Neurologic and Psychiatric Manifestations of Celiac Disease and Gluten Sensitivity


Celiac Disease (CD) is an immune-mediated disease dependent on gluten (a protein present in wheat, rye or barley) that occurs in about 1% of the population and is generally characterized by gastrointestinal complaints. More recently the understanding and knowledge of gluten sensitivity (GS), has emerged as an illness distinct from celiac disease with an estimated prevalence 6 times that of CD. Gluten sensitive people do not have villous atrophy or antibodies that are present in celiac disease, but rather they can test positive for antibodies to gliadin. Both CD and GS may present with a variety of neurologic and psychiatric co-morbidities, however, extraintestinal symptoms may be the prime presentation in those with GS. However, gluten sensitivity remains undertreated and underrecognized as a contributing factor to psychiatric and neurologic manifestiations. This review focuses on neurologic and psychiatric manifestations implicated with gluten sensitivity, reviews the emergence of gluten sensitivity distinct from celiac disease, and summarizes the potential mechanisms related to this immune reaction.

This is a preview of subscription content, access via your institution.


  1. 1.

    Fasano A, Catassi C: Current approaches to diagnosis and treatment of celiac disease: An evolving spectrum. Gastroenterology 120:636–651, 2001

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Bizzaro N, Tozzoli R, Villalta D, Fabris M, Tonutti E: Cutting-edge issues in celiac disease and in gluten intolerance. Clinical Reviews in Allergy and Immunology 2010. doi:10.1007/s12016-010-8223-1

  3. 3.

    Hadjivassiliou M, Grunewald RA, Davies-Jones GA: Gluten sensitivity as a neurological illness. Journal of Neurology, Neurosurgery and Psychiatry 72:560–563, 2002

    Article  CAS  Google Scholar 

  4. 4.

    Hadjivassiliou M, Williamson CA, Woodroofe N: The immunology of gluten sensitivity: Beyond the gut. Trends in Immunology 25:578–582, 2004

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Carteni M, Casolaro V, et al.: Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease. International Archives of Allergy and Immunology 152:75–80, 2010

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Kaukinen K, Turjanmaa K, Maki M, Partanen J, Venalainen R, Reunala T, et al.: Intolerance to cereals is not specific for coeliac disease. Scandinavian Journal of Gastroenterology 35:942–946, 2000

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Bender L: Childhood schizophrenia. Psychiatric Quarterly 27:663–681, 1953

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Dohan FC: Wheat “consumption” and hospital admissions for schizophrenia during World War II. A preliminary report. American Journal of Clinical Nutrition 18:7–10, 1966

    PubMed  CAS  Google Scholar 

  9. 9.

    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. Journal of Neuroimmunology 195:171–175, 2008

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies-Jones GA, Gibson A, Jarratt JA, et al.: Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 352:1582–1585, 1998

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Hadjivassiliou M, Grunewald R, Sharrack B, Sanders D, Lobo A, Williamson C, et al.: Gluten ataxia in perspective: Epidemiology, genetic susceptibility and clinical characteristics. Brain 126:685–691, 2003

    PubMed  Article  Google Scholar 

  12. 12.

    Bhatia KP, Brown P, Gregory R, Lennox GG, Manji H, Thompson PD, et al.: Progressive myoclonic ataxia associated with coeliac disease. The myoclonus is of cortical origin, but the pathology is in the cerebellum. Brain 118 (Pt 5):1087–1093, 1995

    PubMed  Article  Google Scholar 

  13. 13.

    Hadjivassiliou M, Boscolo S, Davies-Jones GA, Grunewald RA, Not T, Sanders DS, et al.: The humoral response in the pathogenesis of gluten ataxia. Neurology 58:1221–1226, 2002

    PubMed  CAS  Google Scholar 

  14. 14.

    Hadjivassiliou M, Kandler RH, Chattopadhyay AK, Davies-Jones AG, Jarratt JA, Sanders DS, et al.: Dietary treatment of gluten neuropathy. Muscle and Nerve 34:762–766, 2006

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    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. Journal of Neurology, Neurosurgery and Psychiatry 66:32–35, 1999

    Article  CAS  Google Scholar 

  16. 16.

    Chin RL, Sander HW, Brannagan TH, Green PH, Hays AP, Alaedini A, et al.: Celiac neuropathy. Neurology 60:1581–1585, 2003

    PubMed  CAS  Google Scholar 

  17. 17.

    Chin RL, Latov N, Green PH, Brannagan TH, 3rd, Alaedini A, Sander HW: Neurologic complications of celiac disease. Journal of Clinical Neuromuscular Disease 5:129–137, 2004

    PubMed  Article  Google Scholar 

  18. 18.

