Dental Information
 




MMR Vaccination and Autism

The Lancet, Volume 354, Number 9182     11 September 1999

By Andrew J Wakefield

Departments of Medicine and Histopathology, Royal Free and University College Medical School, Hampstead, London NW3 2PF, UK

Sir--Hypothesis testing and presentation of the outcome--either positive or negative--is a fundamental part of the scientific process. Accordingly we have published studies that both do,1 and do not2 support a role for measles virus in chronic intestinal inflammation: this is called integrity. The latest of these studies was strongly positive,3 and was accepted by the MRC Review in February, 1998. By contrast, Brent Taylor and colleagues (June 12, p 2026)4 have ignored the rules. They are inappropriately didactic in their conclusions, despite the weakness of their method and the contradictions in their data. A case-series analysis is unlikely to identify a relation between exposure and disease, in which the onset is insidious and in which, very often, there is diagnostic delay.

Taylor et al tested the hypothesis that there should be no temporal clustering of first parenteral concerns with measles, mumps, and rubella (MMR) vaccination. They identified a statistically significant excess risk by 6 months after MMR, which they dismiss, post hoc, as indicating parental recall bias. Had this been the case it should have been seen in both of their vaccine groups--those receiving MMR and those receiving any measles-containing vaccine. The excess risk was seen only in the MMR group; this is a fundamental flaw.

Temporal trends for autism in the USA (California*) and the UK (north-west London)

In 1998 the expected numbers of newly diagnosed autistic children in California should have been 105-263 cases, according to DSM-IV; the actual figure was 1685 new cases. The temporal trend in north-west London is almost identical, although the rise is delayed by about 10 years. The two countries use the same diagnostic criteria. The sequential trends are consistent with the timing of introduction of MMR to both regions.

*Data from Department of Developmental Services, Sacramento, 1987-98 (www.dds.ca.gov).

However, it pales into insignificance compared with their failure to declare the fact of an MMR catch-up campaign that was initiated in 1988 with the introduction of this vaccine. This campaign was targeted at children, whatever their age, who presumably had not received either monovalent mumps or rubella vaccine whatever their exposure status. As such it was a novel and, in terms of safety, untested policy. On the basis of Taylor and colleagues' inclusion criteria, and taking account of the catch-up campaign, then those first birth cohorts who actually received MMR (circa 1986) were precisely those in whom a doubling of the numbers of cases of autism were seen. Thereafter these numbers continue to increase strikingly. Omission of this essential fact--the catch-up campaign--requires explanation lest it be misconstrued.

Can the dramatic increase in autism be ascribed to change in diagnostic practice? Data from the recent California report from the Office of Developmental Services belie this contention. The figure juxtaposes the data from California with those from north-west London. Identical temporal trends are shown, with the rise in autism from a steady baseline value, coinciding with the introduction of MMR vaccine as the single strategy in both countries that use the same diagnostic criteria for autism.

These data expose the danger of not only setting out to prove, rather than to test, hypotheses but also presenting the data whether they are supportive or not. The full story has yet to unfold. In a timely BMJ newspeice,5 Begg who is described as a leading virologist, calls for MMR research to be terminated on the basis of Taylor and co-workers' report and a non-peer-reviewed so-called analysis in Current Problems of Pharmacovigilance. Clearly there are some things that may end-up being terminated as a consequence of these events: research into the possible link between MMR, autism, and bowel disease is not one of them.

Andrew J Wakefield

 

Departments of Medicine and Histopathology, Royal Free and University College Medical School, Hampstead, London NW3 2PF, UK

1 Lewin J, Dhillon AP, Sim R, Mazure G, Pounder RE, Wakefield AJ. Persistent measles virus infection of the intestine: confirmation by immunogold electron microscopy.  Gut  1995; 36: 564-69. [PubMed]

2 Chadwick N, Bruce IJ, Schepelman S, Pounder RE, Wakefield AJ. Measles virus RNA is not detected in inflammatory bowel disease using hybrid capture and reverse transcription followed by polymerase chain reaction.  J Med Virol  1998; 70: 305-11. [PubMed]

