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Neuropsychiatric manifestations in CADASIL

Department of Neurology, Hopital Lariboisière, Université Paris VII, Denis Diderot, Paris, France.
Dialogues in clinical neuroscience 02/2007; 9(2):199-208.
Source: PubMed

ABSTRACT

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) is an inherited small-artery disease of mid-adulthood caused by mutations of the NOTCH3 gene. The disease is responsible for widespread white-matter Iesions associated with lacunar infarctions in varinus subcortical areas. The disease is responsible for migraine with aura and ischemic strokes, and is associated with various degrees of cognitive impairment and with mood disturbances. CADASIL is considered as a unique model to investigate what is known as "subcortical ischemic vascular dementia. "Recent data suggest
that the number of lacunar infarctions and severity of cerebral atrophy are the main magnetic resonance imaging markers associated with cognitive and motor disabilities in this disorder. Mood disturbances are reported in 10% to 20% of patients, most often in association with cognitive alterations. Their exact origin remains unknown; the presence of ischemic lesions within the basal ganglia or the frontal white matter may promote the occurrence of these symptoms. Further studies are needed to better understand the relationships between cerebral lesions and both cognitive and psychiatric symptoms in this small-vessel disease of the brain.

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Available from: PubMed Central
erebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL)
1
is an inherited small-artery disease of mid-adulthood
caused by mutations of the NOTCH3 gene on chromo-
some 19.
2
The exact frequency of CADASIL remains
unknown. The disease has been diagnosed in European,
Asian,African, and American, as well as in Australian fam-
ilies. In France, Germany, and the United Kingdom, several
hundreds of CADASIL families have been identified.
3-6
Based on a register for the disease in the West of Scotland,
Ravzi et al estimated in 2004 that the prevalence of the
NOTCH3 gene mutation was about 4.14 per 100 000 adults
in this population.
7
This frequency is probably underesti-
mated. CADASIL is still underdiagnosed, and may be one
of the most frequent hereditary neurological disorders. It
is considered as a model of “pure” vascular dementia
related to small-vessel disease, and as an archetype of the
so-called “subcortical ischemic vascular dementia,
CADASIL is also responsible for mood disturbances, most
often in association with cognitive impairment.
Pathophysiology
CADASIL is characterized by the presence of white-
matter rarefaction and subcortical ischemic lesions of the
brain, easily detected using magnetic resonance imaging
(MRI). Macroscopic examination of the cerebral tissue
199
Clinical research
C
Copyright © 2007 LLS SAS. All rights reserved www.dialogues-cns.org
Neuropsychiatric manifestations in
CADASIL
Hugues Chabriat, MD, PhD; Marie-Germaine Bousser, MD
Keywords:
CADASIL; MRI; white matter; lacunar infarct; Notch3; mood disorder;
vascular; cognitive impairment; subcortical ischemic vascular dementia
Author affiliations: Dept of Neurology, Hopital Lariboisière, Université Paris VII
Denis Diderot, Paris, France.
Address for correspondence: Prof Hugues Chabriat, Department of Neurology,
Hôpital Lariboisière, Université Paris VII, Denis Diderot, 2 rue Ambroise Paré,
75010 Paris, France
(e-mail: hugues.chabriat@lrb.aphp.fr)
Cerebral autosomal dominant arteriopathy with subcor-
tical infarcts and leukoencephalopathy (CADASIL) is an
inherited small-artery disease of mid-adulthood caused by
mutations of the NOTCH3 gene. The disease is responsi-
ble for widespread white-matter lesions associated with
lacunar infarctions in various subcortical areas. The disease
is responsible for migraine with aura and ischemic strokes,
and is associated with various degrees of cognitive impair-
ment and with mood disturbances. CADASIL is considered
as a unique model to investigate what is known as “sub-
cortical ischemic vascular dementia.” Recent data suggest
that the number of lacunar infarctions and severity of
cerebral atrophy are the main magnetic resonance imag-
ing markers associated with cognitive and motor disabil-
ities in this disorder. Mood disturbances are reported in
10% to 20% of patients, most often in association with
cognitive alterations. Their exact origin remains unknown;
the presence of ischemic lesions within the basal ganglia
or the frontal white matter may promote the occurrence
of these symptoms. Further studies are needed to better
understand the relationships between cerebral lesions and
both cognitive and psychiatric symptoms in this small-ves-
sel disease of the brain.
