CADASIL Management or What To Do When There Is Little One Can Do.

Review
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CADASIL management or
what to do when there is
littleone can do
Expert Rev. Neurother. 9(2), 197210 (2009)
Alberto del RoEspnola*,

MaiteMendiroz*,
Sophie DominguesMontanari,
PatriciaPozo-Rosich,
Esther Sol, Jessica
Fernndez-Morales,
Israel FernndezCadenas and
JoanMontaner
Author for correspondence
Neurovascular Research
Laboratory and Neurovascular
Unit, Institut de Recerca,
Hospital Vall dHebron, PgVall
dHebron 119-129,
08035Barcelona, Spain
Tel.: +34 934 894 073
Fax: +34 934 894 102
31862jmv@comb.es
*Authors contributed equally to

this work
www.expert-reviews.com
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

(CADASIL) is a rare disease that leads to migraine, mood disorders, recurrent lacunar strokes
and early vascular dementia. This autosomal-dominant condition is caused by mutations in the
NOTCH3 gene and is characterized by degeneration of vascular smooth muscle cells. At present,
no evidence-based treatment for CADASIL is available and only relief of symptoms can be offered
to patients. This review focuses on an update of CADASIL management, based on the recent
clinical and basic evidence, and discusses possible new treatment targets for CADASIL.
Keywords : CADASIL notch3 reactive oxygen species sirtuin stroke vascular dementia vascular smooth
muscle cell
Cerebral autosomal dominant arteriopathy

with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, autosomal dominant
disease that plays a major role in hered itary
strokes and vascular cognitive impairment
[1,2] . Although little is known regarding its
epidemiology, it has been reported that prevalence of CADASIL in West Scotland is 1.98
per 100,000 adults, or 4.14 per 100,000 if
also considering the predicted carriers of the
mutation [3] .
The CADASIL syndrome is an adult-onset
systemic angiopathy, characterized by migraine
with aura and recurrent lacunar strokes
that leads to vascular cognitive impairment.
CADASIL patients become unable to walk
without assistance between 56 and 64 years of
age, are bedridden between 59 and 69 years and
die between 61 and 74 years of age [4] . The quality of life of these patients is not only threatened
by recurrent strokes, but also by other disabling
symptoms, such as mood disorders, migraine
and seizures [5,6] .
The disease-causing mutations are located in
the NOTCH3 gene, on the long arm of chromosome 19 [7] . This gene encodes a cytoplasmatic membrane receptor involved in cellular
differentiation and cell cycle regulation [8] . This
receptor is necessary for neuronal and vascular
development during embryogenesis [911] . In
adults, it only remains active on vascular smooth
10.1586/14737175.9.2.197
muscle cells (VSMCs) and pericytes [12] , which

may be the primary cellular type involved in
the syndrome.
Despite all the data collected during the past
10 years, the pathophysiology of CADASIL
remains elusive. At present, there are three theories attempting to explain the mechanism of the
disease, yet none of them has shown conclusive
evidence [13,14] . It is hard to develop an effective
therapy against the disease when the underlying pathogenic mechanisms have not yet been
identified. As a consequence, nowadays there is
no useful treatment to cure CADASIL and we
only have drugs to relieve the symptoms at our
disposal [15] .
The aims of this review are first to help
physicians in the management of CADASIL
patients, and second to introduce the clinicians to the current biological knowledge on
CADASIL syndrome.
Pathophysiology
Mutations associated with CADASIL cluster in

the extracellular domain of Notch3 receptor,
mostly in cysteine residues [16] . The mutated
extracellular domain accumulates in the vicinity of VSMCs as granular osmiophilic material (GOM), which is the histologic pathognomonic hallmark of the disease [17,18] . In
addition, VSMC and neuronal apoptosis have
been seen by the terminal deoxynucleotidyl
2009 Expert Reviews Ltd
ISSN 1473-7175
197
Review
del Ro-Espnola, Mendiroz, Domingues-Montanari etal.
transferase-mediated dUTPbiotin nick end labeling method

in brain tissue of autopsy cases [1921] . Currently, there is no
consensus about the relationship between both processes, GOM
accumulation and apoptosis.
Classically, two theories have been proposed to explain how
CADASIL mutations might influence receptor synthesis and
function, leading to the development of the disease [13] :
The mutated receptor causes protein accumulation, and this
accumulation is cytotoxic, as with the -amyloid protein accumulation in Alzheimers disease. Considering this theory, the
main issue would be to prevent GOM formation that might
take part in the disease course, and to clear those depositions;
The mutated receptor is not functional and, by an unknown
mechanism, the wild-type receptor also becomes useless. Following this theory, the main point would be to recover protein function. In this model, GOM accumulation is only a
consequence of the disease.
Evidence has been raised against both theories, and they have
been used as a proof of the alternative model. Moreover, in May
2007, a third theory was added based on a proteomic experiment with VSMC cultures [14] . Mutated cells were obtained
from umbilical cord of a CADASIL mutation carrier and were
compared with five controls.
The mutated receptor has an altered disulphide bond formation that disables its folding. This causes rough endoplasmic reticulum stress, and this oxidative stress triggers VSMC
apoptosis. A proportion of the mutated receptor can escape
this cycle and is transferred to the cell membrane, but its clearance is diminished and leads to GOM accumulation. In this
latter hypothesis, the main point would be to avoid oxidative
stress of VSMC, and GOM would only be a consequence of
the pathologic process.
Clinical manifestations & diagnosis
Signs and symptoms of CADASIL are migraine (often with severe,

