Part 1 book “Manual of neurologic therapeutics” has contents: Coma, head trauma, and spinal cord injury, epilepsy, dizziness, neck and back pain, sleep disorders, neurooncology, multiple sclerosis and other demyelinating diseases, motor neuropathies and peripheral neuropathies, neuromuscular junction disorders and myopathies.
Manual of Neurologic Therapeutics 7th Edition 2004 Lippincott Williams & Wilkins Philadelphia 530 Walnut Street, Philadelphia, PA 19106 USA LWW.com 0-7817-4646-9 All rights reserved This book is protected by copyright No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the above-mentioned copyright Printed in the USA Library of Congress Cataloging-in-Publication Data Manual of neurologic therapeutics / [edited by] Martin A Samuels.—7th ed p ; cm Includes bibliographical references and index ISBN 0-7817-4646-9 Neurology—Handbooks, manuals, etc.2 Nervous system—Diseases—Handbooks, manuals, etc.I Samuels, Martin A [DNLM:1 Nervous System Diseases—diagnosis—Outlines Nervous System Diseases—therapy—Outlines WL 18.2 M294 2004] RC355.M36 2004 616.8—dc22 2003065888 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices However, the authors, editor, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of this information in a particular situation remains the professional responsibility of the practitioner The authors, editor, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly important when the recommended agent is a new or infrequently employed drug Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice 10 Edited by Martin A Samuels M.D., M.A.C.P., F.A.A.N Neurologist-in-Chief and Chairman Department of Neurology, Brigham and Women’s Hospital, Professor of Neurology, Harvard Medical School, Boston, Massachusetts Secondary Editors James D Ryan Acquisitions Editor Grace R Caputo Developmental Editor Frank Aversa Production Editor Colin J Warnock Manufacturing Manager Patricia Gast Cover Designer Compositor: Techbooks R R Donnelley–Crawfordsville Printer CONTRIBUTING AUTHORS Anthony A Amato M.D Associate Professor of Neurology Harvard Medical School; Chief, Neuromuscular Division, Vice-Chairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Robert W Baloh M.D Professor of Neurology University of California Medical School; Director, Neurootology Laboratory, University of California Medical Center, Los Angeles, California Donald C Bienfang M.D Assistant Professor of Ophthalmology Harvard Medical School; Chief, Division of Neuroophthalmology, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Edward B Bromfield M.D Assistant Professor of Neurology Harvard Medical School; Chief, Division of Epilepsy and Electroencephalography, Brigham and Women’s Hospital, Boston, Massachusetts Kirk R Daffner M.D Associate Professor of Neurology Harvard Medical School; Chief, Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, Boston, Massachusetts David M Dawson M.D Professor of Neurology Harvard Medical School; Senior Neurologist, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Steven K Feske M.D Assistant Professor of Neurology Harvard Medical School; Director, Stroke Division, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Robert B Fogel M.D Instructor in Medicine Harvard Medical School; Physician, Division of Sleep Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Robert D Helme F.R.A.C.P., Ph.D Professor of Neurology University of Melbourne, Carlton, Victoria; Neurologist, Barbara Walker Centre for Pain Management, St Vincent’s Hospital, Fitzroy, Victoria, Australia Galen V Henderson M.D Instructor in Neurology Harvard Medical School; Director, Critical Care and Emergency Neurology, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Santosh Kesari M.D., Ph.D Instructor in Neurology Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Ian Yi-Onn Leong M.B.B.S., M.R.C.P Clinical Tutor Department of Medicine, National University of Singapore, Singapore; Associate Consultant, Department of Geriatric Medicine, Tan Tock Seng Hospital, Singapore Christina M Marra M.D Professor Department of Neurology and Medicine—Infectious Diseases, University of Washington School of Medicine, Seattle, Washington Michael Ronthal M.B.B.Ch., F.R.C.P., F.R.C.P.E Associate Professor of Neurology Harvard Medical School; Senior Neurologist, Department of Neurology, Beth Israel—Deaconess Medical Center, Boston, Massachusetts Martin A Samuels M.D., M.A.C.P., F.A.A.N Professor of Neurology Harvard Medical School; Neurologist-in-Chief and Chairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Egilius L.H Spierings M.D., Ph.D Associate Clinical Professor of Neurology Harvard Medical School; Consultant, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Lewis R Sudarsky M.D Associate Professor of Neurology Harvard Medical School; Director, Movement Disorders Division, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Patrick Y Wen M.D Associate Professor of Neurology Harvard Medical School; Director, Division of Neurooncology, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts David A Wolk M.D Instructor in Neurology Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts John W Winkelman M.D., Ph.D Assistant Professor of Psychiatry Harvard Medical School; Medical Director, Sleep Health Center, Newton, Massachusetts; Physician, Division of Sleep Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts