Article

Clinical Presentation and Histologic Findings at Ileocolonoscopy in Children with Autistic Spectrum Disorder and Chronic Gastrointestinal Symptoms

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Abstract

Background: Children with developmental disorders experience chronic gastrointestinal symptoms. Aims: To examine the nature of these gastrointestinal symptoms and histologic findings in children with autism spectrum/developmental disorders and ileocolonic disease. Methods: Chart review. 143 autism spectrum/developmental disorder patients, with chronic gastrointestinal symptoms, undergoing diagnostic ileocolonoscopy. Results: Diarrhea was present in 78%, abdominal pain in 59% and constipation in 36%. Ileal and/or colonic lymphonodular hyperplasia (LNH), defined as the presence of an increased number of enlarged lymphoid follicles, often with hyperactive germinal centers, was present in 73.2%. Terminal ileum LNH presented visually in 67% and histologically in 73%. Colonic LNH was multifocal and presented histologically in 32%. Ileal and/or colonic inflammation presented in 74%, consisting primarily of active or chronic colitis (69%). Ileal inflammation presented in 35%. Presence of LNH significantly predicted mucosal inflammation. Patients with ileal and/or colonic LNH had lower mean/median age than those without; patients with ileal and/or colonic inflammation had lower mean/median age than those without. There was a significant association between ileo and/or colonic inflammation or LNH, and onset of developmental disorder; plateaued or regressive onset conferred greater risk than early onset. Conclusions: Patients with autism or related disorders exhibiting chronic gastrointestinal symptoms demonstrate ileal or colonic inflam - mation upon light microscopic examination of biopsy tissue. Further work is needed to determine whether resolution of histopathology with appropriate therapy is accompanied by GI symptomatic and cognitive/behavioral improvement.

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... Diarrhea in children with ASD is similar to diarrhea in TD children when defined in terms of texture (Bristol Stool Type V-VII) and frequency (three or more times per day) 7 . Diarrhea in ASD is characteristically extremely malodorous, light colored (beige or yellow), and typically contains significant amounts of undigested food 11 . The authors' unpublished experience is that diarrheal stools are often passed with excessive effort and straining; parents and caretakers often express surprise at the degree of effort needed to pass such loose stools. ...
... A review of 143 patients with ASD and chronic GI symptoms found similar frequencies in underlying intestinal inflammation in all three of these groups (i.e. constipation, diarrhea, and alternating constipation and diarrhea) 11 . ...
... This includes pathway signaling of iCOS-iCOSL, T cell receptor, leukocyte extravasation, TREM1, NF-kappaB, and Toll-like receptor. In the context of the broader ASD inflammatory bowel disease (IBD)-like syndrome previously described 11,[14][15][16][17][18][19][20] , this immune signaling and inflammatory mucosal gene expression profile have been reported previously in both adult and pediatric IBD [21][22][23][24][25] , and specifically in GI-symptomatic children with ASD [26][27][28] . ...
Article
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In children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes: (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.
... It is established that gastrointestinal symptoms occur with greater frequency in children with ASD as compared to typically developing children, though the prevalence estimates of these symptoms vary depending on the methodologies employed [1][2][3][4][5][6][7][8][9][10] . Symptoms most often reported are constipation, diarrhea, abdominal pain and distention, and food intolerances 1,4,5,9 . ...
... It is established that gastrointestinal symptoms occur with greater frequency in children with ASD as compared to typically developing children, though the prevalence estimates of these symptoms vary depending on the methodologies employed [1][2][3][4][5][6][7][8][9][10] . Symptoms most often reported are constipation, diarrhea, abdominal pain and distention, and food intolerances 1,4,5,9 . Potential causes for these symptoms have included gastroesophageal reflux 10 , eosinophilic esophagitis 11 , food allergies 12 , and inflammatory bowel disease (IBD). ...
... Gastrointestinal symptoms in children with ASD have also been attributed to a unique variant of IBD seen only in children with ASD 9,14 . Distinguishing cellular, immunohistochemical, and molecular features of this ASD-associated IBD have been described in the literature from diagnostic endoscopies of the stomach 15 , small intestine [16][17][18][19] , and colon 17,19,20 . ...
Article
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Gastrointestinal symptoms are common in children with autism spectrum disorder (ASD). A significant proportion of children with ASD and gastrointestinal symptoms have histologic evidence of ileocolitis (inflammation of the terminal ileum and/or colon). We previously reported the molecular characterization of gastrointestinal biopsy tissue from ASD children with ileocolitis (ASDIC+) compared to anatomically similar inflamed tissue from typically developing children with inflammatory bowel disease (IBD; i.e. Crohn’s disease or ulcerative colitis) and typically developing children with gastrointestinal symptoms but no evidence of gastrointestinal mucosal inflammation (TDIC−). ASDIC+ children had a gene expression profile that, while primarily overlapping with known IBD, had distinctive differences. The present study confirms these findings and replicates this molecular characterization in a second cohort of cases (ASDIC+) and controls (TDIC−). In these two separate case/control mucosal-based cohorts, we have demonstrated overlap of 59 differentially expressed transcripts (DETs) unique to inflamed ileocolonic tissue from symptomatic ASDIC+ children. We now report that 9 of these 59 transcripts are also differentially expressed in the peripheral blood of the second cohort of ASDIC+ children. This set of transcripts represents a putative blood-based biomarker for ASD-associated ileocolonic inflammation.
