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NEUROLOGY Internal Medicine Board Review Brad Ingram, MD Neurology • • • • Demyelinating diseases Stroke Neuromuscular Movement Disorders • • • • Dementia Headache Epilepsy Neuro-oncology 2 Demyelinating Diseases 3 Multiple Sclerosis • Diagnosis: • Clinical—dissemination in time/space • Paraclinical—MRI brain/c-spine, LP, evoked potentials • Treatment: o Exacerbation • New si/sx lasting >48 hrs with infection/metabolic cause ruled out (pseudo-relapse) • Solumedrol 1 gram/day x 3-5 days o Prevent Relapse • 1st line: IFN b-1a, IFN b-1b, glatiramer acetate • 2nd line: mitoxantrone (cardiotoxicity, leukemia); natalizumab (PML); fingolimod (bradycardia, macular edema) Symptomatic Treatment • Fatigue o R/o medical causes: TSH, B12, CBC o Address sleep hygiene o Exercise and cooling measures • Spasticity: PT, baclofen, tizanidine • Bladder dysfunction: anticholinergics, timed voiding, urology referral • Paroxysmal symptoms: cooling, carbamazepine, gabapentin • Depression: TCAs, SSRIs NMO (Devic’s disease) • Neuromyelitis optica • Recurrent optic neuritis and transverse myelitis • Long segment of demyelination (3 vertebrae) • Peripheral Ab to aquaporin4 • Acute tx: steroids, PLEX • DMTx: rituximab, azathioprine STROKE 7 Basilar Artery Stroke • Symptoms o 75% have prodrome w/stuttering course, presentation very variable o Mild generalized weakness to comatose o The 5 Ds: Dizziness, Diplopia, Dysarthria, Dysphagia, Dystaxia o Hallmark of post. circ. = crossed findings o Locked-in = Quadriplegia, bilateral facial and oropharyngeal palsy but preservation of cortical function and vertical gaze • Treatment: o Respiratory support o IV TPA w/i 4.5 H, IA interventions even beyond 8 hours, heparin infusion in some patients after treatment o Angioplasty either acute or elective • Very high mortality (>90% if locked-in) Stroke etiology • • • • • • • Cardio-embolism (30-40%) Athero-embolism (LVD) (30-50%) Small Vessel Disease (SVD) (20-30%) Non-atherosclerotic vasculopaties (Rare) Thrombophila (up to 15%) Hemodynamic stroke (Watershed infx.) (unkown) Cryptogenic (unknown cause) (up to 30%) Frequency does not add up to 100% b/c etiologic frequency varies by series/population) 9 Basic Stroke Localization Acute treatment of stroke • IV tPA o <4.5 hrs after onset o CT head w/o contrast to r/o ICH absolute mandatory for your hospital to consider stroke treatment! o Dose 0.9mg/kg with max 90mg; 10% bolus then rest over 1 hour o No ASA, NGT, Foley, other procedures x 24 h post-tPA tPA criteria Inclusion Criteria AIS by history and exam Time of onset w/i 3/4.5 hours Normal noncontrasted CT-head (early ischemic signs allowed) Age > 18 years Exclusion Criteria • • • • • • • • • • • Stroke or serious head trauma w/i 3 months Lifetime history of ICH Major surgery w/i 14 days SBP > 185 or DPB >110 (sustained!) OR needing aggressive tx to maintain BP in above range Rapidly improving or minor Sx Sx suggestive of SAH GI or UT-hemorrhage w/i 21 days Arterial puncture @ non-compressible site w/i 7days Seizure at onset of stroke symptoms Coagulopathy: abnormal PT/PTT, Plt.<100000 Hypoglycemia (BG<50) or Hyperglycemia (BG>400) 12 Dense MCA Blurred gray-white junction ADC MAP Diffusion weighted MRI Apparent diffusion coefficient Acute treatment of stroke • IA tPA: less than 6 hours • Endovascular intervention up to 8 hours • If none of the above: o o o o o o Telemetry x 24 hours Permissive HTN (to 220/120) Maintain NPO until dysphagia screen passed ASA 325mg in first 48 hours PT/OT/Speech TTE with bubble, vascular imaging • Change in neuro examthink seizure, cerebral edema, infection, arrhythmia BP Management in AIS Post-tPA • Maintain SBP < 180, DPB < 105 • May continue use of Labetolol 10-20 mg, 1-2 times • If BP control unsatisfactory, use