THE NEUROLOGICAL EXAMINATION The history is MORE important than the exam

Neuro exam can be brief (screening) or more complex (comprehensive) depending on the clinical situation

SUBDIVISIONS OF NEURO EXAM Mentation and Communication, Cranial Nerves, Motor System, Sensory System, Reflexes, Cerebellar function, Station and Gait

EQUIPMENT Penlight, opthalmoscope, sharp object, tongue blade, cotton wisp/tissue, 125Hz tuning fork, reflex hammer

THE EXAM Mental Status Memory (especially short term) recall 3 objects at 5 min Orientation person, place (specifics), time, situation (why are they here) Attention digit span forward and backwards, spelling forwards and backwards (world) Calculations simple calculations (serial 7s) Similarities & Difference, Abstrations Speech/Language Function Listen for spontaneous speech (fluency, aphasic errors) Naming of objects (watch, penlight, band of watch) Repetition (No ifs ands or buts, Christopher Columbus discovered America in 1492) Following 1,2 and 3 part commands Calculation (serial 7s) 1

L/R discrimination

Cranial Nerves I Olefactory (seldom tested) II Optic: visual acuity, papillary reflex, fundoscopic exam, visual fields (AFFERENT optic reflex) III, IV, VI Oculomotor, Trochlear, Abducens: Pupillary reflex (III), EOM, lid elevation (ptosis) (III-EFFERENT optic reflex) V Trigeminal: sensation on face (divisions 1,2,3), masseter, temporalis, pterygoid muscles, corneal reflex (AFFERENT) VII Facial: muscles of facial expression, taste to anterior 2/3 of tongue (EFFERENT corneal reflex) ba-ba-ba VIII Vestibulocochlear: hearing and vestibular function (rub fingers outside ear, whisper, check balance/gait) IX Glossopharyngeal: pharyngeal sensation X Vagus: palate elevation, vocal cord function (listen to speech, check gag, observe palatal elevation) ka-ka-ka XI Accessory: trapezius and sternocleidomastoids XII Hypoglossal: Tongue movement (protrude tongue, press against cheek, observe for atrophy or fasiculations) ta-ta-ta

Motor Exam Evaluate Strength proximal/distal, right/left, upper/lower Evaluate for arm drift (hold arms in front and close eyes, if falls down they may have weakness) Functional tests in lower extremities stand on heels/toes, hop on each foot Evaluate muscle tone upper and lower extremities (spasticity or rigidity) Evaluate for atrophy or fasiculations

Reflexes Upper extremities Biceps, triceps, brachioradialis Other finger flexors, pectoralis, Hoffman sign (flick nail on middle finger and watch if thumb flexion, may be abnormal if unilateral) 2

Lower extremities Patellar, achilles Check for ankle clonus Plantar reflex (cutaneous reflex, not DTR) Use mildly noxious stimulus but avoid withdrawal in ticklish people Start over lateral foot, move forward, cross over medially just proximal to ball of foot Watch for first movement of toes (not reliable if whole foot jerks away)

Sensory Exam Position/vibration measure dorsal columns Sharp/temperature measures spinothalamic tract Crude touch distributed among both tracts Stereognosis, graphesthesia cortical sensations (need crude sensations to be intact) Double simultaneous stimulation - cortical sensation (neglect if extinction is present on one side) Compare: L/R (usually brain dysfunction) Proximal/Distal (if distal loss usually polyneuropathy) UE/LE and sensory level (spinal cord)

TIPS for sensory exam dont over interpret minor differences, try to quantify numb area (100, 95, 50, 25), for vibration testing, use yourself as a control, for position sense only a few degrees are needed to discriminate (dont use major excursions), for sharpness test both broken end of cotton swab and soft tip and ask if #1 or #2 is sharper

Coordination Upper extremities F-N, F-F-N, RAM (roll arms) (finger to nose, rapid alt mvmts) Lower extremities heel-knee-shin, toe-finger Classic cerebellar signs dysmetria (overshooting inability to estimate distance), dyssynergia (dyskinesia), dysdiadochokinesis (difficulty with RAM) Cannot diagnose cerebellar dysfunction if patient is weak (slowness and clumsiness of movement)

Station and Gait 3

Test normal walking and watch for: Assymetric arm swing (hemiparesis) Circumduction and toe catch (hemiparesis) Steppage gait (ankle dorsiflexion weakness pt slaps foot down) Shuffling gait, increased kyphosis, decreased arm swing, slow on turns (Parkinsons disease) Wide base (truncal ataxia usually cerebellar, occasionally dorsal column)

Check standing (station) Unsteady, weaving with feet together and eyes open cerebellar Steady with feet together and eyes open, but unsteady when eyes closed + Romberg sign (dorsal column) Check tandem gait heel to toe (usually cerebellar if abnormal, but can be vestibular and occasionally due to mild weakness or dorsal column dysfunction)

POLYNEUROPATHY DEFINITION OF POLYNEUROPATHY Syndrome of dysfunction or disease of peripheral nerves Similar presentation regardless of etiology Most pts will present with both motor and sensory symptoms that usually start in the feet and can go on to involve the hands or arms

DETERMINE THE TIME COURSE Acute vs. Chronic Acute (uncommon) Guillain-Barre syndrome (most common) Porphyria Diphtheria Drugs Toxins Tick paralysis Vasculitis or CT disease

Chronic (months years with insidious onset) 4

 Progression Steady (most common) Stepwise (mononeuritis multiplex) Relapsing-remitting (would suggest chronic demyelinating neuropathy or intermittent exposures/toxic exposures)

DETERMINE THE FIBER TYPES INVOLVED Fiber Types nerve fibers are classified by fiber side and modality carried ***Small sensory unmyelinated fibers that convey pain and temperature Large sensory myelinated, convey proprioception, touch, vibration Motor large diameter, myelinated, activate muscle contraction Autonomic small, unmyelinated

Useful to determine which fiber type is involved by looking at positive vs. negative symptoms Negative (lack of function) weakness, atrophy, sensory loss, hyporeflexia, hypotension, anhidrosis Positive (over-functioning) cramping, fasciculations, burning sensations, hyperhyrosis, parasthesias

Most polyneuropathies show involvement of sensory and motor involvement (pts usually notice sensory symptoms first) Large fiber neuropathy (motor + sensory) vibration/touch, weakness, loss of DTRs; little autonomic or pain/temp loss Pure sensory neuropathies are uncommon and usually indicate damage to the dorsal root ganglion; when they do occur, they are subacute and are classified as one of four types: Paraneoplastic syndrome Postinfectious processes Sjogrens syndrome Pyridoxine (B6) intoxication

Pure motor hereditary neuropathies, Pb poisoning, porphyrias and GBS Small sensory DM, amyloid, toxins (EtOH), drugs (antiretrovirals), hereditary diseases 5

 DISTRIBUTION OF POLYNEUROPATHY Distal > Proximal gradients classic Due to axonal damage, length dependent, dying back pattern longest nerves are affected first resulting in a stocking glove pattern

Nearly all polyneuropathies are symmetric Asymmetric neuropathies rule out toxic, metabolic and genetic conditions Asymmetric neuropathy suggests mononeuritis multiplex or superimposed radiculopathy Mononeuritis Multiplex asymmetric nerve involvement with step-wise progression Ddx vascultitis, DM, inflammatory demyelinating PN, mutliple entrapments(hereditary vs acquired), Cryoglobulinemia, Infectious(lyme, leprosy), Infiltration(granulomatous dx, CA)

DETERMINE THE UNDERLYING NERVE PATHOLOGY Axonal most common (DM most common etiology) Most are chronic and progressive

Deymyelinating damage to myelin sheath (marked slowing of conduction velocities) Demonstrated by electrodiagnostic testing or bx Indicates a favorable process Common Demyelinating Polyneuropathies Mixed Hereditary HMSN (hereditary motor and sensory neuropathy) Acquired AIDP(GBS), CIDP, Multifocal Motor Neuropathy, Diptheria, Toxic

DETERMINE IF

THERE IS A

FAMILY HISTORY OF NEUROPATHY?

Clinical Clues: - These are common in neuropathies Foot deformity (pes cavus, hammer toes) Long-standing PN Very slow progression 6 Few positive symptoms Family history

 DETERMINE IF THERE IS ANY ASSOCIATED MEDICAL ILLNESSES? Thorough H&P Many medical conditions are highly associated with PN DM, CA, CT dx, HIV and deficiency states

DIABETIC NEUROPATHY Most common cause of neuropathy Pathogenesis Polyol pathway Microvascular ischemia Advanced glycosolation end products Inflammation Growth factor/insulin deficiency Ion channel dysfunction Dysfunctional fatty acid metabolism

Leading cause of all 3 major categories of polyneuropathy Generalized neuropathies large, small and autonomic involvement Compressive focal neuropathies carpal tunnel syndrome, ulnar neuropathy, peroneal neuropathy of fibular head Non-compressive focal/multifocal amyotrophy, cranial neuropathies, CN VI, mononeuritis multiplex

DETERMINE IF THERE HAS BEEN ANY EXPOSURES? Occupational (relatively uncommon although most patients report exposure) establish clear temporal relationship between exposure and development of neuropathy; should see some improvement with removal of exposure Cancer chemotherapeutic agents Routine prescription medications statins, anticonvulsants, antiretrovirals

 DIAGNOSTIC TESTING Clinical Electrodiagnostic EMG or quantitative sensory testing Laboratory general chemistries, CSF if indicated (especially if demyelinating) Radiologic MRI, X-ray, CT May need to look for cancer or radiculopathy

HEREDITARY NEUROPATHIES HMSN (Hereditary Motor Sensory Neuropathy) = CMT (Charcot Marie Tooth)

CLASSIFICATION OF HEREDITARY NEUROPATHIES HMSN I-IV (Hereditary Motor and Sensory Neuropathies) HSAN I-V (Hereditary Sensory and Autonomic Neuropathies) HMN I-VII (Hereditary Motor Neuropathies) CMTX (Charcot-Marie-Tooth, X-linked) HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)

HMSN I (CMT I) Most common subtype* Key pathologic feature demyelinating neuropathy Genetics Autosomal dominant with variable phenotypes Onset before age 20 Duplication of the PMP22 gene (opposite of HNPP) Positive family history

Clinical features 8

Distal weakness Peroneal atrophy Distal and symmetric sensory loss loss of vibration and proprioception distally ed DTRs, not hyperreflexic! Pes cavus high-arched feet with hammer toes Bilateral foot drop Palpable nerves

Electrodiagnostic Testing slowed conduction Uniform slowing to <75% lower limit of normal without conduction block/temporal dispersion Little change over time within the same patient (variation within family members)

Nerve Biopsy hypertrophic nerves with onion bulb formation (attempt to remyelinate)

HMSN II (CMT II) Key pathologic feature axonal loss Clinical features (Similar presentation to CMT I) Middle-aged patient (d/o of adulthood) Slowly progressive weakness and atrophy Positive FH Distal muscle weakness and atrophy Distal and symmetrical sensory loss (stocking glove) ed DTRs Do not see + symptoms as in acquired PN

Electrodiagnostic Testing normal nerve conduction velocities with sensory and motor amplitudes Neurogenic changes (distal > proximal) with decreased recruitment

Genetics multiple gene mutations with AD inheritance

 HMSN III (CMT III) Dejerines Sottas Key pathologic feature demyelinating PN Clinical Features Childhood onset Proximal and truncal weakness Sensory ataxia Absent DTRs

Nerve biopsy absent or very thin myelin sheaths with onion bulb formation Electrodiagnostic Testing very slow (or unillicitable) conduction velocities Genetics all types of inheritance (AD, AR, sporadic)

HMSN IV (CMT IV) Rare Autosomal recessive Early onset Slow nerve conduction

CMT-X Considered to be an intermediate for CMT Genetics Most cases are linked to Connexin 32 mutations X-linked (females are asymptomatic carriers)

Clinical Features similar features as CMT I Childhood onset Slowing of lower extremities > upper extremities

