What is CADASIL?

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary autosomal dominant disease affecting all the small cerebral arteries. It causes subcortical infarcts and damages the white matter (leukoencephalopathy) and it is due to various mutations of the Notch3 gene situated on chromosome 19.

Epidemiology
Initially described in Europe, the disease has now been observed in families with very different ethnic backgrounds, on all continents. At present, there are more than four hundred families in Europe. There has not yet been any real epidemiological study of CADASIL in France. The authors of a study carried out in the West of Scotland in 2002 listed 22 patients with CADASIL from seven families out of a population of 1,418,990. Considering the relatives of these patients, who risk being carriers of the mutated gene, the researchers estimated the prevalence to be 4.15/100,000 inhabitants. It is, though, likely that the frequency of the disease is as yet underestimated.

Clinical description
The initial clinical signs, which are observed in 20% to 30% of patients, are the onset of migraine with aura starting between the ages of 20 and 40. Cerebral infarcts (ischemic strokes) are observed in 70% to 80% of patients with onset usually around the age of 50. There are also cognitive disorders (difficulties with concentration and attention, memory loss), to a greater or lesser extent. These difficulties occur very early in the development of the disease but do not become significant until the 50 to 60 years age span. These cognitive difficulties may lead to a change in social life and, eventually, to almost constant dementia in the terminal phase of the illness, combined with difficulties in walking and balance. In 10% to 20% of cases, there are also psychiatric disorders and, in 5% to 10% of patients, there are epileptic seizures.

Migraines with aura (i.e. migraines accompanied by neurological signs) are reported by one in four patients The frequency of the migraines is extremely variable, ranging from twice a week to one every 3 or 4 years. Symptoms of the aura are, in order of frequency, visual, sensory, aphasic or motor. A visual aura manifests itself in various forms, most frequently as a scintillating scotoma and less often as blurring of vision or as a homonymous lateral hemianopsia. Speech disorders during attacks of migraine with aura can often be summarised as difficulties in expressing oneself, with reduced verbal fluency.

More than one-half of patients suffer migraine with atypical aura i.e. sudden-onset migraines with aura, « basilary » migraine or « hemiplegic » migraine. In a few cases, the migraines may be extremely severe such as those seen with familial hemiplegic migraine. They produce episodes of confusion, lack of vigilance, coma and hyperthermia (possibly lasting for several hours or several days).

Some 70% to 85% of patients report the occurrence of an ischemic event which can be a neurological deficiency of sudden onset resolving in less than 24 hours (TLA transient ischaemic attack) or a permanent neurological deficiency. In most cases these signs indicate a minor stroke resulting in traditional signs (lacunar syndrome caused by the occlusion of a small artery: pure sensory deficit, pure motor deficit, or sensorimotor deficit of one side of the body or ataxic hermiparesis). These cerebral infarcts can occur in the absence of any of the usual vascular risk factors (arterial hypertension, diabetes, or hypercholesterolemia).

Mood disturbance are observed in one in five patients. They may be early (up to 10% of patients), sometimes inuagural and lead to an error or delay in diagnosis. Some patients describe symptoms of severe depression suggesting melancholia, alternating, in a few cases, with episodes of mania (this can lead to the presumptive diagnosis of bipolar disorder). Apathy (loss of motivation) is a frequent sign of the disease, depending on the location of the brain lesions. It is not always secondary to depression.

Cognitive disorders (difficulties with executive functions, attention and memory) are extremely frequent but of variable severity during the course of the illness. Alteration of the executive functions (planning, anticipation, adjustment, self-correction and mental flexibility) is the earliest symptom most frequently observed and it can be almost imperceptible for many years. Damage to the executive functions is frequently associated with attention and concentration disorders. Gradually, with age, the decline becomes more acute with the onset of apathy, often the most observable feature, and deficiencies in motor functions (tasks such as drawing or writing done using external resources), suggestive of diffuse cerebral damage. However, there is very rarely any severe aphasia (language difficulties), apraxia (difficulties with voluntary behaviors) or agnosia (difficulty with the recognition of objects, people or places with visual difficulties), all features frequently observed in Alzheimer's disease. Semantic memory (linked to knowledge) and recognition are often maintained. Cognitive decline commonly appears gradually, often in the absence of any ischaemic events. This development may therefore suggest a degenerative disease. Sometimes, the patient suddenly worsens, in stages.

Dementia (cognitive difficulties that affect the patient's everyday life and lead to a loss of independence) is observed in one-third of patients, especially after the age of 60. Its frequency increases with age and approximately 60% of patients over the age of 60 have dementia. It is often associated with other signs of the gravity of the disease e.g. difficulty with walking, urinary incontinence and, sometimes, a pseudo-bulbar palsy (difficult swallowing, spasmodic laughter or crying).

Despite the diffuse damage to small arteries in all organs, the clinical manifestations of the disease are only neurological and restricted to the brain.