Nicardipine infusion (start @ 5mg/hr) • A-line not necessary, but preferred No tPA • Do not treat BP unless SBP > 220 or DBP > 120 • Treat BP if patient shows signs of cardiac ischemia AND has clinical features of decompensation (pain, tachycardia, de novo arrhythmia etc.) • If BP requires tx, monitor carefully for neurological deterioration 16 Secondary prevention • Risk factors are universal for vascular disease • Manage HTN, DLD, DM2 • Antiplatelet agent o Aspirin 81mg or 325mg o Aspirin + dipyridamole o Clopidogrel 75mg • Indications for warfarin o Intracardiac thrombus o Artificial heart valve o Non-valvular Afib (lone Afib and secondary Afib may require other considerations) o Large areas of cardiac hypokinesis TIA ABCD2 score predicts risk at 2, 7, and 90 days after stroke; helps determine urgency of w/u • Age ≥ 60 y: 1 pt • BP≥140/90: 1 pt • Clinical features: U/l weakness (2 pts), speech change (1 pt) • Duration: 10-59 min (1 pt), 60+ min (2 pts) • DM: 1 pt • < 4 low risk • 4-5 moderate risk • > 5 high risk 18 Carotid Artery Dissection Intimal flap Carotid artery dissection • Unilateral HA in 2/3 • Miosis/ptosis (oculosympathetic dysfunction) in <50% • Transient monocular blindness in 50-95% • Causes: o Trauma (50%) o Connective tissue disease o Fibromuscular dysplasia • Dx: CTA, MRA, angiography • Tx: heparin infusioncoumadin, endovascular stenting Carotid artery stenosis • Symptomatic CAS: o Either CEA or angioplasty + stent o Stent if radiation anticipated o Surgery is best done within 4-6 weeks after stroke • Asymptomatic CAS. Consider CEA or stent if: o o o o Stenosis >70% age <80 years life expectancy > 5 years Center with low (<3%) perioperative complication rate Neuromuscular 22 65 y/o myasthenic woman is admitted with a productive cough. She is given a dose of levofloxacin for CAP. The next morning, she feels weaker and complains of shortness of breath worse with standing than with laying flat. She can count to 10 on a single breath and is unable to converse in full sentences. What is the best next step? A. B. C. D. E. Increase Mestinon to 60mg q4h. Increase prednisone to 60mg qday Increase supplemental O2. STAT pulmonary mechanics Start plasma exchange. Neuromuscular Respiratory Failure ¨ ¨ Respiratory failure does not occur until the respiratory muscle strength has fallen to 2030% of normal. Signs of impending respiratory failure: Dysphagia Progressive quadraparesis with inability to lift head off bed Weak voice Bifacial weakness Wet voice Inability to complete sentences Neuromuscular Respiratory Failure • Pulmonary mechanics: o FVC <15mL/kg o NIF <-30 cmH20 • Rapid shallow breathing index • Do not wait for ABG changes or sat drop!!!! • BiPAP doesn’t compensate for bulbar dysfunction or evacuation of secretions. 26 Myasthenia Gravis • Ab-mediated attack on post-synaptic NMJ • Dx: AchR Ab, MUSK Ab*, EMG, Tensilon test • Tx: o Crisis—PLEX, IVIg, respiratory support o Suppression—prednisone (low, slow—may cause exacerbation), azathioprine, mycophenolate o Symptomatic—pyridostigmine (Mestinon) o Consider thymectomy if young, AchR Ab+ • Avoid FQ, Li, aminoglycosides, Mg, CCBs, and macrolides Neuralgic amyotrophy • Brachial neuritis/plexitis (Parsonage-Turner) o Postinfectious, post-vaccination, idiopathic o Severe pain followed by subacute, progressive weakness/atrophy o Tx: analgesics, PT/OT. • Diabetic lumbosacral radiculopathy (Bruns-Garland) o Subacute, progressive o Unilateral, pain in thigh, buttocks, low back with LE weakness, sensory loss, and ↓reflexes without bladder/bowel involvement o Assoc w/rapid wt loss or change in glycemic control o MRI L-spine normal. EMG peripheral dysfunction. CSF ↑protein. o Tx: PT. Usually good recovery in months. 