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.
ReviewCADASIL
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 (130)
- et al.
Chronic familial vascular encephalopathy
Lancet
(1977) - et al.
Identification of a key recombinant narrows the CADASIL gene region to 8 cM and argues against allelism of CADASIL and familial hemiplegic migraine
Genomics
(1996) - et al.
Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Lancet
(1995) - et al.
Progressive supranuclear palsy phenotype secondary to CADASIL
Parkinsonism Relat Disord
(2003) - et al.
[CADASIL with minimal symptoms after 60 years]
Rev Neurol
(2006) - et al.
Angiographic complications in CADASIL
Lancet
(1997) - et al.
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis
Lancet
(2001) - et al.
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients
Lancet
(1997) Huntington's disease
Lancet
(2007)- et al.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12
Nat Genet
(1993)
Summary of the proceedings of the First International Workshop on CADASIL. Paris, May 19–21, 1993
Stroke
Encéphalopathie sous-corticale progressive (Binswanger) à évolution rapide chez deux soeurs
Med Hellen
Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease
Acta Neuropathol
Familiäre zerebrale Gefäberkrankung
Zbl Allgemein Pathologie Bd
Familiäre zerebrale arteriosklerose
Zbl Allg Path Bd
Hereditary multi-infarct dementia
Eur Neurol
Familial subcortical dementia with arteriopathic leukoencephalopathy. A clinico-pathological case
Rev Neurol
A familial disorder with subcortical ischemic strokes, dementia, and leukoencephalopathy
Neurology
Slowly progressive familial dementia with recurrent strokes and white matter hypodensities on CT scan
Ital J Neurol Sci
Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
Brain
Recurrent stroke in a family with diffuse white-matter abnormalities and muscular lipidosis—a new mitochondrial cytopathy
J Neurol
Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy
Stroke
Autosomal dominant leukoencephalopathy and subcortical ischemic stroke. A clinicopathological study
Stroke
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval
Am J Hum Genet
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
Nature
The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland
J Neurol Neurosurg Psychiatry
De novo mutation in the Notch3 gene causing CADASIL
Ann Neurol
Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis
Stroke
The phenotypic spectrum of CADASIL: clinical findings in 102 cases
Ann Neurol
The natural history of CADASIL: a pooled analysis of previously published cases
Stroke
Apathy: a major symptom in CADASIL
Neurology
Autosomal dominant migraine with MRI white-matter abnormalities mapping to the CADASIL locus
Neurology
Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL
Arch Neurol
The influence of genetic and cardiovascular risk factors on the CADASIL phenotype
Brain
Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL
Acta Neuropathol
“CADASIL coma”: an underdiagnosed acute encephalopathy
J Neurol Neurosurg Psychiatry
New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: migraine as the prominent clinical feature
J Neurol Neurosurg Psychiatry
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: from stroke to vessel wall physiology
J Neurol Neurosurg Psychiatry
A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials
Stroke
Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients
Brain
CADASIL presenting as bipolar disorder
Psychosomatics
Cognitive alterations in non-demented CADASIL patients
Cerebrovasc Dis
Cognition in CADASIL
Stroke
Cognitive profile in CADASIL
J Neurol Neurosurg Psychiatry
The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia
Am J Psychiatry
Intracerebral hemorrhages in CADASIL
Neurology
Large cerebral artery involvement in CADASIL
Neurology
Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Medicine
Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study
Stroke
Recurrent hemiplegia, normal MRI, and NOTCH3 mutation in a 14-year-old: is this early CADASIL?
Neurology
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Contributed equally