Regressive Autism, Ileal-Lymphoid Nodular Hyperplasia and Measles Virus by David Thrower

Autism and Autism Increases

The Link Between Autism and a Novel Form of Inflammatory Bowel Disease

The Link Between Inflammatory Bowel Disease and Measles Virus

The Link Between Measles Virus and Vaccination with MMR

References

Autism and Autism Increases

• Autism is a complex disorder of learning and behaviour, usually starting early in childhood. The number of children diagnosed with autism and related disorders on the autistic spectrum has increased dramatically in many countries during the past fifteen years

• Many parents have reported the onset of regressive autism following immunisation , for example by Wakefield (1) and during a 2001 US study (2)

• A number of independent researchers have reported large recent increases in autism, for example Blaxill in 2001 (3).

• A May 2006 statement (4) by the US Centers for Disease Control and Prevention admitted that 1 in 175 US children was autistic, and that some 300,000 children across the US within the 4-17 years age-range now have a diagnosis of autism. The US House of Representatives member David Weldon has commented that “For eight years, I’ve had parents and clinicians coming to me saying we have an epidemic of autism, and many people in Government are reluctant to accept that……..the CDC has really, finally, admitted that we have an epidemic.” (5)

• On a proportionate basis, using the US CDC figure, the UK could have an estimated quarter of this number, perhaps 75,000. The Scottish Schools Census (6) has recorded a 325% increase in pupils with a primary diagnosis of autism in seven years, from 820 in 1998 to 3,484 in 2005. If reflected across the UK, on a crude pro-rata basis, this would give a figure amongst school-age children of 38,000, to which would need to be added children under school age and children awaiting diagnosis. The UK total might therefore be in the 45,000-75,000 range for children under 19. Official UK Government data is still at an early stage.

• Independent study has confirmed that the observed major US increases are real. A 2002 study (7) by the MIND Institute at the University of California at Davis stated that “the unprecedented increase in autism in California is real and cannot be explained away by artificial factors such as misclassification and criteria changes”, nor by in-migration. The study confirmed firm evidence of a major rise.

• A 2003 study by Yeargin-Allsopp, Rice et al (8) and funded by the US Centers for Disease Control found that autism was running at a rate of 1 in 294 amongst children ages 3-10 in metropolitan Atlanta, US, in 1996 (the accepted preponderance of autism amongst males rather than females would mean a significantly higher rate than this would have existed amongst males). The study concluded that the rate of autism was higher than rates found in US studies during the 1980s and early 1990s, but was consistent with more recent studies.

• A 2003 study by Gurney, Fritz et al (9) found that, examining special educational disability data from the Minnesota Department of Children, Families & Learning, from 1981-82 through to 2001-02, prevalence rates of autism rose substantially over time within single-age groups, and increased from year to year within birth cohorts, and that ASD prevalence amongst children ages 6-11 years rose from 1 in 3,333 in 1991-92 to 1 in 192 in 2001-02. The same study found that the trend showed no sign of abatement, nor any corresponding decrease in any special educational disability to suggest any diagnostic substitution (re-classification) as an explanation for the trend. It also did not ascribe increases to criteria changes.

• A 2003 paper by Yazbak (10) reported that autism had greatly increased across the US. For example, DSM-IV (i.e profound) autism had increased in California by 97% in the four years up until it being reported by the State Department of Developmental Services in early 2003, compared with increases of only 29% for mental retardation and only 16% for cerebral palsy. Autism across the US as identified by Individuals with Disabilities Education Act data had risen from 12,000 in 1992-93 to 119,000 in 2001-02 (it has since risen to 166,000).

• A 2004 review by Blaxill (11) reported that autism in the US increased from less than 1 in 3,333 (3 per 10,000) in the 1970s to greater than 1 in 333 (30 per 10,000) in the late 1990s, a tenfold increase. In the UK, autism rose from less than 1 in 1000 (10 per 10,000) in the 1980s to roughly 1 in 333 (30 per 10,000) in the 1990s. Reported rates for the full spectrum of autistic spectrum disorder rose from the 5-10 per 10,000 range to the 50-80 per 10,000 range in the two countries during this period.

