Cerebral Autosomal Dominant Arteriopathy

What is Cerebral Autosomal Dominant Arteriopathy?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a fairly uncommon genetic disease that mainly affects the nervous system. It’s characterized by the thickening of small to medium-sized blood vessels in the brain. This isn’t caused by common conditions like atherosclerosis or deposits of a protein called amyloid, but it can block blood flow, causing damage to the brain.

The main symptoms of this condition are migraines with a visual disturbance called aura, early onset of recurrent diseases affecting small blood vessels, mood disorders, and progressive thinking and memory problems culminating in early dementia. CADASIL can be identified by a specific pattern on a type of brain scan called a magnetic resonance imaging (MRI) scan, and it can be diagnosed through genetic testing or a skin biopsy.

Unfortunately, as of now, there are no treatments that can reverse or slow down the progression of CADASIL. Treatment mostly consists of efforts to reduce cardiovascular risk, such as managing blood pressure and cholesterol levels.

What Causes Cerebral Autosomal Dominant Arteriopathy?

CADASIL was initially known as a heritable disease that affected very small blood vessels, and the cause wasn’t well-understood. The genetic root of CADASIL was later discovered in 1996 by Joutel and his team. They found multiple mutations in genes making a protein called NOTCH3, found on chromosome 19. Of all the diseases inherited by mutations in one specific gene, CADASIL is the most commonly inherited one affecting miniature blood vessels. The disease is passed down in such a way that if a parent has it, there’s a 50% chance they will pass it to their child. Interestingly, even within the same family, the disease can present differently in different people.

The abnormal NOTCH3 protein, unearthed as the one behind CADASIL, leads to a build-up of part of this protein in the muscular layer of tiny and medium-sized vessels in the brain. This results in the blood vessel walls becoming thicker and harder, a process known scientifically as intimal hyperplasia and hyalinization. A hallmark of CADASIL is the presence of granular osmiophilic material, which just means tiny, stain-attracting granules, located between the muscle cells of the vessels.

Risk Factors and Frequency for Cerebral Autosomal Dominant Arteriopathy

CADASIL, a genetic condition, is estimated to affect at least 5 in every 100,000 people, although some studies suggest this number could be even higher due to underdiagnosis. Interestingly, it doesn’t seem to favor any particular gender, but men might experience more severe symptoms. People of Asian descent are believed to have the highest risk of developing it. Lifestyle habits such as smoking and having high blood pressure can contribute to suffering a stroke at a young age, a common complication associated with this condition.

• CADASIL affects at least 5 in 100,000 people.
• Underdiagnosis could mean that the number is higher.
• Both men and women can have it, but men might have more severe symptoms.
• People of Asian descent have the highest risk.
• Smoking and high blood pressure can lead to early-age strokes in CADASIL patients.

Signs and Symptoms of Cerebral Autosomal Dominant Arteriopathy

CADASIL, a type of disease affecting the brain’s blood vessels, can start showing symptoms at any age between 20 and 70 years. However, it most commonly starts around the age of 30. The symptoms and progression of the disease vary greatly between individuals.

The most common initial symptom, seen in about 55% of people diagnosed with CADASIL, is a type of severe headache known as a migraine with aura. This symptom is slightly more common in women than in men, and less common among people of Asian heritage.

About 60% to 85% of people with CADASIL experience problems related to decreased blood flow to the brain, like mini-strokes or small areas of brain damage. These issues can lead to physical problems like difficulty with movement or sensation. In some cases, CADASIL may cause a sudden severe illness that can sometimes develop from a severe headache.

• Migraine with aura: about 55% of patients
• Mini-strokes or small areas of brain damage: 60% to 85% of patients
• Sudden severe illness: less common

Additionally, about 60% of people with CADASIL experience cognitive impairment, such as difficulty with thinking, memory, and understanding, which can gradually worsen to a condition called vascular dementia. Mental health issues, like depression, panic disorder, bipolar disorder, schizophrenia, and lack of interest or enthusiasm, are also found in about 25% to 30% of patients.

• Cognitive impairment that may progress to vascular dementia: about 60% of patients
• Mental health issues: about 25% to 30% of patients

Testing for Cerebral Autosomal Dominant Arteriopathy

CADASIL is a condition to consider if your patient has a strong family history of strokes and dementia at an early age. It’s worth noting though that this condition is probably underdiagnosed. The most precise way to confirm CADASIL is by using genetic testing or skin biopsy. However, a cheaper initial screening tool has been suggested by Pescini and his team. This tool takes into account common symptoms of the disease like migraines, brief episodes of reduced blood flow to the brain (TIA), typical characteristics of the disease on brain scans, and the family’s history of the disease.

If CADASIL is highly suspected, the first step to confirm it would be genetic testing for a NOTCH3 mutation in the blood. However, keep in mind that about 4% of CADASIL patients will not show this mutation in their genetic test due to unknown genetic alterations. In these cases, skin biopsy with examination for accumulation of a specific substance known as granular osmiophilic material (GOM) can be performed.

Alternatively, CADASIL can be identified by its unique appearance on an MRI scan. The images from the MRI scan reveal abnormal bright spots in certain areas of the brain. It’s crucial to note that these markers are seen in younger patients, typically by the average age of 30, and almost always in patients over 35 years of age. The only glitch is that similar lesions can be seen in older patients with severe microvascular disease due to the widespread nature of their disease. More typically, findings of small brain infarctions and tiny brain bleeds are also seen in CADASIL patients. These are less distinctive indicators but can reinforce the suspicion of CADASIL when found in younger patients.

