Weekday Morning Report

Subspecialty: NeurologyFebruary 26, 2010

Ankur Kalra, MD

HISTORY & PHYSICALCASE PRESENTATION

History & Physical48 year old African American female

Left-sided headache; left-sided weakness

History of chronic daily headaches

Current headache: Insidious in onsetDifferent in character from headaches in pastAssociated with double vision; left sided weakness

of the face, arm, and legNo history of fever, neck stiffness

History & PhysicalHistory of residual weakness from previous

cerebrovascular accidentsCurrent weakness worse than one at baselineAssociated with decreased sensations on left side

No history of bladder or bowel incontinence

No history of seizures

No history of loss of consciousness

History & PhysicalPast medical history

Gastroesophageal reflux Essential hypertension Migraine headache Recurrent cerebrovascular accidents in the past (first at

age 35 years)

Medication history Antiplatelet: Aspirin; Dipyridamole Antihypertensives: Lisinopril; Hydrochlorothiazide;

Carvedilol; Amlodipine; Clonidine Lipid lowering: Simvastatin Analgesia: Acetaminophen-butalbital-caffeine

History & PhysicalSocial history

No tobacco, alcohol, or recreational drug use

Family historyStroke (father, aunts, grandfather) (40s – 50s)

History & PhysicalPhysical examination

T 97 F HR 80 beats/min BP 167/95 – 237/109 – 173/77 mm Hg RR 18 breaths/min SaO2 100 per cent on room air

CV: normal first & second heart sounds; no murmurs, rubs, or gallops

RS: normal vesicular breathing; no added sounds GI: soft; non tender; non distended; bowel sounds

present

History & PhysicalNeurologic examination

Awake, alert, and oriented to time, place, and person No dysarthria Bilateral cranial nerve VI palsy; other cranial nerves

intact Motor strength 4/5 in left upper, and lower extremities

5/5 in right upper, and lower extremities Needle prick sensation decreased on the left side No pronator drift No dysmetria Normal affect

INVESTIGATIONSCASE PRESENTATION

InvestigationsHb 11.5 WBC 6.6 Platelet 264

Na 139 K 3.3 Cl 100 HCO3 27 BUN 14 Cr 0.6

Glucose 141

Calcium 9.2

PT/INR 11.6/1.0

aPTT 25.8

Cardiac enzymes negative

InvestigationsChest X Ray No acute cardiopulmonary disease

EKG Normal sinus rhythm

CT Head without contrastNo acute bleedMild white matter changes: nonspecificLargest area of abnormal signal intensity in

subcortical matter of right frontal lobeRecommend diffusion weighted MRI

InvestigationsMRI Brain without/with contrast

No acute ischemic eventMild nonspecific white matter changes

MRA Head & Neck unremarkable

2 D Echo: moderate concentric LVH; EF 60 – 65%

CT Angiography Head without/with contrastMinimal irregularity and thickening of

proximal basilar artery

MRV Head normal

DIFFERENTIALCASE PRESENTATION

Differential DiagnosisProthrombotic states

Protein C deficiencyProtein S deficiencyAntithrombin III deficiencyResistance to activated protein CProthrombin gene 2021A mutationAntiphospholipid syndromeElevated homocysteine levels

Differential Diagnosis Inflammatory conditions

Primary vasculitidesTakayasu arteritisGiant cell arteritisPolyarteritis nodosaPrimary angiitis

Secondary vasculitidesCollagen vascular diseaseBacterial meningitisHIVSyphilisTuberculosisFungal infection

INVESTIGATIONSCASE PRESENTATION

InvestigationsHbA1c 6.3

TSH 3.54

ESR 32 mm/hour (high)

CRP 2.20 mg/dL (high)

ImmunologyANA negativeENA to SSA/SSB negativeANCA negative

InvestigationsCoagulation

Protein C 104 % (normal)Protein S 102 % (normal)Activated protein C resistance 3.8 (normal)Lupus anticoagulant screen

Dilute Russel Viper Venom Time negativeHexagonal Phase Phospholipid Neutralization

negativeΒ2 glycoprotein I negativeProthrombin gene 20210A mutation negativeFactor II mutation negative

