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Biological and other studies which lend credence to the notion that MMRand/or autism may be related to gastrointestinal disorders.

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Biological and other studies which lend credence to the notion that MMR and/or autism may be related to gastrointestinal disorders.

 

Neuropsychobiology 2002 Jan;45(1):1-6

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Activation of the inflammatory response system in autism.

Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M.

University Center of Child and Adolescent Psychiatry, Antwerp, Belgium.

Background/Aim: There is now some evidence that autism may be accompanied by abnormalities in the inflammatory response system (IRS). Products of the IRS, such as proinflammatory cytokines, may induce some of the behavioral symptoms of autism, such as social withdrawal, resistance to novelty and sleep disturbances. The main aim of the present study was to examine whether autism is accompanied by an activation of the IRS. Methods: We measured the production of interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA), interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by whole blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R) and IL-1RA. Results: This study showed a significantly increased production of IFN-gamma and IL-1RA and a trend toward a significantly increased production of IL-6 and TNF-alpha by whole blood of autistic children. There were no significant differences in the serum concentrations of IL-6, IL-2R and IL-1RA between autistic and normal children. Conclusions: These results suggest that autism may be accompanied by an activation of the monocytic (increased IL-1RA) and Th-1-like (increased IFN-gamma) arm of the IRS. It is hypothesized that increased production of proinflammatory cytokines could play a role in the pathophysiology of autism. Copyright 2002 S. Karger AG, Basel

PMID: 11803234 [PubMed - in process]

Med Sci Monit 2002 Sep-Oct;8(1):BR22-6

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Use of secretin in the treatment of childhood autism.

Kaminska B, Czaja M, Kozielska E, Mazur E, Korzon M.

Department and Clinic of Pediatrics, Gastroenterology and Pediatric Oncology, Medical University, Gdansk, Poland.

The paper presents current views concerning childhood autism. The authors present the concepts of etiology of this disorder, emphasizing the role of negative psychical stimuli in early childhood and the role of mother's contact with the child. Organic factors, including genetic background, developmental abnormalities of the nervous system, teratogenic factors and perinatal traumas are also taken into consideration. The role of metabolic factors and enterohormones, particularly those belonging to the secretin group and their effect on the function of the gastrointestinal tract and central nervous system is emphasized. We discuss signs which may be indicative of first symptoms of autism in different age groups. A typical symptom of autism is no development of speech, observed from infancy, taking the form of complete mutism at later stages. It has been emphasized that most pathologic symptoms result from altered perception of external stimuli, which arouse fear and anxiety. Autistic patients may suffer from gastrointestinal tract disturbances such as abdominal pains and diarrhea. Methods used hitherto in the therapy of childhood autism, mainly by psychologists and psychiatrists, as well as some attempts of pharmacological treatment, are presented. The structure and function of secretin, as well as its effects on the motor and secretory function of the stomach and the exocrine function of the pancreas are discussed. The role of secretin in diagnostic tests, among others in the diagnosis of gastrinoma, is emphasized. We also present the history of the application of secretin in the therapy of childhood autism.

PMID: 11782669 [PubMed - in process]

J Child Neurol 2001 May;16(5):357-63

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A study of novel polymorphisms in the upstream region of vasoactive intestinal peptide receptor type 2 gene in autism.

Asano E, Kuivaniemi H, Huq AH, Tromp G, Behen M, Rothermel R, Herron J, Chugani DC.

Department of Pediatrics, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit 48201, USA.

We investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene as a candidate gene for autism. We searched for mutations in the VIPR2 gene in autistic individuals, and 10 novel polymorphisms were identified. Three polymorphisms in the upstream region were studied in detail, and there was no significant difference in the frequencies between the autistic group (n = 14) and unrelated controls (n = 52). The distribution of the genotypes in two of the three polymorphisms differed somewhat between autistic subjects with gastrointestinal problems and those without. Moreover, there was a trend showing a correlation between the genotypes for the third polymorphism and the severity of stereotypical behavior as ranked by the Gilliam Autism Rating Scale. These preliminary results suggest that VIPR2 may have a role in gastrointestinal symptoms and stereotypical behaviors in autism, although a larger collection of samples suitable for transmission disequilibrium tests is necessary to validate the results.

PMID: 11392521 [PubMed - indexed for MEDLINE]

J Pediatr 2001 Mar;138(3):366-72

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Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism.

Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH.

University Department of Paediatric Gastroenterology, the Inflammatory Bowel Diseases Study Group, Royal Free and University College School of Medicine, London, United Kingdom.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

PMID: 11241044 [PubMed - indexed for MEDLINE]

Med Hypotheses 2001 Aug;57(2):186-91

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Application of genomeceuticals to the molecular and immunological aspects of autism.

Brudnak MA.

MAK Wood Inc., Thiensville, Wisconsin 53024, USA. makwood@earthlink.net

Autism is a developmental disease affecting as many as 1 in 300 children and is often characterized as a mental disorder originating in infancy that is associated with self-absorption, inability to interact socially, behavior, and language dysfunction (e.g. echolalia). Current theories indicate an important role of diet in the development of disease. It is thought that, as a result of maldigestion of casein and gluten, opioid-type peptides, or exorphins, are produced. Additionally, because of the time-frame of development of the disease, there has been an association with childhood vaccination. Consequently, prevailing therapies attempt to address these causes in one, or a combination, of three ways: diet restriction (removing casein and gluten); supplementation with exogenous enzymes; and probiotic bacteria. Until recently, none of the therapies addressed the molecular mechanisms that may be at work in the development and progression of autism. This paper presents potential molecular and cellular mechanism related to autism as well as discusses their application to the treatment of the disease through the application of genomeceuticals. Additionally, a link between developmentally associated aberrant immune and inflammatory responses, and autism is suggested and explored. Copyright 2001 Harcourt Publishers Ltd.

