Gluten-related neurological disorders (GRND) represent a spectrum of neurological manifestations that are triggered by gluten. In coeliac disease, a T-cell mediated enteropathy is triggered by gluten in genetically predisposed individuals. The underlying pathological mechanism of the neurological dysfunction is not yet clear. The aim of this review is to collate existing neuropathological findings in GRND as a means of aiding the understanding of the pathophysiology. A systematic search of the Pubmed Database yielded 188 articles, of which 32 were included, containing 98 eligible cases with a description of pathological findings in GRND. In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes. In patients with large-fiber neuropathy, nerve biopsies revealed axonopathy, loss of myelinated fibers and focal and perivascular infiltration by inflammatory cells. Inflammatory infiltrate was also observed in muscle in myopathy and in cerebrum of patients with encephalopathy and patients with epilepsy. Such changes were not seen in skin biopsies from patients with small fiber neuropathies. The findings from this systematic review suggest an immune mediated pathogenesis for GRND. Future research should focus on the characterization of the inflammatory cell infiltrates and identifying target epitopes.

Currently, the gold standard for diagnosis of coeliac disease (CD) is based on serology and gastroduodenoscopy with histology of duodenal mucosal biopsies. The aim of this study was to evaluate the potential of faecal volatile organic compounds (VOCs) analysis as a novel, non-invasive tool to discriminate between CD in remission in patients on a gluten-free diet (GFD), refractory coeliac disease (RCD) and controls without CD. Patients with an established diagnosis of CD on a GFD, RCD and healthy controls (HC) were instructed to collect a faecal sample. All subjects completed questionnaires on clinical symptoms, lifestyle and dietary information. Faecal VOCs were measured using gas chromatography-ion mobility spectrometry. A total of 13 CD, 7 RCD and 10 HC were included. A significant difference in VOC profiles between CD and RCD patients (area under the curve (AUC) ± 95% CI: 0.91 (0.79–1) p = 0.000) and between CD and HC (AUC ± 95% CI: 0.71 (0.51–0.91) p = 0.0254) was observed. We found no significant differences between faecal VOC patterns of HC and RCD. Based on faecal VOCs, CD could be discriminated from RCD and HC. This implies that faecal VOC analysis may hold potential as a novel non-invasive biomarker for RCD. Future studies should encompass a larger cohort to further investigate and validate this prior to application in clinical practice.

Transglutaminase 6 antibodies are not yet mainstream in neuro-coeliac disease Worldwide 1% of the population suffers from a gluten related disorder (GRD) that severely impacts ones life, and no therapeutic treatment, except a gluten-free diet, is available. GRD's are a group of immune mediated diseases triggered by the ingestion of gluten. Well known is coeliac disease (CD) that presents with enteropathy. Some patients present exclusively with extra-intestinal manifestations such as skin involvement in dermatitis herpetiformis (DH). Over the last fifty years, patients with gluten sensitivity presenting with neurological symptoms have been described more and more. These symptoms include e.g. cerebellar ataxia and peripheral neuropathies and were thus far considered to be a rare manifestation of GRD. Thus, the diagnosis of neuro-coeliac disease is not yet based on objective and verifiable clinical and/or pathological criteria set by international working groups, such as those of the international Society for the Study of Celiac Disease, the European Society of Pediatric Gastroenterology and Nutrition or Neurological Societies. It would be recommended that groups working on neuro-coeliac disease bundle their forces to obtain a large international cohort of patients to standardize the clinical and pathological picture of this disease. The Sheffield group, led by professor Hadjivassiliou, is one of the leading groups working on neuro-coeliac disease. In the past they have shown that cerebellar ataxia in gluten sensitive patients coincides with white matter abnormalities and neuropathology. Moreover, they found that Transglutaminase (TG) 6 antibodies are overrepresented in the serum of these patients [1]. Serum markers in CD include the presence of TG2 antibodies, and in DH elevated levels of TG3 antibodies can be found [2,3]. In a previous issue of this journal, Panagiotis Zis et al. present a cross-sectional study on 28 patients with peripheral neuropathies, i.e. sensory ganglionopathy, symmetrical axonal neuropathy or mononeuritis multiplex. The notion that TG6 antibodies were enhanced in cerebellar ataxia patients, and that TG6 is considered to be a Transglutaminase more specific to the central nervous system, they now questioned whether TG6 antibodies were elevated in gluten sensitive patients with peripheral neuropathy. The prevalence of TG6 antibodies was 50% compared to 4% in the healthy population, suggesting that TG6 involvement is not confined to the central nervous system alone, but also can affect the peripheral nervous system. In addition, in CD more than 95% of patients share the HLA DQ2 or DQ8 haplotype, whereas of the patients in this study only 62% shared those HLA haplotypes. Moreover, TG2 antibodies were also elevated in this population [4]. As mentioned the so-called neuro-coeliac disease manifestations are not well studied by neurologists and neuroscientists and

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Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction was even more prominent with a median reduction of 81.3% compared to NNC. Marked increased numbers of both CD3+ and CD8+ cells were observed in the NeuroCD but not in SCA patients. This coincided with significantly more microglial reactivity in NeuroCD patients. These findings demonstrate that the massive loss of Purkinje cells in the cerebellum of neuro CD patients is accompanied by local innate and T-cell mediated immune responses.

Background: Coeliac disease (CD) has an estimated prevalence of $1% in Europe with a significant gap between undiagnosed and diagnosed CD. Active case finding may help to bridge this gap yet the diagnostic yield of such active case finding in general practice by serological testing is unknown. Objective: The aim of this study was to determine (1) the frequency of diagnosed CD in the general population, and (2) to investigate the yield of active case finding by general practitioners. Methods: Electronic medical records of 207.200 patients registered in 49 general practices in The Netherlands in 2016 were analysed. An extensive search strategy, based on International Classification of Primary Care codes, free text and diagnostic test codes was performed to search CD-or gluten-related contacts. Results: The incidence of CD diagnosis in general practice in 2016 was 0.01%. The prevalence of diagnosed CD reported in the general practice in the Netherlands was 0.19%, and considerably higher than previously reported in the general population. During the one year course of the study 0.95% of the population had a gluten-related contact with their GP; most of them (72%) were prompted by gastrointestinal complaints. Serological testing was performed in 66% (n ¼ 1296) of these patients and positive in only 1.6% (n ¼ 21). Conclusion:The number of diagnosed CD patients in the Netherlands is substantially higher than previously reported. This suggests that the gap between diagnosed and undiagnosed patients is lower than generally assumed. This may explain that despite a high frequency of gluten-related consultations in general practice the diagnostic yield of case finding by serological testing is low. KEY POINTSThe diagnostic approach of GPs regarding CD and the diagnostic yield is largely unknown Case finding in a primary health care practice has a low yield of 1.6% CD testing was mostly prompted by consultation for gastrointestinal symptoms There is a heterogeneity in types of serological test performed in primary care ARTICLE HISTORY