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Ciaccio EJ, Lee AR, Lebovits J, Wolf RL, Lewis SK, Ciacci C, Green PHR. Psychological, Psychiatric, and Organic Brain Manifestations of Celiac Disease. Dig Dis 2024; 42:419-444. [PMID: 38861947 DOI: 10.1159/000534219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/07/2023] [Indexed: 06/13/2024]
Abstract
INTRODUCTION Celiac disease is an autoimmune condition that affects approximately 1% of the population worldwide. Although its main impact often concerns the small intestine, resulting in villous atrophy and nutrient malabsorption, it can also cause systemic manifestations, particularly when undiagnosed or left untreated. METHOD Attention is directed to the possible psychological, psychiatric, and organic brain manifestations of celiac disease. Specific topics related to the influence and risk of such manifestations with respect to celiac disease are defined and discussed. Overall, eighteen main topics are considered, sifted from over 500 references. RESULTS The most often studied topics were found to be the effect on quality of life, organic brain dysfunction and ataxia, epilepsy, Down syndrome, generalized psychological disorders, eating dysfunction, depression, and schizophrenia. For most every topic, although many studies report a connection to celiac disease, there are often one or more contrary studies and opinions. A bibliographic analysis of the cited articles was also done. There has been a sharp increase in interest in this research since 1990. Recently published articles tend to receive more referencing, up to as many as 15 citations per year, suggesting an increasing impact of the topics. The number of manuscript pages per article has also tended to increase, up to as many as 12 pages. The impact factor of the publishing journal has remained level over the years. CONCLUSION This compendium may be useful in developing a consensus regarding psychological, psychiatric, and organic brain manifestations that can occur in celiac disease and for determining the best direction for ongoing research focus.
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Affiliation(s)
- Edward J Ciaccio
- Department of Medicine - Celiac Disease Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Anne R Lee
- Department of Medicine - Celiac Disease Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Jessica Lebovits
- Department of Medicine - Celiac Disease Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Randi L Wolf
- Teachers College, Columbia University, New York, New York, USA
| | - Suzanne K Lewis
- Department of Medicine - Celiac Disease Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Carolina Ciacci
- Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, Università degli Studi di Salerno, Salerno, Italy
| | - Peter H R Green
- Department of Medicine - Celiac Disease Center, Columbia University Irving Medical Center, New York, New York, USA
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Perilli L, Carbone S, Novelletto LF, Santangelo A, Curcio MR, Lotti F, Grosso S. Should We Rule out Celiac Disease in Recurrent Headache Disorders? A Review of the Literature. J Clin Med 2024; 13:2615. [PMID: 38731144 PMCID: PMC11084386 DOI: 10.3390/jcm13092615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 04/20/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Recurrent headaches, encompassing migraine and tension-type headaches, represent prevalent conditions affecting individuals across different age groups, exerting a substantial influence on daily functioning and quality of life. Headaches serve as common manifestations of underlying health issues. Among these, celiac disease, an autoimmune disorder activated by gluten consumption, has emerged as a noteworthy concern. Recent research indicates a correlation between celiac disease and heightened susceptibility to headaches, particularly migraines. Celiac disease (CD) is an immune-mediated systemic, widespread disorder presenting a heterogeneous constellation of symptoms with a relatively easy diagnosis and therapy. Among signs and symptoms exhibited in celiac disease patients, headache is one of the most common neurological issues addressed among both adults and children. Headache disorders and CD are highly prevalent in the general population; for this reason, any causal association between these conditions and the role of a gluten-free diet (GFD) has been debated. The aim of this manuscript is to review the current scientific literature regarding the potential association between CD and headaches and the beneficial effects of a GFD. Among the various authors, in our opinion, the current state of the evidence suggests a significant role for the early screening of CD during the initial diagnosis of recurrent headaches, either in adults or children.
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Affiliation(s)
- Lorenzo Perilli
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Samanta Carbone
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Luca Franco Novelletto
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Andrea Santangelo
- Pediatric Neurology, Department of Pediatrics, Santa Chiara Hospital, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy
| | - Maria Rosaria Curcio
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Federica Lotti
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Salvatore Grosso
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
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Abstract
OBJECTIVE There are no definitive results about either the presence of exact comorbidity between celiac disease (CD) and attention-deficit/hyperactivity disorders (ADHD) or etiology. We intend to screen ADHD-related cognitive and behavioral traits in children with biopsy-proven CD and investigate the possible association of these traits with certain vitamin levels, body-mass index, and gluten-free diet (GFD) compliance. METHOD A total of 85 children with biopsy-proven CD (the ages of 8-18 years) were compared with age and sex-matched 72 healthy controls in terms of demographics, psychiatric symptoms, certain vitamin levels, and anthropometric measurements. RESULTS ADHD-like cognitive issues, such as inattention and learning difficulties, as well as psychosomatic symptoms and poor prosocial behavior, were all associated with GFD noncompliance in childhood CD. CONCLUSION Untreated CD may predispose to ADHD-resembling symptoms. Physicians should be aware of the probability of ADHD misdiagnosing due to ADHD-resembling cognitive and behavioral traits in untreated CD.
