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What is the Optimal Method Assessing for Persistent Villous Atrophy in Adult Coeliac Disease?
Coleman, SH, Rej, A, Baggus, EMR, Lau, MS, Marks, LJ, Hadjivassiliou, M, Cross, SS, Leffler, DA, Elli, L, Sanders, DS
Journal of gastrointestinal and liver diseases : JGLD. 2021;(2):205-212
Abstract
BACKGROUND AND AIMS Methods of assessing gluten-free diet (GFD) adherence in adults with coeliac disease (CD) include serological testing, dietitian evaluation, questionnaires and repeat duodenal biopsies. Persisting villous atrophy (VA) is associated with CD complications, however gastroscopy with biopsies is expensive and invasive. This study aimed to assess the abilities of a duodenal bulb (D1) biopsy and the Celiac Dietary Adherence Test (CDAT) to detect persisting VA in adults with CD. METHODS A prospective observational study of adult CD patients referred for follow-up duodenal biopsies was performed. Quadrantic biopsies were taken from the second part of the duodenum (D2), in addition to a D1 biopsy. Patients underwent follow-up serological testing, and completed the CDAT and Biagi Score. These non-invasive adherence markers were compared against duodenal histology. RESULTS 368 patients (mean age 51.0 years, 70.1% female) had D1 and D2 biopsies taken at follow-up gastroscopy. Compared to D2 biopsies alone, additional D1 biopsies increased detection of VA by 10.4% (p<0.0001). 201 patients (mean age 50.3 years, 67.7% female) completed adherence questionnaires and serology. When detecting VA, sensitivities and specificities of these markers were 39.7% and 94.2% for IgA- tTG, 38.1% and 96.4% for IgA-EMA, 55.6% and 52.2% for CDAT and 20.6% and 96.4% for the Biagi score. CONCLUSIONS Bulbar biopsies increase detection of persisting VA by 10.4%. Serology, CDAT and Biagi performed poorly when predicting VA. The gold standard for predicting persisting VA remains repeat biopsy.
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Gluten and Autism Spectrum Disorder.
Croall, ID, Hoggard, N, Hadjivassiliou, M
Nutrients. 2021;(2)
Abstract
An expanding body of literature is examining connections between Autism Spectrum Disorder (ASD) and dietary interventions. While a number of specialist diets have been suggested as beneficial in ASD, gluten has received particularly close attention as a potentially exacerbating factor. Reports exist suggesting a beneficial effect of the gluten-free diet (GFD) in ameliorating behavioural and intellectual problems associated with ASD, while epidemiological research has also shown a comorbidity between ASD and coeliac disease. However, both caregivers and clinicians have expressed an uncertainty of the value of people with ASD going gluten-free, and as the GFD otherwise receives considerable public attention a discussion which focuses specifically on the interaction between ASD and gluten is warranted. In this review we discuss the historical context of ASD and gluten-related studies, and expand this to include an overview of epidemiological links, hypotheses of shared pathological mechanisms, and ultimately the evidence around the use and adoption of the GFD in people with ASD.
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How to manage adult coeliac disease: perspective from the NHS England Rare Diseases Collaborative Network for Non-Responsive and Refractory Coeliac Disease.
Baggus, EMR, Hadjivassiliou, M, Cross, S, Penny, H, Urwin, H, Watson, S, Woodward, JM, Sanders, DS
Frontline gastroenterology. 2020;(3):235-242
Abstract
Adult coeliac disease (CD) affects approximately 1% of the population. Most patients diagnosed will respond to a gluten-free diet; however, up to 30% may have persisting symptoms. Such patients may have ongoing issues associated with adherence, non-responsive CD or refractory CD. This article provides a clinical overview of how to manage this group of patients with persisting symptoms, including an investigational algorithm and details of how to contact the National Health Service England Rare Diseases Collaborative Network for Non-Responsive and Refractory Coeliac Disease. We hope this will be a valuable source of contemporary information for all UK gastroenterologists and internationally.
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Psychiatric Manifestations of Coeliac Disease, a Systematic Review and Meta-Analysis.
Clappison, E, Hadjivassiliou, M, Zis, P
Nutrients. 2020;(1)
Abstract
BACKGROUND Coeliac disease (CD) is increasingly prevalent and is associated with both gastrointestinal (GI) and extra-intestinal manifestations. Psychiatric disorders are amongst extra-intestinal manifestations proposed. The relationship between CD and such psychiatric disorders is not well recognised or understood. AIM: The aim of this systematic review and meta-analysis was to provide a greater understanding of the existing evidence and theories surrounding psychiatric manifestations of CD. METHODOLOGY An online literature search using PubMed was conducted, the prevalence data for both CD and psychiatric disorders was extracted from eligible articles. Meta analyses on odds ratios were also performed. RESULTS A total of 37 articles were included in this review. A significant increase in risk was detected for autistic spectrum disorder (OR 1.53, 95% CI 1.24-1.88, p < 0.0001), attention deficit hyperactivity disorder (OR 1.39, 95% CI 1.18-1.63, p < 0.0001), depression (OR 2.17, 95% CI 2.17-11.15, p < 0.0001), anxiety (OR 6.03, 95% CI 2.22-16.35, p < 0.0001), and eating disorders (OR 1.62, 95% CI 1.37-1.91, p < 0.00001) amongst the CD population compared to healthy controls. No significant differences were found for bipolar disorder (OR 2.35, 95% CI 2.29-19.21, p = 0.43) or schizophrenia (OR 0.46, 95% CI 0.02-10.18, p = 0.62). CONCLUSION CD is associated with an increased risk of depression, anxiety, eating disorders as well as ASD and ADHD. More research is required to investigate specific biological explanations as well as any effect of gluten free diet.
