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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Summary

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  • 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 capsule1

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

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  • 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.

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  • 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.

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  • 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.

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  • 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 cure; antiplatelet therapy, vascular risk-factor control and migraine management

Differential diagnosis

Imaging differential Differentiating feature
Sporadic small vessel disease / Binswanger Confluent deep white matter disease that characteristically spares the anterior temporal poles and external capsule
Cerebral amyloid angiopathy Lobar, posterior-predominant microbleeds and cortical superficial siderosis; temporal poles spared
Fabry disease Pulvinar T1 hyperintensity; posterior white matter change
CARASIL / CARASAL and other hereditary SVD Overlapping white matter disease; distinguished genetically
MELAS Cortical/subcortical lesions not confined to vascular territories, with a lactate peak on MRS

  1. Ruchoux et al. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 1997. Journal of neuropathology and experimental neurology - Open in new tab. ↩