Neurological manifestation of coeliac disease with particular emphasis on gluten ataxia and immunological injury: a review article
Gastroenterology and Hepatology from Bed to Bench,
Vol. 14 No. 1 (2021),
26 January 2021
,
Page 1-7
https://doi.org/10.22037/ghfbb.v14i1.1885
Abstract
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.
Keywords: Coeliac disease, Gluten ataxia, Gluten enteropathy.
(Please cite as: Osman D, Umar S, Muhammad H, Nikfekr E, Rostami K, Ishaq S. Neurological manifestation of coeliac disease with particular emphasis on gluten ataxia and immunological injury: a review article. Gastroenterol Hepatol Bed Bench 2021;14(1):1-7).
- Coeliac disease
- Gluten ataxia
- Gluten enteropathy
How to Cite
References
Dubé C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 2005;128:S57-67.
Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural basis for gluten intolerance in celiac sprue. Science 2002;297:2275-9.
Megiorni F, Pizzuti A. HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing. J Biomed Sci 2012;19:88.
Marsh MN. Grains of truth: evolutionary changes in small intestinal mucosa in response to environmental antigen challenge. Gut 1990;31:111-4.
Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009;373:1480-93.
West J, Logan RF, Hill PG, Khaw K. The iceberg of celiac disease: what is below the waterline? Clin Gastroenterol Hepatol 2007;5:59-62.
Rampertab SD, Pooran N, Brar P, Singh P, Green PH. Trends in the presentation of celiac disease. Am J Med 2006;119:355.
Kochhar GS, Singh T, Gill A, Kirby DF. Celiac disease: Managing a multisystem disorder. Cleve Clin J Med 2016;83:217-27.
Collin P, Salmi TT, Hervonen K, Kaukinen K, Reunala T. Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease. Ann Med 2017;49:23-31.
Bianchi M, Bardella MT. Bone in celiac disease. Osteoporosis Int 2008;19:1705-16.
Duggan JM, Duggan AE. Systematic review: the liver in coeliac disease. Aliment Pharmacol Ther 2005;21:515-8.
Metso S, Hyytiä-Ilmonen H, Kaukinen K, Huhtala H, Jaatinen P, Salmi J, et al. Gluten-free diet and autoimmune thyroiditis in patients with celiac disease. A prospective controlled study. Scand J Gastroenterol 2012;47:43-8.
Leeds JS, Hopper AD, Hurlstone DP, Edwards SJ, McAlindon ME, Lobo AJ, et al. Is exocrine pancreatic insufficiency in adult coeliac disease a cause of persisting symptoms? Aliment Pharmacol Ther 2007;25:265-71.
Emilsson L, Carlsson R, Holmqvist M, James S, Ludvigsson JF. The characterisation and risk factors of ischaemic heart disease in patients with coeliac disease. Aliment Pharmacol Ther 2013;37:905-14.
Rubio-Tapia A, Rahim MW, See JA, Lahr BD, Wu TT, Murray JA. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. Am J Gastroenterol 2010;105:1412-20.
Silvester JA, Rashid M. Long-term follow-up of individuals with celiac disease: an evaluation of current practice guidelines. Can J Gastroenterol 2007;21:557-64.
Ring Jacobsson L, Friedrichsen M, Göransson A, Hallert C. Does a Coeliac School increase psychological well‐being in women suffering from coeliac disease, living on a gluten‐free diet? J Clin Nurs 2012;21:766-75.
Meyer D, Stavropolous S, Diamond B, Shane E, Green PH. Osteoporosis in a North American adult population with celiac disease. Am J Gastroenterol 2001;96:112-9.
Mahadev S, Laszkowska M, Sundstrom J, Bjorkholm M, Lebwohl B, Green PHR, et al. Prevalence of Celiac Disease in Patients With Iron Deficiency Anemia-A Systematic Review With Meta-analysis. Gastroenterology 2018;155:374-82.
Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203-8.
Laurikka P, Nurminen S, Kivelä L, Kurppa K. Extraintestinal manifestations of celiac disease: Early detection for better long-term outcomes. Nutrients 2018;10:1015.
Pinto-Sánchez MI, Bercik P, Verdu EF, Bai JC. Extraintestinal manifestations of celiac disease. Dig Dis 2015;33:147-54.
Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic disorders in patients with celiac disease. Pediatrics 2004;113:1672-6.
