Gluten Ataxia Research Articles

Cerebellar Abnormalities on Proton MR Spectroscopy and Imaging in Patients With Gluten Ataxia: A Pilot Study

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and right cerebellum and structural changes in various brain regions of patients with gluten ataxia (n = 6, age range 40–65 years) and compared it with healthy controls (n = 10, 40–55 years). Volumetric 3-D T1 and T1-weighted magnetic resonance imaging (MRI) in the three planes (axial, coronal, and sagittal) of the whole brain and single-voxel 1H- magnetic resonance spectroscopy (MRS) of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model (6.1–4A) while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites (N-acetyl aspartate + N-acetyl aspartate glutamate, glycerophosphocholine + phosphocholine, and total creatine) were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of (total brain, cerebellum, and cerebrum); reduction in the volumes of cerebellum lobe (X) and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients.

P235 Cerebellar ataxia in primary Sjogren’s syndrome: is gluten sensitivity the answer?

Abstract Background/Aims Cerebellar ataxia is an uncommon neurological complication of Primary Sjogren’s Syndrome (PSS), with case reports being the highest level of evidence available. The underlying disease pathogenesis is unknown, although an immunologically mediated mechanism seems plausible. Gluten sensitivity is common amongst patients with PSS and is a known cause of immune-mediated ataxia (gluten ataxia). We aimed to investigate the presence of ataxia in patients with PSS seen in the joint rheumatology-neurology clinics at our institution, and determine if gluten sensitivity is responsible for cerebellar ataxia in some of these patients. Methods A retrospective review of all patients who attend the rheumatology and joint rheumatology-neurology clinics was conducted. Patient data including patient demographics, the presence of gluten sensitivity-related antibodies (anti-tissue transglutaminase 2, anti-gliadin IgG and IgA, endomysial antibodies, anti-transglutaminase 6 IgG and IgA), were collected. Patients attending the rheumatology clinics with PSS were asked about the presence of any symptoms of unsteadiness. Such patients underwent MR spectroscopy of the cerebellum looking for any evidence of abnormal cerebellar metabolites (N-acetylaspartate-to-creatine (NAA/Cr) ratio <1). Electrophysiology results in the form of nerve conduction studies (NCS) or electromyography (EMG) were also collected. Results We identified 45 patients with symptoms of impaired balance. Not all of the 236 patients with PSS who regularly attend the rheumatology clinics were assessed for any evidence of loss of balance. Nonetheless, at least 45 out of 236 patients (19.1%) complained of balance problems. The majority of these patients were female (41/45, 91.1%) with a mean age of 64.3 years. Thirty-three out of 45 patients with ataxia (73.3%) tested positive for one or more of gluten sensitivity-related antibodies, with IgA TG6 being the most common (17/33 patients, 51.5%). Out of the 33 gluten sensitive patients, 25 had MR spectroscopy of the cerebellum and 17/25 (68%) had an abnormal NAA/Cr ratio. Twenty-two patients had NCS/EMG studies performed, of which 13 (59.1%) had either a sensory-motor neuropathy or sensory ganglionopathy. Conclusion The high prevalence of gluten sensitivity-related autoantibodies, combined with objective evidence of ataxia, suggest that gluten sensitivity may be responsible for the majority of cases of ataxia in PSS. The presence of a neuropathy in some of these patients suggests that sensory ataxia may also be contributing to the impaired balance in some of these patients. There is, however, a cohort of patients with ataxia and PSS who are not gluten sensitive. These patients may well have primary autoimmune cerebellar ataxia (PACA). Whilst a therapeutic response to a gluten free diet in patients with gluten ataxia has already been established, it remains to be seen if those patients with PSS and ataxia who have no evidence of gluten sensitivity may benefit from immunosuppression. Disclosure F. Kon: None. M. Akil: None. R. Kilding: None. K. Kuet: None. P. Shanmugarajah: None. N. Hoggard: None. M. Hadjivassiliou: None.

Gluten-related disorders

Gluten-related disorders are a heterogeneous group of clinical entities caused by intolerance to wheat, rye, and barley flour components. They occur in 3?5% of genetically predisposed persons and, based on pathogenic and clinical features, are classified into celiac disease, non-celiac gluten sensitivity, and wheat allergy. There are also specific entities such as dermatitis herpetiformis or gluten ataxia, which can occur either within the celiac disease or independently. This article based on the current knowledge shows the basic details of the pathogenesis, clinical expression, diagnosis, and treatment of these disorders.