Pathology onion bulbs are NOT seen

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 HNPP (HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES) Recurrent, painless, focal mononeuropathies Genetics AD (PMP 22 gene deletion) Onset can be at any age (commonly after age 20) Electrodiagnostic Testing slowing at site of nerve entrapment Nerve Biopsy swelling of nerve fibers

HSAN (HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES) 5 major subtypes Most subtypes are recessive except for the most common subtype (which is dominant) Congenital insensitivity to pain, sensory neuropathies, painless ulcers of feet, charcot joints, bony deformities, fevers of unknown origin (autonomic dysfunction)

SUMMARY History chronic, insidious, age of onset, FH, temporal course (slow, painless progression) Neurological exam distal lower extremity weakness and atrophy, high arched feet, hammer toes, stocking glove sensory loss (proprioception/vibration), lose DTRs in symmetrical fashion EMG/NCS demyelinating vs. axon loss Genetic Testing PMP gene duplication for CMT IA has highest yield Biopsy remains useful as genetic testing is not always helpful

DEMENTIA DEFINITION OF DEMENTIA Disorder of memory function and cognitive impairment that interferes with daily function and independence Areas of impairment Memory Orientation 11

Visuospatial perception Language Higher executive functions (planning, organizing, sequencing)

DEMENTIA VS. DELIRIUM Delirium Refers to a disturbance of consciousness Reduced awareness, attention and disorganized thinking is common Waxing and waning LOC Develops over a short time (hrs to days) Reversible cause of cognitive dysfunction Typically due to a general medical condition Dementia Implies a stable, sustained consciousness Progressive (not reversible) course Develops over months to years Implies neurodegenerative disorder

DEMENTIA VS. DEPRESSION It is sometimes difficult to distinguish the two, especially in the elderly Sometimes you can treat the depression and see if the dementia improves

MILD COGNITIVE IMPAIRMENT MCI implies that there is Subjective decline in memory Preserved daily functioning (uninhibited) Does not meet dementia criteria

Subtypes of MCI Amnestic MCI memory only dysfunction Multiple domain MCI memory + cognitive problems 12

Single nonmemory domain MCI non-memory dysfunction

There is an ed risk to developing dementia (especially AD) later in life Could this be just age related cognitive decline? This is controversial

WHO GETS DEMENTIA? Most common in the elderly 5% of people age 65-70 45% of people over age 85 Women = Men Dementia changes may start early in life HTN and other vascular risk factors may predispose all patients to dementia

Hereditary forms of dementia can occur in younger people CAUSES OF DEMENTIA Alzheimers Disease 50-80% - Most common Lewy Body Dementia 20% Mixed Alzheimers 10% Depression 5-10% Vascular Dementia 5%

Metabolic, Drugs, Infections, Structural lesions, Hydrocephalus, Parkinsons <5% each Picks Disease, other Frontal Dementias, Huntingtons Disease <1% each

DEMENTIA WORK-UP GOOD history (with family members present) Thorough physical and neuro exam Lab studies r/o reversible causes Thyroid function tests ESR CBC Electrolytes (including Ca) 13 Renal function (BUN/Cr) LFTs Ammonia Infectious studies (HIV, RPR, Tb)

Heavy metal screen (Pb, Hg, Arsenic)

Imaging studies MRI is the overall best modality look for strokes, hippocampal atrophy and other lesions CT is better for ICH chronic subdural hemorrhage, hemorrhage due to amyloid angiopathy (cortical bleeds), hemorrhage due to HTN (subcortical bleeds) PET (and SPECT) expensive and not often used, radioactive exposure Tag glucose and see if brain is working as it should be

Cisternogram for NPH evaluation

EEG if any suspicion of subclinical status epilepticus May be normal May show abnormal generalized slow waves May show intermittent focal slow waves in temporal areas Slowing, reduction in amplitude, and disorganized alpha rhythms
1. Orientation a. b. Year, season, day, date, month State, country, town, hospital, floor

Consider LP (fungal infection, protein, 14-3-3, etc) Cognitive Testing for Dementia Mini Mental Status Exam (Folstein) 87% sensitive, 82% specific Score out of 30 >24 Normal 21-24 Mild 10-20 Moderate <10 Severe Repeat tests at each visit

2.

Registration a. Name 3 words

3.

Attention & Calculation a. b. Serial 7s or world backwards Recall 3 words

Clock Drawing Test typical for left sided neglect but there is a formal scoring for clock drawing that can be correlated with degree of dementia

14

Formal Neuropsychiatric Testing Areas Tested Memory, Concentration, Visual-Spatial, Problem Solving, Counting, Language Tests Performed most commonly used is ADAS-cog test

DEFINING THE TYPE OF DEMENTIA Rule out reversible causes Match the clinical features of the patient with characteristics of known dementia types It is not uncommon to make the wrong diagnosis Even neurologists are correct only 80% of the time when AD diagnosis is made For now, the treatment is similar for all forms of dementia

ALZHEIMERS DISEASE General: Most common form of dementia Estimated 4 million people in US with AD Estimated 16 million people in US with AD by 2050 Direct and indirect costs of $100 billion/year Age is biggest risk factor (risk doubles with every 5 years) 2% of people 65-69 4% of people 70-74 8% of people 75-79 16% of people 80-85

APO e4 alleles (homozygous s the risk) History of previous head trauma is a risk (and Downs syndrome patients)

Neuropathology: Final formal dx is made only at autopsy 15

Brain atrophy Neuritic plaques and Neurofibrillary tangles (CA1 layer of hippocampus, subiculum)

Neuroradiology: MRI/CT Shows brain atrophy r/o masses, strokes, hemorrhage and other lesions Compare to hippocampus volume standards

SPECT scan and PET scan Radiotagged metabolite or glucose and shows bilateral temporoparietal hypometabolism/ hypoperfusion Expensive, not often done

DEMENTIA WITH LEWY BODIES Cognitive problems (develop early or first) Variability and fluctuations of cognitive problems memory, executive dysfunction, verbal blocking, spatial or geographic disorientation, visuospatial impairment, misidentification of people, visual hallucinations, illusions, delusions, agitation, anxiety

Motor dysfunction (Parkinsonism) Autonomic dysfunction (orthostatic hypotension) Sleep disorders (primarily REM sleep disorders) Lewy body pathology (cortex, subcortical, spinal cord) round, intracytoplasmic inclusions

NORMAL PRESSURE HYDROCEPHALUS Triad (course is usually weeks to months) Gait apraxia (magnetic gait usually first manifestation) Urinary incontinence Dementia

Imaging 16

 LP

CT shows large ventricles (out of proportion to sulci) Radioisotope diffusion study (CSF flow study)

Normal or low opening pressure (<200) Gait improvement after LP (high volume tap, remove 30cc) Miller Fisher Test (but dementia may not improve right after tap)

Treatment VP shunt

VASCULAR DEMENTIA (multi-infarct dementia) Can occur in conjunction with AD or other dementias No uniform diagnostic criteria Clues to dx: History of previous strokes or TIAs Cognitive deficits associated with strokes Evidence of infacts Stepwise cognitive decline (sometimes with long plateaus)

Series of small strokes leading to a in intellectual function Incidence of post stroke dementia 6-32% at 3 months Risk factors for vascular dementia (same as for stroke) Age Sex (M>F) HTN HLP Hyperhomocysteinemia Lipoprotein a Poorly controlled DM Embolic source (Afib, cardiac valves, etc) Hypercoagulable disorders Genetic factors (moya moya, mt disorders, etc)

Treatment Rapid assessment and treatment with strokes IV or intra-arterial tPA 17

Anticoagulation when indicated Bp, BG management

Good Secondary Stroke Prevention Therapy Antiplatelet therapy (ASA, Plavix, Aggrenox) Lipid lowering agents (statin) Good bp control Good BG control Treatment of high homocysteine, lipoprotein a Behavioral changes (diet, exercise, smoking cessation)

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 FRONTOTEMPORAL DEMENTIA (FTD) Group of neurodegenerative dementia disorders in which the frontal and temporal lobes are involved Patients usually show personality changes first with speech, memory and cognition decline over time No effective tx for these disorders Modified Neary Criteria for FTD classification Types of FTDs: Picks disease Progressive nonfluent aphasia FTD with motor neuron disease FTD with parkinsonism Semantic dementia Progressive apraxia

Picks Disease Frontal and temporal lobe atrophy seen on autopsy with pick bodies seen (tau proteins) in cortex Clinical findings impulsivity, poor judgment, poor organizational skills, neglect of social and personal responsibilities (cleanliness) also have syn-nuclein, ubiquitinDO NOT HAVE 14-3-3 (CJD protein)

Frontotemporal atrophy seen on MRI as disease progresses Usually starts in 40s to 60s No treatment is available

DEMENTIA TREATMENT If reversible, treat the underlying cause (ex: hypothyroidism) Disease modifying agents (there is no cure!) Tacrine (Cognex) rarely used due to liver issues Cholinesterase inhibitors Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Remnyl) ACh seems to slow down progression and preserve memory

Memantine (Namenda) Anti-glutamate med Lots of side effects, expensive, minimal benefits Used in addition to cholinesterase inhibitors

Symptomatic treatments Depression SSRIs Movement disorders usually parkinsonism (tx with Parkinsons drugs) Psychosis/Sun-downing newer atypical antipsychotics have fewer side effects

Care issues Supervision and safety at home becomes an issue Financial issues Progressively increasing care and monitoring Likely will eventually require nursing home care May require hospice/palliative care

DISEASES OF MUSCLE AND MOTOR NEURONS DISEASES OF MUSCLE Clinical Features Weakness is usually proximal Upper extremities washing hair, shaving, putting on make-up Lower extremities climbing stairs, arising from chair, stepping up curb

No sensory loss Usually no pain

Classes of Muscle Disease Dystrophies heterogenous group of inherited disorder muscle disorders Clinical onset in infancy, childhood or adulthood

Classification is based on genetics and abnormalities of muscle proteins Duchenne and Becker Muscular Dystrophy (know this section; how to tell the difference) X-linked recessive (appears in males, females sometimes symptomatic), 1/3 are spontaneous Frequency of DMD is 1/3500 live births; BMD is 1/35000 live births Abnormality of gene coding for the muscle membrane protein dystrophin (usually a large deletion, but may be a point mutation or substitution) Dystrophin is virtually absent in DMD and ed or altered in BMD Clinical Features of DMD Onset early in childhood Proximal weakness Gowers maneuver Large calves(pseudohypertrophy)
muscle replaced by fat or CT

ed Lumbar lordosis Falling by age 6-7 Cant walk by age 12 Cardiomyopathy is common Death by respiratory failure of CMO by age 20

Toe walking(Achilles shortening) Evaluation of DMD

CK markedly elevated (usually 1000s with normal<200) EMG is myopathic Dx most commonly made by genetic testing Deleltion in dystrophin gene in 70% Muscle bx needed for dx in others (severe myopathic changes, staining for dystrophin absent or virtually absent)

Becker Muscular Dystrophy Similar to DMD but milder with a later onset Diagnosed in the same manner as DMD Muscle bx reveals dystrophin staining to be or irregular but not absent Treatment of DMD and BMD (NO cure) Corticosteroids Usually initiated after age 5

Slows progression Side effects growth retardation, weight gain, changes in behavior

Symptomatic Tx bracing, wheelchairs, therapy to prevent contractures Genetic counseling is important Fascioscapulohumeral (FSH) Muscular Dystrophy Weakness of face, shoulder, girdle muscles (horizontal/downsloping clavicles) May present in infancy, childhood, adolescence Autosomal Dominant inheritance 90-95% of patients have deletions on the long arm of chromosome 4 Tx symptomatic Emery-Dreifuss Muscular Dystrophy Weakness of proximal limbs and of distal lower extremities (joint contractures are common) Cardiac involvement is common (conduction block, CMO) Monitor heart closely and tx CHF (heart is major cause of death in these patients) Pacemaker is commonly needed Usually X-linked, but may be dominant (X-linked deficiency of Emerin, muscle membrane protein) Diagnosed via DNA testing Symptomatic tx of weakness assistive devices, therapy, wheelchairs Oculopharyngeal Muscular Dystrophy Late onset (usually 5th or 6th decade) Clinical eye muscle weakness and ptosis initially, difficulty swallowing, facial weakness, proximal limb weakness Autosomal Dominant Rimmed vacuoles on muscle bx (not specific) Diagnosed via DNA testing Limb-Girdle Muscular Dystrophies (family of disorders)