© 2007, LLS SAS Dialogues Clin Neurosci. 2007;9:199-208.
Page 1
shows a diffuse myelin pallor and rarefaction of the
hemispheric white matter, sparing the U fibers.
8
Lesions
predominate in the periventricular areas and centrum
semi-ovale. They are associated with lacunar infarcts
located in the white matter and basal ganglia (lentiform
nucleus, thalamus, caudate).
9,10
The most severe hemi-
spheric lesions are the most profound.
8,11,12
In the brain
stem, the lesions are more marked in the pons, and are
similar to the pontine ischemic rarefaction of myelin
described by Pullicino et al.
13
Small, deep infarcts and
dilated Virchow-Robin spaces are also associated with
the white-matter lesions.
In CADASIL, the walls of cerebral and leptomeningeal
arterioles are thickened with a significant reduction of
the lumen
8
; thus, penetrating arteries in the cortex and
white matter appear stenosed.
14,15
Some inconstant fea-
tures are similar to those reported in patients with hyper-
tensive encephalopathy
16
: duplication and splitting of
internal elastic lamina, adventitial hyalinosis and fibro-
sis, and hypertrophy of the media. However, a distinctive
feature is the presence of a granular material within the
media extending into the adventitia.
8,11,17-21
The periodic
acid Schiff (PAS) positive staining suggested the presence
of glycoproteins; staining for amyloid substance and
elastin is negative.
9,11
Immunohistochemistry does not
support the presence of immunoglubulins. In contrast,
the endothelium of the vessels is usually spared.
Sometimes, the smooth muscle cells are not detectable,
and are replaced by collagen fibers.
16
On electron
microscopy, the smooth muscle cells appear swollen and
often degenerated, some of them with multiple nuclei.
There is a granular, electron-dense, osmiophilic material
(GOM) within the media.
22
This material consists of gran-
ules of about 10 to 15 nm in diameter. It is localized close
to the cell membrane of the smooth muscle cells, where
it appears very dense. The smooth muscle cells are sepa-
rated by large amounts of this unidentified material.
CADASIL is caused by stereotyped mutations of the
NOTCH3 gene.
2
Unlike other members of the Notch
gene family whose expression is ubiquitous, the
NOTCH3 gene is expressed only in vascular smooth mus-
cle cells
23
of arterial vessels.
24
It encodes a single-pass
transmembrane receptor of 2321 amino-acids, with an
extracellular domain containing 34 epidermal growth fac-
tor-like (EGF) repeats (including 6 cystein residues) and
3 Lin-12 repeats associated with an intracellular and a
transmembrane domains.
2,25
This cell surface receptor
mediates signal transduction with receptor ligands such
as Jagged (Jag) and Delta (D) on neighboring cells which
are also type 1 transmembrane receptors.
2,25-27
Domenga
et al showed that NOTCH3 is required specifically to
generate functional arteries in mice by regulating arter-
ial differentiation and maturation of vascular smooth
muscle cells.
28
The stereotyped mis-sense mutations
2
or
deletions
29
responsible for CADASIL are within epider-
mal-growth-factor-like (EGF-like) repeats and only
located in the extracellular domain of the NOTCH3 pro-
tein.
30-32
All mutations responsible for the disease lead to
an uneven number of cystein residues.
The NOTCH3 protein usually undergoes complex pro-
teolytic cleavages, leading to an extracellular and a trans-
membrane fragment.
33
After cleavage, these two frag-
ments form a heterodimer at the cell surface of smooth
muscle cells. In CADASIL, the ectodomain of the
NOTCH3 receptor accumulates within the vessel wall of
affected subjects.
23
This accumulation is found near but
not within the characteristic granular osmiophilic mate-
rial seen on electron microscopy. It is observed in all vas-
cular smooth mucle cells, and in pericytes within all
organs (brain, heart, muscle, lungs, skin). An abnormal
clearance of the NOTCH3 ectodomain from the smooth
muscle cell surface is presumed to cause this accumula-
tion.
23,34,35
The exact mechanisms underlying this phe-
nomenon have not yet been elucidated.
Vascular abnormalities observed in the brain are also
detectable in other organs or territories.
