What Is CADASIL?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, usually called CADASIL, is an inherited condition that causes stroke and other impairments.

This condition affects blood flow in small blood vessels, particularly cerebral vessels within the brain. The muscle cells surrounding these blood vessels (vascular smooth muscle cells) are abnormal and gradually die. In the brain, the resulting blood vessel damage (arteriopathy) can cause migraines, often with visual sensations or auras, or recurrent seizures (epilepsy).

Damaged blood vessels reduce blood flow and can cause areas of tissue death (infarcts) throughout the body. An infarct in the brain can lead to a stroke. In individuals with CADASIL, a stroke can occur at any time from childhood to late adulthood, but typically happens during mid-adulthood.

People with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy often have more than one stroke in their lifetime.

Recurrent strokes can damage the brain over time. Strokes that occur in the subcortical region of the brain, which is involved in reasoning and memory, can cause progressive loss of intellectual function (dementia) and changes in mood and personality.

CADASIL Effects

Notch 3 antibody, characteristic in CADASIL

Notch 3 antibody, characteristic in CADASIL.
Credit: Nephron, CC BY-SA 3.0

Many people with CADASIL also develop leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI).

The age at which the signs and symptoms of CADASIL first begin varies greatly among affected individuals, as does the severity of these features.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy may start with attacks of migraine with aura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 and 55 years of age. The disease progresses to subcortical dementia associated with pseudobulbar palsy and urinary incontinence.

Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing transient ischemic attacks or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70).

A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. It is worthy of note that ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia.

CADASIL is not associated with the common risk factors for stroke and heart attack, such as high blood pressure and high cholesterol, although some affected individuals might also have these health problems.

Genetic Causes

Mutations in the NOTCH3 gene cause CADASIL. The NOTCH3 gene provides instructions for producing the Notch3 receptor protein, which is important for the normal function and survival of vascular smooth muscle cells.

When certain molecules attach (bind) to Notch3 receptors, the receptors send signals to the nucleus of the cell. These signals then turn on (activate) particular genes within vascular smooth muscle cells.

NOTCH3 gene mutations lead to the production of an abnormal Notch3 receptor protein that impairs the function and survival of vascular smooth muscle cells. Disruption of Notch3 functioning can lead to the self-destruction (apoptosis) of these cells. In the brain, the loss of vascular smooth muscle cells results in blood vessel damage that can cause the signs and symptoms of CADASIL.

Treatment

No specific treatment for CADASIL is available.

Most treatments for patients’ symptoms – including migraine and stroke – are similar to those without CADASIL, but these treatments are almost exclusively empiric, as data regarding their benefit to CADASIL patients is limited. Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages.

Control of high blood pressure is particularly important incerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients. Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients’ cerebral hemodynamic parameters, although treatment of comorbidities such as high cholesterol is recommended.

Stopping oral contraceptive pills may be recommended. Some authors advise against the use of triptan medications for migraine treatment, given their vasoconstrictive effects, although this sentiment is not universal. As with other individuals, people with CADASIL should be encouraged to quit smoking.

Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T; CADASIL Group of Vas-Cog
The pathogenesis of CADASIL: an update
J Neurol Sci. 2004 Nov 15;226(1-2):35-9.