 Mildly or severely ed CK May be AD or AR Abnormalities in a variety of muscle membrane constituents Usually diagnosed via muscle biopsy Congenital Myopathies always present at birth (unlike muscular dystrophies) Defined based on the histological appearance of their muscle biopsies central core disease, nemaline myopathy, centronuclear myopathy, congenital fiber-type disproportion, myofibrillar myopathy

Central Core Disease

Nemaline Disease

Congenital Fiber Type Disproportion

Usually these are floppy babies Some are severe resulting in respiratory distress and death; others go on to become weak children and adults with relatively nonprogressive disorders

Inflammatory Myopathies Polymyositis Clinical Features Relatively rapid onset of weakness over days to weeks Predominantly proximal arms and legs No sensory loss, often no pain, but pain may occur with CT disease (not uncommon) Other organ involvement myocarditis with CHF, ILD (anti-Jo-1 antibodies) Diagnostic Evaluation serum CK level (up to 50x normal) EMG myopathic features Muscle bx (definitive test) inflammation, muscle fiber destruction, necrosis Treatment and Prognosis

 Mechanism cell-mediated response directed against muscle fibers Tx immunosuppressive drugs (prednisone, azathioprine, methotrexate) Outcome good to excellent recovery (unless muscle necrosis has been severe) Dermatomyositis Clinical Features Most frequent in childhood Rash (heliotrope eyelids) sun-sensitive areas Progressive weakness over weeks to months Calcifications in subCu tissue, more commonly in children ed incidence of malignancy in adults Diagnostic Evaluation serum CK level (up to 50x normal) EMG myopathic features Muscle bx (definitive test) perifascicular atrophy, perivascular inflammation Treatment and Progranosis Mechanism humorally-mediated microangiopathy (around blood vessels) Tx immunosuppressive drugs (prednisone, azathioprine, methotrexate, IVIG*) Outcome good to excellent recovery generally Inclusion Body Myositis Individuals over 50 years of age Very slowly progressive over many years Finger flexors, quadriceps most affected CK modestly elevated, <10 times normal EMG demonstrates a mixed myopathic and neurogenic pattern Muscle bx inflammation and rimmed vacuoles (inclusion bodies) not specific Probably not autoimmune but may be degenerative (due to amyloid deposition)

 Tx generally responds poorly to immunosuppressive therapy Outcome progresses slowly over many years

Metabolic Myomathies Endocrine Myopathies Hyperthyroidism proximal weakness and ophthalmoplegia Hypothyroidism muscle aching, cramps, fatigue, elevated CK Disorders of glycogen metabolism muscle pain with exertion (McArdles dx) Disorders of lipid metabolism

Mitochondrial Kearns-Sayre Syndrome progressive external ophthalmoplegia (PEO), retinitis pigmentosa, heart block, CSF protein Myoclonus epilepsy with ragged red fibers Mt encephalopathy with lactic acidosis and stroke-like episodes Pure PEO Pure skeletal myopathy

Myotonic Dystrophy(Know this!) Clinical Features Temporalis and masseter wasting Wasting of the sternocleidomastoid muscle swan neck deformity Ptosis Weakness facial, distal, proximal Grip weakness and myotonia Gradual progression over years Autosomal dominant inheritance Electrodiagnostic studies myotonic discharges on needle exam Mental Retardation (mild severe) Cardiac dysfxn conduction defect Cataracts, frontal balding Endocrine abnormalitites abnormal GTT, gynecomastia, testicular atrophy GI motility disturbances

Etiology and Genetics Type I repeated trinucleotide sequence (CTG) in a gene on chromosome 19 which codes for a protein kinase (more repeats more severe disease; anticipation in successive generations) Type II proximal myotonic myopathy (repeat expansion in the zinc finger on protein 9 gene on chromosome 3q)

MOTOR NEURON DISEASES Inherited Disorders of the LMN Spinal Muscular Atrophies group of hereditary disorders characterized by proximal weakness Classification of SMAs SMA I (Werdnig-Hoffman disease, acute infantile SMA) Onset birth to age 6 months Cannot sit without support Mild joint contractures Hypotonia Trouble with suck or swallow Lifespan <2 years SMA II (intermediate, chronic infantile SMA) Onset 6-12 months Can usually sit independently Never stand or walk Scoliosis is common SMA IV (adult) Onset usually in 2nd or 3rd decade of life Normal lifespan Genetics of SMA AR (survival motor neural gene accounts for SMA I, II and III, NOT IV) Electrodiagnosis of SMA Lifespan 70% alive at 25 years old SMA III (Kugelberg-Welander disease, chronic juvenile) Onset after age 1 Can walk, frequently falls, trouble walking up and down stairs at age 2-3 years Proximal limb weakness; legs more severely affected > arms Scoliosis common Normal lifespan

 Sensory nerve conduction studies are normal Motor nerve conduction studies are usually normal or may show decreased amplitudes Needle EMG demonstrates fibrillation potentials, positive sharp waves, and large motor units with decreased recruitment (neurogenic pattern) Treatment of SMA Supportive care Trial of Riluzole is underway Bulbar and Spinal Muscular Atrophy (Kennedys Disease) Clinical Features Onset usually in 3rd or 4th decade Gynecomastia Testicular atrophy, impotence Progressive weakness affecting proximal muscles Genetics X-linked Only males are slightly symptomatic; Females are carriers (occasionally mild weakness) CAG trinucleide repeat expansion on the androgen receptor gene Bulbar weakness dysarthria, dysphagia, tongue fasciculations Reflexes decreased or absent No UMN findings

Infections Poliovirus enterovirus rarely seen in US that affects the anterior horn cells and CN nuclei Clinical Features Aseptic meningitis followed by paralysis Usually asymmetric ed or absent reflexes 10-15% of patients with motor system involvement develop CN dysfunction Respiratory failure may occur (iron lung) Postpolio Syndrome

 Combination of neuromuscular and orthopedic symptoms in patients with a h/o polio in the remote past fatigue, muscle pain, joint pain, weakness, or previously affected or unaffected muscle atrophy, respiratory insufficiency, dysphagia Pathophysiology loss of motor neurons at the time of acute disease motor units in which there are many more muscle fibers supplied by each motor neuron excessive demand on motor units drop out of muscle fibers, motor units or both West Nile Virus Clinical Features Acute, flaccid paralysis, usually without sensory loss Commonly accompanies presentation with meningitis or encephalitis Reflexes decreased or absent Pathogenesis Anterior horn cell disease transmitted mainly by Culex mosquitoes Diagnosis Serum and CSF can be tested for antibodies to WNV by ELISA Treatment and Outcome Outcome is usually poor with partial recovery documented with high-dose steroids Trials of IVIG ongoing; Vaccinations under development No success yet with antivirals

Acquired Disorders of the UMN and LMN Amyotrophic lateral sclerosis Epidemiology 1.2-2 per 100,000 population About 5,000-6,000 new cases per year in US Prevalence 4-6 per 100,000 M:F = 1.5:1 Disease primarily of late middle life (average onset 52-66) but can affect much younger pts Presenting Symptoms Muscle weakness, usually asymmetric (most common) No ocular involvment

 Muscle cramps Fatigue Weight loss Respiratory symptoms (exertional dyspnea, nocturnal dyspnea)

Pts who present with fasciculations as their CC rarely have ALS Bowel/bladder dysfunction, vision disturbances, and sensory disturbances are usually ABSENT at presentation

Findings on exam (combination rarely seen in other neuro disorders) UMN signs spasticity LMN atrophy, fasciculations

Types of ALS Classical 2/3 of patients with ALS Begins with weakness of the limbs, usually asymmetric Muscles of speech and swallowing are eventually affected Progressive Bulbar Palsy 25% of patients with ALS Limited to muscles of speech/swallowing (weakness, atrophy, fasciculations of tongue) Usually progresses to classical ALS Progressive Muscular Atrophy 8% of patients with ALS LMN signs only (atrophy, fasciculations) Primary Lateral Sclerosis very rare UMN signs only (spasticity) Must be distinguished from spinal cord compression or other spinal cord dx

Cognitive Dysfunction in ALS Classically weve been taught that ALS usually spares cognition Recent studies have shown that up to 50% of pts with ALS may have cognitive impairment (usually frontotemporal dementia) more common with bulbar involvement

Mechanism of ALS Progressive weakness due to death of motor neurons in the cortex, brainstem, and spinal cord UMN cortical motor neurons, descending spinal cord pathways

 LMN anterior horn cells, CN motor nuclei Sensory and autonomic neurons are largely spared Pathogenesis thought to be related to oxidative stress OR glutamate-mediated excitotoxicity Glutamate transporters appear to be downregulated Accumulation of glutamate near motor neuron produces damage Familial ALS 5-10% of cases are familial Clinically indistinguishable from sporadic ALS Inheritance is usually autosomal dominant Approximately 20% of familial cases have been shown to be associated with mutations in the copper/zinc superoxide dismutase gene (ALS1) Most forms of adult-onset familial ALS have not been linked to any genetic loci Diagnosis Relies heavily on physician judgment as there is no single test which can dx ALS (tests are used to exclude other disorders) Nerve Conduction Studies and EMG Normal sensory nerve studies Findings of denervation in at least 2 muscles of different nerves/roots in 2 or more limbs Course and Prognosis Gradual progression, often asymmetric Eventually, impairment of swallowing, respiration resp insufficiency or aspiration PNA Mean duration 27-43 months (5 year survival = 9-40%, 10 year survival = 8-16%) Treatment attempts to slow but will not stop progression Antioxidants unproven efficacy (vitamin E, CoQ10) Riluzole anti-glutamate drug Modest positive benefit in prolonging lifespan (2-3 months on average) Does no reverse or stop ALS Only FDA-approved drug to Tx ALS

 Symptom Management Respiratory failure Difficulty swallowing Drooling (sialorrhea) Communication devices Emotional lability Pain, cramps, spasticity Depression

 Advanced Directives Future of ALS Nerve growth factors and stem cells are under investigation

EPILEPSY DEFINITIONS Seizure discrete epileptic event due to transient, hypersynchronous, abnormal neuronal behavior (too many neurons all trying to do the same thing at the same time overpowering normal activity of the brain) Epilepsy recurrent, unprovoked seizures (NOT epilepsy if there is a reason)

EPIDEMIOLOGY
1/ 100

people have epilepsy

1/10 will have a single seizure If you live long enough, the prevalence of epilepsy is greater in the elderly than in children (7-8/100)

CAUSES OF SEIZURES/EPILEPSY ~50% of the time there is no identifiable cause Tumors Vascular Malformations Stroke in ~10% of people Trauma (especially with depressed skull fracture 50% of the time) Malformations of the brain External Causes metabolic, EtOH, anoxia, drugs (can be reversed and are not causes of epilepsy) Causes are related to age: Very Young perinatal injury, metabolic causes, congenital malformation, infection Middle aged infection, trauma (most common etiology in 19-35 age group) Very Old tumors, vascular disease, dementia

 CLASSIFICATION OF EPILEPSY KNOW SIMPLE VS COMPLEX Focal (partial) onset differs on level of awareness Simple partial Consciousness intact Signs/symptoms vary (depending where it starts) Motor (Jacksonian motor) spreads down arm Somatosensory numbness Autonomic papillary changes, piloerection Psychic dj vu (common), fear, anxiety Complex partial Impaired consciousness (blank stare)