... In ASD children with GI symptoms who undergo endoscopic and histologic examinations, inflammatory pathology is reported with high frequency [9][10][11][12]. Features of the GI disease reported originally -ileocolonic lymphoid nodular hyperplasia (LNH) and ileocolitis -have since been expanded to include esophagitis [9], atypical focal gastritis [13], and enteritis [12,14,15]. ...
... In ASD children with GI symptoms who undergo endoscopic and histologic examinations, inflammatory pathology is reported with high frequency [9][10][11][12]. Features of the GI disease reported originally -ileocolonic lymphoid nodular hyperplasia (LNH) and ileocolitis -have since been expanded to include esophagitis [9], atypical focal gastritis [13], and enteritis [12,14,15]. Further analyses of the inflammatory infiltrate in the mucosa and the associated mucosal cytokine profiles have not only confirmed the presence of disease, but suggest characteristic features that distinguish the lesions in ASD children from the more welldescribed inflammatory bowel diseases (IBDs), i.e. ...
... Despite the published evidence [9][10][11][12][13][14]16], the debate still continues [3,29,30] as to whether children with ASD and GI symptoms and non-specific mucosal infiltrates have conventionally recognized forms of IBD, a novel IBD phenotype, or no disease at all. ...
Article
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Gastrointestinal symptoms are common in children with autism spectrum disorder (ASD) and are often associated with mucosal inflammatory infiltrates of the small and large intestine. Although distinct histologic and immunohistochemical properties of this inflammatory infiltrate have been previously described in this ASD(GI) group, molecular characterization of these lesions has not been reported. In this study we utilize transcriptome profiling of gastrointestinal mucosal biopsy tissue from ASD(GI) children and three non-ASD control groups (Crohn's disease, ulcerative colitis, and histologically normal) in an effort to determine if there is a gene expression profile unique to the ASD(GI) group. Comparison of differentially expressed transcripts between the groups demonstrated that non-pathologic (normal) tissue segregated almost completely from inflamed tissue in all cases. Gene expression profiles in intestinal biopsy tissue from patients with Crohn's disease, ulcerative colitis, and ASD(GI), while having significant overlap with each other, also showed distinctive features for each group. Taken together, these results demonstrate that ASD(GI) children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease. Although we report qPCR confirmation of representative differentially expressed transcripts determined initially by microarray, these findings may be considered preliminary to the extent that they require further confirmation in a validation cohort.
... A metaanalysis of 84 studies of GI dysfunction in autism patients identified a median prevalence of 22.2% for constipation, 13% for diarrhea, and 46.8% for any GI symptom [Holingue et al., 2018]. Additional studies have identified that 60-74% of children patients with autism experience inflammation of the small or large intestine [Horvath, Papadimitriou, Rabsztyn, Drachenberg, & Tildon, 1999;Krigsman et al., 2010]. ...
... Changes in GI tract mucosal morphology are reported in both the clinical setting and in animal models of autism, therefore we assessed for similar changes in Nlgn3 −/− mice. For example, partial villus atrophy [Horvath et al., 1999], cryptitis, and crypt branching [Krigsman et al., 2010] have been documented in patients with autism. Mice with modified serotonin reuptake transporter (SERT) function due to the autism-associated rare coding variant Ala56 (G56A) showed reduced villus height and crypt depth [Margolis et al., 2016]. ...
Article
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Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin‐3 are associated with autism. Mice lacking Neuroligin‐3 (Nlgn3−/−) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3−/− mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3−/− mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3−/− mice had similar numbers of neurons expressing the pan‐neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3−/− mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3−/− mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3−/− mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3−/− mice, these findings suggest that Neuroligin‐3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2019. © 2019 The Authors. Autism Research published by International Society for Autism Research published byWiley Periodicals, Inc. Lay Summary People with autism commonly experience gut problems. Many gene mutations associated with autism affect neuronal activity. We studied mice in which the autism‐associated Neuroligin‐3 gene is deleted to determine whether this impacts gut neuronal numbers or motility. We found that although mutant mice had similar gut structure and numbers of neurons in all gut regions examined, they had distended colons and faster colonic muscle contractions. Further work is needed to understand how Neuroligin‐3 affects neuron connectivity in the gastrointestinal tract.
... These symptoms include abdominal pain, chronic diarrhea and or constipation, and gastro esophageal reflux disease [10]. GI disease has been confirmed via endoscopy in several studies [95][96][97]. Inflammation was found throughout the GI tract, with reflux esophogitis, stomach inflammation, duodenum and abnormal carbohydrate digestive enzyme activity. Other studies have found chronic patchy inflammation and lymphonodular hyperplasia. ...
... Other studies have found chronic patchy inflammation and lymphonodular hyperplasia. This is different than the pattern seen in classical inflammatory bowel disease, with infiltration of T cells and plasma cells into the epithelial layers of the mucosa [68,97]. Lymphocyte infiltration into the epithelial layers of the gut lining and crypt cells has been found on endoscopy. ...
Article
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Autism is the fastest growing developmental disorder in the world today. The prevalence of autism in the US has risen from 1 in 2500 in 1970 to 1 in 88 children today. People with autism present with repetitive movements and with social and communication impairments. These impairments can range from mild to profound. The estimated total lifetime societal cost of caring for one individual with autism is $3.2 million US dollars. With the rapid growth in this disorder and the great expense of caring for those with autism, it is imperative for both individuals and society that techniques be developed to model and understand autism. There is increasing evidence that those individuals diagnosed with autism present with highly diverse set of abnormalities affecting multiple systems of the body. To this date, little to no work has been done using a whole body systems biology approach to model the characteristics of this disorder. Identification and modelling of these systems might lead to new and improved treatment protocols, better diagnosis and treatment of the affected systems, which might lead to improved quality of life by themselves, and, in addition, might also help the core symptoms of autism due to the potential interconnections between the brain and nervous system with all these other systems being modeled. This paper first reviews research which shows that autism impacts many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological. These systems interact in complex and highly interdependent ways. Many of these disturbances have effects in most of the systems of the body. In particular, clinical evidence exists for increased oxidative stress, inflammation, and immune and mitochondrial dysfunction which can affect almost every cell in the body. Three promising research areas are discussed, hierarchical, subgroup analysis and modeling over time. This paper reviews some of the systems disturbed in autism and suggests several systems biology research areas. Autism poses a rich test bed for systems biology modeling techniques.
