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Subclinical Neurological Abnormalities in Children With Celiac Disease Receiving a Gluten-free Diet

Cakir, D*; Tosun, A; Polat, M; Celebisoy, N; Gokben, S; Aydogdu, S; Yagci, RV; Tekgul, H

Journal of Pediatric Gastroenterology and Nutrition: September 2007 - Volume 45 - Issue 3 - p 366–369
doi: 10.1097/MPG.0b013e31806907e8
Short Communication

Objectives: Because clinically evident manifestations are frequent in adults with celiac disease (CD), we aimed to investigate whether early neurological abnormalities may be detected in children with CD.

Methods: Electroencephalography, electromyography, and somatosensory evoked potentials were performed in children with CD receiving a gluten-free diet.

Results: The neurophysiological tests revealed subclinical neurological abnormalities associated with CD in 3 (11%) of 27 children: 2 had peripheral polyneuropathy documented with electromyography, and 1 had prolonged latencies in somatosensory evoked potential. Magnetic resonance imaging showed abnormalities in 2 (7.4%) of children: pontine demyelinization in 1 and cortical atrophy in the other.

Conclusions: Because the rate of neurological problems is increased in children with CD, neurological abnormalities should be carefully investigated early after the diagnosis of CD is made.

*Departments of Pediatrics, Turkey

Pediatric Neurology, Turkey

Neurology, Turkey

Pediatric Gastroenterology and Nutrition, Ege University Medical School, Izmir, Turkey

Received 26 January, 2006

Accepted 4 January, 2007

Address correspondence and reprint requests to Prof Dr Hasan Tekgul, Division of Pediatric Neurology, Department of Pediatrics, Ege University Medical School, Izmir 35100, Turkey (e-mail:

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Celiac disease (CD), also known as gluten enteropathy, is an immune-mediated inflammatory enteropathy caused by intolerance to gluten in wheat, barley, and rye (1–4). During the past 2 decades, a growing body of overt neurological disorders such as cerebellar ataxia, epilepsy, polyneuropathy, and dementia has been reported, mainly in adults with CD (5–8). Anecdotal reports suggest that the nervous system may be affected during childhood; however, this issue has not been systematically evaluated in children with CD.

In this cross-sectional study we investigated subclinical neurological abnormalities in children with CD receiving a gluten-free diet, using neurophysiological tests—electroencephalography (EEG), electromyography (EMG), and somatosensory evoked potentials (SEP)—and magnetic resonance imaging (MRI).

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From the Outpatient Follow-up Program of Celiac Patients in the Pediatric Gastroenterology and Nutrition Division, Ege University Hospital, 27 young patients (18 female and 9 male) with CD were consecutively included in the study between 1998 and 2002. All of the patients received a gluten-free diet for at least 30 months.

First, each patient underwent a standardized neurological examination by an experienced pediatric neurologist (H.T.). The neurophysiological tests (EEG, EMG, SEP) and MRI studies were performed on all 27 children to define the subclinical neurological abnormalities. Written informed parental consent was obtained before the patients were enrolled in the study.

The diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition (9). The duodenal biopsy specimens were fixed in formaldehyde solution and examined histologically. Intestinal mucosa was assessed as normal or as manifesting villous atrophy, lymphocyte infiltration, and crypt hyperplasia. Complete blood count; liver and renal function tests; determinations of calcium, magnesium, folic acid, and vitamin B12 levels; and coagulation tests were also done in all of the patients.

For statistical analysis, the cohort was separated into 2 groups based on the results of the neurophysiological tests and MRI studies. Group 1 included the CD patients with subclinical neurological abnormalities (n = 5). Group 2 included CD patients without neurological abnormalities (n = 22). The groups were compared in terms of clinical features (age, age at diagnosis, duration of symptoms, duration of gluten-free diet, height, body weight, and diet compliance) and histopathological findings. The Mann-Whitney U test and the Fisher exact test were used for statistical analysis of the data, and P < 0.05 was used for statistical significance.

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The clinical and laboratory features of the study group are given in Table 1. Five patients were grouped as monosymptomatic (short stature only) and 22 as polysymptomatic (abdominal pain, failure to thrive, and chronic diarrhea). The mean age at diagnosis in monosymptomatic CD patients (12.7 ± 3.0 years) was higher than in polysymptomatic CD patients (6.7 ± 4.3 years; P < 0.05).



Five children (18.51%) had subclinical neurological abnormalities documented with neurophysiological tests and MRI (Table 2). Two (7.4%) children had peripheral polyneuropathy documented with EMG. One had a pattern of axonal motor and sensory polyneuropathy, and other had a pattern of pure sensory polyneuropathy. One patient (7-year-old boy) had abnormal SEP with prolonged central conduction time. A single seizure (febrile seizures in 2 and afebrile seizure in 1) was noted in 3 children with normal EEG results. All of these patients also had normal EMG, SEP, and MRI results.