9,11
The granular
and osmiophilic material surrounding the smooth mus-
cle cells as seen with electron microscopy is also present
in the media of arteries located in the spleen, liver, kid-
neys, muscle, and skin, and also in the wall of carotid and
aortic arteries.
9,11,36
Altered histochemical binding of plant
lectins have been recently identified in the vessel walls of
peripheral arteries.
37
These vascular lesions can be
detected by nerve or muscle biopsy.
38,39
The presence of
the granular osmiophilic material in the skin vessels now
allows confirmation of the intra vitam diagnosis of
CADASIL using punch skin biopsies,
11,40-43
although the
sensitivity and specificity of this method have not yet
been completely established. In some cases, the vessel
changes may be focal, requiring a thorough evaluation of
the biopsy specimen.
44
Joutel et al proposed using anti-
NOTCH3 antibodies to reveal the accumulation of
NOTCH3 products within the vessel wall in CADASIL
patients as an alternative diagnostic method.
45
Transgenic mice expressing mutant NOTCH3 develop
the vascular alterations characteristic of CADASIL.
46
Clinical research
200
Page 2
Experimental data show an impaired autoregulation of
cerebral blood flow in these mice and suggest a
decreased relaxation or increased resistance of cerebral
vessels.
47
In addition, flow-induced dilation was signifi-
cantly decreased and pressure-induced myogenic tone
significantly increased in these arteries suggestive of
impaired vascular mechanotransduction.
48
Neuropsychiatric manifestations
The natural history of CADASIL is summarized in
Figure 1. The first clinical manifestations in CADASIL
are attacks of migraine with aura, occurring between the
ages of 20 and 40 years.
4,41,49
They are observed in 20% to
30% of patients.
Ischemic manifestations, the most frequent clinical man-
ifestations, are reported in 60% to 80% of patients, usu-
ally during the fourth and fifth decade.
Neuropsychiatric manifestations include mood distur-
bances and various degrees of cognitive impairment.
They are observed at all stages of the disorder.A marked
decline in cognitive performance is reported in most indi-
viduals after age 50 years. Dementia is usually detected
at age >60 years, and is found nearly constantly at the end
stage of the disorder.
4,41,49
Psychiatric symptoms, mainly
episodes of mood disturbances, are reported in 10% to
20% of patients during the course of the disease.
4,5
Cognitive impairment
Symptomatic patients can remain several years without
any neuropsychological decline.
50
However, cognitive
impairment and dementia represent the second com-
monest clinical manifestation in CADASIL, after acute
ischemic symptoms.
The onset of cognitive deficit is usually mild and insidi-
ous, and its exact time is often difficult to ascertain. The
cognitive changes may appear a long time before tran-
sient ischemic attacks (TIAs) or stroke.
51
Cross-sectional
studies
52-55
have shown that early in the disease, cognitive
functions, most frequently attention and executive func-
tions, may be impaired. In a recent series of 42 patients,
attention and executive functions were affected in nearly
90% of patients aged between 35 and 50.
55
These distur-
bances are often associated with alterations in attention
and memory suggestive of dysfunction within the sub-
cortical-frontal network.
52,55,56
In contrast, other functions
such as verbal episodic memory and visuopatial abilities
are usually preserved, and may remain spared until the
late stages of the disease.
Some tests are particularly sensitive to the detection of
the early cognitive changes.They include digit span back-
wards and forwards, the Trail Making Test part B, the
Stroop test, and the Wisconsin Card Sorting test. The
errors of CADASIL patients may predominantly affect
the time measure in timed tasks (Stroop, Trail Making
Test, symbol digit, digit cancellation) though errors in
monitoring are also observed to a lesser extent.
54
Patients
may also show poor strategy and planning when com-
pleting tasks such as the Wisconsin Card Sorting Test and
the Rey-Osterreith memory test. Memory deficit may be
associated with executive dysfunction, but its profile is
usually distinct from dementias primarily involving the
mesiotemporal temporal cortex such as Alzheimer’s dis-
ease. This is illustrated by procedures such as those used
in the Grober and Buschke test. This test allows differ-
entiation of different phases of memory processes, and is
likely to show the preservation of the encoding process
even though the retrieval is impaired. It is composed of:
(i) an encoding phase where 16 words belonging to 16
different semantic categories have to be retrieved; (ii) 3
phases of free recall and cued recall (the last being
delayed); and (iii) a recognition test. In CADASIL, this
test distinguishes a pattern characterized by low scores
in immediate and delayed free recall, improving with
cues and associated with relatively intact recognition.
