Diagnostic Pitfalls in CADASIL: MRI Red Flags and Variant Interpretation Across Three Adults
Yasho Gondi1, Mohanad Ahmad1, Omar Hage-Hassan1, Aisha Siddiqui1, Farah Abdelhak1, Karen Krajewski1, Kashiff Ariff2, Kumar Rajamani1
1Neurology, Detroit Medical Center/ Wayne State University, 2Garden City
Objective:
To describe the clinical features, MRI “red flags,” and genetic findings of three adults evaluated for suspected CADASIL and to highlight diagnostic pitfalls that mimic epilepsy or multiple sclerosis.
Background:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small-vessel disease caused by NOTCH3 variants. Clinical overlap with epilepsy and multiple sclerosis (MS) can delay diagnosis. Characteristic MRI patterns, particularly anterior temporal pole T2/FLAIR hyperintensities, together with gene testing, aid recognition. 

Design/Methods:
We performed a retrospective review of three adults evaluated at our center whose presentations suggested CADASIL. We extracted clinical features, family history, MRI topography, and clinical-grade sequencing results for NOTCH3 and, when available, COL4A1/2. 
Results:

Case 1: 43-year-old man with new headache, dysarthria, left facial droop, confusion, and a family history of early strokes. MRI showed acute diffusion-positive infarcts in the right frontal lobe and thalamus and confluent white-matter hyperintensities with anterior temporal pole involvement. Sequencing identified NOTCH3 c.1268A>G (p.Tyr423Cys).  

Case 2: 51-year-old man previously diagnosed with MS presented with early-onset dementia and hallucinations without a family history of stroke or migraine. MRI demonstrated diffuse white-matter disease. Sequencing identified NOTCH3 c.545G>A (p.Arg182His) and COL4A2 c.610G>A (p.Val204Met).  

Case 3: 70-year-old woman with epilepsy, dementia, recurrent falls, and a family history of stroke and migraine presented with acute mental-status change. MRI demonstrated extensive leukoencephalopathy with corpus callosum involvement, anterior temporal pole hyperintensities, and old lacunar infarcts. Sequencing identified NOTCH3 c.245G>T (p.Cys82Phe). 
Conclusions:

Two cysteine-altering NOTCH3 variants (p.Tyr423Cys and p.Cys82Phe) were concordant with CADASIL in cases showing anterior temporal pole involvement, whereas a non-cysteine NOTCH3 variant (p.Arg182His) co-occurred with a rare COL4A2 missense change. These cases illustrate common diagnostic pitfalls, including Seizure-like or Multiple Sclerosis-like presentations. Emphasizing MRI “red flags,” cautious variant interpretation, and early genetic counseling may reduce misdiagnosis and guide family screening and vascular risk management. 

10.1212/WNL.0000000000215021
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.