3 Montgomery SM, Morris DL, Pounder RE, et al. Paramyxovirus infections in childhood and subsequent inflammatory bowel disease.  Gastroenterology  1999; 116: 796-803. [PubMed]

4 Taylor B, Miller E, Farringdon CP, et al. MMR vaccine and autism: no epidemiological evidence for a causal association.  Lancet 1999; 353: 2026-29. [Text]

5 Bower H. New research demolishes link between MMR vaccine and autism. BMJ 1999; 318: 1643.

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children

A J Wakefield, S H Murch, A Anthony, J Linnell, D M Casson, M Malik, M Berelowitz, A P Dhillon, M A Thomson, P Harvey, A Valentine, S E Davies, J A Walker-Smith

http://www.thelancet.com/journal/vol351/iss9106/full/llan.351.9103.original_research.7540.1

Inflammatory Bowel Disease Study Group, University Departments of Medicine and Histopathology (A J Wakefield FRCS, A Anthony MB, J Linnell PhD, A P Dhillon MRCPath, S E Davies MRCPath) and the University Departments of Paediatric Gastroenterology (S H Murch MB, D M Casson MRCP, M Malik MRCP, M A Thomson FRCP, J A Walker-Smith FRCP,), Child and Adolescent Psychiatry (M Berelowitz FRCPsych), Neurology (P Harvey FRCP), and Radiology (A Valentine FRCR), Royal Free Hospital and School of Medicine, London NW3 2QG, UK

Correspondence to: Dr A J Wakefield

Summary
Introduction
Patients and methods
Results
Discussion
References

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, and immunological profiles were 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.

Lancet 1998; 351: 637-41

See Commentary

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.

Patients and methods

12 children, consecutively referred to the department of paediatric gastroenterology with a history of a pervasive developmental disorder with loss of acquired skills and intestinal symptoms (diarrhoea, abdominal pain, bloating and food intolerance), were investigated. All children were admitted to the ward for 1 week, accompanied by their parents.

Clinical investigations

We took histories, including details of immunisations and exposure to infectious diseases, and assessed the children. In 11 cases the history was obtained by the senior clinician (JW-S). Neurological and psychiatric assessments were done by consultant staff (PH, MB) with HMS-4 criteria.1 Developmental histories included a review of prospective developmental records from parents, health visitors, and general practitioners. Four children did not undergo psychiatric assessment in hospital; all had been assessed professionally elsewhere, so these assessments were used as the basis for their behavioural diagnosis.

After bowel preparation, ileocolonoscopy was performed by SHM or MAT under sedation with midazolam and pethidine. Paired frozen and formalin-fixed mucosal biopsy samples were taken from the terminal ileum; ascending, transverse, descending, and sigmoid colons, and from the rectum. The procedure was recorded by video or still images, and were compared with images of the previous seven consecutive paediatric colonoscopies (four normal colonoscopies and three on children with ulcerative colitis), in which the physician reported normal appearances in the terminal ileum. Barium follow-through radiography was possible in some cases.

Also under sedation, cerebral magnetic-resonance imaging (MRI), electroencephalography (EEG) including visual, brain stem auditory, and sensory evoked potentials (where compliance made these possible), and lumbar puncture were done.

Laboratory investigations

Thyroid function, serum long-chain fatty acids, and cerebrospinal-fluid lactate were measured to exclude known causes of childhood neurodegenerative disease. Urinary methylmalonic acid was measured in random urine samples from eight of the 12 children and 14 age-matched and sex-matched normal controls, by a modification of a technique described previously.2 Chromatograms were scanned digitally on computer, to analyse the methylmalonic-acid zones from cases and controls. Urinary methylmalonic-acid concentrations in patients and controls were compared by a two-sample t test. Urinary creatinine was estimated by routine spectrophotometric assay.

Children were screened for antiendomyseal antibodies and boys were screened for fragile-X if this had not been done before. Stool samples were cultured for Campylobacter spp, Salmonella spp, and Shigella spp and assessed by microscopy for ova and parasites. Sera were screened for antibodies to Yersinia enterocolitica.

Histology

Formalin-fixed biopsy samples of ileum and colon were assessed and reported by a pathologist (SED). Five ileocolonic biopsy series from age-matched and site-matched controls whose reports showed histologically normal mucosa were obtained for comparison. All tissues were assessed by three other clinical and experimental pathologists (APD, AA, AJW).