Intrusions may occur in the free recall task. This profile
supports preservation of the encoding process, and
anatomically, of the mesiotemporal cortex. It is still
observed in about two thirds of CADASIL patients with
dementia.
55
With aging, the cognitive decline becomes more homoge-
nous, with significant changes in all cognitive domains.
This extension cannot be ascribed solely to the deterio-
ration of executive performances, but appears to be
related to additional alterations in instrumental activities,
CADASIL—neuropsychiatric manifestations - Chabriat and Bousser Dialogues in Clinical Neuroscience - Vol 9
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Figure 1. Natural history of CADASIL. MRI, magnetic resonance imaging
Dementia
Ischemic events
Mood disorders
Migraine with aura
Abnormal MRI
20 30 40 50 6070 Age (y)
Page 3
language, and visuospatial abilities, and suggests a diffuse
cortical dysfunction well beyond the subcortical-frontal
circuits.
55
The development of cognitive impairment
appears sometimes to be associated with the occurrence
of stroke. Nevertheless, a cognitive deficit and even a
dementia state may also occur in patients without any
clinical history of stroke. The cognitive profile of
CADASIL patients was analyzed before and after the
occurrence of strokes in two cross-sectional studies, and
showed some discrepant results.Amberla et al
53
reported
that executive functions were more widely affected, with
a significant mental slowing in CADASIL patients with
a positive history of stroke. Conversely, Buffon et al
observed that visuospatial abilities were mostly impaired
in patients with stroke.
55
The cognitive deficit most often
progresses in the total absence of ischemic events, mim-
icking in some cases a degenerative dementia.
5,57,58
The
temporal progression of cognitive symptoms varies
among subjects from rapid and marked deterioration to
stable or even slightly improving performances.
59
Dementia is reported in one third of symptomatic
patients at the late phase of the disorder.The frequency
of dementia increases considerably with age. Thus, about
60% of patients older than 60 years are demented,
4
and
more than 80% of deceased subjects were reported to be
demented before death.
5
When dementia is present, the
neuropsychological deficit is usually extensive, involving
not only executive functions, attention, and memory, but
also reasoning and language performances.
55
Dementia
is often associated with apathy. Conversely, severe apha-
sia, apraxia or agnosia are rare.
55,56
In addition, demented
individuals have a relative preservation of recognition
and semantic memory.
55
Noteworthily, two thirds of them
present improvement of memory with cues, which sug-
gests that the encoding process is preserved even at the
late stage of the disease, in contrast with the pattern of
memory impairment in Alzheimer’s disease. Dementia is
observed in the absence of any other clinical manifesta-
tions in 10% of cases.
55
The frequency and severity of the
cognitive decline are variable in different members of a
given family. The variable location and severity of cere-
bral tissue damage may play a key role in this variabil-
ity.
60,61
Dementia is always associated with pyramidal signs. Gait
difficulties are present in 90%, urinary incontinence in
80% to 90%, and pseudobulbar palsy in half of demented
individuals. At the end stage of the disorder, CADASIL
patients become bedridden. In a large retrospective study
in 411 patients, Opherk et al found that the median age
at onset for inability to walk without assistance was 59
years in men and 62 in women, and for bedriddenness, 62
years in men and 66.5 years in women.
Psychiatric symptoms
About one fifth of CADASIL patients experienced
episodes of mood disturbances.Their frequency is widely
variable between families.
5,62
Episodes of major depres-
sion were reported by 10% of the 80 CADASIL patients
investigated by Peters et al. In some cases, antidepressant
drugs were found to be inefficient in relieving symptoms
during the most severe episodes.
Few affected subjects have had severe depression of the
melancholic type alternating with typical manic episodes
suggesting bipolar mood disorder.
63
Based on this obser-
vation, the potential role of the NOTCH3 gene was thus
investigated in familial forms of bipolar disorder, but the
results were negative.
64
The location of ischemic lesions
in basal ganglia and the frontal location of white-matter
lesions may play a key role in the occurrence of such
mood disturbances in CADASIL patients.
65,66
In addition to the mood disorders, a variety of psychiatric
manifestations can occur in CADASIL patients.
Agoraphobia, addiction to alcohol, and psychotic symp-
toms have been already reported.