56-y/o WM c/o 1-month h/o intermittent weakness of the left foot, a 6month h/o progressive R UE weakness, and 1-year h/o muscle cramps. He says he feels lately as if he is “catching” his foot on things when ambulating. Denies dyspnea, dysphagia, pain, bowel or bladder impairment. Neuro exam reveals normal speech, language, and mental status. His tongue appears atrophic with fasciculations. He has diffuse weakness and atrophy of the proximal muscles in the R UE; fascics are noted. L UE strength and bulk are normal. Mod weakness of the distal muscles in the L LE is noted, with fascics present in both LE. DTRs are brisk in the UE and LE, and toes are upgoing. Sensory exam is normal. Labs and imaging are normal. What diagnosis is most likely? A. Amyotrophic lateral sclerosis B. Cervical myelopathy C. Chronic inflammatory demyelinating polyradiculoneuropathy D. Primary lateral sclerosis Motor neuron disease Signs DDx UMN Hyperreflexia Spasticity Weakness ALS PLS Myelopathy Spastic paraparesis B12 deficiency LMN Weakness Atrophy Fasciculations Decreased tone Spinal muscular atrophy Heavy metal exposure Kennedy disease • ALS o o o o o o Both UMN and LMN Multisegmental (bulbar + at least 2 spinal regions) Cognition, sphincter function, sensory spared Likely to need trach/PEG 50% die in 3 years Riluzole is the only disease modifying therapy. Cervical myelopathy • Symptoms: o Intermittent neck/shoulder pain or stiffness o May have pain, paresthesia, weakness in radicular pattern o “Numb, clumsy hands” o Intrinsic hand muscle atrophy o Spasticity, stiffness in LE. Gait change. o Loss of vib/proprioception +/- sensory level o Hyperreflexic. +Babinski –jaw jerk o Emergency if bowel/bladder change • DDx: B12 myelopathy, Cu-deficiency, NO-toxicity, dural AV-fistula, spinal compression, HIV myelopathy, ALS • MRI c-spine is best study • Tx: surgery, treat pain Myopathies Critical illness Difficult to wean from vent Diffuse, flaccid weakness involving the limb, neck, diaphragm Avoid paralytics Steroid induced Normal CK, EMG Dx with muscle biopsy—type 2b atrophy Tx: PT, stop steroids Endocrine Proximal weakness, normal CK hyperthyroidism, hypothyroidism, hyperparathyroidism, or vitamin D deficiency. Toxic—statins, AZT, colchicine, hydroxychloroquine Inflammatory Myopathies Inclusion body myositis >50yo. Quads/hand & feet flexors. Dysphagia Mild ↑ CK mild Ubiquitin+ inclusion bodies, denervation Polymyositis May overlap with connective tissue disease ↑CK, antiJo-1 Ab Endomysial inflammation. +Necrosis Dermatomyositis • • • • Older age = higher risk for underlying cancer Painful proximal muscle weakness Perivascular inflammation. No necrosis. ↑CK; antiMi-2 Ab Myotonic dystrophy AD chr 19; CTG repeats Difficulty releasing grip Hand cramps Hatchet facies Frontal balding Bilat ptosis Drooping mouth Prog muscle weakness Gynecomastia Cataracts Cardiac conduction defects Diabetes Peripheral neuropathies Classification Signs and Symptoms Major Diagnostic Considerations Autonomic neuropathy Orthostatic hypotension Constipation Early satiety Erectile dysfunction Amyloidosis Diabetes mellitus Paraneoplastic syndrome Small-fiber neuropathy Burning extremity pain without weakness Normal reflexes Diabetes mellitus Impaired glucose tolerance Acquired sensorimotor neuropathy Distal sensory loss and ↓ reflexes Distal extremity weakness Diabetes mellitus Monoclonal gammopathy Toxic (chemotherapy) Polyradiculoneuropathy Severe weakness Sensory loss Areflexia GBS CIDP Amyloidosis Motor neuropathy Asymmetric weakness Muscle atrophy Multifocal motor neuropathy Motoneuron disease Guillain-Barre Syndrome • Ascending paralysis is classic • Evolves over days • May progress to resp failure, autonomic instability or involve CN • CSF: ↑protein, normal cell count • EMG/NCS: Slowed conduction/block • Tx: Supportive, plasmapheresis, IVIg (NO STEROIDS) • Good px: Young, mild disease, not