long-lasting aura), lacunar strokes, mood disorders and vascular
cognitive impairment [5,6] . Patients become seriously disabled and
die in their 60s, mainly due to respiratory problems, similar to
individuals suffering from dementia [4] . In a small but significant
proportion of patients (9%), seizures are also present [2225] .
On MRI, there is prominent leukoaraiosis usually affecting
the external capsule and the anterior temporal pole. Brain MRI
appears clearly affected after the age of 35years, which is a good
marker for CADASIL suspicion [26] . Lacunar infarcts are located
in the external capsule, basal ganglia and anterior temporal pole,
whereas the corpus callosum and most infratentorial regions
(except the pons) are spared [27] . Microhemorrhages are found
in the thalamus, basal ganglia, corticalsubcortical junction
and deep structures. Their prevalence and main location varies
between the examined cohorts [2830] .
There are several infrequent clinical features: intracerebral
hemorrhages [3133] , encephalopathy [3438] , mental retardation
[3941] and, finally, retinal and optic nerve abnormalities, which
may be due to irrigation deficiency [38,4244] .
198
Other signs have also been reported, such as multiple simultaneous strokes [45] , cortical infarct [46] , cerebellar stroke [47] ,
spinal cord infarcts [48] , VirchowRobin spaces dilation [49] ,
arteriovenous malformations and aneurysms [50] . Regarding
dermatological signs, generalized erythematous macules and
patches [51] , and varicose veins [52] have been referred. There are
also documented movement disorders: parkinsonism, including
progressive supranuclear palsy [53] , and facial dystonia [54] . This
latter group of signs and symptoms has been documented only
in a single family, and their implication in CADASIL phenotype
needs to be proven.
Several reports have been published showing the presence of
oligoclonal bands and complement factorB in the cerebrospinal
fluid, both characteristics of multiple sclerosis [55,56] . However,
no relationship between CADASIL and multiple sclerosis has
been demonstrated [57] . Conversely, anticipation phenomenon,
or earlier onset in succeeding generations, may also be present in
CADASIL [25,58] .
When physicians detect patients highly suggestive of CADASIL,
three diagnostic tests can be considered:
Genetic testing, either by direct sequencing or denaturing
HPLC of the 224 exons of the NOTCH3 gene. It only requires
a blood sample and, thus, is the most comfortable test for the
patient [59] ;
Immunohistochemistry in small vessels of a skin biopsy sample,
with a monoclonal antibody against the extracellular domain
of the Notch3 receptor [12,60] ;
Electron microscopy in the same skin biopsy sample to assess
GOM accumulation directly [61] .
These three tests are the main tools to reach a diagnosis, and
could be combined to optimize the process. Genetic testing is the
gold standard when the complete gene is studied, because it has a
sensitivity and specificity very close to 100%, but it is time- and
money-consuming. The usual solution is to reduce the number
of exons studied, but that decreases test sensitivity; although a
sensitivity of 95% can be obtained by sequencing 23 of the 33
exons of the NOTCH gene [60] . The antibody has been proven to
be highly effective, with sensitivity up to 90%, but not complete
specificity, which is approximately 98% [12,60] . In a disease with
such a low prevalence, it could be used only as a complementary
or first-step test. Electron microscopy has high specificity (100%)
but its sensitivity is low (57%) [62] . However, sensitivity varies
depending on the number of vessels examined. Thus, it could be
used as a confirmative test (Table1) .
In our center, we start with genetic testing of the exons where
mutations are found more frequently. This is because of the
minor invasiveness when compared with skin biopsy; because,
if the pathogenic mutation is found, family members could be
studied as well; and because it offers the best sensitivity, which
is mandatory in any screening test.
If the result of testing these frequent mutated exons is negative, then skin biopsy for electronic microscopy and immuno
histochemistry tests are considered. When both tests are negative,
Expert Rev. Neurother. 9(2), (2009)
Review
Update of CADASIL management
Table 1. Predictive values of the currently available diagnostic tests.

Study
Diagnostic test
Sensitivity
(%)
Specificity
(%)
PPV (%)
NPV (%)
Ref.
Joutel etal. (2001)
Genetic testing (23 exons)
95.00
100
100
99.90
[60]
Lesnik Oberstein etal.

(2003); Joutel etal. (2001)
Immunohistochemistry
90.48
98.68
58.39
99.80
[12,60]
Malandrini etal. (2007)
Electron microscopy
57.00
100
100
99.13
[62]
In order to calculate both predictive values, we have considered 2% as the prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy when there is a clinical suspicion, as reported in a previous British screening [105].
NPV: Negative predictive value; PPV: Positive predictive value.
we consider studying exon 25 of NOTCH3, involved in another

