Understanding the Brain

Autistic enterocolitis

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"Autistic enterocolitis" is a controversial term first used by discredited[1] British gastroenterologist Andrew Wakefield to describe a number of common clinical symptoms and signs which he contends are distinctive to autism. The existence of autistic enterocolitis is unproven, as Wakefield's fraudulent[2][3] studies used inadequate controls, he suppressed negative findings in his now retracted reports, and multiple attempts to replicate his results have been unsuccessful.[4]

Reviews in the medical literature have found no link between the MMR vaccine and autism or with bowel disease.[5][6][7][8]

Most of Wakefield's coauthors later retracted the conclusions of the original paper proposing the hypothesis,[9] and Wakefield has been found guilty of manipulating patient data and misreporting results in the paper by the General Medical Council.[10][11] His work was later identified to be falsified and described as an "elaborate fraud".[2][3]

Background

Until the 1970s, autism was rarely accepted to be a distinctive diagnosis, but, following changes to the Diagnostic and Statistical Manual of the American Psychiatric Association it is diagnosed much more often. How much of this increase is due to greater diagnostic vigilance by doctors, changes in diagnostic categories, or an actual increase in prevalence, remains unclear. Late-onset autism cases are estimated at 25% and reported by sources including the British Medical Journal as not having changed in recent years.[12]

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 refuted its existence.[13] Thus, it is not generally accepted that the types of colitis diagnosed in autistic individuals are either unique to autism, or more common in autistic people than in the general population.[14]

Lancet study

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.[15]

According to parents, onset of behavioral symptoms was linked to recent (within two weeks) immunization with MMR vaccine in eight of the children diagnosed with developmental disorders. The most consistent report was lymphoid nodular hyperplasia of the terminal ileum in nine of the children. This feature has also been reported to be very common in non-autistic children.[16] A variety of colonic and rectal mucosal features were reported in eight cases. Biopsies of the ileum were reported to have shown reactive lymphoid follicular hyperplasia in seven. Biopsies of the colon were reported to have shown a diffuse mononuclear cell infiltrate in six.

Wakefield and his colleagues said they described features of regressive autism with bowel disorders, or what Wakefield would later call autistic enterocolitis, although these findings have been questioned, with claims that the association of features is substantially an artifact of preselection of vaccinated children with both developmental disorders and bowel symptoms for a UK lawsuit:[17]

  • Most of the children were reported to have swelling of the lymphoid tissue lining the intestines, particularly near where the small and large intestines meet, and inflammation of the large intestine, associated with constipation, diarrhea and, in some cases, pain.
  • In some affected children, impaired cellular immunity to common recall antigens, with low numbers of circulating white blood cells were reported.
  • A specific measles protein signal is claimed to have been detected in inflamed lymphoid tissue.
  • In some cases, loss of speech and language, bowel disturbances, self-injury, and a self-limited diet, associated with cravings for particular foods.
  • Allergies, food intolerances are also reported in some children.

In an April 2010 investigation into the origins of claims for "autistic enterocolitis", reporter Brian Deer revealed in the BMJ that the original pathology results on the children in the study (obtained from the Royal Free hospital) had been subjected to wholesale changes, from normal to abnormal, in the medical school.[11] On 2 January 2011, Deer provided two tables comparing the data on the twelve children, showing the original hospital data and the data with the wholesale changes as used in the 1998 Lancet article.[18]

A 2011 article in the British Medical Journal described how the data in the study had been falsified by Wakefield so it would arrive at a predetermined conclusion.[2] An accompanying editorial in the same journal described Wakefield's work as an "elaborate fraud" which led to lower vaccination rates, putting hundreds of thousands of children at risk and diverting energy and money away from research into the true cause of autism.[3]

Discredited link to MMR vaccinations

Wakefield has hypothesized that autistic enterocolitis is an emergent IBD phenotype that follows from exposure to the vaccinations given to children during a period when their immune systems are rapidly developing. Other research, however, rejects this hypothesis, and other groups have not reproduced Wakefield's findings.[19] Researchers have identified a high incidence of bowel symptoms in autistic children before the MMR vaccine was licensed.[20] It was also revealed that, prior to the publication of Wakefield's studies alleging a connection between the MMR vaccine and autistic enterocolitis, he had received over £400,000 from lawyers attempting to sue vaccine manufacturers. This conflict of interest, which Wakefield denies, has led many to criticize Wakefield and his results. The British General Medical Council has launched an inquiry into possible dishonesty by Wakefield regarding his research.[21]