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Affiliation(s)
- Ayşegül Efe
- University of Health Sciences, Dr. Sami Ulus Maternity, Children's Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Ayşegül Tok
- University of Health Sciences, Dr. Sami Ulus Maternity, Children's Health and Diseases Training and Research Hospital, Ankara, Turkey
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Elwenspoek MM, Thom H, Sheppard AL, Keeney E, O'Donnell R, Jackson J, Roadevin C, Dawson S, Lane D, Stubbs J, Everitt H, Watson JC, Hay AD, Gillett P, Robins G, Jones HE, Mallett S, Whiting PF. Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling. Health Technol Assess 2022; 26:1-310. [PMID: 36321689 PMCID: PMC9638887 DOI: 10.3310/zuce8371] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma. OBJECTIVES The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care. DESIGN (1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives. DATA SOURCES For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used. REVIEW METHODS For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed. RESULTS People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents (n = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research. LIMITATIONS The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet. CONCLUSIONS Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia). FUTURE WORK Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed. STUDY REGISTRATION This study is registered as PROSPERO CRD42019115506 and CRD42020170766. FUNDING This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Martha Mc Elwenspoek
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Howard Thom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Athena L Sheppard
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Edna Keeney
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Rachel O'Donnell
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Joni Jackson
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Cristina Roadevin
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Sarah Dawson
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | | | | | - Hazel Everitt
- Primary Care Research Centre, Population Sciences and Medical Education, University of Southampton, Southampton, UK
| | - Jessica C Watson
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Alastair D Hay
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Peter Gillett
- Paediatric Gastroenterology, Hepatology and Nutrition Department, Royal Hospital for Sick Children, Edinburgh, UK
| | - Gerry Robins
- Department of Gastroenterology, York Teaching Hospital NHS Foundation Trust, York, UK
| | - Hayley E Jones
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Sue Mallett
- Centre for Medical Imaging, University College London, London, UK
| | - Penny F Whiting
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Gaur S. The Association between ADHD and Celiac Disease in Children. CHILDREN (BASEL, SWITZERLAND) 2022; 9:781. [PMID: 35740718 PMCID: PMC9221618 DOI: 10.3390/children9060781] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/11/2022] [Accepted: 05/13/2022] [Indexed: 11/17/2022]
Abstract
UNLABELLED Controversy around the association between celiac disease (CeD) and attention deficit hyperactive disorder (ADHD) was addressed by a systematic review in 2015, ultimately showing no association. Since 2015, there have been several studies showing an association between celiac disease and attention deficit hyperactive disorder. This is an updated systematic review. BACKGROUND Most experts agree on the recommendation to not screen as part of the standard of care for ADHD in persons with CeD or vice versa. Simultaneously, they propose that untreated patients with CeD and neurological symptoms such as chronic fatigue, inattention, pain, and headache could be predisposed to ADHD-like behavior, namely inattention (which may be alleviated by following a gluten-free diet). The inattentive subtype of ADHD that encompasses the symptoms of inattention is phenotypically heterogeneous, as it includes the clinical construct of sluggish cognitive tempo (SCT). SCT symptoms overlap with the neurological manifestations of CeD. METHODS A systematic search (PRISMA) of PubMed, Google Scholar, EMBASE, Web of Science, Stanford Lane, SCOPUS, and Ovid was conducted for articles up to 21 February 2022. Of these, 23 studies met the criteria. RESULTS Out of the 23 studies, 13 showed a positive association between ADHD and CeD. Most studies that showed a positive association had been published in the last five years. Inconsistencies in the results remain due to the heterogeneous methodology used, specifically for ADHD and the outcome questionnaires, as well as a lack of reporting on ADHD subtypes. CONCLUSION There is an association between ADHD and celiac disease. The current methodological limitations will be lessened if we examine the subtypes of ADHD.
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Affiliation(s)
- Sonia Gaur
- Department of Psychiatry, Stanford School of Medicine, 401 Quarry Road, Stanford, CA 94305, USA
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Sharma N, Singh K, Senapati S. Celiac disease poses significant risk in developing depression, anxiety, headache, epilepsy, panic disorder, dysthymia: A meta-analysis. Indian J Gastroenterol 2021; 40:453-462. [PMID: 34839445 DOI: 10.1007/s12664-021-01215-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/30/2021] [Indexed: 02/04/2023]
Abstract
Celiac disease (CD) primarily affects the small intestine. Previous studies have identified higher incidences of neuropsychiatric diseases among CD patients compared to non-CD controls. Genome-wide association studies have identified >60 non-human leukocyte antigen (HLA) genes associated with CD, where estimated 15% genes have role in neurological health. We carried out a systematic review and meta-analysis to estimate the potential risk conferred by CD in developing neuropsychiatric diseases. Literature search was performed till June 2019. Incidences of neuropsychiatric diseases were compared among CD and non-CD controls. Funnel plots and Egger's tests were used to evaluate publication bias and estimate study effects. Qualities of the included studies were estimated using Newcastle-Ottawa Scale. Quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Odds of developing neuropsychiatric diseases among CD were evaluated by computing meta-odds ratio (Manten-Haenszel method) and Z test p-value using random and fixed effect models based on the degree of study heterogeneity. Thirteen non-randomized case-control studies were found eligible. Subjects suffering from CD were found to have significantly more risk to develop depression (p<1.00E-05; OR=1.60 [1.37-1.86]), anxiety (p=0.05; OR=1.41 [1.00-1.97]), headache (p<0.1.00E-05; OR=3.27 [2.46-4.34]), epilepsy (p<1.00E-04; OR=11.90 [3.78-37.43]), panic disorder (p<1.00E-04; OR=4.64 [2.22-9.70]), and dysthymia (p=2.00E-03; OR=5.27 [1.83-15.22]). CD is a major predisposing factor in developing array of common neuropsychiatric diseases. Shared biological processes and molecular networks could play a crucial role in disease co-occurrence. Detailed molecular evidences are needed to establish the cause-effect relationship between these diseases.
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Affiliation(s)
- Nidhi Sharma
- Immunogenomics Laboratory, Department of Human Genetics and Molecular Medicine, School of Life Sciences, Central University of Punjab, Bathinda, 151 401, India
| | - Kavita Singh
- Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurugram, 122 002, India
- Centre for Chronic Disease Control, New Delhi, 110 016, India
- Rollins School of Public Health, Emory University, Atlanta, USA
| | - Sabyasachi Senapati
- Immunogenomics Laboratory, Department of Human Genetics and Molecular Medicine, School of Life Sciences, Central University of Punjab, Bathinda, 151 401, India.
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Kedem S, Yust-Katz S, Carter D, Levi Z, Kedem R, Dickstein A, Daher S, Katz LH. Attention deficit hyperactivity disorder and gastrointestinal morbidity in a large cohort of young adults. World J Gastroenterol 2020; 26:6626-6637. [PMID: 33268951 PMCID: PMC7673962 DOI: 10.3748/wjg.v26.i42.6626] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/03/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although the association of attention deficit hyperactivity disorder (ADHD) with psychiatric disorders is well known, its association with somatic diseases is unclear. Only few studies have investigated the gastrointestinal (GI) morbidity in adult patients with ADHD.
AIM To measure gastrointestinal comorbidity and its burden on healthcare in young adults with ADHD.
METHODS The cohort included subjects aged 17-35 years recruited to the Israel Defense Forces in 2007-2013, 33380 with ADHD and 355652 without (controls). The groups were compared for functional and inflammatory conditions of the gastrointestinal tract and clinic and specialist visits for gastrointestinal symptoms/disease during service (to 2016). Findings were analyzed by generalized linear models adjusted for background variables.