hyperacute, improvement within 1 week MOVEMENT DISORDERS 37 PD Medications • Dopamine agonists o ropinirole, pramipexole o Initial tx for early disease o AE: compulsive behavior, orthostatic hypotension, nausea, vomiting, hallucinations, sleep attacks, pedal edema • Levodopa-carbidopa o Gold standard o Long-term use assoc with tolerance and dyskinesias, difficult to distinguish from disease progression o AE: nausea, orthostatic hypotension, hallucinations o **Watch out for NMS-like symptoms in pts who are NPO** PD Medications • COMT inhibitors o Entacapone, tolclapone o Delay metabolism of Sinemet; give with Sinemet o AE: nausea, diarrhea, hepatotoxicity • MAO-B inhibitors o Selegiline, rasagiline o AE: N/V, hallucinations, psychosis • Amantadine, anticholinergics o Mostly for tremor, very early disease o AE: psychosis, cognitive decline o Stop 1st if pt has altered mental status Parkinson disease • Tremor o Resting o “pill-rolling” o asymmetric • Rigidity o Cog-wheel, lead pipe o freezing • Akinsesia/Bradykinesia o Festination o Masked facies o Decreased blinking • Postural Instability o Stooped posture o En bloc turns o Falls (often backwards) • Non-motor symptoms: constipation, depression, poor sleep, autonomic instability, drooling, dementia (late) Other diseases producing Parkinsonism • Drug induced Parkinsonism o Usually bilateral at presentation o Exposure to antipsycotics, dopamine-blockade • Progressive Supranuclear Palsy o Early falls (backward), symmetric bradykinesia, axial rigidity, vertical gaze impairment (can’t look up) o Lack of tremor or dopa-response • Lewy Body Dementia o Parkinsonism, dementia, hallucinations, autonomic instability o Worse with dopamine; sensitive to meds • Multiple Systems Atrophy o Ataxia, dysautonomia DEMENTIA 42 Dementia • Must involve impairment in multiple domains: memory, language, spatial skills, judgment, and problem solving • Decline in cognitive function with preserved ADLs = mild cognitive impairment o 10-15%/yr progression to dementia • Work-up of dementia includes: o o o o CBC, TSH, B12, CMP CT head or MRI brain Screening for depression Optional: RPR, HIV, LP Alzheimer Dementia By far most common type, Tau-opathy 50% prevalence by age 90 Short term> long-term memory impairment 1st language problem = anomia Behavior impaired in late disease (agitation/aggression) • Usually no focal signs or gait impairment • Tx: • • • • • o Acetycholinesterase inhibitors (donepezil, galantamine) o NMDA receptor antagonists (memantine)—late disease only Less common dementias • Vascular o Step-wise deterioration o Should have focal neuro deficits, but sometimes difficult to determine due to multi-focality o Will see multiple infarcts (typically) on MRI • Frontotemporal lobar (Pick’s) o Insidious, onset <65 yrs o Behavior change: hypersexuality, disinhibition, irritability, poor attention, perseveration o Nonfluent aphasia o Can Dx by PET Less common dementias • Diffuse Lewy body o Fluctuating cognition o Parkisonism, hallucinations, autonomic dysfunction • Creutzfeldt-Jakob Disease o Rapidly progressive dementia with myoclonus o ↑ CSF 14-3-3 • Normal pressure hydrocephalus o Wet, wacky, wobbly o MRI brain then CSF drainage o Tx: low pressure VPS • May improve gait and incontinence • Symptoms <1 yr in duration Wernicke Encephalopathy • Encephalopathy, eye movement abnormalities, ataxia • Inadequate intake or absorption of thiamine • At risk: alcoholics, malnourished patients (any reason), chronic gastritis, repetitive vomiting • Always give thiamine before glucose!! • Prognosis depends on severity. 