Briani C, Zara G, Alaedini A, Grassivaro F, Ruggero S, Toffanin E, et al. Neurological complications of celiac disease and autoimmune mechanisms: a prospective study. J Neuroimmunol 2008;195:171-5.
Hadjivassiliou M, Sanders DS, Grünewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol 2010;9:318-30.
Degterev DA, Damulin IV, Parfenov AI. Neurological disorders associated with gluten sensitivity. Ter Arkh 2017;89:99-102.
Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 1999;66:32-5.
Chin RL, Sander HW, Brannagan TH, Green PH, Hays AP, Alaedini A, et al. Celiac neuropathy. Neurology 2003;60:1581-5.
Ghadami MR. Celiac disease and epilepsy: the effect of gluten-free diet on seizure control. Pediatrics 2016;3:52-08.
Spina M, Incorpora G, Trigilia T, Branciforte F, Franco G, Di FG. Headache as atypical presentation of celiac disease: report of a clinical case. Med Surg Pediatr 2001;23:133-5.
Yelland GW. Gluten‐induced cognitive impairment (“brain fog”) in coeliac disease. J Gastroenterol Hepatol 2017;32:90-93.
Makhlouf S, Messelmani M, Zaouali J, Mrissa R. Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet. Acta Neurol Belg 2018;118:21-7.
Trovato CM, Raucci U, Valitutti F, Montuori M, Villa MP, Cucchiara S, et al. Neuropsychiatric manifestations in celiac disease. Epilepsy Behavior 2019;99:106393.
Mearns ES, Taylor A, Craig T, Kelly J, Puglielli S, Leffler DA, et al. Neurological manifestations of neuropathy and ataxia in celiac disease: a systematic review. Nutrients 2019;11:380.
Bürk K, Farecki M, Lamprecht G, Roth G, Decker P, Weller M, et al. Neurological symptoms in patients with biopsy proven celiac disease. Movement Disorders 2009;24:2358-62.
Hadjivassiliou M, Sanders DD, Aeschlimann DP. Gluten-related disorders: gluten ataxia. Dig Dis 2015;33:264-8.
Ashizawa T, Xia G. Ataxia. Continuum: Lifelong Learning in Neurology 2016;22:1208.
Juliano AF, Policeni B, Agarwal V, Burns J, Bykowski J, Harvey HB, et al. ACR Appropriateness Criteria® Ataxia. J Am College Radiol 2019;16:S44-56.
Akbar U, Ashizawa T. Ataxia. Neurol Clin 2015;33:225-48.
Cooke WT, Smith WT. Neurological disorders associated with adult celiac disease. Brain 1966;89:683-722.
Wills AJ, Unsworth DJ. Gluten ataxia 'in perspective'. Brain 2003;126:E4-5.
-. Hadjivassiliou M, Sanders DS, Woodroofe N, Williamson C, Grunewald RA. Gluten ataxia. Cerebellum 2008;7:494-498.
Masson C. Gluten-induced ataxia. Presse Med 2003;32:243-5.
Hadjivassiliou M, Rao DG, Grìnewald RA, Aeschlimann DP, Sarrigiannis PG, Hoggard N, et al. Neurological dysfunction in coeliac disease and non-coeliac gluten sensitivity. Am J Gastroenterol 2016;111:561.
Diaconu G, Burlea M, Grigore I, Anton DT, Trandafir LM. Celiac disease with neurologic manifestations in children. Rev Med Chir Soc Med Nat Iasi 2013;117:88-94.
Pennisi M, Bramanti A, Cantone M, Pennisi G, Bella R, Lanza G. Neurophysiology of the “celiac brain”: Disentangling gut-brain connections. Front Neurosci 2017;11:498.
Joubert B, Rostasy K, Honnorat J. Immune-mediated ataxias. Handb Clin Neurol 2018;155:313-32.
Nanri K, Yoshikura N, Kimura A, Nakayama S, Otomo T, Shimohata T, et al. Cerebellar Ataxia and Autoantibodies. Brain Nerve 2018;70:371-82.
Mitoma H, Adhikari K, Aeschlimann D, Chattopadhyay P, Hadjivassiliou M, Hampe CS, et al. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias. Cerebellum 2016;15:213-32.
Sato K, Nanri K. Gluten Ataxia: Anti-Transglutaminase-6 Antibody as a New Biomarker. Brain Nerve 2017;69:933-40.
Nanri K, Shibuya M, Taguchi T, Hasegawa A, Tanaka N. Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia. Diagn Pathol 2011;6:14.
