clinical evidence for the link between autism and a novel form of
inflammatory bowel disease
•
clinical evidence for the link between inflammatory bowel disease and
measles virus
•
clinical evidence for the link between measles virus and vaccination with MMR
•
some of the other wider safety concerns over MMR
(A) 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. Full publication
references are at the end of these notes.
•
The possible association between MMR vaccine, regressive autism and
intestinal symptoms was first recounted 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 Wakefield and
colleagues at the Royal Free were reported in The Lancet as a clinical
case series in February 1998 (1). 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 still stands as an important initial clue as to the
causes of regressive autism.
•
A group of researchers led by
Horvath (2) 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 (3) 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 (4) 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 (5) 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 (6) published in September 2002 by Wakefield, Anthony,
Montgomery et al 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 (7)
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 (8) published by Ashwood, Murch et al 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 (9) by Torrente, Anthony et al 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 (10) by Ashwood, Anthony et al 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 (11) by
Jyonouchi, Geng et al 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 published letter
(12) by Balzola, Barbon et al, 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 (13) 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
(14) by Wakefield, Ashwood et al 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
(15) 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.
(B) 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 (16) by
Uhlmann,
Sheils et al, noting that measles virus nucleoprotein (N antigen) had been
detected in association with follicular dendritic cells (FDC) in patients, and
seeking molecular confirmation of this result, found that :solution phase RT PCR
yielded specific measles virus N gene amplification in affected children
(10/10), and identified distinct measles virus genome in FDC reactive follicular
centres by in-cell RNA amplification. None of the normal controls showed any
evidence of measles virus genome. The data highlighted a possible causal link
between measles virus infection and ileo-colonic lymphoid nodular hyperplasia in
affected children.
•
A paper (17) 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 (18) 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 (19) 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 (20)
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.
An early-report presentation by
Walker, Hepner et al, at the International Meeting for Autism Research,
Montreal, June 2006, reported that PCR analysis on terminal ileum biopsy tissue
from an initial 82 patients found 70 (85%) positive for measles virus f-gene
amplicon. These preliminary results confirm earlier findings of measles virus
RNA in the terminal ileum. Full publication of this study is anticipated.
The above studies provide
significant evidence for a link between measles virus and ileal lymphoid nodular
hyperplasia, with the latter’s earlier-demonstrated onward link with regressive
autism.
(C) The Link Between Measles
Virus and Vaccination with MMR
•
A July 2002 paper (21) 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 (22) 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 (23) 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 (24) 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 (25) 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 (26) 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”.)
Taken together, with the Walker,
Hepner et al study, the above points to MMR as the means by which measles virus
enters and persists in the gut, leading to ileal-lymphoid nodular hyperplasia,
and in turn leading to regressive autism. The evidence to fully explain the
complete causational mechanism by which this occurs is still emerging, and
clearly requires further urgent research.
The intestinal disease has the
features of a viral disease. Measles virus is known to infect the intestine, and
produces the features described originally by Wakefield and colleagues in 1998.
All the findings described in
the 1998 Lancet report by the Wakefield team - including the discovery of a
possible new type of inflammatory bowel disease, have therefore been
subsequently independently confirmed by other researchers in the US, in Italy
and in Venezuela.
The studies suggest that in some
children, brain damage leading to autism may be secondary to, or occur in
parallel with, a disease in the intestine, and that vaccine strain measles virus
has become the prime suspect in this complex investigation.
The findings to date have
important implications for our understanding and treatment of the complex
disorder of regressive autism.
(D) Wider Safety Concerns Over
MMR:
It is also instructive to
examine the original, and any subsequent, safety studies of MMR.
•
An authoritative independent review by the Cochrane Collaboration
(27) of the safety studies of MMR vaccine concluded that “the design and
reporting of safety outcomes in MMR vaccine studies, both pre- and
post-marketing, are largely inadequate”. It further confirmed that
neither before nor after the introduction of the MMR vaccine were proper
safety trials carried out.
•
A more recent review (28) from the same organization identified that safety
studies for the single measles vaccine were better than those conducted for
MMR: “We found only limited evidence of safety of MMR compared to the single
component vaccines, that had a low risk of bias”. The authors of the
Cochrane reviews were highly critical of the safety studies of MMR, which
they stated “need to be improved”. Cochrane mentioned a specific
concern that safety studies followed up the children involved for no more
than three weeks, except for one study that lasted just six weeks.
•
Concern over MMR’s safety has
been expressed (29) by a key former scientific adviser to the UK licensing
authorities. Dr. Peter Fletcher, former Principal Medical Officer in the (then)
UK Medicines Division, who was medical assessor to the Committee on Safety of
Medicines, commented: “Evidence on safety was very thin”, and “Too few children
were followed for a sufficient time... Big numbers were necessary, and computerised databases were already in place to permit this, but it was not
done... Caution should have ruled the day... There should have been strong
encouragement to conduct a 12-month observational study on 10,000-15,000
children...” (this was not done) "The granting of a product licence was premature.”