Clinical course and prognosis
The typical progression of the disease begins with the onset of migraine with aura when the patient is in his 30's followed by transient or constituted ischaemic cerebral events a decade later and the gradual onset of cognitive difficulty, problems with balance and walking as the patient approaches the age of sixty. Loss of independence with motor and cognitive handicaps is frequent after the age of 60 (Figure 1)

This profile is not constant because of significant variability in the course of the disease, sometime between several members of the same family (i.e. having the same genetic abnormality). In some cases, the disease can produce an early handicap at age of 40.Conversely, in other cases, the first signs of the disease may not appear until age of 70.
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Figure1: A summary of the natural history of the disease

Diagnosis
Magnetic resonance imaging (MRI) is essential for the diagnosis of this disease. Abnormal MRI signals (abnormalities in the white matter of the brain) are sometimes detected before the onset of the first symptoms of disease. These abnormalities appear between the ages of 20 and 35 and can therefore remain inconsistent in this age group. On the other hand, after the age of 35, all the carriers of the mutated gene have MRI abnormalities suggestive of the disease, whether or not they have any symptoms. The total absence of MRI abnormalities after the age of 35 should cast doubt on the diagnosis.



Several types of abnormality may be observed (Figure 2).
Figure 2: Illustration of the MRI abnormalities detected on the following sequences: FLAIR (A), T1 (B) and gradient echo (C)

White-matter hypersignals (A)is constant when major symptoms of the disease are present. They are observed on T2 weighted sequences which show extensive hyperintense areas within the white matter of the brain associated with more focal abnormalities within the deep gray nuclei, thalamus and brain stem. The extent of white matter hypersignals is variable and increases with age. In patients under the age of 40, signal anomalies are usually punctiforms or nodular and are symmetrically distributed. Gradually, as the disease develops, hypersignals become confluent and extend to the entire white matter. The presence of these signal anomalies in the anterior temporal lobes (more than 2 out of 3 patients) is very important from the diagnostic point of view because of their great specificity. They are usually not seen in cerebral arterial diseases caused by hypertension
or diabetes.

Lacunar infarcts (B) are detected on T1 weighted images in the form of limited zones with hypointense signal. They are punctiform or wider depending on the cavity forming as a secondary feature after a minor infarct. These lesions are observed in approximately two out of every three patients with abnormalities in the white matter of the brain. They are present within the white matter, deep gray nuclei and brain stem. The total volume of these lesions correlates strongly with the clinical severity of the disease.

Microbleeds (C) are seen in one out of three patients, on average, using gradient echo sequences or (T2* sequences) since they are very sensitive to the accumulation of haemoglobin by-products in cerebral tissue. The bleeds do not usually produce any specific signs but their presence seems, in most cases, to be associated with greater damage to the vascular wall and greater severity of the disease.                                                                                        

Diagnosis
CADASIL is a hereditary familial disease. The mode of transmission is autosomal dominant(found with the same frequency in both male and female patients, 50% of children born to a person with the disease have the genetic abnormality) (Figure 3).

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Family tree showing the autosomal dominant transmission and the results of the MRI scan. The diagnosis should be discussed with patients who have symmetrical lesions in the white matter of the brain and a clinical history of migraine with aura, TIA or brain infarction, mood alternations or cognitive difficulties of unexplained origin.

It is essential to question patients and seek clinical histories in other members of the family suggestive of the disease. A history of multiple sclerosis (an incorrect diagnosis of multiple sclerosis is sometimes made for young patients after a first clinical event), cerebral vascular events or gradualonset dementia with motor deficit in relatives should point to a family history of cerebral small vessels disease. However, the total absence of any family history should not lead to the diagnosis being discarded because of the possibility of a new mutation in the gene responsible, causing new, sporadic cases.

The presence on an MRI showing T2 or FLAIR hypersignal, with symmetrical distribution in the cerebral white matter, especially in the anterior temporal lobes increases the likelihood of diagnosis (CADASIL) because of the specific nature of these signs.

Testing for other causes of damage to the small cerebral arteries (standard blood test, search for an inflammatory syndrome, search for vascular risk factors with tests for hypercholesterolaemia, homocysteinaemia or fasting glucose, or ultrasound investigations of cervical and intracranial arteries) is usually negative.

If there is a strong suspicion of the diagnosis, a conventional angiography should be avoided because of the risk of severe neurological symptoms (severe headache, migraine with marked aura) which can, in some cases, be serious. This examination is usually normal, although it may sometimes show narrowing of the small arteries. An MRI scan is preferable if seeking to investigate the state of the medium and large arteries.

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To confirm the diagnosis, genetic testing must always be carried out. The gene involved is the Notch3 gene, situated on the short arm of chromosome 19. It consists of 33 exons including 23 exons (2 to 24) which encode for EFG-like motifs with six cysteine residues. To date, all the mutations responsible for the disease have been located within these exons (exons 2 to 24). The mutations are highly stereotypical and all of them lead to the addition or loss of one cysteine in one of the EGF-like motifs. The presence of a mutation of this type confirms diagnosis of the disease beyond all doubt. Within the French population, the mutation lies within exons 3 or 4 of the Notch3 gene in 70% of cases while in 90% to 95% of cases, the mutation is located in one of the following 12 exons: 2, 3, 4, 5, 6, 7, 8, 11, 12, 18, 19 or 20. In the absence of any known mutation in the patient's family, exons 3 and 4 (70% sensitivity) are tested first, followed by exons 2, 5, 6, 7, 8, 11, 12, 18, 19 or 20 (95% sensitivity). If there are very strong pointers to the diagnosis (hence the importance of sending the clinical data and MRI scan) and if the previous analysis has been negative, screening can be extended to the last mutated exons in the gene in a very small number of CADASIL patients. The sensitivity of the screening of 23 exons encoding for the EGF areas in the Notch3 gene is estimated to be close to 100 %.

