"That Paper" by Andrew Wakefield, MB, BS, FRCS, FRCPath

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HISTORICAL PERSPECTIVE
By Andrew Wakefield, MB, BS, FRCS, FRCPath
Andrew Wakefield, MB, BS, FRCS, FRCPath, is an academic gastroenterologist. He graduated in Medicine from St. Mary’s Hospital (part of the University of London) in 1981, pursuing a career in gastrointestinal surgery with a particular interest in inflammatory bowel disease. He qualified as Fellow of the Royal College of Surgeons in 1985, and in 1996 was awarded a Wellcome Trust Traveling Fellowship to study small-intestine transplantation in Toronto, Canada. Discoveries made during his work in Canada led him to return to the United Kingdom to pursue the study of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. In 1998, Dr. Wakefield and his colleagues at the Royal Free Hospital in London reported a novel inflammatory bowel disease in children with developmental disorders such as autism; the condition later became known as autistic enterocolitis. He was awarded the Fellowship of the Royal College of Pathologists in 2001. Dr. Wakefield is involved in many scientific research collaborations in the United States and abroad centering on the immunologic, metabolic, and pathologic changes occurring in inflammatory bowel diseases such as autistic enterocolitis, links between intestinal disease and neurologic injury in children, and the possible relationship of these conditions to environmental causes, such as childhood vaccines. During the course of his work on childhood developmental disorders, Dr. Wakefield was increasingly convinced of the need for a research-oriented, integrated biomedical and educational approach to these disorders, in order to translate clinical benefits for affected children into measurable developmental progress; this is the driving aim of Thoughtful House Center for Children in Austin, Texas. He has published over 130 original scientific articles, book chapters, and invited scientific commentaries.
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n February 28, 1998, twelve colleagues and I published a case series paper in The Lancet, a respected medical journal, as an “Early Report”1. The paper described the clinical findings in 12 children with an autistic spectrum disorder (ASD) occurring in association with a mildto-moderate inflammation of the large intestine (colitis). This was accompanied by swelling of the lymph glands in the intestinal lining (lymphoid nodular hyperplasia), predominantly in the last part of the small intestine (terminal ileum). Contemporaneously, parents of 9 children associated onset of symptoms with MMR exposure, 8 of which were reported in the original paper (see also Child PH’s story on following page). The significance of these findings has been overshadowed by misunderstanding, misrepresentation, and a concerted, systematic effort to discredit the work. This effort, and specifically the complaint of a freelance journalist and an intense political desire to subvert enquiry into issues of vaccine safety and legal redress for vaccine damage, culminated in the longest running and most expensive fitness to practice case ever to come before the United Kingdom’s medical regulator, the General Medical Council. At this point, the evidence is in and the outcome is awaited. Now, and only now, with all of the contemporaneous documentation available, is it timely to review both the original paper and its legacy.
Background From the late 1980s, my team at the Royal Free Medical School, the Inflammatory Bowel Disease Study Group, published extensively on possible causes and mechanisms of inflammatory bowel disease (e.g., Crohn’s disease). This involved examination of a possible causal role for measles and measles vaccine. In May 1995, parents started contacting me with the story that their normally developing child had regressed into autism or an autism-like state, with onset in the majority of cases soon after MMR vaccine. At around the same time, the children had developed chronic gastrointestinal (GI) symptoms similar to those described by Dr. Lenny Gonzalez in the July 2009 edition of The Autism File2 . Despite what were often debilitating intestinal symptoms, many indicative of abdominal pain, few of these children had undergone physical examination, let alone been investigated. Mention of the MMR vaccine had often alienated parents further from their child’s health care providers. Many doctors attributed the onset of symptoms to coincidence and were content to leave it at that. Conversely, at the Royal Free a systematic plan of clinical care and research was designed in order to help affected children. The first report on these children appeared in February 1998. The purpose of this series of articles is to review The Lancet
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hild *PH’s story, as originally told by his mother, did not cite MMR as the culprit. Eighteen months of normal development was followed by regression, giving rise to what several doctors labeled “secondary autism.” Loss of developmental milestones was accompanied by loss of coordination (he could no longer throw and catch a ball), his gait became, “awkward and stiff like an old man,” and he could no longer go from sitting to standing unaided. He lost the twenty words that he had gained and developed secondary fecal incontinence. At eighteen months of age, severe episodes of abdominal pain started that were associated with screaming and drawing his knees to his chest. He developed a pattern of chronic loose bowel motions with undigested food from two years of age. He went from the 97th centile for weight at 1 year of age to the 50th by age 2. His diet went from being varied to very restricted, consisting of refined carbohydrates and at least ten 200ml cartons of orangeflavored drink per day.