... These symptoms include abdominal pain, chronic diarrhea and or constipation, and gastro esophageal reflux disease [10]. GI disease has been confirmed via endoscopy in several studies [95][96][97]. Inflammation was found throughout the GI tract, with reflux esophogitis, stomach inflammation, duodenum and abnormal carbohydrate digestive enzyme activity. Other studies have found chronic patchy inflammation and lymphonodular hyperplasia. ...
... Other studies have found chronic patchy inflammation and lymphonodular hyperplasia. This is different than the pattern seen in classical inflammatory bowel disease, with infiltration of T cells and plasma cells into the epithelial layers of the mucosa [68,97]. Lymphocyte infiltration into the epithelial layers of the gut lining and crypt cells has been found on endoscopy. ...
Conference Paper
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Autism is the fastest growing developmental disorder in the world today. People with autism present with stereotypy and with social and communication impairments. Research has shown that autism has roots in many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological. These systems interact in complex and highly interdependent ways. Autism poses a rich test bed for systems biology modeling techniques. This paper reviews some of the systems disturbed in autism and suggests several systems biology research areas.
... Thus, irritability, social withdrawal, stereotypy, hyperactivity, or inappropriate speech were found more often in autistic children with frequent GI symptoms than in children without frequent GI symptoms, during a large-scale CHARGE study conducted between 2003 and 2011 [5]. Similarly, a recent study by Ferguson et al. [22] in a sample of 340 children and adolescents with ASD found internalizing symptoms such as anxiety symptoms, withdrawn behavior, and depression to predict GI complaints in older children (age [6][7][8][9][10][11][12][13][14][15][16][17][18], and externalizing problem behavior, such as aggressive behavior associated with nausea in children aged 2-5. Reviewing the data recorded in PubMed databases of the last 15 years regarding the correlations between the autistic cognitive deficiencies and GI abnormalities (Table 1), we have found some studies bringing relevant data in this matter, as presented in the table below. ...
Article
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Background and Objectives: Gastrointestinal disturbances have been frequently, but not unanimously, reported in autism spectrum disorder (ASD) individuals. Thus, digestive symptoms, such as constipation, diarrhea, abdominal bloating, and pain have been reported to correlate to the various maladaptive behaviors in ASD children, such as irritability, social withdrawal, stereotypy, hyperactivity, and even language regression. In this context, the present study provides an overview on the prevalence of the gastrointestinal (GI) disorders in ASD and the correlation between these and ASD symptoms and comorbidities and subsequently discusses the metabolic and microbiome factors underlying the effects of GI disorders in ASD. Materials and Methods: For our analysis of GI symptoms in children with ASD, we have searched peer-reviewed journals from 2005 to 2017 in PubMed databases that addressed the specificity of GI symptoms in ASD and included correlations of GI and ASD symptoms. The criteria for inclusion were clear quantitative mentioning of GI modifications, GI symptoms correlation with specific ASD symptoms or comorbidities, an appropriate methodology for defining ASD, and larger size samples. For this topic, only studies on human patients and original research were considered. A subsequent search in PubMed databases in journals from 2000 to 2017 we analyzed 13 articles on the mechanisms underlying the impact of GI dysfunctions in ASD, including gut microbial dysbiosis, immune reactivity, genetics, and altered neurotransmitters on the gut–brain axis. Results: In the 18 original research studies that we selected out of an initial 327 studies, despite the different methodology, a predominant 83% highlighted the increased prevalence of GI symptoms in ASD patients. Constipation was most frequently cited, appearing in 12 of the studies (80%), followed by diarrhea reports in eight studies (53%). The association between cognitive and behavioral deficits and GI disorders was suggested in certain groups of ASD individuals. Conclusion: The evidence presented so far by numerous studies seems to indicate that GI dysfunctions are of particular relevance in ASD, underlined by various abnormalities along the nervous connections between the central nervous system and the gut, such as impaired parasympathetic activity and increased endocrine stress response. Sufficiently large size samples and standardized methodology are required for future studies to clarify the complex interactions between GI disturbances and ASD symptoms.
... Russo and Andrews (2010) demonstrated that autistic children were almost seven times more likely to suffer gastro-oesophageal reflux, twice as likely to suffer chronic diarrhoea, three times as likely to suffer constipation, and nine times more likely to suffer irritable bowel syndrome (IBS), than their non-autistic siblings. Furthermore, Krigsman et al (2010) found ileal and/or colonic inflammation present in 74% of autistic children with gastrointestinal symptoms upon diagnostic ileocolonoscopy. Intestinal hyperpermeability has also been observed in autistic patients (Li 2005, Bihari 2006). ...
... In ASD, behavioral symptoms and impaired cognitive skills are often accompanied by various comorbidities, with GI symptoms being the most common and worsening GI symptoms aggravate behavioral symptoms [24,41,42,43]. ...