small-vessel disease different from CADASIL, but affecting
the same gene [63] . Owing to its low sensitivity, detection of
GOM by electronic microscopy is only useful when positive
and it is difficult to study patients relatives. If GOM are not
found, CADASIL cannot be ruled out. On the contrary, when
immunohistochemistry is positive, it is highly probable that the
patient is affected, but this should be proved by sequencing the
rest of the gene to find the pathogenic mutation. If not found,
an option might be to study NOTCH3 at the mRNA level to
detect expression changes or possible midintronic mutations that
modify the splicing process, although the mutant allele might
not be detected.
When CADASIL diagnosis is reached, a neurological examination, psychometric evaluation and brain MRI, including
T2-weighted, fluid attenuated inversion recovery and gradient echo sequences, are recommended. At this point, all current medication and adjuvant treatments should be reconsidered. Unfortunately, there is no evidence-based treatment for
CADASIL, but symptoms can be relieved following general treatment recommendations. In addition, some drugs or proceedings
should be avoided (Table 2) .
Migraine
Treatment of migraine crises
A migraine crisis should be managed with simple oral analgesics, such as paracetamol or NSAIDs (e.g., aspirin, ibuprofen,
naproxen and diclofenac) and anti-emetic drugs (metoclopramide and domperidone) when necessary. Triptans are not generally recommended because of their relative contraindication
in patients at risk of cerebrovascular diseases, but there is a lack
of evidence about their safety among CADASIL patients [64] .
Although ergot derivatives block VSMC -adrenergic receptors,
inducing vasoconstriction, it is unknown whether this action
has significant effects on CADASIL vasculopathy. Otherwise,
they are contraindicated because of their vascular side effects.
All these drugs should be given when conservative management
has failed. Stress avoidance and lifestyle changes, especially
regarding sleep and dietary habits, can be useful to diminish
the number of crises. Predisposing or trigger factors, such as
menstruation or depression, are not always avoidable but may
be treatable. As a general rule, all acute drug therapy should
be administered early in the attack, and combined with rest
and sleep.
Mild stage
Moderate stage
Severe stage
Relieving symptoms
Regarding the clinical features, we propose

to distinguish three stages of the disease:
mild stage, characterized by disabling signs
and symptoms (migraine and seizures);
moderate stage, mostly represented by
recurrent strokes and mood disorders; and
severe stage, when patients develop progressive cognitive impairment and vascular cognitive impairment (Figure 1) . Special
situations, such as pregnancy and genetic
counseling, will also be discussed.
Migraine with aura

Mood disorders
Lacunar strokes
Vascular dementia
Mild stage
At this stage, patients are young and most

have been unaware of suffering such a
genetic disease for a long time. Usually,
they receive diagnosis after several years
of symptoms when a familiar is genetically
confirmed.
20
30
40
50
60
70
Age
(years)
Figure 1. Clinical stages of cerebral autosomal dominant arteriopathy with

subcortical infarcts and leukoencephalopathy (CADASIL). The figure shows the
three clinical stages of CADASIL regarding MRI changes and clinical signs andsymptoms.
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Review
Table 2. Allowed and contraindicated drugs for

cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy.
Table 2. Allowed and contraindicated drugs for

cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy.
Recommended
Recommended
Not recommended
Migraine attack
Simple oral analgesics
Aspirin 500mg/8h*
Ibuprofen 400600mg/8h*
Naproxen 750mg/12h*
Diclofenac 50mg/12h
Paracetamol 5001000mg/8h*
Antiemetic
Metoclopramide 10mg
Domperidone 20mg
Pregnancy
Triptans: vascular risk
Ergot derivatives:
vascular risk
Migraine prophylaxis
b-blockers
Atenolol 25100mg daily
Metoprolol 50100mg daily
Propanolol 80160mg daily
Bisoprolol 510mg daily
Amitryptiline 10150mg daily
Flunarizine 2.55mg daily
Topiramate 2550mg daily#
Sodium valproate 3001000mg daily
Gabapentin 300800mg daily #
Selective serotonin-reuptake inhibitors
Fluoxetine 20mg daily
Acetazolamide 125250mg daily**
Contraindicated under antiplatelet treatment.

Safe during pregnancy (FDA, class B).
Advisable to follow mood side effects.
Recommended when migraine coexists with depression.

#
Recommended when migraine coexists with epilepsy.
**
Possible future therapy.
May improve pseudobulbar syndrome symptoms.
Improves some executive functions.
Possibly useful but more evidence is necessary.

##
More evidence is necessary regarding safety.
Migraine prophylaxis
Ischemic stroke
Cholinesterase inhibitors
Donepezil 510mg daily [88]
Rivastigmine 612mg twice daily
Galantamine 8mg twice daily
Memantine 510mg twice daily
200
Aspirin (FDA, classD)

is not recommended,
mainly during the
third trimester
Selective serotonin-reuptake inhibitors

Fluoxetine 2040mg daily
Citalopram 20mg daily
Paroxetine 20mg daily
Sertraline 50mg daily
Vascular dementia
Preeclampsia
l-arginine (20g/500ml intravenously daily
for 5days followed by 4g/day orally for
2weeks)
Migraine
Paracetamol 5001000mg /8h
(FDA,classB)
Metoprolol 50100mg daily
(FDA,classB)
Fluoxetine 20mg daily (FDA, classB)
Sertraline 50mg daily (FDA, classB)
Magnesium (trimagnesium dicitrate)
600mg daily
Stroke
Clopidogrel 75mg daily (FDA, classB) ##
Enoxaparin/fraxiparine (FDA, classB)
*
Mood disorders (depression)
Secondary prevention
Aspirin 50325mg daily
Clopidogrel 75mg daily
Aspirin 50325mg (once daily) plus
extended-release dipyridamole 200mg
(twice daily)
Atorvastatin 80mg daily
Not recommended
Angiography: risk
forstroke
Anticoagulants: risk
for brain bleeding
Prophylactic drugs can be considered to reduce the number

