International Journal of Celiac Disease
ISSN (Print): 2334-3427 ISSN (Online): 2334-3486 Website: Editor-in-chief: Samasca Gabriel
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International Journal of Celiac Disease. 2018, 6(3), 76-82
DOI: 10.12691/ijcd-6-3-5
Open AccessReview Article

Celiac Disease and Neurological Manifestations of Gluten Sensitivity. What Do They Share in Common?

Rubén Peña1, 2, Gabriela Román1, 2, Natalia Zuloaga1, 2 and Magdalena Araya1,

1Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile

2Fellow, Pediatric Gastroenterology and Nutrition Program, Faculty of Medicine, University of Chile, Santiago, Chile

Pub. Date: January 04, 2019

Cite this paper:
Rubén Peña, Gabriela Román, Natalia Zuloaga and Magdalena Araya. Celiac Disease and Neurological Manifestations of Gluten Sensitivity. What Do They Share in Common?. International Journal of Celiac Disease. 2018; 6(3):76-82. doi: 10.12691/ijcd-6-3-5


Knowledge on the clinical, autoimmune, genetic and more recently microbiome and epigenetic interactions in celiac disease (CD) is consistently improving; however, the pathogenic mechanisms of neurological manifestations of gluten sensitivity (NMGS) and their potential relationship with CD remain unclear. Difficulties in assessing both conditions include their highly variable clinical manifestations and the insufficient sensitivity and specificities of currently available diagnostics tools. Patients with neurological manifestations that respond to gluten withdrawal may or may not present enteropathy and others having demonstrable mucosal damage may or may not respond to GFD. Current pathogenic hypotheses that may relate both conditions, the spectrum of clinical manifestations, diagnostic problems, including differences in types and subtypes of antibodies described for diagnosis and the effects of gluten-free diet are reviewed. The evidence show that decisions based on clinical data may be successful for patient management, but do not allow drawing conclusions on the relations between CD and NMGS.

