Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Summary
- CADASIL is a hereditary small vessel disease characterised by recurrent subcortical infarcts, cognitive decline, and migraine with aura
- Caused by mutations in the NOTCH3 gene, leading to accumulation of granular osmiophilic material (GOM) in small arteries
- MRI shows characteristic white matter hyperintensities, lacunar infarcts, and microbleeds, particularly in the anterior temporal lobes and external capsule
Pathophysiology
- Autosomal dominant inheritance pattern
- Mutations in NOTCH3 gene on chromosome 19p13.1
- Encodes a transmembrane receptor protein involved in cell signaling
- Accumulation of GOM in vascular smooth muscle cells
- Leads to thickening of vessel walls and luminal narrowing
- Progressive degeneration of vascular smooth muscle cells
- Impaired cerebral blood flow and chronic ischaemia
Demographics
- Prevalence: 2-5 per 100,000 individuals
- Age of onset: typically 30-50 years
- No gender predilection
- Most common in Caucasian populations, but reported worldwide
Diagnosis
- Clinical presentation:
- Recurrent ischaemic strokes
- Cognitive decline and dementia
- Migraine with aura
- Mood disturbances
- Genetic testing:
- Sequencing of NOTCH3 gene
- Skin biopsy:
- Electron microscopy to detect GOM in arterioles
Imaging
- MRI findings:
- T2/FLAIR hyperintensities in white matter
- Anterior temporal lobe involvement (90% of cases)
- External capsule involvement (80% of cases)
- Lacunar infarcts in basal ganglia, thalamus, and pons
- Microbleeds on susceptibility-weighted imaging (SWI)
- Cerebral atrophy in advanced stages
- CT findings:
- Less sensitive than MRI
- May show hypodensities in white matter and lacunar infarcts
- A 55-year-old patient with no cardiovascular risk factors presented with recurrent headache.
- MRI showed a confluent leukoencephalopathy, involving the external capsules and anterior temporal lobes, and lacunar infarcts.
- There were deep and lobar microhaemorrhages.
- 50-year-old patient with no cardiovascular risk factors had recurrent strokes.
- MRI showed a severe burden of small vessel disease, multiple lacunar infarcts and mixed distribution microhaemorrhages.
- 50-year-old patient presented with a homonymous hemianopia and mixed sensory and motor deficits.
- MRI showed an acute left thalamic infarct and a diffuse leukoencephalopathy that involved the external capsules and anterior temporal lobes.
- Alongside the classical intracranial features of CADASIL, MRI showed multiple dorsal column hyperintensities.
- With no evidence of a metabolic or demyelinating cause, findings were ascribed to a CADASIL-related myelopathy.
Treatment
- No specific cure available
- Management focuses on symptom control and prevention of complications:
- Antiplatelet therapy for stroke prevention
- Migraine prophylaxis and treatment
- Blood pressure control
- Smoking cessation
- Cognitive rehabilitation
- Genetic counseling for family members
- Experimental therapies under investigation:
- NOTCH3 antisense oligonucleotides
- Anti-aggregation agents targeting GOM formation
Differential diagnosis
| Differential Diagnosis | Distinguishing Feature |
|---|---|
| Vascular Dementia | Temporal pole involvement on MRI in CADASIL |
| Binswanger's Disease | Genetic testing positive for NOTCH3 mutation in CADASIL |
| Cerebral Amyloid Angiopathy | Lobar microhaemorrhages with posterior predominance and cortical superficial siderosis in CAA; temporal pole sparing in CAA |
| MELAS Syndrome | Absence of stroke-like episodes and normal lactate levels in CADASIL |
| Fabry Disease | Absence of systemic manifestations (skin, kidney, heart) in CADASIL |
| Sporadic Small Vessel Disease | Family history and earlier age of onset in CADASIL |
| CNS Vasculitis | Lack of inflammatory markers and normal angiography in CADASIL |