of attacks or when there is inadequate symptom control or
long-lasting aura, as in the general migraine population [201] .
Wellknown first-line prophylactic treatments, such as b-blockers
[65] , flunarizine [66] , amitryptiline [67] and topiramate [68] , should
be used carefully because of their potential adverse effects on
mood and cognition. Sodium valproate, a second-line option
in general migraine patients [69] , could be useful when epilepsy
coexists, as well as the other antiepileptic drugs. Although evidence of efficacy is far from robust, gabapentin [70] is a good
option owing to the safety profile of this drug. Moreover, selective serotonin-reuptake inhibitors (SSRIs), although of uncertain
value in preventing migraine crises [71] , might be useful in those
patients with concomitant mood disorders. It has been suggested
that acetazolamide, a carbonic anhydrase inhibitor, might be a
promising prophylatic treatment in CADASIL patients, probably
by increasing cerebral perfusion to oligemic cortical areas [72] .
Acetazolamide infusion induces a significant increase in cerebral
perfusion, even within areas with impaired cerebral vasoreactivity in CADASIL patients, especially in the cortex [73] . Specific
studies are necessary to prove its efficacy in these patients. Before
any treatment, patients should be advised to maintain a regular
lifestyle, with regular sleep, meals, exercise and management of
stress, perhaps through relaxation techniques. Even though the
efficacy of magnesium, riboflavin and coenzyme Q10 are low

at best, their safety profile makes them alternative treatment
options, as in general migraine patients [66] .
Moderate stage
Most CADASIL patients are diagnosed in this phase, when they

present with lacunar strokes usually without vascular risk factors.
At this moment, we should focus on preventing recurrent strokes
to reduce the disease progression.
Review
Although statins might have beneficial actions on the vascular

system, Peters etal. found no significant improvement on cerebral
vasoreactivity in 24 CADASIL subjects who were treated with
up to 80mg of atorvastatin for 8 weeks [83] . All the conditions
and lifestyle characteristics identified as risk factors for stroke,
such as high blood pressure, diabetes mellitus, high cholesterol,
hyperhomocysteinemia, obesity, physical inactivity and heavy
alcohol intake, should be strictly controlled.
Stroke rehabilitation
Stroke: acute management
As mentioned earlier, transient ischemic attacks and strokes are

found in approximately 85% of CADASIL patients [74] , usually
as typical classic lacunar syndromes with high recurrence rates,
leading to severe disability. There is no drug tested in acute stroke
in CADASIL patients and, as a rule, we treat them as we do the
general stroke population. Since CADASIL is a small-vessel disease, patients do not usually benefit from recanalization therapy,
but tissue plasminogen activator should be administered when
patients meet the criteria. Although rare, strokes involving a territory of a large vessel have also been described [46] . In these cases,
a complete ultrasound examination of cervical and intracranial
arteries is required, as well as a cardiac and aortic arch examination looking for a source of emboli. An interesting point is that
angiography is contraindicated in CADASIL patients, since it
may provoke strokes [75] .
Stroke preventive therapy
At primary prevention level, no evidence-based measures have

been tested in order to prevent strokes in asymptomatic CADASIL
patients. Since smoking increases the risk of stroke in patients
with CADASIL, this habit should be avoided [76] . Different studies suggest that progression of CADASIL is faster in patients who
also have increased blood pressure [7779] . Nevertheless, there is a
lack of data regarding the effect of antihypertensive drug intake
on disease progression.
These patients have an age-related increased risk of intra
cerebral microbleeds [30] . Even though aspirin-associated intra
cerebral hemorrhage has been reported [80] , further research is
needed to determine if the presence of microbleeds and use of
anti-thrombotics may be associated with intracerebral hemorrhage in patients with CADASIL. Conversely, whether antiplatelets are effective for the secondary prevention of stroke is not well
known, and specific trials are necessary. Meanwhile, following
general recommendations of stroke management guidelines,
low- or medium-dose aspirin (50325mg) can be useful in secondary prevention of ischemic cerebrovascular events, as well as
clopidogrel or the combination of aspirin and extended-release
dypiridamole. Moreover, triflusal, which seems to cause fewer
bleeding complications than aspirin, is also an acceptable option
for preventing recurrent stroke [81,82] . In the end, the selection
of an antiplatelet agent should be individualized on the basis
of patient risk-factor profiles and tolerance. By contrast, other
anticoagulants are contraindicated in CADASIL, as they may
provoke hemorrhagic events [30] .
After an acute stroke, CADASIL patients should receive multidisciplinary early active rehabilitation, providing the patient is
clinically stable. Rehabilitation should be continued as long as
perceptible recovery is taking place. Physiotherapy and occupational therapy might be helpful but the optimal mode of delivery
is yet unclear [81] .
Mood disorders
No studies have been performed to test the effects of different

drugs in CADASIL-related mood disorders. However, it is widely
known that SSRIs can be useful in depression, and SSRIs might
have an additional benefit in modulating pseudobulbar syndrome
[84] . Nevertheless, the use of SSRI remains controversial regarding the risk of both ischemic and hemorrhagic strokes. A higher
risk of ischemic stroke has been recently described in patients
currently taking SSRIs [85] . However, Swenson etal. performed a
systematic review, that failed to find an association between SSRI
intake and higher risk of adverse cardiovascular events, including
stroke [86] . Recently, a casecontrol study has found no association
between SSRI intake and increased risk of intracerebral hemorrhage [87] . Further studies are needed to assess the cardiovascular
risk of these drugs; meanwhile, they may be effective in improving
depressive symptoms in CADASIL patients.
Severe stage
By this time, the patient is severely disabled and the therapy is

