CNS involvement in Fabry disease: Clinical and imaging studies before and after 12 months of enzyme...

CNS involvement in Fabry disease: Clinicaland imaging studies before and after 12 monthsof enzyme replacement therapyL. JARDIM

3,4*, L. VEDOLIN

1

, I. V. D. SCHWARTZ3

, M. G. BURIN3

, C. CECCHIN3

,

L. KALAKUN3

, U. MATTE3

, F. AESSE2

, C. PITTA-PINHEIRO2

, J. MARCONATO2

and R. GIUGLIANI3,5

1Department of Neuroradiology, Ma‹ e de Deus Center, Porto Alegre;2Department of Neuroradiology, Hospital Moinhos de Vento, Porto Alegre;3Medical Genetics Service, Hospital de Cl|¤ nicas de Porto Alegre, Porto Alegre;4Department of Internal Medicine and 5Department of Genetics, UniversidadeFederal do Rio Grande do Sul, Brazil

*Correspondence: Medical Genetics Service, Hospital de Clinicas de Porto Alegre,Rua Ramiro Barcelos 2350, 90.035-003 Porto Alegre, Brazil.E-mail: [email protected]

MS received 15.12.03 Accepted 12.02.04

Summary: We report the clinical and radiological central nervous system (CNS)¢ndings of 8 Fabry disease patients, before (8/8) and after (7/8) 12 months ofenzyme replacement therapy (ERT) with agalsidase-alpha. Eight biochemicallyproven Fabry disease patients (from four families) were included. Patients wereevaluated at baseline and at regular intervals during 12 months of ERT. Evalu-ations included a thorough, standardized neurological examination, and magneticresonance imaging (MRI) and angiography (MRA). Brain proton magneticresonance spectroscopy (MRS) was also performed in 5/8 patients. The presenceand location of grey- and white-matter lesions, the presence of vascular occlusionor ectasia on MRA and the metabolite ratios on MRS were determined, as wellas their relation to age, symptoms and neurological examination. Neurologicalexamination showed few abnormalities in these patients: scores varied (on a 0^100scale) fromzero to5, at baseline and in the 12thmonthofERT.Themost consistent¢ndings on MRI were asymmetric, widespread patterns of deep white-matter(WM) lesions, hyperintense on T2 and FLAIR-weighted images, found in 4/8patients at baseline, predominantly in frontal and parietal lobes. These lesionsdid not correlate with other clinical variables, although there was a trend towardsan association of the lesions with age and hearing loss. The youngest patient withMRI lesions was 24 years old. After 12 months of ERT, MRI was normal in 3/7,showed the same WM lesions in 2/7, and showed worsening of WM lesions in2/7 patients (from the same family). Abnormal MRS metabolite ratios were

J. Inherit.Metab.Dis. 27 (2004) 229^240# SSIEM and Kluwer Academic Publishers. Printed in the Netherlands

229

detected at baseline in 4/5 patients. While neurological examination remainedalmost normal during the 12 months of ERT, new small-vessel CNS involvementstill appeared in 2/7 patients. We do not know why ERT was not able to preventthis in these two related male patients. This could be due either to their older ages(46 and 36 years), or to a more pathogenic mutation. We conclude that MRIwas more sensitive than neurological examination in detecting CNS involvementand progression in Fabry disease in the time interval studied.

Fabry disease (McKusick 301500), a rare X-linked inherited disorder, results fromde¢cient activity of the enzyme a-galactosidase (a-Gal A) (NM___000169) andprogressive lysosomal deposition of globotriaosylceramide (GL-3) in the vascularendothelium. In the classic form, ¢rst symptoms are acroparaesthesias,angiokeratomas, hypohidrosis and proteinuria, with onset in childhood or ado-lescence (Desnick et al 2001). There is a gradual deterioration of renal functionto end-stage renal disease (ESRD) between the third and ¢fth decades. In middleage, most males successfully managed for ESRD develop cardiovascular and/orcerebrovascular disease, mainly due to multifocal small-vessel involvement.

