardation; and up to 50 percent eosinophils in blood. The status of this disease is uncertain. Focal dermal hypoplasia. Also a disease limited to females. Areas of dermal hypoplasia with protrusions of subcutaneous fat, hypo- and hyperpigmentation, scoliosis, syndactyly in a few, short stature, thin body habitus. Intelligence is occasionally subnormal. Other rare entities are neurocutaneous melanosis, neuroectodermal melanolysosomal disease with mental retardation, progeria, Cockayne syndrome, and ataxia-telangiectasia (see Chap. 37; also Gomez, 1987).
Dysraphism, or Rachischisis: Meningocele, Encephaloceles, and Spina Bifida Included under this heading is the large number of disorders of fusion of dorsal midline structures of the primitive neural tube, a process that takes place during the first 3 weeks of postconceptual life. Exogenous factors are presumed to be operative in most cases but there are genetic forms. The most extreme form is anencephaly, as described earlier; it is characterized by the absence of the entire cranium at birth, and the undeveloped brain lies in the base of the skull, a small vascular mass without recognizable nervous structures. An eventration of brain tissue and its coverings through an unfused midline defect in the skull is called an encephalocele. Frontal encephaloceles may deform the forehead or remain occult. Associated defects of the frontal cortex, anterior corpus callosum, and optic-hypothalamic structures, as well as cerebrospinal fluid (CSF) leakage into
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frontal or ethmoid sinuses, pose a risk of meningitis. Some of these children are relatively normal mentally. Far more severe are the posterior encephaloceles, some of which are enormous and are attended by grave neurologic deficits such as blindness, ataxia, and mental retardation. However, lesser degrees of the defect are well known and may be small or hidden, such as a meningoencephalocele connected with the rest of the brain through a small opening in the skull. Small nasal encephaloceles may cause no neurologic signs, but if they are mistaken for nasal polyps and snipped off, CSF fistulae result. A failure of development of the midline portion of the cerebellum referred to earlier, forms the basis of the Dandy-Walker syndrome (Fig. 38-2). A cyst-like structure, representing the greatly dilated fourth ventricle, expands in the midline, causing the occipital bone to bulge posteriorly and displace the tentorium and torcula upward. In addition, the cerebellar vermis is aplastic, the corpus callosum may be deficient or absent, and there is dilatation of the aqueduct as well as the third and lateral ventricles. Even more frequent are abnormalities of closure of the vertebral arches. These take the form of a spina bifida occulta, meningocele, and meningomyelocele of the lumbosacral or other regions. In spina bifida occulta, the cord remains inside the canal and there is no external sac, although a subcutaneous lipoma or a dimple or wisp of hair on the overlying skin may mark the site of the lesion. In meningocele, there is a protrusion of only the dura and arachnoid through the defect in the vertebral
laminae, forming a cystic swelling usually in the lumbosacral region; the cord remains in the canal, however. In meningomyelocele, which is 10 times as frequent as meningocele, the cord (more often the cauda equina) is extruded also and is closely applied to the fundus of the cystic swelling. The incidence of spinal dysraphism (myeloschisis), like that of anencephaly, varies widely from one locale to another, and the disorder is more likely to occur in a second child if one child has already been affected (the incidence then rises from 1 per 1,000 to 40 to 50 per 1,000). Etiology Exogenous factors (e.g., potato blight in Ireland) were many times implicated in an increased rate of both myeloschisis and anencephaly, but the effects of starvation and vitamin deficiency could never be separated from the potential effect of a toxic factor. It has now been established by numerous case-control and randomized treatment trials that inadequate intake of folate in early pregnancy is associated with an increased risk of these malformations. Folic acid, given before the 28th day of pregnancy is protective; vitamin A may also have slight protective benefit. Similar associations have been found with less certainty with exposure during pregnancy to certain antiepileptic drugs, particularly valproic acid and carbamazepine. Maternal diabetes and possibly obesity have been risk factors in some epidemiologic studies, as summarized by Mitchell and colleagues. The greatest risk, however, almost 30-fold higher, attaches to a previous pregnancy affected with spina bifida in particular.
Figure 38-2. Dandy-Walker syndrome. MRI showing agenesis of the midline cerebellum and large midline cyst, representing the greatly dilated fourth ventricle, which occupies almost the entire posterior fossa. A. Axial view. B. Sagittal view.
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Diagnosis As with anencephaly, the diagnosis can often be inferred from the presence of alpha-fetoprotein in the amniotic fluid (sampled at 15 to 16 weeks of pregnancy) and the deformity confirmed by ultrasonography in utero. Blood contamination is a source of error in the fetoprotein test (Milunsky). Acetylcholinesterase immunoassay, done on amniotic fluid, is another reliable means of confirming the presence of neural tube defects. In the case of meningomyelocele, the child is born with a large externalized lumbosacral sac covered by delicate, weeping skin. The defect may have ruptured in utero or during birth, but more often the covering is intact. There is severe dysfunction of the cauda equina roots or conus medullaris contained in the sac. Stroking of the sac may elicit involuntary movements of the legs. As a rule the legs are motionless, urine dribbles, keeping the patient constantly wet, there is no response to pinprick over the lumbosacral dermatomal zones, and the tendon reflexes are absent. In contrast, craniocervical structures are normal unless a Chiari malformation is associated, as it often is (see further on). Differences are noted in the neurologic picture depending on the level of the lesion. If the lesion is entirely sacral, bladder and bowel sphincters are affected but legs escape; if lower lumbar and sacral, the buttocks, legs, and feet are more impaired than hip flexors and quadriceps; if upper lumbar, the feet and legs are sometimes spared and ankle reflexes retained, and there may be Babinski signs. The two common complications of these severe spinal defects are meningitis and progressive hydrocephalus from a Chiari malformation (see below). The subject of spina bifida and neural tube defects was reviewed by Botto and colleagues and by Mitchell and coworkers. Treatment Prevention by the administration of folate during pregnancy is obviously paramount. Opinions as to proper management of the established lesion vary considerably. Excision and closure of the coverings of the meningomyelocele in the first few days of life are advised if the objective is to prevent fatal meningitis. After a few weeks or months, as hydrocephalus reveals its presence by a rapid increase in head size and enlargement of the ventricles on the CT scan, a ventriculoperitoneal shunt is required. Less than 30 percent of such patients survive beyond 1 year and the long-term results of treating these patients have not been encouraging. Lorber and colleagues report that 80 to 90 percent of their surviving patients are mentally retarded to some degree and are paraplegic. The decision to undertake rather formidable surgical procedures is being questioned more frequently. Exceptionally, patients with meningomyelocele, and most of those with lumbar meningocele, are mentally normal.
Other Developmental Spinal Defects Including Tethered Cord The problems of meningomyelocele and its complications are so largely pediatric and surgical that the neurologist seldom becomes involved—except perhaps in the initial evaluation of the patient—in the treatment of meningeal infection, or in the case of shunt failure with decompensation of hydrocephalus. Of greater interest to the neurologist are a series of closely related abnormalities that produce symptoms for the first time in late childhood, adolescence,
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or even adult life. These include sinus tracts with recurrent meningeal infections, lumbosacral lipomas with low tethering of the spinal cord (“tethered cord”) causing an early childhood or delayed radicular or spinal cord syndrome; diastematomyelia, cysts, or tumors with spina bifida and a progressive myeloradiculopathy; and the Chiari malformation and syringomyelia that first present in adolescence or adult life. These abnormalities are described below. Another class of disorders involves an occult lumbosacral dysraphism that is not inherited but is a result of faulty development of the cell mass that lies caudal to the posterior neuropore (normally this undergoes closure by the twenty-eighth day of embryonic life). Occult spinal dysraphism of this type is also associated with meningoceles, lipomas, and sacrococcygeal teratomas. Another well-recognized anomaly is agenesis of the sacrum and sometimes the lower lumbar vertebrae (caudal regression syndrome). Interestingly, in 15 percent of such cases, the mother is diabetic (Lyon and Evrard). Here there is flaccid paralysis of legs, often with arthrogrypotic contractures and urinary incontinence. Sensory loss is less prominent, mental function develops normally, and there is no hydrocephalus. Sinus tracts in the lumbosacral or occipital regions are of importance, for they may be a source of bacterial meningitis at any age. They are often betrayed by a small dimple in the skin or by a tuft of hair along the posterior surface of the body in the midline. (The pilonidal sinus should not be included in this group.) The sinus tract may lead to a terminal myelocystocele and be associated with dermoid cysts or fibrolipomas in the central part of the tract. Cloacal defects (no abdominal wall and no partition between bladder and rectum) may be combined with anterior meningoceles. Evidence of sinus tracts should be sought in instances of unexplained meningitis, especially when there has been recurrent infection or the cultured organism is of nosocomial dermal origin. Of great interest are congenital cysts and tumors, particularly lipoma and dermoid, that arise in the filum terminale and attach (tether) the cord to the sacrum. Progressive symptoms and signs are produced as the spine elongates during development, thereby stretching the caudally fixed cord (Fig. 38-3). Some of these children have bladder and leg weakness soon after birth. Others deteriorate neurologically at a later age (generally between 2 and 16 years, sometimes later—see below). Complex disturbances of bladder function that produce urgency and incontinence beginning in the second or third decade may be the only manifestation, or the bladder symptoms may be combined with impotence (in the male) and numbness of the feet and legs or foot-drop (Pang and Wilberger). Several of our adult patients have had unusual visceral reflex reactions, such as involuntary defecation or priapism with stimulation of the abdomen or perineum. According to most surgeons, it is not the myelolipoma but the tethering of the cord that gives rise to symptoms; removal of the tumor is of little benefit unless the cord is detached from the sacrum at the same time. This may be difficult, for the lipoma may be fused with the dorsal surface of the spinal cord. Diastematomyelia is another unusual abnormality of the spinal cord often associated with spina bifida. Here a bony spicule or fibrous band protrudes into the spinal canal from the body of one of the thoracic or upper lumbar vertebrae and divides the spinal cord into halves for a variable vertical
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Figure 38-3. MRI of an adult with tethered cord and the typical lipoma at its caudal extent (arrow). The conus lies behind the lower lumbar vertebra. No dysraphism is present. The main features were a flaccid bladder, asymmetrical weakness and atrophy of the forelegs, and a degree of spasticity in the legs.
extent. In extreme examples, the division of the cord may be complete, each half with its own dural sac and complete set of nerve roots. This longitudinal fissuring and doubling of the cord are spoken of as diplomyelia. With body growth, the restriction created by the bone spicule leads to a traction myelopathy, presenting with pain and progressive sensory, motor, and bladder symptoms, sometimes as late as adult life. Removal of the fibrous-bony spicule and untethering of the spinal cord have been beneficial in some cases. Syringomyelia (see also Chap. 44). This is a developmental cavity within the cervical cord, extending a variable distance caudally or rostrally, and usually associated with an ArnoldChiari malformation that is described below. There are a variety of other neurodevelopmental spinal abnormalities in the high cervical region, such as fusion of atlas and occiput or of cervical vertebrae (Klippel-Feil syndrome), congenital dislocation of the odontoid process and atlas, platybasia, and basilar impression. These abnormalities are discussed in Chap. 44, with other diseases of the spinal cord.
consistent of which are (1) extension of a tongue of cerebellar tissue posterior to the medulla and cord that extends into the cervical spinal canal; (2) caudal displacement of the medulla and the inferior part of the fourth ventricle into the cervical canal; and (3) a frequent but not invariable association with syringomyelia or a spinal developmental abnormality. These and associated anomalies were first clearly described by Chiari (1891). Several translations of his original material, but they have been criticized as inaccurate. Arnold’s name is attached to the syndrome, but his contribution to our understanding of these malformations was relatively insignificant. Use of the double eponym Arnold-Chiari malformation is so entrenched that a dispute over its propriety serves little purpose. Chiari recognized four types of abnormalities. In recent years, the term has come to be restricted to Chiari’s types I and II—i.e., to cerebellomedullary descent without and with a meningomyelocele, respectively. Type III Chiari malformation is no more than a high cervical or occipitocervical meningomyelocele with cerebellar herniation, and type IV consists only of cerebellar hypoplasia. It should be emphasized that a proportion of normal individuals have a small tongue of the posterior cerebellum protruding by a few millimeters below the lower lip of the foramen magnum; this is usually of no significance and does not justify inclusion as a Chiari malformation. Several other morphologic features are characteristic of the true Chiari anomaly. The medulla and pons are elongated and the aqueduct is narrowed. The displaced tissue (medulla and cerebellum) occludes the foramen magnum; the remainder of the cerebellum, which is small, is also displaced so as to obliterate the cisterna magna. The foramina of Luschka and Magendie often open into the cervical canal, and the arachnoidal tissue around the herniated brainstem and cerebellum is fibrotic. All these factors are probably operative in the production of hydrocephalus, which is always associated. Just below the herniated tail of cerebellar tissue there is a kink or spur in the spinal cord, which is pushed posteriorly by the lower end of the fourth ventricle. In this fully expressed form of the malformation, a meningomyelocele is nearly always found. It should again be emphasized that hydromyelia or syringomyelia of the cervical cord are commonly associated findings and the main theories of causation of the latter are based on the change in CSF dynamics produced by the Chiari malformation. Developmental abnormalities of the cerebrum, particularly polymicrogyria may coexist, and the lower end of the spinal cord may extend as low as the sacrum (i.e., a tethered cord). There are usually cranial bony abnormalities as well. The posterior fossa is small; the foramen magnum is enlarged and grooved posteriorly. Nishikawa and colleagues suggested that smallness of the posterior fossa with overcrowding is the primary abnormality leading to the brain malformation. Often the base of the skull is flattened or infolded by the cervical spine (basilar impression).
Clinical Manifestations
Chiari Malformation Encompassed by this term are a constellation of related congenital anomalies at the base of the brain, the most
In type II Chiari malformation (with meningomyelocele), the problem becomes one of progressive hydrocephalus. Cerebellar signs cannot be discerned in the first few
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months of life. However, lower cranial nerve abnormalities—laryngeal stridor, fasciculations of the tongue, sternomastoid paralysis (causing head lag when the child is pulled from lying to sitting), facial weakness, deafness, bilateral abducens palsies—may be present in varying combinations. If the patient survives to later childhood or adolescence, one of the syndromes that are more typical of the type I malformation may become manifest. In the more common type I Chiari malformation (without meningocele or other signs of spinal dysraphism), neurologic symptoms may not develop until adolescence or adult life. The symptoms are those of (1) increased intracranial pressure, mainly headache, (2) progressive cerebellar ataxia, (3) progressive spastic quadriparesis, (4) downbeating nystagmus, or (5) the syndrome of cervical syringomyelia (segmental amyotrophy and sensory loss in the hands and arms, with or without pain). Or the patient may show a combination of disorders of the lower cranial nerves, cerebellum, medulla, and spinal cord (sensory and motor tract disorders), usually in conjunction with headache that is mainly occipital. This combination of symptoms is easily mistaken for multiple sclerosis or a tumor at the foramen magnum. The symptoms are usually chronic but may have an acute onset after sustained or forceful extension of the neck, as, for example, after a long session of dental work, hairdressing in women, or chiropractic manipulation. The physical habitus of such patients may be normal, but approximately 25 percent have signs of an arrested hydrocephalus, or a short “bull neck.” When basilar impression (a congenital abnormality of the occipital bone that invaginates the posterior atlas into the cranial cavity) and a Chiari malformation coexist, it may be impossible to decide which of the two is responsible for the clinical findings. The nature and severity of headache that are reasonably attributable to a Chiari malformation is somewhat unclear. Occipitonuchal pain with coughing, position change, or the Valsalva maneuver is the most dependable association, but even then, decompression may not relieve the symptoms. Exertional headache alone is a questionable association. Only large and genuine malformations, not minor descent of the tonsils should be considered causative. More generalized headaches may or may not be explained by the finding of a Chiari malformation and the advisability of a surgical treatment then depends on the degree of disability created by other aspects of the malformation. Further discussion of this subject is found in Chap. 10. The tongue of cerebellar tissue and the kinked cervical cord obstruct the upward flow of CSF and give a highly characteristic imaging profile, particularly on sagittal MRI (Fig. 38-4). Inspection of the axial sections of scans at the level of the foramen magnum demonstrates crowding of the upper cervical canal by inferiorly displaced cerebellar tissue, but one must be aware of the variations in the normal position of the cerebellar tonsils at this level. A slight descent of the cerebellar tonsils that is reversible is also seen with low cerebrospinal fluid pressure and not indicative of a Chiari malformation. Recent inceptions in phase contrast MRI technology allow the imaging of CSF flow in the region of the foramen magnum but the relevance to choosing patients for surgical decompression has not been clarified (see summary by Menick). The CSF in Chiari malformation is usually normal but may show an elevated
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Figure 38-4. Chiari-type malformation and developmental syringomyelia. T1-weighted MRI of the low-lying cerebellar tonsils below the foramen magnum and behind the upper cervical cord (upper arrow) and the syrinx cavity in the upper cord (lower arrow).
pressure and protein level in some cases for unexplained reasons.
Treatment The treatment of Chiari malformation and any associated basilar impression is far from satisfactory. If clinical progression is slight or uncertain, it is probably best to do nothing. If disability by way of spasticity, ataxia, pain, or lower cranial nerve disease is increasing, upper cervical laminectomy and enlargement of the foramen magnum are indicated. Often this halts the progress of the neurologic illness, arrests the hydrocephalus, or results in some improvement. The outcome, in our experience, has been less satisfactory when decompression was performed mainly for intractable headache, but there have been exceptions, especially when exertion or Valsalva maneuver elicits the symptoms, particularly headache. The surgical procedure must be done cautiously. Opening of the dura and extensive manipulation of the malformation or excision of herniated cerebellum may aggravate the symptoms or even cause death. The surgical series reported by Alzate and colleagues is representative. Craniovertebral decompression (suboccipital and C-1) and selective placement of shunt from a syrinx cavity to the adjacent subarachnoid space was recommended by these authors for patients with a large cavity with obliteration of the subarachnoid space. Emphasis was placed on proper patient selection, but the analysis of 66 cases, as in most other
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reports, was retrospective. (This reference is part of a very informative monograph that includes historical references.) As alluded to earlier, the role of phase-contrast MRI of CSF flow around the foramen magnum in selecting patients for decompression is unknown. The treatment of an associated syringomyelia and other developmental abnormalities in this region is discussed further in Chap. 44 under “Intramedullary Syringomyelic Syndrome.” We are unable to comment on the use by a limited number of neurosurgeons of posterior fossa decompression for the treatment of chronic fatigue syndrome and all manner of other symptoms except to say that it is entirely illogical, even when a Chiari malformation is detected.
CHROMOSOMAL ABNORMALITIES (KARYOTYPIC CHROMOSOMAL DYSGENESES) A mid-twentieth-century discovery of outstanding significance was the recognition of a group of developmental anomalies of the brain and other organs associated with a demonstrable abnormality of the karyotype of autosomal and sex chromosomes. Jacobs and Lejeune almost simultaneously were the first to note a triplication of the twentyfirst chromosome in the Down syndrome, and there followed the discovery of a number of other trisomies as well as deletions or translocations of other autosomal chromosomes and a lack or excess of one of the sex chromosomes. Such an event must take place sometime after the formation of the oocyte, during the long period when it lies fallow in the ovary or during the process of conception or germination and first cell divisions. Thus, all the cells in the embryo may carry the changed chromosome, or only some of them may carry it, the latter condition being called mosaicism. The precise manner in which triplication or some other imperfection of a chromosome is able to derail the pathways of ontogenesis is a mystery. In some instances, a chromosomal imperfection may result from the lack of a gene or a distortion or fragmentation of an unstable gene, as in the fragile X syndrome. These germ line alterations are to be distinguished from acquired partial duplications and deletions of parts of genes that occur as acquired somatic mutations in many tremors and from variations in copy number of segments of genes that are emerging as possible explanations for a number of diseases such as autism. Certain chromosomal abnormalities are incompatible with life, and it has been found that the cells of many abortuses and stillborns show abnormal karyotypes. Conversely, the organism may survive and exhibit any one of many syndromes, of which the following are the most frequent: (1) Down syndrome (mongolism, trisomy 21); (2) one type of arrhinencephaly (trisomy 13, Patau syndrome); (3) trisomy 18 (Edwards syndrome); (4) cri-du-chat syndrome (deletion of short arm of chromosome 5); (5) monosomy 21 (so-called antimongolism); (6) ring chromosomes; (7) Klinefelter syndrome (XXY); (8) Turner syndrome (XO); (9) others (XXXX, XXX, XYY, YY, XXYY); (10) fragile X syndrome, the most common form of inherited mental retardation; (11) Williams syndrome; and (12) Prader-Willi and Angelman syndromes.
There are numerous less-frequent types, some of which are also discussed below because they have special neurologic interest. The overall frequency of chromosomal abnormalities in live births is 0.6 percent (see the review by Kalter and Warkany). For a comprehensive account of the chromosomelinked disorders the reader is referred to the article by Lemieux and for speculations on the nature of genetic retardations, can be found in the article by Nokelainen and Flint.
Down Syndrome (Trisomy 21) Described first in 1866 by Langdon Down, this is easily the best known of the chromosomal dysgeneses. Its frequency is 1 in 600 to 700 births, and it accounts for approximately 10 percent of all cases in every large series of cases of severe mental retardation. Familiarity with the condition permits its recognition at birth, but the somatic appearance becomes more obvious with advancing age. The round head, open mouth, stubby hands, slanting palpebral fissures, and short stature impart an unmistakable appearance. The ears are low-set and oval, with small lobules. The palpebral fissures slant slightly upward and outward owing to the presence of medial epicanthal folds that partly cover the inner canthi (hence the old term mongolism). The bridge of the nose is poorly developed and the face is flattened (hypoplasia of the maxillae). The tongue is usually enlarged, heavily fissured, and protruded. Gray-white specks of depigmentation are seen in the irides (Brushfield spots). The little fingers are often short (hypoplastic middle phalanx) and incurved (clinodactyly). The fontanels are patent and slow to close. The hands are broad, with a single transverse (simian) palmar crease and other characteristic dermal markings. Lenticular opacities and congenital heart lesions (septal and other defects), as well as gastrointestinal abnormalities (stenosis of duodenum), are frequent. The patient with Down syndrome is slightly below average size at birth and is characteristically of short stature at later periods of life. The height attained in adult life seldom exceeds that of a 10-year-old child. Hypotonia of the limbs is a prominent finding. At first, the Moro response is reduced or absent, and feeding is difficult. Most affected children do not walk until 3 to 4 years of age; their acquisition of speech is delayed, but over 90 percent talk by 5 years. The IQ is variable, and that of a large group follows a Gaussian curve with the median IQ being 40 to 50 and the range, 20 to 70. A placid, docile, and affectionate personality characterizes most Down patients. A high incidence of atlantoaxial instability puts these individuals at risk of traumatic spinal cord compression in athletic ventures. An increased incidence of myelocytic and lymphocytic leukemia takes its toll. A number of patients have had embolic strokes and brain abscesses secondary to cardiac abnormalities and there is disproportionate occurrence of the rare cerebrovascular disorder known as moyamoya (Chap. 34). Life expectancy is later shortened by the almost universal development of Alzheimer disease by the 40th year of life. This is explained by the presence on the duplicate copy of chromosome 21 of the gene for the precursor of the protein amyloid, a central factor in the development of Alzheimer disease. As Alzheimer disease develops, the usual clinical picture is marked by inattentiveness, reduced
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speech, impairment of visuospatial orientation, loss of memory and judgment, and seizures. One cannot distinguish the Down syndrome with the common triplication of chromosome 21 from that caused by a translocation of one arm. The triplication is found mostly in the offspring of older mothers, whereas the less-frequent translocation is found equally in the offspring of young and older women. In other subtypes of the Down syndrome, referred to as mosaics, some cells share in the chromosomal abnormality and others are normal. Affected individuals have atypical forms of the syndrome, and some such individuals are of normal intelligence. The genetic changes that lead to cerebral maldevelopment and dysmorphic physical features are just beginning to be understood. A connection to genes that code for enzymes of folate has been suggested (among other mechanisms). The genetic aspects, as well as features pertaining to the medical care of these patients, are well summarized by Roizen and Patterson. They emphasize the high frequency of enteric sprue (celiac disease) and hypothyroidism and the need for screening for these conditions. Laboratory and Pathologic Findings Brain weight is approximately 10 percent less than average. The convolutional pattern is rather simple. The frontal lobes are smaller than normal, and the superior temporal gyri are thin. There are claims of delayed myelination of cerebral white matter and also of immature and poorly differentiated cortical neurons. Alzheimer neurofibrillary changes and neuritic plaques are practically always found in Down patients who are older than 40 years of age, as mentioned. It is possible to make the diagnosis of Down syndrome by demonstrating the chromosomal abnormalities in cells of the amniotic fluid. About one-third of pregnant mothers also have an abnormal elevation of serum alpha-fetoprotein in the second trimester of pregnancy. Other independent predictors of fetal Down syndrome are elevated serum chorionic gonadotropin and decreased estriol (Haddow et al). One can uncover a considerable proportion of the Down population by prenatal screening for these serum markers and by performing amniocentesis on women with positive tests to search for the chromosomal abnormality. Early detection is aided by the absence on imaging of a nasal bone between 11 and 14 weeks, at which time it is normally detected (Cicero et al).
3.
4. 5.
6.
7.
8.
Other Chromosomal Dysgeneses These are listed here with brief descriptions of their main features. 1. Trisomy 13 (Patau syndrome). Frequency 1 in 2,000 live births, more female than male, average maternal age 31 years, microcephaly and sloping forehead, microphthalmos, coloboma of iris, corneal opacities, anosmia, lowset ears, cleft lip and palate, capillary hemangiomata, polydactyly, flexed fingers, posterior prominence of heels, dextrocardia, umbilical hernia, impaired hearing, hypertonia, severe mental retardation, death in early childhood. 2. Trisomy 18. Frequency 1 in 4,000 live births, more in females, average maternal age 34 years, slow growth,
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occasional seizures, severe mental retardation, hypertonia, ptosis and lid abnormalities, low-set ears, small mouth, mottled skin, clenched fists with index fingers overlapping the third finger, syndactyly, rocker-bottom feet, shortened big toe, ventricular septal defect, umbilical and inguinal hernias, short sternum, small pelvis, small mandible, death in early infancy. Cri-du-chat syndrome (deletion in short arm of chromosome 5). Abnormal cry, like a kitten, severe mental retardation, hypertelorism, epicanthal folds, brachycephaly, moon face, antimongoloid slant of palpebral fissures, micrognathia, hypotonia, strabismus. Ring chromosomes. Mental retardation with variable physical abnormalities. Klinefelter syndrome (XXY). Only males affected. Eunuchoid appearance, wide arm span, sparse facial and body hair, high-pitched voice, gynecomastia, small testicles, usually mentally retarded but not severely so; high incidence of psychosis, asthma, and diabetes. Turner syndrome (XO). Only females affected. Triangular face, small chin, occasionally hypertelorism and epicanthal folds, widely spaced nipples, clinodactyly, cubitus valgus, hypoplastic nails, short stature, webbed neck, delayed sexual development, mild mental retardation. The manner of inheritance of the X chromosome may have bearing on the patient’s personality and level of functioning, as noted in Chap. 21. Colpocephaly. A rare type of malformation of the brain consisting of marked dilatation of the occipital horns of the lateral ventricles, thickening of the overlying rim of cortical gray matter, and thinning of the white matter. The associated clinical picture comprises mental retardation, spasticity, seizures, and visual abnormalities (because of optic nerve hypoplasia). This disorder is probably of diverse causation, but it is listed here with the chromosomal abnormalities because some cases have been associated with the mosaicism for trisomy 8 (Herskowitz et al). The term colpocephaly is often used incorrectly to apply to all forms of ventricular enlargement (including hydrocephalus) associated with abnormal development of the brain. Fragile X syndrome (see further on for additional clinical details in the section on mental retardation). This abnormality is among the most common inherited forms of mental retardation, estimated to occur in 1 of every 1,500 male live births and accounting for 10 percent of severe mental retardation in males. Females, with two X chromosomes, are affected about half as frequently, and then only to a slight degree. With the advent of new markers for the detailed structure of chromosomes, Lubs observed an unusual site of frequent breakage (“fragility”) on the X chromosome and related it to a syndrome that included mental retardation, flaring ears, elongated facies, slightly reduced cranial perimeter, normal stature, and enlarged testes. More recently, rare progressive ataxia has been reported in adults who harbor the chromosomal abnormality and had displayed little or no cognitive deficiency. The chromosomal fragility appears to be due to a heritable, unstable CGG repeating sequence in the X chromosome. Affected individuals have over 230
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repeats and carriers have 60 to 230 repeats. The prolonged sequence inactivates a gene (FMR1) that codes for an RNA-binding protein of as yet an unknown connection to brain function. The genetics of this and other retardations was reviewed by Nokelainen and Flint. Rousseau and colleagues described a simple and sensitive test using DNA analysis for the diagnosis of the syndrome both prenatally and after birth. Because of mosaicism, the length of the triplet repeat does not directly relate to the degree of expression of retardation, and the fragile X alteration occasionally turns up in mentally normal males; in some instances, the male children of their daughters have the disease. In some of the cases we have observed, the intellectual deficit has been mild in degree and the main abnormalities have taken the form of troublesome behavior, logorrhea, an autistic type of gaze aversion, and asociality. These and other neurobehavioral features of the syndrome and its unique pattern of inheritance (it is neither recessive nor dominant) have been discussed by Shapiro. 10. Williams syndrome. Described by J.C.P. Williams and colleagues of Australia from the perspective of a supravalvular aortic stenosis and a year later by Beuren and colleagues, this unique combination of cerebral maldevelopment and cardiovascular abnormalities has been traced in most patients to a microdeletion on chromosome 7 in the region of the gene that codes for the protein elastin. Its frequency is 1 in 20,000 newborns. Further discussion of clinical features of this syndrome is found later in the chapter. 11. Prader-Willi and Angelman syndromes. The Prader-Willi syndrome was already mentioned in relation to the hyperphagia of hypothalamic disorders (adiposogenital dystrophy, Froehlich syndrome). It is not uncommon (1 in 20,000 births) and affects both sexes equally. Hypotonia (floppy infant), areflexia, small stature, dysmorphic facies, and hypoplastic genitalia are evident, and arthrogryposis may be present at birth. After the first year, mental retardation becomes obvious and obesity, due to hyperphagia, becomes prominent. Patients are identified by the “H3O” mnemonic, referring to hypomentia, hypotonia, hypogonadism, and obesity. The disorder is associated with a deletion at 15q11-q13 (a so-called microdeletion, as in Williams syndrome), which can be identified by a combination of cytogenetic and DNA analyses. In 70 percent of cases the disease is caused by a noninherited deletion from the paternal X chromosome. 12. The Angelman syndrome, another cause of severe mental retardation, is associated with the identical chromosomal abnormality to that found in the PraderWilli syndrome, but there is usually a maternally inherited single-gene defect. The difference in phenotype derives from a complex genetic phenomenon termed spatially restricted imprinting. The phenotype comprises severe mental retardation, microcephaly, refractory seizures, absence of speech, ataxia, inappropriate laughter, prominent jaw, thin upper lip, and prolonged tongue. Outstanding are an unusual marionette-like stance coupled with a persistent tendency to laugh and
smile (hence the old name “happy puppet syndrome”; see also Chap. 37). 13. Rett syndrome, discussed more fully further on, is mentioned here because it is to the result of a dominant defect on the X chromosome. It affects 1 of every 10,000 to 15,000 girls. After 6 to 18 months of normal development, motor skills and mental abilities seem slowly to regress. Certain handwringing and other stereotyped hand movements appear as the disease progresses and are characteristic. Several generalizations can be made about these chromosomal dysgeneses. First, the autosomal ones are often lethal (Rett syndrome is an exception), and they almost always have a devastating effect on cerebral growth and development, whether the infant survives or not. Anomalies of nonneural and a degree of externally visible dysmorphism structures are regularly present—an association so constant that one may safely predict that an otherwise normally formed infant will not have a detectable chromosomal defect. However, only in the Down syndrome and trisomy 13 (and possibly trisomy 18) are the physiognomy and bodily configuration highly characteristic. Surprisingly, some of the most grotesque disfigurements, such as anencephaly and multiple severe congenital anomalies, are not related to a morphologic abnormality of chromosomes. By contrast, an insufficiency of sex chromosomes induces only subtle effects on the brain, affecting intellect and personality; to some extent this is true of supernumerary sex chromosomes (XYY, for example). The basic abnormality of the brain underlying the mental retardation in many of these chromosomal dysgeneses has not been ascertained. The cerebrum is slightly small, but only minor changes are seen in the convolutional pattern and cortical architecture in conventional microscopic preparations. Neurocellular methodologies to date are not sufficiently advanced to reveal the fundamental cerebral abnormality.
Teratologic Deformations of the Nervous System A number of observations have repudiated the former belief that the human embryo is naturally shielded against exogenous causes of maldevelopment. Irradiation during the first trimester, rubella and CMV infections, severe hypothyroidism of the mother during this same period, and the action of alcohol, vitamin A, and thalidomide have all been observed, among a multitude of other agents, to give rise to serious disorders of development. Quite relevant to the neurologist, the offspring of mothers receiving anticonvulsant drugs during the early months of pregnancy have a slightly increased risk of developing birth defects (approximately 5 percent, compared to 3 percent for the general population—see “Teratogenic Effects of Antiepileptic Medications” in Chap. 16). Cleft lip and palate are the most common anomalies attributable to anticonvulsant drugs; other craniofacial defects, spina bifida, minor cardiac defects, and dysraphisms have also been reported at a slightly increased rate. Claims and counterclaims have been made concerning the pathogenicity of numerous other substances. Mainly, the data are from ani-
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mals given amounts far in excess of any possible therapeutic doses in humans. The data from humans are so meager from a multitude of such substances that they are not discussed here. The reader may refer to the article by Kalter and Warkany for further information.
THE PHAKOMATOSES (CONGENITAL NEUROECTODERMOSES) As stated earlier, there are two broad categories of neurocutaneous diseases. In one, the infant is born with a special type of skin disease or develops it in the first weeks of life; in the other forms, the cutaneous abnormality, although often present in minor degree at birth, later evolves as quasineoplastic disorders. The quasineoplastic disorders to which van der Hoeve in 1920 applied the term phakomatoses (from the Greek phakos, meaning “mother spot,” “mole,” or “freckle”) are tuberous sclerosis, neurofibromatosis, and cutaneous angiomatosis with central nervous system (CNS) abnormalities, which have many features in common: hereditary transmission, involvement of organs of ectodermal origin (nervous system, eyeball, retina, and skin), slow evolution of lesions in childhood and adolescence, a tendency to form hamartomas (benign tumor-like formations because of maldevelopment), and a disposition to fatal malignant transformation. These disorders are discussed below and listed in Table 38-4.
Tuberous Sclerosis (Bourneville Disease) Tuberous sclerosis is a congenital disease of hereditary type in which a variety of lesions, because of a limited hyperplasia of ectodermal and mesodermal cells, appear in the skin, nervous system, heart, kidney, and other organs. It is characterized by the triad of adenoma sebaceum, epilepsy, and mental retardation. Hypomelanotic skin macules (“ash-leaf” lesions) and the subepidermal fibrotic “shagreen patch” are diagnostic features. It is stated that Virchow recognized scleromas of the cerebrum in the 1860s and that von Recklinghausen reported a similar lesion combined with multiple myomata of the heart in 1862, but Bourneville’s articles, appearing between 1880 and 1900, presented the first systematic accounts of the disease and it was he who related the cerebral lesions to Table 38-4
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those of the skin of the face. Vogt (1890) fully appreciated the significance of the neurocutaneous relationship and formally delineated the triad of facial adenoma sebaceum, epilepsy, and mental retardation. “Epiloia,” a term for the disease introduced by Sherlock in 1911, never gained general acceptance. These and other historical aspects are reviewed in Gomez’s monograph.
Epidemiology The disease has been described in all parts of the world and is equally frequent in all races and in both sexes. Heredity is self-evident in only a minority of cases—50 percent in some series and as little as 14 percent in the series of Bundag and Evans (cited by Brett). The disease is determined by two autosomal dominant genes (see below), but it has been estimated as 1 in 20,000 to 300,000. The disease is inherited in an autosomal dominant fashion but with variable penetrance. The abnormal gene may be in one of two sites—the long arm of chromosome 9, designated as TSC 1 (hamartin), or in the short arm of chromosome 16, TSC 2 (tuberin), which is common. A wide variety of mutations have been described and both alleles must be affected for expression of the disease (“loss of heterozygosity”). Approximately 15 percent of sporadic cases show no identifiable mutation and tend to have milder manifestations, perhaps on the basis of mosaicism. Hamartin and tuberin function as tumor suppressor proteins and interact to suppress cell growth. This may, in part, explain the proclivity to develop various growths and hamartomas. The cerebral lesions and two of the three associated skin lesions of tuberous sclerosis are of this type. Several hypotheses relating to neuronal migration or to excessive secretion of growth factors have been proposed to link the inactivation of these genes with the pathogenesis of the characteristic lesions. Much of the work in understanding the function of these two proteins and their role in tumor formation has been performed in Drosophila and are summarized in the extensive review by Crino and colleagues. The disease involves many organs in addition to the skin and brain and it may assume a diversity of forms, the least severe of which (i.e., the forme fruste) is difficult to diagnose; hence, one cannot be precise about its incidence. Tuberous sclerosis accounts for about 0.66 percent of the mentally retarded in institutions and 0.32 percent of epileptics. The medical literature contains a number of reports of patients whose mentality is preserved and who have never had convulsions.
THE CONGENITAL NEUROECTODERMOSES True phakomatoses 1. Tuberous sclerosis 2. Neurofibromatosis Cutaneous angiomatosis with abnormalities of the central nervous system 1. (Sturge-Weber syndrome) 2. Dermatomal hemangiomas and spinal vascular malformations 3. Epidermal nevus (linear sebaceous nevus) syndrome 4. Osler-Weber-Rendu disease 5. von Hippel-Lindau disease 6. Ataxia-telangiectasia (Louis-Bar disease) 7. Fabry disease
Etiology and Pathogenesis The cellular elements within the nodular cerebral lesions (called tubers; see below) are abnormal in number, size, and orientation. The tumor-like growths in different organs may include cells of more than one type (e.g., fibroblasts, cardiac myoblasts, angioblasts, glioblasts, and neuroblasts), and their number is locally excessive. Something appears to have gone awry with the proliferative process during embryologic development, yet it is kept under control, in the sense that only rarely do the growths undergo malignant transformation. Highly specialized cells within the lesions may attain
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giant size; neurons 3 to 4 times normal size may be observed in the cerebral scleroses. These facts emphasize the potentially blastomatous character of the process. Surgically resected tubers show activation of a cell-size control pathway (mammalian target of rapamycin [mTOR]); this is in keeping with the effects of TSC mutations on this cascade and probably explains the giant neurons as mentioned further below.
Clinical Manifestations (Table 38-5) The disease may be evident at the time of birth (the diagnosis has been made by CT scan in neonates), but more often the infant is judged at first to be normal. In approximately 75 percent of cases, attention is drawn to the disease initially by the occurrence of focal or generalized seizures or by slowed psychomotor development. As with any condition that leads to mental retardation, the first suspicion is raised by delay in reaching normal maturational milestones. Whatever the initial symptom, the convulsive disorder and mental retardation become more prominent within 2 to 3 years. The facial cutaneous abnormality, adenoma sebaceum, appears later in childhood, usually between the fourth and tenth years, and is progressive thereafter. As the years pass, the seizures change pattern. In the first year or two they take the form of massive flexion spasms with hypsarrhythmia (irregular dysrhythmic bursts of high-voltage spikes and slow waves in the EEG). As many as 25 percent of patients with these types of seizures have been found to have tuberous sclerosis. Later, the seizures change to more typical generalized motor and psychomotor attacks or atypical petit mal. Any one of the seizure types may be brief, especially if the patient is receiving antiepileptic medication. Focal neurologic abnormalities, which one might expect to occur from the size and location of some of the lesions, are distinctly uncommon. Mental function continues to deteriorate slowly. Exceptionally there is a spastic weakness or mild choreoathetosis Table 38-5 MANIFESTATIONS OF TUBEROUS SCLEROSIS Cutaneous and Ectodermal Shagreen patch Facial angiofibromas (adenoma sebaceum) Ungular and subungual fibromas Hypomelanotic skin macules (more than 3) Multiple dental enamel pits Bone cysts Hamartomatous rectal polyps Gingival fibromas Retinal achromatic patch Multiple renal cysts Cardiac rhabdomyoma Renal angiomyolipoma Lymphangiomatosis Neural Seizures Developmental delay Cortical tubers Subependymal nodules Subependymal giant cell “astrocytoma” Retinal hamartoma
of the limbs and in a few cases an obstructive hydrocephalus develops. As in any state of severe mental retardation, a variety of nonspecific motor peculiarities—such as constant crying, muttering, stereotypical rocking and swaying movements, and digital mannerisms—may be observed. In nearly half of the cases, affective and behavioral derangements, often of hyperkinetic and aggressive type, are added to the intellectual deficiency. The lack of parallelism in the severity of the epilepsy, the mental deficit, and cutaneous abnormalities has been noted by all clinicians who have wide experience with this disease. Some patients are subject to recurrent seizures while retaining relatively normal mental function; in others, trivial skin lesions or a retinal phakoma (see below) may suggest the diagnosis in a mentally normal person with few seizures. In such cases, recognition may elude competent neurologists and dermatologists. As a general rule, early onset of seizures is predictive of mental retardation. Gomez and colleagues suggested that the seizures damage the brain, a point with which we tend to agree in part. However, it seems likely that both the epilepsy and mental retardation are the product of severe involvement of the brain by the lesions of tuberous sclerosis. Limitation of space allows no more than a catalogue of the other visceral abnormalities in tuberous sclerosis. In about half the cases, gray or yellow plaques (in reality gliomatous tumors) may be found in the retina in or near the optic disc or at a distance from it. It is from this lesion, called a phakoma, that van der Hoeve derived the term that is applied to all neurocutaneous diseases of this class. About half of all benign rhabdomyomas of the heart are associated with tuberous sclerosis; if located in the wall of the atrium, they may cause conduction defects. Other benign tumors of mixed cell type (angiomyolipomas) have been found in the kidneys, liver, lungs, thyroid, testes, and gastrointestinal tract. Cysts of the pleura or lungs, bone cysts in digits, and zones of marbling or densification in bones are some of the less common abnormalities. In approximately 90 percent of patients with tuberous sclerosis, congenital hypomelanotic macules—“ash-leaf” lesions—formerly mistaken for partial albinism or vitiligo, appear before any of the other skin lesions (Fitzpatrick et al). Gold and Freeman, as well as Fitzpatrick and colleagues, emphasized the frequency of these leukodermic lesions and their value in the diagnosis of tuberous sclerosis during infancy, before the appearance of the other characteristic cutaneous lesions. The hypomelanotic areas are arranged in linear fashion over the trunk or limbs and range in size from a few millimeters to several centimeters; their configuration is oval, with one end round and the other pointed, in the shape of an ash leaf. A Wood lamp, which transmits only ultraviolet rays, facilitates the demonstration of the ash-leaf lesions because of the absence of melanoblasts, which normally absorb light in the ultraviolet range (360-nm wavelength). These lesions become pink when rubbed and contain sweat glands; they are not usually present on the face or head. There is occasionally a white tuft of hair (poliosis). Electron microscopic examination of the hypomelanotic lesions shows a normal or reduced number of melanocytes, but their dopa reaction is reduced and melanosomes are small.
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The well-developed facial lesions (adenomas of Pringle), pathognomonic of tuberous sclerosis, are present in 90 percent of patients older than 4 years of age. Although called “adenoma sebaceum,” these nodules are actually angiofibromas; the sebaceous glands are only passively involved (Fig. 38-5). Typically they are red to pink nodules with a smooth, glistening surface, and they tend to be limited to the nasolabial folds, cheeks, and chin; sometimes they also involve the forehead and scalp. The earliest manifestation of facial angiofibromatosis may be a mild erythema over the cheeks and forehead that is intensified by crying. The occurrence of large plaques of connective tissue on the forehead is usually expressive of a severe form of the disease. On the trunk, the diagnostic lesion is the “shagreen patch” (in reality a plaque of subepidermal fibrosis) found most often in the lumbosacral region. It appears as a flat, slightly elevated, flesh-colored area of skin 1 to 10 cm in diameter, with a “pigskin,” “elephant hide,” or “orange peel” appearance (Fig. 38-6). Another common site of fibromatous involvement is the nail bed; subungual fibromas usually appear at puberty and continue to develop with age. Other common skin changes, not in themselves diagnostic, include fibroepithelial tags (soft fibromas), café-au-lait spots, and port-wine hemangiomas.
Pathology The brain exhibits a number of diagnostic anomalies. Broadening, unnatural whiteness, and firmness of parts of some of the cerebral convolutions are simulated by no other disease. These are the tubers after which the disease is named. On the surface of the brain, they range in width from 5 mm to 2 or 3 cm. Their cut surface reveals a lack of demarcation from cortex and white matter and the presence of white flecks of calcium; these, which are readily seen on CT scans and MRI, are called brain stones (see below and Fig. 38-7). The walls of the lateral ventricles may be encrusted with white or pink-white masses resembling candle gutterings. When calcified, they appear in radiographs as curvilinear opacities that follow the outline of the ventricle. Rarely, nodules of abnormal tissue
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Figure 38-6. Shagreen patch on the skin of the lower back in a young patient with tuberous sclerosis.
are observed in the basal ganglia, thalamus, cerebellum, brainstem, and spinal cord. Under the microscope the tubers are seen to be composed of interlacing rows of plump, fibrous astrocytes (much like an astrocytoma, though lacking in glial fibrillar protein). In the cerebral cortex and ganglionic structures, derangements of architecture result from the presence of abnormal-appearing cells: greatly enlarged “monstrous,” or “balloon” neurons and glia cells—often difficult to distinguish from one another. Also, displaced normal-sized neurons contribute to the chaotic histologic appearance. Gliomatous deposits may obstruct the foramina of Monro or the aqueduct or floor of the fourth ventricle, causing hydrocephalus. Neoplastic transformation of abnormal glia cells, a not infrequent occurrence, usually takes the form of a large-cell astrocytoma, less often of a glioblastoma or meningioma. Recently, certain relationships have been drawn between the balloon cells of this disease and similar cells in focal cortical dysplasias (see Crino and colleagues for details). The phakomas of the retina are also composed mainly of neuronal and glial components, but occasionally there is an admixture of fibrous tissue.
Diagnosis
Figure 38-5. Adenoma sebaceum of tuberous sclerosis.
When the full combination of seizures and mental and dermal abnormalities is conjoined, the diagnosis is selfevident. It is the early stage of the disease and the formes frustes that give trouble, and here the experienced dermatologist can be of great help. Epilepsy—i.e., flexion spasms in infancy—and delay in psychomotor development are by no means diagnostic of tuberous sclerosis, as they occur in many diseases. It is in these cases, and also in every sizable population of the epileptic or mentally retarded, especially when the family history is unrevealing, that a search for the dermal equivalents of the disease—the hypomelanotic ash-leaf spots, adenoma sebaceum, collagenous skin patch, phakoma of the retina, or subungual or gingival fibromas—is so rewarding. The finding of any one of these lesions provides confirmation
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Figure 38-7. Tuberous sclerosis. A. MRI showing multiple hamartomas. B. Subependymal nodules are demonstrated on CT, where their calcific nature has led them to be termed "brain stones.”
of the partial and atypical case. Adenoma sebaceum may occasionally occur alone and is easily confused with acne vulgaris in the adolescent. The history of epilepsy or demonstration of mental retardation are helpful but neither is a requisite for the diagnosis of tuberous sclerosis (see the monograph by Gomez). The most useful laboratory measures for corroborating the disease are the CT scan and MRI (see Fig. 38-7). The calcific tuber lesions tend to be periventricular and are particularly well shown on the CT scan, whereas MRI is more sensitive in detecting the hamartomatous giant cell subependymal and subcortical lesions. There is an absence of edema in the surrounding tissue. Roach and colleagues have indicated that an increasing number of cortical lesions demonstrated with MRI appear to correlate with an increased impairment of neurologic function. Clinics that treat large numbers of these patients recommend imaging of the kidneys and lungs and, in children, echocardiography. Serial examinations to detect enlargement of the subependymal tumors is advised annually for those younger than age 21 years and every 2 to 3 years thereafter, but the best course of action if a glioma emerges has not been clearly established.
are patients who are not mentally impaired and who undergo dermabrasion of the facial lesions for cosmetic reasons, with the knowledge that these slowly regrow. To an increasing degree, neurosurgeons are excising single epileptogenic cortical tubers in otherwise relatively normal children. There are about 15 specialized centers in the United States, and several abroad, that are expert at caring for these patients and establishing a regimen of radiologic surveillance. (See http://www.tsalliance.org for further information including guidelines for testing and surveillance.)
Course and Prognosis In general, the disease advances so slowly that years must elapse before one can be sure of progression. Of the severe cases, approximately 30 percent die before the fifth year, and 50 to 75 percent before attaining adult age. Worsening is mainly in the mental sphere. Status epilepticus accounted for many deaths in the past, but improved medication therapy has reduced this hazard. Neoplasias take their toll; the authors have had several such patients who died of malignant gliomas arising in striatothalamic regions.
Treatment Nothing can be offered in the way of prevention other than genetic counseling. Antiepileptic therapy of the standard type suppresses the convulsive tendency more or less effectively and should be applied assiduously. Adrenocorticotropic hormone (ACTH) suppresses the flexor spasms in infancy and tends to normalize the EEG for a time. It is usually pointless to attempt the excision of tumors, especially in severely affected individuals (with the exception of renal hamartomas that impair kidney function). There
Neurofibromatosis of von Recklinghausen Neurofibromatosis (NF) is a comparatively common hereditary disease in which the skin, nervous system, bones, endocrine glands, and sometimes other organs are the sites of a variety of congenital abnormalities, often taking the form of benign tumors. The typical clinical picture, usually identifiable at a glance, consists of multiple circumscribed areas of increased skin pigmentation accompanied by dermal and neural tumors of various types.
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The condition known as multiple idiopathic neuromas was the subject of a monograph by R.W. Smith in 1849; even at that time, he referred to examples recorded by other writers. It was von Recklinghausen, however, who, in 1882, gave the definitive account of its clinical and pathologic features. The subsequent studies of the disease by Yakovlev and Guthrie; Lichtenstein; Riccardi; and Martuza and Eldridge; and more recently by Créange and colleagues; and the comprehensive monographs of Crowe and colleagues and of Riccardi and Mulvihill are informative references that provide a complete analysis of the clinical, pathologic, and genetic data pertaining to the disease. Epidemiology Crowe and associates calculated the prevalence of the disease to be 30 to 40 per 100,000, with the expectancy of 1 case in every 2,500 to 3,300 births over 50 years ago and these rates pertain in the all series from the current era. Approximately half of their cases had affected relatives, and in all instances the distribution of cases within a family was consistent with an autosomal dominant mode of inheritance. The disease has been observed in all races in different parts of the world, and males and females are about equally affected. Cause and Pathogenesis The hereditary nature of NF has been appreciated for a century. More recently, it has been established that NF comprises two distinct disorders, the genes for which are located on different chromosomes. Both are inherited in an autosomal dominant pattern with a high degree of penetrance, but half the cases are a result of spontaneous mutations. The classic form of the disease with multiple neurofibromas, described below, is caused by a mutation located near the centromere on chromosome 17 in a gene called neurofibromin (Barker et al). The second type, in which the main feature is bilateral acoustic nerve neuromas, described further on, is caused by a mutation in the merlin gene (also called schwannomin). These two forms of NF have been loosely referred to as peripheral and central, respectively, but the terms neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are less confusing (Martuza and Eldridge) and are used in the following discussion. The large size of the NF1 gene (60 exons) and the widely scattered mutations has made genetic testing complex but such testing is available. Virtually all families manifest different mutations and there have been no clear associations between specific mutations and phenotypic characteristics except that the rare complete deletion leads to early onset multiple neurofibromas, mental retardation, and facial dysmorphism. The pathogenesis is less obscure now that the genes implicated in both diseases have been identified. Both involve tumor suppression. As with tuberous sclerosis, there is a suggestion of a disorder that allows low-grade ectodermal cell proliferation without tumor transformation. Cellular elements derived from the neural crest (i.e., Schwann cells, melanocytes, and endoneurial fibroblasts, the natural components of skin and nerves) proliferate excessively in multiple foci, and the melanocytes function abnormally. The hormones and growth factors involved in this proliferative process and the mechanism by which it occurs are as obscure as they are in tuberous sclerosis. It is known, however, that most of the numerous mutations in the NF1 gene lead to premature termination of protein
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synthesis and a consequent “loss of function.” This is in keeping with the tumor suppressor characteristics of the gene and the emergence of neoplasms in the presence of homozygous mutations.
Neurofibromatosis Type 1 (Classic, or Peripheral, NF) (Table 38-6) In the majority of patients, spots of hyperpigmentation (café-au-lait lesions) and cutaneous and subcutaneous neurofibromatous tumors are the basis of clinical diagnosis. Pigmentary changes in the skin are nearly always present at birth, but neurofibromas are infrequent at that age. Both lesions increase in number and size during late childhood and adolescence. There may be a spurt of new lesions at puberty or during pregnancy. Exceptionally, a neurofibroma of a cranial nerve or a spinal root (sometimes with compression of the cord), disclosed during imaging of the spine or a neurosurgical intervention, may be the initial manifestation of the disease. In a large series of patients with neurofibromatosis (Crowe et al), approximately onethird were found to have only the cutaneous manifestations that were noted while being examined for symptoms of some other disease; that is to say, the NF was asymptomatic. Usually these are the patients with the slightest degree of cutaneous abnormality. Of the remaining twothirds, most consulted a physician because of the disfigurement produced by the skin tumors or because some of the neurofibromas were producing neurologic symptoms. The patches of cutaneous pigmentation, appearing shortly after birth and occurring anywhere on the body, constitute the most obvious clinical expression of the disease. They are approximately oval in shape and vary in size from a 1 to 2 mm to many centimeters, and in color from a light to dark brown (the term café-au-lait is applied) and are rarely associated with any other pathologic state (Fig. 38-8).
Table 38-6 MANIFESTATIONS OF NEUROFIBROMATOSIS TYPE 1 Cutaneous and ectodermal Café-au-lait spots (generally 6 or more of > 5 mm diameter prepubertal and >15 mm postpubertal)a Axillary and integumentary freckling (Crowe sign)a Lisch nodules (hamartomas of the iris)a Bony lesions including sphenoid dysplasia or thinning of long bone cortex, pseudoarthrosesa Increased incidence of chronic myeloid leukemia, neurofibrosarcoma (malignant transformation of neurofibroma), rhabdomyosarcoma, pheochromocytoma Short stature Neural Neurofibromasa Cutaneous (most common) Subcutaneous Nodular plexiform Diffuse plexiform Seizures Optic pathway gliomaa Risk of cerebral astrocytoma, brainstem glioma Hypertension a
Denotes main diagnostic criteria, in addition to having an affected firstdegree relative.
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Figure 38-8. Typical large café-au-lait spot. The presence of 6 or more hyperpigmented lesions, each larger than 1.5 cm after puberty (>5 mm prepubertal), is diagnostic of neurofibromatosis type 1.
They do not appear to change in number as the patient ages, but they do enlarge during puberty and become more pigmented. In a survey of pigmented spots in the skin, Crowe and associates found that 10 percent of the normal population had one or more spots of this type; however, anyone with more than 6 such spots, some exceeding 1.5 cm in diameter in postpubertal individuals (bigger than 0.5 mm in prepubertal ones), nearly always proved to have neurofibromatosis. Of their 223 patients with NF, 95 percent had at least 1 spot and 78 percent had more than 6 large spots. Freckle-like or diffuse pigmentation of the axillae and other intertriginous areas (groin, under breast) and small, round, whitish spots are characteristic; when coupled with café-au-lait patches, they are together virtually pathognomonic of the disease. The appearance of multiple cutaneous and subcutaneous tumors in late childhood or early adolescence is the other principal feature of the disease. The cutaneous tumors are situated in the dermis and form discrete soft or firm papules varying in size from a few millimeters to a centimeter or more (molluscum fibrosum; Fig. 38-9). They assume many shapes—flattened, sessile, pedunculated, conical, lobulated, and so on. They are flesh-colored or violaceous and often topped with a comedo. When pressed, the soft tumors tend to invaginate through a small opening in the skin, giving the feeling of a seedless raisin or a scrotum without a testicle. This phenomenon, spoken of as “buttonholing,” is useful in distinguishing the lesions of this disease from other skin tumors, e.g., multiple lipomas. A patient may have anywhere from a few of these dermal tumors to hundreds. The subcutaneous neural tumors, which are also multiple, take two forms: (1) firm, discrete nodules attached to a nerve or (2) an overgrowth of subcutaneous tissue, sometimes reaching enormous size. The latter, which are called plexiform neuromas (also pachydermatocele, elephantiasis neuromatosis, la tumeur royale), occur most often in the face, scalp, neck, and chest, and may cause hideous disfigurement. When palpated, they feel like a bag of worms or strings; the bone underlying the tumor may thicken. Neurofibromas are easily distinguished from lipomas, which are soft, unattached to the
Figure 38-9. Molluscum fibrosum nonneural skin tumors of von Recklinghausen disease.
skin or nerve, and not accompanied by any neurologic disorder. An exception to this last statement is the rare disease of multiple symmetrical lipomatosis with axonal polyneuropathy (Launois-Bensaude disease). As a rule, congenital neurofibromas tend to be highly vascular and invasive and are especially prominent in the orbital, periorbital, and cervical regions. They may be accompanied by hypertrophy of a segment of the body (a sign also seen in the arteriovenous malformation of Klippel-Trenaunay-Weber syndrome). When the hyperpigmentation lesion overlies a plexiform neurofibroma and extends to the midline, one should suspect an intraspinal neurofibroma tumor at that level. Another unique finding is the Lisch nodule. This is a small whitish spot (actually a hamartoma) in the iris that was present in 94 percent of Riccardi’s type 1 cases, but was not found in patients with NF2 or in normal individuals (Fig. 38-10 and below). Headache, hydrocephalus, and tumors involving the optic pathways, meningiomas, gliomas, and malignant peripheral nerve tumors are common, even among adults, according to the survey of 158 patients by Créange and col-
Figure 38-10. Hamartomas of the iris (Lisch nodules), typical of neurofibromatosis type 1.
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leagues; also, pain was a common symptom in adults and often related to a malignant peripheral nerve sheath tumor. Other abnormalities associated less consistently with type 1 (peripheral) NF include bone cysts, pathologic fractures (pseudoarthrosis), cranial bone defects with pulsating exophthalmos (sphenoid bone dysgenesis), bone hypertrophy, precocious puberty, pheochromocytoma, scoliosis, syringomyelia, nodules of abnormal glia cells in brain and spinal cord, and macrocephaly, rarely with obstructive hydrocephalus as a result of overgrowth of glial tissue around the sylvian aqueduct and fourth ventricle. Some degree of intellectual impairment is common; it was found in 40 percent of Riccardi’s series of 133 patients. But in our experience, the figure is much lower and the impairment is usually not profound. Learning difficulty, developmental disorder, and hyperactivity have been more frequent abnormalities, occurring in almost 40 percent of patients. Rosman and Pearce have ascribed mental retardation in NF to congenital malformation of the cerebral cortex (cortical dysgenesis). The incidence of seizures is about 20 times higher than that in the general population, but these tend not to be a very frequent or intractable problem. Exceptionally, NF is associated with peroneal muscular atrophy, congenital deafness, and partial albinism (Bradley et al). In childhood, progressive blindness is a particularly dire complication from a tumor mass composed mainly of astrocytes (optic glioma). The tumor may involve one or both optic nerves. The diagnosis comes to mind at once in a child with any of the cutaneous manifestations of NF and this tumor. Uncertainty as to its nature arises from the fact that the neuropathologist may be unable to decide between a benign hamartoma and a grade 1 astrocytoma. Progressive enlargement in a succession of MRI scans may be needed to affirm its nature. It needs to be stated that neurofibromas of the spinal roots occur regularly in patients without NF (see Chap. 44). Whether multiple such lesions implicate NF is not clear.
Neurofibromatosis Type 2 (Acoustic, or Central, NF) This condition is considerably less frequent than NF1. Here there is an absence or paucity of cutaneous lesions. Progressive deafness and the demonstration by enhanced CT or MRI of bilateral acoustic neuromas afford accurate diagnosis (see Fig. 31-18). Also, an acoustic neuroma developing before age 30 years is suspect as being caused by NF2. Other cranial or spinal neurofibromas, meningioma (sometimes multiple), and glioma may be added to the syndrome of deafness or may occur prior to its emergence. Juvenile cataracts of the subcortical or capsular variety are seen in some affected patients. Analysis for the NF2 gene has become available from several laboratories. The genetics and affected protein (merlin or schwannomin) are discussed in “Cause and Pathogenesis” above.
Familial Schwannomatosis As commented in Chap. 31 in the discussion of acoustic neuroma, it is now apparent that the propensity to develop mul-
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tiple schwannomas can also be inherited as a dominant trait, without the vestibular tumors characteristic of NF2. This trait maps to a genetic locus on chromosome 22 that is distinct from the one for NF2. It has been estimated that 2 to 5 percent of schwannomas requiring resection are from this disease. The current diagnostic criteria are based on the presence of two of more schwannomas without vestibular nerve tumors in an individual older than age 18 years, as summarized in a thorough review by MacCollin and colleagues. Pain is the dominant problem.
Pathology of NF1 and NF2 The cutaneous tumors are characterized by a rather thin epidermis whose basal layer may or may not be pigmented. The collagen and elastin of the dermis is replaced by a loose arrangement of elongated connective tissue cells. The lack of compactness of the normal dermal collagen allows the palpable opening in the skin. The pigmented (café-au-lait) lesions contain only the normal numbers of melanocytes; the dark color of the skin is instead the result of an excess of melanosomes in the melanocytes. Some of the abnormally large melanosomes measure up to several microns in diameter. The nerve tumors are composed of a mixture of fibroblasts and Schwann cells (except the optic nerve tumors, which contain a combination of astrocytes and fibroblasts). Predominance of one or the other of these cells in the nerve is the basis of the diagnosis of neurofibroma or schwannoma. Palisading of nuclei and sometimes encircling arrangements of cells (Verocay bodies) are features of both (see Chap. 31). Occasionally, along spinal roots or sympathetic chains, one may find a tumor made up of partially or completely differentiated nerve cells, a typical ganglioneuroma. Clusters of abnormal glia cells may be found in the brain and spinal cord, and, according to Bielschowsky, they imply a link with tuberous sclerosis that has never been proved. Clinically and genetically, the two diseases are quite independent. Malignant degeneration of the tumors is found in 2 to 5 percent of cases; peripherally they become sarcomas and centrally, astrocytomas or glioblastomas (Fig. 38-11).
Diagnosis If skin tumors and café-au-lait spots are numerous and Lisch nodules are present in the iris, the identification of the disease as type 1 neurofibromatosis offers no difficulty. A history of the illness in antecedent and collateral family members makes diagnosis even more certain. Doubt arises most frequently in patients with bilateral acoustic neuromas or other cranial or spinal neurofibromas or schwannomas with no skin lesions or only a few random ones. The tendency for these forms of NF to have few skin lesions is well known, but differentiation of type 1 from type 2 may be uncertain unless genetic studies are undertaken. Plexiform neuromas with muscle weakness because of nerve involvement and abnormalities of underlying bone may be confused with other tumors, especially in young children, who tend to have few café-au-lait spots and few cutaneous tumors. Hypertrophy of a limb requires differentiation from other developmental anomalies including Klippel-TrenaunayWeber Syndrome.
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and an occasional case of precocious puberty, hydrocephalus, or mental retardation. Because of the many potentially dangerous conditions that accompany classic NF, the initial clinical evaluation should be supplemented by a number of ancillary examinations that may include measurement of IQ, EEG, slitlamp examination of irides, visual and auditory evoked responses, and CT scans or MRI of cranium and, sometimes, of the spine and mediastinum. In the series reported by Duffner and colleagues, 74 percent of cases had abnormal signals in T2-weighted images of the basal ganglia, thalamus, hypothalamus, brainstem, and cerebellum. The EEG was abnormal in 25 percent. If there is suspicion of a pheochromocytoma, 24-h urine should be tested for metabolites of epinephrine. Each of these tests not only is an aid to diagnosis but also is essential to the effective management of the illness.
Treatment
Figure 38-11. Neurofibromatosis type 1. T1-weighted MRI in the sagittal plane demonstrating a glioma involving the optic chiasm and brainstem (above). T2-weighted axial image showing multiple foci of hyperintensity, presumably hamartomas (below).
As already mentioned, Crowe and coworkers expressed the view that 80 percent of patients with von Recklinghausen disease can be diagnosed by the presence of more than 6 café-au-lait spots. Of the remaining 20 percent, those older than 21 years of age will be found to have multiple cutaneous tumors, axillary freckling, and a few pigmented spots; in those younger than 21 years of age with no dermal tumors and only a few café-au-lait patches, a positive family history and radiographic demonstration of bone cysts will be helpful in some instances. Café-au-lait spots and cutaneous tumors should always be sought, for they may help the neurologist diagnose an otherwise obscure progressive spinal syndrome, a cerebellopontine angle syndrome, bilateral deafness, progressive blindness,
The skin tumors should not be excised unless they are cosmetically objectionable or show an increase in size, suggesting malignant change. The effects of radiotherapy on these lesions are so insignificant that they do not justify the risk of exposure. Plexiform neuromas about the face pose especially difficult problems. Here one must resort to plastic surgery, but the results are not always satisfactory because the growths may encompass distal branches of cranial nerves (with risk of greater paralysis after surgical excision) or alter the underlying bone, the latter being either eroded from pressure or hypertrophied from increased blood supply. Cranial and spinal neurofibromas are amenable to excision, and the gliomas and meningiomas usually demand surgical measures as well. Here the differentiation of hamartomas from gliomas of structures such as the optic nerves, hypothalamus, or pons may be difficult. Bilateral optic nerve gliomas are usually treated with radiation; unilateral ones are excised. Peripheral nerve tumors that have undergone malignant (sarcomatous) degeneration pose special surgical problems. Affected individuals should be advised not to have children, a precaution that may not be necessary because fertility, especially in males, seems to be reduced by the disease. Prognosis varies with the grade of severity, being most favorable in those with only a few lesions. But the disease is always progressive, and the patient should remain under surveillance.
Other Cutaneous Angiomatoses with Abnormalities of the Central Nervous System There are at least 7 additional diseases in which a cutaneous or ocular vascular anomaly is associated with an abnormality of the nervous system: (1) meningo- or encephalofacial (encephalotrigeminal) angiomatosis with cerebral calcification (Sturge-Weber syndrome); (2) dermatomal hemangiomas and spinal vascular malformations (sometimes with limb hypertrophy, as also occurs in Klippel-Trenaunay-Weber syndrome and in neurofibromatosis); (3) the epidermal nevus (linear sebaceous nevus)
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syndrome; (4) familial telangiectasia (Osler-Rendu-Weber disease); (5) hemangioblastoma of cerebellum and retina (von Hippel-Lindau disease); (6) ataxia-telangiectasia (Louis-Bar disease); and (7) angiokeratosis corporis diffusum (Fabry disease). The last three disorders are considered elsewhere: ataxia-telangiectasia and Fabry disease with the inherited metabolic disorders in Chap. 37, and von Hippel-Lindau disease below and with hemangioblastoma in Chap. 31.
Meningo- or Encephalofacial Angiomatosis with Cerebral Calcification (Sturge-Weber Syndrome) A vascular nevus is observed at birth to cover a large part of the face and cranium on one side (in the territory of the ophthalmic division of the trigeminal nerve). In one-quarter of the cases the nevus is bilateral. The lesions vary in extent, the most limited being an involvement of only the upper eyelid and forehead, and the most extensive being the entire head and even other parts of the body. The skin lesion is deep red (port-wine nevus) and its margins may be flat or raised; soft or firm papules, evidently composed of vessels, cause surface elevations and irregularities. Orbital tissue, especially the upper eyelid, is almost invariably involved; congenital buphthalmos may enlarge the eye before birth and glaucoma may develop later in that eye, causing blindness. The choroid is implicated in some cases. The increased cutaneous vascularity may result in an overgrowth of connective tissue and underlying bone, giving rise to a deformity like that of the KlippelTrenaunay-Weber syndrome. Indications of cerebral disease appear as early as the first year of life or later in childhood; the most frequent clinical manifestations are unilateral seizures followed by increasing degrees of spastic hemiparesis with smallness of the arm and leg, hemisensory defect, and homonymous hemianopia, all on the side contralateral to the trigeminal nevus. Skull films (usually normal just after birth) taken after the second year reveal a characteristic “tramline” calcification, which outlines the involved convolutions of the parietooccipital cortex. CT scanning and MRI show the abnormalities of the involved cortex at an earlier age. This condition has been referred to as the Sturge-Weber syndrome, as it was W. Allen Sturge who, in 1879, described a child with sensorimotor seizures contralateral to a facial “port-wine mark,” and Parkes Weber (1922, 1929), who gave the first radiographic demonstration of the atrophy and calcification of the cerebral hemisphere ipsilateral to the skin lesion. This eponym overlooks the important intervening contributions of Kalischer (1897, 1901), who first described the meningeal angioma in conjunction with the facial one; of Volland (1913), who demonstrated the intracortical calcific deposits; and of Dimitri (1923), who described the characteristic double-contoured radiographic shadows. Krabbe (1932, 1934) showed conclusively that the calcification lay not in the blood vessels (as Dimitri and many others had concluded), but in the second and third layers of the cortex (see Wohlwill and Yakovlev for historical review and bibliography). It is not the case that all cranial hemangiomas affect the cerebrum; the common facial nevi, especially the flat midline ones and the elevated strawberry nevi, are of no neurologic significance. And a cerebral–meningeal angiomatosis may be present without skin lesions. The involvement of the upper
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eyelid is of greatest importance since nearly all such cases are associated with cerebral lesions (Barlow). There seems to be a close correlation between the persistence or maldevelopment of the embryonic vascular plexus of the eyelid and forehead and that of the occipitoparietal parts of the brain. When the nevus lies entirely below the upper eyelid or high on the scalp, a cerebral lesion is usually absent, although in a few instances such an angioma has been associated with a vascular malformation of the meninges overlying the brainstem and cerebellum. In angiograms, the abnormal meningeal vessels, which are largely veins, are not well seen; thus they can be distinguished from true arteriovenous malformations. These purely meningeal venous nevi are rarely the source of subarachnoid or cerebral hemorrhage and they do not enlarge to form a mass. The cortical lesion is, however, destructive of cortical tissue, which is replaced by glial tissue that calcifies. One explanation holds that diversion of blood to the meninges during seizures causes progressive ischemia of the cerebral cortex. Barlow has stated that the seizures themselves are responsible for the progressive neurologic deficits and that a special effort should be made to prevent them by carefully regulated medical therapy. Occasionally surgical excision of intractable discharging foci may be necessary, but often this may not be feasible in view of the magnitude of the cerebral lesion. Radiotherapy is unsuccessful in reducing the skin blemish; sensitive individuals usually try to hide it with cosmetics. There is little literature on treating the brain vascular malformation with endovascular techniques. Although the encephalotrigeminal syndrome is of congenital origin, its cause and pathogenesis are unknown. Familial coincidence has been observed but is exceptional. No chromosomal abnormality has been demonstrated.