Ethical approval and consent

Investigations were approved by the Ethical Practices Committee of the Royal Free Hospital NHS Trust, and parents gave informed consent.

Results

Clinical details of the children are shown in tables 1 and 2. None had neurological abnormalities on clinical examination; MRI scans, EEGs, and cerebrospinal-fluid profiles were normal; and fragile X was negative. Prospective developmental records showed satisfactory achievement of early milestones in all children. The only girl (child number eight) was noted to be a slow developer compared with her older sister. She was subsequently found to have coarctation of the aorta. After surgical repair of the aorta at the age of 14 months, she progressed rapidly, and learnt to talk. Speech was lost later. Child four was kept under review for the first year of life because of wide bridging of the nose. He was discharged from follow-up as developmentally normal at age 1 year.

Table 1: Clinical details and laboratory, endoscopic, and histological findings

Child Age (years) Sex Abnormal laboratory tests Endoscopic findings Histological findings
1 4 M Hb 10·8, PCV 0·36, WBC 16·6 Ileum not intubated; aphthoid ulcer Acute caecal cryptitis and chronic non-specific
(neutrophilia), lymphocytes 1·8, ALP 166 in rectum colitis
2 9·5 M Hb 10·7 LNH of T ileum and colon; patchy loss of Acute and chronic non-specific colitis: reactive ileal
vascular pattern; caecal aphthoid ulcer lymphoid hyperplasia
3 7 M MCV 74, platelets 474, eosinophils 2·68, LNH of T ileum Acute and chronic non-specific colitis: reactive ileal
IgE 114, IgG1 8·4 and colonic lymphoid hyperplasia
4 10 M IgE 69, IgG1 8·25, IgG4 1·006, ALP 474, AST 50 LNH of T ileum; loss of vascular pattern in Chronic non-specific colitis: reactive ileal and colonic
rectum lymphoid hyperplasia
5 8 M LNH of T lieum; proctitis with loss of Chronic non-specific colitis: reactive ileal lymphoid
vascular pattern hyperplasia
6 5 M Platelets 480, ALP 207 LNH of T ileum; loss of colonic vascular Acute and chronic non-specific colitis: reactive ileal
pattern lymphoid hyperplasia
7 3 M Hb 9·4, WBC 17·2 (neutrophilia), ESR 16, IgA 0·7 LNH of T ileum Normal
8 3·5 F IgA 0·5, IgG 7 Prominent ileal lymph nodes Acute and chronic non-specific colitis: reactive ileal
lymphoid hyperplasia
9 6 M LNH of T ileum; patchy erythema at Chronic non-specific colitis: reactive ileal and colonic
hepatic flexure lymphoid hyperplasia
10 4 M IgG1 9·0 LNH of T ileum and colon Chronic non-specific colitis: reactive ileal lymphoid
hyperplasia
11 6 M Hb 11·2, IgA 0·26, IgM 3·4 LNH of T ileum Chronic non-specific colitis
12 7 M IgA 0·7 LNH on barium follow-through; Chronic non-specific colitis: reactive colonic
colonoscopy normal; ileum not intubated lymphoid hyperplasia
LNH=lymphoid nodular hyperplasia; T ileum=terminal ileum. Normal ranges and units: Hb=haemoglobin 11·5-14·5 g/dL; PCV=packed cell volume 0·37-0·45; MCV=mean cell volume 76-100 pg/dL; platelets 140-400 109/L; WBC=white cell count 5·0-15·5 109/L; lymphocytes 2·2-8·6 109/L; eosinophils 0-0·4 109/L; ESR=erythrocyte sedimentation rate 0-15 mm/h; IgG 8-18 g/L; IgG1 3·53-7·25 g/L; IgG4 0·1-0·99 g/L; IgA 0·9-4·5 g/L; IgM 0·6-2·8 g/L; IgE 0-62 g/L; ALP=alkaline phosphatase 35-130 U/L; AST=aspartate transaminase 5-40 U/L.

