Clinical Neurology 5th edition (February 9, 2002): by David A. Greenberg, Michael J. Aminoff, Roger P. Simon By McGraw-Hill/Appleton & Lange By OkDoKeY Clinical Neurology Contents Editors Dedication Preface Chapter 1: Disorders of Consciousness Chapter 2: Headache & Facial Pain Chapter 3: Disorders of Equilibrium Chapter 4: Disturbances of Vision Chapter 5: Motor Deficits Chapter 6: Disorders of Somatic Sensation Chapter 7: Movement Disorders Chapter 8: Seizures & Syncope Chapter 9: Stroke Chapter 10: Coma Chapter 11: Neurologic Investigations Appendices A: The Neurologic Examination B: A Brief Examination of the Nervous System C: Clinical Examination of Common Isolated Peripheral Nerve Disorders Frequently Used Neurological Drugs Selected Neurogenetic Disorders Dedication To Our Families Editors David A. Greenberg, MD, PhD Professor and Vice-President for Special Research Programs Buck Institute for Age Research Novato, California Michael J. Aminoff, MD, DSc, FRCP Professor of Neurology Department of Neurology School of Medicine University of California, San Francisco Roger P. Simon, MD Robert Stone Dow Chair of Neurology Director of Neurobiology Research Legacy Health Systems Portland, Oregon Frequently Used Neurological Drugs Drug Brand Use Sizes (mg)1 Usual dose2 Alteplase (rt-PA) Activase Stroke — 0.9 mg/kg IV Amantadine Symmetrel Parkinsonism 100 100 mg bid Amitriptyline Elavil Headache, pain 10,25,50,75,100,150 10–150 mg qd Aspirin Ecotrin TIA/stroke, headache 81,325,500,650,975 81 mg qd–650 mg q4–6h Baclofen Lioresal Spasticity 10,20 5 mg tid–20 mg qid Benztropine Cogentin Movement disorders 0.5,1,2 1–2 mg qd–bid Bromocriptine Parlodel Parkinsonism 2.5,5 1.5–20 mg bid Carbamazepine Tegretol Seizures, pain 100,200,400 200–600 mg bid Carbidopa/levodopa Sinemet Parkinsonism 10/100,25/100,25/250, 50/200 25/250 mg tid–qid Clonazepam Klonopin Seizures, myoclonus 0.125,0.25,0.5, 1,2 0.5–6.5 mg tid Clopidogrel Plavix TIA/stroke 75 75 mg qd Cyclobenzaprine Flexeril Pain 10 10–20 mg tid Dihydroergotamine Migranal Headache 4 4 mg IN Donepezil Aricept Alzheimer's disease 5, 10 5–10 mg qhs Entacapone Comtan Parkinsonism 200 200 mg up to 5 times daily Ethosuximide Zarontin Seizures 250 250–500 mg qd Fosphenytoin Cerebyx Seizures 150,750 22.5–30 mg/kg IV Gabapentin Neurontin Seizures, pain 100,300,400 300–1200 mg tid Glatiramer Copaxone Multiple sclerosis 20 20 mg SC qd Haloperidol Haldol Movement disorders 0.5, 1,2,5,10,20 1–5 mg tid Heparin — TIA/stroke — 1000 U/hr3 Ibuprofen Motrin Headache, pain 200,300,400,600,800 200–800 mg qid Indomethacin Indocin Headache, pain 25,50,75 25–50 mg tid Interferon beta-1A Avonex Multiple sclerosis 0.003 0.003 mg IM q week Interferon beta-1b Betaseron Multiple sclerosis 0.25 0.25 mg Lamotrigine Lamictal Seizures 25,100,150,200 150–250 mg bid Meclizine Antivert Vertigo 12.5, 25, 50 25 mg q6h Metoclopramide Reglan Headache 5,10 10–30 mg qid Naproxen Naprosyn Headache, pain 200,250,375,500 250–500 mg bid Naratriptan Amerge Headache 1,2.5 2.5 mg q4h × 1–2 Nimodipine Nimotop Subarachnoid hemorrhage 30 60 mg q4h Nortriptyline Pamelor Headache, pain 10,25,50,75 10–150 mg qhs Pergolide Permax Parkinsonism 0.05,0.25,1 1–5 mg tid Phenobarbital Luminal Seizures 15,30,60,100 60 mg bid–tid Phenytoin Dilantin Seizures, pain 30,50,100 300–400 mg qd Pramipexole Mirapex Parkinsonism 0.125,0.25,1,1.5 0.5–1.5 mg tid Primidone Mysoline Seizures, tremor 50,250 250 mg tid–qid Prochlorperazine Compazine Headache 5,10,25 5–10 mg tid–qid Propranolol Inderal Headache, tremor 10,20,40,80,90,120,160 20–120 mg bid Pyridostigmine Mestinon Myasthenia gravis 60,180 6–120 mg tid Riluzole Rilutek ALS 50 50 mg q12h Ropinirole Requip Parkinsonism 0.25,0.5,1 0.25–8 mg tid Selegiline