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CADASIL Mimicking Primary Angiitis of the Central Nervous System
Stefan T. Engelter, MD;
Stephan Rueegg, MD;
Eberhard C. Kirsch, MD;
Felix Fluri, MD;
Alphonse Probst, MD;
Andreas J. Steck, MD;
Philippe A. Lyrer, MD
Arch Neurol. 2002;59:1480-1483.
ABSTRACT
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Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) and primary angiitis of the central nervous
system (PACNS) share several clinical and radiological features. However,
digital subtraction angiogram (DSA) is generally reported as normal in CADASIL,
whereas lumen irregularities in distal cerebral arteries indicate PACNS.
Objective To describe a potential pitfall of DSA interpretation, which led to
the tentative diagnosis of PACNS in a CADASIL patient.
Patient and Methods Single case observation.
Results A 47-year-old man sustained recurrent subcortical infarcts. He had mild
hypercholesterolemia and migraine. His family history was unremarkable. The
underlying cause of stroke could not be elucidated. Transcranial Doppler sonography
revealed decreased intracranial blood flow velocities compatible with CADASIL.
Lumen irregularities of several peripheral intracranial arteries were seen
on DSA, which suggested PACNS. CADASIL was confirmed by results from skin
biopsy and genetic testing.
Conclusions First, in patients with CADASIL, DSA can show segmental lumen irregularities
in distal cerebral arteries suggestive of PACNS. Second, the potential role
of transcranial Doppler sonography to distinguish CADASIL from PACNS deserves
further testing.
INTRODUCTION
CEREBRAL AUTOSOMAL dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) is clinically characterized by recurrent subcortical
infarcts (70%), migraine (38%) mostly with aura, psychiatric disturbances
(30%), cognitive impairment (28%), and epilepsy (10%) in middle-aged patients.1 Despite autosomal dominant inheritance, family history
may be unremarkable because of mild symptoms in other family members or because
of spontaneous mutations.2 CADASIL shares several
clinical symptoms and magnetic resonance imaging (MRI) features with primary
angiitis of the central nervous system (PACNS).3
We present a patient with CADASIL whose clinical presentation, unremarkable
family history, and results of cerebral digital subtraction angiogram (DSA)
first suggested PACNS, whereas the results of transcranial Doppler sonography
(TCD) were more indicative of CADASIL. Skin biopsy findings of granular osmiophilic
material within the basal lamina surrounding vascular smooth muscle cells
and genetic testing (presence of notch 3 mutation) eventually confirmed CADASIL.
REPORT OF A CASE
A 47-year-old man had migraine attacks with prolonged aura since age
23 years. At the age of 32 years, he was hospitalized due to transient left-sided
hemiparesis, episodes of depersonalization, and clumsiness of the left hand.
These symptoms were interpreted as prolonged migraine aura. Ten years later,
he developed right-sided sensorimotor hemiparesis. He recovered completely
within 3 months. In the past 2 years, he developed progressive emotional instability
with aggressive outbursts that were successfully treated with carbamazepine.
Three weeks prior to hospital admission, the patient had sudden onset of vertigo
and severe disturbance of balance.
Neurological examination findings revealed dysarthria and severe brachiofacial
spastic hemiparesis with slight hemihypesthesia on the left side. Extensor
plantar response was present on both sides. Perioral reflexes were brisk.
Findings from computed tomography (not shown) and MRI (Figure 1) revealed multiple chronic subcortical lesions bilaterally
and an acute ischemic lesion in the right internal capsule. Findings from
Doppler and duplex sonography of the extracranial arteries were normal; no
atherosclerosis was recorded. Transesophageal echocardiography and 24-hour
electrocardiograph monitoring revealed no abnormalities. There was no patent
foramen ovale. Cerebrospinal fluid examination results showed a slightly elevated
protein level (0.069 g/dL [reference, <0.048 g/dL]) but were otherwise
normal. Laboratory testing did not indicate systemic vasculitis, coagulopathy,
or sarcoidosis. Hematocrit levels were normal (41% [reference, 38%-52%]).
The only vascular risk factor present was moderate hypercholesterolemia (266
mg/dL [6.9 mmol/L]). Cerebral DSA revealed segmental narrowing of several
peripheral arterial branches within the territories of the anterior cerebral
artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery
bilaterally and a mild dilatation of proximal portions of major cerebral arteries
(Figure 2). Findings on DSA (most
notably the peripheral irregularities) were considered indicative of PACNS.
