Silent neurological involvement in biopsy-defined coeliac patients

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Neurological SciencesOfficial Journal of the ItalianNeurological Society ISSN 1590-1874 Neurol SciDOI 10.1007/s10072-013-1448-z

Silent neurological involvement in biopsy-defined coeliac patients

Basar Bilgic, Demet Aygun, Ali BilginArslan, Ali Bayram, Filiz Akyuz, SerraSencer & Hasmet A. Hanagasi

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ORIGINAL ARTICLE

Silent neurological involvement in biopsy-defined coeliac patients

Basar Bilgic • Demet Aygun • Ali Bilgin Arslan •

Ali Bayram • Filiz Akyuz • Serra Sencer •

Hasmet A. Hanagasi

Received: 5 March 2013 / Accepted: 17 April 2013

� Springer-Verlag Italia 2013

Abstract Coeliac disease (CD) is an autoimmune disease

of small intestine associated with sensitivity to gluten. The

clinical manifestations are often of gastrointestinal nature,

although the disease may be present asymptomatically as

well. It is a chronic disease and in the absence of overt

neurological involvement, extended gluten exposure may

give rise to silent or subtle morphological and white-matter

changes in central nervous system. The present study

investigates such changes using brain volumetry and the

assessment of white-matter tissue in CD patients without

neurological symptoms. Seventeen CD patients without any

neurological involvement were included in the study and

went under neurological evaluation and anatomical MRI.

Individual gray- and white-matter, and subcortical structure

volumes were acquired for using automated volumetric

analyses. The observed white-matter hyperintensities

(WMH) evaluated using Age-Related White-Matter Chan-

ges scale. Findings show a bilateral decrease in cortical

gray-matter and caudate nuclei volumes in CD compared to

controls. Negative correlations were found between the

duration of the disease and the volumes of the affected

regions. Cerebellum was seemingly unaffected. In addition,

significantly higher proportion of WMH was found in CD

patients, specifically in bilateral frontal and occipitoparietal

cortices. We observed a significant gray-matter and caudate

nucleus atrophy in the CD patients in the absence of marked

neurological symptoms. Present findings point out to a need

for histopathological investigations potentially focusing on

anti-TG2 antibodies, and serial volumetric analyses on the

CD-related cortical and subcortical changes.

Keywords Coeliac disease � Neurological involvement �White-matter � Cortical atrophy � Volumetry

Introduction

Coeliac disease (CD) is an immune-mediated inflammatory

disorder of the small intestine due to gluten sensitivity

leading to alteration of the mucosal architecture and

impairment in the absorption of nutrients in the intestine,

especially in the proximal small bowel [1]. Diagnosis of

the disease is based on clinical suspicion and a following

confirmation by laboratory tests and duodenal biopsy.

Genetic testing can also be performed to confirm a sus-

pected diagnosis in special cases.

The prevalence of CD in the healthy population is

approximately 1 % [2–5]. While the clinical presentation is

highly variable, diarrhea and weight loss are usually

present. Extraintestinal involvement including neurological

symptoms may be seen even in the absence of obvious

B. Bilgic (&) � D. Aygun � H. A. Hanagasi

Department of Neurology, Behavioral Neurology and Movement

Disorders Unit, Istanbul Faculty of Medicine, Istanbul

University, Istanbul, Turkey

e-mail: [email protected]

A. B. Arslan

Department of Cognitive, Linguistic and Psychological Sciences,

Brown University, Providence, RI 02912, USA

A. Bayram

Department of Neuroscience Research Center, Istanbul

Neuropsychiatry Hospital, Istanbul, Turkey

F. Akyuz

Department of Gastrohepatology, Istanbul Faculty of Medicine,

Istanbul University, Istanbul, Turkey

S. Sencer

Department of Radiology, Istanbul Faculty of Medicine, Istanbul

University, Istanbul, Turkey

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Neurol Sci

DOI 10.1007/s10072-013-1448-z

Author's personal copy

intestinal symptoms suggesting the gluten sensitivity as a

systemic autoimmune disease with diverse manifestations.

Cerebellar ataxia [6], peripheral neuropathy [7], and gluten

encephalopathy [8] are the most common neurological

symptoms for CD and they may either accompany the

disease or may be present at the onset of the disease.

Both white-matter and gray-matter of the brain can be

involved in CD patients with neurological symptoms.