celiac disease neurological manifestation gluten sensitivity

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[1]  Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. Journal of pediatric gastroenterology and nutrition. 2012 Jan; 54(1): 136-60.
[2]  Ludvigsson JF, Lebwohl B, Rubio-Tapia A, Murray JA, Green PH, Ekbom A. Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy. Journal of gastroenterology. 2013 Dec; 48(12): 1324-31.
[3]  Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. The American journal of gastroenterology. 2013 May; 108(5): 656-76; quiz 77.
[4]  Hill ID, Fasano A, Guandalini S, Hoffenberg E, Levy J, Reilly N, et al. NASPGHAN Clinical Report on the Diagnosis and Treatment of Gluten-related Disorders. Journal of pediatric gastroenterology and nutrition. 2016 Jul; 63(1): 156-65.
[5]  Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC medicine. 2012 Feb 07; 10: 13.
[6]  Catassi C, Bai JC, Bonaz B, Bouma G, Calabro A, Carroccio A, et al. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Oct; 5(10): 3839-53.
[7]  Cooke WT T-SW. Neurological disorders associated with adult coeliac disease. Brain, behavior and evolution. 1966; 89: 683-722.
[8]  Pennisi M, Bramanti A, Cantone M, Pennisi G, Bella R, Lanza G. Neurophysiology of the "Celiac Brain": Disentangling Gut-Brain Connections. Frontiers in neuroscience. 2017; 11: 498.
[9]  Cheng J, Kalliomaki M, Heilig HG, Palva A, Lahteenoja H, de Vos WM, et al. Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease. BMC gastroenterology. 2013 Jul 11; 13: 113.
[10]  Dicke WK, Weijers HA, Van De Kamer JH. Coeliac disease. II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr. 1953 Jan; 42(1): 34-42.
[11]  Green PH, Jabri B. Coeliac disease. Lancet. 2003 Aug 2; 362(9381): 383-91.
[12]  Arnason JA, Gudjonsson H, Freysdottir J, Jonsdottir I, Valdimarsson H. Do adults with high gliadin antibody concentrations have subclinical gluten intolerance? Gut. 1992 Feb; 33(2): 194-7.
[13]  Lagerqvist C, Dahlbom I, Hansson T, Jidell E, Juto P, Olcen P, et al. Antigliadin immunoglobulin A best in finding celiac disease in children younger than 18 months of age. Journal of pediatric gastroenterology and nutrition. 2008 Oct; 47(4): 428-35.
[14]  Rostami Nejad M, Rostami K, Pourhoseingholi MA, Nazemalhosseini Mojarad E, Habibi M, Dabiri H, et al. Atypical presentation is dominant and typical for coeliac disease. Journal of gastrointestinal and liver diseases : JGLD. 2009 Sep; 18(3): 285-91.
[15]  Cianferoni A. Wheat allergy: diagnosis and management. Journal of asthma and allergy. 2016; 9: 13-25.
[16]  Iqbal U, Chaudhary A, Karim MA, Anwar H, Merrell N. Refractory Celiac Disease Successfully Treated With Azathioprine. Gastroenterology research. 2017 Jun; 10(3): 199-201.
[17]  Lanzini A, Lanzarotto F, Villanacci V, Mora A, Bertolazzi S, Turini D, et al. Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Alimentary pharmacology & therapeutics. 2009 Jun 15; 29(12): 1299-308.
[18]  Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-term follow-up of celiac adults on gluten-free diet: prevalence and correlates of intestinal damage. Digestion. 2002; 66(3): 178-85.
[19]  Newnham ED, Shepherd SJ, Strauss BJ, Hosking P, Gibson PR. Adherence to the gluten-free diet can achieve the therapeutic goals in almost all patients with coeliac disease: A 5-year longitudinal study from diagnosis. Journal of gastroenterology and hepatology. 2016 Feb; 31(2): 342-9.
[20]  Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet. 1996 Feb 10; 347(8998): 369-71.
[21]  GKT H. Neurological and psychiatric complications in coeliac disease. 1997. In: Gobbi G, Anderman F, Naccarato S, (eds). Epilepsy and other neurological disorders in coeliac disease. London: John Libbey
[22]  Sattar N, Lazare F, Kacer M, Aguayo-Figueroa L, Desikan V, Garcia M, et al. Celiac disease in children, adolescents, and young adults with autoimmune thyroid disease. The Journal of pediatrics. 2011 Feb; 158(2): 272-5 e1.
[23]  Hogg-Kollars S, Al Dulaimi D, Tait K, Rostami K. Type 1 diabetes mellitus and gluten induced disorders. Gastroenterology and hepatology from bed to bench. 2014 Fall; 7(4): 189-97.
[24]  Anania C, De Luca E, De Castro G, Chiesa C, Pacifico L. Liver involvement in pediatric celiac disease. World journal of gastroenterology : WJG. 2015 May 21; 21(19): 5813-22.