Accordingly, the patient was treated with prednisone (1 mg/kg body weight)
and oral cyclophosphamide (150 mg/d). Findings from TCD revealed low mean
flow velocities in the major intracranial arteries (Table 1), as recently reported in CADASIL patients.5
A skin biopsy was performed, which showed granular osmiophilic material within
the basal lamina of vascular smooth muscle cells in small subcutaneous arterioles.
Genetic testing (Laboratoire Cytogénétique, E. Tournier-Lasserve,
MD, Hôpital Lariboisiere, Paris, France) revealed a mutation of the
notch 3 gene with a nucleotide substitution (CGC TGC) at position 475
on exon 4. CADASIL was diagnosed, and the immunosuppressive therapy was stopped.
Within the next 3 months, the patient recovered only slowly with persistent
severe left-sided hemiparesis.
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Figure 1. Magnetic resonance imaging of
subcortical infarcts and leukoencephalopathy in a patient with CADASIL (cerebral
autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
A representative T2-weighted magnetic resonance image demonstrates multiple
areas of high-signal intensity in the periventricular white matter bilaterally.
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Figure 2. Digital subtraction angiogram
(DSA) of a patient with CADASIL (cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy). Selective DSA (oblique
view, magnified) of the left internal carotid artery shows multifocal vessel
narrowing in the peripheral anterior cerebral artery territories (small arrows).
In addition, mild segmental arterial dilatation can be seen in the proximal
middle cerebral artery (large arrow).
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Transcranial Doppler Sonography of a Patient With CADASIL*
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COMMENT
From his mid-thirties on, our patient had recurrent subcortical brain
infarcts without evidence of an underlying atherothrombotic or embolic disease,
of a coagulopathy, or of systemic vasculitis. Investigation results were negative
until DSA showed focal lumen irregularities with multiple stenosis of distal
intracranial arteries. In the clinical context of an unremarkable family history,
as yet unexplained recurrent subcortical strokes, and (slightly) abnormal
cerebrospinal fluid findings (increased protein), these DSA findings suggested
PACNS.6 However, clinical signs and symptoms
of PACNS are unspecific. In addition, angiographic findings in PACNS have
a sensitivity of 80% and a specificity of only 30%,7
indicating a moderate diagnostic yield. Of interest, brain biopsy has a sensitivity
of only 53% and a specificity of 87%.7 Despite
the limited diagnostic utility of both methods, the diagnosis of PACNS in
most cases essentially relies on angiographic or biopsy findings.7 Differential diagnosis of PACNS includes systemic
vasculitis, central nervous system infection (eg, human immunodeficiency virus,
syphilis), lymphoma, demyelinating disease, drug use (eg, cocaine or amphetamine),
sarcoidosis, and rare vasculopathies such as fibromuscular dysplasia and moyamoya
disease.6-7 However, none of these
diseases was confirmed in our patient.
A recent case report3 illustrates the
difficulties in distinguishing CADASIL from PACNS owing to similar clinical
presentation and MRI appearance. Although it has been reported that most CADASIL
patients have normal DSA results,8-9
this patient, like ours, showed multifocal segmental intracranial stenosis,
which first suggested PACNS. A positive history of stroke at mid-adulthood
in several first-degree relatives provided the clue to CADASIL in this patient,3 whereas our patient lacks a positive family history
of stroke or dementia.
Concerning CADASIL and DSA findings in the literature, at an international
CADASIL workshop it was reported8(pp705-706)
that
cerebral angiography was performed in at least one affected member
in all studied [ie, eight] families. It was essentially normal except in the
family from . . . with dolichomega-arteries, and in one . . . with angiographic
aspect suggestive of fibromuscular dysplasia. . . . they most likely were
associated conditions.