• A 2005 study by Newschaffer, Falb et al (12) reported further confirmation of increases, that increase were real and not a case of past misdiagnosis, and were not due to greater awareness or diagnostic switching. Clear cohort differences were apparent, with the greatest increases for birth cohorts born between 1987-92. Diagnostic substitution (re-classification) did not explain these increases. The authors concluded that “the drastic increase in the prevalence of autism classification presents a major challenge”.

The above evidence offers confirmation that autism, a historically relatively rare condition, is now found at a greatly-increased rate amongst US and UK children, and that there has been a real increase. Increased numbers are not down to greater awareness, re-classification, altered criteria, past misdiagnosis or better recognition.

The Link Between Autism and a Novel Form of Inflammatory Bowel Disease

There is now ample evidence, confirmed by independent groups of researchers, of a link between regressive autism and a novel form of inflammatory bowel disease.

• The possible association between MMR vaccine, regressive autism and intestinal symptoms was first reported by parents to Dr. Andrew Wakefield, a UK gastroenterologist at the Royal Free Hospital, London, in 1995. The first group of children presenting in this way to Dr. Wakefield and colleagues at the Royal Free were reported in The Lancet as a clinical case series in February 1998 (13). Although the interpretation put on this paper at the time was the subject of intense controversy  -  particularly in the absence of corroborative clinical research by other researchers at that time  -  the strong evidence of a hitherto-unreported link between autism and a novel intestinal disease, ileal-lymphoid nodular hyperplasia, has not been disputed, and stands as an important initial clue as to the causes of regressive autism.

• A group of researchers led by Horvath (14) subsequently independently reported in 1999 upon patients with autism who had gastrointestinal symptoms, including a study of 36 children with autism that found grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15 (42%) and chronic duodenitis in 24 (67%).

• Further research published in September 2000 (15) by Wakefield, Anthony et al confirmed that ileal-lymphoid nodular hyperplasia (ILNH) was found in 54 out of 58 (93%) children with autism or other disorders (50 with autism, 5 Aspergers, 2 disintegrative disorder, one ADHD, one schizophrenia, one dyslexia), but only 5 out of 35 (14.3%) normal controls, pointing to a very strong ILNH-autism link.

• Research published in 2001 by Furlano, Anthony et al (16) reported on ileocolonoscopy performed on 21 consecutively-evaluated children with autistic spectrum disorders and bowel symptoms, and made “blinded” comparisons with 8 children who had a histologically normal ileum and colon, plus 10 developmentally-normal children with ILNH, 15 with Crohn’s Disease, and 14 with ulcerative colitis. The study confirmed a distinct lymphocytic colitis in the children with ASD, in which the epithelium appeared particularly affected, offering further corroboration for gut epithelial dysfunction in autism.

• Research reported in 2001 by Buie (17) reported that, as a result of over 400 gastrointestinal endoscopies with biopsies and evaluation of digestive enzyme function, on children with autism, he had found the presence of chronic inflammation of the intestinal tract, although the incidence was less frequent than in the Royal Free Hospital group of patients reported by Wakefield et al, and that biopsy results indicated the presence of chronic inflammation of the digestive tracts, including esophagitis, gastritis and enterocolitis. Ileal lymphoid nodular hyperplasia, as first found by the Royal Free study, had been found in 15 of 89 children examined for it.

• A review published in September 2002 by Wakefield, Anthony, Montgomery et al (18) noted that as early as 1986, a researcher named Soddy had noted that recurrent gastrointestinal upsets were a constant feature of autistic children, and that in a systematic analysis of an unselected population of 385 children on the autistic spectrum, clinically-significant gastrointestinal symptoms occurred in 46%, compared with 10% of 97 developmentally-normal controls, strongly suggesting a gastrointestinal-autism link. Mucosal lesions in the small and large intestine were consistent with an autoimmune pathology, and suggested the possibility of an autoimmune response leading to cerebral damage.

