Abstract
The aim was to determine the prevalence of coeliac disease (CD) in paediatric patients with migraine. Serum tissue transglutaminase IgA (tTGA) antibodies and IgA concentrations were measured in 73 patients with migraine (age range 6-17 years) and the control group (n = 147). Patients having positive tTGA antibodies underwent duedonal biopsy. Four patients (5.5%) from the study group and one (0.6%) from the control group had positive tTGA antibody titres (P < 0.05). Three patients with migraine had normal duedonal histology and were considered as potential CD. One patient from the study group and one from the control group declined to have biopsy. tTGA antibody is considered as a reliable indicator for the presence of CD. However, some patients with positive antibodies may have normal biopsy initially and are classified as having potential CD. Our finding of a higher prevalance of tTGA antibodies in paediatric migraine patients suggests that an association between migraine and CD might exist.
Introduction
Coeliac disease (CD) is a T-cell-mediated chronic autoimmune disease that develops in genetically predisposed individuals. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy and crypt hyperplasia in the small intestine. The common presentation symptoms and signs of CD include diarrhoea, abdominal pain, weight loss, malnutrition and fatigue. Although CD was primarily thought to be a gluten enteropathy, it is now considered to be a multisystem disorder, with most patients being asymptomatic or presenting with only extraintestinal manifestations (1). Among these manifestations, various neurological syndromes, including ataxia, peripheral neuropathy, dementia, myopathy, cerebral vasculitis, brainstem encephalitis and epilepsy, have been found to be associated with CD (1–12). Although migraine has been reported to be associated with classical gluten enteropathy (1), it has not been studied extensively in asymptomatic CD. The aim of this study was to determine the prevalance of CD in children and adolescents with migraine, using tissue transglutaminase IgA (tTGA) antibodies and intestinal biopsy.
Patients and methods
All children and adolescents aged 6–17 years attending the Child Neurology Outpatient Clinic at Baskent University Ankara Hospital between May 2004 and January 2006 and fulfilling the criteria for migraine according to the International Headache Society (IHS) (13) were asked to particitate in the study. All patients were examined by the same child neurologist. All patients had undergone complete physical and neurological examination, and a structured interview concerning the characteristics of headache, associated symptoms and medications had been obtained in each patient. Patients with previous suspicion of CD were excluded. Of 95 patients diagnosed as having migraine, 73 (age 12.01 ± 3.07 years, 41 female) were enrolled. Thirty patients had migraine with aura.
The control group comprised of 147 patients (85 female), with similar age distribution (11.82 ± 3.25 years) and with minor respiratory illness and no history of recurrent headache or gastrointestinal problems. Serum samples were obtained from the patient and control groups for determination of tTGA antibody and IgA analysis.
The potential significance of a positive test was explained to the parents of all children participating in the study. Patients having positive tTGA antibodies underwent endoscopic duedonal biopsy for the confirmation of CD. Written informed consent was obtained from all parents. The study was approved by the Baskent University Faculty of Medicine Ethics Committee.
Laboratory methods
A commercially available enzyme-linked immunosorbent assay (Orgentec Diagnostica GmbH ORG 540A, Mainz, Germany) was used to test for tTGA antibodies. The cut-off level defining a positive result was set as 10 U/ml.
Statistical analyses
All statistical calculations were performed using SPSS software (Statistical Package for the Social Sciences, version 11.5; SSPS Inc., Chicago, IL, USA). The results are presented as the mean +
Results
Four patients (5.5%) from the study group and one (0.6%) from the control group had positive tTGA antibodies (P = 0.043). One patient with migraine with aura was tTGA+ (3.3%) (Table 1). When compared with the percentage of tTGA positivity in patients without aura (6.9%), this difference was not statistically significant (P = 0.63). All patients and controls had normal serum IgA levels.
Patients with postive tTGA titres
Three patients from the study group had undergone duedonal biopsy, which revealed normal histology and were considered to show potential CD. One patient from the study group and one from the control group declined to have biopsy. Cranial magnetic resonance imaging (MRI) was also obtained in patients with tissue transglutaminase antibody positivity. It was normal in three patients and showed a hyperintensity of millimetric size in subcortical white matter on T2-weighted images in one.
Discussion
Coeliac disease has also been termed gluten-sensitive enteropathy because the small intestine is the main target of injury; however, the clinical manifestations are extremely diverse, suggesting the disorder is in fact multisystemic. Although malabsorption, steatorrhoea and weight loss are the classical manifestations of CD, it can present with extraintestinal manifestations and is underdiagnosed unless screening is undertaken.