4,5,67
The observation of
schizophrenia in association with CADASIL appears
anecdotal.
68
Most often, psychiatric manifestations are observed in
patients after diagnosis and a history of ischemic symp-
toms with signal abnormalities at MRI examination.
However these episodes can be inaugural, and may lead
to misdiagnosis.
5,62,69
Leyhe et al recently reported two
cases admitted to a gerontopsychiatric hospital with psy-
chopathological manifestations at the onset of the disor-
der.
70
The first case was a 66-year-old man who was
described as a reserved, peaceful, and calm person and
who became irritable, started to neglect himself and his
duties, and presented a submanic episode which mildly
improved after treatment with neuroleptic drugs. The
patient started to consume alcohol again after years of
abstinence. The second case was a 62-year-old woman
with a 2-year episode of depressive symptoms who was
initially successfully treated by amitriptyline. She was
admitted to hospital because she deteriorated despite
medication, developing paranoid ideas and melancholia.
The psychopathological symptoms slowly improved on a
Clinical research
202
Page 4
combination of antidepressant and anxiolytic drugs and
neuroleptics. In both cases, the MRI examination and the
family history were essential for diagnosis.
Correlations with cerebral tissue lesions
MRI is crucial for the diagnosis of CADASIL, and is
much more sensitive than computerized tomography
(CT)-scan. It is always abnormal in patients with neuro-
logical symptoms other than migraine attacks.
1,5,41,71,72
MRI
signal abnormalities can also be detected during a
presymptomatic period of variable duration. They are
observed as early as 20 years of age. After age 35, all sub-
jects having the affected gene have an abnormal MRI.
1,71
The frequency of asymptomatic subjects with abnormal
MRI decreases progressively with aging, and becomes
less than 5% after 60 years.
72
MRI shows, on T2-weighted images, widespread areas of
increased signal in the white matter associated with focal
hyperintensities in basal ganglia, thalamus, and brain
stem (Figure 2).
72,73
The extent of white-matter signal
abnormalities is highly variable. It increases dramatically
with age. In subjects under 40 years of age,T2 hypersig-
nals are usually punctuate or nodular with a symmetrical
distribution, and predominate in periventricular areas
and within the centrum semi-ovale. Later in life, white-
matter lesions are diffuse and can involve the whole of
white matter, including the U fibers under the cortex.
72-75
Scores of severity based on semiquantitative rating scales
significantly increase with age, not only in the white mat-
ter but also in basal ganglia and brain stem. Frontal and
occipital periventricular lesions are constant when MRI
is abnormal.The frequency of signal abnormalities in the
external capsule (two thirds of cases) and in the anterior
part of the temporal lobes (60%) is noteworthy and par-
ticularly useful for differential diagnosis with other small-
vessel diseases.
76-78
T2 hyperintensities can be detected in
the corpus callosum.
75,79
Brain stem lesions predominate
in the pons in areas irrigated by perforating arteries and
can involve the mesencephalon.
74
In contrast, the medulla
is usually spared.
On T1-weighted images, punctiform or larger focal
hypointensities are frequent in the same areas and are
detected in about two thirds of individuals with T2 hyper-
intensities
72
(Figure 2). They are observed both in the
white matter and the basal ganglia, but also in the brain
stem and correspond mostly to lacunar infarctions.
Numerous hypointensities on T1-weighted images may
also correspond to Virchow-Robin spaces which are
more frequent and extensive in CADASIL than in
healthy subjects. MRI signal abnormalities within the
temporal white matter in CADASIL and particularly
within the subcortical white matter, are considered as a
characteristic feature of the disease. They are also caused
by a distension of the perivascular space of perforating
arteries at the level of the junction of gray and white mat-
ter, and by spongiosis in the surrounding parenchyma.
80
In contrast with the extent of white-matter hyperinten-
sites weakly associated with the clinical severity,
54
the
degree of white-matter microstructural damage mea-
sured with diffusion tensor imaging (DTI) appears
strongly related to the clinical status in CADASIL.
81
This
is in agreement with the correlations observed between
the clinical status and the load of T1 lesions within the
white matter, which suggests that the degree of tissue
destruction or neuronal loss is crucial for the appearance
of disability in CADASIL.
