Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome

Signs and symptoms

The condition may begin with migraine with aura, subcortical transient ischemic attacks or strokes, or mood disorders between ages 35 and 55. It progresses to subcortical dementia with pseudobulbar palsy and urinary incontinence. Ischemic strokes occur in about 85% of symptomatic individuals, with a mean onset around age 46. A classic lacunar syndrome appears in at least two-thirds of patients; hemispheric strokes are less common.

Strokes typically happen without traditional cardiovascular risk factors. Recurrent silent strokes often lead to cognitive decline and overt subcortical dementia. A case presenting as schizophreniform organic psychosis has been reported.

Diagnosis

MRIs show hypointensities on T1-weighted images and hyperintensities on T2-weighted images, typically multiple confluent white matter lesions around the basal ganglia, periventricular white matter, and pons, similar to Binswanger disease. These lesions appear even in asymptomatic individuals with the mutated gene. Definitive diagnosis requires sequencing the whole NOTCH3 gene from a blood sample. Because CADASIL is a systemic arterial disease, skin biopsies are often used to detect the mutation in small and medium-size arteries.

Treatment

There is no specific treatment for CADASIL. Symptom management for migraine and stroke relies mostly on trial and error, as evidence for these approaches in CADASIL is scarce. Antiplatelet drugs like aspirin, dipyridamole, or clopidogrel may reduce stroke risk, but anticoagulants are often avoided because of a tendency toward microhemorrhages. Controlling high blood pressure is especially important.

Short-term use of atorvastatin did not improve cerebral blood flow, though treating conditions like high cholesterol is still advised. Stopping oral contraceptive pills may be suggested. Some experts recommend against triptans for migraine due to their vasoconstrictive effects, though this view is not unanimous; newer options like lasmiditan, ubrogepant, and rimegepant, which lack vasoconstriction, are promising but untested in CADASIL. Smoking cessation is encouraged.

In one small study, about a third of CADASIL patients showed cerebral microhemorrhages on MRI. L-arginine has been proposed as a treatment, but no clinical studies support its use as of 2017. Donepezil, used for Alzheimer’s, did not improve executive function in CADASIL patients.

Society and culture

John Ruskin has been suggested to have had CADASIL, with visual disturbances consistent with the disease possibly influencing his criticism of Whistler's Nocturne in Black and Gold, leading to a libel trial. Research into Friedrich Nietzsche's illness has suggested CADASIL rather than tertiary syphilis as the cause of his mental illness and death. The composer Felix Mendelssohn's death at age 37 from a stroke has been potentially linked to CADASIL; his sister Fanny Hensel was similarly affected.

James Dewar, vocalist for Robin Trower, died at age 59 from complications of CADASIL. In the movie The Sea Inside, a character is stated to have CADASIL. In the Netflix 2023 limited series The Fall of the House of Usher, the main character Roderick Usher has a CADASIL diagnosis, and much of the storyline surrounds his attempts to find a cure; the series is based on the life's work of Edgar Allan Poe.

Did You Know?

• The underlying pathology is progressive hypertrophy of smooth muscle cells in blood vessels.
• Granular osmiophilic deposits are seen on electron microscopy due to abnormal Notch3 protein accumulation.
• A consensus significant loss of beta sheet structure of the Notch3 protein has been predicted using in silico analysis.