"Retraction of an interpretation"

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 administration 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, 10 of the 13 authors issued a statement in the Lancet entitled "Retraction of an interpretation".[9] In this, the authors retracted the conclusion section of the paper, formally known in the Lancet and in many biomedical journals, as the "interpretation". The section of the paper retracted said:

"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."

In the retraction, issued in March 2004, they said:

"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."

The authors also said:

"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."

Just before the retraction, criticism arose over the fact that the Royal Free Hospital had received £55,000 in August 1996 from lawyers preparing to sue MMR manufacturers for support of Dr. Wakefield's research. Wakefield asserted that the donation was to fund a second clinical study; some of the children involved were subjects in both studies.[22] However, it was subsequently revealed by The Sunday Times of London that Wakefield had personally been paid more than £400,000.[21]

Wakefield, who did not sign the retraction, currently faces disciplinary charges before the General Medical Council over the conduct of this research.[23] In February 2009 The Sunday Times reported that Wakefield had manipulated patient data and misreported results in his 1998 paper, creating the appearance of a link with autism.[10]

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".[7][8]

U.S. Court of Federal Claims

On February 12, 2009, three Special Masters of the United States Court of Federal Claims rendered three opinions[24] in three "test cases" that were proceeding in that court, each of which addressed causation issues relating to MMR vaccine and autism spectrum disorders (ASDs). The opinions were critical of Arthur Krigsman and his testimony about autistic enterocolitis, which the court described as a "new form of gastrointestinal [GI] disorder." Typical of their criticism was the following passage found at page 199 of the opinion in the Snyder case[25]: "Doctor Krigsman was qualified to testify about gastroenterology [but his] qualifications to establish the validity of a new form of gastrointestinal disorder, unrecognized by other authorities in the field, were ... sadly lacking." The court noted that the "medical textbooks" do not recognize autistic enterocolitis, but did not opine as to whether the rapidity with which ASD cases have increased in recent years may be a factor in the lagging recogniztion of a GI-ASD connection. At page 27, the same opinion stated that "Dr. Krigsman’s testimony about autistic enterocolitis as a diagnostic entity was speculative."