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What Child PH’s mother did not tell us in 1996 was that, contemporaneously, she too had linked her son’s problems to MMR vaccine. Our description of this child in The Lancet faithfully reiterated the onset of symptoms following an episode of otitis media as his mother had reported but made no mention of the MMR. The reason for this discordance in the narrative provides a valuable lesson: the reaction of successive doctors to the suggestion that MMR might have been involved ranged from patronizingly dismissive to outright hostile. Mentioning the vaccine was beginning to negatively impact their ability to get help for their son. By the time they came to the Royal Free Hospital, the father had urged his wife not to mention the MMR again in order to avoid discrimination by doctors who considered her to be crazy. So it was that a potentially important element of the clinical history in this child had been corrupted by the arrogance of those who “knew better.” *Initials have been changed.
Myths: The Lancet paper
  was funded by the Legal Aid Board (LAB)4 False – Not one penny of LAB money was spent on The Lancet paper. An LAB grant was provided for a separate viral detection study. This latter study, completed in 1999, does disclose the source of funding. The Lancet paper had been submitted for publication before the LAB grant was even available to be spent. my involvement as a medical expert was kept “secret”5 False – at least one year before publication, my senior co-authors6, the head of department and the dean of the medical school7, and the CEO of the hospital were informed by me. This fact was also reported in the national press 15 months prior to publication8. children were “sourced” by lawyers to sue vaccine manufacturers5 False – Children were referred, evaluated, and investigated on the basis of their clinical symptoms alone, following referral from the child’s physician9. children were litigants10 False – at the time of their referral to the Royal Free, the time material to their inclusion in The Lancet paper, none of the children were litigants. I had an undisclosed conflict of interest11 False – The Lancet’s disclosure policy at that time was followed to the letter. Documentary evidence confirms that the editorial staff of The Lancet was fully aware that I was working as an expert on MMR litigation well in advance of the paper’s publication12. did not have Ethics Committee (EC) approval5 False – The research element of the paper that required such an approval, detailed systematic analysis of children’s intestinal biopsies, was covered by the necessary EC approval13. I “fixed” data and misreported clinical findings14 False – There is absolutely no basis in fact for this claim and it has been exposed as false15. findings have not been independently replicated12 False – The key findings of LNH and colitis in ASD children have been independently confirmed in 5 different countries16. has been retracted by most of the authors17 False – 11 of 13 authors issued a retraction of the interpretation that MMR is a possible trigger for syndrome described. This remains a possibility and a possibility cannot be retracted. the work is discredited18 False – Those attemping to discredit the work have relied upon the myths above. The findings described in the paper are novel and important19.