Simple

Complex

Consciousness preserved

Consciousness impaired automatisms

Secondarily Generalized
Consciousness impaired Bilateral cerebral involvement Tonic-Clonic (Grand Mal)

Duration ~1 minute (frontal lobe seizures can be VERY brief without post-ictal period) Simple or reactive automatisms (tend to do exact same thing every time, may be a common movement cough, smack lips, wring hands, rub leg, pick at clothes) Amnestic for event Post-ictal confusion (several minutes several hours, HA, sleepy, confusion) Signs/symptoms vary depending on starting location (like simple partial)

Secondarily generalized Starts as simple or complex and progresses/spreads to involve entire brain (may be rapid)

Generalized seizures entire brain is involved from the onset (both sides) Types Absence (petit-mal), Tonic-clonic (grand-mal), clonic-tonic-clonic, clonic, tonic, myoclonic, atonic

Tonic-Clonic Seizures Loss of consciousness Ictus:

 Patients usually fall, Muscular rigidity (tonic) Respiration inhibited (respiratory muscles tonic) discrete cry as air is exhaled Rhythmic jerking (clonic) usually happens first 1-5 minutes Tongue-biting/injury can occur, Bladder/bowel incontinence Post-ictal confusion

Absence Seizure Brief loss of consciousness (10-20 seconds) Staring spell (abrupt onset and abrupt ending) No post-ictal period Subtle myoclonic movements Simple automatisms may occur Common in children and most children outgrow them (although can extend into adulthood) EEG 3/sec generalized spike-and-wave discharges Precipitants hyperventilation, flashing lights

Myoclonic Seizure Brief, shocklike muscle contractions (head, arms) Usually bilateral symmetrical Consciousness preserved More frequent on awakening (ask new onset absence/tonic clonic patients if they experience this) Can occur in series and may progress into tonic-clonic seizure Most myoclonus in hospital is post-anoxic and the patients EEG will NOT show typical spike and wave pattern

Tonic (can also have just clonic with only jerking) Stiffening of extremities Usually brief, bilateral May be repetitive Most common in children

Atonic (worst variety) Impaired consciousness (VERY brief) Sudden loss of muscle tone (helmets) Head drop, fall, injury common Tx corpus callosotomy (split 2 hemispheres)

CLASSIFICATION OF EPILEPSY (similar classification to seizures) Localization Related Idiopathic (no known cause) Symptomatic (can find cause) Cryptogenic (unknown)

Generalized Idiopathic (BNFC, CAE, JAE, JME) Cryptogenic or symptomatic (West, LGS, myoclonic-astatic) Symptomatic No specific etiology (early myoclonic encephalopathy) Specific syndromes

Undetermined if focal or generalized Both generalized and focal seizures Neonatal seizures Severe myoclonic epilepsy of infancy

Landau-Kleffner

Special syndromes Situation-related Febrile convulsions Isolated seizures Metabolic/toxic

EVALUATION OF EPILEPSY Routine EEG will only be positive in 50% of people initially Abnormalities we may see focal slowing, sharp waves and spikes

STATISTICS ON EPILEPSY ~2.6 million people in US with epilepsy (1999) Less than half are controlled on meds >181,000 new cases/year

Direct costs $1.7 billion Indirect costs $10.8 billion

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HEADACHE PATHOPHYSIOLOGY OF HEADACHE Pain pathways Small, myelinated a-delta fibers (sharp) and Unmyelinated c-fibers (aching, burning) dorsal horn of spinal cord or the trigeminal nucleus caudalis(face) cross over to spinothalamic pathway thalamus (VPM, VPL) sensory cortex and association areas

Vascular Theory of Migraine Aura phase spasm

Headache phase vasodilation (stretching)

Neural Theory of Migraine Spreading cortical depression Release of peptides from nerve endings dilation of local vasculature neurogenic inflammation

Proposed Mechanism Stimulus (external or internal) crosses cortex of brain diminished blood flow at cortex along with increase blood flow at brainstem which has interplay with trigeminal nerve signals to blood vessels dilation increase permeability neurogenic inflammation

CLASSIFICATION OF HEAD PAIN Secondary HA is symptom of another disease (ex: tumor) Trauma, infection (meningitis, cerebritis), vascular malformation (aneurysm, AVM), vascular lesion (stroke, bleed), CSF disorder (pseudotumor cerebri, post-LP), metabolic/toxic (cocaine, oxygen), substance (caffeine, cocaine), mass, psychiatric

Primary HA is disease itself (ex: migraine)

SECONDARY HEADACHE DISORDERS Red Flags Worst of Life First of Life Change in pattern Associated focal neurological dysfunction Lack of response to abortive meds Age > 50 Fever Meningismus

Diagnostic Tests for Red Flags Head CT Brain MRI Cerebral Angiogram LP Blood Tests Does not respond to abortive tx

 Intracranial Neoplasms No predictable pattern 20% IN have HA at presentation 60% IN have HA during course of disease Valsalva, position change, exertion can exacerbate pain (classic description)
2

/3 mild-moderate, 1/3 severe, 85% intermittent

High-Altitude Headache know criteria 2 of the following criteria AND the 3 criteria below
Bilateral pain, frontal pain, dull/pressure, mild to moderate, aggravated by straining/bending/movement

Ascent to altitude above 2500m HA develops within 24 hours after ascent HA resolves within 8 hours after descent

Subarachnoid Bleed Acute onset, severe headache (thunderclap,

worst HA of my life)

CT misses SAH 10% of time Dx with CT, LP and/or angiogram (tx aneurysm if discovered)

n/v, stiff neck, photophobia Sentinel bleed (HA hours to weeks before)

Spontaneous ICA Dissection RARE (often following trauma) 70% between ages 35-50 Moderate-severe, unilateral throbbing pain 62% periorbital/forehead; 41% temporal/top of head; 53% face/maxillary 60-75% will give history of TIA/CVA in downstream vascular territory Also find Horners, carotid bruit, neck pain Dx w/ carotid U/S, MRA and/or angiogram Tx w/ anticoagulation and symptomatic tx

Somatoform Disorder Comorbid depression/anxiety Multiple doctors/pain centers, very long list of failed treatments (quick failures) Neuropsychological testing and counseling

 Cerebral Infection (meningitis, encephalitis, abscess) HA, fever, stiff neck, n/v, photophobia, lethargy, seizure Viral/bacterial/atypical Dx with CT, MRI* with contrast and LP (determine organism)

Substance Abuse Drug seeking behavior, multiple doctors/pharmacies, lost prescriptions, runs out of medicine, late/weekend calls, desperate calls, not interested in other treatment

Pseudotumor Cerebri (Benign Intracranial Hypertension) Young, obsese, female Holocephalic, refractory HA, possible vision loss NSAID, Retin A association h/o trauma, meningitis, SAH Papilledema CT slit like ventricles LP opening pressure (normal 12-18) with dramatic improvement after tap Tx weight loss, Dimox ( CSF production)

Medication Overuse HA (Analgesic rebound HA) More common in migraine sufferers NSAID, Tylenol >5day/week Narcotics, Barbs, Triptans, Ergotamines >3day/week Tx remove offending agent

PRIMARY HEADACHE DISORDERS Migraine (most common to seek medical attention) At least 5 episodes HA with at least two of: Location unilateral Characteristic pulsating

Intensity moderate to severe Exacerbators aggravated by routine activity

Duration 4-72 hours During HA at least one of: n/v photophobia, phonophobia

Acute Treatment NSAIDs Triptans Ergotamine Phenothiazines Narcotics

Childhood Periodic Syndromes (fall into migraine category) Cyclical vomiting At least 5 attacks Episodic, stereotypical, intense n/v Duration 1 hour 5 days Abdominal migraine 5+ attacks Abdominal pain (duration 1-72 hours) Midline or poorly localized Dull or just sore Moderate-severe Benign paroxysmal vertigo of childhood Associated with 2 or more: Anorexia Nausea Vomiting Pallor No other cause can be found Vomiting occurs 4+ times/hr for at least 1 hour Symptom-free between attacks No other cause can be found

 5+ attacks Multiple episodes of severe vertigo without warning (resolves spontaneously) Normal neurological exam

Normal audiometric and vestibular tests between attacks Normal EEG

Tension-type (most common experienced) Pressing/tightening Bilateral; frontal and/or occipital Associated neck/shoulder tightness May have ONE nausea, photophobia, phonophobia Duration 30 min to 7 days Tx NSAIDs, muscle relaxant, heat/cold, relaxation techniques (biofeedback)

Brief HA Primary Stabbing HA Brief (<30 sec) Severe, sharp Unilateral, variable No trigger More frequent with migraine sufferers Dx none Tx Indocin

Cluster HA Men > Women Severe, unilateral, peri-orbital/temple Ipsilateral autonomic symptom (ptosis, miosis, nasal congestion, tearing) Duration (15-180 minutes) Frequency qid to 8/day Tx steroid, verapamil, triptan (abortive), O2

Paroxysmal Hemicrania (PHC)

Severe, unilateral Periorbital/temple Ipsilateral autonomic symptom Duration 2-45 minutes (briefer than cluster)

Frequency 1-40/day (more than cluster) Dx none Tx Indocin (daily tx)

Short-lasting Unilateral Neuralgiform HA with Conjunctival Injection and Tearing (SUNCT)

Stabbing, severe, unilateral, orbital 8:1 women Ipsilateral conjunctival injection and tearing Duration 10-120 seconds Frequency 1/day to 30/hour Cutaneous triggers Dx none Tx Lamictal

Hypnic HA Most between 67-84 years old Moderate to severe throbbing pain Unilateral or holocephalic No associated features Occurs about same time every night (few hours after bed) Duration 15-30 minutes Frequency 1-3/night Tx Lithium Exertional HA

Running, swimming, weight lifting Benign orgasmic cephalalgia Severe HA, explosive onset just before or during orgasm Occipital, retro-orbital or generalized Testing may be indicated Tx NSAID, triptan, inderal, indocin before activity

Chronic Daily Headache 15 or more days/month

Analgesic rebound HA Chronic Tension-type HA Transformed migraine

Neuralgias (Trigeminal Neuralgia) Very severe lighting Brief, but multiple Face (V2/V3 > V1) Cutaneous triggers Dx none Tx CBZ, GBP, TCA

MANAGEMENT STRATEGIES Stratified HA Management develop individual plan for each patient Theory Primary or secondary disorder Co-morbid issues depression, anxiety, insomnia, stressors, physical condition, substance abuse Specific treatment infection, tumor, vascular malformation Education understand dx, why choosing specific treatment, prognosis Pattern/lifestyle issues food (caffeine, cheese, MSG, nitrite, citrus, yeast), stress, hormonal changes, weather changes, sleep changes, diet changes Prophylaxis preventative medication (TCA, beta-blockers, AED, SSRIs, CCB), exercise, heat, biofeedback Pain treatment individualize according to theory Migraine NSAID, Triptan, Ergotamine, Narcotic Cluster Triptan, Oxygen, Narcotic Tension NSAID, Muscle Relaxant Brief NSAID, Narcotic

MEMORY AND COGNITIVE DISORDERS CORTICAL FUNCTIONS AND BEHAVIOR There is a neurobiological bases for consciousness, sensory, and motor functions, mental and emotional processes that relates to cortex anatomy and physiology Neurobehavioral development is based upon both biological and learned influences There are diverse cortical modifications (cerebral plasticity) that continue throughout life and provide the neural bases for learning and adaptation to diverse and changing environments Behavior Neurology/Neuropsychology focuses on human cognition, memory, emotion, language, behavior, and adaptation in relationship to health and brain diseases A wide variety of syndromes can contribute to these symptoms