The diagnosis can rarely be made by a skin biopsy (punch biopsy) which shows the status of small vessels. There are two possible approaches - a study of the vessels under an electron microscope showing the accumulation that is characteristic of the disease within the wall of small vessels, known as GOM (granula osmiophilic material), or a study using an anti-Notch3 antibody which, under the microscope, highlights the accumulation of Notch3 protein within the vascular wall. Both of these methods are highly sensitive but technically fairly difficult to use. At present, these tests are carried out less and less frequently because molecular testing has become easier. Genetic diagnosis is possible before symptoms of the disease appear, in the other members of an affected family. However, genetic testing is only carried out on healthy subjects with no clinical signs of the disease who have not had any previous test within the setting of a specialist multidisciplinary consultation. After a neurological assessment (neurologist), a psychological evaluation (interview with a psychologist) and a genetic consultation (geneticist), the patient's request is assessed jointly by all the practitioners and a cooling-off period of several weeks is suggested before any blood test. The patient may request not to be informed of the results of the test throughout the procedure, until the final results are ready. Clinical and psychological follow-up are always proposed once the results have been given.

No genetic testing is currently carried out on minors who are symptom-free.

Etiology/pathophysiology
The symptoms of the disease are mainly produced by the lesions occurring within the brain as the disease progresses. The lesions observed in the white matter correspond to demyelination (loss of myeline sheaths which are manufactured by the oligodendrocytes in the white matter) and to a loss of axons in the brain's neurons. These lesions are associated with minor infarcts occurring mainly deep inside the brain as a result of an interruption in the blood flow to an area supplied by a small artery. The infarcts can leave a small cavity or hole known as a « lacune ». Traces of tiny hemorrhages may also be visible in one-third of patients. The latest cerebral imaging studies show that it is mainly the accumulation of minor infarcts in the brain that explains the severity of the disease during CADASIL.

The lesions in the white matter and the deep infarcts are due to a reduction in cerebral perfusion. A decrease in blood flow in the brain was observed within the white matter and sometimes, in a more diffuse manner, within patients' brains. Permanent reduction in blood supply (and, therefore, in oxygen provided by the red blood cells) would appear to become more severe as the disease progresses and this explains the gradual accumulation of cerebral lesions and the increasing acuteness of symptoms.

CADASIL is a disease affecting mainly the walls of the small arteries (arterioles) in the brain and other organs. In many cases, the artery walls thicken; in some, they become fibrous. The smooth muscle cells in the central layer of the vessel wall (media) are abnormal or are gradually disappearing. Around them, there is a granular substance called GOM (granular osmiophilic material) which is typical of the disease and visible under an electron microscope. The exact origin of the GOM deposits is currently unknown. Recent work has shown that part of the Notch3 gene, which is a receptor on the surface of the membranes of smooth muscle cells, builds up near the GOM in the vessel walls. Recent research in human subjects and mice with the genetic abnormality showed that the wall of the small arteries did not contract or dilate normally. It may be that the narrowing of certain vessels, in addition to this abnormal reaction, produces the loss of perfusion observed in CADASIL patients.

We do not yet know why mutations in the Notch3 gene, which lead to an abnormality in the Notch3 receptor of the smooth muscle cell in the blood vessel, also lead to a build-up of protein, the appearance of GOM and the degeneration of smooth muscle cells in the vessel wall. The important part played by the Notch3 gene in the development of small arteries has, however, been clearly demonstrated.

Treatment
No specific preventive treatment for this disease is known to date in CADASIL patients. Because of the occurrence of cerebral infarcts, aspirin is traditionally used as secondary prevention but the benefit of this treatment when the disease is already present has not been demonstrated. The possible occurrence of intracranial hemorrhages, although rare, suggests that the use of anticoagulants would, on the other hand, be risky.

For migraine with aura, vasoconstrictors are not recommended because of the theoretical risk of a reduction in cerebral blood flow in patients in a precarious haemodynamic condition with decreased cerebral blood flow. NSAIDs and analgesics are therefore recommended as first-line treatment of migraine.

The usefulness of acetylcholinesterase inhibitors was recently assessed as a means of helping patients with cognitive difficulties. This study found no significant treatment effect of Donepezil on cognition as assessed by the primary efficacy measure but improvements were noted on several measures of executive function.

All the hypotensive treatments (neuroleptics, anti-hypertensives) must be used with care because of the possible risk of a decrease in cerebral blood flow in patients with reduced cerebral perfusion. On the other hand, physiotherapy is essential and must be widely prescribed when motor signs and difficulties with walking and balance are present, especially after a stroke. Speech therapy is prescribed to improve communication and language abilities when necessary. Psychological support is crucial at every stage of the disease, both for the patient and for the family and carers. It should include ways of dealing with the psychological consequences resulting from neurological deficiency, an assessment of psychological disorders directly linked to the disease,
ways of dealing with the consequences of the handicap within the family unit and psychological counseling because of the familial and hereditary nature of the disease.

