CADASIL

Introduction

The acronym CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is for an autosomal dominant inherited cerebral small-vessel disease responsible in adults for subcortical infarcts and leukoencephalopathy . Mutations in NOTCH3 gene on chromosome 19 are responsible for the disease. CADASIL is observed in all countries worldwide. Hundreds of families have been reported in Europe. In a region of the West of Scotland of 1,418,990 individuals, 22 cases confirmed by genetic testing were detected that allows estimating the prevalence of the disease at 1.98 per 100,000 adults.

Clinical Manifestations

The earliest clinical manifestations reported in nearly half of patients are attacks of migraine with aura that most often occur between 20 and 30 years. Ischemic events are reported by 70–80% of patients and usually occur around 50 years. Cognitive alterations of variable importance are present early during the course of the disease but they become evident between 50 and 60 years. Dementia is almost constant at the final stage of the disease and associated with severe gait and balance disturbances .

Unlike attacks of migraine without aura whose frequency in CADASIL is close to that observed in the general population, migraine attacks with aura are detected with a frequency more than five times higher than in the general population. Age at first attacks of migraine with aura is extremely variable from one individual to another; mean age is around 30 years and appears earlier in women (26 years) compared with men (35 years) . The frequency of attacks is extremely variable from one subject to another, from two attacks per week to one attack every 4 years. The triggers are those usually reported during migraine attacks. In addition to migraine attacks with typical aura, more than half of patients report at least one atypical aura evoking basilar migraine, hemiplegic migraine, aura without headache, or aura of sudden onset. Some patients may even develop severe attacks leading to confusion, coma, hyperthermia, visual or motor deficit for several days, sometimes associated with cerebral edema, and intracranial hypertension.

Between 70% and 85% of patients have at least a transient ischemic attack or an ischemic stroke. The average age at onset of ischemic stroke is between 45 and 50 years (range 20–70 years) with no significant difference between women and men. Most manifestations are similar to those of typical lacunar syndromes. Some observations of territorial infarction have been rarely reported. The cerebral ischemic events can occur in the absence of any vascular risk factor. The real impact of vascular risk factors on the clinical phenotype of CADASIL is still poorly known. Active smoking was found to have a negative predictive value on the occurrence of ischemic events and clinical worsening. Brain hemorrhages are possible but exceptional. They have been observed in about a dozen of cases in the literature.

About 5–10% of patients can present with epileptic seizures, sometimes with partial, most commonly with generalized, seizures. The majority of epileptic individuals already had one or more cerebral infarction. Seizures can be observed in the absence of any visible cortical lesion on conventional MRI. They are usually well controlled by conventional treatments.

Mood disorders affect about 20% of patients; their frequency seems to vary within families. They can be inaugural. Some patients can present with episodes mimicking severe depression. Depressive symptoms may alternate with manic episodes as in bipolar disorder. Conventional antidepressants seem to be effective in the vast majority of cases.

Apathy defined as a lack of motivation responsible for a reduction in voluntary goal-directed activities is frequently detected during the progression of the disease (30–40% of cases). Apathetic patients seem to have a more severe clinical presentation than those free from apathy.

Decline in cognitive performances that can lead to dementia represents the second clinical manifestation of the disease after ischemic stroke. The profile of the initial cognitive deficit is usually heterogeneous. Executive dysfunction is the most frequent deficit. It can be detected even in young patients, decades before the onset of other manifestations of the disease. These cognitive changes frequently include alterations of attention and working memory. Cognitive decline increases over years and becomes progressively more diffuse and homogeneous and can include decrease of performances in all cognitive domains. Memory deficit of hippocampal type can even be observed in 20% of patients with CADASIL with memory alterations at the end stage of the disease. Cognitive decline may evolve acutely or increase progressively even in the absence of any ischemic event. Dementia is observed in one-third of symptomatic patients. Its frequency increases with age; it affects about 60% of patients over 60 years and is observed in 80% of subjects before death. When dementia is present, cognitive deficit is often extensive and involves executive function, attention, and memory, as well as reasoning and language. Severe aphasia, apraxia, or agnosia is rarely observed. Semantic memory and recognition are preserved. Dementia can remain isolated in 10% of cases. It is frequently associated with gait disturbances, urinary incontinence, and pseudobulbar palsy. The final stage of the disease is characterized by progressive loss of independence with severe disability. Mean age at death is estimated around 64.6 years for men and 70.7 years for women.