The MRI examinations revealed abnormal findings in 2 (7.4%) children. One patient had cortical atrophy on MRI examination; however, she did not have any cognitive abnormalities or any other neurological symptoms or signs. A second patient had pontine demyelinization on MRI (Fig. 1A). Magnetic resonance spectroscopy (MRS) was also performed in the second patient to investigate the cerebral metabolic profile in the pontine area, and revealed an increased choline peak and a decreased N-acetyl-aspartate (NAA) peak, which may have indicated neuronal axonal loss in the pontine area (Fig. 1B).

FIG. 1

FIG. 1

Age, age at diagnosis, duration of symptoms, mean height and weight, total blood count, and serum calcium, magnesium, folic acid, and vitamin B12 levels were not statistically different between the patients with (group 1) and without (group 2) subclinical neurological abnormalities. Neurological abnormalities were more common in patients with short stature (P < 0.05). Additionally, subclinical neurological abnormalities were more common in patients who were noncompliant with a gluten-free diet (60% vs 13.63%).

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Several neurological problems, including epilepsy, migraine, peripheral neuropathy, cerebellar ataxia, myopathy, dementia, and learning difficulties have been increasingly reported in adult patients with CD, in rates of 10% to 30% (8,10–12). These neurological disorders may not be overt in the early period of CD in childhood, however. Here we report the rate of subclinical neurological abnormalities (18.8%) in children with CD.

The association of epilepsy and CD has been demonstrated in several studies. Some studies have shown an increased prevalence (13–15); however, recent data led us to the conclusion that the incidence of epilepsy in patients with CD is no different from that in the general population. In the study by Chapman et al (7), the rate of epilepsy was 5% in the adult population. Additionally, Pengiran Tengah et al (16) reported epilepsy in 1.1% of 801 adult CD patients. They postulated that there was no reasonable correlation between epilepsy and CD. Similarly to these data, in our study no children had diagnoses of epilepsy associated with CD. A single seizure was noted in 3 children (febrile seizures in 2 and afebrile seizure in 1) with normal EEG results. There were no additional seizures during follow-up.

Peripheral neuropathy can be the presenting manifestation or a late finding in CD, and it is seen several years after the symptoms begin (17). Luostarinen et al (18) showed the prevalence of neuropathy in adult patients with CD to be 23%. In our pediatric population, only 2 patients (7%) had subclinical peripheral neuropathy documented with EMG. The exact pathogenesis of peripheral neuropathy is unclear. There are conflicting reports about the relationship of peripheral neuropathy with gluten or vitamin depletion (19). Our patients had normal vitamin B12 and folic acid levels. One of them was noncompliant with a gluten-free diet.

Gluten-sensitive ataxia is an immune-mediated disease that is part of the spectrum of gluten sensitivity, and it accounts for up to 40% of cases of idiopathic sporadic ataxia. Ataxia is a result of immunological damage to the cerebellum, the posterior columns of the spinal cord, and peripheral nerves (20,21). It is a late and rare complication of CD. In our group none of the patients had the clinical manifestation of ataxia, but 2 patients had peripheral neuropathy documented with EMG, and 1 patient had an abnormal SEP response indicating spinal cord abnormality. These findings may be attributed to the age of the cohort and to the shorter duration of disease.

In some studies degenerative changes in the brain resulting in dementia have been reported in patients with CD (12). Collin et al (22) reported 5 patients with dementia: 4 with cerebral atrophy and 1 with cerebellar atrophy. In 2 of these cases vitamin B12 deficiency and folic acid deficiency were identified, but progression continued despite vitamin support and gluten-free diet. In the present study only 2 patients had MRI abnormalities. One patient had cerebral atrophy on MRI without cognitive abnormalities or any other neurological symptoms or signs. A second patient had pontine demyelinization on MRI examination (Fig. 1A). MRS revealed a decreased N-acetyl aspartate/creatine ratio in the pontine area (Fig. 1B). This patient also had an increased choline peak in the pons, which may represent an intermediate metabolite step in the affected lesion. Additional MRS in patients with CD may provide new information related to the understanding of the pathophysiology of neuronal involvement in patients with celiac disorders.

In conclusion, CD is associated with subclinical neurological abnormalities in a considerable number of pediatric cases. These neurological disorders should be investigated with systematic use of neurophysiological tests and MRI.

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Celiac disease; Neurological abnormalities; Magnetic resonance imaging; Electromyography; Electroencephalography

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