DEDICATION This book is dedicated to the original contributors to the Manual of Neurologic Therapeutics They were all members of a single group of residents in the neurology training program at the Massachusetts General Hospital when the idea was hatched almost 30 years ago They have all gone on to distinguished careers in neurology Telmo M Aquino Raymond J Fernandez Robert D Helme Daniel B Hier Richard C Hinton Stephen M Sagar Thomas M Walshe Howard D Weiss FOREWORD It is to the classic monographs of Erb, Hughings Jackson, Gowers, K Wilson, and their contemporaries that all scholars of neurology turn for knowledge of many of the common diseases of the human nervous system These writings summarize the personal observations—clinical and pathological—of the author himself, expressed in the lucid and elegant language of the era The author’s reputation attested to the verity of the observations But perusal of these landmark documents reveals little in the nature and future prospects of therapy or means of prevention As a consequence, neurology became known as a large branch of medicine with a multitude of diagnosable diseases bereft of therapy All this has changed Because of prodigious advances in biochemistry, neuropathology, and genetics, new methods of therapy have been devised, or at least conceptualized, for many of the previously recognized diseases as well as new disorders disclosed by the application of these methods In fact, such an aggregation of new information about therapies of neurologic diseases has emerged that several neurologists have judged that a monograph devoted to the subject was warranted This was surely the reasoning of Professor Martin A Samuels, who undertook this task many years ago The success of his venture is reflected in the continued demand for the Manual of Neurologic Therapeutics, now in its 7th edition Professor Samuels, like many others who had received their specialty education in our residency program at the Massachusetts General Hospital, brings to his subject a keen knowledge of neurology and a high motivation to advance the understanding of established methods of therapy in neurology As a member of the staff of the neurology service of the Massachusetts General Hospital, I have enjoyed and benefited from my association with Professor Samuels both during the period when he was a graduate student and later, as an esteemed faculty colleague I applaud his latest medical literary contribution Raymond D Adams M.D Boston, Massachusetts PREFACE TO THE FIRST EDITION Until very recently the neurologist’s primary task was to categorize and organize the structure and pathologic alterations of the nervous system In fact, neurology has long been known as a discipline with elegantly precise and specific diagnostic capabilities but little or no therapeutic potentiality Further, many surgeons, pediatricians, and internists have traditionally thought of the neurologist as an impractical intellectual who spends countless hours painstakingly localizing lesions while ignoring pragmatic considerations of treatment Perhaps this conception is largely attributable to the peculiar complexity of the nervous system and the consequent relative naivete of physicians in their understanding of its functions Many of the classic descriptions of disease states in other medical disciplines were completed in the last century; in neurology, these have only been described in the past generation, and only in the last ten years has neurology begun to be characterized by subcellular mechanistic concepts of disease This maturity has meant that the neurologist is now as much involved in the therapeutic aspects of his specialty of medicine as any of his colleagues Certain neurologic diseases, such as epilepsy, have been treatable for relatively long periods of time, but understanding of the subcellular mechanisms of other diseases has led to newer, more effective forms of therapy An example of this is the enlarged understanding we now have of the biochemical alterations in Parkinson disease, and the resultant therapeutic implications Now, much as the endocrinologist treats diabetes with insulin and the cardiologist treats congestive heart failure with digitalis, the neurologist treats Parkinson disease with l-dopa In all these situations, the underlying condition is not cured; rather, an attempt is made to alter the pathophysiologic processes by utilizing a scientific understanding of the function of the diseased system This manual embodies a practical, logical approach to the treatment of neurologic problems, based on accurate diagnosis, that should prove useful to both clinician and student No attempt is made to reiterate the details of the neurologic examination; it is assumed that the reader is competent to examine the patient—although particularly important or difficult differential diagnostic points are mentioned when appropriate In this regard, it should be emphasized that this manual is only a guide to diagnosis and therapy, and each patient must be treated individually The manual is organized to best meet the needs of the clinician facing therapeutic problems Thus, the first seven chapters are concerned with symptoms, such as dizziness and headache, while the last ten consider common diseases, such as stroke and neoplasms I thank the many colleagues and friends