60,81,82
The exact mechanisms of cognitive dysfunction in
CADASIL remain unknown.The main hypothesis is that
accumulation of subcortical lesions may damage in par-
ticular the striato-cortical circuits linking basal ganglia to
frontal cortical areas, with possible secondary cortical
degeneration.
60
This hypothesis is supported by evidence
of strong correlations between cortical atrophy and the
cognitive decline in the disease in both imaging and neu-
ropathological studies. As described previously, severe
cortical metabolic depression has indeed been observed
by positron-emission tomography (PET) study in associ-
ation with basal ganglia and thalamic infarcts in a
CADASIL—neuropsychiatric manifestations - Chabriat and Bousser Dialogues in Clinical Neuroscience - Vol 9
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Figure 2. MRI of a 56-year-old woman with CADASIL suffering from
depression and with executive dysfunction, and showing diffuse
white-matter hyperintensities and small deep infarcts located in
the thalamus and within the centrum semi-ovale.
Page 5
demented patient.The postmortem brain examination of
a CADASIL case showed evidence of a diffuse loss of
cortical neurons associated with cholinergic denerva-
tion.
83
In a recent neuropathological study, Viswanathan
et al reported the presence of widespread neuronal apop-
tosis in the cerebral cortices of four CADASIL patients.
Semiquantitative analysis suggested that the degree of
cortical neuronal apoptosis was related to the extent of
white matter lesions and to the intensity of axonal dam-
age in subcortical areas
84
and was associated with the
severity of cognitive impairment. Therefore, subcortical
axonal damage may induce cortical apoptosis through
deafferentation and/or retrograde neuronal degeneration
in CADASIL.
Disruption of cortical connections may affect striatocor-
tical circuits relaying to the thalamus and basal ganglia
as well as cortical networks. This is supported by recent
DTI findings from Sullivan et al, who observed: (i) a
strong correlation between mean diffusivity measured in
the thalamus (which could reflect either direct patholog-
ical damage or secondary degeneration due to disruption
of white matter tracts relaying in this structure) and exec-
utive dysfunction
85
; (ii) executive performances also cor-
related with mean diffusivity in the anteroposterior fas-
ciculus of the cingulum bundle which connects the
dorsolateral prefrontal lobe with more posterior cortical
regions including the hippocampal formation.
86
Other clinical manifestations
In contrast with migraine without aura, whose frequency
is identical to that estimated in the general population,
migraine with aura is reported in 20% to 40% of
CADASIL patients, a frequency 4- to 5-fold higher than
in the general population. Among pedigrees, this fre-
quency appears extremely variable. The mean age at
onset is between 28 to 30 years,
49,87
with a wide range from
6 to 48 years. In the largest series, that of Vahedi et al, the
frequency of attacks appears extremely variable among
affected individuals, from two per week to one to every
3 to 4 years.
87
Triggering factors of migraine with aura are
similar to those of migraine in the general population
(stress, flashing lights, fatigue, physical exercise, head
trauma, strong smells, etc).
87
The most frequent symptoms
are visual, sensory, or aphasic. Motor symptoms are
reported in one fifth of CADASIL patients who have
attacks of migraine with aura. In contrast with the aura
symptoms reported in the general population, more than
half of patients have a history of atypical aura such as
basilar, hemiplegic, or prolonged aura (International
Headache Society criteria
88
). A few patients even suffer
from severe attacks with unusual symptoms such as con-
fusion, fever, meningitis or coma,
89-91
exceptionally
reported in migraine with aura.
92,93
Ischemic manifestations are the most frequent clinical
events in CADASIL: 60% to 85% of patients have had
TIAs or completed strokes.
4-6,94
They occur at a mean age
of 45 to 50 years (extreme limits from 20 to 70 years).
4,5,20,41
Age of onset does not differ between men and women.
In a recent follow-up study, Peters et al estimated the
incidence rate of stroke at 10.4 per 100 person-years.
59
Two thirds of them are classical lacunar syndromes: pure
motor stroke, ataxic hemiparesis, pure sensory stroke,
sensory-motor stroke.
5
Other focal neurologic deficits of
abrupt onset are less frequent: dysarthria, either isolated
or associated with motor or sensory deficit, monoparesis,
paresthesiae of one limb, isolated ataxia, nonfluent dys-
phasia, hemianopia.
5
Five percent to 10% of CADASIL patients experience
seizures, either focal or generalized.