White-matter abnormalities which can either be diffuse or

focal tend to be more localized in the occipitoparietal and

frontoparietal regions but they usually do not give rise to

any neurological symptoms [9, 10].

There are several studies on the gray-matter changes

reporting cerebral and cerebellar atrophy in CD patients [8,

10–12]. However, a quantitative investigation of the cere-

bral and cerebellar volume changes in CD in patients

without neurological involvement is still not present in the

literature.

It was reported that there may be a silent involvement in

the nervous system and skin during the course of CD [6].

The opposite case is also true considering that pure neu-

rological involvement and typical intestinal histopatholo-

gical changes can be seen in some CD patients, but not

with intestinal symptoms [13]. These findings highlight the

importance of a diagnostic tool that is suitable for detecting

silent progression of the disease. In this regard, the success

of magnetic resonance imaging (MRI)-based brain volu-

metry using automated segmentation techniques in dis-

covering the involvement and progression even in the silent

presymptomatic period of many chronic degenerative and

immune-mediated diseases of the central nervous system

[14, 15] suggests the potential utility of these techniques in

the case of CD.

The goal of this study was to investigate whether there

are any volume changes in the cerebrum and cerebellum

using a reliable automated MRI segmentation technique

[16] and Age-Related White-Matter Changes (ARWMC)

scale [17], in addition to identifying and quantifying the

white-matter hyperintensities (WMHs) in biopsy-proven

CD patients without any neurological complaints.

Methods

Subjects

Seventeen diet-treated CD patients (14 woman; mean

age ± SD 42.4 ± 12.1) without any known neurological

involvement who attended the gastroenterology outpatient

clinic of Istanbul University Faculty of Medicine between

2009 and 2010 were included in the study. There was no

history of neurological symptoms except for headache in

the patients. For all patients with positive serology, using

diagnostic guidelines published by European Society for

Pediatric Gastroenterology, Hepatology, and Nutrition in

1990, the definite diagnosis had been based on biopsies of

the small intestine. All patients underwent detailed clinical

neurologic examination and MRI. Electromyography

(EMG) and nerve conduction tests were performed to

evaluate the peripheral nervous system function. In addi-

tion, International Co-operative Ataxia Rating Scale (ICAR

Scale) [18] and Mini Mental Status Evaluation (MMSE)

[19] were also applied to all patients to evaluate the

coordination skills and mental status.

Seventeen neurologically healthy individuals (13

woman; mean age ± SD 42.5 ± 13.7 years) were included

as a control group in the imaging part of the study. None of

them had hypertension, diabetes mellitus and hyperlipid-

emia and their mean MMSE score was 29.23 ± 1.09. All

subjects gave written informed consent for participation in

this study, which was approved by the Istanbul University,

Istanbul Faculty of Medicine Ethics Committee.

Image acquisition and processing

Two successive high-resolution T1-weighted images were

acquired for each subject using a 1.5-T MR scanner with

8-channel head coil. The pulse sequence parameters were:

TR/TE = 8.6/4.0 s, flip angle = 8�, FOV = 240 mm,

acquired voxel size = 1.25/1.25/1.2 mm (reconstructed =

0.94/0.94/1.2 mm), 150 coronal slices without gap, scan

duration = 7.23 min (per volume). The acquired image

files were used in the morphometric analysis. FreeSurfer

4.05 was used to conduct cerebral and cerebellar volume

analysis. This procedure, described previously [16], auto-

matically segmented B40 unique structures based on their

voxel densities and a neuroanatomic label was assigned to

each voxel in a given cranial volume on the basis of

probabilistic information estimated automatically from a

manually labeled training set. Each individual segmenta-

tion was then visually inspected for accuracy. We focused

on cerebral and cerebellar gray-matter and white-matter

volumes, as well as the volumes of more specific structures

including basal ganglia (caudate nucleus, pallidum, puta-

men), limbic areas (hippocampus, amygdala), thalamus and

brainstem.

In addition, fluid-attenuated inversion recovery (FLAIR)

images were also obtained in the axial plane (slice thick-

ness 5 mm) for the assessment of WMH with the ARWMC

scale.

Statistical analysis

Descriptive statistics were applied to demographic and

clinical variables. Neural volumes were compared using

analysis of covariance (ANCOVA) test, controlling for age

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at the time of the scan and total intracranial volume fol-

lowed by a Post-hoc Tukey test. Mann–Whitney test was

applied to compare WMHs. Relationships between neural

volumes, WMHs, and clinical variables were assessed

using the Spearman correlation test. A value of p \ 0.05

was considered statistically significant for all tests.