RESULTS Compared to controls, the ADHD group had more diagnoses of functional gastrointestinal disorders (referred to as FGID), namely, dyspepsia [odds ratio (OR): 1.48, 95% confidence interval (CI): 1.40-1.57, P < 0.001], chronic constipation (OR: 1.64, 95%CI: 1.48-1.81, P < 0.001), and irritable bowel syndrome (OR: 1.67, 95%CI: 1.56-1.80, P < 0.001) but not of organic disorders (inflammatory bowel disease, celiac disease). They had more frequent primary care visits for gastrointestinal symptoms [rate ratio (RR): 1.25, 95%CI: 1.24-1.26, P < 0.001] and referrals to gastrointestinal specialists (RR: 1.96, 95%CI: 1.88-2.03, P < 0.001) and more episodes of recurrent gastrointestinal symptoms (RR: 1.29, 95%CI: 1.21-1.38, P < 0.001). Methylphenidate use increased the risk of dyspepsia (OR: 1.49, 95%CI: 1.28-1.73, P < 0.001) and constipation (OR: 1.42, 95%CI: 1.09-1.84, P = 0.009).
CONCLUSION ADHD in young adults is associated with an excess of FGID and increased use of related health services. Research is needed to determine if an integrative approach treating both conditions will benefit these patients and cut costs.
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Affiliation(s)
- Sivan Kedem
- Medical Corps, Israeli Defense Forces, Ramat-Gan 52621, Israel
- Medical School, Hebrew University - Hadassah Medical Center, Jerusalem 91120, Israel
| | - Shlomit Yust-Katz
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 77096, Israel
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva 49100, Israel
| | - Dan Carter
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 77096, Israel
- Department of Gastroenterology, Sheba Medical Center, Ramat-Gan 52361, Israel
| | - Zohar Levi
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 77096, Israel
- Department of Gastroenterology, Beilinson Hospital, Rabin Medical Center, Petach Tikva 49100, Israel
| | - Ron Kedem
- Medical Corps, Israeli Defense Forces, Ramat-Gan 52621, Israel
| | - Adi Dickstein
- Medical Corps, Israeli Defense Forces, Ramat-Gan 52621, Israel
| | - Salah Daher
- Medical Corps, Israeli Defense Forces, Ramat-Gan 52621, Israel
- Department of Gastroenterology and Hepatology, Hebrew University - Hadassah Medical Center, Jerusalem 91120, Israel
| | - Lior H Katz
- Medical Corps, Israeli Defense Forces, Ramat-Gan 52621, Israel
- Department of Gastroenterology and Hepatology, Hebrew University - Hadassah Medical Center, Jerusalem 91120, Israel
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Sabino L, Marino S, Falsaperla R, Pisani F, Massimino C, Pavone P. Celiac disease and headache in children: a narrative state of the art. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:e2020056. [PMID: 32921753 PMCID: PMC7717030 DOI: 10.23750/abm.v91i3.8224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 02/18/2019] [Indexed: 11/23/2022]
Abstract
Celiac disease (CD) is one of the most important entity of the wide spectrum of gluten-related disorders (GRDs). It is well known that neurological manifestation can be present either at the onset of CD, or appear during the development of the pathology, and different can be the neurologic findings. Clinical features are very variable, ranging from typical manifestations of gastrointestinal involvement to neurologic symptom. The most frequent neurologic signs reported were headache, epileptic seizure, migraine, mental retardation, ataxia and attention deficit and hyperactive disorder. Headache either in form of migraine, or in non-specific form represents one of the main clinical presentation in CD. The aim of this work is to provide a narrative review of the pediatric literature focused on the cephalalgic features of children with CD evaluating the potential benefits of a gluten free diet (GFD). Papers were identified by searching for related literature in Medline (PubMed) and Embase using the words "Celiac Disease" and "Headache" or "Migraine" by specifying "children"/"paediatric age" for reports published since 1972 till 31th October 2018. According to our inclusion criteria, a total of 25 papers has been evaluated. Although it is still controversial if headache is prevalent in CD children a correct compliance to a GFD seems to improve the neurological symptoms even if the underlying pathogenic relationship between CD and neurologic system involvement is still not fully understood.
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Affiliation(s)
- Luca Sabino
- Pediatric and Pediatric Emergency Department, University Hospital "Policlinico-Vittorio Emanuele" and cPediatric Clinic, Department of Clinical and Experimental Medicine, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy.
| | - Silvia Marino
- aPediatric and Pediatric Emergency Department, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy;.
| | - Raffaele Falsaperla
- aPediatric and Pediatric Emergency Department, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy.
| | - Francesco Pisani
- Child Neuropsychiatric Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.
| | - Carmen Massimino
- cPediatric Clinic, Department of Clinical and Experimental Medicine, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy.
| | - Piero Pavone
- Pediatric Clinic, Department of Clinical and Experimental Medicine, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy.
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Ertürk E, Wouters S, Imeraj L, Lampo A. Association of ADHD and Celiac Disease: What Is the Evidence? A Systematic Review of the Literature. J Atten Disord 2020; 24:1371-1376. [PMID: 26825336 DOI: 10.1177/1087054715611493] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Objective: This article tries to answer the question whether or not there is evidence for a relationship between celiac disease (CD) and ADHD. A review of the current literature on this topic is provided. Method: PUBMED/MEDLINE, Web of Science, and Google scholar were searched to include all published trials on ADHD and CD (no date limitation, both noncontrolled and controlled trials). In addition, the reference list of included studies was screened to find other relevant articles. Results: Eight studies report a possible association between CD and ADHD; however, the results are inconsistent. Only three out of eight studies report a positive correlation between ADHD and CD. Conclusion: Up till now, there is no conclusive evidence for a relationship between ADHD and CD. Therefore, it is not advised to perform routine screening of CD when assessing ADHD (and vice versa) or to implement gluten-free diet as a standard treatment in ADHD.
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Kumperscak HG, Rebec ZK, Sobocan S, Fras VT, Dolinsek J. Prevalence of Celiac Disease Is Not Increased in ADHD Sample. J Atten Disord 2020; 24:1085-1089. [PMID: 27647622 DOI: 10.1177/1087054716666953] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Objective: The purpose of the present study was to examine the prevalence of celiac disease (CD) in children and adolescents with ADHD. Method: In all, 102 participants between 4 and 18 years of age diagnosed with ADHD participated in the study (M = 12.8 years; 84 boys and 18 girls). CD was diagnosed according to the adapted guidelines of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPHGAN). Results: Among 102 tested children and teenagers with ADHD, we did not find anyone with suspected CD, so further diagnostic procedures for CD were not indicated. Conclusion: In our sample of children and teenagers with ADHD, the prevalence of CD was not higher than in the general population. On the basis of the obtained results and the results of similar studies, we conclude that there are not enough data to support screening for CD and the introduction of a gluten-free diet in children with ADHD unless there are additional indications.
