Confirm CADASIL with the phenotype, MRI and genetics together
CADASIL should not be diagnosed from white-matter lesions alone. The work-up combines age and type of neurological events, migraine history, cognitive or psychiatric symptoms, family history and brain MRI with molecular testing. MRI may show confluent white-matter hyperintensities, lacunes and cerebral microbleeds; involvement of the anterior temporal poles and external capsules can support the diagnosis but is not required in every patient.
A pathogenic NOTCH3 variant can establish the diagnosis
GeneReviews states that CADASIL is established by a heterozygous pathogenic or likely pathogenic NOTCH3 variant, or by characteristic skin-biopsy findings when molecular testing is not definitive. A variant of uncertain significance does not by itself prove or exclude CADASIL. This distinction matters because broad sequencing increasingly finds NOTCH3 variants whose clinical significance must be interpreted in context.
Broader genetic testing may be better when the phenotype is atypical
Early-onset stroke and cerebral small-vessel disease can also result from other inherited disorders, including HTRA1-related disease, COL4A1/COL4A2-related angiopathy and Fabry disease. If the MRI pattern, inheritance or systemic features do not fit classic CADASIL, a specialist may recommend a multigene small-vessel-disease panel rather than repeated isolated NOTCH3 testing.
Family history helps, but an apparently negative pedigree does not exclude CADASIL
CADASIL is classically autosomal dominant, but a family history may look negative because relatives were mildly affected, died before typical manifestations, were misdiagnosed, or have not been tested. Predictive testing of healthy adult relatives should be separated from diagnostic testing of a symptomatic patient and should be performed with formal genetic counseling.
Skin biopsy is now a selective diagnostic tool
When genetic testing is inconclusive but clinical suspicion remains high, skin biopsy can demonstrate granular osmiophilic material on electron microscopy and abnormal NOTCH3 accumulation by immunohistochemistry. It is not required when a clearly pathogenic NOTCH3 variant already establishes the diagnosis, and interpretation should be performed by an experienced laboratory.
There is no proven disease-modifying treatment for CADASIL
Current management cannot remove the underlying NOTCH3 arteriopathy. Treatment therefore targets complications and modifiable risk. Conventional vascular risk factors such as hypertension, diabetes, smoking and hypercholesterolaemia should be addressed, while overly aggressive blood-pressure reduction or other changes that could worsen cerebral perfusion should be individualized rather than copied from a generic internet protocol.
Antiplatelet and anticoagulant decisions require specialist review
The American Heart Association scientific statement advises against routine antiplatelet therapy for primary stroke prevention in CADASIL. Aspirin monotherapy may be considered after ischaemic stroke, but evidence for efficacy is limited. Long-term anticoagulation should not be used simply because CADASIL is present; when another strong indication such as high-risk atrial fibrillation exists, the expected benefit must be weighed against haemorrhage and cerebral-microbleed burden.
Migraine, cognition and psychiatric symptoms need their own care plan
Migraine with aura can precede stroke by years. Cognitive slowing, executive dysfunction, mood symptoms and apathy may also become clinically important. These problems should be treated as separate management targets with neurologic, neuropsychological, psychiatric and rehabilitation input as needed rather than assuming that stroke prevention alone covers the disease burden.
UKE Hamburg has an explicit CADASIL vascular clinic pathway
The vascular outpatient clinic at University Medical Center Hamburg-Eppendorf states that it manages rare and complicated cerebrovascular diseases, cerebral vasculitis and inherited vascular disorders including CADASIL. It also serves as a specialist consultation point for referring physicians, making UKE a relevant destination for difficult diagnosis, MRI interpretation and secondary-prevention questions.
Heidelberg combines rare-neurovascular expertise with CADASIL genetic diagnostics
Heidelberg University Hospital lists rare neurovascular disease among the focus areas of its Center for Rare Neurological Diseases, including juvenile stroke and cerebral angiitis. Its published neurovascular standards include a CADASIL diagnostic pathway based on clinical context, temporal-predominant cerebral microangiopathy, family history and genetic testing, while the hospital's international office can route records to the appropriate specialist team.
What to send for a German CADASIL second opinion
A useful review needs enough information to decide whether the diagnosis itself is secure and what management question remains open.
- Brain MRI source images, ideally including FLAIR, T2 and susceptibility-sensitive SWI/T2* sequences
- MRI reports and any prior CT scans
- Complete NOTCH3 genetic report with exact variant nomenclature and laboratory classification
- Any prior multigene panel, exome or genome results
- Family pedigree or written history of stroke, migraine, dementia or psychiatric disease
- Timeline of TIAs, ischaemic strokes, intracerebral haemorrhage and migraine with aura
- Current antiplatelet, anticoagulant, blood-pressure and lipid-lowering medication
- Blood-pressure history and major vascular risk factors
- Neuropsychological or cognitive testing if performed
- Exact question: confirm CADASIL, reinterpret a NOTCH3 variant, review inherited small-vessel-disease differential, plan family testing, or review secondary stroke prevention
Acute stroke symptoms require local emergency treatment
Sudden weakness, speech disturbance, facial droop, visual loss, severe imbalance, loss of consciousness or a new severe neurological deficit require immediate local emergency stroke assessment. A planned international second opinion is appropriate only after the acute event has been stabilized.
Official sources
Sources last checked 2026-09-02. Clinical pathways, eligibility and hospital procedures can change; confirm current requirements directly with the treating center.
- Vascular outpatient clinic – inherited vascular disease including CADASIL — University Medical Center Hamburg-Eppendorf (UKE) ↗
- Center for Rare Neurological Diseases – rare neurovascular diseases — Heidelberg University Hospital ↗
- Standards of the Neurovascular Outpatient Clinic – CADASIL diagnostic pathway — Heidelberg University Hospital ↗
- CADASIL – diagnosis, management and genetic counseling — GeneReviews / NCBI Bookshelf ↗
- Management of Inherited CNS Small Vessel Diseases: The CADASIL Example — American Heart Association / Stroke ↗