[25]  Hadjivassiliou M, Sanders DS, Grunewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. The Lancet Neurology. 2010 Mar; 9(3): 318-30.
[26]  Fasano A. Celiac Disease, Gut-Brain Axis, and Behavior: Cause, Consequence, or Merely Epiphenomenon? Pediatrics. 2017 Mar; 139(3).
[27]  Leonard MM, Sapone A, Catassi C, Fasano A. Celiac Disease and Nonceliac Gluten Sensitivity: A Review. Jama. 2017 Aug 15; 318(7): 647-56.
[28]  Kupfer SS, Jabri B. Pathophysiology of celiac disease. Gastrointestinal endoscopy clinics of North America. 2012 Oct; 22(4): 639-60.
[29]  Araya M, Oyarzun A, Lucero Y, Espinosa N, Perez-Bravo F. DQ2, DQ7 and DQ8 Distribution and Clinical Manifestations in Celiac Cases and Their First-Degree Relatives. Nutrients. 2015 Jun 18; 7(6): 4955-65.
[30]  Kotze LM, Nisihara R, Utiyama SR, Kotze LR. Absence of HLA-DQ2 and HLA-DQ8 does not exclude celiac disease in Brazilian patients. Rev Esp Enferm Dig. 2014 Dec; 106(8): 561-2.
[31]  Motta PM LM, Marinic K, Picón SO, Stafuza MG, Habegger de Sorrentin A. Alta frecuencia de DQ8 en la población celíaca de la provincia del Chaco, Argentina. Acta Gastroenterol Latinoam. 2014; 44: 16-21.
[32]  Vazquez H, de la Paz Temprano M, Sugai E, Scacchi SM, Souza C, Cisterna D, et al. Prevalence of celiac disease and celiac autoimmunity in the Toba Native Amerindian community of Argentina. Canadian journal of gastroenterology & hepatology. 2015 Nov-Dec; 29(8): 431-4.
[33]  Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Human immunology. 2003 Apr; 64(4): 469-77.
[34]  Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Annals of neurology. 2008 Sep; 64(3): 332-43.
[35]  Hadjivassiliou M, Sanders DD, Aeschlimann DP. Gluten-related disorders: gluten ataxia. Digestive diseases. 2015; 33(2): 264-8.
[36]  Sturgeon C, Lan J, Fasano A. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model. Annals of the New York Academy of Sciences. 2017 Jun; 1397(1): 130-42.
[37]  Garcia-Quintanilla A, Miranzo-Navarro D. Extraintestinal manifestations of celiac disease: 33-mer gliadin binding to glutamate receptor GRINA as a new explanation. BioEssays : news and reviews in molecular, cellular and developmental biology. 2016 May; 38(5): 427-39.
[38]  Absah I, Rishi AR, Gebrail R, Snyder MR, Murray JA. Lack of Utility of Anti-tTG IgG to Diagnose Celiac Disease When Anti-tTG IgA Is Negative. Journal of pediatric gastroenterology and nutrition. 2017 May; 64(5): 726-9.
[39]  Villanueva M RM, Araya M. IgA and IgG Antitransglutaminase 2 Antibodies in the Diagnosis of Celiac Disease. Int J Celiac Disease. 2017; 5(2): 43-7.
[40]  Hadjivassiliou M, Duker AP, Sanders DS. Gluten-related neurologic dysfunction. Handbook of clinical neurology. 2014; 120: 607-19.
[41]  Smith LB, Lynch KF, Kurppa K, Koletzko S, Krischer J, Liu E, et al. Psychological Manifestations of Celiac Disease Autoimmunity in Young Children. Pediatrics. 2017 Mar; 139(3).
[42]  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 May 7; 80(19): 1740-5.
[43]  Luostarinen L, Himanen SL, Luostarinen M, Collin P, Pirttila T. Neuromuscular and sensory disturbances in patients with well treated coeliac disease. Journal of neurology, neurosurgery, and psychiatry. 2003 Apr; 74(4): 490-4.
[44]  Pacitto A, Paglino A, Di Genova L, Leonardi A, Farinelli E, Principi N, et al. Celiac Disease Presenting with Peripheral Neuropathy in Children: A Case Report. International journal of environmental research and public health. 2017 Jul 14; 14(7).
[45]  Mata S, Renzi D, Pinto F, Calabro A. Anti-tissue transglutaminase IgA antibodies in peripheral neuropathy and motor neuronopathy. Acta neurologica Scandinavica. 2006 Jul; 114(1): 54-8.
[46]  Chin RL, Sander HW, Brannagan TH, Green PH, Hays AP, Alaedini A, et al. Celiac neuropathy. Neurology. 2003 May 27; 60(10): 1581-5.
[47]  Chin RL, Latov N, Green PH, Brannagan TH, 3rd, Alaedini A, Sander HW. Neurologic complications of celiac disease. Journal of clinical neuromuscular disease. 2004 Mar; 5(3): 129-37.
[48]  Vieira C, Jatoba I, Matos M, Diniz-Santos D, Silva LR. Prevalence of celiac disease in children with epilepsy. Arquivos de gastroenterologia. 2013 Oct-Dec; 50(4): 290-6.
[49]  Parisi P, Pietropaoli N, Ferretti A, Nenna R, Mastrogiorgio G, Del Pozzo M, et al. Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. Seizure. 2015 Feb; 25: 181-3.