Treatment Options for Cerebral Autosomal Dominant Arteriopathy

CADASIL is a severe disease that gradually worsens over time and ultimately leads to death. As of now, we don’t have a specific medical treatment that can alter the course of this disease. If patients have migraines, they’re given common pain remedies. However, due to the medicines’ potential to tighten blood vessels, it’s advised to avoid Triptans and ergots.

If patients are suffering from an acute stroke due to a blood clot, they may receive a drug injection that helps dissolve the clot, only if they meet specific criteria. In the long run, patients are mostly treated like those with chronic small-vessel disease, with a focus on reducing heart disease risks. This includes controlling blood pressure, quitting smoking, taking cholesterol-lowering drugs, maintaining a healthy diet, managing weight, and using anti-blood clotting drugs.

Quitting smoking is especially emphasized, but considering that CADASIL isn’t caused by fatty deposits in the arteries, the use of anti-blood clotting drugs can be questionable. And since patients with CADASIL frequently have small bleeds in their brain, any blood thinning therapy must be used carefully.

Meanwhile, the treatment for other symptoms, such as migraines and depression, is just like how anyone else would be treated. Over the years, clinical symptoms can progress from migraines, brain cell damage due to inadequate blood supply, to a condition called vascular dementia which affects memory and thinking skills. CADASIL greatly reduces the lifespan of both men and women. Additionally, patients diagnosed with CADASIL should be offered genetic counseling.

As for the latest research developments, scientists have discovered a mutation in the NOTCH3 gene that causes CADASIL. Experimental treatments being studied based on this discovery include an approach involving molecules called antisense oligonucleotides(ASO), which helps correct genetic mutations, and an immunotherapy approach using a lab-made antibody that targets a part of the NOTCH3 protein.

What else can Cerebral Autosomal Dominant Arteriopathy be?

When doctors are trying to diagnose health problems related to the brain, there are many conditions they keep in mind. Here are some of the conditions they consider:

Older individuals with conditions such as diabetes or high blood pressure should be checked for traditional small blood vessel disease. The pattern of affected areas during an MRI scan can help further identify this problem.

Multiple sclerosis is another possibility. However, an MRI scan will show different signs. Also, it doesn’t usually involve the optic nerves and spinal cord as CADASIL does.

Fabry disease is an inherited condition that can cause small blood vessel disease and strokes from an early age. Genetically passed on as an X-linked inheritance, it can also result in small basal ganglia stones.

CARASIL or Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy is similar to CADASIL. It also presents at an early age and can lead to spinal degenerative disease and hair loss, but migraines are usually not associated with this.

Cerebral Amyloid Angiopathy is another condition similar to CADASIL in that both conditions can lead to an increased risk of dementia, stroke, and internal brain bleeding. Both of these conditions occur because of an over-accumulation of proteins that cause degeneration of the smooth muscle layer in the brain’s blood vessels.

There are also other inherited conditions like leukoencephalopathies and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) to consider.

Lastly, there are other potential causes for strokes and internal bleeding in younger individuals. These include primary CNS vasculitis, reversible cerebral vasoconstriction syndrome (RCVS), inflammatory amyloid angiopathy, venous thrombosis, septic emboli, metastatic disease, and toxic/metabolic exposures.

Furthermore, white matter abnormalities observed on imaging could be due to a range of conditions:

• Acute disseminated encephalomyelitis
• Behçet disease
• HIV encephalopathy and AIDS dementia complex
• Lyme disease
• Neurosarcoidosis
• Neurosyphilis

As you can see, identifying a specific diagnosis can be complex, which is why doctors must consider numerous possibilities based on symptoms, history, and medical tests.

What to expect with Cerebral Autosomal Dominant Arteriopathy

The symptoms of CADASIL can differ greatly from person to person, but sadly, the condition always gets worse over time. Most people with CADASIL who are older than 58 find themselves unable to walk. By the time they reach 65, about 65% of them will need full-time care. On average, CADASIL substantially shortens life expectancy, with men usually passing away at around 64.4 years and women at about 70.7 years.

Possible Complications When Diagnosed with Cerebral Autosomal Dominant Arteriopathy

CADASIL is a disease whereby the deep white matter small arteries enforce non-amyloid intimal and medial growths which results in recurring small vessel deep white matter strokes and reduced blood flow to the brain (global cerebral hypoperfusion). Over time, these conditions can cause the brain to shrink (progressive cortical atrophy), leading to cognitive impairment and eventually dementia. Interestingly, patients with CADASIL also get tiny cerebral bleeds (microhemorrhages), similar to what is observed in other small vessel diseases like persistent high blood pressure (chronic hypertension) or amyloid angiopathy. These microhemorrhages are visible in a specific type of MRI scan called susceptibility sequences.

Preventing Cerebral Autosomal Dominant Arteriopathy

Quitting smoking and keeping high blood pressure under control are two risk factors which can be managed to improve health. These changes can make a big difference because they can be controlled or modified by the individual.

It’s vital to consider genetic counselling, especially because this disease is often inherited from parent to child in a pattern known as ‘autosomal dominant inheritance’. This involves learning about the genetic aspects of the disease, which can impact healthcare decisions and help make the right choices for the family.

Given that this disease tends to worsen over time and can cause significant disability, it’s important to have clear plans in place for end-of-life care and long-term support. By having these discussions early on, individuals can ensure their care is aligned with their preferences and values.