Results

Demographics and clinical findings are presented in

Table 1. Gastrointestinal symptoms (abdominal pain,

diarrhea, and bloating) were present at the onset for all

patients except for one who presented with anemia. Three

patients also had dermatitis herpetiformis. Only one patient

had an onset before 18-year-old and the others were adult-

onset patients. As a vascular risk factor only 2 of 17

patients had diabetes mellitus but there were no patients

with hypertension or hyperlipidemia. All patients were on

gluten-free diet and none of them had any vitamin defi-

ciency or malabsorption syndrome at the time of MRI

acquisition. ICAR scale total score was 0 for each patient

and MMSE scores of the all patients were [28. These

findings reflect normal cerebellar functions and at least

there were no major cognitive deficits in CD patients.

Nerve conduction studies were within the normal limits

with respect to age.

Univariate analyses corrected for total intracranial vol-

ume (ICV) and age at the time of the scan revealed that

CD was associated with a bilateral decrease in cortical

gray-matter and caudate nuclei volumes compared to

control subjects. There was no atrophy found in the cer-

ebellar cortex, cerebellar white-matter, and dentate

nucleus. Detailed results are given in Table 2. Significant

negative correlations were found between the duration of

the disease and the volumes of the affected regions (left

caudate nucleus: r = -0.37, p = 0.028, right caudate

nucleus: r = -0.47, p = 0.005, left cortical gray-matter:

r = -0.49, p = 0.003, right cortical gray-matter: r = -0.50,

p = 0.03).

Total scores along with bilateral frontal and occipito-

parietal and right basal ganglia subscores of ARWMC

scale revealed significantly higher proportion of WMHs in

the CD patients (Table 3). Disease duration seemingly had

no effect on affected regions (left frontal: r = -0.055;

right frontal: r = 0.088; right parieto-occipital: r = 0.117;

left parieto-occipital: r = 0.133; right basal ganglia:

r = 0.160; whole brain total: r = 0.08, p [ 0.1 for all

correlations).

Discussion

Even though the presence of cerebellar atrophy is well

documented in the ataxic CD patients [10], little is known

about the cortical, deep brain nuclei and white-matter

changes in CD patients without any overt neurological

symptoms. We observed a significant gray-matter and

caudate nucleus atrophy in the CD patients without any

neurological symptoms where the duration of the CD was

found to be significantly correlated with the volume of

these structures. Although neurological involvement may

be seen in a frequency ranging between 10 and 22.5 %

among the established CD patients [18, 19], the etiology of

the neurological symptoms still remains unclear. The

presence of neurological symptoms in patients without any

enteropathy strongly suggests that this is due to an

immune-mediated mechanism rather than a nutritional

deficit. Also in line with this view, diffuse infiltration of T

lymphocytes in the cerebellar white-matter was shown in

patients with cerebellar ataxia due to CD [20, 21]. A few

histopathological studies are available for the CD patients

with cerebral atrophy and the only remarkable finding was

the nonspecific gliosis in the subcortical and deep white-

matter [12, 22]. One histopathological study mentioning

the atrophy of the caudate nucleus and putamen beside the

atrophy of cerebellum also stated that no immune-mediated

changes were observed in the atrophic areas [23]. But it

should be kept in mind that neither of these studies inclu-

ded the analysis of specific immune depositions such as

anti-TG2 (transglutaminase) depositions. With the lack of

sufficient evidence, the first explanation on the etiology of

the cortical and basal nuclei volume loss found in our study

may be the direct involvement of the caudate and cortical

gray-matter. Activation of TG2 and deamidation of gluten

peptides seems to be the core mechanism for the devel-

opment of the disease and anti-TG2 antibodies found to be

deposited in the small bowel mucosa of the patients even

without any intestinal symptoms [24]. Widespread depo-

sition of these antibodies has also been found around the

blood vessels of the brain in CD patients with neurological

Table 1 Demographic and clinical characteristics of coeliac disease

patients

Coeliac disease patients (n = 17)

Age (years) 42.4 ± 12.18 (18–60)

Age at onset 31.4 ± 12.84 (5–54)

Male/female 3/14

Disease duration (years) 10.5 ± 4.63 (6–20)

Presented with GI symptoms 13/14

Dermatitis herpetiformis 3/14

MMSE score 29.6 ± 0.7 (28–30)

Data are expressed as the mean ± SD (range)

GI Gastrointestinal, MMSE mini mental state examination

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symptoms [25]. In line with these findings, these autoan-

tibodies could play a role in the pathogenesis of the cortical

gray-matter and caudate nucleus atrophy seen in CD

patients, but it is still unknown how the cerebellum, fre-

quently involved in CD patients with CNS involvement,

remains unaffected from this ongoing pathological process.