Article
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Introduction: In autism spectrum disorders (ASD), complex gene-environment interactions contribute to disease onset and progress. Given that gastro-intestinal dysfunctions are common in ASD, we postulated involvement of microbial dysbiosis in ASD and investigated, under a case-control design, the influence of DNA polymorphisms in the CLEC7A gene that encodes a pivotal fungal sensor, Dectin-1. Material and methods: DNAs from 478 ASD patients and 351 healthy controls (HC) were analyzed for the CLEC7A rs16910631G/A and rs2078178 A/G single nucleotide polymorphisms (SNPs). Differences in the distribution of allele, genotype and haplotype by Chi-square testing and nonparametric analysis by Kruskal-Wallis/Mann-Whitney tests, where appropriate, were performed. The free statistical package R.2.13 software was used for the statistical analysis. Results: We found that the CLEC7A rs2078178 G allele and GG genotype were more prevalent in HC as compared to ASD but failed to reach statistical significance for the latter (pc = 0.01, 0.06 respectively). However, after phenotype-based stratification, the CLEC7A rs2078178 G allele and GG genotype were found to be significantly more frequent in the Asperger group as compared to other ASD subsets (pc = 0.02, 0.01), a finding reinforced by haplotype analysis (rs2078178/rs16910631 G-G/G-G) (pc = 0.002). Further, intellectual quotient (IQ)-based stratification of ASD patients revealed that IQ values increase linearly along the CLEC7A rs2078178 AA, AG and GG genotypes (p = 0.05) and in a recessive manner (GG vs. AA+AG p = 0.02), further confirmed by haplotype distribution (CLEC7A rs2078178-16910631; A-G/A-G, A-G/G-G and G-G/G-G, p = 0.02, G-G/G-G vs. others, p = 0.01). Conclusion: Our data suggest that the genetic diversity of CLEC7A gene influences the ASD phenotype by behaving as a disease specifier and imply that the genetic control of innate immune response could determine the ASD phenotype.
... These findings indicate that the GI and immune problems encountered in autism are related to a range of behavioural and developmental abnormalities, and are associated with peripheral blood markers of inflammation, consistent with other reports 21,22,23,24,25 . Current scientific and medical knowledge regarding the clinical features and pathogenesis of ASDs calls for proper diagnosis and treatment 20 . ...
Conference Paper
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the course of autism: The science and intervention. OA Autism 2014 Jan 10;2(1):1. Meeting report Competing interests: None declared. Conflict of interests: None declared. All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript. All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure. Abstract Introduction The international conference, "Changing the Course of Autism: the Science and Intervention", organised by the UK charities Autism Treatment Trust (ATT) and Treating Autism (TA), provided a platform for a panel of international autism researchers and clinicians to present their latest research, current understanding of the pathologies associated with autism and interventions targeting these pathologies. The conference was held at the Royal College of Physicians of Edinburgh, in Scotland, on the 12 th and 13 th of June 2013. Meeting report The central topics discussed were: dysfunction of the immune and gastrointestinal systems, the role played by the environment, importance of diet and nutrition, the health-comorbidity issues associated with the condition and the impact of environment and medical problems on the brain. Implications for diagnosis and intervention were also discussed. Discussion Autism is a neurodevelopmental condition now affecting 1 child in 50 in the USA and 1 child in 66 in the UK. For the last two decades, the numbers of affected children have continued to rise world-wide, without any sign of reducing. Identifying the environmental and genetic factors at play is essential to develop effective remedial and preventive intervention strategies. The condition is commonly associated with a range of health problems with the most commonly encountered affecting the immune and digestive systems as well as metabolism. These can be identified through appropriate biomedical testing and clinical investigations. Treating these abnormalities can lead to significant improvements in the child's health, development, social communication skills and behaviour. The current state of scientific and medical understanding of the condition enables to propose a convincing paradigm to explain the pathologies and developmental features of the condition. Conclusion From the standpoint of public health and human rights, this framework makes it imperative to expand our understanding of how to choose the best treatment routes for affected individuals, and to implement these measures without delay.
... and "Although more research is necessary to uncover the etiology of autism, the hyperimmune response to measles virus might indicate virus reactivation that triggers a misguided humoral immune response in children with the disorder." Finally, far from being "discredited" and "flawed" as suggested in latest editorials published in the BMJ [7], the "Wakefield's hypothesis", which indicates that there is "a pattern of colitis and ileallymphoidnodular hyperplasia in children with developmental disorders" [3], is now supported by more independent research [8][9][10][11][12]. Notably, several respectable publications suggest that the principal findings of the Wakefield's 1998 Lancet study should not be discarded nor ignored. ...
Article
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There is a considerable body of experimental evidence suggesting potential efficacy of a diet devoid of gluten and casein in ameliorating some of the core and peripheral symptoms of autism spectrum conditions. Although phenotypic details of best- and non-responders to dietary change remain under investigation, the range of biological mechanisms implicated during intervention is growing. The question of how diet works remains unanswered. We discuss three prospective modes of action used alone and in combination to explain the effects of a gluten- and casein-free diet on autism spectrum conditions focussed on direct or co-morbid consequences of: i) gluten sensitive enteropathy or coeliac disease, ii) food allergy and/or atopic disease, and iii) underlying hyperpermeability of the gastrointestinal tract (leaky gut) and subsequent passage of biologically-active peptide and related species into the central nervous system. No single theory offers a universal explanation for the biological basis of dietary effectiveness despite individual associa- tions with various cases of autism. Impaired intestinal barrier function is a common denominator and represents a promising area for investigation. Furthermore, a number of key points derived from each model offer testable markers for experimental evaluation onwards to ascertaining potential responsiveness to such dietary intervention in autism.