    Morris JS, Ajdukiewicz AB, Read AE: Neurological disorders and adult coeliac disease. Gut 11:549–554, 1970

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Pfaender M, D’Souza WJ, Trost N, Litewka L, Paine M, Cook M: Visual disturbances representing occipital lobe epilepsy in patients with cerebral calcifications and coeliac disease: A case series. Journal of Neurology, Neurosurgery and Psychiatry 75:1623–1625, 2004

    Article  CAS  Google Scholar 

  20. 20.

    Arroyo HA, De Rosa S, Ruggieri V, de Davila MT, Fejerman N: Epilepsy, occipital calcifications, and oligosymptomatic celiac disease in childhood. Journal of Child Neurology 17:800–806, 2002

    PubMed  Article  Google Scholar 

  21. 21.

    Hernandez MA, Colina G, Ortigosa L: Epilepsy, cerebral calcifications and clinical or subclinical coeliac disease. Course and follow up with gluten-free diet. Seizure 7:49–54, 1998

    CAS  Google Scholar 

  22. 22.

    Canales P, Mery VP, Larrondo FJ, Bravo FL, Godoy J: Epilepsy and celiac disease: Favorable outcome with a gluten-free diet in a patient refractory to antiepileptic drugs. Neurologist 12:318–321, 2006

    PubMed  Article  Google Scholar 

  23. 23.

    Cernibori A, Gobbi G: Partial seizures, cerebral calcifications and celiac disease. Italian Journal of Neurological Sciences 16:187–191, 1995

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Fois A, Vascotto M, Di Bartolo RM, Di Marco V: Celiac disease and epilepsy in pediatric patients. Child’s Nervous System 10:450–454, 1994

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Peltola M, Kaukinen K, Dastidar P, Haimila K, Partanen J, Haapala AM, et al.: Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity. Journal of Neurology, Neurosurgery and Psychiatry 80:626–630, 2009

    Article  CAS  Google Scholar 

  26. 26.

    Hadjivassiliou M, Rao DG, Wharton SB, Sanders DS, Grunewald RA, Davies-Jones AG: Sensory ganglionopathy due to gluten sensitivity. Neurology 75:1003–1008, 2010

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Hadjivassiliou M, Chattopadhyay AK, Grunewald RA, Jarratt JA, Kandler RH, Rao DG, et al.: Myopathy associated with gluten sensitivity. Muscle and Nerve 35:443–450, 2007

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    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. American Journal of Gastroenterology 98:625–629, 2003

    PubMed  Article  Google Scholar 

  29. 29.

    Poloni N, Vender S, Bolla E, Bortolaso P, Costantini C, Callegari C: Gluten encephalopathy with psychiatric onset: Case report. Clinical Practice and Epidemiology in Mental Health 5:16, 2009

    PubMed  Article  Google Scholar 

  30. 30.

    Kieslich M, Errazuriz G, Posselt HG, Moeller-Hartmann W, Zanella F, Boehles H: Brain white-matter lesions in celiac disease: A prospective study of 75 diet-treated patients. Pediatrics 108:E21, 2001

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Addolorato G, Capristo E, Ghittoni G, Valeri C, Masciana R, Ancona C, et al.: Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: A longitudinal study. Scandinavian Journal of Gastroenterology 36:502–506, 2001

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    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 24:311–317, 2003

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Carta MG, Hardoy MC, Boi MF, Mariotti S, Carpiniello B, Usai P: Association between panic disorder, major depressive disorder and celiac disease: A possible role of thyroid autoimmunity. Journal of Psychosomatic Research 53:789–793, 2002

    PubMed  Article  Google Scholar 

  34. 34.

    Niederhofer H, Pittschieler K: A preliminary investigation of ADHD symptoms in persons with celiac disease. Journal of Attention Disorders 10:200–204, 2006

    PubMed  Article  Google Scholar 

  35. 35.

    Genuis SJ, Bouchard TP: Celiac disease presenting as autism. Journal of Child Neurology 25:114–119, 2010

    PubMed  Article  Google Scholar 

  36. 36.

    De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, et al.: Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: Regression after a gluten-free diet. Journal of Internal Medicine 242:421–423, 1997

    PubMed  Article  Google Scholar 

  37. 37.

    Samaroo D, Dickerson F, Kasarda DD, Green PH, Briani C, Yolken RH, et al.: Novel immune response to gluten in individuals with schizophrenia. Schizophrenia Research 118:248–255, 2010

    PubMed  Article  Google Scholar 

  38. 38.

    Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophrenia Research 37:94–100, 2011

    Google Scholar 

  39. 39.

    Addolorato G, Mirijello A, D’Angelo C, Leggio L, Ferrulli A, Vonghia L, et al.: Social phobia in coeliac disease. Scandinavian Journal of Gastroenterology 43:410–415, 2008

    PubMed  Article  Google Scholar 

  40. 40.