Cross-reactivity between different transglutaminase iso-

zymes could be an explanation to this diversity. Studies

including extensive histopathological analysis are needed

to determine the impact of these immune depositions. It

Table 2 Mean (standard deviation) volumes for various structures in coeliac and and normal control subjects measured with an automated

volumetric method (Freesurfer)

Data CD patients (n = 17) Control (n = 17) F pb

L Cerebellar white-matter 13.312 ± 2.185 (9.138–15.979) 13.324 ± 1.802 (9.278–16.032) 0.00 0.999

L Cerebellar cortex 50.260 ± 6.598 (36.297–65.668) 49.578 ± 6.429 (34.765–60.314) 0.16 0.696

L Thalamus 7.024 ± 0.839 (5.398–8.324) 7.059 ± 0.852 (5.936–8.249) 0.02 0.892

L Caudate 3.063 ± 0.396 (2.075–3.735) 3.346 ± 0.539 (2.390–4.154) 4.70 0.038c

L Putamen 4.809 ± 0.564 (4.031–5.781) 4.747 ± 0.622 (3.461–5.987) 0.16 0.692

L Pallidum 1.468 ± 0.148 (1.201–1.815) 1.415 ± 0.218 (1.043–1.822) 0.92 0.345

L Hippocampus 3.953 ± 0.260 (3.501–4.426) 3.896 ± 0.472 (3.079–4.817) 0.36 0.555

L Amygdala 1.393 ± 0.164 (1.043–1.732) 1.338 ± 0.154 (1.058–1.572) 1.61 0.214

L Cerebral white-matter 217.399 ± 29.749 (169.391–269.867) 210.365 ± 26.673 (151.865–258.584) 0.60 0.444

L Cerebral cortex 218.970 ± 20.239 (177.545–273.188) 236.301 ± 27.169 (203.517–297.075) 4.88 0.035c

R Cerebellar white-matter 13.294 ± 2.025 (10.477–17.238) 13.245 ± 1.744 (9.277–15.705) 0.01 0.917

R Cerebellar cortex 52.394 ± 6.686 (39.897–69.880) 50.612 ± 6.495 (35.540–61.699) 0.92 0.346

R Thalamus 6.506 ± 0.780 (5.101–7.943) 6.536 ± 0.661 (5.416–7.492) 0.02 0.890

R Caudate 3.080 ± 0.328 (2.351–3.725) 3.359 ± 0.481 (2.575–4.168) 6.08 0.020c

R Putamen 4.589 ± 0.557 (3.879–5.472) 4.589 ± 0.518 (3.831–5.842) 0.00 0.985

R Pallidum 1.346 ± 0.130 (1.121–1.566) 1.343 ± 0.226 (1.043–1.955) 0.00 0.936

R Hippocampus 4.031 ± 0.369 (3.316–4.639) 4.019 ± 0.373 (3.086–4.562) 0.04 0.839

R Amygdala 1.462 ± 0.203 (1.123–1.885) 1.459 ± 0.143 (1.116–1.739) 0.01 0.908

R Cerebral white-matter 220.487 ± 27.297 (174.207–264.506) 213.566 ± 29.193 (153.023–270.422) 0.64 0.430

R Cerebral cortex 220.308 ± 21.565 (172.246–274.522) 239.054 ± 28.561 (207.336–297.537) 5.42 0.027c

Brainstem 20.998 ± 3.155 (16.134–26.104) 20.253 ± 2.595 (16.462–24.864) 0.891 0.353

Volumes are in cubic millimeters. Data are expressed as the mean ± SD (range)

CD Coeliac disease, F Fisher’s exact testa For each neuroanatomic volume, ANCOVA statistical test covariate with ıntracranial volume (ICV) and age is performedb p value of the ANCOVAc Significant difference after post-hoc analysis between groups performed with Tukey test

Table 3 Mean (standard

deviation) scores of ARWMC

scale

Data are expressed as the

mean ± SD (range)

ARWMC Age-related white-

matter changes, CD coeliac

diseasea p value of the Mann–Whitney

testb Signifant difference after

Mann–Whitney test (p \ 0.05)