The disease is panethnic, with an incidence of around 1 in 60 000 males (Desnicket al 2003). Fabry disease predominantly a¡ects males, although carrier(heterozygous) females can also be a¡ected to a mild or more severe degree, owingto their random X-chromosomal inactivation.

In the classic form, when the cerebrovascular disease begins, cerebralvasculopathy can be well visualized on cranial T2 and £uid-attenuated inversionrecovery (FLAIR) magnetic resonance imaging (MRI) as multiple hyperintenselesions, typically present in deep grey matter, brainstem and deep white matterof the hemispheres supplied by the perforating arteries (Crutch¢eld et al 1998;Kolodny and Pastores 2002; Moore et al 2001). Proton MR spectroscopy (MRS)and angiographic ¢ndings were described by Tedeschi and colleagues (1999) andMitsias and Levine (1996), respectively. A reduction of cortical and subcorticalN-acetylaspartate (NAA) on MRS and vascular ectasia were noted by the authors.

The purpose of this investigation was to report the clinical and radiological CNS¢ndings of 8 Fabry disease patients before (8/8), during (8/8) and after (7/8) 12months of enzyme replacement therapy (ERT) with agalsidase-alpha. The patternand distribution of the lesions on MRI, magnetic resonance angiography (MRA),and MRS is emphasized.

PATIENTS AND METHODS

Eight Fabry disease patients (7 males, 1 female), from four families, were included inthis study. Seven patients completed 12 months of ERT. The eighth case wasincluded later in the trial and has not completed 12 months of ERT yet: onlyher baseline data are analysed here. Diagnosis of Fabry disease was con¢rmedby demonstration of reduced activity of a-galactosidase A in plasma and/orleukocytes (Table 1). The investigations described below started immediately

230 Jardim et al

J. Inherit. Metab. Dis. 27 (2004)

Tabl

e1

Clin

ical

and

neur

oim

agin

gfe

atur

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patien

tsat

base

line

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tAge

(yea

rs)

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to-

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activity

inleuk

ocytes

ðnm

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1ml�

1 Þ

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ia>1g/24

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ocardiog

ram

ECG

CNS

symptom

s

NEscore

(mainCNS

¢nding

s)

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dde

epW

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sat

thec

arotid

distribu

tion

(onM

Rþ)

MRS

pattern

A1

471.

73þ

LA

and

LV

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rgem

ent

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mpl

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ral

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)

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/Cr

B3

310.

21�

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r

C4

270.

33þ

LA en

larg

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tan

din

crea

sed

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CNS involvement in Fabry disease 231

before inclusion of these individuals in an open-label protocol with agalsidase-alpha,0.2mg/kg per week, and continued at regular intervals during a period of 12 months.The only concomitant medication was carbamazepine, used to control acroparaes-thesias. There were no cases of hypertensive disorder, tabagism, hyperlipidaemia orother chronic diseases. This study was approved by the Ethics Committee of the insti-tution where it was performed and informed consent was obtained from all patients.

The mean age of the group at the beginning of the investigation was 32 years (range24^47 years). The main initial complaints (hypohidrosis and acroparaesthesias) werefound in 7/8 patients. Only two patients showed proteinuria (>1 g/24h). Heartabnormalities, still asymptomatic, were more common than kidney disease: 4/8patients presented some echocardiographic abnormality (such as left atrial andventricular enlargements), and 7/8 showed ECG manifestations (mainly delays inintraventricular conduction) (Table 1).

A standard neurological examination (NE) was performed in these patients. Inorder to quantify these ¢ndings, the neurological examination generated a score thatvaried from zero (normal examination) to 100 (completely abnormal). For the pur-poses of the present analysis, NE scores were subdivided into those due to centralnervous system involvement (CNS score; range 0^85) and those due to peripheralnervous system involvement (PNS score; range 0^15); the latter comprising thesensitive examination only, since none of the cases in this study showed absentre£exes or amyotrophies.