Neurological manifestations of CD have been described for decades and are estimated to occur in 6–10% of patients with CD (14). In Luostarinen's series, 7% of patients newly diagnosed with CD presented initially with neurological symptoms (12). There was a striking paucity of gastroenterological symptoms in this group despite severe neurological disease. Ataxia and peripheral neuropathy are the most frequently described manifestations; however, numerous other manifestations, including epilepsy with occipital calcifications, have also been described to be associated with CD.
Migraine headache occurs frequently in children and adolescents. Its prevalence in children and adolescents has been examined in a large number of papers. Studies applying the IHS criteria have reported prevalence rates of between 3 and 11% (15–19). Migraine was reported to be associated with classical gluten enteropathy in some studies and case reports (1, 20). Zelnic et al. investigated the presence of neurological disorders, including migraine, in patients with classical CD and found those disorders to be more common in children with CD than in controls (1).
Gabrielli et al. reported positive serology for CD in a significantly higher percentage of adult patients with migraine than in a control group (4.4 vs. 0.4%) (21).
There are a limited number of studies about the prevalance of CD in paediatric patients with migraine. Lahat et al. studied the prevalance of coeliac antibodies in children with various neurological disorders including migraine and found no difference with the control group (22). The only study suggesting an association between paediatric migraine and CD was by Borgna-Pignatti and co-workers (23). They found one CD in a series of 87 patients with migraine.
Although biopsy of small bowel is the diagnostic ‘gold standard’ for CD, antibody testing is a useful screening method. With a sensitivity of 94% and specificity of 99%, tTGA antibodies are one of the preferred screening tests for CD (24). However, some patients with positive serology do not show histopathological findings. ‘Potential coeliac’ refers to patients who do not have a diagnostic biopsy consistent with CD, but show serological abnormalities (25). These patients might develop villous atrophy on repeated biopsies performed 1–4 years later and should be followed up closely (25, 26). We have no data on the prevalance of CD in the paediatric population in Turkey, but have found a higher prevalance of tTGA antibodies in patients with migraine than in the control group. Although the small intestinal biopsy specimens showed normal histology in three patients, these patients can be considered as potential CD and are planned to be followed up closely.
No study has specifically investigated any association between the migraine subtypes and CD. We have found no difference regarding tTGA positivity in patients with or without aura, but since the number of patients within each group was small, it is difficult to draw a definite conclusion.
The mechanisms of the neurological involvement in CD are unclear. Nutritional, immunological and inflammatory factors have been speculated to be involved in the pathogenesis of various neurological manifestations in patients with CD. CD is an autoimmune disorder, and tissue transglutaminase has been identified as the major autoantigen. It is thought to be integral to the maintainance of vascular endothelial integrity and cellular apoptosis (27–30). Although several hypotheses exist, the mechanisms underlying migraine headaches are still unknown. An autoimmune response against tissue transglutaminase in brain vascular endothelium might be postulated as a possible mechanism underlying migraine, although the exact mechanisms of pathogenesis remain to be elucidated.
In a prospective study, 20% of 75 diet-treated CD patients had unilateral and bilateral T2 hyperintense white-matter lesions in brain MRI (31). There was no correlation between these lesions and dietary compliance or neurological or electroencephalographic abnormalities. It was concluded that white-matter lesions may represent an extraintestinal manifestation of the underlying disease process. We have performed brain MRI in patients having positive serology for CD and found only a millimetre-sized white-matter lesion in one patient. Since hyperintense white-matter foci have also been identified in migraine patients (32, 33), we cannot derive any conclusion from this finding.
The potential value of a gluten-free diet in the treatment or prevention remains unproved in various neurological conditions. Although some reports have described limited benefit from diet (34, 35), numerous studies have shown no significant benefit and, moreover, many patients may still develop neurological complications despite a gluten-free diet (36–38). Since the indications for diet treatment in patients with ‘potential’ CD are questionable, we have not offered the treatment at this point.
In conclusion, the presence of tTGA antibody is considered to be a reliable indicator for the presence of CD. However, some patients with positive antibodies may have a normal biopsy initially and be classified as having potential CD. Our finding of a higher prevalance of tTGA antibodies in migraine patients suggests that an association between migraine and CD might exist in the paediatric age group and that further studies should be performed.
Footnotes
Acknowledgements
This study was supported by a research grant from Baskent University.