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Aim The aim of this article was to review and conduct a meta-analysis of the paediatric literature on the neurology of coeliac disease.
Method We conducted a review of paediatric studies published in English assessing neurological illness in coeliac disease identified through a MEDLINE search (1950–2009). Calculation of computed relative risk, odds ratio, and risk difference was performed using the fixed effect method if applicable.
Results Fifteen studies were analysed (11 772 participants). The meta-analysis showed that (1) the relative risk of epilepsy in individuals with coeliac disease, and of coeliac disease in individuals with epilepsy, compared with the general population, was 2.1 and 1.7, respectively, and the risk difference was close to zero, indicating that it was probably a chance association; and (2) the relative risk of headache in individuals with the disease compared with comparison groups was 3.2. In two studies, cerebellar ataxia was documented in 2.7 to 5.4% of participants; in two further studies, the risk of cerebellar dysfunction was zero. Two studies found an association between coeliac disease and peripheral neuropathy. Brain white matter lesions were recorded in two other studies. An association between autism and coeliac disease is disputed.
Interpretation Children with coeliac disease are at risk of developing neurological complications, but the risk is lower than in adulthood. The discrepancy might be due to short disease duration, early elimination of gluten from the diet, stricter adherence to diet, or different susceptibility to immune-mediated disorders.
Coeliac disease is a chronic, immune-mediated, inflammatory disorder triggered by the ingestion of grains containing gluten by genetically susceptible individuals expressing the HLA class II molecules DQ2 or DQ8.1 The clinical manifestations of the disease vary greatly, and range from typical gastrointestinal manifestations to absent, minimal, or unusual intestinal complaints with extraintestinal manifestations or disorders.1
The overall prevalence of coeliac disease varies between 0.7% and 2% in the general population, and between 0.4% and 1.3% in the childhood population.2 In adults, among the numerous extraintestinal manifestations and/or disorders of coeliac disease, the wide spectrum of neurological and psychiatric conditions reported includes peripheral neuropathy, cerebellar ataxia, myelopathy, myopathy, brainstem encephalitis, epilepsy, headache, and autism.3 The prevalence of neurological complications in adults with the disease has been estimated to be as high as 26%.3 Further data suggest that antibodies associated with the disease occur in 16 to 57% of individuals with neurological dysfunction.3
The pathogenesis of neurological manifestations in coeliac disease is multifactorial. The disease is characterized by malabsorption, and some neurological complications may, therefore, be secondary to vitamin B12 deficiency (e.g. myelopathy and neuropathy), vitamin D malabsorption (e.g. myopathy), or vitamin E deficiency (e.g. cerebellar ataxia and myopathy).3 However, neurological complications are also frequently reported in individuals without malabsorption, leading to the hypothesis that other factors may play a role in the pathogenesis of neurological defects. Emerging evidence suggests possible humoral mechanisms for both neuropathy and ataxia. Immunoglobulin (Ig) G antibody reactivity to peripheral nerve antigens has been recorded in individuals with coeliac disease and peripheral neuropathy.4 A humoral mechanism has also been postulated for gluten ataxia. Hadjivassiliou et al.5 detected antibodies against Purkinje cells in sera from individuals with coeliac ataxia as well as cross-reactivity between anti-gliadin antibodies and epitopes on Purkinje cells. However, other authors did not confirm these findings.6 Whether these antibodies are pathogenic or only a non-specific marker is still unclear. Few evidence-based data (mostly anecdotal) are available for these issues in children, the incidence varying according to the selection criteria and the individual’s characteristics. In this article we provide a meta-analysis and systematic review of the existing paediatric literature on the neurology of coeliac disease, and we try to answer the question of whether there is evidence of a causal relationship between the disease and neurological conditions.
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A systematic survey of the literature indicates that individuals with coeliac disease have an increased risk of developing (at least some) neurological complications during childhood (e.g. headache, peripheral neuropathy, and white matter disease). The overall prevalence of neurological involvement in children is lower than in adults. Such a discrepancy may have different explanations: (1) the relatively short duration of illness in children might not be sufficient do determine nervous system involvement;5 (2) early elimination of gluten from the diet may prevent the development of neurological manifestations; (3) strict adherence to a GFD may play a preventative role (dietary compliance is higher in childhood than in adolescence or adulthood); (4) the two populations may differ in susceptibility to immune-mediated disorders, for example children are more prone to natural autoimmune phenomena, and T cells in children with coeliac disease recognize a wider spectrum of gliadin and gluten peptides than in adults.
The main limitations of the present review are: (1) the paucity of available studies in the paediatric age group; (2) the fact that some studies labelled as purely paediatric or childhood studies analysed mixed (age) populations (e.g. extension of age limits towards adolescence and young adulthood); (3) clustering of all participants with neurological disorders into single studies; (4) clustering of heterogeneous conditions into one group as if they were single disorders (e.g. epilepsy in participants with coeliac disease); and (5) poorly defined clinical criteria for inclusion in specific neurological categories (e.g. ataxia, epilepsy, and headache).
What this paper adds
We provide a meta-analysis and a systematic review of the paediatric literature on the neurology of coeliac disease.
Our data shows that children with coeliac disease are at risk of developing neurological complications, but the risk is lower than in adulthood.