Eldepryl Parkinsonism 5 5 mg bid Sumatriptan Imitrex Headache 25,50,100 PO; 6 SC; 5,20 nasal spray 25–100 mg × 1–3; 6 mg SC × 1–2; 20 mg IN × 1–2 Tacrine Cognex Alzheimer's disease 10,20,30,40 10–20 mg qid Tiagabine Gabitril Seizures 4,12,16,20 8–28 mg bid Ticlopidine Ticlid TIA/stroke 250 250 mg bid Tolcapone Tasmar Parkinsonism 100,200 100–200 mg tid Topiramate Topamax Seizures 25,100,200 200 mg bid Trihexyphenidyl Artane Movement disorders 2,5 1 mg qd–5 mg tid Valproic acid Depakote Seizures, headache 125,250,500 250–650 mg tid Verapamil Calan Headache 40,80,120,180,240 80 mg tid Vigabatrin Sabril Seizures 500 1–4 g/d Warfarin Coumadin TIA/stroke 1,2,2.5,3,4,5,6,7.5,10 5 mg qd4 Zolmitriptan Zomig Headache 2.5,5 2.5 mg q2h × 1–4 Zonisamide Zonegran Seizures 100 100–400 mg/d 1 Includes extended- or sustained-release preparations, but not liquid formulations. 2 Typical maintenance doses in adults, given orally unless stated otherwise (IM = intramuscular; IN = intranasal, IV = intravenous, SC = subcutaneous). Consult prescribing information for indications and contraindications, drug interactions, adverse drug effects, safety in pregnancy and breastfeeding, doses in hepatic or renal failure, and recommended initial doses. 3 Adjusted according to partial thromboplastin time (PTT) or international normalized ratio (INR). 4 Adjusted according to prothrombin time (PT) or international normalized ratio (INR). Preface The fifth edition of Clinical Neurology, like its predecessors, offers a problem-oriented approach to neurology based on the authors' experience in teaching medical students and house staff at the University of California, San Francisco. Chapters are organized according to problems such as headache, seizures, stroke, and coma, because these are the conditions for which patients usually seek medical care. Careful history taking and neurologic examination are emphasized, as these remain the cornerstones of neurologic diagnosis, even in an era of technologic diagnostic advances. The need to update this book arises from two main sources: rapid expansion of knowledge about the molecular basis of neurologic diseases and recent innovations in the treatment of disorders such as headache, epilepsy, stroke, Parkinson's disease, and multiple sclerosis. Accordingly, increased prominence has been given to molecular mechanisms of diseases—for example, Alzheimer's disease and the polyglutamine disorders, including Huntington's disease. Sections on treatment have been updated and expanded to reflect the introduction of new therapies for neurological disorders. The summary tables of therapeutic drugs and genetic disorders inside the front and back covers, which were introduced in the last edition, have been revised to maintain currency. Key Concepts is a new feature that has been introduced in this issue. In the beginning of each chapter, some of the major concepts are presented with numbered icons. These same numbered icons appear within the text to indicate where these specific points are discussed in the chapter. We thank our colleagues, who have contributed their expert advice to the preparation of this new edition of Clinical Neurology, especially Lydia Bayne, Megan Burns, Chadwick Christine, Paul Garcia, Alisa Gean, Cheryl Jay, Catherine Lomen-Hoerth, Neil Raskin, Tom Shults, and Norman So. The staff at McGraw-Hill have been enormously helpful in moving this book through editing and production. We hope our efforts will help to demystify clinical neurology for students and practitioners and contribute to providing patients better and more focused diagnosis and treatment. David A. Greenberg Michael J. Aminoff Roger P. Simon Novato, San Francisco, and Portland February 2002 