CADASIL

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Epidemiology and History:

Autosomal Dominant arteriopathy

- first described as familial multi-infarct dementia in 1977

- known over the years as familial Binswanger's disease

- term CADASIL coined in early 1990's

- chromosome linkage in 1993 and gene identified in 1996

Mainly described in European families but occurs in worldwide in different ethnic groups

- not uncommon in right clinical scenario but rare amongst all-comers with small vessel infarcts

Clinical Features:

1) Migraine with Aura:

- in 20-40% or more

- often visual or sensory auras but can be prolonged or severe with hemiplegia

- onset from childhood to late 20's / 30's

- frequency can vary from single attack to recurrent episodes

2) Small Vessel Infarcts:

- in 70-90%

- occur at young age (peak age is 30-50)

- often classic lacunar syndromes in young adults (even in 20's)

- recurrent / multiple (even more on imaging)

- may progress to pseudobulbar palsy, gait & urinary disturbance

3) Dementia:

- early-onset dementia (cognitive decline) of vascular type

- especially frontal / subcortical in nature

- typically impaired executive functioning, bradyphrenia and poor attention

- memory loss develops with progression to death usually in 60's

- may even occur in abscence of clear history of preceding strokes

Imaging (CLICK HERE to see examples):

- periventricular & subcortical leukoencephalopathy with multiple white matter hyperintensities on T2

- may be seen even in asymptomatic patients ("carriers")

- lacunar infarcts in basal ganglia, white matter, or brainstem (sparing of cortex)

- almost always involvement of external capsule (sensitive finding)

- most specific abnormality is involvement of anterior temporal pole

- some say that angiography is relatively contraindicated since it does not contribute to diagnosis and carries risk of complications

Pathology:

- vascular changes in small/medium-sized vessels of almost all organs

- despite clinical involvement seen only in CNS

- granular osmophilic material (GOM) found on EM in vessel walls

- within thickened basal lamina

- this finding is pathognomonic for CADASIL

- this material contains notch3 gene product as component (see below for genetics)

- basophilic / PAS positive material on microscopic examination of thickened leptomeningeal and penetrating arteries of brain biopsy

- no amyloid (low risk of rupture unlike inherited amyloid angiopathies)

- skin biopsy can also be performed (specific but lower sensitivity)

Genetics:

- notch3 gene on chromosome 19p13

- this gene is highly conserved between nematodes and humans

- encodes a transmembrane receptor protein which regulates cell differentiation during development

- function in adults not known

- majority (70-80%) of mutations in exons 3 & 4

- almost 30 point mutations identified

- genetic testing available (but expensive and takes time, not fully sensitive)

Treatment:

- none known or tested

References:

Bousser M, Tournier-Lasserve ET.  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: from stroke to vessel wall physiology.  J Neurol Neurosurg Psychiatry 2001; 70: 285-7.

Markus HS, Martin RJ, et al.  Diagnostic strategies in CADASIL.  Neurology 2002; 59: 1134-8.

Viitanen M, Kalimo H.  CADASIL: Hereditary arteriopathy leading to multiple brain infarcts and dementia.  Ann NY Acad Sci 2002; 977: 273-84.

Abe K, Murakami T, et al.  Clinical features of CADASIL.  Ann NY Acad Sci 2002; 977: 266-72.

Last update: May 2003

Reviewed by: Pending Review

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