ORGANIZATIONS FEATURES TO CORTICAL FUNCTION Primary motor and sensory cortical areas (visual, auditory, olefactory, gustatory, motor cortex) Modal association areas each primary sensory and motor cortical area has dedicated cortical association areas to mediate perception memory and knowledge Multimodal association areas modal areas converge into multimodal cortical areas for integration fo processing (adds complexity and flexibility to cognition and behavior) Cortical-subcortical networks extensive combinations of brain areas for inter-relating autonomic, visceral, hormonal, motor and cognitive processes Key pathways interconnect brain areas Lesions at the connecting areas (ex: corpus callosum) can lead to disconnection syndromes Certain cortical areas (prefrontal) are devoted to control of behavior such as activation and inhibition. Such self-regulation is key to adjustment and adaptation If you have a lesion at the primary area, it will be clear-cut As it gets into the association areas, the symptoms become more complex

The occipital lobe demonstrates that there are clear differences between a lesion in the primary area (loss of vision) and the association areas (loss of space, motion, form, color)

COMMON CORTICAL NEUROBEHAVIORAL SYNDROMES Occipital Lobe

Key words vision, visual perception, form, color, motion, spatial visual processing streams Common diseases affecting occipital lobe stroke in the posterior cerebral artery, hypotensive episodes causing anoxic damage to watershed areas, head injuries Upper occipital-parietal processing stream subserves spatial and motion vision Spatial motion (akinetopsia) Spatial reaching-visual guidance of hand movements (optic ataxia) Perceiving multiple spatial elements at the same time (simultanagnosia or Balint syndrome) ex: inability to shift attention from different dimensions of space (near/far, L/R, etc)

Lower occipital-temporal processing stream subserves form and color vision Reading (alexia) Object recognition (visual object agnosia) Face recognition (Prosopagnosia) as soon as they hear voice/see gait, theyll recognize person Color perception (achromatopsia)

Parietal Lobe Key words somatosensory*, higher sensory integration, spatial cognition, language Common diseases affecting the parietal lobe stroke of MCA, tumors, malformations, Alzheimers Disease Left inferior parietal lobe subserves aspects of language, arithmetic, somatosensory and body schema functions Wernickes Aphasia fluent, paraphasic speech (word substitutions, word salad, jargon speech) Impaired comprehension of language and visual forms of comprehension are impaired (they are thinking correctly but their comprehension is minimal) Impaired naming (anomia), repetition, writing (agraphia), and calculations (acalcula), apraxia (inability to perform skilled motor movement) not a motor deficit, but cognitive deficit (execution is off)

Gerstmann syndrome finger agnosia (cant tell which finger you are touching if their eyes are closed), agraphia, R-L disorientation (on self and/or others), acalculia (impaired calculations)

Right inferior parietal lobe subserves many aspects of spatial attention and cognition Damage to this region is associated with hemispatial neglect L body and world is ignored Constructional apraxia and spatial acalculia (clock drawing, getting ingredients out for a meal)

Temporal Lobe Key words language, audition, memory, emotion Common diseases affecting the temporal lobe stroke of the MCA, tumors, aneurysms, malformations, head injury, Alzheimers Disease, hypotensive episodes, epilepsy Primary auditory cortex ipsilateral & contralateral pathways from ear to Heschls gyrus, posterior extent of superior temporal gyrus (damage causes cortical deafness) Lateral (MCA) auditory association cortex in L and R hemispheres Left damage causes anomia and loss of aural comprehension of speech (known as Wernickes aphasia or pure word deafness) Right damage causes loss of nonverbal sound recognition (phone ringing, dark barking), voice recognition, emotional intonation of speech Bilateral damage causes loss of recognition of all sounds (auditory agnosia)

Medial (PCA) limbic lobe and short term memory (parahippocampal gyrus and hippocampus) Left damage causes loss of verbal learning and new memory retention Right damage causes loss of visual (spatial, nonverbal) learning and new memory retention (faces, locations, sounds, designs, objects) Bilateral damage causes profound loss of learning and new memory retention (clinical amnesia when both L and R are damaged)

Frontal Lobe Key words motor, premotor, prefrontal, executive functions, emotions, psychological growth and adaptation Common diseases affecting the frontal lobe stroke of ACA, head injury, tumors, aneurysms, degenerative disease, epilepsy

Primary motor and premotor cortices damage causes hemiparesis, apraxias, dysarthrias, and Brocas aphasia (left) Prefrontal cortices damage causes frontal lobe syndromes (area is greatly enlarge in humans) Superior mesial areas (necessary for initiation, motivation, drive) damage causes loss of motivation, initiation, akinesia, mutism Dorsolateral areas (necessary for cognitive abilities of organization, planning, goal-directed behavior, select and revise strategies, establishing goals, perspective taking) damage causes disorganization, perseveration, lack of goal-directed behavior Orbital areas (necessary for social judgment, social appropriateness, empathy, emotional regulation, adjustment in life, olfaction) damage causes anosmia (loss of olfaction), acquired social-emotional impairments; impulsive behavior, erratic moral judgment, poor empathy and social relationships, sometimes violence and criminal behavior

SUMMARY Be aware of these disorders so that they can be detected Work up underlying etiology (can the cause be treated?) Refer for neuropsychological examination and treatment Consider medication trials (cholinergic, dopaminergic, low dose stimulants) Follow-up care MULTIPLE SCLEROSIS PATHOLOGY CNS demyelination Is the target the myelin or the oligos that make the myelin? Early MS Inflammatory, demyelinating illness Later MS Degenerative with axon dropout (also have some axon loss later in the disease) Biopsy shows macrophages in the MS area

EPIDEMIOLOGY 1:1,000 (a lot depends on definition) Female:Male = 5:3 (although women tend to do better)

 Fraternal twins 3% concordance rate, identical twins 30% concordance rate (genetics + environmental) MS improves with pregnancy (especially 3rd trimester) ed as you go away from the equator (northern latitudes, ?vitamin D)

CLINICAL PRESENTATION Exacerbatting-Remitting 85% Primary Progressive 15% Optic neuritis decreased vision and possible pain in affected eye, afferent pupil defect (responds less to light) Diploplia possible INO (some type of brainstem lesion) Sensory deficit very common Ataxia severe intention tremor (especially with finger to nose) Motor weakness (>in legs), spasticity, Bladder spasticity There is extreme variability over time between patients

LAB EVALUATION CSF ed IgG (95%) because more is being made in CNS (suggests this is an immune illness, but may be seen in infection or paraneoplastic processes) Brain MRI (abnormal in 90%) Evoked Potentials (90%) VisualER, BrainstemAuditoryER, SensoryER Suspect MS Brain MRI with enhancement is done first, if abnormal and history/exam is concordant, that is enough to diagnose MS If there is a question (not concordant), evoked potentials and/or CSF is necessary

TREATMENT Symptomatic Treatment

Limb spasticity baclofen(may make pt weaker), dantrolene(LFTs), intrathecal baclofen pump Bladder spasticity detrol, oxybutinin -anticholinergic (parasympatholytic meds) Depression very important! Trigeminal neuralgia Epilepsy

Specific Treatment Exaccerbation (always r/o UTI) Prednisolone x5 days followed by prednisone taper Disease Modifying Agents interferon (when treating have to do CBC and LFTs) Copaxone (side effect: liver or renal toxicity ???) Naventrone chemo agent

CLINICALLY ISOLATED SYNDROME Patient comes in with optic neuritis or myelitis Do they have MS? Nobody can say but it has been investigated MRI If patient has 0 lesions, they have a 12% chance of having MS at 5 years If patient has 12 lesions, they have a 75% chance of having MS at 5 years (may define as having MS)

THINGS THAT MAKE MS WORSE Gamma-interferon Block TNF Block alpha - 4

PARKINSONS DISEASE WHAT IS PARKINSONS DISEASE Biochemical Abnormality Loss of pigmented neurons (DA producing cells) of the pars compacta of the substantia nigra in early stages <50% DA cell loss is asymptomatic ~70% DA loss before symptom manifestations Severity of DA loss best correlates with bradykinesia in PD

In advanced disease cell loss extends to locus ceruleus, cortex and in the basal forebrain

Early Signs and Symptoms Cardinal characteristics Resting tremor Bradykinesia Rigidity Postural instability pull test (less specific) *Asymmetric motor signs (early sign)

Other characteristics Micrographia Masked face Slowing of ADLs Stooped, shuffling gait arm swing when walking Difficulty arising from a chair Difficulty turning in bed Sialorrhea Hypophonic speech Loss of the sense of smell Foot dystonia

 Genetics PARK2 (early onset PD, AR inheritance with sx in 20-30) Only affects a minority of patients (uncommon to run in families) PARK gene affects ubiquitin-ligase system

WHAT IS NOT PARKINSONS DISEASE Neurodegenerative Disorders with Parkinsonism Progressive Supranuclear Palsy Supranuclear downgaze palsy, square wave jerks Upright posture/frequent falls Pseudobulbar emotionality Furrowed brow/stare

Corticobasal Degeneration Unilateral, coarse tremor Limb apraxia/limb dystonia/alien limb (contraction, inability to do spontaneous movements w/o thinking)

Multiple System Atrophy (will eventually develop all MSA syndromes together) Shy-Drager syndrome (MSA-P) Parkinsonism + autonomic insufficiency (orthostasis, impotence) Death within 5 years of developing autonomic signs

Striatonigral degeneration (MSA0P) Parkinsonism + tremor less prominent Olivopontocerebellar atrophy (MSA-C) Parkinsonism + cerebellar signs

Diffuse Lewy Body Disease Early onset of dementia (dementia and PD within 2 years of each other) usually PD doesnt start with dementia (diffuse lewy body disease DOES) Delusions and hallucinations Agitation

Also has REM activity

Alzheimers Disease Dementia is the primary clinical syndrome Rest tremor is rare

Essential Tremor Most commonly encountered movement disorder Postural and kinetic tremor affecting arms, head, tongue or voice (rest tremor can occur) spill food Genetically inherited (AD) with variable penetrance and usual onset is after age 40 (100% expression by age 70) Does not mortality and only 15% suffer significant disability Long plateau intervals followed by sudden worsening ( amplitude or # of body areas affected)

Majority of individuals report transient improvement of tremor with modest amounts of ethanol Head and Voice tremor is indicative of ESSENTIAL TREMORS Familial, improves with alcohol Drug-Induced Parkinsonism Crucial to r/o since most cases are reversible Careful med history Common offending agents: Antipsychotics haloperidol, chlorpromazine, thioridizine, perphenazine, risperidone, olanzapine Antiemetics metoclopramide, prochlorperazine DA depletors methyldopa, reserpine, tetrabenazine

Treatment STOP offending medication

Toxin-Induced Parkinsonism MPTP, Carbon monoxide, Manganese, Cyanide

HOW DOES PARKINSONS DISEASE PROGRESS? Early PD Wide therapeutic window Early complications (year 5-10) may experience dystonia and wearing off

 Advanced PD no middle ground and in order to relieve sx of PD the patient must tolerate side effects of dyskinesia/dystonia

COMPLICATIONS OF ADVANCED PARKINSONS DISEASE Wearing off as more DA neurons are lost, the brain does not have storage capacity to store drug (eventually approach carbidopa/levadopa half-life of 90 minutes) Dyskinesias involuntary writhing movements of neck, facial expression muscles, leg muscles (occurs most commonly at peak dose) Orthostatic hypotension can be meds (but also is advancing disease) Hallucinations/psychosis may be upsetting and patient will be unlikely to mention to doctor (animals or children, escalate into frightening hallucinations, pts with co-existing dementia are most at risk) Affective disorders panic attacks, mania

INITIAL TREATMENT OF PARKINSONS DISEASE When to begin therapy? Definitive neuroprotective therapy not yet available (to slow disease progression) Timing of symptomatic therapy in individual should begin with emergence of disability (degree of functional impairment, lifestyle of patient)

Symptomatic Treatment Pharmacological Levodopa Levodopa requires active transport across the gut-blood and blood-brains barriers Rapid peripheral decarboxylation to DA without a decarboxylase inhibitor (carbidopa, benserazide) Side effects nausea, postural hypotension, dyskinesias motor fluctuations DA Agonists (bromocriptine, pergolide, ropinirole, pramipexole, apomorphine) Stimulate DA receptors directly and thus do not depend on degenerating neurons to provide therapeutic effects Can be used as monotherapy in early PD or with CD/LD as adjunctive therapy May delay onset of motor complications

