CADASIL

CADASIL is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the commonest hereditary small vessel disease of the brain. It is caused by variants in NOTCH3.

The estimated prevalence is about 2 to 5 in every 100,000 adults, though population studies of pathogenic variants suggest it is more common. It affects men and women equally.

Genetics. Autosomal dominant; almost all pathogenic variants add or remove a cysteine residue in the epidermal growth factor like repeats of NOTCH3, with hotspots in exons 3 and 4. Each child of an affected parent has a 50% risk.

Course. Migraine with aura begins at about 30 years, mood disorder at 40 to 50, ischaemic events at 45 to 50, and dementia and gait disorder by 60 to 65. Phenotype varies within families.

Pathophysiology.

Accumulation of the NOTCH3 extracellular domain and granular osmiophilic material in the vessel wall damages smooth muscle cells and pericytes, thickening small arteries and reducing cerebral blood flow.

Lacunes, white matter damage and microbleeds follow, with strategic subcortical involvement causing apathy and executive dysfunction.

• Migraine with aura in about 20 to 40%, often with prolonged or atypical aura.
• Recurrent lacunar strokes and TIAs.
• Mood disturbance, apathy and depression.
• Cognitive decline with executive dysfunction progressing to dementia, with gait disturbance and incontinence.
• Less common: seizures, acute encephalopathy and subcortical haemorrhage.

• MRI: confluent white matter hyperintensities, early involvement of the anterior temporal poles and external capsules, lacunes and microbleeds.
• NOTCH3 sequencing (targeted exons first, then full gene) with genetic counselling is the diagnostic test.
• Skin biopsy with electron microscopy for granular osmiophilic material, or NOTCH3 immunostaining, is used when genetic testing is unclear.
• Neuropsychological testing and mood screening for baseline.

Differential diagnosis. Sporadic small vessel disease, multiple sclerosis, CARASIL, other monogenic small vessel diseases (COL4A1, HTRA1, retinal vasculopathy with cerebral leukodystrophy), mitochondrial disease and vasculitis.

• No disease modifying treatment exists; management addresses risk factors and symptoms.
• Control vascular risk factors: stop smoking, treat hypertension to under 130/80 mmHg, diabetes and dyslipidaemia, and maintain physical activity.
• Aspirin 75 mg orally once daily for secondary prevention after an ischaemic event, long term. Maximum 100 mg daily in this indication. Monitor bleeding and dyspepsia and check full blood count. Avoid in active peptic ulcer, bleeding disorders and aspirin sensitive asthma; use caution when eGFR is under 10; avoid in children under 16; benefit is not proven and microbleeds raise bleeding risk. Avoid anticoagulants unless there is a clear separate indication.
• Avoid catheter angiography and, where possible, procedures with high ischaemic risk and prolonged hypotension.
• Migraine: treat attacks with analgesics and avoid vasoconstrictor drugs during prolonged or atypical aura; preventive treatment individualised.
• Depression and apathy: treat with psychological therapy and antidepressant drugs through specialist input.
• Rehabilitation, occupational therapy, falls prevention and cognitive support; palliative care in advanced disease.

Monitoring. Annual review of cognition, mood, vascular risk and function; MRI only when clinical change occurs.

Referral and escalation. Clinical genetics for family counselling and predictive testing; neurology for diagnosis and acute events; memory clinic for dementia.

Special groups. Women with migraine with aura should avoid oestrogen containing contraception. Pregnancy: plan and monitor, and expect attacks of aura or encephalopathy postpartum.