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The legacy of The Lancet paper
The first demonstration of intestinal pathology in ASD
GI symptoms are common in children with autism, and these symptoms are frequently associated with intestinal inflammation. Treatment of GI inflammation may lead to symptomatic improvement in both GI and behavioral symptoms21. paper for what it was, what it did and didn’t say, and to examine the legacy of the paper in the light of subsequent events. Study design The Lancet paper – the first in a series of related papers – is a case series: This is stated explicitly in the first line of the paper: “...a consecutive series of children with chronic entero-colitis and regressive developmental disorder”1. A typical example of how basic epidemiological textbooks define and describe a case series is found in Hennekens and Buring3: “Case series studies describe the experience of a single patient or a group of patients with a similar diagnosis. These types of study, in which typically an astute clinician identifies an unusual feature of a disease or a patient’s history, may lead to formulation of a new hypothesis… At that time an analytic study (most frequently using a case-control approach), can [then] be done to investigate possible causal factors.” [emphasis added] The crucial design feature which differentiates the case series from other designs is its lack of requirement to select participants on the basis of either the exposure (e.g., MMR) or the outcome of interest (e.g., autism). A case series does not require – and should not employ – strict inclusion or exclusion criteria. Rather, it should function to observe similar presentations in groups of patients that appear to share other common features in order to raise hypotheses that later may be tested in the appropriate study design framework (e.g., a case-control study). The Lancet paper does exactly what is required of a case series. It states immediately what the report sets out to do: no particular developmental disorder was stated, no particular features or timing of onset were required, no particular initial exposure was necessary, no specific outcome was predicted, and no causal association was claimed. Of note, we have been criticized for not having controls in the study; that is, developmentally normal children included for the purpose of comparison. While controls are not usually part of a
The first demonstration of abnormal vitamin B12 metabolism in ASD
Now the subject of major clinical and research activities in autism, ranging from study of genetic differences in B12/folate metabolism to treatment with active forms of B12.
The first study to report a re-challenge effect of a measles containing vaccine (MCV)
Follow up indicates that intestinal inflammation is significantly worse in re-challenge ASD children than children receiving only one measlescontaining vaccine (MCV)22 .
First study to seek evidence of a mitochondrial disorder by measurement of lactate: pyruvate in cerebrospinal fluid
“Mito” disorders appear to be common in ASD children and may be acquired. The U.S. government conceded that vaccines triggered autism in Hannah Poling, a child with “mito” disorder24 .
case series, we went beyond what would normally be required and did include controls – 19 age-matched children (5 for microscopic examination of tissues and 14 for measurement of urinary methylmalonic acid [MMA]). This would have been evident upon a proper reading of the paper. Finally, Hennekens and Buring3 make the crucial point that the purpose of a case series is to generate new hypotheses about potential causation. It is not designed to investigate possible causality. The Lancet paper was hypothesis generating; it stimulated a series of subsequent papers – rarely if ever acknowledged by critics – that confirmed and characterized the bowel disease as novel, relatively frequent, and potentially treatable and tested ideas about causation19. Among the critics there has been some confusion on this point, which is evident, for example, in a widely quoted analysis of the paper by Professor Trisha Greenhalgh20 that raises and attempts to answer a series of questions, including: Was the research hypothesis clearly stated? She observes, “The paper does not state a research hypothesis at all.” This is quite true. Case series studies are neither required nor expected to do so. Having established that there was no hypothesis, Professor Greenhalgh goes on to pose the ridiculous question:
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Was this design an appropriate way to test the research hypothesis? She concludes that the study design was not an appropriate way to test “the research hypothesis.” However, since she has already identified the fact that no hypothesis was stated, she rather begs the question as to which hypothesis the study was not designed to test. It soon becomes clear that it was her hypothesis that the study did not test. Her conclusion that “the study design was incapable of proving the [MMR] link one way or the other” is, of course, entirely accurate as we had already indicated in the paper on page 641, paragraph 2, lines 1 and 21 : “We did not prove an association between measles, mumps and rubella vaccine and the syndrome described…” and paragraph 5, lines 4-6: Further investigations are needed to examine this syndrome and its possible relation to the vaccine.” Professor Greenhalgh ventures even further off course when she asks: Were the study’s conclusions supported by the data? It is not clear whether Professor Greenhalgh is referring to the authors’ conclusions – i.e., that the data do not demonstrate a causal link between the disorder and MMR exposure and that further research is required, or whether she is asking if the data support her own hypothesis. In the former case, the data clearly support our conclusions. Not surprisingly, they do not support Professor Greenhalgh’s hypothesis – that MMR causes the syndrome described. She continues: If the answer to [the question above] is “no,” would a more robust study design have been practically possible to test the study’s main hypothesis? Having inserted her own hypothesis, Professor Greenhalgh answers her question with a resounding “yes.” That she does appear satisfied, on the basis of
