Neuropsychiatric manifestation of celiac disease: A case-control study in North India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0975-2870.194183
Background: Celiac disease (CD) is an immune-mediated disease dependent on gluten. Prevalence of CD is about 1% and beside gastrointestinal complaints, neuropsychiatric symptoms may represent an atypical feature of CD. Some studies suggest that a gluten-free diet is effective in treating them. Settings and Design: This case-control study of 49 cases was done during the period of January to March 2013. Aim: To know the spectrum of psychiatric manifestations and cognitive functions in children with CD. Materials and Methods: We took 49 diagnosed cases of CD (based on the demonstration of IgA tissue transglutaminase antibodies and duodenal biopsy) and compared with demographically matched control group (n = 50) on Seguin Form Board Test for cognitive functions and Behavioral Summarized Evaluation-Revised scale for assessment of psychiatric and behavior disturbances. All possible psychiatric diagnosis was made on the basis of International Statistical Classification of Disease and Related Health Problems-Tenth Revision criteria. Statistical Analysis: Statistical analyses were done by using Chi-square test and two-tailed P-values. Results: Neuropsychiatric manifestations were seen in 29% of cases as against 4% of controls which was statistically significant (P=0.001). Only four cases and 1 control fount to be mild mental retardation (P = 0.16). Autism, dyslexia, developmental delay, disruptive behavior disorder, and tic disorder present in cases were not found. Conclusion: Clinical manifestations of CD vary from typical malabsorption syndrome to neuropsychiatric manifestations. Those psychiatric patients who are not responding to standard pharmacological modalities, a diagnosis of CD should be taken into consideration. Only behavioral problem can be the sole clinical manifestation of CD. Keywords: Celiac disease, neurocognition, neuropsychiatric manifestations
Celiac disease (CD) is also known as celiac sprue, gluten intolerance, gluten-sensitive enteropathy. Immune-mediated damage to the mucosa of the small intestine characteristically induces villous atrophy and crypt hyperplasia and it resolves with gluten-free diet. [1] The clinical presentation of CD varies from a classical malabsorption syndrome to psychiatric manifestations like depression, anxiety, autism, and attention deficit hyperactivity disorder, [1],[2] etc., which usually respond to a gluten-free diet. [3],[4] Considering the paucity of study, we planned this study to know the spectrum of psychiatric manifestations and cognitive functions (intelligence) in children presenting with CD.
Study design This study was a case-control study conducted during the period of January to March 2013 at a tertiary care center in North India. Children <18 years of age with CD either newly diagnosed or already diagnosed (on gluten-free diet for >3 months duration) were recruited in the study group. Informed consent was taken from the parents of all patients. Diagnosis of CD was based on the demonstration of IgA tissue transglutaminase antibodies and duodenal biopsy showing pathological changes suggestive of CD. An equal number of age, sex, and socioeconomically matched controls were taken from the patients admitted in pediatric hospital for nonserious illness or from their family members. All cases (n = 49) and controls (n = 50) were subjected to detailed clinical history, thorough physical examination and relevant laboratory investigations were recorded in a set proforma. All patients were questioned regarding the intestinal and extra intestinal manifestation of CD. Children with <18 years of age with proven CD were included in the study. Children with known cause of neurological disease, with history of perinatal insult, with chronic disease like chronic liver disease, chronic kidney disease, etc., and very sick patients were excluded from the study. All the participants were examined by the pediatrician and psychiatrist. Final diagnosis was made based on International Statistical Classification of Disease and Related Health Problems-Tenth Revision criteria. All patients underwent complete CNS examination. Behavioral Summarized Evaluation-Revised (BSE-R) scale for assessment of psychiatric and behavior disturbances [5] and Seguin Form Board Test for cognitive functions [6] were applied. The study was conducted after obtaining approval from the Institutional Review Board and permission was sought from the concern authorities. Statistical Methods Statistical analyses were performed by using Chi-square test and two-tailed P-values. During analyses, P-values (two-tailed) <0.05 were considered statistically significant. Observations The observations made were as follows: [Table 1] shows that our study population consisted of 99 subjects; 49 patients with CD and 50 control subjects, matched for age, sex, and socioeconomic status.
The mean ages of the patients with CD and the control subjects were 7.36 ± 3.47 years and 7.53 ± 3.45 years, respectively. There was no significant difference in age, sex, and distribution of socioeconomic status of cases and controls (P > 0.05). The most common presenting feature in CD patients were gastrointestinal tract (GIT) manifestations (93.88%) followed by anemia and growth retardation (63.26% each), various vitamin deficiencies (36.73%) and neurocognitive and psychiatric manifestation (28.57%). Among GIT manifestation, patients most commonly presented with diarrhea which was present in 82% of cases, followed by abdominal distension (65%), pain abdomen (61%), anorexia (57%), increase appetite and vomiting (12% each) and constipation in 8% of cases [Table 2].
[Table 3] shows that after psychiatric assessment of cases and controls with BSE-R scale, heteroaggression was found in 16 cases followed by aloneness in 11 cases, abnormal eye contact in eight cases, lack of initiative in seven cases and poor social interaction in five cases while 5 controls shows heteroaggression and two controls shows abnormal eye contact. Patients of CD scored more in the items of aloneness, abnormal eye contact, and heteroaggression which is statistically significant (P < 0.05).