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Affiliation(s)
- Hojka G Kumperscak
- Paediatrics Clinic, University Clinical Center Maribor, Maribor, Slovenia
| | - Ziva K Rebec
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Sanja Sobocan
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Valerija T Fras
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Jernej Dolinsek
- Paediatrics Clinic, University Clinical Center Maribor, Maribor, Slovenia
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11
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Psychiatric Manifestations of Coeliac Disease, a Systematic Review and Meta-Analysis. Nutrients 2020; 12:nu12010142. [PMID: 31947912 PMCID: PMC7019223 DOI: 10.3390/nu12010142] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/30/2019] [Accepted: 01/03/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Coeliac disease (CD) is increasingly prevalent and is associated with both gastrointestinal (GI) and extra-intestinal manifestations. Psychiatric disorders are amongst extra-intestinal manifestations proposed. The relationship between CD and such psychiatric disorders is not well recognised or understood. Aim: The aim of this systematic review and meta-analysis was to provide a greater understanding of the existing evidence and theories surrounding psychiatric manifestations of CD. Methodology: An online literature search using PubMed was conducted, the prevalence data for both CD and psychiatric disorders was extracted from eligible articles. Meta analyses on odds ratios were also performed. Results: A total of 37 articles were included in this review. A significant increase in risk was detected for autistic spectrum disorder (OR 1.53, 95% CI 1.24–1.88, p < 0.0001), attention deficit hyperactivity disorder (OR 1.39, 95% CI 1.18–1.63, p < 0.0001), depression (OR 2.17, 95% CI 2.17–11.15, p < 0.0001), anxiety (OR 6.03, 95% CI 2.22–16.35, p < 0.0001), and eating disorders (OR 1.62, 95% CI 1.37–1.91, p < 0.00001) amongst the CD population compared to healthy controls. No significant differences were found for bipolar disorder (OR 2.35, 95% CI 2.29–19.21, p = 0.43) or schizophrenia (OR 0.46, 95% CI 0.02–10.18, p = 0.62). Conclusion: CD is associated with an increased risk of depression, anxiety, eating disorders as well as ASD and ADHD. More research is required to investigate specific biological explanations as well as any effect of gluten free diet.
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12
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Julian T, Hadjivassiliou M, Zis P. Gluten sensitivity and epilepsy: a systematic review. J Neurol 2019; 266:1557-1565. [PMID: 30167878 PMCID: PMC6586915 DOI: 10.1007/s00415-018-9025-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The aim of this systematic review was to establish the prevalence of epilepsy in patients with coeliac disease (CD) or gluten sensitivity (GS) and vice versa and to characterise the phenomenology of the epileptic syndromes that these patients present with. METHODOLOGY A systematic computer-based literature search was conducted on the PubMed database. Information regarding prevalence, demographics and epilepsy phenomenology was extracted. RESULTS Epilepsy is 1.8 times more prevalent in patients with CD, compared to the general population. CD is over 2 times more prevalent in patients with epilepsy compared to the general population. Further studies are necessary to assess the prevalence of GS in epilepsy. The data indicate that the prevalence of CD or GS is higher amongst particular epileptic presentations including in childhood partial epilepsy with occipital paroxysms, in adult patients with fixation off sensitivity (FOS) and in those with temporal lobe epilepsy (TLE) with hippocampal sclerosis. A particularly interesting presentation of epilepsy in the context of gluten-related disorders is a syndrome of coeliac disease, epilepsy and cerebral calcification (CEC syndrome) which is frequently described in the literature. Gluten-free diet (GFD) is effective in the management of epilepsy in 53% of cases, either reducing seizure frequency, enabling reduced doses of antiepileptic drugs or even stopping antiepileptic drugs. CONCLUSION Patients with epilepsy of unknown aetiology should be investigated for serological markers of gluten sensitivity as such patients may benefit from a GFD.
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Affiliation(s)
- Thomas Julian
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
| | - Marios Hadjivassiliou
- Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
| | - Panagiotis Zis
- Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
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13
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Zis P, Julian T, Hadjivassiliou M. Headache Associated with Coeliac Disease: A Systematic Review and Meta-Analysis. Nutrients 2018; 10:1445. [PMID: 30301194 PMCID: PMC6213149 DOI: 10.3390/nu10101445] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 09/25/2018] [Accepted: 09/29/2018] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVE The aim of this systematic review was to explore the relationship between coeliac disease (CD) and headache. The objectives were to establish the prevalence of each entity amongst the other, to explore the role of gluten free diet (GFD), and to describe the imaging findings in those affected by headaches associated with CD. METHODOLOGY A systematic computer-based literature search was conducted on the PubMed database. Information regarding study type, population size, the age group included, prevalence of CD amongst those with headache and vice versa, imaging results, the nature of headache, and response to GFD. RESULTS In total, 40 articles published between 1987 and 2017 qualified for inclusion in this review. The mean pooled prevalence of headache amongst those with CD was 26% (95% CI 19.5⁻33.9%) in adult populations and 18.3% (95% CI 10.4⁻30.2%) in paediatric populations. The headaches are most often migraine-like. In children with idiopathic headache, the prevalence of CD is 2.4% (95% CI 1.5⁻3.7%), whereas data for adult populations is presently unavailable. Brain imaging can be normal, although, cerebral calcifications on CT, white matter abnormalities on MRI and deranged regional cerebral blood flow on SPECT can be present. GFD appears to be an effective management for headache in the context of CD, leading to total resolution of headaches in up to 75% of patients. CONCLUSIONS There is an increased prevalence of CD amongst idiopathic headache and vice versa. Therefore, patients with headache of unknown origin should be screened for CD, as such patients may symptomatically benefit from a GFD.
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Affiliation(s)
- Panagiotis Zis
- Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK.
| | - Thomas Julian
- Medical School, University of Sheffield, Sheffield S10 2TN, UK.
| | - Marios Hadjivassiliou
- Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK.
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14
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Abstract
There is a growing interest in the extraintestinal manifestations of common pediatric gastrointestinal diseases, such as inflammatory bowel disease and celiac disease. This article specifically focuses on the neurological symptoms that manifest because of these disorders and their treatments. Many neurological symptoms have been reported in association with these diseases, including neuropathy, myopathy, ataxia, headache, and seizures, among others. It is currently believed that these neurological symptoms are largely overlooked by practitioners and could be a red flag for earlier diagnosis. However, additional research, especially in the pediatric population, is warranted to further elaborate on the causality and pathophysiology of these neurological symptoms.
