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Cerebrovasc Dis 2011;31:294–299
Basilar Artery Diameter Is a Potential
Screening Tool for Fabry Disease in
Young Stroke Patients
Andreas Fellgiebel a Isabel Keller a, b Peter Martus c, d Stefan Ropele c, f
Igor Yakushev a Tobias Böttcher c, e Franz Fazekas c, f Arndt Rolfs c, e
a Department of Psychiatry and b Institute of Neuroradiology, University of Mainz, Mainz , c Stroke in Young Fabry
Patients Study Group and d Department of Biostatistics and Clinical Epidemiology, Charité University Medicine,
Berlin , and e Albrecht Kossel Institute for Neuroregeneration, Medical Faculty, University of Rostock, Rostock ,
Germany; f Department of Neurology, Medical University Graz, Graz , Austria
Basilar artery Fabry disease Young stroke patients
A b s t r a c t
B a c kg r o u n d : Fabry disease (FD) is a rare hereditary lysosomal
storage disease that has been highlighted as a possible
etiology of stroke at a young age. Enlarged basilar artery diameters
(BADs) have been demonstrated in FD, and we hypothesize
that they might be useful for the screening of FD
in young stroke patients. The aim of this study was to compare
BADs of young stroke patients without FD to those of
FD patients and of healthy age-matched controls. Methods:
BADs were measured using MR angiography in 3 age- and
gender-matched groups: 25 FD patients (aged 36.5 8 11.0
years), 26 non-FD stroke patients and 20 healthy controls.
Results: Compared to the non-FD stroke patients, FD patients
had significantly enlarged BADs. FD patients could be
significantly separated from stroke patients by BADs (area
under the curve = 0.89, 95% confidence interval 0.81–0.98).
Eighty-six percent of all subjects could be correctly classified
by BADs (sensitivity 84%, specificity 88.5%). Conclusions:
Enlarged BADs were able to detect FD within a cohort of FD,
© 2010 S. Karger AG, Basel
Accessible online at:
Received: July 15, 2010
Accepted: November 4, 2010
Published online: December 22, 2010
stroke patients and healthy controls. BAD measurement
could be an easily obtainable and sensitive screening tool for
FD in young stroke patients. Copyright © 2010 S. Karger AG, Basel
The neurological hallmarks of Fabry disease (FD), an
inherited multisystemic lysosomal storage disorder  ,
include small fiber neuropathy as well as cerebral micro-
and macroangiopathy  . The prevalence of ischemic
stroke has been reported to be about 12 times greater in
FD patients than that expected in a comparable general
population  . Cerebrovascular events in males typically
occur at an early age and preferentially within the territory
of the posterior circulation. In females, cerebrovascular
events occur a mean of 10 years later  .
Conventional MRI shows micro- and macroangiopathic
changes such as progressive white matter lesions at
an early age, increased signal intensity in the pulvinar on
T 1 -weighted MRI (‘pulvinar sign’) as well as tortuosity
and dilatation of the larger vessels  .
We recently found significantly enlarged basilar artery
diameters (BADs) in FD patients compared to healthy
Dr. A. Fellgiebel
Department of Psychiatry, University Hospital of Mainz
Untere Zahlbacher Strasse 8, DE–55131 Mainz (Germany)
Tel. +49 6131 176 789, Fax +49 6131 176 690
E -M a i l f e l l g i e b e l @ psychiatrie.klinik.uni-mainz.de
controls  . Using a BAD cutoff of 2.67 mm derived by
receiver-operating curve (ROC) analysis, patients could
be separated from controls with an accuracy of 87%. This
favorable diagnostic utility was clearly superior to all other
applied structural MR measurements such as global
white matter lesion load, global mean diffusivity and diameters
of the remaining larger vessels of the circle of
There is evidence that the proportion of undiagnosed
FD within the cohort of young cryptogenic stroke patients
is much higher (5% of males and 2.4% of females
aged 18–55 years in cryptogenic stroke, corresponding to
1.2% of all young stroke patients) than previously expected
 . A recent study supports these results  . To investigate
further the prevalence of FD in stroke patients, a
large international screening study for FD (SIFAP –
Stroke in Young Fabry Patients) has been initiated in an
unselected cohort of more than 5,000 young stroke patients
(aged 18–55 years) in 46 centers in Europe. Enrollment
has been successfully completed (January 2010).