focused on maintaining the cognitive status and trying to help
patients to live with their handicaps.
Vascular cognitive impairment treatment
A double-blind, placebo-controlled trial evaluating the efficacy and safety of donepezil, a cholinesterase inhibitor, in
168 CADASIL patients with subcortical vascular cognitive
impairment has been performed recently [88] . Although donepezil was not found to improve general cognition, it seems that this
drug could improve some executive functions, such as processing
speed and attention [89] .
In addition, other cholinesterase inhibitors, such as rivastigmine
and galantamine, might be valuable, since a cholinergic deficit has
been reported in the brain and cerebrovascular fluid of patients
with vascular cognitive impairment [21,90] . Posada etal. conducted
an open pilot trial of galantamine in four CADASIL patients.
Clinical improvement was achieved in one subject, stabilization
was noticed in two and one patient was forced to retire because
of the side effects [91] . The small sample size and the absence of a
201
Review
Table 3. Possible surrogate markers for future clinical trials.

Study
Test
Measurable clinical variables

orassociated variables
Test and
Patients
clinical variable
(n)
correlation*
Ref.
Battery of tests in asymptomatic

subjects
Subtle changes in
cognitivecapacities
No
12
[106]
Cognitive impairment (memory and

executive function)
Yes
49
[107]
95
[108]
Psychologic test
Trojano etal. (1998)
Amberla etal. (2004) Digit span forwards

Digit span backwards
Peters etal. (2005)
Yes
Letter fluency task
No
Trail Making Test A and B
No
StroopII and III

Trail Making TestA and B
Symbol digit
Benisty etal. (2008)
Yes
ReyOsterreich memory
Timed measures and error

monitoring. Cognitive impairment
on executive function
Yes
Yes
Yes
Digit cancellation
Yes
Maze task
Yes
Category fluency test
Yes
NINDSAIREN scale for SIVD
Dementia
Yes
115
[109]
Cerebral vasoreactivity
Yes
58
[110]
Doppler blood flow tests

Pfefferkorn etal.
(2001)
TCD of CO2 reactivity in MCA

Mean blood flow velocity in MCA
Yes
Liebetrau etal.
(2002)
Arteriovenous transit time

bysonography
Reflect microvascular changes,

trend with mRS
Yes
34
[111]
Harju etal. (2004)
Retinal capillary blood flow with

Doppler
Disability (mRS)
Yes
22
[112]
Singhal etal. (2005)
Bilateral simultaneous TCD on MCA

after CO2
Cerebral vasoreactivity
andautoregulation
No
44
[113]
Other peripheral blood flow tests

Manabe etal. (2001)
Nocturnal blood pressure dip
Indirect measurement
ofvasoreactivity
Yes
15
[114]
Hussain etal. (2004)
Angiotensin stimulation of skin

biopsyarteries
Vasoreactivity level
Yes
24
[115]
Noradrenaline stimulation of skin

biopsyarteries
Viswanathan etal.
(2006)
Measurement of systolic blood

pressure
Stenborg etal. (2007) Forearm plethysmography with

intra-arterial Ach or SNP
Yes
Presence of microhemorrhages
Yes
147
[79]
Endothelium-dependent
vasodilatation
Yes
30
[116]
Flow-mediated vasodilatation
No
Pulse wave method
No
Indicates whether authors have found a correlation or not (yes or no) between clinical variables and the tests proposed. Negative results are only shown when
conflicting data appears in the literature.
Ach: Acetylcholine; CAMCOG: Cambridge cognitive examination; CBF: Cerebral blood flow; cho: Choline; cr: Creatine; DSM: Diagnostic & Statistical Manual of
Mental Disorders; MCA: Middle cerebral artery; MDRS: Mattis dementia rating scale; MMSE: Mini-mental state examination; mRS: Modified Rankin scale;
NAA:N-Acetylaspartate; NINDSAIREN: National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherch et lEnseignement
en Neurosciences; SIDAM: Structured interview for the diagnosis of the Alzheimer-type, multi-infarct dementia and dementias of other etiology; SIVD: Subcortical
ischemic vascular dementia; SNP: Sodium nitroprusside; SPECT: Single photon emission-computed tomography; TCD: Transcranial Doppler; TMT B: Trail making
testB; WMH: White matter hyperintensities.
*
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Review

Study
Test

Test and
Patients
clinical variable
(n)
correlation*
Ref.
Nuclear detection of specific molecules (PET, SPECT)

Mellies etal. (1998)
Regional CBF by SPECT
Dementia (NINDSAIREN)
Yes
11
[117]
Tatsch etal. (2003)
Regional cerebral metabolic rate of

glucose by PET
Cerebral metabolism, CBF and

neuronal loss
Yes
11
[118]
Tuominen etal.
(2004)
Regional cerebral metabolic rate of

glucose by PET
Cerebral metabolism, CBF and

neuronal loss without dementia
(mRS<2; MMSE>29)
Yes
14
[119]
Vascular changes and

therapeuticeffectiveness
Yes
50
[120]
Yes
147
[79]
Disability (mRS)
Yes
20
[121]
10
[122]
110
[27]
Biopsies and ultrastructural study