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Affiliation(s)
- Melissa Shapiro
- From the Section of Gastroenterology, Department of Pediatrics, Drexel University College of Medicine, St. Christopher's Hospital for Children, Philadelphia, PA
| | - David A Blanco
- From the Section of Gastroenterology, Department of Pediatrics, Drexel University College of Medicine, St. Christopher's Hospital for Children, Philadelphia, PA.
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15
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Cámara-Lemarroy CR, Rodriguez-Gutierrez R, Monreal-Robles R, Marfil-Rivera A. Gastrointestinal disorders associated with migraine: A comprehensive review. World J Gastroenterol 2016; 22:8149-8160. [PMID: 27688656 PMCID: PMC5037083 DOI: 10.3748/wjg.v22.i36.8149] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 08/03/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research.
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16
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Nenna R, Petrarca L, Verdecchia P, Florio M, Pietropaoli N, Mastrogiorgio G, Bavastrelli M, Bonamico M, Cucchiara S. Celiac disease in a large cohort of children and adolescents with recurrent headache: A retrospective study. Dig Liver Dis 2016; 48:495-498. [PMID: 26826905 DOI: 10.1016/j.dld.2015.12.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 11/23/2015] [Accepted: 12/27/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The clinical picture of celiac disease is changing with the emergence of subclinical forms and growing evidence reporting associated neurological disorders. AIMS To establish the prevalence of celiac disease in children suffering from recurrent headache. METHODS In our retrospective study we collected charts from 1131 children attending our tertiary care Centre for Paediatric Headache over the period 2001-2012. They were screened for celiac disease and positive patients were referred to our Operative Unit for Coeliac disease and confirmed positive children underwent upper endoscopy with multiple duodenal biopsies. Celiac children started a gluten-free diet. RESULTS 883 children (481 females; median age, 9.8 years, range 3-19) performed celiac disease screening, and among them, 11 children (7 females; median age, 8.2 years, range: 4.8-13.9) were diagnosed with celiac disease. Seven children (5 females, median age, 11.9 years, range: 10.3-13.9) had been diagnosed as celiac prior to the neurological evaluation. The prevalence of celiac disease in our sample is 2.04% vs. 1.2% of the general population (p=0.034). CONCLUSIONS Our study demonstrates, on a large series, that celiac disease prevalence is doubled in patients with chronic headache. Screening for celiac disease could be advised as part of the diagnostic work-up in these paediatric patients, particularly among pharmacological non-responders.
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Affiliation(s)
- Raffaella Nenna
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy.
| | - Laura Petrarca
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Paola Verdecchia
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Matteo Florio
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Nicoletta Pietropaoli
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Gerarda Mastrogiorgio
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Maria Bavastrelli
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Margherita Bonamico
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Department of Paediatrics and Infant Neuropsychiatry, "Sapienza" University of Rome, Rome, Italy
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17
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Abstract
Comorbid conditions frequently occur in pediatric headaches and may significantly affect their management. Comorbidities that have been associated with pediatric headaches include attention-deficit or hyperactivity disorder, autism, developmental disabilities, depression, anxiety, epilepsy, obesity, infantile colic, atopic disorders, inflammatory bowel disease, and irritable bowel syndrome. The goal of this article is to review these comorbidities associated with pediatric headache, thereby empowering child neurologists to identify common triggers and tailor management strategies that address headache and its comorbidities.
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Affiliation(s)
- Howard Jacobs
- Department of Pediatrics, Ohio State University School of Medicine, Columbus, OH
| | - Samata Singhi
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Jack Gladstein
- Departments of Pediatrics and Neurology, University of Maryland School of Medicine, Baltimore, MD.
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18
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Parisi P, Pietropaoli N, Ferretti A, Nenna R, Mastrogiorgio G, Del Pozzo M, Principessa L, Bonamico M, Villa MP. Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. Seizure 2015; 25:181-183. [PMID: 25457448 DOI: 10.1016/j.seizure.2014.09.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/16/2014] [Accepted: 09/30/2014] [Indexed: 10/24/2022] Open
Abstract
PURPOSE To determine whether celiac children are at risk for EEG-neurological features and sleep disordered breathing (SDB), and whether an appropriate gluten-free diet (GFD) influences these disorders. METHODS We consecutively enrolled 19 children with a new biopsy-proven celiac disease (CD) diagnosis. At CD diagnosis and after 6 months of GFD, each patient underwent a general and neurological examination, an electroencephalogram, a questionnaire about neurological features, and a validated questionnaire about SDB: OSA (obstructive sleep apnea) scores<0 predict normality; values>0 predict OSA. RESULTS At CD diagnosis, 37% of patients complained headache that affected daily activities and 32% showed positive OSA score. The EEG examinations revealed abnormal finding in 48% of children. After 6 months of GFD headache disappeared in 72% of children and EEG abnormalities in 78%; all children showed negative OSA score. CONCLUSION According to our preliminary data, in the presence of unexplained EEG abnormalities and/or other neurological disorders/SDB an atypical or silent CD should also be taken into account.
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Affiliation(s)
- P Parisi
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy
| | - N Pietropaoli
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy
| | - A Ferretti
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy
| | - R Nenna
- Celiac Disease and Malabsorptive Diseases Unit, Department of Pediatrics, Sapienza University, Viale Regina Margherita 324, 00161 Rome, Italy
| | - G Mastrogiorgio
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy
| | - M Del Pozzo
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy
| | - L Principessa
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy
| | - M Bonamico
- Celiac Disease and Malabsorptive Diseases Unit, Department of Pediatrics, Sapienza University, Viale Regina Margherita 324, 00161 Rome, Italy
| | - M P Villa
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy.
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19
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Abstract
Acute ataxia is not an uncommon childhood complaint. It most commonly occurs in young patients secondary to a postinfectious cerebellitis, which is typically associated with a very good prognosis and recovery. In adolescence, acute cerebellar ataxia is more often the product of an etiology likely to progress into a chronic disorder without recovery to preillness baseline. In the present case, the authors describe a 15-year-old girl with subacute cerebellar ataxia of presumed immune-mediated etiology that advanced into a chronic cerebellar ataxia. Due to a family history, celiac disease was suspected as the origin of the ataxia; biopsy ruled out enteropathy, and the severe, abrupt radiological changes to the patient's cerebellum are inconsistent with the reported sequelae of gluten ataxia. This case serves as a discussion for diagnostic challenges in adolescent patients with acute cerebellar ataxia with long-term sequelae as well as providing an adjunct discussion on the neurological complications of celiac disease.