PMID: 11461171 [PubMed - indexed for MEDLINE]

Dig Dis Sci 2000 Apr;45(4):723-9

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Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism.

Kawashima H, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A.

Department of Paediatrics, Tokyo Medical University, Japan.

It has been reported that measles virus may be present in the intestine of patients with Crohn's disease. Additionally, a new syndrome has been reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is not known whether the virus, if confirmed to be present in these patients, derives from either wild strains or vaccine strains. In order to characterize the strains that may be present, we have carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn's disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. As controls, we examined healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected to nested PCR for detection of specific regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples were sequenced directly, in nucleotides 8393-8676 (H region) or 5325-5465 (from noncoding F to coding F region). One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.

PMID: 10759242 [PubMed - indexed for MEDLINE]

Am J Gastroenterol 2000 Sep;95(9):2285-95

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Comment in:

·         Am J Gastroenterol. 2000 Sep;95(9):2154-6.


Enterocolitis in children with developmental disorders.

Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Berelowitz M, Walker-Smith JA.

University Department of Medicine, Royal Free and University College Medical School, London, United Kingdom.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.

PMID: 11007230 [PubMed - indexed for MEDLINE]

J Pediatr 1999 Nov;135(5):559-63

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Comment in:

·         J Pediatr. 1999 Nov;135(5):533-5.

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Gastrointestinal abnormalities in children with autistic disorder.

Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT.

Department of Pediatrics, University of Maryland School of Medicine, Baltimore, USA.

OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

PMID: 10547242 [PubMed - indexed for MEDLINE]

 

Lancet 1998 Feb 28;351(9103):637-41

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Comment in:

·         Lancet. 1998 Feb 28;351(9103):611-2.

·         Lancet. 1998 Jul 18;352(9123):234-5.

·         Lancet. 1998 Mar 21;351(9106):905-6; discussion 908-9.

·         Lancet. 1998 Mar 21;351(9106):906-7; discussion 908-9.

·         Lancet. 1998 Mar 21;351(9106):906; discussion 908-9.

·         Lancet. 1998 Mar 21;351(9106):907-8; discussion 908-9.

·         Lancet. 1998 Mar 21;351(9106):907; discussion 908-9.

·         Lancet. 1998 Mar 21;351(9106):907; discussion 908-9.

·         Lancet. 1998 Mar 21;351(9106);905; discussion 908-9

·         Lancet. 1998 May 2;351(9112):1355-6; discussion 1356.

·         Lancet. 1998 May 2;351(9112):1355; discussion 1356.

·         Lancet. 1998 May 2;351(9112):1355; discussion 1356.

·         Lancet. 1998 May 2;351(9112):1356.

·         Lancet. 1998 May 2;351(9112):1357.

·         Lancet. 1998 May 2;351(9112):1357.

·         Lancet. 1998 May 2;351(9112):1357-8.

·         Lancet. 1998 May 2;351(9112);1358

·         Lancet. 2000 Jul 8;356(9224):160-1.

·         Lancet. 2000 Jul 8;356(9224):161.

·         Lancet. 2000 Jul 8;356(9224):161-2.

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Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA.

Inflammatory Bowel Disease Study Group, University Department of Medicine, Royal Free Hospital and School of Medicine, London, UK.

BACKGROUND: We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder. METHODS: 12 children (mean age 6 years [range 3-10], 11 boys) were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, and immunological profiles were examined. FINDINGS: Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioural disorders included autism (nine), disintegrative psychosis (one), and possible postviral or vaccinal encephalitis (two). There were no focal neurological abnormalities and MRI and EEG tests were normal. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age-matched controls (p=0.003), low haemoglobin in four children, and a low serum IgA in four children. INTERPRETATION: We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.

PMID: 9500320 [PubMed - indexed for MEDLINE]

J Assoc Acad Minor Phys 1998;9(1):9-15

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Improved social and language skills after secretin administration in patients with autistic spectrum disorders.

Horvath K, Stefanatos G, Sokolski KN, Wachtel R, Nabors L, Tildon JT.

Department of Pediatrics, University of Maryland School of Medicine, Maryland, USA.

We report three children with autistic spectrum disorders who underwent upper gastrointestinal endoscopy and intravenous administration of secretin to stimulate pancreaticobiliary secretion. All three had an increased pancreaticobiliary secretory response when compared with nonautistic patients (7.5 to 10 mL/min versus 1 to 2 mL/min). Within 5 weeks of the secretin infusion, a significant amelioration of the children's gastrointestinal symptoms was observed, as was a dramatic improvement in their behavior, manifested by improved eye contact, alertness, and expansion of expressive language. These clinical observations suggest an association between gastrointestinal and brain function in patients with autistic behavior.

PMID: 9585670 [PubMed - indexed for MEDLINE]

Acta Paediatr 1996 Sep;85(9):1076-9

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Abnormal intestinal permeability in children with autism.

D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O.

Institute of Pediatrics, La Sapienza University of Rome, Italy.

We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. Compared to the controls, these nine patients showed a similar mean mannitol recovery, but a significantly higher mean lactulose recovery (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities.

PMID: 8888921 [PubMed - indexed for MEDLINE]

 

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