Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic condition associated with migraine with aura, recurrent ischemic stroke, cognitive decline, mood disturbance and typical neuroimaging findings.

• CADASIL has a variable phenotype with some common characteristics, which are listed below.
  • Migraine, usually with aura, is common, with onset usually occurring in the third decade of life. Atypical migraine events may occur, and migraine risk may increase during pregnancy or in early postpartum periods.
  • Ischaemic episodes – transient ischemic attacks and/or stroke – occur in 85% of affected individuals, with onset usually occurring in the fifth decade of life (though they have been reported in individuals between 20 and 70 years of age).
  • Cognitive impairment (manifesting initially with executive dysfunction) occurs in up to 75% of affected individuals and can begin as early as the fourth decade of life.
  • Dementia (often progressing in a stepwise fashion due to recurrent ischaemic events) and psychiatric disturbances can occur, including apathy and depression.
  • There can be acute reversible encephalopathy (for example, altered consciousness, visual hallucinations, seizures and/or focal neurologic deficits).
• Brain MRI is the most useful imaging method to demonstrate the radiologic features of CADASIL. The first MRI anomalies, which include small, well-circumscribed lacunes as well as less well-demarcated T2 hyperintensities, are usually identified in the temporal poles. Over time, the burden of white matter lesions increases to include the periventricular, frontoparietal and external capsular regions. Microhaemorrhages may be detected on gradient echo imaging.​
• The symptoms of CADASIL are progressive, leading to death at a mean of 23 years from onset.
• Onset of symptoms in childhood are rare and, where present, should prompt consideration of alternative diagnoses in tandem. Migraine is common in both children and adults and should not be considered to be a diagnostic feature in isolation.

CADASIL is caused by heterozygous, cysteine-altering pathogenic variants in the NOTCH3 gene on chromosome 19. The NOTCH3 protein is important for the survival and function of vascular smooth muscle cells, including the neurovascular supply. Disruption to NOTCH3 functioning can lead to vascular smooth muscle cell damage and death.

All described pathogenic variants are located within epidermal growth factor-like repeat (EGFr) domains of NOTCH3. The spectrum includes missense variants (95%), splice site variants and small in-frame deletions. Pathogenic variants in EGFr domains one to six are usually associated with a classic CADASIL phenotype and are fully penetrant. Alternatively, variants in EGFr domains 7 to 34 have been shown to have a higher population frequency (about 1 in 300) and to predispose to a milder small-vessel disease, and non-penetrance is possible.

Signs and symptoms overlapping those of CADASIL may be present in other inherited conditions, such as cerebral autosomal recessive arteriopathy subcortical infarcts and leukoencephalopathy (CARASIL), mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS) and HTRA1-related conditions, as well as conditions without a known genetic basis. For this reason, clinicians considering genomic testing may need to consider a wider differential diagnosis in the absence of a known NOTCH3 variant in the family, or where testing for this is negative.

CADASIL is an autosomal dominant condition and most affected individuals have an affected parent; de novo pathogenic variants appear to be rare. Presymptomatic testing for unaffected individuals is available when a disease-causing variant has been identified in an affected family member. Testing in children is rarely indicated and should be offered only where typical symptoms are present. When genomic testing returns a positive result, it is advisable to discuss the case with your local clinical genetics service to enable you to support family members whose genetic status may be revealed by the result.

There is no treatment of proven efficacy for CADASIL. Care should be co-ordinated with follow-up provided by a specialist multidisciplinary team where possible.

In the acute setting

• Acute transient ischemic attack and acute stroke in patients with CADASIL should be managed following the general principles of stroke medicine. There is no evidence to suggest that systemic intravenous thrombolysis improves outcomes after a small vessel occlusion, and individuals with CADASIL may be at increased risk of intracerebral haemorrhage with thrombolytic therapy. In the event of large vessel occlusion (which is unlikely to be related to CADASIL), the benefit of thrombolysis and/or mechanical thrombectomy outweighs the potential risk of haemorrhage.
• Migraine should be treated symptomatically using typical standards of care. There is a potential relative contraindication for the group of medications known as triptans based on a hypothetical concern of increased stroke risk due to vasospasm. Firm evidence to support this is not yet available.

Prevention of primary manifestations

• For secondary stroke prevention, treatment should encompass all available risk reduction strategies – for example, management of hypertension, dyslipidaemia and hyperglycaemia – and smoking cessation may be particularly important. Antiplatelet therapy may be considered for prevention of stroke and/or transient ischemic attacks, but efficacy has not been proven. Other than situations in which there is a clear indication for anticoagulant therapy, such as atrial fibrillation or deep venous thrombosis, oral anticoagulants should generally be avoided due to the risk of intracerebral haemorrhage secondary to microbleeds.
• Prophylactic treatment may be considered according to normal standard care for management of migraine.

For clinicians

• Alex, the Leukodystrophy Charity (Alex TLC): NHS England patient service and registry (information on the NHS England inherited white matter disorders diagnostic and management service (all ages))
• Alex TLC: What is leukodystrophy?
• GeneReviews: CADASIL
• NHS England: National Genomic Test Directory
• NICE: Migraine
• Stroke Research Group, University of Cambridge: CADASIL

For patients

• Alex, the Leukodystrophy Charity (Alex TLC)
• Alex TLC: What is leukodystrophy?
• CADASIL Support UK