In eight children, the onset of behavioural problems had been linked, either by the parents or by the child's physician, with measles, mumps, and rubella vaccination. Five had had an early adverse reaction to immunisation (rash, fever, delirium; and, in three cases, convulsions). In these eight children the average interval from exposure to first behavioural symptoms was 6·3 days (range 1-14). Parents were less clear about the timing of onset of abdominal symptoms because children were not toilet trained at the time or because behavioural features made children unable to communicate symptoms.

One child (child four) had received monovalent measles vaccine at 15 months, after which his development slowed (confirmed by professional assessors). No association was made with the vaccine at this time. He received a dose of measles, mumps, and rubella vaccine at age 4·5 years, the day after which his mother described a striking deterioration in his behaviour that she did link with the immunisation. Child nine received measles, mumps, and rubella vaccine at 16 months. At 18 months he developed recurrent antibiotic-resistant otitis media and the first behavioural symptoms, including disinterest in his sibling and lack of play.

Table 2 summarises the neuropsychiatric diagnoses; the apparent precipitating events; onset of behavioural features; and age of onset of both behaviour and bowel symptoms.

 

Table 2: Neuropsychiatric diagnosis
Child Behavioural Exposure identified Interval from exposure to Features associated with Age at onset of first symptom
diagnosis by parents or doctor first behavioural symptom exposure Behaviour Bowel
1 Autism MMR 1 week Fever/delirium 12 months Not known
2 Autism MMR 2 weeks Self injury 13 months 20 months
3 Autism MMR 48 h Rash and fever 14 months Not known
4 Autism? MMR Measles vaccine at 15 months Repetitive behaviour, 4·5 years 18 months
Disintegrative followed by slowing in development. self injury,
disorder? Dramatic deterioration in behaviour loss of self-help
immediately after MMR at 4·5 years
5 Autism None--MMR at 16 Self-injurious behaviour started at 4 years
months 18 months
6 Autism MMR 1 week Rash & convulsion; gaze 15 months 18 months
avoidance & self injury
7 Autism MMR 24 h Convulsion, gaze avoidance 21 months 2 years
8 Post-vaccinial MMR 2 weeks Fever, convulsion, rash & 19 months 19 months
encephalitis? diarrhoea
9 Autistic spectrum Recurrent otitis media 1 week (MMR 2 months previously) Disinterest; lack of play 18 months 2·5 years
disorder
10 Post-viral Measles (previously 24 h Fever, rash & vomiting 15 months Not known
encephalitis? vaccinated with MMR)
11 Autism MMR 1 week Recurrent "viral pneumonia" 15 months Not known
for 8 weeks following MMR
12 Autism None--MMR at 15 months Loss of speech development and Not known
deterioration in language skills noted
at 16 months
MMR=measles, mumps, and rubella vaccine.

Laboratory tests

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.

Figure 1: Urinary methylmalonic-acid excretion in patients and controls

p=Significance of mean excretion in patients compared with controls.

Endoscopic findings

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.

Figure 2: Endoscopic view of terminal ilium in child three and in a child with endoscopically and histologically normal ileum and colon

Greatly enlarged lymphoid nodule in right-hand field of view. A and B=child three; C=normal ileum. Remainder of mucosal surface of` terminal ileum is a carpet of enlarged lymphoid nodules.Histological findings

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.

Figure 3: Biopsy sample from terminal ileum (top) and from colon (bottom) 

A=child three; lymphoid hyperplasia with extensive, confluent lymphoid nodules. B=child three; dense infiltration of the lamina propria crypt epithelium by neutrophils and mononuclear cells. Stained with haematoxylin and eosin.

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.

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.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.

Addendum:

Up to Jan 28, a further 40 patients have been assessed; 39 with the syndrome.

Contributors

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.

Acknowledgments

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.

References

1 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th edn. Washington DC, USA: American Psychiatric Association, 1994.