Selected Neurogenetic Disorders Disorder Gene Locus Protein Inh1 PRE2 Alzheimer's disease, familial APP 21q21.3–q22.05 Amyloid b A4 precursor protein AD Alzheimer's disease, familial PS1 14q24.3 Presenilin-1 AD Alzheimer's disease, familial PS2 1q31–q42 Presenilin-2 AD Alzheimer's disease, susceptibility APOE 19q13.2 Apolipoprotein E AD Amyotrophic lateral sclerosis, familial SOD1 21q22.1 Superoxide dismutase-1 AD Ataxia-telangiectasia ATM 11q22.3 Unknown AR Benign neonatal epilepsy 1 KCNQ2 20q13.2 Voltage-gated K channel AD Benign neonatal epilepsy 2 KCNQ3 8q24 Voltage-gated K channel AD CADASIL3 NOTCH3 19p13.2–p13.1 Notch-3 AD Centronuclear myopathy MYF6 12q21 Myogenic factor-6 AD Cerebral amyloid angiopathy CST3 20p11 Cystatin C AD Charcot-Marie-Tooth disease, type IA PMP22 17p11.2–p12 Peripheral myelin protein-22 AD Charcot-Marie-Tooth disease, type IB MPZ 1q22 Myelin protein zero AD Charcot-Marie-Tooth disease, X-linked CX32 Xq13.1 Connexin-32 XLR Choreoacanthocytosis CHAC 9q21 Chorein AR Creutzfeldt-Jakob disease, familial PRNP 20pter-p12 Prion protein AD Dentatorubral-pallidoluysian atrophy DRPLA 12p13.31 Atrophin-1 AD CAG Duchenne/Becker dystrophy DMD Xp21.2 Dystrophin XLR Emery-Dreifuss muscular dystrophy LMNA 1q21.2 Lamin A/C AD/AR Episodic ataxia 1 KCNA1 12p13 Shaker-related K channel AD Episodic ataxia 2 CACNL1A4 19p13 Ca channel a 1A subunit AD Familial hemiplegic migraine 1 CACNL1A4 19p13 Ca channel a 1A subunit AD Friedreich's ataxia FRDA1 9q13–q21.1 Frataxin AR GAA Generalized epilepsy with febrile seizures plus 1 SCN1B 19q13 Na channel type 1, b1 subunit AD Generalized epilepsy with febrile seizures plus 2 SCN1A 2q24 Na channel type 1, a subunit AD Generalized epilepsy with febrile seizures plus 3 GABRG2 5q31.1–q33.1 GABA receptor, g subunit AD A 2 Hereditary spastic paraplegia SPG7 16q24.3 Paraplegin AR Huntington's disease HD 4p16.3 Huntingtin AD CAG Hyperkalemic periodic paralysis SCN4A 17q23.1–q25.3 Na channel type IV, a subunit AD Hypokalemic periodic paralysis CACNL1A3 1q32 Ca channel a subunit AD 1S Limb-girdle dystrophy 1A TTID 5q31 Myotilin AD Limb-girdle dystrophy 1C CAV3 3p25 Caveolin-3 AD Limb-girdle dystrophy 2A CAPN3 15q15.1–q21.1 Calpain-3 AR Limb-girdle dystrophy 2B DYSF 2p13.3–13.1 Dysferlin AR Limb-girdle dystrophy 2D SGCA 17q12 a-Sarcoglycan AR Limb-girdle dystrophy 2E SGCB 4q12 b-Sarcoglycan AR Limb-girdle dystrophy 2F SGCD 5q3 d-Sarcoglycan AR Limb-girdle dystrophy 2G TCAP 17q12 Telethonin AR Malignant hyperthermia/central core RYR1 19q13.1 Ryanodine receptor AD MELAS4 MTTL1 — (Mitochondrial tRNA for leucine) Mito Ménière's disease COCH 14q12–q13 Cochlin AD MERRF5 MTTK — (Mitochondrial tRNA for lysine) Mito Myoclonic epilepsy CSTB 21q22.3 Cystatin B AR Myotonia congenita CLCN1 7q35 Chloride channel 1 AD/XLR Myotonic dystrophy 1 DMPK 19q13.2–13.3 Myotonin-protein kinase AD CTG Nemaline myopathy 1 TPM3 1q22–q23 Tropomyosin-3 AD Nemaline myopathy 1 or 2 ACTA1 1q42.1 Skeletal muscle type 4, a-actin AD/AR Nemaline myopathy 2 NEB 2q22 Nebulin AR Neurofibromatosis 1 NF1 17q11.2 Neurofibromin AD Neurofibromatosis 2 NF2 22q12.2 Schwannomin AD Nocturnal frontal lobe epilepsy 1 CHRNA4 20q13.2–q13.3 Nicotinic receptor, a subunit AD 4 Nocturnal frontal lobe epilepsy 3 CHRNB2 1p21 Nicotinic receptor, b subunit AD 2 Oculopharyngeal dystrophy PABP2 14q11.2–q13 Poly(A)-binding protein-2 AD Paramyotonia congenita SCN4A 17q23.1–q25.3 Na channel type 4, a subunit AD Parkinson's disease, familial type 1 SNCA 4q21–q23 a-Synuclein AD Parkinson's disease, juvenile PDJ 6q25.2–q27 Parkin AR Rippling muscle disease CAV3 3p25 Caveolin-3 AD Spinal and bulbar muscular atrophy AR Xq11–q12 Androgen receptor XLR CAG Spinal muscular atrophy, types I-III SMN1, NAIP 