All MRI data were obtained with a 1.5 T system (Signa, GE Medical Systems,Milwaukee, WI, USA) equipped with a standard circularly polarized head coil,at baseline and after 12 months of ERT. The following image sequences wereacquired: (1) sagital T1-weighted image (TR/TE¼ 580/14); (2) axialFLAIR-weighted image (TR/TE¼ 9000/1000); (3) axial and coronal T2-weightedimages (TR/TE: 4000/99); (4) 3D time-of-£ight (TOF) MRA; and (5) MRS.MRI was performed at the beginning and after 12 months of ERT. The presence,location, distribution and intensity patterns of the white-matter lesions and vascularocclusion or ectasia on MRA were evaluated as well as their relation to age, symp-toms and neurological examination.

MRS was performed at baseline in 5/8 patients and was repeated after 12 monthsin 3 of them, using point-resolved spectroscopy (PRESS) with single-voxel protonbrain examination (PROBE^SV) with the parameters TR/TE¼ 1500/35. The voxelsize was 8 mm3 and was carefully positioned at the right frontal white matter toavoid contamination from bone. MRS was performed only in the frontal lobe, whereno white-matter lesions were seen in MRI. When repeated, the same area in thefrontal lobe was imaged, in order to ensure comparisons between baseline and after12 months of ERT. The spectroscopic data were transferred to a workstationand spectral reconstruction was achieved automatically by SAGE software. Allpostprocessing of data was performed blinded to the patient status and metaboliteratios were categorized as follows: (1) normal or abnormal NAA/creatine (Cr) ratioand (2) normal or abnormal choline (Cho)/Cr. NAA/Cr was considered low if theratio was 1.5 or less and an increased Cho/Cr ratio was de¢ned as 1 or more,as previously described in the literature (Kantarci et al 2003; Widjaja et al 2003).

232 Jardim et al

First, relations between some variables were investigated at baseline. Amongthem, age was considered a dependent variable, and the characteristics of thegroup�presence or not of hearing loss, vertigo, hyperre£exia, and white-matter(WM) lesions�were de¢ned as independent variables. Comparisons between groupswere performed using Student’s t-test for means. The e¡ect of age on NE score wasassessed by the Spearman correlation coe⁄cient. Second, CNS and PNS scoresat baseline (before ERT), and after 3, 6 and 12 months of ERT, were comparedusing ANOVA linearity test. All analyses were performed with the SPSS 10.0 forWindows.

RESULTS

Baseline ¢ndings: General baseline clinical characteristics of the sample aresummarized in Table 1. The present patients had several complaints related toperipheral disease, such as acroparaesthesias, which will not be mentioned here.Symptoms related to the CNS were few: 3/8 complained of hearing loss; 4/8 ofdizziness, and one of reduced sensation in the right half of the face. A previous his-tory of a transient ischaemic attack, manifested by acute vertigo and hearing lossthat resolved without residual sign, was obtained from the older patient (case 1),and happened 2 years before the present investigation.NE CNS scores showed few abnormalities in these patients: their scores varied

from 0 to 5 (range 0^85). The abnormalities consisted of unilateral hearing losson fork examination (Weber or Rinne test abnormal) in 3/8 cases, generalhyperre£exia in 2/8 cases, and frontal release signs in 1/8 patient. All hypoacusicpatients also complained of dizziness. A trend relating age to NE score, hearingloss, vertigo and white-matter lesions in MRI was seen, but without statisticalsigni¢cance. For example, the average age of the 3 patients with white-matter lesionswas 35 years, while that of the remaining 4 patients was 26 years.The most consistent ¢ndings were asymmetric widespread patterns of deep WM

lesions, hyperintense on T2- and FLAIR-weighted images, found in 4/8 patientsat baseline. All patients with abnormal MRI (4/8) showed these ¢ndings, predomi-nantly in frontal and parietal lobes. The lesions were typically nodular in appearanceand ranged in size from several millimetres to more than 1 centimetre. One patient(1/4) had a hypointense lesion on FLAIR, interpreted as lacunar infarct. The lesionsoccurred mostly at the carotid distribution. None had grey-matter, temporal lobe orposterior fossa lesions, cortical infarct or brain atrophy on MRI. Theyoungest patient with lesions was 24 years old (Figure 1). These lesions were inter-preted as ischaemic microangiopathy and showed a trend in relation to age andto hearing loss. One patient had vascular ectasia. No vascular occlusion wasobserved on MRA.Abnormal MRS metabolite ratios were detected in the majority of patients (5/6).

