This 42-year-old man suffered from typical migraine attacks with (strictly unilateral) aura, but recently the frequency of the attacks had increased and atypical, prolonged visual auras had occurred. Structural and vascular causes had to be considered. An MRI scan showed lacunar lesions and extensive leukoencephalopathy. This typical image and the remarkable family history raised the suspicion of CADASIL, confirmed at DNA analysis by the NOTCH3 gene. Additional laboratory and cardiac screening ruled out other causes of (young) stroke.

CADASIL is a hereditary microangiopathy caused by mutations in the NOTCH3 gene on chromosome 19. Many different mutations in this gene have been found. The main features of CADASIL are ischemic episodes, cognitive deficits, migraine with aura, and mood disorders. The course of the disease can vary between families and between members of the same family.

Migraine affects 20–40 % of mutation carriers and often is the presenting symptom, with a mean age of onset in the mid-20s. Most CADASIL patients suffer from migraine with aura. The aura can vary from typical visual symptoms to extensive sensorimotor involvement, speech problems, and hemiplegia. Auras are often prolonged and atypical. CADASIL can also lead to sudden coma.

Of symptomatic individuals, 70–85 % experience (recurrent) ischemic episodes (transient ischemic attacks or strokes). After migraine, ischemic events are the most frequent presenting symptoms, with a reported mean age of onset of 41–49 years, ranging between 20 and beyond 60 years.

Cognitive deficits are also frequent in CADASIL and include attention deficits, mental slowness, and executive disorders. The cognitive decline is attributed to leukoencephalopathy and (multiple) lacunar infarctions. Cognitive disorders, however, can also be found before the onset of ischemic stroke. Most patients experience gradual cognitive deterioration, finally progressing to a subcortical dementia. In addition, 20–30 % of CADASIL patients suffer from psychiatric disorders, mostly mood disorders. Epileptic seizures, probably secondary to (multiple) strokes, have been reported in 5–10 % of patients.

Neuroimaging features of CADASIL (Table 8.1) include white matter signal hyperintensities (leukoencephalopathy) and lacunar lesions. In symptomatic patients, white matter hyperintensities are symmetrically distributed and are located in the periventricular and deep white matter. Within the white matter, lesions occur mostly in the frontal lobe, followed by the temporal and parietal lobes. Distinctive for young (20–30 years) and often asymptomatic mutation carriers is the presence of white matter abnormalities in the anterior temporal lobes, with the rest of the white matter unaffected (apart from periventricular caps). The presence of lacunar lesions increases significantly with age, and begins to appear in the fourth decade. These lesions are most frequently located in the deep white matter, but can also be present in the basal ganglia, thalamus, internal and external capsules, and brainstem.