47 Transient global amnesia Age >50 Paroxysmal, transient loss of memory Immediate recall and long-term memory spared Pts usually anxious, repeat same question Mental status and neuro exam normal, although temporal “UBO’s” have been described • MRI brain and EEG usually normal • Spontaneously resolves in <24 hours • • • • • HEADACHE 49 Migraine Diagnosis • ~90% of pts w/CC of mod-sev recurrent HA have migraine • At least 2 of the following: o Unilateral, not side locked, pulsating, worsens with routine physical activity • At least 1 of the following: o N/V, photophobia, phonophobia • Classic (~20%): with aura • Common: no aura • Variants: hemiplegic, basilar, acephalgic Migraine treatment • Abortive o NSAIDS, caffeine containing analgesics o Triptans o Antiemetics + ergots • Prophylactic—determined by freq of HA and degree of interference with daily activities o Propranolol, verapamil o Topiramate, valproic acid o SSRIs, amitriptyline • Sleep hygiene and avoidance of triggers • In pregnancy: Tylenol, Reglan, Fioricet • Can use triptans in pts who are breast-feeding Ménière’s disease Recurrent, disabling vertigo Usually 4th to 6th decades Attacks last hours N/V + cochlear symptoms (tinnitus, ear fullness, and/or hearing loss) • Tx: • • • • o Acute—meclizine, benzodiazepines, antiemetics o Prophylactic—diuretics, low-Na diet Giant Cell Arteritis • Suspect if new onset HA after age 50 • Sx: HA, scalp tenderness, painless sudden blindness, jaw claudication, arthalgias (PMR), weight loss, fatigue • ESR >100, low Hct, high plt, high CRP • Start prednisone 60mg qd when suspected • Dx with temporal artery bx • Complications: blindness, stroke, MI, aortic dissection 53 Benign positional vertigo • • • • • Most common cause of dizziness Sudden, brief episodes of mod-intense vertigo Nausea +/- vomiting, gait instability Triggered by change in head position Dix-Hallpike+ o upbeating torsional nystagmus with fast component that rotates toward affected ear o fatigable • Tx: particle repositioning maneuvers, antihistamines, anticholinergics Causes of Vertigo BPPV Labyrinthitis Meniere’s CP angle tumour Brain stem Character of Paroxysmal vertigo Gradual onset Paroxysmal, Episodic or over hours spontaneous persistent, insidious Often constant Course Frequent attacks then recovery Constant then Severe attacks Progressive recovery with remission Usually improves with time Duration 10-20 sec. (< 1 min) Persistent Can be persistent Positional Yes, turning head to one side Days, dynamic Hours to days symptoms may persist weeks No, may be No, may be exacerbated exacerbated by movement by movement May or may not Yes Hearing loss No Yes No, may be No, may be exacerbated exacerbated by movement by movement Usually no CN 3 palsy • Look at the pupil! o Pupil sparing is usually ischemic and likely to be benign. o If pupil involved, aneurysm until proven otherwise. • Examine CN IV, VI, V to r/o cavernous sinus involvement. • Risk factors: age>50, DM, HTN, giant cell arteritis • Diabetic 3rd nerve palsy: o Painful, ptosis, EOM weakness, pupil spared o Full recovery by 3 months CN 3 palsy • Just remember that any isolated 3rd nerve palsy, partial or not, deserves a w/u • Always consider the worst case scenario: aneuryms • Less likely with pupil sparing partial 3rd, but if uncertain, perform w/u to r/u aneurysm • Don’t let anybody tell you otherwise! 57 EPILEPSY 58 Seizures • Partial—originates from a focus o Simpleretained consciousness o Complexaltered consciousness • Generalized: GTC, absence, atonic, etc • Symptomatic o o o o o Hyper- or hypo- glycemia Drug withdrawal—EtOH or benzos Uremia Meningitis Tumor • Risks: head injury w/LOC, h/o meningitis/encephalitis, febrile sz, family hx Single Seizure • Was it a seizure? • Look for provoking factor o UDS, CBC, Chem8, ?LP • Don’t usually start AED • Risk for recurrence: o partial seizure, Todd paralysis, a family history of epilepsy, age greater than 65 years, and abnormal findings on neurologic examination • MRI brain with and without • EEG o Interictal EEG abnormal in 25-50% with