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what can only be described as a complete misunderstanding of The Lancet study’s design, is cause for concern. In turn, the failure of the Department of Health (whose Web site directed people via the National Health Service Executive to her analysis) to appreciate the potential impact of this deeply flawed document on the perceptions of many thousands of worried parents is alarming. Notwithstanding Professor Greenhalgh’s follies, one should never underestimate the importance of the case series as a starting point for medical discovery. It is the tried and tested mode of the description of human disease syndromes, including Kanner’s autism, Asperger’s syndrome, and Heller’s disease (disintegrative disorder). One final word on the matter endorses this perspective: “Clinical situations in which a case report or case series is an appropriate type of study include the following: a doctor notices that two babies born in his hospital have absent limbs (phocomelia). Both mothers had taken a new drug (thalidomide) in early pregnancy. The doctor wishes to alert his colleagues worldwide to the possibility of drug related damage as quickly as possible (McBride, in The Lancet 1961). Anyone who thinks ‘quick and dirty’ case reports are never scientifically justified should remember this example.” And the source of this invaluable piece of advice? Dr. Trisha Greenhalgh, author of “How to Read a Paper”24 . “Coincidence” Coincidence – often the first resort of skeptical physicians – refers, in this context, to the chance occurrence of autistic symptoms being identified in the second year of life, at around the same time as MMR is given. Regularly advanced as an explanation for the parents’ story, coincidence is a conclusion of last resort – one that should be arrived at only after diagnostic due diligence has excluded alternative causes for neurological deterioration in a child. Meticulous attention should be paid to the parental history, and
Meticulous attention should be paid to the parental history, and the practice of claiming coincidence without first excluding possible causes has no place in clinical medicine.
the practice of claiming coincidence without first excluding possible causes has no place in clinical medicine. Where an infection such as herpes simplex or Epstein-Barr virus (mono) has preceded autistic regression, the medical literature shows that extensive testing has been undertaken, the cause identified, and the child treated accordingly25. In contrast, when MMR vaccination has preceded autistic regression, little, if any, attempt has been made to investigate children appropriately. The case of Bailey Banks is one of those rare instances where this has been done and for whom the United States vaccine court ruled that MMR caused his ASD26 . Bailey’s MRI, performed 16 days post-MMR for encephalopathy, revealed abnormalities of brain myelin consistent with acute disseminated encephalomyelitis (ADEM), an autoimmune brain inflammation that can follow measles or a measles vaccine. The lesson is that every attempt should be made to evaluate children during the course of their regression since, as in the case of ADEM, abnormalities of brain myelin may be transient and not evident on an MRI performed two years after exposure. The fact that the parents of The Lancet children described loss of fecal and/or urinary continence in four cases and ataxia (clumsiness) in six – the latter being a reported adverse reaction to MMR vaccine 27 – is more than enough indication for thorough neurological workup. The history of regression with loss of acquired skills in a previously normal or near-normal child should ring alarm bells and initiate a systematic approach to differential diagnosis. It was with this in mind that Professor Walker-Smith, one of the world’s leading pediatric gastroenterologists and senior author of The Lancet paper, wrote in 1997:
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HISTORICAL PERSPECTIVE
Re-challenge with a measles vaccine
Child RT* was monitored closely in his first year due to wide bridging of his nose. He was discharged from follow up as developmentally and physically normal by 15 months of age. He later received a single measles vaccine following which he stopped “cruising” around furniture and regressed to crawling. His learning plateaued and, by 20 months, he had lost words; soon thereafter, he stopped talking altogether. General ill health developed in his second year with ear, chest, and throat infections, and diarrhea with abdominal pain. According to his mother’s story, two weeks after an MMR vaccine, at 4.5 years of age, he “disappeared” and “lost all skills and communication.” While at 10 months of age he had been able to build a tower of bricks, his play skills declined to the point that, “now he [was] lost as to what to do with them.” In addition, he became clumsy, started head banging, and developed repetitive behaviors. He lost his self-help skills; for example, before the MMR booster he could feed himself with a spoon, afterwards he could no longer even hold a cup. The history of Child RT’s GI problems is also instructive. His records state: “The diarrhoea became a problem at between 1-1½ years of age [after his single measles vaccine]…it generally contains undigested food. His diarrhea became significantly worse from 4½ years of age [after his MMR]...” Failure to thrive, a cardinal sign of pediatric inflammatory bowel disease, was evident from the GP’s records; he was reported to be “dropping off centile charts.” This failure to thrive continued and took another downturn at the same time that his diarrhea worsened, when he was noted to have dropped from the 9th to the 2nd centile for weight. Further examination of MMR rechallenge is currently under way. *Initials have been changed.
