|| brian deer |||MMR: THE LANCET PAPER|
MMR scare: the Andrew Wakefield Lancet paper which launched claims into medical research
This page is research from an investigation by Brian Deer for The Sunday Times of London and the UK's Channel 4 Television into a campaign linking the MMR children's vaccine with autism. | Go to part I: The Lancet scandal | Go to part II: The Wakefield factor
This version of the
February 1998 Lancet paper which triggered the MMR scare,
republished for analysis, omits three visual figures from
the printed paper: a graph titled "urinary
methylmalonic-acid excretion in patients and
controls," pictures titled "endoscopic view of
terminal ileum in child three and in a child with
endoscopically and histologically normal ileum and
colon," and "Biopsy sample from terminal ileum
and from colon". The continuing investigation
unearthed an earlier version of this paper, which permitted a comparative analysis, revealing major differences
All children were antiendomyseal-antibody negative and common enteric pathogens were not identified by culture, microscopy, or serology. Urinary methylmalonic-acid excretion was significantly raised in all eight children who were tested, compared with age-matched controls (p=0·003; figure 1). Abnormal laboratory tests are shown in table 1.
The caecum was seen in all cases, and the ileum in all but two cases. Endoscopic findings are shown in table 1. Macroscopic colonic appearances were reported as normal in four children. The remaining eight had colonic and rectal mucosal abnormalities including granularity, loss of vascular pattern, patchy erythema, lymphoid nodular hyperplasia, and in two cases, aphthoid ulceration. Four cases showed the "red halo" sign around swollen caecal lymphoid follicles, an early endoscopic feature of Crohn's disease.3 The most striking and consistent feature was lymphoid nodular hyperplasia of the terminal ileum which was seen in nine children (figure 2), and identified by barium follow-through in one other child in whom the ileum was not reached at endoscopy. The normal endoscopic appearance of the terminal ileum (figure 2) was seen in the seven children whose images were available for comparison. [note: figures 1 - 3 are omitted from this online version]
Histological findings are summarised in table 1.
Terminal ileum A reactive lymphoid follicular hyperplasia was present in the ileal biopsies of seven children. In each case, more than three expanded and confluent lymphoid follicles with reactive germinal centres were identified within the tissue section (figure 3). There was no neutrophil infiltrate and granulomas were not present.
Colon The lamina propria was infiltrated by mononuclear cells (mainly lymphocytes and macrophages) in the colonic-biopsy samples. The extent ranged in severity from scattered focal collections of cells beneath the surface epithelium (five cases) to diffuse infiltration of the mucosa (six cases). There was no increase in intraepithelial lymphocytes, except in one case, in which numerous lymphocytes had infiltrated the surface epithelium in the proximal colonic biopsies. Lymphoid follicles in the vicinity of mononuclear-cell infiltrates showed enlarged germinal centres with reactive changes that included an excess of tingible body macrophages.
There was no clear
correlation between the endoscopic appearances and the
histological findings; chronic inflammatory changes were
apparent histologically in endoscopically normal areas of
the colon. In five cases there was focal acute
inflammation with infiltration of the lamina propria by
neutrophils; in three of these, neutrophils infiltrated
the caecal (figure 3) and rectal-crypt epithelium. There
were no crypt abscesses. Occasional bifid crypts were
noted but overall crypt architecture was normal. There
was no goblet-cell depletion but occasional collections
of eosinophils were seen in the mucosa. There were no
granulomata. Parasites and organisms were not seen. None
of the changes described above were seen in any of the
normal biopsy specimens.
We describe a pattern of colitis and ileal-lymphoid-nodular hyperplasia in children with developmental disorders. Intestinal and behavioural pathologies may have occurred together by chance, reflecting a selection bias in a self-referred group; however, the uniformity of the intestinal pathological changes and the fact that previous studies have found intestinal dysfunction in children with autistic-spectrum disorders, suggests that the connection is real and reflects a unique disease process.
Asperger first recorded the link between coeliac disease and behavioural psychoses.4 Walker-Smith and colleagues5 detected low concentrations of alpha-1 antitrypsin in children with typical autism, and D'Eufemia and colleagues6 identified abnormal intestinal permeability, a feature of small intestinal enteropathy, in 43% of a group of autistic children with no gastrointestinal symptoms, but not in matched controls. These studies, together with our own, including evidence of anaemia and IgA deficiency in some children, would support the hypothesis that the consequences of an inflamed or dysfunctional intestine may play a part in behavioural changes in some children.
The "opioid excess" theory of autism, put forward first by Panksepp and colleagues7 and later by Reichelt and colleagues8 and Shattock and colleagues9 proposes that autistic disorders result from the incomplete breakdown and excessive absorption of gut-derived peptides from foods, including barley, rye, oats, and caesin from milk and dairy produce. These peptides may exert central-opioid effects, directly or through the formation of ligands with peptidase enzymes required for breakdown of endogenous central-nervous-system opioids,9 leading to disruption of normal neuroregulation and brain development by endogenous encephalins and endorphins.