[50]  Kurien M, Ludvigsson JF, Sanders DS, Zylberberg HM, Green PH, Sundelin HEK, et al. Persistent mucosal damage and risk of epilepsy in people with celiac disease. European journal of neurology: the official journal of the European Federation of Neurological Societies. 2018 Mar; 25(3): 592-e38.
[51]  Gobbi G. Coeliac disease, epilepsy and cerebral calcifications. Brain & development. 2005 Apr; 27(3): 189-200.
[52]  Struck AF, Beinlich BR, Rutecki PA. A Case of Celiac Disease, Epilepsy, and Cerebral Calcifications With Temporal Lobe Epilepsy. WMJ : official publication of the State Medical Society of Wisconsin. 2015 Jun; 114(3): 116-7; quiz 8.
[53]  Gobbi G, Bouquet F, Greco L, Lambertini A, Tassinari CA, Ventura A, et al. Coeliac disease, epilepsy, and cerebral calcifications. The Italian Working Group on Coeliac Disease and Epilepsy. Lancet. 1992 Aug 22; 340(8817): 439-43.
[54]  Bashiri H, Afshari D, Babaei N, Ghadami MR. Celiac Disease and Epilepsy: The Effect of Gluten-Free Diet on Seizure Control. Advances in clinical and experimental medicine: official organ Wroclaw Medical University. 2016 Jul-Aug; 25(4): 751-4.
[55]  Gabrielli M, Cremonini F, Fiore G, Addolorato G, Padalino C, Candelli M, et al. Association between migraine and Celiac disease: results from a preliminary case-control and therapeutic study. The American journal of gastroenterology. 2003 Mar; 98(3): 625-9.
[56]  Nenna R, Petrarca L, Verdecchia P, Florio M, Pietropaoli N, Mastrogiorgio G, et al. Celiac disease in a large cohort of children and adolescents with recurrent headache: A retrospective study. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2016 May; 48(5): 495-8.
[57]  Balci O, Yilmaz D, Sezer T, Hizli S. Is Celiac Disease an Etiological Factor in Children With Migraine? Journal of child neurology. 2016 Jun; 31(7): 929-31. PubMed PMID: 26887413.
[58]  Addolorato G, Di Giuda D, De Rossi G, Valenza V, Domenicali M, Caputo F, et al. Regional cerebral hypoperfusion in patients with celiac disease. The American journal of medicine. 2004 Mar 1; 116(5): 312-7.
[59]  Albany C, Servetnyk Z. Disabling osteomalacia and myopathy as the only presenting features of celiac disease: a case report. Cases journal. 2009 Jan 7; 2(1): 20.
[60]  Karaahmet OZ, Unlu E, Karaahmet F, Gurcay E, Cakci A. Myopathy related to vitamin D deficiency in patient with celiac disease. Muscle & nerve. 2014 Jul; 50(1): 147-8.
[61]  Suthar R, Sankhyan N, Thapa BR, Singhi P. Proximal Myopathy: A Rare Presentation of Celiac Disease. Journal of child neurology. 2013 Nov; 28(11): 1485-8.
[62]  Woods W. Coeliac disease: the great imitator. The Medical journal of Australia. 2004 Oct 4; 181(7): 371.
[63]  Lurie Y, Landau DA, Pfeffer J, Oren R. Celiac disease diagnosed in the elderly. Journal of clinical gastroenterology. 2008 Jan; 42(1): 59-61.
[64]  Lichtwark IT, Newnham ED, Robinson SR, Shepherd SJ, Hosking P, Gibson PR, et al. Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Alimentary pharmacology & therapeutics. 2014 Jul; 40(2): 160-70.
[65]  Yelland GW. Gluten-induced cognitive impairment ("brain fog") in coeliac disease. Journal of gastroenterology and hepatology. 2017 Mar; 32 Suppl 1: 90-3.
[66]  Carta MG, Hardoy MC, Usai P, Carpiniello B, Angst J. Recurrent brief depression in celiac disease. Journal of psychosomatic research. 2003 Dec; 55(6): 573-4.
[67]  Cicarelli G, Della Rocca G, Amboni M, Ciacci C, Mazzacca G, Filla A, et al. Clinical and neurological abnormalities in adult celiac disease. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2003 Dec; 24(5): 311-7.
[68]  Bushara KO. Neurologic presentation of celiac disease. Gastroenterology. 2005 Apr; 128(4 Suppl 1): S92-7.
[69]  Campagna G, Pesce M, Tatangelo R, Rizzuto A, La Fratta I, Grilli A. The progression of coeliac disease: its neurological and psychiatric implications. Nutrition research reviews. 2017 Jun; 30(1): 25-35.
[70]  Karwautz A, Wagner G, Berger G, Sinnreich U, Grylli V, Huber WD. Eating pathology in adolescents with celiac disease. Psychosomatics. 2008 Sep-Oct; 49(5): 399-406.
[71]  van Hees NJ, Van der Does W, Giltay EJ. Coeliac disease, diet adherence and depressive symptoms. Journal of psychosomatic research. 2013 Feb; 74(2): 155-60.
[72]  De Leo L, Aeschlimann D, Hadjivassiliou M, Aeschlimann P, Salce N, Vatta S, et al. Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure. Journal of pediatric gastroenterology and nutrition. 2018 Jan; 66(1): 64-8.