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Did they read the paper?
Ari Brown, MD
Spokesperson for the American Academy of Pediatrics and the Immunization Action Coalition “This flawed study concluded that the rise in autism was related to giving the combination vaccine of measles-mumps-rubella (MMR).”31
Professor Sir Michael Rutter, FRS
Expert prosecution witness GMC, expert witness on behalf of MMR vaccine manufacturers “Publication of a study claiming a casual relationship between measles, mumps and rubella (MMR) vaccine and autism spectrum disorders (ASD) sparked a heated debate...”32
Professor Eric Fombonne
Expert witness on behalf of MMR vaccine manufacturers ”Recent reports claim to have identified another variant of autism (called ‘autistic enterocolitis’) in children referred to a gastroenterology department. The hypothesis has involved 3 separate claims: 1) that a new phenotype of autism associated with developmental regression and gastro-intestinal symptoms has emerged as a consequence of measles-mumps-rubella vaccination...”33
“[These children] have not had the level of investigation which we would regard as adequate for a child presenting with such a devastating condition.”28 Despite evident neurological symptoms, despite the proximity of onset to a viral exposure, and despite additional physical symptoms such as pain and diarrhea, a diagnosis of autism trumped the need for anything but minimal investigation by “mainstream” autism practitioners for the majority of these children. Coincidence and re-challenge Where a child with regressive autism has received more than one dose of a measles-containing vaccine (MCV),
exacerbation of existing symptoms and/ or recurrence of transient symptoms associated with the first dose is frequently reported. Properly documented, the Institute of Medicine’s Vaccine Safety Committee accepts the “re-challenge” effect as evidence of causation29. In order to examine this in the setting of MMR and autistic enterocolitis and to overcome the concern about parental recall of events that may have occurred many years before, we conducted a study comparing the severity of intestinal inflammation between children oncevaccinated and those twice-vaccinated with an MCV. Our hypothesis was that the disease should be more severe in those exposed twice if the disease were caused by the vaccine22 . There was a significantly higher prevalence of active chronic colitis
Despite evident neurological symptoms, despite the proximity of onset to a viral exposure, and despite additional physical symptoms such as pain and diarrhea, a diagnosis of autism trumped the need for anything but minimal investigation by “mainstream” autism practitioners for the majority of these children.
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(involving pus-forming cells) in those children given an MMR or MR booster compared with those receiving only one dose, supporting a causal association. This apparent re-challenge effect is currently being examined in a large population of U.S. children to see if the finding is reproducible. Diligent science The quest for precision can become a hostage to fortune, as the microscopic analysis of The Lancet children’s tissues was to prove. There are few people in the world with Professor Walker-Smith’s knowledge of the microscopic appearances of inflammatory disease of the intestine in children. So it was that, in the absence of a pediatric pathologist expert in this field at the Royal Free, Professor Walker-Smith conducted a weekly review of his patients’ tissues and identified the fact that disease was being missed in some children. In order to reduce this risk and to standardize the reporting of the ASD children’s biopsies, all tissues were subsequently examined by a single senior pathologist with expertise in bowel disease. His findings were recorded on a specially designed chart to document specific features of tissue damage30. This record formed the basis of what was subsequently reported in The Lancet. Few case-series go to this level of precision. In the hands of someone determined to discredit the work, however, discrepancies between the routine clinical report (which may have come, for example, from a pathologist with an interest in brain disease or gynecological pathology) and the standardized expert analysis were falsely reported in the national media as “fixing” of the data. I was specifically accused of this31, although I had no part in scoring the reviews. It is notable that despite five years of investigation by the GMC no charge of scientific fraud has been made against any of the defendants. The allegation of fraud was made by Brian Deer, the same freelancer who had initiated the GMC enquiry, continuing his litany of false allegations. There is no evidence at all that the data had been “fixed” as was alleged, and the newspaper in question has failed to produce any, despite a request to do so from the Press Complaints Commission.
