**2. Clinical picture**

CADASIL is an inherited cerebrovascular disorder, whose main clinical features are migraine with aura, recurrent subcortical ischemic attacks, strokes, vascular dementia, cognitive impairment, psychiatric disturbances, and apathy [8–16]. Due to the rarity of the disease, CADASIL is often overlooked and misdiagnosed; nevertheless, the combined symptomatic and asymptomatic prevalence of CADASIL is estimated at least 10.7 per 100,000 adults [11, 12, 17–20]. Migraine with aura is an early sign, with average onset in the third decade of life, and it is typically reported to occur in 20–40% of patients [9, 21]. Transient ischemic attacks (TIA) or lacunar ischemic strokes are the most common signs, occurring in up to 85% of individuals with a mean onset in the fifth or sixth decade; usually they take the form of clinical lacunar syndromes [21, 22]. The second most frequent clinical manifestation is cognitive impairment, often leading to dementia, which occurs in a very high proportion of patients by the age of 50 years. Mood disturbances are reported in 20% of CADASIL patients, presenting as severe depressive episodes [21]. Moreover, researchers recognize apathy, which is independent from depression, as a major clinical manifestation, affecting about 40% of patients [23]. Patients with CADASIL exhibit, even more rarely, other clinical manifestations such as seizures in 5–10% of cases [22]; intracerebral hemorrhages [24], mostly in hypertensive patients, in 16–25% of cases [25, 26]; and, in a few cases, territorial infarcts [27], deafness [6], and parkinsonism [28]. All symptomatic patients present typical magnetic resonance imaging (MRI) findings, including noticeable signal abnormalities with hyperintense lesions on the T2-weighted images in the subcortical white matter, basal ganglia, and thalamus (a crucial difference from multiple sclerosis, a frequent mimic of CADASIL) [1, 6, 29–33]. Anterior temporal lobe hyperintensities may be more specific than external capsule changes and appear in young presymptomatic subjects [34]. In the vast majority of patients, brain MRI abnormalities precede the onset of symptoms by 10–15 years; thus, brain MRI is crucial for the diagnosis of CADASIL. Although marked population differences in the clinical and radiological manifestation of CADASIL have been recognized, potentially due to differences in underlying genetic mutations [21, 35–37], in the proper clinical evaluation based on symptoms suggestive of CADASIL, confluent anterior temporal pole white matter changes show sensitivity and specificity of 89 and 86%, respectively, based on case series. From a pathological point of view, CADASIL patients have a systemic nonamyloid, non-atherosclerotic angiopathy affecting the walls of small blood vessels [38, 39]. The accumulation of granular osmiophilic material (GOM) within the smooth muscle cell basement membrane and the surrounding extracellular matrix is pathognomonic [40–42]. Because the arteriopathy in CADASIL is systemic, GOM deposits, which contain Notch3 proteins, among other poorly defined components [40, 43, 44], can be detected in arteries of many different organs, including dermal arterioles. In fact, actually GOMs are detected in skin biopsies, but the reported

*Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy… DOI: http://dx.doi.org/10.5772/intechopen.87248*

sensitivity is variable [45, 46]. CADASIL is inherited dominantly, with over 500 families detected worldwide and de novo cases observed sporadically [47].