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The Role of Oxidative Stress in Peripheral Neuropathy.
Mallet, ML, Hadjivassiliou, M, Sarrigiannis, PG, Zis, P
Journal of molecular neuroscience : MN. 2020;(7):1009-1017
Abstract
Peripheral neuropathy (PN) is a common disease affecting about 5% of the general population after the age of 50. Causes of PN are numerous and include genetic, diabetes, alcohol, vitamin deficiencies, and gluten sensitivity among others. This systematic review aimed to study the association between oxidative stress and PN in an attempt to better understand PN pathogenesis. A computer-based, systematic search was conducted on the PubMed database, and ensuing data from included articles was analyzed and discussed in this review. Sixty-nine papers were eligible and were used for this review. Peripheral neuropathy is associated with an increase of reactive oxygen species and a decrease in endogenous antioxidants. Genetic predisposition to oxidative damage may be a factor. Antioxidant treatment is promising regarding treatment. Though further research is necessary to better understand the underlying mechanism, it is evident that oxidative stress is implicated in the pathogenesis of - or is at least systematically present in - PN.
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The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review.
Rouvroye, MD, Zis, P, Van Dam, AM, Rozemuller, AJM, Bouma, G, Hadjivassiliou, M
Nutrients. 2020;12(3)
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Coeliac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten in genetically susceptible individuals. A wide range of extraintestinal manifestations has been attributed to CD, changing the classic perception of a disease limited to the intestine, to a multisystem disorder. The aim of this study was to analyse the published neuropathology of confirmed cases of gluten-related neurological dysfunction to aid our understanding of the pathogenesis. CD can therefore manifest with dental problems, consequences of malabsorption, skin and neurological disorders. This study is a systematic review of thirty-two neurological disorder focused studies. Results show that: - the neuropathological findings in gluten-related neurological disorders are widespread and not limited to the cerebellum. - the pathology is immune mediated and not related to vitamin or trace elements deficiencies. - the pathophysiology of neurological damage in the context of gluten sensitivity has an immune mediated basis. - more gluten-related neurological disorders affected men (57%), which was even higher in the ataxia group (76%). - transglutaminase 6 antibodies might be helpful in the diagnostic workup of gluten-related neurological disorders. Authors conclude that the current evidence is suggestive of both humoral and cell-mediated immunological responses. Further research is required to investigate the underlying neuropathological mechanism by characterisation of the inflammatory cell infiltrate and identification of target epitopes.
Abstract
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.
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Gluten sensitivity and epilepsy: a systematic review.
Julian, T, Hadjivassiliou, M, Zis, P
Journal of neurology. 2019;(7):1557-1565
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Abstract
OBJECTIVE The aim of this systematic review was to establish the prevalence of epilepsy in patients with coeliac disease (CD) or gluten sensitivity (GS) and vice versa and to characterise the phenomenology of the epileptic syndromes that these patients present with. METHODOLOGY A systematic computer-based literature search was conducted on the PubMed database. Information regarding prevalence, demographics and epilepsy phenomenology was extracted. RESULTS Epilepsy is 1.8 times more prevalent in patients with CD, compared to the general population. CD is over 2 times more prevalent in patients with epilepsy compared to the general population. Further studies are necessary to assess the prevalence of GS in epilepsy. The data indicate that the prevalence of CD or GS is higher amongst particular epileptic presentations including in childhood partial epilepsy with occipital paroxysms, in adult patients with fixation off sensitivity (FOS) and in those with temporal lobe epilepsy (TLE) with hippocampal sclerosis. A particularly interesting presentation of epilepsy in the context of gluten-related disorders is a syndrome of coeliac disease, epilepsy and cerebral calcification (CEC syndrome) which is frequently described in the literature. Gluten-free diet (GFD) is effective in the management of epilepsy in 53% of cases, either reducing seizure frequency, enabling reduced doses of antiepileptic drugs or even stopping antiepileptic drugs. CONCLUSION Patients with epilepsy of unknown aetiology should be investigated for serological markers of gluten sensitivity as such patients may benefit from a GFD.
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Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease.
Zis, P, Hadjivassiliou, M
Current treatment options in neurology. 2019;(3):10
Abstract
PURPOSE OF REVIEW The aim of this paper was to overview the current literature in order to establish the available treatment options for the neurological manifestations of gluten-related disorders (serologically confirmed gluten sensitivity and coeliac disease). RECENT FINDINGS A range of debilitating neurological manifestations is increasingly being recognized in patients with gluten sensitivity with and without enteropathy even in the absence of gastrointestinal symptoms. Ataxia is the commonest neurological manifestation, followed by peripheral neuropathy. Epilepsy, headache, encephalopathy, various movement disorders, cognitive impairment, and muscle disorders have also been linked to gluten sensitivity and coeliac disease and are discussed in this review. Strict gluten-free diet is an effective first-line treatment of the neurological manifestations of gluten-related disorders. Very few patients will require additional immunosuppressive treatment usually in the form of mycophenolate.