In some cases, ischemic stroke at a young age is the
first manifestation of the disease  . Therefore, a reliable
and easily detectable screening parameter for FD in
young cryptogenic stroke patients would be highly desirable.
An enlarged BAD might serve well as this parameter.
However, diameters of the cerebral blood vessels between
FD and common stroke patients have not yet been
systematically compared. The aim of the present study
was to determine the reliability and diagnostic utility of
BADs for the identification of FD in a mixed cohort of
patients with FD, young non-FD stroke patients and
Subjects and Methods
Pa t i e n t s
For this study, we used the imaging data of 25 clinically affected
FD patients (2 with ischemic stroke) and 20 healthy controls.
Demographical and clinical characteristics are given in table
1 . All patients were recruited at the Children’s Hospital, University
of Mainz, Germany. The Mainz Severity Score Index was
used to assess overall disease severity in FD. Total Mainz Severity
Score Index scores ranged from 2 to 37 (median 22), indicating
mild to moderate disease involvement  . More details of the enrollment
procedure and the clinical characteristics of the patient
group have been published previously  . These patients were
randomly matched for age and gender with 26 patients of the
SIFAP group (ClinicalTrials.gov, identifier: NCT00414583) who
had experienced an acute ischemic stroke and in whom FD had
been excluded by genetic testing (complete sequencing of the exons
as well as the exon-intron boundaries). From all SIFAP patients,
a detailed MRI has been documented and analyzed accord-
Basilar Artery in FD and Young Stroke
Table 1. Demographical, clinical and stroke characteristics of patients
FD Stroke HC
Subjects 25 26 20
Women 15 17 11
Mean age 8 SD, years 36.5 8 11.0 39.8 8 10 36.8 8 10.0
Age range, years 20–56 20–54 21–56
Ischemic stroke total 2 (8) 26 (100) 0
Large-vessel disease 1 (50) 4 (15) 0
Small-vessel disease 1 (50) 1 (4) 0
Cardioembolism 0 7 (27) 0
Other etiology 0 7 (27) 0
Undetermined or multiple
possible etiologies 0 7 (27) 0
Vascular territory of stroke
Anterior circulation 0 7 (27) 0
Middle circulation 0 13 (50) 0
Posterior circulation 2 (100) 6 (23) 0
S troke subtype according to TOAST criteria ; FD = Fabry
disease; stroke group = patients from the SIFAP cohort with acute
ischemic stroke, exclusion of FD; HC = healthy controls; figures
in parentheses indicate percentage of total number of subjects
within the cohort or of total number of strokes within the cohort.
ing to a standardized protocol at the University of Graz (S.R., F.F.).
The study was approved by the local Ethics Committee, and all
subjects gave written informed consent.
Me a s u re m e n t s
Data on FD patients and healthy controls were obtained on a
1.5-tesla system with gradients of 40 mT/m (Magnetom Sonata;
Siemens), Institute of Neuroradiology, University Medicine of
Mainz, Mainz, Germany. To assess the larger intracranial vessels,
time-of-flight (TOF) sequences were conducted. In the SIFAP cohort,
TOF angiograms were obtained by different scanners (25 !
Siemens: Avanto 9 ! , Symphony 12 ! , Sonata 2 ! , Harmony Expert
1 ! and Trio 1 ! ; 1 ! Philips Achieva). Except for the Trio (3.0
T), all scanners had a 1.5-tesla system. Slice thickness ranged between
0.59 and 1.23 mm, and the range of voxel sizes was 0.11–
0.32 mm  .
Measurement procedures have been reported in detail previously
 and were performed by 2 independent readers (I.K. and
P.M.) without knowledge of the individuals’ diagnoses.