Research
Current research work covers two areas:
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1) clinically, there is a need to define all the clinical and MRI parameters required to set up therapeutic testing in the future for a rare disease that develops slowly, over several decades, and to gain greater insight into prognostic factors and factors that might explain the variable degrees of severity of this disease,

2) there is a need for research into the molecular mechanisms that lead from the genetic abnormality in the Notch3 gene to the lesions observed in the walls of the blood vessels. This is being done using animal models of the disease.

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Frequently asked questions about CADASIL - This document has been produced by ORPHANET in collaboration with CERVCO (D. Hervé, H. Chabriat) and CADASIL France Association.  Source: CADASIL, Encyclopédie Orphanet Grand Public, avril 2008

http://www.orpha.net/data/patho/Pub/fr/CADASIL-FRfrPub1001v01.pdfhttp://www.cervco.fr/pathologies/CADASIL.1.All.maladies.en.htm

What is CADASIL ?
CADASIL is a genetic disease affecting small arteries in the brain. It results in a reduction of blood flow to certain areas of the brain, causing symptoms widely variable from one patient to another. The most common clinical manifestations of this disease, which appear in adulthood, include migraine attacks, psychiatric disorders and cerebrovascular accidents (CVA or strokes- see later in this article), the latter responsible for troubles with speech, memory, vision etc.
The term CADASIL was proposed in 1993 by French researchers while in search of a name for this disease. It is an abbreviation in English which stands for “Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencelopathy”.  

The term “cerebral arteriopathy” means an illness of the arteries (blood vessels transporting blood flow from the heart to all organs) in the brain area.

The term “autosomal dominant” specifies how the disease transmits from one generation to another since it is a hereditary disease.

The term “Infarcts” corresponds to a sudden stop of blood flow to an area of the body which is, in case of CADASIL, the “subcortical” zone, a particular area of the brain.

Finally, the word 'Leukoencelopathy” refers to brain lesions resulting from this disease (see later in this article).
How many people are affected by this disease ?

The prevalence of CADASIL (i.e. number of affected persons in a population at a given time) is not known precisely, but it is estimated at 1 out of 24,000 persons. This prevalence measure is probably underestimated.
Who may contract this disease? Is it spread all over France and around the world ?

This disease affects men as much as women. Symptoms appear in adulthood, generally between the age of 30 and 40 years.

Initially detected in Europe, CADASIL has since then been observed among populations of very different origins around the world.

What causes this disease ?
This disease is caused by an anomaly (mutation) of a gene named NOTCH3.

An artery is a kind of flexible tube made up of many concentric layers (or “tunica”). One of these is a solid elastic muscle layer which helps maintain the artery diameter and facilitate blood circulation. The NOTCH3 gene plays a role in the formation of this muscular layer.
(http://www.ulb.ac.be/erasme/edu/fcc/hypertension/images/sch_artere_400.gif)

As a result of the anomaly of NOTCH3 gene, the arteries muscular layer becomes damaged and it degenerates progressively. The arteries walls become less elastic and the blood flow becomes more difficult.
Although this condition affects small arteries for all organs, its effects manifest only in the brain area, causing neurological disorders which are described in the following section.

Certain areas of the brain which are supplied by these small arteries, are deprived of blood flow and hence oxygen (infarctions or strokes) due to this anomaly condition. In another way, oxygen is necessary for cells to function and grow. As these small infarctions keep recurring in a certain area of the brain, symptoms will start appearing and become worse gradually.

Is it contagious ?
No, CADASIL is not contagious; it is rather a genetic hereditary disease.

What are the symptoms of this disease ?
The disease is caused by an anomaly of arteries since birth, but the first symptoms do not generally appear until adulthood (between 30 and 40 years of age). Symptoms vary widely from one person to another, even including within the same family (although these people share the same genetic anomaly). In effect, all patients do not exhibit the full range of manifestations described below. Likewise, the intensity levels of these symptoms as well as the related handicap conditions are unpredictable and very variable.

Migraine Attacks
Migraine attacks are common throughout the course of the disease and often represent the first symptom. These migraines tend to be very intense (often on one side of the head), sometimes accompanied with nausea, vomiting and an intolerance against sounds and lights (need to be in quiet place and dark room). Migraine headaches may appear by themselves, but often they are preceded by abnormal sensations called “aura”. Migraines attacks with aura affect one out of four patients. The frequency of these attacks varies, from two per week to one occurrence every three or four years.

The forewarning signs or auras vary based on each patient. They last on average 20 to 30 minutes, followed by onset of migraine headache. Often, signs include vision problems: bright forms passing before eyes, colored spots, sudden appearance of a bright and flickering point in the center of field of vision (scintillating scotoma) and, more rarely, blurred vision or loss of half field of vision (hemianopsia).

Other signs may also occur like sensory disturbances such as: numbness, tingling sensations, feelings of pins and needles, muscle weakness, even paralysis on one side of body. Sometimes, these problems may spread to the entire body.