4,20,95
They are usually
reported in patients with a positive history of stroke.
Epilepsy is usually well-controlled by current antiepilep-
tic drugs.
Other neurological manifestations have occasionally
been reported in CADASIL. Parkinsonism has been
diagnosed in a a few patients whose clinical presentation
can mimic, in rare cases, progressive supranuclear palsy.
96
Deafness of acute or rapid onset has been reported in a
few subjects, but its exact frequency remains unknown.
71
Rufa et al reported an acute unilateral visual loss sec-
ondary to a nonarteritic ischemic optic neuropathy in a
single 60-year-old case who was demented, but this had
occurred 33 years earlier at age 27.
97
The lack of cranial nerve palsy, spinal cord disease, and
symptoms of muscular origin is noteworthy in CADASIL.
The exact cause of the radiculopathy reported in one case
by Ragno et al remains undetermined.
98
Recently, several
cases belonging to Italian and Chinese families with clin-
ical and electrophysiological signs of peripheral sensori-
motor neuropathy were described.
99,100
Conclusion
Neuropsychiatric manifestations are common in
CADASIL, a genetic small-vessel disease leading to
“subcortical ischemic vascular dementia.
Clinical research
204
Page 6
Cognitive alterations are frequent, and can be detected
at the early stages of the disorder, as early as the third
decade. They can remain insidious for several years,
mainly involving executive functions and attention. A
decline in cognitive performances is usually observed
after the fifth decade, in association with the recurrence
of ischemic manifestations, which leads progressively to
dementia associated with pseudobulbar plasy, gait dis-
turbances, and motor impairment.
Psychiatric episodes may also occur during the course of
the disorder, rarely before 40 years, most frequently after
the occurrence of ischemic events during the fifth or sixth
decade. Episodes of mood disorders, the most frequent
psychiatric symptoms, are rarely isolated and are often
associated with executive dysfunction. When they are
inaugural, different features such as their resistance to
antidepressant drugs, the association with neurological
signs (pyramidal symptoms, cognitive alterations), and
the detection of white-matter MRI abnormalities, as well
as a positive family history of stroke and dementia, are
helpful for raising the diagnosis of CADASIL.
CADASIL is a unique model to investigate the relation-
ships between subcortical ischemic lesions and the cog-
nitive and psychiatric status in small vessel diseases.
Further studies are needed to better understand the
exact impact of cerebral tissue lesions, and the role of
their distribution or of their severity on the occurrence
of cognitive and psychiatric symptoms in this disorder.
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Manifestaciones psiquiátricas en CADASIL
CADASIL (arteriopatía cerebral autonómica domi-
nante con infartos subcorticales y leucoencefalo-
patía) es una enfermedad heredada, que afecta
pequeñas arterias durante la adultez media y es
causada por mutaciones del gen Notch3. La enfer-
medad es la responsable de extensas lesiones de la
sustancia blanca asociadas con infartos lacunares en
varias áreas subcorticales. La enfermedad es res-
ponsable de migraña con aura y accidentes vascu-
lares isquémicos, y se asocia con deterioro cognitivo
de grado variable y con trastornos del ánimo.
CADASIL se considera un modelo único para estu-
diar lo que se conoce como “demencia vascular
isquémica subcortical”. Datos recientes sugieren
que el número de infartos lacunares y la gravedad
de la atrofia cerebral son los principales marcado-
res en las imágenes de resonancia nuclear magné-
tica que se asocian con las incapacidades cognitivas
y motoras en esta enfermedad. Los trastornos del
ánimo ocurren en el 10% a 20% de los pacientes, y
con gran frecuencia se asocian con alteraciones cog-
nitivas. Aun no se conoce el origen exacto de estos
síntomas, pero la presencia de lesiones isquémicas
en los ganglios basales o en la sustancia blanca
frontal puede facilitar la aparición de estos. Se
requiere de futuros estudios para una mejor com-
prensión de la relación entre las lesiones cerebrales
y los síntomas cognitivos y psiquiátricos en esta
enfermedad cerebral de pequeños vasos.