Celiac Disease, Beyond the Bowel: A Review of Its Neurological Manifestations.

Celiac disease (CD) is a multi-systemic autoimmune condition that causes a hyperinflammatory response when gluten is ingested. There has been a shift in the clinical presentation of CD from a mere malabsorption disorder to an autoimmune condition that affects multiple organ systems, which could increase the rate of hospitalizations and a decreased quality of life. This article has compiled various studies that have explored the neurological manifestations of celiac disease, their epidemiology, possible pathogenic mechanisms, diagnosis, and treatment. The most common neurological conditions include gluten ataxia (GA), gluten neuropathy, gluten encephalopathy, and epilepsy which usually present as sporadic diseases which are difficult to diagnose in the absence of gastrointestinal (GI) symptoms. The treatment for most of these conditions is a gluten-free diet (GFD) regardless of GI involvement.

More Than Celiac Disease - Five Gluten-induced Pathologies

Gluten can induce several conditions. However, a lot of people and even medical practitioners only associate gluten pathology with its most severe form neglecting other pathologies. In addition to this, clinical manifestations of celiac disease are not always classic and for this reason, many cases are diagnosed late, being characterized by intricate symptoms that can be attributed to other conditions. In the present study, we try to bring a systematization of the five major gluten-induced manifestations: celiac disease, non-celiac gluten sensitivity, wheat allergy, gluten ataxia, and dermatitis herpetiformis.

The Gluten-Free Diet for Celiac Disease and Beyond.

The gluten-free diet (GFD) has gained popularity beyond its main medical indication as the treatment for gluten-induced immune-mediated disorders such as celiac disease (CD), dermatitis herpetiformis, gluten ataxia, wheat allergy, and non-celiac gluten sensitivity. However, the diet carries some disadvantages such as elevated costs, nutritional deficiencies, and social and psychological barriers. The present work aims to review indications, proven benefits, and adverse events of a gluten-free diet. Close follow-up with patients following the diet is recommended. More data is needed to assess the effectiveness of the diet in managing mental and cognitive disorders and to establish a connection between the brain and gluten.

Gluten-Free Cereal Products and Beverages: A Review of Their Health Benefits in the Last Five Years.

In the past decades, food products and beverages made from gluten-free cereals were initially created for certain groups of people who experience gluten-related disorders such as wheat allergies, gluten ataxia, non-celiac gluten sensitivity, and the most well-known, celiac disease. Nowadays, the consumption of gluten-free products is not only restricted to targeted groups, but it has become a food trend for normal consumers, especially in countries such as the UK, the US, and some European countries, who believe that consuming a gluten-free product is a healthier choice compared to normal gluten-containing products. However, some research studies have disapproved of this claim because the currently available gluten-free products in the market are generally known to be lower in proteins, vitamins, and minerals and to contain higher lipids, sugar, and salt compared to their gluten-containing counterparts. The use of other gluten-free cereals such as sorghum, millet, and teff as well as pseudo cereals such as buckwheat and quinoa has gained significant interest in research in terms of their various potential health benefits. Hence, this review highlights the potential health benefits of some gluten-free cereals and pseudo cereals apart from corn and rice in the last decade. The potential health benefits of gluten-free products such as bread, pasta, crackers, and cookies and the health benefits of some other non-alcoholic beverages made from gluten-free cereals and pseudo cereals are reported.

Downbeat nystagmus: a clinical review of diagnosis and management.

This review will extensively cover the clinical manifestations, causes, diagnostic evaluation, and management strategies of downbeat nystagmus (DBN). Historically, MRI to assess for structural lesions at the cervicomedullary junction has been the primary diagnostic test in the evaluation of DBN since the 1980s. In recent years, there is increasing awareness of nonstructural causes of DBN including gluten ataxia, nutritional deficiencies, and paraneoplastic syndromes, among others. Medical management with aminopyridines has become first-line therapy in addition to disease-specific therapies. DBN is a common form of acquired nystagmus and the differential diagnosis remains broad, including both benign and potentially fatal causes. For practical purposes, the causes can be categorized as structural vs. nonstructural with MRI as the ideal, initial diagnostic study to differentiate the two. General therapeutic options include pharmacotherapy to enhance Purkinje cell function, strabismus surgery or prisms to shift null points, and behavioural changes. Disease-specific treatment is necessarily broad, though a significant proportion of patients will be idiopathic.