 Most pts will require supplementation with LD Side effects n/v, dizziness, postural hypotension, HA, drowsiness, somnolence, dyskinesias, confusion, hallucinations, paranoia, erythromelalgia, pulmonary and retroperitoneal fibrosis, pleural effusion and pleural thickening, Raynauds phenomena 1st give levadopa then give this COMT inhibitors (Tolcapone, Entacapone) catecholamone-O-methyltransferase inhibitor Given with LD to decrease dose needed Side effects diarrhea, orthostasis, dyskinesias, confusion, acute fulminate hepatic necrosis* with tolcapone but NOT entacapone MAO-B inhibitors (Selegiline) Blocks DA metabolism (by MAO) in the brain (unlikely neuroprotective) Side effects insomnia, hallucinations, nausea, orthostatic hypotension Potential interactions with TCAs and SSRIs Anticholinergics (Trihexyphenidyl, Benztropine, Ethopropazine) DA depletion leads to cholinergic over activity Effective mainly for tremor and rigidity (not good with bradykinesia) Side effects dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention (BAD, and limit use) Start low and go slow (but will need a high dose to effectively tx PD symptoms) Amantadine Exact MOA unknonwn ( release of stored DA, inhibit presynaptic reuptake of catecholamines, DA receptor agonism, NMDA/AMPA receptor blockade) Tremor, bradykinesia, rigidity & dyskinesias Side effects autonomic, psychiatric, levedo reticularis Surgical Bilateral STN Stimulators

Restorative Treatments (experimental only) Transplantation fetal tissue transplants of neural tissue (not great results, moratorium)

Neurotrophic factors

NON-MOTOR COMPLICATIONS IN PARKINSONS DISEASE Drug-Induced Psychosis (most common reason for nursing home placement) Attempt to PD meds to minimum needed to maintain mobility often leaving CD/LD as only PD med Tx atypical antipsychotic agents (clozapine, quetiapine)

Hypersexuality Rare (1-3% of pts with advanced PD (M>F) Associated with psychosis in most cases Tx atypical antipsychotics

Dementia 20-40% of PD pts develop dementia (features similar to AD and Lewy body dementia) Clinically, dementia associated with PD had both features of cortical and subcortical dementia Impairment of visuospacial skills are most frequently reported Standard office test of cognitive function used in pts with AD do not correlate well in pts with PD Presence of dementia s risk for tx associated psychosis Tx anticholoinesterase meds (not well studied)

Depression Occurs in 20-30% of pts with PD Level of motor disability does NOT correlate with severity of depression PD pts often require treatment for depression Responds to typical meds Concerns about interactions with SSRIs (tyramine reaction) ECT is effective in treating depression and may provide temporary benefits to PD motor symptoms but post-ECT delirium limits the use of ECT

Mania

Small % of pts treated for PD can develop acute mania Young onset pts more frequently reported to suffer mania Lithium impairs DA release in the brain and should be avoided in pts with PD

REHABILITATION REHABILITATION a process in which each disabled person reaches the maximum physical functional and psychological recovery possible within the limits of their disability Some patients may return to their baseline, some may set a new baseline

REHABILITATION SEEKS TO MAXIMIZE: Mobility often means ambulation but can be wheelchair mobility Activities of Daily Living Community Activities transportation, shopping Speech and Cognition Psychosocial adjustment how person re-enters socity

DOMAINS OF WHO INTERNATIONAL CLASSIFICATION OF FUNCTIONING Pathology (disease, diagnosis) Impairment (symptoms and signs) Activities (disability, behavior) Participation (handicap, social roles)

REHABILITATION MODEL VS. MEDICAL MODEL Medical Model: Focus on diagnosis of illness Heavy reliance on diagnostic studies

Specific treatments (medication, surgery, etc)

Rehabilitation Model: Focus on activities (disability, behavior) Concerned with participation in community and social roles Focus on individual needs Interdisciplinary team approach In addition to specific treatment, often focuses on adaptation

DISABILITY IS MULTIFACTORIAL Medical Factors Severity of neurological deficit predicts disability Concurrent medical conditions (acute and chronic)

Non-Medical Factors Previous functional abilities Previous living arrangements Availability of family and social support systems Personal finances Patient/family goals, expectations, and preferences Willingness/ability to participate in rehabilitation

CONDITIONS APPROPRIATE FOR REHABILITATION Pediatric: Trauma Cerebral palsy Developmental disabilities Congenital deformities (myelomeningocele, limb deformities) Neuromuscular disorders (muscular dystrophy)

Other special conditions (vent weaning)

Adult: Stroke (most common) Traumatic brain injury Other brain conditions (tumor, encephalitis) Spinal cord injury Other special conditions (transverse myelitis) Multiple sclerosis Parkinsons disease & other movement d/o NM disorders (neuropathies, myopathies) Complex fractures Multitrauma Sports injuries Hip fractures Joint replacements Amputations Deconditioning Cardiac conditions Pulmonary conditions

COMPREHENSIVE REHABILITATION TEAM Rehabilitation physician Rehabilitation nursing Physical therapy Occupational therapy Speech therapy Rehabilitation psychology Social worker Recreational therapy Nutrition

POST-ACUTE REHABILITATION SERVICES REHAB DOESNT JUST OCCUR IN THE HOSPITAL Rehabilitation hospitals and units Skilled nursing facilities (SNFs) hospital based vs. free-standing nursing homes Long term care hospitals (LTAC) hospitalization must be >20 days Outpatient programs hospital vs. free standing Home health programs

CRITERIA FOR HOSPITAL REHABILITATION SERVICES Patient has had a functional loss Patient is medically stable

 Multidisciplinary rehabilitation necessary Patient has realistic, documentable rehabilitation goals Patient is actively able to participate in 3 hours of therapy daily, 5 days a week

IMPAIRMENT CATEGORIES FOR HOSPITAL-BASED REHABILITATION IN THE US Neurological Disorders (40%) stroke, traumatic brain dysfunction, traumatic spinal cord dysfunction Orthopedic Disorders (30%) LE fracture, joint replacement Other Conditions (30%)

ALLOWABLE MEDICAL ISSUES IN REHABILITATION PATIENTS

Dysphagia/feeding problems

DVT and PE prophylaxis Pain Pressure ulcers

Contractures Spasticity Depression

Bowel/bladder management Infections (UTIs, PNA) SPECIFIC REHABILITATION STRATEGIES Physical Training

Primary focus is on improving motor function and mobility Common PT strategies: Muscle strengthening Promote ROM Training of skilled motor activities Improvement balance and ambulation Teach safe transfers Teach wheelchair mobility Orthotic recommendations Orthosis device which provides support or improves fxn of a movable part of the body (brace)

 Occupational Therapy Primary focus is enhancing functional activities (ADLs, community activities) Recommend adaptive equipment and home modificatyions UE rehabilitation strengthening, ROM, functional activities, orthopedic hand OT Specialized function driving evaluations, job adaptations

Speech/Language Pathology Evaluate and treat speech/language disorders aphasia, agraphia, alexia Evaluate and treat disorders of articulation or phonation Evaluate and treat swallowing disorders (clinical vs. diagnostic) Videofluoroscopy (modified barium swallow) Fiberoptic endoscopic evaluation (direct visualization of pharynx/vocal cords)

Participate in cognitive evaluation and cognitive therapy

Recreational Therapy getting patient back into the community

DISCHARGE ISSUES (from hospital to outpatient rehab) Adequate training/education of patient/family Assessment of home adaptation/equipment needs Assessment of need for further rehabilitation, and smooth transition to another level of care

SUBACUTE REHABILITATION Comprehensive rehab for persons with acute illness or injury (less intensive than hospital but more than nursing home) Goal-oriented treatment requiring the services of an interdisciplinary team Requires frequent (daily to weekly) patient assessment and review of the clinical course Treatment plan for a limited time period (several weeks to several months)

HOME HEALTH REHABILITATION Less intensive 1-2 hours of therapy 2-3 times/week

 Patient must be home bound Professional care must be medically necessary, but part time and intermittent Emphasis on function in the home and family training Home health aides may be available 3x/week to assist with ADLs

HOME ADAPTATION Ramps 1 inch grade for each 1 foot of length Doors 2 inch clearance on each side for wheelchairs, handle adaptations Bathroom 5-6 ft wide for wheelchair turning, elevated toilet seat, grab bars Other rooms rearrange furniture and rugs

ASSISTIVE TECHNOLOGY Low Tech adaptive clothing, eating utensils, reachers High Tech augmentative communication devices, computerized environmental control systems, adaptive driving Hand controls, spinner knob, left foot accelerator, right turn signal extension, gas pedal extension

FAMILY AND SOCIAL ADJUSTMENT ISSUES Caregiver depression/burnout Changes in family roles Vocational issues Changes in leisure activities Financial adjustments Loss of social supports

 Loss of driving Sexuality and intimacy

Physiatrists physical rehabilitation medical doctors

SPINAL CORD AND NEUROLOGICAL LOCALIZATION GROSS ANATOMY There are 8 cervical roots and 7 cervical vertebrae Spinal cord ends at L1-L2, Vertebrae continue down In the lower vertebra, there is not concordance between the cord level and vertebral level

Cord = CNS, Roots = PNS

VASCULAR ANATOMY Anterior spinal artery is formed from the vertebral artery Radicular arteries run with the nerve roots Cord ischemia can be seen with AA (due to damage to radicular as) typically thoracic aneurysms Intramedullary cord (P) CORD LESIONS Intramedullary gliomas, myolitis Extramedullary meningiomas, neurofibromas Extradural metastases, disk bulges, abscess, bleed Extramedullary intradural (A) (contains CSF) Extradural epidural (D)

CLINICAL ANATOMY Pain/temp fibers enter spinal cord (dorsal nerve roots), synapse in posterior horn, decussate at level of cord, and ascend in spinothalamic tract Position fibers enter spinal cord, ascend in posterior columns, synapse in lower medulla and decussate Both of these sensory fibers go to the thalamus

 Corticospinal fibers come from internal capsule and decussate the in pyramids (lower medulla) and travel down to the anterior horn cells and exit as ventral nerve roots Central canal blind pouch in the adult, lined with ependymal cells (can get ependymomas) If a lesion is above the decussation at the medulla, sensory and motor abnormalities will be contralateral If a lesions is below the decussation at the medulla, sensory and motor abnormalities will be ipsilateral Bladder level S2-S3 (dont get involvement unless cord lesion is bilateral)

Brown-Sequard Syndrome Hemisection of the spinal cord Clinical findings position ipsilateral below the lesion (posterior column) pain contralateral from one level below the lesion (lateral spinothalamic tract) pain ipsilateral at the level of the lesion (PNS) local abnormality Weakness ipsilateral from the lesion below (lateral corticospinal tract) Atrophy and fasciculations ipsilateral at the level of the lesion (damage to ventral motor neurons at the level of the lesion) local abnormality reflexes above the lesion reflexes below the lesion

Disk Bulge Will see local findings as in Brown-Sequard If posterior (dorsal) compression pain(pin) at the level of the lesion If anterior (ventral) compression Atrophy and fasciculations at the level of the lesion

STROKE MANAGEMENT STROKE FACTS 3rd leading cause of death (>160,000 deaths per year) 750,000 strokes/year (every 45 seconds someone suffers a stroke)

 >4 million stroke survivors (most survive their stroke) Leading cause of adult disability (90% have deficit) Many strokes are preventable Twice as many women die from stroke every year than breast cancer

NON-MODIFIABLE RISK FACTORS FOR STROKE Age Incidence doubles each decade after age 55 Gender Incidence 19% higher for men than women Race AA men have a 98% and AA women a 77% high death rate than their Caucasian countearts