Four patients (4/5) had a high Cho/Cr ratio and one (1/5) had a low NAA/Crratio. Three patients with abnormal MRS had no lesions on MRI. One patient (1/6)had a normal metabolite ratio on MRS.


Results after 12 months of ERT: Seven (male) patients completed 12 months ofERT. The average of NE CNS scores obtained at baseline and at the 3rd, 6thand 12th months of ERT were 2.07, 2, 1.7 and 1.8, respectively. Comparing oneto another, no statistical signi¢cance was obtained. In fact, all these CNS scoreswere only slightly abnormal, considering that the scale varied from 0 (completelynormal NE) to 100.

The averages of NE PNS scores were 2.37, 1.7, 2.44 and 1.87, respectively at 0,3, 6 and 12 months after ERT, with no statistical di¡erence between them. Twopatients stood out in the sample: cases 1 and 2, who seemed to show a progressionof sensitivity loss in spite of receiving ERT. These two patients were older thanthe average of this group. Both belonged to the same family (Table 2).

MRI at the 12th month remained normal in 3 out of 7 patients, showed the sameWM lesions in 2 cases and showed worsening of WM lesions in the other 2 patients.These patients were those who (cases 1 and 2) belonged to the same family and were,again, the oldest ones. One of them (case 1) presented with a transient ischaemicattack in the 6th month of ERT: he presented with sudden dizziness, vertigoand hearing loss, which resolved in less than 24 h. The new MRI showed WM lesionprogression mainly at the left frontal lobe (Figure 2).

MRS was repeated after 12 months in 3/6 patients. The NAA/Cr ratio wasreduced in one patient (case 2); this patient had WM lesion progression on MRI.In another patient (case 3) the Cho/Cr ratio was increased at baseline and improved12 months after ERT. Interestingly, this patient had a slightly better CNS score onneurological examination after ERT. The metabolite ratios did not change inthe third patient (case 4).

Figure 1 Neurological examination CNS scores during 12 months of ERT

234 Jardim et al


Tabl

e2G

ener

al¢n

ding

sof

cent

ral(

CN

S)an

dpe

riph

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nerv

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dfr

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exam

inat

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and

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and

fam

ilies

(thi

sta

ble

includ

eson

lyth

e7

patien

tswho

com

plet

ed12

mon

ths

ofERT)

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(mutation,

whe

nkn

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enu

mbe

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atba

selin

e(y

ears

)

Progression

ofCNS

scores,o

nne

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exam

ination

(ran

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85)

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atter

lesion

sonM

RI

Progression

ofPN

Sscores

onne

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exam

ination

(ran

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15)

A(m

utat

ion

still

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own)

147

2to

2aW

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0.45

to4

(wor

seni

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236

4to

3aW

orse

ning

0.2

to4.

2(w

orse

ning

)

B(m

utat

ion

still

unkn

own)

331

1.5

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0.1

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utat

ion

W34

9X;

TG

Gto

TA

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427

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16

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ean

dat

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999)



DISCUSSION

In the present cohort, baseline and 12 month neurological examinations were eithernormal or only slightly abnormal. The most common alteration on neurologicalexamination was hearing loss on fork tests, and this ¢nding showed a tendencyto correlate with disease duration, inferred from the patient’s age. Recently,progressive hearing loss and sudden deafness have been reported as highly prevalentamong Fabry disease patients: 12/22 individuals (54%), with an average age of 39years (Germain et al 2002). Perhaps the present ¢ndings would reproduce these fea-tures if our patients were older.