5q12.2–13.3 Survival motor neuron 1 ± neuronal apoptosis inhibitory protein AR Spinocerebellar ataxia 1 SCA1 6p23 Ataxin-1 AD CAG Spinocerebellar ataxia 2 SCA2 12q24 Ataxin-2 AD CAG Spinocerebellar ataxia 3 SCA3 14q24.3–q31 Ataxin-3 AD CAG Spinocerebellar ataxia 6 CACNL1A4 19p13 Ca channel a subunit AD CAG 1A Spinocerebellar ataxia 7 SCA7 3p21.1–p12 Ataxin-7 AD CAG Spinocerebellar ataxia 10 SCA10 22q13 Ataxin-10 AD ATTCT Spinocerebellar ataxia 12 SCA12 5q31–q33 Ataxin-12 AD CAG Torsion dystonia DYT1 9q34 TorsinA AD Wilson's disease ATP7B 13q14.3–q21.1 Cu-transporting ATPase a peptide AR 1 Inheritance (AD = autosomal dominant, AR = autosomal recessive, Mito = mitochondrial, XLR = X-linked recessive). 2 Polynucleotide repeat expansion (A = adenine, C = cytosine, G = guanine, T = thymine). CAG codes for glutamine. 3 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 4 Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. 5 Myoclonus epilepsy associated with ragged-red fibers. Chapter 1 Disorders of Consciousness Clinical Neurology Disorders of Consciousness 1 I. Approach to Diagnosis History General physical examination Neurologic examination Laboratory investigations II. Acute confusional states Drugs Endocrine disturbances Electrolyte disorders Nutritional disorders Organ system failure Meningitis, encephalitis & sepsis Vascular disorders Head trauma Seizures Psychiatric disorders III. Dementia Cerebral disorders without extrapyramidal features Cerebral disorders with extrapyramidal features Systemic disorders Pseudodementia IV. Amnestic syndromes Acute amnesia Chronic amnesia Chapter References KEY CONCEPTS Disorders of consciousness include disorders in which the level of consciousness (arousal or wakefulness) is impaired, such as acute confusional states and coma, and those in which the level of consciousness is normal but the content of consciousness (cognitive function) is altered, such as dementia and amnestic disorders. An acute confusional state can be most readily distinguished from dementia by the time course of the impairment: acute confusional states are acute or subacute in onset, typically developing over hours to days, whereas dementia is a chronic disorder that evolves over months or years. Certain causes of acute confusional state must be identified urgently because they may lead rapidly to severe structural brain damage or death, and prompt treatment can prevent these complications: hypoglycemia, bacterial meningitis, subarachnoid hemorrhage, and traumatic intracranial hemorrhage. The most common causes of dementia are Alzheimer's disease, dementia with Lewy bodies, and vascular dementia; treatable causes of dementia are rare, but are important to diagnose. Consciousness is awareness of the internal or external world, and disorders of consciousness can affect either the level of consciousness or the content of consciousness. Disturbances of the Level of Consciousness Abnormalities of the level of consciousness are characterized by impaired arousal or wakefulness, and they result from acute lesions of the ascending reticular activating system (Figure 1–1) or both cerebral hemispheres. The most severe degree of depressed consciousness is coma, in which the patient is unresponsive and unarousable. Less severe depression of consciousness results in an acute confusional state or delirium, in which the patient responds to at least some stimuli in a purposeful manner but is sleepy, disoriented, and inattentive. In some acute confusional states, agitation predominates or alternates with drowsiness, and may be accompanied by autonomic changes (fever, tachycardia, hypertension, sweating, pallor, or flushing), hallucinations, and motor abnormalities (tremor, asterixis, or