The Cerebral microangiopathy Is an inherited disease that causes multiple cerebral infarctions as it affects blood flow. It is also called CADASIL for its acronyms"Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts,
Specifically, it damages the smaller blood vessels (hence the microvascular disease) of the brain so that the muscle cells surrounding these vessels are altered and die slowly.
This will cause a reduction of the blood flow giving rise to diverse problems as strong Migraines , Epilepsy, paralysis of any part of the body, Mood disorders , memory loss and even dementia .
Definition and other denominations
This disease was first described by Sourander & Wålinder in 1977; Through the follow-up of three generations of a Swedish family, in which several of their members had suffered multiple cerebral infarctions ending in dementia. However, the acronyms CADASIL were not established until 90.
It is currently considered the most common form of hereditary cerebral angiopathy.
It is also denominated with the following terms:
- CADASIL or autosomal dominant Cerebral Arteriopathy with subcortical infarctions.
- Cerebral Arteriopathy with subcortical and Leukoencephalopathy .
- Family vascular leukoencephalopathy.
- Hereditary dementia of the multi-infarct type
Origin
Cerebral microangiopathy appears to arise from mutations in the NOTCH3 gene on chromosome 19q12. This gene is responsible for sending the necessary instructions to produce a protein that is added to the receptor NOTCH3.
This receptor is normally found on the surface of smooth muscle cells of blood vessels and is essential for proper functioning of such cells.
This disease would result from the production of an abnormal protein that binds to NOTCH3 receptors, altering the function and survival of smooth muscle cells. That is, these cells can end up self-destructing through a process called Apoptosis .
In addition, an increase in thickness and fibrosis occurs in the walls of the arteries, facilitating this the occurrence of cerebral infarcts.
This disease is usually hereditary, with an autosomal dominant pattern. This means that a single copy of the mutated gene by either parent can cause the disease.
However, there are some rare cases in which new mutations occur in this gene without a family history of microangiopathy.
symptom
The most typical symptoms of this disease are: migraine, repeated strokes, psychiatric disorders and dementia. However, it is not necessary for all of them to be present to make the diagnosis; It being important to note that the severity and mode of onset of symptoms can vary greatly.
The age at which the first symptoms of this disease appear usually varies, although usually the first signs can appear over 20 years. However, the most notable and serious symptoms are manifested several years later.
Brain microangiopathy usually begins to appear in early adulthood through severe headaches known as migraine.
These migraines are sometimes related to focal neurological problems and are often migraine with aura, which means that before the pain appears certain sensory, visual or linguistic signs.
These pains can cause Cerebrovascular ischemic episodes Recurrent, the most distinctive feature of this disease.
It is likely that those affected throughout their lives will suffer a stroke Or more than one, and can occur at any time from infancy to late adulthood. However, it usually occurs in the middle of adulthood.
According to a study centered on the genus of Gunda et al. (2012), migraine with aura is present mainly in women of about 50 years or less, whereas strokes occur more frequently in men of the same age. In addition, it seems that over that age men suffer from greater cognitive impairment than women.
Because of the damage to which the brain is subjected, there is a Slow cognitive impairment And progressive that is identified with dementia is usually found a profile that is characterized by dysfunction in frontal areas and deficits in retrieving memories stored in memory, while the language remains intact.
If strokes occur in the Subcortical part of the brain (The deepest), can lead to a progressive loss of cognitive functions affecting memory, emotional establishment and regulation, and movement.
Cerebral microangiopathy may also be associated with hypertension and cerebral amyloid angiopathy. It is common to develop, on the other hand, Leukoencephalopathy .
Here are a few related symptoms:
- Transient ischemic attacks (TIA)
- Intracerebral hemorrhage
- Seizures .
- Pseudobulbar palsy.
- Apraxia of gait , Noting that more than half of those over 60 could not walk without assistance.
- Movement disorders or Parkinson's disease .
- Psychomotor retardation.
- Mood disorders Which oscillate between 10 and 20% of those affected: apathy, depression...
- Psychosis .
- Vertigo .
- Urinary incontinence.
- Weakness in varying degrees.
- Sensory deficits (also varies according to the patient).
Prevalence
Cerebral microangiopathy is a very rare condition, however, the exact prevalence is unknown, as are its mortality rates.
In Europe, a prevalence of this disease has been estimated to range from 1 in 50,000 to 1 in 25,000. However, there is a need to know more about prevalence since it has appeared worldwide and in all ethnic groups.
It appears that the age of onset of stroke is 45 or 50 years, while deaths may occur more commonly over 61 years (provided that it takes more than 23 years presenting symptoms).
This disease seems to affect both men and women alike, although gender seems to be important as to the severity of the disease, so that men usually die earlier than women.
Causes
A study by Schmieder (2011) proposes as predisposing factors:
- Heart diseases
- Mellitus diabetes
- Hypercholesterolemia
However, according to Okroglic et al. (2013), the risk factors of this condition are still not clear at the same time as the number of diagnoses is increasing. Therefore, they performed a study that focused on finding the factors that increased brain damage, finding that they influenced:
- An older age.
