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Original Paper

Cerebrovasc Dis 2011;31:294–299

DOI: 10.1159/000322558

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

Key Words

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

1015–9770/11/0313–0294$38.00/0

Accessible online at:

www.karger.com/ced

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 [1] ,

include small fiber neuropathy as well as cerebral micro-

and macroangiopathy [2] . 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 [3] . 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 [4] .

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 [2] .

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 [5] . 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

Willis.

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

[6] . A recent study supports these results [7] . 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 [4] . 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

healthy controls.

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 [9] . More details of the enrollment

procedure and the clinical characteristics of the patient

group have been published previously [10] . 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

Patients

Table 1. Demographical, clinical and stroke characteristics of patients

and controls

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

Stroke subtype

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 [8]; 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 [3] .

Measurement procedures have been reported in detail previously

[5] 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.

Sensitivity

1.0

0.8

0.6

0.4

0.2

0

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

Patients

95% CI (z-score)

0 0.2 0.4 0.6 0.8 1.0

1 – specificity

4

3

2

1

0

–1

Basilar artery

Fi g . 2 . ROC curves of basilar artery diameters. Fabry disease (n =

25) versus stroke (n = 26) patients.

Post. Med.

Ant.

FD patients

Carot. Comp.

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

0.5).

Discussion

Basilar artery

Post. Med. Ant. Carot. Comp.

Stroke patients

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

[5] . Whereas a number of etiological factors has been

suggested for the FD-associated microangiopathy [12] ,

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 [4] . 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 [16] . 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 [17] , it remains to be studied if

ERT can reduce the progression of brain structural alterations

or the probability of subsequent cerebrovascular

events.

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 [18] . 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 [11] .

This potential weak point concerning the validity of the

BAD must not necessarily imply a disadvantage of the

298

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

morphological information.

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 [23] , as well as hypertensive fibrohyalinosis

[24] 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.

Conclusion

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.

Disclosure Statement

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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