whose criticism and comments were useful in the preparation of this book, in particular Drs G Robert DeLong, C Miller Fisher, George Kleinman, James B Lehrich, Steven W Parker, Henry C Powell, E P Richardson, Jr., Maria Salam, Bagwan T Shahani, Peter Weller, James G Wepsic, and Robert R Young In addition I am indebted to Sara Nugent and Helen Hyland for their assistance in the preparation of the many manuscripts, and to Diana Odell Potter, formerly of Little, Brown and Company, for her editorial skills Jane Sandiford, formerly of Little, Brown, and Kathleen O’Brien and Carmen Thomas of Little, Brown provided invaluable assistance in the final preparation of this material Deep appreciation goes to Lin Richter, Editor-in-Chief of the Medical Division, Little, Brown and Company, for her support throughout this effort I further thank Jon Paul Davidson, also formerly of Little, Brown, for his valuable encouragement and help early in the course of this project Much support and encouragement was derived from my new colleagues in the Peter Bent Brigham Hospital Neurology Section, The Longwood Avenue Neurology Program, and the West Roxbury Veterans Administration Hospital A great deal of inspiration came from the birth of my daughter Marilyn, and my deepest thanks go to my wife, Linda, who provided constant encouragement, editorial skill, and infinite patience Martin A Samuels PREFACE Once the last bastion of therapeutic nihilism, neurology has now clearly entered the era of intense therapy for virtually every class of disease that affects the nervous system Consequently, the modern neurology department is now subdivided into a dozen clinical subspecialties, each with its own group of experts, often with their own postresidency specialized fellowship training programs General neurology still exists but it is usually practiced in a consultative mode in either the hospital or the ambulatory setting Now, the movement disorder specialist is as different from the epileptologist as the hematologist is from the endocrinologist Basic research in the neurosciences is routinely translated into new drugs, devices, and procedures aimed at ameliorating disorders in almost all the major categories of disease Even neurodegeneration, traditionally the most therapeutically resistant class of disease, is beginning to crack under the influence of molecular genetics and its translation into drugs that may slow or prevent cell death In this context, the original contributors to the Manual of Neurologic Therapeutics all agreed that the 7th edition would require a major reorganization and that the sections needed to be written by experts who had dedicated their careers to each of the various areas of concentration Furthermore, to be optimally accessible in both office and bedside venue, the Manual needed to be presented in a format conducive to electronic presentation as well as print reproduction Thus, the information contained here is presented in a more consistent format than previously, with better use of headings and less reliance on a traditional outline The 7th edition contains an entire chapter on neurologic intensive care, now a well-defined subspecialty Epilepsy management currently involves not only an array of new drugs but also innovative strategies such as vagal nerve stimulation and a greater emphasis on earlier surgical treatment Neurootology encompasses the common complaint of dizziness, emphasizing both pharmacologic and physical therapy approaches to treatment Back and neck pain, still among the most common complaints in all of medicine, are now evaluated with much improved diagnostic tests, which lead to more precise treatment An entire chapter is dedicated to sleep disorders, an enormous area of disability in which major new advances in therapy have occurred Cancer neurology now involves a complex array of chemotherapy, radiation therapy, and new cutting edge treatments using monoclonal antibodies No area has changed more substantively than multiple sclerosis, in which fresh magnetic resonance imaging-influenced diagnostic criteria and several immunomodulatory drugs have substantively altered the clinical course of the disease The area of neuromuscular diseases has been influenced enormously by the use of potent treatment for immune-mediated diseases and better diagnostic precision using molecular techniques applied to blood and muscle biopsy specimens Pain management has become an art and science of its own, deserving of its own chapter in this edition The triptan drugs, currently numbering seven, have changed the approach to migraine, and many other headache syndromes are now more clearly classified and specifically treated The management of acute stroke has dramatically changed even in the four years since the th edition, with widespread use of not only intravenous thrombolytic drugs but also sophisticated interventional techniques aimed at extracting cerebral emboli and opening narrowed vessels with angioplasty and stenting The advances in Parkinson disease and other movement disorders reflect the widespread availability of new dopamine receptor agonists and the use of deep brain stimulation in advanced and drug-resistant disease Even Alzheimer disease is now treated with some success using a class of anticholinesterase drugs, and other dementias are more clearly classified and