• A June 2002 presentation (19) by Krigsman to the US Congressional Committee on Government Reform reported that a large percentage of his autistic patients suffered from chronic unexplained gastrointestinal symptoms. Of 43 patients, the majority had a clear history of developmental regression, after previous normal development, suffering gradual or precipitous decline between age 12 months and 18 months. Most regressive children also exhibited poor growth. Patients had undergone colonoscopy. Findings were that the lymphoid nodules of the terminal ileum were markedly enlarged, thus confirming the early work of the Royal Free team. Evaluation of biopsy specimens confirmed that 65% had colitis, 51% had active colitis, 40% had chronic colitis, 7% had eosinophilic colitis, 90% had lymphoid nodular hyperplasia of the terminal ileum, and 35% had neither active nor chronic nor eosinophilic colitis. Patterns of inflammation were patchy and unpredictable, but findings were similar and consistent from patient to patient within affected sub-groups.

• A November 2003 paper published by Ashwood, Murch et al (20) reported on the examination of 52 affected autistic children, compared with 25 histologically-normal developmentally-normal controls and a further 54 histologically-inflamed but developmentally-normal controls. Analysis of intestinal biopsies in regressive-autistic children indicated a novel lymphocytic enterocolitis with autoimmune features, though the precise linkage between the finding and cognitive functions still remained unclear. The study concluded that it provided further evidence of a pan-enteric mucosal immunopathology in children with regressive autism, that is distinct from other previously-known inflammatory bowel diseases.

• An April 2004 paper by Torrente, Anthony et al (21) identified, following earlier reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, that the gastritis in regressive autism was clearly distinct from that in Crohn’s and other conditions, pointing to a distinctive form of gastritis being linked with regressive autism.

• A November 2004 paper by Ashwood, Anthony et al (22) found that molecules (cytokines) produced by immune cells in the intestine, that cause or control inflammation, showed an abnormal pattern in autistic children compared with non-autistic children. The pattern was different to other forms of intestinal inflammation, and the disease resembled a longstanding viral disease of the intestine, not unlike the intestinal inflammation seen on patients with other viral infections such as HIV-associated enteropathy (intestinal disease) that often accompanies infection with HIV.

• A February 2005 paper by Jyonouchi, Geng et al (23) further confirmed the original ileal-lymphoid nodular hyperplasia/regressive autism link first reported by the Wakefield team in 1998. The study again found evidence of marked inflammatory and immune abnormalities in children with autism associated with gastrointestinal symptoms.

• An April 2005 letter (24), Pan-Enteric 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?, reported that a 28-year-old male with regressive autism, severe constipation, bloating, abdomen distension and symptoms of gastroesophageal reflux was examined. Gastroscopy under general anaesthesia revealed hemorrhagic gastritis with inflammatory pseudopolypsthat had reached the pylorum, with a pearl-necklace appearance, and a panenteric IBD-like disease consistent with previously-published descriptions of autistic enterocolitis was finally diagnosed. The wireless capsule images were the first to be obtained beyond the limits of the duodenum and terminal ileum, and demonstrated the potential for the entire bowel to be implicated in this inflammatory disease.

• A May 2005 study (25) by Balzola, Daniela et al reported on 9 consecutive patients (range 7-30 years) with autism and chronic intestinal symptoms (abdominal pain, bloating, constipation and/or diahorrea). Routine blood and stool tests and gastroscopy and colonoscopy with multiple biopsies were performed under sedation, and wireless enteroscopy capsules were used in three of the adult patients. Gastroscopy revealed mucosal gastritis in 4 patients, esophagitis in 1 patient and duodenitis in 1 patient, and histological findings showed chronic inflammation of the stomach and duodenum in 6 patients, inconsistent with celiac disease. The authors reported that preliminary findings were strongly consistent with previous descriptions of autistic enterocolitis, and supported a not-coincidental occurrence. They showed for the first time a small-intestinal involvement, suggesting a pan-enteric localization of this new inflammatory bowel disease.