    Hauser W, Janke KH, Klump B, Gregor M, Hinz A: Anxiety and depression in adult patients with celiac disease on a gluten-free diet. World Journal of Gastroenterology 16:2780–2787, 2010

    PubMed  Article  Google Scholar 

  41. 41.

    Ludvigsson JF, Reutfors J, Osby U, Ekbom A, Montgomery SM: Coeliac disease and risk of mood disorders—a general population-based cohort study. Journal of Affective Disorders 99:117–126, 2007

    PubMed  Article  Google Scholar 

  42. 42.

    Ruuskanen A, Kaukinen K, Collin P, Huhtala H, Valve R, Maki M, et al.: Positive serum antigliadin antibodies without celiac disease in the elderly population: Does it matter? Scandinavian Journal of Gastroenterology 45:1197–1202, 2010

    PubMed  Article  Google Scholar 

  43. 43.

    Corvaglia L, Catamo R, Pepe G, Lazzari R, Corvaglia E: Depression in adult untreated celiac subjects: Diagnosis by the pediatrician. American Journal of Gastroenterology 94:839–843, 1999

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Atladottir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, et al.: Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124:687–694, 2009

    PubMed  Article  Google Scholar 

  45. 45.

    Valicenti-McDermott MD, McVicar K, Cohen HJ, Wershil BK, Shinnar S: Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatric Neurology 39:392–398, 2008

    PubMed  Article  Google Scholar 

  46. 46.

    de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. Journal of Pediatric and Gastroenterology Nutrition 51:418–424, 2010

    Article  Google Scholar 

  47. 47.

    Knivsberg AM, Reichelt KL, Hoien T, Nodland M: A randomised, controlled study of dietary intervention in autistic syndromes. Nutritional Neuroscience 5:251–261, 2002

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Whiteley P, Haracopos D, Knivsberg AM, Reichelt KL, Parlar S, Jacobsen J, et al.: The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutritional Neuroscience 13:87–100, 2010

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Hsu CL, Lin CY, Chen CL, Wang CM, Wong MK: The effects of a gluten and casein-free diet in children with autism: A case report. Chang Gung Medical Journal 32:459–465, 2009

    PubMed  Google Scholar 

  50. 50.

    Vojdani A, O’Bryan T, Green JA, McCandless J, Woeller KN, Vojdani E, et al.: Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutritional Neuroscience 7:151–161, 2004

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Kalaydjian AE, Eaton W, Cascella N, Fasano A: The gluten connection: The association between schizophrenia and celiac disease. Acta Psychiatrica Scandinavica 113:82–90, 2006

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Graff H, Handford A: Celiac syndrome in the case histories of five schizophrenics. Psychiatric Quarterly 35:306–313, 1961

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Dohan FC, Grasberger JC, Lowell FM, Johnston HT, Jr., Arbegast AW: Relapsed schizophrenics: More rapid improvement on a milk- and cereal-free diet. British Journal of Psychiatry 115:595–596, 1969

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Dohan FC, Grasberger JC: Relapsed schizophrenics: Earlier discharge from the hospital after cereal-free, milk-free diet. American Journal of Psychiatry 130:685–688, 1973

    PubMed  CAS  Google Scholar 

  55. 55.

    Singh MM, Kay SR: Wheat gluten as a pathogenic factor in schizophrenia. Science 191:401–402, 1976

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Dohan FC, Levitt DR, Kushnir LD: Abnormal behavior after intracerebral injection of polypeptides from wheat gliadin: Possible relevance to schizophrenia. Pavlovian Journal of Biological Science 13:73–82, 1978

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Rice JR, Ham CH, Gore WE: Another look at gluten in schizophrenia. American Journal of Psychiatry 135:1417–1418, 1978

    PubMed  CAS  Google Scholar 

  58. 58.

    Vlissides DN, Venulet A, Jenner FA: A double-blind gluten-free/gluten-load controlled trial in a secure ward population. British Journal of Psychiatry 148:447–452, 1986

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Potkin SG, Weinberger D, Kleinman J, Nasrallah H, Luchins D, Bigelow L, et al.: Wheat gluten challenge in schizophrenic patients. American Journal of Psychiatry 138:1208–1211, 1981

    PubMed  CAS  Google Scholar 

  60. 60.

    Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, et al.: Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophrenia Bulletin 37:94–100, 2011

    PubMed  Article  Google Scholar 

  61. 61.

    Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Leister F, et al.: Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biological Psychiatry 68:100–104, 2010

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Jin SZ, Wu N, Xu Q, Zhang X, Ju GZ, Law MH, et al. A study of circulating gliadin antibodies in schizophrenia among a Chinese population. Schizophrenia Bulletin 2010. doi:10.1093/schbul/sbq111

  63. 63.