Dermatomal Hemangiomas with Spinal Vascular Malformations A hemangioma of the spinal cord may rarely be accompanied by a vascular nevus in the corresponding dermatome, as was first pointed out by Cobb. Such nevi are most frequent on the arm and trunk. When the cutaneous lesion involves an arm or leg, there may be enlargement of the entire limb or fingers in combination with underdevelopment of certain other parts (Klippel-Trenaunay-Weber syndrome). Some of these angiomatous syndromes combine a spinal or retinal-diencephalic arteriovenous malformation (AVM) with a nevus of the trunk or face, respectively. Such cases provide a link to the common AVMs described in Chap. 34.
Epidermal Nevus Syndrome This is a closely related congenital neurocutaneous disorder in which a specific skin lesion (epidermal nevus or linear sebaceous nevus) is associated with a variety of hemicranial and neurologic abnormalities. The skull and brain abnormalities are ipsilateral to the nevus. One-sided thickening of the bones of the skull is characteristic. Mental retardation, seizures, and hemiparesis are the usual neurologic manifestations and have their basis in a wide variety of cerebral lesions—unilateral cerebral atrophy, porencephalic cyst, leptomeningeal hemangioma, arteriovenous malformation, and atresia of cerebral arteries and
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veins. The somatic and neurologic abnormalities of this syndrome have been comprehensively reviewed by Solomon and Esterley and by Baker and associates.
Hereditary Hemorrhagic Telangiectasia (Osler-Rendu-Weber Disease) This vascular anomaly is transmitted as an autosomal dominant trait. To date, two mutant genes have been identified as causes of this disease: endoglin and novel kinase. The small arteriovenous malformations affect the skin, mucous membranes, gastrointestinal and genitourinary tracts, lungs, and occasionally the nervous system. The basic lesion is probably a defect in the vessel wall, and the main complication, bleeding, is thought to be a result of the mechanical fragility of the vessel. Located sparsely in the skin of any part of the body, these vascular lesions first appear during childhood, enlarge during adolescence, and may assume spidery forms, resembling the cutaneous telangiectases of cirrhosis in late adult life. The lesions range from the size of a pinhead to 3 mm or more, are bright red or violaceous, and blanch under pressure. The significance of the lesions lies in their hemorrhagic tendency. During adult years they may give rise to severe and repeated epistaxis or gastric, intestinal, or urinary tract bleeding and result in an iron-deficiency anemia. Pulmonary fistulas constitute another important feature of the generalized vascular dysplasia; patients with such lesions are particularly subject to brain abscesses and less so to bland embolic strokes. The angiomas of this disease may infrequently form in either the spinal cord or brain, where they can produce acute hemorrhage, or as in one of our patients, there may be an intermittently progressive focal thalamic syndrome resulting from enlargement of the vascular lesions or possibly from a succession of small hemorrhages. Repeated unexplained gastrointestinal, genitourinary, intracranial, or intraspinal hemorrhages warrants a search for small cutaneous lesions, which are easily overlooked. Satellite lesions tend to form after obliteration of an angioma.
von Hippel-Lindau Disease This is a genetic disease of multiple neoplasms, specifically by the presence of a hemangioblastoma, sometimes multiple (these are discussed with other cerebral tumors in Chap. 31). The tumor is situated in the cerebellum in most cases, but may also arise in the brainstem or spinal cord. In addition to the characteristic cerebellar tumor with its nodule within a cyst, half of these patients have retinal hemangioblastomas and somewhat fewer develop renal cell cancer; an even smaller number have a pheochromocytoma, pancreatic tumors or cysts, or cystadenomas. Polycythemia vera is an interesting feature in a few cases. The cerebellar hemangioblastoma typically develops in the fourth decade and causes symptoms of ataxia and headache. On imaging studies, the lesions have a striking appearance of a cyst with a nodule contained in its wall, and angiography demonstrates the highly vascular nature of the nodule, which represents the actual neoplasm (see Fig. 31-13). The other identifying features of the disease, retinal hemangiomas, are smaller but indistinguishable histo-
logically from the craniospinal ones. They are multiple and bilateral, usually appearing earlier than the cerebellar lesions but remaining asymptomatic until they become extensive (retinal detachment is one feature). Their diagnosis is made by funduscopy, by which a large feeding vessel leading to an irregularly shaped ovoid tumor in the retina can usually be appreciated. Imaging studies of the cranium that use dye enhancement will reveal them as well. Inheritance is autosomal dominant with variable but high penetrance by older age. The causative mutation is in the VHL gene located on chromosome 3. This is a tumor suppressor gene that is inactivated by the mutation and may induce oncogenesis by increasing the expression of vascular mitogenic factors such as vascular endothelial growth factor (VEGF) but the precise mechanisms are not known. Renal cell cancer is a serious component of the disease, occurring in up to 60 percent of cases, but the tumors, although multiple, tend initially to be small and of low grade. Nonetheless, renal cancer accounts for one-third of deaths from the disease, the remainder being largely the result of complications of the cerebellar neoplasm. An extensive review of the subject was written by Losner and colleagues. Mentioned here is the cerebellar gangliocytoma of Lhermitte-Duclos disease. There are no cutaneous malformations but small vascular anomalies in the brain and elsewhere may accompany the cerebellar tumor as discussed in Chap. 31 (see Fig. 31-15).
RESTRICTED DEVELOPMENTAL ABNORMALITIES OF THE NERVOUS SYSTEM In the course of clinical practice, one encounters a remarkable number of restricted disorders of the nervous system, many of which are transmitted from generation to generation as a mendelian, usually dominant, trait. Of the more severe ones, only a few of the more striking examples are described here. Milder and more restricted conditions, such as stuttering and dyslexia, that are pervasive in the population are described in Chap. 28. The reader may turn to books on genetics or teratology for an account of such oddities as hereditary unilateral ptosis, hereditary Horner syndrome, pupillary inequalities, jaw winking, and absence of a particular skeletal muscle.
Bifacial and Abducens Palsies (Möbius Syndrome) The syndrome of congenital facial diplegia with convergent strabismus is referred to as Möbius syndrome, although Von Graefe had described it earlier. Its presence at birth is disclosed by the lack of facial movements and of full eye closure. A review of the subject in the English literature was written by Henderson, and a more recent analysis of 37 affected individuals was written by Harriëtte and colleagues. In Henderson’s study of 61 cases of the congenital facial diplegia syndrome, there were 45 instances of associated abducens palsy, 15 of complete external ophthalmoplegia, 18 of lingual palsy, 17 of clubfeet, 13 of a brachial disorder, 6 of mental defect, and 8 of an absent pectoral muscle. Thus the overlap with other neuromuscular and CNS abnormalities is evident.
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Moreover, at least two configurations of brainstem dysfunction have been proposed, one because of a lack of the facial nerve nucleus and the other in the nerve, perhaps acquired in type, based on electrophysiologic studies, but we have no basis to judge the validity of this. Harriëtte and coworkers emphasize the frequency of hypoplastic or dysplastic tongue, palatal involvement, and general motor clumsiness. They suggest that the disorder represents a widespread form of brainstem maldevelopment. Early in life the mouth hangs open, the lower lip is everted, and there is difficulty in sucking. Usually this syndrome can be distinguished from the facial palsy of forceps or birth injury by its bilaterality and the other associated weaknesses. Occasionally, more than one family member is affected (usually in a pattern suggesting autosomal dominant inheritance). The cause of this peculiar condition is not known. The few adequate pathologic studies have shown a paucity of nerve cells in the motor nuclei of the brainstem, changes that also characterize the Fazio-Londe type of muscular dystrophy discussed in Chap. 50. Rarely, there may be an aplasia of facial muscles. The Möbius syndrome is also referred to in Chap. 47 in relation to restricted palsies of myopathic and nuclear origin. Partial paralysis of facial muscles that dates from birth and cannot be attributed to obstetric trauma is not infrequent. In a common type, the lower lip on one side remains immobile when the child smiles or cries; the lip on the unaffected side is drawn downward and outward, resulting in a prominent asymmetry of the lower face. Often it is not appreciated that the side that droops during crying is the normal side (Hoefnagel and Penry).
Congenital Lack of Lateral Gaze (Cogan Oculomotor Apraxia) Children with this congenital defect are unable to turn their eyes to either side volitionally or on command. Attempting to look to the right, the child turns the head to the right (there is no associated apraxia of head turning), but the eyes lag and turn to the left. As a result, the patient has to overshoot the mark with the head in order to attain ocular fixation. Once the eyes fixate, the head returns to the primary position. To compensate for the deficiency of eye movements, the patient develops jerky thrusting movements of the head, which characterize all attempts at voluntary gaze. Caloric stimulation of the labyrinth causes tonic movement of the eyes but not nystagmus, as in the normal person. Also, optokinetic nystagmus cannot be induced. Vertical eye movements are normal. A similar ocular condition may occur in conjunction with ataxia-telangiectasia and in Gaucher disease. Children with oculomotor apraxia are slow to walk; Ford observed one such child whose sibling had an absence of the vermis of the cerebellum. Aside from this observation, the anatomic basis of the condition has not been studied.
CONGENITAL ABNORMALITIES OF MOTOR FUNCTION (CEREBRAL PALSY) In this group of congenital disorders, a major disturbance of motor function, usually nonprogressive, has been present
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since infancy or early childhood. The popular terms for these conditions have been infantile cerebral paralysis (Freud) and cerebral palsy. The latter name is neither appropriate nor useful from the physician’s viewpoint, collocating as it does diseases of widely differing etiologic and anatomic types, wherein the hereditary and acquired and the intrauterine, natal, and postnatal diseases lose their identity. But the name has been adopted as a slogan by fund-raising societies and for rehabilitation clinics throughout the United States, hence it will not soon disappear from medical terminology. The term, often abbreviated CP, is still being used indiscriminately to designate every conceivable cognitive and motor disorder of corticospinal, extrapyramidal, cerebellar, and even neuromuscular type in infants and children.
Etiology of the Congenital Cerebral Motor Disorders Motor abnormalities that have had their onset early in life are numerous and diverse in their clinical manifestations. Marked prematurity is an associated factor in a large proportion of cases. Each year, approximately 50,000 infants weighing less than 1,500 g are born in the United States; approximately 85 percent survive. Of these, 5 to 15 percent have a motor disorder of cerebral origin and 25 to 30 percent are found to be mentally impaired at school age (Volpe, 1995; also Hack et al). It is helpful to categorize a given case according to the extent and nature of the motor abnormality. A careful history of prenatal, perinatal, or postnatal insults to the developing nervous system must be sought; certain correlations of these factors with the resulting pattern of neurologic deficit are outlined below. Most patients with these motor abnormalities reach adult years. Many but not all have epilepsy in addition to the motor abnormalities and there is an unavoidable overlap in considering the causes and mechanisms of these three clinical states. The following discussion is given from the perspective of the three major etiologic syndromes: matrix hemorrhages in the immature infant, hypoxic-ischemic encephalopathy, and certain other developmental motor abnormalities including those due to intrauterine stroke.
Germinal Matrix (Subependymal) Hemorrhage in Premature Infants In low-weight and premature immature infants (20 to 35 weeks’ gestational age), there sometimes occurs, within a few days after birth, a catastrophic decline in cerebral function, usually preceded by respiratory distress (hyaline membrane disease) with spells of cyanosis and apnea. Also evident are deficiencies of brainstem automatisms (sucking and swallowing), bulging of the fontanels, and sanguineous CSF. If the infant becomes completely unresponsive, death usually ensues within a few days. Autopsy discloses a small lake of blood in each cerebral hemisphere (often asymmetrically distributed), occupying the highly cellular (subependymal) germinal matrix zone, near the caudate nucleus at the level of the foramen of Monro. This region is supplied by the lenticulostriate, choroidal, and Heubner
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recurrent arteries and is drained by deep veins, which enter the vein of Galen. In approximately 25 percent of cases, the blood remains loculated in the matrix zone, while in the majority it ruptures into the lateral ventricle or adjacent brain tissue. In a series of 914 consecutive autopsies in newborns, subependymal hemorrhage was found in 284 (31 percent); practically all of these neonates were of low birth weight, according to Banker and Bruce-Gregorios. Lesser degrees of this cerebral hemorrhage are now being identified by ultrasonography (Fig. 38-12) and CT scans, and it is apparent that many infants with smaller hemorrhages survive. Some rapidly develop an obstructive hydrocephalus and require a ventricular shunt. In others, the hydrocephalus stabilizes and there is clinical improvement. Several series of surviving cases have now been followed for many years. Those in whom the hemorrhage was more extensive are often left with motor and intellectual handicaps. Viewed from the perspective of cerebral palsy, just over half of the patients in the Swedish series of Hagberg and Hagberg with spastic diplegia had matrix hemorrhages, leukomalacia (see further on), or both. Congenital hemiplegia or quadriplegia was observed at a lower frequency. In another series of 20 cases of posthemorrhagic hydrocephalus (Chaplin et al), 40 percent had significant motor deficits and more than 60 percent had IQ scores of less than 85. In an experience with 12 less severely affected surviving cases (mean birth weight 1.8 kg and gestational age of 32.3 weeks), R.D. Adams noted that only 1 had a residual spastic diplegia and 9 had IQs in the low-normal or normal range (personal communication). The cause of matrix hemorrhage is not entirely clear. In all probability it is related to greatly increased pressure in the thin-walled veins of the germinal matrix coupled with a lack of adequate supporting tissue in these zones. During periods of unstable arterial or venous blood pressure that occur with the pulmonary disorders of immature infants, these thin-walled vessels rupture. These infants are also prone to the development of another characteristic lesion of the cerebral white matter (periventricular leukomalacia; see below), and the neurologic deficits resulting from these two lesions may be additive. Treatment Control of the respiratory distress of prematurity may reduce the incidence of matrix hemorrhages and periventricular leukomalacia. Claims have been made that the administration of indomethacin ethamsylate, a drug that
Figure 38-12. Ultrasonograph demonstration of matrix hemorrhage in a premature infant (arrow).
subependymal
reduces capillary bleeding, and the intramuscular injection of vitamin E for the first 3 days after birth and possibly the use of betamethasone or other corticosteroids appears to be of value in reducing the incidence of periventricular hemorrhage (Benson et al; Sinha et al; see also Volpe [1989] for discussion of control of cerebral hemodynamics and effects of medications in the neonatal period). Acetazolamide and furosemide, which reduce the formation of spinal fluid, have been widely used in the treatment of posthemorrhagic hydrocephalus. However, in a large-scale controlled study, the effects were negligible and shunt placement was required to control worsening hydrocephalus (see International PHVD Drug Trial Group in the references).
Periventricular Leukomalacia These are zones of necrosis of white matter in the deep territories of cortical and central arteries. They lie lateral and posterolateral to the lateral ventricles, in a position to involve the occipital radiations and the sensorimotor fibers in the corona radiata (first described by Banker and Larroche; see also Shuman and Selednik). The white matter lesions occur in about one-third of cases of subependymal hemorrhage as mentioned, but they may develop independently in both premature and full-term infants who have suffered hypotension and apnea. In a study of 753 preterm infants, those born at 28 weeks’ gestation or less were at highest risk of this complication; the combination of intrauterine infection and premature rupture of membranes carried a 22 percent risk (Zupan et al). Survivors often manifest cerebral hemiplegia or diplegia and variable degrees of mental impairment. The motor disorder is usually more severe than the cognitive and language impairment. Increasingly, small lesions of this nature are being identified in term infants by cerebral imaging including ultrasound. The mechanism of this type of periventricular infarction has been debated, and the terminology and clinical features, insofar as they overlap with germinal matrix hemorrhage, have been confusing. In recent years, most theories and experimental evidence converge on the notion that these represent regions of venous ischemia and infarction.
Hypoxic-Ischemic Damage and Neonatal Encephalopathy It has been estimated that in the range of 1 to 6 of every 1,000 live births manifests a neonatal encephalopathy (as quoted in the review by Ferriero). The seriousness of the condition is further emphasized by the associated mortality rate of 20 percent in the newborn period and the 25 percent rate of neurodevelopmental disability in survivors. Little’s conception of the hypoxic-ischemic form of “birth injury,” enunciated in 1862, has been reconsidered over the years. Although it is evident that many newborns suffer some degree of perinatal asphyxia, relatively few seem to manifest brain damage. Moreover, many, if not most, infants with a variety of cerebral motor syndromes appear to have passed the parturitional (perinatal) period without mishap, indicating the greater importance of other prenatal and postnatal causative factors. Nonetheless, severe neonatal asphyxia of term or pre-
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term babies can be an important cause of spastic, dystonic and ataxic syndromes, often accompanied by seizures and mental subnormality. One has the impression that the brain tolerates hypoxia and reduced blood flow in the immediate postnatal period better than at any other time in life. Indeed, animal experimentation supports this view. Not until the arterial oxygen tension is reduced dramatically to 10 to 15 percent of normal does brain damage occur, and even then the impaired function of other organs contributes to the damage. It is probably correct to think of the encephalopathy in terms of both hypoxia and ischemia, both of which usually occur in utero and are expressed postnatally by recognizable clinical syndromes. Fenichel (1990), following the original work of Sarnat and Sarnat and of Levene and colleagues, has found it helpful to divide the encephalopathies that follow a complicated birth into three purely descriptive groups according to their severity, each having a prognostic value beyond that of the Apgar score: (1) In newborns with mild hypoxic-ischemic encephalopathy, the symptoms are maximal in the first 24 h and take the form of hyperalertness and tremulousness of the limbs and jaw (the “jittery baby”) and a low threshold of the Moro reaction. The tone of the limbs is normal except for a mild increase in head lag during traction. The reflexes are brisk and there may be ankle clonus. The anterior fontanel is soft. The EEG is normal. Recovery is usually complete and the risk of handicap is low. (2) Newborns with moderate hypoxicischemic encephalopathy are lethargic, obtunded, and hypotonic, with normal movements. After 48 to 72 h, the neonate may improve (having passed through a jittery hyperactive phase) or worsen, becoming less responsive in association with convulsions, cerebral edema, hyponatremia, and hyperammonemia from liver damage. The EEG is abnormal. Fenichel associates epileptiform activity and voltage suppression with an unfavorable outcome. Abnormal visual and auditory evoked potentials are other poor prognostic signs. (3) In neonates with severe hypoxicischemic encephalopathy, stupor or coma is present from birth; respirations are irregular, requiring mechanical ventilation. There are usually convulsions within the first 12 h. The limbs are hypotonic and motionless even during attempts to elicit the Moro response. Sucking and swallowing are depressed or absent, but pupillary reactions and eye movements may at first be retained, only to be lost as the coma deepens. It is in the second and third categories, i.e., the states of moderate to severe encephalopathy, where correction of the respiratory insufficiency and the metabolic abnormalities permits survival that a number of motor abnormalities (corticospinal, extrapyramidal, and cerebellar) and mental retardation eventually emerge. Included in the category of severe hypoxic-ischemic encephalopathy are also newborns with a variety of developmental anomalies of the brain and other organs. However, clouding the issue of causality is the absence of perinatal complications in a large number of children with cerebral palsy and the large number of normal babies who are born after complicated deliveries. This important issue, which has become a central theme in medicolegal practice, is discussed further on. Notably, only a
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few cases result from often blamed intrapartum factors such as forceps delivery, breech presentation, cord prolapse, abruptio placentae, and maternal fever. In addition, such infants may have been exposed to certain prenatal risk factors (toxemia of pregnancy, antepartum uterine hemorrhage, maternal hypotension, and certain epidemiologic associations such as hypothyroidism or fertility treatment), or their growth may have been abnormal (small-for-date babies). Some of these babies are born at term; others are premature, and the birth process may or may not have been abnormal. One must then consider the possibility, originally pointed out by Sigmund Freud, that the abnormality of the birth process, instead of being causal, was actually the consequence of prenatal pathology. The latter might include preterm intrauterine hypoxia-ischemia. Other evidence of multifactorial etiology in the “causation” of cerebral palsy has been provided by Nelson and Ellenberg, who found that maternal mental retardation, birth weight below 2,000 g, and fetal malformation were among the leading predictors. Breech presentation was another factor, and one-third of these cases also had some noncerebral malformation. Twenty-one percent of the 189 children in their series had also suffered some degree of asphyxia. Additional determinants were maternal seizures, a motor deficit in an older sibling, two or more prior fetal deaths, hyperthyroidism in the mother, preeclampsia, and eclampsia. In children with cerebral diplegia born at term, likely contributory factors that were operative in nearly half included toxemia of pregnancy, low birth weight for age, placental infarction, and intrauterine asphyxia. The factors enumerated above are involved to different degrees in the outcome of pregnancies but are informative because they bring to light the significant proportion of cases of cerebral birth injury in which hypoxia-ischemia, matrix hemorrhages, and leukomalacia were not operative. In this group, can be included the symmetrical porencephalies and hydranencephalies. Thus the complexity of assigning a cause for cerebral palsy is evident. In respect to the motor disorders discussed below, hypoxic-ischemic perinatal injury is still the most commonly specified cause of neonatal encephalopathy but is often unrelated to a permanent defect of cerebral palsy. This statement has been amply confirmed by a large and often cited study from Western Australia that detected neonatal encephalopathy in 3.8 of 1,000 live term births but was able to identify causative intrapartum factors alone in only 5 percent (Badawi et al). Furthermore, only 10 percent of all the infants with neonatal encephalopathy developed spastic quadriplegia, according to Evans and colleagues. Imaging studies of cerebral palsy have increasingly appeared and it has even been suggested, perhaps with excessive enthusiasm, that all such children undergo scanning. Cowan and colleagues (2003) used MRI to determine the proportion of infants with a neonatal encephalopathy who had antenatal brain injury. Excluding those with major congenital malformations or obvious chromosomal abnormalities, 80 percent of cases had no established lesion or brain atrophy. In contrast, those with only seizures and no
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neonatal encephalopathy in 69 percent of cases had evidence of antenatal damage on MRI; infarctions because of thrombophilic disorders were most common. An MRI–clinical correlative study of children with cerebral palsy by Bax and colleagues in The European Cerebral Palsy Study came to similar conclusions but found that periventricular leukomalacia of prematurity was the most common MRI change, present in 42 percent of infants, followed in frequency by basal ganglionic damage (13 percent), cortical-subcortical lesions (9 percent), malformations (9 percent), and focal infarcts (7 percent). These authors found a correspondence between the clinical and MRI findings. These studies demonstrate the utility of MRI in identifying neonatal forms of encephalopathy and indicate that few are the result of obstetric accidents. Added difficulty is caused by the fact that the clinical signs of perinatal injury may emerge only when the maturational process of the nervous system exposes them at a later period of life. Woodward and coworkers suggested that the MRI pattern is predictive of developmental outcome in preterm infants, but this requires corroboration. This field has been sullied by an unprecedented rise in malpractice litigation, spawned in part by the belief that early detection of asphyxia and rapid delivery would have prevented the motor, epileptic, and cognitive problems of birth injury. The fallacy of this assumption is highlighted both by the above comments and by the observation that the incidence of cerebral palsy has not changed in term infants over the past 30 years, despite the institution of fetal monitoring and more frequent cesarean sections.
Clinical Syndromes of Congenital Spastic Motor Disorders The most frequent motor disorder evolving from the four major categories of neonatal cerebral disease—matrix hemorrhage, periventricular leukomalacia, hypoxic-ischemic encephalopathy, kernicterus (discussed further on)—is spastic diplegia; i.e., a motor disturbance that is severe in the lower limbs and mild in the upper, as discussed below. In addition, hypoxic-ischemic injury occurring in the term or preterm infant may take the form of a hemiplegia, double hemiplegia (quadriplegia), or a mixed pyramidal–extrapyramidal or spastic–ataxic syndrome. A second form of motor disorder is characterized by the development of severe spastic quadriplegia and mental retardation. The major insult is usually intrapartum asphyxia and attendant fetal distress. Usually such infants will have required resuscitation and will have had low 5min Apgar scores and seizures, which have important predictive value in this circumstance. The pathologic lesions of the brain in this second group consist of hypoxicischemic infarction in distal fields of arterial flow, primarily in the cortex and white matter of parietal and posterior frontal lobes, leaving a ulegyric sclerotic cortex. A third group, discussed below, is characterized mainly by extrapyramidal abnormalities, combining athetosis, dystonia, and ataxia in various proportions. After reviewing the results of several large series of congenital and neonatal motor disorders, we have concluded that spastic diplegia occurs in 10 to 33 percent of cases, spastic quadri-
plegia in 19 to 43 percent, extrapyramidal forms in 10 to 22 percent, and mixed forms in 9 to 20 percent. Spastic Diplegia (“Little Disease”) The pattern of paralysis is more variable than the term spastic diplegia implies; actually, several subtypes may be distinguished: paraplegic, diplegic, quadriplegic, pseudobulbar, and generalized. Pure paraplegic and pseudobulbar types are relatively rare. The eponymic “Little disease” has been applied mainly to the spastic diplegic type, but it also has been attached to all forms of motor cerebral palsy in some older writings. Usually all four extremities are affected, but the legs much more than the arms, which is the real meaning of diplegia. Hypotonia—with retained tendon reflexes and hypoactivity—is usually present initially. Only after the first few months will evident weakness and spasticity appear, first in the adductors of the legs. The plantar reflexes, which often take on ambiguous direction in the normal infant, here are clearly extensor, a finding that is pathologic at any later age. Also, stiff, awkward movements of the legs, which are maintained in an extended, adducted posture when the infant is lifted by the axillae, often do not attract attention until several weeks or months have passed. Seizures occur in approximately one-third of the cases, and it is not uncommon to observe a delay in all developmental sequences, especially those that depend on the motor system. Once walking is attempted, usually at a much later date than usual, the characteristic stance and gait become manifest. The slightly flexed legs are advanced stiffly in short steps, each describing part of an arc of a circle; adduction of the thighs is often so strong that the legs may actually cross (scissors gait); the feet are flexed and turned in with the heels not touching the floor. In the adolescent and adult, the legs tend to be short and small, but the muscles are not markedly atrophic, as they are in spinal muscular atrophy. Passive manipulation of the limbs reveals spasticity in the extensors and adductors and slight shortening of the calf muscles. The arms may be affected only slightly or not at all, but there may be awkwardness and stiffness of the fingers and, in a few, pronounced weakness and spasticity. In reaching for an object, the hand may overpronate and a grasp may be difficult to release. Speech may be well articulated or noticeably slurred, and in some instances the face is set in a spastic smile. Scoliosis is frequent and may secondarily give rise to root compression and impaired respiratory function. As a rule, there is no disturbance of sphincteric function, although delay in acquiring voluntary bowel and bladder control is usual. Athetotic postures and movements of the face, tongue, and hands are present in some patients and may actually conceal the spastic weakness. One subtype of spastic diplegia is associated with a relatively slight diminution in head size and of intelligence. As indicated above, there is no unifying neuropathology; the condition occurs independently of matrix hemorrhages and periventricular leukomalacia as well as with them. The frequency of cerebral spastic diplegia, which is closely related to the degree of prematurity, has declined significantly since the introduction of neonatal intensive care facilities, and there is reason to believe that genetic factors are of more importance.
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Infantile Hemiplegia and Quadriplegia Hemiplegia is a common condition of infancy and early childhood. The functional difference between the two sides may be noticed soon after birth, but more often it is not perceived by the mother until after the first 4 to 6 months of life. In a second group, the child is in excellent health for a year or longer before the abrupt onset of hemiplegia (see below). In hemiplegia that dates from earliest infancy—i.e., congenital hemiplegia—the parents first notice that movements of prehension and exploration are carried out with only one arm. A manifest hand preference at an early age should always raise the suspicion of a unilateral motor defect. The affection of the leg is usually recognized later, i.e., during the first attempts to stand and walk. Sitting and walking are usually delayed by a few months. In the older child, there is evident hyperactivity of tendon reflexes and usually a Babinski sign. The arm is held flexed, adducted, and pronated, and the foot assumes an equinovarus posture. Sensory and visual field defects can be detected in some patients. A mental slowness may be associated with infantile hemiplegia but is less common and lesser in degree than with cerebral diplegia. There may also be speech delay, regardless of the side of the lesion; when this is present, there is usually mental retardation and bilaterality of motor abnormality. Convulsions occur in 35 to 50 percent of children with congenital hemiplegia, and these may persist throughout life. They may be generalized but are frequently unilateral and limited to the hemiplegic side (or the contralateral side if the hemiplegia is severe). After a series of seizures, the weakness on the affected side will be increased for several hours or longer (Todd paralysis). Gastaut and associates have described a hemiconvulsive–hemiplegic syndrome in which progressive paralysis and cerebral atrophy are attributed to the convulsions. As months and years pass, the osseous and muscular growth of the hemiplegic limbs is impeded, leading to an obvious hemiatrophy of the body. With respect to the causation of congenital hemiplegia, it is generally agreed that perinatal asphyxia is only one of the possibilities. In the series of 681 children with “cerebral palsy” collected by Hagberg and Hagberg, there were 244 with hemiplegia of whom 189 were full-term babies and 55 were preterm. Prenatal risk factors were identified in only 45 percent, and mostly in the infants born prematurely. In nearly half of the cases, there was no clue as to the time in the intrauterine period when the cerebral lesion occurred. In another group—acquired infantile hemiplegia—a normal infant or young child, usually between the ages of 3 and 18 months, develops a massive hemiplegia, with or without aphasia, within hours. The disorder often begins with seizures, and the hemiplegia may not be recognized until the seizures have subsided. In Banker’s series of autopsy cases, there was arterial or venous thrombosis in some cases, but instances without vascular occlusions were found. Some of the latter cases, in which arteriography had been normal, may have been embolic, possibly of cardiac origin. In the recent era, imaging has shown a large area of cerebral infarction, consistent with a stroke in the territory of the middle cerebral artery (Fig. 38-13). If the stroke occurs at an early age, the recovery of speech may be complete, though reduced scholastic capacity remains. The degree of recovery of motor function varies.
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Figure 38-13. MRI of an adult with congenital hemiplegia. There is severe encephalomalacia mainly in the territory of the right middle cerebral artery.
Often, as the deficit recedes, the arm becomes involved by athetotic, tremulous, or ataxic movements; there may be an interval of months or years between the hemiplegia and the athetosis. Destructive lesions underlie most of the cases of infantile hemiplegia and some cases of bilateral hemiplegia (as well as many cases of seizures in the first few days of life). The pathologic change is essentially that of ischemic necrosis. In many cases, the lesions must have been acquired in utero. Precipitant delivery, fetal distress, and prepartum uterine hemorrhage may have been indications, more so than causes, of the process. What is most notable is that the ischemia tends to affect the tissues lying in arterial cortical border zones; there may also be venous stasis with congestion and hemorrhage occurring particularly in the deep central structures such as the basal ganglia and periventricular matrix zones. If they are purely hypoxic, the lesions should be bilateral. Myers has reproduced such lesions in the neonatal monkey by reducing the maternal circulation for several hours. As the lesions heal, the monkeys develop the same gliotic changes in the cortex and white matter of the cerebrum (lobar sclerosis) and the “marbling” (état marbré) that characterizes the brains of patients with spastic diplegia and double athetosis (see below). The quadriplegic state differs from bilateral hemiplegias in that the bulbar musculature is often involved in the latter and mental retardation is more severe. The condition is relatively rare and is usually a result of a bilateral cerebral lesion. However, one should also be alert to the possibility of a high cervical cord lesion. In the infant, this is usually the result of a fracture dislocation of the cervical spine
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incurred during a difficult breech delivery. Similarly, in paraplegia, with weakness or paralysis limited to the legs, the lesion may be either a cerebral or a spinal one. Sphincteric disturbances and a loss of somatic sensation below a certain level on the trunk always point to a spinal localization. Congenital cysts, tumors, and diastematomyelia are more frequently causes of paraplegia than of quadriplegia. Another recognized cause of infantile paraplegia is spinal cord infarction from thrombotic complications of umbilical artery catheterization.
Extrapyramidal Syndromes The spastic cerebral diplegias discussed above shade almost imperceptibly into the congenital extrapyramidal syndromes. These children are found in every cerebral palsy clinic, and, ultimately, they reach adult neurology clinics. Corticospinal tract signs may be absent and the student, familiar only with the syndrome of pure spastic diplegia, is always puzzled as to their classification. Some cases of extrapyramidal type are undoubtedly attributable to severe perinatal hypoxia and others to diseases such as erythroblastosis fetalis with kernicterus. To state the probable pathologic basis and future course of these illnesses, it is useful to separate the extrapyramidal syndromes of prenatal-natal origin (which usually become manifest during the first year of life) from the acquired or hereditary postnatal syndromes, such as familial athetosis, Wilson disease, dystonia musculorum deformans, and the hereditary cerebellar ataxias, which become manifest later. Double Athetosis This is probably the most frequent of the congenital extrapyramidal disorders. Two types stand out—one that is caused by hyperbilirubinemia or Rh incompatibility (kernicterus; see below) and hypoxic-ischemic encephalopathy. With control of neonatal hyperbilirubinemia (by use of anti-Rh immune globulin, exchange transfusions, and phototherapy), kernicterus has almost disappeared, whereas the severe hypoxic-ischemic form regularly continues to be seen. Rarely, a congenital, nonhemolytic icterus or a glucose-6-phosphate dehydrogenase deficiency produces the same syndrome. Like the spastic states, double athetosis may not be recognized at birth but only after several months or a year has elapsed. In some cases, the appearance of choreoathetosis is for unexplained reasons delayed for several years; it may seem to progress during adolescence and even early adult life. It must then be differentiated from some of the inherited metabolic and degenerative extrapyramidal diseases. Chorea and athetosis dominate the clinical picture, but bewildering combinations of involuntary movements—including dystonia, ataxic tremor, myoclonus, and even hemiballismus—may be found in a single case. At times, we have been unable to classify the movement disorder because of its complexity. It should be noted that practically all instances of double athetosis are also associated with a defect in voluntary movement. Choreoathetosis in infants and children varies greatly in severity. In some, the abnormal movements are so mild as to be misinterpreted as restlessness or “the fidgets”; in others, every attempted voluntary act provokes violent involuntary spasms, leaving the patient nearly helpless.
The clinical features of choreoathetosis and other involuntary movements are discussed in Chap. 4. Early hypotonia, followed by delayed motor development, is the rule in these cases. Erect posture and walking may not occur until the age of 3 to 5 years and may never be attained in some patients. Tonic neck reflexes or fragments thereof tend to persist well beyond their usual time of disappearance. The plantar reflexes are usually flexor, although they may be difficult to interpret because of the continuous flexion and extension of the toes. Sensory abnormalities are not found. Because of the motor and speech impairment, patients are often erroneously thought to be mentally slow. In some, this conclusion is doubtless correct, but intellectual function is adequate in many others. A variety of rehabilitative measures have been tried: physiotherapy, surgery, sensory integrative therapy, progressive patterned movement, and various undocumented forms of neuromuscular facilitation. We agree with Hur, who has critically reviewed this subject, that properly controlled studies provide no proof of the success of any of them. Surely, with growth and development, new postures and motor capacities are acquired. The less-severely affected patients make successful occupational adjustments. The more-severely affected children rarely achieve a degree of motor control that permits them to live independently. One sees some of these unfortunate persons bobbing and twisting laboriously as they make their way in public places. Imaging studies are seldom of diagnostic value. Mild cerebral atrophy and loss of volume of the basal ganglia are seen in some cases, and cavitary lesions are present in some of the severe anoxic encephalopathies. The EEG is rarely helpful unless there are seizures. The most frequent pathologic finding in the brain has been a whitish, marble-like appearance of the putamen, thalamus, and border zones of the cerebral cortex. These whitish strands represent foci of nerve cell loss and gliosis with condensation of bands of transversing myelinated fibers—so-called status marmoratus (état marbré). This lesion does not develop if the insult occurs after infancy, i.e., after myelination has completed its early developmental cycle. Kernicterus This is now a rare cause of extrapyramidal motor disorder in children and adults. Such cases are the neurologic sequelae of erythroblastosis fetalis secondary to Rh and ABO blood incompatibilities or to a deficiency of the hepatic enzyme glucuronosyltransferase. The symptoms of kernicterus appear in the jaundiced neonate on the second or third postnatal day. The infant becomes listless, sucks poorly, develops respiratory difficulties as well as opisthotonos (head retraction), and becomes stuporous as jaundice intensifies. The serum bilirubin is usually greater than 25 mg/dL. In acidotic and hypoxic infants (e.g., those with low birth weight and hyaline membrane disease), the kernicteric lesions develop with much lower levels of serum bilirubin. A proportion of infants with this disease die within the first week or two of life. Many of those who survive are mentally retarded, deaf, hypotonic, and totally unable to sit, stand, or walk. There are exceptional patients, however, who are mentally normal or at most only slightly limited. They develop a variety of persistent neurologic sequelae—choreoathetosis, dystonia, and rigidity of the
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limbs—a picture not too different from that of cerebral spastic diplegia with involuntary movements. Kernicterus should always be suspected if an extrapyramidal syndrome is accompanied by bilateral deafness and paralysis of upward gaze. Later, in childhood there may be a greenish pigmentation of the dental enamel. Neonates who die in the acute postnatal stage of kernicterus show a unique yellow staining (icterus) of nuclear masses at one time was called the “Kern nuclei” and gave the disease its name in the basal ganglia, brainstem, and cerebellum. In those surviving this postnatal insult, the pathologic changes consist of a symmetrically distributed nerve cell loss and gliosis in the subthalamic nucleus, the globus pallidus, the thalamus, and the oculomotor and cochlear nuclei; these lesions are the result of the hyperbilirubinemia. In more than 30 cases examined by R.D. Adams, the immature cerebral cortex including the hippocampus was spared. In the newborn, unconjugated bilirubin can pass through the poorly developed blood–brain barrier into these nuclei, where it is assumed to be directly toxic. Acidosis and hypoxia exacerbate the effect. Also in the newborn, the development of hyperbilirubinemia is enhanced by a transient deficiency of the enzyme glucuronosyltransferase, essential for the conjugation of bilirubin. Hereditary hyperbilirubinemia, caused by lack of this enzyme (Crigler-Najjar syndrome), may exhibit the same effects on the nervous system at a later period of infancy or childhood as hyperbilirubinemia because of Rh incompatibility. Immunization, phototherapy, and exchange transfusions designed to prevent high levels of unconjugated serum bilirubin have been shown to protect the nervous system from the toxic effects of erythroblastosis fetalis. If the blood bilirubin level can be held to less than 20 mg/dL (10 mg/dL in premature infants), the nervous system may escape perinatal damage. The effective use of these measures has practically eradicated this disease. Both kernicterus and ischemic état marbré must be differentiated clinically from hereditary choreoathetosis, the Lesch-Nyhan syndrome, and—later in life, from ataxiatelangiectasia and Friedreich ataxia.
Congenital and Neonatal Ataxias In these patients, difficulty in standing and walking cannot be attributed to spasticity or paralysis. Hypotonia and poverty of movement are the initial motor abnormalities—as they are in athetoid cerebral palsy. The cerebellar deficit becomes manifest only later when the patient begins to sit, stand, and walk. There may or may not be a delay in reaching the normal motor milestones. Attempts to attain sitting balance early on reveal an unsteadiness that is not soon overcome, even with practice. Reaching for a proffered toy is accomplished by jerky, incoordinated movements. The first steps are unsteady, as would be expected, with many tumbles, but the gait remains clumsy. Instability of the trunk may be accompanied by similar, more or less rhythmic bobbing movements of the head—titubation. Despite the severity of the ataxia, the muscles are of normal size, and voluntary movements, although weak in some patients, are possible in all the limbs. The tendon reflexes are present, and the plantar reflexes are either flexor or extensor. In some cases, the ataxia
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is later associated with spasticity rather than hypotonia (spastic-ataxic diplegia). Relative improvement may occur in later years. In the older child, a cerebellar gait, ataxia of limb movements, nystagmus, and uneven articulation of words are readily distinguished from myoclonus, chorea, athetosis, dystonia, and tremor. In only a few cases have the pathologic changes been studied. Aplasia or hypoplasia of the cerebellum has been observed, but sclerotic lesions of the cerebellum are more common. The CT scan or MRI verifies the cerebellar atrophy. However, in a few cases of a cerebellar-like tremor in adults under our care that had been attributed to neonatal injury the MRI did not show cerebellar atrophy. A cerebral and cerebellar lesion may coexist in patients with congenital ataxia, which is the reason for the term cerebrocerebellar diplegia. Several risk factors have been identified in the congenital ataxias. Most importantly, cerebellar ataxia may be the most prominent or sole effect of neonatal ischemia-hypoxia. A genetic factor is operative in some cases (Hagberg and Hagberg). Radiation of the maternal abdomen during the first trimester of pregnancy is said to have resulted in cerebellar hypoplasia. Mercury poisoning in utero is another cause of congenital ataxia. The many cases that are not the result of a degenerative condition, some of which are described just below, remain unexplained in our experience. Pontocerebellar Hypoplasias and Joubert Syndrome Aside from the congenital ataxia described above, there are several rare familial forms in which a failure of cerebellar development is associated with mental retardation. What has now come to be called Joubert syndrome was reported in a family in which the central feature is dysgenesis of the vermis; mental retardation; episodic hyperpnea; irregular, jerky eye movements; and unsteady gait in 4 of 6 siblings. In other reports, choroidal-retinal colobomas, polydactyly, cryptorchidism, and prognathism have been mentioned. Detailed examination of the cerebra of such individuals has been lacking but the MRI has a characteristic configuration of a “molar tooth sign” that reflects a deep invagination caused by vermian hypoplasia with a narrow cleft separating the cerebellar hemispheres and thickening of the superior cerebellar peduncles. Several genetic loci have been implicated, most acting as recessive traits. In the Gillespie syndrome, a combination of aniridia, cerebellar ataxia, and mental retardation is the denominating feature. In the Paine syndrome, a familial disorder with developmental delay and mental retardation, there is microcephaly, spasticity, optic hypoplasia, and myoclonic ataxia, the last presumably related to the cerebellar hypoplasia. These dysgeneses and the disequilibrium syndrome reported from Sweden are unified by the cerebellar ataxia; in the past, they were categorized as ataxic cerebral palsies. Imaging studies demonstrate the cerebellocerebral abnormality. Genetic factors are operative in some, but matters pertaining to etiology remain obscure (see the older monograph by Harding for details). One form of a pure nonprogressive congenital cerebellar hypoplasia has been mapped to a gene locus on chromosome Xq; it does not appear to be related to the fragile X syndrome, which may cause ataxia and tremor in adults as noted further on. Differential Diagnosis of the Congenital Ataxias T h e congenital ataxias must be distinguished from the pro-
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gressive hereditary ataxias. The latter are likely to begin at a later age than the congenital ones. Some hereditary ataxias are intermittent or episodic, one of which is responsive to acetazolamide and is the result of an abnormality of the calcium channel as discussed in Chaps. 5 and 37. Also to be distinguished from the ataxias of congenital and neonatal origin is an acute cerebellar ataxia of childhood, which can usually be traced to a viral infection or postinfectious encephalitis, particularly after chickenpox. The opsoclonus-myoclonus (“dancing eyes”) syndrome of Kinsbourne is another postinfectious disease peculiar to childhood (see Chaps. 14 and 39). The cerebellar ataxia in this disease may be overshadowed by polymyoclonus, which mars every attempted movement. With improvement, under the influence of corticosteroids, a cerebellar disorder of speech and movement becomes evident. A majority of the patients in which the disease became chronic (16 of the 26 cases followed by Marshall et al) were found later to be mentally slowed. The cause of the disease has never been established. An occult neuroblastoma or other tumor is uncovered occasionally. In the differential diagnosis of these acute forms of cerebellar ataxia, one must not overlook intoxication with phenytoin, barbiturates, or similar drugs.
The Flaccid Paralyses and the “Floppy Infant” (Table 38-7; See also Chaps. 39 and 48) The rare cerebral form of generalized flaccidity, first described by Foerster and called cerebral atonic diplegia, has already been alluded to in the discussion of cerebral palsy. It can usually be distinguished from the paralysis of spinal and peripheral nerve origin and congenital muscular dystrophy by the retention of postural reflexes (flexion of the legs at the knees and hips when the infant is lifted by the axillae), preservation of tendon reflexes, and coincident failure of mental development. The Prader-Willi syndrome, discussed earlier in the chapter, also presents at first as a generalized hypotonia. The syndrome of infantile spinal muscular atrophy (Werdnig-Hoffmann disease) is the leading example of flaccid
Table 38-7 CAUSES OF CONGENITAL HYPOTONIA—THE FLOPPY INFANT SYNDROME I. Cerebral A. Cerebral atonic diplegia (Foerster) B. Prader-Willi syndrome C. Idiopathic slackness II. Spinal A. Werdnig-Hoffman spinal muscular atrophy B. Spinal cord natal injury III. Myopathic A. Polymyopathies—central core, nemaline, rod-body, myotubular, fiber-type disproportion B. Infantile muscular dystrophy C. Myotonic dystrophy D. Polymyositis IV. Neuropathic A. Inflammatory demyelinating neuropathy (See also Chap. 52.)
paralysis of lower motor neuron type. Perceptive mothers may be aware of a paucity of fetal movements in utero; in most cases the motor defect becomes evident soon after birth or the infant is born with arthrogrypotic deformities. Several other types of familial progressive muscular atrophies have been described in which the onset is in early or late childhood, adolescence, or early adult life. Weakness, atrophy, and reflex loss without sensory change are the main features and are discussed in detail in Chap. 39. A few patients suspected of having infantile or childhood muscular atrophy prove, with the passage of time, to be merely inactive “slack” children, whose motor development has proceeded at a slower rate than normal. Others may remain weak throughout life, with thin musculature. These and several other congenital myopathies—central core, rod-body, nemaline, mitochondrial, myotubular, and fibertype disproportion and predominance—are described in Chap. 52. Unlike Werdnig-Hoffmann disease, the effects of many of them tend to diminish as the natural growth of muscle proceeds. Rarely, polymyositis and acute idiopathic polyneuritis manifest themselves as a syndrome of congenital hypotonia. Infantile muscular dystrophy and lipid and glycogen storage diseases may also produce a clinical picture of progressive atrophy and weakness of muscles. The diagnosis of glycogen storage disease (usually the Pompe form) should be suspected when progressive muscular atrophy is associated with enlargement of the tongue, heart, liver, or spleen. The motor disturbance in this condition may be related in some way to the abnormal deposits of glycogen in skeletal muscles, although it is more likely the result of degeneration of anterior horn cells that are also distended with glycogen and other substances. Certain forms of muscular dystrophy (myotonic dystrophy and several types of congenital dystrophy) may also be evident at birth or soon thereafter. The latter may have led to arthrogryposis and clubfoot (see Chap. 52 for an extensive discussion of the congenital neuromuscular disorders). Brachial plexus palsies, well-known complications of dystocia, usually result from forcible extraction of the fetus by traction on the shoulder in a breech presentation or from traction and tipping of the head in a shoulder presentation. The effects of such injuries are sometimes lifelong. Their neonatal onset is betrayed later by the small size and inadequate osseous development of the affected limb. Either the upper brachial plexus (fifth and sixth cervical roots) or the lower brachial plexus (seventh and eighth cervical and first thoracic roots) suffer the brunt of the injury. Upper plexus injuries (Erb palsy) are about 20 times more frequent than lower ones (Klumpke palsy). Sometimes the entire plexus is involved. Further details are found in Chap. 46. Facial paralysis, because of forceps injury to the facial nerve immediately distal to its exit from the stylomastoid foramen, is another common (usually unilateral) peripheral nerve affection in the newborn. Failure of one eye to close and difficulty in sucking make this condition easy to recognize. It must be distinguished from the congenital facial diplegia that is often associated with abducens palsy, i.e., the Möbius syndrome discussed earlier in the chapter. In most cases of facial paralysis caused by physi-
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cal injury, function is recovered after a few weeks; in some, the paralysis is permanent and may account for lifelong facial asymmetry.
Treatment The avoidance of the ostensible causes of cerebral palsy has been discussed in previous sections and endlessly in the medical literature. None of the usually assigned causes of birth injury, particularly perinatal hypoxia-ischemia, explains most cases. Attempts to ameliorate brain injury by the use of hypothermia, a technique that has met with success in adult cardiac arrest, have given conflicting results. A randomized trial by Shankaran and colleagues using systemic hypothermia administered to infants with neonatal encephalopathy or a need for resuscitation showed a reduction in death or moderate to severe disability from 62 to 44 percent. Hypothermia was applied soon after birth, at a mean of about 4 hours. The effects were seen mostly among infants with only moderate and not severe encephalopathy and none of the measures of mental and psychomotor disability was improved by cooling. Previous trials had shown no difference in outcomes but used different techniques, mainly selective cerebral cooling. Cooling appears promising but requires further study, and at the time of this writing, has not been widely adopted. It is also unclear if the short-term followup will be reflected at school age and beyond. Once the motor features of cerebral palsy have been established, assistive devices, stretching therapy, and conventional orthopedic measures for joint stabilization and relief of spasticity are all useful. Injection of botulinum toxin for the relief of spasticity has gained wide favor and is now used early in the child’s life to preempt deformities. Most published trials have been too small, however, to allow firm conclusions to be drawn about the durability of this treatment. Finally, hyperbaric oxygen treatment of children with cerebral palsy was ineffective in a randomized trial conducted by Collet and colleagues, despite periodic claims to the contrary. In summary, it can be said that all these forms of disabling motor abnormalities rank high as important issues in neuropediatrics. In attempts at prevention, steps have been taken in most hospitals to identify and eliminate risk factors. Indeed, better prenatal care, reduction in premature births, and control of respiratory problems in critical care wards have reduced their incidence and prevalence. Physical and mental therapeutic measures appear to be helpful, but many of the methods have been difficult to evaluate in a nervous system undergoing maturation and development. The neurologist can contribute most by segregating groups of cases of identical pattern and etiology and in differentiating the congenital groups of delayed expressivity from the treatable acquired diseases of this age period. Woefully lacking are critical neuropathologic studies.
INTRAUTERINE AND NEONATAL INFECTIONS Throughout the intrauterine period the embryo and fetus are subject to particular infections. Because the infective
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agent must reach the fetus through the placenta, it is evident that the permeability of the latter at different stages of gestation and the immune status of the maternal organism are determinative. We include a discussion of these intrauterine infections here because some of them may lead to malformations or destructive lesions of the brain and, later in life, must be distinguished from developmental abnormalities. Until the third to fourth month of gestation, the large microbial organisms—such as bacteria, spirochetes, protozoa, and fungi—cannot invade the embryo, even if the mother harbors the infection. Viruses, however, may do so, specifically rubella, CMV, HIV, and possibly others. The rubella virus enters embryonal tissues during the first trimester, Treponema pallidum in the fourth to fifth postconceptional months, and Toxoplasma after that period. Bacterial meningitis (except for that caused by Listeria monocytogenes, described below) is essentially a perinatal infection contracted during or immediately after parturition. Neonatal herpes simplex encephalitis, as a result of the type 2 (genital) virus, is also usually acquired by passage through an infected birth canal. Some cases of HIV infection may be acquired during delivery, but most are a result of transplacental transmission. The main neonatal infections—toxoplasmosis, rubella, CMV, and herpes—have been commonly designated by the acronym TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex). With the persistence of Listeria, the rise of AIDS infections, and a marked reduction in rubella infections, the mnemonic LATCH, which includes Listeria and AIDS, might be more appropriate. Infants with any of these infections share certain common features, such as low birth weight, prematurity, congenital heart disease, purpura, jaundice, anemia, microcephaly or hydrocephaly, cerebral calcifications, chorioretinitis, cataracts, microphthalmia, and pneumonitis; as a corollary, if any combination of these features is manifest, one should suspect one of these infectious agents and take measures to identify it. However, all these clinical manifestations are unlikely to be present in any one infant, and in the cases of rubella and CMV, only a small percentage of infected infants will show major systemic signs or symptoms. Nevertheless, on clinical grounds alone, certain infections can be identified and others excluded. For example, cerebral calcifications are present mainly in toxoplasmosis and CMV encephalopathy, being rare in rubella and absent in herpes simplex virus (HSV) encephalitis; the calcifications are widely disseminated in toxoplasmosis (Fig. 3814) and have a periventricular distribution in CMV infection. Cardiac lesions are present only with rubella, and deafness occurs only with CMV and rubella. Thus, there are clinical signposts to guide the clinician in selecting the appropriate diagnostic tests. And importantly, in considering neonatal infections, one must also search for other, less-common infectious types (see Chaps. 32 and 33). Added difficulty in the diagnosis of embryonal and fetal infections arises when the mother has been entirely asymptomatic. Isolation of the organism from fetal and neonatal tissues is possible, but usually they are inaccessible, and it may be impossible to demonstrate antibodies or
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Figure 38-14. CT scan from a retarded adult with healed congenital toxoplasmosis. There is hydrocephalus and multiple calcifications in the white matter. Contrast this image with Fig. 38-7, which shows the periventricular calcifications of tuberous sclerosis.
other immune responses because of the early stage of the infection or limitations of the infant’s immune response.
Congenital Rubella Gregg, in 1941, first reported the association of maternal rubella and congenital cataracts in the neonate. His observations were quickly verified, and soon it became widely known that cataracts, deafness, congenital heart disease, and mental retardation constituted a kind of tetrad diagnostic of this disease. That a virus could affect so many tissues, causing in essence a noninflammatory developmental disorder of multiple organs, was a novel concept, and it raised the interesting prospect that other viruses might have similar effects. Surprisingly, however, only CMV and possibly HSV have been incriminated in embryonal-developmental neuropathology. A large number of other viruses (e.g., influenza, Epstein-Barr, hepatitis) have been implicated in human teratogenesis, but in none is the relationship beyond doubt. It is now well established that most instances of congenital rubella infection occur in the first 10 weeks of gestation and that the earlier the infection occurs, the greater the risk to the fetus. However, there may be some risk beyond the first trimester, up to the twenty-fourth week, according to Hardy. Following the experience of the massive rubella epidemics of 1964 and 1965, the congenital rubella syndrome has been expanded to include low birth weight; sensorineural deafness, sometimes unilateral (the most common complication); microphthalmia; pigmentary degeneration of the retina (saltand-pepper chorioretinitis); glaucoma, cloudy corneas, and cataracts of special type (the latter two abnormalities usually
cause visual impairment); hepatosplenomegaly, jaundice, and thrombocytopenic purpura; and patent ductus arteriosus or interventricular septal defect. There may be one, a few, or many of these abnormalities, in various combinations. The mental retardation is severe and may be accompanied by seizures and motor defects such as hemiplegia or spastic diplegia and rarely by seizures. Psychiatric symptoms, some resembling autism, are said to occur. Infection of the fetus after the first trimester results in a less impressive neonatal syndrome. The infant may seem lethargic and fail to thrive. The cranium is abnormally small. Only a cardiac abnormality, deafness, or chorioretinitis may provide clues to the diagnosis. The CSF later may show an increase of mononuclear cells and an elevated protein. The infection may persist for a year or longer. Foci of calcification are rare, and CT scanning and MRI are of little help in diagnosis. The maternal infection may be so mild that it is passed off as minor; but even when it is evident, the fetus is spared in approximately 50 percent of cases. Diagnosis can be verified in the neonate by demonstrating immunoglobulin (Ig) M antibodies to the virus or by the isolation of the virus from the throat, urine, stool, or CSF. Also, the virus has been obtained from cells in the amniotic fluid. In subsequent pregnancies, the fetus has been normal in our experience. The neuropathology is of considerable interest. In the nervous system of fetuses exposed to maternal rubella in the first trimester, R.D. Adams found no visible lesions by light microscopy, even though the virus had been isolated from the brain by Enders (personal communcations). At this period of development there is no inflammatory reaction because of the absence of polymorphonuclear leukocytes, lymphocytes, and other mononuclear cells in the fetus. At birth the brain is usually of normal size, and there may be no discernible lesions. There may be a mild meningeal infiltration of lymphocytes, and a few zones of necrosis and vasculitis with later calcification of vessels are seen, as are small hemorrhages, presumably related to the thrombocytopenia. Smallness of the brain and delay in myelination have been observed in children who died at 1 to 2 years of age. None of the brains in Adam’s series was malformed. Rubella virus continues to be recoverable from the CSF for at least 18 months after birth. A form of delayed progressive rubella encephalitis in childhood is also known and is described in Chap. 33 under “Progressive Rubella Panencephalitis.” Because there is no treatment for the active infection, the obvious approach to the problem of congenital rubella infection is to make sure that every woman of childbearing age has been vaccinated against rubella or has antibodies as a result of infection prior to pregnancy. The widespread use of rubella vaccine has reduced the chance of major outbreaks, but sporadic infections continue to be seen, and outbreaks of epidemic proportions continue to occur in developing countries.
Congenital Cytomegalovirus Infection For many years it was known that there were swollen cells containing intranuclear and cytoplasmic inclusions in the tissues of some infants who died in the first weeks and months of life. This cytologic change seemed related to the fatalities.
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In 1956 and 1957, three different laboratories isolated what has come to be called the human cytomegalovirus (see Weller). This has proved to be the most frequent intrauterine viral infection, rivaled in the current era only by HIV. CMV disease is widespread in the general population. Although cervicitis is common, the virus is probably transmitted to the fetus transplacentally. Infection of the fetus usually occurs in the first trimester of pregnancy, sometimes later, by way of an inapparent maternal viremia and infection of the placenta. The newborn can also be infected in the course of delivery or afterward by the mother’s milk or by transfusions. However, only a small proportion of women known to harbor the virus give birth to infants with active infection. The likelihood of the fetus being infected is much greater if the seronegative mother becomes infected for the first time during pregnancy. In one study, 18 percent of infants born to such mothers were symptomatic at birth, and 25 percent became blind, deaf, or mentally retarded within a few years (Fowler et al). In mothers with recurrent CMV infection, the infants were asymptomatic at birth, and only a few developed serious sequelae. Evidently, the presence of maternal antibodies before conception protects against congenital CMV infection. Early infection of the fetus may result in a malformation of the brain; later, there is only inflammatory necrosis from encephalitis in parts of the normally formed brain. Disseminated inflammatory foci have been observed in the cerebrum, brainstem, and retinae. Here there were aggregates of lymphocytes, mononuclear cells, and plasma cells. The mononuclear histiocytes (microglia cells) contain inclusion bodies; some astrocytes are similarly affected. Granulomas form and later calcify, particularly in the periventricular regions. Often there is hydrocephalus. In the low-birth-weight or full-term infant, the clinical picture is one of jaundice, petechiae, hematemesis, melena, direct hyperbilirubinemia, thrombocytopenia, hepatosplenomegaly, microcephaly, mental defect, and convulsions. Cells in the urine may show cytomegalic changes. There is a pleocytosis and an increased protein in the CSF. Congenital CMV infections pose a much greater problem than does rubella. There is no way of identifying the infected fetus prior to birth or to prevent inapparent infections in the pregnant woman. As indicated above, if the pregnant woman has measurable titers of antibodies to CMV at the time of conception, her infant is relatively protected. Moreover, some infected infants (with viruria) may appear normal at birth but develop neural deafness and mental retardation several years later. Viral replication in infected organs continues after the first year and health workers are at risk. A second child may be infected. There is no known treatment. The difficulties in prenatal diagnosis of maternal infection preclude planned abortion. Routine serologic testing should be done on every young woman of childbearing age. Until an effective vaccine becomes available, pregnancy should be avoided if a sexual partner is infected.
Congenital HIV Infection and AIDS In the United States, approximately 10 percent of cases of AIDS have occurred in women, almost all of them of
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childbearing age, and the rate of new cases is increasing at a faster rate among them than among men. The numbers are higher in many developing countries and particularly in parts of Africa. In children, practically all instances of AIDS come from an HIV-infected mother (“vertical transmission”). The infection may be acquired in utero, during delivery, or from breast-feeding. The relative importance of each of these modes of transmission has not been settled. It is estimated that HIV infection and AIDS occur in 15 to 30 percent of infants born to HIV-seropositive mothers (see Prober and Gerson). Infected infants present special difficulties in diagnosis, and the infection runs a more accelerated course in them than in adults. In the perinatal period, infected and noninfected infants can only rarely be distinguished clinically, and laboratory diagnosis is hampered by the presence of maternally derived antibody to HIV. The initial clinical signs usually appear within a few months after birth; practically all infected infants become ill before their first birthday, and very few are asymptomatic beyond 3 years of age. Early signs consist of lymphadenopathy, splenomegaly, hepatomegaly, failure to thrive, oral candidiasis, and parotitis. In the European Collaborative Study, comprising 600 children born to HIV-infected mothers, 83 percent of infected children showed laboratory or clinical features of HIV infection by 6 months of age. By 12 months, 26 percent had clinical symptoms of AIDS and 17 percent had died of HIV-related diseases. Once AIDS is established in children, it does not differ materially from the syndrome in adults as described in Chap. 33. There is often a delay in the attainment of psychomotor milestones. Or after a period of normal development, a psychomotor decline begins, with corticospinal or peripheral nerve signs, often with pleocytosis in the CSF. The typical giant cell AIDS encephalitis, neuritis, and myelitis are easily distinguished from CMV encephalitis and toxoplasmosis. Infected children are also subject to a variety of opportunistic infections, including bacterial meningitis, toxoplasmosis, CMV encephalitis, fungal infections (cryptococcosis, aspergillosis, candidiasis), herpes simplex, syphilis, zoster, and mycobacterial meningitis. There may also be vascular lesions, with infarction or hemorrhage and lymphoid neoplasia. These are discussed in Chaps. 32 and 33. To date, there is little that one can do for these children, but this may be changing with the current use of 3-drug antiretroviral therapy.
Congenital Toxoplasmosis This tiny protozoan Toxoplasma gondii, occurring freely or in pseudocyst form, is a frequent cause of meningoencephalitis in utero or in the perinatal period of life. The disease exists in all parts of the world but is more frequent in Western European countries, particularly in those with hot, humid climates, than it is in the United States. The mother is most often infected by exposure to cat feces, handling uncooked infected mutton or other meat, or eating partially cooked meat, but she is nearly always asymptomatic or has only a mild fever and cervical lymphadenopathy. The precise times of placental and fetal invasion are unknown, but presumably they occur late in the gestational
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period. The clinical syndrome usually becomes manifest in the first days and weeks of postnatal life, when seizures, impaired alertness, hypotonia, weakness of the extremities, progressive hydrocephalus, and chorioretinitis appear. The retinal lesions consist of large pale areas of destroyed retina surrounded by deposits of pigment. If the infection is severe, the maculae are destroyed; optic atrophy and microphthalmos follow. We have several times observed hemiplegias in older infants, first on one side and then on the other, followed by tension hydrocephalus. The latter is present in about one-third of the cases. The CSF contains a moderate number of white blood cells, mostly lymphocytes and mononuclear cells, and the protein content is in the range of 100 to 400 mg/dL (i.e., a higher protein content than all other neonatal infections except bacterial meningitis). The glucose values are normal. Fewer than 10 percent of infected children recover; the others are mentally retarded, with seizures and paralysis. In those without symptoms of infection at birth, the outcome is better. Granulomatous masses and zones of inflammatory necrosis abut the ependyma and meninges. The organisms, 6 to 7 mm in length and 2 to 4 mm in width, are visible in and near the lesions. Microcysts may also be found, lying free in the tissues without surrounding inflammatory reaction. The necrotic lesions calcify rapidly and, after several weeks or months, are readily visible in plain films of the skull. These appear in periventricular and other regions of the brain as multiple nodular densities (see Fig. 38-14). In adults, often in association with AIDS, the disease takes the form of a rapidly evolving meningitis and multifocal encephalitis in conjunction with myocarditis, hepatitis, and polymyositis. This syndrome is described in Chap. 32, as are the diagnostic tests and current treatment. In the infant, infections such as rubella, syphilis, CMV disease, and herpes simplex must be considered in the differential diagnosis. The most reliable means of diagnosis is the IgM indirect fluorescent antibody test, performed on umbilical cord blood. Passive transfer of IgG antibody from mother to fetus takes place, but its presence in the fetus is not proof of active infection. In women who develop antibodies in the first 2 or 3 months of pregnancy, treatment with spiramycin (Rovamycine) prevents fetal infection. Once the fetus is infected, pyrimethamine and sulfadiazine must be used. A later second pregnancy is not affected.
Congenital Neurosyphilis The clinical syndromes and pathologic reactions of congenital neurosyphilis of the newborn are similar to those of the adult, as described in Chap. 32. Such differences that exist are determined principally by the immaturity of the nervous system at the time of spirochetal invasion. The syphilitic infection may be transmitted to the fetus at any time from the fourth to the seventh months. The fetus may die, with resulting miscarriage or stillbirth, or may survive only to be born with florid manifestations of secondary syphilis. The dissemination of the spirochetes throughout the body, the time of appearance of the secondary manifestations,
and the time of formation of antisyphilitic antibodies (reagin) in the blood are all governed by the same biologic principles that apply to adult syphilis. At birth, the spirochetemia may not have had time to cause syphilitic antibodies to appear; hence a negative Venereal Disease Research Laboratory (VDRL) reaction in umbilical cord blood does not exclude congenital syphilis. In unselected groups of syphilitic mothers, 25 to 80 percent of fetuses have been infected, and in 20 to 40 percent of those infected, the CNS is invaded as judged by the finding of abnormal CSF. The types of congenital neurosyphilis (asymptomatic and symptomatic meningitis, meningovascular disease, hydrocephalus, general paresis, and tabes dorsalis) are the same as those in the adult except for the great rarity of tabes dorsalis. The classic Hutchinson triad (dental deformities, interstitial keratitis, and bilateral deafness) is infrequently observed in complete form. The sequence of neurologic syndromes is also the same as in the adult, all stemming basically from chronic spirochetal meningitis. The infection may become symptomatic in the first weeks and months of postnatal life, meningovascular lesions and hydrocephalus reaching maximal frequency during the period from 9 months to 6 years. An early form of syphilitic meningoencephalitis may occur at 1 to 2 years and result in severe mental retardation. More often, a congenital paresis and tabes usually appear between the ninth and fifteenth years. The pathologic basis of the neurosyphilitic syndromes is discussed in Chap. 32. Fewer cases of congenital neurosyphilis are being observed as the years pass, but there may be a recrudescence of the disease in HIV-infected patients. If the syphilitic mother is treated before the fourth month of pregnancy, the fetus will not be infected. The affected infant may be normal at birth or exhibit only mucocutaneous lesions, hepatosplenomegaly, lymphadenopathy, and anemia. In the neonatal period, there are no signs of meningeal invasion, or there may be only asymptomatic meningitis. If the latter is actively treated until the CSF is normal, vascular lesions of brain and spinal cord, hydrocephalus, general paresis, and tabes dorsalis will not develop. Congenital syphilis must be considered a potential, albeit rare, cause of epilepsy and mental retardation. Once the syphilitic infection has been treated in early life and rendered inactive (acellular CSF, normal protein), the occurrence of a congenital infection can only be substantiated by an accurate history; the finding of the syphilitic stigmata in the eyes, teeth, and ears; or a positive serologic reaction in the CSF. Treatment of syphilis in the child follows along the same lines as treatment of the syphilitic adult (Chap. 32), with appropriate adjustment of dosage in accordance with the child’s weight.
Other Viral and Bacterial Infections Several other infections of late fetal life or the neonatal period are only mentioned here, for to describe them all would be excessive and would elucidate no new neurologic principles. Meningitis as a result of the small gram-positive rod L. monocytogenes may be acquired in the usual way, at the time of passage through an infected birth canal or in
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utero, as a complication of maternal and fetal septicemia because of this organism. In the latter case, it causes abortion or premature delivery. Neonatal bacterial meningitis with this organism is a particularly devastating and often fatal type of bacterial infection, not easily diagnosed unless the pediatrician is alert to the possibility of a silent meningitis in every case of neonatal infection. Coxsackievirus B, polioviruses, other enteroviruses, and arboviruses (western equine) seem to be able to cross the placental barrier late in pregnancy and cause encephalitis or encephalomyelitis in the near-term fetus, which is indistinguishable from the disease in the very young infant. Herpes zoster may occur in utero, leaving cutaneous scars and retarding development. Or zoster may appear soon after birth, the infection having been contracted from the mother. Only later in childhood can varicella induce an autoimmune perivenous demyelination and possibly a direct infection, affecting predominantly the cerebellum (Chap. 33), or it may precede the now rare Reye syndrome. Epstein-Barr virus is another frequent cause of meningoencephalitis. In some instances, it may present as aseptic meningitis or a Guillain-Barré type of acute polyneuritis. This infection tends to affect the nervous system of children rather than that of adults, but there are exceptions to this comment. It is estimated that approximately 2 percent of children and adolescents with this infection have some type of neurologic dysfunction; rarely will this be the only manifestation of the disease. Stupor, chorea, and aseptic meningitis were the main neurologic findings in the case reported by Friedland and Yahr, and acute cerebellar ataxia and deafness were observed in the case of Erzurum and associates (see also Chaps. 32 and 33).
EPILEPSIES OF INFANCY AND CHILDHOOD The major types of seizure disorder have already been discussed in some detail in Chap. 16. In bringing them up here, attention is drawn to the fact that epilepsy is mainly a disease of infancy and childhood. Approximately 75 percent of epileptics fall into these age periods, and some of the most interesting and unique types of seizures are peculiar to these epochs of life. Epilepsies that are observed exclusively in infants and children are benign neonatal convulsions; benign myoclonic epilepsy of infancy; febrile seizures (both genetic and acquired); infantile spasms of West; absence seizures; the Lennox-Gastaut syndrome; rolandic and occipital paroxysms and other benign focal epilepsies; and the juvenile myoclonic epilepsies. One principle that emerges is that the form taken by seizures in early life is in part age-linked. Neonatal seizures are predominantly partial or focal; infantile seizures take the form of myoclonic flexor (sometimes extensor) spasms; and the various forms of petit mal are essentially diseases of childhood (4 to 13 years). The motor phenomena of epilepsy in young children are often termed myoclonic, but this should not be confused with other, later-occurring epilepsies that are endowed with the same name. Furthermore, certain epileptic states tend to occur only during certain epochs of life—one type of febrile seizure from 6 months to 6 years, generalized or temporal spike-wave
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activity with benign motor and complex partial seizures from 6 to 16 years, and juvenile myoclonic epilepsy in the mid- and late-adolescent years. In general, idiopathic epilepsy, so called because the cause cannot be determined, is predominantly a pediatric neurologic problem. This is not to say that seizures of unknown cause do not occur for the first time in adult life but rather that the onset of such seizures is far more frequent in childhood and tends to diminish once adulthood is reached. The clinical characteristics of infantile and childhood seizures, including those of genetic origin, are fully described in Chap. 16.