Brulin etal. (2002)
Skin biopsy and morphometric study
Plasmatic Biomarkers
Viswanathan etal.
(2006)
Determination of hemoglobin 1Ac

levels
MRI studies
Metabolite measurement in proton MR spectroscopy
Auer etal. (2001)
Ratio NAA/(NAA+cr+cho)
calculation
Ratio Cho/(NAA+cr+cho) calculation
Macri etal. (2006)
Ratio NAA/cr calculation

Ratio Cho/cr calculation
Ratio NAA/cho calculation
Yes
Neuronal loss, early cognitive
impairment (without
neuropsychologic tests)
Yes
Presence of dementia and stroke
Yes
Yes
Yes
Direct measurements on MRI

Singhal etal. (2005)
Scheltens score on MRI
Subcortical white matter score on MRI Presence of dementia

anddepression
Yes
Cumurciuc etal.
(2006)
Dilation of VirchowRobin spaces
Progression of vascular wall lesions
Yes
50
[49]
Jouvent etal. (2007)
Brain parenchymal fraction on MRI
Lesion volume and VirchowRobin

spaces, disability (mRS) and
cognitive impairment (MMSE)
Yes
129
[123]
Liem etal. (2007)
Infarct lesion load on MRI
Cognitive dysfunction (CAMCOG,

Wechsler memory scale, TMT B)
Yes
62
[124]
OSullivan etal.
(2007)
Hipocampal volume on MRI
Cognitive impairment (MDRS,

MMSE)
Yes
142
[125]
Viswanathan etal.
(2007)
Volume of lacunar lesions on MRI
DSM-IV (dementia), cognitive

impairment (MDRS & MMSE),
disability (Barthel index and mRS)
Yes
147
[126]
Jouvent etal. (2008)
3D MRI study of cortical morphology
Cerebral atrophy, lesion load,

disability (mRS) and cognitive
impairment (MDRS)
Yes
54
[127]
*
203
Review

Study
Test

Test and
Patients
clinical variable
(n)
correlation*
Ref.
Chabriat etal. (1999) Diffusion tensor MRI
Disability (mRS) and cognitive

impairment (MMSE)
Yes
26
[128]
Iannucci etal. (2001)
Magnetization transfer ratio on

cerebralMRI
Brain tissue damage, disability (mRS) Yes

and cognitive impairment (SIDAM)
45
[129]
Molko etal. (2001)
Diffusion tensor MRI on subcortical

graymatter
Infarcts load, cognitive impairment

(MMSE)
Yes
32
[130]
Rocca etal. (2001)
Magnetization transfer ratio on

cervical cord MRI
Correlation of cervical cord and

brain lesions
Yes
25
[131]
Molko etal. (2002)
Peak height

impairment (MMSE) at baseline,
mRS increase on follow-up
Yes
19
[132]
Dichgans etal. (2003) Subvoxel free fluid content on MRI
Disability (mRS)
Yes
13
[133]
Holtmanspotter etal. MRI histograms

(2005)
Progression of disease (mRS, NIH

stroke scale, SIDAM)
Yes
71
[134]
Bruening etal. (2001) Regional CBF on WMH (using

contrast)

impairment (MMSE)
Yes
24
[135]
Viswanathan etal.
(2006)
Disability (mRS)
Yes
147
[79]
Short afferent inhibition on MRI
Cholinergic activity, cholinomimetic

therapy monitoring
Yes
20
[136]
Diffusion tensor images
Whole brain trace of diffusion tensor
Yes
Gradient echo spin
Cholinergic activity
Manganelli etal.
(2007)
*
placebo group are serious limitations of this study, but this kind
of assay may, at least, help us to increase the clinical experience
with these patients.
Memantine, a low-affinity glutamate NMDA receptor antagonist, might be a second-line option, since this drug has shown a
small beneficial effect in moderate-to-severe Alzheimers disease.
However, this effect on cognition was not clinically detectable
in those with vascular cognitive impairment [92] ; thus, we do not
have enough evidence about this treatment. Finally, the choice of
the pharmacologic agent should be based on tolerability, adverseeffect profile, ease of use and cost of medication [93] . Nevertheless,
specific clinical trials should be carried out if we want to determine the real efficacy of these drugs for improving cognition
among CADASIL patients.
Supportive care (i.e., practical help, emotional support and
counseling) is necessary for affected individuals and their families [202] . Although no specific group gives support to CADASIL
patients, some foundations or associations may be quite helpful for
204
them, such as the Huntingtons Disease Society of America [203] ,

the United Leukodystrophy Foundation [204] or the Alzheimers
Association [205] .
Other general measures in supporting individuals with dementia, such as avoiding pressure ulcer, gastrostomy or respiratory
physiotherapy, ought to be considered when necessary.
Pregnancy
In the general population, ischemic cerebrovascular complications during gestation and puerperium are rare (8.1 per 100,000
pregnancies) [94] . Nevertheless, transient neurologic symptoms
and preeclampsia appear to be common in CADASIL patients,
particularly in women older than 30years of age. Roine etal.
reported data from a Finnish group of 39 CADASIL women
who had been pregnant and found that preeclampsia was more
frequent (10.3%) in CADASIL patients than in the general population (35%) [95,96] . In addition, in 15 of the 19 complicated
pregnancies, neurological events appeared during puerperium
and, in 82% of the symptomatic group, these symptoms were the