managed Neuroophthalmology has become a major segment of neurologic practice, a fact that is reflected in an entire chapter now dedicated to that group of disorders The most prevalent of the toxic and metabolic disorders have undergone an alteration in approach based on a better understanding of the nervous system’s reaction to perturbations in its milieu Moreover, the array of infectious agents affecting the nervous system continues to change as new diseases emerge and the approach with antibiotics undergoes reassessment The 17 chapters of the 7th edition of the Manual of Neurologic Therapeutics are all brand new; all written by noted experts in the particular area Emphasis has been placed on practical management, with consideration of the essentials of diagnosis and pathophysiology The impressive progress in neurologic therapeutics is seen in the increased bulk of the book, now twice its original size To complete the quarter century cycle since the book was first published, the foreword to the th edition is written by Dr Raymond D Adams, to whom the 1st edition was dedicated Martin A Samuels Boston, Massachusetts Contents Authors DEDICATION FOREWORD PREFACE TO THE FIRST EDITION PREFACE Contents Coma, Head Trauma, and Spinal Cord Injury Epilepsy Dizziness Neck and Back Pain Sleep Disorders Neurooncology Multiple Sclerosis and Other Demyelinating Diseases Motor Neuropathies and Peripheral Neuropathies Neuromuscular Junction Disorders and Myopathies 10 Chronic Pain 11 Headache and Facial Pain 12 Stroke and Cerebrovascular Disorders 13 Movement Disorders 14 Behavioral Neurology and Dementia 15 Neuroophthalmology 16 Toxic and Metabolic Disorders 17 Infections of the Central Nervous System Subject Index P.304 TABLE 9-3 CONGENITAL MYOPATHIES Disease Inheritance Gene/Chromosome Central core myopathy AD Ryanodine receptor (RYR1)/19q13.1 Multicore/minicore myopathy AD, AR, sporadic Some caused by mutations in Selenoprotein N1 AR AR/AD Nebulin/2q21.2-q22; α-actin/1q42 Mild early onset form AD Rare: α-tropomyosin (TMP3)/1q21-q23 NOTE: Most AD kinships not map to this locus Adult onset form Sporadic Unknown X-linked Myotubularin/Xp28 Late infantile type AR, perhaps AD Unknown Late childhood/adult type AD Unknown Congenital fiber type disproportion Sporadic Unknown Reducing body myopathy Most appear sporadic; ? AR in some Unknown Fingerprint body myopathy Most sporadic Unknown Sarcotubular myopathy Unknown Hyaline body myopathy Unknown; Single report in two brothers Unknown; single case Sporadic or AR Cap myopathy Unknown Unknown Zebra body myopathy Unknown Unknown Myofibrillar myopathy (desmin myopathy, cytoplasmic or spheroid body myopathy) AD AR Sporadic Desmin/2q35 αB-crystallin/11q21 ?/chromosome 12 Desmin/2q35 unknown Tubular aggregate myopathy Type AD Unknown Type AR Unknown Type Sporadic Unknown Nemaline myopathy Severe infantile form Centronuclear/myotubular myopathy Severe neonatal type Trilaminar myopathy Unknown Unknown Clinical Features Onset: Infancy or childhood, occasionally adulthood; proximal limbs and mild facial weakness; skeletal anomalies; risk for MH Onset: Infancy or childhood; proximal and facial muscles; rare EOM weak; cardiomyopathy and respiratory weakness; skeletal anomalies; risk for MH Infantile onset: severe generalized hypotonia/weakness; respiratory weakness; skeletal anomalies; usually fatal in first year of life Most common subtype Onset: Infancy or childhood; mild generalized hypotonia and weakness; facial muscles; rare ptosis, EOM weak; dysmorphic facies and skeletal anomalies Onset in adult life; mild proximal and occasionally distal weakness; no facial or skeletal anomalies Severe neonatal hypotonia and weakness; respiratory weakness; ptosis and EOM weak; poor prognosis in most Most common subtype Onset: Late infancy or early childhood; generalized weakness and hypotonia; facial and EOM weakness, ptosis; facial anomalies Onset in late childhood or adulthood; mild proximal and/or distal predominance; facial and EOM muscles variable involved: no skeletal or facial anomalies Onset in infancy; generalized nonprogressive weakness; occasional respiratory weakness; skeletal and facial anomalies Onset in infancy to adulthood; generalized or proximal weakness; May have facial, respiratory or asymmetric weakness; skeletal anomalies Infantile onset; Slowly or nonprogressive proximal weakness Onset: Infancy; slow progressive proximal with or without distal weakness Infantile onset; generalized weakness; skeletal anomalies Onset in infancy or early childhood; proximal or scapuloperoneal weakness Onset in infancy; generalized weakness; skeletal anomalies Onset in infancy or childhood; generalized weakness that may be asymmetric and worse in arms Onset in infancy or late adulthood; distal, scapuloperoneal, or generalized weakness; cardiomyopathy Onset: Childhood or early adulthood; limb-girdle weakness Onset: Infancy; congenital myasthenia; fatigable weakness Adult onset: myalgia AD, autosomal dominant; AR, autosomal recessive; EOM weakness, ophthalmoparesis; BSAPPs, brief duration, small amplitude, polyphasic potentials P.305 P.306 PATHOPHYSIOLOGY A variety of mutations has been identified for the specific forms of congenital myopathy PROGNOSIS The congenital myopathies were initially considered as nonprogressive, although it is now clear that progressive weakness