CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a genetic small-vessel disease typically seen in adults, characterised by the NOTCH3 gene mutation, accumulation of granular osmiophilic material, and white matter hyperintensities on T2-weighted and FLAIR MRI.
Description
CADASIL is the most common form of hereditary stroke disorder, and it is a systemic vasculopathy affecting multiple systems but predominantly involving the small cerebral vessels. It is autosomal dominant, primarily affects the small penetrating arterioles, and results in subcortical infarcts, lacunar infarcts and leukoencephalopathy.
Pathogenesis
CADASIL is caused by mutations in the NOTCH3 gene located on chromosome 19, which codes for a transmembrane receptor protein found in vascular smooth muscle cells. The resultant defective protein leads to the accumulation of granular osmiophilic material in and around vascular smooth muscle cells, causing progressive stenosis and ultimately occlusion of small to medium perforating vessels.
Subtypes
As a monogenic disorder, there are no recognised subtypes of CADASIL.
Epidemiology, Risk Factors & Associations
- Most cases are diagnosed in adults between the ages of 30-50 years.
- Men and women are equally affected.
- Smoking and hypertension can exacerbate the course of the disease.
Clinical Features
- Migraines, often with aura, in early adulthood.
- Mood disturbances including depression and apathy.
- Subcortical dementia of gradual onset.
- Recurrent strokes leading to stepwise progression of disability.
Complications
- Stroke: CADASIL is one of the most common causes of inherited stroke disorders.
- Cognitive decline: A significant proportion of patients develop dementia.
Pathological Features
Histopathology
- Macroscopic: No macroscopic changes are seen in the brain tissue.
- Microscopic: Characterised by thickening of the walls of small- to medium-sized arteries due to the accumulation of granular osmiophilic material.
Serology
- Genetic testing is used to identify mutations in the NOTCH3 gene.
Biochemistry
- No specific biochemical changes are seen in CADASIL.
Radiological Features
General Features
- Typically demonstrates subcortical, periventricular, and deep- white matter changes
- The most common location of early disease is the temporal pole and external capsule
- There is relative sparing of cortical gray matter, subcortical U fibres, and occipital and orbitofrontal regions.
- Cerebral microhemorrhages later stages, seen in approximately 45% of cases
- Cerebral atrophy occurs over time
- Lesions usually do not enhance.
CT
- Non-contrast: Can show lacunar infarcts and white matter hypoattenuation.
MRI
- T1: White matter changes are typically hypointense.
- T2 and FLAIR: Hyperintensities in the white matter of the anterior temporal lobes and external capsules. White-matter hyperintensities on T2/fluid-attenuated inversion-recovery (FLAIR) sequences can be seen throughout subcortical, periventricular, and deep white matter, as well as lacunar infarcts in deep-gray structures.
- T1 Gad+: No enhancement is usually seen.
- SWI/GRE: Cerebral microhaemorrhage
Diagnosis
Diagnosis is made through a combination of clinical features, imaging findings, and ultimately genetic testing confirming a NOTCH3 mutation.
Differential Diagnosis
- Multiple Sclerosis: Typically shows periventricular lesions oriented perpendicular to the ventricles (“Dawson’s fingers”). MRI would show lesion enhancement post-gadolinium, which would not be seen in CADASIL.
- Binswanger disease: More common in older adults with a history of hypertension. Imaging may appear similar, but without the anterior temporal lobe involvement seen in CADASIL.
Prognosis
There is significant heterogeneity in the severity and progression of symptoms in CADASIL. Overall, the condition is progressive, with most patients becoming disabled within 10-20 years of diagnosis due to recurrent strokes and cognitive decline.
Management
There is no cure for CADASIL, and management is largely supportive, focusing on symptomatic treatment and stroke prevention measures such as controlling hypertension and avoiding smoking. The care of CADASIL patients involves a multi-disciplinary team, including neurologists, genetic counsellors, and physical therapists.