• Also in 2005, a further paper by Wakefield, Ashwood et al (26) was published, assessing ileocolonic lymphoid nodular hyperplasia in ASD and normal control children. Some 148 consecutive children with ASD, with gastrointestinal symptoms, were investigated by ileocolonoscopy, with 74 ASD children and 23 normal controls undergoing upper gastrointestinal endoscopy. The presence of lymphoid nodular hyperplasia was significantly greater in ASD children compared with controls, in the ileum (129 out of 144, compared with 8 out of 27 controls), and in the colon (88 out of 148, compared with 7 out of 30 controls). Comparative percentages were 90% vs 30% and 59% vs 23%. This was whether or not controls had co-existent colonic inflammation. The severity of ILNH was significantly greater in ASD children compared with controls, with moderate-to-severe ILNH present in 98 out of 144 ASD children compared with 4 out of 27 controls; percentages were 68% and 15%. On histopathological examination, hyperplasic lymphoid follicles were significantly more prevalent in the ileum of ASD children (84 out of 138, or 61%) compared with normal controls (2 out of 23, or 9%). The data thus further corroborated the finding that ileal lymphoid nodular hyperplasia is a significant pathological finding in autistic children.
• Additionally in 2005, a study (27) was published by Gonzalez, Lopez et al, seeking evidence of immunological alterations in 68 autistic children ages 22 months to 11 years and presenting with digestive systems, and examining biopsies from their digestive tracts. Endoscopies and colosopies were undertaken, with biopsies of the esophagus, stomach, duodenum and colon, with verification of presence of inflammation, eosiophil infiltration, lymphoid nodular hyperplasia and CD-4 and CD-8 cells. The results were that lymphoid nodular hyperplasia was discovered in 2/68 esophagus, 6/68 stomachs, 8/68 duodenums and 36/68 (53%) of colons. Eosiophil infiltration with more than 20 eosiphils per field were found in 3/68 eosphagus, 1/68 stomach, 8/68 duodenum and 24/68 (35%) colons. Inflammatory reactions were found in 56/68 (82%) esophogitis, 64/68 (94%) gastritis, and all (100%) presented with duodenitis and colitis. CD-4/CD-8 relationship existed of >3 in 42/68 (62%) and <1 in 16/68. The authors concluded that the children presented immunological and immunohistochemical alterations of the biopsies of their digestive tracts, and that there was a significant finding of lymphoid nodular hyperplasia, eosiophilinfiltration, and that prevalence of greater CD-4 than CD-8 cells in the inflammation of the intestinal wall demonstrated in favour of a Th2 type allergic reaction.

Taken together, the above now provide very convincing evidence from a number of wholly-independent groups of researchers of a link between the novel inflammatory bowel disease of ileal lymphoid nodular hyperplasia and regressive autism.

The Link Between Inflammatory Bowel Disease and Measles Virus

These autism/inflammatory bowel disease findings were followed by findings that linked the novel form of inflammatory bowel disease with persistent measles virus in the gut of affected children:

• A paper (29) presented in the year 2000 by Singh to the US House of Representatives Committee on Government Reform reported a hyperimmune response to the measles virus, with an association between measles virus antibody levels and incidence of brain autoantibody.

• An April 2000 paper (30) presented by O’Leary to the Committee on Government Reform reported the investigation whether measles virus was present n the gut biopsies of autistic children, and if so, where and how much. The paper reported that the biopsies of 24 out of 25 (96%) of the autistic children examined were positive for measles virus, and that amongst normal (non-autistic) controls, only 1 out of 15 children (6.6%) were positive, strongly suggesting a connection between measles virus and autism.