On the other hand, cerebrovascular manifestations are a well-known complicationof Fabry disease. They result mainly from multifocal small-vessel involvement andmay include thrombosis, transient ischaemic attacks, basilar artery ischaemiaand aneurysm, seizures, hemiplegia, hemianaesthesia, aphasia, labyrinthine dis-orders, or frank cerebral haemorrage. Vascular involvement usually appears inmiddle age (Crutch¢eld et al 1998; Desnick et al 2001; Kolodny and Pastores 2002;Mitsias and Levine 1996). In the present case series, a widespread pattern of deepwhite-matter lesions seemed to precede neurological events. Indeed, 4/9 patientsalready showed white-matter lesions, although only one (case 1) had a previous his-tory of transient ischaemic attacks. In the same line of evidence, these individualshad an almost benign neurological examination, with minor abnormalities. Thesepreclinical white-matter lesions showed a trend (without statistical signi¢cance)of association with older age. However, perhaps the most unexpected ¢nding on

Figure 2 Axial FLAIR. MRI at baseline (A) and after 12 months of ERT (B) in case 1,showing worsening of WM lesions

236 Jardim et al


MRI was the established WM lesions in the 24-year-old patient. As far as we know,this is the youngest Fabry disease patient with CNS lesions on MRI ever reported.

In the seven patients who completed 12 months of ERT, MRI remained normal in3/7, showed the same WM lesions found in baseline studies in 2/7, and showed anincrease in the number of WM lesions in the other 2/7 patients. The present studyis an open-label protocol, so we cannot compare these ¢ndings with what happensduring one year in untreated subjects. The natural history of Fabry disease shouldbe sought in the historical data present in the literature. Observational cohort studieson Fabry disease are not common. A cross-sectional study of the British cohort of 98male and 60 female Fabry disease carriers was reported, describing the cumulativeprobability of death, the age of onset of symptoms and the frequencies of signsand symptoms, among other data (MacDermot et al 2001a,b). CNS involvementwas evaluated by the age of the ¢rst cerebrovascular or transient ischaemic attacks,so we cannot compare our ¢ndings with these data. Another large cohort of 55 maleFabry disease patients has been reported by the group of Bethesda (Crutch¢eld et al1998; Schi¡mann 2001). The latter reports focused on the progression of cerebrallesions seen on MRI of the head, so that some comparison can be attempted withthe present results. According to the Kaplan^Meier curve obtained by those authors,by the age of 32 (the mean age of the present sample), around 5% of the individualsalready had MRI lesions; at 40 years, this proportion was 40%. The curve showsan acute fall between 38 and 40 years of age, revealing that the fourth decade isthe critical period, where an increase of 35% of MRI lesions appeared. What com-parison can be traced here? Although the time of observation of the present study,one year on ERT, could be criticized as not being su⁄cient to detect and quantifyneurological deterioration, it was already su⁄cient to present an increase ofMRI lesions in Fabry disease, in 2/7 patients (or 30% of the sample) who were 36^46years oldHcoincidentally the same age group with high risk for MRI lesions, accord-ing to Crutch¢eld and colleagues (1998). Despite the lack of a control group, we canassume that the present increase of WM lesions followed the natural history of thedisease in CNS, at least when using the curves already published in the literature.

The distribution of MRI-detectable lesions was typical of a small-vessel disease. Incontrast to previous studies (Crutch¢eld et al 1998), our data showed that themajority of lesions presented in areas supplied by the anterior circulation, mostlyat the deep and periventricular WM of the frontal and parietal lobes. Althoughwe do not know the reasons, our data suggest that this distribution could occurin Fabry disease. The ¢ndings of Moore and colleagues (2002b), who found elevatedcerebral blood £ow in both middle and posterior cerebral artery, seem to support theinvolvement of anterior circulation.

Assessment of WM metabolites using proton MRS has been shown to be ane¡ective noninvasive diagnostic tool that can be used to monitor biochemicaland metabolic changes in CNS disease. Tedeschi and colleagues (1999) were the ¢rstto describe abnormal metabolite ratios on MRS in Fabry disease. The authorsstudied nine Fabry disease patients and found a di¡use pattern of NAA/Cr ratioreduction. In contrast, in our study there was just one patient (1/6), and another12 months after ERT (1/3), with this pattern. One possible explanation for this



¢nding could be the technique employed: those authors used a multivoxel approachwhile we performed a single-voxel technique at the frontal lobe. In addition, weused 1.5 as the lower limit of normal NAA/Cr ratio, which could decrease oursensitivity to detect NAA/Cr alteration. As described by others, we believe thatthis reduction could re£ect neuronal death or dysfunction.

