Abstract
BACKGROUND: Migraine with aura (MA) is a hallmark feature of CADASIL, a hereditary small-vessel disease caused by NOTCH3 mutations. While MA is prevalent in CADASIL, its underlying mechanisms remain unclear, and the links observed can be questioned or debated. This study examined the prevalence, clinical characteristics, and pathophysiology of MA in patients with CADASIL. METHODS: Clinical and experimental data were reviewed to assess MA prevalence, aura characteristics, sex differences, and pathophysiological insights from CADASIL models to confirm the indisputable pathophysiological links between migraine and aura and this unique genetic model of cerebral small vessel disease. RESULTS: MA was 10-20 times more prevalent in patients with CADASIL than in the general population, with frequent atypical and prolonged auras. The altered sex distribution and delayed onset suggest disease-specific mechanisms. Experimental data also revealed heightened susceptibility to cortical spreading depression (CSD) in preclinical CADASIL models, linked to greater fragility in maintaining cortical ionic homeostasis. CONCLUSION: The high prevalence and distinct MA features, as well as the data obtained at the preclinical level, strongly support a causal relationship mediated by neurovascular dysfunction in CADASIL. Accumulating data in this condition sheds new light on the much-debated relationship between migraine and cerebrovascular diseases.