first clinical manifestations of CADASIL. This higher incidence
of preeclampsia is not surprising if we consider the pathogenic
role of impaired cerebral hemodynamics and endothelial dysfunction in CADASIL [97] . Peters etal. have recently described
an enhanced l-arginine-induced vasoreactivity in CADASIL
patients compared with controls, suggesting endothelial dysfunction in CADASIL [97] . Interestingly, the authors suggest
that, by enhancing vasodilatation, l-arginine may be a possible
therapeutic approach for CADASIL. Nevertheless, a limiting
factor could be headache, a frequent adverse effect associated
with l-arginine treatment. In this sense, l-arginine supplementation seems promising in reducing blood pressure in patients with
gestational hypertension [98] .
Even if migraine usually improves during pregnancy, some
patients may need prophylactic treatment. In these cases, a
b-blocker, metoprolol, is an acceptable first-line option as well
as sertraline or fluoxetine (US FDA, classB). A good alternative option in these patients is magnesium. Paracetamol is safe
throughout pregnancy and may be useful to ameliorate acute
migraine crisis. (FDA, classB). Regarding secondary prevention of stroke, it should be remembered that aspirin should be
avoided in pregnant women during the first trimester (FDA,
classD) because of its potentially teratogenic effect. Clopidogrel
may be an alternative (FDA, classB) although more studies
should be performed in order to determine the real teratogenic
effect of this drug. Regardless, these pregnancies should be
monitored carefully.
Genetic counseling
Patients with CADASIL should receive proper disease and

genetic information to help them make informed medical and
personal decisions. Regarding asymptomatic individuals, it is
advisable to follow the guidelines for presymptomatic testing
for Huntingtons disease. An interview should be carried out in
order to assess the possible impact of positive and negative test
results; informed consent is necessary and records should be
kept confidential. The recommended evaluation is molecular
genetic testing.
Review
During childhood, consensus holds that underaged individuals should not be tested in the absence of symptoms, mainly
to allow them to decide if they want this information, since
predictive testing only provides the presence of mutation and is
not useful in predicting either clinical onset or progression of
the disease. The identification of effective primary prevention
therapies might modify this statement. Nevertheless, symptomatic individuals below 18 years of age usually benefit from having
a specific diagnosis established.
While prenatal testing of adult-onset disorders is unusual,
it is possible to perform a prenatal diagnosis of CADASIL
[99] . When the disease-causing mutation has been previously
identified in a family, DNA may be extracted from fetal cells
obtained by amniocentesis or chorionic villus sampling to
perform a molecular analysis. Furthermore, preimplantation
genetic diagnosis may be considered as a reproductive option,
since CADASIL a dominant, highly penetrant and potentially
serious disease [100] .
Expert commentary & five-year view
Since CADASIL is an orphan disease (very-low-prevalence illness)

and since, according to market conditions, the pharmaceutical
industry is reluctant to support research into drugs for rare diseases, an effective treatment for CADASIL is, thus, difficult to
develop. Nevertheless, recent changes in national public-health
programs, such as the Orphan Drugs strategy in the EU, raise
hope for finding a helpful drug for these conditions.
Fortunately, research on CADASILs pathogenesis and biomarkers may contribute to new drug findings. Interestingly,
Ihalainen et al. have identified 11 differentially expressed
proteins, which are involved in protein degradation and folding, contraction of VSMCs and cellular stress, in genetically
genuine cultured human CADASIL VSMCs by proteomic
analysis [14] . Some of these proteins might be a possible target
for researchers developing new drugs. In addition, since endoplasmic reticulum stress and increased reactive oxygen species
(ROS) concentration seem to play a role in pathogenesis, drugs
modulating or reversing these reactions underlying cell damage
from oxidative stress, such as B(6)-vitamin-derived molecules
Key issues
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-vessel
disease manifesting as migraine with aura, mood disorders, recurrent lacunar strokes and vascular cognitive impairment.
CADASIL is diagnosed on the basis of skin biopsy and molecular genetic testing, but it may be overlooked or misdiagnosed.
Migraine attacks can be aborted with simple analgesics, and triptans are generally not recommended because of their potential
vascular side effects.
Angiography is not recommended due to its high risk of cerebrovascular events in CADASIL patients.
Regarding stroke prevention, anticoagulants are contraindicated owing to the risk of hemorrhagic stroke.
l-arginine, if tolerated, might be a promising treatment for enhancing cerebral vasodilatation.
Donepezil did not improve general cognition, but it could improve some executive functions, such as processing speed and attention.
Pregnancies should be carefully followed in CADASIL women. Prenatal testing and preimplantational diagnosis are possible for families
in which the disease-causing mutations have been identified.
Resveratrol, a SIRT1 enhancer, appears to be a good candidate for testing in future clinical trials.
Further clinical trials and basic research are necessary to improve evidence-based management in CADASIL patients.
205
Review
[101] ,
appear to be promising future therapeutics in CADASIL