    Reichelt KL, Landmark J: Specific IgA antibody increases in schizophrenia. Biological Psychiatry 37:410–413, 1995

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Boscolo S, Sarich A, Lorenzon A, Passoni M, Rui V, Stebel M, et al.: Gluten ataxia: Passive transfer in a mouse model. Annals of the New York Academy of Sciences 1107:319–328, 2007

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Sander HW, Magda P, Chin RL, Wu A, Brannagan TH, 3rd, Green PH, et al.: Cerebellar ataxia and coeliac disease. Lancet 362:1548, 2003

    PubMed  Article  Google Scholar 

  66. 66.

    Burk K, Melms A, Schulz JB, Dichgans J: Effectiveness of intravenous immunoglobin therapy in cerebellar ataxia associated with gluten sensitivity. Annals of Neurology 50:827–828, 2001

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D: Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Annals of Neurology 64:332–343, 2008

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Alaedini A, Okamoto H, Briani C, Wollenberg K, Shill HA, Bushara KO, et al.: Immune cross-reactivity in celiac disease: Anti-gliadin antibodies bind to neuronal synapsin I. Journal of Immunology 178:6590–6595, 2007

    CAS  Google Scholar 

  69. 69.

    Palova-Jelinkova L, Rozkova D, Pecharova B, Bartova J, Sediva A, Tlaskalova-Hogenova H, et al.: Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. Journal of Immunology 175:7038–7045, 2005

    CAS  Google Scholar 

  70. 70.

    Thomas KE, Sapone A, Fasano A, Vogel SN: Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. Journal of Immunology 176:2512–2521, 2006

    CAS  Google Scholar 

  71. 71.

    Ashkenazi A, Krasilowsky D, Levin S, Idar D, Kalian M, Or A, et al.: Immunologic reaction of psychotic patients to fractions of gluten. American Journal of Psychiatry 136:1306–1309, 1979

    PubMed  CAS  Google Scholar 

  72. 72.

    Pavol MA, Meyers CA, Rexer JL, Valentine AD, Mattis PJ, Talpaz M: Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia. Neurology 45:947–950, 1995

    PubMed  CAS  Google Scholar 

  73. 73.

    Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, et al.: The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Annals of Internal Medicine 107:293–300, 1987

    PubMed  CAS  Google Scholar 

  74. 74.

    Hadjivassiliou M: Glutamic acid decarboxylase as a target antigen in gluten sensitivity: The link to neurological manifestations? Proceedings of the 11th International Symposium on Celiac Disease. Belfast, 2004

  75. 75.

    Williamson S, Faulkner-Jones BE, Cram DS, Furness JB, Harrison LC: Transcription and translation of two glutamate decarboxylase genes in the ileum of rat, mouse and guinea pig. Journal of the Autonomic Nervous System 55:18–28, 1995

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Volta U, De Giorgio R, Granito A, Stanghellini V, Barbara G, Avoni P, et al.: Anti-ganglioside antibodies in coeliac disease with neurological disorders. Digestive and Liver Diseases 38:183–187, 2006

    Article  CAS  Google Scholar 

  77. 77.

    Santoro M, Thomas FP, Fink ME, Lange DJ, Uncini A, Wadia NH, et al.: IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block. Annals of Neurology 28:373–377, 1990

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Molander M, Berthold CH, Persson H, Andersson K, Fredman P: Monosialoganglioside (GM1) immunofluorescence in rat spinal roots studied with a monoclonal antibody. Journal of Neurocytology 26:101–111, 1997

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Hadjivassiliou M, Maki M, Sanders DS, Williamson CA, Grunewald RA, Woodroofe NM, et al.: Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 66:373–377, 2006

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Pynnonen PA, Isometsa ET, Verkasalo MA, Kahkonen SA, Sipila I, Savilahti E, et al.: Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with coeliac disease: A prospective follow-up case-series study. BMC Psychiatry 5:14, 2005

    PubMed  Article  Google Scholar 

  81. 81.

    Hallert C, Sedvall G: Improvement in central monoamine metabolism in adult coeliac patients starting a gluten-free diet. Psychological Medicine 13:267–271, 1983

    PubMed  Article  CAS  Google Scholar 

Download references

Conflict of interest

All authors report no conflicts of interest.

Author information



Corresponding author

Correspondence to Deanna L. Kelly.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jackson, J.R., Eaton, W.W., Cascella, N.G. et al. Neurologic and Psychiatric Manifestations of Celiac Disease and Gluten Sensitivity. Psychiatr Q 83, 91–102 (2012).

Download citation


  • Gluten
  • Schizophrenia
  • Neurologic
  • Immune
  • Celiac
  • Psychiatric