Review Neuropsychiatric manifestations in celiac disease Chiara Maria Trovato a , Umberto Raucci b , Francesco Valitutti a , Monica Montuori a , Maria Pia Villa c , Salvatore Cucchiara a , Pasquale Parisi c, ⁎ a Maternal and Child Health Department, Pediatric Gastroenterology and Liver Unit, Sapienza - University of Rome, Italy b Pediatric Emergency Department, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy c NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Sant'Andrea Hospital, Rome, Italy abstract article info Article history: Received 29 April 2019 Revised 17 June 2019 Accepted 27 June 2019 Available online xxxx Celiac disease (CD) is a systemic, chronic immune-mediated disorder elicited by gluten and related prolamines in genetically susceptible subjects. Main manifestations of CD involve the digestive tract; however, a growing body of evidence supports the theory that symptoms may occur in every part of the body. It is known that some pa- tients with CD can be asymptomatic, and additionally, the incidence of “nonclassical” CD with extraintestinal pre- sentation is apparently increasing. We aimed to perform a thorough review of existing evidence for neurological manifestations of CD, providing an up-to-date description of prevalence and examining the pathogenetic mech- anisms possibly involved. Neurological presentations are rare in children but as many as 36% of adult patients present with neurological findings. With severe malnutrition after progression of CD, different vitamin deficiencies may develop. Such problems can in turn overlap with previous neurological abnormalities including ataxia, epilepsy, neuropathy, dementia, and cognitive disorders. Here, the most prevalent clinical manifestations in adults and children have been discussed in further detail. Further research is needed to achieve a complete understanding of the nervous system involvement in CD, but clinicians should always remember that neurological and psychiatric symptoms might be part of the CD spectrum of manifestations. © 2019 Published by Elsevier Inc. Keywords: Celiac disease Neurological manifestations Psychiatric manifestation Ataxia Neuropathy Epilepsy Child 1. Introduction Celiac disease (CD) is a systemic, chronic immune-mediated disor- der elicited by gluten and related prolamines in genetically susceptible individuals and characterized by the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy, making it most common genetically based food intolerance in the world [1,2]. The prev- alence of CD varies from 0.5%–1% in the general population to 4.5% among first degree relatives of patients affected with CD [3,4], and it is seemingly increasing over time [5,6]. Clinical presentation of CD can be extremely variable, ranging from silent to symptomatic to celiac cri- sis [7]. Nowadays, prevalence of the classic form of CD seems to be de- creasing, while incidence of nonclassical CD with extraintestinal presentation is apparently increasing [8]. In literature, the rates of extra- intestinal manifestation of CD are similar in adults and in children. Ane- mia, fatigue, headache, and psychiatric disorders are most commonly observed among adults; in children, short stature, fatigue, and headache are more represented [8]. Among extraintestinal symptoms, neurologic disorders, such as cerebellar ataxia, peripheral neuropathy, and epi- lepsy, have been recognized as both complications and initial manifes- tation of CD [9,10], and they have been described since 1966 [11]. Nevertheless, a wide range of neurological manifestations (such as mi- graine, epilepsy, encephalopathy, chorea, brain stem dysfunction, mye- lopathy, mononeuritis multiplex, and Guillain-Barré-like syndrome) could be considered as extraintestinal manifestations of CD [12]. Neuro- logical presentations as the first signs of CD are rare in children but as many as 36% of adult patients present with neurological changes. With severe malnutrition after progression of CD, different vitamin de- ficiencies may develop. Such problems can in turn overlap with previ- ous neurological abnormalities including ataxia, epilepsy, neuropathy, dementia, and cognitive disorders [13]. The first step for celiac diagnosis is searching for autoantibodies; IgA total and antitransglutaminase IgA Epilepsy & Behavior 99 (2019) 106393 ⁎ Corresponding author at: Child Neurology, Pediatric Headache & Sleep Disorders Centre, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Via Di Grottarossa, 1035–1039, 00189 Rome, Italy. E-mail address: pasquale.parisi@uniroma1.it (P. Parisi). https://doi.org/10.1016/j.yebeh.2019.06.036 1525-5050/© 2019 Published by Elsevier Inc. Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh