Elsevier

The Lancet Neurology

Volume 8, Issue 7, July 2009, Pages 643-653
The Lancet Neurology

Review
CADASIL

https://doi.org/10.1016/S1474-4422(09)70127-9Get rights and content

Summary

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.

Introduction

CADASIL is the acronym for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy suggested in 1993 to designate and characterise a hereditary disease of small cerebral arteries that affects middle-aged adults and leads to disability and dementia.1, 2 CADASIL was possibly first described by van Bogaert in 1955 as “Binswanger's disease with a rapid course in two sisters”.3 Before 1993, six additional families with similar patterns of presentation were reported under various terms.4, 5, 6, 7, 8, 9, 10, 11, 12

In 1976, one of us (M-GB) saw a 50-year-old man with a lacunar infarct and extensive leucoencephalopathy. The tentative diagnosis was Binswanger's disease, but the absence of hypertension was atypical and led us to undertake a systematic study of his family. The data were reported under three different names13, 14, 15 until the relevant gene on chromosome 19 could be mapped.1 Linkage studies in other families enabled further refinement of this genetic interval16, 17 and identification of the mutated gene as NOTCH3 (Notch homolog 3).18

Since then, CADASIL has been reported in more than 500 families worldwide, but its overall prevalence is unknown. A small study from Scotland, UK, provided an estimate of 4·15 cases per 100 000.19 However, the actual prevalence could be much higher because sporadic cases occur.20 CADASIL has been reported to account for 2% of cases of lacunar stroke with leucoaraiosis in patients younger than 65 years and for 11% of cases in those younger than 50 years.21

In this Review, we present the main clinical, neuroimaging, pathological, and therapeutic features of CADASIL, and discuss the molecular, genetics, and pathophysiological features of this disorder.

Section snippets

Clinical presentation

Although the clinical presentation of CADASIL varies substantially between and within families, this disease is essentially characterised by five main symptoms—migraine with aura, subcortical ischaemic events, mood disturbances, apathy, and cognitive impairment. These symptoms vary in frequency with age and duration of disease.22, 23, 24, 25

Neuroimaging and other investigations

Subcortical infarcts and leucoencephalopathy are best detected by use of MRI. Their presence is crucial for the diagnosis of CADASIL, particularly in patients with misleading presentations such as epilepsy, depression, hemiplegic migraine, progressive cognitive decline, or psychiatric manifestations.

Pathology

Macroscopic examination of the brain shows changes typical of chronic small-artery diseases of the brain: diffuse myelin pallor and rarefaction of the hemispheric white matter predominating in periventricular areas and centrum semiovale; lacunar infarcts located in white matter and basal ganglia; and dilated Virchow-Robin spaces. In the cortex, which was thought to be unaffected, there is widespread neuronal apoptosis (particularly in layers three and five) that is more extensive in the

Treatment

At present, there is no treatment of proven efficacy for CADASIL, either for the disease or for the main symptoms. Treatment is thus entirely pragmatic.

Migraine with aura rarely requires prophylactic treatment as the frequency of attacks is low in most patients. If required, the usual prophylactic drugs such as antiepileptic drugs or β blockers can be used. According to anecdotal reports, acetazolamide has been found to be effective.123, 124 For acute treatment, we avoid vasoconstrictors such

Conclusions and future directions

CADASIL has gained great interest as a model for the more common forms of ischaemic cerebral small-artery diseases and subcortical ischaemic vascular dementia.127 The clinical presentation, profile of neuropsychological deficits, and neuroimaging abnormalities of CADASIL closely resemble those of sporadic small-artery diseases with subcortical ischaemic vascular dementia. The main difference is, however, the absence in CADASIL of Alzheimer's-type pathological changes that are common in elderly

Search strategy and selection criteria

References for this Review were identified through searches of PubMed between January, 1975, and March, 2009, with combinations of the search terms “familial” or “hereditary” and “vascular dementia” or “stroke” (before 1993) and “CADASIL” (after 1993). Only papers published in English and that included a substantial number of patients or original results were reviewed. Reports of isolated cases or of newly described mutations in NOTCH3 were not included.

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