CADASIL

CADASIL is a rare inherited disorder that affects the blood vessels in the brain, causing symptoms that can include migraine headaches, strokes, and changes in memory and thinking. Understanding this condition can help patients and families navigate the challenges it presents.

Table of contents

• What is CADASIL?
• Who can get CADASIL?
• What causes CADASIL?
• Symptoms of CADASIL
• How CADASIL is diagnosed
• Treatment and management
• What to expect over time

What is CADASIL?

CADASIL is a rare inherited disorder that happens when the thickening of blood vessel walls blocks the flow of blood to the brain. The name CADASIL is short for “cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.”^[1]

To break this down: cerebral refers to the brain, autosomal dominant means it is a genetic disorder where only one copy of the abnormal gene is needed to cause the condition, arteriopathy means a disease that affects the arteries, subcortical refers to the region of the brain below the outer layer, infarcts are small areas of tissue that have died due to inadequate blood supply, and leukoencephalopathy refers to diseases that affect the white matter of the brain.^[5]

The condition primarily affects small blood vessels in the white matter of the brain. CADASIL is the most common form of hereditary stroke disorder.^[4]

Who can get CADASIL?

Anyone can get CADASIL. The disorder is found worldwide, affects both men and women, and happens in people of all races and ethnicities.^[1] While the true frequency in the general population is difficult to determine because CADASIL is often misdiagnosed or goes undiagnosed, studies have found a prevalence of approximately 1.98 to 4.14 per 100,000 adults.^[8]

CADASIL is inherited in an autosomal dominant pattern. In other words, if one parent carries the genetic mutation, the risk of their children inheriting the mutation is 50%.^[5] Often there is a family history of the disorder, but it can also be caused by a spontaneous genetic mutation that happens for unknown reasons.^[1]

What causes CADASIL?

CADASIL is caused by a mutation in the Notch3 gene, which is located on chromosome 19. This gene is responsible for making a protein which helps in the function of vascular smooth muscle cells, the muscle cells that make up the walls of blood vessels.^[1]

When there is a genetic mutation in Notch3, this protein accumulates abnormally in the blood vessel walls, which causes the walls to thicken and narrow. This impairs the movement of blood through the vessel and can lead to ischemic events such as stroke.^[5] The mutation affects the small blood vessels in the white matter of the brain, and the underlying problem is progressive thickening of the smooth muscle cells in blood vessels.^[4]

Symptoms of CADASIL

Symptoms and onset of the disorder can be different among people, but signs typically appear between the ages of 20 and 40 years, with some individuals not showing signs until later in life. While rare, symptoms can begin in childhood as well.^[1] Individuals with CADASIL usually notice these symptoms between the ages of 30 and 50, and they tend to develop slowly over many years.^[5]

Common symptoms of CADASIL include:^[1]

• Migraine headaches with aura (migraine accompanied by sensory disturbances, such as visual or speech disturbances, fatigue, or tingling)
• Multiple strokes progressing to dementia
• Confusion or coma (caused by acute encephalopathy, which is a temporary disruption of normal brain function that can accompany CADASIL)
• Progressive decline in memory and thinking skills
• Mental health issues, including apathy, depression, and bipolar disorder

Less common symptoms of CADASIL include:^[1]

• Seizures
• Vision problems
• Slow movements and tremors (parkinsonism)
• Numbness or weakness
• Rapid onset of vertigo, nausea/vomiting, and abnormal gait

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.^[4]

Cognitive decline may eventually progress to dementia, specifically vascular dementia, which is dementia caused by lack of blood to several areas of the brain.^[5] Mood changes may include depression, anxiety, irritability, and apathy.^[5]

How CADASIL is diagnosed

A doctor will diagnose CADASIL based on a person’s symptoms, family history, and characteristic changes in the brain that are found using MRI (magnetic resonance imaging), which is a type of scan that creates detailed pictures of the inside of the body.^[1]

Brain changes that may be seen on MRI include:^[1]