• A February 2002 paper (31) by Uhlmann, Wakefield, O’Leary et al investigated  the presence of persistent measles virus in the intestinal tissue of 91 autistic patients with new-variant inflammatory bowel disease (ileal-lymphoid nodular hyperplasia, or ILNH). Patient samples were provided by the Royal Free Hospital, London. The patients were ages 3-14, and 77 out of 91 were male. There were 70 developmentally-normal controls ages 0-17 years, 47 out of 70 being boys. Of these, 19 had normal ileal biopsies, 13 had mild non-specific chronic inflammatory changes, 3 had ILNH and had been investigated for abdominal pain, 8 had Crohn’s Disease, one had ulcerative colitis, and 26 had undergone appendicectomy for abdominal pain including appendicitis. The results were that 75 out of 91 patients with a histologically-confirmed diagnosis of ileal-lymphoid nodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue, compared with 5 out of 70 controls. Using TaqMan RT-PCR techniques, 70 out of 91 affected children were positive for measles virus, compared with 4 out of 70 controls. Of the controls, measles virus was not detected in normal children or children with isolated ileal-lymphoid nodular hyperplasia. However, 4 out of 26 appendicectomy samples harboured measles virus genome; the study suggested that the prevalence of measles virus in the general population warranted further investigation. The study concluded that the data confirmed an association between the presence of gut pathology and of measles virus in children with developmental disorder. The study did not exclude the presence of alternative infections to measles virus.

• A February 2004 paper (32) presented by Singh to the US Institute of Medicine, Washington DC, measured antibodies in autistic children to five viruses, measles, mumps, rubella, CMV  and human herpes virus 6. Researchers found that the antibody level of the measles virus alone, and not the other four, was significantly higher in autistic children than in normal children. The research also found a correlation between measles antibody and brain autoimmunity, which was marked by myelin basic protein antibodies. The two markers correlated in over 90% of the autistic children tested for them, suggesting a causal link between measles virus and autoimmunity in autism. The serology to other viruses and other brain autoantibodies did not show this correlation. This suggested a temporal link of measles virus in the etiology of autism.

Taken with the present study by Walker, Hepner et al, this provides significant evidence for a link between measles virus and ileal lymphoid nodular hyperplasia, with the latter’s already-demonstrated onward link with regressive autism.

The Link Between Measles Virus and Vaccination with MMR

• A July 2002 paper (33) presented by O’Leary reported that the strain of measles virus used in MMR had been detected in the gut tissue of 12 autistic children. Medical histories had indicated that each of the children had developed autism after the date of receipt of MMR, and none had exhibited outward signs of measles infection before becoming autistic

• An April 2000 study (34) by Kawashima, Takayuki et al confirmed that, amongst 8 patients with Crohn’s Disease, 3 patients with ulcerative colitis and 9 patients with autistic enterocolitis, and 8 children who were either healthy or who had SSPE, SLE or HIV-1, 1 out of 8 patients with CD, 1 out of 3 patients with UC and 3 out of 9 patients with autism were positive for measles virus. Controls were all negative. The sequences from patients with CD shared the characteristics of wild-strain measles virus. The sequences from patients with UC and from patients with autism were consistent with vaccine strain measles virus. These results were consistent with patients’ medical histories, and point to a connection between autism and vaccine-strain measles virus.

• A May 2002 paper (35) by Singh, Nelson, Jensen and Bradstreet found that a significant percentage of autistic children examined had antibodies to myelin basic protein (up to 88% positive) and to MMR (up to 65% positive). Normal children did not exhibit these antibodies. The analysis of paired samples (serum and cerebral spinal fluid from 7 autistic children also revealed a high degree of serological association between MMR and myelin basic protein. Some 50% of CSF had MMR antibodies, 86% of CSF had MBP antibodies, 75% of sera had MMR antibodies and 100% of sera had MBP antibodies. Therefore there was a strong correlation between MMR antibodies and myelin basic protein antibodies. By using monoclonal antibodies, the authors characterized that the MMR antibodies were due to the measles sub-unit, but not to the mumps or rubella sub-units, of MMR. In the light of this, the authors suggested that in some cases of autism, MMR might cause autoimmunity, and it might be doing so by bringing on an atypical measles infection that manifests neurological symptoms.