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Affiliation(s)
- Robert C Stowe
- 1Department of Neurology and Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, KY, USA
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20
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Stevens LJ, Kuczek T, Burgess JR, Stochelski MA, Arnold LE, Galland L. Mechanisms of behavioral, atopic, and other reactions to artificial food colors in children. Nutr Rev 2013; 71:268-81. [PMID: 23590704 DOI: 10.1111/nure.12023] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Laura J Stevens
- Department of Nutrition Science; Purdue University; West Lafayette; Indiana; USA
| | - Thomas Kuczek
- Department of Statistics; Purdue University; West Lafayette; Indiana; USA
| | - John R Burgess
- Department of Nutrition Science; Purdue University; West Lafayette; Indiana; USA
| | - Mateusz A Stochelski
- Department of Nutrition Science; Purdue University; West Lafayette; Indiana; USA
| | - L Eugene Arnold
- Department of Psychiatry; Ohio State University; Columbus; Ohio; USA
| | - Leo Galland
- Foundation for Integrated Medicine; New York; New York; USA
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21
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Abstract
OBJECTIVE Although it is well known that celiac disease (CD) is associated with neurologic disorders, association with psychiatric problems is not well defined. In this report, we aimed to detect CD prevalence in patients with attention-deficit hyperactivity disorder (ADHD). METHODS A total of 362 patients between the ages 5 and 15 years with the diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria and 390 sex- and age-matched healthy children were included in the present study. Serum levels of tissue transglutaminase (tTg) immunoglobulin (Ig) A and IgG were studied in both groups. Serum IgA levels were also studied in patients with positive tTG IgG for the exclusion of selective IgA deficiency. Endoscopic duodenal biopsy was provided in seropositive patients, whose parents approved the procedure. Biopsy samples were evaluated according to Marsh-Oberhuber classification. RESULTS tTg IgA was positive in 4 patients with ADHD (1.1%). Endoscopic duodenal biopsy was suggestive of CD in one of them (0.27%). tTg IgA was positive in 3 of control group patients (0.8%). Duodenal biopsy of the only patient from control group, who underwent upper gastrointestinal endoscopy, revealed normal intestinal mucosa. CONCLUSIONS The seropositivity rates for CD were found similar in ADHD and control groups. Thus, neither routine screening for CD nor empirical recommendation of gluten-free diet seems necessary in children with ADHD.
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22
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Lionetti E, Francavilla R, Pavone P, Pavone L, Francavilla T, Pulvirenti A, Giugno R, Ruggieri M. The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis. Dev Med Child Neurol 2010; 52:700-707. [PMID: 20345955 DOI: 10.1111/j.1469-8749.2010.03647.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIM The aim of this article was to review and conduct a meta-analysis of the paediatric literature on the neurology of coeliac disease. METHOD We conducted a review of paediatric studies published in English assessing neurological illness in coeliac disease identified through a MEDLINE search (1950-2009). Calculation of computed relative risk, odds ratio, and risk difference was performed using the fixed effect method if applicable. RESULTS Fifteen studies were analysed (11 772 participants). The meta-analysis showed that (1) the relative risk of epilepsy in individuals with coeliac disease, and of coeliac disease in individuals with epilepsy, compared with the general population, was 2.1 and 1.7, respectively, and the risk difference was close to zero, indicating that it was probably a chance association; and (2) the relative risk of headache in individuals with the disease compared with comparison groups was 3.2. In two studies, cerebellar ataxia was documented in 2.7 to 5.4% of participants; in two further studies, the risk of cerebellar dysfunction was zero. Two studies found an association between coeliac disease and peripheral neuropathy. Brain white matter lesions were recorded in two other studies. An association between autism and coeliac disease is disputed. Interpretation Children with coeliac disease are at risk of developing neurological complications, but the risk is lower than in adulthood. The discrepancy might be due to short disease duration, early elimination of gluten from the diet, stricter adherence to diet, or different susceptibility to immune-mediated disorders.
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Affiliation(s)
- Elena Lionetti
- Department of Pediatrics, University of Catania, Catania, Italy.
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23
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Alehan F, Ozçay F, Erol I, Canan O, Cemil T. Increased risk for coeliac disease in paediatric patients with migraine. Cephalalgia 2008; 28:945-9. [PMID: 18624809 DOI: 10.1111/j.1468-2982.2008.01630.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The aim was to determine the prevalence of coeliac disease (CD) in paediatric patients with migraine. Serum tissue transglutaminase IgA (tTGA) antibodies and IgA concentrations were measured in 73 patients with migraine (age range 6-17 years) and the control group (n = 147). Patients having positive tTGA antibodies underwent duodenal biopsy. Four patients (5.5%) from the study group and one (0.6%) from the control group had positive tTGA antibody titres (P < 0.05). Three patients with migraine had normal duodenal histology and were considered as potential CD. One patient from the study group and one from the control group declined to have biopsy. tTGA antibody is considered as a reliable indicator for the presence of CD. However, some patients with positive antibodies may have normal biopsy initially and are classified as having potential CD. Our finding of a higher prevalance of tTGA antibodies in paediatric migraine patients suggests that an association between migraine and CD might exist.
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Affiliation(s)
- F Alehan
- Divisions of Child Neurology, Baskent University of Medicine, Ankara, Turkey.
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24
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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; 152:244-249. [PMID: 18206697 DOI: 10.1016/j.jpeds.2007.06.042] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Revised: 05/17/2007] [Accepted: 06/28/2007] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To determine the frequency of neurologic manifestations in children with gluten sensitivity (GS) and the frequency of GS in children with neurologic disease. STUDY DESIGN A total of 835 children with GS (based on positive titers for serum anti-gliadin antibody [AGA], anti-endomysial antibody [EMA], and anti-tissue transglutamine [tTG] antibody and a positive gut biopsy), representing the local childhood GS population in the town of Catania, Italy, were recruited, prospectively followed up, and screened for neurologic and psychiatric disturbances between 1991 and 2004. Serum AGA, EMA, and anti-tTG antibody titers were estimated in a prevalence sample of 630 consecutive children with neurologic disorders of unknown cause despite full investigation, 300 children with known neurologic syndromes, and 300 healthy children who served as controls. Statistical significance was assessed by the chi(2) test and Yates' chi(2) test. RESULTS Neurologic or psychiatric problems were noted in 15 of 835 children with GS (1.79%) with previously diagnosed GS enteropathy (GSE). In 7 of 630 children (1.1%) with a cryptogenic neurologic disorder, GS was identified based on GS autoantibody screening. These 22 children had febrile seizures, epilepsy, headache, mental retardation, neuropathy, and bipolar disorder; no children had ataxia or cerebellar disturbances. The HLAs were DQ2 (n = 16), DQ8 (n = 4), and DQ2/DQ8 (n = 2). Two of the 300 healthy controls (0.66%) had GS. CONCLUSIONS Based on our findings, the prevalence of neurologic/psychiatric manifestations in this group of children with GS was low but slightly higher than that in the controls (P = .041). Children with known (P = .772) and cryptogenic (P = 1.0) neurologic disorders did not exhibit a higher prevalence of GS.