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The damage done to my reputation and to that of my colleagues as well as the personal price for pursuing a valid scientific question while putting the patients’ interests above all others is trivial compared with the impact of these falsehoods on the children’s access to appropriate and necessary care.
Paradoxically, the price paid for diligent science has been a headline proclaiming fraud. No doubt the intended goal – to reinforce the false belief that the work is discredited – has worked for some. The damage done The damage done to my reputation and to that of my colleagues as well as the personal price for pursuing a valid scientific question while putting the patients’ interests above all others is trivial compared with the impact of these falsehoods on the children’s access to appropriate and necessary care. My experience is intended as a cynical example to discourage others. As a consequence, many physicians in the United Kingdom and United States will not risk providing the care that is due to these children. There is a pervasive and openly stated bias against funding and publication of this work, and I have been excluded from presenting at meetings on the instructions of the sponsoring
pharmaceutical company. It has been an effective exercise in public relations and selling newspapers. But it will fail – it will fail because nature cannot be deceived. It has always been a privilege working with these children and their families. It is my hope that before too long the tide will turn and that, in addition, my teacher and mentor Professor Sir Stanley Peart, FRS, will come to realize that I have never forsaken his instruction. In the next edition of The Autism File, Dr. Wakefield will continue his analysis of “That Paper” and its legacy.
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References
1
Wakefield, A. et al., Ileal lymphoid nodular hyperplasia, nonspecific colitis and pervasive developmental disorder in children. The Lancet 1998;351:637-641. Gonzalez L., Gastrointestinal Pathology in Autism Spectrum Disorders: the Venezuelan Experience. The Autism File. 2009;32:34-37. Hennekens C., Buring, J. (1987) Epidemiology in Medicine. Mayrent, S.L (Ed.), Lippincott, Williams and Wilkins. Allegation by Brian Deer to The Lancet Editor Richard Horton, February 2004 and January 2008. General Certificate of School Education (GCSE) Biology exam (higher tier). Assessment and Qualifications Alliance. http://www.aqa.org.uk/ (home page). See also: http://www.ageofautism.com/2009/06/poisoningyoung-minds.html Sunday Times. February 2004.
17 Evidence of Horton R., to the General Medical Council; statement of Horton R., The Lancet 2004;363:820-821. 18 19
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22 Wakefield, A., Gastrointestinal co-morbidity, autistic regression and measles-containing vaccines: positive re-challenge and biological gradient effects. Medical Veritas 2006;3:796-802. 23 Poling, J. and Poling, T., Vaccines, autism and our daughter Hannah. The New York Times. 2008 . And Poling, J., et al., Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol, 2006; 21(2):170–2. And Oliveira, G., et al., Epidemiology of autism spectrum disorder in Portugal: Prevalence, clinical characterization, and medical conditions. Dev Med Child Neurol, 2007; 49(10):726–33. And Reuters, Mitochondrial dysfunction, vaccines and autism: 1 in 50 children at risk. Press Release 2008 [cited January 11, 2009]. Available online at http://www.reuters.com/article/pressRelease/idUS188644+28-Mar-2008+PRN 20080328. And Kirby, D., The next big autism bomb [Web newsletter] 2008 [cited January 6, 2009] Available online at http://www.huffingtonpost.com/david-kirby/the-next-big-autism-bombb93627. html?show+comment_id= 12157235. And Elliot, H., et al., Pathogenic mitochondrial DNA mutations are common in the general population. Am J Human Genetics 2008;83:254–60. And Filipek, P., et al., Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann Neurol, 2003; 53: 801–4. 24 25
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Correspondence between Dr. Wakefield and Professor WalkerSmith, February 3, 1997 and February 20, 1997. Correspondence between Dr. Wakefield and Professor AJ Zuckerman, March 24, 1997. ‘“A shot in the dark.” The Independent, 27 1997 . Statement of Walker-Smith J. The Lancet 2004;363:822-823.