can occur Some forms are particularly associated with a poor prognosis and death in infancy or early childhood (e.g., X-linked myotubular myopathy, infantile-onset nemaline rod myopathy) DIAGNOSIS Congenital myopathies can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern Definitive diagnosis of a congenital myopathies requires muscle biopsy The serum CK level is either normal or only mildly elevated Nerve conduction studies are normal EMG demonstrates increased muscle membrane instability and myopathic motor units in myotubular/centronuclear, myofibrillar, and occasionally nemaline and central core myopathies Genetic testing is not commercially available TREATMENT There are no medical treatments available to improve strength or slow deterioration Treatment is largely supportive as discussed with the muscular dystrophies Physical and occupational therapies are important to reduce contractures and improve mobility and function Patients may benefit from bracing and other orthotic devices It is important to advise patients and families of the risk of MH in central core and multicore myopathies ACID MALTASE DEFICIENCY Part of "9 - Neuromuscular Junction Disorders and Myopathies " BACKGROUND Acid maltase deficiency is an autosomal recessive disorder caused by defects in the lysosomal acid maltase (α-glucosidase) pathway There are three recognized clinical subtypes of acid maltase deficiency: o o o A severe infantile form (also known as Pompe disease) A juvenile-onset type An adult-onset variant The incidence is the less than 1/100,000 newborns PATHOPHYSIOLOGY The disorder is caused by mutations encoding for acid maltase (α-glucosidase) on chromosome 17q21-23 P.307 PROGNOSIS Infantile acid maltase deficiency is progressive and invariably fatal by years of age secondary to cardiorespiratory failure Respiratory failure usually leads to death in the second or third decade of life in the juvenile form of the disease DIAGNOSIS Clinical Features Infantile acid maltase deficiency: o o The cardinal features of the disease include profound cardiomegaly, macroglossia, and mild to moderate hepatomegaly Infants demonstrate progressive weakness and hypotonia within the first months of life Feeding difficulties and respiratory muscle weakness are common The juvenile form of the disease usually presents in the first decade of life with proximal greater than distal weakness and respiratory muscle weakness The adult-onset form of acid maltase deficiency usually begins in the third or fourth decade with generalized proximal greater than distal muscle weakness and the respiratory muscles weakness Laboratory Features Deficiency of α-glucosidase activity can be demonstrated in muscle fibers, fibroblasts, leukocytes, lymphocytes, and urine Echocardiograms can show progressive hypertrophic cardiomyopathy Serum CK levels are elevated to variable degrees in all forms of the disease ECGs can demonstrate left axis deviation, a short PR interval, large QRS complexes, inverted T waves, ST depression, or persistent sinus tachycardia Pulmonary function tests show a restrictive defect with decreased FVC, reduced maximal inspiratory and expiratory pressures, and early fatigue of the diaphragm Electrophysiologic Findings Sensory and motor nerve conduction are typically normal Needle EMG reveals abundant fibrillation potentials, positive sharp waves, and myotonic or pseudomyotonic potentials Voluntary MUAPs demonstrate the typical alterations noted in chronic myopathic disorders Histopathology The characteristic light microscopy feature is the formation of vacuoles within type and fibers The vacuoles react strongly to periodic acid—Schiff (PAS) and are sensitive to diastase These vacuoles also stain intensely to acid phosphatase confirming that the vacuoles filled with glycogen are secondary lysosomes TREATMENT There is no specific treatment for acid maltase deficiency other than supportive therapy for associated cardiorespiratory complications Respiratory muscles can be affected preferentially and therefore one must follow the pulmonary functions closely Early respiratory insufficiency may be managed by noninvasive mechanical ventilatory support (e.g., BiBAP) Prenatal diagnosis is possible with amniocentesis or chorionic villous sampling DEBRANCHER ENZYME DEFICIENCY Part of "9 - Neuromuscular Junction Disorders and Myopathies " P.308 BACKGROUND Debrancher enzyme deficiency, also known as Cori—Forbes disease, accounts for approximately 25% of glycogen storage disease PATHOPHYSIOLOGY Caused by mutations in the debrancher enzyme gene located on chromosome 1p21 PROGNOSIS The course is slowly progressive but mild, and life span is not affected DIAGNOSIS Clinical Features Onset of muscle weakness is usually in the third to fourth decade of life and is slowly progressive Approximately, one third of the cases begin in infancy or early childhood, and motor milestones can be delayed There is prominent atrophy and weakness of distal limb muscles in about 50% of patients Cardiomyopathy can also complicate debrancher deficiency LABORATORY FEATURES Debrancher enzyme deficiency can be demonstrated with biochemical assay of muscle, fibroblasts, or lymphocytes Serum CK levels are elevated two to 20 times normal ECGs can reveal conduction defects and arrhythmias Echocardiogram may reveal findings suggestive of hypertrophic obstructive