Blood vessels are the structures that blood flows through, allowing oxygen to be carried to every cell around the body. These blood vessels are elastic and are able to expand or contract to make sure that the right pressure within the vessels is maintained to help pump blood around the body.1 The walls of blood vessels are made up of elastic and smooth muscle tissues that allow for their expansion and contraction, but changes to these tissues can negatively affect how they transport blood around the body.1
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a condition that affects the blood vessels of the brain. CADASIL can cause reduced blood flow to the brain, which can lead to migraines, seizures and strokes, amongst other problems.
In this article, we will explore what CADASIL is, what causes it, its diagnosis and treatment, and what to do if you or a family member has CADASIL.
CADASIL can be quite a daunting term to look at, let alone understand. Let's break it down into smaller sections:
- Cerebral - Refers to the brain.
- Autosomal dominant is a type of condition that is inherited from parents.
- Arteriopathy - disease of the arteries (type of blood vessel).
- Subcortical Infarcts - blockage of the small arteries located toward the core of the brain, preventing blood flow to brain tissue.
- Leukoencephalopathy is a disease that changes the white matter areas of the brain with the death of the insulating layer of nerves (myelin).
Together, these terms describe CADASIL, the condition that's inherited from parents and causes problems with the arteries of the brain. The problems with these arteries can then cause blockages, preventing oxygen from reaching parts of the brain and resulting in areas of the brain dying.
CADASIL occurs in roughly two to four people per 100,000 and is caused by inheriting a genetic mutation from parents.2 There are two copies of every gene, one from a person's mother and one from their father. Different genes follow different modes of inheritance, meaning some conditions need one faulty gene to get the condition, while some need both copies of the gene to be faulty. In the case of CADASIL, it follows a mode of inheritance called autosomal dominance. This means that only one of the two genes needs to be faulty for the condition to be present.3
The gene in question in CADASIL patients is the NOTCH3 gene. It codes for a receptor in the smooth muscle of arteries. This receptor is important in how the smooth muscle is controlled and how it functions.4 Mutations in this gene can lead to the receptor produced being faulty. Faulty NOTCH3 receptors produced from these mutations can't control the smooth muscle as well and can lead to the loss of smooth muscle in the artery walls.5
Symptoms and clinical presentation
People with CADASIL may begin to see symptoms between the ages of 20 and 40. However, most symptoms are seen after 50 years old.6
Symptoms of CADASIL include:6
- Cognitive impairment
- Stroke-like episodes
- Mood disorders
- Other neurological symptoms
Migraines: Severe headaches that are usually felt as a throbbing in one side of the head. Migraines caused by CADASIL can also be classed as migraines with aura. These are migraines that come and go and can affect your vision as well as cause a facial tingling sensation.
Cognitive impairment: The deterioration in mental abilities, which can range between mild to severe. Mental abilities affected can include:
- Ability to remember certain things or people
- Ability to learn new things
- Ability to concentrate on a task/conversation
- Difficulty speaking or understanding language.
Stroke-like symptoms: These can include weaknesses in the limbs and face on one side of the body, poor coordination, speech and balance, feelings of numbness in addition to changes in senses such as sight, smell, taste and hearing.
Mood Disorders: People with CADASIL are also affected emotionally. Common ways that they are affected include depression as well as having sudden and uncontrolled mood swings.
Other Neurological Symptoms: People with CADASIL are also more likely to fall into alcohol addiction as well as gain a fear of leaving the house.
Diagnosis of CADASIL
People who have the symptoms above are checked for CADASIL with three different diagnostic stages. These include:
- Brain scans
- Genetic testing
- Skin biopsies
Brain scans: Patients with potential CADASIL are looked at using brain scans such as magnetic resonance imaging (MRI). These scans look for specific abnormalities in the brain, such as areas of damage to the white matter of the brain, small bleeds and signs of inflammation.7
Genetic Testing: Genetic testing includes taking a blood sample. From this, the DNA within can be assessed to see if there are any genetic mutations of the NOTCH3 gene. There are 100s of mutations linked to the NOTCH3 gene. For mutations that are more fully understood, this may be enough to diagnose CADASIL. For mutations that we don’t fully understand, a skin biopsy will be done to confirm CADASIL.8
Skin Biopsy: Skin biopsies may be done to confirm if relatively unknown NOTCH3 mutations are significant enough to cause CADASIL. In patients with CADASIL, the faulty NOTCH3 receptor produced causes a build-up of a substance called granular osmiophilic material (GOM). GOM deposits are a marker of CADASIL and can be used to diagnose the condition when looking at smooth muscle cells from a skin biopsy.9
Treatment and management
Unfortunately, there aren’t any cures for CADASIL, and its treatment focuses instead on treating the symptoms and slowing its progression.
For people with CADASIL who get migraines, medication is used to both help relieve the effects of the migraine as well as prevent them from happening. Painkiller medications such as paracetamol with codeine, aspirin and sumatriptan are commonly used to help ease migraine pain. Medications such as amitriptyline, propranolol and pizotifen are given to prevent migraines from happening.10
In patients with signs of cognitive decline, CRT can help improve cognitive abilities that have been affected. This will include meeting with therapists and working on certain exercises to try and improve specific cognitive abilities such as memory, communication or attention.11
Reducing the effects of CADASIL
Lifestyle changes: As CADASIL can increase the chances of having a stroke, trying to reduce other causes of stroke can be beneficial. In overweight/obese people, as well as those with high blood pressure and CADASIL, doing more exercise and making healthier diet changes can reduce their chances of having a stroke. Additionally, stopping smoking also reduces the chances of having a stroke.8
Medication: CADASIL patients can be given antithrombotic medication such as aspirin and clopidogrel. These help to prevent blood clots from forming in the blood vessels, reducing the chance of a stroke happening.12
Supportive care is available for patients with CADASIL as well as family members. Emotional support can help people with CADASIL who are having difficulties coping with changes as well as those with depression or anxiety. Support is also there for family members so that they can better help their family member with the symptoms of CADASIL as well as gaining a better understanding of the condition. Organisations such as The Brain Charity and CADASIL Support UK are also on hand to help.