Zis P, Sarrigiannis PG, Rao DG, Hoggard N, Sanders DS, Hadjivassiliou M. Cerebellar ataxia with sensory ganglionopathy; does autoimmunity have a role to play? Cerebellum Ataxias 2017;4:20-1.
Hadjivassiliou M, Martindale J, Shanmugarajah P, Grunewald RA, Sarrigiannis PG, Beauchamp N, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry 2017;88:301-9.
Howell MD, Smith JR, Austin RK, Kelleher D, Nepom GT, Volk B, et al. An extended HLA-D region haplotype associated with celiac disease. Proc Natl Acad Sci U S A;85:222-6.
Dolinsek J, Urlep D, Karell K, Partanen J, Micetic-Turk D. The prevalence of celiac disease among family members of celiac disease patients. Wien Klin Wochenschr 2004;116:8-12.
Sollid LM, Qiao S, Anderson RP, Gianfrani C, Koning F. Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics 2012;64:455-60.
Lindfors K, Mäki M, Kaukinen K. Transglutaminase 2-targeted autoantibodies in celiac disease: Pathogenetic players in addition to diagnostic tools? Autoimmun rev 2010;9:744-9.
Troncone R, Discepolo V. Celiac disease and autoimmunity. J Pediatr Gastroenterol Nutr 2014;59:S9-11.
Gianfrani C, Troncone R, Mugione P, Cosentini E, De Pascale M, Faruolo C, et al. Celiac disease association with CD8 T cell responses: identification of a novel gliadin-derived HLA-A2-restricted epitope. J Immunol 2003;170:2719-26.
Marsh MN, Crowe PT. 5 Morphology of the mucosal lesion in gluten sensitivity. Baillière's clin Gastroenterol 1995;9:273-93.
Lorand L, Iismaa SE. Transglutaminase diseases: from biochemistry to the bedside. FASEB J 2019;33:3-12.
Eckert RL, Kaartinen MT, Nurminskaya M, Belkin AM, Colak G, Johnson GV, et al. Transglutaminase regulation of cell function. Physiol Rev 2014;94:383-417.
Sollid LM, Jabri B. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr Opin Immunol 2011;23:732-8.
Green P, Alaedini A, Sander HW, Brannagan T, Latov N, Chin RL. Mechanisms underlying celiac disease and its neurologic manifestations. Cell and Mol Life Sci 2005;62:791-9.
Sárdy M, Kárpáti S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 2002;195:747-57.
Bürk K, Bösch S, Müller CA, Melms A, Zühlke C, Stern M, et al. Sporadic cerebellar ataxia associated with gluten sensitivity. Brain 2001;124:1013-9.
Mittelbronn M, Schittenhelm J, Bakos G, De Vos RA, Wehrmann M, Meyermann R, et al. CD8 /perforin /granzyme B effector cells infiltrating cerebellum and inferior olives in gluten ataxia. Neuropathology 2010;30:92-6.
Wilkinson ID, Hadjivassiliou M, Dickson JM, Wallis L, Grunewald RA, Coley SC, et al. Cerebellar abnormalities on proton MR spectroscopy in gluten ataxia. J Neurol Neurosurg Psychiatry 2005;76:1011-3.
Zis P, Rao DG, Sarrigiannis PG, Aeschlimann P, Aeschlimann DP, Sanders D, et al. Transglutaminase 6 antibodies in gluten neuropathy. Dig Liver Dis 2017;49:1196-200.
Thomas H, Beck K, Adamczyk M, Aeschlimann P, Langley M, Oita RC, et al. Transglutaminase 6: a protein associated with central nervous system development and motor function. Amino Acids 2013;44:161-77.
Grenard P, Bates MK, Aeschlimann D. Evolution of Transglutaminase Genes: Identification of a Transglutaminase Gene Cluster on Human Chromosome 15q15 structure of the gene encoding transglutaminase x and a novel gene family member, transglutaminase z. J Biol Chem 2001;276:33066-78.
Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses 2009;73:38-440.
Hadjivassiliou M, Boscolo S, Davies–Jones G, Grünewald RA, Not T, Sanders DS, et al. The humoral response in the pathogenesis of gluten ataxia. Neurology 2002;58:1221-6.
Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol 2008;64:332-43.
Cristofanilli M, Gratch D, Pagano B, McDermott K, Huang J, Jian J, et al. Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes. Mult Scler 2017;23:1707-15.