cardiomyopathy Electrophysiologic Findings Sensory and motor nerve conduction are typically normal Needle EMG reveals abundant fibrillation potentials, positive sharp waves, and myotonic or pseudomyotonic potentials Voluntary MUAPs demonstrate the typical alterations noted in chronic myopathic disorders Histopathology Muscle biopsies demonstrate a vacuolar myopathy with abnormal accumulation of glycogen in the subsarcolemmal and intermyofibrillar regions of muscle fibers These vacuoles stain intensely with PAS but are partially diastase-resistant Furthermore, in contrast to acid maltase deficiency, these vacuoles not stain with acid phosphatase, suggesting that the glycogen does not primarily accumulate in lysosomes TREATMENT There is no specific medical therapy for the muscle weakness P.309 Patients are best managed by preventing fasting hypoglycemia through frequent low-carbohydrate feedings and maintaining a high-protein intake Supportive therapy is required for patients with clinical manifestations of congestive heart failure BRANCHING ENZYME DEFICIENCY Part of "9 - Neuromuscular Junction Disorders and Myopathies " BACKGROUND Branching enzyme deficiency, also known as Andersen disease and polyglucosan body disease, is caused by the deficiency of the enzyme capable of creating the branched glycogen molecule, which results in an accumulation of polysaccharide in the liver, CNS, and skeletal and cardiac muscles PATHOPHYSIOLOGY Caused by mutations within the gene for glycogen branching enzyme located on chromosome PROGNOSIS Course is variable DIAGNOSIS Clinical Features There is a neuromuscular form of the disease with which patients manifest primarily with muscle weakness and cardiomyopathy Weakness and atrophy can be predominantly proximal or distal There is also a form of branching enzyme deficiency, often referred to as polyglucosan body disease, which manifests mainly in adults as progressive upper and lower motor neuron loss, sensory nerve involvement, cerebellar ataxia, neurogenic bladder, and dementia Laboratory Features Deficiency of branching enzyme may be demonstrated in muscle The serum CK level may be normal or slightly elevated ECG can demonstrate progressive conduction defects leading to complete AV block Echocardiogram may reveal a dilated cardiomyopathy Electrophysiologic Findings Sensory and motor nerve conduction findings are typically normal Needle EMG reveals abundant fibrillation potentials, positive sharp waves, and myotonic or pseudomyotonic potentials Voluntary MUAPs demonstrate the typical alterations noted in chronic myopathic disorders Histopathology Routine light and electron microscopy reveal deposition of varying amounts of finely granular and filamentous polysaccharide (polyglucosan bodies) in the CNS, peripheral nerves (axons and Schwann cells), skin, liver, and cardiac and skeletal muscles These polyglucosan bodies are PAS-positive and diastase-resistant P.310 TREATMENT Liver transplantation has been performed in some children No other medical therapies have been demonstrated to be effective Long-term follow-up (mean, 42 months) has shown that most of the patients became free of liver, neuromuscular, and cardiac dysfunction Treatment is otherwise supportive DYNAMIC GLYCOGEN STORAGE DISORDERS Part of "9 - Neuromuscular Junction Disorders and Myopathies " BACKGROUND These include myophosphorylase (McArdle disease), phosphofructokinase, phosphorylase b kinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, and β-enolase deficiencies and are very similar and are associated with exertional cramps and occasionally myoglobinuria with mild exercise Thus, these are considered the dynamic glycogen storage disorders as opposed to the above-described acid maltase, debrancher, and branching enzyme deficiencies that are associated with nondynamic, fixed weakness PATHOPHYSIOLOGY These disorders are caused by mutations in the respective genes PROGNOSIS Approximately 50% of patients experience myoglobinuria related to exercise, while a third of these individuals have various degrees of renal failure As many as one third of patients develop mild, fixed proximal weakness as a result of recurrent bouts of rhabdomyolysis DIAGNOSIS Clinical Features The major symptom is exercise intolerance, which usually starts in childhood Exertional muscle pain, cramps, and myoglobinuria develop later and the diagnosis is usually made by the second or third decade of life Some patients note a second-wind phenomena in which after the onset of mild exertional myalgias or cramps, the individual may continue with the exercise at the previous or a slightly reduced level following a brief period of rest Overt myoglobinuria is rarely noted in children and primarily manifests in the second or third decades Most patients essentially have normal physical examinations between attacks of muscle cramping Laboratory Features Serum CK levels are invariably elevated at baseline The exercise forearm test can be used to diagnosis various disorders of glycolysis o The forearm muscles are exercised by having the patient rapidly and strenuously open and close the hand for minute Immediately after exercise and then 1, 2, 4, 6, and 10 minutes after exercise, blood samples are again taken and analyzed for lactate and ammonia P.311 o o The normal response is for lactate and ammonia levels to rise