SEVERE FORMS OF MENTAL RETARDATION The subject of mental retardation was introduced in Chap. 28, where it was pointed out that two major categories of this disorder have been delineated. In one, and by far the more common group, the mental limitation is relatively mild, allowing the individual to succeed with training and education; it is often familial and is featured by a lack of definite neurologic abnormalities (except possibly a slightly higher incidence of seizures) and the absence of neuropathologic changes. A large part of this group, falling between 2 and 3 standard deviations below the normal mean IQ, probably are the lower end of the Gaussian curve of intelligence, the converse of which is genius. This group is, however, contaminated with a small number of defined diseases of the nervous system occurring in a less-severe form. In a second group, the degree of mental retardation is usually more severe (IQ of 50 to 70), and yet more so in the third group (IQ less than 50 or not measurable because of limitations of cooperation or physical impediments). Most of the cases in the second and third groups are nonfamilial, and a wide variety of neuropathologic changes are in evidence. The subdivisions are not absolute, for there are a few metabolic and developmental diseases in which mental retardation is profound yet with no somatic or neurologic abnormalities and, most importantly, well-defined neuropathologic changes are lacking. Here we refer to conditions such as Rett syndrome, autism, and the X-linked mental retardation syndromes (Renpenning and fragile X types). In this chapter, these major types of severe mental retardation are described. The overall frequency of severe mental retardation cannot be stated precisely. Rough estimates place the figure at 0.2 to 0.4 percent of the general population and at approximately 10 percent of the general retarded segment of society. It is important to emphasize that in a large proportion of individuals with severe mental retardation, a particular congenital abnormality or anomaly of development cannot at present be traced to any of the disorders reviewed in the preceding pages. More precisely stated, when groups of such severely retarded patients are studied clinically, a reasonably accurate etiologic determination of the underlying brain disease can be made in only slightly more than half. According to Penrose, chromosomal abnormalities account for 15 percent, single-gene disorders for 7 percent, and environmental agents for 20 percent. More recent studies of
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the subtelomeric parts of chromosomes reportedly find abnormalities in another 7 percent of severely retarded children (Knight et al). No cause is found for the remaining cases. Males outnumber females 3 to 1. For purposes of comparison, our figures, obtained from a study of 1,372 patients at the Walter E. Fernald School in the 1970s, are presented in Table 38-8. However, from the neuropathologic standpoint, the examination of the brains of the severely retarded by conventional histopathologic methods discloses lesions in approximately 90 percent, and in fully three-quarters of the entire group, an etiologic diagnosis can be determined or tentatively assigned. Many of the remaining 10 percent lack definite pathologic changes, but their brains are lighter in weight by 10 to 15 percent than age-matched normal brains. Interestingly, the proportion of vascular, hypoxic-ischemic, metabolic, and genetic lesions in this group of severely retarded individuals is much the same as is found in a group selected on the basis of “cerebral palsy.” Here it is important to repeat a point made earlier and in Chap. 28: A few of the severely disabled and a large majority of the mildly retarded do not have a recognizable cerebral pathology or exhibit any of the familiar and conventional signs of cerebral disease. Although the milder forms of mental retardation tend to be familial, this does not by itself separate them from the severe forms of mental retardation. There are several types of hereditary mental retardation, in which the retardation may be severe and in some of which there may be maldevelopment of the cerebral cortex. These are discussed further on.
Clinical Characteristics of the Severely Retarded These cases can be broadly divided into four groups. In one large group, designated dysmorphic retardation, a variTable 38-8 CAUSES OF SEVERE AND MILD MENTAL RETARDATION IN 1,372 PATIENTS AT THE W.E. FERNALD STATE SCHOOL IN THE 1970S NUMBER OF PATIENTS DISEASE CATEGORY
Acquired destructive lesions Chromosomal abnormalities Multiple congenital anomalies Developmental abnormality of brain Metabolic and endocrine diseases Progressive degenerative disease Neurocutaneous diseases Psychosis Cause unknown
IQ 50
% OF ALL PATIENTS
278
79
26.0
247
10
18.7
64
16
5.8
49
16
4.7
38
5
3.1
5
7
0.9
4 7 385
0 6 156
0.3 1.0 39.5
ety of physical deformities, including microcephaly, is commonly present. In a second group, with multiple-system retardation, the mental retardation is linked to nonskeletal abnormalities (e.g., hepatosplenomegaly, hematologic and skin disorders), which provide reliable clues to the underlying somatic disease. In a third group, neurologic retardation, somatic abnormalities are lacking but a configuration of neurologic signs leads to the diagnosis. In the fourth group, and the most difficult one to clarify, that comprising uncomplicated retardation, there are no or minimal somatic, visceral, or neurologic abnormalities. One is then forced to turn to special features of the mental retardation itself for identification of the underlying disease. Table 38-9 elaborates a reasonable classification of the types of mental retardation. The profoundly retarded infant with a virtually untestable IQ is identified early in life because he does not sit, stand, or walk. If any one of these motor activities is acquired, it appears late and is imperfectly performed. Language never develops; at most a few spoken words or phrases are understood and fewer are uttered, or the patient only vocalizes in a meaningless way. Such a person may not even indicate bodily needs for food, drink, excretion, and so on. Usually the patient is continuously idle and interacts little with people and objects. Only the most primitive emotional reactions are exhibited, often without connection to an appropriate stimulus. Physical growth is usually retarded, nutrition may be poor, and susceptibility to infections is increased. Sphincteric control may never be attained and, if attained, is precarious. When the mental defect is less severe than described above, falling into the IQ ranges of 20 to 45, or 45 to 70, there may be somatic neurologic abnormalities. If specific motor defects do not coexist, then sitting, standing, and walking are achieved but not at the expected times. The existence of a mental defect is most clearly evidenced by a delay in psychomotor development and a failure to speak by the second or third postnatal year. The patient does not acquire the usual household and play activities as well as other children. However, delay in speech development must not, by itself, be taken as a mark of mental retardation, for in some children a unique delay in speech can be an isolated abnormality as described in Chap. 28, with subsequent normal development of speech and mental ability. Toilet training may be difficult to accomplish in the retarded child, but, again, bedwetting may be a problem in an otherwise normal child. Also, the deaf child may have to be considered separately; here the problem becomes apparent by an indifference to noise and reduced vocalization (stereotypy of babbling). More thorough analyses of cognitive functions in the moderately retarded child have been undertaken by O’Connor and Hermelin, Pulsifer, and others. These authors measured the efficiency of visual and auditory perception, adequacy of communication, relations between language development and thought, crossmodal sensory encoding, alertness, attention, and memory. It was concluded that none of these functions was specifically impaired. Instead, the retarded child could not properly encode new information because the memory systems and the stock of past assimilated knowledge were insufficient to
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Table 38-9 TYPES OF SEVERE MENTAL RETARDATION I. Dysmorphic defect with somatic developmental abnormalities in nonnervous structures A. Those affecting cranioskeletal structures 1. Microcephaly 2. Macrocephaly 3. Hydrocephalus (including myelomeningocele with Chiari malformation and associated cerebral anomalies) 4. Down syndrome 5. Cretinism (congenital hypothyroidism) 6. Mucopolysaccharidoses (Hurler, Hunter, and Sanfilippo types) 7. Acrocephalosyndactyly (craniostenosis) and other craniosomatic abnormalities 8. Arthrogryposis multiplex congenita (in certain cases) 9. Rare specific syndromes: De Lange 10. Dwarfism, short stature: Russel-Silver dwarf, Seckel bird-headed dwarf, Rubinstein-Taybi dwarf, Cockayne-Neel dwarf, etc. 11. Hypertelorism, median cleft face syndromes, agenesis of corpus callosum B. Those affecting nonskeletal structures 1. Neurocutaneous syndromes: tuberous sclerosis, Sturge-Weber, neurofibromatosis 2. Congenital rubella syndrome (deafness, blindness, congenital heart disease, small stature) 3. Chromosomal disorders: Down syndrome, some cases of Klinefelter syndrome (XXY), XYY, Turner (XO) syndrome (occasionally), and others 4. Laurence-Moon-Biedl syndrome (retinitis pigmentosa, obesity, polydactyly) 5. Eye disorders: toxoplasmosis (chorioretinitis), galactosemia (cataract), congenital rubella 6. Prader-Willi syndrome (obesity, hypogenitalism) II. Nondysmorphic mental defect without somatic anomalies but with cerebral and other neurologic abnormalities A. Cerebral spastic diplegia B. Cerebral hemiplegia, unilateral or bilateral C. Congenital choreoathetosis or ataxia 1. Kernicterus 2. Status marmoratus D. Congenital ataxia E. Congenital atonic diplegia F. Syndromes resulting from hypoglycemia, trauma, meningitis, and encephalitis G. Associated with other neuromuscular abnormalities (muscular dystrophy, cerebellar ataxia, etc.) H. Cerebral degenerative diseases (lipidoses) I. Associated with inborn errors of metabolism (phenylketonuria, other aminoacidurias, organic acidurias, Lesch-Nyhan syndrome) J. Congenital infections (some cases of congenital syphilis, cytomegalic inclusion disease) III. Genetic mental defect with minor or no signs of somatic abnormality or neurologic disorder A. Infantile autism, Renpenning, Williams, fragile X, Partington, and Rett syndromes
provide a framework of items and categories with which new information could be integrated. Some patients also seemed unable, perhaps on the basis of this encoding problem, to extract from perceived material selective features that could be interpreted. Furthermore, they were unable to deal with an array of sensory experiences like normal children. The complexity of these mental operations, which we would reduce to a global failure of the normal processes of apperception and integration, was called by Piaget a “failure of assimilation and accommodation.” However, within the spectrum of mental retardation, apart from cognitive impairments, there are curious differences in behavior and personality, even in those with more or less the same IQ. Some individuals with moderately severe retardation are pleasant and amiable and achieve a satisfactory social adjustment. This is particularly notable in patients with Down and Williams syndromes. At the opposite end of the behavioral scale are the syndromes of autism and that of Smith-Magenis and of DeLange, in which the individual fails to manifest normal interpersonal social contact, including communicative language. The phenylketonuric child is usually irritable, unaffectionate, and implacable, and the same is said of certain other forms of retardation, discussed earlier in the section on retardation with dwarfism. Regarding differences in motor activity levels, many retarded individuals are slow, clumsy, and relatively aki-
netic. Others, as many as half, display an incessant hyperactivity characterized by a restless, seemingly inquisitive searching of the environment. When thwarted, they may exhibit a low frustration tolerance. They may be destructive and recklessly fearless and impervious to the risk of injury. Some exhibit a peculiar anhedonia that renders them indifferent to both punishment and reward. Other aberrant types of behaviors, such as violent aggressiveness and self-mutilation, are common. Rhythmic rocking, head-banging, incessant arm movements—so-called rhythmias or movement stereotypies—are observed in the majority of those who are severely and moderately severely retarded. These movements are maintained hour after hour without fatigue and may be accompanied by breathing sounds, squeals, and other exclamations. A number of them tend to be particularly common in certain forms of retardation: hand-flapping in autism, handwringing in Rett syndrome, and hand-waving in Down syndrome and other disorders. Self-stimulation, even hurtful—such as striking the forehead or ears or biting the fingers and forearms—seems to be compulsive or perhaps to provide some sort of satisfaction. It is not that these rhythmias are by themselves abnormal, for some of them occur for brief periods in normal babies, but that they persist. Nevertheless, many moderately retarded persons, when assigned to a simple task such as putting
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envelopes in a box, can continue this activity under supervision for several hours. In the least-severe types of retardation, all the mental activities are intact but subnormal. The point to be made is that all aspects of intellectual life, personality, and deportment are affected in slightly differing degrees and that these effects have a neurologic basis. There is more than a hint that in particular diseases, because of their anatomy, the cognitive experience, affective life, and behavior are affected in special ways. The group of moderately retarded, like the severely retarded, is divisible into groups with somatic systemic and neurologic abnormalities, although the proportions are not the same. There are fewer of the dysmorphic type and more of the nondysmorphic, nonneurologic group.
Etiology of Severe Mental Retardation From Table 38-1 it is obvious that many diseases can blight the development and maturation of the brain. Some of these are acquired and some are congenital and hereditary. Some affect all parts of the organism, giving rise to associated dermal, skeletal, and visceral abnormalities, while others affect only the nervous system in particular patterns. With respect especially to the milder degrees of mental retardation, in all populations thus far studied, infants of extremely low birth weight are more likely to have disabilities, brain abnormalities, and poorer language development and scholastic achievement (Chap. 28). Mild mental retardation also tends to correlate with lower social status, which must relate in some manner to biological factors, as pointed out in the Scottish Low-Birth-Weight Study. Viral and spirochetal infections and parturitional accidents are other common causes. They act acutely and are theoretically preventable. The factor of malnutrition during the fetal or infantile period of life as a cause of severe mental retardation has received considerable attention because it is a worldwide problem. Animal experiments by Winick and others demonstrated that severe undernutrition in early life leads to behavioral abnormalities and biochemical and morphologic changes in the brain, which may be permanent (see Chap. 41). Galler studied a group of infants in Barbados who were severely malnourished during the first year of life and then given an adequate diet. These children were followed to adulthood and compared with normally nourished siblings. No effect was observed on physical growth, but there were persistent attention deficits in 60 percent of the undernourished group and in only 15 percent of controls. The IQ scores of the former were also lower. Unfortunately, genetic factors could not be completely controlled for. In general, it may be said that the data showing mental retardation to be caused by malnutrition, while suggestive, are far from convincing. Severe protein-calorie malnutrition in the first 8 months of life, which induces kwashiorkor, has been reported to retard mental development. However, such patients are said to regain mental function when fed. The authors have been impressed with the ability of the nervous system to withstand the effects of nutritional deficiency, perhaps better than any other organ. The action of exogenous toxins during pregnancy is another factor to be considered. Severe maternal alcohol-
ism has been linked to a dysmorphic syndrome and mental retardation, but the findings of several studies have not been consistent (see Chap. 42); a similar problem attaches maternal exposure to anticonvulsant medications (see Chap. 16). Surprisingly, maternal addiction to opiates, while causing an opiate withdrawal in infants for weeks or even months (Wilson et al), seems not to result in permanent injury to the nervous system. The importance of exposure to extremely small amounts of environmental lead is also controversial. The effect of psychologic deprivation on cognitive development has been of interest. Following the observations that complete isolation of young female monkeys had a devastating effect on their later sexual and nurturing behavior, the idea became popular that such deprivation might cause faulty mental development in humans. Orphaned and neglected babies were found to be inactive, apathetic, and backward in comparison with those who were constantly stimulated by caring mothers. But surprisingly, when nurtured properly at a later time, these babies soon caught up with their peers. This general idea of psychologic deprivation has been the basis of many interesting educational programs for poor and neglected children. To this day, however, it has not been proven that sensory, emotional, and psychologic deprivations of a degree observed in humans are the causes of severe mental retardation or repeated scholastic failure. The controversies regarding the effects of prematurity, maternal hypertension, and eclampsia, which are often associated with neonatal cerebral pathology and slowed psychomotor development, have been mentioned earlier in this chapter. The problem is complex and the arguments pro and con have been elaborated by Haywood and Wachs.
Differentiation of Types of Retardation: Clinical Approach As a particular guide to the pediatrician and neurologist who must assume responsibility for the diagnosis and management of backward children harboring a wide array of diseases and maldevelopments of the nervous system, the following clinical approach is suggested. First, as already described, there is an advantage in setting aside as one large group those who are only mildly retarded from those who have been severely delayed in psychomotor development since early life. With regard to the former group, having no obvious neurologic signs or physical stigmata, one should nevertheless initiate a search for the common metabolic, chromosomal, and infective diseases. In this large group, one must be sure that their deficit is a general one and not one of hearing, poor sight, or the special isolated language and attention deficits described in Chaps. 23 and 28. For patients with moderately severe and very severe cognitive deficits, one begins with a careful physical examination, searching specifically for somatic stigmata and neurologic signs. Abnormalities of eyes, nose, lips, ears, fingers, and toes are particularly important, as are head circumference and a variety of neurologic abnormalities, as outlined in Table 38-9. Data so obtained allow classification into one of three categories, as follows:
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In those with somatic abnormalities (with or without obvious neurologic signs), one assumes the presence of a maldevelopment of the brain, possibly caused by a chromosomal abnormality. The psychomotor retardation is usually severe and often nongenetic and, as a rule, has a well-defined neuropathology. Diagnosis is determined by the gestalt of physical signs. The possible maldevelopments are numerous and diverse and are summarized in Tables 38-1 and 38-9; some of the main ones are described earlier in the chapter. Inevitably, one turns to the several atlases to denominate the syndromes (Holmes et al; Jones). In the group in which the abnormalities are confined to the nervous system, attention is focused on a larger number of diseases, many caused by exogenous factors such as perinatal hypoxia-ischemia, pre- or postnatal infections, trauma, and so on. There are usually conspicuous neurologic signs. The degree of mental retardation is variable, depending on the location and extent of a demonstrable neuropathology. Usually the family history is negative, but careful questioning of parents regarding the pregnancy, delivery, and early postnatal period and examination of hospital records from birth may disclose the nature of the neurologic insult. The third category is one in which neither somatic anomalies nor focal neurologic signs are present, or if present, they are minimal. The more severely retarded of this special group are represented by the following disease states: autism (Asperger-Kanner syndrome), the Rett and Williams syndromes, and the fragile X and Renpenning syndromes. All of these but autism are now known to have a genetic basis as noted earlier in the chapter and are described together below. The practical importance of this clinical approach is that it directs the intelligent use of laboratory procedures for confirmation of the diagnosis. CT scanning and MRI are useful in clarifying maldevelopment and neurologic diseases but are seldom helpful in the third group of cases. EEG confirms seizure discharges when there is uncertainty as to the nature of episodic neural dysfunction. Karyotyping and genetic studies are useful in group 1 and rarely in group 2. A major pitfall in this clinical approach is in mistaking a hereditary metabolic disease for a developmental one. Here one is helped by the fact that manifestations of the metabolic diseases are not usually present in the first days of life; they appear later and are progressive and often associated with specific visceral abnormalities. However, some metabolic diseases are of such slow progression that they appear almost stable, especially the late-onset ones, such as one type of metachromatic leukodystrophy, late-onset Krabbe leukodystrophy, adult adrenoleukodystrophy, and adult hexosaminidase deficiency (see Chap. 37).
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individuals. A large kindred in whom mental retardation was inherited in an X-linked pattern was first reported by Martin and Bell in 1943. It was in such a family, with Xlinked mental retardation, that Lubs, in 1969, discovered a fragile site at the distal end of the long arm of the X chromosome; subsequently, it was established that there is an unstable inherited CGG repeating sequence at this site, which leads to breakage, as discussed previously. At first, it was assumed that the fragile X syndrome was only an example of the Renpenning syndrome (an X-linked hereditary mental retardation in males; see below) until it was pointed out that in this latter condition, stature was reduced, as was the cranial circumference, and further that the X chromosomes of the Renpenning patients were normal. The nature of chromosomal breakage that can be attributed to an expanded trinucleotide repeat sequence of the FMR1 gene and a resultant loss of protein function were discussed earlier in “Other Chromosomal Dysgeneses.” In some series, fully 10 percent of mentally retarded males have this fragile X chromosomal abnormality, although 2 to 4 percent is more accurate according to other series. Females are sometimes affected, but their mental function is only slightly reduced. Affected males have only mild dysmorphic features (large ears, broad forehead, elongated face, and enlarged testes) that may not become obvious until puberty. Others are somatically normal. Behavioral problems of one sort or another are almost universal. Pulsifer, whose review of the neuropsychologic aspects of mental retardation is recommended, lists self-injurious, hyperactive, and impulsive behaviors as the most common. The hand-flapping that is more characteristic of autism may be seen. Fragile X Premutation Syndrome of Adults As discussed in Chap. 5, a curious form of progressive adult onset ataxia and tremor, previously thought to be of a degenerative type, has been discovered to be caused by a “premutation” of the fragile X gene (50 to 200 trinucleotide repeats). Some of these patients have characteristic symmetrical signal MRI changes in the middle cerebellar peduncles in the T2 sequence. Other unusual late presentations have been described, including a spastic paraparesis without ataxia or tremor (Cellini et al). A report by Grigsby and coworkers suggests that cognitive function may be diminished in these men, but only when adjusted for their level of education and not compared to normative data; the observation requires confirmation and any suggestions that a fragile X premutation is responsible for dementia in adults should be accepted cautiously. The permutation expansion may be manifest in women as premature ovarian failure. In contrast to the mutation that causes mental retardation, this disorder is thought to be related in some way to an excess of messenger RNA. Several papers suggest that the premutation may also be the cause of some cases of mild retardation and autistic-like behavior.
Fragile X Syndrome (See earlier discussion under
Rett Syndrome
“Other Chromosomal Dysgeneses”) Great interest has been evinced in this syndrome, which some geneticists hold accountable at least in part for the preponderance of males among institutionalized retarded
This is yet another hereditary form of mental retardation, but one that affects girls. None of the cases in the extensive studies of Hagberg and coworkers (1983) was male. The responsible spontaneous mutation has been shown to relate
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to a defect at chromosomal site Xq28, making it one of the X-linked mental retardations. A fatal outcome in boys because of a severe neonatal encephalopathy explains the expression of the disease only in girls, who are mosaics for the mutation. The involved gene, MECP2, is responsible for suppressing various other genes at critical stages of development (see Dunn and MacLeod). It has this effect by binding to methylated DNA. Defective function of the gene leads to an alteration in synaptogenesis and neural connectivity (Neul and Zoghbi). Severe inactivation of gene expression causes classic Rett syndrome, but it has become apparent that incomplete expression and mosaicism lead to a number of partial syndromes, including nonspecific mental retardation, tremor, psychiatric disturbances, and autism-like presentations. Prevalence studies from Sweden indicate an occurrence of 1 per 10,000 girls; thus Rett syndrome is more common than phenylketonuria. Although most cases appear to be sporadic, there is a high familial incidence and some degree of concordance in twins (this is still uncertain). The syndrome is usually marked by withdrawn behavior that simulates autism, dementia, ataxia, loss of purposeful hand movements, and respiratory irregularities. Highly characteristic is a period of 6 to 18 months of normal development followed by the rapid appearance and progression of all these signs, and then by relative stability for decades. Spasticity, muscle wasting, scoliosis, and lower limb deformities may become evident in the late stages of the illness. Handwringing and similar stereotypes are very typical features (and are different in subtle ways from the hand-flapping of autistic children). Armstrong and Naidu, who have reviewed the neuropathology of Rett syndrome, have drawn attention to a number of subtle cortical abnormalities, most of which are consistent with disruption of the postnatal integrative phase of cerebral development; however, not all cases showed these abnormalities. There is generally a decrease in brain size, most marked frontally. Dendritic branching is reduced in several areas. The MRI scan is normal, but some patients show frontal or cerebellar atrophy in their teenage years.
Partington Syndrome This is yet another X-linked type of mental retardation, which in its fully expressed form is associated with prominent dystonia of the hands and sometimes of the feet, or ataxia. Like Rett syndrome, discussed above, variations in gene expression appear to cause other syndromes including myoclonic epilepsy, West syndrome, autism, and nonspecific retardation, as well as lissencephaly. The mutated gene, termed Aristaless-related homeobox (ARX), is involved with regulation of protein-DNA interactions. The subject is reviewed by Sherr.
Renpenning Syndrome A similar type of hereditary, male-sex-linked mental retardation was described by Renpenning and associates (and subsequently associated with Renpenning’s name). The originally described family comprised 21 males in 2 generations of Mennonites in western Canada whose IQs
ranged from 30 to 40. As with the fragile X syndrome, female siblings may show slight degrees of retardation. Affected members were small in stature and slightly microcephalic but otherwise free of somatic and neurologic abnormalities.
Williams Syndrome This inherited form of mental retardation is manifest in both males and females and was mentioned earlier under “Other Chromosomal Dysgeneses.” It is characterized by mild mental retardation but with striking retention and even precocity or superiority of musical aptitude and social amiability. In some instances, a retained facility for writing permits the production of long, written descriptions; yet at the same time, these subjects are barely able to draw simple objects. The child is physically slow and has minor but distinctive somatic changes (wide mouth, almond-shaped eyes, upturned nose, small pointed ears), together imparting an “elfin appearance.” There is often an unusual sensitivity to auditory stimuli. The delay in acquisition of communicative speech and defects in visual, spatial, and motor skills make these children seem more deficient than they actually are. Striking sociability and empathy set them apart; they represent virtually the converse of autism in this respect. Memory for musical scores—such as memorizing parts of a complete symphony after one hearing—may be prodigious. By the use of high-resolution cytogenetics, the disease has been traced in 90 percent of cases to a microdeletion on chromosome 7 in the region of the gene that controls the production of elastin (Nickerson et al). This is of interest because an index feature of these cases is supravalvular aortic stenosis. It is not known whether there is a characteristic brain pathology, but one 35-year-old patient examined by Golden and associates showed no cerebral abnormalities except for Alzheimer changes, mainly plaque formation in the entorhinal cortex and amygdala. A most interesting related finding by Somerville and colleagues is that duplication at the same site on chromosome 7 implicated in Williams syndrome can cause a delay in the acquisition of expressive speech.
Doublecortin Mutations Among the disorders of cerebral sulcation, lissencephaly and the related disorder of subcortical band heterotopia are usually associated with severe defects in mental development. However, in female carriers, other mutations in the doublecortin gene (DCX) on the X chromosome have given rise to mild nondysmorphic mental retardation and cryptogenic epilepsy (see Guerrini and colleagues). Thus this disorder joins the group of X-linked mental retardations with minimal dysmorphic features and has implications for the understanding of X-chromosome inactivation in female carriers.
Autism (Kanner-Asperger Syndrome; Autistic Spectrum Disorders) This condition was described almost simultaneously by Kanner in Baltimore (in 1943) and Asperger in Vienna (in 1944). Among a large group of retarded children, Kanner
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observed exceptional ones who appeared to be asocial, lacking in communicative skills both verbal and nonverbal, and committed to repetitive ritualistic behaviors. At the same time certain intellectual capacities—such as focused attention, retentive memory, skilled sensory and motor aptitudes, and capacity for visuospatial perception—were often retained or overly developed. In other words, the disorder pervaded only certain aspects of mental development. It is the gestalt of negative and positive aptitudes that sets this syndrome apart from other types of retardation. Kanner incorrectly ascribed the condition to psychosocial factors—such as a cold, aloof parent—and regarded it as a psychopathy. The implication that these children are literally “autistic”—i.e., that they have a rich inner psychic life or dream world out of relation to reality—is an assumption wholly without foundation. Asperger, whose observations included somewhat older children who were less completely disabled, later ascribed the retardation (also incorrectly) to a metabolic disease, possibly related to hyperammonemia. Opinion varied as to the relationship between the severe Kanner syndrome and the less-severe Asperger syndrome. The authors have taken the more modern view that these forms of autism represent a single syndrome of varying severity, with similar pathologic underpinnings but possibly of multiple etiologies, including genetic. Some 1 percent of autistic children are of normal or superior intelligence. Despite many claims to the contrary, there is no evidence of a psychogenesis. However, as Rapin points out, behavioral modification and special education are beneficial for less-severely affected children. The overall prevalence of the autistic state has been calculated at 4.5 to 20 per 10,000. Although there is said to be no familial tendency, this is almost certainly incorrect; we have seen the disease in both identical twins and in brothers, and small familial subgroups are known to exist. Autistic traits, without the full syndrome, are being found with increasing frequency in sibs and other family members, suggesting a polygenic inheritance. DeMyer found that 4 of 11 monozygotic twins were concordant for autism and that siblings have a 50 times greater risk of developing the disorder than normal children. Bailey and associates and also LeCouteur and associates have reported a concordance rate in monozygotic twins of 71 percent for the autistic spectrum disorder (as defined below) and 92 percent for an even broader phenotype of disordered social communication and stereotypic or obsessive behaviors. DeLong finds an increased incidence of bipolar disease in the families of one group of autistic children and superior mathematical aptitudes in other family members. The recent elucidation of microdeletions and microduplications within chromosome 16p by Weiss and the Autism Consortium is the first hint of a genetic locus for susceptibility to autism. Despite a high degree of penetrance, the importance of these findings is as a biologic direction for research as it explains no more than 1 percent of cases.
Clinical Features The autistic child is ostensibly normal at birth and may continue to be normal in achieving early behavioral sequences
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until 18 to 24 months of age. Then an alarming regression occurs, sometimes fairly abruptly. In some instances, the abnormality appears even before the first birthday and the child is identified as different in some way by the mother; or, if there had been a previously autistic child, she recognizes the early behavioral characteristics of the disorder. The level of activity is reduced or increased. There may be less crying and an apparent indifference to surroundings. Toys are ignored or held tenaciously. Spinning toys or running water may hold a strange fascination for the child. Cuddling may be resisted. Motor developments, on the other hand, proceed normally and may even be precocious. Later there may be an unusual sensitivity to all modes of sensory stimulation. Occasionally the onset appears to have a relationship to an injury or an upsetting experience. Regardless of the time and rapidity of onset, the autistic child exhibits a disregard for other persons; this is typically quite striking but can be subtle in milder cases. Little or no eye contact is made, and the child is no more interested in another person than in an article of furniture. Proffered toys may be manipulated cleverly, placed in lines, or rejected. Insistence on constancy of environment may reach a point where the patient becomes distraught if even a single one of his possessions has been moved from its original place and remains distressed until it is replaced. If speech develops at all, it is automatic (echolalic) and not used effectively to communicate. A repertoire of elaborate stereotyped movements—such as whirling of the body, manipulating an object, toe-walking, and particularly hand-flapping—are characteristic. It is important to point out, that in any sizable group of autistic children there is a wide range of deficits in sociability, drive, affect, and communicative (verbal and gestural behavior) ability, ranging from an averbal, completely isolated state to considerable language skill and some capacity for attachment to certain people as well as for scholastic achievement. However, the IQ of the majority is below 70 and in 20 percent it is below 35; 1 percent, however, have normal or superior intelligence. In this higher-functioning group, taken to typify the Asperger syndrome, the child may be unusually adept or even supernormal in reading, calculating, drawing, or memorizing (“idiot savant”) while still having difficulty in adjusting socially and emotionally to others and in interpreting the actions of others. Many are clumsy and inept in athletic activities. The least degree of deficit allows success in a professional field but with handicap in the social sphere. We take the current emphasis on the term autistic spectrum disorders to reflect a concept that each of the core elements of autism (in social, language, cognitive, and behavioral domains) may occur in widely varying degrees of severity. This view expands the diagnosis to many children who are highly functional except for a tendency to gaze aversion and other “soft signs,” together called “pervasive developmental disorder” (Filipek). There is also crossover with a number of namable mental retardations as noted below. Rapin, drawing on a large clinical experience, has carefully documented the linguistic, cognitive, and behavioral features of the syndrome. She uses the term semantic-pragmatic disorder to designate the characteristic problem with language and behavior and to distinguish it from other forms of develop-
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mental disorders and mental retardation. There is a striking ability to understand isolated facts but not to comprehend concepts or conceptual groupings; consequently, these children and adults seem to have difficulty generalizing from an idea. Temple Grandin, a patient with a high-functioning Asperger type of autism who has written of her experiences and has been described by Sacks, indicates that she thinks in pictures rather than in semantic language. She reports a curious comfort from being tightly swaddled and has a highly developed emotional sensibility to the experiences of cattle, which has allowed her success in reforming and designing abattoirs. According to Eisenberg, who reviewed many of Kanner’s original cases and followed many other cases into adult life, one-third never spoke and remained social isolates, one-third acquired a rudimentary language devoid of communicative value, and the remainder were functional to various degrees, possessing an affected, stilted, colorless speech. It is in the latter group, representing the mildest degrees of autism, that one finds eccentrics, the mirthless, flat personalities, unable to adapt socially and habitually avoiding eye contact but sometimes possessing certain unusual aptitudes in memory, mathematics, factual knowledge, history, and science. Rutter, who has written extensively on the subject, says that the degree of language impairment and lowered intelligence predicts outcome; those who do not speak by 5 years of age never learn to speak well. As mentioned, elements of autism, but not the whole syndrome with its positive and negative attributes, may appear in other diseases that interfere with brain development, specifically fragile X and Rett syndromes, and fragmentary similarities are found in a few children with phenylketonuria, tuberous sclerosis, Angelman syndrome, and, rarely, Down syndrome—but these patients are easily distinguished from those with the far more common type of autism. Bolton and Griffiths have made the intriguing observation that autistic traits in patients with tuberous sclerosis correspond to the finding of tubers in the temporal lobe, and DeLong and Heinz point out that patients with seizures from bilateral (but not unilateral) hippocampal sclerosis may fail to develop (or may lose) language ability as well as failing to acquire social skills after a period of normal development, in a manner similar to autism.
Etiology and Pathology of Autism The basis of childhood autism is as much a mystery today as it was when Kanner and Asperger described it. Most of these children are physically normal except for a slightly larger head size, on average, but with no other somatic anomalies. Despite instances in which the onset of mental and behavioral regression seems to be quite sudden, no environmental factors, including the often-mentioned measles-mumpsrubella (MMR) vaccination, mercury exposure, and food allergies, have been credibly connected to autism. The genetic microdeletions and microduplications described earlier have given few hints as to the biologic cause. The EEG is normal, as is CT or MRI. The significance of cerebellar vermal changes, reported originally by Courchesne and colleagues, remains uncertain (Filipek). In the few brains examined postmortem, no lesions of any of the conventional types have been found. In 5 brains studied in serial sections
by Bauman and Kemper, smallness of neurons and increased packing density were observed in the medial temporal areas (hippocampus, subiculum, entorhinal cortex), amygdala and septal nuclei, and mammillary bodies. In a subsequent review of the neuropathology, Kemper and Bauman concluded that three changes stood out: a curtailment of the normal development of neurons in the limbic system; a decrease in the number of Purkinje cells that appears to be congenital; and agerelated changes in the size and number of the neurons in the diagonal band of Broca (located in the basal frontal and septal region), as well as in the cerebellar nuclei and inferior olive. The latter changes were inferred from studying the brains of autistic children who died at different ages, and they gave the appearance of a progressive or ongoing pathology that continues into adult life. These findings are in keeping with the concept of autism as a neurodevelopmental disorder, but they allow only speculation regarding the derivation of the clinical features of the disease. An increased concentration of platelet serotonin and low serum serotonin is detected in many but not all patients; also, serum oxytocin is reduced. The biologic significance of these findings is unclear.
Course, Treatment, and Prognosis The disease is essentially nonprogressive although some patients, as they grow older, begin to manifest additional visuoperceptive or auditory defects. In the typical case, the outcome is bleak, although many less affected children show improvement in social relationships and schoolwork when given a serotonin reuptake inhibitor, sometimes in very small doses (DeLong; Filipek, personal communication). Administration of the peptide secretin had produced a number of anecdotal successes, but this could not be reproduced in controlled studies. Selective serotonin reuptake inhibitors (e.g., fluoxetine, citalopram) have also shown some benefit in managing repetitive behaviors and mood swings such that medications in this class are being widely prescribed to autistic children. In addition, serious behavioral changes such as self-injurious activities, aggression, and severe tantrums have been treated with drugs such as risperidone. These represent a therapeutic advance but, as pointed out by Hollander and colleagues in their review of the drug treatment of autism, the patients studied were selected for the severity and type of their symptoms for which reason these medications cannot be expected to be of help to all autistic individuals.
Management of Mental Retardation Because there is little or no possibility of treating most of the diseases underlying mental retardation and there is no way of restoring function to a nervous system that is developmentally subnormal, the objective is to assist in planning for the patient’s care, training, education, and social adjustment. The parents must be guided in forming realistic attitudes and expectations. Psychiatric and social counseling may help the family to maintain gentle but firm support of the patient so that he can acquire, to the fullest extent possible, good work habits and a congenial personality. Most individuals with an IQ above 60 and no other handicaps can be trained to live an independent life; spe-
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cial schooling may enable them to learn skills useful in a vocation. Social factors that contribute to underachievement must be sought and eliminated if possible. If the IQ is below 20, institutionalization is almost inevitable, for few families can provide the long-term custodial care that is needed. Well-run institutions are usually better than community homes because they offer many more facilities (medical, educational, recreational). Often institutional care is necessary for individuals with IQs of 20 to 50. Patients in this group, if stable in temperament and relatively well adjusted to society, can work under supervision, but they rarely become vocationally independent. For the more severely retarded, special training in hygiene and self-care is the most that can be expected.
Great care must be exercised in recommending institutionalization. Whereas the need will be all too apparent in the gravely retarded by the first or second year of life, the less-severely affected are difficult to evaluate at an early age. As stated earlier, psychologic tests alone are not altogether trustworthy. It is best to observe the patient over a period of time. As noted in Chap. 28, the method of evaluation suggested long ago by Fernald has a ring of soundness, albeit in quite dated terms. It should include observations of (1) the physical, medical, and neurologic findings; (2) family background; (3) developmental history; (4) school progress or lack thereof; (5) performance tests; (6) social behavior; (7) industrial efficiency; (8) behavioral disinhibition, which was called in Fernald’s time “moral behavior”; and (9) intelligence as measured by psychological tests.
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39 Degenerative Diseases of the Nervous System
The adjective degenerative has no great appeal to the modern neurologist. It is also not an entirely satisfactory term medically, as it implies an inexplicable decline from a previous level of normalcy to a lower level of function—an ambiguous conceptualization of disease that satisfies neither clinician nor scientist. Moreover, it gives no hint as to the fundamental causation of a process and in all likelihood combines a number of mechanisms under one nondescript term. It would be tempting to attribute all progressive disease of the nervous system that are of unknown cause to degeneration. The problem is that many degenerative diseases of mundane type are caused in a proportion of cases by germ line genetic changes. All are currently called degenerative, but this nosology may be a transitional method of holding a place while awaiting more refined understanding. What is lacking at the moment is a precise subcellular mechanism for cellular loss; i.e., knowing the mutation that is associated with a disease is not equivalent to understanding the cause of an illness. In future editions of this book, it is very likely that an increasing number of degenerative diseases will be relegated to different and perhaps new categories. It is becoming increasingly evident that many of the diseases included in this category depend on genetic factors, or at least they appear in more than one member of the same family, in which case they are more properly designated as heredodegenerative. Even more diseases, not differing in any fundamental way from the heredodegenerative ones, occur sporadically, i.e., as isolated instances in given families. For diseases of this type, Gowers in 1902 suggested the term abiotrophy, by which he meant a lack of “vital endurance” of the affected neurons, resulting in their premature death. This concept embodies an unproven hypothesis—that aging and degenerative changes of cells are based on the same process. Understandably, contemporary neuropathologists are reluctant to attribute to simple aging the diverse processes of cellular diseases that are constantly being revealed by ultrastructural and molecular genetic techniques. The reader may be perplexed by the inconsistent use of the terms atrophy and degeneration, both of which are applied to diseases of this category. Spatz argued they are different on purely histopathologic grounds. Atrophy is an anatomical term that specifies a gradual wasting and loss of a system of neurons, leaving in their wake no degradative products and only a sparsely cellular gliosis. Degeneration is
a clinical and pathologic term that refers to a process of neuronal, myelin, or tissue breakdown, the degradative products of which evoke a reaction of phagocytosis and cellular astrogliosis. There are many examples of diseases that were formerly classed as degenerative but are now known to have a genetic, metabolic, toxic, or nutritional basis, or to be caused by a “slow virus” or a nonviral transmissible agent. It seems reasonable to expect that an increasing number of diseases whose causes are now unknown will find their way into these categories, many of which are likely to be based on subcellular pathologies. As was pointed out in Chap. 29 on aging, more than half of the normal life cycle of an organism involves a slow deterioration of organ function. Such changes in the nervous system are manifest in every sensory and motor system and in all cerebral functions. The basis of these aging changes is theoretically at the neuronal level, but the focus is not understood. A fundamental problem is the distinction of these aging deteriorations from degenerative disease. When the latter appears in adult life, one must assume that the clinical presentation is modified to some extent by life-cycle phenomena—the patient’s function being a sum of both processes. However, their separation is of fundamental importance in diagnosis and therapeutics. Much new and essential information has been gained regarding the biologic derangements that lead to neuronal death and dysfunction by investigating the inherited forms of degenerative diseases. The application of the techniques of molecular genetics to these diseases have given stunning results. Even when the hereditary form of a degenerative condition is rare in comparison to sporadic type and does not entirely conform on clinical grounds to idiopathic disease, general principles have been exposed that are common to the mechanisms of both forms of the same disorder. This approach holds promise for effective treatment of what heretofore have been considered progressive and incurable diseases. For these reasons, and because the well-educated neurologist should have some understanding of this evolving field, this chapter places considerable emphasis on mutations that cause degenerative neurologic conditions. As a result of this emphasis, it has been proposed that all degenerative diseases be classified according to their genetic and molecular abnormalities. However, when one notes the diversity of pathologic change that may accompany a single, seemingly unitary gene abnormality or,
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reciprocally, the diversity of genetic defects that may underlie a single phenotype, this type of classification does not prove immediately helpful to the clinician. In other words, the practice of creating new disease categories to encompass all of the molecular and pathologic changes associated with a particular type of neuronal degeneration offers no great advantage in practice. We believe the most powerful clinical approach is based on an awareness of constellations of clinical features that relate to degeneration of neural systems. Until such time as the causation of the degenerative neurologic diseases is known, there must be a name and a place for a group of diseases that are united only by the common attribute of gradually progressive disintegration of part or parts of the nervous system.
General Clinical Characteristics of Degenerative Diseases The diseases included in the degenerative category have two outstanding characteristics: (1) they affect specific parts or functional systems of the nervous system and (2) they begin insidiously, after a long period of normal nervous system function and pursue a gradually progressive course. Frequently, it is impossible to assign a date of onset. The patient or the patient’s family may give a history of the abrupt appearance of disability, particularly if some injury, infection, surgical procedure, or other memorable event coincided with the initial symptoms. A skillfully taken history will reveal that there had been subtle symptoms that had been present for some time but had attracted little attention. Whether trauma or other stress can actually evoke or aggravate a degenerative disease is a question that cannot be answered with certainty; at present, evidence to this effect is purely anecdotal. Instead, these degenerative disease processes, by their very nature, appear to develop de novo, without relation to known antecedent events, and their symptomatic expressions are late events in the pathologic process, occurring only when the degree of neuronal loss reaches or exceeds a “safety factor” for the functioning of a particular neuronal system. Irreversibility of clinical manifestations is another feature common to all the neurodegenerative conditions. The familial occurrence of degenerative disease is of great importance both clinically and for scientific reasons as just mentioned, but such information is often difficult to obtain on first contact with the patient. The family may be small or widely scattered, so that the patient is unaware of the health of other members. The patient or the patient’s relatives may be reluctant to admit that a neurologic disease has tainted the family. Furthermore, it may not be realized that an illness is hereditary if other members of the family have a much more or much less severe or a different form of the disorder than the patient. Or paternity may be in question. Sometimes only the careful examination of other family members will disclose the presence of a hereditary disease. Also, it should be remembered that familial occurrence of a disease does not necessarily mean that it is inherited, but may indicate instead that more than one member of a family had been exposed to the same infectious or toxic agent. As a rule, the degenerative diseases of the nervous system are inexorably progressive and, with few exceptions, are
uninfluenced by any medical or surgical measures, so that dealing with a patient with this type of illness may be an anguishing experience for all concerned. However, several of these diseases are characterized by periods of relative stability; moreover, many symptoms can be alleviated by skillful management and the physician’s interest and advice are invaluable to the patient and his family by way of providing support, perspective, and information.
General Pathologic and Pathogenic Features Most of the degenerative diseases are characterized by the selective involvement of anatomically and physiologically related systems of neurons. This feature is exemplified by amyotrophic lateral sclerosis (ALS), in which the pathologic process is limited to motor neurons of the cerebral cortex, brainstem, and spinal cord, and by the progressive ataxias, in which only the Purkinje cells of the cerebellum are affected. Many other examples could be cited (e.g., Friedreich ataxia, Parkinson disease) in which discrete neuronal systems disintegrate, leaving others unscathed. Thus these degenerative diseases have been also appropriately called system atrophies. The selective vulnerability of certain systems of neurons is not an exclusive property of the degenerative diseases; several different processes of known cause have similarly circumscribed effects on the nervous system. In many degenerative diseases, the pathologic changes are somewhat less selective and eventually quite diffuse, but still restricted, largely to certain groups of neurons. Even then, there is an early tendency to involve special categories of neurons. As one would expect of any pathologic process that is based on the slow wasting and loss of neurons, not only the cell bodies but also their dendrites, axons, and myelin sheaths disappear, unaccompanied by an intense tissue reaction or cellular response because of the slowness of the process. The cerebrospinal fluid (CSF) shows little, if any, change, or at most a slight increase in protein content in all the degenerative diseases. Moreover, because these diseases invariably result in tissue loss (rather than in new tissue formation, as occurs with neoplasms or inflammations), radiologic examination shows either no change or only a volumetric reduction (atrophy) with a corresponding passive enlargement of the CSF compartments. These radiologic findings distinguish the neuronal atrophies from other large classes of progressive disease of the nervous system, namely, tumors, infections, and other processes of inflammatory type. At the cellular level, several processes characterize the death of individual cells. The term apoptosis has been borrowed from embryology to specify many of the diverse mechanisms that lead to neuronal degeneration. The original meaning of the term refers to a naturally occurring cell death during development that is driven by the expression of genes over a short period of time (i.e., “programmed” cell death), leaving no trace of a pathologic reaction. The process of pathologic neuronal degeneration is quite different in that it refers to a series of changes in mature neurons that occur over a protracted period of time, leading to cell death and often leaving a discrete glial scar, but not to regional tissue necrosis. In many models of degenerative
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disease, this process involves activation of specialized genes, although the time course and cellular morphology are not apoptotic in the original sense of the term. It is increasingly apparent that mechanisms other than programmed cell death will prove central to understanding the degenerative diseases, and that the clinical features of these conditions are manifest even before cellular destruction occurs. For example, interference with synaptic signaling and dysfunction of supporting glia cells are equally important to morphologic neuronal death. It will become clear in the following discussion that another common theme in the study of degenerative diseases is that of aggregation within specific neurons of normal cellular proteins such as amyloid, tau, synuclein, ubiquitin, and huntingtin. In some cases, the protein is overproduced as a result of the simple fact of a triplication or overactivity of its gene. In other instances, enzymatic cleavage of a normal precursor protein yields a product with physical properties that lead to its aggregation (as happens with amyloid in Alzheimer disease) or, there may be failure of the normal mechanisms of protein removal, resulting in its excess accumulation. Consequently, the biologic and the physicochemical properties of these proteins have assumed great importance and the mechanisms by which they interfere with cellular function and ultimately cause cell death are central areas of modern research.
CLINICAL CLASSIFICATION Because grouping of the degenerative diseases in terms of etiology is not currently possible (except that a hereditary or genetic factor can be recognized in some), we resort for practical purposes to a division based on the presenting clinical syndromes and their pathologic anatomy. Although this is the most elementary mode of classification of naturally occurring phenomena, it is a necessary prelude to diagnosis and scientific study and preferable to a purely genetic or molecular classification, and certainly an improvement on a haphazard listing of diseases by the names of the neurologists or neuropathologists who first described them. For reasons given in the introduction to this chapter, this approach remains the most potent in analyzing the problem presented by an individual patient. The main clinical categories are as follows: I. Syndrome of progressive dementia, other neurologic signs being absent or inconspicuous A. Diffuse cerebral atrophy 1. Alzheimer disease 2. Diffuse cerebral cortical atrophy of non-Alzheimer type 3. Some cases of Lewy-body disease B. Circumscribed cerebral atrophies including primary progressive aphasias and progressive visuospatial disorders 1. Pick disease (“lobar sclerosis”) 2. Frontotemporal dementias including primary progressive aphasias II. Syndrome of progressive dementia in combination with other neurologic abnormalities
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Huntington disease (chorea) Lewy-body disease Some cases of Parkinson disease Corticobasal ganglionic degeneration Cortical-striatal-spinal degeneration (Jakob disease) F. Dementia-Parkinson-amyotrophic lateral sclerosis complex G. Cerebrocerebellar degeneration H. Familial dementia with spastic paraparesis, amyotrophy, or myoclonus I. Polyglucosan body disease J. Frontotemporal dementia with parkinsonism or ALS III. Syndrome of disordered posture and movement A. Parkinson disease B. Multiple system atrophy (striatonigral degeneration and Shy-Drager syndrome) C. Progressive supranuclear palsy D. Dystonia musculorum deformans E. Huntington disease (chorea) F. Acanthocytosis with chorea G. Corticobasal ganglionic degeneration H. Lewy-body disease I. Restricted dystonias, including spasmodic torticollis and Meige syndrome J. Essential tremor K. Gilles de la Tourette disease IV. Syndrome of progressive ataxia A. Spinocerebellar ataxias (early onset) 1. Friedreich ataxia 2. Non-Friedreich, early onset ataxia (with retained reflexes, tremor, hypogonadism, myoclonus, and other disorders) B. Cerebellar cortical ataxias 1. Holmes type of familial pure cerebellar-olivary atrophy 2. Late-onset cerebellar atrophy C. Complicated hereditary and sporadic cerebellar ataxias (later onset ataxia with brainstem and other neurologic disorders) 1. Olivopontocerebellar degenerations (OPCA) a. Clinically pure (Dejerine-Thomas type) b. With extrapyramidal and autonomic degeneration (multiple system atrophy) c. Conjoined with spinocerebellar degeneration (Menzel type) 2. Dentatorubral degeneration (Ramsay Hunt type) 3. Dentatorubropallidoluysian atrophy (DRPLA) 4. Machado-Joseph (Azorean) disease 5. Other complicated late onset, autosomal dominant ataxias with pigmentary retinopathy, ophthalmoplegia, slow eye movements, polyneuropathy, optic atrophy, deafness, extrapyramidal features, and dementia V. Syndrome of slowly developing muscular weakness and atrophy A. Motor disorders with amyotrophy 1. Amyotrophic lateral sclerosis
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2. Progressive spinal muscular atrophy 3. Progressive bulbar palsy 4. Kennedy syndrome and other hereditary forms of progressive muscular atrophy and spastic paraplegia 5. Motor neuron disease with frontotemporal dementia B. Spastic paraplegia without amyotrophy 1. Primary lateral sclerosis 2. Hereditary spastic paraplegia (Strümpell-Lorrain) VI. Sensory and sensorimotor disorders (neuropathies; see Chap. 46) A. Hereditary sensorimotor neuropathies—peroneal muscular atrophy (Charcot-Marie-Tooth); hypertrophic interstitial polyneuropathy (DejerineSottas) B. Pure or predominantly sensory or motor neuropathic C. Riley-Day autonomic degeneration VII. Syndrome of progressive blindness or ophthalmoplegia with or without other neurologic disorders (see Chap. 13) A. Pigmentary degeneration of retina (retinitis pigmentosa) B. Stargardt disease C. Mitochondrial disorders (see Chap. 38) 1. Progressive external ophthalmoplegia with or without deafness or other system atrophies (Kearns-Sayre syndrome) 2. Leber hereditary optic neuropathy (see Chap. 13) 3. Leigh necrotizing encephalopathy VIII. Syndromes characterized by degenerative neurosensory deafness (see Chap. 15) A. Pure neurosensory deafness B. Hereditary hearing loss with retinal diseases C. Hereditary hearing loss with system atrophies of the nervous system
DISEASES CHARACTERIZED MAINLY BY PROGRESSIVE DEMENTIA Alzheimer Disease This is the most common and important degenerative disease of the brain, having an immense societal impact. Some aspects of the intellectual deterioration that characterizes this disease were described in Chap. 21, under “The Neurology of Dementia,” and the still ambiguous relationship of this disease to the aging process was fully discussed in Chap. 29. There it was pointed out that some degree of shrinkage in size and weight of the brain, i.e., “atrophy,” is an inevitable accompaniment of advancing age, but that these changes alone are of relatively slight clinical significance and uncertain structural basis (e.g., whether the loss of brain weight aging is the result of a simple depletion of neurons). By contrast, severe degrees of diffuse cerebral atrophy that evolve over a few years
are invariably associated with dementia, and the underlying pathologic changes in these cases most often prove to be those of Alzheimer disease. As also commented on in Chap. 29, the rate of cerebral atrophy, specifically of the hippocampus and medial parts of the temporal lobes, is accelerated in the early stages of Alzheimer disease, and longitudinal studies by magnetic resonance imaging can identify individuals who will subsequently develop the disease (Rusinick). The now outdated practice of giving Alzheimer disease and senile dementia the status of separate diseases is attributable to the relatively young age (51 years) of the patient originally studied by Alois Alzheimer in 1907. Such a division is illogical, as the two conditions, except for their age of onset, are clinically and pathologically indistinguishable. There is, in fact, a smooth, exponential, age-dependent increase in incidence after 40 years of age. Whether it is useful to classify separately the differing and infrequent heredofamilial forms of Alzheimer disease is an open question.
Epidemiology Although Alzheimer disease has been described at every period of adult life, the majority of patients are in their sixties or older; a relatively small number have been in their late fifties or younger. It is one of the most frequent mental illnesses, making up some 20 percent of all patients in psychiatric hospitals and a far larger proportion in nursing homes. In Rochester, Minnesota, the incidence rate for dementia in general is 187 cases per 100,000 population per year, and for presumed Alzheimer disease, 123 cases per 100,000 annually (Schoenberg et al). The incidence rate of clinically diagnosed Alzheimer disease is similar throughout the world, and it increases comparably with age, approximating 3 new cases yearly per 100,000 persons younger than age 60 years and a staggering 125 new cases per 100,000 of those older than age 60 years. The prevalence of the disease per 100,000 population is near 300 in the group aged 60 to 69 years; it is 3,200 in the 70- to 79-year-old group and 10,800 in those older than age 80. In the year 2008, there were estimated to be more than 2 million persons with Alzheimer disease in the United States. Prevalence rates, which depend also on overall mortality, are 3 times higher in women, although it does appear that the incidence of new cases is only slightly disproportionate in women. The survival of patients with Alzheimer disease is reduced to half the expected rate, mainly because of respiratory and cardiovascular causes and inanition, but also for other reasons that are not entirely clear. Several putative epidemiologic risk factors for Alzheimer disease, such as birth order, mother’s age at birth, family history of Down syndrome, and head injury, seem marginal at best and in some instances may be a result of selection bias. Whether low educational attainment is a risk factor for the development of Alzheimer disease or, conversely, whether cognitively demanding occupations or higher native intelligence protects against dementia has not been settled. Provocative data indicating that inherent endowment is important were presented in Chap. 21 (Katzman; Cobb et al).
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The familial occurrence of Alzheimer disease has been well established. In less than 1 percent of such cases there is a dominant inheritance pattern (Nee et al; Goudsmit et al; see further). Reports of substantial familial aggregations of dementia without a specific pattern of inheritance also suggest the operation of more than one genetic factor. Many studies have documented an increase in the risk of ostensibly sporadic Alzheimer disease among first-degree relatives of patients with this disorder. Again, this risk is disproportionately greater in females, adding to the evidence that women in general are at slightly higher risk for Alzheimer disease (Silverman et al). Li and coworkers have provided evidence that patients with an earlier age of onset of Alzheimer disease (before age 70 years) are more likely to have relatives with the disease than are patients with later onset. Genetic studies are difficult to carry out because the disease does not appear at the same age in a given proband. Even in identical twins, the disease may develop at the age of 60 years in one of the pair and at 80 years in the other. Death from other causes may prevent its detection.
Clinical Features (See also Chap. 21) The onset of mental changes is usually so insidious that neither the family nor the patient can date the time of its beginning and most patients come to attention months or years after the decline began. Occasionally, however, the process becomes manifest by an unusual degree of confusion in relation to a febrile illness, an operation, mild head injury, or the institution of a new medication. Other patients have as their initial complaints dizziness, mental fogginess, nondescript headaches, or other vaguely expressed and changeable somatic symptoms. The gradual development of forgetfulness is the major symptom. Small day-to-day happenings are not remembered. Seldom-used names become particularly elusive. Littleused words from an earlier period of life also tend to be lost. Appointments are forgotten and possessions misplaced. Questions are repeated again and again, the patient having forgotten what was just discussed. It is said that remote memories are preserved and recent ones lost (the Ribot law of memory), but this is only relatively true and it is difficult to check the accuracy of distant personal memories. For example, Albert and associates, who tested Alzheimer patients’ recognition of dated political events and pictures of prominent people past and present, found that some degree of memory loss extends to all decades of life (neuropsychologic testing is discussed further on). Once the memory disorder has become pronounced, other failures in cerebral function become increasingly apparent. The patient’s speech is halting because of failure to access the needed word. The same difficulty interrupts writing. Vocabulary becomes restricted, and expressive language becomes stereotyped and inflexible. Comprehension of spoken words seems at first to be preserved, until it is observed that the patient does not carry out a complicated request; even then it is uncertain whether the request was not understood because of inattention or because it was forgotten. Almost imperceptible at first, these disturbances of language become increasingly apparent as the disease
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progresses. The range of vocabulary and the accuracy of spelling are reduced. Finally, after many years of illness, there is a failure to speak in full sentences; the finding of words requires a continuous search; and little that is said or written is fully comprehended. There is a tendency to repeat a question before answering it, and later there may be a rather dramatic repetition of every spoken phrase (echolalia). The deterioration of verbal skills has by then progressed beyond a groping for names and common nouns to an obvious anomic aphasia. Other elements of receptive and executive aphasia are later added, but discrete aphasias of the Broca or Wernicke type are characteristically lacking. In general, there is a paucity of speech and a quantitative reduction in mentation. Skill in arithmetic suffers a similar deterioration. Faults in balancing the checkbook, mistakes in figuring the price of items and in making the correct change; all these and others progress to a point where the patient can no longer carry out the simplest calculations (acalculia or dyscalculia). In some patients, visuospatial orientation becomes defective. The car cannot be parked; the arms do not find the correct sleeves of the jacket or shirt; the corners of the tablecloth cannot be oriented with the corners of the table; the patient turns in the wrong direction on the way home or becomes lost. The route from one place to another cannot be described, nor can given directions be understood. As this state worsens, the simplest of geometric forms and patterns cannot be copied. Late in the course of the illness, the patient forgets how to use common objects and tools while retaining the necessary motor power and coordination for these activities. The razor is no longer correctly applied to the face; the latch of the door cannot be unfastened; and eating utensils are used awkwardly. Finally, only the most habitual and virtually automatic actions are preserved. Tests of commanded and demonstrated actions cannot be executed or imitated. Ideational and ideomotor apraxia are the terms applied to the advanced forms of this motor incapacity, as described in Chaps. 3 and 22. As these many amnesic, aphasic, agnosic, and apraxic deficits declare themselves, the patient at first seems unchanged in overall motility, behavior, temperament, and conduct. Social graces, whatever they were, are retained in the initial phase of the illness, but troublesome alterations gradually appear in this sphere as well. Imprudent business deals may be made. Restlessness and agitation or their opposites—inertia and placidity—become evident. Dressing, shaving, and bathing are neglected. Anxieties and phobias, particularly fear of being left alone, may emerge. A disturbance of the normal day and night sleep patterns is prominent in some patients. A poorly organized paranoid delusional state, sometimes with hallucinations, may become manifest. The patient may suspect his elderly wife of having an illicit relationship or his children of stealing his possessions. A stable marriage may be disrupted by the patient’s infatuation with a younger person or by sexual indiscretions, which may astonish the community. The patient’s affect coarsens; he is more egocentric and indifferent to the feelings and reactions of others. A gluttonous appetite sometimes develops, but more often eating is neglected, resulting in gradual weight loss. Later, grasping
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and sucking reflexes and other signs of frontal lobe disorder are readily elicited (Neary et al), sphincteric continence fails, and the patient sinks into a state of relative akinesia and mutism, as described in Chap. 21. Difficulty in locomotion, a kind of unsteadiness with shortened steps but with only slight motor weakness and rigidity, frequently supervenes. Elements of parkinsonian akinesia and rigidity and a fine tremor can be perceived in patients with advanced stages of the disease. Ultimately, the patient loses the ability to stand and walk, being forced to lie inert in bed and having to be fed and bathed, the legs curled into a fixed posture of paraplegia in flexion (in essence, a persistent vegetative state). The symptomatic course of this tragic illness usually extends over a period of 5 or more years, but judging from pathology studies, the pathologic course has a much longer asymptomatic duration. This concept of a preclinical stage is supported by the detailed studies of Linn and colleagues, who found that a lengthy period (7 years or more) of stepwise decline in memory and attention span preceded the clinical diagnosis. Throughout this period, corticospinal and corticosensory functions, visual acuity, ocular movements, and visual fields remain intact. If there is hemiplegia, homonymous hemianopia, and the like, either the diagnosis of Alzheimer disease is incorrect or the disease has been complicated by a stroke, tumor, or subdural hematoma. Exceptions to this statement are rare. The tendon reflexes are little altered and the plantar reflexes almost always remain flexor. There is no sensory or cerebellar ataxia. Convulsions are rare until late in the illness, when up to 5 percent of patients reportedly have infrequent seizures. Occasionally, widespread myoclonic jerks or mild choreoathetotic movements are observed late in the illness. Eventually, with the patient in a bedfast state, an intercurrent infection such as aspiration pneumonia or some other disease mercifully terminates life. The sequence of neurologic disabilities may not follow this described order and one or another deficit may take precedence, presumably because the disease process, after becoming manifest in the memory cortex of the temporal lobes, affects a particular part of the associative cortex earlier or more severely in one patient than in another. This allows a relatively restricted deficit to become the source of early medical complaint long before the full syndrome of dementia has declared itself. There are at least four limited deficits of this type, each of which may be mild enough to qualify as a minimal cognitive impairment (MCI), as follows: 1. Korsakoff amnesic state The early stages of Alzheimer disease are usually dominated by a disproportionate failure of retentive memory, with integrity of other cognitive abilities. This may be the sole difficulty for many years. In such patients, immediate memory (essentially a measure of attention), tested by the capacity to repeat a series of numbers or words, is intact; it is the shortand long-term (retentive) memory that fails. Retentive memory may become impaired to the point where the patient can recall nothing of what he had learned a minute or two previously. Yet as a business executive, for example, he may continue to make acceptable deci-
sions if the work uses long-established habit patterns and practices. In such cases, the temporal horns tend to be enlarged more than the rest of the ventricular system, reflecting the disproportionate atrophy of the inferomedial temporal lobes. 2. Dysnomia The forgetting of words, especially proper names, may first bring the patient to a neurologist. Later the difficulty involves common nouns and progresses to the point where fluency of speech is seriously impaired. Every sentence is broken by a pause and search for the wanted word; if this is not found, a circumlocution is substituted or the sentence is left unfinished. When the patient is given a choice of words, including the one that was missed, there may be a failure of recognition. Repetition of the spoken words of others, at first flawless, later brings out a lesser degree of the same difficulty. The naming defect is evident with even simple tests, e.g., asking the patient to generate a list of farm animals or car brands—a test that may elicit only three or four responses. A more extensive examination entails asking the patient to name as many items as possible in each of three categories in 1 min—vegetables, tools, and clothing. Alzheimer patients fall well below a score of 50 items. Duplicating our own experience, Chawluk and associates and Mesulam have described patients in whom an aphasic disorder began with anomia and eventually affected reading, writing, and comprehension without the additional intellectual and behavioral disturbances of dementia. Such patients, if followed for a sufficiently long period, develop a more general dementia, sometimes as long as 5 years or more after the onset of aphasia. This syndrome of “primary progressive aphasia” may also represent a focal degenerative disorder (lobar atrophy of Pick or frontotemporal dementia), distinct from Alzheimer disease (Lippa et al; Kirshner et al). Usually the electroencephalogram (EEG) is normal or shows only a mild degree of left frontotemporal slowing, but MRI discloses a focal atrophy in the language areas (Caselli et al). 3. Visuospatial disorientation Parietooccipital functions are sometimes deranged in the course of Alzheimer disease and may fail while other functions are relatively preserved. When it occurs in a pure form, it has been termed posterior cortical dementia (see Renner et al). As remarked above and in Chap. 22, prosopagnosia (impaired facial recognition), losing one’s way in familiar surroundings or inability to interpret a road map, to distinguish right from left, or to park or garage a car, and difficulty in setting the table or dressing are all manifestations of a special failure to orient the schema of one’s body with that of surrounding space. Exceptionally, there is a neglect of stimuli in one visual field. In the late states, some of these patients develop the Balint syndrome or Gerstmann syndrome (Tang-Wai et al; McMonagle et al). 4. Paranoia and other personality and mood changes Frequently, at some point in the development of Alzheimer dementia, paranoia or bizarre behavior occasionally assume prominence. This may appear before the more obvious memory or language defects announce themselves. The patient becomes convinced that relatives are
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stealing his possessions or that an elderly and even infirm spouse is guilty of infidelity. He may hide his belongings, even relatively worthless ones, and go about spying on family members. Hostilities arise, and wills may be altered irrationally. Many of these patients are constantly worried, tense, and agitated. Of course, paranoid delusions may be part of a depressive psychosis and of other dementias, but most of the elderly patients in whom paranoia is the presenting problem seem not to be depressed, and their cognitive functions are for a time relatively well preserved. It is tempting to think that a very early degenerative change of the limbic cortices has exposed a lifelong trait of suspiciousness, but this is purely hypothetical. Sometimes other oddities of behavior will presage the oncoming dementia. Social indiscretions, rejection of old friends, embarking on imprudent financial ventures, or an amorous pursuit that is out of character are examples of these types of behavioral change. It has been our impression that each of the restricted clinical disorders described above is only relatively pure. Careful testing of mental function—and this is of diagnostic importance—frequently discloses subtle abnormalities in several cognitive spheres. Initially, most patients have a disproportionate disorder of the temporoparietal cortices, reflected by an earlier impairment on the performance parts of the Wechsler Adult Intelligence Scale. Within several months to a year or two, the more generalized aspects of mental deterioration become apparent, and the aphasic–agnosic–apraxic aspects of the syndrome become increasingly prominent. If one of the foregoing restricted deficits remains uncomplicated over a period of many years, one is justified in suspecting a cause other than Alzheimer disease, such as Binswanger disease, hydrocephalus, frontotemporal dementia (see further on), or embolic infarctions of the temporal or parietal lobes. Although it is true that most patients with Alzheimer disease walk normally until relatively late in their illness, infrequently a short-stepped gait and imbalance draw attention to the disease and worsen slowly for several years before cognitive manifestations become evident. The general decrepitude in appearance that accompanies the middle and late stages of the disease in many patients is commented on in Chap. 21. For research purposes and to establish certain inclusive and exclusive criteria for the diagnosis of Alzheimer disease, a work group of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Diseases Association (ADRDA) proposed the following criteria: (1) dementia defined by clinical examination, the Mini-Mental Scale (see Table 21-6), the Blessed Dementia Scale, or similar mental status examination; (2) patient older than age 40 years; (3) deficits in two or more areas of cognition and progressive worsening of memory and other cognitive functions, such as language, perception, and motor skills (praxis); (4) absence of disturbed consciousness; and (5) exclusion of other brain diseases (McKhann et al; Tierney et al, 1988). Using these criteria, the correct diagnosis is achieved in more than 85 percent of patients, but this is
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not surprising given that Alzheimer disease is overwhelmingly the most common cause of adult dementia. Most cases are identifiable without resorting to restrictive lists such as these, especially if the patient is observed serially over a period of months or years.