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Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by difficulties in communication and by repetitive and stereotypic behaviors, as well as by social impairment, attention, cognitive, and learning defects. ASDs present in early childhood and their prevalence has increased significantly to 1/150 children. Despite a number of theories, the actual reasons for this increase are still not clear. There is no reliable screening test, and no definite pathogenesis or curative therapy. Consequently, there is a major gap hampering development of effective treatments. To review recent publications on ASDs pathogenesis and treatment with emphasis on neuroimmune processes and new therapeutic approaches. Mostly original papers (450) on epidemiology, possible pathogenesis or treatment of ASDs in Medline from 1990 to May 2009 were reviewed. All authors contributed to this review. Increased oxidative stress and immune dysregulation are present in ASDs. Mast-cell activation may contribute to gut-blood-brain barrier disruption and brain inflammation. No effective treatments have emerged. Well-designed clinical trials with nonpsychotropic drugs were few and ASD characteristics varied considerably, making conclusions difficult. Psychotropic drugs are often used for stereotypic and aggressive behaviors. Unique combinations with antioxidant and anti-inflammatory flavonoids hold promise. New potential translational research areas and possible treatments are suggested.
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Objectives: To investigate whether measles, mumps, and rubella (MMR) vaccination is associated with bowel problems and developmental regression in children with autism, looking for evidence of a "new variant" form of autism. Design: Population study with case note review linked to independently recorded vaccine data. Setting: Five health districts in north east London. Participants: 278 children with core autism and 195 with atypical autism, mainly identified from computerised disability registers and born between 1979 and 1998. Main outcome measures: Recorded bowel problems lasting at least three months, age of reported regression of the child's development where it was a feature, and relation of these to MMR vaccination. Results: The proportion of children with developmental regression (25% overall) or bowel symptoms (17%) did not change significantly (P value for trend 0.50 and 0.47, respectively) during the 20 years from 1979, a period which included the introduction of MMR vaccination in October 1988. No significant difference was found in rates of bowel problems or regression in children who received the MMR vaccine before their parents became concerned about their development (where MMR might have caused or triggered the autism with regression or bowel problem), compared with those who received it only after such concern and those who had not received the MMR vaccine. A possible association between non-specific bowel problems and regression in children with autism was seen but this was unrelated to MMR vaccination. Conclusions: These findings provide no support for an MMR associated "new variant" form of autism with developmental regression and bowel problems, and further evidence against involvement of MMR vaccine in the initiation of autism.
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We have reported lymphocytic colitis in children with regressive autism, with epithelial damage prominent. We now compare duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation and 18 histologically normal controls. Immunohistochemistry was performed for lymphocyte and epithelial lineage and functional markers. We determined the density of intraepithelial and lamina propria lymphocyte populations, and studied mucosal immunoglobulin and complement C1q localisation. Standard histopathology showed increased enterocyte and Paneth cell numbers in the autistic children. Immunohistochemistry demonstrated increased lymphocyte infiltration in both epithelium and lamina propria with upregulated crypt cell proliferation, compared to normal and cerebral palsy controls. Intraepithelial lymphocytes and lamina propria plasma cells were lower than in coeliac disease, but lamina propria T cell populations were higher and crypt proliferation similar. Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.
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To assess whether children with autism are more likely to have a history of gastrointestinal disorders than children without autism. Nested case-control study. UK General Practice Research Database. Children born after 1 January 1988 and registered with the General Practice Research Database within 6 months of birth. Chronic inflammation of the gastrointestinal tract, coeliac disease, food intolerance, and recurrent gastrointestinal symptoms recorded by the general practitioner. 9 of 96 (9%) children with a diagnosis of autism (cases) and 41 of 449 (9%) children without autism (matched controls) had a history of gastrointestinal disorders before the index date (the date of first recorded diagnosis of autism in the cases and the same date for controls). The estimated odds ratio for a history of gastrointestinal disorders among children with autism compared with children without autism was 1.0 (95% confidence interval 0.5 to 2.2). No evidence was found that children with autism were more likely than children without autism to have had defined gastrointestinal disorders at any time before their diagnosis of autism.
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A multi-site study of 351 children with Autism Spectrum Disorders (ASD) and 31 typically developing children used caregiver interviews to describe the children's early acquisition and loss of social-communication milestones. For the majority of children with ASD who had experienced a regression, pre-loss development was clearly atypical. Children who had lost skills also showed slightly poorer outcomes in verbal IQ and social reciprocity, a later mean age of onset of autistic symptoms, and more gastrointestinal symptoms than children with ASD and no regression. There was no evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination. The implications of these findings for the existence of a 'regressive phenotype' of ASD are discussed.
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Despite epidemiologic evidence to the contrary, claims of an association between measles-mumps-rubella vaccination and the development of autism have persisted. Such claims are based primarily on the identification of measles virus nucleic acids in tissues and body fluids by polymerase chain reaction. We sought to determine whether measles virus nucleic acids persist in children with autism spectrum disorder compared with control children. Peripheral blood mononuclear cells were isolated from 54 children with autism spectrum disorder and 34 developmentally normal children, and up to 4 real-time polymerase chain reaction assays and 2 nested polymerase chain reaction assays were performed. These assays targeted the nucleoprotein, fusion, and hemagglutinin genes of measles virus using previously published primer pairs with detection by SYBR green I. Our own real-time assay targeted the fusion gene using novel primers and an internal fluorescent probe. Positive reactions were evaluated rigorously, and amplicons were sequenced. Finally, anti-measles antibody titers were measured by enzyme immunoassay. The real-time assays based on previously published primers gave rise to a large number of positive reactions in both autism spectrum disorder and control samples. Almost all of the positive reactions in these assays were eliminated by evaluation of melting curves and amplicon band size. The amplicons for the remaining positive reactions were cloned and sequenced. No sample from either autism spectrum disorder or control groups was found to contain nucleic acids from any measles virus gene. In the nested polymerase chain reaction and in-house assays, none of the samples yielded positive results. Furthermore, there was no difference in anti-measles antibody titers between the autism and control groups. There is no evidence of measles virus persistence in the peripheral blood mononuclear cells of children with autism spectrum disorder.
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Objectives: To assess whether children with autism are more likely to have a history of gastrointestinal disorders than children without autism. Design: Nested case-control study. Setting: UK General Practice Research Database. Subjects: Children born after 1 January 1988 and registered with the General Practice Research Database within 6 months of birth. Outcome measures: Chronic inflammation of the gastrointestinal tract, coeliac disease, food intolerance, and recurrent gastrointestinal symptoms recorded by the general practitioner. Results: 9 of 96 (9%) children with a diagnosis of autism (cases) and 41 of 449 (9%) children without autism (matched controls) had a history of gastrointestinal disorders before the index date (the date of first recorded diagnosis of autism in the cases and the same date for controls). The estimated odds ratio for a history of gastrointestinal disorders among children with autism compared with children without autism was 1.0 (95% confidence interval 0.5 to 2.2). Conclusions: No evidence was found that children with autism were more likely than children without autism to have had defined gastrointestinal disorders at any time before their diagnosis of autism.
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Few studies have compared gastrointestinal problems in children with an autism spectrum disorder with and without a history of language regression. A cross-sectional study was conducted with structured interviews in 100 children with autism spectrum disorder, using a gastrointestinal questionnaire and a familial autoimmune questionnaire. By parental report, children with language regression more frequently exhibited an abnormal stool pattern (40% vs 12%, P = 0.006) and had an increased family history of celiac disease or inflammatory bowel disease (24% vs 0%, P = 0.001) and of rheumatoid arthritis (30% vs 11%, P = 0.03). Among 35 children with a family history of autoimmune disease, an abnormal stool pattern was reported more frequently in those with language regression (78% vs 15%, P = 0.001) than in those without. An association was observed between children with language regression, a family history of autoimmune disease, and gastrointestinal symptoms. Additional studies are needed to examine a possible shared autoimmune process.
Article
In this retrospective analysis we searched for a constellation of signs or symptoms attributable to childhood lymphonodular hyperplasia (LNH). Of 147 children with documented LNH reviewed, 43% had lesions in the small bowel, and 57% in the large bowel. Children in this study presented with complaints of abdominal pain (58%) and bright red blood per rectum (32%). Physical examination revealed little except right lower quadrant (RLQ) abdominal tenderness and "fullness" in 35%. The pain was periumbilical, dull-cramping, rarely acute, and nonradiating. The hematochezia was most commonly streaky red in mucoid strands adhering to the stools, with no associated tenesmus. Three clinical patterns emerged: (a) Under 1 year of age most patients were male, with painless bleeding and pancolonic LNH. (b) Between 2 and 6 years, although the LNH was predominantly colonic, pain and bleeding occurred equally. (c) From 7 years old on, the main symptom was abdominal pain, but LNH distribution was nearly equal between the small bowel and the colon. To date, our long-term follow-up of the children with isolated LNH has revealed no sequelae.
Flexible endoscopy, performed after oral bowel preparation and under moderate intravenous sedation, proves to be well tolerated, safe and highly effective in the diagnosis and management of children with IBD. At St Bartholomew's Hospital it is performed as the investigation of first choice, on the basis that it supplies colour documentation, histopathological and (where relevant) bacteriological evidence, which achieves certain confirmation or exclusion in almost every case and in the shortest possible time. Biopsies must always be taken, as mucosa of normal appearance can show either microscopic ulcerative colitis or Crohn's disease. When there are the characteristic 'aphthoid' ulcers, visual diagnosis of Crohn's disease is reasonably certain, particularly in early-stage disease, although amoebic and other infective causes of colitis can give misleadingly similar appearances. The endoscopist can usually inspect (and almost always biopsy) the terminal ileum, and can expect many children to show the prominent 'nodular lymphoid hyperplasia' which is essentially a normal finding-though sometimes misdiagnosed radiologically as being Crohn's deformity. However, it is important that radiological assessment by barium follow-through complements colonoscopy in view of the not infrequent cases of intestinal Crohn's disease in children where the proximal small intestine is involved, even if the colon and terminal ileum are spared.
Article
Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension. Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function. Seventy-five percent of the autistic children (27/36) had an increased pancreatico-biliary fluid output after intravenous secretin administration. Nineteen of the 21 patients with diarrhea had significantly higher fluid output than those without diarrhea. Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggests an upregulation of secretin receptors in the pancreas and liver. Further studies are required to determine the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder.
Article
We report a child who developed autoimmune lymphoproliferative syndrome (ALPS) secondary to a heterozygous dominant negative mutation in the death domain of the Fas receptor. Previously developmentally normal, he had symptoms of autism with rapid regression in developmental milestones coincident with the onset of lymphoproliferation and autoimmune hemolytic anemia. Low-dose steroid therapy induced early and complete remission in the ALPS phenotype. There was subjective improvement, followed by objective improvement in speech and developmental milestones. We propose that autism may be part of the autoimmune disease spectrum of ALPS in this child, and this case represents a novel manifestation and target organ involvement in this disease.
Article
Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0-3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2-13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely. Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001). A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.
