In the year 1977, a unique condition was reported to be seen in multiple members of a family. This disorder was characterized by multiple strokes and neuropsychiatric symptoms, and was seen in young adults of both sexes. It was a genetic condition that would soon be identified as CADASIL. CADASIL stands for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, and its clinical symptoms include a history of migraine with aura, recurrent stroke in mid-adulthood, mood disturbances, problems with walking, cognitive decline and dementia. Neuroimaging almost always reveals diffuse white matter lesions and subcortical infarcts. Exactly 40 years since its first description, CADASIL is the most frequent, yet under-diagnosed, cause of genetic stroke and vascular dementia.
Generally speaking, when someone has a stroke, they are typically well taken care of with regards to the gold standard of treatment and management for stroke. There is, however, an important bigger picture that’s not taken into consideration, and is the single most reason why such a serious condition as CADASIL is missed- About 1 in 10 patients who get a stroke before they are 50 years old likely have CADASIL. As an important clinical practice, CADASIL must be considered in any patient with:
- Stroke (approximately 75% CADASIL patients have had at least one stroke or Transient Ischemic Attack (TIA) between 40 and 50 years of age)
- Migraine, with or without aura (seen in 30-40% CADASIL patients)
- Multiple abnormalities on neuroimaging (especially if the external capsule and anterior temporal lobe areas are particularly affected)
- Progressive dementia (especially significant in the absence of strokes)
- Mood disturbance is observed in one in five patients
It is essential to ask questions about the clinical histories of other members of the families that may be suggestive of CADASIL. Importantly, a history of multiple sclerosis is also significant as, sometimes, young patients with CADASIL may be misdiagnosed as having multiple sclerosis after a first clinical event. Overall, cerebral vascular events, or gradual onset dementia with motor deficit in relatives are red flags. Having said that, the absence of family history cannot be taken as evidence to rule out CADASIL, as there can be significant clinical variability in symptoms presented by CADASIL carriers in the same family. In addition, there is a possibility of a new mutation in the gene responsible (see below) causing sporadic cases. Family history should be used to raise the index of suspicion, and not to rule out the possibility.
If clinical history +/- family history raises a strong suspicion of CADASIL, it is recommended to avoid conventional angiography on account of the risk of severe neurological symptoms that, in some cases, can be serious. While such angiography may sometimes show narrowing of the small arteries, it is not risk-free for someone who may have CADASIL, and is usually normal. Instead, an MRI is preferred as a safe means for the investigation of medium and large arteries.
To confirm the diagnosis, genetic testing must always be carried out. The only gene known to cause CADASIL is the NOTCH3 gene. A NOTCH3 mutation is required for diagnosis. In fact, NOTCH3 mutations are very common in populations of South Asia with an incidence of 1.17%. This means that at least 1 in every 100 South Asian has a NOTCH3 mutation that is known to cause this serious, yet often missed, genetic condition.
Genetic testing for CADASIL is key in the accurate diagnosis and effective management of patients. Furthermore, genetics can help identify at-risk, asymptomatic family members BEFORE they have strokes. With limited interventions for controlling the natural progression of CADASIL, patients can use their genetic diagnosis to make healthy lifestyle choices aimed at minimizing risk of additional injury to the blood vessels. Examples of such risk factors include:
- Hypertension
- Diabetes
- Hypercholesterolemia
- Obesity
- Smoking
- Lack of exercise
- Insufficient fluid intake
- Unhealthy dietary choices
These risk factors are controllable and can contribute significantly to prevention of avoidable insults to health and well being.
In addition to risk reduction, genetic testing can inform important medical decisions with regards to treatment such as:
- Anticoagulant therapy is considered risky because of the possibility of intracranial hemorrhages.
- Aspirin is a good choice for primary prevention. The benefit of aspirin therapy has not yet been established in those who have had symptoms.
- Vasoconstrictors typically used in cases of migraine with aura are not recommended in patients with CADASIL because of the risk of a reduction in cerebral blood flow. Instead, NSAIDs and analgesics are recommended as first-line treatment of migraine.
- Hypotensive drugs also come with a risk of decreasing cerebral blood and should, therefore, be used with caution in CADASIL patients
- Finally, contraceptive pills are also a risk factor. Therefore, women may be advised to stop using the pill or, if necessary, switch to a preparation having lower estrogen content (less than 50 µg estrogen).
In conclusion, genetic testing for those patients (and at-risk relatives) suspected with CADASIL can provide an accurate diagnosis that can facilitate appropriate clinical decisions for treatment and management. Speak to a genetic counselor and find out if you and your family may benefit from genetic testing for CADASIL.
