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enterocolitis and autistic spectrum disorders

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Colitis is one of the common comorbid conditions with autism. The general view among gastroenterologists is that this is not different in type from colitis in other people and conditions. Autistic enterocolitis is the distinguishing name first used by Dr. Andrew Wakefield for this. He regards it as peculiar to autism. Up to fifty percent of children with autistic spectrum disorders experience persistent gastrointestinal problems, with mild to moderate degrees of inflammation in both the upper and lower intestinal tract.[1] The term is starting to come into wider use as other researchers examine enterocolitis in autism. The presence of lymphoid nodular hyperplasia and colitis in autistic children, termed "autistic enterocolitis", with various gastrointestinal symptoms investigated a number of years after immunisation is not in doubt [2].

Background[edit]

Until the 1970s, autism was considered a very rare condition, but it is diagnosed much more often nowadays, whether due to increased diagnostic vigilance by doctors, changes of diagnostic categories, or an actual increase in incidence. Estimates of the percentage of late-onset autism cases range from 20% to 80%, with the lower percentage reported by sources including the British Medical Journal as not having changed in recent years.[3] Wakefield, however, contends that a regressive syndrome "may reflect a subset of children with developmental disorders with distinct etiological and clinical features."[4]

Despite others describing common bowel features, there have been no peer reviewed studies yet published, as of 2006, corroborating the existence of autistic enterocolitis; other studies have explicitly denied its existence.[5] [6]. Thus, it is not generally accepted that the types of colitis found in autism are unique to autism.[7]To date, no adequately controlled study has been published comparing the gut pathology of autistic and non-autistic children.

The Lancet study[edit]

When Wakefield and his colleagues first reported in 1998 a possible association between autistic regression, IBD, and MMR vaccines in the Lancet, they evaluated a dozen children with pervasive developmental disorders, apparent developmental regression, and intestinal symptoms, referred to the Royal Free Hospital.

Onset of behavioral symptoms was linked to recent (within two weeks) immunization with MMR vaccine in six of the children diagnosed with autism. An autism diagnosis was not linked to MMR vaccination, or the link was tenuous, in the remaining six. The most consistent finding was lymphoid nodular hyperplasia of the terminal ileum in nine of the children. This feature has also been reported in non-autistic children.[8] A variety of colonic and rectal mucosal abnormalities was seen in eight cases. Biopsies of the ileum showed reactive lymphoid follicular hyperplasia in seven. Biopsies of the colon showed a diffuse mononuclear cell infiltrate in six.

Wakefield and his colleagues say they have described features of regressive autistism with bowel disorders, or autistic enterocolitis, although these findings have been questioned:

  • A vast majority of the children have chronic swelling of the lymphoid tissue lining the intestines, particularly near where the small and large intestines meet, and chronic inflammation of the large intestine, producing abdominal pain and alternating constipation and diarrhea.
  • Affected children exhibit impaired cellular immunity to common recall antigens; the numbers of circulating white blood cells are low.
  • A specific measles protein signal has been detected in immune cells of inflamed lymphoid tissue; another such indication is that affected children often have raised levels of measles-specific antibodies in their bloodstream.
  • A loss of speech and language accompanied by symptoms of excessive thirst, bowel disturbances, self-injury, and a self-limited diet associated with cravings for particular foods.
  • Allergies, food intolerances, and recurrent upper respiratory tract infections unresponsive to conventional treatments are also prominent features of this sub-group.

IBD and regressive autism[edit]

Although also characterized by intestinal lymphoid tissue disease activity, the primary symptoms and diagnostic criteria of the syndrome are behavioral and developmental. Age, dose of infection and the interaction of two or more viruses are claimed to be factors leading to regressive autism. According to Wakefield, "it is possible that the emergence of this new type of autism is related to a different pattern of exposure to environmental triggers."

Abnormal metabolites of macro-nutriments have been found in the urine of autistic children, suggesting an incomplete or insufficient intra-intestinal digestion.[9]

IBD has emerged during the last century as an increasingly common diagnosis, while Crohn's disease has become the dominant IBD phenotype. In a long term study of a group of children born in Great Britain during 1970, details of acute childhood infections were collected. Childhood exposure to measles and mumps within a twelve month period was found to be a significant risk for both later Crohn's disease and ulcerative colitis, although critics have questioned the figures.[10]

In contrast to regressive autism, development is abnormal from birth, or very soon after, in the classical condition. The classical features of autism are absent for a high proportion of children. The emerging behavioral phenotype is of regression in a previously developmentally normal child.