Article
We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.
Article
We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.
Article
To discover the prevalence and significance of lymphonodular hyperplasia (LNH) of the lower gastrointestinal tract, the authors did a retrospective analysis of a consecutive series of children using colonoscopy to evaluate persistent and severe gastrointestinal symptoms. The authors also sought to discover in more detail how often subjects with LNH of the terminal ileum (TI) or colon show an association with food allergy (FA). The analysis included a consecutive series of 140 children evaluated at the Oulu University Hospital using colonoscopy, which extended to the TI in 74 of these children. A total of 102 patients underwent gastroduodenoscopy. The disease category was assessed using endoscopic, histopathologic, and clinical information. To diagnose FA, a masked or an open food challenge was administered to all patients who aroused any suspicion of food-related exacerbation of symptoms. Of 140 patients, LNH of the colon was diagnosed in 46 subjects, 9 of 38 patients had colitis, 1 of 8 patients had Crohn disease, and 36 of the remaining 94 subjects did not have colitis. Twelve patients of the 22 with LNH of the colon (55%) showed concomitant LNH on the bulb of the duodenum. Lymphonodular hyperplasia of the TI was diagnosed in 53 of the 74 subjects in whom TI could be visualized. It was seen in most patients without colitis (80%), in one half the subjects with colitis (48%), and in one quarter of those with Crohn disease (25%). Among the whole study group 37 (26%) could be defined as having FA. It was more prevalent in patients with (52%) than in those without (13%) LNH of the colon ( P < 0.001). The presence of LNH in the TI also showed some association with FA ( P < 0.05), but less than did LNH of the colon. We consider LNH on the mucosa of the colon or TI common but not an innocent bystander. Significantly related to a diagnosis of gastrointestinal FA in this study, it is an expression of mucosal immune response. If detected on the colon, FA should be considered, whereas if present in TI, it may be related to FA but also to a variety of other immunologically active disease states.
Article
Autistic disorder is a pervasive developmental disorder manifested in the first 3 years of life by dysfunction in social interaction and communication. Many efforts have been made to explore the biologic basis of this disorder, but the etiology remains unknown. Recent publications describing upper gastrointestinal abnormalities and ileocolitis have focused attention on gastrointestinal function and morphology in these children. High prevalence of histologic abnormalities in the esophagus, stomach, small intestine and colon, and dysfunction of liver conjugation capacity and intestinal permeability were reported. Three surveys conducted in the United States described high prevalence of gastrointestinal symptoms in children with autistic disorder. Treatment of the digestive problems may have positive effects on their behavior.
Article
We could identify no report that describes the prevalence of gastrointestinal disorders in a representative group of children with a diagnosis of autism compared with appropriate controls. Thus, we found no evidence upon which to base a confident conclusion as to whether gastrointestinal symptoms are more common in children with than without autism. However, the frequency of gastrointestinal symptoms observed in population-based samples of autistic children indicate that gastrointestinal problems are not nearly as common in children with autism as reports from pediatric gastroenterology clinics suggest.
Article
The purpose of this study was to estimate the prevalence of chronic gastrointestinal symptoms in a general population of children with autism or autistic spectrum disorder (ASD). The study site was a clinic specializing in ASD in a large pediatric medical center serving a 10 county area in the midwestern USA. In a sample of 137 children, age 24-96 months, classified as having autism or ASD by the Autism Diagnostic Observation Schedule-Generic, 24 percent had a history of at least one chronic gastrointestinal symptom. The most common symptom was diarrhea, which occurred in 17 percent. There was no association between chronic gastrointestinal symptoms and a history of developmental regression. The potential phenotypic association between autism and gastrointestinal symptoms is discussed.
Article
Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepithelial lymphocytes in surface, foveolar and glandular epithelium. Proliferation of foveolar epithelium was similarly increased in autism, Crohn's disease and H. pylori compared to controls. A striking finding, seen only in 20/25 autistic children, was colocalized deposition of IgG and C1q on the subepithelial basement membrane and the surface epithelium. These findings demonstrate a focal CD8-dominated gastritis in autistic children, with novel features. The lesion is distinct from the recently recognized focal gastritis of Crohn's disease, which is not CD8-dominated. As in the small intestine, there is epithelial deposition of IgG.
Article
To investigate the incidence of cow's milk allergy as evidenced by milk challenge and the findings of endoscopic and immunohistochemical examinations in children with chronic and refractory constipation. Thirty-five study subjects (mean age, 8.3 +/- 3.3 years; range, 3-15 years; 17 girls) and 15 control subjects (mean age, 11.7 +/- 3.2 years; range, 2-15 years; 9 girls) were studied by colonoscopy and a 4-week cow's milk elimination and challenge. Lymphoid nodular hyperplasia was the most prominent endoscopic finding in half of the subjects (46%), mostly occurring patchily in the transverse colon. Histologic findings other than lymphoid accumulation and mildly increased density of eosinophils were few. During the milk elimination and with supportive medication, 83% of subjects remitted. Constipation and/or other gastrointestinal or skin symptoms relapsed only in one third (34%) during the cow's milk challenge, these having significantly higher densities of intraepithelial gammadelta + T cells ( P <.001) in the biopsy samples of the terminal ileum as compared with the control subjects. We were able to find formal evidence for the presence of cow's milk allergy in children with chronic constipation.
Article
Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)–1 and tumor growth factor–β1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain. Ann Neurol 2005 An Erratum has been published for this article in Ann Neurol 57: 304, 2005.