Boscolo S, Lorenzon A, Sblattero D, Florian F, Stebel M, Marzari R, et al. Anti transglutaminase antibodies cause ataxia in mice. PLoS One 2010;5:e9698.
Hadjivassiliou M, Aeschlimann P, Sanders DS, Maki M, Kaukinen K, Grunewald RA, et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 2013;80:1740-5.
Anheim M, Degos B, Echaniz-Laguna A, Fleury M, Grucker M, Tranchant C. Ataxia associated with gluten sensitivity, myth or reality? Rev Neurol 2006;162:214-21.
Lin CY, Wang MJ, Tse W, Pinotti R, Alaedini A, Green PHR, et al. Serum antigliadin antibodies in cerebellar ataxias: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2018;89:1174-80.
Abele M, Schols L, Schwartz S, Klockgether T. Prevalence of antigliadin antibodies in ataxia patients. Neurology 2003;60:1674-5.
Bushara K, Hallett M. Prevalence of antigliadin antibodies in ataxia patients. Neurology 2004;62:1237-8.
Wong D, Dwinnel M, Schulzer M, Nimmo M, Leavitt BR, Spacey SD. Ataxia and the role of antigliadin antibodies. Canad J Neurol Sci 2007;34:193-6.
Hadjivassiliou M, Grunewald RA, Sanders DS, Zis P, Croal I, Shanmugarajah PD, et al. The Significance of Low Titre Antigliadin Antibodies in the Diagnosis of Gluten Ataxia. Nutrients 2018;10:10.
Volta U, De Giorgio R, Granito A, Stanghellini V, Barbara G, Avoni P, et al. Anti-ganglioside antibodies in coeliac disease with neurological disorders. Dig liver Dis 2006;38:183-7.
Catassi C, Bai JC, Bonaz B, Bouma G, Calabrò A, Carroccio A, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 2013;5:3839-53.
Hadjivassiliou M, Grünewald RA, Kandler RH, Chattopadhyay AK, Jarratt JA, Sanders DS, et al. Neuropathy associated with gluten sensitivity. J Neurol 2006;77:1262-6.
Ruggieri M, Incorpora G, Polizzi A, Parano E, Spina M, Pavone P. Low prevalence of neurologic and psychiatric manifestations in children with gluten sensitivity. J Pediatr 2008;152:244-9.
Rodrigo L, Hernandez-Lahoz C, Lauret E, Rodriguez-Pelaez M, Soucek M, Ciccocioppo R, et al. Gluten ataxia is better classified as non-celiac gluten sensitivity than as celiac disease: a comparative clinical study. Immunol Res 2016;64:558-64.
Kurppa K, Paavola A, Collin P, Sievanen H, Laurila K, Huhtala H, et al. Benefits of a Gluten-free diet for Asymptomatic Patients with Serologic Markers of Celiac Disease. Gastroenterology 2014.
Hadjivassiliou M, Grunewald RA, Sanders DS, Shanmugarajah P, Hoggard N. Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia. Neurology 2017;89:705-9.
Hutchinson JM, West NP, Robins GG, Howdle PD. Long-term histological follow-up of people with coeliac disease in a UK teaching hospital. QJM 2010;103:511-7.
Hadjivassiliou M, Davies-Jones GA, Sanders DS, Grunewald RA. Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry 2003;74:1221-4.
Therrien A, Kelly CP, Silvester JA. Celiac Disease: Extraintestinal Manifestations and Associated Conditions. J Clin Gastroenterol 2019.
Zis P, Hadjivassiliou M. Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease. Curr Treat Options Neurol 2019;21:10-7.
Brar P, Lee S, Lewis S, Egbuna I, Bhagat G, Green PH. Budesonide in the treatment of refractory celiac disease. Am J Gastroenterol 2007;102:2265.
Ryan BM, Kelleher D. Refractory celiac disease. Gastroenterology 2000;119:243-51.
Abdallah H, Leffler D, Dennis M, Kelly CP. Refractory celiac disease. Curr Gastroenterol Rep 2007;9:401-5.
Bürk K, Melms A, Schulz JB, Dichgans J. Effectiveness of intravenous immunoglobin therapy in cerebellar ataxia associated with gluten sensitivity. Ann Neurol 2001;50:827-8.
Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006;66:1717-20.
- Abstract Viewed: 59 times
- PDF Downloaded: 70 times