Prognosis and life expectancy
CADASIL progression can vary between people. The mutations each person has can influence how quickly the condition progresses, as well as at what age symptoms are first seen.13
Due to the increased risk of stroke in people with CADASIL, the decline in cognitive ability is usually seen after 50 years old. However, this depends on the patient and the mutation, with the cognitive decline seen in some people with CADASIL after 35 years old.6
As cognitive decline is progressive, eventually, the level of cognitive decline will be classed as dementia, which is a major cause of death in people with CADASIL.13 Dementia is usually seen in people with CADASIL after 60 years old. However, they may struggle to walk on their own around the age of 60. On average, people with CADASIL cannot leave their bed by 67 years old.6
As CADASIL commonly leads to dementia, the quality of life deteriorates as time goes on. More and more attention will be required to care for those with the condition. Eventually, constant nursing care will be required to look after them.13
Genetic counselling and family planning
As CADASIL is an inherited condition, anyone with the condition has a 50% chance that they have a family member also affected by the condition. Genetic counselling is available to those family members to see if anyone else also has CADASIL but also to see if they carry the NOTCH3 mutation.14
Genetic counselling is also available to those with a family history of CADASIL and who want to have children. They can find out if they carry a NOTCH3 mutation as well as the risk of their child having CADASIL.14
In summary, CADASIL is a condition inherited from the parents and caused by mutations to the NOTCH3 gene. There are many different mutations to the NOTCH3 gene and the specific mutation can change the severity of symptoms as well as the age that they appear. Common symptoms include migraines, cognitive impairment and stroke-like symptoms. Diagnosis of CADASIL primarily includes brain scans such as MRIs as well as genetic testing to identify specific mutations.
Unfortunately, there are no specific treatments for CADASIL, and current treatments focus on treating and preventing migraines and strokes as well as therapy to help overcome the impact of strokes. These symptoms gradually worsen as time goes on, often leading to dementia. Genetic testing is also available for those with family members of those with CADASIL to see the chances of them carrying the same mutation or the chances of having children with CADASIL.
- Tucker WD, Arora Y, Mahajan K. Anatomy, blood vessels. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 8]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK470401/
- Narayan SK, Gorman G, Kalaria RN, Ford GA, Chinnery PF. The minimum prevalence of CADASIL in northeast England. Neurology [Internet]. 2012 Mar 27 [cited 2023 Sep 8];78(13):1025–7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310314/
- Lewis RG, Simpson B. Genetics, autosomal dominant. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 8]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557512/
- Louvi A, Artavanis-Tsakonas S. Notch and disease: A growing field. Semin Cell Dev Biol [Internet]. 2012 Jun [cited 2023 Sep 8];23(4):473–80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369912/
- Papakonstantinou E, Bacopoulou F, Brouzas D, Megalooikonomou V, D’Elia D, Bongcam-Rudloff E, et al. NOTCH3 and CADASIL syndrome: a genetic and structural overview. EMBnet J [Internet]. 2019 [cited 2023 Sep 8];24:e921. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583802/
- Chabriat H, Bousser MG. Neuropsychiatric manifestations in CADASIL. Dialogues Clin Neurosci [Internet]. 2007 Jun [cited 2023 Sep 8];9(2):199–208. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181851/
- Schoemaker D, Quiroz YT, Torrico-Teave H, Arboleda-Velasquez JF. Clinical and research applications of magnetic resonance imaging in the study of CADASIL. Neurosci Lett [Internet]. 2019 Apr 17 [cited 2023 Sep 8];698:173–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661177/
- Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, et al. Monogenic cerebral small‐vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Euro J of Neurology [Internet]. 2020 Jun [cited 2023 Sep 8];27(6):909–27. Available from: https://onlinelibrary.wiley.com/doi/10.1111/ene.14183
- Lorenzi T, Ragno M, Paolinelli F, Castellucci C, Scarpelli M, Morroni M. CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material. Brain Behav [Internet]. 2017 Mar [cited 2023 Sep 8];7(3):e00624. Available from: https://onlinelibrary.wiley.com/doi/10.1002/brb3.624
- Glover PA, Goldstein ED, Badi MK, Brigham TJ, Lesser ER, Brott TG, et al. Treatment of migraine in patients with CADASIL. Neurol Clin Pract [Internet]. 2020 Dec [cited 2023 Sep 8];10(6):488–96. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837435/
- Lo Coco D, Lopez G, Corrao S. Cognitive impairment and stroke in elderly patients. Vasc Health Risk Manag [Internet]. 2016 Mar 24 [cited 2023 Sep 8];12:105–16. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818041/
- Manini A, Pantoni L. Cadasil from bench to bedside: disease models and novel therapeutic approaches. Mol Neurobiol [Internet]. 2021 [cited 2023 Sep 8];58(6):2558–73. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128844/
- Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533–9.
- Di Donato I, Bianchi S, De Stefano N, Dichgans M, Dotti MT, Duering M, et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (Cadasil) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Medicine [Internet]. 2017 Feb 24 [cited 2023 Sep 8];15(1):41. Available from: https://doi.org/10.1186/s12916-017-0778-8