GLUTEN ATAXIA - A COMMON, COMMONLY MISDIAGNOSED DISEASE

The objective of our research was to raise awareness of neurologists and family physicians about gluten ataxia and improve the diagnostic approaches. Methods. PubMed and Google Scholar resources were used to write the review article. Discussion. It is incredibly important not to overlook treatable courses of ataxia. One of these diseases is gluten ataxia. Early diagnosis and timely treatment (gluten-free diet) of gluten ataxia leads to a significant improvement of clinical symptoms and prevents their progression. Gluten ataxia is one of the most common and commonly misdiagnosed ataxia. Its prevalence among all ataxias is 15% and reaches 40% among all idiopathic sporadic ataxias (Hadjivassiliou M., Sanders D.D., Aeschlimann D.P., 2015). Keywords: gluten ataxia, celiac disease, gluten-related disorders.

Recognition and management of rapid-onset gluten ataxias: case series

BackgroundMost immune-mediated cerebellar ataxias, including those associated with gluten sensitivity (Gluten Ataxia), tend to present subacutely and usually progress gradually. Acute presentations with rapid progression outside the context of paraneoplastic cerebellar degeneration require prompt diagnosis and early access to disease-modifying immunotherapy in order to avert severe and permanent neurological disability.Case presentationsWe describe three cases of rapid-onset Gluten Ataxia, an immune-mediated cerebellar ataxia due to gluten sensitivity. We detail their presentation, clinical and neuroimaging findings, and our treatment strategy with immunotherapy.ConclusionsOur cases highlight the potential for immune-mediated cerebellar ataxias to present acutely, with rapid-onset symptoms and devastating neurological consequences. We caution against the diagnosis of ‘post-infective cerebellitis’ in adults, and advocate early consideration of an immune-mediated cerebellar ataxia and initiation of immunotherapy to prevent irreversible cerebellar damage.

Immune-Mediated Cerebellar Ataxias

Autoimmune mechanisms insult the cerebellum, resulting in the development of cerebellar ataxias (CAs). These immune-mediated cerebellar ataxias (IMCAs) include gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration (PCD), antiglutamate decarboxylase 65 antibody-associated CA (anti-GAD ataxia), and primary autoimmune cerebellar ataxia (PACA). Cell-mediated mechanisms are assumed to be involved in PCD, whereas accumulating evidence shows that anti-GAD antibodies decrease the amount of GABA released which leads to functional synaptic deficits. The therapeutic benefits of immunotherapies vary depending on the etiology of the disease. Early intervention is recommended while the cerebellar reserve can be preserved.

FORMULATION OF GLUTEN-FREE BREAD WITH DIFFERENT LEVELS OF HYDROXYPROPYL METHYLCELLULOSE, RAW BANANA FLOUR AND PROOF TIME: MODELLING, PROXIMATE AND SENSORY ANALYSES

Semi-urbanization has increased the demand of bakery products triggering variousgluten-related disorders including Celiac Disease (CD), Non-celiac Gluten Sensitivity (NCGS), Gluten Ataxia and Wheat Allergy. Among these, CD accounts for nearly 1-2%global population. Gluten withdrawal- cornerstone treatment for CD is a bumpy road with nutritional deficiencies and poor quality of life. Additionally, there is a surge of people intentionally avoiding gluten for various reasons. The present work intends to optimize a formula for a gluten free (GF) bread and determine the effect of prooftime, hydroxypropyl methylcellulose (HPMC) and raw banana flour at different levels on moisture content, bake loss, specific volume, texture parameters andcrust-crumb brightness (L*) using response surface methodology (RSM) based on central composite rotatable design (CCRD).The results revealed moisture content, hardness, springiness, resilience and crust-crumb L*were significantly affected. Different proof time levels altered moisture content, bake loss and colour parameters with no influence on textural parameters. Increasing levels of HPMC impeded bake loss and crumb lightness but exacerbated hardness. Nonetheless, on its interaction with raw banana flour, there was antagonistic effect on hardness. Addition of raw banana flour darkened the bread. Thus, optimal conditions (HPMC 2%, raw banana flour 37.16% and proof time 40mins) were appliedto produce good quality bread. Furthermore, sensory and proximateanalyses of optimum GF bread were compared to whole wheat bread depicting higherprotein-fat content, lower carbohydrate content and overall acceptability score of 7.88for the former; the demand for which is steadily and incessantly expanding

Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms.

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.