CD patients (n = 17) Control (n = 17) pa

L Frontal 0.888 ± 0.580 (0–2) 0.388 ± 0.690 (0–2) 0.025b

R Frontal 0.777 ± 0.540 (0–2) 0.277 ± 0.570 (0–2) 0.011b

L Parieto-occipital 1.000 ± 1.080 (0–3) 0.277 ± 0.460 (0–1) 0.013b

R Parieto-occipital 1.000 ± 1.080 (1–3) 0.222 ± 0.420 (0–1) 0.007b

L Temporal 0.222 ± 0.420 (0–1) 0.111 ± 0.320 (0–1) 0.385

R Temporal 0.111 ± 0.320 (0–1) 0.111 ± 0.320 (0–1) [0.999

L Basal ganglia 0.444 ± 0.780 (0–3) 0.055 ± 0.230 (0–1) 0.051

R Basal ganglia 0.444 ± 0.610 (0–2) 0.055 ± 0.230 (0–1) 0.017b

L Infratentorial 0.166 ± 0.380 (0–1) 0.166 ± 0.380 (0–1) [0.999

R Infratentorial 0.166 ± 0.380 (0–2) 0.055 ± 0.230 (0–1) 0.302

Total score 5.294 ± 3.804 (0–14) 1.556 ± 1.977 (0–6) 0.001b

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was also reported that sera of the CD patients may evoke a

mitochondrial-dependent apoptosis in vitro [26]. Hadjiv-

assiliou et al. [22] used the term ‘‘neurotoxic antibodies’’

for these possible antibodies in their comprehensive

review. The identity of these antibodies and their role in the

neurodegenerative processes, however, are unclear.

Atrophy in our treated patients may be related to the

possibly immune-mediated pathological process before the

beginning of the treatment. Unlike the effect of treatment

on intestinal symptoms, cognitive impairments in CD

patients do not usually respond to gluten-free diet or

immunotherapies [12] and neurological problems may

even develop despite strict adherence to a gluten-free diet

[27, 28]. In line with these findings, even though all of our

patients declared that they are adhered to a gluten-free diet,

atrophy may also represent a treatment-unresponsive CNS

involvement of the CD.

Even though the identification and the classification of

the WMH in CD patients have been improved with

advanced MRI technology and reliable white-matter scor-

ing scales, the etiology underlying these abnormalities still

remains obscure. Kieslich et al. [9] reported white-matter

lesions in 20 % of the diet-treated pediatric CD patients

where the majority of the patients did not have any neu-

rological symptoms. These kinds of silent white-matter

abnormalities may also be seen in other inflammatory

bowel disease such as Crohn’s disease and ulcerative

colitis [29]. On the other hand, CD patients may develop

more serious white-matter diseases such as progressive

leukoencephalopathy with life-threatening neurological

symptoms even they are on gluten-free diet [30, 31].

Although there is evidence that involvement of the white-

matter in leukoencephalopathies in the course of CD is

immune-mediated [30], no histopathological study is

available about the nature of the silent white-matter

abnormalities seen in CD patients. Both types of white-

matter abnormalities may reflect a continuum where the

silent WHM sit at one end and leukoencephalopathies at

the other end.

Axonal damage due to white-matter involvement may

also lead to retrograde neurodegeneration in CD patients

with a similar mechanism suggested in multiple sclerosis

(MS), another immune-mediated disease of the CNS.

Recent longitudinal studies have suggested that gray-mat-

ter atrophy is likely to be secondary to white-matter injury

in the early stage of MS [32, 33]. There are other examples

of white-matter diseases where the white-matter lesion load

has an effect on gray-matter volume [34–37].

One limitation of the study presented here is the lack of the

extensive neuropsychological tests to document the clinical

significance of the cortical and subcortical atrophy. MMSE is

only a brief screening instrument and has a limited capacity

to demonstrate subtle cognitive changes. Although all the

patients have MMSE scores greater than the universally

accepted cut-off point for dementia ([24), they may still

have subtle cognitive deficits that went undetected because

they do not interfere with their daily activities.

In conclusion, our study supports the hypothesis that CD

without overt neurological symptoms is associated with

both gray- and white-matter changes. Further studies with

histopathological focus and serial volumetric analyses are

clearly necessary to fully understand the mechanism of the

cortical and subcortical changes associated with CD.

Conflict of interest None.

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