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Affiliation(s)
- Martino Ruggieri
- Department of Pediatrics, University of Catania, Catania, Italy; Institute of Neurological Sciences, National Research Council, Catania, Italy
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25
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Cassol CA, De Pellegrin CP, Wahys MLC, Pires MMDS, Nassar SM. [Clinical profile of Santa Catarina members of Brazilian Celiac Association]. ARQUIVOS DE GASTROENTEROLOGIA 2007; 44:257-65. [PMID: 18060282 DOI: 10.1590/s0004-28032007000300015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2006] [Accepted: 06/25/2007] [Indexed: 01/29/2023]
Abstract
BACKGROUND Celiac disease is an enteropathy induced by gluten in genetically predisposed individuals. AIM To establish the demographic and clinical characteristics of this disease in Santa Catarina State, Brazil. METHODS A descriptive transversal study was performed involving members of a regional celiac association, to whom a questionnaire focusing various aspects of the disease was sent. RESULTS From a total of 506 members, 145 (28.7%) were enrolled in the study--all of them biopsy-proven celiacs. Their mean age was 30.8 years (range, 3.3-82.5 years). Female to male rate was 2.1:1. The mean age at diagnosis was 16 years for men and 26.7 years for women. Most frequently reported symptoms were: abdominal distention (71.8%), abdominal pain (71%) and diarrhea (65.5%). Anemia, aphthous ulcers and constipation were more related by women, while diarrhea and low weight were more frequent in men. Only 42.1% of the participants had been submitted to biopsies compatible with a correct investigation of the disease (44.2 % had been submitted to biopsy only after gluten exclusion of the diet and 11.7% did not mentioned whether they were in a gluten-free diet when biopsied). Only 61.4% had been submitted to serological tests for diagnostic or dietary control purposes. Associated diseases were related by 65% of the individuals, of which the most common was lactose intolerance (33%). Vitaminic or mineral supplementation was indicated to 45% and only 32.5% have had bone mineral density measured. Of these, 59% had altered results. CONCLUSIONS The results suggest a tendency of diagnosis of celiac disease in older ages, specially among women. This may indicate the necessity of improving public and medical knowledge in Santa Catarina concerning the diagnosis and treatment of this disease.
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Affiliation(s)
- Clarissa Araujo Cassol
- Departamento de Pediatria, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC.
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Borhani Haghighi A, Ansari N, Mokhtari M, Geramizadeh B, Lankarani KB. Multiple sclerosis and gluten sensitivity. Clin Neurol Neurosurg 2007; 109:651-653. [PMID: 17537569 DOI: 10.1016/j.clineuro.2007.04.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2007] [Revised: 04/16/2007] [Accepted: 04/19/2007] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To compare the frequency of gluten sensitivity in patients with multiple sclerosis (MS) and healthy controls. PATIENTS AND METHODS The patients were 161 clinically definite MS patients who referred to neurology outpatient clinic of Nemazee Hospital, Shiraz, south of Iran from March 2004 to October 2005. IgG and IgA antigliadin antibodies were measured by enzyme immuno assay (EIA) method. The test of IgA antitranstissue glutaminase (tTG) and duodenal biopsy were carried out in patients with either IgA or IgG AGA positive sera. Antigliadin antibodies were also measured for 166 age and sex matched control group. RESULTS Neither IgG nor IgA antigliadin antibodies showed significant differences between MS patients and controls. Anti-tTG antibody and histopathologic studies were negative in all patients with positive IgG or IgA antigliadin antibodies results. Mean values of IgG and IgA antigliadin antibodies in MS patients with different sex, age, course, and functional systems involvement were not significantly different. CONCLUSION Gluten sensitivity is not associated with MS in Iran.
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Affiliation(s)
- Afshin Borhani Haghighi
- Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Islamic Republic of Iran.
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Bermejo Velasco PE, Burgos García A. [Neurological complications of celiac disease]. Med Clin (Barc) 2006; 127:500-507. [PMID: 17043005 DOI: 10.1157/13093268] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Braverman ER, Chen TJH, Schoolfield J, Martinez-Pons M, Arcuri V, Varshavskiy M, Gordon CA, Mengucci J, Blum SH, Meshkin B, Downs BW, Blum K. Delayed P300 latency correlates with abnormal Test of Variables of Attention (TOVA) in adults and predicts early cognitive decline in a clinical setting. Adv Ther 2006; 23:582-600. [PMID: 17050501 DOI: 10.1007/bf02850047] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Delayed P300 latency identifies dementia better than the Mini-Mental Status Exam and, in some cases, the Wechsler Memory Scale (WMS-III). The purpose of this study was to determine whether the outcome of an objective Test of Variables of Attention (TOVA) correlates with the findings of an electrophysiologic test-P300 latency-in patients 40 y of age or older. Adult attention deficit disorder may be an important premorbid marker of memory dysfunction or dementia. In males, the means for P300 latency and age-adjusted P300 latency were significantly greater for patients classified as SD-BL (significantly deviant or borderline: TOVA<-1.0) than for those categorized as normal (TOVA(3)0) for attention failure (ie, omissions [P<.010] and commissions [P<.005]) but not for response time or for variability. Males with >2 SD-BL quarters had significantly delayed P300 latency and age-adjusted P300 latency compared with males who had 0 SD-BL quarters (P<.020) and 1 SD-BL quarter (P<.005). In females, the means for P300 latency and age-adjusted P300 latency were significantly delayed for those grouped as SD-BL than for those labeled normal for response time (P<.001) and variability (P<.010), but not for omissions or for commissions. Females with >2 SD-BL quarters had significantly delayed P300 latency and age-adjusted P300 latency compared with females who had 0 SD-BL quarters (P<.005) and 1 SD-BL quarter (P<.010). Results suggest that TOVA abnormalities may be an indicator of delayed P300 and attention disorder. Recent research correlates TOVA abnormalities with impaired WMS scores of early dementia. Coupling of TOVA assessment findings with results of P300, Mini-Mental Status Exam, and WMS-III may allow for enhanced accuracy in the diagnosis and evaluation of the complex pathway of failing attention, memory, and cognition that leads to dementia.