Speech disorders may also appear, often manifesting as difficulties in finding the right word (aphasia) or ability to articulate. Aura may also manifest as feeling of depression, anxiety and restlessness. Patient may also suffer from a “simple” migraine i.e. without aura. However, migraines without aura are neither more common among CADASIL patients nor than in the general population. Migraine attacks may be excruciatingly painful, even unbearable and may last several hours, sometimes even several days. Sometimes, migraine headaches are severe enough to require hospitalization.

Cerebrovascular Accidents (CVA or strokes)
Cerebrovascular accidents, or commonly called “strokes”, appear along the course of the disease when an area of the brain is suddenly deprived of blood flow (infarction or ischemia). Recurrent CVAs are the most common signs of this disease, affecting more than 3 out of 4 patients. They occur often between the age of 40 and 50.
They may also lead to other sudden symptoms of impairment such as: paralysis of a half of body (hemiplegia) or loss of sensitivity of a part of the body, speech troubles, balance or motion coordination.
These disturbances may disappear within 24 hours, but they may become constant as the disease is progressing. When they are temporary, they are referred as “transient” CVAs whereas they are considered “permanent’’ CVAs if the disorders are irreversible.

Psychiatric and cognitive disorders
Mood disturbances occur in about 20% of all cases, either after a stroke or at any point of time along the course of the disease. Some patients may present signs of deep depression, loss of motivation or loss of interest in job, activities, projects (apathy) etc. In some rare instances, stages of depression alternate with stages of hyperactivity (e.g. wild spending sprees, odd behavior, various excessive tendencies etc.) likewise to manic-depressive behaviors. These psychiatric disorders may be the root cause of mistaken diagnosis, especially if they are the first signs of the disease.
So called “cognitive” disorders may appear as well, even at the early stages of the illness. However, they become more notable between the age of 50 and 60 years. These disorders manifest as problems with concentration, attention or memory loss troubles of variable degree. The affected people have difficulty organizing an activity, planning or taking initiative. They also struggle to adapt to new situations or handle changes in their daily lives. As such, these disorders impair the patient’s executive functions (organizational, planning), intellectual flexibility or mental agility.

Progression towards dementia
With age, the intellectual decline may accentuate, either progressively or gradually by stages (sudden and important impairments). Troubles with attention and memory become more discernible, as does the loss of initiative. The worsening of these disorders may lead to an unavoidable loss of independence: this is referred to as stage of dementia or dementia syndrome.
Dementia is observed in one third of patients, but its frequency increases with age. After the age of 60, about 60% of patients suffer some symptoms of dementia.
Dementia may be associated with other signs such as troubles with walking, inability to hold bladder pressure (urinary incontinence), and in some cases, difficulties to swallow (dysphagia).

Epilepsy
In less than 10% of cases, patients suffer also epileptic seizures. These seizures present a wide range of manifestations: spasms or convulsions (muscular jerking, shaking, stiffening), sensory disturbances (tingling sensations, numbness, auditory or visual hallucinations such as hearing sounds or seeing things which are not present etc.), psychological disturbances (panic attacks, memory troubles, confusion, loss of awareness, blackouts (i.e. sudden loss of touch with surrounding environment and the person does not remember afterwards) or even excessive salivation, urinary leakages etc The crisis may affect the entire body (generalized crisis) or most often a part or half a body (partial crisis).

How can these symptoms be explained ?
The periods of oxygen deprivation, due to inadequate blood flow, damage certain areas of the brain causing brain lesions. In effect, after a few minutes, without blood supply, some cells are damaged permanently. More precisely, it is the “white” matter of the brain which is the most damaged as a result of this disease. That is why it is called “leukoencephalopathy” (“leuko” means “white” in Greek). The white matter is composed of bundles of “cables”, called axons which are extensions of nervous cells or neurons. These cables are wrapped by a protector coat called myelin, similar to the insulator coat of electric wires.

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Figure 2
Nervous cells are connected by “axons” which are wrapped by a white coat of myelin.
These axons together constitute an entire network cable in the brain, all of this making up the white matter.
Lesions are formed amidst this white matter area during the course of CADASIL.
Courtesy http://www.handicapinfos.com

Myelin facilitates transmission of nervous message which controls the functioning of the brain. Among CADASIL patients, because of recurrent small infarctions and micro-hemorrhages, the myelin is damaged, even destroyed (this is known as “demyelination”) in some areas of the brain. This degenerative process hampers or prevents the transmission of nervous messages in the brain. It is responsible for the gradual loss of independence.

Periods of interrupted blood flow seem to be more and more frequent and severe as the disease is evolving, which explains the progressive accumulation of cerebral lesions and the worsening of symptoms. When a lesion appears in the brain, it is permanent but other circuits provide a recovery capacity to compensate for this deficit. However, as this capacity declines gradually, the disorders become more and more obvious.
It is still not known why some people develop a more serious form of this disease than others.

How does the disease evolve ?