InvestigationsInfectious Disease

Lyme antibody negativeHIV negativeRPR negative

InvestigationsCSF normal protein; no hypoglycorrhachia; no

white cells; 58 red blood cells IgG/albumin ratio HighLyme antibody nonreactiveMyelin basic protein normal rangeOligoclonal bands absentVDRL nonreactive

CSF culture No growth

IS THIS A ZEBRA?CASE PRESENTATION

Differential DiagnosisMetabolic disorders

CADASILMELASFabry diseaseMenke’s disease

CADASILCerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

REVIEW

CADASILReported worldwide

Prevalence of mutation carriers 1 in 50,000 to 1 in 121,000

One or more of the following four manifestations: Ischemic episodesCognitive deficitsMigraine with auraPsychiatric disturbances

CLINICAL FEATURESCADASIL

CADASILClinical features

Ischemic stroke and TIAMost frequent presentation85 per cent of symptomatic individualsAge at onset 19 to 67 yearsMedian age 51 years (men); 53 years (women)Classic lacunar syndromes (pure motor, pure

sensory, sensorimotor, dysarthria-clumsy hand)Ischemic events are recurrent and disabling

CADASILClinical features

Cognitive deficitsSecond most common feature60 per cent of symptomatic individuals75 per cent of mutation carriers develop dementiaLacunar lesion volume, global brain atrophy, and age

independent predictorsLoss of executive function; verbal fluency

CADASILClinical features

Migraine with aura30 per cent of CADASIL casesEarly signUsually the first symptom with age of onset before 40Develop hemiplegic, or basilar migraine; isolated

auraSeverity of migraine decreases following first strokeDifficult to differentiate hemiplegic migraine from an

ischemic event

CADASILClinical features

Psychiatric disturbances25-30 per cent of patientsAdjustment disorder, depression, panic attacks,

hallucinatory syndromesKey feature: apathy – primary loss of motivation with

diminished speech, motor activity, and emotional expression

CADASILClinical features

CADASIL and pregnancy40 per cent with neurologic deficitsInitial presentation in pregnancyComplications include TIA, migraine, and

preeclampsia-like symptom complex

NEUROIMAGINGCADASIL

CADASILNeuroimaging

Magnetic Resonance Imaging (MRI)Small circumscribed regions isointense to CSF on T1,

and T2-weighted imagesLess well demarcated T2-hyperintensities of variable

size: variable degree of hypointensity on T1-weighted images clearly distinct from CSF

Subcortical white matter, brainstem, subcortical gray matter

CADASILNeuroimaging

Magnetic Resonance Imaging (MRI)Temporal lobe and external capsule hyperintensitiesSubcortical lacunar lesionsCerebral microbleeds

31 to 69 per cent of patients Not specific for CADASIL 2 mm – 5 mm multifocal areas of hemosiderin deposition

Brain atrophy

DIAGNOSISCADASIL

CADASILDiagnosis

Positive family history of stroke and dementiaTypical clinical featuresTypical brain MRIPlus one or both:

Documentation of NOTCH 3 mutation by genetic analysis

Documentation of characteristic ultrastructural deposits within small blood vessels by skin biopsy

CADASILDiagnosis

Genetic screening80 different mutationsNotch3 transmembrane receptor of (epidermal

growth factor) EGF-like repeat domain95 per cent missense mutationsHighly stereotyped; involve cysteine residues85 per cent exons 2 – 6Skin biopsy if genetic screening negative

CADASILDiagnosis

Skin biopsyEM: Granular osmiophilic material (GOM) within

vascular basal lamina of arteries, arterioles, and precapillaries

Extracellular domain of Notch3 transmembrane receptor in vascular media

MANAGEMENTCADASIL

CADASILManagement

General issuesGeneral principles of stroke medicineLow dose aspirinAdequate blood pressure control (increased systolic

pressure associated with brain atrophy and cerebral microbleeds)

Adequate glycemic control with HbA1c < 7.0No role of anticoagulation

CADASILManagement

Symptomatic therapyEmotional lability with pathologic crying or laughing –

selective serotonin reuptake inhibitors (SSRI)Migraine headache – nonpharmacologic therapy;

NSAID; triptans contraindicated

NOTCH 3 GENE MUTATIONGENETIC ANALYSIS RESULTS NEXT WEEK

THANK YOUNEXT PRESENTATION: MARCH 16, 2010