MODIFIABLE RISK FACTORS HTN * Cardiac disease Atrial fibrillation DM Smoking EtOH abuse Hyperlipidemia Asymptomatic Carotid Stenosis

STROKE IN YOUNG PATIENTS (~1/4 of strokes occur in patients <65 years of age) Clotting disorders Migraine BCP Illicit drug use (cocaine, amphetamines) Arterial dissection (trauma) PFO Autoimmune disorders (lupus)

TIA OR MINI-STROKE RESOLVES IN 24 HRS Transient neurological event often lasting 5-15 minutes with complete resolution of symptoms TIAs are a warning sign of stroke (>1/3 all persons who experience a TIA will go ont to have a full stroke often within 1 month) Symptoms of TIAs are the same as for stroke (pathophysiology is the same as well)

 STROKE SYMPTOMS Sudden onset and negative symptoms are classic Numbness or weakness of face, arm or leg, especially on one side of the body Sudden severe HA with no known cause (SAH) Sudden trouble seeing in one or both eyes Sudden confusion, trouble speaking or understanding Sudden trouble walking, dizziness, loss of balance or coordination

DIAGNOSIS OF STROKE History (time of symptom onset*, precipitating factors, seizure activity, change in stroke deficit over time) important in determining treatment options Awake from sleep Small vessel thrombotic After exercise Cardioembolic Todds paralysis dysfunctional brain activity from a seizure that looks like a stroke

Coexisting medical problems (stroke/vascular risk factors) Exam (V/S most importantly bp, cranial/cervical bruits, cardiac exam, neuro exam)

COMMON PATTERNS OF STROKE Left (Dominant) Hemisphere Stroke Aphasia Right hemiparesis R-sided sensory loss (touch, temp, pain) Right visual field defect Poor right conjugate gaze Dysarthria Gerstmann Syndrome Difficulty reading, writing, or calculating

Right (Non-Dominant) Hemisphere Stroke Left-sided sensory loss Extinction of L-sided stimuli Inattention (neglect) ed awareness of L side of body

Spatial disorientation L hemiparesis L visual field defect

Poor left conjugate gaze Dysarthria

Brainstem, Cerebellum, Posterior Hemisphere Stroke Motor or sensory loss in all four limbs Crossed signs unique Limb or gait ataxia Dysarthria Dysconjugate gaze Nystagmus Amnesia PCA Bilateral visual field defects n/v vertigo perioral parasthesias

Lacunar Stroke Syndromes small vessel, end artery occlusions (unique in that they have no cortical deficits) Hemimotor (pure motor) Hemisensory (pure sensory) Hemiataxia/hemiparesis Dysarthria/clumsy hand Sensoriomotor

Wallenberg Stroke lateral medullary stroke No motor deficits Sx Dizziness, vertigo, n/v Horners syndrome, numbness of hemi-face and other side of body

STROKE MIMICS (positive before negative symptoms, gradual onset) Seizure with Todds paralysis Migraine-related event Hypoglycemic event Psychiatric

 NIH STROKE SCALE measures of acute stroke severity (predicts management and outcomes) LOC Best gaze (eye movements) Visual fields (visual quadrants) Facial palsy (facial paralysis) Motor movement (arm and leg) Limb ataxia (F-N) Sensory (noxious stimulus) Best language (comprehension) Dysarthria (articulation) Extinction and inattention
(neglect)

Distal motor function (finger)

 DEFINITION OF STROKE Sudden brain damage Lack of blood flow to the brain caused by a clot or rupture of a blood vessel Ischemic most common (85-90%) Hemorrhagic bleeding around or into the brain

THERAPEUTIC TIME WINDOW From the time of initial blockage there is a certain time in which the brain is dependent on limited or poor blood flow and brain is potentially salvageable (often <3-6 hours) Penumbra potentially salvageable brain around core of dead brain Relies on collateral blood flow

NEWER MRI TECHNIQUES Diffusion imaging relies on abnormal intracellular water content Perfusion imaging darker = likelihood of salvage Gradient echo sequence MR angiography look at vascular anatomy

ACUTE ISCHEMIC STROKE TREATMENT Thrombolytic Therapy IV recombinant tissue plasminogen activator (t-PA) Alteplase Massively underutilized Inclusion Criteria: >18 years of age (not absolute) Clinical dx of ischemic stroke 69

 Measurable neurological deficit Clearly defined time of stroke onset (<90 minutes or 91-180 (3hrs) minutes before treatment) Baseline CT showing no evidence of ICH Exclusion Criteria: Rapidly improving or minor sx CT scan showing evidence of ICH h/o ICH Seizure at stroke onset Stroke or head trauma <3 mons Major surgery or trauma <2 weeks GI or UT hemorrhage <3 weeks SBP >185; DBP>110 Aggressive Tx to lower bp Glucose <50 or >400 Symptoms of SAH Arterial puncture at noncompressible site or LP<1 week Platelets <100,000 Heparin <48 hrs with aPTT Pregnant or lactating females PT>15 on PO anticoagulants

Administration of t-PA 0.9mg/kg with maximum dose 90mg 10% as IV bolus with remainder via 1 hour infusion Pay careful attention to bp maintaining <185/110 70

 No anticoagulants or antiplatelet agents for 24 hours Individuals receiving t-PA did 30% better than placebo group wrt disability at 3 months The sooner one pursues IV t-PA, the better the outcome (<90 minutes better than <120, but can be given out to 180 minutes) Complications ICH is not dramatic if properly select patients (6% bleed vs. 30% clinical benefit) Intra-arterial thrombolysis Mainly applied to large vessel occlusions with severe disabling strokes that often dont respond to IV t-PA

Neuroprotective Agents/Hypothermia Many classes of agents have been tested (NMDA blockers, CCB, glycine antagonists) These trials have been negative thus far Hypothermia can reduce stroke volumes and improve stroke outcomes (trials of cooling devices)

Anticoagulant therapy (Heparin, LMWH) All trials have shown neutral or negative data wrt these agents Potential indications for IV heparin: Crescendo TIAs Stroke in evolution/stuttering stroke Mild-moderate stroke and potential high risk source (cardioembolic, high-grade stenosis, aterial dissection, hypercoagulable state) Basilar artery thrombosis Venous sinus thrombosis

Antiplatelet therapy Other (Ancrod, Abciximab, Argatroban) Surgical Options Decompressive hemicraniectomy/duroplasty (non-dominant hemisphere) Urgent carotid endarterectomy 71

 IMPORTANT CLINICAL VARIABLES IN ACUTE STROKE MANAGEMENT Blood pressure (map between 50-150 autoregulation is well maintained) In stroke zone autoregulation is impaired and is a linear curve, such that with small drops in blood pressure, there can be significant in perfusion Keep map>80 and <135 (?arterial line, CVP monitoring) Tx high bps labetolol, nicardipine Tx low bps NSS, albumin, DA, Neosynephrine

IV volume (needs to be euvolemic or even a little hypervolemic) Serum glucose (<120-150) insulin if necessary Temperature (<36.5-37) Oxygenation/Hct >30 Head elevation at 15-30 degrees to maximize perfusion and risk of aspiration MEDICAL COMPLICATIONS OF STROKE Cardiac arrhythmias, MI, prolonged QT (10% of patients) Pulmonary aspiration pneumonia Vascular DVT, PT GI stress ulcers, GI bleeding, bowel dysfunction Urinary UTI (d/c foley) Metabolic Hyponatremia, malnutrition Psych depression (common) MSK contractures, pressure sores

ETIOLOGY OF STROKE

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hemorrhage

(Unknown etio)

DIAGNOSTIC STUDIES MRI (brain), diffusion/perfusion, MR angiography CT (brain), CT angiography, xenon CT Carotid duplex Transcranial dopper study Conventional cerebral arteriography Brain SPECT imaging Echo (TTE or TEE) Cardiac telemetry/Holter monitoring Additional labs Protein C/S, ATIII, APC resistance, Factor V Leidin, ESR, ANA, antiphosplipid antibodies, homocystine level, ?urine drug screen

INTRACEREBRAL HEMORRHAGE MANAGEMENT Optimal bp management (<160/90) Complete reversal of anticoagulation (FFP, cryoprecipitate, platelets) Seizure precautions (blood = irritant) ICP issues (hyperventilation, mannitol, skull decompression) 73

 STROKE PREVENTION (#1 importance) CHRONIC TREATMENT OF STROKE Medical Treatment Antiplatelet therapy which you choose is cost, compliance, side effects and risk factors ASA least effective but better than nothing (use if stroke occurred with nothing on board) Clopidogrel more effective than ASA but some risk Aggrenox (ASA + dipyridamole) best effect with good safety profile Combination GP IIb/IIIa antagonists

Anticoagulation therapy How choose between antiplatelet and anticoagulation? What is the stroke etiology? Cardioembolic, hypercoagulable states, arterial dissection anticoagulant Most others antiplatelet

Surgical Treatment Carotid endarterectomy Symptomatic >70% stenosis superior to medical therapy 50-69% stenosis selective benefit (men, stroke, hemispheric event) <50% stenosis no benefit ing benefit with advanced age Surgical morbidity/mortality must be <5% if considering Asymptomatic >60% stenosis consider possible (however most wait until >80%) Surgical morbidity/mortality should be <3% if considering Aggressive Risk Factor Modification 74

HTN <140/90, <130/85 in DM Hyperlipidemia LDL<100, HDL>40-50, TC<200, TG<150 DM HbA1c<7% Smoking cessation EtOH intake <2 drinks/day (any type of EtOH) Physical activity 30-60 minutes on most days Weight <120% idea weight Medications: ACE inhibitors/ARBs stabilize vascular endothelial function (30-50% risk) Vitamin therapy (B6, B12, folic acid, avoiding hyperhomocystenemia) Niacin ( lipoprotein a levels) AVOID Estrogen replacement therapy Antibiotics/statins ( high sensitivity CRP levels and stroke risk)

STROKE AND ATRIAL FIBRILLATION

Age <65 <65 65-75 65-75 >75 Major Risk Factors No major risk factors Major risk factors No major risk factors Major risk factors All patients Recommendations ASA Warfarin (INR 2.5) ASA or warfarin Warfarin (INR 2.5) Warfarin (INR 2.5)

Major risk factors previous TIA, stroke or systemic embolism, poor LV function, HTN RECOVERY STROKE

Motor recovery stimulants, limb restraint therapy, motor stimulation, botox injections for spacisity Aphasia recovery DA against (bromocriptine) for expressive speech deficits, Aceytlcholinesterase inhibitors (Aricept) for comprehension/memory deficits Aggressive outpatient PT/OT/ST programs ?Neuron transplantation, nerve growth factors

TREATMENT STRATEGIES IN EPILEPSY 75

 ORIGINAL TREATMENT OPTIONS only 5 major drugs discovered and used over the years Phenobarbital (1912) Phenytoin (1938) most prescribed antiepileptic drug in US Ethosuximide (1962) limited use Carbamazepine (1974) Tegratol Valproic acid (1978) Depakote

NEWER ANTIEPILEPTICS larger increase in number of drugs compared to previous Felbamate (Felbatol) Gapapentin (Neurontin) Lamotrigine (Lamictal) Topiramate (Topamax) Tiagabine (Gabitril) Oxcarbazepine (Trileptal) Levetiracetam (Keppra) Zonisamide (Zonegran)

MECHANISM OF ACTION ALL PROPOSED MECHANISMS

Drug CBZ PHT VPA Barbs BZD Ethosux GPT LTG TPM TGB OXC LVT ZNM Selective Sodium Channel Blockers ++ ++ ++ + GABA Receptor Activators (GABA is -) T-Ca2+ Channel Current Blockers Excitatory Current Blockers + + ? + ++ ++ + ++ ++ ++ Unknown ++ + + ++

++

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Newer drugs have varied MOAs

ISSUES TO CONSIDER IN EPILEPSY TREATMENT Seizure Type All drugs except ethosuximide shown to be effective in partial onset seizures Most used in monotherapy Pb, PHT, CBZ, VPA, LTG, OXC CBZ has become the gold std