One aspect of impaired intestinal function that could permit increased permeability to exogenous peptides is deficiency of the phenyl-sulphur-transferase systems, as described by Waring.10 The normally sulphated glycoprotein matrix of the gut wall acts to regulate cell and molecular trafficking.11 Disruption of this matrix and increased intestinal permeability, both features of inflammatory bowel disease,17 may cause both intestinal and neuropsychiatric dysfunction. Impaired enterohepatic sulphation and consequent detoxification of compounds such as the phenolic amines (dopamine, tyramine, and serotonin)12 may also contribute. Both the presence of intestinal inflammation and absence of detectable neurological abnormality in our children are consistent with an exogenous influence upon cerebral function. Lucarelli's observation that after removal of a provocative enteric antigen children achieved symptomatic behavioural improvement, suggests a reversible element in this condition.13
Despite consistent gastrointestinal findings, behavioural changes in these children were more heterogeneous. In some cases the onset and course of behavioural regression was precipitous, with children losing all communication skills over a few weeks to months. This regression is consistent with a disintegrative psychosis (Heller's disease), which typically occurs when normally developing children show striking behaviour changes and developmental regression, commonly in association with some loss of coordination and bowel or bladder function.14 Disintegrative psychosis is typically described as occurring in children after at least 2-3 years of apparently normal development.
Disintegrative psychosis is recognised as a sequel to measles encephalitis, although in most cases no cause is ever identified.14 Viral encephalitis can give rise to autistic disorders, particularly when it occurs early in life.15 Rubella virus is associated with autism and the combined measles, mumps, and rubella vaccine (rather than monovalent measles vaccine) has also been implicated. Fudenberg16 noted that for 15 of 20 autistic children, the first symptoms developed within a week of vaccination. Gupta17 commented on the striking association between measles, mumps, and rubella vaccination and the onset of behavioural symptoms in all the children that he had investigated for regressive autism. Measles virus18,19 and measles vaccination20 have both been implicated as risk factors for Crohn's disease and persistent measles vaccine-strain virus infection has been found in children with autoimmune hepatitis.21
We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described. Virological studies are underway that may help to resolve this issue.
If there is a causal link between measles, mumps, and rubella vaccine and this syndrome, a rising incidence might be anticipated after the introduction of this vaccine in the UK in 1988. Published evidence is inadequate to show whether there is a change in incidence22 or a link with measles, mumps, and rubella vaccine.23 A genetic predisposition to autistic-spectrum disorders is suggested by over-representation in boys and a greater concordance rate in monozygotic than in dizygotic twins.15 In the context of susceptibility to infection, a genetic association with autism, linked to a null allele of the complement (C) 4B gene located in the class III region of the major-histocompatibility complex, has been recorded by Warren and colleagues.24 C4B-gene products are crucial for the activation of the complement pathway and protection against infection: individuals inheriting one or two C4B null alleles may not handle certain viruses appropriately, possibly including attenuated strains.
Urinary methylmalonic-acid concentrations were raised in most of the children, a finding indicative of a functional vitamin B12 deficiency. Although vitamin B12 concentrations were normal, serum B12 is not a good measure of functional B12 status.25 Urinary methylmalonic-acid excretion is increased in disorders such as Crohn's disease, in which cobalamin excreted in bile is not reabsorbed. A similar problem may have occurred in the children in our study. Vitamin B12 is essential for myelinogenesis in the developing central nervous system, a process that is not complete until around the age of 10 years. B12 deficiency may, therefore, be a contributory factor in the developmental regression.26
We have identified a chronic enterocolitis in children that may be related to neuropsychiatric dysfunction. In most cases, onset of symptoms was after measles, mumps, and rubella immunisation. Further investigations are needed to examine this syndrome and its possible relation to this vaccine.
Up to Jan 28, a further 40 patients have been assessed; 39 with the syndrome.
A J Wakefield was the senior scientific investigator. S H Murch and M A Thomson did the colonoscopies. A Anthony, A P Dhillon, and S E Davies carried out the histopathology. J Linnell did the B12 studies. D M Casson and M Malik did the clinical assessment. M Berelowitz did the psychiatric assessment. P Harvey did the neurological assessment. A Valentine did the radiological assessment. JW-S was the senior clinical investigator.
This study was supported
by the Special Trustees of Royal Free Hampstead NHS Trust
and the Children's Medical Charity. We thank Francis Moll
and the nursing staff of Malcolm Ward for their patience
and expertise; the parents for providing the impetus for
these studies; and Paula Domizo, Royal London NHS Trust,
for providing control tissue samples.
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