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Weekday
Morning Report
Subspecialty: Neurology
February 26, 2010
Ankur Kalra, MD
HISTORY & PHYSICAL
CASE PRESENTATION
History & Physical
48 year old African American female
Left-sided headache; left-sided weakness
History of chronic daily headaches
Current headache:
Insidious in onset
Different in character from headaches in past
Associated with double vision; left sided weakness of the
face, arm, and leg
No history of fever, neck stiffness
History & Physical
History of residual weakness from previous
cerebrovascular accidents
Current weakness worse than one at baseline
Associated with decreased sensations on left side
No history of bladder or bowel incontinence
No history of seizures
No history of loss of consciousness
History & Physical
Past 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 & Physical
Social history
No tobacco, alcohol, or recreational drug use
Family history
Stroke (father, aunts, grandfather) (40s – 50s)
History & Physical
Physical 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 & Physical
Neurologic 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
INVESTIGATIONS
CASE PRESENTATION
Investigations
Hb 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
Investigations
Chest X Ray No acute cardiopulmonary disease
EKG Normal sinus rhythm
CT Head without contrast
No acute bleed
Mild white matter changes: nonspecific
Largest area of abnormal signal intensity in
subcortical matter of right frontal lobe
Recommend diffusion weighted MRI
Investigations
MRI Brain without/with contrast
No acute ischemic event
Mild nonspecific white matter changes
MRA Head & Neck unremarkable
2 D Echo: moderate concentric LVH; EF 60 – 65%
CT Angiography Head without/with contrast
Minimal irregularity and thickening of proximal
basilar artery
MRV Head normal
DIFFERENTIAL
CASE PRESENTATION
Differential Diagnosis
Prothrombotic states
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Resistance to activated protein C
Prothrombin gene 2021A mutation
Antiphospholipid syndrome
Elevated homocysteine levels
Differential Diagnosis
Inflammatory conditions
Primary vasculitides
Takayasu arteritis
Giant cell arteritis
Polyarteritis nodosa
Primary angiitis
Secondary vasculitides
Collagen vascular disease
Bacterial meningitis
HIV
Syphilis
Tuberculosis
Fungal infection
INVESTIGATIONS
CASE PRESENTATION
Investigations
HbA1c 6.3
TSH 3.54
ESR 32 mm/hour (high)
CRP 2.20 mg/dL (high)
Immunology
ANA negative
ENA to SSA/SSB negative
ANCA negative
Investigations
Coagulation
Protein C 104 % (normal)
Protein S 102 % (normal)
Activated protein C resistance 3.8 (normal)
Lupus anticoagulant screen
Dilute Russel Viper Venom Time negative
Hexagonal Phase Phospholipid Neutralization negative
Β2 glycoprotein I negative
Prothrombin gene 20210A mutation negative
Factor II mutation negative
Investigations
Infectious Disease
Lyme antibody negative
HIV negative
RPR negative
Investigations
CSF normal protein; no hypoglycorrhachia; no white
cells; 58 red blood cells
IgG/albumin ratio High
Lyme antibody nonreactive
Myelin basic protein normal range
Oligoclonal bands absent
VDRL nonreactive
CSF culture No growth
IS THIS A ZEBRA?
CASE PRESENTATION
Differential Diagnosis
Metabolic disorders
CADASIL
MELAS
Fabry disease
Menke’s disease
CADASIL
Cerebral Autosomal Dominant Arteriopathy with
Subcortical Infarcts and Leukoencephalopathy
REVIEW
CADASIL
Reported worldwide
Prevalence of mutation carriers 1 in 50,000 to 1 in
121,000
One or more of the following four manifestations:
Ischemic episodes
Cognitive deficits
Migraine with aura
Psychiatric disturbances
CLINICAL FEATURES
CADASIL
CADASIL
Clinical features
Ischemic stroke and TIA
Most frequent presentation
85 per cent of symptomatic individuals
Age at onset 19 to 67 years
Median age 51 years (men); 53 years (women)
Classic lacunar syndromes (pure motor, pure sensory,
sensorimotor, dysarthria-clumsy hand)
Ischemic events are recurrent and disabling
CADASIL
Clinical features
Cognitive deficits
Second most common feature
60 per cent of symptomatic individuals
75 per cent of mutation carriers develop dementia
Lacunar lesion volume, global brain atrophy, and age
independent predictors
Loss of executive function; verbal fluency
CADASIL
Clinical features
Migraine with aura
30 per cent of CADASIL cases
Early sign
Usually the first symptom with age of onset before 40
Develop hemiplegic, or basilar migraine; isolated aura
Severity of migraine decreases following first stroke
Difficult to differentiate hemiplegic migraine from an ischemic
event
CADASIL
Clinical features
Psychiatric disturbances
25-30 per cent of patients
Adjustment disorder, depression, panic attacks, hallucinatory
syndromes
Key feature: apathy – primary loss of motivation with
diminished speech, motor activity, and emotional expression
CADASIL
Clinical features
CADASIL and pregnancy
40 per cent with neurologic deficits
Initial presentation in pregnancy
Complications include TIA, migraine, and preeclampsia-like
symptom complex
NEUROIMAGING
CADASIL
CADASIL
Neuroimaging
Magnetic Resonance Imaging (MRI)
Small circumscribed regions isointense to CSF on T1, and
T2-weighted images
Less 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
CADASIL
Neuroimaging
Magnetic Resonance Imaging (MRI)
Temporal lobe and external capsule hyperintensities
Subcortical lacunar lesions
Cerebral microbleeds
31 to 69 per cent of patients
Not specific for CADASIL
2 mm – 5 mm multifocal areas of hemosiderin deposition
Brain atrophy
DIAGNOSIS
CADASIL
CADASIL
Diagnosis
Positive family history of stroke and dementia
Typical clinical features
Typical brain MRI
Plus one or both:
Documentation of NOTCH 3 mutation by genetic analysis
Documentation of characteristic ultrastructural deposits
within small blood vessels by skin biopsy
CADASIL
Diagnosis
Genetic screening
80 different mutations
Notch3 transmembrane receptor of (epidermal growth factor)
EGF-like repeat domain
95 per cent missense mutations
Highly stereotyped; involve cysteine residues
85 per cent exons 2 – 6
Skin biopsy if genetic screening negative
CADASIL
Diagnosis
Skin biopsy
EM: Granular osmiophilic material (GOM) within vascular
basal lamina of arteries, arterioles, and precapillaries
Extracellular domain of Notch3 transmembrane receptor in
vascular media
MANAGEMENT
CADASIL
CADASIL
Management
General issues
General principles of stroke medicine
Low dose aspirin
Adequate blood pressure control (increased systolic pressure
associated with brain atrophy and cerebral microbleeds)
Adequate glycemic control with HbA1c < 7.0
No role of anticoagulation
CADASIL
Management
Symptomatic therapy
Emotional lability with pathologic crying or laughing –
selective serotonin reuptake inhibitors (SSRI)
Migraine headache – nonpharmacologic therapy; NSAID;
triptans contraindicated
NOTCH 3 GENE MUTATION
GENETIC ANALYSIS RESULTS NEXT WEEK
THANK YOU
NEXT PRESENTATION: MARCH 16, 2010