myoclonus). Figure 1–1. Brainstem reticular activating system and its ascending projections to the thalamus and cerebral hemispheres. Disturbances of the Content of Consciousness Many pathologic conditions can impair the content of consciousness without altering the level of consciousness. Examples include isolated disorders of language or memory due to focal brain lesions and widespread deterioration of mental function ( dementia) from more diffuse, chronic pathologic processes. Dementia differs from acute confusional states in several respects (Table 1–1), and distinguishing between between these two syndromes is the pivotal step in evaluating a patient with altered consciousness. Table 1–1. Differences between acute confusional states and dementia. The time course of the disorder—acute or subacute in acute confusional states and chronic in dementia—is the single most helpful differentiating feature. Confusional states, dementia, and circumscribed memory disorders are discussed in this chapter. Coma is discussed in Chapter 10. I. APPROACH TO DIAGNOSIS Evaluation of the patient with a suspected disorder of consciousness is aimed first at characterizing the nature of the disorder (eg, acute confusional state, coma, dementia, amnestic syndrome) and second at determining the cause. The approach used is outlined below. HISTORY History of Present Illness The history should establish the time course of the disorder and provide clues to its nature and cause. Confusional states are acute to subacute in onset, whereas dementias are chronic disorders. In an acute confusional state, the observations of others may be the only historical information available. When dementia is suspected, it is useful to have access to a relative or close acquaintance who can furnish details about the patient's previous level of functioning; the time when dysfunction became evident; and the nature of any changes in personality, behavior, mood, intellect, judgment, memory, or facility with language. Associated problems such as gait disorders, incontinence, and headaches should also be explored. Prior Medical History A. CARDIOVASCULAR SYSTEM A history of stroke, hypertension, vasculitis, or cardiac disease may suggest a vascular cause of a confusional state or multiinfarct dementia. B. DIABETES Cognitive disturbance in diabetic patients may result from a hyperosmolar nonketotic state or insulin-induced hypoglycemia. C. SEIZURE DISORDER A history of epilepsy suggests ongoing seizures, a postictal state, or head trauma in a confused patient. D. HEAD TRAUMA Recent head trauma suggests intracranial hemorrhage. Remote head trauma may produce amnestic syndrome or chronic subdural hematoma with dementia. E. ALCOHOLISM Alcoholism predisposes patients to acute confusional states from intoxication, withdrawal, postictal state, head trauma, hepatic encephalopathy, and Wernicke's encephalopathy. Chronic memory disturbance in an alcoholic is likely due to Korsakoff's syndrome. F. DRUG HISTORY A confusional state can result from overdose with insulin, sedative-hypnotics, opioids, antidepressants, antipsychotic agents, or hallucinogens, or from sedative drug withdrawal. Elderly patients may be more sensitive to the cognitive side effects of drugs that are well tolerated by younger patients. G. PSYCHIATRIC HISTORY A history of psychiatric illness may suggest overdose with psychotherapeutic drugs such as benzodiazepines, antidepressants, or antipsychotic agents; a previously undiagnosed medical disorder capable of producing organic psychosis (hypothyroidism, vitamin B deficiency); or a functional disorder masquerading as an acute 12 confusional state or dementia. H. OTHER Individuals who engage in unprotected