•
A year-2000 review (30 by
Wakefield & Montgomery examined early safety studies of MMR, by Buynak et al
1969, Stokes et al 1971, Minekawa et al 1974, Schwartz et al 1975, Crawford and
Gremillion 1981, and Miller et al 1987. The Buynak study identified viral
“interference”, but the follow-up period was only 12 days. The Stokes study
revealed persistent gastrointestinal problems in the US trial children, but the
follow-up was only 28 days. Stokes compared 228 MMR children with 106
unvaccinated controls. Data, from Philadelphia and Costa Rica and San Salvador,
was merged - a major methodological error. Gastroenteritis was found to be
significantly more common in the Philadelphia vaccines (24%) compared with the
unvaccinated Philadelphia controls (5.6%). No significant difference was found
between the vaccinated and the unvaccinated in Costa Rica and San Salvador
because of high ambient levels of gastroenteritis anyway (50% in vaccines, 44%
in controls). Combining all the data masked these instructive differences. There
was also significant “unrelated” illness in 39% of Philadelphia vaccines (otitis,
allergy, viral infection, abdominal pain), compared with 12.2% in controls. The
potential relevance of this was not seen at time. The Minekawa study confirmed
viral interference. The follow-up period was only 15 days. The Schwartz study
also merged its data, so provided insufficient insight, and again follow-up was
only 21 days. The study looked at two different populations, 282 children in
Ohio and 926 children in Santo Domingo, Dominican Republic. Again, the merging
of data from different countries was a serious error. No data was provided to
permit analysis of adverse events. Crawford and Gremillion’s study of USAF
recruits confirmed viral interference, but the follow-up period was only 19
days. Some 512 vaccines were compared with 835 unvaccinated controls. The study
noted increased fever and diarrhoea in those that received measles and rubella
vaccines simultaneously. But the potential effect of trivalent vaccine was only
seen as additive instead of potentially synergistic - a key point. The Eddes
study (a small UK study) in 1991 compared reactions to MMR with monovalent
measles vaccine. High rates of gastrointestinal disorders (41.9% and 37.8%) were
found, but the authors dismissed these as normal background illness. The Dr.
Elizabeth Miller study noted that diarrhoea was common (26% of vaccinees), but
the follow-up again was only 21 days. This was a major missed opportunity to
follow up a large cohort. The Stokes, Schwartz, Miller and Eddes studies were
therefore all too small or too superficial to pick up uncommon adverse events. The Plesner et al study of gait disturbance following MMR (Acta Paediatrica,
2000, 89, 58-63) confirmed an association, and indicated that more severe
cerebellar ataxias following MMR may be associated with residual cognitive
deficits.
Cochrane was forced to conclude
that “the safety record of MMR is probably best attested by its almost universal
use.” Or to put it another way, “the best evidence of MMR’s safety we can find
is that fact that it’s being widely used” - hardly a scientific test of a
product’s actual safety, particularly when the evidence of problems is through a
hitherto-unsuspected link between MMR and autism, that would not have been
monitored prior to 1998.
References
(on the link between autism and
a novel form of inflammatory bowel disease)
(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, 28th February 1998
(2) 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
(3) Wakefield, Anthony et al,
Enterocolitis in Children with Developmental Disorders, American Journal of
Gastroenterology, Sept 2000, Vol 95, No. 9, pp2285-2295
(4) 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
(5) Paper by Dr. Timothy Buie,
Harvard Massachusetts General Hospital, presented to the Oasis 2001 Conference
for Autism, Portland, Oregon, November 2001
(6) 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
(7) 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
(8) 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
(9) 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
(10) 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
(11) 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
(12) 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
(13) 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
(14) 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
(15) 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)
(16) 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
(17) 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
(18) 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
(19) 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
(20) 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)
(21) Paper presented by O’Leary, Coombe Women’s Hospital and Trinity College Dublin to the Pathological Society
of Great Britain and Ireland, July 2002
(22) 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
(23) 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 102nd General Meeting of the American Society for Microbiology,
Salt Lake City, Utah, May 2002
(24) Bitnun et al, Measles
Inclusion-Body Encephalitis Caused by the Vaccine Strain of Measles Virus,
Clinical Infectious Diseases Journal, 1999, 29 855-61 (October)
(25) 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
(26) Wakefield, Stott and Limb,
Gastrointestinal Comorbidity, Autistic Regression and Measles-Containing
Vaccines; Positive Re-challenge and Biological Gradient, Medical Veritas 3
(2006) 796-802
Again, taken with the latest
study by Walker, Hepner et al, this now provides evidence that it is highly
likely that MMR vaccine is the source of the measles virus that is in turn
linked via significant evidence with ileal lymphoid nodular hyperplasia, which
in turn is strongly and convincingly linked with regressive autism.
(on wider safety concerns over
MMR vaccine)
(27) Jefferson, Price et al,
Unintended Events Following Immunisation with MMR; A Systematic Review, Vaccine,
2003; 21: pp3954-3960
(28) Demicheli, Jefferson et al,
Vaccine For Measles, Mumps and Rubella in Children (Review), The Cochrane
Collaboration, published Wiley & Sons, UK, from The Cochrane Library, 2005,
Issue 4, art. No. CD004407
(29) Commentary by Dr. Peter
Fletcher, Journal of Adverse Drug Reactions & Toxicology, 2001, 20 (1), 47 63
Oxford University
(30) Wakefield & Montgomery
Through A Glass Darkly (A Look Back At MMR’s Safety Trials), Journal of
Adverse Drug Reactions, 2000 19(4), 265-283