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Sunday Times. February 2004 and January 2008. General Certificate of School Education (GCSE) Biology exam (higher tier). Assessment and Qualifications Alliance. http://www. aqa.org.uk/ (home page). See also http://www.ageofautism. com/2009/06/poisoning-young-minds.html
10 11 Sunday Times. February 2004. Also, Horton R., The Lancet 2004;363:820-821. 12 Moody J., Complaint to GMC vs Horton R., Zuckerman A., Pegg M.,and Salisbury D. (pending). 13 Ethical Practices Committee approval 162/95. Date of approval September 5, 1995. Carroll, M. to Walker-Smith, J. 14 15
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Complaint to Press Complaints Commission. Wakefield vs Deer and the Sunday Times. (see www.cryshame.org). In addition to the UK: Gonzalez, L., et al., Endoscopic and Histological Characteristics of the Digestive Mucosa in Autistic Children with gastro-Intestinal Symptoms. Arch Venez Pueric Pediatr, 2005;69:19-25. And Balzola, F., et al., Panenteric IBD-like disease in a patient with regressive autism shown for the first time by wireless capsule enteroscopy: Another piece in the jig-saw of the gut-brain syndrome? American Journal of Gastroenterology, 2005. 100(4): p. 979-981. And Krigsman, A., et al., http://www.cevs.ucdavis.edu/Cofred/Public/Aca/ Web Sec.cfm?confid=238&webid=1245 (last accessed June 2007) (paper submitted for publication) And Balzola, F., et al., Autistic enterocolitis: Confirmation of a new inflammatory bowel disease in an Italian cohort of patients. Gastroenterology 2005;128(Suppl. 2);A-303. And Galiatsatos, P., et al., Autistic enterocolitis: Fact or fiction. Canadian Journal of Gastroenterology. 2009;23:95-98.
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Horvath K., et al., High prevalence of gastrointestinal symptoms in children with autistic spectrum disorder (ASD). J Pediatr Gastroenterol Nutr 2000, 31:S174. And Melmed, R., et al., Metabolic markers and gastrointestinal symptoms in children with autism and related disorders. J Pediatr Gastroenterol Nutr 2000, 31:S31–S32. And Horvath, K. and Perman, J., Autistic disorder and gastrointestinal disease. Current Opinion in Pediatrics 2002, 14:583–587. And Furlano, R., et al., Quantitative immunohistochemistry shows colonic epithelial pathology and γδ-T cell infiltration in autistic enterocolitis. J Pediatrics 2001;138:366-372. And Torrente, F., et al., Enteropathy with T cell infiltration and epithelial IgG deposition in autism. Molecular Psychiatry. 2002;7:375-382. And Torrente, F. et al., Focalenhanced gastritis in regressive autism with features distinct from Crohn’s and helicobacter pylori gastritis. Am. J. Gastroenterol. 2004;4:598-605. And Ashwood, P. et al., Intestinal lymphocyte populations in children with regressive autism: Evidence for extensive mucosal immunopathology. J. Clin. Immunol. 2003;23:504-517. And Ashwood. P., et al., Spontaneous mucosal lymphocyte cytokine profiles in children with regressive autism and gastrointestinal symptoms: Mucosal immune activation and reduced counter regulatory interleukin-10. Journal of Clinical Immunology. 2004:24:664-673. And Wakefield, A., Enterocolonic encephalopathy, autism and opioid receptor ligands. Alimentary Pharmacology & Therapeutics. 