three to four times the baseline levels o A rise in lactate levels but not ammonia is seen in myoadenylate deaminase deficiency (probably nonpathogenic deficiency) o In myophosphorylase, phosphofructokinase, phosphoglycerate mutase, phosphoglycerate kinase, phosphorylase B kinase, β-enolase, and lactate dehydrogenase deficiencies, the ammonia levels rise appropriately, but the lactic acid does not If neither the lactate nor the ammonia levels increase, the test is inconclusive and implies that the muscles were not sufficiently exercised Electrodiagnostic Findings EMG and nerve conduction studies are usually normal Histopathology Excessive accumulation of glycogen in the subsarcolemmal and intermyofibrillar areas are usually observed on light microscopy and EMG Staining for myophosphorylase and phosphofructokinase can be performed and absence of staining is evident in these disorders Enzyme activities can be assayed for definitive diagnosis of the specific subtypes of glycogen storage disease TREATMENT Intense isometric exercises such as weight lifting and maximum-aerobic exercises such as sprinting should be avoided Patients with McArdle disease should be instructed on moderating their physical activity and in obtaining a ―second wind‖ response Any bout of moderate exercise should be preceded by to 15 minutes of low-level warm-up activity to promote the transition to the second wind Oral glucose or fructose loading before activities may be effective in McArdle disease but may be deleterious in phosphofructokinase deficiency Patients with myoglobinuria should be admitted to the hospital and hydrated to prevent acute tubular necrosis Patients may benefit from a mild to moderate aerobic conditioning A mild to moderate exercise program improves exercise capacity by increasing cardiovascular fitness and the supply of necessary metabolic substrates to muscle CARNITINE DEFICIENCY Part of "9 - Neuromuscular Junction Disorders and Myopathies " BACKGROUND Carnitine deficiency is the most common disorder of lipid metabolism Carnitine deficiency systemic or only evident in muscle Muscle carnitine deficiency may be primary or secondary to some other myopathic disorder PATHOPHYSIOLOGY Primary carnitine deficiency has been linked to mutations in the sodium-dependent carnitine transporter protein gene (OCTN2) located on chromosome 5q33.1 P.312 PROGNOSIS Course and response to replacement therapy with carnitine are variable DIAGNOSIS Clinical Features Primary muscle carnitine deficiency usually manifests in childhood or early adult life, but infantile onset has also been described Progressive proximal muscle weakness and atrophy develop Cardiac involvement with ventricular hypertrophy, congestive heart failure, and arrhythmias occurs in some patients A secondary deficiency of carnitine may result from a variety of disorders, including respiratory chain defects, organic aciduria, endocrinopathies, dystrophies, renal and liver failure, and malnutrition or as a toxic effect of certain medications It is not clear whether patients with secondary carnitine deficiency truly develop myopathic symptoms Laboratory Features Plasma and tissue carnitine levels are severely decreased in the primary systemic carnitine deficiency, whereas the deficiency is much less (25%—50% normal) in secondary forms of carnitine deficiency Only muscle carnitine levels are decreased in primary muscle carnitine deficiency Serum CK levels are normal in approximately 50% of patients with the myopathic form of the disease but can be elevated to as much as 15 times normal Electrophysiologic Findings Motor and sensory nerve conduction studies are normal Needle EMG is often normal but some patients with profound weakness have increased insertional activity Short-duration, small-amplitude, polyphasic MUAPs that recruit early can be observed Histopathology Muscle fibers contain numerous vacuoles and abnormal accumulation of lipid Muscle carnitine level is dramatically decreased (less than to 4% of normal) TREATMENT Oral L-carnitine (2—6 g/d) has benefited some, but not all patients, with carnitine deficiency Treatment is otherwise supportive CARNITINE PALMITYLTRANSFERASE (CPT) DEFICIENCY Part of "9 - Neuromuscular Junction Disorders and Myopathies " BACKGROUND Carnitine palmitoyltransferase (CPT) deficiency is the most common cause of myoglobinuria P.313 PATHOPHYSIOLOGY Caused by mutations in the CPT2 gene located on chromosome 1p32 Deficiency of CPT impairs the transport of acylcarnitine across the inner mitochondrial membrane Thus, the generation of ATP from fatty-acid metabolism is impaired PROGNOSIS Persistent weakness after attacks of myoglobinuria is uncommon but may occur DIAGNOSIS Clinical Features The typical clinical presentation is muscular pain and cramping following intense or prolonged exertion Symptoms may also be triggered by fasting or recent infection Myoglobinuria is a common feature of this disease and renal failure can occur Most patients become symptomatic by the second decade Between attacks, the physical examination is usually normal Laboratory Features Serum CK levels are usually normal, except when the patient performs intense physical activities or fasts for prolonged periods Electrophysiologic Findings EMG and NCS findings are typically normal between attacks of myoglobinuria Histopathology There is usually