Drug Side Effects Many side effects are common among all the AEDs Neuro HA, tiredness, asthenia (lack of desire to do anything), dizziness GI nausea, constipation, diarrhea

Unique side effects: Pb memory, drowsiness, Dupuytrens contractures PHT gingival hyperplasia, facial hair (may be irreversible), cerebellar atrophy CBZ hyponatremia ( renal excretion), weight gain VPA weight gain (more than CBZ), tremor, alopecia !increases LTG! ESM GI FBM liver failure, aplastic anemia, HA, weight loss GPN weight gain LTG rash if increase too quickly (Stevens Johnsons) TPM weight loss, cognitive, renal stones OXC hyponatremia LEV behavior (irritability), bad interactions with Valproic Acid ZNS weight loss, renal stones, psychosis 77

 Drug Interactions Pharmacokinetics AED Metabolism Protein Binding Effects on liver enzymes PB 50% liver, 50% renal Low Potent inducer PHT Liver High Potent inducer CBZ Liver Moderate Potent inducer VPA Liver High Inhibitor ESM Liver Low None GBP Renal Low None LTG Liver Low None TPM 80% renal if uninduced Low Mild induction TGB Liver High, but low conc None known OXC Liver Low Mild induction LEV Renal Low None ZNS 50% liver Low None Interactions occur between the different AEDs which can or the level of one another

Womens Issues Pregnancy All old AEDs known to birth defects CBZ, VPA risk of spina bifida Cardiac and craniofacial defects Little known on newer AEDs LTG has most data (same birth defect rate as general population) OCP use/hormones Effects of hormones on seizures Estrogen shown to seizure threshold Progesterone shown to protect against seizures Effects of seizures on hormones birth rate in women with epilepsy Effects of AED on hormones PB, PHT, CBZ, OXC, TPM effectiveness of OCP PB, PHT, CBZ also known to SHBG (s free estrogen concentration) 78

 ABSENCE SEIZURES Must rule out other seizure types Myoclonic and tonic-clonic may frequently co-exist with absence seizures Juvenile myoclonic epilepsy mixture of absence, myoclonic and tonic-clonic

Important in drug choice and treatment length Ethosuximide only effective in absence seizures (30% of these kids will have a tonic-clonic seizure at some point in their life)

SPECTRUM OF COVERAGE Cover multiple seizure types: VPA ALL seizures LTG covers all, may worsen rare form of myoclonic seizures TPM covers most, ?absence LEV probably covers all ZNS covers all

CBZ, PHT, GPN, TGB can worsen some seizures (myoclonic, absence) dont worry about this with newer AEDs

ISSUES IN THE ELDERLY Differences in liver and renal function ( liver metabolism, Creatinine clearance is ) Often on multiple medications Better to have AED with low protein binding and no enzyme induction (GBP, LTG, LEV*, ZNS, OXC, TPM)

Osteoporosis Pb, CBZ, PHT all shown to risk of osteoporosis (possibly due to enzyme inducing effects?) Little known about newer AEDs (but have little enzyme induction effect)

More prone to adverse effects (at lower doses) 79

Studies have shown that drugs are equally effective but new drugs have lower side effects

More prone to injury with seizures More prone to status epilepticus and have complications Poorer outcome associated with very young and very old (suggests need for more aggressive treatment)

ADDITIONAL TREATMENT OPTIONS Only 50% of patients achieve seizure-freedom with first AED Only 65% of patients achieve this status with 3 drugs Surgery Temporal lobectomy, lesional, corpus callostomy (helpful in atonic seizures), nonlesional Pts with mesotemporal sclerosis are most resistant to drug therapy but most responsive to surgical treatment

VNS Therapy Mild electrical pulses applied to the L vagus nerve in the neck send signals to the brain Automatic intermittent stimulation Magnet use allows patient/caregiver on-demand stimulation and on-demand side effect control Assured compliance

CONCLUSIONS Older AEDs are well established with years of experience (and cheaper) Newer AEDs offer several advantages over older AEDs: Better tolerated Fewer to no drug interactions Several that are broad spectrum ?LTG safer in pregnancy L more expensive 80

OVERVIEW OF NEUROMUSCULAR JUNCTION DISORDERS TYPES OF NMJ DISORDERS Post-synaptic (Myasthensia Gravis) Pre-synaptic (Lambert Eaton Myasthenic Syndrome, Bolutlism)

MYASTHENIA GRAVIS Autoimmune disorder immune system makes circulating antibodies directed at the nicotinic ACh receptor (pos-synaptic) ACh is released normally but cannot act at receptor

Epidemiology Rare, but not uncommon 20-70 cases per 1 million in US Bimodal peak of age of onset Women between age 20-40 (younger women) Men between 40-60 (older men) Women:Men = 3:2

Familial occurrence is rare (1st degree relatives do have higher incidence of other autoimmune dx)

Clinical features Initially involves ocular muscles (60%) Virtually all pts will have ocular involvement within 2 year of onset of MG About 10% remain localized to eyes Ptosis (unilateral or bilateral) EOM weakness may be asymmetrical 81

May mimic 3, 4 or 6 CN palsy MG does NOT affect pupillary function

Difficulty chewing, speaking or swallowing Speech is often nasal (weakness of soft palate) or slurred (weakness of tongue, lips and face) Fatigue and generalized weakness (consider in all patients with generalized weakness, even w/o eye involvement) HALLMARK = pathologic fatigability (weakness with activity, improves with rest) Neck flexor weakness may be present No abnormality of cognition, sensory function or autonomic function MGFA Classification system

Differential Diagnosis Multiple Sclerosis (Bilateral INO) ALS (asymmetric weakness) Periodic Paralysis (gen. muscle weakness) GBS (ascending weakness) Myositis (proximal weakness) Botulism (general limb weakness) LEMS (proximal weakness) Thyroid (ptosis, fatigue)

There are many drugs that can exacerbate or induce myasthenia gravis Antibiotics especially aminoglycosides Cardiovascular Drugs blockers (use with caution) Other steroids, phenytoin, D-pennicillamine

Diagnostic Studies Ice Test (not pathognomonic) apply ice to eye w/ ptosis for 1 min, should improve (= +Ice Test) Lab Studies ANA, RF Thyroid function tests ACh receptor antibody levels (binding, blocking, modulating) helpful if +, does not exclude if 82

Anti-striated muscle antibody (useful in thymoma) Anti-MUSK antibody (IgG ab to muscle-specific tyrosine kinase) generalized MG ESR(inflammatory dx), cbc, liver and renal profile, electrolytes

Tensilon Test Edrophonium short acting ACh esterase inhibitor Patient should be on cardiac monitor, atropine at bedside Test dose of 2 mg given IV, if no improvement after 1 min, give rest of dose (total 10 mg) Must use an objective parameter to determine if it is positive or negative (ex: eyelid drooping, restriction of EOM, etc)

Electrodiagnostic Study Routine nerve conduction studies to exclude a neuropathy or myopathy Repetitive nerve stimulation look for decrement (yield higher in proximal muscles, but more technically demanding) If there is a decrement with slow stimulation, do fast stimulation as well (SFEMG)

Imaging studies (to exclude thymoma)

Treatment Goal is to achieve remission Rate of progression may determine aggressiveness of therapy Pharmacological agents Pyridostigmine Usually first line therapy in symptomatic patients Start low and titrate as tolerated Side effects (cholinergic excess) abdominal cramping, increased salivation, diarrhea) Too much may precipitate a cholinergic crisis (may look like MG is worsening) Immunosuppressive therapy usually necessary in most patients; Must monitor various blood parameters to make sure no toxicity develops (dose adjust based on wbc level) 83

 Prednisone Start slow and titrate upward (there can be a transient worsening of MG symptoms) Benefit starts after about 6-8 weeks Side effects

Azathioprine Start with a test dose for one week and then increase (can re-test after wash-out) Warn patient about flu-like syndrome (severe aches and pains) Benefit seen in 4-6 months Monitor cbc (wbc 4500) and LFTs Small increased risk of malignancy (with long term therapy) Cyclosporine Start low and titrate up Benefit in 2-4 months Monitor cbc (wbc), renal profile, bp, trough level Cyclophosphamide Reserved for when other agents fail Start low and titrate up Caution about hemorrhagic cystitis Mycophenolate mofetil (been used in transplant medicine for years, shows benefit in MG) Alternative when standard drugs fail Start low and titrate up cbc (wbc) monitoring must be done closely IVIG (for acute treatment) Mechanism not well understood Useful when vascular access is a problem 84

Side effects HA, chills, fever, aseptic meningitis(rare), renal failure Premedicate with Tylenol and Benadryl

Plasma Exchange (for acute treatment) Venous access often a problem Remove circulating immune complexes from blood 5-6 exchanges over 2 weeks Risks fluid imbalance, hypercoagulation, may need central line if friable veins

Thymectomy General agreement that thmectomy should be performed in MG patients under age 60 Thymoma should be removed Thymectomy should be done with patient is medically stable (electively, NOT urgent) Clinical improvement delayed by 6 months 1 year after surgery

Myasthenic Crisis Neurological emergency Admit to ICU Exclude and treat underlying infection often precipitates crisis Stop anticholinesterase treatment (Tensilon test works in theory but not in clinical practice) Plasma exchange

LAMBERT-EATON MYASTHENIC SYNDROME (LEMS) Inadequate release of ACh at pre-synaptic terminal due to IgG directed against voltage gated calcium channel

Clinical Features 85

Fatigability and weakness in limb-girdle distribution Weakness worse in AM and better at end of day (opposite of MG) Short period of exercise may improve symptoms Mild degree of ocular and bulbar involvement in some patients Autonomic involvement common (dry mouth, orthostasis, impotence) Proximal weakness Diminshed DTRs Up to 50% can be associated with a malignancy (small cell lung cancer) more common in men

Electrodiganostic Study Low amplitude CMAP Decrement on slow RNS (slow repetitive stimulation still causes decrement) Increment at high rates RNS (as you exercise quickly/fast repetitive stimulation, strength improves)

Treatment Search for underlying malignancy Trial of pyridostigmine (often little benefit) Aggressive immunotherapy Guanidine HCl enchances release of ACh (but too risky) 2,4-daminopyridine increases duration of presynaptic action potential (blocks K efflux) Plasma exchange, IVIG

Other things on the exam: Cranial Nerve Palsies related to diabetes: VI Chronic Atrial Fib w/sx of stroke: 1st step in management is: o DO NOTHING 1 ? on stroke location: parietal lobe, cannot recognize object in hand 86

Amantadine helps the most of all the drugs with the dyskinesias of Parkinson's Disease Carbamazepine is an autoinducer, Valproic increases concentration of lamotrigine Chin tremor is almost always parkinson's disease (along with resting tremor) The KEY difference between simple and complex partial seizures is level of consciousness NOT automatisms When patients with PD come into the hospital you don't STOP drugs, and the last drug you change is the sinemet (levodopa/carpidopa), keep it same dose but t.i.d. Read the questions carefully - a.fib question and fiber type question There is increassed IgG (oligoclonal bands) in the CSF with MS because there is more made in the CSF. Reflexes: S1- achilles, patellar - L3/4, bicpes - C5/6; triceps - C7/8 ( you need to know this in order to answer a question) phenytoin causes gingival hyperplasia cardiac problems are a cardinal feature of Duchenne's Know which AED do not work on the sodium channels NO rehab questions, no EEG, no EMG/NCS Gerstman Syndrome was on there You can use lithium to treat cluster headaches Acetozolamide can help with pseudotumor cerebri MG - can be made worse by steroids and beta blockers, but the correct answer is aminoglycosides Juvenile Huntingintons characterized by anticipation Juvenille Myoclonic Epilepsy need AEDs for life You give ppl benzos when they have alcohol intoxication because of tonic-clonic seizures NOT to prevent status epilepiticus Wilsons causing psychosis in 16 year old. Understand how Internuclear ophthalmoplegia works

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