Pathology In the advanced stages of the disease, the brain presents a diffusely atrophied appearance and its weight is usually reduced by 20 percent or more. Cerebral convolutions are narrowed and sulci are widened. The third and lateral ventricles are symmetrically enlarged to varying degrees. Usually, the atrophic process involves the frontal, temporal, and parietal lobes, but cases vary considerably. The extreme atrophy of the hippocampus, the most prominent finding visible on MRI (mainly coronal images), is diagnostic in the proper clinical circumstances. Microscopically, there is widespread loss of nerve cells. Early in the disease this is most pronounced in layer II of the entorhinal cortex. In addition to marked neuronal loss in the hippocampus, adjacent parts of the medial temporal cortex—namely, the parahippocampal gyri and subiculum—are affected. The anterior nuclei of the thalamus, septal nuclei, and diagonal band of Broca, amygdala, and particular brainstem parts of the monoaminergic systems are also depleted. The cholinergic neurons of the nucleus basalis of Meynert (the substantia innominata) and locus ceruleus are also reduced in number, a finding that has aroused great interest because of its putative role of the former in memory function (see below). In the cerebral cortex, the cell loss predominantly affects the large pyramidal neurons. Residual neurons are observed to have lost volume and ribonucleoprotein; their dendrites are diminished and crowd one another owing to the loss of synapses and neuropil. Astrocytic proliferation is in evidence as a compensatory or reparative process, most prominent in layers III and V. Moreover, three microscopic changes give this disease its distinctive character (Fig. 39-1): (1) The presence within the nerve cell cytoplasm of thick, fiber-like strands of silverstaining material, also in the form of loops, coils, or tangled masses (Alzheimer neurofibrillary changes or “tangles”). These strands are composed of a hyperphosphorylated form of the microtubular protein tau and appear as pairs of helical filaments when studied ultrastructurally. (2) Spherical deposits of amorphous material scattered throughout the cerebral cortex and easily seen with periodic acid-Schiff (PAS) and silver-staining methods; the core of the aggregates is the protein amyloid, surrounded by degenerating nerve terminals (neuritic plaques). Amyloid is also scattered throughout the cerebral cortex in a nascent “diffuse” form, without organization or core formation and then is appreciated mainly by immunohistochemical methods, as well as deposition in the walls of small blood vessels near the plaques, so-called congophilic angiopathy. (3) Granulovacuolar degeneration of neurons, most evident in the pyramidal layer of the hippocampus. Probably, this last change is reactive and least important in diagnosis. Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex, but it is the
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standing the neurobiology of these degenerative diseases. This subject is discussed further in the section on Parkinson disease. It is of historical interest that Alzheimer was not the first to describe plaques, one of the hallmarks of the pathologic state. Miliary lesions (Herdchen) had been observed in senile brains by Blocq and Marinesco in 1892 and were named senile plaques by Simchowicz in 1910. In 1907, Alzheimer described the case of a 51-year-old woman who died after a 5-year illness characterized by progressive dementia. Throughout the cerebral cortex he found the characteristic plaques, but he also noted, thanks to the use of Bielschowsky’s newly devised silver impregnation method, a clumping and distortion of fibrils in the neuronal cytoplasm, the neurofibrillary change that now, appropriately, carries Alzheimer’s name. Figure 39-1. Photomicrograph of Alzheimer amyloid plaques and neurofibrillary tangles.
neurofibrillary tangles and quantitative neuronal loss, not the amyloid plaques, that correlate best with the severity of the dementia (Arriagada et al). If any part of the brain is disproportionately affected, it is the hippocampus, particularly the CA1 and CA2 zones (of Lorente de Nó) and the entorhinal cortex, subiculum, and amygdala. These parts have abundant connections with other parts of the temporal lobe cortex and dentate gyrus of the hippocampus and undoubtedly account for the amnesic component of the dementia. The associative regions of the parietal lobes are another favored site. Only a few tangles and plaques are found in the hypothalamus, thalamus, periaqueductal region, pontine tegmentum, and granule-cell layer of the cerebellum. Experienced neuropathologists recognize a form of Alzheimer disease, particularly in older patients (75 years), in which there are senile plaques but few or no neuronal tangles (about 20 percent of 150 cases reported by Joachim et al). Another problem for the neuropathologist is to distinguish between the normal aged brain and that of Alzheimer disease. It is not unusual to find a scattering of senile plaques in individuals who were ostensibly mentally normal during life. Anderson and Hubbard studied 27 demented individuals aged 64 to 92 years and 20 agematched nondemented controls. In the former, 3 to 38 percent of the hippocampal neurons contained neurofibrillary tangles; in all but 2 of the controls, the number of hippocampal neurons with tangles fell below 2.5 percent. Hence, the difference between plaques and tangles in the aging brain and in Alzheimer disease is largely quantitative. Also of interest is the observation of Joachim and associates that 18 percent of Alzheimer cases had sufficient neuronal loss and Lewy bodies in the substantia nigra to justify a diagnosis on histopathologic grounds of Parkinson disease. Leverenz and Sumi found that 25 percent of their Alzheimer patients showed the pathologic (and clinical) changes of Parkinson disease, a much higher incidence than can be attributed to chance. Similarly, of 11 patients with progressive supranuclear palsy (discussed further on) reported by Gearing and coworkers, 10 were demented and 5 had the neuropathologic features of Alzheimer disease. These mixed cases present problems not only of classification but also in under-
Pathogenesis Careful analyses of the plaques and neuronal fibrillary changes have been made in the last few decades in an attempt to elucidate the mechanism of Alzheimer disease. Several histologic techniques assist in this endeavor, including refined methods for silver impregnation that stain both amyloid and its main constituent (beta-amyloid protein [Aβ]); immunostaining using antibodies specific to such proteins as ubiquitin, neuronal tau protein, and beta-amyloid protein; and visualization of β pleated protein sheets using thioflavine S and Congo red with ultraviolet and polarized light. Tau (an acronym for “tubulin associated unit” but composed chemically of beta2-transferrin) is a discrete cytoskeletal protein that promotes the assembly of microtubules, stabilizes their structure, and participates in synaptic plasticity in a yet to be defined manner. In the pathologic circumstances of Alzheimer disease, progressive supranuclear palsy, and frontotemporal dementia (see further on), tau is hyperphosphorylated and aggregates, resulting in an overloading of the perikarya and neurites with paired helical filaments comprising neurofibrillary tangles. Electrophoretically, tau moves with the β 2-globulins and is thought to function as a transferrin, i.e., it binds iron and delivers it to the cell. Its concentration can be measured in the CSF and serum, but this has not yet proven clearly to be useful as a diagnostic test. The Aβ protein is a small portion of a larger entity, the amyloid-protein precursor (APP), which is normally bound to neuronal membranes. As shown in Fig. 39-2, the Aβ protein is cleaved from APP by the action of proteases termed α, β, and γ secretase. One current hypothesis, developed by Selkoe and others, focuses on the manner in which APP is cleaved by these enzymes to give rise to different-length residues of Aβ. During normal cellular metabolism, APP is cleaved by either α or β secretase. The products of this reaction are then cleaved by the γ -secretase isoform of the enzyme. The sequential cleavage by α and then γ produces tiny fragments that are not toxic to neurons. However, cleavage by β and then γ results in a 40-amino-acid product, Aβ 40, and a longer 42-aminoacid form. The latter Aβ 42 form is toxic in several models of Alzheimer disease, and it has been proposed that the ratio of Aβ 42 to Aβ 40 is critical to the neuronal toxicity of amyloid. Several pieces of evidence favor the view that elevation of the levels of Aβ 42 leads to aggregation of amyloid and then to neuronal toxicity. It appears that the diffuse depo-
CHAPTER 39
α
β
γ
NH2
COOH* APP
β secretase *
APPsβ
Down syndrome
β stub
ᵧ secretase
*
Apo E
*
A β 42
Fibrillogenesis
Amyloid neurotoxicity
ᵧ
*Mutations in APP, β or secretase, and the Apo E4 allele enhance toxicity. Figure 39-2. Diagram of proteolysis of amyloid precursor protein (APP). When APP is cleaved sequentially by β secretase and then secretase, the resulting amyloid protein can be 40 (Aβ 40) or 42 (Aβ 42) amino acids in length. The latter favors the formation of aggregated fibrillary amyloid protein (fibrillogenesis) rather than normal APP degradation. The fibrillary form of amyloid is neurotoxic, a mechanism favored as the cause of cell damage in Alzheimer disease. Formation of Aβ 42 is promoted by mutations, either in the APP gene itself or in the presenilins. In Down syndrome, excess production of APP and its product Aβ 42 is caused by triplication of the long arm of chromosome 21, the location of the APP gene. The Apo E4 allele is associated with inadequate clearance of Aβ 42 and is another mechanism that promotes fibrillogenesis. (Modified by permission from Sisodia SS, St. George–Hyslop PH: γ -Secretase, notch, Aβ and Alzheimer’s disease: Where do the presenilins fit in? Nat Rev Neurosci 3:281–290, 2002.)
sition of Aβ 42 precedes the formation of better-defined neurofibrils and plaques. The fact that the gene coding for APP is located on chromosome 21, one of the regions linked to one type of familial Alzheimer disease and the duplicated chromosome in Down syndrome, in which Alzheimer changes almost inevitably occur with aging (see further on), suggests that the overproduction of amyloid and all its Aβ residues are causative factors in the disease. Furthermore, the ratio of Aβ 42 to Aβ 40 is increased in Down syndrome. Another suggestive connection has been the finding that there are genetic defects in the genes encoding APP and in a pair of endosomal proteins termed presenilin 1 and 2 in some familial forms of Alzheimer disease. The presenilins interact with, or may be a component of, γ secretase, the enzyme that produces the Aβ 42 fragment. Mutations of presenilin 1 and 2 also increase the relative levels of Aβ 42. It should be noted that mutations of the APP and presenilin genes explain fewer than 0.1 percent of Alzheimer cases (Terry). Transgenic mice that express human Alzheimer disease-associated mutations in APP or presenilin genes develop plaques with Aβ 42 but not neurofibrillary tangles. There is also a provocative
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relationship in Alzheimer between certain circulating proteins, particularly beta-amyloid and selected isoforms of the apolipoprotein E (Apo E) lipoproteins, as discussed further on. Fig. 39-2 summarizes the current notions of amyloid metabolism and the role of Aβ 42. Many of the relationships and mechanisms depicted in the figure are derived from the understanding of genetic forms of Alzheimer disease; the extent to which they will be implicated in the idiopathic disease is unknown. However, some form of disruption in these mechanisms is likely to be involved in the sporadic disease. It must be emphasized, however, that there is still uncertainty regarding the relationship of amyloid deposition to the loss of neurons and brain atrophy. Alternatively, soluble oligomers of Aβ amyloid may be the toxic agents, whereas the emphasis until now has been on the effects of visible assemblies of insoluble amyloid fibrils. Others have questioned the amyloid hypothesis and pointed to an imprecise relationship between amyloid deposition and neuronal loss, even suggesting that aggregated amyloid is in some way a protective mechanism of cells. The finding of a reduced number and enlargement of synapses in affected cortex early in the disease by DeKosky and Scheff and others could be interpreted as either the first sign of neuronal death or the result of the neuronal loss. Amyloid deposition would then be a later, secondary phenomenon. The importance of neurofibrillary tangles has also been questioned, and the manner in which amyloid deposition relates to tangle formation is unclear. Unexplained also is prominent senile plaque formation in some cases and neurofibrillary tangles in others. One prevalent view is that the tangles are a secondary phenomenon. In their review, Hardy and Selkoe, authoritative investigators in this field, pointed out that “Although the amyloid hypothesis offers a broad framework to explain AD pathogenesis, it is currently lacking in detail, and certain observations do not fit easily with the simplest version of the hypothesis.” Nonetheless, the amyloid hypothesis is currently the strongest. In recent years, some of the subcellular mechanisms that are deranged by the presence of intracellular or extracellular amyloid have been elucidated. These are too complex and uncertain to list here, but they are among the most promising findings in this field of research. It is our view that vascular changes do not have an important or direct role in the pathogenesis of Alzheimer disease, but several groups hold a different opinion. It was long ago established that Alzheimer disease is not caused by any of the usual types of arteriosclerosis. Probably the deposition of amyloid in the walls of cerebral vessels and a reduction in the number of small blood vessels are secondary phenomena. On the other hand, several studies have indicated that the presence of cerebral infarctions, small or large, accelerates the deposition of amyloid and the development of neurofibrillary tangles in the brains of Alzheimer patients (see further on). Not surprisingly, cerebrovascular disease also exaggerates the rate of progression and degree of dementia. How this relates to the illdefined entity called arteriosclerotic, multiinfarct, or vascular dementia has not been clear to the authors (see further on). A similar relationship between Alzheimer disease and previous head injuries is even more tentative but has led
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to speculation that several types of brain injuries are conducive to the development of Alzheimer change and amyloid deposition, as if they were part of a reparative response. No relationship to premorbid personality traits earlier in life has been established, but an intriguing finding from what has become known as the “nun study” suggests that poorer linguistic capability early in life corresponded to the development of Alzheimer disease with aging (D.A. Snowden et al). In this study, the autobiographies of 93 nuns, written in their twenties, were rated for linguistic and ideational complexity. Of 14 sisters who died in late life, deterioration of cognitive function and neuropathologically proven Alzheimer disease occurred in 7 who had a low “idea density” in their writings and in none of 7 whose writings were cognitively more complex. Obviously this type of correlation requires further study and is subject to several interpretations, but the general notion of “cognitive reserve” having either a protective property or simply hiding mental decline, has emerged from numerous other studies. Also, there has been a general notion, confirmed by a few studies such as the one by Verghese and colleagues, that an active mental life may reduce the severity of mental decline with aging, but firm conclusions cannot be made from the available information. Neurotransmitter Abnormalities Considerable interest was created in the late 1970s by the finding of a marked reduction in choline acetyltransferase (ChAT) and acetylcholine in the hippocampus and neocortex of patients with Alzheimer disease. This loss of cholinergic synthetic capacity was attributed to a reduction in the number of cells in the basal forebrain nuclei (mainly the nucleus basalis of Meynert), from which the major portion of neocortical cholinergic terminals originate (Whitehouse et al). However, a 50 percent reduction in ChAT activity has been found in regions such as the caudate nucleus, which show neither plaques nor tangles (see review of Selkoe). The specificity of the nucleus basalischolinergic-cortical changes has been questioned for other reasons as well. For one, Alzheimer brain also shows a loss of monoaminergic neurons and a diminution of noradrenergic, gabanergic, and serotonergic functions in the affected neocortex. The concentration of amino acid transmitters, particularly of glutamate, is also reduced in cortical and subcortical areas (Sasaki et al). The Alzheimer cortex shows a decreased concentration of several neuropeptide transmitters—nota-
bly substance P, somatostatin, and cholecystokinin—but it has not been determined whether any of these biochemical abnormalities, including the cholinergic ones, are primary or are secondary to heterogeneous neuronal loss. Nevertheless, the administration of cholinomimetics—either acetylcholine precursors (e.g., choline or lecithin), degradation inhibitors (e.g., physostigmine), or muscarinic agonists that act directly on postsynaptic receptors—have had a mild and unsustained therapeutic effect (see further under “Treatment”). Chase and associates have demonstrated a 30 percent reduction in cerebral glucose metabolism in Alzheimer disease, greatest in the parietal lobes, but this seems most likely to be secondary to tissue loss in these regions. Even if not of pathogenic significance, it finds value as a diagnostic marker of the disease. The significance of aluminum in the genesis of neurofibrillary tangles, as was once proposed, has never been validated. Recently, it has been suggested that the use of estrogen by postmenopausal women or of antiinflammatory agents in men or women delays the onset of the disease or might reduce its occurrence, but neither of these approaches has been adequately corroborated. Genetic Aspects of Alzheimer Disease (Table 39-1) Of great importance was the aforementioned series of discoveries in patients with inherited forms of Alzheimer disease, of defective genes that code for errant APPs localized to chromosome 21 near the β-amyloid gene (St. George-Hyslop et al). As mentioned, this also provided an explanation for the Alzheimer changes that characterize the brains of practically all patients with the trisomy 21 defect (Down syndrome) who survive beyond their twentieth year; they overproduce amyloid as a result of the triplication of the gene. But gene defects on chromosome 21 are responsible for only a small proportion of familial cases and a minuscule percentage of disease overall. Other kindreds with familial Alzheimer disease have been linked to rare mutations of the presenilin genes on chromosome 14 (presenilin 1; Sherrington et al), accounting in some series for up to 50 percent of familial cases, and on chromosome 1 (presenilin 2), which may account for many of the remaining ones (Levy-Lahad et al). These are summarized in Table 39-1. The age of onset of the disease in these familial forms, as in the Down cases, is earlier than that in sporadic forms. Notable is the common occurrence of asynchronous myoclonus, epilepsy, aphasia, and paratonia in many of the familial cases.
Table 39-1 GENETIC DEFECTS AND RISK FACTORS ASSOCIATED WITH ALZHEIMER DISEASE NOTATION
CHROMOSOME
GENE
APP
21
PS1 PS2 Apo E
14 1 19
Amyloid precursor protein Presenilin 1 Presenilin 2 Apolipoprotein E
UBQLN1 Trisomy 21
9 21
Ubiquilin 1 Amyloid precursor protein
AD, autosomal dominant; SNP, single nucleotide polymorphism.
GENETICS
AGE
AD
Early
AD AD Haplotype
Early Early Late
SNP Triploidy
Late Middle age
CLINICAL FEATURES
Rare but clinically simulates sporadic Alzheimer disease As above As above These variants modify susceptibility to typical Alzheimer disease Familial cases only Alzheimer change is almost universal in Down syndrome
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It has been clear for some time that an excess or aberrant amyloid alone are incomplete explanations for the disease. Apo E, a regulator of lipid metabolism that has an affinity for Aβ in Alzheimer plaques, has been found to be another genetic marker, but one that only modifies the risk of acquiring Alzheimer disease. Of the several isoforms of Apo E, the presence of E4 (and its corresponding allele e4 on chromosome 19) is associated with a tripling of the risk of developing sporadic Alzheimer disease (Roses; Strittmatter et al; Polvikoski et al). This is the same allele that contributes to an elevated low-density lipoprotein fraction in the serum. Possession of two e4 alleles virtually assures the development of disease in those who survive to their eighties. The e4 allele also modifies the age of onset of some of the familial forms of the disease. In contrast, the e2 allele is underrepresented among Alzheimer patients. For these reasons it has been proposed that Apo E, by interacting with APP or tau protein in some way, modifies the formation of plaques. Indeed, possession of the e4 allele correlates with increased deposition of Aβ in the brain (McNamara). As pointed out by Hardy, Apo E appears to act at a point in the pathogenesis that is after the various genetic mutations have influenced the cellular pathology that ostensibly causes Alzheimer disease. However, these statistical relationships do not invariably connect an allele to the disease in a particular individual. In other words, the e4 allele does not act as a mendelian trait but as a susceptibility (risk) factor. It follows that many, if not most, individuals who develop Alzheimer disease do not have the risk allele. Moreover, many individuals with the e4 allele live into their seventies and eighties without developing Alzheimer disease. All that can be stated with certainty is that, on average, the presence of the e4 allele accelerates the appearance of Alzheimer disease by about 5 years. Another modifying gene has been found in familial cases only at the UBQLN1 (ubiquilin 1) site, coding for a protein that interacts with PS1 and PS2 and participates in proteasomal degradation. Studies of the molecular genetics of Alzheimer disease are yielding new information at such an astonishing rate that much of the foregoing text will rapidly be outdated. Useful basic reviews of this subject are Martin (1999) and Selkoe.
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Figure 39-3. Top: Alzheimer disease. Axial CT section demonstrating severe generalized cerebral cortical atrophy and moderately severe ventricular enlargement. Bottom: Pick disease. Pronounced selective atrophy of the frontal and temporal lobes. (Reproduced by permission from Lee SH, Rao KCVG, Zimmerman RA: Cranial MRI and CT. New York, McGraw-Hill, 1992.)
Diagnostic Studies CT scanning and MRI are useful, but not definitive, ancillary tests (Fig. 39-3). In patients with advanced Alzheimer disease, the lateral and third ventricles are enlarged to about twice normal size and the cerebral sulci are widened. Coronal MRI of the medial temporal lobes reveals a disproportionate atrophy of the hippocampi and a corresponding enlargement of the temporal horns of the lateral ventricles. Early in the disease, however, the changes do not exceed those found in many mentally intact old persons. For this reason, one cannot rely solely on imaging procedures for diagnosis. CT and MRI scans are most valuable in excluding alternative causes of dementia such as brain tumor, subdural hematoma, cerebral infarction, and hydrocephalus. The EEG undergoes mild diffuse slowing, but only late in the course of the illness. The CSF is also normal, although occasionally the total protein is slightly elevated. Using the
constellation of clinical data, CT scanning, and MRI in the context of the age of the patient and time course of the disease, the diagnosis of dementia of Alzheimer type is made correctly in 85 to 90 percent of cases. Of considerable value in our experience have been studies of cerebral blood flow (single-photon emission tomography [SPECT]) and metabolism (positron emission tomography [PET]), which early in the illness often, but not always, show diminished activity in the parietal association regions and the medial temporal lobes. In most cases, when such changes are evident, the diagnosis was already obvious on clinical grounds. Newer PET ligand agents that bind to amyloid, such as the “Pittsburgh compound” are more sensitive in identifying and plotting the course of Alzheimer disease but their specificity in clinical work is just being studied.
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Neuropsychologic tests in the typical case show disproportionate deterioration in memory and verbal access skills. Testing is particularly useful when there is a serial decline in ability. Certain aspects of attention and executive function in Alzheimer disease that also show changes in Alzheimer disease were reviewed by Perry and Hodges. The use of these examinations is described in Chap. 21. There is no firm biologic marker of Alzheimer disease with the exception of an imprecise association with the disease-modifying e4 apolipoprotein allele mentioned earlier. The ratio of Aβ to tau in the cerebrospinal fluid (paradoxically low in Alzheimer disease) is used in some clinics, but is not yet well enough validated for routine use (Maddalena et al).
Differential Diagnosis (See also Table 21-3) Formerly, when virtually all forms of dementia were untreatable, there was little advantage to either the patient or the family in ascertaining the cause of the cerebral disease. Such patients were customarily left at home or committed to an institution for the care of the psychiatrically or chronically ill. The potentially treatable forms of dementia are those caused by normal-pressure hydrocephalus; chronic subdural hematoma; the dementia of AIDS; paraneoplastic limbic encephalitis; nutritional deficiencies (thiamine—WernickeKorsakoff syndrome, Marchiafava-Bignami disease, pellagra, vitamin B12 deficiency); chronic drug intoxication (e.g., alcohol, sedatives); multiple cerebral infarctions; certain endocrine and metabolic disorders (myxedema, Hashimoto encephalopathy, neurosyphilis and other chronic meningitides, Cushing disease, chronic hepatic encephalopathy); frontal and temporal lobe tumors; cerebral vasculitis; sarcoidosis; Whipple disease; multiple sclerosis; and perhaps above all, the pseudodementia of depression. Exclusion of most of these diseases is readily accomplished by sequential outpatient evaluations or by a brief admission to a hospital, where examinations of blood and CSF, EEG, CT, MRI, and neuropsychologic testing can be undertaken. In rare and desperate situations, brain biopsy may be justified in the diagnosis of dementia. A perspective, albeit from a biased sample, is given in the series reported by Warren and colleagues of 90 consecutive biopsies, performed between 1989 and 2003, for the diagnosis of dementia. More than half provided a diagnosis, mostly Alzheimer, Creutzfeldt–Jakob disease, and inflammatory disorders. However, in the modern era, reasonable assurances must be given to the neurosurgeon that prion disease is unlikely. One problem in differential diagnosis is the distinction between a late-life depression and a dementia, especially when some degree of both are present. Observation over several weeks or more, and the patient’s demeanor, makes the distinction obvious. Multiinfarct dementia is usually not difficult to separate from Alzheimer dementia, as discussed further on. The dementia of normal-pressure hydrocephalus may also be confused with Alzheimer dementia (Chap. 30). The problem of distinguishing Alzheimer disease from a more “benign” form of memory decline associated with aging comes up frequently in practice, as discussed further
on. These several treatable conditions is discussed in Chaps. 21, 30, 34, and 49. Often we have been confident on clinical grounds that a patient had Alzheimer disease, only to have revealed at autopsy that progressive supranuclear palsy, Lewy-body disease, Pick disease, another non-Alzheimer degeneration of the frontal lobes, or cortical-basal-ganglionic degeneration was the cause. All are discussed later in this chapter.
Treatment There is no evidence that any of the previously proposed forms of therapy for Alzheimer disease—cerebral vasodilators, stimulants, L-dopa, massive doses of vitamins B, C, and E, gingko biloba and many others—has any salutary effect. Trials of oral physostigmine, choline, and lecithin have yielded mostly negative or uninterpretable results, and the evidence favoring the currently popular cholinergic precursors and agonists and acetylcholinesterase inhibitors, such as donepezil, is valid but only modest. With regard to the latter group of drugs, several large trials have demonstrated a slight prolongation of the patient’s ability to sustain an independent life, but such evidence generally requires that the medications be taken for 6 to 12 months. The salutary effects on memory are harder to demonstrate. Despite trials that have failed to demonstrate benefit (c.f., AD 2000 Collaborative Group), the balance of evidence favors the use of these medications. Side effects may include nausea or diarrhea in a small number of patients. The families of our patients report from time to time that the medication caused insomnia or increased confusion. It is worth mentioning that when the acetylcholine receptor antagonist succinylcholine is used prior to general anesthesia, its effects may be prolonged in patients taking the above drugs. The use of trazodone, haloperidol, thioridazine, risperidone, and related drugs may suppress some of the aberrant behavior and hallucinations when these are problems, making life more comfortable for both patient and family, but several trials suggest that their general application causes more problems than it solves and they must often be discontinued in response to adverse effects. The randomized trial conducted by Schneider and coworkers found that olanzapine, quetiapine, and risperidone for the treatment of psychosis, aggression, or agitation with Alzheimer disease were approximately as good as placebo in relieving these symptoms, largely because the drugs were not tolerated. Olanzapine was slightly preferable in those who continued taking the medication. However, the clinician is left with little recourse but to use this class of medications or haloperidol so as to control unmanageable behavior. Small doses of diazepines, such as lorazepam, are useful when sleep is severely disturbed, but they often increase confusion as well. The N-methyl-D-aspartate (NMDA) glutaminergic antagonists, specifically memantine (20 mg daily), have also been tried. In a study of memantine by Reisberg and colleagues of 252 patients (187 of whom completed the trial), there were better results on a few scales that reflected functional behavior compared to the use of placebo, but there was no change in three main measures of cognitive performance. Because the side effects were ostensibly minor, this drug has been approved for use in late-stage Alzheimer disease
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and in conjunction with cholinergic drugs. Hallucinosis or agitation may occur and require discontinuation. A provocative series of animal experiments that demonstrated the possibility of removal of plaques by immunization against amyloid has led to human studies with a similar vaccination. One trial was stopped because of the occurrence of an immune encephalitis in a few patients, but in autopsy material there were indications that this novel approach may have had the desired effect of reducing amyloid deposition. Revised vaccines are being formulated for further testing of this novel approach. Given the state of therapeutics for Alzheimer disease, important is the general management of the demented patient, which should proceed along the lines outlined in Chap. 21, keeping in mind that the physician’s counsel is often the family’s main resource for important medical and social decisions.
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hydrocephalus from multiple subarachnoid hemorrhages or a hydrocephalus ex vacuo from cerebral atrophy. Similarly, some cases of what has come to be called primary progressive aphasia (see further on) have Alzheimer change and amyloid plaque deposition as the primary pathologic change. A close relationship between Pick, Alzheimer, and Parkinson diseases was demonstrated in a large family with dysphasic dementia (Morris et al). Other isolated combinations, wherein Alzheimer disease, hypothyroidism, hypopituitarism, or neurosyphilis were conjoined, were probably a matter of chance and prove nothing. From time to time, other unusual and meaningful associations come to light, such as dementia with motor neuron disease or the cases of familial dementia with spastic paraplegia reported by Worster-Drought and by van Bogaert and their associates (see later in this chapter). Here, neurofibrillary change is the most prominent feature whereas amyloid plaques are negligible in number or absent.
Associated Pathologic States As indicated earlier, the histologic changes of Alzheimer disease have a number of interesting associations. Amyloid plaques and tangle deposition are far more common in the brains of patients with Parkinson disease (20 to 30 percent) than in the brains of age-matched controls (Hakim and Mathieson). These findings partly explain the high incidence of dementia in patients with Parkinson disease (see further on). As mentioned, with the advance of Alzheimer disease, extrapyramidal features may emerge. In such cases, Burns and colleagues have found changes in the substantia nigra including accumulation of synuclein and tau. Another association between the two diseases is apparent in the Guamanian Parkinson–dementia complex, which is also discussed below. In this entity, the symptoms of dementia and parkinsonism are related to neurofibrillary changes in the cerebral cortex and substantia nigra, respectively; senile plaques and Lewy bodies are unusual findings. Alzheimer disease in relation to the Down syndrome, first noted by Jervis, is now widely recognized. The characteristic plaques and neurofibrillary tangles appear in the third decade; they increase with age and are present in practically all patients with the Down syndrome who are older than 40 years of age. The basis for excess amyloid production in Down syndrome was discussed earlier. There are rare instances, such as those reported by Malamud and Lowenberg and by Loken and Cyvin, in which dementia begins in late childhood, with the finding at postmortem examination of the typical Alzheimer lesions in the cerebral cortex and basal ganglia. The clinical picture in these juvenile and early adult cases has been more varied than in the older ones. In some, paucity of speech, mutism, tremor, stooped posture, marked grasp and suck reflexes, and pyramidal and cerebellar signs leading to inability to stand or walk have appeared at various stages of the disease. The finding of neurofibrillary changes (and to a lesser extent of plaques) in boxers (“punch-drunk” syndrome, or dementia pugilistica) is another interesting ramification of the Alzheimer disease process. Hydrocephalus is present also, but there is insufficient information to determine whether this is the result of a normal-pressure tension
Lobar Atrophies (Pick Disease and Frontotemporal Dementia) This category of disease has evolved and the nosology is uncertain because each illness may be identified by its characteristic histopathologic changes or clinical and imaging or genetic features. The notion of lobar atrophy was introduced in 1892 when Arnold Pick of Prague described a special form of cerebral degeneration in which the atrophy was circumscribed (most often in the frontal or temporal lobes), with involvement of both gray and white matter; hence the term he applied was lobar rather than cortical sclerosis. In 1911, Alzheimer presented the first careful study of the microscopic changes, followed by even more complete analyses of the pathologic changes by the prominent neuropathologists of the age. The pathologic change associated with this category of disease may be any one of several types: Pick inclusion bodies, neurofibrillary tangles, other inclusions, or with no characteristic changes except for neuronal loss. Contrariwise, gliosis and mild spongiform changes in the superficial layers of cortex, and even typical plaque and tangle pathology, have all been associated with syndromes of gross atrophy of the frontal or temporal lobes. Furthermore, several terms have been applied to the forms of lobar atrophy, frontotemporal dementia being the most common and perhaps a most appropriate one as it corresponds to a clinical syndrome without committing to a histopathologic or biologic cause (see below). In contrast to Alzheimer disease, in which the atrophy is relatively diffuse, the pathologic change in lobar atrophy is circumscribed and often asymmetrical. The atrophy may extend to the island of Reil and the amygdaloid-hippocampal structures. In some instances, atrophy of the caudate nuclei has been pronounced, almost to the degree seen in Huntington chorea. The thalamus, subthalamic nucleus, substantia nigra, and globus pallidus may also be affected, but to a lesser degree. The parietal lobes are involved less frequently than the frontal and temporal lobes. The affected gyri become paper thin, resembling the kernel of a dried walnut. The cut surface reveals not only a marked narrowing of the cortical ribbon but a grayish
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appearance and reduced volume of the underlying white matter. The corpus callosum and anterior commissure share in the atrophy but almost certainly as secondary phenomena. The overlying pia-arachnoid is often thickened, and the ventricles are enlarged. The pre- and postcentral, superior temporal, and occipital convolutions are relatively unaffected and stand out in striking contrast to the wasted parts. Pick insisted that the disease involves the association areas but this is not always so. The salient histologic feature of Pick disease is a loss of neurons, most marked in the first three cortical layers. Surviving neurons are often swollen, and some contain argentophilic (Pick) bodies within the cytoplasm that allow at least one way to name the disease. Ultrastructurally, the Pick bodies are made up of straight fibrils, thus differing from the paired helical filaments that characterize Alzheimer disease. These bodies predominate in the medial parts of the temporal lobes, especially in the atrophic hippocampi. “Ballooning” of cortical neurons is found mainly in the frontal cortex, and in such cases atrophy of the basal ganglia and substantia nigra is especially frequent and severe. A heavy astrocytic gliosis is seen in both the cortex and subcortical white matter. Amyloid plaques and Alzheimer neurofibrillary changes are seen in the atrophic zones in only some of the cases, as alluded to earlier, and there is granulovacuolar degeneration of neurons in the hippocampus, but not to the degree seen in Alzheimer disease. It is the lobar atrophy and marked changes in the underlying white matter that provide the unifying elements of all the lobar atrophies. These changes are readily appreciated by imaging studies.
Clinical Features Whether the diagnosis of Pick disease as defined by the presence of the argentophilic inclusions can be made on purely clinical grounds is doubtful. Our predictions as to the existence of the pathologic changes and their differentiation from those of Alzheimer disease and the entity of “frontotemporal dementia” (described below) have been difficult. Wilson distinguished two patterns of abnormal behavior in Pick disease: in one, the patient is talkative, lighthearted, cheerful or anxious, constantly on the move, occupied with trifles, and attentive to every passing incident; in the other, the patient is taciturn, inert, emotionally dull, and lacking in initiative and impulse. Probably these two patterns represent predominantly temporal and frontal types described below. According to Tissot and colleagues, the frontal, temporal, and parietal lobes are all affected in 75 percent of patients by the time the disease terminates. The cause of Pick disease is unknown. Although most cases are sporadic, Sjögren and associates concluded from a genetic survey of the cases in Stockholm that it may be transmitted as a dominant trait with polygenic modification. A Dutch family with almost 100 percent penetrance over several generations was reported by Schenk. Women seem to be affected more often than men. The course of the illness usually extends for 2 to 5 years, occasionally
longer, and nothing is known that can be done therapeutically except to postpone the end by careful nursing.
Frontotemporal Dementia This descriptive term has been used by neurologists and neuropathologists to refer to a clinical syndrome that is associated with degeneration of the frontal and temporal lobes. Many such instances have proved to be examples of Alzheimer disease and, in lesser numbers, Pick disease as noted above. For many years neuropathologists have been aware of instances of dementia that are identical clinically and in their gross pathology (severe gyral atrophy) to the Alzheimer and Pick types but do not show the characteristic histologic changes of either. Many do, however, exhibit tau-staining material in neurons of the affected regions. In a few familial cases, this is attributable to mutations in the gene on chromosome 17 that encodes the tau protein. These mutations alter the proportions of different isoforms of this protein and lead both to tau accumulation and its hyperphosphorylation. Indeed, many cases of frontotemporal dementia are associated with tau gene mutations (Basun et al). However, abnormal aggregates of tau have been identified in practically all neurodegenerative atrophies and, of course, form the main constituent of the paired helical filaments (neurofibrillary tangles) of Alzheimer disease, and in progressive supranuclear palsy where they are abundant, although of slightly different structure. From the observations of Brun and Passant and of Neary and associates, pure tau-reactive cases actually outnumber Pick disease when the latter is strictly defined by the cortical white matter degeneration and Pick inclusions, but the distinctions between the two have not always been clear from writings on the subject. Some of the clinical aspects of frontotemporal dementia are discussed in Chap. 21, but broadly speaking, the patients under consideration present the personality and behavioral abnormalities that include apathy, perseveration, poor judgment and abstraction, bizarre affect, and a general disengagement. Insight is almost always impaired, and some subjects become euphoric or display repetitive compulsive behaviors. An initial diagnosis of depression has been common. Other psychiatric symptoms such as sociopathic and disinhibited behavior with aspects of hyperorality and hyperphagia may predominate. (All of Wilson’s comments, noted above in relation to Pick disease, pertain here as well.) Alternatively, aphasic or word-finding syndrome corresponding to lateral temporal lobe degeneration may be the initial presenting and predominant feature, sometimes for several years, before other manifestations of dementia become evident. Utilization behavior (the compulsive use of implements and tools put before the patient) is common in the frontal type. Cases with early and pronounced difficulty with language are included on clinical grounds in the category of “primary progressive aphasias,” discussed further on. In all instances CT, MRI, and functional imaging demonstrate the disproportionate atrophy and hypofunction of one lobe of the cerebrum. A proportion of patients with frontotemporal dementia have parkinsonian features, but this is more characteristic of corticobasal-ganglionic degeneration
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(see further on). A form of motor neuron disease is also linked to frontotemporal dementia in a small number of cases. This is particularly the case in the Guamanian (now called western Pacific) variety and in the heredofamilial frontotemporal atrophy linked to a mutation on chromosome 17. In recent writings on this subject, the term frontotemporal dementia has come to be used in a highly restricted sense, being assigned to cases that show only tau-staining material in neurons. Most of the cases are sporadic, but the inherited variety linked to chromosome 17, in which parkinsonism is prominent, supports its distinction as a separate entity; it is in these cases that the intraneural deposition of tau is most striking, in both the frontotemporal cortex and the substantia nigra. Nonetheless, a frontotemporal dementia identical to that of the tau-reactive cases has been observed in others without any tau staining of neurons. Some of the frontally predominant cases have shown only marked vacuolation (microcavitation) of the affected cortex; cases of the latter type have been described in patients with ALS (where tau staining has been found in the anterior horn cells). In such cases, amyloid plaques and neurofibrillary tangles are no more abundant than expected for the age of the patient. In sum, the relationship between Pick disease and frontotemporal dementia is still uncertain, hence the appeal of the term Pick complex that has appeared in the literature. The clinical and gross pathologic findings—a regional frontotemporal atrophy of the cerebrum, bilateral or unilateral—are nearly identical in the two disorders. A measure of the confusion among experts in the field is highlighted in the monograph by Kertesz, in which votes were taken regarding various terminologies and opinion was considerably divided.
Primary Progressive Aphasia Focal disturbances, particularly aphasia and apraxia, occur early and prominently in certain patients with lobar atrophy, indicating a lesion in the left frontal or temporal lobes. Viewed from another perspective, a prominent language disorder has been described in almost two-thirds of all patients with temporal lobe atrophy. At first, the patient speaks less and has word-finding difficulty (anomia), but language structure is intact (Mesulam, 1982); later, he may forget and misuse words and soon fails to understand much of what is heard or read. Speech becomes a “medley of disconnected words and phrases” and eventually is reduced to an incomprehensible jargon. Later, dysarthria and apraxia become apparent and finally, the patient is mute, seemingly without impulse to speak, with a complete loss of the ability to form words (Snowden et al, 1992). In a less-common form, there is early comprehension difficulty followed by verbal perseveration, but fluency is retained. The above descriptions conform also to what is now called primary progressive aphasia, and it is notable that according to Mesulam (2003), who has studied the condition extensively, 60 percent of these cases show no characteristic pathologic change, 20 percent have Pick bodies, and a similar proportion show the typical changes of Alzheimer disease in the affected cortical region. A clear familial tendency has not been
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found. Chapter 23 can be consulted for details of the aphasic disorders.
Posterior Cortical Atrophy This regional variant of cortical degeneration has been only slightly less frequent than primary progressive aphasia in our practices. The syndrome is that of apperceptive visual disturbance that includes fragments of the Balint and the Gerstmann syndromes. The result is progressive and ultimately severe visuospatial difficulty with a relative preservation of memory. Patients under our care have had a vague sense of visual disorientation followed over months by difficulty in seeing or recognizing objects in front of them. Many have alexia with agraphia while others have acalculia or the other elements of the Gerstmann syndrome. Several eventually become cortically blind. The average age of onset is about 60 years. The most common pathologic change in most reports has been characteristic of Alzheimer disease.
Lewy-body Dementia Next to Alzheimer disease, diffuse Lewy-body disease, or Lewy-body dementia, has been the most frequent pathologic diagnosis established in most series of globally demented patients. Reports of this condition have been increasing steadily since the original communication by Okazaki and colleagues in 1961 (see review by Kosaka). The disease is defined by the diffuse involvement of cortical neurons with Lewy-body inclusions and by an absence or inconspicuous number of neurofibrillary tangles and amyloid plaques. To some extent, increased recognition of this disorder is a result of improved histologic techniques, particularly the ability to detect ubiquitin and synuclein, main components of the Lewy body, by immunostaining. Because the Lewy bodies in cortical neurons are not surrounded by a distinct halo, as they are in the substantia nigra in cases of Parkinson disease, they were not readily appreciated until the development of these techniques. That aggregated α-synuclein is the main component of the Lewy body will undoubtedly prove important in understanding both Parkinson disease and Lewy-body dementia.
Clinical Features The disease in its typical form is marked by parkinsonian features, dementia and a frequent tendency to episodic delirium, especially nocturnally, and rapid eye movement (REM) sleep behavior disorder. Diagnostic criteria have been offered by a working group that require 2 of 3 of the following: a parkinsonian syndrome (usually symmetric), fluctuations in behavior, and hallucinations (McKeith et al). Burkhardt and colleagues, in an analysis of 34 cases of diffuse Lewy-body disease, found that the characteristic syndrome was one of progressive dementia in an elderly patient with the additional late onset of parkinsonism in many cases. In Lennox’s summary of 75 cases published up to 1990, parkinsonism, particularly with prominent limb and axial rigidity, was a prominent feature in 90 percent once the illness was fully developed, and almost half had tremor of the Parkinson type (different from other series).
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Byrne and associates, as have many others, pointed out that episodic confusion, hallucinations, and paranoid delusions were a feature of Lewy-body dementia; such psychotic features are generally uncharacteristic of Alzheimer and lobar dementias, and only then in advanced stages. In Lennox’s review, one-third of patients had these swings in behavior, but as the illness advanced, the amnesia, dyscalculia, visuospatial disorientation, aphasia, and apraxia did not differ from those of Alzheimer disease. In the cases reported by Fearnley and coworkers, there was a supranuclear gaze palsy simulating that of progressive supranuclear palsy. These overlapping clinical features make diagnosis difficult unless the more specific feature of episodic psychosis is prominent. For this reason, the disease also properly belongs in the category of dementias that are accompanied by other prominent neurologic features, as noted earlier under “Clinical Classification.” Difficulty in diagnosis arises because the movement disorder may be either mild or prominent and may occur as an early or a late manifestation. The parkinsonian features may respond favorably to Ldopa, but only for a limited time and sometimes at the expense of causing an agitated delirium or hallucinations that would be uncharacteristic of early idiopathic Parkinson disease (Hely et al); in many others, the response to Ldopa is inconsistent. Some patients also have orthostatic hypotension corresponding to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord or in the sympathetic ganglia, thereby simulating striatonigral degeneration or Shy-Drager syndrome (see further on). Others have commented on an extreme sensitivity of such patients to neuroleptic drugs, including increased confusion and greatly worsening parkinsonism or the development of the neuroleptic malignant syndrome. In our experience with Lewy-body disease, the parkinsonian symptoms have been more prominent than they are in progressive supranuclear palsy, and the most characteristic feature besides the movement disorder and a slowly advancing dementia has been a vacuous, anxious state with intermittent psychotic or delirious behavior. With regard to diagnostic testing, only the finding of reduced activity in the posterior parietal cortical regions on PET scans (as in Alzheimer disease) has been found as a relatively consistent, but not invariable, feature.
Other Degenerative Dementias Diffuse Cerebral Atrophy of Non-Alzheimer Type There are other forms of progressive, diffuse brain atrophy leading to dementia that show none of the pathologic features of either Alzheimer or Pick disease, or of any of the other diseases sometimes associated with a dementing illness (i.e., frontotemporal, Parkinson or Lewy-body disease, ALS, and progressive supranuclear palsy). In Sweden, for example, Sjögren has found familial cases of this type, as have Schaumburg and Suzuki in the United States. The clinical picture in these cases has been indistinguishable or has varied only slightly from that of Alzheimer disease and autopsy has disclosed widespread cerebral atrophy that is most pronounced in the frontal
lobes. These cases are characterized by a diffuse neuronal loss, slight glial proliferation, and similarly slight secondary alteration of the white matter. Other instances of sporadic and familial presenile dementia have shown subcortical gliosis or nonspecific cellular changes (atrophy of nerve cells and nuclei, loss of Nissl substance). Some examples of the latter type were in the past described as “Kraepelin disease,” and more recently as “dementia lacking distinctive histologic features” (Knopman et al). Perhaps some of these cases will turn out to be a variant of the “tau” form of frontotemporal dementia discussed above. Notable is the presence of this same nondescript pathologic change in some cases of lobar atrophy, particularly primary progressive aphasia.
Argyrophilic Grain Disease This obscure entity has been connected with a late-life dementia in which behavioral disturbances precede memory difficulty. Whether the finding of argyrophilic grains in the mediotemporal lobe, different from tau-laden neurofibrillary tangles and from the glial inclusions (putatively a defining feature of multiple system atrophy), constitutes a specific entity is not clear to the authors. Probst and Tolnay remarked that these small argyrophilic inclusions are not found in nondemented individuals. It is unlikely that the condition can be identified in life; if it is a genuine entity, it must be rare.
Thalamic Dementia A relatively pure degeneration of thalamic neurons is described from time to time in relation to a progressive dementia, but it must also be rare (Stern; Schulman). Reported cases evolved rapidly (several months) and in some instances were associated with choreoathetosis. Garcin and colleagues described five such instances of subacutely developing dementia, which they considered initially to be examples of Creutzfeldt-Jakob disease. In each case, the pathologic changes consisted primarily of neuronal loss and gliosis of the thalamus. A large kindred characterized by subacute dementia and myoclonus and inherited dementia as an autosomal trait was reported by Little and coworkers. In members of this family, the clinical presentation was also very similar to that of CreutzfeldtJakob disease, however, the evolution was slower and pathologic changes were confined to the thalami, particularly to the mediodorsal and other anterior and medial thalamic nuclei. Transmission of the disease to primates was unsuccessful. We wonder whether some of these cases were unappreciated instances of cerebral deep venous thrombosis, late-onset Leigh disease (subacute necrotizing encephalopathy), or even more unusual prion conditions such as fatal familial insomnia.
Neuroserpinopathy There have been infrequent case reports of dominantly inherited, adult-onset dementia with a fulminant evolution suggestive of encephalopathy and the special feature of seizures. The distinctive feature has been the presence at autopsy of large eosinophilic, PAS-positive intraneu-
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ronal inclusions that contain aggregates of neuroserpin, thus the initial description of “familial encephalopathy with neuronal inclusion bodies.” The serpins are a family of protease inhibitors that include neuroserpin, a protein expressed exclusively in neurons, and α1-antitrypsin. The neuronal inclusions are densest in the deep layers of the cortex and in the substantia nigra. Missense mutations in the gene encoding neuroserpin have been identified as the cause. This newly described disease is reviewed by Lomas and Carrell.
Vascular (Multiinfarct) Dementia A comment is required regarding the group of diseases subsumed under the term vascular dementia and found in all classifications as among the common causes of chronic mental deterioration, second only to Alzheimer disease. Without doubt, as discussed in Chap. 34, multiple cerebral strokes cause increasing deficits that cumulatively qualify as a dementia. At least some of the focal lesions that contribute to the cognitive syndrome can be identified clinically and there is a stepwise decline in function that corresponds to strokes. Admittedly, this type of vascular dementia may be more difficult to recognize when a number of the infarcts are of the relatively silent lacunar type; the mental capacities of such patients may then appear to fail in a gradual and continuous fashion. Memory is relatively spared in the early stages and usually a pseudobulbar state or deterioration in gait accompanies the dementia. The subcortical white matter change of Binswanger disease causes similar diagnostic problems, as discussed in a later section. The authors have doubts about the frequency with which vascular dementia is assumed to occur. Most cases turn out to be Alzheimer disease with one or more visible infarctions. We are inclined toward the point of view expressed in Chap. 21 and summarized in the commentary by Jagust that there may be an undefined, and perhaps synergistic, interaction between strokes and progressive mental decline in patients with Alzheimer disease but the relationship is unproven. Most often it is the degenerative condition of Alzheimer that explains the dementia.
Dementia Caused by Metabolic Diseases (See Chap. 37) In the diagnosis of this large category of chronic dementias, one must consider several nondegenerative disorders in which mental decline may predominate and focal neurologic abnormalities are minimal. Several of the treatable ones were listed earlier in the discussion of Alzheimer disease above, and a larger group is reviewed in Chap. 21 and Table 21-3. Also to be considered, particularly among dementias with onset at an early age, are the inherited metabolic diseases discussed in Chap. 37, chief among which are the leukodystrophies (metachromatic, adrenal, globoid body [Krabbe disease] and the poliodystrophies, neuronal ceroid lipofuscinosis [Kufs disease], GM2 gangliosidosis, and Wilson disease [see “Adult Forms of Inherited Metabolic Diseases” in Chap. 37]). Each of these displays characteristic neurologic features that include in
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the early stages a decline in intellectual function and a general behavioral disorder.
DEMENTING DISEASES IN WHICH OTHER NEUROLOGIC ABNORMALITIES ARE PROMINENT Huntington Disease (Huntington Chorea) This disease, distinguished by the triad of dominant inheritance, choreoathetosis and dementia, commemorates the name of George Huntington, a medical practitioner of Pomeroy, Ohio. In 1872, his paper, read before the Meigs and Mason Academy of Medicine and published later that year in the Medical and Surgical Reporter of Philadelphia, gave a succinct and graphic account of the disease that was based on observations of patients that his father and grandfather had made in the course of their practice in East Hampton, Long Island. Reports of this disease had appeared previously (see DeJong for historical background) but they lacked the completeness of Huntington’s description. In 1932, Vessie was able to show that practically all the patients with this disease in the eastern United States could be traced to about 6 individuals who had emigrated in 1630 from the tiny East Anglian village of Bures, in Suffolk, England. One remarkable family was traced for 300 years through 12 generations, in each of which the disease had expressed itself. To quote Huntington, the rule has been that “When either or both of the parents have shown manifestations of the disease, one or more of the offspring invariably suffer of the disease, if they live to adult life. But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from disease.” Davenport, in a review of 962 patients with Huntington chorea, found only 5 who had descended from unaffected parents. Possibly, in these 5 patients, a parent had the trait, in very mild form, or parentage was in question, because spontaneous mutations are rare. In university hospital centers, this is one of the most frequently observed types of hereditary nervous system diseases and the main cause of progressive chorea at most ages. Its overall frequency is estimated at 4 to 5 per million, and 30 to 70 per million among whites of northern European ancestry. The usual age of onset is in the fourth and fifth decades, but 3 to 5 percent begin before the fifteenth year and some even in childhood, where it takes on special form. In approximately 30 percent, symptoms become apparent after 50 years. The progression of the disease is generally slower in older patients for reasons noted below. Once begun, the disease progresses relentlessly, until only a restricted existence in a nursing home or psychiatric hospital is possible and a medical disease terminates life. Exhaustive genealogic documentation established the cause to be an autosomal dominant gene with complete penetrance (see below). Koller and Davenport have made the observation that young patients usually inherit the disease from their fathers, and older patients from their
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mothers. It has been observed beginning at almost the same age in identical twins. The first important achievement in respect to the biologic understanding of Huntington disease was the discovery by Gusella and colleagues of a marker linked to the Huntington gene and localized to the short arm of chromosome 4. Subsequently, these investigators and others identified the mutation as an excessively long repeat of the trinucleotide CAG within the Huntington gene, the length (number) of which determines not only the presence of the disease, but also the age of onset, longer repeat lengths being associated with an earlier appearance of signs. A rare alternative mutation, termed HDL2 (Huntington disease-like-2), is associated with CATCG repeat expansion of the juntophilin-3 gene, but it is so rare that few clinicians will encounter it (Margolis et al). These discoveries have made possible the development of a genetic test for the measurement of the repeat length that confirms the diagnosis in symptomatic patients and allows screening of asymptomatic individuals. Because there is no treatment for the disease, testing raises certain ethical considerations that must be resolved before its widespread utilization.
Clinical Features The mental disorder assumes several subtle forms long before the more obvious deterioration of cognitive functions becomes evident. In approximately half the cases, slight but annoying alterations of character are the first to appear. Patients begin to find fault with everything, to complain constantly, and to nag other members of the family; they may be suspicious, irritable, impulsive, eccentric, untidy, or excessively religious, or they may exhibit a false sense of superiority. Poor self-control may be reflected in outbursts of temper, fits of despondency, slovenliness, alcoholism, or sexual promiscuity. Disturbances of mood, particularly depression, are common (almost half of the patients in some series) and may constitute the most prominent symptoms early in the disease. Invariably, sooner or later, the intellect begins to fail globally. The patient becomes less communicative and socially withdrawn. The emotional disturbances and changes in personality may reach such proportions as to constitute a virtual psychosis with persecutory delusions or hallucinations. Diminished work performance, inability to manage household responsibilities, and disturbances of sleep may prompt medical consultation. There is difficulty in maintaining attention and concentration and in assimilating new material. Mental flexibility lessens. Simultaneously, there is loss of fine manual skills (see further on). The performance parts of the Wechsler Adult Intelligence Scale show greater loss than the verbal parts. Memory is relatively spared. This gradual dilapidation of intellectual function has been characterized as a “subcortical dementia,” i.e., elements of aphasia, agnosia, and apraxia are observed only rarely and memory loss is not profound. Often the process is so slow, particularly in cases of late onset, that a fair degree of intellectual capacity seems to be retained for many years. The abnormality of movement is subtle at first and most evident in the hands and face; often the patient is merely
considered to be fidgety, restless, or “nervous.” Slowness of movement of the fingers and hands, a reduced rate of finger tapping, and difficulty in performing a sequence of hand movements are early signs. Gradually these abnormalities become more pronounced until the entire musculature is implicated with chorea. The frequency of blinking is increased (the opposite of parkinsonism), and voluntary protrusion of the tongue, like other attempts at sustained posture, is constantly interrupted by unwanted darting movements. In the advanced stage of the disease the patient is seldom still for more than a few seconds. The choreic movements are slower than the brusque jerks and postural lapses of Sydenham chorea, and they involve many more muscles. They tend to recur in stereotyped patterns yet are not as stereotyped as tics. In advanced cases, they acquire an athetoid or dystonic quality. Muscle tone is usually decreased until late in the illness, when there may also be some degree of rigidity, tremor, and bradykinesia, elements suggestive of Parkinson disease. Parkinsonism with rigidity characterizes the Westphal or “rigid” variant, which is more common with a childhood onset, or the HDL2 genetic variant noted earlier. Tendon reflexes are exaggerated in one-third of patients, but only a few have Babinski signs. Voluntary movements are initiated and executed more slowly than normal, but there is no weakness and no ataxia, although speech, which becomes dysarthric and explosive because of incoordination between tongue and diaphragm, may convey the impression of a cerebellar disorder. There is poor control of the tongue and diaphragm. In late-onset cases there may be an almost constant rapid movement of the tongue and mouth, simulating the tardive dyskinesia that follows the use of neuroleptic drugs. These disorders of movement that characterize Huntington chorea are described more fully in Chap. 4. Oculomotor function is subtly affected in most patients (Leigh et al; Lasker et al). Particularly characteristic are impaired initiation and slowness of both pursuit and volitional saccadic movements and an inability to make a volitional saccade without movement of the head. Excessive distractibility may be noticed during attempted ocular fixation. The patient feels compelled to glance at extraneous stimuli even when specifically instructed to ignore them. Upward gaze is often impaired as the illness progresses. As Wilson stated, the relation of the choreic to the mental symptoms “abides by no general rule.” Most often the mental symptoms precede the chorea but they may accompany or follow it, sometimes by many years. Once the movement disorder is fully established, there is nearly always some degree of cognitive abnormality. Exceptional cases have been reported in which the movement disorder existed for 10 to 30 years without mental changes (Britton et al); this would be most characteristic of patients with shorter gene repeat lengths. After 10 to 15 years of symptoms, most patients deteriorate to a vegetative state, unable to stand or walk and eating little; in this late stage, a mild amyotrophy may appear. Noteworthy is the high suicide rate in huntingtonians, as pointed out by Huntington himself (see also Schoenfeld et al). Because there is a higher-than-normal incidence of head trauma, chronic subdural hematoma is another common finding at autopsy.
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The first signs of the disease may appear in childhood, before puberty (even younger than the age of 4 years), and several series of such early onset cases have been described (Farrer and Conneally; van Dijk et al). Mental deterioration at this early age is more often accompanied by cerebellar ataxia, behavior problems, seizures, bradykinesia, rigidity, and dystonia than by chorea (Byers et al). However, this rigid form of the disease (Westphal variant) also occurs occasionally in adults as mentioned above, in some cases because of HDL2. Functional decline is much faster in children than it is in adults (Young et al). At the Huntington gene locus there are normally 11 to 34 (median: 19) consecutive repetitions of the CAG triplet, each coding for glutamine. Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree, or limited to the belowmentioned “senile chorea.” Those with more than 42 repeats almost invariably acquire the signs of disease if they live long enough. Earlier onset in successive generations (anticipation) is well described in the early writings on the subject and is now known to be attributable to increasing lengths of the CAG repeat sequence. The dementia is generally more severe in cases of early onset and with correspondingly longer repeat lengths (15 to 40 years of age) than in those of later onset (55 to 60 years of age). In adult patients with early onset, the emotional disturbance tends to be more prominent initially and precedes the chorea and intellectual loss by years; with older age of onset, choreiform features are more often the initial components; in the middle years, dementia and chorea have their onset at nearly the same age. At the other extreme of age, the first features may become evident in the eighties, with orofacial or other dyskinesias that are mistakenly attributed to an exposure to neuroleptic drugs or called “senile chorea” (see Chap. 4).
Pathology and Pathogenesis Gross atrophy bilaterally of the head of the caudate nucleus and putamen is the characteristic abnormality, usually accompanied by a moderate degree of gyral atrophy in the frontal and temporal regions. The caudatal atrophy alters the configuration of the frontal horns of the lateral ventricles in that the inferolateral borders do not show the usual bulge formed by the head of the caudate nucleus. In addition, the ventricles are diffusely enlarged (Fig. 39-4); in CT scans, the bicaudate-to-cranial ratio is increased, which corroborates the clinical diagnosis in the moderately advanced case. The early articles of Alzheimer and Dunlap and the more recent one of Vonsattel and DiFiglia contain the most authoritative descriptions of the microscopic changes. The latter authors have graded the disease into early, moderately advanced, and far advanced stages. In 5 early but genetically verified cases, no striatal lesion was found, which suggests that the first clinical manifestations are based on a biochemical or infrastructural change. This view is supported by the observation that Huntington patients studied with PET show a characteristic decrease in glucose metabolism in the caudate nuclei, which pre-
Figure 39-4. The upper CT scan is from a 54-year-old mildly demented woman with a 10-year history of Huntington chorea. The bulge in the inferolateral border of the lateral ventricle, normally created by the head of the caudate nucleus (lower scan from a patient of the same age for comparison), is obliterated. There is also a diffuse enlargement of the lateral ventricles.
cedes the volumetric loss of tissue (Hayden et al). The striatal degeneration begins in the medial part of the caudate nucleus and spreads, tending to spare the nucleus accumbens. Of the 6 cell types in the striatum (a differentiation based on size, dendritic arborizations, spines, and axon trajectories), the smaller neurons are affected before the larger ones. Loss of dendrites of the small spiny neurons has been an early finding, while the large cells are relatively preserved and exhibit no special alterations. The lost cells are replaced by fibrous astrocytes. The anterior parts of the putamen and caudate are more affected than
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the posterior parts. Some observers have noted changes in the globus pallidus, subthalamic nucleus, red nucleus, cerebellum and in the pars reticulata of the substantia nigra. In the cerebral cortex, there is slight neuronal loss in layers 3, 5, and 6, with replacement gliosis. Cases are reported with typical striatal lesions but normal cortices in which only chorea had been present during late life. Several neuropathologists have observed marked cell loss and gliosis in the subthalamic nuclei in Huntington-affected children or young adults with chorea and behavior disorders. Mechanism of Disease From the molecular perspective, the pathogenesis of this disease is a direct, but still poorly understood, consequence of the aforementioned expansion of the polyglutamine region of huntingtin (the protein product of the Huntington gene). It has been shown that the mutant huntingtin protein aggregates in the nuclei of neurons. Moreover, the protein accumulates preferentially in cells of the striatum and parts of the cortex affected in Huntington disease. Evidence, particularly that given by Wetz (cited in the review by Bates), suggests that these aggregates may be toxic to neurons, either directly or in their protofibrillary (unaggregated) form. The situation is, however, likely to be more complex, as the bulk of huntingtin deposition is found in cortical neurons, whereas the neuronal loss is predominantly striatal. One theory supports the concept that the polyglutamine complex renders certain cell types unduly sensitive to glutamate-mediated excitotoxicity. More recently, two mechanisms have been proposed based on an interruption of protein transcription by the binding of mutant huntingtin to transcription proteins or that mitochondrial dysfunction occurs directly or through the same transcriptional mechanism, as summarized by Greenamyre. Because polyglutamine expansions are implicated in several neurodegenerative diseases (reviewed in corresponding sections of this chapter), treatments that block their effects on cellular function may be broadly effective in several degenerative diseases.
Diagnosis Once the disease has been observed in its fully developed form, its recognition requires no great clinical acumen. The main difficulty arises in patients who lack a family history but who display progressive chorea, emotional disturbance, and dementia. This difficulty has been largely overcome since the mutation was identified. It is now possible to confirm or exclude the diagnosis by analysis of DNA from a blood sample. The presence of more than 39 CAG repeats at the Huntington locus essentially confirms the disease and gives some indication of the expected time of onset; lesser numbers of repeat length leave room for equivocation and strings between 39 and 42 may not be manifest if the patient does not live long enough to express the illness. Chorea that begins in late life with only mild or questionable intellectual impairment and without a family history of similar disease is a source of diagnostic difficulty. A few cases are because of the earlier mentioned HDL2 mutation and others derive from alternative degenerative conditions (see below). Referring to the problem as “senile chorea” does not solve the problem. Indeed, senile chorea has many causes. We have seen it appear with infections, hyperglycemia, drug
therapy, strokes, and thyrotoxicosis, only to disappear after a few weeks. A few times we have been confronted with the problem of an older patient who displays orolingual dyskinesias that are most characteristic of exposure to neuroleptic drugs but in whom there was no such history of exposures; testing usually disclosed Huntington disease. Chorea in early adult life always raises the question of a late form of Sydenham chorea, of lupus erythematosus with antiphospholipid antibodies, or of cocaine use, but neither familial occurrence nor mental deterioration is part of these processes. A “benign inherited chorea,” transmitted as an autosomal dominant trait without prolongation of a triplet sequence, has been traced to chromosome 14q. It is differentiated from Huntington disease by onset before age 5 years, progressing little, and having no associated mental deterioration (Breedveld et al). Other progressive neurologic disorders inherited as autosomal dominant traits and beginning in adolescence or adult life (e.g., polymyoclonus with or without ataxia, acanthocytosis with progressive chorea, and dentatorubropallidoluysian degeneration) can closely mimic Huntington disease, as described further on; sometimes only the genetic and pathologic findings settle the matter. A midlife progressive chorea without dementia (after more than 25 years of followup) that does not display the Huntington genotype has been reported. In at least one family in which this clinical picture is dominantly inherited, the fundamental defect is a mutation in the gene encoding the light chain of ferritin (Curtis). Affected individuals have axonal changes in the pallidum with swollen, ubiquitin- and tau-positive aggregates; serum ferritin levels may be depressed. The implication of this mutation is that perturbations of iron metabolism may be toxic to neurons, a feature that also characterizes Hallervorden-Spatz disease. Dentatorubropallidoluysian atrophy (DRPLA), sometimes misdiagnosed clinically as Huntington chorea, was described in European families by Warner and associates and is discussed further on. The extrapyramidal manifestations include chorea, myoclonus, and rigidity. Adult-onset chorea and dementia has been described with propionic acidemia; propionic acid is elevated in the plasma, urine, and CSF. This disorder must be added to other metabolic diseases described in Chap. 37 as causes of childhood chorea and dyskinesia— such as glutaric acidemia, keratin sulfaturia, calcification of basal ganglia, phenylketonuria, and Hallervorden-Spatz disease (Hagberg et al). Other problems in differential diagnosis include prion disease, Wilson disease (Chap. 37), acquired hepatocerebral degeneration (Chap. 40), and most often and especially, tardive dyskinesia (Chap. 41). Many drugs in addition to the toxic effects of L-dopa and antipsychotic medications occasionally cause chorea (amphetamines, cocaine, tricyclic antidepressants, lithium, isoniazid, linezolid). The hyperglycemic–hyperosmolar state is well known for producing a variety of generalized or local movement disorders, prominent among them being chorea.
Treatment The dopamine antagonist haloperidol, in daily doses of 2 to 10 mg, is effective in suppressing the movement disorder.
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Because of the danger of superimposing tardive dyskinesia on the chronic disorder, the chorea should be treated only if it is functionally disabling, using the smallest possible dosages. Haloperidol may also help alleviate abnormalities of behavior or emotional lability, but it does not alter the progress of the disease. The authors have not been impressed with the therapeutic effectiveness of other currently available drugs. Levodopa and other dopamine agonists make the chorea worse and, in the rigid form of the disease, evoke chorea. Drugs that deplete dopamine or block dopamine receptors— such as reserpine, clozapine, and particularly tetrabenazine, which has been validated in a controlled study (Huntington Study Group)—suppress the chorea to some degree, but their side effects (drowsiness, akathisia, and tardive dyskinesia) usually outweigh their desired effects. They may be tried in difficult cases. The juvenile (rigid) form of the disease is probably best treated with antiparkinsonian drugs. Preliminary studies of the transplantation of fetal ganglionic tissue into the striatum has achieved mixed results. The psychologic and social consequences of the disease require supportive therapy, and genetic counseling is essential. Antidepression drugs are widely implemented because of the high incidence of depression and suicidality but their efficacy is not clear. Huntington disease pursues a steadily progressive course and death occurs as mentioned, on average 15 to 20 years after onset, sometimes much earlier or later.
Acanthocytosis with Chorea There are two categories of neurologic disease associated with red blood cell acanthocytosis; one with a defect in the red cell lipid membrane (represented by Bassen-Kornzweig disease and the HARP [hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration] syndrome [see Chap. 37]) and a second group that lacks a lipid abnormality. This latter type of neuroacanthocytosis enters into the differential diagnosis of Huntington chorea or unexplained progressive choreas and has the following characteristics: (1) onset in adolescence or early adult life of generalized involuntary movements (described as chorea but including dystonia and tics), usually beginning as an orofacial dyskinesia and spreading to other parts of the body and to other neural systems; (2) mild to moderate mental deterioration with behavioral disturbance in some but not all cases; (3) decreased or absent tendon reflexes and evidence of chronic axonal neuropathy and denervation atrophy of muscles; and (4) the defining feature of acanthocytosis (thorny or spiky appearance of erythrocytes). The main syndrome, and the one to which the term neuroacanthocytosis had for a long time been applied, is caused by an autosomal recessive mutation. However, there are now four additional subtypes, one dominantly transmitted and another X-linked (McLeod type), which is discussed below. These are all in distinction to BassenKornzwieg disease that is caused by an inherent defect in the lipid layer of the red cell membrane (see further on). According to Sakai and coworkers, the acanthocytosis is the result of an abnormal composition of covalently (tightly) bound fatty acids in erythrocyte membrane proteins (palmitic and docosahexanoic acids increased and stearic acid decreased). The acanthocytosis may be over-
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looked when it is mild but can be detected by scanning electron microscopy. The latter may be necessary to undertake in cases of unexplained chorea that have the other features of this disease as genetic testing for the gene (see below) is not widely available. In the series of 19 cases reported by Hardie and colleagues, the manifestations included dystonia, tics, vocalizations, rigidity, and lip and tongue biting; more than half had cognitive impairment or psychiatric features. The average age of onset was 32 years; 7 of the 19 cases were sporadic. The disease has been linked in almost all families to chromosome 9q, where there is a mutation in the gene encoding a large (3,100-amino-acid) protein designated chorein that is involved in cellular protein sorting and trafficking (Rampoldi). Some of the families with dominantly inherited neuroacanthocytosis have mutations in the chorein gene. There is atrophy and gliosis of the caudate nuclei and putamens but no neuronal loss in the cerebral cortex or other parts of the brain. McLeod disease, another disorder with acanthocytosis and the gradual development of chorea in middle to late life, is characterized by degeneration of the caudate and putamen and a myopathy (elevated serum creatine phosphokinase [CPK]). These individuals have fewer facial tics and orofacial features than those with neuroacanthocytosis. McLeod syndrome arises from mutations in a gene on the X chromosome that encodes the KX protein, which binds to surface Kell antigens on red cells. In addition to the primary KX gene mutations, these individuals show diminished Kell antigen expression on the red-cell surface.
Corticostriatospinal Degenerations Included in this category are a heterogeneous group of degenerative diseases in which the symptoms of parkinsonism and corticospinal degeneration present in various combinations. Some of the diseases that make up this group have not been sharply delineated and are difficult to separate from one another. Variants of this category of disease continue to appear, all rare. The authors have observed several patients in whom extreme rigidity, corticospinal signs but no dementia have developed over a period of several years. In the later stages of the disease, the patient, while alert, is totally helpless and unable to speak, swallow, or move the limbs. Only eye movements are retained, and even these are hampered by supranuclear gaze palsies in advanced cases. Intellectual functioning appears to be better preserved than movement but is difficult to assess. Other bodily functions are intact. The course is slowly progressive and ends fatally in 5 to 10 years. There is no family history of similar disease, and there are no clues as to causation. Gilbert and colleagues have described similar cases with signs of Parkinson disease, motor neuron disease, and dementia; in their cases, there were no senile plaques or Lewy bodies. The concurrence of typical motor neuron disease and Parkinson disease may be coincidental, but Qureshi and colleagues described 13 patients in whom both clinical phenomena began within a short time and they considered them to be related. In the variant described by Tandan and colleagues, an autosomal dominant syndrome of Charcot-Marie-Tooth polyneuropa-
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thy was combined with ptosis, parkinsonism, and dementia, again without Lewy bodies or amyloid plaques. Other variants have been described by Schmitt and coworkers and by Mata and colleagues. Hudson reviewed 42 sporadic cases in which ALS-parkinsonism-dementia were combined. Under the title “Spastic Pseudosclerosis,” Jakob, in 1921, described a chronic disease of middle to late adult life, characterized by abnormalities of behavior and intellect; weakness, ataxia, and spasticity of the limbs (chiefly the legs); extrapyramidal symptoms such as rigidity, slowness of movement, tremors, athetotic postures, and hesitant, dysarthric speech; and normal spinal fluid. The pathologic changes were diffuse and consisted mainly of an outfall of neurons in the frontal, temporal, and central motor gyri, striatum, ventromedial thalamus, and bulbar motor nuclei. In one of Jakob’s cases, there were also prominent changes in the anterior horn cells and corticospinal tracts in the spinal cord like those of ALS. The latter finding gave rise to Wilson’s concept of the disease as a corticostriatospinal degeneration. A degenerative and probably familial disorder that had been described earlier by Creutzfeldt was considered by Spielmeyer to be sufficiently similar to the one of Jakob to warrant the designation Creutzfeldt-Jakob disease. As discussed in Chap. 33, the disorder originally described by Creutzfeldt and Jakob has been a source of endless controversy because of its indeterminate character. It has been confused with the subacutely evolving myoclonic dementia, or subacute spongiform encephalopathy, which is now known to be an infection caused by a prion agent. The latter disease bears at best only a superficial resemblance to the one described by Creutzfeldt and Jakob, and the two disorders should be separated. Unfortunately, the use of the eponym for the prion-related disease is so entrenched that attempts to delete it are futile and probably unnecessary. However, the term Jakob disease has been used for the degenerative type of corticostriatospinal degeneration. The Guamanian Parkinson-dementia-ALS complex deserves separate comment because there have been many carefully studied cases with almost uniform clinical and pathologic features. The disease occurs in the indigenous Chamorro peoples of Guam and the Mariana islands, predominantly in men between the ages of 50 and 60 years. Progressive parkinsonism and dementia are combined with upper or lower motor neuron disease (ALS is also common among the Chamorro) leading to death in 5 years. The pathologic changes, described by Hirano and associates, consist of severe cortical atrophy with neurofibrillary tangles and a depopulation of the substantia nigra, but notably no Lewy bodies or amyloid plaques, even with sensitive neurochemical staining. Cases with amyotrophy show a loss of anterior horn cells. The cause of the Guamanian multisystem degeneration is not known, although several studies have incriminated one or more putative neurotoxins in the food supply (see Chap. 43). There are some clinical and pathologic similarities to the form of frontotemporal dementia with motor neuron disease.
Familial Dementia with Spastic Paraparesis Occasionally, the authors have encountered families in which several members developed a spastic paraparesis and a
gradual failure of intellectual function during the middle adult years. The patient’s mental horizon narrowed gradually, and the capacity for high-level thinking diminished; in addition, the examination showed exaggerated tendon reflexes, clonus, and Babinski signs. In one such family, the illness had occurred in two generations; in another, 3 brothers in a single generation were afflicted. Skre described 2 recessive types of hereditary spastic paraplegia in Norway, 1 with onset in childhood, the other with onset in adult life. In contrast to the dominant form (see further on), the recessive types displayed evidence of more widespread involvement of the nervous system, including dementia, cerebellar ataxia, and epilepsy. Also, Cross and McKusick have observed a recessive type of paraplegia accompanied by dementia beginning in adolescence. They named it the Mast syndrome, after the afflicted family. Worster-Drought and others reported the pathologic findings in 2 cases of this type. In addition to senile plaques and neurofibrillary changes, there was demyelination of the subcortical white matter and corpus callosum and a “patchy but gross swelling of the arterioles,” which gave the staining reactions for amyloid (“Scholz’s perivascular plaques”). van Bogaert and associates published an account of similar cases that showed the characteristic pathologic features of Alzheimer disease. Another interesting association of familial spastic paraplegia is with progressive cerebellar ataxia. Fully onethird of the cases that we have seen with such a spastic weakness were also ataxic and would fall into the category of spinocerebellar degenerations. Yet another variant of this group of diseases has been described by Farmer and colleagues; the inheritance in their cases was autosomal dominant, and the main clinical features were deafness and dizziness, ataxia, chorea, seizures, and dementia, evolving in that order. Postmortem examinations of two patients disclosed calcification in the globus pallidus, neuronal loss in the dentate nuclei, and destruction of myelinated fibers in the centrum semiovale.
Adult Polyglucosan Body Disease Under this title, Robitaille and colleagues have described a distinct progressive neurologic disease in adults characterized clinically by spasticity, chorea, dementia, and a predominantly sensory polyneuropathy. Structures that closely resembled Lafora bodies and corpora amylacea were found in large numbers in both central and peripheral neural processes (mainly in axons) and also in astrocytes. These basophilic PAS-positive structures were composed of glucose polymers (polyglucosans) and were readily demonstrated in sural nerve biopsies. Some were also found in the heart and liver. More recently, Rifal and associates reviewed the findings in 25 cases of this disease—one observed by them and 24 reported previously. The dementia was relatively mild, consisting of impairment of retentive memory, dysnomia, dyscalculia, and sometimes nonfluent aphasia and deficits of “visual integration”; this was overshadowed by rigidity and spasticity of the limbs and the peripheral nerve disorder. Bladder dysfunction has been an early sign in some patients including a middle-aged woman
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under our care who had only diffuse white matter changes in the cerebral MRI and a moderate sensory neuropathy. Nerve conduction velocities were diminished and the leg muscles were denervated. Moderate degrees of generalized cerebral atrophy, multifocal areas of white matter rarefaction, and increased iron deposition in the putamina was disclosed by MRI. The finding of polyglucosan axon inclusion in biopsied nerves confirms the diagnosis. The disease has sometimes been misdiagnosed as adrenoleukodystrophy. Its status is unclear to the authors, and there is no treatment. Adult forms of metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe disease, and neuronal ceroid lipofuscinosis (Kufs disease) may present with a similar clinical picture of progressive dementia (Chap. 37) as may Whipple disease or the Wernicke-Korsakoff disease. Quite rare instances of the same syndrome with adult onset have turned out to be caused by phenylketonuria or other aminoacidopathies (see Chap. 37).