Most often, the disease is characterized by the onset of migraine attacks with or without areas after the age of 30, followed by occurrences of vascular accidents about 10 years later, and by progressive appearance of cognitive disorders (concentration problem, memory trouble etc.), balance and walking troubles around the age of 60. After the age of 60, loss of independence and intellectual decline may be more pronounced.
However, the disease severity level varies from one patient to another, including within the same family. The clinical evolution course is more or less quick, with some patients exhibiting a serious handicap very early, around the age of 40 while others, for example, do not show the first symptoms until after 60 years.

DIAGNOSIS

How can CADASIL be detected? What are complementary tests and what are they for ?
Initial disease diagnosis is based on MRI scans (Magnetic Resonance Imaging). This painless exam is conducted to gather precise brain images by placing the patient inside a device which produces a magnetic field. MRI diagnosis is complemented with genetic testing.

In case of CADASIL, MRI scans detect lesions characteristic of the disease inside the white cerebral matter (Figure 3). These lesions generally appear between the age of 20 and 35, but they may remain present for many years without causing any symptoms. After the age of 35, all individuals who are carriers of the abnormal NOTCH3, with or without symptoms, will show under MRI anomalies indicative of CADASIL. The count and seriousness of these anomalies will increase with age.
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Figure 3
Illustration of anomalies observed via MRI in the white matter area of a CADASIL patient. The affected areas, shown as light spots, return an abnormal signal.
http://cervco.aphp.fr/pathologies.xml


CADASIL diagnosis can be confirmed through detection of NOTCH3 gene anomalies in blood samples. This procedure requires strict oversight and follow-ups.

Is it possible that CADASIL can be misdiagnosed with other diseases? Which ones? How can one tell the differences between these diseases ?
CVAs or strokes are relatively common among the general population, especially with older people with diabetes, hypertension, smokers or high cholesterol level. For this reason, CADASIL is not being strongly associated with first symptoms of strokes. However, characteristic brain lesions shown on visual MRI scans may alert the physician towards a very distinctive disease. Diagnosis of CADASIL is more straightforward when there are already confirmed cases in the family. However, MRI scan and genetic testing remain necessary to confirm the diagnosis since neurological symptoms may be caused by other illnesses. Among “similar” diseases, the list includes notably those such as progressive multifocal leukoencelopathy (PML), multiple sclerosis (MS), cerebral amyloid angiopathy (CAA) or even Alzheimer.


GENETIC ASPECTS OF THE DISEASE

What are the risks of transmission to children? What are the risks to other family members ?
CADASIL is a hereditary genetic disease. Its transmission mode is autosomal dominant, which means that an affected person has a probability of 1 out of 2 to transmit the abnormal gene to his/her children (Figure 4). All individuals who inherit this abnormal gene will sooner or later develop symptoms of this disease. However, its severity may vary considerably from one patient to another, included even within the same family.

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Figure 4
In this schema, the father has the mutated NOTCH3 gene (A) which is responsible for CADASIL disease. He has a risk of 1 out of 2 to transmit this gene to his children who in turn will also develop this disease. The transmission is in similar fashion if the mother is affected.

In certain exceptional cases being identified, the mutation of NOTCH3 gene occurs “by accident” (de novo mutation) without being inherited from either parent.

Can one detect this disease among people at risk before it manifests itself ?
Before symptoms start to appear, screening test may be prescribed to family members of an affected person (pre-symptomatic test). It is used to determine if the person carries the genetic anomaly and thus, if he/she will one day develop the disease.

However, genetic testing of a person who does not manifest any symptoms of the disease is only undertaken within the confine of a specialized consultation and thorough medical as well as psychological oversight. No testing can be done to any minor person who does not have any symptom.

After an assessment with a neurologist to allow the concerned individual in obtaining information about CADASIL, it must be followed by a meeting with a psychologist and a geneticist. Since the decision to undergo or not this pre-symptomatic test may be complex and hard to handle, hence, the concerned person must be informed and advised to the most extent possible. The psychologist may be in a position to evaluate the psychological state of the subject, state of his/her thoughts, and questions about the disease, as well as his/her capacity to handle a difficult diagnosis. The geneticist’s role is to explain the test in question and how to interpret its results.

When the person decides to take the test, a reflection waiting period of one to two months is required before taking blood samples. At any time, it is possible that the individual may change mind or choose not to learn about the results. It is always recommended that a medical and psychological follow-up be accompanied after the results are announced (usually about 3 months after blood sample is taken), regardless whether they are positive or negative.

Can this disease be detected via prenatal or pre-implantation diagnosis ?

In the case of families where the disease is particularly severe, a request for prenatal diagnosis may be considered.
The purpose of prenatal diagnosis is to determine during pregnancy period, if the future child is a carrier of the mutation and thus, will develop the disease in adulthood (in this case, parents may request a medical abortion). The prenatal diagnosis is done by taking samples of liquid which the embryo is bathed in (amniocentesis) or a placenta biopsy (chorionic villus sampling).

It is also possible to prescribe a pre-implantation genetic diagnosis (PGD). The test is carried out to detect the genetic anomaly responsible for the disease in embryos obtained through in vitro fertilization. This procedure may be used to select embryos which do not carry the genetic anomaly in order to implant them in the uterus and thus, sparing parents later hardship of late-term abortions.