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Abstract
In this study, we measured tissue transglutaminase IgA antibody for the serologic screening of celiac disease in 70 children with epilepsy. A pathologic titer of tissue transglutaminase IgA antibody was found in eight patients (4.7%). Small intestinal biopsies were performed in all antibody-positive patients, and two of them had small bowel histology typical of celiac disease (1.17%). Six had normal histology and were considered to have potential celiac disease. The prevalence of celiac disease in the epileptic group was 1.17%. None of the serum samples of 103 healthy children comprising the control group were positive for tissue transglutaminase IgA antibody. Therefore, we suggest that epileptic children be screened for celiac disease. (J Child Neurol 2006;21:6-7).
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Affiliation(s)
- Buket Dalgiç
- Department of Pediatric Gastroenterology, Gazi University, Ankara, Turkey.
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Vaknin A, Eliakim R, Ackerman Z, Steiner I. Neurological abnormalities associated with celiac disease. J Neurol 2005; 251:1393-7. [PMID: 15592736 DOI: 10.1007/s00415-004-0550-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2003] [Revised: 04/20/2004] [Accepted: 05/10/2004] [Indexed: 10/26/2022]
Abstract
BACKGROUND Celiac disease (CD) is a gluten-sensitive enteropathy in genetically susceptible individuals. Anecdotal reports suggest that the nervous system might be affected in the disorder, but the severity and prevalence of such an involvement have not been systematically evaluated. MATERIALS AND METHODS Analysis of files of CD patients diagnosed between 1980 and 1999 for neurological abnormalities. Diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition. RESULTS Of 148 CD patients, 18 (12%) had 21 neurological disorders that could not be attributed to any other condition including muscle abnormality (3), epilepsy (3), psychiatric disease (4), peripheral neuropathy (3), cerebrovascular disease (1), myelopathy (1) and Down syndrome (2). Other disorders probably unrelated to CD were present in 8 patients. CONCLUSION If this association is not coincidental, both the central and the peripheral nervous systems may be affected in CD by a spectrum of neurological disorders that are either the outcome of CD or share the same pathogenesis with the enteropathy.
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Affiliation(s)
- Adi Vaknin
- Department of Neurology, Hadassah University Hospital, Jerusalem, Israel
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Briani C, Ruggero S, Zara G, Toffanin E, Ermani M, Betterle C, Guariso G. Anti-ganglioside antibodies in children with coeliac disease: correlation with gluten-free diet and neurological complications. Aliment Pharmacol Ther 2004; 20:231-5. [PMID: 15233704 DOI: 10.1111/j.1365-2036.2004.02016.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Emerging evidence points to humoural mechanisms in neurological complications of coeliac disease. Immunoglobulin G anti-ganglioside antibodies have been reported in coeliac disease patients with neuropathy, suggesting an immune response to peripheral nerve antigens. No data are so far available on anti-ganglioside antibodies in coeliac disease children or on antibody modifications after gluten-free diet. AIM To evaluate the presence of antibodies to ganglioside antigens in children with coeliac disease, their modification after gluten-free diet, and possible correlations with neurological manifestations. METHODS Sera from 42 coeliac disease children, before and after gluten-free diet, were tested by enzyme-linked immunosorbent assay for the presence of antibodies (immunoglobulin M, immunoglobulin A, immunoglobulin G) to gangliosides. Thirty-five sera of age-matched children with dyspepsia were used as control. RESULTS High anti-ganglioside antibodies titres were present in two patients. In one patient, antibody titre reversed after gluten-free diet, whereas in the other one the titre increased after diet. Neither one complained of neurological symptoms. CONCLUSIONS Anti-ganglioside antibodies do not seem to correlate with gluten ingestion or with neurological manifestations in children with coeliac disease. Mechanisms different from gluten exposure may be implicated in the antibody production. An ongoing prospective study will help clarify the role, if any, of these antibodies in coeliac disease.
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Affiliation(s)
- C Briani
- Department of Neurosciences, University of Padova, Italy.
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Schrödl D, Kahlenberg F, Peter-Zimmer K, Hermann W, Kühn HJ, Mothes T. Intrathecal synthesis of autoantibodies against tissue transglutaminase. J Autoimmun 2004; 22:335-40. [PMID: 15120757 DOI: 10.1016/j.jaut.2004.02.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2003] [Revised: 01/28/2004] [Accepted: 02/19/2004] [Indexed: 10/26/2022]
Abstract
Anti-tissue transglutaminase (tTG) antibodies (AtTGA) are typically found in serum of patients with untreated coeliac disease (CD). tTG catalyses crosslinking of peptides an activity supposed to be important in neurological disorders. tTG occurs in cerebrospinal fluid (CSF) and its assay in CSF was suggested to be diagnostically useful. However, nothing is known about AtTGA in CSF. Therefore, in 129 unselected CSF-serum pairs IgA- and IgG-AtTGA were assayed by ELISA using human recombinant tTG. For comparison, IgA- and IgG-anti-gliadin antibodies (AGA), typically coexisting with AtTGA were measured. Albumin, total IgA and IgG and further parameters were determined according to routine programme recommended by the European CSF consensus group. AtTGA were detected in 27 (IgA) and in 63 (IgG) CSF samples. Antibody indices (AI) could be calculated for AtTGA from 21 (IgA) and from 61 (IgG) sample pairs. AI for AtTGA was >2 in 11 (IgA) and in 22 (IgG) sample pairs, hinting to intrathecal antibody synthesis. AI for AGA was >2 only for 1 (IgA) and 2 (IgG) sample pairs. Patients with normal routine findings had significantly higher AI for IgA-AtTGA than patients with abnormal findings. This is the first demonstration of AtTGA in CSF and their intrathecal synthesis. The pathogenetic relevance of this new autoantibody species remains to be clarified.
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Affiliation(s)
- Dominik Schrödl
- Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig, Liebigstrasse 27, D-04103 Leipzig, Germany
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Abstract
A variety of neurological disorders have been reported in association with coeliac disease including epilepsy, ataxia, neuropathy, and myelopathy. The nature of this association is unclear and whether a specific neurological complication occurs in coeliac disease remains unproved. Malabsorption may lead to vitamin and trace element deficiencies. Therefore, patients who develop neurological dysfunction should be carefully screened for these. However, malabsorption does not satisfactorily explain the pathophysiology and clinical course of many of the associated neurological disorders. Other mechanisms proposed include altered autoimmunity, heredity, and gluten toxicity. This review attempts to summarise the literature and suggests directions for future research.
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Millichap JG. Celiac Antibodies and Neurologic Disorders. Pediatr Neurol Briefs 2000. [DOI: 10.15844/pedneurbriefs-14-9-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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