DISEASES CHARACTERIZED BY ABNORMALITIES OF POSTURE AND MOVEMENT Parkinson Disease This common disease, known since ancient times, was first cogently described by James Parkinson in 1817. In his words, it was characterized by “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.” Strangely, his essay contained no reference to rigidity or to slowness of movement and it stressed unduly the reduction in muscular power. The same criticism can be leveled against the term paralysis agitans, which appeared for the first time in 1841 in Marshall Hall’s textbook Diseases and Derangements of the Nervous System and has fallen out of
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use, but was such a common term in the literature that it is included here. The natural history of the disease is of interest. As a rule, it begins between 45 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age, and most series contain a somewhat larger proportion of men. Trauma, emotional upset, overwork, exposure to cold, “rigid personality,” and so on, were among many factors that have been suggested over the years as predisposing to the disease, but there is no convincing evidence to support any such claims. A possible relationship to repeated cerebral trauma and to the “punch-drunk” syndrome (dementia pugilistica) has been particularly problematic and is unresolved despite several celebrated cases (Lees). A protective effect of smoking and coffee drinking has emerged in some epidemiologic studies but is marginal. Idiopathic Parkinson disease is observed in all countries, all ethnic groups, and all socioeconomic classes, although the incidence in African Americans is only onequarter that in whites. There may be an increased incidence in rural compared to urban areas. In Asians, the incidence is one-third to one-half that in whites. The disease is frequent in North America, where there are approximately 1 million affected patients, constituting about 1 percent of the population over the age of 65 years. The incidence in European countries where vital statistics are kept is similar. Genetic Aspects Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent. A lack of concordance of Parkinson disease in twins was at first thought to negate the role of genetic factors, but a study of dopamine metabolism using PET scanning showed that 75 percent of asymptomatic twins of Parkinson patients had evidence of striatal dysfunction, whereas only a small portion of dizygotic twins showed these changes (Piccini et al). These data suggest a substantial role for an inherited trait in cases of ostensibly sporadic disease (see below regarding the better defined inherited forms). Although familial cases are decidedly rare (Table 39-2), Golbe and colleagues advanced the understanding of the
Table 39-2 GENETIC DEFECTS ASSOCIATED WITH PARKINSON DISEASE NOTATION
CHROMOSOME
GENE
Park1
4q21
Park2
6q25
α-synuclein parkin
Park3 Park5
2p13 4p14
Park6 Park7
GENETICS
AGE OF ONSET
LEWY BODIES
SPECIAL FEATURES
Two main mutations—A53T, A30P—promote oligomerization of α-synuclein. Accounts for 50% of early onset inherited PD; 20% of “sporadic” early onset cases. Resembles idiopathic PD. Gene is ubiquitin carboxyterminal hydrolase L1. Mutations decreased recycling of ubiquitin monomers. Mitochondrial gene. Slow progression; gene plays role in cellular response to oxidative stress. Ashkenazic Jews. Protein is dardarin, a novel kinase. Gene is implicated in the formation and identity of dopaminergic neurons.
AD
30–40 years
+
AR
20–40 years
–
UCH-L1
AD AD
Late onset 50’s
– +
1p35-36 1p36
PINK1 DJ-1
AR AR
varies 30’s
?
Park8
12 cent
LRRK2
AD
late
±
NR4A2
2q22
NURR1
AD
AD, autosomal dominant; AR, autosomal recessive; PD, Parkinson disease.
?
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genetics of the disease by describing two large kindreds (probably related and originating from a small town in southern Italy) in which 41 patients in 4 generations were affected. The illness was characteristic of Parkinson disease both clinically and pathologically, the only unusual features being a somewhat earlier onset (mean age: 46 years), a relatively rapid course (10 years from onset to death), and a low incidence of tremor (only 8 of the 41 patients). The dominantly inherited parkinsonism described by Dwork and associates also differed clinically (onset in the third decade, prominence of dystonia) and pathologically (absence of Lewy bodies) from classic Parkinson disease. It was in the latter kindred and in 3 Greek families that Polymeropoulos and colleagues identified a locus on chromosome 4q that contained a mutation in the gene encoding the protein αsynuclein, a main component of the Lewy body. Other families in which there have been mendelian patterns of inheritance have gene defects at other sites. These genetic data were reviewed by Dunnett and Björklund. It is now clear that while such mutations are uncommon in the usual lateonset sporadic form of Parkinson disease, they are predominant in earlier-onset cases (see below). Table 39-2 summarizes the main mutations causing Parkinson disease or very similar appearing syndromes. Of equivalent interest has been the discovery of polymorphisms in genes other than the ones noted above. The mutation that has received most attention recently has been at the LRRK2 (leucine-rich repeat kinase) site. It is implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin) is a cytoplasmic component that is widely distributed in the brain and peripheral nerves. It has been estimated that mutations in the gene (mainly one common one, G20195) are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease. The gene acts as a dominant trait but penetrance of the defect increases with age, being 85 percent at 70 years. Therefore, there may not be a family history evident. The clinical syndrome in most respects simulates the native disease, according to Papapetropoulos and colleagues, but several other series have noted the absence of tremor. The genetics of this disorder, also called Park8, are reviewed by Brice. Several other gene defects are of interest in familial parkinsonism. One is a dominantly inherited mutation in the gene Nurr1, whose normal function is to specify the identity of dopaminergic neurons. Another is in recessively inherited parkinsonism caused by defects in the gene DJ-1, a protein that is essential for the normal neuronal response to oxidative stress. Also, a disease-causing mutation in the gene termed PINK, corresponding to Park6, codes for a mitochondrial kinase, therefore implicating this cellular structure in some forms of Parkinson disease (Valente et al). Presumably, dopaminergic neurons are compromised in some manner by these defects. There has also been emphasis on mutations on 1 of 12 exons in the so-called Park2 gene, which codes for the protein parkin (see Table 39-2). The most common types are point mutations or deletions in exon 7, but abnormalities of the other exons evince similar syndromes. Homozygous mutations generally give rise to early onset disease,
but certain hemizygous changes (in exon 7) are associated with a later onset. The resultant syndromes have been termed parkin disease to distinguish them from the idiopathic variety. It has been estimated by Khan and colleagues that 50 percent of families that display an early onset of Parkinson disease and 18 percent of sporadic cases with early onset (before age 40 years) harbor mutations in this gene. Perhaps of greater clinical interest is finding that up to 2 percent of late-onset cases are a result of parkin mutations, and 1 percent because of the aforementioned LRRK2 gene. Sequencing of these genes is now available in commercial laboratories for the purposes of detecting mutations and polymorphisms. From a clinical perspective, the presentation of the lateonset cases with parkin mutations has been quite variable. Collectively, they can often be identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication; also, they have a low threshold for dyskinesias induced by L-dopa. We can also corroborate from experience with our own patients an excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs. A second feature has been that most of these patients may enjoy a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms. Several series, particularly those of Lohmann and associates and of Khan and colleagues, have indicated that there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. The sensitivity to medication and sleep benefit have long been known as the distinguishing components of juvenile-onset parkinsonism with dopa-responsive dystonia (Segawa disease), which proves also to be derived from one of the parkin mutations.
Clinical Features A tetrad of hypo- and bradykinesia, resting tremor, postural instability, and rigidity are the core features of Parkinson disease. These are evident as an expressionless face, poverty and slowness of voluntary movement, “resting” tremor, stooped posture, axial instability, rigidity, and festinating gait. Much can still be gained from perusal of the often-cited study by Hoehn and Yahr, published in 1967 before the widespread use of L-dopa. Table 39-3 is
Table 39-3 INITIAL SYMPTOMS IN PATIENTS WITH PARKINSON DISEASE Tremor Gait disturbance Stiffness Slowness Muscle aches Loss of dexterity Handwriting disturbance Depression, nervousness, other psychiatric disturbance Speech disturbance
70% 11% 10% 10% 8% 7% 5% 4% 3%
Source: Adapted from Hoehn and Yahr’s study of 183 idiopathic cases, 1967.
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reproduced from that paper. The manifestations of basal ganglionic disease are fully described in Chap. 4, and only certain diagnostic problems and nuances of the clinical picture need be considered here. The early symptoms may be difficult to appreciate and are often overlooked by family members because they evolve slowly and tend to be attributed to the natural changes of aging. Speech becomes soft, monotonous and cluttered. For a long time the patient may not be conscious of the inroads of the disease. At first the only complaints may be of aching of the back, neck, shoulders, or hips and of vague weakness. Slight stiffness and slowness of movement or a reduction in the natural swing of one arm during walking are ignored until one day it occurs to the physician or to a member of the family that the patient has the overall cast of Parkinson disease. Infrequency of blinking, as originally pointed out by Pierre Marie, is an early sign. The usual blink rate (12 to 20/min) is reduced in the parkinsonian patient to 5 to 10/min, and with it there is a slight widening of the palpebral fissures, creating a stare. A reduction in movements of the small facial muscles imparts the characteristic expressionless “masked” appearance (hypomimia). When seated, the patient makes fewer small shifts and adjustments of position than the normal person (hypokinesia), and the fingers straighten and assume a flexed and adducted posture at the metacarpophalangeal joints. The characteristic tremor, which usually involves a hand, is often listed as the initial sign; but in at least half the cases observant family members will already have remarked on the patient’s relative slowness of movement. In about one-quarter of cases the tremor is mild and intermittent, or evident in only one finger or one hand. The tremor of the fully developed case takes several forms, as was remarked in Chap. 6. The 4-per-second “pill-rolling” tremor of the thumb and fingers, although most characteristic, is seen in only about half the patients. It is typically present when the hand is motionless, i.e., not used in voluntary movement (hence the commonly used term resting tremor). Complete relaxation, however, reduces or abolishes the tremor, so that the term tremor in the position of repose is actually a more accurate descriptor. Volitional movement dampens it momentarily. The rhythmic beat coincides with an alternating burst of activity in agonist and antagonist muscles in the electromyogram (EMG); hence the description alternating tremor is applied. The arm, jaw, tongue, eyelids, and foot are less often involved. Even the least degree of tremor is felt during passive movement of a rigid part (cogwheel phenomenon, or Negro sign, or at least this is the ostensible explanation for cogwheeling). The tremor shows surprising fluctuations in severity and is aggravated by walking and excitement, but its frequency remains constant (Hunker and Abbs). It bears repetition that one side of the body is typically involved before the other with tremor and rigidity, and the tremor in particular remains asymmetrical as the illness advances. Lance and associates have called attention to the high incidence of a second essential type of tremor in Parkinson disease—a fine, 7- to 8-per-second, slightly irregular, action tremor of the outstretched fingers and hands. This tremor, unlike the slower one, persists throughout volun-
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tary movement, is not evident with the limb in a resting position, and is more easily suppressed by relaxation. Electromyographically, it lacks the alternating bursts of action potentials seen in the typical tremor and resembles, if not equates with, essential tremor (see Table 6-1). It is subject to modulation by different medications than those used for the alternating Parkinson tremor. The patient may have either type of tremor or both. Rigidity is less often an early finding. Once rigidity develops, it is constantly present and can be felt by the palpating fingers and as a salience of muscle groups even when the patient relaxes. When the examiner passively moves the limb, a mild resistance appears from the start (without the short free interval that characterizes spasticity) and it continues evenly throughout movement in both flexor and extensor groups, being interrupted to a variable degree only by the cogwheel phenomenon. Rigidity and its cogwheel component are elicited or enhanced by having the patient engage the opposite limb in a motor task requiring some degree of concentration, such as tracing circles in the air or touching each finger to the thumb. In the muscles of the trunk, postural hypertonus predominates in the flexor groups and confers on the patient the characteristic flexed posture. Other particulars of the parkinsonian appearance of muscle tone, stance, and gait are discussed in detail in Chaps. 4 and 7. Here, a few additional points should be made regarding the quality of volitional and postural movements. The patient is slow and ineffective in attempts to deliver a quick hard blow; he cannot complete a rapid (ballistic) movement. On the EMG, the normal single burst of agonist–antagonist–agonist sequence of energizing activity is replaced by several sequential brief bursts, according to Hallett and Khoshbin. Alternating movements, at first successful, become progressively impeded if performed repetitively and, finally, they are blocked completely or adopt the rhythm of the patient’s alternating tremor. The patient has great difficulty in executing two motor acts simultaneously. In the past the impaired facility of movement had been attributed to rigidity, but the observation that certain surgical lesions in the brain abolished rigidity without affecting movement refuted this interpretation. Thus slowness and lack of natural movements (bradykinesia and hypokinesia, respectively) are not derived from rigidity but are independent manifestations of the disease. The bradykinetic deficits underlie the characteristic poverty of movement, reflected also by infrequency of swallowing, slowness of chewing, a limited capacity to make postural adjustments of the body and limbs in response to displacement of these parts, a lack of small “movements of cooperation” (as in arising from a chair without first adjusting the feet), absence of arm swing in walking, and most of the other aspects of the parkinsonian countenance. Despite a perception of muscle weakness, the patient is able to generate normal or near-normal power, especially in the large muscles; however, in the small ones, strength is slightly diminished. As the disorder of movement worsens, all customary activities show the effects. Handwriting becomes small (micrographia), tremulous, and cramped, as first noted by Charcot. Speech softens and seems hurried, monotonous
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and mumbling (cluttered): the voice becomes less audible and, finally, the patient only whispers. Caekebeke and coworkers refer to the speech disorder as a hypokinetic dysarthria and attribute it to combined respiratory, phonatory, and articulatory dysfunctions. There is a failure to fully close the mouth. The consumption of a meal takes an inordinately long time. Each morsel of food must be swallowed before the next bite is taken. Walking becomes reduced to a shuffle; the patient frequently loses balance, and in walking forward or backward seems to be “chasing” the body’s center of gravity with a series of increasingly rapid short steps in order to avoid falling (festination). Defense and righting reactions are faulty. Falls do occur, but surprisingly infrequently given the degree of postural instability. Gait is improved by sensory guidance, as by holding the patient at the elbow. Obstacles such as door thresholds have the opposite effect, at times causing the patient to “freeze” in place. Getting in and out of a car or elevator or walking into a room or in a hall become particularly difficult. Difficulty in turning over in bed is a similarly characteristic feature as the illness advances, but the patient rarely volunteers this information. Several of our patients have fallen out of bed at a frequency that suggests a connection to their reduced mobility combined with slowed corrective or defensive postural movements. Shaving or applying lipstick becomes difficult, as the facial muscles become more immobile and rigid. Persistent extension or clawing of the toes, jaw clenching, and other fragments of dystonia, often quite painful, may enter the picture and are sometimes early findings. (These are particularly resistant to treatment.) A special problem of camptocormia occurs in some Parkinson patients wherein an extreme forward flexion of the spine and correspondingly severe stooping occur. It appears to be a type of axial dystonia when it occurs with Parkinson disease. The deformity resolves when the patient is supine or pushes upward on the handles of a walker. This symptom is associated with a variety of other diseases, some of them muscular. We have not been impressed that it is ameliorated by L-dopa. Why some patients with Parkinson disease are extremely bent over and others are not at all affected is unknown. As noted above, these various motor impediments and tremors characteristically begin in one limb (more often the left) and spread to one side and later to both sides until the patient is quite helpless. Yet in the excitement of some unusual circumstance (as escaping from a fire, for example), the patient with all but the most advanced disease is capable of brief but remarkably effective movement (kinesis paradoxica). Regarding elicitable neurologic signs, there is an inability to inhibit blinking in response to a tap over the bridge of the nose or glabella (Myerson sign) but grasp and suck reflexes are not present unless dementia supervenes and buccal and jaw jerks are rarely enhanced. Commonly there is an impairment of upward gaze and convergence; if prominent or noted early in the disease, this sign suggests more the possibility of progressive supranuclear palsy. Bradykinesia may extend to eye movements, in that there is a delay in the initiation of gaze to one side, slow-
ing of conjugate movements (decreased maximal saccadic velocity), hypometric saccades, and breakdown of pursuit movements into small saccades. There are no sensory findings, but a wide variety of paresthetic and other sensory complaints and discomforts are common. Drooling is troublesome; an excess flow of saliva has been assumed, but actually the problem is probably one of failure to swallow with normal frequency. Seborrhea and excessive sweating are claimed to be secondary as well, the former due to failure to cleanse the face sufficiently, the latter to the effects of the constant motor activity but this explanation seems lacking to us; an autonomic disturbance is more plausible. Postural instability can be elicited by tugging at the patient’s shoulders from behind and noting the lack of a small step backward to maintain balance often with a fall or the initiation of backward festination. The tendon reflexes vary, as they do in normal individuals from being barely elicitable to brisk. Even when parkinsonian symptoms are confined to one side of the body, the reflexes are usually equal on the two sides, and the plantar responses are flexor. Exceptionally, the reflexes on the affected side are slightly brisker, which raises the question of corticospinal involvement, but the plantar reflex remains flexor. In these respects, the clinical picture differs from that of corticobasal ganglionic degeneration, in which rigidity, hyperactive tendon reflexes, and Babinski signs are combined with apraxia (see further on). There is a tendency in some patients to have orthostatic hypotension and sometimes syncope; this has been attributed by Rajput and Rozdilsky to cell loss in the sympathetic ganglia. However, these features are not as prominent as in multiple-system atrophy (ShyDrager syndrome). It is worth mentioning that several of our younger Parkinson patients with recurrent syncope proved to have cardiac arrhythmias; hence other causes of fainting must be considered. As mentioned earlier, Parkinson disease may be complicated by dementia, a feature described by Charcot. The reported frequency of this combination varies considerably based on the selection of patients and type of testing. An estimate of 10 to 15 percent (Mayeux et al) is the generally accepted figure and matches our experience. The incidence increases with advancing age and duration of disease, approaching 65 percent in Parkinson patients older than 80 years of age, but mental decline may become apparent in patients in their late fifties. The pathologic basis of the dementia is discussed below. The overall course of the disease is quite variable. In the majority of patients, the mean period of time from inception of the disease to a chairbound state is 7.5 years, but with a wide range (Hoehn and Yahr; Martilla and Rinne). As much as 10 percent of cases remain relatively mild and only very gradually progressive, and such patients may remain almost stable for 10 years or more. Hemiparkinson–Hemiatrophy Syndrome Mentioned here is a syndrome described by Klawans and elaborated in a series of 30 patients by Wijemanne and Jankovic. The typical case shows atrophy in one or more body parts, including at times the face, often since childhood, and usually quite subtle. Signs of progressive parkinsonism or
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dystonia begin in midlife on the atrophic side and, for the most part, are responsive to L-dopa, but some, such as Klawans’ original patients, are resistant. Several types of early life cerebral injury underlie the syndrome, but half of patients have no such lesion evident. Understanding of the idiopathic cases is limited. Those with deep brain lesions may be experiencing a slow degeneration of basal ganglia pathways.
Diagnosis The two main difficulties are to distinguish typical Parkinson disease from the many parkinsonian syndromes caused by other degenerative conditions and by medications or toxins, and to distinguish the Parkinson tremor from other types. It is worth noting that Parkinson disease is far more common than any of the syndromes that resemble it with the possible exception of essential tremor. Bradykinesia and rigidity of the limbs and axial musculature are symptoms shared with other forms of parkinsonism, but mainly in Parkinson disease does one see an early sign of “resting” alternating tremor that is more prominent in one arm. When not all the typical signs are evident, there is no alternative but to reexamine the patient at several-month intervals until it is clear that Parkinson disease is present or until the signature of another degenerative process becomes evident (e.g., early falls and vertical gaze impairment in progressive supranuclear palsy; dysautonomia with fainting, bladder, or vocal cord signs in multiple system atrophy; early and rapidly evolving dementia or intermittent psychosis in Lewy-body disease; or apraxia in corticobasal ganglionic degeneration). Highly symmetrical findings, particularly tremor, suggest an alternative to idiopathic Parkinson disease. If the symptoms warrant, a beneficial and sustained response to levodopa or a dopamine agonist also gives a reasonably secure, although not entirely conclusive, indication of the presence of Parkinson disease (see further on). The other parkinsonian syndromes are for the most part changed only slightly or only for a few weeks by the drug. Conversely, although some experts disagree, we have adhered to the notion that complete resistance of the symptoms to L-dopa early in the illness makes the diagnosis unlikely. The epidemic of encephalitis lethargica (von Economo encephalitis) that spread over Western Europe and the United States after the First World War left great numbers of parkinsonian cases in its wake. No definite instance of this form of encephalitis had been recorded before the period 1914 to 1918, and very few have been seen since 1930; hence, this type of postencephalitic parkinsonism is no longer a diagnostic consideration. However, a Parkinson-like syndrome has been described following other forms of encephalitis, particularly with Japanese B virus, West Nile virus, and eastern equine encephalitis. In the few cases caused by these viruses that we have observed, there has been fairly symmetrical rigidity, hypokinesia, and little or no tremor. An “arteriopathic” or “arteriosclerotic” form of Parkinson disease was at one time much diagnosed but we have never been entirely convinced of its reality, referring to
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damage to the substantia nigra as a result of vascular disease or to a syndrome that closely resembles Parkinson disease as a result of atherosclerotic white matter damage. Nonetheless, a number of authoritative clinicians are of the opinion that patients with a vascular cause have a predominantly “lower half” parkinsonism in which shuffling gait, stickiness on turning, and falling are disproportionate to other features. There is no tremor, and little or no response to L-dopa (see Winikates and Jankovic). MRI in such cases has shown substantial white matter changes in both cerebral hemispheres. In the few cases attributable to vascular parkinsonism that have come to our attention with autopsy material, there have been Lewy bodies in the appropriate locations. Pseudobulbar palsy from a series of lacunar infarcts or from Binswanger disease can cause a clinical picture that simulates certain aspects of Parkinson disease, but unilateral and bilateral corticospinal tract signs, hyperactive facial reflexes, spasmodic crying and laughing, and other characteristic features distinguish spastic bulbar palsy from Parkinson disease. Of course, the elderly parkinsonian patient is not impervious to cerebrovascular disease, and the two conditions overlap, but differentiating the predominantly gait or dementing disorders of widespread vascular brain damage from idiopathic Parkinson disease is not difficult. Normal-pressure hydrocephalus can undoubtedly produce a syndrome resembling Parkinson disease, particularly in regard to gait and postural instability, and at times extending to bradykinesia; but rigid postures, slowness of alternating movements, hypokinetic ballistic movements, and resting tremor are not part of the clinical picture. The gait tends to be short-stepped but not shuffling and there is more of a tendency to retropulsion than there is in Parkinson disease. Sometimes a lumbar puncture gives surprising benefit, indicating hydrocephalus as the cause of the motor slowing and gait disorder. Essential tremor is distinguished by its fine, quick quality, its tendency to become manifest during volitional movement and to disappear when the limb is in a position of repose, and the lack of associated slowness of movement or of flexed postures. Cogwheeling of minor degree may be associated. The head and voice are more often truly tremulous in essential tremor than in Parkinson disease. Some of the slower, alternating forms of essential tremor are difficult to distinguish from parkinsonian tremor; one can only wait to see whether it is the first manifestation of Parkinson disease. A markedly asymmetrical or unilateral tremor favors Parkinson disease. Also as noted, a faster oscillation is often mixed with the slow alternating Parkinson tremor, but the fast-frequency tremor is only occasionally an opening feature of the disease. Progressive supranuclear palsy (see further on) is characterized by rigidity and dystonic postures of the neck and shoulders, a staring and immobile countenance, and a tendency to topple when walking—all of which are vaguely suggestive of Parkinson disease. Early and frequent falls are particularly suggestive of this disease, not being atypical of Parkinson disease until its late stages. Inability to produce vertical saccades and, later, paralysis of upward and downward gaze and eventual loss of lateral gaze with retention of reflex eye movements establish
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the diagnosis of PSP in most cases. Strict adherence to the diagnostic criteria for Parkinson disease also permits its differentiation from corticostriatospinal, striatonigral, and corticobasal ganglionic degeneration, as well as MachadoJoseph disease, all of which are discussed in other parts of this chapter. Paucity of movement, unchanging attitudes and postural sets, and a slightly stiff and unbalanced gait may be observed in patients with an anergic or hypokinetic type of depression. Because as many as 25 to 30 percent of parkinsonian patients are depressed, the separation of these two conditions is at times difficult. The authors have seen patients who were called parkinsonian by competent neurologists but whose movements became normal when antidepressant medication or electroconvulsive therapy was given. Several such patients have nonetheless insisted that levodopa helps them in some nondescript way. The rapid onset of parkinsonism should suggest exposure to neuroleptic medications (used at times as antiemetics and gastric motility agents [metoclopramide]), a variant of Creutzfeldt-Jakob disease, an unusual postinfectious or paraneoplastic illness, or viral encephalitis. The implicated drugs may also evoke an inner restlessness, a “muscular impatience,” an inability to sit still, and a compulsion to move about much like that which occurs at times in the parkinsonian patient (akathisia). Even the newer antipsychosis medications, favored specifically because of a putative lack of extrapyramidal effects, may be at fault. All in all, if one adheres to the strict definition of Parkinson disease—bradykinesia, hypokinesia “resting” tremor, postural changes and instability, cogwheel rigidity, and response to L-dopa—errors in diagnosis are few. Yet in a series of 100 cases, studied clinically and pathologically by Hughes and associates, the diagnosis was inaccurate in 25 percent. The reasons are that about this number of Parkinson patients fail to display the characteristic tremor and approximately 10 percent are said to not respond to Ldopa. These authors noted that early dementia and autonomic disorder and the presence of ataxia and corticospinal signs were reliable guides to an alternate diagnosis.
Pathology and Pathogenesis The most constant and pertinent finding in both idiopathic and postencephalitic Parkinson disease is a loss of pigmented cells in the substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus). The substantia nigra is visibly pale to the naked eye; microscopically, the pigmented nuclei show a marked depletion of cells and replacement gliosis, and some of the remaining cells have reduced quantities of melanin, findings that enable one to state with confidence that the patient must have suffered from Parkinson disease. Also, many of the remaining cells of the pigmented nuclei contain eosinophilic cytoplasmic inclusions, surrounded by a faint halo, called Lewy bodies (Fig. 39-5). These are seen in practically all cases of idiopathic Parkinson disease. They were generally absent in postencephalitic cases, but there were neurofibrillary tangles within nigral cell in that disorder. Both of these cellular abnormalities appear occasionally in the
Figure 39-5. Photomicrograph of a round Lewy-body inclusion in the cytoplasm of a nigral neuron. (Hematoxylin and eosin [H&E] staining.) (Courtesy of M. Frosch, MD, PhD.)
substantia nigra of aged, nonparkinsonian individuals. Possibly the individuals with Lewy bodies would have developed Parkinson disease if had they lived a few more years. Many of the inherited forms of Parkinson disease also lack Lewy bodies. Noteworthy is the finding by McGeer and colleagues that nigral cells normally diminish with age, from a maximal complement of about 425,000 to 200,000 at age 80 years. Tyrosine-hydroxylase, the rate-limiting enzyme for the synthesis of dopamine, diminishes correspondingly. However, these authors and others have found that in patients with Parkinson disease the number of pigmented neurons is reduced to 30 percent or less of that in age-matched controls. Using more refined counting techniques, Pakkenberg and coworkers estimated the average total number of pigmented neurons to be 550,000 and to be reduced in absolute numbers by 66 percent in Parkinson patients. (The number of nonpigmented neurons was reduced in Parkinson cases by only 24 percent.) Thus aging contributes importantly to nigral cell loss, but the cell depletion is so much more marked in Parkinson disease that some factor other than aging must also be operative. Other depletions of cells are widespread as mentioned, but they have not been quantitatively evaluated and their significance is less clear. There is neuronal loss in the mesencephalic reticular formation, near the substantia nigra. These cells project to the thalamus and limbic lobes. In the sympathetic ganglia, there is slight neuronal loss and Lewy bodies are seen. This is also true of the pigmented nuclei of the lower brainstem as well as of neuronal populations in the putamen, caudatum, pallidum, and substantia innominata. On the other hand, dopaminergic neurons that project to cortical and limbic structures, to caudate nucleus and nucleus accumbens, and to periaqueductal gray matter and spinal cord are affected little or not at all. The lack of a consistent lesion in either the striatum or the pallidum is noteworthy. An alternative hypothesis offered by Braak and Tredici is that the substantia nigra compacta
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is affected only late in the pathobiology of Parkinson disease. Their study found that the earliest changes in the brain occur in the dorsal glossopharyngeal-vagal and anterior olfactory nuclei, and only later did they arise in the midbrain nuclei. This theory accommodates a variety of clinical features and potential environmental triggers to the disease. Lang suggested that this pattern explains some of the nondopaminergic features of the disease and offers other avenues for therapy. Statistical data relating Parkinson and Alzheimer diseases are difficult to assess because of different methods of examination from one series to another (Quinn et al, 1986). Nevertheless, the overlap of the two diseases is more than fortuitous, as indicated earlier in this chapter. The majority of the demented Parkinson patients shows some Alzheimertype changes but there are some in whom few plaques or neurofibrillary changes could be found or who display cortical neuronal loss accompanied by widespread distribution of Lewy bodies, marking the process as Lewy-body dementia. Of great interest has been the observation, both in humans and in monkeys, that a neurotoxin (known as MPTP [1methyl-4-phenyl-1,2,3,6-tetrahydropyridine]) produces irreversible signs of parkinsonism and selective destruction of cells in the substantia nigra. The toxin, an analogue of meperidine, which was self-administered by addicts, binds with high affinity to monoamine oxidase, an extraneural enzyme that transforms MPTP to a toxic metabolite, pyridinium MPP (1-methyl-4-phenylpyridinium). The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentration to destroy the cells. The precise mechanism by which MPTP produces the Parkinson syndrome is unsettled. One hypothesis is that the inner segment of the globus pallidus is rendered hyperactive because of reduction of the influence of gamma-aminobutyric acid (GABA) of the subthalamic nucleus. The hypothesis of some other environmental toxin as a cause of Parkinson disease has been greatly stimulated by the MPTP findings (see Uhl et al; also the review by Snyder and D’Amato). Indeed, Parkinson disease is slightly more frequent in industrialized countries and agrarian regions where organophosphates are commonly used, but its universal occurrence would argue against this hypothesis. Despite extensive study, to date no chemical toxin, heavy metal, or infection has been incriminated in the causation of Parkinson disease. Some plausible theories hold that a toxin might be implicated only on a genetic background predisposing to the disease. The MPTP disease serves as a model for the neurophysiologic and neurochemical changes of Parkinson disease because of destruction of the substantia nigra, but in most other respects it does not reflect the naturally occurring disorder (including the absence of Lewy bodies). Numerous observations have implicated the nuclear and synaptic protein α-synuclein, the main component of Lewy bodies in both the sporadic and inherited forms of Parkinson disease, as well as in Lewy-body disease. Synuclein, a normal component of the synapse, exists in a soluble unfolded form, but in high concentrations it aggregates into filaments, which are the main (but not the only) constituent of the Lewy body. Immunostaining techniques disclose additional less-specific proteins, such as ubiquitin and tau within the Lewy bodies. Furthermore, in families with a rare
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autosomal dominant form of Parkinson disease, several different mutations on chromosome 4 code for an aberrant form of synuclein that decreases its stability and promotes its aggregation (Polymeropoulos et al). A family has also been described in which the cause of Parkinson disease is an extra nonmutant copy of the α-synuclein gene (Singleton et al) comparable to the circumstance or triplication of chromosome 21 in the Alzheimer disease of Down syndrome. Additionally, some cases of familial parkinsonism result from mutations that control the removal of α-synuclein from the cell via proteasomal pathways. Together, these findings indicate that instability or misfolding of α-synuclein or its deficient removal may be a primary defect in the disease. The protofibrillary form of the protein (i.e., a soluble protein in the cytosol) is also toxic to dopaminergic neurons. These processes are accelerated by defects in heat shock proteins that chaperone α-synuclein into and out of the cell (see Fig. 39-2). Curiously, Lewy bodies are not found in patients with most of the parkin mutations. Parkin is a ubiquitin protein ligase that participates in the removal of unnecessary proteins from cells through the proteasomal system (Fig. 39-6). Attachment of parkin and ubiquitin to cytosolic proteins is understood to be an obligatory step in the disposal of proteins by proteosomes. Mutations in the parkin gene lead either to an inadequacy or misfolding of synuclein, resulting in its accumulation, or to the disruption of disposal of proteins in dopamine-producing cells. The importance of the ubiquitination pathway in this disease is further highlighted by the report that parkinsonian features are present in a family with mutations in ubiquitin carboxyterminal hydrolase L1 (UCHL-1; see Table 39-2). Figure 39-6 illustrates these relationships and the processing of synuclein in the cell. It must be emphasized that most of the notions illustrated are speculative or are derived from the molecular study of familial Parkinson disease and therefore may not apply to the sporadic process. Several other gene defects are of interest in familial parkinsonism. One is a dominantly inherited mutation in the gene Nurr1, whose normal function is to specify the identity of dopaminergic neurons. Another is in recessively inherited parkinsonism because of defects in the gene DJ-1, a protein that is essential for the normal neuronal response to oxidative stress. Also, a disease-causing mutation in the gene termed PINK, corresponding to Park6, codes for a mitochondrial kinase, implicating this cellular structure in some forms of Parkinson disease (Valente et al). Presumably, dopaminergic neurons are compromised in some manner by these defects. It is hoped that the genetic mutations that give rise to Parkinson disease will expose the molecular pathophysiology of the disease. As discussed earlier, several sites are implicated in the familial forms of Parkinson disease, most related to the gene that codes for synuclein, the main component of the Lewy body. This conceptually links familial Parkinson disease with Alzheimer disease and possibly with ALS, all potential sequelae of toxic protein aggregation.
Treatment Although there is no current treatment that clearly halts or reverses the neuronal degeneration underlying Parkinson
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α-synuclein mut
α-synucleindup
UCH-L1mut Molecular crowding E1
parkinmut
Hsps
Dopamine
E2
α-synuclein-dopamine
E3
adduct formation Protofibrils
Ubiquitinated protein
Fibrils
Proteasome
Degraded protein
Lewy bodies
disease, methods are now available that afford considerable relief from symptoms. Treatment can be medical or surgical, although reliance is placed mainly on drugs, particularly on L-dopa (Table 39-4). The following sections are necessarily detailed so as to give the clinician a full comprehension of the use and side effects and interactions of these drugs. L-Dopa and L-Dopa–Modifying Drugs At present, Ldihydroxyphenylalanine (L-dopa) is unquestionably the most effective agent for the treatment of Parkinson disease and the therapeutic results, even in those with far advanced disease, are much better than have been obtained with other drugs. Carbidopa/levodopa or an agonist preparation is introduced only when the symptoms begin to interfere with work and social life or falling becomes a threat, and then these drugs are used at the lowest possible dose. As mentioned earlier, some degree of response is so nearly universal that many neurologists view responsiveness to L-dopa as a diagnostic criterion. The theoretical basis for the use of this compound rests on the observation that striatal dopamine is depleted in patients with Parkinson disease but that the remaining diseased nigral cells are still capable of producing some dopamine by taking up its precursor, L-dopa. The number of neurons in the striatum is not diminished and they remain receptive to ingested dopamine acting through the residual nigral neurons. Over time, however, the number of remaining nigral neurons becomes inadequate and the receptivity to dopamine of the striatal target neurons becomes excessive, possibly as a result of denervation hypersensitivity; this results in both a reduced response to
Neurotoxicity
Figure 39-6. Schematic diagram of proposed mechanisms of α-synuclein toxicity in Parkinson disease. In this model, αsynuclein levels are elevated by (a) duplication of one copy of the α-synuclein gene; (b) point mutations in the α-synuclein gene that generate excessive accumulations of synuclein; or (c) mutations in parkin and UCH-L1 genes that reduce normal removal of synuclein by the proteosomes. The excess of synuclein polymerizes to form protofibrils, a process that is enhanced by defects in heat shock proteins (Hsps) or by the action of dopamine, which binds to synuclein. In turn, this leads to formation of Lewy bodies. This model attributes the neurotoxicity to either the protofibrils or the Lewy bodies. (Adapted by permission from Eriksen JL, Dawson TM, Dickson DW, Petrucelli L: Caught in the act: αSynuclein is the culprit in Parkinson’s disease. Neuron 40:453–456, 2003.)
L-dopa and to paradoxical and excessive movements (dyski-
nesias) with each dose. Most patients tolerate the drug initially, experiencing few serious adverse effects and showing dramatic improvement, especially in hypokinesia and tremor after several days or sooner (there are exceptions). However, the side effects and limitations of L-dopa become considerable as the drug therapy continues and the disease progresses as discussed below. By combining L-dopa with a decarboxylase inhibitor (carbidopa or benserazide), which is unable to penetrate the central nervous system (CNS), decarboxylation of L-dopa to dopamine is greatly diminished in peripheral tissues. This permits a greater proportion of L-dopa to reach nigral neurons and, at the same time, reduces the peripheral side effects of L-dopa and dopamine (nausea, hypotension, confusion). Combinations of carbidopa-levodopa are available in a 1:10 or 1:4 ratio and the benserazide-levodopa combination is available in a 1:4 ratio. The initial dose of levodopa-carbidopa is typically one-half to one of a 25/100-mg tablet given bid or tid and increased slowly until optimum improvement is achieved, usually up to 4 tablets administered 5 or more times daily as the disease advances, or a similar dose of the 25/250-mg combination. A class of catechol-O-methyltransferase (COMT) inhibitors, typified by entacapone, extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability, as in the case of carbidopa). A combination of L-dopa, carbidopa, and a COMT inhibitor is available in a single pill.
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Table 39-4 DRUGS COMMONLY USED IN THE TREATMENT OF PARKINSON DISEASE MEDICATION
STARTING DOSE
TARGET DOSE
MAIN BENEFIT
SIDE EFFECTS
Reduction of tremor and bradykinesia; less effect on postural difficulties May prolong L-dopa effects
Nausea, dyskinesias, orthostatic hypotension, hallucinations, confusion
Orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations
L-Dopa
Carbidopa-L-dopa (Sinemet)
25/100 mg tid
Up to 50/250 mg q3h
Controlled release carbidopa-L-dopa Dopamine agonists Ropinirole
25/100 mg tid
Up to 50/200 mg q4h
0.25 mg tid
9 to 24 mg/d
Moderate effects on all aspects; reduced motor fluctuations of L-dopa
0.125 mg tid
0.75 to 3 mg/d
As above
100 mg/d
100 mg bid–tid
Smoothing of motor fluctuations
Leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
0.5 mg/d
Up to 4 mg/d
Tremor reduction, less effect on other features
0.5 mg bid
Up to 2 mg tid
As above
Atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis As above
Pramipexole Glutamate antagonist Amantadine (Symmetrel) Anticholinergics Benztropine (Cogentin) Trihexyphenidyl (Artane) COMT inhibitors Entacapone
200 mg with L-dopa
MAO-inhibitors Rasagiline
0.5 mg 5 mg
Selegiline
Prolonged effect of L-dopa
Urine discoloration, diarrhea, increased dyskinesias
1 mg daily
Reduced “off” time, potential neuroprotection
Hypertensive crisis with tyramine-rich foods and sympathomimetics
5 mg bid
Potential neuroprotection
Long-acting preparations of levodopa-carbidopa may provide slightly longer effect and reduce dyskinesias in some patients (Hutton and Morris) in the advanced stages of disease, but our experience with these drugs given earlier in the course of disease has given less-predictable results. The absorption of the long-acting drug, however, is approximately 70 percent, often necessitating a slight increase in total dose. To facilitate the treatment of morning rigidity and tremor, the long-acting tablet can be given late in the previous evening. Each patient requires empirical adjustment of the dose and timing of medication and then generally does well by maintaining a relatively regular medication schedule, supplemented by small intercalated doses when needed. The effect of L-dopa may be virtually immediate (i.e., after absorption, which occurs over 30 to 40 min) but there is a further cumulative effect over several days of consistent dosing. The principles that guide the adjustment of dosing (end-of-dose wearing off, dyskinesias, freezing, confusion) are discussed further on. Dopamine Agonists These drugs have a direct dopaminergic effect on striatal neurons, thereby partially bypassing the depleted nigral neurons. They have found a place both as the initial treatment, replacing L-dopa in this role, and in modulating the effects of L-dopa later in the illness. However, dopamine agonists are consistently less potent than L-dopa in managing the main features of Parkinson disease and, in higher doses, they produce similar undesirable motor and cognitive side effects (see further
on). They are favored because they are associated with fewer dyskinetic motor complications. Bromocriptine, pergolide, and lisuride are synthetic ergot derivatives whose action in Parkinson disease is explained by their direct stimulating effect on dopamine (D2) receptors located on striate neurons. The nonergot dopamine agonists ropinirole and pramipexole have a similar type and duration of effectiveness. Pergolide, and the related drug cabergoline, are no longer used because of the risk of cardiac valvular damage, particularly at higher dose levels. Why dyskinesias are less frequent with ropinirole than with L-dopa is not known. Some specialists attribute this simply to their lower potency. All these drugs should be introduced cautiously. For example, the initial dose of pramipexole is 0.125 mg tid, following which the dosage is doubled weekly to a total of 3 to 4.5 mg/d if the medication is used without L-dopa. These drugs usually permit a gradual reduction in levodopa-carbidopa dose by approximately 50 percent. Their duration of action is slightly longer than that of L-dopa and they cause less nausea, but otherwise the action and side effects of the two drugs are much the same. These medications are also undoubtedly useful in smoothing the effects of L-dopa. The addition of small doses of one of these agents to a stable regimen of Ldopa to reduce dyskinesias requires careful titration over several weeks and a reduction of the total L-dopa dose (see further on). Our experience is in general agreement with that of Marsden, who found that of 263 patients given dopamine
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agonists as the sole treatment, 181 had abandoned medication after 6 months because of lack of effect or adverse reactions. Nevertheless, the fact that a large enough proportion of patients continue to benefit for up to 3 to 5 years indicates that the initial use of dopamine agonists has merit (see also Rascol et al). A recent development of some interest is a transdermally absorbed dopamine agonist such as rotigotine. Several trials suggest that the transdermal system can maintain a stable plasma level of the drug. In the study by LeWitt and associates, the main effect was a doubling of “on” time without unwanted dyskinesias. The effects on the quality of life in Parkinson patients appear to be positive but minor in degree. The patch is currently withdrawn from use because of local skin reactions. Even small doses of dopaminergic drugs, when first introduced, may induce orthostatic hypotension, but most patients are quite tolerant of them. They may also produce abrupt and unpredictable sleepiness and patients should be warned of this possibility in relation to driving. In some individuals, particularly the elderly, dopamine agonists may produce hallucinosis or confusion; these problems are most profound in patients who are later determined to have Lewy-body disease (see further on). More data are required to judge the efficacy of the current trend of initiating therapy with a dopamine agonist rather than with L-dopa. Adjunctive Medications Because of the side effects of levodopa and of dopaminergic agents, some neurologists avoid all types of pharmacotherapies if the patient is in the early phase of the disease and the parkinsonian symptoms are not troublesome. When the predominant manifestation is tremor, very satisfactory results can be obtained in some patients for up to several years with anticholinergic agents alone. The anticholinergic drugs have little effect on the postural, hypokinetic, and other manifestations of disease. Koller’s study, which quantified the effect of anticholinergic medication on tremor and compared it to Ldopa, concluded that there was considerable variability in response between patients but that L-dopa was on average more effective. Nonetheless, anticholinergic agents have long been in use for the treatment of tremor in younger patients and we still use them occasionally, either in conjunction with L-dopa or in patients who cannot tolerate the latter drug. The optimum dosage level is the point at which the greatest relief from tremor is achieved within the limits of tolerable side effects, mainly dry mouth. In older patients, one must be alert to changes in cognitive function, hallucinations, and prostatic obstruction. Several synthetic preparations of anticholinergic drugs are available, the most widely used ones being trihexyphenidyl (beginning with 1 to 2 mg/d and increased up to 6 to 8 mg over several weeks) and benztropine mesylate (1 to 4 mg/d in divided doses). When it has been available, we have also had success with the related agent ethopropazine (50 to 200 mg daily in divided doses; but it has become difficult to obtain). The effects on tremor are cumulative and may not be evident for several days. To obtain maximum benefit from the use of these drugs, they should be given in gradually increasing dosage to the point where toxic effects appear: dryness of the mouth (which can be
beneficial when drooling of saliva is a problem), blurring of vision from pupillary mydriasis, constipation, and urinary retention (especially with prostatism). Tremor abates in several days and most of our patients have become tolerant to the dry mouth after several weeks. Pyridostigmine, propantheline, or glycopyrrolate can be given to reduce the dryness. With higher dose ranges, mental slowing, confusional states, hallucinations, and impairment of memory in elderly patients—specifically if there is already some degree of forgetfulness—are side effects that limit usefulness. Occasionally, further benefit may accrue from the addition of another antihistaminic drug, such as diphenhydramine or phenindamine. The antiviral agent amantadine (100 mg bid) has mild or moderate benefit for tremor, hypokinesia, and postural symptoms. In some patients, it reduces L-dopa–induced dyskinesias (see further on). Its mechanism of action is unknown but antagonism of NMDA or release of stored dopamine has been proposed. It should be noted that amantadine commonly causes leg swelling, may worsen congestive heart failure, and can have an adverse effect on glaucoma, as well as exaggerate the cognitive changes associated with anticholinergic medications. Finally, the monoamine oxidase inhibitors described just below as neuroprotective agents have a beneficial effect on motor fluctuations induced by L-dopa and may have a slight independent beneficial effect on the main Parkinson symptoms as described in several trials, such as the one reported by Rascol and colleagues. Neuroprotective Agents An additional approach, still controversial, has been to initiate treatment early in the course of the disease with a monoamine oxidase-B inhibitor, with the aim of reducing oxidative stress in dopaminergic neurons. The DTAATOP trial conducted by The Parkinson Study Group (1989) reported a slowing of disease progression but later followup showed little difference. Other agents in this class, notably rasagiline, have given similar mixed results in brief studies including the ADAGIO trial. The difficulty in assessing the benefit of these agents has to do with their mild but definite symptomatic motor effects. A credible long-term study has reported that early initiation of the treatment with bromocriptine (now little used) did not reduce mortality or motor disability over 14 years and that any reduction in motor complications was not sustained (Katzenschlager et al). Nonetheless, we institute one of these medications in many patients. Following this same line of reasoning, several studies, most still disputed or unconfirmed, have suggested that ropinirole, pramipexole, and even L-dopa have “neuroprotective” effects in Parkinson disease. Also, the proposal that the progression of symptoms, as measured by a variety of scales, is slowed has not been fully corroborated. Technical problems in interpreting these results are discussed at length in the reviews by Wooten and by Clarke and Guttman. The uncertainties here have to do with clinical grading systems, functional imaging techniques, and points of comparison to treatment with L-dopa. The notion that the administration of L-dopa early in the disease might reduce the period over which it remains
CHAPTER 39
effective has been largely dispelled, but some neurologists continue to adhere to it. Cedarbaum and colleagues, who reviewed the course of the illness in 307 patients over a 7year period, found no evidence that the early initiation of Ldopa treatment predisposed to the development of fluctuations in motor response or to dyskinesia and dementia. In fact, the findings of the “Elldopa” trial by The Parkinson Study Group (2004) were that functional and other measures were better in patients who had taken L-dopa for 40 weeks and then stopped the medications than in those who received no medication. Also, the large multicenter study reported by Diamond and colleagues indicated that patients who were given L-dopa early in the disease actually survived longer and with less disability than those who began the medication late in the course; that is, L-dopa may have itself been neuroprotective. However, there have been many alternative interpretations of these data. Finally, attempts to slow the disease by vitamin antioxidants such as vitamin E have met with mixed, but generally negative, results. A possible exception was the trial of coenzyme Q10 by Shults and colleagues. Massive doses of this agent, 1,200 mg/d, were found to offer marginal advantages on the progression over 6 to 18 months as measured by certain scores of overall daily function but not on most neurologic scales. Further study of this approach is advised. Side Effects of L-Dopa Treatment and Their Management The side effects of L-dopa are at times significant to the degree that its continuation cannot be tolerated. Some patients are at first troubled by nausea, although this can be mitigated by taking the medication with meals. Nausea usually disappears after several weeks of continued use or can be allayed by the specific dopaminergic chemoreceptor antagonist domperidone. A few have mild orthostatic hypotensive episodes. The most troublesome effects of L-dopa as the disease advances, usually after several years of treatment, are endof-dose reduction in efficacy and the induction of involuntary “dyskinetic” movements—restlessness, head wagging, grimacing, lingual-labial dyskinesia, blepharospasm, and especially, choreoathetosis and dystonia of the limbs, neck, and trunk. A decline in efficacy at the end of the dose interval, typically 2 to 4 h, may be treated by more frequent dosing, the addition of dopaminergic agonist, or a COMT inhibitor. The on–off or off phenomenon is a rapid and sometimes unpredictable change—in a matter of minutes or from one hour to the next—from a state of relative freedom from symptoms to one of nearly complete immobility. Both dyskinesias and severe “off” periods appear in approximately 75 percent of patients within 5 years. Few patients escape these opposing effects, forcing an increased frequency of administration and usually a reduction in dosage. If involuntary movements are induced by relatively small doses of L-dopa, the problem may be suppressed to some extent by the addition of direct-acting dopaminergic agents or by the concurrent administration of amantadine. The use of lower doses of long-acting preparations of Ldopa may also be helpful in reducing dyskinesias and the atypical antipsychotic medications have been said to be useful but carry their own risks.
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The onset of psychiatric symptoms coincident with the use of L-dopa may also present problems and is to be expected eventually in 15 to 25 percent of patients, particularly in the elderly. Depression, although frequent, is only occasionally a serious problem, even to the point of suicide. Delusional thinking may also occur in these circumstances. This combination of movement and psychiatric disorders is difficult to treat, and one is faced with instituting an antidepressant regimen or perhaps using one of the newer classes of antipsychotic medications that have the least extrapyramidal side effects (see below and Chap. 50). While the selective serotonin reuptake inhibitors have been useful in cases of apathetic depression, they may cause slight worsening of parkinsonian symptoms. In our hands, trazodone has been helpful in treating depression and insomnia, the latter also being a major problem in some patients. Excitement and aggressiveness appear in a few. A return of libido may lead to sexual assertiveness. Other curious effects of excessive drive from L-dopa and dopamine agonists have been pathologic gambling (the same has been seen in treatment of restless legs syndrome) and cross-dressing (Quinn et al, 1983). Confusion and outright psychosis (hallucinations and delusions) are seen in advanced cases of Parkinson disease when high doses of L-dopa are required and the disease has been present for many years. This may first be treated by reducing the dose of the drug. If this is not tolerated, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine may be given in low doses. The side effects of these drugs include sleepiness, orthostatic hypotension, and sialorrhea. As noted above, clozapine has been said to provide an additional benefit of suppressing dyskinesias in advanced Parkinson disease (Bennett et al) but it requires surveillance of the white blood cell count because of the idiosyncratic occurrence of agranulocytosis in up to 2 percent of patients. Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened. The anticonvulsant valproate is also said to be useful in this circumstance, but in our hands it has not been as effective as clozapine and related drugs. Despite its lesser tendency to produce rigidity, olanzapine, and probably the other similar agents, in high doses may slightly worsen motor disability. An important note of warning: Anticholinergic agents or Ldopa should not be discontinued abruptly in advanced Parkinson disease. If abruptly discontinued, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome, sometimes fatal, has been induced by such withdrawal. Reducing the medication dose over a week or so is usually adequate. With progressive loss of nigral cells, there is an increasing inability to store L-dopa and periods of drug effectiveness become shorter. In some instances, the patient becomes so sensitive to L-dopa that 50 to 100 mg will precipitate choreoathetosis; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and the on–off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations. Some patients function quite well in the
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morning and much less well in the afternoon, or vice versa. In such cases, and for end-of-dose and on–off phenomena, one must titrate the dose of L-dopa and use more frequent dosing during the 24-h day; combining it with a dopamine agonist or a long-acting preparation may be helpful. Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications may reduce the on–off phenomenon. Based on the notion that alimentary-derived amino acids compete for absorption of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor fluctuations (Pincus and Barry). Symptoms can sometimes be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch. Moreover, this dietary regimen may permit the patient to reduce slightly the total daily dose of L-dopa. Such dietary manipulation is worth trying in appropriate patients; it is not harmful, and most of our patients with advanced disease who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa. A novel observation by Pierantozzi and colleagues has been that the absorption of L-dopa may be influenced by the presence of gastric Helicobacter pylori infection and that eradication of the organism was associated with longer “on” time.
Initiating Drug Treatment for Parkinson Disease It has been general practice to begin treatment only when the patient’s daily activities are impaired by bradykinesia or tremor. Therefore, treatment is guided very much by the patient’s sense of disability and by direct querying about dressing, walking, writing, work ability, and athletic pursuits. Until more independent data is produced favoring a neuroprotective strategy, no strong opinion can be offered in favor of starting L-dopa or a dopamine agonist before symptoms are troubling. Many clinicians initiate treatment with small amounts of a dopamine agonist, at least as much for the putative delay of dyskinesias that they offer in comparison to starting L-dopa. Alternatively, carbidopa/L-dopa tid can be initiated and supplemented over a month with a dopamine agonist. The side effects and subtleties of dosing are explained in the sections above on each of these classes of drug. The issue of also starting a MAO inhibitor such as rasagiline have already been discussed. For cases in which tremor is the predominant and most disabling feature, particularly in patients younger than about 65 years of age, trihexyphenidyl alone may be tried, short of producing side effects.
Surgical Measures Until recently, success with L-dopa had practically replaced the use of the ablative surgical therapy pioneered by Cooper. This involved the stereotactic placement of lesions in the globus pallidus, ventrolateral thalamus, or subthalamic nucleus, contralateral to the side of the body chiefly affected. The best results were obtained in relatively young patients, in whom unilateral tremor or rigidity rather than akinesia were predominant. The symptoms that responded least well to surgical therapy in Cooper’s patients were postural imbalance and instability, paroxys-
mal akinesia, bladder and bowel disturbances, dystonia, and speech difficulties. More recently, through the work of Laitinen, Leksell, and others, this mode of therapy has been revived and advanced by the newer technique of implanted electrical stimulators. The implantation of electrodes involves the placement, under precise stereotactic control, of a wire in the posterior and ventral (medial) part of the subthalamic nucleus or the internal segment of the globus pallidus. Also, most patients experience enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias. The improvement in “offstate” bradykinesia is lost after several years. Bilateral stimulation of the subthalamic nucleus has produced improvement in all features of the disease, but least of all in gait and balance (Limousin et al). A study by the Deep-Brain Stimulation for Parkinson’s Disease Group demonstrated at least short-term benefit in motor fluctuations after the bilateral implantation of stimulating electrodes in the subthalamic nuclei and the durability of this effect in subsequent studies ranged from 2 to 7 years. The patients chosen were those who had failed to derive benefit from medications. A randomized, blinded trial by Deuschl and colleagues confirmed this effect and demonstrated an overall improvement in the quality of life at 6 months. The benefit with bilateral stimulation of the globus pallidus has been somewhat less and this target has not been abandoned. Several groups have pointed out that cognitive function is not improved and may even decline. The ideal patient for deep-brain stimulation is currently considered to be an individual who, to maintain mobility, requires a dose of L-dopa that produces unacceptable dyskinesias and who is constantly cycling between on and off periods. Dystonia, when present as part of the native disease or as a result of medication, may also benefit by this treatment. However, some patients appear to do very well with the introduction of brain stimulation early in the course of illness. All patients with implanted electrodes require frequent initial contact with a physician experienced in programming the stimulator. Some patients can make minor adjustments, or even turn off the stimulator on their own with a small control device that has preset limits. Presumably, the high-frequency electrical impulses cause a disruption of local neuronal activity that is the functional equivalent to an ablative lesion, but the effects may be more complex by way of stimulating neurotransmitter release. The observed improvement in the L-dopa–induced dyskinesias has led to the earlier more liberal use of subthalamic stimulators. But as with ablative surgery, the durability of the benefit is uncertain. Readjustment of the frequency of the stimulus and breakage of the wire are minor problems. Hemorrhage into the basal ganglia and local infection near the stimulator has occurred in a small number of patients so treated. The cerebral implantation of embryonic adrenal medullary tissue from 8- to 10-week-old human fetuses has provided a modest but undeniable improvement in motor function (Spencer et al; Freed et al) and some patients appear to have benefited from the striatal implantation of human fetal and porcine nigral cells and autologous adrenal cells. The study by Freed and colleagues found a small improvement on a
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global scale that measures functional, psychologic, and neurologic aspects only in younger patients. These procedures are hampered by many difficulties, mainly in obtaining tissue and the failure of grafts to survive but also the problem of uncontrollable dyskinesias in some patients. Much of the enthusiasm for these procedures has temporarily subsided. Investigation into their possible usefulness continues. Another provocative approach has been the delivery of neural trophic factors or stem cells to the area of the substantia nigra through a small catheter. All results have to be considered preliminary. Ancillary Treatments In the management of the patient with Parkinson disease, one must not neglect the maintenance of general health and neuromuscular efficiency by a program of exercise, activity, and rest; physical therapy and exercises such as those performed in yoga may be of help in achieving these ends. Sleep may be aided by soporific antidepressants. Postural imbalance and falls can be greatly mitigated by the use of a cane or walking frame. A number of excellent exercise programs have been devised specifically for patients with Parkinson disease, and measures such as massage and yoga have their advocates. Our position has been that any activity that keeps the patient moving and committed is of great value. Speech exercises help the motivated patient. Hypotensive episodes respond to fludrocortisone or midodrine given each morning. Focal dystonias of the foot are partially treatable with local injections of botulinum toxin. In addition, the patient often needs emotional support in dealing with the stress of the illness, with the anxiety that seems to be an integral part of the disease in some patients, in comprehending the future, and in carrying on courageously in spite of it.
Multiple System Atrophy (Striatonigral Degeneration, Shy-Drager Syndrome, Olivopontocerebellar Degeneration) As the name multiple system atrophy indicates, this depicts a group of disorders characterized by neuronal degeneration mainly in the substantia nigra, striatum, autonomic nervous system, and cerebellum. Following a report in 1964 by Adams and colleagues of what was then called striatonigral degeneration, many patients were recognized in whom the changes of striatonigral and olivopontocerebellar degeneration were combined and who had symptoms and signs of cerebellar ataxia and parkinsonian manifestations. The pathologic changes of striatonigral degeneration were found by chance in 4 middle-aged patients, in 3 of whom a parkinsonian syndrome had been described clinically, none with a family history of similar disease. Rigidity, stiffness, and akinesia had begun on one side of the body, then spread to the other, and progressed over a 5-year period but with minimal characteristic tremor of idiopathic Parkinson disease. A flexed posture of the trunk and limbs, slowness of all movements, poor balance, mumbling speech, and a tendency to faint when standing were other elements. There was an early onset cerebellar ataxia in the fourth patient that was later obscured by a Parkinson syndrome. The postmortem examinations disclosed extensive loss of neurons in the zona compacta of the substantia nigra, but notably, there were no Lewy bodies or neurofibrillary tan-
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gles in the remaining cells. Even more striking were the degenerative changes in the putamina and to a lesser extent in the caudate nuclei. Secondary pallidal atrophy (mainly a loss of striatopallidal fibers) was present. In the patient with ataxia there was, in addition, advanced degeneration of the pons, olives, and cerebellum (see below in the discussion of olivopontocerebellar degeneration). More than half of the patients with striatonigral degeneration have orthostatic hypotension, which proves at autopsy to be associated with loss of intermediolateral horn cells and of pigmented nuclei of the brainstem. This combined parkinsonian and autonomic disorder, still referred to as the Shy-Drager syndrome, was alluded to in Chaps. 18 and 26. In addition to orthostatic hypotension, other features of autonomic failure include impotence, loss of sweating, dry mouth, miosis, and urinary retention or incontinence. Vocal cord palsy is an important and sometimes initial manifestation of the disorder; it may cause dysphonia or stridor and airway obstruction requiring tracheostomy. A dusky discoloration of the hands as a sign of this disorder was ascribed to poor control of cutaneous blood flow by Klein and colleagues. A diagnostic problem arises in that orthostatic hypotension is also observed in up to 15 percent of patients with Parkinson disease, a feature that may be exaggerated by medications, but the degree of drop in blood pressure is far greater and more frequent in patients with this form of multiple system atrophy. Recognizing that the clinical and pathologic features of striatonigral degeneration, with or without autonomic failure, can coexist with olivopontocerebellar atrophy, Graham and Oppenheimer proposed the term multiple system atrophy (MSA), which has gained wide acceptance. Several large series of cases of this complex syndrome have been published, providing a perspective on the frequency and nature of its component syndromes. Either parkinsonism or cerebellar ataxia may predominate. In many writings they are categorized as MSA-P and MSA-C, respectively depending on whether they display predominantly parkinsonism or cerebellar ataxia. In this nosology, cases in which autonomic failure as described above as the Shy-Drager syndrome have been denominated as MSA-A. In the Brain Tissue Bank of the Parkinson Disease Society of Great Britain, MSA accounted for 13 percent of patients who had been identified during life as having idiopathic Parkinson disease. All of the patients with MSA had one or more symptoms of autonomic failure (postural hypotension, urinary urgency or retention, urinary or fecal incontinence, impotence) and dysphonia or stridor. Babinski signs were present in half the patients and cerebellar ataxia in one-third. Tremor was rare. Males were affected more often than females. In a comparable series of 100 patients (67 men and 33 women) studied by Wenning and coworkers (1994), the disease began with a striatonigral-parkinsonian syndrome in approximately half; often it was asymmetrical to begin with. Mild tremor was detected in some but in only a few was it of the “resting” Parkinson type. In nearly half, the illness began with autonomic manifestations; orthostatic hypotension occurred eventually in almost all patients, but it was disabling in only a few. Cerebellar features dominated the initial stages of the disease in only 5 percent, but ataxia was eventually obvious in half the larger
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group. This ataxic clinical presentation of multiple system atrophy will be elaborated further in the section on the degenerative cerebellar ataxias. The extrapyramidal illness, on the whole, is more severe than in Parkinson disease, as more than 40 percent of patients are confined to a wheelchair or otherwise severely disabled within 5 years. These observations generally match the findings in the group described by Quinn and colleagues (1986), but they emphasized that pyramidal signs were present in 60 percent. Colosimo and colleagues reviewed the clinical findings in 16 pathologically verified cases of MSA and found that several signs, namely, relative symmetry of the signs and rapid course, the lack of response to L-dopa, absence or minimal amount of tremor, and the early presence of autonomic disorders, reliably distinguished this syndrome from Parkinson disease. These observations are in keeping with our own and we would add that abnormalities of eye movement are not prominent in MSA. Additional features occurring occasionally in MSA are remarked upon in other series; anterocollis or dystonia of the lower facial muscles, for example, are striking in a few cases. It is noteworthy that levodopa has had little or no effect or has made these patients worse early in the disease but we have seen exceptions. The lack of L-dopa effect is probably attributable to the loss of striatal dopamine receptors. The diagnosis of MSA has been aided modestly by imaging techniques. Both MRI and CT scanning frequently show atrophy of the cerebellum and pons in those with cerebellar features. The putamina are hypodense on T2-weighted MRI and may show an increased deposition of iron in the parkinsonian form. Studies with PET have disclosed impairment of glucose metabolism in the striatum and to a lesser extent in the frontal cortex, a reflection, no doubt, of the loss of functioning neuronal elements in these parts. In the cerebellar form, a “hot cross bun” sign has been emphasized; it reflects atrophy of the pontocerebellar fibers that manifest high T2 signal intensity in an atrophic pons. Finally, despite the concurrence of striatonigral degeneration, olivopontocerebellar degeneration, and the ShyDrager syndrome, each of these disorders occurs in almost isolated clinical form; we therefore retain their original designations. Pathology In recent years, attention has been drawn to the presence of abnormal staining material in the cytoplasm of astroglia and oligodendrocytes and in some neurons as well. These cytoplasmic aggregates have been referred to as glial cytoplasmic inclusions (Papp et al). Although they bear little resemblance morphologically to other discrete inclusions that have come to be accepted as characteristic of certain degenerative CNS diseases (e.g., Lewy bodies) they nonetheless contain α-synuclein (the main component of Lewy bodies). It is not clear to us whether these glial cytoplasmic accumulations represent a histopathologic hallmark of MSA as suggested by Chin and Goldman and by Lantos, as their presence is not specific; they have been identified in practically every degenerative disease that has been subjected to sensitive silver impregnation stains. Many types of inclusions are, of course, nonspecific, as, for example, α-synuclein–positive inclusions have been detected in several neurodegenera-
tive syndromes. Appropriate control studies to determine whether the glial inclusions are found in nondegenerative lesions in brain (at the edge of an infarct, for example) are needed. Also lacking is information about the frequency of these cytoplasmic inclusions in relation to the aging brain.
Progressive Supranuclear Palsy In 1963, Richardson, Steele, and Olszewski crystallized medical thought about a clinicopathologic entity—progressive supranuclear palsy (PSP)—to which there had been only ambiguous reference in the past. The condition is not rare. By 1972, when Steele reviewed the subject, 73 cases (22 with postmortem examinations) had been described in the medical literature. Rare familial clusters have been described in which the pattern of inheritance is compatible with autosomal dominant transmission (Brown et al; de Yébenes et al). Rojo and coworkers described 12 pathologically confirmed pedigrees and made note of the variable phenotypical expression of the disease even within a single pedigree. No toxic, encephalitic, racial, or geographic factor has been incriminated.
Clinical Features The disease has its onset typically in the sixth decade (range: 45 to 75 years), with some combination of difficulty in balance, abrupt falls, visual and ocular disturbances (giving the syndrome its name), slurred speech, dysphagia, and sometimes vague changes in personality, including apprehensiveness and fretfulness suggestive of an agitated depression. The most common early complaint is unsteadiness of gait and unexplained falling without loss of consciousness. The patient has difficulty in describing his imbalance, using terms such as “dizziness,” “toppling,” or an ambiguous problem with walking. At first, the neurologic and ophthalmologic examinations may be unrevealing, and it may take a year or longer for the characteristic syndrome comprising supranuclear ophthalmoplegia, pseudobulbar palsy, and axial dystonia to develop fully. Difficulty in voluntary vertical movement of the eyes, often downward but sometimes only upward, and later impairment of voluntary saccades in all directions are characteristic. A related but more subtle sign has been the finding of hypometric saccades in response to an optokinetic drum or striped cloth moving vertically in one direction (usually best seen with stripes moving downward). Later, both ocular pursuit and refixation movements are delayed and diminished in amplitude and eventually all voluntary eye movements are lost, first the vertical ones and then the horizontal ones as well. However, if the eyes are fixated on a target and the head is turned slowly, full movements can be obtained, demonstrating the supranuclear, nonparalytic character of paralysis of ocular pursuit. Other prominent oculomotor signs are sudden jerks of the eyes during fixation, “cogwheel” or saccadic choppiness of pursuit movements, and hypometric saccades of long duration (Troost and Daroff). The Bell phenomenon (reflexive upturning of eyes upon forced closure of the eyelids)
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and the ability to converge are also lost eventually, and the pupils become small but remain round and reactive to both light and to accommodative stimuli. The upper eyelids may be retracted, and the wide-eyed, unblinking stare impart an expression of perpetual surprise. Blepharospasm and involuntary eye closure are prominent in some cases. In the late stages, the eyes may be fixed centrally and all oculocephalic and vestibular reflexes are lost. It should be emphasized, however, that a proportion of patients do not demonstrate these eye signs for a year or more after the onset of the illness. We have also followed several patients who had no disorder of eye movement during life but in whom the typical pathologic changes of PSP were nonetheless found. In one such patient, there was a subcortical type of dementia; in another, focal limb dystonia and parkinsonism. Furthermore, other degenerative conditions can manifest a supranuclear vertical gaze disorder, although never to the extent seen in PSP; these include corticobasal-ganglionic degeneration, Lewy-body disease, Parkinson disease, and Whipple disease. The gait disturbance and repeated falling have proved difficult to analyze, as discussed in Chap. 7. Walking becomes increasingly awkward and tentative; the patient has a tendency to totter and fall repeatedly, but has no ataxia of gait or of the limbs and does not manifest a Romberg sign or orthostatic tremor. Some patients tend to lean and fall backward (retropulsion). One of our patients, a large man, fell repeatedly, wrecking household furniture as he went down, yet careful examination provided no clue as to the basic defect in this “toppling” phenomenon. Along with the oculomotor and balance disorders, there is a gradual stiffening and extension of the neck (in one of our patients it was sharply flexed in a manner consistent with camptocormia) but this is not an invariable finding. The face acquires a staring, “worried” expression with a furrowed brow (a result of the tonic contraction of the procerus muscle), made more striking by the paucity of eye movements. A number of our patients have displayed mild dystonic postures of a hand or foot, especially as the illness advanced but occasionally early on. The limbs may be slightly stiff and there are Babinski signs in a few cases. The stiffness, slowness of movement, difficulty in turning and sitting down, and hypomimia may suggest a diagnosis of Parkinson disease. However, the facial expression of the PSP patient is more a matter of tonic grimace than of lack of movement, and the lack of tremor, the erect rather than stooped posture, and prominence of oculomotor abnormalities serve to distinguish the two disorders. The signs of pseudobulbar palsy are eventually prominent, and this feature, along with the eye movements, distinguishes the process most conspicuously from other degenerative conditions. The face becomes less expressive (“masked”), speech is slurred in a slowed spastic fashion, the mouth tends to be held open, and swallowing is difficult. Forced laughing and crying, said to be infrequent, have been present in about half of our cases late in the course. Many patients complain of sleep disturbances. The total sleep time and REM sleep are reduced, and spontaneous awakenings during the night are more frequent and longer than in normal individuals of the same age. Complaints of urinary frequency and
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urgency have also been frequent in advanced cases under our care. The diagnosis often proves difficult to make if the main features are not outstanding. Other features, such as tremor, palilalia, myoclonus, chorea, orofacial dyskinesias, and disturbances of vestibular function, are observed in some cases. Finally the patient becomes anarthric, immobile, and quite helpless. Dementia of some degree is probably present in many cases, but is mild in most. Some patients do become forgetful and appear apathetic and slow in thinking; many others are irritable or at times euphoric. Dubois and colleagues proposed an “applause sign” as distinctive to this disease; the patient fails to stop clapping after being asked to do so only 3 times, but we are unable to corroborate this. By MRI one can, in advanced cases, visualize the atrophy of the dorsal mesencephalon (superior colliculi, red nuclei) giving rise to a “mouse ears” configuration (Fig. 39-7), but these changes may not be evident. Several specific measurements of midbrain atrophy have been proposed; for example, there is little overlap between PSP, multiple system atrophy, and Parkinson disease in the ratio of midbrain-to-pons cross-sagittal area, according to Oba and colleagues. The CSF remains normal. Nonetheless, the diagnosis continues to rest on the clinical features, mainly affecting eye movements. Pathology Postmortem examinations have disclosed a bilateral loss of neurons and gliosis in the periaqueductal gray matter, superior colliculus, subthalamic nucleus, red nucleus, pallidum, dentate nucleus, and pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus. The expected loss of the myelinated fiber bundles arising from these nuclear structures has also been commented upon. The remarkable finding has been the neu-
Figure 39-7. Progressive supranuclear palsy. T2-weighted axial MRI showing the atrophic dorsal midbrain that gives rise to the “mouse ears” appearance.