While prenatal diagnosis and PGD are technically feasible, recourse to these procedures however is only undertaken in exceptional cases. In effect, CADASIL is a disease which does not manifest until adulthood and its severity varies from one patient to another, even within the same family. Hence, even though certain family members are being or have been affected severely by this disease when they were relatively young, nothing implies that their future children will also present such severe symptoms at early age even if they are carriers of the mutated gene.
These developments represent a lengthy journey which requires a close monitor by the medical team in charge.
Treatment, Care Program, Prevention

Is there a treatment for this pathology? What are its benefits ?
Actually, there is no treatment either to cure the disease or to prevent it. It is nonetheless possible to treat symptoms along as they appear with the goal of improving quality of life for patients. Research studies are underway in order to identify new avenues of treatment to delay its occurrence
.
Treatment for Migraines
Traditional analgesics (pain killers) such as paracetamol, ibuprofen and aspirin (non-steroidal anti-inflammatory drugs- NSAID) are used for treatment of migraines attacks. However, they are often not sufficient enough.
Medications normally used to treat migraines, so called “vasoconstrictor drugs” are not recommended for CADASIL patients because they would incur contraction of vessels and increase risks of reducing blood flow to the brain.

Treatment for cerebral vascular accidents (CVA)
Aspirin is traditionally prescribed after the first stroke for preventive purpose. It improves blood fluidity and reduces the formation of blood clots (platelets), which is among most common root cause of strokes among the general population. On the other hand, such benefit of aspirin is not clearly demonstrated among CADASIL patients. When in doubt, most physicians prescribe this medication anyway, with doses varied based on patients, unless in case of adverse conditions (stomach ulcers, allergies etc.).

Treatment for mood disorders
Psychiatric disorders, which may translate into signs of depression or manic-depressive symptoms, may be treated by anti-depressant medications, but these drugs prove sometimes not effective enough or even ineffective.

What are other therapy options ?

After a stroke, kinesiotherapy is necessary for taking charge of inevitable motor disorders (walking, balance …). In case of speech disorders, rehabilitation via speech and language therapy is recommended. In case of severe aftermaths (for example, paralysis), psychomotricity and ergo therapy would help patients manage their handicap and accept their body image such that they may best adapt to the new environment.

As to treatment for cognitive disorders, it may call for peer group participation (for example with other patients) to help stimulate the patient, prevent his/her isolation and to minimize the feeling of burden on others.
In the case of loss of independence (intellectual decline, behavior disorders, severe motor troubles), the patient may have a need for specialized home care, even specialized nursing homes where he/she will be assisted in daily routines (hygiene, feeding).

Is there need for psychological support ?
A psychological support is often necessary, in all stages of the disease, for the patient as well as the family.
The diagnosis announcement is a difficult moment, where there is a mix of feelings of injustice, powerlessness and despair, in such that it is a disease which has no treatment, the evolution course cannot be predicted and which leads inevitably to physical and intellectual decline.

In addition, since it is a family disease, the fear of transmitting (or having transmitted) it to one’s own children is intense and often coupled with a feeling of guilt. Psychological support may help to better accept this situation and better handle the anxiety associated to this disease.

For the family (siblings, children), psychological support is important to help arrive to a decision between taking the screening test or accepting to live in the uncertainty and carrying on with current life projects. For individuals which know themselves to be affected but have not yet developed symptoms, or family members who do not know if they are carriers of the mutated gene, it is “natural” to worry at every least neurological sign (headaches, tingling feeling on one limb ..). However, CADASIL may not be directly the cause and two people with the same genetic anomaly do not necessarily share the same symptoms or the same clinical evolution course. The assistance of a psychologist, in combination with various means of relaxation, may help dissipate these anguishes.

What can be done to help oneself ?

There is no particular recommendation, but it is always preferable to have good hygiene habits and not to smoke (as it increases risk of strokes). It is also advised to have regular blood pressure checkup.
Generally, to avoid taking unnecessary risks, hormone treatment of menopause is only prescribed if it shows to bring real benefits (e.g. cure for hot flashes) and only with limited duration. Concerning contraceptives, pills that only contain progestin (without estrogen) are preferable to traditional pills.

How can the disease be monitored ?

Follow-up of CADASIL patients is handled by consultations with neurologists at specialized hospital facilities. In France, there is a reference center for vascular diseases of the central nervous system (its address can be found under the website www.orphanet.fr). Visits and exams frequency is determined by the medical team.
Nevertheless, certain symptoms should alert the patient and his/her immediate family and prompt them for an emergency exam. Such is a stroke which may cause vision or language disorders, sudden difficulties in moving one’s limb (causing problem in writing for example), troubles with motion coordination etc. Similarly, in cases of severe headaches with or without aura or epilepsy attacks, it is advised that the patient consult at once his/her physician.

What type of information is important to know or share in case of emergency ?

In case of emergency, it is important to communicate CADASIL diagnosis to physicians so that they may avoid certain treatments or exams. In effect, anticoagulant medications, sometimes prescribed after a stroke, are not recommended for CADASIL patients since it may lead to bleeding risk in the brain. Likewise, cerebral arteriography (medical test used to image cerebral blood arteries) must be avoided so as not to trigger sometimes severe migraine attacks. Finally, it is utmost imperative to notify medical personnel about current treatment in effect and drug dosage. This precaution prevents risks of incompatible medications and potential overdose.