disease. In the same way, increasing silent information regulator (SIRT)1 has been found to protect cells against amyloidb-induced ROS production and DNA damage in Alzheimers
disease, thereby reducing apoptotic death in vitro [102] . SIRT1
belongs to the sirtuins family, a new family of enzymes that
regulate gene silencing, DNA repair, rDNA recombination and
apoptosis, thus extending lifespan. Resveratrol, a polyphenolic
SIRT1 activator, is considered to be a potential drug for the
treatment of neurodegenerative [103] and metabolic diseases [104] ;
in fact, clinical trials in Type2 diabetic patients are currently
in progress. Hence, according to the third model attempting to
explain CADASIL, in which ROS production plays a central
role, resveratrol seems promising as a future CADASIL therapeutic and further research will help to elucidate its efficacy
in these patients.
Regarding diagnosis of CADASIL, it would be interesting
to develop new tests in order to facilitate screening of the disease. Finally, although it is highly difficult to recruit patients
considering the low prevalence of rare diseases, clinical trials
are mandatory to test effective drugs for CADASIL. Several
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Acknowledgement
The authors would like to thank Anna Vilalta for help with manuscript
preparation.
Financial & competing interests disclosure
This study was funded by the stroke research network (RENEVAS). A del
Ro-Espnola has a grant from the Vall dHebrn Research Institute; M
Mendiroz is the recipient of a grant from the Instituto de Salud Carlos III
for medical research training (FI05/00081); S Domingues-Montanari is the
recipient of a grant from the Ramn Areces Fundation; P Pozo-Rosich has
a grant for Post-Medical Sanitary Specialization (postMIR); and I
Fernndez-Cadenas has a post-doctoral research contract from RENEVAS.
The authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
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Affiliations

Alberto del Ro-Espnola

Neurovascular Research Laboratory and
Neurovascular Unit, Vall dHebrn
Hospital, Neurology and Medicine
Departments-Universitat Autnoma de
Barcelona, Spain
Maite Mendiroz
Barcelona, Spain
Sophie Domingues-Montanari
Barcelona, Spain
Patricia Pozo-Rosich
Barcelona, Spain
Esther Sol
Molecular Biology Unit, Biochemistry
Department, Vall dHebrn Hospital,
Barcelona, Spain
Jessica Fernndez-Morales
Neurovascular Unit. Vall dHebrn
Barcelona, Spain
Israel Fernndez-Cadenas
Barcelona, Spain
Joan Montaner
Neurovascular Unit, Institut de Recerca,
Hospital Vall dHebron, Pg Vall dHebron
119-129, 08035 Barcelona, Spain
Tel.: +34 934 894 073
Fax: +34 934 894 102
31862jmv@comb.es
Websites
201
BASH British Association for the Study

of Headache
www.bash.org.uk
202
Genereviews: Lesnik Oberstein SA, Boon

E, Dichgans M. CADASIL (Cerebral
Autosomal Dominant Arteriopathy with
Subcortical Infarcts and
Leukoencephalopathy)
www.ncbi.nlm.nih.gov/bookshelf/br.
fcgi?book=gene&part=cadasil
203
Huntingtons Disease Society of America

www.hdsa.org
204
United Leukodystrophy Foundation

www.ulf.org
205
Alzheimers association
www.alz.org

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Alberto del RoEspnola*,

*Authors contributed equally to

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy

muscle cells (VSMCs) and pericytes [12] , which

Mutations associated with CADASIL cluster in

2009 Expert Reviews Ltd

del Ro-Espnola, Mendiroz, Domingues-Montanari etal.

transferase-mediated dUTPbiotin nick end labeling method

Signs and symptoms of CADASIL are migraine (often with severe,

Update of CADASIL management

Table 1. Predictive values of the currently available diagnostic tests.

Joutel etal. (2001)

Genetic testing (23 exons)

Lesnik Oberstein etal.

Malandrini etal. (2007)

we consider studying exon 25 of NOTCH3, involved in another

Regarding the clinical features, we propose

Migraine with aura

At this stage, patients are young and most

Figure 1. Clinical stages of cerebral autosomal dominant arteriopathy with

del Ro-Espnola, Mendiroz, Domingues-Montanari etal.

Table 2. Allowed and contraindicated drugs for

Table 2. Allowed and contraindicated drugs for

Contraindicated under antiplatelet treatment.

Advisable to follow mood side effects.

Recommended when migraine coexists with depression.

May improve pseudobulbar syndrome symptoms.

Improves some executive functions.

Possibly useful but more evidence is necessary.

Aspirin (FDA, classD)

Selective serotonin-reuptake inhibitors

Mood disorders (depression)

Prophylactic drugs can be considered to reduce the number

Update of CADASIL management

efficacy of magnesium, riboflavin and coenzyme Q10 are low

Most CADASIL patients are diagnosed in this phase, when they

Although statins might have beneficial actions on the vascular

Stroke: acute management

As mentioned earlier, transient ischemic attacks and strokes are

At primary prevention level, no evidence-based measures have

No studies have been performed to test the effects of different

By this time, the patient is severely disabled and the therapy is

del Ro-Espnola, Mendiroz, Domingues-Montanari etal.

Table 3. Possible surrogate markers for future clinical trials.

Measurable clinical variables

Battery of tests in asymptomatic

Cognitive impairment (memory and

Amberla etal. (2004) Digit span forwards

Peters etal. (2005)

Letter fluency task

Trail Making Test A and B

StroopII and III

Benisty etal. (2008)

Timed measures and error

Category fluency test

NINDSAIREN scale for SIVD

Doppler blood flow tests

TCD of CO2 reactivity in MCA

Arteriovenous transit time

Reflect microvascular changes,