S t a t i s t i c a l An a ly s e s
Descriptive statistics are shown as mean values and standard
deviations. Group comparisons were analyzed using the 2 test for
categorical variables; Student’s t tests were applied when distributions
differed not significantly from normal as determined by the
Kolmogorov-Smirnov Z test (p ! 0.05). Z transformation of the
patients’ artery diameters was conducted with respect to the
healthy controls. Correlations were analyzed with Spearman rank
Cerebrovasc Dis 2011;31:294–299 295
Table 2. Group differences of larger vessel diameters (mm, means 8 SD)
Cerebral artery diameters FD Stroke HC p (FD vs. stroke) p (stroke vs. HC)
Anterior cerebral artery 1.7 8 0.31 (0.33) 1.7 8 0.40 (0.24) 1.5 8 0.31 n.s. (n.s.) n.s.
Middle cerebral artery 2.5 8 0.23 (0.80) 2.1 8 0.40 (–0.29) 2.2 8 0.30 0.001 (0.001) n.s.
Posterior cerebral artery 1.6 8 0.32 (0.63) 1.4 8 0.32 (0.10) 1.4 8 0.31 n.s. (n.s.) n.s.
Carotid artery 2.9 8 0.48 (0.70) 2.6 8 0.54 (–0.04) 2.6 8 0.46 0.019 (0.018) n.s.
BAD 3.3 8 0.59 (2.6) 2.45 8 0.5 (0.1) 2.4 8 0.36 < 0.0005 (
Fi g . 1. Standardized larger vessel diameters
(95% CIs, Z scores) of Fabry disease
(FD) and stroke patients. post. = Posterior
cerebral artery; med. = middle cerebral
artery; ant. = anterior cerebral artery;
carot. = carotid artery; comp. = composite
z-score (mean Z over all arteries), referring
to normal controls (Z standardization, see
also table 2). FD patients showed increased
diameters of the larger cerebral vessels (see
table 2) while there were no significant
changes in stroke patients.
As for interrater reliability of MR-angiographic measurements,
comparisons between both readers showed
no systematic bias (p = 0.64) and a very high correlation
of 0.99 (p ! 0.001) between both readers. The values averaged
from both readers varied between 1.40 and 3.30
(range = 1.90). Ninety-five percent of all discrepancies lie
between –0.15 and 0.15 with no systematic pattern detectable.
Within the MRIs of the SIFAP cohort, neither
slice thickness nor voxel sizes correlated with the artery
Basilar Artery in FD and Young Stroke
95% CI (z-score)
0 0.2 0.4 0.6 0.8 1.0
1 – specificity
Fi g . 2 . ROC curves of basilar artery diameters. Fabry disease (n =
25) versus stroke (n = 26) patients.
diameters (Spearman rank correlation p 1 0.5). Also no
independent influence of the different scanner types on
BADs could be detected using univariate ANOVA (p 1
Post. Med. Ant. Carot. Comp.
This study investigated the potential diagnostic utility
of BADs in identifying FD in a mixed cohort of FD patients,
age- and gender-matched subjects with a history of
acute ischemic stroke and healthy controls. In the present
study, we found that enlarged BADs were characteristic
of subjects with FD, but not of young patients suffering
from acute stroke of other etiologies, in whom FD was
excluded by genetic assessment. Accordingly, measurements
of BADs separated subjects with FD from young
stroke patients as well as from healthy controls with a
high accuracy. Specifically, at a cutoff value of 2.98 mm
the accuracy of this parameter was 84%, which means
that 44 patients out of 51 were correctly classified as FD
or non FD-stroke patients.
The alteration of the basilar artery morphology in FD
has been documented repeatedly [5, 11–13] . We recently
showed that, among other MRI findings which are known
to be indicative for FD, especially white matter lesions,
the enlarged BAD was by far the best MR morphological
characteristic to separate FD patients from normal controls
 . Whereas a number of etiological factors has been
suggested for the FD-associated microangiopathy  ,
the nature of macroangiopathy in FD, especially the pronounced
involvement of the basilar artery, is still unclear.
Cerebrovasc Dis 2011;31:294–299 297
We speculate that autonomic dysfunction is a leading
mechanism for the dilatation of the larger brain vessels
and causes, possibly enforced by secondary hemodynamic
changes, the pronounced involvement of the basilar artery
[5, 14, 15] .