sexual intercourse, intravenous drug users, recipients of contaminated blood or clotting factor transfusions, the sexual partners of all these persons, and infants of infected mothers are at particular risk for developing acquired immunodeficiency syndrome (AIDS). Family History The family history can point to a heredodegenerative disorder, such as Huntington's disease, as the cause of dementia. GENERAL PHYSICAL EXAMINATION A general physical examination helps to classify the disorder as either an acute confusional state or dementia and may suggest a systemic disease as its cause (Table 1–2 and Table 1–3). Table 1–2. Clinical features helpful in the differential diagnosis of acute confusional states. Table 1–3. Clinical features helpful in the differential diagnosis of dementia. Vital Signs & General Appearance Fever, tachycardia, hypertension, and sweating occur in many confusional states, but meningitis or sepsis must receive early consideration in the febrile patient. Hypertension should raise the possibility of hypertensive encephalopathy, intracranial hemorrhage, renal disease, or Cushing's syndrome. Hypothermia occurs with exposure to cold, ethanol or sedative drug intoxication, hypoglycemia, hepatic encephalopathy, Wernicke's encephalopathy, hypothyroidism, or shock. In most dementias, the patient does not appear acutely ill unless a systemic disorder is also present. Skin & Mucous Membranes Jaundice suggests hepatic disease, and lemon-yellow coloration of the skin may occur in vitamin B deficiency. Coarse dry skin, dry brittle hair, and subcutaneous 12 edema are characteristic of hypothyroidism. Petechiae are seen in meningococcemia, and petechiae or ecchymoses may reflect coagulopathy caused by liver disease, disseminated intravascular coagulation, or thrombotic thrombocytopenia purpura. Hot, dry skin is characteristic of intoxication with anticholinergic drugs. Cushing's syndrome may be associated with acne. Hyperpigmentation of the skin may be evidence of Addison's disease. Needle tracks associated with intravenous drug use suggest drug overdose, AIDS, or infective endocarditis. Head & Neck Examination of the head may reveal signs of trauma, such as scalp lacerations or contusions, postauricular hematoma (Battle's sign), periorbital hematoma (raccoon eyes), hemotympanum, or cerebrospinal fluid (CSF) otorrhea or rhinorrhea. Percussion of the skull over a subdural hematoma may cause pain. Meningeal signs, such as neck stiffness on passive flexion, thigh flexion upon flexion of the neck (Brudzinski's sign), or resistance to passive extension of the knee with the hip flexed (Kernig's sign), are seen in meningitis and subarachnoid hemorrhage. Chest & Abdomen Cardiac murmurs may be associated with infective endocarditis and its neurologic sequelae. Abdominal examination may reveal a source of systemic infection or suggest liver disease. Rectal examination may provide evidence of gastrointestinal bleeding, which often precipitates hepatic encephalopathy. NEUROLOGIC EXAMINATION Mental Status Examination Evaluation of mental status (Table 1–4) helps to classify a disorder as a confusional state, dementia, a circumscribed cognitive disturbance (aphasia, amnesia), or a psychiatric illness. The mental status examination is most useful if performed in a standardized fashion, and complex functions can be adequately evaluated only when the basic processes upon which they depend are preserved. Thus, memory, language, calculation, or abstraction cannot be reliably assessed in a patient who is poorly arousable or inattentive. The Minimental Status Examination (Table 1–5) is often used as a rapid bedside screening test for dementia. Table 1–4. Comprehensive mental status examination.