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CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19.Joutel A, Corpechot C, Ducros A, et al. Notch 3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707-710. PMID 8878478 The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease.Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet 1995;346:934-939 PMID 7564728
Pathophysiology The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels. Mutations in the Notch 3 gene (on the short arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth-muscle cells both in cerebral and extracerebral vessels,Joutel A, Andreux F and Gaulis S et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients, J Clin Invest 105 (2000), 597–605. PMID 10712431 seen as granular osmiophilic deposits on electron microscopy.Ruchoux MM, Guerouaou D, Vandenhaute B et al. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Acta Neuropathol (Berl) 89 (1995), 500–512. PMID 7676806 Interestingly, the Notch 3 gene is in the same locus as the gene for familial hemiplegic migraine.
Clinical Features CADASIL may start with attacks of migraine with aura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 to 55 years of age. The disease progresses to subcortical dementia associated with pseudobulbar palsy and urinary incontinence.
Diagnosis MRI is the diagnostic modality of choice. Hypointensities on T1-weighted images and hyperintensities on T2-weighted images, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia, periventricular white matter, and the pons, and are similar to those seen in Binswanger disease. Ropper AH, Brown RH (eds) Cerebrovascular Diseases in Adams and Victor's Principles of Neurology. 2005 McGraw-Hill, New York ISBN 007141620 These white matter lesions are also seen in asymptomatic individuals with the mutated gene.Tournier-Lasserve E, Joutel A, Melki J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps on chromosome 19q12. Nat Genet 1993;3:256-259. PMID 8485581The disease may also be diagnosed by screening for the mutated Notch 3 gene; however, this method is costly and laborious. Since CADASIL is a systemic arteriopathy, evidence of blood vessel damage is seen in small- and medium-sized arteries. It has therefore been suggested that skin biopsies could be used for diagnosis;Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001 15;358(9298):2049-51. PMID 11755616 however, the lack of widespread availability of a monoclonal antibody required for diagnosis, limit the utility of this method.
Clinical Course Strokes in CADASIL - Strokes or TIAs are the most common initial presentation of CADASIL. Ischemic strokes are the most frequent presentation of CADASIL with approximately 85% of symptomatic individuals developing transient ischemic attacks or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30-70). A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. Notably, ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia.
Treatment No specific treatment is available. However, in some occasions, anti-coagulants can be used to slow down the disease and help prevent strokes. Given the propensity for cardiovascular and cerebrovascular complications, minimizing vascular risk factors and implementing therapy for primary or secondary prevention of stroke and myocardial infarction seems prudent. Stopping oral contraceptive pills is justified particularly in cases with migraine with aura. Aggressive treatment of hypercholesterolemia and hypertension is reasonable although the utility of statins and antihypertensive agents in the absence cardiovascular risk factors is unknown. Homocysteine levels are elevated in CADASIL and treatment with folic acid is reasonable. The role of anti-platelet agents and anticoagulation is unknown; anti-platelet therapy appears justifiable whereas anticoagulation may be inadvisable given the propensity for microhemorrhages.
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