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rofibrillary degeneration of many of the residual neurons. The neurofibrillary tangles are thick and often composed of single strands, either twisted or in parallel arrangement. The neurons of the cerebral cortex have been involved in some cases (shown by staining of tau protein), but these changes do not correlate with dementia. The cerebellar cortex is usually spared. The cause and nature of this disease are obscure. Studies with PET demonstrate a decrease in blood flow, most marked in the frontal lobes, and a lesser extent of oxygen utilization in central structures (Leenders et al). Striatal dopamine formation and storage are significantly decreased when compared with control values. Much current interest has been directed to the neurofibrillary tangles and tau deposition in PSP and a potential link to the tau pathology displayed in frontotemporal dementia and in corticobasalganglionic degeneration (see below). As summarized by Golbe, certain tau gene haplotypes on chromosome 17p (the same site implicated in familial frontotemporal dementia) are more often associated with PSP than in unaffected individuals, but other factors, environmental or genetic, must also be involved. It is intriguing that the tau-gene haplotype of frontotemporal dementia is not found in PSP. PSP should be suspected whenever an older adult inexplicably develops a state of imbalance, frequent falls with preserved consciousness, and variable extrapyramidal symptoms, particularly dystonia of the neck, ocular palsies, or a picture resembling pseudobulbar palsy. If the classic abnormalities of eye movements are present, the diagnosis is not difficult. When only a parkinsonian syndrome without tremor is present, the main diagnostic consideration is striatonigral degeneration or the corticobasalganglionic syndrome, described below. Treatment L-Dopa has been of slight and unsustained benefit in some of our patients, and combinations of Ldopa and anticholinergic drugs have been entirely ineffective in others. A marked response to these drugs should, of course, suggest the diagnosis of Parkinson disease. Recently, the drug zolpidem, a gabanergic agonist of benzodiazepine receptors, has been reported to ameliorate the akinesia and rigidity of PSP (Daniele et al); however, these observations require corroboration. Benztropine or trihexyphenidyl have been somewhat helpful in reducing dystonia but botulinum injections may be a better alternative if there are focal signs. Treatment of the sleep difficulties and urinary incontinence are of great assistance to the patient and family. A feeding tube becomes necessary in advanced cases. Observing the decline of these patients and the limitations of treatment is a frustrating ordeal for all involved.
Corticobasal Degeneration Most neurologists have observed elderly patients in whom the essential abnormality was a progressive asymmetrical extrapyramidal rigidity combined with signs of corticospinal disease. Sometimes a mild postural action tremor beginning unilaterally and suggestive in some respects of Parkinson disease has been added. The parkinsonism is generally unresponsive to L-dopa. These cases have come to be known by the names corticobasal-gangli-
onic or cortical-basal degeneration and like sounding terms. The clinical relation of such cases is indeterminate to corticostriatospinal degeneration described earlier, and based on the finding of tau inclusions, to frontotemporal dementia, Pick disease, and to progressive supranuclear palsy. Wenning and colleagues (1998) have described a series of such patients in whom the diagnosis was confirmed at postmortem examination. The most common early symptom was an asymmetrical clumsiness of the limbs, in half of the patients, with rigidity and, in one-fifth, with tremor; these features are now considered to be the most characteristic early features of the process. As the illness progressed, almost all the patients developed an asymmetric or unilateral akinetic-rigid syndrome, which may be considered the essential motor disorder of this disease and various forms of gait disorder and dysarthria. Stimulus-induced or spontaneous myoclonus and pyramidal signs, mentioned in other reports and frequent in our cases, were not prominent in their series; limitations of vertical gaze and frontal lobe release signs eventually became apparent in half. Eventually, the patients, although able to exert considerable muscle power, cannot effectively direct their voluntary actions. Attempts to move a limb to accomplish some purposeful act might result in a totally inappropriate movement, always with great enhancement of rigidity in the limb and in other affected parts, or the limb may drift off and assume an odd posture, such as a persistent elevation of the arm without the patient’s awareness—a kind of catalepsy. The disorder of limb function has some of the attributes of a limb-kinetic or an ideomotor apraxia (see Chap. 3), but the hand postures, involuntary movements, and changes in tone are at times more of the type described as “alien hand.” Some patients exhibit anosognosia, Babinski signs, impaired eyelid or ocular motion (upgaze paresis or abnormal saccadic movements), lingual dyskinesias, frontal release signs, myoclonus, or dysarthria. Another distinct group has dementia as an early feature, as described by Grimes and colleagues, but mental deterioration is more often late and may not occur in all patients. Occasionally, there is some involvement of lower motor neurons with resulting amyotrophy. Several of our patients had myoclonus as an early feature, one displaying it only on one side of the face, the other in an arm. The condition progresses for 5 years or more before some medical complication overtakes the patient. Postmortem examination of patients, reported by Rebeiz and colleagues disclosed a combination of findings that stamps the disease process as unique. Cortical atrophy (mainly in the frontal motor–premotor and anterior parietal lobes) was associated with degeneration of the substantia nigra and, in one instance, of the dentatorubrothalamic fibers. The loss of nerve cells was fairly marked, but there was no gross lobar atrophy, as occurs in Pick disease. The neuronal degeneration was more on one side of the brain than the other. There was moderate gliosis in the cortex and underlying white matter. Many of the residual nerve cells were swollen and chromatolytic with eccentric nuclei, a state that was called achromasia by Rebeiz and colleagues; it resembled the central chromatolysis of axonal reaction. More recently, in more than half the cases, the affected neurons and adjacent glia have been
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shown to be filled with a particular configuration of tau protein, thereby theoretically linking the disease to frontotemporal dementia and Pick disease. The remaining cases have shown tau deposition that is more similar to that of progressive supranuclear palsy, or Alzheimer pathology, or nonspecific cell loss with replacement gliosis. Both CT and MRI have demonstrated asymmetrical cerebral and pontine atrophy, and PET studies have revealed thalamoparietal metabolic asymmetries—a greater reduction of glucose metabolism on the side of the most extensive lesion (Riley et al). There are no clues as to the cause and pathogenesis of this disease. There is no family history. No organ other than the CNS is affected. The progression is relentless. None of the drugs in common use for spasticity, rigidity, and tremor has been helpful. We know of no attempt to transfer the disease to primates. The disease bears some resemblance to corticostriatospinal degeneration (“spastic pseudosclerosis”) of Jakob, discussed earlier. The relation of these diseases to the corticopallidospinal and the pallidopyramidal syndromes first described by Davison (1932, 1954) is also uncertain. The features of 8 such cases of a “pallidopyramidal” syndrome were summarized by Tranchant and associates in 1991.
Dystonic Disorders Dystonia Musculorum Deformans (Torsion Dystonia) Dystonia as a symptom was discussed in Chaps. 4 and 6. Here we are concerned with a disease or diseases of which dystonia is the major manifestation. Schwalbe’s account, in 1908, of 3 siblings of a Jewish family who were afflicted with progressive involuntary movements of trunk and limbs probably represents the first description of a disease in which severe and progressive dystonia was the sole manifestation. In 1911, Oppenheim contributed other cases and coined the term dystonia musculorum deformans in the mistaken belief that the disorder was primarily one of muscle and always associated with deformity. Flatau and Sterling, in the same year, first suggested that the disease might have a hereditary basis and gave it the more accurate name torsion dystonia of childhood. At first the condition was considered by some to be a manifestation of hysteria; only later was it recognized as a neurologic entity with a predilection for individuals of Eastern European Jewish origin. Soon thereafter, a second hereditary form of torsion dystonia, affecting non-Jews, was observed. The recessive form begins in early childhood, is progressive over a few years, and is restricted to Jewish patients. The dominant form begins later, usually in late childhood and adolescence, progresses more slowly, and is not limited to any ethnic group. As indicated in Chap. 6, most instances of idiopathic (primary) dystonias that come to our attention, particularly the segmental or restricted types, do not conform to the classic hereditary disorders as defined above, although some may represent limited variants of the disease. In general, these more restricted types have a later onset and a relatively milder, more slowly progressive course, with a tendency to
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involve an axial or distal region alone. Only the paravertebral, cervical, or cranial muscles may be involved (focal dystonia including torticollis and writer’s cramp), with little change from year to year. The clinical classification of the predominantly adult-onset dystonias is made more complex by the fact that both the restricted and generalized forms may be sporadic or genetic. Molecular genetic studies, although still incomplete, hold the promise of clarifying the classification of the heritable dystonias. More than 10 types have been distinguished by genetic mapping, as summarized by Németh. The most important of these is an abnormal gene (DYT1) on chromosome 9q, which codes for the protein torsin A in both Jewish and non-Jewish families. The most common DYT1 mutation, causing deletion of a single glutamate from the torsin A peptide, is found in most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET scanning demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene. The function of torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Walker and Shashidharan). German Mennonite families with restricted adult-onset dystonia (torticollis and spasmodic dysphonia) have an unrelated mutation at 18p; a rare X-chromosome mutation that causes dystonia has also been described. Another form of dystonia with myoclonus is caused by mutations in the gene encoding v-sarcoglycan, a transmembrane protein. A unique, dopa-sensitive dystonia, described below, arises from a dominantly transmitted defect in the protein guanosine triphosphate (GTP) cyclohydrolase (see below, under “Hereditary Dystonia-Parkinsonism [Segawa Syndrome, Juvenile Dopa-Responsive Dystonia]”). Although DYT1 and other similar mutations account for the majority of inherited cases of generalized dystonia, they are implicated in an undefined but probably relatively small proportion of the more restricted dystonias (see further on). Some individuals in families affected with generalized dystonia will demonstrate only localized forms (e.g., writer’s cramp or torticollis). The general rule stated above still holds, namely, that the inherited variety (dystonia musculorum deformans) related to DYT1 manifests early in life and begins in one limb and then spreads to most muscles of the body, while in the common dystonias (mostly sporadic but some heritable) the disease remains confined to the craniocervical or another region, does not generalize, and has an adult onset. Clinical Features The first manifestations of the generalized disease may be rather subtle. Intermittently, and usually after activity (late in the day), the patient (usually a child between 6 and 14 years of age, less often an adolescent) begins to invert one foot, to extend one leg and foot in an unnatural way, or to hunch one shoulder, raising the question of a nervous tic. As time passes, the motor distur-
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bance becomes more persistent and interferes increasingly with the patient’s activities. Soon the muscles of the spine and shoulder or pelvic girdle become implicated in involuntary spasmodic twisting movements. The cardinal feature of these severe dystonic muscle contractions is the simultaneous contraction of both agonists and antagonists at a joint. These cocontraction spasms are intermittent at first; in intervals that are free of the dystonia, muscular tone and volitional movements are normal. In some instances, the muscles are hypotonic. Gradually, the spasms become more frequent; finally, they are continuous and the body may become grotesquely contorted, as shown in Fig. 4-5A. Lateral and rotatory scoliosis uniformly result as secondary deformities. For a time, recumbency relieves the spasms but later on, position has no influence. The hands are seldom involved, although at times they may be held in a fisted posture. Cranial muscles do not escape, and in a few instances a slurring, staccato-type speech was the initial manifestation. Uncontrollable blepharospasm was the initial disorder in one of our patients; in two others, severe dysarthria and dysphagia were the first signs, caused by dystonia of the tongue, pharyngeal, and laryngeal muscles. Other manifestations include torticollis, tortipelvis, dromedary gait, propulsive gait, action tremor, myoclonic jerks during voluntary movement, and mild choreoathetosis of the limbs. Excitement worsens the dystonia and sleep abolishes it. As the years pass the postural distortion may become fixed to the point where it does not disappear even in sleep. Tendon reflexes are normal, corticospinal signs are absent, and there is no ataxia, sensory abnormality, convulsive disorder, or dementia. Pathology No agreement has been reached concerning the pathologic substrate of the disease. In cases of symptomatic dystonia, such as the ferrocalcinosis of Hallervorden-Spatz disease, the lesions of Wilson disease, kernicterus, état marbré of neonatal hypoxia, or the CT lucencies of familial striatal necrosis, lesions have been observed in the basal ganglia. However, in the hereditary forms, which are the subject of this section, one cannot be certain of any specific lesions that would account for the clinical manifestations. The brain is grossly normal and the ventricular size is not increased. According to Zeman, who reviewed all the reported autopsy studies up to 1970, there were no significant changes in the striatum, pallidum, or elsewhere. This means only that the techniques being used (qualitative analysis of random sections by light microscopy) are inadequate or the problem is subcellular. The report by McNaught and colleagues of perinuclear inclusions in periaqueductal neurons by the use of special immunostaining methods is provocative. Dopamine β-hydroxylase is elevated in the plasma of patients with the autosomal dominant form of the disease and the plasma norepinephrine levels are also raised but the meaning of these findings is not clear; PET scan changes were mentioned earlier. Treatment Early in the course of the illness, several drugs including L-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism
(described below) responds well to small doses of L-dopa and dopamine agonists and is exceptional in this respect. Burke and coworkers advocate the use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus. Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. Approximately 70 percent of the patients in Cooper’s series in the 1950s were moderately to markedly improved by unilateral or bilateral operations and, based on a 20-year followup study, the improvement was usually sustained. More recent studies report a somewhat less favorable but nonetheless clear-cut improvement (see Tasker et al; Andrew et al). The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. Newer techniques employing stimulators and implanted electrodes may give better results.
Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia) This process is discussed here because its main characteristic is a dystonia that is responsive to L-dopa, but most cases also have features of parkinsonism, which is why it was included in the discussion of hereditary forms of Parkinson disease, especially in young patients. Following the description of the syndrome by Segawa and colleagues in 1976, others drew attention to this unique form of hereditary dystonia (Allen and Knopp; Deonna; Nygaard and Duvoisin). The pattern of inheritance is autosomal dominant and there is no ethnic predilection. Nygaard and colleagues found a linkage to the gene on chromosome 14q for the protein GTP cyclohydrolase 1 (GCH1 gene) that is implicated in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. It is likely that mutation impairs the generation of dopamine, a prediction that accords with responsiveness of the parkinsonian and dystonic features to L-dopa. In one autopsied case (an accidental death), there was a reduction in the amount of tyrosine hydroxylase in the striatum and depigmentation but no cell loss in the substantia nigra (Rajput et al). The affected enzyme was reduced in the striatum, as was the level of dopamine. The dystonic manifestations usually become evident in childhood, usually between 4 and 8 years of age; females outnumber males in a ratio of 3:2. Often the legs are first affected by intermittent stiffening, with frequent falls and peculiar posturing, sometimes the feet assuming an equinovarus position. The arms become involved as well as the truncal muscles; retrocollis or torticollis may appear. Within 4 to 5 years, all parts of the body, including the bulbar muscles, are involved. Mild parkinsonian features (rigidity, bradykinesia, postural instability) can usu-
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ally be detected early in the course of the illness, but more characteristically they are added to the clinical picture several years later. In our own patients, and in several of those of Deonna, there was rigidity of the limbs as well as slowness of movement and a tremor at rest, all aspects more parkinsonian than dystonic. In still others, the clinical picture has been one of cerebral spastic diplegia. A remarkable feature is the disappearance or marked subsidence of the symptoms after a period of sleep and worsening as the day progresses. This diurnal variation is shared with many of the inherited forms of Parkinson disease listed in Table 39-2. Fluctuations of symptoms with exercise and menses and in the first month of pregnancy have been observed in some cases. The unique feature of this juvenile dystonia-parkinsonism syndrome is the dramatic response of both the dystonic and parkinsonian symptoms to treatment with L-dopa. As little as 10 mg/kg/d may eliminate the movement disorder and permit normal functioning. Unlike idiopathic Parkinson disease, the medication can be continued indefinitely without the development of tolerance, wearing-off effects, or dyskinesias. Segawa disease accounts for some cases that had in the past been reported as juvenile Parkinson disease.
Torticollis and Other Restricted Dyskinesias and Dystonias (See Chap. 6) With advancing age, a large variety of focal or regional movement disorders come to light. Various neurophysiologic abnormalities, summarized in Chap. 6, have been implicated. In the common restricted dystonias, localized groups of adjacent muscles manifest arrhythmic cocontracting spasms (i.e., agonist and antagonist muscles are activated simultaneously). The patient’s inability to suppress the dystonia and the recognition that it is for the most part beyond voluntary control distinguishes it from tics, habit spasms, and mannerisms described in Chap. 6. If the muscle contraction is frequent and prolonged, it is accompanied by an aching pain that may mistakenly be blamed for the spasm and the involved muscles may gradually undergo hypertrophy. Worsening under conditions of excitement and stress and improvement during quiet and relaxation are typical of this group of disorders and contributed in the past to the mistaken notion that the spasms had a psychogenic origin. The most frequent and familiar type is torticollis, wherein an adult, more often a woman, becomes aware of a turning of the head to one side while walking. Usually this condition worsens gradually to a point where it may be more or less continuous, but in some patients it remains mild or intermittent for years on end. When followed over the years, the condition is observed to remain limited to the same muscles (mainly the scalene, sternocleidomastoid, and upper trapezius). Rarely, the torticollis is combined with dystonia of the shoulder, arm, and trunk; tremor; facial spasms; or dystonic writer’s cramp. Other restricted dyskinesias involve the neck in combination with facial muscles, the orbicularis oculi (blepharospasm and blepharoclonus), the throat and respiratory muscles (spastic dysphonia, orofacial dyskinesia, and respira-
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tory and phonatory spasms), the hand in writer’s cramp (graphospasm) or musician and other performing artist’s dystonia, and proximal leg and pelvic-girdle muscles, where dyskinesia is elicited by walking. All these conditions and their treatments are discussed fully in Chap. 6.
Other Forms of Hereditary Dystonia Several familial movement-induced (kinesogenic) dystonic syndromes and a type that is not kinesogenic and arises suddenly in adolescence, at times with parkinsonian features, have been described. There are other degenerative diseases that combine hereditary dystonia with neural deafness and intellectual impairment (Scribanu and Kennedy) and with amyotrophy in a paraplegic distribution (Gilman and Romanul). These are also discussed in greater detail in Chap. 6. Other important symptomatic dystonias that fall into the category of hereditary dystonia were described in Chap. 37. These are Hallervorden-Spatz disease and calcification of the basal ganglia; of course, Wilson disease may have dystonia as a central feature. Many extrapyramidal diseases, including idiopathic Parkinson disease and progressive supranuclear palsy may include fragmentary dystonias of the hand, foot, face, or periorbital muscles.
SYNDROME OF PROGRESSIVE ATAXIA This topic was introduced in Chap. 5 and some of the congenital and acute acquired varieties are mentioned there. Here we consider the chronic, progressive forms of cerebellar disease. Although most of these are familial and are more or less confined to this part of the nervous system, a number of other systems may be involved to varying degrees. Most of the chronic progressive cerebellar diseases are subsumed under the “system atrophies,” but no one classification designed to bring order to this category of diseases has proved satisfactory and a preferable genetic classification is emerging. Wilson wrote that “the group of degenerative conditions strung together by the common feature of ataxia is one for which no very suitable classification has yet been devised,” a statement that is not as appropriate today as when it was written 75 years ago. Even recent insights provided by the tools of molecular genetics are not clinically precise as the same gene abnormality may be expressed by a number of different syndromes. The clinical classification proposed by Harding (1993) represented a scholarly effort to meet this goal. Setting aside those of congenital type and those caused by a metabolic disorder, she grouped the ataxias by age of onset, pattern of heredity, and associated features. A modification of the classifications of Greenfield and of Harding, which is included in the introductory listing of this chapter, still has value. It divides the progressive cerebellar syndromes into three main groups: (1) the spinocerebellar ataxias, with unmistakable involvement of the spinal cord (Romberg sign, sensory loss, diminished tendon reflexes, Babinski signs); (2) the pure cerebellar ataxias, with no other associated neurologic disorders; and (3) the
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complicated cerebellar ataxias, with a variety of pyramidal, extrapyramidal, retinal, optic nerve, oculomotor, auditory, peripheral nerve, and cerebrocortical accompaniments including what is now referred to as multiple system atrophy. Without doubt, the advances in molecular genetics of recent years have greatly altered our understanding of the inherited ataxias and has already disclosed a large number of unexpected relationships between mutations and other neural and nonneural disorders. These data are incorporated at appropriate points in the following discussion in Table 39-5, and at the end of this section. Inherited ataxias of early onset (before the age of 20 years) are usually of recessive type; those of later onset are more likely have a dominant pattern but may be autosomal recessive. Table 39-5 lists several types of ataxias that have a genetic basis. At the same time, it should be emphasized that many in our patients with chronic progressive ataxia have no family history of a similar ataxia and do not harbor one of the commonly recognized mutations.
Early Onset Spinocerebellar Ataxias (Predominantly Spinal) Friedreich Ataxia This is the prototype of all forms of progressive spinocerebellar ataxias and accounts for about half of all cases of hereditary ataxias in most large case series (86 of 171 patients collected by Sjögren); its incidence among Europeans and North Americans is 1.5 cases per 100,000 per year. Friedreich, of Heidelberg, began in 1861 to report on a form of familial progressive ataxia that he had observed among nearby villagers. It was already known through the writings of Duchenne that locomotor ataxia was the prominent feature of spinal cord syphilis, i.e., tabes dorsalis, but it was Friedreich who demonstrated a nonsyphilitic hereditary type. This concept was greeted with skepticism, but soon Duchenne himself affirmed the existence of the new disease and other case reports appeared in England, France, and the United States. In 1882, in a thesis on this subject
Table 39-5 GENETIC DEFECTS ASSOCIATED WITH HEREDITARY SPINOCEREBELLAR ATAXIA (SCA) NOTATION
AGE OF ONSET
Atrophin
ADa
Childhood
Chorea, dystonia, seizures, dementia
Ataxin-1
ADa
Variable
SCA2
Ataxin-2
ADa
Teens
SCA3 (MachadoJoseph) SCA6
Ataxin-3
ADa
Teens
alpha1A calcium channel Ataxin-7
ADa
Adult
ADa
Late teens
AD
Infantile Adult
AD
Teens–adult
10–25% of dominant ataxias; spasticity, polyneuropathy, ophthalmoparesis, dementia Neuropathy, ophthalmoparesis, extrapyramidal features 25% of dominant ataxias, spasticity, neuropathy, extrapyramidal features 20% of dominant ataxias; dysarthria, nystagmus, posterior column signs Retinal degeneration, hearing loss, ophthalmoplegia, spasticity Fulminant, with large CAG expansion Sensory neuropathy, spasticity; there is rapid infantile variant Seizures, personality change
AD AD AD AD
Adult Adult Childhood Teens–adult
Mild phenotype Head and hand tremor Mental retardation Myoclonus, tremor
AD ADa
Varies Variable
Head and hand tremor Cognitive decline, seizures, extrapyramidal features
AD
Childhood
Tremor, cognitive defects, facial dyskinesia
AR
Teens
Vitamin E transport protein
AR
Childhood
Spinocerebellar ataxia, neuropathy, cardiomyopathy, arrhythmia Spinocerebellar ataxia, neuropathy, cardiomyopathy, arrhythmia
KCNA
AD
Teens
Limb stiffness, dizziness, visual blurring
alpha1A calcium channel CACNB4
AD
Teens
Nystagmus, vertigo, weakness
AD
Teens
Seizures, myoclonus, nystagmus
SCA7 SCA8 SCA10 SCA11 SCA12 SCA13 SCA14 SCA16 SCA17 SCA with tremor Friedreich ataxia Friedreich ataxia variant Episodic Episodic ataxia with myokymia Paroxysmal episodic ataxia Episodic ataxia a
CLINICAL AND MISCELLANEOUS FEATURES IN ADDITION TO ATAXIA
GENETICS
Progressive Dentatorubropallidoluysian atrophy SCA1
CAG expansion.
GENE
CTG repeat (noncoding) ATTCT repeat (ataxin-10) TTBK2 PPP2R2B, CAG repeat KCNC3 Protein kinase C gamma ITPR1 TATA box binding protein Fibroblast growth factor 14 Frataxin
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by Brousse of Montpelier, Friedreich’s name was attached to the entity. Genetic linkage studies led to the assignment of the gene mutation to chromosome 9q13-2 and subsequently, it was shown that in virtually all cases the mutation is an expansion of a GAA trinucleotide repeat within a gene that codes for the protein frataxin. (It is of interest that this mutation is within an intron). In a small proportion of cases, the mutation is a missense mutation rather than an expansion. In either case, the consequence of the mutation is a reduction in levels of frataxin and loss of its function. This is consonant with the recessive pattern of inheritance. Cases in which the mutation allows the presence of some residual protein have a milder course. A current hypothesis is that frataxin is a mitochondrial matrix protein whose function is to prevent intramitochondrial iron overloading. Clinical Features Ataxia of gait is nearly always the initial symptom. Difficulties in standing steadily and in running are early symptoms. The hands usually become clumsy months or years after the gait disorder and dysarthric speech appears after the arms are involved (this is rarely an early symptom). Exceptionally the ataxia begins rather abruptly after a febrile illness, and one leg may become clumsy before the other. In some patients, pes cavus and kyphoscoliosis are evident well before the neurologic symptoms; in others, they follow by several years. The characteristic foot deformity takes the form of a high plantar arch with retraction of the toes at the metatarsophalangeal joints and flexion at the interphalangeal joints (hammertoes). A notable feature in more than half of patients is a cardiomyopathy. The myocardial fibers are hypertrophic and may contain iron-reactive granules (Koeppen). Many of the patients die as a result of cardiac arrhythmia or congestive heart failure. For this reason, it is essential that affected individuals have a cardiologic assessment including electrocardiography and echocardiography. The cardiomyopathy of Friedreich disease can develop insidiously but with fulminant consequences. Kyphoscoliosis and restricted respiratory function are additional important contributory causes of death. Harding (1993) observed that approximately 10 percent of these patients have diabetes mellitus and a similar proportion have impaired glucose tolerance. In the fully developed state, the abnormality of gait is of mixed sensory and cerebellar type, aptly called tabetocerebellar by Charcot. According to Mollaret, the author of an authoritative monograph on the disease, the cerebellar component predominates, but in our relatively small series we have been as impressed almost as much with the sensory (tabetic) aspect. The patient stands with feet wide apart, constantly shifting position to maintain balance. Friedreich referred to the constant teetering and swaying on standing as static ataxia. In walking, as with all sensory ataxias, the movements of the legs tend to be brusque, the feet resounding unevenly and irregularly as they strike the floor, and closure of the eyes causes the patient to fall (Romberg sign). This is one component of the spinal aspect (posterior columns) of the disease. Attempts to correct the imbalance may result in abrupt, wild movements. Often there is a rhythmic tremor of the head. In the fully expressed disease the arms are grossly ataxic, and both action and intention tremors are manifest.
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Speech is slow, slurred, explosive, and, finally, almost incomprehensible. Breathing, speaking, swallowing, and laughing may be so incoordinated that the patient nearly chokes while speaking. Holmes (1907a) remarked on an ataxia of respiration that causes “curious short inspiratory whoops.” Facial, buccal, and arm muscles may display tremulous and sometimes choreiform movements. Although mentation is generally preserved, emotional lability has been sufficiently prominent to provoke comment by others. Horizontal nystagmus may be present with the eyes in the primary position and is increased on lateral gaze. Rotatory and vertical nystagmus is rare. Ocular movements usually remain full, and pupillary reflexes are normal. The facial muscles may seem slightly weak, and deglutition may become impaired. Amyotrophy occurs late in the illness and is usually slight but it may be extreme in patients with an associated neuropathy (see below). The tendon reflexes are abolished in nearly every case; rarely, they may be obtainable when the patient is examined early in the illness (see below). Plantar reflexes are extensor and flexor spasms may occur even with complete absence of tendon reflexes (another manifestation of the spinal component). The abdominal reflexes are usually retained until late in the illness. Loss of vibratory and position sense is invariable from the beginning; later, there may be some diminution of tactile, pain, and temperature sensation as well. Sphincter control is usually preserved. Variants of Friedreich Ataxia In one important variant of Friedreich ataxia the tendon reflexes are preserved or even hyperactive and the limbs may be spastic. It is the finding of the aberrant frataxin gene that links these unusual cases to Friedreich ataxia; some are associated with hypogonadism. Harding (1981) found 20 such cases among her 200 familial ataxias at the National Hospital, London. Nevertheless, the distinction between classic Friedreich ataxia and ataxia with retained tendon reflexes is an important one clinically, insofar as kyphoscoliosis and heart disease do not occur in the latter group and the prognosis is better. Two of our Friedreich patients had occasional seizures. There are many additional forms of spinocerebellar ataxia, most displaying mainly a cerebellar atrophy, that may simulate Friedreich disease, but due to different mutations. These are taken up below. Laboratory Testing Laboratory tests of diagnostic value are the measurement of sensory nerve conduction velocities and amplitudes, which for the most part are normal because peripheral neuropathy is not a component of the process. Electrocardiography and echocardiography may demonstrate the heart block and ventricular hypertrophy. The CT scans and MRI seldom reveal a significant degree of cerebellar atrophy but the spinal cord is small. There is no consistent abnormality of blood or CSF. No consistent biochemical abnormalities have been demonstrated. Genetic testing for the length of the GAA trinucleotide repeat segment is available. Pathology The spinal cord is thin. The posterior columns and the corticospinal and spinocerebellar tracts are all depleted of myelinated fibers, and there is a mild gliosis that does not replace the bulk of the lost fibers. The nerve cells in the Clarke column and the large neurons of the dorsal root ganglia, especially lumbosacral ones, are reduced in number—but perhaps not to a degree that
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would fully explain the posterior column degeneration. The posterior roots are thin. Betz cells are also diminished in some cases, but the corticospinal tracts are relatively intact down to the medullary–cervical junction. Beyond this point, they are degenerated, but to a lesser degree than the posterior columns. The nuclei of cranial nerves VIII, X, and XII all exhibit a reduction of cells. Slight to moderate neuronal loss is seen also in the dentate nuclei, and the middle and superior cerebellar peduncles are reduced in size. Some depletion of Purkinje cells in the superior vermis and neurons in corresponding parts of the inferior olivary nuclei can be seen. Many of the myocardial muscle fibers degenerate and are replaced by fibrous connective tissue. By way of exploring the anatomic basis of the clinical findings, pes cavus is not different from that seen in other neuromuscular diseases of early onset with mild hypertonus of the long extensors and flexors of the feet. These also cause amyotrophy of intrinsic foot muscles and foreshortening of the foot when the bones are still malleable. The kyphoscoliosis is probably a result of imbalance of the paravertebral muscles. The tabetic aspects of the disease are explained by the degeneration of large cells in the dorsal root ganglia and the large sensory fibers in nerves, dorsal roots, and the columns of Goll and Burdach. The loss of large neurons in the sensory ganglia also causes abolition of tendon reflexes. Cerebellar ataxia is attributable to a combined degeneration of the superior vermis, and the dentatorubral pathways but also the spinocerebellar tracts, in various combinations. Corticospinal lesions account for the weakness and Babinski signs and contribute to the pes cavus. Diagnosis Friedreich disease and its variants must be distinguished from familial cerebellar cortical atrophy described next, and from familial spastic paraparesis with ataxia, as well as from peroneal muscular atrophy and the Levy-Roussy syndrome, which are discussed also with the hereditary neuropathies in Chap. 46. It is advisable to assay serum vitamin E levels, as a rare but treatable inherited deficiency of a vitamin E transport protein causes a spinocerebellar syndrome with areflexia in children that resembles Friedreich disease (see Chap. 41). The absence of dysarthria and of skeletal or cardiac abnormalities in the vitamin-deficiency illness may be helpful. Exceptionally, a cardiac disturbance has been seen in the vitamin deficiency. A form of chronic inflammatory demyelinating polyneuropathy has long since overtaken tabes dorsalis as the most frequent type of areflexic ataxia. It bears a superficial resemblance to Friedreich ataxia when the onset is in early life, but lacks dysarthria and Babinski signs. A form of spinocerebellar degeneration related to human T-cell lymphotrophic virus type I (HTLV-I), causing so-called tropical spastic paraparesis, as well as the vacuolar myelopathy of AIDS multiple sclerosis, syringomyelia, and cervical spondylosis, must be included in the differential diagnosis of late-onset cases. Genetic testing settles the matter. Treatment Not much can be said on this subject because there is little effective therapy. A double-blind crossover study by Trouillas and associates found that the administration of oral 5-hydroxytryptophan modified the cerebellar symptoms. This drug is serotonergic and is
known to suppress posthypoxic action myoclonus. Apart from this form of treatment, with which we have had no experience, no therapeutic measures are known to alter the course of the disease. In several small trials, idebenone, an antioxidant (the short-chain analogue of coenzyme Q10), reduced the progression of left ventricular hypertrophy, a substantial risk factor for arrhythmias and sudden death in these patients, but it did not affect the ataxia. These results are summarized in an article by Filla and Moss. Heart failure, arrhythmias, and diabetes mellitus are treated by the usual medical measures and it bears repetition that careful evaluation of the cardiac disorder may prevent premature death. Surgery for scoliosis and foot deformities may be helpful in selected cases.
Predominantly Cerebellar (Cortical, Holmes Type) Hereditary and Sporadic Ataxia Soon after the publication of Friedreich’s descriptions of a spinal type of hereditary ataxia, reports began to appear of somewhat different diseases in which the ataxia was related to degenerative changes in the cerebellum and brainstem rather than in the spinal cord. Claims of their independence from the spinal type were based largely on a later age of onset, a more definite hereditary transmission (usually of autosomal dominant type), the persistence or hyperactivity of tendon reflexes, and associations with ophthalmoplegia, retinal degeneration, and optic atrophy. Several of these clinical features, particularly briskness of tendon reflexes, are alien to the classic form of Friedreich ataxia. By 1893, Pierre Marie thought it desirable to create a new category of hereditary ataxia that would embrace all of the non-Friedreich cases. He collated the familial cases of progressive ataxia that had been described by Fraser, Nonne, Sanger Brown, and Klippel and Durante (see both Greenfield and Harding [1993] for references) and proposed that all of them were examples of an entity to which he applied the name hérédo-ataxie cérébelleuse. Marie’s proposition was based almost entirely on clinical observations not his own but those made by the aforementioned authors. Later, as members of these families died, postmortem examinations disclosed that Marie’s hereditary cerebellar ataxia included not one but several disease entities. Indeed, as pointed out by Holmes (1907b) and later by Greenfield, in 3 of the 4 families the cerebellum showed no significant lesions at all. Yet there was by then no doubt of the existence of a separate class of predominantly cerebellar atrophies, some purely cortical and others associated with a variety of noncerebellar disorders.
Clinical Features Holmes (1907a) described a family of 8 siblings, of whom 3 brothers and 1 sister were affected by a progressive ataxia, beginning with a reeling gait and followed by clumsiness of the hands, dysarthria, tremor of the head, and a variable nystagmus, but without additional features to implicate disease of the spinal cord or brainstem. It may be taken as the prototype of pure cerebellar cortical degeneration. The ataxia begins insidiously, usually in the fourth decade but with wide variability in age of onset, and progresses
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slowly over many years. Ataxia of gait, instability of the trunk, tremor of the hands and head, and slightly slowed, hesitant speech is the usual clinical picture. Nystagmus is rare and intelligence is usually preserved. The patellar reflexes may be slightly increased but this may be apparent based on the pendular character of reflexes in cerebellar disease; the plantar reflexes are flexor and the ankle jerks are present but there are exceptions and probably mark the process as one of the other genetic ataxias. The differential diagnosis in the nonfamilial cases is quite broad, including many acquired types of ataxias discussed in Chap. 5 (see Table 5-1) and at the end of this section. Pathology Postmortem examination of the Holmestype cases discloses symmetrical atrophy of the cerebellum involving mainly the anterior lobe and vermis, the latter being more affected. Purkinje cells are absent in the lingula, centralis, and pyramis of the superior vermis and reduced in number in the quadrangularis, flocculus, biventral, and pyramidal lobes. The other cerebellar cortical neurons and granule cells and dorsal and medial parts of the inferior olivary nuclei are diminished less so. The white matter is slightly pale in myelin stains. The vermian atrophy and that of adjacent parts of the cerebellum can be visualized with clarity in MRIs (Fig. 39-8). The vague similarity of the pathologic (and clinical) changes to those of alcoholic cerebellar degeneration is at once apparent and should raise the question of an alcoholicnutritional cause in sporadic cases (Chap. 41); in serious alcohol-nutritional disease, there usually is an accompanying polyneuropathy and reduced ankle reflexes.
Fragile X Tremor–Ataxic Premutation Syndrome This type of mental retardation caused by an unstable extended trinucleotide repeat sequence and breakage of the X-chromosome is discussed in Chap. 38. Here we refer to a
Figure 39-8. Familial cortical cerebellar atrophy. T1-weighted MRI in the sagittal plane showing marked atrophy of vermis and enlargement of fourth ventricle. The brainstem is only mildly atrophic. Compare with Fig. 39-9 in which the cerebellum and pons are atrophic.
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relatively newly described degenerative process with onset in mid- or late adulthood, mainly but not exclusively in men, and consisting of gait or limb ataxia and mild tremor. The process affects carriers of a “premutation” who have 50 to 200 CGG repeat sequences in the FMR1 gene. In contradistinction to the full mutation of over 200 repeats, there is apparently a buildup of messenger ribonucleic acid (mRNA) in the adult form that interferes in some way with cellular function. Aggregating several studies, the frequency of this genetic abnormality among otherwise unassignable adult ataxia cases is less than 10 percent. The entire clinical spectrum has yet to be defined but our experience with two patients featured mild progressive gait ataxia in the sixth decade that was misattributed to normal-pressure hydrocephalus, and an intermittent hand tremor that was probably ataxic in nature. Some reports have included a parkinsonian syndrome and more consistently, a mild frontal dementia, making the distinction from frontotemporal dementia difficult. Many cases have been confused with multiple-system atrophy. T2 and fluid-attenuated inversion recovery (FLAIR) signal changes in the cerebellar peduncles are characteristic of some cases, but this was not found in our cases, which showed only midline cerebellar atrophy. This imaging finding may be indicative of the disease, however, in the context of a midlife, slowly progressive ataxia. A family history of mental retardation may be a hint to diagnosis and some proportion of individuals with the premutation have subnormal intelligence. A study of the neuropathology by Greco and colleagues showed cerebral and cerebellar spongiform white matter change and both intranuclear and astrocytic inclusions. Their report demonstrated a correspondence between the quantity of trinucleotide repeats and the number of inclusion bodies.
Familial and Sporadic Forms of Complicated Cerebellar Atrophy with Brainstem and Extrapyramidal Features A sporadically occurring disorder closely resembling the Holmes type of cortical cerebellar degeneration but with additional features of brainstem atrophy was described in 1900 by Déjérine and André-Thomas, who named it olivopontocerebellar atrophy (OPCA). As more cases of this type were collected, an autosomal dominant hereditary pattern was evident in some, and one or more long tracts in the spinal cord were found to have degenerated. About half the cases later developed the parkinsonism with degeneration of nigral cells and, in a few, of striatal cells, thereby marking the disease as a form of striatonigral degeneration that is essentially a form of multiple system atrophy (see earlier discussion of this entity and below). Notable findings in both the sporadic and the familial forms of many of the variants of cerebellar atrophy are extensive degeneration of the middle cerebellar peduncles, cerebellar white matter, and pontine, olivary, and arcuate nuclei; loss of Purkinje cells has been variable. Most likely this degeneration represents a “dying back” of axons of the cerebellar, pontine, and olivary nuclei with secondary myelin degeneration. Extreme atrophy of the
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medullary olivary nuclei, evident on MRIs (Fig. 39-9) identifies a special process that conforms to OPCA. Although the associated features in each of the inherited cerebellar degenerations do not create categories that conform to newer genetic classifications, they are nonetheless recognizable and clinically useful. Many modern texts use a genetic system exclusively to categorize these diseases. Konigsmark and Weiner had subdivided them in the past into types, including a dominantly inherited OPCA (of Menzel); a recessive type (of Fickler-Winkler); a dominant type with retinal degeneration; one with spastic paraplegia and areflexia; and with dementia, ophthalmoplegia, and extrapyramidal signs. To these had been added cases of OPCA with neuropathy and slowed eye movements (Wadia type), of which we have seen 2 cases, and cases with dystonia and a variety of other clinical findings, most in single families (hemiballismus, athetosis, contractures of the legs, fixed pupils, ophthalmoplegia, ptosis, gaze palsy, deafness, retinal degeneration, mental retardation and epilepsy, claw foot and scoliosis, incontinence, parkinsonian symptoms and signs, plethora of presentations including a neonatal type. Some of these variants are detailed below. Cases of sporadic olivopontocerebellar atrophy are more common than the familial variety and tend to occur at an older age; nystagmus, optic atrophy, retinal degeneration, ophthalmoplegia, and urinary incontinence are generally not observed. However, there are numerous cases that include mild extrapyramidal and neuropathic signs, slow eye movements, dystonia, impairment of vertical saccadic eye movements (thus simulating progressive supranuclear palsy), a vocal cord paralysis that is typical of MSA, and deafness. The relationship of olivopontocerebellar atrophy to MSA was discussed in the section on “Multiple System Atrophy (Striatonigral Degeneration, Shy-Drager Syndrome, Olivopontocerebellar Degeneration),” but we
Figure 39-9. Olivopontocerebellar atrophy. MRI in the sagittal plane demonstrating both vermian atrophy (short arrow) and smallness of the pons (long arrow). (Reproduced by permission from Bisese JH: Cranial MRI. New York, McGraw-Hill, 1991.)
emphasize that OPCA occurs as often independently of extrapyramidal degeneration for which reason we retain a separate designation.
Cerebellar Atrophy with Prominent Basal Ganglionic Features Machado-Joseph-Azorean Disease (SCA3) A special form of hereditary ataxia with brainstem and extrapyramidal signs has been described in patients mainly, but not exclusively, of Portuguese-Azorean origin. The disorder is characterized by an autosomal dominant pattern of inheritance and by a slowly progressive ataxia beginning in adolescence or early adult life in association with hyperreflexia, extrapyramidal features, dystonia, bulbar signs, distal motor weakness, and ophthalmoplegia. There is usually no impairment of intellect and in the examples the authors have seen, the extrapyramidal symptoms were mainly rigidity and slowness of movement. This conjunction of a Parkinson syndrome with cerebellar ataxia is reminiscent of MSA except for an earlier age of onset and the prominence in some cases of dystonia, amyotrophy, and ophthalmoplegia. Postmortem examination discloses a degeneration of the dentate nuclei and spinocerebellar tracts and a loss of anterior horn cells and neurons of the pons, substantia nigra, and oculomotor nuclei. An affected Azorean family named Joseph was described in 1976 by Rosenberg and colleagues under the name of autosomal dominant striatonigral degeneration. Using the term Azorean disease of the nervous system (now better known as Machado-Joseph disease), Romanul and colleagues described yet another family of Portuguese-Azorean descent, many members of which were affected by a syndrome comprising a progressive ataxia of gait, parkinsonian features, limitation of conjugate gaze, fasciculations, areflexia, nystagmus, ataxic tremor, and extensor plantar responses; the pathologic changes closely resembled those described by Woods and Schaumburg. Romanul and coworkers compared the genetic, clinical, and pathologic features of their cases with those described in other Portuguese-Azorean families and concluded that all of them represent a single genetic entity with variable expression. This concept of the disease has been corroborated by the further observations of Rosenberg and of Fowler who studied 20 patients with the MachadoJoseph-Azorean disease over a 10-year period and more recently by genetic testing. Cancel and colleagues found an unstable number of CAG repeating sequences in a gene, ataxin-3, and named the disorder spinocerebellar ataxia type 3 (SCA3). The disease is not limited to Azoreans. Cases conforming to the above descriptions have now been observed among African American, Indian, and Japanese families (Sakai et al; Yuasa et al; Bharucha et al). There are no signs of polyneuropathy, which is the main feature of another disease in Portuguese emigrants caused by amyloid deposition, described by Nakano and colleagues as “Machado disease,” this being the name of the progenitor of the afflicted family. Early clinical diagnosis of Machado-Joseph disease is possible by the finding of dysmetric horizontal and verti-
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cal saccades (Hotson et al). In fully developed cases, the MRI findings are characteristic—reduced width of the superior and middle cerebellar peduncles, atrophy of the frontal and temporal lobes, and smallness of the pons and globus pallidus (Murata et al). There is no treatment of proven value.
Multiple System Atrophy with Predominant Ataxia (See multiple system atrophy in earlier section) This entity has been discussed with the degenerative disorders of the basal ganglia earlier in the chapter. Here it is pointed out that a number of cases of sporadic progressive ataxia in mid- and late life are attributable to this process and have been termed MSA-C to signify the predominant cerebellar feature. The extrapyramidal, corticospinal, or autonomic aspects of the illness may or may not become evident only with continued observation or by pathologic examination. Some guidance as to the frequency of MSA as the cause of otherwise undifferentiated sporadic ataxia is given in the study by Abele and colleagues who found that it accounts for almost one-third of cases, but the precise number is open to question as pathologic examinations were not made.
Dentatorubropallidoluysian Atrophy (DRPLA) This is a rare familial disorder, described mostly in Japan and in small European pockets, in which symptoms of cerebellar ataxia are coupled with those of choreoathetosis and dystonia and, in a few instances, parkinsonism, myoclonus, epilepsy, or dementia. Pathologically there is degeneration of the dentatorubral and pallidoluysian systems. The main consideration when chorea is a prominent feature is the separation of this disorder from Huntington disease. The gene defect in DRPLA is an unstable CAG trinucleotide repeat on chromosome 12 that codes for the protein atrophin. This same mutation has been defined in affected families from throughout the world (e.g., Warner et al). As with Huntington chorea (where the expanded polyglutamine tract is in the protein huntingtin), this disease is inherited as an autosomal dominant trait and shows an inverse correlation between the age of onset and the size of the gene expansion (anticipation). When chorea predominates early in the illness, there may be difficulty distinguishing DRPLA from Huntington disease. The diagnosis is confirmed by means of DNA analysis.
Dentatorubral Degeneration This is a rare and still nebulous entity but it is probably distinct from the condition described above, under “Dentatorubropallidoluysian Atrophy.” There are several instructive features. In 1921, Ramsay Hunt published an account of 6 patients (2 of whom were twin brothers) in whom myoclonus was combined with progressive cerebellar ataxia. The age of onset in the 4 nonfamilial cases was between 7 and 17 years, and the cerebellar ataxia followed the myoclonus by an interval of 1 to 20 years. Hunt named the disorder dyssynergia cerebellaris myoclonica. There were signs of Friedreich ataxia in the twin brothers; postmor-
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tem examination of one showed cerebellar atrophy, degeneration of the posterior columns and spinocerebellar tracts but not of the corticospinal tracts. In 1947, Louis-Bar and van Bogaert reported a similar case and noted, in addition to the above findings, degeneration of the corticospinal tracts and loss of fibers in the posterior roots. Thus the pathology was identical to that of Friedreich ataxia except for the more severe atrophy of the dentate nuclei. Earlier (1914), under the title of dyssynergia cerebellaris progressiva, Hunt had drawn attention to a progressive disease in young individuals manifest by what he considered to be a pure cerebellar syndrome but one of his cases was revealed at autopsy to be Wilson disease. Hunt’s reports emphasize the hazard of classifying cerebellar ataxias on the basis of clinical findings alone, a point made effectively by Holmes.
Paroxysmal Ataxias (See Chap. 5) Two adult forms of hereditary cerebellar ataxia are paroxysmal in nature. In one (EA-2 for episodic ataxia, type 2), the episodes occur without explanation and last several hours; vertigo is a prominent feature of the attacks. Between attacks the patient is normal or has only minimal ataxia and nystagmus (Griggs et al). These ataxic episodes are prevented strikingly by the administration of oral acetazolamide. The disorder has been found to be a mutation of the calcium channel gene on chromosome 19. A similar but physiologically and genetically unrelated paroxysmal ataxia (EA-1) is characterized by episodes that may be precipitated by exercise and by the presence of muscle myokymia (rippling) between attacks. Vertigo does not occur and acetazolamide is less effective or not effective at all. The disorder is caused by an abnormality of the potassium channel gene on chromosome 12. Both of these episodic ataxias are therefore “channelopathies” (see Chap. 54). Also of interest is spinocerebellar atrophy type 6, a progressive condition in which a mutation has been traced to same gene implicated in the EA-2 acetazolamideresponsive paroxysmal ataxia, but this disorder is not paroxysmal and results in progressive ataxia, dysarthria, and loss of proprioception.
Genetics of the Heredodegenerative Ataxias (Table 39-5) The many familial degenerative ataxic disorders described in the preceding pages are genetically distinct. As indicated, the autosomal recessive type of Friedreich ataxia is the result of an expanded GAA repeat in the frataxin gene (Campuzano et al), quite different from the dominant form. The direct molecular test for the GAA expansion is useful for diagnosis, particularly for atypical cases with late onset (Dürr et al). The rarer recessive spinocerebellar ataxia associated with vitamin E deficiency arises from mutations in the gene that encodes an alpha tocopherol (vitamin E) transport protein, as mentioned above. Among the autosomal dominant cerebellar ataxias of later onset, molecular and gene studies have identified numerous mutant genes. Of these autosomal dominant ataxias, 8
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are known to be caused by expanded CAG-trinucleotide repeats (SCA types 1, 3, 6, and 7, 12, 17, as well as DRPLA). Undoubtedly others will be discovered. However, the mechanisms by which the expanded polyglutamine molecule leads to neuronal cell death remain uncertain. It is likely that differences in the clinical manifestations of these disorders will reflect differences in the patterns of expression of the affected proteins; i.e., each is expressed in different populations of neurons and at different stages in development. This raises the possibility that the cascade of events that triggers neuronal degeneration is similar in each of the diseases with a CAG expansion and that a therapy might be discovered that is effective in all of them. The special case of fragile X premutation that may cause ataxia and tremor in adults is addressed in Chap. 38. Table 39-5 summarizes the genes, terminology, related neural abnormalities, and clinical features of the cerebellar atrophies.
Differential Diagnosis of the Degenerative Ataxias (See also Table 5-1) Sporadic forms of cerebellar ataxia in adults are in some instances traceable to strokes involving cerebellar pathways (Safe et al). These are, of course, of acute onset. Some cases of ataxia are alcoholic-nutritional in origin, and a few are related to excessive use of drugs or therapeutic medications, especially anticonvulsants, which may in a few cases cause a slowly progressive and permanent ataxia. Organic mercury induces subacute cerebellar degeneration, and adulterated heroin causes a more abrupt and severe ataxic syndrome. The paraneoplastic variety of cerebellar degeneration often enters into the differential diagnosis; it occurs mostly in women with breast or ovarian cancers and evolves much more rapidly than any of the heredodegenerative forms. The more rapid onset of ataxia and the presence of anti-Purkinje cell antibodies (anti-Yo; see “Paraneoplastic Cerebellar Degeneration” in Chap. 31) are central to identifying the nature of this disease. From time to time one observes a similar idiopathic variety of subacute cerebellar degeneration, particularly in women who have no neoplasm and lack the specific antibodies of the paraneoplastic disease (Ropper). Rare cases of ataxia have been associated with celiac disease and Whipple disease, as noted in Chap. 5. Ataxia may also be an early and prominent manifestation of CreutzfeldtJakob disease caused by a transmissible prion (see Chap. 33) or of an inherited metabolic disease (Chap. 37). Of the latter, late-onset GM2 gangliosidosis may simulate cerebellar degeneration in adults (Chap. 37). Rare cases of aminoacidopathy manifesting for the first time in adult life have also provoked a cerebellar syndrome (see Chap. 37).
Hereditary Polymyoclonus The syndrome of quick, arrhythmic, involuntary single or repetitive twitches of a muscle or group of muscles was described in Chap. 6, where it was pointed out that the condition has many causes. Chapter 37 discusses those caused by hereditary metabolic diseases. Familial forms are known, one of which, associated with cerebellar ataxia, was discussed earlier (dyssynergia cerebellaris myoclonica of Ramsay Hunt). But there is another disease, known as
hereditary essential benign myoclonus, that occurs in relatively pure form unaccompanied by ataxia (termed essential, or familial, myoclonus; see Chap. 6). In this condition, it is difficult to evaluate coordination because willed movement is interrupted by myoclonus that may be mistaken for intention tremor. Only by slowing the voluntary movement can the myoclonus be reduced or eliminated. This myoclonic disease is inherited as an autosomal dominant trait. It becomes manifest early in life; once established, it persists with little or no change in severity throughout life, often with rather little disability. It can, by its natural course, be differentiated from some of the hereditary metabolic diseases such as the Unverricht and Lafora types of myoclonic epilepsy, the lipidoses, tuberous sclerosis, and myoclonic disorders that follow certain viral infections and anoxic encephalopathy. Of interest is the response of this form of movement disorder to certain pharmacologic agents, notably clonazepam, valproic acid, and 5-hydroxytryptophan, the amino acid precursor of serotonin, particularly when these agents are used in combination (postanoxic myoclonus responds to the same medications). The main clinical distinctions are from juvenile myoclonic epilepsy (Chap. 16), drug-induced myoclonus, particularly lithium and opiates; renal failure and other acquired metabolic disorders; asterixis; and from the startle responses and some of the diseases that have this sign as their main characteristic (Chap. 6). Creutzfeldt-Jakob subacute spongiform encephalopathy may cause difficulty in diagnosis initially but the course of illness clarifies the situation rapidly. Myoclonus is also one component of the complex movement disorder in corticobasal-ganglionic degeneration that was described in an earlier section.
SYNDROME OF MUSCULAR WEAKNESS AND WASTING WITHOUT SENSORY CHANGES Motor System Disease This general term designates a group of progressive degenerative disorders of motor neurons in the spinal cord, brainstem, and motor cortex, manifest clinically by muscular weakness, atrophy, and corticospinal tract signs in varying combinations. It is for the most part a disease of middle life and progresses to death in a matter of 2 to 5 years or longer in exceptional cases. Customarily, motor system disease is subdivided into several subtypes on the basis of the grouping of symptoms and signs. The most frequent form, in which amyotrophy and hyperreflexia are combined, is ALS (amyotrophy is the term applied to denervation atrophy and weakness of muscles). Less frequent are cases in which weakness and atrophy occur alone, without evidence of corticospinal tract dysfunction; for these the term progressive spinal muscular atrophy is used. When the weakness and wasting predominate in muscles innervated by the motor nuclei of the lower brainstem (i.e., muscles of the jaw, face, tongue, pharynx, and larynx), it is customary to speak of progressive bulbar palsy). In a small proportion of patients, the clinical state is dominated by spastic weakness, hyperreflexia, and Babin-
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ski signs, with lower motor neuron aspects becoming apparent only at a later stage of the illness, or not at all. This is designated primary lateral sclerosis, an infrequent form of motor system disease in which the degenerative process remains confined to the corticospinal pathways (Pringle et al). The pure spastic paraplegias without amyotrophy may represent a special class of disease hence they are described separately. There are also relatively common familial forms of spastic paraplegia in which the disease is confined to the corticospinal tracts or, in some cases, combined with posterior column or other neurologic signs. Furthermore, an important group of special spinal muscular atrophies occurs in infancy and childhood and are the leading cause of heritable infant mortality and, after cystic fibrosis, the most frequent form of serious childhood autosomal recessive disease (Pearn). The best known is the Werdnig-Hoffmann type of infantile spinal muscular atrophy (SMA type I); but there are other forms beginning in later childhood, adolescence, or early adult life (SMA types II and III, or the Wohlfart-Kugelberg-Welander type). Despite the clinical heterogeneity of the heritable childhood spinal muscular atrophies, they all derive from mutations in the SMN gene (see below; see Gilliam et al; Brzustowicz et al). This group of early onset spinal muscular atrophies is separate genetically from a familial form of ALS. History Credit for the original delineation of amyotrophic lateral sclerosis is appropriately given to Charcot. With Joffroy in 1869 and Gombault in 1871, he studied the pathologic aspects of the disease. In a series of lectures given from 1872 to 1874, he provided a lucid account of the clinical and pathologic findings. Although called Charcot disease in France, amyotrophic lateral sclerosis (the term recommended by Charcot) has been preferred in the Englishspeaking world. Duchenne had earlier (1858) described labioglossolaryngeal paralysis, a term that Wachsmuth in 1864 changed to progressive bulbar palsy. In 1869, Charcot called attention to the nuclear origin of progressive bulbar palsy, and in 1882 Déjérine established its relationship to ALS. Most authors credit Aran and Duchenne with the earliest descriptions of progressive spinal muscular atrophy, which they believed to be of myogenic origin. This interpretation was, of course, incorrect; Cruveilhier, a few years later, noted the slender anterior roots, and soon thereafter the disease was brought into line with ALS as a spinal muscular atrophy.
Amyotrophic Lateral Sclerosis This is a common disease, with an annual incidence rate of 0.4 to 1.76 per 100,000 population. Men are affected nearly twice as often as women. Most patients are older than age 45 years at the onset of symptoms, and the incidence increases with each decade of life (Mulder). The disease occurs in a random pattern throughout the world except for a dramatic clustering of patients among inhabitants of the Kii peninsula in Japan and in Guam, where ALS is often combined with dementia and parkinsonism. In approximately 10 percent of cases the disease is familial, being inherited as an autosomal dominant trait with age-dependent penetrance. The familial cases do not differ fundamentally in their symptoms and clinical course from nonfamilial ones, although as a group
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the former have an earlier age of onset, an equal distribution in men and women, and a slightly shorter survival. Unusual environmental associations are reported from time to time, for example, an increased incidence among Italian professional football players (Chio et al, 2005) and among soldiers who had served in various regions. All of these are questionable on methodologic grounds (they are retrospective case control epidemiologic studies) but further exploration is warranted. In the most typical forms of disease, the onset is perceived by the patient as weakness in a distal part of one limb. This is noted first as an unexplained tripping from slight foot-drop, or by awkwardness in tasks requiring fine finger movements (handling buttons and automobile ignition keys), stiffness of the fingers, and slight weakness or wasting of the hand muscles on one side. In other words, features related to upper and to lower motor neuron degeneration (or both) may appear insidiously in one limb. Cramping beyond what seems natural and fasciculations of the muscles of the forearm, upper arm, and shoulder girdle also appear. The earliest manifestation of the lower motor neuron component of this disease is often volitional cramping—for example, leg cramps as the patient turns in bed during the early morning hours. As the weeks and months pass, the other hand and arm become similarly affected. Before long, the triad of atrophic weakness of the hands and forearms, fasciculations, slight spasticity of the arms or legs, and generalized hyperreflexia—all in the absence of sensory change—leaves little doubt as to the diagnosis. Muscle strength and bulk diminish in parallel or there is a relative preservation of power early in the illness. Despite the amyotrophy, the tendon reflexes are notable for their liveliness. Babinski and Hoffmann signs are variably present; surprisingly, they may not appear even as the illness progresses. Abductors, adductors, and extensors of fingers and thumb tend to become weak before the long flexors, on which the handgrip depends, and the dorsal interosseous spaces become hollowed, giving rise to the “cadaveric” or “skeletal” hand. The muscles of the upper arm and shoulder girdles are typically involved later. There is a general tendency for adjacent areas to be involved before more distant ones. When an arm is the first limb affected, all this occurs while the thigh and leg muscles seem relatively normal, and there may come a time in some cases when the patient walks about with useless, dangling arms. Later the atrophic weakness spreads to the neck, tongue, pharyngeal, and laryngeal muscles, and eventually those in the trunk and lower extremities yield to the onslaught of the disease. The affected parts may ache and feel cold, but true paresthesias, except from poor positioning and pressure on nerves, do not occur or are minor. Sphincteric control is well maintained even after both legs have become weak and spastic, but many patients acquire urinary and sometimes fecal urgency in the advanced stages of the disease. The abdominal reflexes may be elicitable even when the plantar reflexes are extensor. Extreme spasticity is rarely seen. Coarse fasciculations are usually evident in the weakened muscles but may not be noticed by the patient until the physician calls attention to them. Fasciculations are almost never the sole presenting feature of ALS—a clinical truism with which one can reassure physicians and medical students who fear, on the basis of persistent focal mus-
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cle twitching in the thumb, face, foot, or forearm, that they are developing the disease. The course of this illness, irrespective of its particular mode of onset and pattern of evolution, is progressive. There may be periods lasting weeks or months during which the patient observes no advance in symptoms but clinical changes can nonetheless be detected. Half the patients succumb within 3 years of onset and 90 percent within 6 years (Mulder et al). Clinical variations that occur with regularity and have distinguishing clinical features are described below. Other Patterns of Clinical Evolution In addition to the special configurations discussed further on, there are many patterns of neuromuscular involvement other than the one just described. A leg may be affected before the hands. A foot-drop with weakness and wasting of the pretibial muscles may be incorrectly attributed to peroneal nerve compression until weakness of the gastrocnemius and other muscles betray more widespread involvement of lumbosacral neurons. In our experience, this crural amyotrophy has been less frequent than the brachial-manual type. Another variant is early involvement of thoracic, abdominal, or posterior neck muscles, the last being one of the causes of head lolling and camptocormia (forward bending of the neck and trunk) in older individuals. Yet another pattern is of early diaphragmatic weakness; such cases come to attention because of respiratory failure. A symmetrical proximal limb or shoulder-girdle amyotrophy with onset at an early age is also known and simulates muscular dystrophy (Wohlfart-Kugelberg-Welander disease, discussed in a later section of this chapter. On several occasions we have observed a pattern involving the arm and leg on the same side, first with spasticity and then with some degree of amyotrophy; this has been called the hemiplegic, or Mills variant. However, this clinical condition more often turns out to be a result of multiple sclerosis. The first and dominant manifestations of motor neuron disease may be a spastic weakness of the legs, in which case a diagnosis of primary lateral sclerosis is tentatively made (discussed further on); only after a year or two do the hand and arm muscles weaken, waste, and fasciculate, making it obvious that both upper and lower motor neurons are diseased. Early on, a spastic bulbar palsy with dysarthria and dysphagia, hyperactive jaw jerk and facial reflexes, but without muscle atrophy, may be the initial phase of disease. As the disease advances, very mild distal sensory loss may be observed in the feet without explanation, but, if the sensory loss is a definite and early feature, the diagnosis must remain in doubt. Approximately 5 percent of cases of ALS are observed in conjunction with a frontotemporal dementia; less commonly, there is an association with a Parkinson syndrome (see Table 37-3).
Progressive Muscular Atrophy This purely lower motor neuron syndrome is more common in men than in women, reportedly in a ratio of 4:1. It probably encompasses several diseases of the lower motor neuron, only some of which are manifestations of ALS.
These purely lower motor neuron amyotrophies tend to progress at a slower pace than the usual case of ALS, some patients surviving for 15 years or longer. Chio and colleagues (1985), who analyzed the factors affecting life expectancy in 155 patients with progressive muscular atrophy (PMA), found that younger patients had a more benign course: the 5-year survival was 72 percent in patients with an onset before age 50 years and 40 percent in patients with onset after age 50 years. Some of the most chronic varieties of PMA are familial. It has been revealed that the original report of a familial variety of this illness by William Osler described a family now known to have had a mutation in the SOD1 gene, as discussed below. In about half the patients, the illness takes the form of a symmetrical (sometimes asymmetrical) wasting of intrinsic hand muscles, slowly advancing to the more proximal parts of the arms; less often, the legs and thighs are the sites of the initial atrophic weakness; or the proximal parts of the limbs are affected before the distal ones. Fascicular twitchings and cramping are variably present. Otherwise they differ from ALS only in that the tendon reflexes are diminished or absent and signs of corticospinal tract disease cannot be detected. Nonetheless, many cases of ostensible PMA are found to have indications of corticospinal tract degeneration at autopsy (Ince et al). The main disease to be distinguished from PMA is an immune-mediated motor neuropathy that occurs with or without multifocal block of electrical conduction (Chap. 46), and various muscle diseases that produce a similar pattern of weakness, notably, inclusion body myopathy and polymyositis. The presence of a paraproteinemia, specifically immunoglobulin (Ig) M with antibodies against GM1 ganglioside, or the finding of focal conduction block or sensory nerve abnormalities on the EMG implies the presence of an autoimmune neuropathy disease rather than one of motor neuron type.
Progressive Bulbar Palsy Here reference is made to a condition in which the first and dominant symptoms relate to weakness and laxity of muscles innervated by the motor nuclei of the lower brainstem, i.e., muscles of the jaw, face, tongue, pharynx, and larynx. This weakness gives rise to an early defect in articulation, in which there is difficulty in the pronunciation of lingual (r, n, l), labial (b, m, p, f ), dental (d, t), and palatal (k, g) consonants. As the condition worsens, syllables lose their clarity and run together, until, finally, the patient’s speech becomes unintelligible. In other patients, slurring is a result of spasticity of the tongue, pharyngeal, and laryngeal muscles; the speech sounds as if the patient were eating food that is too hot. Usually the voice is modified by a combination of atrophic and spastic weakness. Defective modulation with variable degrees of rasping and nasality is another characteristic. The pharyngeal reflex is lost, and the palate and vocal cords move imperfectly or not at all during attempted phonation. Mastication and deglutition become impaired; the bolus of food cannot be manipulated and may lodge between the cheek and teeth and the pharyngeal muscles do not force it properly into the esophagus. Liquids and small particles of food find their way into the trachea or
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nose. The facial muscles, particularly of the lower face, weaken and sag. Fasciculations and focal loss of tissue of the tongue are usually early manifestations; eventually the tongue becomes shriveled and lies useless on the floor of the mouth. The chin may also quiver from fascicular twitchings, but the diagnosis should not be made on the basis of fasciculations alone, in the absence of weakness and atrophy. The jaw jerk may be present or exaggerated at a time when the muscles of mastication are markedly weak. In fact, spasticity of the jaw muscles may be so pronounced that the slightest tap on the chin will evoke clonus and blinking; rarely, attempts to open the mouth elicit a “bulldog” reflex (jaw snaps shut involuntarily). Spastic weakness of the oropharyngeal muscles may be the initial manifestation of bulbar palsy and may at times surpass signs of atrophic weakness; pseudobulbar signs (pathologic laughing and crying) may reach extreme degrees. This is the only common clinical situation in which spastic and atrophic bulbar palsy coexist. Strangely, the ocular muscles always escape. As with other forms of motor system disease, the course of bulbar palsy is inexorably progressive. Eventually the weakness spreads to the respiratory muscles and deglutition fails entirely; the patient dies of inanition and aspiration pneumonia, usually within 2 to 3 years of onset. Approximately 25 percent of cases of motor system disease begin with bulbar symptoms, but rarely, if ever, does the sporadic form of progressive bulbar palsy run its course as an independent syndrome (pure heredofamilial forms of progressive bulbar palsy in the adult are known, e.g., Kennedy disease, discussed further on). In general, the earlier the onset of the bulbar involvement, the shorter the course of the disease.
Primary Lateral Sclerosis This entity, like ALS, can be a form of motor neuron disease, although most cases appear to be examples of a unique degenerative process. Many patients in whom the signs of corticospinal tract degeneration betray the presence of ALS will develop indications of lower motor neuron disease within 1 year, usually earlier. Approximately 20 percent, however, have a slowly progressive corticospinal tract disorder that begins with a pure spastic paraparesis; later, the arms and oropharyngeal muscles become involved and the disease remains one solely of the upper neurons. These cases have distinctive neuropathologic features and are designated as primary lateral sclerosis (PLS), a term originally suggested by Erb in 1875. A historical review of the subject appears in the article by Pringle and colleagues. The typical case begins insidiously in the fifth or sixth decade with a stiffness in one leg, then the other; there is a slowing of gait, with spasticity predominating over weakness as the years go on. Walking is still possible with the help of a cane for many years after the onset, but eventually this condition acquires the characteristic features of a severe spastic paraparesis. Over the years, finger movements become slower, the arms become spastic, and, if the illness persists for decades, speech takes on a pseudobul-
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bar lilt. There are no sensory symptoms or signs. The legs are often found to be surprisingly strong, the difficulty in locomotion being attributable to rigid spasticity. About half the patients eventually acquire spasticity of the bladder. Pringle and associates suggest that a diagnostic criterion of the disease is progression for 3 years without evidence of lower motor neuron dysfunction. Pathologic studies in a limited number of cases have disclosed a relatively stereotyped pattern of reduced numbers of Betz cells in the frontal and prefrontal motor cortex, degeneration of the corticospinal tracts, and preservation of motor neurons in the spinal cord and brainstem (Beal and Richardson; Fisher; Pringle et al). The corticospinal tract lesions are identical to those in typical ALS. Whether some of these cases are examples of late-onset familial spastic paraplegia (see further on) has not been extensively explored with molecular techniques. Diagnosis of PLS Many patients who have only restricted bilateral signs of upper motor neuron disease prove to have multiple sclerosis, a slow compression of the spinal cord by spondylosis or meningioma, or the myelopathic form of adrenoleukodystrophy (affected males or female carriers). In a few, tropical spastic paraplegia, HIV myelopathy, or a familial type of spastic paraplegia (described further on) will be uncovered. Exceptionally, progressive spastic paraparesis have been linked to an adult onset of phenylketonuria or other aminoacidopathies, to vitamin B12 deficiency or to the fragile X premutation syndrome.
Laboratory Features of Motor Neuron Disease Investigation provides useful confirmatory evidence even in the typical clinical syndrome. The EMG, as expected, displays widespread fibrillations (evidence of active denervation) and fasciculations and enlarged motor units (denoting reinnervation), and motor nerve conduction studies reveal only slight slowing, without focal motor conduction block. If the atrophic paresis is restricted to an arm or hand, raising the question of cervical spondylosis, evidence of denervation in many widely separated somatic segments favors the diagnosis of ALS. In questionable cases, it is good practice to insist that denervation be demonstrated in at least three limbs before concluding that the process is ALS. (The currently favored “El-Escorial” criteria that are used for the purposes of clinical research mandate that this finding be present.) Widespread denervation of the paraspinal muscles and of the genioglossus or facial muscles is also strongly indicative of the disease but electromyographic testing of these muscles demands considerable experience and is uncomfortable for patients. A muscle biopsy is sometimes helpful in corroborating neurogenic denervation. Sensory nerve action potentials should be normal; tests of motor nerve conduction have a normal velocity, but the amplitudes become progressively lower as the disease progresses—in the earliest stages, they too may be normal. When in a typical case the amplitudes of sensory nerve action potentials are reduced, there is usually an underlying entrapment neuropathy, diabetes, or other late-life neuropathy. Sensory evoked potentials are mildly abnormal in a proportion of patients, but the explanation for this finding is unclear. (Sensory com-
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plaints and minimal sensory loss have been commented on above.) The CSF protein is usually normal or marginally elevated. Serum creatine kinase is moderately elevated in patients with rapidly progressive atrophy and weakness, but it is just as often normal. Motor evoked potentials elicited from the cortex are also prolonged in patients with prominent corticospinal signs. In this group, the MRI may show slight atrophy of the motor cortices and wallerian degeneration of the motor tracts (Fig. 3910). These changes may be diagnostically useful and appear as increased FLAIR and T2 signal intensity in the posterior limb of the internal capsule, descending motor tracts of the brainstem, and spinal cord, all of which are subtle and may be missed. All of these laboratory findings, particularly the degeneration of the lateral columns of the cord and changes in the internal capsules, pertain also to primary lateral sclerosis with the notable exception of EMG findings of denervation and of elevations of creatine kinase (CK).