Article
A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFα, IL-2, IL-4, IFNγ, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p+TNFα+ cells in ASD children was significantly greater compared with noninflamed controls (p+IL-2+ and CD3+IFNγ+, and epithelial CD3+IL-4+ cells were more numerous in ASD children than in noninflamed controls (p+IL-10+ cells were fewer in ASD children than in noninflamed controls (p+TNFα+ and CD3+IFNγ+ were more frequent in ASD children than in noninflamed controls (p+IL-10+ cells were fewer in ASD children than in nondisease controls (p+TNFα+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.
Article
Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities.
Article
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
Article
This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.
Article
The prevalence of pervasive developmental disorders has increased in recent years. Links with the measles component of the measles-mumps-rubella vaccine and the cumulative exposure to thimerosal through other vaccines have been postulated. The purpose of this work was to estimate the pervasive developmental disorder prevalence in Montreal, Canada, in cohorts born from 1987 to 1998 and evaluate the relationship of trends in pervasive developmental disorder rates with: (1) changes in cumulative exposure to ethylmercury (thimerosal) occurring through modifications in the immunization schedule of young children and (2) trends in measles-mumps-rubella vaccination use rates and the introduction of a 2-measles-mumps-rubella dosing schedule during the study period. We surveyed 27749 children born from 1987 to 1998 attending 55 schools from the largest Anglophone school board. Children with pervasive developmental disorders were identified by a special needs team. The cumulative exposure by age 2 years to thimerosal was calculated for 1987-1998 birth cohorts. Ethylmercury exposure ranged from medium (100-125 microg) from 1987 to 1991 to high (200-225 microg) from 1992 to 1995 to nil from 1996 onwards when thimerosal was entirely discontinued. Measles-mumps-rubella coverage for each birth cohort was estimated through surveys of vaccination rates. The immunization schedule included a measles-mumps-rubella single dose at 12 months of age up to 1995, and a second measles-mumps-rubella dose at 18 months of age was added on after 1996. We found 180 children (82.8% males) with a pervasive developmental disorder diagnosis who attended the surveyed schools, yielding a prevalence for pervasive developmental disorder of 64.9 per 10000. The prevalence for specific pervasive developmental disorder subtypes were, for autistic disorder: 21.6 of 10000; for pervasive developmental disorder not otherwise specified: 32.8 of 10000; and for Asperger syndrome: 10.1 of 10000. A statistically significant linear increase in pervasive developmental disorder prevalence was noted during the study period. The prevalence of pervasive developmental disorder in thimerosal-free birth cohorts was significantly higher than that in thimerosal-exposed cohorts (82.7 of 10000 vs 59.5 of 10000). Using logistic regression models of the prevalence data, we found no significant effect of thimerosal exposure used either as a continuous or a categorical variable. Thus, thimerosal exposure was unrelated to the increasing trend in pervasive developmental disorder prevalence. These results were robust when additional analyses were performed to address possible limitations because of the ecological nature of the data and to evaluate potential effects of misclassification on exposure or diagnosis. Measles-mumps-rubella vaccination coverage averaged 93% during the study interval with a statistically significant decreasing trend from 96.1% in the older birth cohorts (1988-89) to approximately 92.4% in younger birth cohorts (1996-1998). Thus, pervasive developmental disorder rates significantly increased when measles-mumps-rubella vaccination uptake rates significantly decreased. In addition, pervasive developmental disorder prevalence increased at the same rate before and after the introduction in 1996 of the second measles-mumps-rubella dose, suggesting no increased risk of pervasive developmental disorder associated with a 2-measles-mumps-rubella dosing schedule before age 2 years. Results held true when additional analyses were performed to test for the potential effects of misclassification on exposure or diagnostic status. Thus, no relationship was found between pervasive developmental disorder rates and 1- or 2-dose measles-mumps-rubella immunization schedule. The prevalence of pervasive developmental disorder in Montreal was high, increasing in recent birth cohorts as found in most countries. Factors accounting for the increase include a broadening of diagnostic concepts and criteria, increased awareness and, therefore, better identification of children with pervasive developmental disorders in communities and epidemiologic surveys, and improved access to services. The findings ruled out an association between pervasive developmental disorder and either high levels of ethylmercury exposure comparable with those experienced in the United States in the 1990s or 1- or 2-dose measles-mumps-rubella vaccinations.
Metabolic markers and gastrointestinal symptoms in children with autism and related disorders
  • R Melmed
  • C Schneider
  • R Fabes
  • L Phillips
  • K Reichelt
Melmed R, Schneider C, Fabes R, Phillips L, Reichelt K. Metabolic markers and gastrointestinal symptoms in children with autism and related disorders. Journal of Pediatric Gastroenterology and Nutrition. 2000;31(Suppl 2): S31-2.
Endoscopic and Histological Characteristics of the Digestive Mucosa in Autistic Children with gastro-Intestinal Symptoms: A Preliminary Report
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  • K Lopez
  • M Martinez
Gonzalez L, Lopez K, Martinez M, et al. Endoscopic and Histological Characteristics of the Digestive Mucosa in Autistic Children with gastro-Intestinal Symptoms: A Preliminary Report. GEN Suplemento Especial de Pediatria. 2005;1:41-7.
Prevalence and links with immunizations
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  • R Zakarian
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  • D Mclean-Heywood
Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D. Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and links with immunizations. Pediatrics. 2006;118(1):139–50.
Intestinal lymphonodular hyperplasia of childhood: Patterns of presentation
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  • C Leftridge
Colon A, DoPalma J, Leftridge C. Intestinal lymphonodular hyperplasia of childhood: Patterns of presentation. Journal of Clinical Gastroenterology. 1991;13(2):163-6.