CEREBRAL AUTOSOMAL DOMINANT ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY (CADASIL)

Abstract

BACKGROUND Cerebral autosomal dominant arteriopathy with subcortical intarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain. The affected gene was mapped in 1993 to chromosome 19. This mapping was essential in defining the natural history of the disease. REVIEW SUMMARY CADASIL can start with attacks of migraine with aura occurring at a mean age of 30 years. The most frequent clinical manifestations are subcortical transient ischemic attacks or completed strokes usually observed between 40 and 50 years of age. The stroke events are sometimes associated with severe mood disturbances. The disease leads progressively to a subcortical dementia associated with pseudobulbar palsy and urinary incontinence. Mean age at death is 65 years. The severity of the clinical presentation is greatly variable between and within families. Magnetic resonance imaging (MRI) is always abnormal in symptomatic subjects. On T2-weighted images areas of increased signals in white matter and basal ganglia and on T1-weighted images, it shows a decreased signal in the same regions. Signal abnormalities can be observed a long time before the onset of clinical manifestations, as they are present in asymptomatic young family members. The severity of the MRI findings dramatically increases with age. Pathologic studies show a widespread pallor of white matter and multiple small intarcts in both the white matter and basal ganglia, associated with a small artery disease of the brain. Electron microscopy studies show that the medium of the small arteries is thickened by a granular, eosinophilic, and nonamyloid material of undetermined origin that surrounds the smooth muscle cells. These ultrastructural abnormalities have been observed in other arteries, particularly in muscular and skin arteries. The gene of CADASIL is mapped to chromosome 19 in close vicinity to the locus of familial hemiplegic migraine and to that of acetazolamicle-responsive cerebellar paroxysmal ataxia. CONCLUSION CADASIL should be suspected in subjects with a history of unexplained subcortical ischemic strokes, attacks of migraine with aura, mood disorders, or subcortical dementia whenever they are associated with MRI signal abnormalities in white matter and basal ganglia. These findings should prompt a genealogical study including all first-and second-degree relatives. CADASIL is an underdiagnosed cause of subcortical strokes.