2002;16:663-674. And Uhlmann, V., et al., Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Molecular Pathology 2002;55:84-90. And Sabra. A., et al., Ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children. The Lancet, 1998;352:234-235. And Sabra, A., et al., Linkage of ileal-lymphoid-nodular hyperplasia (ILNH), food allergy and CNS developmental: evidence for a non-IgE association. Ann Allergy Asthma Immunol, 1999;82:8. And Valicenti-McDermott M., et al., Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. Developmental and Behavioral Pediatrics. 2006;27:128-136. And Richler, J., Luyster, R., Risi, S., Hsu, Wan-Ling, Dawson, G., Bernier, R., et al., Is there a ‘regressive phenotype’ of autistic spectrum disorder associated with the measles-mumps-rubella vaccine? A CPEA study. Autism Dev. Dis. 2006, 36:299-316. And Sandler, R., Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol. 2000;15:429-435. And Parracho, H., Differences between the gut flora of children with autistic spectrum disorders and that of healthy children. Journal of Medical Microbiology. 2005;54:987-991.
20 Greenhalgh T., A critical appraisal of the Wakefield, et al., paper. http://briandeer.com/mmr/lancet-greenhalgh .htm
Greenhalgh, T. How to Read a Paper. BMJ 2001;326:106-106.
DeLong, R., et al., Acquired reversible autistic syndrome in acute encephalopathic illness in children. Child Neurology. 1981;38:191-194. And Gillberg. C., Brief report: onset at age 14 of a typical autistic syndrome. A case report of a girl with herpes simplex encephalitis. J. Aut. Dev. Dis. 1986;16:369-375. And Shenoy, S., et al., Response to steroid therapy in autism secondary to autoimmune lympho-proliferative syndrome J. Pediatrics 2000;136:682-687.
26 Health and Human Services vs Bailey Banks. http://www. ageofautism.com/2009/02/why-is-the-media-ignoring-thebailey-banks-autism-vaccine-decision.html 27 Plesner, A., Gait disturbance after measles mumps rubella vaccine. The Lancet 1995;345:316. And Plesner A., et al., Gait disturbance interpreted as cerebellar ataxia after MMR vaccination at 15 months of age: a follow-up study. Acta Paediatrica 2000;89:58-63. 28 Correspondence: Walker-Smith, J.A. to Pegg, M. (Chairman Ethical Practices Committee). November 11, 1996. 29 Stratton, K., et al., Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. 1994: National Academies Press. 30 Wakefield, A., Enterocolitis in children with developmental disorder. American Journal of Gastroenterology 2000;95:22852295. And Wakefield, A., Autistic enterocolitis: Is it a histological entity? Histopathology 2006;50:380-384. 31 Complaint against Brian Deer and the Sunday Times to Press Complaints Commission (see www.cryshame.org) 32 Deer, B. , “MMR doctor Andrew Wakefield fixed data on autism,” Sunday Times. February 8, 2009 33 Brown, A. & Fields D. Baby 411. Windsor Peak Press, Boulder, CO. 2004;12:245
Walker-Smith J., et al., Ileo-caecal lymphoid nodular hyperplasia, ileo-colitis with regressive behavioural disorder and food intolerance: a case study. J. Paediatric gastroenterology and Nutrition. 1997;25:Suppl 48:A31 And Balzola. F., et al., Beneficial behavioural effects of IBD therapy and gluten/casein-free diet in an Italian cohort of patients with autistic enterocolitis followed over one year. Gastroenterology:2008;4:S1364.
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Acknowledgements: My enormous gratitude is due to Dr. Carol Stott, PhD, and to readers of The Autism File for their stoic support.
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44 THE AUTISM FILE | www.autismfile.com | info@autismfile.com REPRINTED WITH PERMISSION © THE AUTISM FILE ISSUE 33 2009