We found a signi¢cant increase in the Cho/Cr ratio in 4/6 Fabry disease patients.To our knowledge, this ¢nding has not yet been published in the literature. Inter-estingly, in one patient (case 3) the Cho/Cr ratio was increased at baseline andreduced 12 months after ERT. Also, this patient had a slightly better CNS scoreon neurological examination after ERT. As described previously, increased cholineprobably re£ects increased membrane synthesis and/or increased number of cells.We speculate that this increased metabolite ratio could re£ect a cell response tothe CNS GL-3 accumulation. The signi¢cance of these ratios should be con¢rmedby additional studies.

The comparison of the neurological examination evolution with that of MRI, inthis cohort, allows certain inferences. First, in spite of the fact that neuorologicalexamination remained almost normal during these 12 months of ERT, multifocalsmall-vessel involvement of CNS continues to take place. Second, MRI was moresensitive than standard neurological examination for detecting CNS involvementand progression, over the same interval, in Fabry disease. Although the role ofMRS in Fabry disease remains unknown, we believe that this method could be usedin the future to evaluate disease extension and response to therapy.

We do not know why ERT was not able to prevent the aggravating picture of WMin cases 1 and 2 (two male patients). Indeed, it was possible that, without ERT, thesepatients would have even worse evolutions than those that were actually observed.One of them (case 1) presented with a transient ischaemic attack in the 6th monthof ERT: he presented with sudden dizziness, vertigo and hearing loss, which resolvedin less than 24 h. An unresolved question was whether this patient might have had afull stroke had he not been receving ERT. Nevertheless, one can speculate aboutthe evidence of a larger than usual involvement of CNS in these two related patients.First, this could be due to their older ages, 47 and 36 years old at the beginning ofERT. There is only one other case 46 years old, but she is female, in whom a milderphenotype was expected (Desnick et al 2003; MacDermot et al 2001b). Second, sincethe two cases with worsening MRI were related, another possible explanation is thattheir mutation, or their genetic background, would be more deleterious to CNS smallvessels. This hypothesis is hard to sustain, however. Although more than 300mutations have been identi¢ed, no clear genotype^phenotype correlation has beenestablished, to our knowledge. The fact that PNS scores of both cases also worsenedhelps both hypothesesHage-related or genotype-related worsening of CNS ¢ndings.

The randomized, placebo-controlled, double-blind studies of enzyme replacementtherapy (alpha-galactosidase A) for the treatment of Fabry disease that have beenpublished so far did not use CNS parameters, such as MRI or neurologicalexamination, as primary end-points (Eng et al 2001; Schi¡man and Kopp 2001).The e¡ect of ERT on CNS, in related studies of the same patients, was evaluatedthrough the study of their regional cerebral blood £ow, measured by [15O]H2O

238 Jardim et al


and positron emission tomography and transcranial Doppler studies (Moore et al2001; Moore et al 2002a, b). These studies have shown signi¢cant improvementin abnormal vascular responses after 18^24 months of treatment. However, asthe authors have stated, the relation between the increased risk of stroke in Fabrydisease and the increased regional cerebral blood £ow remained unclear. Morerecently, three reports on CNS e¡ects of ERT showed that there were enhancementsof lesions after ERT in some patients (Leech and Johnson 2003; Mehta et al 2003;Wilcox et al 2003). These ¢ndings were probably similar to ours.

Despite the small sample size and the short period of treatment of the presentobservations, we concluded that MRI seemed to be a better parameter than neuro-logical examination for following the CNS evolution of the present Fabry diseasepatients. MRI also showed that white-matter lesions, although still silent, canprogress in some patients despite 12 months of ERT. Additional follow-up andcomparison with other cohorts under ERT are necessary for interpretation of theseresults.

ACKNOWLEDGEMENTS

The authors thank Dr Gregory Pastores for the molecular investigation of case 4.The cost of the ERT protocol, including clinical and laboratory evaluations, wassupported by TKT.

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CNS involvement in Fabry disease: Clinical and imaging studies before and after 12 months of enzyme...

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