Manifestations neuropsychiatriques du
CADASIL
Le CADASIL, ou Cerebral autosomal dominant arte-
riopathy with subcortical infarcts and leukoence-
phalopathy est une affection héréditaire des petites
artères cérébrales survenant chez l’adulte d’âge
moyen, due à des mutations du gène Notch3. La
maladie est responsable de lésions diffuses de la
substance blanche associées à des infarctus lacu-
naires au niveau des régions sous-corticales céré-
brales. Elle est à l’origine de crises de migraine avec
aura, d’accidents ischémiques cérébraux et est asso-
ciée à différents degrés d’altération cognitive et à
des troubles de l’humeur. CADASIL est considéré
comme un modéle unique d’étude des “démences
sous-corticales d’origine ischémique”. Des données
récentes suggèrent que le nombre d’infarctus lacu-
naires et la sévérité de l’atrophie cérébrale sont les
principaux marqueurs de la maladie associés au
handicap cognitif et moteur de la maladie. Les
troubles de l’humeur sont rapportés par 10 à 20 %
des patients, le plus souvent en association avec des
altérations cognitives. Leur origine exacte demeure
indéterminée, la présence de lésions ischémiques au
niveau des noyaux gris ou au sein de la substance
blanche frontale pourrait favoriser l’apparition de
ces symptômes. Des études complémentaires sont
nécessaires pour mieux comprendre les relations
entre les lésions cérébrales et les symptômes cogni-
tifs et psychiatriques observés au cours de cette
maladie des petits vaisseaux du cerveau.
Page 7
Clinical research
206
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Clinical research
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  • Source
    • "Testing which is particularly sensitive for the detection of the early cognitive changes can then be performed such as digit span back-forwards, TMT-B, Stroop, and WCST tests. These tests have revealed that patients with CADASIL show preservation of encoding processes even though memory retrieval is im- paired [23]. There is currently no treatment with a proven efficacy for CADASIL. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by variable manifestations of migraine, recurrent transient ischemic attack or lacunar strokes, cognitive decline, and mood disturbances. However, manic episodes have rarely been documented as an initial symptom of CADASIL and bipolar disorder presenting as the first manifestation in CADASIL has not been reported previously from evaluations by psychiatrists or psychological testing by psychologists. Case presentation A 53 year old woman developed symptoms of mania in her 50s leading to a personality change involving a continuously labile mood and irritability over a number of years. Neuropsychological testing revealed an intact memory, but impairment in attention and executive function. In the Rorschach test, she showed a high level of cognitive rigidity. Magnetic resonance imaging findings were very consistent with a diagnosis of CADASIL, which was confirmed by genetic testing for NOTCH3 mutations. Atypical antipsychotics proved to be helpful in treating her manic symptoms and for behavior control. Conclusion We present a novel case of CADASIL that first presented as bipolar disorder. We contend that when patients show a late onset personality change or chronically irritable mood that deteriorates over many years, an organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients.
    Full-text · Article · Jun 2014 · BMC Psychiatry
  • Source
    • "The data support the notion that overall the BG function is altered compared with healthy volunteers, and that frequency of attacks would seem to further alter this processing. In addition, standard MR studies of migraine patients have reported lesions [18,19] in the basal ganglia; potentially favoring the interpretation that such changes are caused by the increased migraine frequency rather than causing the frequency to increase. In support of this, migraine is reportedly more frequent in patients with known basal ganglia disorders [26],. "
    [Show abstract] [Hide abstract] ABSTRACT: With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF). In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain. Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.
    Full-text · Article · Sep 2011 · Molecular Pain
  • [Show abstract] [Hide abstract] ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by the defective NOTCH3 gene, which encodes a transmembrane receptor; over 170 different mutations are known. The main clinical features are migraine with aura (often atypical or isolated), strokes, cognitive decline/dementia and psychiatric symptoms. Executive and organizing cognitive functions are impaired first, memory is affected late. Typical MRI findings are T2 weighted hyperintensities in temporopolar white matter and the capsula externa. Smooth muscle cells in small arteries throughout the body degenerate and vessel walls become fibrotic. In the brain, this results in circulatory disturbances and lacunar infarcts, mainly in cerebral white matter and deep gray matter. The exact pathogenesis is still open: a dominant-negative toxic effect is suggested, possibly related to Notch3 misfolding. Diagnosis is reached either by identifying a pathogenic NOTCH3 mutation or by electron microscopic demonstration of granular osmiophilic material in a (skin) biopsy. Only symptomatic treatment is available at present.
    No preview · Article · Nov 2008 · Future Neurology
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