Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Genotype-Misphenotype Study.

Background and Objectives: Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by pathogenic Methods: We conducted a retrospective cohort study to compare genetically or histopathologically confirmed CADASIL patients with and without a prior MS misdiagnosis. Patients were classified into high-risk, medium-risk, low-risk, or unknown-risk by the location of their Results: Of 107 CADASIL patients (mean age 57.5 ± 13.4 years), 11 (10.2%) were misdiagnosed with MS. In prespecified adjusted logistic regression models, absence of prior stroke (adjusted odds ratio [OR] 4.60; 95% CI 1.02-20.68), Asian race (adjusted OR 20.74; 95% CI 3.21-134.18), asymmetric external capsule white matter hyperintensity (WMH) (adjusted OR 53.34; 95% CI 4.06-701.08), and absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90-82.01) were independently associated with misdiagnosis. The median time to diagnostic correction was 14.45 months (range 1.18-138.07), during which 5 patients (45.5%) received unnecessary MS therapies and 2 experienced documented adverse events. Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons but were not independently associated after adjustment. Discussion: In this multicenter tertiary-care cohort, approximately 1 in 10 patients with CADASIL had been misdiagnosed as MS, an error associated with Asian race, absence of a stroke history, and atypical neuroimaging patterns leading to worse functional outcomes and inappropriate treatments. A high index of suspicion for CADASIL is critical in patients presenting with atypical or late-onset demyelinating disease. Larger studies are needed to understand the role of medium-risk variants in misdiagnosis.