Can this disease be prevented?

Up to now, there is no demonstrable effective means to prevent the occurrence or manifestations of CADASIL.

What are the effects of the disease on lifestyles, family, professional, social, academic, sports?

To be diagnosed with a progressive disease which sooner or later will lead to physical and intellectual impairment is extremely challenging, since one can predict neither the severity of the handicap nor the speed of progression, which vary widely from one person to another. Neurological disorders will end up affecting critical functions such as walking or speech thus causing serious handicaps. The patient may remain in a stable condition for a while but impairment occurrences to the active lifestyle may require an interruption of professional activity or, at the very least, a reorientation or a reorganization of work schedule. Besides, in case of a stroke, an often lengthy rehabilitation following a hospital stay is always necessary for patients to reestablish and recuperate the most abilities possible.

For individuals already presenting symptoms as well as those knowing (or believing) to have the disease, the feeling of living under a permanent threat may be hard to handle and is a source of great anguish. Also, it is particularly difficult to accept the unpredictable nature of this disease.

When the disease is at an advanced stage, the patient loses gradually one’s independence and become unable to handle daily tasks (e.g. toilet, meals etc.). To the patient’s immediate entourage, the mood disturbances, psychological disorders coupled with motor difficulties or inevitable incontinence are very hard to deal with. They often become cause for social isolation since friends and sometimes even family do not always understand the behavioral changes of the affected individual. The patient, when he/she is unable to make decisions, must sometimes be placed under legal guardianship. The guardian, often a family member, must take responsibility of financial planning in place of the patient.

In a later stage of the disease, in order to relieve the burden of supporting the patient at home, external recourses (e.g. care services, nurses, nurse-aides, assisted living, maid service or admittance to a specialized facility) may be implemented. These periods of “respite” for the family are of utmost importance.

Pregnancy
It is possible to bear children when one is affected by CADASIL or is a carrier of the genetic anomaly responsible for the disease. Pregnancy does not seem to increase risks of strokes and it does not trigger symptoms in women with no previous manifestations of the disease.
However, in the months after birth delivery, risk of migraine attacks with aura would increase. Thus, it is important to discuss with one’s physician about pregnancy plan or notify if one is pregnant since the physician could evaluate risks for the mother and future baby and insure proper monitoring.  

To know more

What research is being done ?

The goal of the research is to determine precisely the mechanisms that trigger NOTCH3 gene anomaly and lead to lesions to cerebral arteries. To this end, mice carrying NOTCH3 gene anomaly have been produced. Factors, affecting the symptoms severity as well as disease progression, which vary from one patient to another are also under study. In the treatment area, clinical trials are being conducted to evaluate the effectiveness of drugs such as “vasodilators” or “neuroprotectors”. These studies are being researched by different medical teams around the world.

How to get in touch with other patients of this disease ?
You may join various Patient Associations of this disease. Internet Addresses may be obtained by contacting the Information Services for Rare Diseases at 08 10 63 19 20 (Toll Free, charged as local call) or visiting Orphanet website (www.orphanet.fr).



Social Assistance in France
It is important to get in touch with proper parties for assistance to administrative procedures. Useful information about legislation and patient rights may be obtained through hospital case workers or patients associations. In other cases, Regional Services for Assistance and Information (SRAI – Services Regionaux d’Aides et d’Informations) provide help and assist families in daily procedures by putting them in touch with intervention personnel (e.g. Kinesitherapy technicians, Ergotherapy technicians, social workers etc.)

In France, some CADASIL patients may be covered 100% by Social Security for reimbursements of medical expenses (co-pay exemption). Sessions of Kinesitherapy and Language/Speech therapy are covered by Social Security. Patients may apply for handicap-eligible benefits by applying with the Department Services for Handicapped People (MDPH- Maisons Departmentales des Personnes Handicappees). Depending on each case, handicap compensation aid may be granted to the patient. Finally, a handicap card allows any handicapped person, adult or minor, with a handicap status exceeding 80%, to benefit from certain tax exemption or public transportation discounts. The Handicap ID Card and parking sticker may be applied for parking benefits in handicapped zones. Rehabilitation in specialized facilities is under the supervision of the Commission for Rights and Independence of Handicapped People (CDAPH- Commision des Droits et de l’Autonomie des Personnes Handicappes) within the umbrella of MDPH organization.

For more details, please consult the Orphanet booklet “Living with a rare disease in France: Aid and Assistance” which documents legislations in effect, assistance, programs for education and professional intervention available for people affected by rare diseases.

Thank you to Service de Neurologie, Centre de Référence des maladies Vasculaires rares du Cerveau et de l'Oeil (CERVCO), Hôpital Lariboisière, Paris, France for allowing giving CADASIL TWHH permission to provide for this detailed information on CADASIL: http://www.cervco.fr/pathologies/CADASIL.2.All.maladies.en.htm

Collaboration Orphanet: www.orpha.net
Doctor Dominique Hervet, Professor Hughes Chabriat
CERVCO, Neurology Department, Lariboisière Hospital, Paris
Association CADASIL FRANCE
French Association of Advisors in Genetics



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