• Subcortical strokes (which happen in the part of the brain below the cortex, the outer layer of the brain)
• Changes in the brain’s white matter
• Small areas of bleeding (cerebral microbleeds)
• Brain atrophy (shrinkage of brain tissue)

MRI scans show multiple white matter lesions of various sizes, concentrated around certain areas of the brain. These white matter lesions are also seen in people who have the mutated gene but do not yet have symptoms. While MRI can show the progression of white matter changes even decades before onset of symptoms, these characteristic brain changes are not unique to CADASIL and can happen with other disorders.^[1][4]

A doctor can confirm a CADASIL diagnosis by:^[1]

• Genetic testing. A blood test of the DNA to look for Notch3 genetic mutations. The definitive test is sequencing the whole Notch3 gene, which can be done from a sample of blood.^[4]
• Skin biopsy. CADASIL creates changes in the blood vessels that can be seen in other parts of the body, such as the skin. As CADASIL is a systemic arterial disease, evidence of the mutation can be found in small and medium-size arteries, so skin biopsies can be used for diagnosis.^[1][4]

Treatment and management

There is no cure or effective treatment for CADASIL right now.^[1] Treatment focuses on management of symptoms and reducing risk factors.^[7]

Stroke prevention is important. Given their higher risk for stroke, people with CADASIL should take steps to prevent stroke. This includes controlling high blood pressure, cholesterol, and glucose levels.^[1] Recent studies have shown that other risk factors for stroke, particularly smoking and high blood pressure, are associated with earlier onset of stroke and increased rate of damage on MRI brain scans in CADASIL sufferers. Therefore it is important to address these common stroke risk factors. An active lifestyle with regular exercise and avoiding being overweight is also recommended.^[14]

Antiplatelet medications such as aspirin are often used in an effort to prevent blood clots in cerebral arteries. Aspirin has been shown to reduce the risk of recurrent stroke by about 20% for common stroke. Therefore, although it has not been tested specifically in CADASIL patients, most doctors would recommend that patients with CADASIL who have had stroke take a small dose of aspirin (75-300mg/day). An alternative to aspirin is clopidogrel (75mg/day).^[14] However, the benefit of antiplatelet agents for CADASIL has not been established, and due to the potential presence of microbleeds, these drugs may increase the risk of bleeding in the brain in CADASIL patients.^[11]

Migraine treatment should address both acute (rescue) and preventive strategies. Standard migraine painkillers can be taken during attacks of migraine. There is no evidence that triptans or ergot derivatives are contraindicated, despite earlier concerns. For preventive treatment, acetazolamide and valproic acid have shown effectiveness.^[11] If migraine attacks are frequent, normal migraine prevention therapies seem effective.^[14]

Mental health support is important. It is important to look for, and treat when necessary, depression in patients with CADASIL. This can be treated with standard anti-depressant drugs and cognitive behavioral therapy.^[14] Standard treatments for psychiatric disturbances should be applied in a symptom-driven manner.^[11]

The use of certain medications requires caution. Oral anticoagulants may increase the risk of bleeding in the brain. However, if there is a clear indication for anticoagulation (such as atrial fibrillation), the benefit of treatment would likely outweigh the potential risk of hemorrhage.^[11] The use of statins (cholesterol-lowering drugs) has not shown any benefit in CADASIL patients.^[11]

What to expect over time

Symptoms usually progress slowly. By age 65, most individuals with CADASIL will have cognitive impairment or dementia.^[1] The majority of persons with CADASIL have cognitive problems and dementia by this age, and some will become dependent due to multiple strokes.^[6]

The severity of CADASIL can vary widely within families. For example, within one family one member may have strokes in their forties or fifties while another may still be well when they are seventy. This variation is not fully understood. Common risk factors such as smoking and high blood pressure make stroke occur earlier in patients with CADASIL, but this does not fully account for the differences within families. Other unknown factors, including genes other than the Notch3 gene, may alter the severity of the disease.^[19]

In the long run, researchers hope that a better understanding of how the underlying genetic abnormality causes CADASIL will allow them to discover how this results in blood vessel damage, and lead to the development of drugs to prevent this damage. However, this is likely to be a number of years away.^[14]