• An earlier 1999 paper (36) by Bitnun has previously and independently confirmed the presence of measles virus in the brain tissue of a previously-healthy child following exposure to MMR, when the child had no history of wild measles infection.

• A February 2004 paper (37) by Bradstreet, O’Leary, Sheils et al to the US Institute of Medicine, and subsequently published later that year, reported that three children with regressive autism had undergone cerebrospinal fluid assessment, including for measles virus. All three had had concomitant onset of gastrointestinal symptoms and had already had measles virus genomic RNA detected in biopsies of ileal-lymphoid nodular hyperplasia. None of the cases nor non-autistic controls had any history of measles exposure other than possibly via MMR. Serum and cerebrospinal fluid samples were also evaluated for antibodies to measles virus and myelin basic protein. The result was that measles virus f-gene was present in the cerebrospinal fluid of all three autistic cases but not in non-autistic controls. Further, serum anti-myelin basic protein autoantibodies were detected in all children with autistic encephalopathy. Anti-MBP and measles virus antibodies were detected in the CSF of two cases, but the third had neither. The study concluded that the findings were consistent with a measles-virus etiology for autistic encephalopathy, indicating the possibility of a virally-driven cerebral immunopathology in some cases of regressive autism. The virus genome found in the autistic children was “exclusively consistent with vaccine strain”.

• A May 2006 study (38) by Wakefield, Stott and Limb investigated the hypothesis as to whether a dose-response effect of measles-containing vaccine on intestinal pathology existed. If it did exist, this would constitute evidence of a causal association. In the study, children with normal early development and autistic-like developmental regression were divided into two groups. Children were divided into two groups: some 23 re-exposed children, i.e. those who had received more than one dose of a measles-containing vaccine (MCV), and 23 children who had received only one dose of MCV. The groups were matched for sex, age and time that had elapsed from first exposure to time of endoscopy. Comparisons made included secondary gastrointestinal (GI) and related physical symptoms,, and “observer-blinded” scores of endoscopic and histological disease. The results were that re-exposed children scored significantly higher than only-once-exposed for secondary physical symptoms, including incontinence, presence of severe ileal-lymphoid nodular hyperplasia, the number of biopsies with epithelial damage, and number of children with acute inflammation. Markers of acute inflammation include number of children affected, and proportion of biopsies affect. The conclusion of the study was that the data confirmed a re-challenge effect (i.e. a double-hit effect) of measles-containing vaccines on symptoms, and also confirmed a biological gradient effect upon intestinal pathology. These findings thus link exposure to measles-containing vaccines to autistic-like regression and enterocolitis. (Note: it was stated in April 2001 by the Vaccine Safety Committee of the US Institute of Medicine that in the context of MMR and autism “challenge re-challenge would constitute strong evidence of an association”.

References

(on autism)

(1) Wakefield et al, Inflammatory Bowel Disease Study Group, Royal Free Hospital, London, Ileal Lymphoid Nodular Hyperplasia, Non-Specific Colitis and Pervasive Developmental Disorder in Children, Lancet, 28th February 1998

(2) Jyonouchi, Sun and Le, Department of Pediatrics, University of Minnesota, Pro-inflammatory and Regulatory Cytokine Production Associated with Innate and Adaptive Immune Responses in Children with Autism Spectrum Disorders and Developmental Regression, Journal of Neuroimmunology, 120 (2001) 170-179

(3) Blaxill, The Rising Incidence of Autism, Associations with Thimerosal, presented to the US Institute of Medicine, July 2001

(4) Statement by Dr. Jose Cordero on behalf of the US Centers for Disease Control and Prevention, based on CDC data on 24,673 children, 4^th May 2006, source Reuters

(5) Interview with ABC News, 4^th May

(6) Source: The Scottish Executive, Edinburgh.

(7) Study by Byrd et al, MIND Institute, University of California at Davis, The Epidemiology of Autism in California, October 2002

(8) Yeargin-Allsopp, Rice et al, Prevalence of Autism in a US Metropolitan Area, Journal of the American Medical Association, 2003, Jan 1^st, 289: (1): pp49-55.

