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.
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.
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).
to 85% of patients report
the occurrence of an ischemic
event which can be a neurological deficiencyof sudden onset resolving in
less than 24 hours (TIA 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 sensori-motor 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
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
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 behaviour) 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.
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).
Clinical course and prognosis
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, sometimes 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.
Figure1: A summary of the natural history of the disease
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
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.
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).
Figure 3: 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 gradual-onset 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
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
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
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.
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 haemorrhages 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.
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 haemorrhages, although rare,
suggests that the use of anticoagulants would, on the other hand, be
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
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
Current research work covers two areas:
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.