no gross abnormality noted on light microscopic examination of muscle tissue An increase in the lipid content of muscle is detectable in muscle tissue examined by EMG Enzyme analysis on muscle tissue can confirm the deficiency TREATMENT Patients with CPT deficiency should be cautioned to avoid any situation that provokes muscle pain and puts them at risk for myoglobinuria The physiologic effect of fasting should be explained, and the patient should be warned not to attempt exercise under such conditions The use of glucose tablets or candy bars during exercise may raise exercise tolerance slightly If myoglobinuria is noted, the patient should be admitted to the hospital, and renal function should be monitored MITOCHONDRIAL MYOPATHIES Part of "9 - Neuromuscular Junction Disorders and Myopathies " BACKGROUND Refers to disorders with identifiable mitochondrial DNA mutations, enzyme deficiencies, and structural abnormalities P.314 Mitochondrial DNA (mtDNA) encodes for 22 transfer RNA (tRNAs), two ribosomal RNAs (rRNAs), and 13 mRNAs There appears to be some nuclear control of replication of the mitochondrial genome The 13 mRNAs are translated into 13 polypeptide subunits of the respiratory chain complexes Most mitochondrial proteins are encoded by nuclear DNA and these proteins are translated in the cytoplasm and subsequently are transported into the mitochondria PATHOPHYSIOLOGY Mutations have been identified in several of the mtDNA genes encoding for tRNA Disorders with these mutations [e.g., myoclonic epilepsy and ragged red fibers (MERRFs) and mitochondrial myopathy lactic acidosis and stroke (MELAS)] have a typical mitochondrial inheritance pattern (e.g., only from mother to both male and female children) Some disorders are caused by mutations in nuclear genes responsible for replication of mtDNA [e.g., mitochondrial DNAdepletion syndromes, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), and progressive external ophthalmoplegia (PEO)] These disorders may be inherited in an autosomal recessive or dominant manner Other disorders are associated with single large deletions of mtDNA but occur sporadically [e.g., Kearn—Sayre syndrome (KSS)] PROGNOSIS Dependent of the specific subtype A reduced life expectancy is associated with most of the disorders DIAGNOSIS Clinical Features The clinical presentations of the different forms of mitochondrial myopathies are quite heterogeneous Findings include short stature, scoliosis, ptosis, ophthalmoparesis, proximal weakness, cardiomyopathy, neuropathy, hearing loss, optic neuropathy, pigmentary retinopathy, endocrinopathy, myoclonic seizures, ataxia, headaches, stroke-like symptoms (including cortical blindness), gastroparesis, and intestinal pseudoobstruction Laboratory Features Serum CK may be normal or elevated ECG may show conduction abnormalities in some disorders (e.g., KSS) Serum and CSF lactate levels may be normal or elevated Histopathology The histopathologic abnormalities on muscle biopsies of the various mitochondrial myopathies are nonspecific Oxidative enzyme stains (NADH, SDH, and COX) are also routinely used to diagnose mitochondrial myopathies Mitochondrial abnormalities are reflected on the modified Gomori trichrome stain in which subsarcolemmal accumulation of abnormal mitochondria stains red and gives the abnormal muscle fibers their characteristic appearance (ragged red fibers) P.315 Ultrastructural alterations in mitochondria are apparent on EMG These abnormalities include an increased number of normal-appearing mitochondria, enlarged mitochondria with abnormal cristae, and mitochondria with paracrystalline inclusions Specific mitochondrial enzymes (components of the respiratory chain) may show reduced activity Genetic testing: o Mutations in mitochondrial DNA may be demonstrated in leukocytes but specificity is increased looking for the mutations in muscle tissue TREATMENT There are no proven medical therapies for most mitochondrial myopathies Patients and their physicians need to be aware that patients with mitochondrial myopathies can be very sensitive to sedating medications and anesthetic agents leading to alveolar hypoventilation and respiratory failure Hormone replacement is given for associated specific endocrinopathies Ankle foot orthoses may be beneficial in patients with distal lower limb weakness I recommend patients take coenzyme Q (children's dose is 30 mg daily; adults are given 150—1,200 mg daily) Likewise, I tell patients to take creatine monohydrate (5—10 g/d) Patients with MERRF and an associated myoclonic seizure disorder should be treated with antiepileptic medication (e.g., valproic acid) Pacemaker insertion may be required because of the associated cardiac 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Association of Neurological Surgeons (AANS), and the Joint Section on Neurotrauma & Critical Care of the AANS and Congress of Neurological Surgeons P .16 ACUTE SPINAL CORD INJURY Part of "1 - Coma,... and Myopathies 10 Chronic Pain 11 Headache and Facial Pain 12 Stroke and Cerebrovascular Disorders 13 Movement Disorders 14 Behavioral Neurology and Dementia 15 Neuroophthalmology 16 Toxic and... antibiotics undergoes reassessment The 17 chapters of the 7th edition of the Manual of Neurologic Therapeutics are all brand new; all written by noted experts in the particular area Emphasis has been