Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and...

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by pathogenic NOTCH3 variants, can be misdiagnosed as multiple sclerosis (MS) due to overlapping clinical and radiologic features. Although initially described in European cohorts, prevalence of pathogenic NOTCH3 variants may be higher among Asian populations. Misdiagnosis may delay appropriate management and expose patients to ineffective and potentially harmful therapies. This study aimed to estimate the proportion of CADASIL patients with prior MS misdiagnosis presenting to a multicenter tertiary-care cohort and to identify associated clinical and genetic features and consequences of this diagnostic error.

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 NOTCH3 variant in the epidermal growth factor-like repeat (EGFr) domain. Prespecified logistic regression models were used to evaluate factors independently associated with MS misdiagnosis, adjusting for age, sex, race, and prior stroke history.

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.

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.