Pathology The principal finding in ALS is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem. Large alpha motor neurons tend to be affected before small ones. In addition to neuronal loss, there is evidence of slight gliosis and proliferation of microglia cells. Many of the surviving nerve cells are small, shrunken, and filled with lipofuscin. It is not uncommon to detect ubiquitin inclusions in threads, skeins, or dense aggregates within the affected neurons by special stains. Occasionally, there is another ill-defined cytoplasmic inclusion body. According to some reports, swelling of the proximal axon is an early finding, presumably antedating visible changes in the cell body itself. The anterior roots are thin, and there is a disproportionate loss of large myelinated fibers in motor nerves (Bradley et al). The muscles show typical denervation atrophy of different ages. Whitehouse and coworkers found a depletion of muscarinic, cholinergic, glycinergic, and benzodiazepine receptors in regions of the spinal cord where motor neurons had disappeared. The corticospinal tract degeneration is most evident in the lower parts of the spinal cord, but it can be traced up through the brainstem to the posterior limb of the internal capsule and corona radiata by means of fat stains, which show the macrophages that accumulate in response to chronic myelin degeneration. There is a loss of Betz cells in the motor cortex; this is manifest as a slight frontal lobe atrophy on the MRI, but it is not a prominent finding in most cases of ALS (Kiernan and Hudson). Other fibers in the ventral and lateral funiculi are depleted, imparting a characteristic pallor in myelin stains. Some pathologists have interpreted this as evidence of involvement of nonmotor neurons and hence object to the term motor system disease. However, this condition of more diffuse pallor may be a result of a loss of collaterals of motor neurons that contribute to the lamina propria. One observes the same effect in long-standing poliomyelitis. In cases of familial ALS resulting from mutations in the SOD1 gene, the nonmotor systems seem to be more affected (Cudkowicz et al).
Figure 39-10. T2-weighted MRI showing signal changes that reflect wallerian change in the corticospinal tracts at the level of the internal capsule (top, arrow) and the pons (bottom) in a case of ALS.
Neuropathologic studies of cases of ALS with dementia are few in number. In addition to the usual loss of motor neurons, these cases have shown an extensive neuronal loss, gliosis, and vacuolation involving the frontal premotor area, particularly the superior frontal gyri and the inferolateral cortex of the temporal lobes. The histologic changes of Alzheimer or Pick disease have not been seen in our cases; neurofibrillary degeneration has been observed but is
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inconsequential in comparison to that seen in the Guamanian Parkinson-dementia-ALS complex (Finlayson et al; Mitsuyama). Attempts to transmit this ALS–dementia syndrome to subhuman primates have been unsuccessful.
Diagnosis of ALS The early clinical picture of motor system disease is closely simulated by a centrally placed cervical spondylotic bar or ruptured cervical disc, but with these conditions there is usually pain in the neck and shoulders, limitation of neck movements, and sensory changes, and the lower motor neuron changes are restricted to one or two spinal segments. The EMG is helpful if not decisive in differentiating these disorders. A mild hemiparesis or monoparesis because of multiple sclerosis may be, for a time, difficult to distinguish from early ALS and from primary lateral sclerosis. Progressive spinal muscular atrophy may be differentiated from peroneal muscular atrophy (Charcot-Marie-Tooth neuropathy) by the lack of family history, the complete lack of sensory change, and different EMG patterns, as described in Chap. 46. Motor system disease beginning in the proximal limb muscles may be misdiagnosed as an inflammatory myopathy or a limb-girdle type of muscular dystrophy. The main considerations in relation to progressive bulbar palsy are myasthenia gravis and, less often, inflammatory myopathy, muscular dystrophy, and especially the inherited (Kennedy) type of bulbospinal atrophy, which is discussed further on. The spastic form of bulbar palsy may suggest the pseudobulbar palsy of lacunar disease and can be a prominent part of the progressive supranuclear palsy described earlier in the chapter. A crural form of PMA may be confused with diabetic polyradiculopathy or polymyositis. A major consideration is the differentiation of PMA from a chronic motor polyneuropathy, particularly the form that displays multifocal conduction block. Extensive nerve conduction studies and EMG examinations are necessary to distinguish the two; these neuropathic processes are discussed with the peripheral neuropathies in Chap. 46. The presence of an IgM monoclonal paraproteinemia or of specific antibodies directed against the GM1 ganglioside are usually indicative of the immune motor neuropathy, but in half of the cases these laboratory tests are negative. There is also a rare form of subacute poliomyelitis (possibly viral) in patients with lymphoma or carcinoma; it leads to an amyotrophy that progresses to death over a period of several months. Chapter 31 discusses this paraneoplastic variety of motor system disease in greater detail. Because it may produce a motor-predominant radiculopathy, chronic Lyme infection is sometimes considered in the differential diagnosis of ALS. Some clinics screen for Lyme antibodies using both an enzyme-linked immunosorbent assay (ELISA) and the more sensitive and specific Western immunoblot, but we have never detected such a case and doubt there is much similarity. Infrequently, we have seen myelopathic motor findings and motor radiculopathy with vitamin B12 deficiency, and there are exceptional reports of myeloradiculopathy with lead poisoning; we sometimes include tests for these conditions. Another entity that may simulate ALS is inclusion
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body myositis (IBM), an atypical myopathy that begins asymmetrically and involves distal muscles, usually without much elevation of serum CPK levels. In a recent series of 70 patients with this condition, 13 percent were initially diagnosed as having ALS (Dabby et al). Features distinguishing the IBM cases included normal corticospinal function, preservation of deep tendon reflexes in weak muscles, and finger flexor weakness. One concludes from this series that a detailed, quantitative EMG and possibly a muscle biopsy are indicated in cases that display predominantly lower motor features. Fully developed ALS is difficult to confuse with these conditions. Acid maltase deficiency may also simulate ALS in causing fatigability and early respiratory failure. Over the years, the authors have occasionally encountered young men with localized and asymmetrical amyotrophy of the leg or forearm that became arrested and did not advance over a decade or two. Several reports of such a partial cervical spinal amyotrophy have appeared in recent years (Hirayama et al; Moreno Martinez et al). In the type described by Hirayama and associates, young men are affected with progressive and asymmetrical amyotrophy of the forearm and hand that has been traced to ligamentous hypertrophy in the ventral spinal canal. This causes a compression of the cervical spinal cord, presumably a chronic ischemic effect (see Chap. 46). In a familial variety of pure restricted amyotrophy, only the vocal cords became paralyzed over a period of years in adult life; only later were the hands affected. Some patients who have recovered from paralytic poliomyelitis may develop progressive muscular weakness 30 or 40 years later; the nature of this relationship is obscure. We favor the explanation that atrophy of anterior horn cells with aging brings to light a critically depleted motor neuron population (see further on). It appears to progress little if at all. An observation of interest is the finding of a form of progressive spinal muscular atrophy in patients with GM2 gangliosidosis, the storage disease that presents in infancy as Tay-Sachs disease (Kolodny and Raghavan). The onset is in late adolescence and early adult life and the atrophic paralysis is progressive, so that this condition is often mistaken for Wohlfart-Kugelberg-Welander disease or ALS. A number of cases of this type have been discovered in Ashkenazi Jews by the use of lysosomal enzyme analysis. The differential diagnosis of the purely spastic state of primary lateral sclerosis is broad and has been listed earlier. An estimate of the frequency of all the aforementioned alternative diagnoses may be appreciated from a study of cases by Visser and colleagues that were initially presumed to be PMA but turned out to represent another process. In 17 of 89 patients the diagnosis proved to be anti-GM1 motor conduction block, chronic inflammatory demyelinating polyneuropathy, and various myopathies. This notwithstanding, ALS or the more discrete forms of motor system disease rarely offer any difficulty in diagnosis.
Pathogenesis The pathogenesis of the sporadic form of motor system disease is not known. Some insight has been afforded by analyses of the 10 percent of ALS cases that are caused by gene
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Table 39-6 GENETIC DEFECTS ASSOCIATED WITH ALS NOTATION
CHROMOSOME
GENE
GENETICS
AGE OF ONSET
SOD1
21q
Superoxide dismutase
AD
Adult
DCTN
2q
Dynactin
AD
Adult
CytoC ALS2
mtDNA 2q33
Cytochrome-c oxidase GEF/alsin
Mitochondrial AR
Adult Juvenile
SETX VAPB
9q34 20q
Senataxin Vesicle-associated membrane protein
AD AD
Juvenile Adult
mutations. They are inherited in an autosomal dominant pattern (Table 39-6). Of these, approximately 25 percent harbor mutations in a gene that codes for the cytosolic enzyme Cu-Zn superoxide dismutase (SOD1; Rosen et al). More than 100 different mutations have been identified in this particular gene. SOD1 is extremely abundant, accounting for perhaps 0.5 percent of all cytoplasmic protein. It is therefore not surprising that several aspects of neuronal function might be compromised by the toxic properties of the mutant SOD1 protein. Recent studies indicate that the demise of motor neurons is a consequence of pathology in both the motor neurons themselves and in the surrounding nonneuronal cells (Clement et al) and evidence supports the notion that mutant SOD1 protein aggregates may cause excitotoxic glutaminergic activity and mitochondrial dysfunction. The SOD1 gene is not, however, altered in sporadic cases of ALS or its variants. A rare and recessively inherited childhood form of motor neuron disease (affecting corticospinal more than spinal motor neurons) has been attributed to mutations in a gene whose protein (alsin) is a component of the neuronal cellsignaling pathways. Yet another rare childhood-onset form of disease arises from mutations in the senataxin gene, a DNA helicase that probably assists in chromatin folding and unfolding. (It is of interest that a recessively inherited mutation in the same gene transmits a recessive form of ataxia with oculomotor disorder.) In several families, a mutation has been detected in a protein that is involved in the transport of vesicles in neurons. Table 39-6 summarizes these various genetic forms of motor neuron disease. Trauma, particularly traction injury of an arm, has been reported occasionally as an antecedent event in patients with ALS, but a causative relationship has not been established. Younger and coworkers have found a higher incidence of paraproteinemia in patients with motor system disease than can be accounted for by chance. Many other examples of disordered immune function have been described but a coherent explanation of ALS as an autoimmune disease has not emerged. It has never been proved that intoxication with heavy metals (lead, mercury, aluminum) can cause motor system disease, although there are reports of concurrent myelopathic and radicular motor signs in patients with lead intoxication. There is little evidence that such cases represent a reactivation of a virus or the presence of some other infectious agent. The progressive weakness that occurs some 30 to 40 years after recov-
CLINICAL FEATURES
Clinically and pathologically similar to sporadic ALS Slowly progressive with predominant bulbar features Prominent spasticity Very slowly progressive, predominantly corticospinal Very slowly progressive Similar to sporadic ALS
ery from polio should not be confused with PMA, as already indicated. Finally, we have had occasion to see patients who, many years after a severe electrical injury that passed through the region of the cord, developed a progressive and severe amyotrophy of the arms; other such extraordinary cases are known (see Chap. 44).
Treatment With the exception of riluzole, discussed below, there is no specific treatment for any of the motor neuron diseases. Supportive measures, however, are exceedingly important. In initial office visits, it has been our practice to give the patient some idea of the seriousness of the condition; but in early discussions we avoid the devastating statement that ALS is invariably fatal. Typically, patients and family members will ask explicitly about these matters in subsequent visits; such data as are appropriate to the patient’s circumstances and character can be conveyed at that time, usually with the caveat that any individual may outlive the standard survival statistics. The antiglutamate agent riluzole was shown by Bensimon and colleagues to slow the progression of ALS and improve survival in patients with disease of bulbar onset. However, it added only 3 months of life at best. This claim has been confirmed in several followup studies, although again the benefit has been marginal. Several additional agents are reported to have been effective in an SOD1 transgenic model of ALS. These are presently undergoing study in ALS patients. Guanidine hydrochloride and injections of cobra venom, gangliosides, interferons, high-dose intravenous cyclophosphamide, and thyrotropin-releasing hormone are but some of a long list of agents that are said to arrest the disease process, but these claims have been discredited. An attempt can be made to reduce the spasticity with medications, such as baclofen or tizanidine, or by subarachnoid infusions of baclofen via an implanted lumbar pump. Initial intrathecal test doses are given to predict a response to the pump infusions of baclofen, but this test may fail; consequently, in severe cases it may be advisable to proceed with a constant infusion for several days. Some degree of improved comfort from a reduction in the extreme rigidity is usually the most that can be expected. Some relief from spasticity may also be afforded by the use of benzodiazepines or sometimes dantrolene. These approaches are most suitable for cases of primary lateral
CHAPTER 39
sclerosis, which can be expected to progress slowly and for a long period. At all stages of ALS, physical therapy is useful in maintaining mobility, but overwork of the muscles leading to fatigue and cramps should be avoided. Physical therapy is invaluable, for example, for avoiding contractures of the fingers and shoulders. Occupational therapy is likewise helpful, particularly assessments of the patient’s function in the home. Important in the management of ALS is periodic monitoring of respiratory function. We typically perform pulmonary function tests every few months after the first year or so of illness. Our experience has been that the vital capacity in cubic centimeters can be estimated by multiplying the highest number to which a patient can count with one deep breath by 100. Thus, the ability to count to 25 with a full effort in a single breath corresponds to a vital capacity of approximately 2.5 L. Significant practical advances have been made in the respiratory management of ALS. The introduction of bilevel positive airway pressure (BiPAP) has allowed patients to sleep better and reduce daytime somnolence. Many patients do not initially tolerate the device, usually because of maladjusted face masks or excessive applied airway pressures. Almost always, a seasoned pulmonary technologist can find solutions to these problems. It is appropriate to begin BiPAP at (or before) the earliest sign of carbon dioxide retention, a state that is heralded by disruption of sleep, nightmares, early morning headaches, and daytime drowsiness. The second device that has greatly improved respiratory care in these patients has been the “Cough Assist” machine, essentially a device that executes an artificial cough by first insufflating the lungs and then rapidly applying negative pressure, thereby facilitating clearing of the airways. A handheld version looks like a kazoo and has a fluttering diaphragm that sets up vibratory waves in the airways as the patient exhales. It has been our impression that patients with weak diaphragms can reduce the frequency of pneumonia by the twice-daily use of one of these devices. With noninvasive respiratory assistance, it may be possible to defer tracheostomy for months or years. Ultimately, as the diaphragm fails, BiPAP is needed not only at night but also during the day. As BiPAP use approaches 20 to 24 h per day, patients must usually address the difficult question of tracheostomy and mechanical ventilation. We broach this subject early enough in the course of the disease to allow ample time for discussion and reflection. In practice, most patients elect not to undergo tracheostomy and full ventilation. Another important issue regards nutrition. As oropharyngeal palsy progresses, food should be cut into small pieces and dry foods, such as toast, avoided; milk shakes and preparations of the same consistency are ideal at this stage. Speech therapists are capable of teaching patients methods to adapt to declining bulbar function and at the same time minimizing aspiration. Ultimately, in our experience, nearly all ALS patients will need a feeding tube to maintain normal hydration and caloric intake. Although we adopt a neutral position regarding full ventilation, we tend to urge patients to undergo placement of a feeding tube. This clearly increases survival and improves quality of life by preventing dehydration and recurrent aspiration. Lap-
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aroscopic and radiologic technologies for the placement of a gastrostomy tube render the procedure swift and nearly painless. Some patients have tubes inserted as outpatients and then start gastric feeding within a day or two. Other devices, often guided by the physical and occupational therapist, may be of great assistance to the patient and family as the disease progresses. These include a mechanized bed and structural accommodations in the home that facilitate entry of a wheelchair and the safe use of the bath or shower as well as thick-handled utensils. Ambulation aids, beginning with simple canes (first one, then two) followed by a walker (preferably with basket and seat) and then a wheelchair (manual or electric) are of value in maintaining a sense of independence and assuring safety. As the disease enters its later stages, access to the neurologist and, if desired, regular visits for advice are very reassuring to the patient and family. Hospice-type care is often needed in the last weeks of illness for patients who can otherwise be cared for at home, and morphine or similar drugs as well as antianxiety agents can be used liberally to ease discomfort, respiratory distress, and anxiety in the final days.
Heredofamilial Forms of Progressive Muscular Atrophy These diverse diseases are the concern mainly of child neurology. They are presented here because they fall within the category of system degenerations, often of inherited type.
Spinal Muscular Atrophy (Werdnig-Hoffman Disease) The classic form of spinal muscular atrophy was described by Werdnig in 1891 and 1894, by Hoffmann in 1893, and, at about the same time by Thomsen and Bruce. All involved infants. Further clinical analyses, however, indicated the inadequacy of this narrow grouping for the large group of spinal muscular atrophies. Brandt, in his study of 112 Danish patients, found that in about one-third the weakness was present at birth, and in 97 the onset was in the first year of life; in 9 patients, the disease was not recognized until after the first year of life. In 1956, Walton, and later Wohlfart and colleagues and Kugelberg and Welander (see below), identified milder forms of spinal muscular atrophy in which the onset was between 2 and 17 years and walking was still possible in adult life. Byers and Banker, in a study of 52 patients, subdivided them into three groups on the basis of age of onset; in one group the disease was recognized at birth or in the first month or two of life; in a second, between 6 and 12 months; and in a third, after the first year. In their last group, it was not unusual for the patient to survive into adolescence and adult life. In a few of the late onset types, signs of corticospinal tract involvement are conjoined, and Bonduelle has also included some patients with areflexia, pes cavus, Babinski signs, choreiform movements, and mental retardation in this group. More recently, the designations SMA I, II, and III have been introduced, based largely on the age of onset (Table 39-7).
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Table 39-7 CLASSIFICATION OF THE SPINAL MUSCULAR ATROPHIES (SMA) TYPE
INHERITANCE
AGE OF ONSET
CLINICAL FEATURES
SMA I (infantile, Werdnig-Hoffmann)
Autosomal recessive
Preterm to 6 months
SMA II (intermediate type)
Autosomal recessive
6 to 15 months
SMA III (WohlfartKugelbergWelander) Kennedy syndrome (bulbospinal atrophy)
Autosomal recessive or dominant
1 year to adolescence
Delayed motor development, proximal leg weakness
X-linked (CAG repeat expansion), less often autosomal dominant Autosomal recessive, rarely dominant
Early adulthood
Scapuloperoneal or distal atrophy, oropharyngeal weakness, gynecomastia, oligospermia
Slowly progressive
Childhood to early adolescence
Progressive bulbar and respiratory failure
Survival for years, respiratory failure
Fazio-Londe disease
Genetic Aspects of Spinal Muscular Atrophies Familial spinal muscular atrophy that begins in infancy and childhood is inherited mainly as an autosomal recessive trait. All the SMA phenotypes in children have been mapped to the same chromosome: 5q11.2-13.3 (Brzustowicz et al; Gilliam et al; Munsat et al). The mutations affect the gene at what has been termed the “survival of motor neuron” (SMN) site. The SMN protein participates in forming protein-RNA complexes (so-called small nuclear ribonucleoproteins and RNA) that are essential for gene splicing. Within the SMN locus there are two genes: SMN1, which generates a full-length, fully functional form of SMN, and SMN2, which makes a truncated, partially functional SMN. Making matters more complex, some individuals have more than two copies of SMN2. As a result, loss of both copies of SMN1 may cause very severe SMA in some individuals (in whom only one copy of SMN2 compensates for loss of SMN1), while others with multiple copies of SMN2 have milder disease. Thus, the amount of SMN1 and SMN2 protein determines the severity of disease. Although affected siblings demonstrate very similar clinical patterns of disease, the same gene error gives rise to very different phenotypes in different families, so that additional modifying posttranscriptional or nongenetic attributes must be playing a role. Less often, autosomal dominant and X-linked patterns of inheritance have been found, usually in adults. Clinical Manifestations of Early Onset Classic WerdnigHoffmann Type (SMA I) The most frequent form of these spinal muscular atrophies, the severe infantile type, is a common disease, occurring once in every 20,000 live births. After cystic fibrosis, it is the most frequent cause of death from a recessively inherited disease. Characteristically the infant, usually born normally, is noted from birth to be unnaturally weak and limp (“floppy”). Some mothers report that fetal movement in utero had been less than expected or lacking altogether. In severe cases, arthrogryposis at the ankles and wrists or dislocation of the hips is noted at birth (arthrogryposis and its differential diagnosis is discussed in Chap. 52 on the congenital neuromuscular disorders). The muscle weakness in these children is generalized from the beginning, and death comes early, usually within
Neonatal hypotonia (floppy baby), weakness of sucking and swallowing, may have arthrogryposis, unable to sit Proximal weakness, fasciculation, fine hand tremor, unable to stand
PROGNOSIS
Few survive 1 year
Variable; death from respiratory complications Slowly progressive, variable outcome
the first year. Other infants seem to develop normally for several months before the weakness becomes apparent. In these, the trunk, pelvic, and shoulder-girdle muscles are at first disproportionately affected, while the fingers and hands, toes and feet, and cranial muscles retain mobility. Hypotonia accompanies the weakness, and because passive displacement of articulated parts in testing muscle tone is easier to judge than power of contraction at this early age, it may be singled out as the dominant clinical characteristic. As a rule, the tendon reflexes are unobtainable. Volume of muscle is diminished but is difficult to evaluate in the infant because of the coverings of adipose tissue. Fasciculations are seldom visible except sometimes in the tongue. Perception of tactile and painful stimuli is undiminished, and emotional and social development measures up to age. As the months pass, the weakness and hypotonia progress gradually and spread to all of the skeletal muscles except the ocular ones. Intercostal paralysis with a degree of collapse of the chest is the rule. Respiratory movements become paradoxical (abdominal protrusion with chest retraction). The cry becomes feeble, and sucking and swallowing are less efficient. Such infants are unable to sit unless propped, and they cannot hold up their heads without support and cannot roll over or support their weight when placed on their feet. Their posture is characteristic: arms abducted and flexed at the elbow, legs in the “frog position” with external rotation and abduction at hips and flexion at hips and knees. If the effects of gravity are removed, all muscles continue to contract; i.e., there is paresis, not paralysis. Until late in the illness, these children appear bright-eyed, alert, and responsive. Infants in whom the disease becomes apparent only after several months of life have a less-rapid decline than those affected in utero or at birth. Some of the former become able to sit and creep and even to walk with support; those with later onset may survive for several years and even into adolescence or early adult life, as already mentioned. Laboratory data of confirmatory value are few. Muscle enzymes in the serum are usually normal or rarely ele-
CHAPTER 39
vated. The EMG, if performed at a late enough stage of development, displays fibrillations, proving the denervative basis of the weakness. Motor unit potentials are diminished in number and, in the more slowly evolving cases, some are larger than normal (giant or polyphasic potentials reflecting reinnervation). Motor nerve conduction velocities are normal or fall in the low-normal range (these are normally slower in infants than in adults). Electrophysiologic studies performed in the first few months of life may give ambiguous results. Pathologic Findings Muscle biopsy after 1 month of age reveals a typical picture of group atrophy; shortly after birth this change is difficult to discern. Aside from denervative atrophy, the essential abnormalities are in the anterior horn cells in the spinal cord and the motor nuclei in the lower brainstem. Nerve cells are greatly reduced in number, and many of the remaining ones are in varying stages of degeneration; a few are chromatolytic and contain cytoplasmic inclusions. It is not unusual to see figures of neuronophagia. There is replacement gliosis and secondary degeneration in roots and nerves. Other systems of neurons, including the corticospinal and corticobulbar systems are entirely unaffected. Differential Diagnosis The major problem in diagnosis is to distinguish Werdnig-Hoffmann disease from an array of other diseases that cause hypotonia and delayed motor development in the neonate and infant. The list of disorders that imitates spinal muscular atrophy constitutes a large part of the differential diagnosis of the socalled floppy infant. The congenital myopathies (as described in Chap. 52), the glycogenoses, neonatal myasthenia gravis, Prader-Willi syndrome, and disorders of fatty acid metabolism frequently present in this way. The preservation of tendon reflexes and relative lack of progression of muscle weakness distinguish the latter disorders. Because of the gravity of the diagnosis, muscle biopsy should be performed if there is any suspicion of spinal muscular atrophy. If studied properly, the biopsy usually yields the correct diagnosis. Clinical disorders more or less similar to the spinal muscular atrophies may be identified occasionally in certain hereditary metabolic diseases. For example, Johnson and coworkers have described a patient who began experiencing weakness of the legs, cramping, and fasciculations during adolescence in what proved to be a variant of hexosaminidase A (GM2) deficiency, and biopsy of rectal mucosa showed nerve cells with the typical membranous cytoplasmic bodies of Tay-Sachs disease. Others have reported similar cases. A progressive motor neuron or motor nerve disorder has also been observed in glycogen storage disease affecting anterior horn cells. Motor nerve fibers also suffer damage in metachromatic and globoid body leukoencephalopathies. Certain forms of muscular dystrophy, notably myotonic dystrophy, which is about twice as frequent as WerdnigHoffmann disease, may become manifest in the neonatal period and interfere with sucking and motor development (Chap. 52). As a rule, the weakness is not as severe or diffuse as that in Werdnig-Hoffmann disease. The mother, but not the child, may display myotonia, either elicitable clinically or, if more subtle, with EMG recording. Also, a
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number of polyneuropathies may cause a serious degree of weakness in early childhood. Unfortunately, in respect to the latter, adequate sensory testing is not possible because of the patient’s age, but the CSF protein is often elevated. Again, diagnosis is greatly facilitated by nervemuscle biopsy and measurement of nerve conduction velocities. These velocities are reduced but must be interpreted with caution because of incomplete development of axons and of myelination in the first months of life. The needle EMG examination shows subtle signs of denervation that cannot be easily distinguished from the finding in the spinal muscular atrophies. Examination of parents and siblings may disclose a clinically inapparent neuropathy. Polymyositis of childhood may also simulate both muscular dystrophy and motor neuron disease. Mental retardation with a flaccid rather than spastic weakness of the limbs is another major category of disease that must be distinguished. Also, certain of the polioencephalopathies and leukodystrophies may weaken muscles and abolish tendon reflexes, but usually there is evidence of cerebral involvement. The same may be said of the Down syndrome, cretinism, Prader-Willi syndrome, and achondrodysplasia. Finally, very sick children with celiac disease, cystic fibrosis, and other chronic diseases may be hypotonic to the point of simulating neuromuscular disease. Usually speech is not delayed and tendon reflexes are preserved in these purely medical states, and strength returns as the medical problem is corrected. There remains, after the assiduous study of the “floppy infant,” a group of cases of hypotonia and motor underdevelopment that cannot be classified. The term amyotonia congenita (Oppenheim) was once applied to this entire group but is now obsolete. Walto proposed the term benign congenital hypotonia to designate patients who manifest limp and flabby limbs in infancy and a delay in sitting up and walking but who improve gradually, some completely and others incompletely. It is likely that among this group there are examples of congenital myopathy that await differentiation by application of modern histochemical, ultrastructural, and genetic techniques. Chronic Childhood and Juvenile Proximal Spinal Muscular Atrophy (Wohlfart-Kugelberg-Welander Syndrome) This is a somewhat different form of heredofamilial spinal muscular atrophy, which, as the name indicates, involves the proximal muscles of the limbs predominantly and is only slowly progressive. It was first separated from other forms of motor system disease and from muscular dystrophy by Wohlfart and by Kugelberg and Welander in the mid1950s. In about one-third of the cases the onset is before 2 years of age, and in half, between 3 and 18 years. Males predominate, especially among patients with juvenile and adult onset. The usual form of transmission is by an autosomal recessive pattern; most cases result from mutations in the SMN gene. Families with dominant and sex-linked inheritance have also been described. The disease begins insidiously, with weakness and atrophy of the pelvic girdle and proximal leg muscles, followed by involvement of the shoulder girdle and upper arm muscles. Unlike the sporadic form of spinal muscular atrophy, the Wohlfart-Kugelberg-Welander variety (also listed in other books and monographs as Kugelberg-
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Welander disease) is bilaterally symmetrical from the beginning, and fasciculations are observed in only half the cases. Ultimately the distal limb muscles are involved and tendon reflexes are lost. Bulbar musculature and corticospinal tracts are spared, although Babinski signs and an associated ophthalmoplegia (presumably neural) have been reported in rare instances. The presence of fasciculations and the EMG and muscle biopsy findings—all of which show the characteristic abnormalities of neural atrophy—permit distinction from muscular dystrophy. Cases that have been examined postmortem have shown loss and degeneration of the anterior horn cells. The disease progresses very slowly, and some patients survive to old age without serious disability. In general, the earlier the onset, the less favorable the prognosis; however, even the most severely affected patients retain the ability to walk for at least 10 years after the onset. Admittedly, it is difficult to make a sharp distinction between these cases of Wohlfart-Kugelberg-Welander disease and certain milder instances of Werdnig-Hoffmann disease with onset in late infancy and early childhood and prolonged survival (Byers and Banker).
Kennedy Syndrome (X-Linked Bulbospinal Muscular Atrophy) An unusual pattern of distal muscular atrophy with prominent bulbar signs and, less often, ocular palsies was described by Kennedy and coworkers. The onset has varied from childhood to adult age, but symptoms typically begin in the third decade. Most cases have shown an X-linked pattern of inheritance and a lesser number, an autosomal dominant pattern. The proximal shoulder and hip musculature are involved first by weakness and atrophy, followed in about half of patients by dysarthria and dysphagia. Muscle cramps or twitching often precede weakness. Facial fasciculations and mild weakness are characteristic and may be striking. The tendon reflexes become depressed and may be absent; a mild sensory neuropathy is almost universal. In the family described by Kaeser, in which 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, i.e., scapuloperoneal; it may therefore be mistaken for muscular dystrophy. Two-thirds of patients have gynecomastia, a feature that may first identify affected men in a kindred; oligospermia and diabetes are additional associations. The CK level is elevated, sometimes tenfold, and physiologic studies reveal denervation and reinnervation as well as indications of a mild sensory neuropathy. As in Huntington disease and certain of the spinocerebellar atrophies, the genetic defect is a CAG expansion, in this case in the gene that codes for the androgen receptor on the short arm of the X chromosome (La Spada et al; see Table 39-7). Indeed, the first reported polyglutamine disease was Kennedy syndrome. Lengthened sequences correlate with an earlier age of onset (anticipation, as in Huntington disease) but have no relation to the severity of disease. Androgen receptors have been found on motor neurons of the spinal cord; the subpopulation of motor neurons that is susceptible to both Kennedy syndrome and ALS express abundant surface androgen receptors, but it is not clear whether
this finding has direct pathogenic significance. Neuronal inclusions have recently been described, composed of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. A family with the bulbospinal phenotype but without the CAG expansion has also been reported (Paradiso et al). Other features, such as optic atrophy and sensory neuronopathy, were present in some members of this kindred but are not features of typical cases. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide sequence. Prenatal diagnosis and identification of female carriers are also possible by this method.
Progressive Bulbar Palsy of Childhood (Fazio-Londe Syndrome) Fazio in 1892, and Londe in 1893, described the development of a progressive bulbar palsy in children, adolescents, and young adults. There is progressive paralysis of the facial, lingual, pharyngeal, laryngeal, and sometimes ocular muscles. The illness usually presents with stridor and respiratory symptoms, followed by facial diplegia, dysarthria, dysphagia, and dysphonia. These features become increasingly pronounced until the time of death some years later. In a few patients there is a late development of corticospinal signs, and sometimes ocular palsies. Occasionally, jaw and oculomotor paresis appears, and in one case, there was progressive deafness. The disease is rare, only several dozen well-described examples had been recorded in the medical literature by 1992 (McShane et al). Inheritance may be autosomal dominant, as in Fazio’s original case, and rarely X-linked, but it is more likely to be autosomal recessive. Pathologic examination has shown a loss of motor neurons in the hypoglossal, ambiguus, facial, and trigeminal motor nuclei. In a few cases, the nerve cells in the ocular motor nuclei also were diminished. This disease, the two times we have encountered it, had to be differentiated from myasthenia gravis, a pontomedullary glioma, and brainstem multiple sclerosis.
Hereditary Forms of Spastic Paraplegia Hereditary Spastic Paraplegia (Strümpell-Lorrain Disease) This disease was described by Seeligmuller in 1874 and later by Strümpell in Germany and Lorrain in France; it has now been identified in nearly every part of the world. The pattern of inheritance is usually autosomal dominant, less often recessive (one family has shown X-linked inheritance), and the onset may be at any age from childhood to the senium. Harding (1993) divided the disease into two groups, the more common one beginning before age 35 with a very protracted course and the other with a late onset (40 to 60 years). The latter type often shows sensory loss, urinary symptoms, and action tremor. The clinical picture is that of a gradual development of spastic weakness of the legs with increasing difficulty in walking. The tendon reflexes are hyperactive and the plantar reflexes extensor. In the pure form of the disease, sensory and other nervous functions are entirely intact. If the onset is in childhood, as many cases are, the foot arches become exag-
CHAPTER 39
Degenerative Diseases of the Nervous System
gerated, the feet are shortened, and there is a tightening (pseudocontracture) of calf muscles, forcing the child or adolescent to “toe-walk.” This is a common orthopedic problem and may require surgical correction. In children, the legs appear to be underdeveloped, and in both children and adults they may become quite thin. Sometimes the knees are slightly flexed; at other times the legs are fully extended or hyperextended (genu recurvatum) and adducted. Weakness is variable and difficult to estimate. Sphincteric function is usually retained. Subtle sensory loss in the feet has been reported. The arms are variably involved. In some patients, the arms appear to be spared even though the tendon reflexes are lively. In others, the hands are stiff, movements are clumsy, and speech is mildly dysarthric. Conjoined findings such as nystagmus, ocular palsies, optic atrophy, pigmentary macular degeneration, ataxia (both cerebellar and sensory), sensorimotor polyneuropathy, ichthyosis, patchy skin pigmentation, epilepsy, and dementia have all been described in isolated families (see further on). The few available pathologic studies have shown that, in addition to degeneration of the corticospinal tracts throughout the spinal cord, there is thinning of the columns of Goll, mainly in the lumbosacral regions, and of the spinocerebellar tracts, even when no sensory abnormalities had been detected during life. These were the pathologic findings described by Strümpell in his original (1880) report of 2 brothers with spastic paraplegia; one of them, in addition, had a cerebellar syndrome, but again there were no sensory abnormalities. A reduction in the number of Betz and anterior horn cells has also been reported. Genetic Aspects of Hereditary Spastic Paraplegia Several genetic mutations have given rise to this disease. As of this writing, there are more than 24 hereditary spastic paraplegia (HSP) loci (11 dominant, 9 recessive, 4 Xlinked) and at least 12 HSP genes (Table 39-8). The common uncomplicated autosomal dominant form of disease has been linked to sites on chromosomes 2p, 8q, 14q, and 15q, the 2p variety being most frequent; the recessive vari-
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ety has been linked to 8p, 15q (the most frequent recessive type), and 16q. Some of the recessive types have the unusual feature of thinning of the corpus callosum. The common variety associated with a mutation on chromosome 2p results in great variability of clinical presentation within and among families (see Nielsen et al). Rare Xlinked types are associated with mutations on the long arm of the chromosome, one of which is an allelic variant of the Pelizaeus-Merzbacher gene. In a few of these kindreds the genes responsible for disease have been identified. For example, the most common form is caused by mutations in the SPAST gene (40 percent of dominantly inherited cases), which encodes a membrane protein, spastin. A high frequency of partial deletions of the gene has been found. The other mutation causing dominantly inherited HSP (10 percent of cases) is in SPG3A that codes for the protein atlastin. Rarely, the causative mutation is in the metalloprotease gene paraplegin on the mitochondrial membrane; it is proposed that this defect impairs oxidative phosphorylation. Fink has reviewed the genetics of the hereditary spastic paraplegias. Differential Diagnosis In the diagnosis of this disorder, one should consider an indolent spinal cord or foramen magnum tumor, cervical spondylosis, a spinal from of multiple sclerosis (this was the clinical diagnosis in Strümpell’s original cases), Chiari malformation, compression of the cord by a variety of congenital bony malformations at the craniocervical junction, and a number of chronic myelitides, among them, lupus erythematosus, sarcoidosis, AIDS, adrenomyeloneuropathy, primary lateral sclerosis (described earlier in this chapter), and tropical spastic paraparesis (caused by HTLV-1).
Variants of Familial Spastic Paraplegia The literature contains a large number of descriptions of familial spastic paraplegia combined with other neurologic abnormalities. Some of the syndromes had devel-
Table 39-8 GENETIC DEFECTS ASSOCIATED WITH HEREDITARY SPASTIC PARAPLEGIA (HSP) GENETICS
NOTATION
CHROMOSOME
GENE
AGE OF ONSET
AD AD AD AD AD AD
3A 4 6 10 13 17
14q11 2p22 15q11 12q13 2q24 11q13
Atlastin Spastin NIPA1 KIF5A Heat shock protein Seipin (BSCL2)
Childhood 20s Teens Childhood Adult Variable
AR
7
16q24
Paraplegin
Adult
AR
Spartin
AR
21
15q22
Maspardin
Late teens
XR
1
Xq28
Infancy
XR
2
Xq22
L1 cell adhesion molecule Proteolipid protein
Infancy
CLINICAL AND MISCELLANEOUS FEATURES
Guanylate binding protein 40–50% of HSP; binds to microtubules Golgi membrane protein Kinesin heavy chain−motor protein Located in mitochondrial matrix Silver syndrome: HSP with wasting of hands, feet Mitochondrial chaperone and metalloprotease; optic atrophy, neuropathy, myopathy HSP with wasting of distal limbs, hands, feet Endosomal protein involved in protein transport Mental retardation, hydrocephalus, callosal hypoplasia, spasticity Cognitive impairment, spasticity, ataxia
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oped early in life in conjunction with moderate degrees of mental retardation. In these, the rest of the neurologic picture appeared many years after birth and was progressive. Some idea of the number of these “hereditary paraplegiaplus” syndromes and the diverse combinations in which they may present is conveyed in the review by Gout and colleagues. Again, it is hardly possible to describe each of these symptoms in any degree of detail. The list below includes the best-known entities. But if the term hereditary spastic paraplegia is to have any neurologic significance, it should be applied only to the pure form of the progressive syndrome. The more common “atypical” or “syndromic” cases—with amyotrophy, cerebellar ataxia, tremors, dystonia, athetosis, optic atrophy, retinal degeneration, amentia, and dementia—should be put in separate categories and their identity retained for nosologic purposes until such time as additional biochemical and genetic data related to pathogenesis are forthcoming. The gene mutations found in some of the variant types have been summarized by Fink, but—as with all types of uncomplicated hereditary spastic paraplegia—the mechanisms of neuronal loss are not known. To be separated from these cases are all the congenital nonprogressive types of spastic diplegia and athetosis. The following list includes the best-known entities: 1. Hereditary spastic paraplegia with spinocerebellar and ocular symptoms (Ferguson-Critchley syndrome). This syndrome is characterized by a disorder of gaze, optic atrophy, cerebellar ataxia, and spastic paraparesis. Most impressive are the manifestations of spinocerebellar ataxia beginning during the fourth and fifth decades of life, accompanied by weakness of the legs, alterations of mood, pathologic crying and laughing, dysarthria and diplopia, dysesthesias of limbs, and poor bladder control. The tendon reflexes are lively, with bilateral Babinski signs. Sensation is diminished distally in the limbs. The whole picture resembles a chronic progressive form of multiple sclerosis. In other cases, running through several generations of a family, the extrapyramidal features were more striking; such cases overlap with the following syndromes. 2. Hereditary spastic paraplegia with extrapyramidal signs. Action and static tremors, parkinsonian rigidity, dystonic tongue movement, and athetosis of the limbs have all been conjoined with spastic paraplegia. Gilman and Romanul have reviewed the literature on this subject. In the authors’ experience, the picture of parkinsonism with spastic weakness and other corticospinal signs has been the most frequent combination. 3. Hereditary spastic paraplegia with optic atrophy. This is known as Behr syndrome or optic atrophy-ataxia syndrome, since cerebellar signs are usually conjoined. Some patients also have athetosis. The syndrome is transmitted as an autosomal recessive trait, with onset in infancy and slow progression. 4. Hereditary spastic paraplegia with macular degeneration (Kjellin syndrome). Spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration constitutes the syndrome described in 1959 by Kjellin. Although the mental retardation is stationary, the
spastic weakness and retinal changes are of late onset and progressive. When ophthalmoplegia is added, it is called the Barnard-Scholz syndrome. 5. Hereditary spastic paraplegia with mental retardation or dementia. Many of the children with progressive spastic paraplegia either have been mentally retarded since early life or have appeared to regress mentally as other neurologic symptoms developed. Examples of this syndrome and its variants are too numerous to be considered here but are contained in the review by Gilman and Romanul. The autosomal recessive syndrome of Sjögren-Larsson, with the onset in infancy of spastic weakness of the legs in association with mental retardation, stands somewhat apart because of the associated ichthyosis. 6. Hereditary spastic paraplegia with polyneuropathy. We have observed several patients in whom a sensorimotor polyneuropathy was combined with unmistakable signs of corticospinal disease. The age of onset was in childhood or adolescence, and the disability progressed to the point where the patient was chairbound by early adult life. In two of the cases, a sural nerve biopsy revealed a typical hypertrophic polyneuropathy; in a third case there was only a depletion of large myelinated fibers. The syndrome resembles the myeloneuropathy of adrenoleukodystrophy. 7. Spastic paraparesis with distal muscle wasting (Broyer syndrome). This disorder is transmitted as an autosomal recessive trait. Onset is in childhood with amyotrophy of the hands, followed by spasticity and contractures of the lower limbs. Cerebellar signs (mild), athetosis, and deafness may be added.
SYNDROME OF PROGRESSIVE BLINDNESS (See Chap. 13) There are two main classes of progressive blindness in children, adolescents, and adults: progressive optic neuropathy and retinal degenerations (retinitis pigmentosa and tapetoretinal macular degeneration). Of course, there are many congenital anomalies and retinal diseases beginning in infancy that result in blindness and microphthalmia. Some of those of neurologic interest were described briefly in connection with the hereditary spastic paraplegias and in Chap. 13.
Hereditary Optic Atrophy of Leber Although familial amaurosis was known in the early eighteenth century, it was Leber, in 1871, who gave the definitive description of this disease and traced it through many genealogies. The family studies of Nikoskelainen and coworkers indicate that all daughters of carrier mothers become carriers themselves, a type of transmission that is determined by inheritance of defective mitochondrial DNA from the mother (Wallace et al). Common to all cases is the presence of a pathogenic mitochondrial DNA abnormality (Riordan-Eva et al), but the defect may occur at one of several sites as discussed in Chap. 37. Thus, Leber optic
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atrophy has been added to the growing list of mitochondrial diseases. In most patients, the visual loss begins between 18 and 25 years of age, but the range of age of onset is much broader. Usually the visual loss has an insidious onset and a subacute evolution, but it may evolve rapidly, suggesting a retrobulbar neuritis; moreover, in these latter instances, aching in the eye or brow may accompany the visual loss, just as it does in the demyelinative variety. Subjective visual phenomena are reported by some. Usually both eyes are affected simultaneously, although in some one eye is affected first, followed by the other after an interval of several weeks or months. In practically all cases, the second eye is affected within a year of the first. In the unimpaired eye, abnormalities of visual evoked potentials may antedate impairment of visual acuity (Carroll and Mastaglia). Once started, the visual loss progresses over a period of weeks to months. Characteristically, central vision is lost before peripheral, and there is a stage at which bilateral central scotomata are readily demonstrated. Early on, perception of blue-yellow is deficient, while that of red and green is relatively preserved. In the more advanced stages, however, the patients are totally color-blind. Constriction of the fields may be added later. At first there may be swelling and hyperemia of the discs, but soon they become atrophic. Peripapillary vasculopathy, consisting of tortuosity and arteriovenous shunting, is the primary structural change; this has been present also in asymptomatic offspring of carrier females. As visual symptoms develop, fluorescein angiography shows shunting in the abnormal vascular bed, with reduced filling of the capillaries of the papillomacular bundle. Although patients are left with dense central scotomata, it is of some importance that the visual impairment is seldom complete; in some patients, relative stabilization of visual function occurs. In a few, there may be a surprising improvement. Examination of the optic nerve lesion shows the central parts of the nerves to be degenerated from papillae to the lateral geniculate bodies, i.e., the papillomacular bundles are particularly affected. Presumably axis cylinders and myelin degenerate together, as would be expected from the loss of nerve cells in the superficial layer of the retina. Both astrocytic glial and endoneurial fibroblastic connective tissue are increased. Tests for the three main mitochondrial mutations that give rise to the disorder are now available. Congenital optic atrophy (of which recessive and dominant forms are known), retrobulbar neuritis, and nutritional optic neuropathy are the main considerations in differential diagnosis.
Retinitis Pigmentosa (See Chap. 13) This remarkable retinal abiotrophy, known to Helmholtz in 1851, soon after he invented the ophthalmoscope, usually begins in childhood and adolescence. Unlike the optic atrophy of Leber, which affects only the third neuron of the visual neuronal chain, retinitis pigmentosa affects all the retinal layers, both the neuroepithelium and pigment epithelium (see Fig. 13-1). The incidence of this disorder is
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2 or 3 times greater in males than in females. Inheritance is more often autosomal recessive than dominant; in the former, consanguinity plays an important part, increasing the likelihood of the disease by approximately 20 times. Sex-linked types are also known. It is estimated that 100,000 Americans are afflicted with this disease. The first symptom is usually an impairment of twilight vision (nyctalopia). Under dim light, the visual fields tend to constrict; but slowly, as the disease progresses, there is permanent visual impairment in all degrees of illumination. The perimacular zones tend to be the first and most severely involved, giving rise to partial or complete ring scotomata. Peripheral loss sets in later. Usually both eyes are affected simultaneously, but cases are on record where one eye was affected first and more severely. Ophthalmoscopic examination shows the characteristic triad of pigmentary deposits that assume the configuration of bone corpuscles, attenuated vessels, and pallor of the optic discs. The pigment is caused by clumping of epithelial cells that migrate from the pigment layer to the superficial parts of the retina as the rod cells degenerate. The pigmentary change spares only the fovea, so that eventually the world is perceived by the patient as though he were looking through narrow tubes. The many and diverse syndromes to which retinitis pigmentosa may be linked include: oligophrenia, obesity, syndactyly, and hypogonadism (Bardet-Biedl syndrome); hypogenitalism, obesity, and mental deficiency (LaurenceMoon syndrome); Friedreich and other types of spinocerebellar and cerebellar ataxia; spastic paraplegia and quadriplegia with Laurence-Moon syndrome; neurogenic amyotrophy, myopia, and color-blindness; polyneuropathy and deafness (Refsum disease); deaf mutism; Cockayne syndrome and Bassen-Kornzweig disease; and several mitochondrial diseases, particularly progressive external ophthalmoplegia and Kearns-Sayre syndromes.
Stargardt Disease This is a bilaterally symmetrical, slowly progressive macular degeneration, differentiated from retinitis pigmentosa by Stargardt in 1909. In essence, it is a hereditary (usually autosomal recessive) tapetoretinal degeneration or dystrophy (the latter term being preferred by Waardenburg), with onset between 6 and 20 years of age, rarely later, and leading to a loss of central vision. The macular region becomes gray or yellow-brown with pigmentary spots, and the visual fields show central scotomata. Later the periphery of the retina may become dystrophic. The lesion is well visualized by fluorescein angiography, which discloses a virtually pathognomonic “dark choroid” pattern. Activity in the electroretinogram is diminished or abolished. Both dominantly inherited Stargardt disease and the closely related cone-rod dystrophy have been linked to a defect on chromosome 6p in some families and 13q in others; the less common recessive variety has been mapped to 1p. In the former type, several gene errors code for a transporter protein (termed ABCR) of the photoreceptor. This disease, with its selective loss of cone function, is in a sense the inverse of retinitis pigmentosa. According to Cohan and associates, it may be associated with epilepsy,
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Refsum syndrome, Kearns-Sayre syndrome, Bassen-Kornzweig syndrome, or Sjögren-Larsson syndrome, or with spinocerebellar and other forms of cerebellar degeneration and familial paraplegia.
SYNDROME OF PROGRESSIVE DEAFNESS (See Chap. 15) There is an impressive group of hereditary, progressive cochleovestibular atrophies that are linked to degenerations of the nervous system. These are the subject of an informative review by Konigsmark and are summarized below. Such neurotologic syndromes must be set alongside a group of 5 diseases that affect the auditory and vestibular nerves exclusively: dominant progressive nerve deafness; dominant low-frequency hearing loss; dominant midfrequency hearing loss; sex-linked, early onset neural deafness; and hereditary episodic vertigo and hearing loss. The last of these is of special interest to neurologists because both balance and hearing are affected. It should be pointed out that in 70 percent of cases of hereditary deafness, there are no other somatic or neurologic abnormalities. To date, three separate autosomal mutations have been identified that are associated with this pure “nonsyndromic” type of hereditary deafness, the most common of which is in the connexin gene, as discussed in Chap. 15. In one such family from Costa Rica, the gene codes for a protein that regulates the polymerization of actin, the major cytoskeletal component of the hair cells of the inner ear (see review by Pennisi). A number of mitochondrial disorders have been associated with deafness alone as well as with a number of the better-characterized mitochondrial syndromes (see Chap. 37). The age of onset of hearing loss in the pure forms has been variable, extending well into adulthood.
Hereditary Hearing Loss with Retinal Diseases Konigsmark has separated this overall category into three subgroups: patients with typical retinitis pigmentosa, those with Leber optic atrophy, and those with other retinal changes. With respect to retinitis pigmentosa, four syndromes are recognized in which retinitis pigmentosa appears in combination: with congenital hearing loss (Usher syndrome); with polyneuropathy (Refsum syndrome); with hypogonadism and obesity (Alstrom syndrome); and with dwarfism, mental retardation, premature senility, and photosensitive dermatitis (Cockayne syndrome). Hereditary hearing loss with optic atrophy forms the core of four special syndromes: dominant optic atrophy, ataxia, muscle wasting, and progressive hearing loss (Sylvester disease); recessive optic atrophy, polyneuropathy, and neural hearing loss (Rosenberg-Chutorian syndrome); optic atrophy, hearing loss, and juvenile diabetes mellitus (Tunbridge-Paley syndrome); and opticocochleodentate degeneration with optic atrophy, hearing loss, quadriparesis, and mental retardation (Nyssen-van Bogaert syndrome). Hearing loss has also been observed with other retinal changes, two of which are Norrie disease, with retinal mal-
formation, hearing loss, and mental retardation (oculoacousticocerebral degeneration), and Small disease, with recessive hearing loss, mental retardation, narrowing of retinal vessels, and muscle atrophy. In the former, the infant is born blind, with a white vascularized retinal mass behind a clear lens; later the lens and cornea become opaque. The eyes are small, and the iris is atrophied. In the latter, the optic fundi show tortuosity of vessels, telangiectases, and retinal detachment. The nature of the progressive generalized muscular weakness has not been ascertained.
Hereditary Hearing Loss with Diseases of the Nervous System There are several conditions in which hereditary deafness accompanies degenerative disease of the peripheral or central nervous system. Those associated with mitochondrial encephalopathies have already been mentioned. The other main types with autosomal inheritance include the following: 1. Hereditary hearing loss with epilepsy. The seizure disorder is mainly one of myoclonus. In one dominantly inherited form, photomyoclonus is associated with mental deterioration, hearing loss, and nephropathy (Hermann disease). In May-White disease, also inherited as an autosomal dominant trait, myoclonus and ataxia accompany hearing loss. Congenital deafness and mild chronic epilepsy of recessive type have also been observed (Latham-Monro disease). 2. Hereditary hearing loss and ataxia. Here Konigsmark was able to delineate 5 syndromes, the first two of which show a dominant pattern of heredity, the last three a recessive pattern: piebaldism, ataxia, and neural hearing loss (Telfer-Sugar-Jaeger syndrome); hearing loss, hyperuricemia, and ataxia (Rosenberg-Bergstrom syndrome); ataxia and progressive hearing loss (Lichtenstein-Knorr syndrome); ataxia, hypogonadism, mental deficiency, and hearing loss (Richards-Rundle syndrome); ataxia, mental retardation, hearing loss, and pigmentary changes in the skin (Jeune-Tommasi syndrome). 3. Hereditary hearing loss and other neurologic syndromes (see Table 15-1). These include dominantly inherited sensory radicular neuropathy (Denny-Brown); progressive polyneuropathy, kyphoscoliosis, skin atrophy, eye defects (myopia, cataracts, atypical retinitis pigmentosa), bone cysts, and osteoporosis (FlynnAird syndrome); chronic polyneuropathy and nephritis (Lemieux-Neemeh syndrome); congenital pain asymbolia and auditory imperception (Osuntokun syndrome); and bulbopontine paralysis (facial weakness, dysarthria, dysphagia, and atrophy of the tongue with fasciculations) with progressive neural hearing loss. The onset of the last syndrome occurs at 10 to 35 years of age; the pattern of inheritance is autosomal recessive. The disease progresses to death. It resembles the progressive hereditary bulbar paralysis of Fazio-Londe except for the progressive deafness and loss of vestibular responses. Regrettably, in most of these syndromes, there are no data regarding labyrinthine function.
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The details of these many syndromes are contained in Konigsmark’s review. The main syndromes are listed in Table 15-1 and are summarized here so as to increase
awareness of the large number of hereditary-degenerative neurologic diseases for which the clue is provided by the detection of impaired hearing and labyrinthine functions.
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40 The Acquired Metabolic Disorders of the Nervous System
An important segment of neurologic medicine, and one that is seen with great frequency in general hospitals, are disorders in which a global disturbance of cerebral function (encephalopathy) results from failure of some other organ system—heart and circulation, lungs and respiration, kidneys, liver, pancreas, and the endocrine glands. Unlike the diseases considered in Chap. 37, in which a genetic abnormality affects the metabolic functions of many organs and tissues including the brain, the cerebral disorders discussed in this chapter are strictly secondary to derangements of the visceral organs themselves. They stand at the interface of internal medicine and neurology. Relationships of this type, between an acquired disease of some thoracic, abdominal, or endocrine organ and the brain, have rather interesting implications. In the first place, recognition of the neurologic syndrome may be a guide to the diagnosis of the systemic disease; indeed, the neurologic symptoms may be more informative and significant than the symptoms referable to the organ primarily involved. Moreover, these encephalopathies are often reversible if the systemic dysfunction is brought under control. Neurologists must therefore have an understanding of the underlying medical disorder, for this may provide the means of controlling the neurologic part of the disease. In other words, the therapy for what appears to be a nervous system disease lies squarely in the field of internal medicine—a clear reason why every neurologist should be well trained in internal medicine. Of more theoretical importance, the investigation of the acquired metabolic diseases provides new insights into the chemistry and pathology of the brain. Each visceral disease affects the brain in a somewhat different way and, because the pathogenic mechanism is not completely understood in any of them, the study of these metabolic diseases promises rich rewards to the scientist. Table 40-1 lists the main acquired metabolic diseases of the nervous system according to their most common modes of clinical expression. Not included are the diseases caused by nutritional deficiencies and those caused by exogenous drugs and toxins, which can be considered metabolic in the broad sense; these are discussed in the following chapters.
DISEASES PRESENTING AS CONFUSION, STUPOR, OR COMA (METABOLIC ENCEPHALOPATHY) The syndrome of impaired consciousness, its general features, the terms used to describe it, and the mechanisms involved are discussed in Chap. 17. There it was pointed out that metabolic disturbances are frequent causes of impaired consciousness and that their presence must always be considered when there are no focal signs of cerebral disease and both the imaging studies and the cerebrospinal fluid (CSF) are normal. Intoxication with alcohol and other drugs figures prominently in the differential diagnosis. The main features of the reversible metabolic encephalopathies are confusion, typified by disorientation and inattentiveness and accompanied in certain special instances by asterixis, tremor, and myoclonus, usually without signs of focal cerebral disease. This state may progress in stages to one of stupor and coma. Slowing of the background rhythms in the electroencephalogram (EEG) reflects the severity of the metabolic disturbance. With few exceptions, usually pertaining to cerebral edema and certain cases of hepatic encephalopathy, imaging studies are normal. Seizures may or may not occur, most being associated with particular underlying causes of encephalopathy such as hyponatremia and hyperosmolarity. Laboratory examinations are highly informative in the investigation of the acquired metabolic diseases. In patients with symptoms suggestive of a metabolic encephalopathy the following determinations are usually made: serum Na, K, Cl, Ca, Mg, glucose, HCO3, renal function tests (blood urea nitrogen [BUN] and creatinine), liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, NH3), thyroid function tests (T4 and thyroid-stimulating hormone [TSH]), and osmolality and, in certain cases, oxygen saturation and blood gas determinations. These are almost always supplemented by toxicology tests and measurement of the serum concentrations of relevant medications as discussed in the next chapter. Serum osmolality can be measured directly or calculated from the values of Na, glucose, and BUN (in mg/dL), using the following formula: OSM = 2 × Na + glucose/18 + BUN/3.
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Table 40-1 CLASSIFICATION OF THE ACQUIRED METABOLIC DISORDERS OF THE NERVOUS SYSTEM IN ADULTS I. Metabolic diseases presenting as a syndrome of confusion, stupor, or coma A. Ischemia-hypoxia B. Hypercapnia C. Hypoglycemia D. Hyperglycemia E. Hepatic failure F. Reye syndrome G. Azotemia H. Disturbances of sodium, water balance, and osmolality I. Hypercalcemia J. Other metabolic encephalopathies: acidosis due to diabetes mellitus or renal failure (see also inherited forms of acidosis, in Chap. 37); Addison disease K. Hashimoto disease steroid-responsive encephalopathy L. Myxedema II. Metabolic diseases presenting as a progressive extrapyramidal syndrome A. Acquired hepatocerebral degeneration B. Hyperbilirubinemia and kernicterus C. Hypoparathyroidism III. Metabolic diseases presenting as cerebellar ataxia A. Hypothyroidism B. Hyperthermia C. Celiac sprue disease IV. Metabolic diseases causing psychosis, or dementia A. Cushing disease and steroid encephalopathy B. Hyperthyroid psychosis and hypothyroidism (myxedema) C. Hyperparathyroidism D. Pancreatic encephalopathy
Normal serum osmolality is 270 to 290 mOsm/L. When there is a discrepancy of greater than 10 mOsm/L between the calculated and the directly measured values (osmolal, or osmolar gap), it can be assumed that additional circulating ions are present. Most often they are derived from an exogenous toxin or drug such as mannitol, but renal failure, ketonemia, or an increase of serum lactate may result in the accumulation of small molecules that contribute to the measured serum osmolality. A point to be remembered is that the brain may be damaged, even to an irreparable degree, by a disturbance of blood chemistry (e.g., hypoglycemia, hypoxia) that has vanished by the time the patient is examined.
Ischemic-Hypoxic Encephalopathy Here the basic disorder is a lack of oxygen and of blood flow to the brain, the result of failure of the heart and circulation or of the lungs and respiration. Often, both are responsible and one cannot say which predominates; hence the dually ambiguous allusions in medical records to “ischemic-hypoxic” encephalopathy. This combined encephalopathy in various forms and degrees of severity is one of the most frequent and disastrous cerebral disorders encountered in every general hospital. Reduced to the simplest formulation, a deficient supply of oxygen to the brain is either the result of a failure of cerebral perfusion (ischemia) or of a reduced amount of circulating arterial oxygen, of diminished oxygen saturation, or of insuf-
ficiency of hemoglobin (hypoxia). Although they are often combined, the neurologic effects of ischemia and hypoxia are subtly different. The medical conditions that most often lead to it are as follows: 1. A global reduction in cerebral blood flow (myocardial infarction, ventricular arrhythmia, aortic dissection, external or internal blood loss, and septic or traumatic shock) 2. Hypoxia from suffocation (drowning, strangulation, or aspiration of vomitus, food, or blood; from compression of the trachea by a mass or hemorrhage; tracheal obstruction by a foreign body, or a general anesthesia accident) 3. As a subset of the above, diseases that paralyze the respiratory muscles (Guillain-Barré syndrome, amyotrophic lateral sclerosis, myasthenia, and, in the past, poliomyelitis) or damages the medulla and leads to failure of breathing 4. The special case of carbon monoxide (CO) poisoning (nonischemic hypoxia) The product of blood oxygen content and the cardiac output is the ultimate determinant of the adequacy of oxygen supply to the organs. When blood flow is stable, the most important element in the delivery of oxygen is the oxygen content of the blood. This is the product of hemoglobin concentration and the percentage of oxygen saturation of the hemoglobin molecule. At normal temperature and pH, hemoglobin is 90 percent saturated at an oxygen partial pressure of 60 mm Hg and still 75 percent saturated at 40 mm Hg; i.e., as is well known, the oxygen saturation curve is not linear.
Physiology of Ischemic and Hypoxic Damage A number of physiologic mechanisms of a homeostatic nature protect the brain under conditions of both ischemia and hypoxia. Through a mechanism termed autoregulation, there is a compensatory dilatation of resistance vessels in response to a reduction in cerebral perfusion, which maintains blood flow at a constant rate, as noted in Chap. 34. When the cerebral blood pressure falls below 60 to 70 mm Hg, an additional compensation in the form of increased oxygen extraction allows normal energy metabolism to continue. In total cerebral ischemia, the tissue is depleted of its sources of energy in about 5 min, although longer periods are tolerated under conditions of hypothermia. Also, energy failure because of hypoxia is counteracted by an autoregulatory increase in cerebral blood flow; at a PO2 of 25 mm Hg, the increase in blood flow is approximately 400 percent. A similar increase in flow occurs with a decrease in hemoglobin to 20 percent of normal. In most clinical situations in which the brain is deprived of adequate oxygen, as already commented, there is a combination of ischemia and hypoxia, with one or the other predominating. The pathologic effects of ischemic brain injury from systemic hypotension differ from those caused by pure anoxia. Under conditions of transient ischemia, one pattern of damage takes the form of incomplete infarctions in the border zones between major cerebral arteries (Chap. 34). With predominant anoxia, neurons in portions of the hippocampus
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and the deep folia of the cerebellum are particularly vulnerable. More severe degrees of either ischemia or hypoxia, or the combination, lead to selective damage to certain layers of cortical neurons, and if more profound, to generalized damage of all the cerebral cortex, deep nuclei, and cerebellum. The nuclear structures of the brainstem and spinal cord are relatively resistant to anoxia and hypotension and stop functioning only after the cortex has been badly damaged. The cellular pathophysiology of neuronal damage under conditions of ischemia is discussed in Chap. 34. One mechanism of injury is an arrest of the aerobic metabolic processes necessary to sustain the Krebs (tricarboxylic acid) cycle and the electron transport system. Neurons, if completely deprived of their source of energy, are unable to maintain their integrity and undergo necrosis. However, neuronal cell death occurs through more than one mechanism. The most acute forms of cell death are characterized by massive swelling and necrosis of neuronal and nonneuronal cells (cytotoxic edema). Short of immediate ischemic necrosis, a series of internally programmed cellular events may also propel the cell toward death in a delayed fashion, a process for which the term apoptosis has been borrowed from embryology. There is experimental evidence that certain excitatory neurotransmitters, particularly glutamate, contribute to the rapid destruction of neurons under conditions of anoxia and ischemia (Choi and Rothman); the pertinence of these effects to clinical situations is uncertain. Ultimately, this process may be affected by massive calcium influx through a number of different membrane channels, which activates various kinases that participate in the process of gradual cellular destruction. Free radical generation appears to play a role in membrane dissolution as a result of these processes. As shown in experimental models, one of the reasons for the irreversibility of ischemic lesions may be swelling of the endothelium and blockage of circulation into the ischemic cerebral tissues, the “no-reflow” phenomenon described by Ames and colleagues. There is also a poorly understood phenomenon of delayed neurologic deterioration after anoxia; this may be a result of the blockage or exhaustion of some enzymatic process during the period when brain metabolism is restored.
Clinical Features of Anoxic Encephalopathy Mild degrees of hypoxia without loss of consciousness induce only inattentiveness, poor judgment, and incoordination; in our experience, there have been no lasting clinical effects in such cases, although Hornbein and colleagues found a slight decline in visual and verbal long-term memory and mild aphasic errors in Himalayan mountaineers who had earlier ascended to altitudes of 18,000 to 29,000 ft. These observations make the point that profound anoxia may be well tolerated if arrived at gradually. For example, we have seen several patients with advanced pulmonary disease who were fully awake when their arterial oxygen pressure was in the range of 30 mm Hg. This level, if it occurs abruptly, causes coma. An important derivative observation is that degrees of hypoxia that at no time abolish consciousness rarely, if ever, cause permanent damage to the nervous system. In the circumstances of severe global ischemia with prolonged loss of consciousness, the clinical effects can be quite
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variable. Following cardiac arrest, for example, consciousness is lost within seconds but recovery can be complete if breathing, oxygenation, and cardiac action are restored within 3 to 5 min. Beyond 5 min there is usually permanent injury. Clinically, however, it is often difficult to judge the precise degree and duration of ischemia, because slight heart action or an imperceptible blood pressure may have served to maintain the circulation to some extent. Hence some individuals have made an excellent recovery after cerebral ischemia that apparently lasted 8 to 10 min or longer. Subnormal body temperatures, as might occur when the body is immersed in ice-cold water, greatly prolong the tolerable period of hypoxia. This has led to the successful application of moderate cooling after cardiac arrest as a technique to limit cerebral damage (see further on). Generally speaking, anoxic patients who demonstrate intact brainstem function as indicated by normal pupillary light responses and oculocephalic and oculovestibular reflex eye movements have a more favorable outlook for recovery of consciousness and perhaps of all mental faculties. Conversely, the absence of these brainstem reflexes even after circulation and oxygenation have been restored, particularly pupils that fail to react to light, implies a grave outlook as elaborated further on. If the damage is almost total, coma persists, decerebrate postures may be present spontaneously or in response to painful stimuli, and bilateral Babinski signs can be evoked. In the first 24 to 48 h, death may terminate this state in a setting of rising temperature, deepening coma, and circulatory collapse, or the syndrome of brain death intervenes, as discussed below. Most patients who have suffered severe but lesser degrees of hypoxia will have stabilized their breathing and cardiac activity by the time they are first examined; yet they are comatose, with the eyes slightly divergent and motionless but with reactive pupils, the limbs inert and flaccid or intensely rigid and the tendon reflexes diminished. Within a few minutes after cardiac action and breathing have been restored, generalized convulsions and isolated or grouped myoclonic twitches may occur. Either of these phenomena are poor prognostic signs. With severe degrees of injury, the cerebral and cerebellar cortices and parts of the thalami are partly or completely destroyed but the brainstem-spinal structures survive. Tragically, the individual may survive for an indefinite period in a state that is variously referred to as cortical death, irreversible coma, or persistent vegetative state (see discussion of these subjects in Chap. 17). Some patients remain mute, unresponsive, and unaware of their environment for weeks, months, or years. Long survival is usually attended by some degree of improvement but the patient appears to know nothing of his present situation and to have lost all past memories, cognitive function, and capacity for meaningful social interaction and independent existence (a minimally conscious state, actually a severe dementia; see Chap. 17). One has only to observe such patients and their families to appreciate the gravity of the problem, the family’s anguish, and the tremendous expense of medical care. The only person who does not appear to suffer is the patient.
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With lesser degrees of anoxic-ischemic injury, the patient improves after a period of coma lasting hours or less. Some of these patients quickly pass through this acute posthypoxic phase and proceed to make a full recovery; others are left with varying degrees of permanent disability. The findings on imaging studies vary. The most common early change in cases of severe injury is a loss of the distinction between the cerebral gray and white matter (Fig. 40-1); patients with this finding are invariably comatose and few awaken with a good neurologic outcome. With less severe and predominantly hypotensive-ischemic events such as cardiac arrest, watershed infarctions become evident in the border zones between the anterior, middle, and posterior cerebral arteries (Fig. 40-2). The clinical syndromes associated with watershed infarction are discussed below. Yet another pattern of brain destruction, seen at times also in CO poisoning, consists of striatal damage that is evident more by imaging than by clinical features (Fig. 40-3).
Brain Death Syndrome (See Chap. 17 for a full discussion) This represents the most severe degree of hypoxia, usually caused by circulatory arrest; it is manifest by a state of complete unawareness and unresponsiveness with abolition of all brainstem reflexes. Natural respiration cannot be sustained; only cardiac action and blood pressure are maintained. No electrical activity is seen in the EEG (it is isoelectric). At autopsy one finds that most, if not all, the gray matter of cerebral, cerebellar, and brainstem structures—and in some instances, even the upper cervical spinal cord—has been severely damaged.
Figure 40-1. CT scan without contrast infusion after 1 day cardiac arrest demonstrating the loss of distinction between gray and white matter throughout the cerebral hemispheres. The patient remained comatose and became vegetative.
Figure 40-2. Watershed infarction between the middle and posterior cerebral arteries after brief cardiac arrest. The patient had Balint syndrome.
One must always exercise caution in concluding that a patient has this form of irreversible brain damage, because anesthesia, intoxication with certain drugs, and hypothermia may also cause deep coma and an isoelectric EEG but
Figure 40-3. T2-weighted MRI of striatal damage after anoxia from hanging. The pallidum is spared, in contrast to carbon monoxide poisoning (see Fig. 40-5).
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permit recovery. Therefore it is often advisable to repeat the clinical and laboratory tests after an interval of a day or so, during which time the results of toxic screening also become available. The authors’ experience corroborates the general notion that the vital functions of patients with the brain death syndrome usually cannot be sustained for more than several days; in other words, the problem settles itself. In exceptional cases, however, the provision of adequate fluid, vasopressors, and respiratory support allows preservation of the somatic organism in a comatose state for longer periods.
Posthypoxic Neurologic Syndromes The permanent neurologic sequelae or posthypoxic syndromes observed most frequently are as follows: 1. Persistent coma or stupor, described above 2. With lesser degrees of cerebral injury, dementia with or without extrapyramidal signs 3. Extrapyramidal (parkinsonian) syndrome with cognitive impairment (discussed in relation to CO poisoning) 4. Choreoathetosis 5. Cerebellar ataxia 6. Intention or action myoclonus (Lance-Adams syndrome) 7. Korsakoff amnesic state If hypoperfusion dominates, the patient may also display the manifestations of watershed infarctions that are situated between the end territories of the major cerebral vessels. The main syndromes that become evident soon after the patient awakens are: 1. Visual agnosias including Balint syndrome and cortical blindness (see Chap. 22), representing infarctions of the watershed between the middle and posterior cerebral arteries (see Fig. 40-2) 2. Proximal arm and shoulder weakness, sometimes accompanied by hip weakness (referred to as a “man-in-thebarrel” syndrome), reflecting infarction in the territory between the middle and anterior cerebral arteries. These patients are able to walk, but their arms dangle and their hips may be weak.
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confusion, irritability, and occasionally agitation or mania. Most patients survive this second episode, but some are left with serious mental and motor disturbances (Choi; Plum et al). In still other cases, there appears to be progression of the initial neurologic syndrome with additional weakness, shuffling gait, diffuse rigidity and spasticity, sphincteric incontinence, coma, and death after 1 to 2 weeks. Exceptionally, there is yet another syndrome in which an episode of hypoxia is followed by slow deterioration, which progresses for weeks to months until the patient is mute, rigid, and helpless. In such cases, the basal ganglia are affected more than the cerebral cortex and white matter as in the case studied by our colleagues Dooling and Richardson. Instances have followed cardiac arrest, drowning, asphyxiation, and carbon monoxide poisoning. The imaging features of the white matter disorder are quite striking (Fig. 40-4). A mitochondrial disorder has been suggested as the underlying mechanism.