As shown in [Table 4], neuropsychiatric manifestations were seen in 29% of cases as against 4% of controls which was statistically significant (P = 0.001). Out of 49 cases, 4 (8.2%) cases have mild mental retardation (MR), while 1 (2%) control has mild MR which was not found to be statistically significant (P = 0.16).
[Table 4] shows that 14% of celiac cases show depression as compared to 2% of controls which was statistically significant (P = 0.027). Autism, dyslexia, developmental delay, disruptive behavior disorder, and tic disorder present in cases were not found in controls.
Although in the past CD was primarily considered to be a gluten enteropathy, during the last two decades, its clinical spectrum has been expanded. Among extra intestinal manifestations of CD, there is increasing number of researches that reports neuropsychiatric manifestations. [7],[8],[9],[10],[11],[12],[13] We carefully matched the comparison group with the CD patients to control the effects of age, sex, and socioeconomic status, and thus our findings on psychiatric symptoms are unlikely to be explained by these factors. In the present study, the most common presenting feature in CD patients were classic GI manifestations present in 94% of cases followed by anemia and growth retardation (63.26% each), various vitamin deficiencies (36.73%) and neurocognitive and psychiatric manifestation (28.6%) [Table 4]. Similar findings have been reported earlier. [14] Neurocognitive and psychiatric manifestations were observed in almost 29% (14 out of 49) of celiac cases [Table 4]. Previous researchers reported that 35% of biopsy proven CD experience psychiatric problems [15] which corroborate our results. Amongst neuropsychiatric manifestations in CD cases, most common was the depression seen in 14% of cases followed by mild MR in 8.2% of cases [Table 5]. Disruptive behavior disorder and developmental delay was present in equal proportion (6% each). Dyslexia present in 4% cases. Autism and tic disorder was present in equal proportion (2% each).
As shown in [Table 5], 14.3% of celiac cases depressed as compared to 2.2% of controls which is significantly higher (P = 0.027). Disruptive behavior disorders observed in 6% of cases which was not found in controls. This study clearly demonstrates a strong association between CD and depression (P < 0.05). The prevalence of depression in celiac patients in an earlier study [16] was 17.2%, which corroborates with our study. However, another study [17] found that CD in adolescents was associated with an increased prevalence of depressive (31% vs. 14.3%) and disruptive behavioral disorders (28% vs. 2.2%), particularly in the phase before diet treatment which is not concordant with our study. It may be due to higher mean age 14.2 years for cases and 14.4 years for controls versus 7.36 years for cases and 7.53 years for controls in our study. Dyslexia was present in 2 (4%) celiac cases which were not found in controls. Zelnik N has suggested increased rate of learning disabilities among celiac patients. [18] Among cognitive impairment, mild MR seen in 8.2% of cases compared to 2% of controls (P = 0.16). Hu et al. also show a possible association between progressive cognitive impairment and CD. [19] Atypical autism was observed in 2% of celiac cases, however it was not found in controls. The association between autism and CD has been reported earlier. [20] Developmental delay and tic disorder present in 6% and 2% of celiac cases which were not found in controls. Contrary to our findings, in another study developmental delay and tics were observed in 15.5% and 0.9% of CD cases and 3.3% and 2.4% of controls, respectively. [18] As shown in [Table 4], neuropsychiatric manifestations were seen in 29% of cases as against 4% of controls which is statistically significant (P = 0.001). The present study demonstrates a strong association between neuropsychiatric manifestations and CD (P = 0.001) as compared to controls. Our study corroborates earlier reports of significantly more behavioral disorders and depressive symptoms in children with untreated CD, compared to children with treated CD and to healthy comparison subjects. [5] Since unrecognized CD may predispose the sufferer to serious mental disorders and behavioral problems, so a careful search for neuropsychiatric abnormalities should form part of initial systemic review in every case, both new and old case of CD who is not improving on routine treatment. As the sample size was very small in our study further researches are needed to determine if neuropsychiatric manifestations are directly related to CD or are just coincidental findings. Limitations The sample was highly selective, which may not be a representative sample. Thus, it is possible that our results would not be generalized to an unselected sample. All participants were medicated, so the effect of medication cannot be ruled out. As it is a case-control study, we could have better results if we would have been planned a longitudinal study.
The spectrum of neurocognitive and psychiatric disorders that occur in CD is broader than previously reported and includes depression, disruptive behavior disorder, dyslexia, autism, MR, tic disorder, and developmental delay. Since unrecognized CD may predispose the sufferer to serious mental disorders and behavioral problems, a child having neuropsychiatric symptoms should also be evaluated for CD as they may be the sole presentation of the disease. Future longitudinal prospective studies are required which might better define the full range of the neuropsychiatric disorders and their clinical improvement or reversal of symptoms after putting celiac patients on a gluten-free diet. Moreover relation of gluten-free diet duration and degree of compliance of the diet to the reversal of neuropsychiatric symptoms need to be further evaluated. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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