Potential link to MMR vaccinations[edit]

Central to one of the most acrimonious controversies in autism, Wakefield has hypothesized that autistic enterocolitis is an emergent IBD phenotype that follows from the increased incidence of low-dose compound viral exposures, i.e., exposures associated with the vast increase in the number of vaccinations given to children during a period when their immune systems are rapidly developing. Specifically, Wakefield asserts the autistic enterocolitis syndrome involves increased permeation of neurotoxic substances across the blood-brain barrier during a vulnerable part of brain development, leading to regressive autism. Other research, however, rejects this [11].


Dietary intervention[edit]

Wakefield and his associates at Thoughtful House, an Austin, Texas based autism treatment, research and education center, perform dietary intervention for children with celiac disease, Crohn's disease, and autism and related childhood developmental disorders. Gastrointestinal problems have long been described in association with developmental disorders, and can be difficult to resolve in children with communication and behavioral problems [12].

Dietary intervention has gained attention as a possible means for treating the behavioral pathology of autism, augmenting behavioral interventions. Dietary exclusion of opioid substrate, including grains and milk, is one of the therapeutic approaches. It is claimed that many patients with autism experience chronic diarrhea or constipation, increased intestinal permeability, chronic IBD, and sensitivity to dietary proteins, most frequently gluten and casein, all of which are affected by diet.

"Retraction of an interpretation"[edit]

The Lancet paper has been widely cited as an impetus for concerns regarding the MMR vaccine being a cause of Autism. Wakefield gave interviews after the publication of the paper, including on 60 minutes where he raised concerns regarding administraiton of the MMR vaccine. In the Lancet paper, Wakefield and his co-authors said on the issue:

"We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described. Virological studies are underway that may help to resolve this issue"

In 2004, ten of the authors issued a statement in the Lancet (2004;363:750) entitled "Retraction of an interpretation". In it the authors recommended first that work continue into their new discovery of intestinal problems of autistic children, saying:

"The main thrust of this paper was the first description of an unexpected intestinal lesion in the children reported. Further evidence has been forthcoming in studies from the Royal Free Centre for Paediatric Gastroenterology and other groups to support and extend these findings. While much uncertainty remains about the nature of these changes, we believe it important that such work continues, as autistic children can potentially be helped by recognition and treatment of gastrointestinal problems."

The authors went on to say that they retracted the "interpretation placed upon" their findings but the statement did not retract the findings themselves:

"We wish to make it clear that in this paper no causal link was established between MMR vaccine and autism as the data were insufficient. However, the possibility of such a link was raised and consequent events have had major implications for public health. In view of this, we consider now is the appropriate time that we should together formally retract the interpretation placed upon these findings in the paper, according to precedent."

Some view the decision as a means whereby the co-authors could dissociate themselves from the implication that there was a conclusion that there was any association at all. Others view it as an endeavour to disassociate the primary research into intestinal problems from the MMR/autism controversy so that original work could continue for the benefit of autistic children. Despite the statement the study findings still are always referenced in studies that test the hypothesis of MMR being a cause of autism.

The editor of the Lancet and the authors were taken aback by the furor that arose and the attention the paper received after publication.

Just before the retraction of an interpretation, criticism arose over the fact that the Royal Free Hospital had received £55 000,00 in August 1996 from lawyers preparing to sue MMR manufacturers for support of Dr. Wakefield's research. Later, Wakefield asserted that the donation was to fund a second clinical study; some of the children involved were subjects in both studies.[13]

Wakefield currently faces disciplinary charges, stirred by criticism of his warnings about the safety of the MMR vaccine, before the General Medical Council over the conduct of his research.[14]

Although Wakefield's initial study describing the syndrome has not been corroborated by similar studies around the world, lay newspaper articles by anti-vaccine campaigners frequently claim that is has been [15]. These claims, which are never accompanied by references to the alleged confirmatory studies, have created a great deal of confusion, and usually appear in a context of a campaign against the MMR vaccine.