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Small fiber neuropathy in coeliac disease and gluten sensitivity.
Zis, P, Sarrigiannis, PG, Rao, DG, Sanders, DS, Hadjivassiliou, M
Postgraduate medicine. 2019;(7):496-500
Abstract
Objectives: The commonest types of peripheral neuropathy in the context of Coeliac Disease (CD) and gluten sensitivity (GS) are length-dependent symmetrical sensorimotor neuropathies and sensory ganglionopathies. In patients with such neuropathy, (gluten neuropathy), peripheral neuropathic pain is prevalent suggesting involvement of small fibers. The purpose of this report was to describe the clinical characteristics of patients with CD or GS and pure small fiber neuropathy (SFN). Methods: We reviewed the records of all patients that had been referred to the Gluten-Related Neurological Disorders clinic who had clinical and neurophysiological evidence of SFN. All patients had serological evidence of gluten sensitivity (GS) prior to commencing GFD. All patients were offered a duodenum biopsy. Patients with comorbidities that could cause SFN were excluded. Results: We identified 13 patients (9 males) with SFN and gluten sensitivity. Of 11 patients who underwent duodenal biopsy 10 had evidence of enteropathy (CD). Mean age at onset of pain was 53.5 ± 11.4 years (range 34-72) and mean age of CD/GS diagnosis was 50.8 ± 10.4 years (range 34-68). In 8 patients (61.5%) pain was the presenting feature. Neurophysiological assessment suggested a length-dependent small fiber neuropathy in 11 patients, whereas in 2, a non-length dependent pattern was identifying suggesting that the predominant pathology lies in the dorsal root ganglia. Conclusion: SFN can be a presenting feature of CD and GS and, therefore, screening for CD and GS should be included in the diagnostic workup of patients with idiopathic SFN.
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Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review.
Mearns, ES, Taylor, A, Thomas Craig, KJ, Puglielli, S, Leffler, DA, Sanders, DS, Lebwohl, B, Hadjivassiliou, M
Nutrients. 2019;11(2)
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Coeliac disease (CD) is a chronic, immune-mediated enteropathy in which dietary gluten triggers an inflammatory reaction of the small intestine in genetically predisposed individuals. The clinical presentation of the disease varies broadly and may include both intestinal symptoms and extra-intestinal manifestations, including iron-deficiency anaemia, osteoporosis, dermatitis herpetiformis, and neurological disorders, such as peripheral neuropathies and ataxia (a condition that affects co-ordination, balance and speech). Many patients who present with neurological manifestations of CD have no gastrointestinal symptoms, commonly leading to a delay in diagnosis. The aim of this systematic review was to assess the prevalence of peripheral neuropathies and gluten ataxia. Nine studies on gluten ataxia and 13 on gluten neuropathy were included in this review. The prevalence of both, neuropathy and ataxia, in the general population is very low, but this risk is increased in patients with CD. Estimates of the prevalence of neuropathy in CD patients ranged from 0% to 39%, with an increased risk in older and female patients. Prevalence of gluten ataxia varied from 0% to 6%. Symptoms of gluten neuropathy improve when patients with CD follow a gluten free diet (GFD), whilst the benefits of a GFD for ataxia vary between studies, possibly due to differences in study design. The authors note that this review primarily concentrated on patients with CD (i.e. those with evidence of enteropathy). However, neurological manifestations may exist in the presence of anti-gliadin antibodies alone (gluten sensitivity without evidence of enteropathy), and such patients benefit equally from a GFD. The authors conclude that patients with CD have an increased risk of gluten ataxia and gluten neuropathy, and that clinicians should check for gluten sensitivity in patients with ataxia and neuropathy of unknown origin.
Abstract
Celiac disease (CD) is an immune-mediated gastrointestinal disorder driven by innate and adaptive immune responses to gluten. Patients with CD are at an increased risk of several neurological manifestations, frequently peripheral neuropathy and gluten ataxia. A systematic literature review of the most commonly reported neurological manifestations (neuropathy and ataxia) associated with CD was performed. MEDLINE, Embase, the Cochrane Library, and conference proceedings were systematically searched from January 2007 through September 2018. Included studies evaluated patients with CD with at least one neurological manifestation of interest and reported prevalence, and/or incidence, and/or clinical outcomes. Sixteen studies were included describing the risk of gluten neuropathy and/or gluten ataxia in patients with CD. Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies. Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%⁻6%. Adherence to a gluten-free diet appeared to improve symptoms of both neuropathy and ataxia. The prevalence of gluten neuropathy and gluten ataxia in patients with CD varied in reported studies, but the increased risk supports the need for physicians to consider CD in patients with ataxia and neurological manifestations of unknown etiology.