In their article about the clinical spectrum of CADASIL, Chabriat et
al9(p936) reported that 14 of 45 symptomatic
family members underwent DSA. Findings were normal in 13 patients, while 1
patient had "a narrowing of some small branches of the anterior, middle, and
posterior cerebral arteries." No further clinical data (eg, presence of migraine)
on the patients with abnormal DSA findings were given.8-9
In our patient, TCD findings revealed decreased mean flow velocities
in both MCA and ACA. These findings are in accordance with the results of
a recent TCD study in CADASIL patients that focused on carbon dioxide reactivity
but also reported in detail on mean flow velocities; the 29 CADASIL patients
in the study showed significantly lower MCA mean flow velocities than the
29 age-matched controls.5 Low MCA mean flow
velocities are unspecific, and primary causes include increasing age and high
blood viscosity. Both factors were not applicable in our patient because (1)
his mean blood flow velocities were low (ie, <2 SDs of the mean) compared
with age-matched normal values, and (2) his hematocrit level was normal. Low
mean flow velocities can be present in other forms of subcortical vascular
encephalopathy, most notably in Binswanger disease, which, however, was not
present in our patient. Of interest, Mohr10(p715)
stated that "Binswanger's famous case, no less, may have been CADASIL," and
that "CADASIL may join granulomatous arteritis of the central nervous system
[PACNS] to suggest that the brain vasculature has biological properties somewhat
different from other vascular beds."10(p715)
In contrast to CADASIL patients (with low MCA mean flow velocities),
in all PACNS case studies that include TCD investigations, all 5 patients
had increased MCA mean flow velocities.11-13
These observational data support the assumption that TCD might be helpful
in choosing which further invasive diagnostic tests should be applied (ie,
skin biopsy vs DSA) in patients with signs of a subcortical leukoencephalopathy
of unclear origin. An algorithm for the distinction of both entities would
have clinical implications. First, DSA encompasses an increased complication
rate in CADASIL.14-15 Second,
immunosuppressive therapy is indicated only in PACNS. However, functional
TCD variables such as carbon dioxide reactivity were assessed neither in our
study nor in the mentioned TCD reports in PACNS. Furthermore, this is only
a single case observation. Therefore, a detailed discussion about a possible
future role of TCD in CADASIL and PACNS is beyond the limitations of this
case report and has to await further studies.
Our finding of low MCA and ACA blood flow velocities in CADASIL is in
agreement with hemodynamic studies in CADASIL using MRI,16
positron emission tomography,17 or single-photon
emission computed tomography.18 All these methods
showed reduced cerebral blood flow and cerebral blood volume, especially in
white matter. In addition, carbon dioxide–induced vasoreactivity was
reduced in CADASIL patients.5 Low mean flow
velocity of MCA and ACA as well as low cerebral blood flow, low cerebral blood
volume, and impaired vasoreactivity all point to a dilatation of the major
intracranial arteries in CADASIL. Vasodilatation of the proximal arterial
segments might be interpreted as an attempt to compensate for the lumen reduction
in distal arterial branches as visualized by DSA in our patient. Distal lumen
reduction of small perforating arteries may reflect vascular smooth muscle
cell dysfunction19 or vessel destruction and
replacement by extracellular matrix with superimposed subendothelial fibrous
proliferation.19-20 The fact that
histological alterations in CADASIL are predominantly found in smaller arteries
and arterioles19 might explain our DSA result
of stenosis involving the distal arterial branches rather than the major cerebral
arteries. However, it remains unclear why, in general, DSA findings in CADASIL
have been reported to be normal.
AUTHOR INFORMATION
Accepted for publication February 13, 2002.
Author contributions: Study
concept and design (Drs Engelter, Steck, and Lyrer); acquisition of data (Drs Engelter, Rueegg, Kirsch, Fluri, and Lyrer); analysis and interpretation of data (Drs Engelter, Rueegg,
Kirsch, Probst, and Lyrer); drafting of the manuscript
(Drs Engelter and Rueegg); critical revision of the manuscript
for important intellectual content (Drs Rueegg, Kirsch, Fluri, Probst,
Steck, and Lyrer); obtained funding (Drs Engelter
and Lyrer); administrative, technical, and material support (Drs Kirsch and Probst); study supervision
(Drs Steck and Lyrer).
The study was supported by the Basel Hirnschlag [Stroke]-Fonds, Basel.
We thank Susanna Papa for helpful language assistance.
There are no conflicts of interest involved in the study.
Corresponding author and reprints: Stefan T. Engelter, MD, Neurological
Clinic and Stroke Unit, University Hospital Basle, Petersgraben 4, CH–4031
Basel, Switzerland (e-mail: sengelter{at}uhbs.ch).
From University Hospital Basle, Neurological Clinic and Stroke Unit
(Drs Engelter, Rueegg, Fluri, Steck, and Lyrer), Departments of Neuroradiology
(Dr Kirsch) and Pathology (Dr Probst), Basel, Switzerland.
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