epilepsy o Sensitivity ~90% with 4 EEGs Epilepsy • 2 or more unprovoked seizures • Start with monotherapy. Push to toxicity before adding 2nd AED • Trial of AED withdrawal if sz-free x 2 yrs • Driving laws vary by state. • Special considerations: o Avoid valproate in child-bearing age ♀ o Monotherapy in pregnancy (not necessary to change to Lamictal) o Valproate for JME or myoclonus o Levetiracetam not metabolized by liver o Ethosuximide for absence ONLY o Elderly, partial seizure: gabapentin, lamotrigine Status Epilepticus • Incidence 60/100 000 (varies) • About 1% of patients with epilepsy will go into status per year • Mortality across the board is 2-35%* • Factors associated with poor prognosis: o o o o o Advanced age Prolonged (>60 min) Hyperthermia Associated hypoxia or stroke at onset Other concurrent severe illness 62 Status Epilepticus Convulsive SE • Generalized seizure activity • Subtle SE: dissociation of EEG activity and motor activity • Mortality of > 30% (in some series) Nonconvulsive SE • “Mental status change” • Behavioral changes • Much lower morbidity and mortality • Difficult to recognize 63 Status Epilepticus Tx • ABC’s • Treat the seizures aggressively without worrying about causes initially • While specific treatment for SE started, begin w/u for possible causes if no history available or no obvious cause apparent to you • CT, LP and other labs must not delay treatment! 64 Status Epilepticus Tx • First line = benzodiazepines o 0.1 to 0.2 mg/kg (for LZP), but mostly administered as bolus of 2 to 6 mg IVP, up to 10 mg total o DZP mostly used “on truck” IM o Midazolam not useful IVP, but as an infusion • Second line o Fosphenytoin 20 PE/kg @ up to 150 mg/min. • Brady-arrhythmia, more profound in older patients • Goal level 15 to 25, check after 1 hour o Phenytoin 20 mg/kg @ up to 100mg/hour (recommend 50) o Phenobarbital 20 mg/kg over 15 minutes** 65 Status Epilepticus Tx • Any other AED (Depakote, Keppra, Vimpat) administered in SE is “off label” use, which may be fine, but should be seen as adjunctive medication • Your main goal is to stop SE w/i the hour of it’s onset, bad stuff starts to happen if permitted to persist longer • Co-morbidities are the main determinant of Mortality/Morbidity related to SE 66 NEURO-ONCOLOGY 67 CNS Tumors • 50% tumors are primary: o Astrocytoma—50%of primary • Low grade (WHO 1 and 2) o Slow growing, present with seizure o Resection may be curative with certain subtype • High grade (WHO 3 and 4) o Irregular enhancement, sig surrounding edema o Surgery, radiation, chemo (temozolamide) o Meningioma • Benign, slow-growing, dural based • Surgery or sterotactic radiation o Pituitary adenoma o Schwannoma • MRI brain with and without contrast is best study 69 Primary CNS Lymphoma • • • • • • • Rare; <4% of CNS tumors B-cell NHL Present with neuro deficits, seizures Single homogeneously enhancing deep lesion “Vanish” with steroids Check toxo serology, CSF EBV and flow cytometry Tx: IT MTX and WBRT Brain Mets • More common than primary CNS tumors • Lots of Bad Stuff Kills Glia • • • • • Lung Breast Skin (melanoma) Kidney (renal cell) GI • 70-80% are multiple • Occur anywhere, but favor gray-white junction early • Tx: steroids, surgery if single/few, whole brain radiation if multiple Mets from Renal Cell Cancer CT MRI T1 with Gd Paraneoplastic syndromes Syndrome Antibodies Associated tumor Myasthenia gravis Nicotinic Ach Receptor Striated muscle Thymoma Lambert-Eaton P/Q voltage-gated Ca channel SCLC Cerebellar degeneration Hu Yo other SCLC, neuroblastoma SCLC, ovary, breast Hodgkin lymphoma Brainstem encephalitis Ma-1 Ma-3 SCLC testicle Limbic encephalitis Voltage-gated K channel NMDA receptor SCLC Ovary Neuropathy Mag Hu Waldenstrom macroglobulinemia SCLC, prostate Amphiphysin SCLC, breast Stiff-man syndrome