Neurological manifestation of coeliac disease with particular emphasis on gluten ataxia and immunological injury: a review article.

Coeliac disease (CD) is a gluten-induced enteropathy affecting 1% of the population and has extra intestinal manifestations. One such expression involves nervous system, and CD may present as gluten ataxia (GA), peripheral neuropathy and epileptiform disorder among others. Considerable controversy exists on the exact pathophysiological mechanism of gluten leading to ataxia. It is, however, clear that in intestinal axis tissue transglutaminase 2 (tTG2) is the primary target but in the nervous system, tTG6 may be the causative antigen although its exact role is not clear. Furthermore, it has also been postulated that anti-gangliodise antibodies may play a role in the emergence of central pathology if not the key contender. Moreover, the association of neurological injury with non-coeliac gluten sensitivity (NCGS), a related but pathologically different condition implies an independent mechanism of neuronal injury by gluten in the absence of CD. This review will touch on the salient features of CD and the nervous system and will highlight current controversies in relation to gluten and GA.

Letter to: neurological manifestation of coeliac disease: many immunological markers suggesting a further expression of gluten-induced secondary autoimmunity.

To The Editor [1] I read with great interest the very interesting review article by Osman et al who addressed the issue of neurological manifestations of coeliac disease (CD), with particular emphasis on gluten ataxia and immunological injury (1). They have reviewed in detail the most relevant studies addressing the relationship of CD with cerebellar ataxia (CA) and immunopathology of enteric CD in comparison to neuronal pathology. The role of gluten-free diet (GFD) with special emphasis on its effect on improving symptoms of ataxia was also reviewed. This topic is of great relevance since neurological manifestations can occur in about 10% of CD patients with CA, peripheral neuropathy, seizures, headache, cognitive impartment and various neuropsychiatrist disorders representing potentially extraintestinal manifestations of CD, as properly stated by the authors. Although I consider this review to be of significant interest and very up-to-date, I feel that some issues would have deserved more emphasis owing to their clinical relevance. In particular, when the Author discussed the potential spectrum of neurological manifestations occurring in CD patients, they omitted to mention multiple sclerosis, multifocal leukoencephalopathy, chorea, and attention/memory impairment, all of which are well known to be other neurological disorders potentially associated to CD (2). Of major interest, I would also like to point out that among the autoantibodies potentially detectable in CD patients with neurological manifestations, other than anti-ganglioside antibodies, it is worth mentioning also anti-neuronal antibodies to central/enteric nervous systems detected by indirect immunofluorescence as previously reported (3-5). These antibodies can be considered markers of neurological manifestations as they have been reported in more than 60% of CD patients with neurological manifestations and therefore should be included in the immunological assessment of CD patients due to their major clinical significance. Received: 24 June 2020 Accepted: 29 August 2020 Reprint or Correspondence: Markus Wilhelmi, MD Medical Clinic I, Gastroenterology and Hepatology, Nutritional Medicine, University Hospital, Frankfurt, Germany. E-mail: dr.markus.wilhelmi@gmail.com ORCID ID: 0000-0003-0121-0627

Maintaining a Balanced Diet While Gluten-Free: Treatment Options

The goal of this review is to address the different reasons individuals adopt a gluten-free diet (GFD), including, but not limited to, celiac disease (CD), gluten ataxia (GA), and dermatitis herpetiformis (DH) and non-celiac gluten sensitivity (NCGS). The perceived health benefits and confusion surrounding gluten and gluten-free (GF) options will be addressed. The benefits and challenges of the diet will be discussed. There will be a specific emphasis on how to avoid and correct potential nutritional deficiencies which are commonly seen in patients on a GFD. Several studies have addressed challenges with the GFD including availability, nutrient quality of GF foods, and cost. Data has shown that nutritional deficiencies are common in patients following a GFD. More patients are starting the GFD for symptoms and conditions. It is important to be aware of the nutritional inadequacies of the diet. Counseling by a registered dietitian for individuals following a GFD with or without a gluten-related diagnosis is essential to achieve best outcomes.

