A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials.

BACKGROUND AND PURPOSE Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The aim of this study was to explore the patterns of clinical progression in CADASIL, to check for prognostic variables, and to provide sample size estimates for future therapeutic trials. METHODS Eighty CADASIL subjects (aged 45.7+/-9.9 years [mean+SD]) were followed prospectively during a mean period of 26.3+/-1.1 months. Standardized scales on disability (Rankin), activities of daily living (Barthel index), neurological outcome (National Institutes of Health Stroke Scale [NIHSS]), and cognition (structural interview for diagnosis of Alzheimer dementia and multi-infarct dementia [SIDAM] and Mattis dementia rating scale [MDRS]) were assessed at baseline and at follow-up. RESULTS All but 1 individual completed the protocol. At follow-up, the cohort had deteriorated with respect to all clinical scales: Rankin scores (0.3+/-0.7 [mean change+/-SD]; P=0.001), Barthel index (-5.4+/-15.9; P<0.001), NIHSS scores (1.0+/-2.6; P=0.001), SIDAM scores (-2.1+/-6.4; P=0.004), and MDRS scores (-4.3+18.5; P=0.09). The spectrum ranged from marked worsening to some degree of improvement. Seventeen patients experienced a new stroke. Overall, there were 18 strokes within 173 person-years, giving an average incidence rate of stroke of 10.4 per 100 person-years (95% CI, 5.6 to 15.2). Age at baseline was found to be a predictor of clinical progression. Sample size estimates show that the number of individuals needed to include in an interventional trial (assumed duration 2 years, assumed treatment effect 40%) is 602 when using stroke occurrence as an outcome measure. CONCLUSIONS The clinical course of CADASIL includes periods of acute worsening, chronic progression, stabilization, and improvement. Sample size calculations emphasize the need for surrogate markers of disease progression for future interventional trials.