(9) Gurney, Fritz et al, Analysis of Prevalence Trends of Autism Spectrum Disorder in Minnesota, Archives of Pediatric Adolescent Medicine, 2003, 157: pp622-627

(10) Yazbak, Autism in the United States – A Perspective, Journal of American Physicians and Surgeons, Vol 8, No. 4, Winter 2003

(11) Blaxill, What’s Going On? – The Question of Time Trends in Autism, Public Health Reports, Nov-Dec 2004, Vol 119, pp536-551

(12) Newschaffer, Falb et al, Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, and Divisions of Epidemiology and Clinical Research, University of Minnesota, Minneapolis, National Autism Prevalence Trends from United States Special Education Data, Pediatrics, Vol 115 No. 3 March 2005 pp277-282

(on the link between autism and a novel form of inflammatory bowel disease)

(13) (as per reference (1)) Wakefield et al, Inflammatory Bowel Disease Study Group, Royal Free Hospital London, Ileal Lymphoid Nodular Hyperplasia, Non Specific Colitis and Pervasive Development Disorder in Children, Lancet, 28^th February 1998

 (14) Horvath, Papadimitiou et al, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Gastrointestinal Abnormalities in Children With Autistic Disorder, Journal of Pediatrics, 1999 November, Vol 135 (5), pp559-563

(15) Wakefield, Anthony et al, Enterocolitis in Children with Developmental Disorders, American Journal of Gastroenterology, Sept 2000, Vol 95, No. 9, pp2285-2295

(16) Furlano, Anthony et al, Colonic CD8 and T-Cell Infiltration With Epithelial Damage in Children with Autism, Journal of Pediatrics, 2001; 138; No. 3, 366-372

(17) Paper by Dr. Timothy Buie, Harvard Massachusetts General Hospital, presented to the Oasis 2001 Conference for Autism, Portland, Oregon, November 2001.

(18) Wakefield, Anthony, Montgomery et al, Inflammatory Bowel disease Study Group, Royal Free Hospital, University College Medical School, London, and Coombe Women’s Hospital and Trinity College Dublin, The Concept of Enterocolonic Encepalopathy, Autism and Opioid Receptor Ligands, Aliment Pharmacological Ther, 16: pp663-674.

(19) Presentation by Krigsman to the US Congressional Committee on Government Reform’s June 2002 hearing, The Status of Research into Vaccine Safety and Autism, held in Washington DC.

(20) Ashwood, Murch et al, Royal Free Hospital, London, Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Extensive Mucosal Immunopathology, Journal of Clinical Immunology, Vol 23 No. 6 Nov 2003 pp504-517.

(21) Torrente, Anthony et al, Centre for Pediatric Gastroenterology, Royal Free Hospital and University College Medical School, London, Focal-Enhanced Gastritis in Regressive Autism, With Features Distinct from Crohn’s and Helicobacter Pylori Gastritis, American Journal of Gastroenterology, Vol 99, Issue 4, p598, April 2004

(22) Ashwood, Anthony et al, Spontaneous Mucosal Lymphocyte Cytokine Profiles in Children with Autism and Gastrointestinal Symptoms: Mucosal Immune Activation and Reduced Counter-Regulatory Interleukin-10, Journal of Clinical Immunology, Vol 24, No. 6, November 2004.

(23) Jyonouchi, Geng et al, Department of Pediatrics, New Jersey Medical School, Dysregulated Innate Immune Responses in Young Children with Autistic Spectrum Disorders  -  Their Relationship in Gastrointestinal Symptoms and Dietary Intervention, Neuropsychobiology, February 2005, 51 (2) pp77-85.