Clinical Characteristics and Management of 50 Patients with Anti-GAD Ataxia: Gluten-Free Diet Has a Major Impact

The objective of this study is to report the clinical characteristics and treatment of patients with progressive cerebellar ataxia associated with anti-GAD antibodies. We performed a retrospective review of all patients with anti-GAD ataxia managed at the Sheffield Ataxia Centre over the last 25 years. We identified 50 patients (62% females) with anti-GAD ataxia. The prevalence was 2.5% amongst 2000 patients with progressive ataxia of various causes. Mean age at onset was 55 and mean duration 8 years. Gaze-evoked nystagmus was present in 26%, cerebellar dysarthria in 26%, limb ataxia in 44% and gait ataxia in 100%. Nine patients (18%) had severe, 12 (24%) moderate and 29 (58%) mild ataxia. Ninety percent of patients had a history of additional autoimmune diseases. Family history of autoimmune diseases was seen in 52%. Baseline MR spectroscopy of the vermis was abnormal at presentation in 72%. Thirty-five patients (70%) had serological evidence of gluten sensitivity. All 35 went on gluten-free diet (GFD). Eighteen (51%) improved, 13 (37%) stabilised, 3 have started the GFD too recently to draw conclusions and one deteriorated. Mycophenolate was used in 16 patients, 7 (44%) improved, 2 stabilised, 6 have started the medication too recently to draw conclusions and one did not tolerate the drug. There is considerable overlap between anti-GAD ataxia and gluten ataxia. For those patients with both, strict GFD alone can be an effective treatment. Patients with anti-GAD ataxia and no gluten sensitivity respond well to immunosuppression.

Differential Diagnosis of Idiopathic Cerebellar Ataxia

Cortical cerebellar atrophy has been defined as a sporadic degenerative cerebellar disorder other than multiple system atrophy, whereas the term "idiopathic cerebellar ataxia (IDCA)" has been recently proposed by a Japanese expert group. There is no diagnostic biomarker for IDCA; therefore, the diagnosis largely depends on exclusion of other cerebellar diseases, such as multiple system atrophy and hereditary spinocerebellar ataxia. Other important differential diagnoses include immune-mediated cerebellar ataxia, such as Hashimoto's encephalopathy, gluten ataxia, anti-glutamic acid decarboxylase-positive cerebellar ataxia, alcoholic cerebellar degeneration, and drug-induced ataxia. Secondary cerebellar disorders are treatable and should be recognized and screened.

Gluten Ataxia Associated with Dietary Protein Cross-Reactivity with GAD-65

Cross-reactivity occurs when antibodies formed against an antigen have amino acid sequence homology with another target protein. This allows antibodies formed against the antigen to also bind to similar proteins that share structural similarity. Autoimmune reactions to gluten can lead to sporadic ataxia in susceptible genotypes due to cross-reactivity. With gluten ataxia, dietary consumption of gluten proteins induce immunological cross-reactivity with glutamic-acid decarboxylase-65 (GAD-65) target proteins found in the cerebellum. Implementation of a strict gluten-free diet has been shown to improve the expression of this form of ataxia with most patients in this subgroup. However, there are some subjects that have limited clinical responses to only a strict gluten-free diet. Dietary protein cross-reactivity to other food proteins, besides gluten, that also share structural similarity to GAD-65 may also play a role in this reaction. In this case report, we report of a patient suffering from gluten-ataxia in which a gluten-free diet alone did not generate significant clinical outcomes until other foods that cross-react with GAD-65 were also removed from their diet.

Neurological Manifestations of the Celiac Disease in Children

Gluten-related disorders (GRDs) represent a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. The most common and widely recognized diseases within this spectrum are celiac disease and non-celiac gluten sensitivity. The clinical manifestations are intestinal, but extraintestinal manifestations may also appear, such as neurological or psychiatric. This work will specifically review the neurological or psychiatric manifestations that are more frequently associated with GRD in children. Gluten ataxia, celiac disease, neuropathy, and celiac disease-epilepsy-brain calcifications syndrome are key entities that appear silently or oligosymptomatically on many occasions. However, they are more typical disorders in adult patients. The treatment with a gluten-free diet can usually alleviate the symptoms and, in some cases, even the neurological condition is cured. Other conditions, such as headache, behavioral disorders, or generalized developmental disorders, are more typical in children. The pathophysiological basis of these conditions is not completely well-defined, although it is probably triggered by autoimmune mechanisms. The effective treatment approach is a gluten-free diet, although drugs such as antiepileptics, anti-migraine, immunomodulators, analgesics, or psychotropic drugs can control the clinical symptoms. The diagnosis of GRD should be made in the presence of neurological and psychiatric signs and symptoms, especially if they are of an unclear etiology. Also, the diagnosis should be made early, since their early correction can substantially improve the prognosis in some of these disorders.