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Weekday Morning Report
Subspecialty: NeurologyFebruary 26, 2010
Ankur Kalra, MD
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HISTORY & PHYSICALCASE PRESENTATION
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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
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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
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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
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History & PhysicalSocial history
No tobacco, alcohol, or recreational drug use
Family historyStroke (father, aunts, grandfather) (40s – 50s)
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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
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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
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INVESTIGATIONSCASE PRESENTATION
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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
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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
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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
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DIFFERENTIALCASE PRESENTATION
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Differential DiagnosisProthrombotic states
Protein C deficiencyProtein S deficiencyAntithrombin III deficiencyResistance to activated protein CProthrombin gene 2021A mutationAntiphospholipid syndromeElevated homocysteine levels
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Differential Diagnosis Inflammatory conditions
Primary vasculitidesTakayasu arteritisGiant cell arteritisPolyarteritis nodosaPrimary angiitis
Secondary vasculitidesCollagen vascular diseaseBacterial meningitisHIVSyphilisTuberculosisFungal infection
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INVESTIGATIONSCASE PRESENTATION
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InvestigationsHbA1c 6.3
TSH 3.54
ESR 32 mm/hour (high)
CRP 2.20 mg/dL (high)
ImmunologyANA negativeENA to SSA/SSB negativeANCA negative
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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
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InvestigationsInfectious Disease
Lyme antibody negativeHIV negativeRPR negative
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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
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IS THIS A ZEBRA?CASE PRESENTATION
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Differential DiagnosisMetabolic disorders
CADASILMELASFabry diseaseMenke’s disease
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CADASILCerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
REVIEW
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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
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CLINICAL FEATURESCADASIL
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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
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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
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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
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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
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CADASILClinical features
CADASIL and pregnancy40 per cent with neurologic deficitsInitial presentation in pregnancyComplications include TIA, migraine, and
preeclampsia-like symptom complex
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NEUROIMAGINGCADASIL
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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
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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
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DIAGNOSISCADASIL
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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
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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
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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
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MANAGEMENTCADASIL
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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
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CADASILManagement
Symptomatic therapyEmotional lability with pathologic crying or laughing –
selective serotonin reuptake inhibitors (SSRI)Migraine headache – nonpharmacologic therapy;
NSAID; triptans contraindicated
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NOTCH 3 GENE MUTATIONGENETIC ANALYSIS RESULTS NEXT WEEK
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THANK YOUNEXT PRESENTATION: MARCH 16, 2010