(24) Letter by Balzola, Barbon et al, Department of Gastroenterology, Department of Neuropsychiatry for Children, Department of Pediatric Gastroenterology and Department of Biomedical Sciences and Human Oncology, University of Turin, Pan-Enteric 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?, American Journal of Gastroenterology, 2005; 100 (4) p979

(25) Balzola, Daniela et al, Department of Gastroenterology, Department of Neuropsychiatry for Children, Department of Pediatric Gastroenterology and Department of Biomedical Science and Human Oncology, University of Turin, Autistic Enterocolitis  -  Autistic Enterocolitis: Confirmation of a New Inflammatory Bowel Disease in an Italian Cohort of Patients, paper presented to the American Gastroenterological Association, May 2005 and published in Gastroenterology 2005: 128 Suppl 2, A-303.

(26) Wakefield, Ashwood et al, The Significance of Ileo-Colonic Lymphoid Nodular Hyperplasia in Children with Autistic Spectrum Disorder, European Journal of Gastroenterology and Hepatology, 2005, Vol 17 No. 8.

(27) Gonzalez, Lopez et al, Endoscopic and Histological Characteristics of the Digestive Mucosa in Autistic Children with Gastrointestinal Symptoms: Preliminary Report, G.E.N. Suplemento Especial de Pediatria, no. 1, 2005; pp41-47

 (on the link between inflammatory bowel disease and measles virus)

(28) Uhlmann, Sheils et al, Department of Pathology, Coombe Women’s Hospital Dublin, Trinity College Dublin and Royal Free Hospital London, Measles Virus in Reactive Lympho-Nodular Hyperplasia and Ileo-colitis of Children

 (29) Paper presented by Dr. Vijendra Singh, University of Michigan College of Pharmacy, to the US House of Representatives Committee on Government Reform, Washington DC, 2000

 (30) Paper presented by Professor John O’Leary, Dublin Women’s Hospital, to the US House of Representatives Committee on Government Reform, Washington DC, April 2000

(31) Paper By Uhlmann, Wakefield, O’Leary et al, Potential Viral Pathogenic Mechanism For New Variant Inflammatory Bowel Disease, Journal of Clinical Pathology, Molecular Pathology, 2002, 55, 0-6, published 6th February 2002

(32) Paper by Singh, Department of Biology Center for Integrated Biosystems, Utah State University, Logan, Autism, Vaccines and Immune Reactions, presented to the Institute of Medicine, Washington DC, February 2004

(on the link between measles virus and vaccination with MMR)

(33) Paper presented by O’Leary, Coombe Women’s Hospital and Trinity College Dublin to the Pathological Society of Great Britain and Ireland, July 2002

(34) Kawashima, Takayuki et al, Detection and Sequencing of Measles Virus from Peripheral Mononuclear Cells from Patients with Inflammatory Bowel Disease and Autism, Digestive Diseases & Science, Vol 45, No. 4, April 2000, pp723-729

(35) Singh, Nelson, Jensen and Bradstreet, Abnormal Measles Serology and Autoimmunity in Autistic Children, Journal of Allergy and Clinical Immunology 109 (1) S232, January 2002, and also presented to the 102^nd General Meeting of the American Society for Microbiology, Salt Lake City, Utah, May 2002

(36) Bitnun et al, Measles Inclusion-Body Encephalitis Caused by the Vaccine Strain of Measles Virus, Clinical Infectious Diseases Journal, 1999, 29 855-61 (October)

(37) Bradstreet, O’Leary, Sheils et al, Detection of Measles Virus Genomic RNA in Cerebrospinal Fluid in Children with Regressive Autism by TaqMan RT-PCR: A Report of Three Cases, summarized at the Institute of Medicine, February 2004 and subsequently published as Bradstreet, Dahr et al, Detection of Measles Virus Genomic RNA in Cerebrospinal Fluid of Children with Regressive Autism: A Report of Three Cases, Journal of American Physicians and Surgeons, Vol 9, No. 2 Summer 2004

(38) Wakefield, Stott and Limb, Gastrointestinal Comorbidity, Autistic Regression and Measles-Containing Vaccines; Positive Re-challenge and Biological Gradient, Medical Veritas 3 (2006) 796-802