FD as cause of stroke at a young age still seems to be
underrecognized [6, 7] . Despite the prevailing uncertainty
regarding the prevalence of FD in the young stroke
cohort [4, 7, 13] , ischemic stroke at an early age has been
observed repeatedly as first clinical manifestation of the
disease in FD  . Rapid diagnosis is highly desirable in
light of the possible therapeutic intervention. It is noteworthy
that enzyme replacement therapy (ERT) is available
and has already shown beneficial effects on renal,
cardiac and peripheral nerve function in FD  . Thus,
beyond etiological and prognostic evaluations, young
stroke patients should be screened systematically for FD
to initiate both sufficient reinfarction prophylaxis with
regard to the specific needs of FD patients and ERT to
improve or stabilize the course of the disease. Although
pathologically increased cerebral blood flow in FD could
be reversed under ERT  , it remains to be studied if
ERT can reduce the progression of brain structural alterations
or the probability of subsequent cerebrovascular
In addition to the highlighted diagnostic utility, some
additional aspects contribute to the qualification of basilar
artery measurements using MR angiography (TOF sequences)
as feasible routine tool for the screening of FD
in young stoke patients. Firstly, the high reproducibility
of basilar artery measurements has also been reported by
others  . Moreover, analyses are not time-consuming
(duration of 1 measurement including data processing
about 5–10 min), and the MR angiography is broadly
available, noninterventional and without contrast agent.
Studies validating TOF MR angiography measurements
of the cerebral vessel diameters by phantom studies,
animal models or by digital subtraction angiography
showed sufficient concordance of the different measures
[18–20] . One has to mention that the TOF angiography
without the use of contrast agents is especially sensitive
to fast-flowing blood, because only unsaturated blood
produces a high signal [21, 22] . The disadvantage is that
slowly flowing blood is more difficult to detect by just applying
TOF techniques. Thus, it seems possible that the
technique might overestimate vascular diameters in the
case of FD, especially in the posterior circulation where
the blood flow is known to be significantly elevated  .
This potential weak point concerning the validity of the
BAD must not necessarily imply a disadvantage of the
Cerebrovasc Dis 2011;31:294–299
technique for the diagnostic screening of FD in the young
stroke population. On the contrary, the use of the increased
blood flow information could improve the diagnostic
accuracy of the parameter compared to the exclusively
For the differential diagnosis of ‘false-positive’ basilar
artery enlargements in the stroke population, other cerebrovascular
diseases with macroangiopathy, i.e. other
rare monogenetic vessel diseases like pseudoxanthoma
elasticum  , as well as hypertensive fibrohyalinosis
 or increased cerebral blood flow of other etiology
have to be taken into account.
The study is limited by its retrospective design. Additionally,
only 2 patients (8%) of the FD cohort had previous
stroke as documented on MRI. Although this frequency
is, in light of the young age of the patients (36.5
8 11.0 years), within the expected range and the 2 FD
stroke patients were neither in regard to age (29 and 32
years) nor to BADs (2.6 and 3.43 mm) out of the ranges
of the entire FD cohort, we cannot entirely exclude differences
of macroangiopathy between FD patients with
and without stroke.
We were able to demonstrate significant dilation of the
basilar artery in FD compared to young acute stroke patients.
BADs were able to separate the 2 groups with a
favorable accuracy of 84%. After further prospective validation
using a larger and fully blinded cohort of FD
stroke and non-FD stroke patients, TOF angiogram measurements
of the basilar artery could be added as a simple
FD screening tool to the routine diagnostic workup of
young stroke patients. As ischemic stroke at a young age
can be the first manifestation of FD, such a sensitive and
easily obtainable screening tool would be highly desirable.
Collaborating sponsor of the SIFAP study is Shire Human Genetic
Therapies Inc. (ClinicalTrials.gov, identifier: NCT00414583).
Fellgiebel /Keller /Martus /Ropele /
Yakushev /Böttcher /Fazekas / Rol f s
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