The Wakefield et al. paper (short version)

Summary
Background
We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder.
Methods
12 children (mean age 6 years [range 3–10], 11 boys) were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, examined.
Findings
Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioural disorders included autism (nine), disintegrative psychosis (one), and possible postviral or vaccinal encephalitis (two). There were no focal neurological abnormalities and MRI and EEG tests were normal. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age- matched controls (p=0·003), low haemoglobin in four children, and a low serum IgA in four children.
Interpretation
We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.

Introduction
We saw several children who, after a period of apparent normality, lost acquired skills, including communication. They all had gastrointestinal symptoms, including abdominal pain, diarrhoea, and bloating and, in some cases, food intolerance. We describe the clinical findings, and gastrointestinal features of these children.

Discussion
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. 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 colleagues and later by Reichelt and colleagues 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. The normally sulphated glycoprotein matrix of the gut wall acts to regulate cell and molecular trafficking. Disruption of this matrix and increased intestinal permeability, both features of inflammatory bowel disease, 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.

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. 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. Viral encephalitis can give rise to autistic disorders, particularly when it occurs early in life. Rubella virus is associated with autism and the combined measles, mumps, and rubella vaccine (rather than monovalent measles vaccine) has also been implicated. Fudenberg noted that for 15 of 20 autistic children, the first symptoms developed within a week of vaccination. Gupta 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.

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 incidence or a link with measles, mumps, and rubella vaccine. 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. 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. 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. 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.

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.

— AJ Wakefield, SH Murch, A Anthony, J Linnell, DM Casson, M Malik, M Berelowitz, AP Dhillon, MA Thomson, P Harvey, A Valentine, SE Davies, JA Walker-Smith

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