References

  1. Rose, David (2010-02-03). "Lancet journal retracts Andrew Wakefield MMR scare paper". Times Online. Archived from the original on 2010-02-03. http://www.webcitation.org/5nGfAGGJ9. 
  2. 2.0 2.1 2.2 Deer B (2011). "How the case against the MMR vaccine was fixed". BMJ 342: c5347. doi:10.1136/bmj.c5347. PMID 21209059. http://www.bmj.com/content/342/bmj.c5347.full. 
  3. 3.0 3.1 3.2 Godlee F, Smith J, Marcovitch H (2011). "Wakefield's article linking MMR vaccine and autism was fraudulent". BMJ 342:c7452: c7452. doi:10.1136/bmj.c7452. http://www.bmj.com/content/342/bmj.c7452.full. 
  4. Is it a histopathological entity?
  5. Jefferson T, Price D, Demicheli V, Bianco E (2003). "Unintended events following immunization with MMR: a systematic review". Vaccine 21 (25–26): 3954–60. doi:10.1016/S0264-410X(03)00271-8. PMID 12922131. 
  6. Gerber JS, Offit PA (2009). "Vaccines and autism: a tale of shifting hypotheses". Clin Infect Dis 48 (4): 456–61. doi:10.1086/596476. PMC 2908388. PMID 19128068. http://www.journals.uchicago.edu/doi/full/10.1086/596476. Lay summary – IDSA (2009-01-30). 
  7. 7.0 7.1 Demicheli V, Jefferson T, Rivetti A, Price D (2005). "Vaccines for measles, mumps and rubella in children". Cochrane Database Syst Rev (4): CD004407. doi:10.1002/14651858.CD004407.pub2. PMID 16235361. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004407/frame.html. 
  8. 8.0 8.1 The Cochrane Library (2005-10-19). "The Cochrane Library publishes the most thorough survey of MMR vaccination data which strongly supports its use". http://www.cochrane.org/press/MMR_final.pdf. 
  9. 9.0 9.1 Murch SH, Anthony A, Casson DH, et al. (2004). "Retraction of an interpretation". Lancet 363 (9411): 750. doi:10.1016/S0140-6736(04)15715-2. PMID 15016483. 
  10. 10.0 10.1 Deer B (2009-02-08). "MMR doctor Andrew Wakefield fixed data on autism". Sunday Times (London). http://www.timesonline.co.uk/tol/life_and_style/health/article5683671.ece. Retrieved 2009-02-09. 
  11. 11.0 11.1 Deer B (2010-04-17). "Wakefield's autistic enterocolitis under the microscope". BMJ. http://www.bmj.com/cgi/content/full/340/apr15_2/c1127. Retrieved 2010-04-24. 
  12. Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J (2002). "Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study". BMJ 324 (7334): 393–6. doi:10.1136/bmj.324.7334.393. PMC 65532. PMID 11850369. http://bmj.com/cgi/pmidlookup?view=long&pmid=11850369. 
  13. Black C, Kaye JA, Jick H (2002). "Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database". BMJ 325 (7361): 419–21. doi:10.1136/bmj.325.7361.419. PMC 119436. PMID 12193358. http://bmj.com/cgi/pmidlookup?view=long&pmid=12193358. 
  14. "Does the MMR Jab Cause Autism?". bbc.co.uk. http://www.bbc.co.uk/sn/tvradio/programmes/horizon/mmr_prog_summary.shtml. Retrieved 2007-11-25. 
  15. Wakefield A, Murch S, Anthony A et al. (1998). "Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children". Lancet 351 (9103): 637–41. doi:10.1016/S0140-6736(97)11096-0. PMID 9500320. http://briandeer.com/mmr/lancet-paper.htm. Retrieved 2007-09-05. 
  16. "Wakefield MMR-autism sign was recognized for years: as benign finding in children". Brian Deer. http://briandeer.com/wakefield/ileal-hyperplasia.htm. Retrieved 2007-11-25. 
  17. Deer B (2008-11-02). "The MMR-autism crisis - our story so far". http://briandeer.com/mmr/lancet-summary.htm. Retrieved 2008-12-06. 
  18. "MMR & Autism: Fixing a Link", Tables prepared by Brian Deer as a supplement to his peer reviewed report “How the case against the MMR vaccine was fixed”, published in the BMJ in January 2011 (BMJ 2011;342:c5347).
  19. Thjodleifsson B, Davídsdóttir K, Agnarsson U, Sigthórsson G, Kjeld M, Bjarnason I (December 2002). "Inflammation and Inflammatory Bowel Disease: Effect of Pentavac and measles-mumps-rubella (MMR) vaccination on the intestine". Gut 51 (6): 816–7. doi:10.1136/gut.51.6.816. PMC 1773472. PMID 12427783. http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=12427783. 
  20. "Study found many autistic children with bowel problems before MMR was licensed". Brian Deer. http://briandeer.com/wakefield/coleman-child.htm. Retrieved 2007-11-24. 
  21. 21.0 21.1 Deer, Brian (December 31, 2006). "MMR Doctor given legal aid thousands". The Sunday Times. http://briandeer.com/mmr/st-dec-2006.htm. Retrieved 2007-11-25. 
  22. McKee, Maggie (4 March 2004). "Controversial MMR and autism study retracted". NewScientist.com. http://www.newscientist.com/article.ns?id=dn4743. Retrieved 2007-11-25. 
  23. Deer B (2005-09-11). "MMR scare doctor faces list of charges" (Reprint). Sunday Times. http://briandeer.com/wakefield/gmc-alleges.htm. Retrieved 2007-08-10. 
  24. Court of Federal Claims opinions
  25. Court of Federal Claims opinion in the Snyder case

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