- Having high blood pressure, which has been shown to modulate both the onset of the disease and its development.
- The presence of obesity .
- To present cerebral macroangiopathy.
However, it is stressed that these factors are not essential for the outbreak of cerebral microangiopathy.
How can it be detected?
According to the Antioquia Neuroscience Group (Colombia), if there is paralysis in any area of the body or dementia or thrombosis, or there are several family history that have or have had any of the symptoms, you should go to the doctor. Specifically, an expert in neurology.
If there is a family history of this disease, but the symptoms do not appear; It may be desirable to carry out a Nuclear magnetic resonance To see if there are affections in the white matter.
However, the definitive diagnosis is genetic. As more than 90% of those affected by this disease have mutations in the NOTCH3 gene, genetic testing may be useful and can be done through a small blood sample. These tests are very reliable, since they have a sensitivity close to 100%.
This type of test is also recommended when some symptoms that raise suspicions of the existence of cerebral microangiopathy have been observed but not absolute certainty.
In addition, a screening tool has been developed by Pescini et al. (2012); The CADASIL scale, which aims to select patients who have a high probability of having the disease that the genetic tests should be done.
As we said, it is also essential to undergo an MRI. In affected individuals over 21 years of age, it is usual to observe hyperintensities in the white matter (which in this case means brain alterations) in temporal areas. This will distinguish the presence of cerebral microangiopathy from chronic microvascular ischemia caused by hypertension.
Obviously, the greater the volume of the lesion observed in the resonance images, the more degree of disability will cause the disease in the person.
On the other hand, skin biopsy can be used for diagnosis. Immunostaining of skin samples taken from these patients may be a reliable test to detect the NOTCH3 protein, which is closely linked to the disease.
This technique can also see ultrastructural alterations in the blood vessels of the skin similar to those found in the cerebral arteries.
Forecast
Brain microangiopathy progresses gradually throughout life and the level of involvement it produces can be very heterogeneous, even within the same family.
The mean age of onset of symptoms is 46 years. However, there are very isolated cases that have come to show symptoms at 8 years.
Generally, the prognosis is bad and most affected develop dementia And end up in bed needing constant care.
In fact, approximately 80% of those affected are in a situation of complete dependency somewhat before death. The life expectancy of these patients is usually not very long, with the average age of death being estimated at 68 years.
Treatments
So far there is no definitive cure for cerebral microangiopathy, but treatments can be used to combat the symptoms and make them change certain habits to improve the quality of life of the person, while preventing the progression of the disease.
As the Antioquia Neuroscience group indicates, it is important that these patients are adequately diagnosed, since there are certain treatments that are not effective, such as: Triptans Or drugs designed to combat migraine, cerebral angiography or anticoagulant treatments.
In short, the use of drugs in this type of patients is not recommended because they may increase the risk of intracerebral hemorrhage or even produce no benefit.
However, there are some documented cases of the benefit of Acetazolamide (ACZ) for the improvement of migraine proper of cerebral microangiopathy, but more research is needed.
The ideal is an interdisciplinary approach, combining:
- Neurological follow-up.
- Physical therapy.
- Occupational therapy.
- Periodic assessment and neuropsychological rehabilitation, with the aim of compensating, recovering or improving the cognitive abilities affected.
- Psychiatric care for patients with this type of disorder.
- Modification of habits and customs such as: give up smoking , lose weight Or eliminate excess harmful fats from the diet.
- As a primary prevention, patients and their families should receive all the necessary information to understand the disease, its causes and the existing probability of transmitting or developing it.
References
- Behrouz, R. (November 25, 2015). CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy).
- CADASIL. (S.f.). Retrieved on June 15, 2016, from Neuroscience Group of Antioquia.
- CADASIL. (June 2013). Obtained from Orphanet.
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. (S.f.). Retrieved on June 15, 2016, from Genetics Home Reference.
- Gunda, B., Hervé, D., Godin, O., Brun, M., Reyes, S., Alili, N., et al. (2012). Effects of Gender on the Phenotype of CADASIL. Stroke, 43 (1): 137-41.
- Pescini, F., Nannucci, S., Bertaccini, B., Salvadori, E., Bianchi, S., Ragno, M., et al. (2012). The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. 43 (11): 2871-6.
- Schmieder, R., Schmidt, B., Raff, U., Bramlage, P., Dörfler, A., Achenbach, S., &... Kolominsky-Rabas, P. (2011). Cerebral microangiopathy in treatment-resistant hypertension. Journal of Clinical Hypertension, 13 (8), 582-587.
- Sourander, P. & Wålinder, J. (1977). Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol., 39 (3): 247-54.
- Okroglic, S., Widmann, C., Urbach, H., Scheltens, P., & Heneka, M. (2013). Clinical Symptoms and Risk Factors in Cerebral Microangiopathy Patients. Plos One, 8 (2).