In October 2005, the Cochrane Library published its analysis of 31 "high quality" medical studies which concluded no link could be found between the MMR vaccine and bowel disease, autism or other pervasive developmental disorders. To increase the rigor of the meta-analysis, the criteria of the meta-analysis excluded smaller studies and studies that had the potential for bias. Wakefield's work was specifically excluded in the meta-analysis due to small sample size. With regard to the vaccine, Cochrane said that its survey of research "strongly supports its use."[16]

Wakefield's Research - In his own words - Lecture Presentation - Carnegie Mellon University[edit]

As the executive director of the Thoughtful House Center for Children, Wakefield was invited to Carnegie Mellon University, in Pittsburgh, Pennsylvania to make a lecture presentation on November 17, 2005. Entitled The Seat of the Soul: The Origins of the Autism Epidemic, Wakefield's lecture presented his research into autism and his explanation of "autistic enterocolitis" and its theoretical basis. A moderated panel discussion immediately followed, with panelists including Vicky Debold, RN, PhD, Edward Yazbak, MD, Debbie Darnley-Fisch, MD, and Arthur Krigsman, MD.

The presentation was simulcast on the internet, and the video of the lecture is available online here.

Papers endorsing or replicating Wakefield's research[edit]

  • "Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders", Harumi Jyonouchi, MD, Lee Geng, PhD, Agnes Ruby, BS, Chitra Reddy, MD and Barbie Zimmerman-Bier, MD, Journal of Pediatrics, p 610 (May 2005)
  • "Dysregulated Innate Immune Responses in Young Children with Autism Spectrum Disorders: Their Relationship to Gastrointestinal Symptoms

and Dietary Intervention", Harumi Jyonouchi, MD, Lee Geng, PhD, Agnes Ruby, BS, Barbie Zimmerman-Bier, MD, Department of Pediatrics, New Jersey Medical School (UMDNJ), Neuropsychobiology, vol 51 p 77–85 (2005)

  • "Some aspects about the clinical and pathogenetic characteristics of the presumed persistent measles infections: SSPE and MINE", Paul Richard Dyken, Institute for Research in Childhood Neurodegenerative Diseases, Journal of Pediatric Neurology, vol 2, no 3, p 121-124 (2004)
  • "Spontaneous Mucosal Lymphocyte Cytokine Profiles in Children with Autism and Gastrointestinal Symptoms: Mucosal Immune Activation and Reduced Counter Regulatory Interleukin-10", Paul Ashwood, Andrew Anthony, Franco Torrente and Andrew Wakefield, Journal of Clinical Immunology, vol 24, no 6 (November, 2004)
  • "Panenteric IBD-Like Disease in a Patient with Regressive Autism Shown for the First Time by the Wireless Capsule Enteroscopy: Another Piece in the Jigsaw of this Gut-Brain Syndrome?" Federico Balzola, Valeria Barbon, Alessandro Repici, Mario Rizzetto, Daniela Clauser, Marina Gandione, Anna Sapino, American Journal of Gastroenterology (April, 2005)
  • "Gastrointestinal abnormalities in children with autistic disorder

Karoly Horvath, MD, PhD, John C. Papadimitriou, MD, PhD, Anna Rabsztyn, Cinthia Drachenberg, MD, Journal of Pediatrics, vol 125, no 5

  • "Autistic disorder and gastrointestinal disease", Karoly Horvath, MD, PhD, Jay A. Perman, MD, Pediatrics, vol 14, p 583–587 (2002)

References[edit]

  • BMJJournals.com - 'Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database', Corri Black, James A Kaye, Herschel Jick,' British Medical Journal, vol 325, pp 419-421 (2002)
  • BMJJournals.com - 'Inlammationa and Inflammatory Bowel Disease: Effect of Pentavac and Measles-mumps-rubella (MMR) vaccination on the intestine', B. Thjodleifsson, K. Davídsdóttir, U. Agnarsson, G. Sigthórsson4, M Kjeld1 and I Bjarnason, Gut, vol 51, p 816-817 (2002)
  • Mercola.com - 'Enterocolitis in Children With Developmental Disorders', Andrew Wakefield, A. Anthony, S.H. Murch, M. Thomson, S.M. Montgomery, S. Davies, J.J. O'Leary, D. Phil, M. Berelowitz, J.A. Walker-Smith, American College of Gastroenterology (2000)
  • 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, (1998). "Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children," Lancet, 351, 637-41.
PMID 9500320.

External links[edit]

  • AutismConnect.org - 'New Andrew Wakefield study links autism to novel intestinal illness (Autistic enterocolitis): A British gastroenterologist who now works in Austin has completed a new study on autism which claims to link the disease to a novel intestinal illness', Cox News Service (October 11, 2004)
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