Prognosis of Hypoxic-Ischemic Brain Injury (See also “Prognosis in Coma” in Chap. 17) Several validated models have been developed to predict the outcome of anoxic-ischemic coma. All of them incorporate simple clinical features involving loss of motor, verbal, and pupillary functions in various combinations. The most often cited study of the prognostic aspects of coma following cardiac arrest is the one by Levy and colleagues of 210 patients, which provided the following guidelines: 13 percent of patients attained a state of independent function within 1 year; at the time of the initial evaluation, approxi-
The two watershed syndromes may rarely coexist. The interested reader may consult the appropriate chapter in the text on neurologic intensive care by Ropper and colleagues for further details. There are also watershed areas in the spinal cord (Chap. 44). Seizures may or may not be a problem, and they are often resistant to treatment. Well-formed motor convulsions are infrequent. Myoclonus is more common and may be intermixed with fragmentary convulsions. Myoclonus is a grave sign in most cases but it generally recedes after several hours or a few days. These movements are also difficult to suppress, as noted further on.
Delayed Postanoxic Encephalopathy and Leukoencephalopathy This is a relatively uncommon and unexplained phenomenon. Initial improvement, which appears to be complete, is followed after a variable period of time (1 to 4 weeks in most instances) by a relapse, characterized by apathy,
Figure 40-4. MRI fluid-attenuated inversion recovery (FLAIR) sequence of delayed postanoxic leukoencephalopathy in a patient who had recovered after drowning and deteriorated 2 weeks later.
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mately 25 percent of patients had absent pupillary light reflexes, none of whom regained independent function; by contrast, the presence on admission of reactive pupils, eye movements, and any motor response, a configuration displayed in approximately 10 percent, was associated with a better prognosis in almost 50 percent of cases. The absence of neurologic function in any of these spheres at 1 day after cardiac arrest, unsurprisingly, was associated with an even poorer outcome. Similarly, Booth and colleagues analyzed previously published studies and determined that 5 clinical signs at 1 day after cardiac arrest predicted a poor neurologic outcome or death: (1) absent corneal responses, (2) absent pupillary reactivity, (3) no withdrawal to pain, and (4) the absence of any motor response. The use of somatosensory evoked potentials in the prognostication of coma is discussed in Chaps. 2 and 17. Most workers in the field of coma studies have been unable to establish signs that confidently predict a good outcome. The role of somatosensory evoked potentials in prognosis of coma has been addressed in Chap. 17. In any such case, concurrent intoxication must, of course, be excluded. The question of what to do with patients in such states of protracted coma is a societal as much as a medical problem. The neurologist can be expected to state the level and degree of brain damage, its cause, and the prognosis based on his own and published experience. One prudently avoids heroic, lifesaving therapeutic measures once the nature of this state has been determined with certainty.
Treatment of Hypoxic-Ischemic Encephalopathy Treatment is directed initially to the prevention of further hypoxic injury. A clear airway is secured, cardiopulmonary resuscitation is initiated, and every second counts in their prompt utilization. Oxygen may be of value during the first hours but is probably of little use after the blood becomes well oxygenated. Once cardiac and pulmonary function are restored, there is experimental and clinical evidence that reducing cerebral metabolic requirements by inducing hypothermia has a slight beneficial effect on outcome and may prevent the delayed worsening referred to above. The use of high-dose barbiturates has not met with the same success. Attention is drawn to the randomized trial conducted by Bernard and colleagues of mild hypothermia applied to unconscious patients immediately after cardiac arrest. They reduced the core temperature to 33°C (91°F) within 2 h and demonstrated a doubling of the rate of survival and good outcome. These effects were evaluated by coarse measures of neurologic function, but the effect of hypothermia was corroborated in a smaller trial reported by Zeiner and colleagues. Vasodilator drugs, glutamate blockers, and calcium channel blockers are of no proven benefit despite their theoretical appeal and some experimental successes. Corticosteroids ostensibly help to allay brain (possibly cellular) swelling, but, again, their therapeutic benefit has not been evident in clinical trials. Seizures should be controlled by the methods indicated in Chap. 16. If convulsions are severe, continuous, and
unresponsive to the usual medications, continuous infusion of a drug such as midazolam or propofol, and eventually the suppression of convulsions with neuromuscular blocking agents may be required. Often the seizures cease after a few hours and are replaced by polymyoclonus. For the latter, clonazepam, 8 to 12 mg daily in divided doses may be useful but the commonly used antiepileptic drugs have little effect. A state of spontaneous and stimulus-sensitive myoclonus as well as persistent limb posturing usually presages a poor outcome. The striking disorder of delayed movement-induced myoclonus and ataxic tremor that appear after the patient awakens from an anoxic episode (Lance-Adams myoclonus) is a special issue, which is discussed in Chap. 6. Its treatment usually requires the use of multiple medications. Fever is treated with antipyretics or a cooling blanket combined with neuromuscular paralyzing agents.
Carbon Monoxide Poisoning Strictly speaking, CO is an exogenous toxin, but it is considered here because it produces a characteristic cerebral injury and is frequently associated with delayed neurologic deterioration. The extreme affinity of CO for hemoglobin (more than 200 times that of oxygen) drastically reduces the oxygen content of blood and subjects the brain to prolonged hypoxia and acidosis. Cardiac toxicity and hypotension generally follow. Whether CO also has a direct toxic action on neuronal components is not settled. The effects on the brain for the most part simulate those caused by cardiac arrest. Neurologists are likely to encounter instances of CO poisoning in burn units and in patients who have attempted suicide or have been exposed accidentally to a faulty furnace or to car exhaust in a closed garage. Early symptoms include headache, nausea, dyspnea, confusion, dizziness, and clumsiness. These occur when the carboxyhemoglobin level reaches 20 to 30 percent of total hemoglobin. Exposure to relatively low levels of CO from faulty furnaces and gasoline engines should be suspected as the cause of recurrent headaches and confusion that clear upon hospitalization or other change of venue. A cherry-red color of the skin may appear, but is actually an infrequent finding; cyanosis is more common. At slightly higher levels of carboxyhemoglobin, blindness, visual field defects, and papilledema develop, and levels of 50 to 60 percent are associated with coma, decerebrate or decorticate posturing, seizures in a few patients, and generalized slowing of the EEG rhythms. The initial CT scanning is normal or shows mild cerebral edema; later scans may show a characteristic lesion in the pallidum, as described below. Only if there has been associated hypotension does one see the same types of vascular border-zone infarctions that appear after cardiac arrest. Delayed neurologic deterioration 1 to 3 weeks (sometimes much longer) after CO exposure occurs more frequently than with other forms of cerebral hypoxia. In Choi’s survey, this feature was observed in 3 percent of 2,360 cases of CO poisoning and in 12 percent of those ill enough to be admitted to a hospital. Extrapyramidal features (parkinsonian gait and bradykinesia) predominated.
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Three-quarters of such patients were said to recover within a year. Discrete lesions centered in the globus pallidus bilaterally and sometimes the inner portion of the putamina are characteristic of CO poisoning that had produced coma (Fig. 40-5), but similar focal destruction may be seen after drowning, strangulation, and other forms of anoxia. The common feature among the delayed-relapse patients is a prolonged period of pure anoxia (before the occurrence of ischemia). Basal ganglia lesions may be quite prominent on CT scans even when delayed neurologic sequelae do not occur but they are invariably present between 1 and 4 weeks in patients who develop the delayed extrapyramidal syndrome. In less-severely affected patients we have seen such lesions resolve entirely on CT and MRI and there is no resultant movement disorder. The initial treatment for carbon monoxide exposure is with inspired oxygen. Because the half-life of CO (normally 5 hours) is greatly reduced by the administration of hyperbaric oxygen at 2 or 3 atmospheres, this additional treatment is recommended when the carboxyhemoglobin concentration is greater than 40 percent or in the presence of coma or seizures (Myers et al). According to a trial conducted by Weaver and colleagues, this treatment reduces the incidence of cognitive sequelae from 46 to 25 percent. They administered three hyperbaric sessions in the first 24 h after exposure to CO.
High-Altitude (Mountain) Sickness Acute mountain sickness is another special form of cerebral hypoxia. It occurs when a sea-level inhabitant abruptly ascends to a high altitude. Headache, anorexia, nausea
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and vomiting, weakness, and insomnia appear at altitudes above 8,000 ft; on reaching higher altitudes, there may be ataxia, tremor, drowsiness, mild confusion, and hallucinations. At 16,000 ft, according to Griggs and Sutton, 50 percent of individuals develop asymptomatic retinal hemorrhages, and it has been suggested that such hemorrhages also occur in the cerebral white matter. Extreme altitude sickness may result in fatal cerebral edema. The overexpression of vascular endothelial growth factor (VEGF), a protein originally noted for its effects on vascular permeability, has been implicated as the cause of cerebral edema in the experiments of Schoch and colleagues. With more prolonged exposure at these altitudes or with further ascent, affected individuals suffer mental impairment that may progress to coma. Hypoxemia at high altitudes is intensified during sleep, as ventilation normally diminishes and also by pulmonary edema, another manifestation of mountain sickness. Reference was made earlier to the observation of Hornbein and colleagues of a mild, but possibly lasting, memory impairment even in acclimated mountaineers who had been exposed to extremely high altitudes for several days. Hackett and Roach have reviewed the treatments for altitude illness. Chronic mountain sickness, also called Monge disease (after the physician who described the condition in Andean Indians of Peru), is observed in long-term inhabitants of high-altitude mountainous regions. Pulmonary hypertension, cor pulmonale, and secondary polycythemia are the main features. There is usually hypercarbia as well, with the expected degree of mild mental dullness, slowness, fatigue, nocturnal headache, and, sometimes, papilledema (see below). Thomas and colleagues have called attention to a syndrome of burning hands and feet in Peruvians at high altitude, apparently a maladaptive response to chronic hypoxia. Sedatives, alcohol, and a slightly elevated PCO2 in the blood all reduce tolerance to high altitude. Dexamethasone and acetazolamide prevent and counteract mountain sickness to some extent. The most effective preventive measure is acclimatization by a 2- to 4-day stay at intermediate altitudes.
Hypercapnic Pulmonary Disease
Figure 40-5. Unenhanced CT scan of the brain of a 30-year-old woman who attempted suicide by carbon monoxide inhalation. The only neurologic residua were a mild defect in retentive memory and areas of decreased attenuation in the pallidum bilaterally (arrows).
Chronic obstructive pulmonary disease such as emphysema, fibrosing lung disease, neuromuscular weakness, and, in some instances, inadequacy of the medullary respiratory centers each may lead to persistent respiratory acidosis, with elevated of PCO2 and reduced in arterial PO2. The complete clinical syndrome of chronic hypercapnia described by Austen, Carmichael, and Adams comprises headache, papilledema, mental dullness, drowsiness, confusion, stupor and coma, and asterixis. More typically, only some of these features are found. Some patients have a fast-frequency tremor. The headache tends to be generalized, frontal, or occipital and can be quite intense, persistent, steady, and aching in type; nocturnal occurrence is a feature of some cases. The papilledema is bilateral but may be slightly greater in one eye than in the other, and hemorrhages may encircle the choked disc (a later finding). The tendon reflexes are lively and plantar reflexes may be extensor.
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Intermittent drowsiness, inattentiveness, reduction of psychomotor activity, inability to perceive all the items in a sequence of events, and forgetfulness constitute the more subtle manifestations of this syndrome and may prompt the family to seek medical help. Such symptoms may last only a few minutes or hours, and one cannot count on their presence at the time of a particular examination. In fully developed cases, the CSF is under increased pressure; PCO2 may exceed 75 mm Hg, and the O2 saturation of arterial blood ranges from 85 percent to as low as 40 percent. The EEG shows slow activity in the delta or theta range, which is sometimes bilaterally synchronous. The mechanism of the cerebral disorder is from a direct CO2 narcosis, but the biochemical details are not known. Normally the CSF is slightly acidotic in comparison to the blood and the PCO2 of the CSF is about 10 mm Hg higher than that of the blood. With respiratory acidosis, the pH of the CSF falls (into the range of 7.15 to 7.25) and cerebral blood flow increases as a result of cerebral vasodilatation. However, the brain rapidly adapts to respiratory acidosis through the generation and secretion of bicarbonate by the choroid plexuses. Brain water content also increases, mainly in the white matter. In animal models of hypercarbia, blood and brain NH3 is elevated, which may explain the similarity of the syndrome to that of hyperammonemic liver failure (Herrera and Kazemi). The most effective therapeutic measures are positivepressure ventilation, using oxygen if there is also hypoxia. Oxygen supplementation is, of course, used cautiously in these patients in order to avoid suppressing respiratory drive; marginally compensated patients treated with excessive oxygen have lapsed into coma. Treatment of heart failure, phlebotomy to reduce the viscosity of the blood, and antibiotics to suppress pulmonary infection may be necessary. Often these measures result in a surprising degree of improvement, which may be maintained for months or years. Unlike pure hypoxic encephalopathy, prolonged coma because of hypercapnia is relatively rare and in our experience has not led to irreversible brain damage. Papilledema, myoclonus, and especially asterixis are important diagnostic features. If aminophylline is administered for the treatment of the underlying pulmonary airway disease, there may be a tendency for it to produce seizures. The syndrome is apt to be mistaken for a brain tumor, confusional psychosis of other type, or a disease causing chorea or myoclonus.
of blood glucose is a factor in both the depression of consciousness and residual dementia. The normal brain has a glucose reserve of 1 to 2 g (30 mmol/100 g of tissue), mostly in the form of glycogen. Because glucose is utilized by the brain at a rate of 60 to 80 mg/min, the glucose reserve will sustain cerebral activity for about 30 min once blood glucose is no longer available. Glucose is transported from the blood to the brain by an active carrier system. Glucose entering the brain either undergoes glycolysis or is stored as glycogen. During normal oxygenation (aerobic metabolism), glucose is converted to pyruvate, which enters the Krebs cycle; with anaerobic metabolism, lactate is formed. The oxidation of 1 mol of glucose requires 6 mol of O2. Of the glucose taken up by the brain, 85 to 90 percent is oxidized; the remainder is used in the formation of proteins and other substances, notably neurotransmitters and particularly gamma-aminobutyric acid (GABA). When blood glucose falls, the central nervous system (CNS) can utilize nonglucose substrates to a variable extent for its metabolic needs, especially keto acids and intermediates of glucose metabolism, such as lactate, pyruvate, fructose, and other hexoses. In the neonatal brain, which has a higher glycogen reserve, keto acids provide a considerable proportion of cerebral energy requirements; this also happens after prolonged starvation. However, in the face of severe and sustained hypoglycemia, these alternative substrates are inadequate to preserve the structural integrity of neurons, and eventually adenosine triphosphate (ATP) is depleted as well. If convulsions occur, they usually do so during a period of confusion; the convulsions have been attributed to an altered integrity of neuronal membranes and to elevated NH3 and depressed GABA and lactate levels (Wilkinson and Prockop). The brain is the only organ besides the heart that suffers severe functional and structural impairment under conditions of severe hypoglycemia. Beyond what is described above, the pathophysiology of the cerebral disorder has not been fully elucidated. It is known that hypoglycemia reduces O2 uptake and increases cerebral blood flow. As with anoxia and ischemia, there is experimental evidence that the excitatory amino acid glutamate is involved in the process. The levels of several brain phospholipid fractions decrease when animals are given large doses of insulin. However, the suggestion that hypoglycemia results in a rapid depletion and inadequate production of high-energy phosphate compounds has not been corroborated; some other glucose-dependent biochemical processes must be implicated.
Hypoglycemic Encephalopathy This condition is now relatively infrequent but is an important cause of confusion, convulsions, stupor, and coma; as such, it merits separate consideration as a metabolic disorder of the brain. The essential biochemical abnormality is a critical lowering of the blood glucose. At a level of about 30 mg/dL, the cerebral disorder takes the form of a confusional state and one or more seizures may occur; at a level of 10 mg/dL, there is coma that may result in irreparable injury to the brain if not corrected immediately by the administration of glucose. As with most other metabolic encephalopathies, the rate of decline
Etiology The most common causes of hypoglycemic encephalopathy are: (1) accidental or deliberate overdose of insulin or an oral diabetic agent; (2) islet cell insulin-secreting tumor of the pancreas; (3) depletion of liver glycogen, which occasionally follows a prolonged alcoholic binge, starvation, or any form of severe liver failure; (4) glycogen storage disease of infancy; and (5) an idiopathic hypoglycemia in the neonatal period and infancy; (6) subacute and chronic hypoglycemia from islet cell hypertrophy and islet cell tumors of the pancreas, carcinoma of the stomach, fibrous mesothelioma, carcinoma
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of the cecum, and hepatoma. Supposedly an insulin-like substance is elaborated by these nonpancreatic tumors. In the past, hypoglycemic encephalopathy was a not infrequent complication of “insulin shock” therapy for schizophrenia. In functional hyperinsulinism, as occurs in anorexia nervosa and dietary faddism, the hypoglycemia is rarely of sufficient severity or duration to damage the CNS.
Clinical Features The initial symptoms appear when the blood glucose has descended to about 30 mg/dL, nervousness, hunger, flushed facies, sweating, headache, palpitation, trembling, and anxiety. These gradually give way to confusion and drowsiness or occasionally, to excitement, overactivity, and bizarre or combative behavior. Many of the early symptoms relate to adrenal and sympathetic overactivity and some of the manifestations may be muted in diabetic patients with neuropathy. In the next stage, forced sucking, grasping, motor restlessness, muscular spasms, and decerebrate rigidity occur, in that sequence. Myoclonic twitching and convulsions develop in some patients. Rarely, there are focal cerebral deficits, the pathogenesis of which remains unexplained; according to Malouf and Brust, hemiplegia, corrected by intravenous glucose, was observed in 3 of 125 patients who presented with symptomatic hypoglycemia. Blood glucose levels of approximately 10 mg/dL are associated with deep coma, dilatation of pupils, pale skin, shallow respiration, slow pulse and hypotonia, what had in the past been termed the “medullary phase” of hypoglycemia. If glucose is administered before this level has been attained, the patient can be restored to normal, retracing the aforementioned steps in reverse order. However, once this state is reached, and particularly if it persists for more than a few minutes, recovery is delayed for a period of days or weeks and may be incomplete as noted below. The EEG is altered as the blood glucose falls, but the correlations are imprecise. There is diffuse slowing in the theta or delta range. During recovery, sharp waves may appear and coincide in some cases with seizures. The major clinical differences between hypoglycemic and hypoxic encephalopathy lie in the setting and the mode of evolution of the neurologic disorder. The effects of hypoglycemia usually unfold more slowly, over a period of 30 to 60 min, rather than in a few seconds or minutes. The recovery phase and sequelae of the two conditions are quite similar. A large dose of insulin, which produces intense hypoglycemia, even of relatively brief duration (30 to 60 min), is more dangerous than a series of less-severe hypoglycemic episodes from smaller doses of insulin, possibly because the former impairs or exhausts essential enzymes, a condition that cannot then be overcome by large quantities of intravenous glucose. Reflecting the benignity of repeated minor occurrences, the Epidemiology of Diabetes Interventions and Complications Study Research Group have demonstrated that recurrent hypoglycemic episodes in the course of treatment of diabetes over many years are very well tolerated and do not lead to cognitive decline. A severe and prolonged episode of hypoglycemia may result in permanent impairment of intellectual function as well as other neurologic residua, like those that follow
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severe anoxia. We also have observed states of protracted coma, as well as relatively pure Korsakoff amnesia. However, one should not be hasty in prognosis, for we have observed slow improvement to continue for 1 to 2 years. Recurrent hypoglycemia from an islet cell tumor may masquerade for some time as an episodic confusional psychosis or convulsive illness; diagnosis then awaits the demonstration of low blood glucose or hyperinsulinism in association with the neurologic symptoms. We saw a man in the emergency department whose main complaint was episodic inability to dial a touchtone telephone and a mild mental fogginess; he was found to have an insulinoma. Functional or reactive hypoglycemia is the most ambiguous of all syndromes related to low blood glucose. This condition is usually idiopathic but may precede the onset of diabetes mellitus. The rise of insulin in response to a carbohydrate meal is delayed but then causes an excessive fall in blood glucose, to 30 to 40 mg/dL. The symptoms are malaise, fatigue, nervousness, headache, tremor, and so on, which may be difficult to distinguish from anxious depression. Not surprisingly, the term functional hypoglycemia has been much abused, being applied indiscriminately to a variety of complaints that would now be called chronic fatigue syndrome or simply anxiety. In fact, a syndrome attributable to functional or reactive hypoglycemia is infrequent and its diagnosis requires the finding of an excessive reaction to insulin, low blood glucose during the symptomatic period, and a salutary response to oral glucose. In all forms of hypoglycemic encephalopathy, the major damage is to the cerebral cortex. Cortical nerve cells degenerate and are replaced by microglia cells and astrocytes. The distribution of lesions is similar, although probably not identical to that in hypoxic encephalopathy. The cerebellar cortex is less vulnerable to hypoglycemia than to hypoxia. Auer has described the ultrastructural changes in neurons resulting from experimental hypoglycemia; with increasing duration of hypoglycemia and EEG silence, there are mitochondrial changes, first in dendrites and then in nerve cell soma, followed by nuclear membrane disruption leading to cell death. Treatment of all forms of hypoglycemia obviously consists of correction of the hypoglycemia at the earliest possible moment. It is not known whether hypothermia or other measures will increase the safety period in hypoglycemia or alter the outcome. Seizures and twitching may not stop with anticonvulsants until the hypoglycemia is corrected.
Hyperglycemia Two syndromes have been defined, mainly in diabetics: (1) hyperglycemia with ketoacidosis and (2) hyperosmolar nonketotic hyperglycemia. In diabetic acidosis, the familiar picture is one of dehydration, fatigue, weakness, headache, abdominal pain, dryness of the mouth, stupor or coma, and Kussmaul type of breathing. Usually the condition has developed over a period of days in a patient known or proven to be diabetic. Often, the patient had failed to take a regular insulin dose. The blood glucose level is found to be more than 400 mg/dL, the pH of the blood less than 7.20, and the bicar-
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bonate less than 10 mEq/L. Ketone bodies and β-hydroxybutyric acid are elevated in the blood and urine, and there is marked glycosuria. The prompt administration of insulin and repletion of intravascular volume correct the clinical and chemical abnormalities over a period of hours. A small group of patients with diabetic ketoacidosis, such as those reported by Young and Bradley, develop deepening coma and cerebral edema as the elevated glucose is corrected. Mild cerebral edema is commonly observed in children during treatment with fluids and insulin (Krane et al). Prockop attributed this condition to an accumulation of fructose and sorbitol in the brain. The latter substance, a polyol that is formed during hyperglycemia, crosses membranes slowly, but once it does so, is said to cause a shift of water into the brain and an intracellular edema. However, according to Fishman (1974), the increased polyols in the brain in hyperglycemia are not present in sufficient concentration to be important osmotically; they may induce other metabolic effects related to the encephalopathy. These are matters of conjecture, as the increase of polyols has never been found. The brain edema in this condition is probably a result of reversal of the osmolality gradient from blood to brain, which occurs with rapid correction of hyperglycemia. The pathophysiology of the cerebral disorder in diabetic ketoacidosis is not fully understood. No consistent cellular pathology of the brain has been identified in the cases we have examined. Factors such as ketosis, tissue acidosis, hypotension, hyperosmolality, and hypoxia have not been identified. Attempts at therapy by the administration of urea, mannitol, salt-poor albumin, and dexamethasone are usually unsuccessful, though recoveries are reported. In hyperosmolar nonketotic hyperglycemia, the blood glucose is extremely high, more than 600 mg/dL, but ketoacidosis does not develop, or if it does develop, it is mild. Osmolality is usually in excess of 330 mOsm/L. There is also hemoconcentration and prerenal azotemia. Appreciation of the neurologic syndrome is generally credited to Wegierko, who published descriptions of it in 1956 and 1957. Most of the patients are elderly diabetics but some were not previously known to have been diabetic. An infection, enteritis, pancreatitis, dehydration, or a drug known to upset diabetic control (thiazides, corticosteroids, and phenytoin) leads to polyuria, fatigue, confusion, stupor, and coma. Often the syndrome arises in conjunction with the combined use of corticosteroids and phenytoin (which inhibits insulin release), for example, in elderly patients with brain tumors. The use of osmotic diuretics enhances the risk. Seizures and focal signs such as a hemiparesis, a hemisensory defect, or a homonymous visual field defect are more common than in any other metabolic encephalopathy and may erroneously suggest the possibility of a stroke. Fluids should be replaced cautiously, using isotonic saline and potassium. Correction of the markedly elevated blood glucose requires relatively small amounts of insulin, since these patients often do not have a high degree of insulin resistance.
Hepatic Stupor and Coma (Hepatic or Portal–Systemic Encephalopathy) Chronic hepatic insufficiency with portosystemic shunting of blood is punctuated by episodes of stupor, coma, and other
neurologic symptoms—a state referred to as hepatic stupor, coma, or encephalopathy. It was clearly delineated by Adams and Foley over 50 years ago. This state complicates all varieties of liver disease and is unrelated to jaundice or ascites. Any form of shunting, even without hepatic disease, such as surgical portal–systemic shunt (Eck fistula) is attended by the same clinical picture (see further on). There are also a number of hereditary hyperammonemic syndromes, usually first apparent in infancy or childhood (discussed extensively in Chap. 37) that lead to episodic coma with or without seizures. In all these states, it is common for an excess of protein derived from the diet or from gastrointestinal hemorrhage to induce or worsen the encephalopathy. Additional predisposing factors are hypoxia, hypokalemia, metabolic alkalosis, excessive diuresis, use of sedative hypnotic drugs, and constipation. Reye syndrome, now infrequent, is also associated with very high levels of ammonia in the blood and encephalopathy (see further on).
Clinical Features The clinical picture of acute, subacute, or chronic hepatic encephalopathy consists of a derangement of consciousness, presenting first as mental slowing and confusion, occasionally with hyperactivity, followed by progressive drowsiness, stupor, and coma. The confusional state is combined with a characteristic intermittency of sustained muscle contraction; this phenomenon, which was originally described in patients with hepatic stupor by Adams and Foley and called asterixis (from the Greek sterixis, a “fixed position”). It is now recognized as a sign of various metabolic encephalopathies but is most prominent in this disorder (see Chap. 6). It is conventionally demonstrated by having the patient hold his arms outstretched with the wrists extended, but the same tremor can be elicited by any sustained posture, including that of the protruded tongue. A variable, fluctuating rigidity of the trunk and limbs, grimacing, suck and grasp reflexes, exaggeration or asymmetry of tendon reflexes, Babinski signs, and focal or generalized seizures round out the clinical picture in a few patients. The EEG is a sensitive and reliable indicator of impending coma, becoming abnormal during the earliest phases of the disordered mental state. Foley, Watson, and Adams noted an EEG abnormality consisting of paroxysms of bilaterally synchronous slow or triphasic waves in the delta range, which at first predominate frontally and are interspersed with alpha activity and later, as the coma deepens, displace all normal activity (see Fig. 2-3H). A few patients show only random high-voltage asynchronous slow waves. This syndrome of hepatic encephalopathy is remarkably diverse in its course and evolution. It usually appears over a period of days to weeks and may terminate fatally; or, with appropriate treatment, the symptoms may regress and then fluctuate in severity for several weeks or months. Persistent hepatic coma of the latter type proves fatal in about half of patients (Levy et al). In many patients, the syndrome is relatively mild and does not evolve beyond the stage of mental dullness and confusion, with asterixis and EEG changes. In yet others, a subtle disorder of mood, personality, and intellect may be protracted over a period of many
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months or even years; this chronic but nevertheless reversible mental disturbance need not be associated with overt clinical signs of liver failure (jaundice and ascites) or other neurologic signs. Characteristically in these patients, an extensive portal–systemic collateral circulation can be demonstrated (hence the term portal–systemic encephalopathy) and an association established between the mental disturbance and an intolerance to dietary protein as well as raised blood ammonia levels (Summerskill et al). The diversion of blood from the portal system into the vena cava after ligation of the portal veins was first performed in dogs by Eck in 1877. Probably the first and certainly most striking example in man was the case of pure “Eck” fistula reported by McDermott and Adams, in which a portacaval shunt was created during the removal of a pancreatic tumor. The liver was normal. Episodic coma occurred thereafter whenever dietary protein increased. Consciousness was restored on a protein-free diet, and coma could be induced again by ammonium chloride. Postmortem examination 2 years later confirmed the normal liver and showed cerebral changes of hepatic encephalopathy, as described below. Finally, there is a group of patients (most of whom have experienced repeated attacks of hepatic coma) in whom an irreversible mild dementia and a disorder of posture and movement (grimacing, tremor, dysarthria, ataxia of gait, choreoathetosis) gradually appear. This condition of chronic acquired hepatocerebral degeneration must be distinguished from other dementing and extrapyramidal syndromes (see further on). A few cases of isolated spastic paraplegia (so-called hepatic myelopathy, or more correctly hepatic paraplegia) of unclear nature have also been described. Pant and colleagues demonstrated a dropout of motor neuron cells in the cerebral cortex. The concentrations of blood NH3, particularly if measured repeatedly in arterial blood samples, usually are well in excess of 200 mg/dL, and the severity of the neurologic and EEG disorders roughly parallels to the ammonia levels. With treatment, a fall in the NH3 levels precedes clinical improvement.
Neuropathologic Changes The striking finding by Adams and Foley in patients who died in a state of hepatic coma was a diffuse increase in the number and size of the protoplasmic astrocytes in the deep layers of the cerebral cortex, lenticular nuclei, thalamus, substantia nigra, cerebellar cortex, and red, dentate, and pontine nuclei, with little or no visible alteration in the nerve cells or other parenchymal elements. With periodic acid-Schiff (PAS) staining, the astrocytes were seen to contain glycogen inclusions. These abnormal glia cells are generally referred to as Alzheimer type II astrocytes, having been described originally in 1912 by von Hosslin and Alzheimer in a patient with Westphal-Strümpell pseudosclerosis (or Wilson disease). These astrocytes have been studied by electron microscopy in rats with surgically created portacaval shunts (Cavanagh; Norenberg); the cells show a number of striking abnormalities—swelling of their terminal processes, cytoplasmic vacuolation (distended sacs of rough endoplasmic reticulum), formation of folds in the basement membrane around capil-
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laries, and an increase in both the number of mitochondria and enzymes that catabolize ammonia. Also, some degeneration in myelinated nerve fibers in the neuropil and an increase in the cytoplasm of oligodendrocytes are seen. In chronic cases, neuronal loss in the deep layers of the cerebral and cerebellar cortex and lenticular nuclei is found, as well as vacuolization of tissue (possibly astrocytic) resembling the lesions of Wilson disease. The ubiquitous astrocytic alterations occur to some degree in all patients who die of progressive liver failure and the degree of glial abnormality corresponds generally to the intensity and duration of the neurologic disorder. Possibly, the astrocytic changes affect the synaptic activities of the neurons. The clinical and EEG features of hepatic encephalopathy as well as the astrocytic hyperplasia are more or less specific features of this metabolic disorder. Nevertheless, taken together in a setting of liver failure, they constitute a distinctive clinicopathologic entity.
Pathogenesis of Hepatic Encephalopathy The most plausible hypothesis relates hepatic coma to an abnormality of nitrogen metabolism, wherein ammonia, which is formed in the bowel by the action of urease-containing organisms on dietary protein, is carried to the liver in the portal circulation but fails to be converted into urea because of hepatocellular disease, portal–systemic shunting of blood, or both. As a result, excess NH3 reaches the systemic circulation, where it interferes with cerebral metabolism in a way that is not fully understood. The ammonia theory best explains the basic neuropathologic change. Because the brain is lacking in urea cycle enzymes, Norenberg has proposed that the hypertrophy of the astrocytic cytoplasm and proliferation of mitochondria and endoplasmic reticulum, as well as the increase in the astroglial glutamic dehydrogenase activity, all reflect heightened metabolic activity of these systems within astrocytes associated with ammonia detoxification. Removal of brain ammonia depends on the formation of glutamine, a reaction that is catalyzed by the ATP-dependent enzyme glutamine synthetase, which is compartmentalized to astrocytes. It has been shown in experimental animals that hyperammonemia leads to a depletion of ATP in midbrain reticular nuclei. Whether this is the primary cause of cerebral dysfunction has not been resolved. Numerous alternative theories have been suggested. One is that CNS function in cirrhotic patients is impaired by phenols or short-chain fatty acids derived from the diet or from bacterial metabolism of carbohydrate. Another theory holds that biogenic amines (e.g., octopamine), which arise in the gut and bypass the liver, act as false neurotransmitters, displacing norepinephrine and dopamine (Fischer and Baldessarini). Zieve has presented evidence that mercaptans (methanethiol, methionine), which are also generated in the gastrointestinal tract and removed by the liver, act in conjunction with NH3 to produce hepatic encephalopathy. This theory and others have been largely discounted; they are the subject of reviews by Butterworth and coworkers, by Zieve, by Rothstein and Herlong, and by Jones and Basile, to which the reader is referred for detailed information.
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Also in recent years, manganese has emerged as a potential neurotoxin in the pathogenesis of hepatic encephalopathy (Kreiger et al; Pomier-Layrargues et al). In patients with chronic liver disease and with spontaneous or surgically induced portal–systemic shunts, manganese accumulates in the serum and in the brain, more specifically in the pallidum. This accumulation is readily discernible as a pallidal signal hyperintensity on T1weighted MRI. Following liver transplantation, there is normalization of the MRI changes and of the associated extrapyramidal symptoms. The effects of manganese chelation on such patients have not been well studied and the mechanisms of accumulated manganese in the pathogenesis of hepatic encephalopathy are not known. It is clear, therefore, that any theory of hepatic encephalopathy must incorporate the cerebral effects of hyperammonemia. For some time, it has been known that hepatic encephalopathy is associated with increased activity of the inhibitory transmitter GABA in the cerebral cortex. It has also been observed that increased gabanergic neurotransmission may result from substances that inhibit the binding of endogenous benzodiazepine-like compounds to their receptors (Basile et al). Furthermore, these antagonists are found to have some clinical effect—transient arousal in patients with hepatic encephalopathy. The actions of benzodiazepines are mediated by these receptors; hence the designation GABA-benzodiazepine theory. The practicality of using benzodiazepine receptor antagonists, which are short-acting and reversible (e.g., flumazenil) in the treatment of hepatic encephalopathy, remains to be determined (see Mullen), but they offer an interesting diagnostic test. Until recently, the ammonia and the gabanergic-benzodiazepine hypotheses of the pathogenesis of hepatic encephalopathy had appeared to be unrelated. However, there is evidence, reviewed by Jones and Basile, that ammonia, even in the modestly elevated concentrations that occur in liver failure, inhibits metabolism of GABA by the astrocytes and enhances gabanergic neurotransmission—a concept that unifies hyperammonemia and the neurotransmitter change. A parallel astrocytic dysfunction may lead to disruption of the blood– brain barrier and the brain swelling that is known to occur in cases of acute liver failure.
Treatment Despite the incompleteness of our understanding of the role of disordered ammonia metabolism in the genesis of hepatic coma, an awareness of this relationship has provided the few effective means of treating this disorder: restriction of dietary protein; reduction of bowel flora by oral administration of neomycin or kanamycin, which suppresses the urease-producing organisms in the bowel; and the use of enemas. The mainstay of treatment has been oral lactulose, an inert sugar that is metabolized by colonic bacteria that produce hydrogen ions and shift ammonia to ammonium, which is then eliminated in the stool. The sustained use of oral neomycin carries a risk of renal damage and ototoxicity and has therefore been relegated to second-line therapy. The salutary effect of these therapeutic measures, the common attribute of which is the lowering of the blood NH3, further supports the the-
ory of ammonia intoxication. Ultimately, in cases of intractable liver failure, transplantation becomes a treatment of last resort. Other treatments with lesser value include bromocriptine, the aforementioned diazepine antagonist flumazenil, and keto analogues of essential amino acids. Theoretically, the keto analogues should provide a nitrogen-free source of essential amino acids (Maddrey et al), a treatment that has been largely abandoned, and bromocriptine, a dopamine agonist, should enhance dopaminergic transmission (Morgan et al) but its mechanism is not known. Administration of branched-chain amino acids may result in improvement in mental status but their effects have been variable and associated with an increased mortality (Naylor et al). The transient beneficial effect of the benzodiazepine antagonist flumazenil has already been mentioned; it is used as well as a diagnostic test.
Fulminant Hepatic Failure and Cerebral Edema In acute hepatitis, confusional, delirious, and comatose states also occur but their mechanisms are still unknown. Blood NH3 may be elevated but usually not to a degree that would be expected to cause encephalopathy. Severe acute hepatic failure may cause hypoglycemia, which contributes to the encephalopathy and often presages a fatal outcome but the levels of glucose typically detected do not provide an explanation for the encephalopathy. Cerebral edema is a prominent finding in cases of fulminant hepatic failure and is the main cause of death in patients awaiting liver transplantation. The cerebral edema in these circumstances appears to be related to the rapidity of rise of blood ammonia, but it probably depends as well on additional metabolic derangements that complicate acute liver failure. The combination of rapidly evolving hepatic failure and massive cerebral edema is similar to that observed in the Reye syndrome, described below. CT scanning is an effective means of detecting cerebral edema in patients with fulminant hepatic failure, and according to Wijdicks and colleagues, the degree of cerebral swelling is roughly proportional to the severity of encephalopathy. Because patients with fulminant hepatic failure can survive liver transplantation with few or no neurologic deficits, it is important to recognize cerebral edema before the stage of stupor and increased intracranial pressure has been established. Short of transplantation, death in these cases may sometimes be prevented by monitoring the intracranial pressure (as outlined by Lidofsky et al) and administering osmotic diuretics and hyperventilation, as detailed in Chaps. 31 and 35 for the treatment of intracranial hypertension. Some survivors are nonetheless left with cerebral damage from raised intracranial pressure. An additional issue that arises in assessing cerebral dysfunction in patients with liver disease is the possibility of adverse effects of medications. Individuals with hepatitis C who are treated with interferon-alpha may develop a spectrum of problems ranging from subtle cognitive impairment to a subacutely worsening headache, vomiting, altered consciousness, and focal neurologic findings. The milder syndromes are associated with no or few MRI-visible lesions but the severe ones are usually accompanied by
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signal changes in the white matter of the occipital lobes and elsewhere (posterior leukoencephalopathy; see Fig. 43-1).
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not full agreement as to the pathogenesis of this disorder and the mechanism of aspirin toxicity but mitochondrial dysfunction has been implicated.
Reye Syndrome (Reye-Johnson Syndrome) This is a special type of nonicteric hepatic encephalopathy occurring in children and adolescents and characterized by acute brain swelling in association with fatty infiltration of the viscera, particularly the liver. Although individual cases of this disorder had been described for many years, its recognition as a clinical-pathologic entity dates from 1963, when a large series was reported from Australia by Reye and colleagues and from the United States by Johnson and coworkers. The disorder tended to occur in outbreaks (286 cases were reported to the Centers for Disease Control during a 4-month period in 1974). Mainly, these outbreaks were observed in association with influenza B virus and varicella infections, but a variety of other viral infections were implicated (influenza A, echovirus, reovirus, rubella, rubeola, herpes simplex, Epstein-Barr virus). Later it became apparent that the toxic or adjuvant effects of aspirin given during these infections played an important role in producing the disease. Today, only occasional instances of Reye syndrome are observed now that the association with aspirin administration has become widely known and its use in children with viral infections has been interdicted. Most patients are children, boys and girls being equally affected, but rare instances are known in infants (Huttenlocher and Trauner) and young adults. In most cases, the encephalopathy is preceded for several days to a week by fever, symptoms of upper respiratory infection, and protracted vomiting. These are followed by the rapid evolution of stupor and coma, associated in many cases with focal and generalized seizures, signs of sympathetic overactivity (tachypnea, tachycardia, mydriasis), decorticate and decerebrate rigidity, and loss of pupillary, corneal, and vestibuloocular reflexes. One or two such cases were included in the series of acute “toxic encephalopathy” reported by Lyon and colleagues (see “Acute Toxic Encephalopathy” in Chap. 32). In infants, respiratory distress, tachypnea, and apnea are the most prominent features. The liver may be greatly enlarged, often extending to the pelvis and providing an important diagnostic clue as to the cause of the cerebral changes. Initially there is a metabolic acidosis, followed by a respiratory alkalosis (rising arterial pH and falling PCO2). The CSF is usually under increased pressure and is acellular; glucose values may be low, reflecting the hypoglycemia. The serum ALT, coagulation times, and blood ammonia are increased, sometimes to an extreme degree. The EEG is characterized by diffuse arrhythmic delta activity, progressing to electrocerebral silence in patients who fail to survive. CT and MRI show the cerebral swelling but are difficult to interpret in these young individuals, who lack any adult brain atrophy. The major pathologic findings are cerebral edema, often with cerebellar herniation, and infiltration of hepatocytes with fine droplets of fat (mainly triglycerides); the renal tubules, myocardium, skeletal muscles, pancreas, and spleen are infiltrated to a lesser extent. There are no inflammatory lesions in the brain, liver, or other organs. There is
Prognosis and Treatment In a series of children with blood ammonia levels greater than 500 mg/dL who were treated during the years 1967 to 1974, Shaywitz and colleagues reported a mortality of 60 percent. Once the child became comatose, death was almost inevitable. In more recent years, early diagnosis and initiation of treatment before the onset of coma have reduced the fatality rate to 5 to 10 percent. Treatment consists of the following measures: temperature control with a cooling blanket; nasotracheal intubation and controlled ventilation to maintain PCO2 below 32 mm Hg; intravenous glucose covered by insulin to maintain blood glucose at 150 to 200 mg/dL; administration of lactulose and neomycin enemas; control of intracranial pressure by means of continual monitoring and the use of hypertonic solutions (see Chap. 30); and the maintenance of fluid and electrolyte balance (Trauner). Upon recovery, cerebral function returns to normal unless there had been deep and prolonged coma or protracted elevation of intracranial pressure.
Uremic Encephalopathy Episodic confusion and stupor and other neurologic symptoms may accompany any form of severe renal disease—acute or chronic. The cerebral symptoms attributable to uremia (first described by Addison in 1832) are discerned in normotensive individuals in whom renal failure develops rapidly. Apathy, fatigue, inattentiveness, and irritability are usually the initial symptoms; later, there is confusion, dysarthria, tremor, and asterixis. Infrequently, this takes the form of a toxic psychosis, with hallucinations, delusions, insomnia, or catatonia (Marshall). These symptoms characteristically fluctuate from day to day, or even from hour to hour. In some patients, especially those who become anuric, symptoms may come on abruptly and progress rapidly to a state of stupor and coma. In others, in whom uremia develops more gradually, mild visual hallucinations and a disorder of attention may persist for several weeks in relatively pure form. The EEG becomes diffusely and irregularly slow and may remain so for several weeks after the institution of dialysis. The CSF pressure is normal and the protein is not elevated unless there is a uremic or diabetic neuropathy. In several reports, meningismus and a low-grade mononuclear pleocytosis have been mentioned (Merritt and Fremont-Smith), but we have not encountered this. In acute renal failure, clouding of the sensorium is practically always associated with a variety of motor phenomena. These usually occur early in the course of the encephalopathy, sometimes when the patient is still mentally clear. The patient begins to twitch and jerk and may convulse. The myoclonic twitches involve parts of muscles, whole muscles, or entire limbs and are lightning-quick, arrhythmic, and asynchronous on the two sides of the body; they are incessant during both wakefulness and sleep. At times the move-
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ments resemble those of chorea or an arrhythmic tremor; asterixis is also readily evoked. The motor phenomena are often difficult to classify. Our predecessor authors described the condition as a uremic twitch-convulsive syndrome. The resemblance of uremic encephalopathy to hepatic and other metabolic encephalopathies has been stressed by Raskin and Fishman, yet we are more impressed with differences than with similarities. When the twitch-convulsive syndrome is observed in association with other diseases such as widespread neoplasia, delirium tremens, diabetic coma and lupus erythematosus, the factor of renal failure is ultimately discovered. As the uremia worsens, the patient lapses into a quiet coma. Unless the accompanying metabolic acidosis is corrected, Kussmaul breathing appears and gives way to Cheyne-Stokes breathing and death. Encephalopathy and coma in the patient with renal failure may, of course, be a result of disorders other than uremia itself. Because of the similarity of this syndrome to tetany, measurement should be made of serum calcium and magnesium—and, of course, hypocalcemia and hypomagnesemia do occur in uremia. But often the values for these ions are normal or near normal, and the administration of calcium and magnesium salts has little effect. The altered excretion of drugs leads to their accumulation, sometimes evoking excessive sedation even though serum concentrations are normal. Subdural and intracerebral hemorrhages may complicate uremia (and dialysis) because of clotting defects and hypertension; and uremic patients are prone to infections, including meningitis. Because chronic uremia is so frequently associated with hypertension, a major problem also arises in distinguishing the cerebral effects of uremia from those of severe and accelerated hypertension. Volhard was the first to make this distinction; he introduced the term pseudouremia to designate the cerebral effects of malignant hypertension and to separate them from true uremia. The preferable term, hypertensive encephalopathy, was first used by Oppenheimer and Fishberg. However, the myoclonic-twitch syndrome is not a component of hypertensive encephalopathy. The clinical picture of the latter disorder and its pathophysiology are discussed in “Hypertensive Encephalopathy and Eclampsia” in Chap. 34.
Pathogenesis Opinions vary widely as to the biochemical basis of uremic encephalopathy and the twitch-convulsive syndrome. Restoration of renal function completely corrects the neurologic syndrome, attesting to the absence of structural change and a functional disorder of subcellular type. Whether caused by the retention of organic acids, elevation of phosphate in the CSF (claimed by Harrison et al), or the action of urea or other toxins, among them parathyroid hormone, has never been settled. The data supporting the causative role of urea itself are also ambiguous, just as they are for other putative endogenous agents (see Bolton and Young and the review by Burn and Bates). However, it can be stated that urea itself is not the sole inductive agent, as its infusion does not produce the syndrome in humans or animals.
It would appear that every level of the CNS is affected in uremia, from spinal cord to cerebrum. Cellular changes in the brain or spinal cord are limited to mild hyperplasia of protoplasmic astrocytes in some cases, but never of the degree observed in hepatic encephalopathy. Cerebral edema is notably absent. In fact, CT scans and MRI regularly show an element of cerebral shrinkage. A peripheral neuropathy is also a common complication of uremia and is considered in Chap. 46.
Treatment Improvement of encephalopathic symptoms may not be evident for a day or two after institution of dialysis. Convulsions, which occur in about one-third of cases, often preterminally, may be resistant to treatment until the uremia is addressed. However, some seizures may be suppressed with relatively low plasma concentrations of antiepileptic drugs, the reason being that serum albumin is depressed in uremia, increasing the unbound, therapeutically active portion of a drug. If there are severe associated metabolic disturbances, such as hyponatremia, the seizures may be difficult to control. One must be cautious in prescribing any of a large number of drugs in the face of renal failure, for inordinately high, toxic blood levels may result. Examples that affect the nervous system are aminoglycoside antibiotics (vestibular damage); furosemide (cochlear damage); and nitrofurantoin, isoniazid, and hydralazine (peripheral nerve damage).
“Dialysis Disequilibrium” Syndrome This term refers to a group of symptoms that may occur during and following hemodialysis or peritoneal dialysis as a byproduct of some degree of cerebral edema. The symptoms include headaches, nausea, muscle cramps, nervous irritability, agitation, drowsiness, and convulsions. The headache, which may be bilateral and throbbing and resemble common migraine, develops in approximately 70 percent of patients, whereas the other symptoms are observed in 5 to 10 percent, usually in those undergoing rapid dialysis or in the early stages of a dialysis program. The symptoms tend to occur in the third or fourth hour of dialysis and last for several hours. Sometimes they appear 8 to 48 h after the completion of dialysis. Originally, these symptoms were attributed to the rapid lowering of serum urea, leaving the brain with a higher concentration of urea than the serum and resulting in a shift of water into the brain to equalize the osmotic gradient (reverse urea syndrome). Now it is believed that the shift of water into the brain is akin to water intoxication and is a result of the inappropriate secretion of antidiuretic hormone. The symptoms of subdural hematoma, which in some series had in the past occurred in 3 to 4 percent of patients undergoing dialysis, now being less frequent, may be mistakenly attributed to the disequilibrium syndrome.
Dialysis Encephalopathy (Dialysis Dementia) This is a subacutely progressive syndrome that in the past complicated chronic hemodialysis. Characteristically, the condition begins with a hesitant, stuttering dysarthria,
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dysphasia, and so-called apraxia of speech (encompassing a variety of dysfluent speech patterns), to which are added facial and then generalized myoclonus, focal and generalized seizures, personality and behavioral changes, and intellectual decline. The EEG is invariably abnormal, taking the form of paroxysmal and sometimes periodic sharp-wave or spike-and-wave activity (up to 500 mV and lasting 1 to 20 s), intermixed with abundant theta and delta activity. The CSF is normal except occasionally for increased protein. At first the myoclonus and speech disorders are intermittent, occurring during or immediately after dialysis and lasting for only a few hours, but gradually they become more persistent and eventually permanent. Once established, the syndrome is usually steadily progressive over a 1- to 15-month period (average survival of 6 months in the 42 cases analyzed by Lederman and Henry). A characteristic feature is a transient improvement in speech with the administration of intravenous diazepines. The neuropathologic changes are said to be subtle and consist of a mild degree of microcavitation of the superficial layers of the cerebral cortex. Although the changes are diffuse, they have been found in one study to be more severe in the left (dominant) hemisphere than in the right and more severe in the left frontotemporal operculum than in the surrounding cortex (Winkelman and Ricanati). The disproportionate affection of the left frontotemporal opercular cortex putatively explains the distinctive disorder of speech and language. In the one case we have studied carefully, we could not be certain of any microscopic changes. The most plausible view of the pathogenesis of dialysis encephalopathy is that it represented a form of aluminum intoxication (Alfrey et al), the aluminum being derived from the dialysate or from orally administered aluminum gels. In recent years, this disorder has disappeared, the result, in all likelihood, of the universal practice of purifying the water used in dialysis and thereby removing aluminum from the dialysate. This subject has been reviewed by Parkinson and coworkers.
Complications of Renal Transplantation The risk in immunosuppressed persons of developing a primary lymphoma of the brain or progressive multifocal leukoencephalopathy is well known and has been mentioned in previous chapters. An entirely different encephalopathy that is marked by widespread visual symptoms and edema of the cerebral white matter, evident on the MRI, but mainly occipital, occurs after the administration of cyclosporine and other immunosuppressant drugs. This pattern of “reversible posterior leukoencephalopathy” on MRI is not specific, being seen also in patients with hypertensive encephalopathy, eclampsia, intrathecal methotrexate and other conditions (see Table 43-1 and Fig. 43-1). Systemic fungal infections had in the past been found at autopsy in approximately 45 percent of patients who had had renal transplants and long periods of immunosuppressive treatment; in about one-third of these patients, the CNS was involved. Cryptococcus, Listeria, Aspergillus, Candida, Nocardia, and Histoplasma were the usual organisms. Recent experience suggests a lower rate
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of infection. Other CNS infections that have complicated transplantation are toxoplasmosis and cytomegalovirus (CMV) inclusion disease. We have found examples of Wernicke-Korsakoff disease and central pontine myelinolysis in uremic patients. A bleeding diathesis may result in subdural or cerebral hemorrhage, as already mentioned.
Encephalopathy Associated with Sepsis and Burns (“Septic Encephalopathy”) Bolton and Young have drawn attention to the frequent occurrence, in severely septic patients, of a drowsy or confusional state that is reversible and not explained by hepatic, pulmonary, or renal failure, electrolyte imbalance, hypotension, drug intoxication, or a primary lesion of the brain. They called the condition “septic encephalopathy.” According to their surveys, 70 percent of patients become disoriented and confused within hours of the onset of severe systemic infection; in a few cases, this state may progress to stupor and coma. Notably there are no signs of asterixis, myoclonus, or focal cerebral disorder but paratonia is common, as is the later development of a polyneuropathy. Rapid changes in water balance may occur, leading to the type of osmotic demyelination discussed below. The encephalopathic state that occurs with severe systemic infection may also develop independently of sepsis, as a component of a syndrome of multiple organ failure and, according to some authors, a complication of widespread cutaneous burns (Aikawa et al). Others of our colleagues have questioned the validity of this last category and have instead found explanatory electrolyte disorders (particularly hyponatremia), sepsis, or multiple brain abscesses (Winkleman, personal communication). It has been useful in clinical work to distinguish these encephalopathies of infection and multiorgan failure from those caused by isolated hepatic or renal disease. The lack of a biochemical marker and the confounding effects of hypotension during sepsis (septic shock) leave doubt as to pathogenesis. Altered phenylalanine metabolism and circulating cytokines have been proposed as causes, without firm evidence. Of interest in two of our fatal cases was the presence of brain purpura, but this has otherwise been an infrequent finding. Here, the white matter of the cerebrum and cerebellum was speckled with myriad pericapillary hemorrhages and zones of adjacent necrosis. This pathologic reaction is nonspecific, having also been seen in cases of viral pneumonia, heart failure with morphine overdose, and arsenic poisoning.
Disorders of Sodium, Potassium, and Water Balance Drowsiness, confusion, stupor, and coma, in conjunction with seizures and sometimes with other neurologic deficits, may have as their basis a more or less pure abnormality of electrolyte or water balance. Only brief reference is made here to some of these, such as hypocalcemia, hypercalcemia, hypophosphatemia, and hypomagnesemia, as they are considered in other parts of the text.
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Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone Hyponatremia is defined as a serum sodium level below 135 mEq/L. The hyponatremic state may be isotonic, hypertonic, or hypotonic, depending on the mechanism of reduced sodium concentration. The hypotonic variety is most common in neurologic practice but one also encounters cases of pseudohyponatremia caused by hyperlipidemia or hyperproteinemia (isotonic), hyperglycemic or mannitol-induced hyponatremia (hypertonic), and also cases of water intoxication. The last of these may be associated with systemic hypovolemic (blood loss, salt wasting), hypervolemic (edematous states such as renal, hepatic or heart failure), or isovolemic states (retention of free water). Hypotonic isovolemic hypernatremia is most often a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This state is of special importance because it complicates neurologic diseases of many types: head trauma, bacterial meningitis and encephalitis, cerebral infarction, subarachnoid hemorrhage, cerebral and systemic neoplasm, Guillain-Barré syndrome and the effects of certain medications. SIADH is the result of excretion of urine that is hypertonic relative to the plasma. As the hyponatremia develops, there is a decrease in alertness, which progresses through stages of confusion to coma, often with convulsions. As with many other metabolic derangements, the severity of the clinical effect is related to the rapidity of decline in serum Na. Lack of recognition of this state may allow the serum Na to fall to dangerously low levels, 100 mEq/L or lower. Treatment Most instances of hyponatremia have developed slowly, allowing for maintenance of brain volume by the extrusion from cells of various osmotic substances. Rapid correction of sodium in these circumstances risks a reversal of osmotic gradient and a reduction in brain volume. This, in turn, is associated with a special type of central nervous system demyelination (“osmotic demyelination” and central pontine myelinolysis) discussed below. One’s first impulse is to administer NaCl intravenously, but this must be done cautiously to avoid these complications. Most cases of SIADH respond to the restriction of fluid intake—to 500 mL per 24 h if the serum Na is less than 120 mEq/L and to 1,000 mL per 24 h if less than 130 mEq/L. Even when the Na reaches 130 mEq/L, the fluid intake should not exceed 1,500 mL per 24 h. In extreme and rapidly developing (less than 48 hours) hyponatremia with stupor or seizures, the mechanisms for maintaining cerebral cellular volume have not yet been engaged and therefore infusion of NaCl is necessary to prevent cerebral edema. The amount of NaCl to be infused can be calculated from the current and the target levels of serum Na by assuming that the infused sodium load is distributed throughout the total body water content (0.6 × weight in kilograms): ([target Na – starting Na] × 0.6) × weight (kg) = infused Na load (mEq) The desired volume of normal saline can then be determined by keeping in mind that its sodium concentration is 154 mEq/L and that of 3 percent (hypertonic) saline solution is 513 mEq/L. If hypertonic saline is administered, it is
usually necessary to simultaneously reduce intravascular volume with furosemide, beginning with a dose of 0.5 mg/ kg intravenously, and to increase the dosage until a diuresis is obtained. (As a rule of thumb, 300 to 500 mL of 3 percent saline, infused rapidly intravenously, will increase the serum sodium concentration by about 1 mEq/L/h for 4 h.) Guidelines to prevent an overly rapid correction of Na are elaborated further on in relation to central pontine myelinolysis (no more than 10 mmol/L in the first 24 h). Although the syndrome of SIADH is usually self-limiting, it may continue for weeks or months, depending on the type of associated brain disease. Not all patients with neurologic disorders who manifest hyponatremia have SIADH. Diuretic excess, adrenal insufficiency and salt wasting also produce hypovolemic hyponatremia as a result of natriuresis. When renal salt wasting is seen in the context of a central neurologic disorder, the process has been termed “cerebral salt wasting” (Nelson et al). Sodium loss in these circumstances is attributable to the production by the heart or brain of a potent polypeptide natriuretic factor. As discussed in Chap. 34, under “Subarachnoid Hemorrhage,” the distinction between SIADH and cerebral salt wasting is of more than theoretical importance, insofar as fluid restriction to correct hyponatremia may be dangerous in patients with salt wasting, particularly in those with vasospasm after ruptured intracranial aneurysms. Arieff emphasized the hazards of postoperative hyponatremia in a series of 15 patients, all of them women, in whom severe hyponatremia followed elective surgery. About 48 h after these patients had recovered from anesthesia, their serum Na fell markedly, at which point generalized seizures occurred, followed by respiratory arrest. We are more familiar with acutely developing hyponatremia in the context of prostate surgery, where large amounts of hypotonic fluids are routinely administered both intravenously and intravascularly. A similar syndrome is known in instances of overly zealous fluid resuscitation in children with diabetic ketoacidosis. The mechanisms of neurologic deterioration in all of these cases is likely to be brain edema. An important consideration in the management of severe hyponatremia, as mentioned earlier, is the rapidity with which the abnormality is corrected and the danger of provoking central pontine myelinolysis and related brainstem, cerebellar, and cerebral lesions (extrapontine myelinolysis; osmotic demyelination). These issues are considered below, in the section “Central Pontine Myelinolysis.”
Hypernatremia Hypernatremia (Na >155 mEq/L) and dehydration are observed in diabetes insipidus, the neurologic causes of which include head trauma with damage to the pituitary stalk (Chap. 27), and in nonketotic diabetic coma, protracted diarrhea in infants, and the deprivation of fluid intake in the stuporous patient. The last condition is usually associated with a brain lesion that impairs consciousness. Exceptionally, in patients with chronic hydrocephalus, the hypothalamic thirst center is rendered inactive and severe hypernatremia, stupor, and coma may follow a failure to drink. In hypernatremia from any cause, the brain volume is manifestly reduced in CT scans. Retraction of the cerebral
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cortex from the dura has been known to rupture a bridging vein and cause a subdural hematoma. As is true for hyponatremia, the degree of CNS disturbance in hypernatremia is generally related to the rate at which the serum Na rises. Slowly rising values, to levels as high as 170 mEq/L, may be surprisingly well tolerated. Rapid elevations of sodium shrink the brain, especially in infants. Extremely high levels cause impairment of consciousness with asterixis, myoclonus, seizures, and choreiform movements. In addition, muscular weakness, rhabdomyolysis, and myoglobinuria have been reported. In hypernatremia with hyperosmolality, the brain retains its volume more effectively than do other organs by a compensatory mechanism that has been attributed to the presence of “idiogenic osmoles,” possibly glucose, glucose metabolites, and amino acids. The impairment of neuronal function in this state is not understood. Theoretically one would expect neuronal shrinkage and possibly alteration of the synaptic surface of the cell.
Hypo- and Hyperkalemia The main clinical effect of hypokalemia (≤2.0 mEq/L) is generalized muscular weakness (see Chap. 48). A mild confusional state had been alluded to in the literature but must be very infrequent. The electrolyte condition is readily corrected by adding K to intravenous fluid and infusing it at no more than 4 to 6 mEq/h. Hyperkalemia (>7 mEq/L) also may manifest itself by generalized muscle weakness, although the main effects are changes in the electrocardiogram (ECG), possibly leading to cardiac arrest.
Other Metabolic Encephalopathies Limitation of space permits only brief reference to other metabolic disturbances that may present as episodic confusion, stupor, or coma. The most important members of this group are summarized below. Hypercalcemia This is defined as an elevation of the serum calcium concentration >10.5 mg/dL. If the serum protein content is normal, Ca levels >12 mg/dL are required to produce neurologic symptoms. However, with low serum albumin levels, an increased proportion of the serum Ca is in the unbound or ionized form (upon which the clinical effects depend), and symptoms may occur with total serum Ca levels as low as 10 mg/dL. In young persons, the most common cause of hypercalcemia is hyperparathyroidism (either primary or secondary); in older persons, osteolytic bone tumors, particularly metastatic carcinoma and multiple myeloma, are often causative. Less-common causes are vitamin D intoxication, prolonged immobilization, hyperthyroidism, sarcoidosis, and decreased calcium excretion (renal failure). Anorexia, nausea and vomiting, fatigue, and headache are usually the initial symptoms, followed by confusion (rarely a delirium) and drowsiness, progressing to stupor or coma in untreated patients. A history of recent constipation is common. Diffuse myoclonus and rigidity occur occasionally, as do elevations of spinal fluid protein (up to 175 mg/100 mL). Convulsions are uncommon. Hypocalcemia The usual manifestations are paresthesias, tetany, and seizures. With severe and persistent hypo-
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calcemia, altered mental status in the form of depression, confusion, dementia, or personality change can occur. Anxiety to the point of panic attack is also known. Even coma may result, in which case there may be papilledema as a result of increased intracranial pressure. Aside from the raised pressure, the CSF shows no consistent abnormality. This increase in intracranial pressure may be manifest by headache and papilledema without altered mentation or with visual obscurations. Hypoparathyroidism is discussed again further on, under “Acquired Metabolic Diseases Presenting as Progressive Extrapyramidal Syndromes.” Other Electrolyte and Acid–Base Disorders Severe metabolic acidosis from any cause produces a syndrome of drowsiness, stupor, and coma, with dry skin and Kussmaul breathing. The CNS depression does not correlate with the concentration of ketones. Possibly, there are associated effects on neurotransmitters. It is often not possible to separate the effects of acidosis from those caused by an underlying condition or toxic ingestion. In infants and children, acidosis may occur in the course of hyperammonemia, isovaleric acidemia, maple syrup urine disease, lactic and glutaric acidemia, hyperglycinemia, and other disorders, which are described in detail in Chap. 37. High-voltage slow activity predominates in the EEG, and correction of the acidosis or elevated ammonia level restores CNS function to normal provided that coma was not prolonged or complicated by hypoxia or hypotension. In uncomplicated acidotic coma, no recognizable neuropathologic change has been observed by light microscopy. Encephalopathy as a consequence of Addison disease (adrenal insufficiency) may be attended by episodic confusion, stupor, or coma without special identifying features; it is usually precipitated in the addisonian patient by infection or surgical stress. Hemorrhagic destruction of the adrenals in meningococcal meningitis (Waterhouse-Friderichsen syndrome) is another cause. Hypotension and diminished cerebral circulation and hypoglycemia are the most readily recognized metabolic abnormalities; measures that correct these conditions reverse the adrenal crisis in some instances. Laureno (1993) reviewed the various neurologic syndromes that result from electrolytic disorders.
Central Pontine Myelinolysis (Osmotic Demyelination) Adams, Victor, and Mancall observed a rapidly evolving quadriplegia and pseudobulbar palsy in a young alcoholic man who had entered the hospital 10 days earlier with symptoms of alcohol withdrawal. Postmortem examination several weeks later disclosed a large, symmetrical, essentially demyelinative lesion occupying the greater part of the base of the pons. Over the next 5 years, 3 additional cases (2 alcoholic patients and 1 with scleroderma) were studied clinically and pathologically, and in 1959 these 4 cases were reported by Adams and colleagues under the heading of central pontine myelinolysis (CPM). This term was chosen because it denotes both the main anatomic localization of the disease and its essential pathologic attribute: the remarkably unsystematic dissolution of the sheaths of myelinated fibers and the sparing of neurons. Once attention was focused on this distinctive
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lesion, many other reports appeared. The exact incidence of this disease is not known, but in a series of 3,548 consecutive autopsies in adults, the typical lesion was found in 9 cases, or 0.25 percent (Victor and Laureno).
Pathologic Features One is compelled to define this disease in terms of its pathologic anatomy because this stands as its most characteristic feature, but it has been appreciated in recent years that the pons is not the only structure that may be affected. Transverse sectioning of the fixed brainstem discloses a grayish discoloration and fine granularity in the center of the base of the pons. The lesion may be only a few millimeters in diameter, or it may occupy almost the entire ventral pons. There is always a rim of intact myelin between the lesion and the surface of the pons. Posteriorly, it may reach and involve the medial lemnisci and, in the most advanced cases, other tegmental structures as well. Very rarely, the lesion encroaches on the midbrain but inferiorly it does not extend as far as the medulla. Identical extrapontine myelinolytic foci in the internal capsule, deep cerebral white matter and corpus callosum may occur independently (“extrapontine myelinolysis”). Exceptionally, symmetrically distributed lesions are found in the thalamus, subthalamic nucleus, striatum, amygdaloid nuclei, lateral geniculate body, white matter of the cerebellar folia (Wright et al). Microscopically, the fundamental abnormality consists of destruction of the myelinated sheaths throughout the lesion, with relative sparing of the axons and intactness of the nerve cells of the pontine nuclei. These changes always begin and are most severe in the geometric center of the pons, where they may proceed to frank necrosis of tissue. Reactive phagocytes and glia cells are in evidence throughout the demyelinative focus, but oligodendrocytes are depleted. Signs of inflammation are conspicuously absent. This constellation of pathologic findings provides easy differentiation of the lesion from infarction and the inflammatory demyelination of multiple sclerosis and postinfectious encephalomyelitis. Microscopically, the lesion resembles that of Marchiafava-Bignami disease (Chap. 41), with which it is rarely associated. In the chronic alcoholic, Wernicke disease is often associated with osmotic demyelination, but the lesions bear no resemblance to one another in terms of topography and histology.
serum sodium concentration, with which the process is closely aligned, are discussed below. In many patients there are no symptoms or signs that betray the pontine lesion, presumably because it is so small, extending only 2 to 3 mm on either side of the median raphe and involving only a small portion of the corticopontine or pontocerebellar fibers. In others, its presence is obscured by coma from a metabolic or other associated disease. Prior to the inception of MRI only a minority of cases, exemplified by the first patient observed by Adams, Victor, and Mancall, were recognized during life. In this patient, a serious alcoholic with delirium tremens and pneumonia, there evolved, over a period of several days, a flaccid paralysis of all 4 limbs and an inability to chew, swallow, or speak (thus simulating occlusion of the basilar artery). Pupillary reflexes, movements of the eyes and lids, corneal reflexes, and facial sensation were spared. In some instances, however, conjugate eye movements are limited, and there may be nystagmus. With survival for several days, the tendon reflexes become more active, followed by spasticity and extensor posturing of the limbs on painful stimulation. Some patients are left in a state of mutism and paralysis with relative intactness of sensation and comprehension (pseudocoma, or locked-in syndrome). The capacity of CT scanning, but especially MRI, to visualize the pontine lesion has greatly increased the frequency of premortem diagnoses. The MRI discloses a characteristic “batwing” lesion of the pons in typical cases (Fig. 40-6), although this change may become evident only several days after the onset of symptoms. Brainstem auditory evoked responses also disclose the lesions that encroach upon the pontine tegmentum.
Clinical Features The two sexes are affected equally, and the patients do not fall into any one age period. Whereas the cases first reported had occurred in adults, there are now many reports of the disease in children, particularly in those with severe burns (McKee et al). More than half the cases have appeared in the late stages of chronic alcoholism, often in association with Wernicke disease and polyneuropathy. Most cases occur in the context of other serious medical conditions, and diseases with which osmotic demyelination has been conjoined are chronic renal failure being treated with dialysis, hepatic failure, advanced lymphoma, cancer, cachexia from a variety of other causes, severe bacterial infections, dehydration and electrolyte disturbances, acute hemorrhagic pancreatitis, and pellagra. The changes in
Figure 40-6. T2-weighted MRI showing the typical lesion of central pontine myelinolysis in an alcoholic patient.
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Variants of this syndrome are being encountered with increasing frequency. Two of our elderly patients, with confusion and stupor but without signs of corticospinal or pseudobulbar palsy, recovered; however, they were left with a severe dysarthria and cerebellar ataxia lasting many months. After 6 months, these patients’ nervous system function was essentially restored to normal. In reference to the pathogenesis of this lesion, originally both patients had serum Na levels of 99 mEq/L, but information about the rate of correction of serum Na was not available. Another of our patients developed a typical locked-in syndrome after the rapid correction of a serum sodium of 104 mEq/L. He showed large symmetrical lesions of the frontal cortex and underlying white matter but no pontine lesion (by MRI). Brainstem infarction caused by basilar artery occlusion may be simulated by pontine myelinolysis. Sudden onset or step-like progression of the clinical state, asymmetry of long tract signs, and more extensive involvement of tegmental structures of the pons as well as the midbrain and thalamus are the distinguishing characteristics of vertebrobasilar thrombosis or embolism. On MRI studies, an evolving infarction shows signal changes on diffusionweighted imaging, while the primary finding in osmotic demyelination is brightness of the T2-weighted images. Massive pontine demyelination in acute or chronic relapsing multiple sclerosis rarely produces a pure pontine syndrome. The clinical features and context provide the clues to correct diagnosis.
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base of the pons, have a susceptibility to rapid increase in serum osmolality. Karp and Laureno, on the basis of their experience and that of Sterns and colleagues, have suggested that the hyponatremia be corrected by no more than 10 mEq/L in the initial 24 h and by no more than about 21 mEq/L in the initial 48 h.
ACQUIRED METABOLIC DISEASES PRESENTING AS PROGRESSIVE EXTRAPYRAMIDAL SYNDROMES These syndromes are usually of mixed type; i.e., they include a number of basal ganglionic and cerebellar symptoms in various combinations. They emerge as part of acquired chronic hepatocerebral degeneration or chronic hypoparathyroidism or as sequels to kernicterus, hypoxic, or hypoglycemic encephalopathy. The basal ganglionic– cerebellar symptoms that result from severe anoxia and hypoglycemia were described in the preceding section and in Chaps. 4 and 5. Kernicterus and calcification of the basal ganglia and cerebellum are considered in Chap. 37 and further on in this chapter. Acquired hypoparathyroidism may also lead to calcification of the basal ganglia and an extrapyramidal disorder. Choreiform movements are also observed in patients with hyperosmolar coma and with severe hyperthyroidism, ascribed by Weiner and Klawans to a disturbance of dopamine metabolism.
Etiology and Pathogenesis As mentioned in the section on hyponatremia, a rapid rise in serum osmolality to normal or higher-than-normal levels is an almost obligate antecedent of this process. One encounters this most commonly in the rapid correction of hyponatremia. In cases related to the correction of hyponatremia, the initial serum sodium concentration is less than 130 mEq/L and usually much lower; this was the case in all the patients reported by Burcar and colleagues and by Karp and Laureno. Laureno (1983) demonstrated the importance of serum sodium in the pathogenesis of this disease experimentally. Dogs made severely hyponatremic (100 to 115 mEq/L) had the electrolyte disorder corrected rapidly by infusion of hypertonic (3 percent) saline; this led to spastic quadriparesis and pontine and extrapontine lesions were found at autopsy, indistinguishable in their distribution and histologic features from those of the human disease. Hyponatremia alone or slowly corrected hyponatremia (
