What is the management and treatment of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)?

From the Guidelines

The management of CADASIL should focus on counseling on smoking cessation and treatment of hypertension and other vascular risk factors to reduce the risk of incident stroke, as recommended by the 2024 guideline for the primary prevention of stroke 1. The goal of managing CADASIL is to control symptoms and prevent stroke-like episodes, as there is currently no disease-modifying treatment available.

• Blood pressure control is crucial, with a target below 130/80 mmHg, and can be achieved using antihypertensives like ACE inhibitors or ARBs.
• Lifestyle modifications are essential, including smoking cessation, regular physical activity, maintaining a healthy weight, and limiting alcohol consumption.
• Migraine, a common symptom, can be treated with standard prophylactic medications, while avoiding vasoconstrictors like triptans.
• Cognitive decline should be monitored regularly, and genetic counseling should be offered to patients and families due to the autosomal dominant inheritance pattern. The disease is caused by mutations in the NOTCH3 gene, affecting small blood vessels in the brain, leading to progressive damage to white matter and recurrent small strokes, which explains why management focuses on vascular risk reduction and symptom control rather than targeting the underlying genetic defect 1.
• Further research is needed to develop disease-modifying therapies, including gene therapies, for genetic syndromes like CADASIL, and to evaluate the roles of vascular risk factor modification, antiplatelet therapy, and calcium channel blockers in stroke prevention 1.

From the Research

Management and Treatment of CADASIL

The management and treatment of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) are primarily focused on alleviating symptoms and preventing further complications, as there is currently no cure for the disease 2, 3, 4, 5.

Current Treatment Approaches

• The treatment of CADASIL is largely supportive and aimed at managing the symptoms, such as migraine with aura, recurrent ischemic events, and psychiatric disturbances 2, 3, 5.
• There is no specific therapy available to stop or delay the progression of CADASIL, but research is ongoing to develop therapeutic strategies for this devastating neurological disease 6.
• The use of hematopoietic growth factors, such as stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF), has shown promise in improving cognitive function and inhibiting Notch3 mutation-induced vascular smooth muscle cell degeneration in mouse models of CADASIL 6.

Diagnostic Considerations

• The diagnosis of CADASIL can be made on the basis of characteristic white-matter hyperintensities in T2-weighted MRI, which may precede symptoms by more than a decade 3, 4.
• The identification of the mutation of the NOTCH 3 gene responsible for the disorder has given great impetus to research to understand the molecular and vascular pathogenesis of the disease 3, 4.
• The diagnosis can also be made on the basis of accumulation of pathognomonic basophilic, PAS-positive and in electron microscopy osmiophilic material between degenerating smooth muscle cells in dermal arteries 4.

Future Directions

• Further research is needed to understand the pathogenesis of CADASIL and to develop effective therapeutic strategies for this disease 6.
• The study of CADASIL may provide insights into the more common sporadic forms of subcortical cerebral ischemia and vascular dementia, as it provides a pure genetic model for these conditions without the confounding factors of comorbidities and advanced age 3.