2 Bhatt HR, Green A, Linnell JC. A sensitive micromethod for the routine estimations of methylmalonic acid in body fluids and tissues using thin-layer chromatography.  Clin Chem Acta  1982; 118: 311-21. [PubMed]

3 Fujimura Y, Kamoni R, Iida M. Pathogenesis of aphthoid ulcers in Crohn's disease: correlative findings by magnifying colonoscopy, electromicroscopy, and immunohistochemistry.  Gut  1996; 38: 724-32. [PubMed]

4 Asperger H. Die Psychopathologie des coeliakakranken kindes.  Ann Paediatr  1961; 197: 146-51. [PubMed]

5 Walker-Smith JA, Andrews J. Alpha-1 antitrypsin, autism and coeliac disease. Lancet 1972; ii: 883-84.

6 D'Eufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism.  Acta Paediatrica  1996; 85: 1076-79. [PubMed]

7 Panksepp J. A neurochemical theory of autism.  Trends Neurosci  1979; 2: 174-77. [PubMed]

8 Reichelt KL, Hole K, Hamberger A, et al. Biologically active peptide-containing fractions in schizophrenia and childhood autism.  Adv Biochem Psychopharmacol  1993; 28: 627-43. [PubMed]

9 Shattock P, Kennedy A, Rowell F, Berney TP. Role of neuropeptides in autism and their relationships with classical neurotransmitters.  Brain Dysfunction  1991; 3: 328-45. [PubMed]

0 Waring RH, Ngong JM. Sulphate metabolism in allergy induced autism: relevance to disease aetiology, conference proceedings, biological perspectives in autism, University of Durham, NAS 35-44.

11 Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ. Disruption of sulphated glycosaminoglycans in intestinal inflammation.  Lancet  1993; 341: 711-41. [PubMed]

12 Warren RP, Singh VK. Elevated serotonin levels in autism: association with the major histocompatibility complex.  Neuropsychobiology 1996; 34: 72-75. [PubMed]

13 Lucarelli S, Frediani T, Zingoni AM, et al. Food allergy and infantile autism.  Panminerva Med  1995; 37: 137-41. [PubMed]

14 Rutter M, Taylor E, Hersor L. In: Child and adolescent psychiatry. 3rd edn. London: Blackwells Scientific Publications: 581-82.

15 Wing L. The Autistic Spectrum. London: Constable, 1996: 68-71.

16 Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study.  Biotherapy  1996; 9: 13-17. [PubMed]

17 Gupta S. Immunology and immunologic treatment of autism. Proc Natl Autism Assn Chicago 1996; 455-60.

18 Miyamoto H, Tanaka T, Kitamoto N, Fukada Y, Takashi S. Detection of immunoreactive antigen with monoclonal antibody to measles virus in tissue from patients with Crohn's disease.  J Gastroenterol  1995; 30: 28-33. [PubMed]

19 Ekbom A, Wakefield AJ, Zack M, Adami H-O. Crohn's disease following early measles exposure.  Lancet  1994; 344: 508-10. [PubMed]

20 Thompson N, Montgomery S, Pounder RE, Wakefield AJ. Is measles vaccination a risk factor for inflammatory bowel diseases?  Lancet  1995; 345: 1071-74. [PubMed]

21 Kawashima H, Mori T, Takekuma K, Hoshika A, Hata A, Nakayama T. Polymerase chain reaction detection of the haemagglutinin gene from an attenuated measles vaccines strain in the peripheral mononuclear cells of children with autoimmune hepatitis.  Arch Virol  1996; 141: 877-84. [PubMed]

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26 Dillon MJ, England JM, Gompertz D, et al. Mental retardation, megaloblastic anaemic, homocysteine metabolism due to an error in B12 metabolism.  Clin Sci Mol Med  1974; 47: 43-61. [PubMed]

Correspondence

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children

The Lancet, Volume 352, Number 9123, 18 July 1998

Sir--A J Wakefield and co-workers1 have identified a new relation between gastrointestinal disease and developmental disorders in children; it opens a new avenue for the study of the gastrointestinal tract and other diseases that may be immunologically mediated. Their findings of ileal-lymphoid-nodular hyperplasia and non-specific colitis gastrointestinal manifestations in connection with autistic-spectrum disorders is the first description of this relation, with strong data suggesting the anatomical and histological alteration of the gut in such disorders. Although these workers suggest possible mechanism(s) of increased permeability for exogenous molecules they do not offer any explanation for these gastrointestinal alterations. The endoscopic and histopathological findings of ileal-lymphoid-nodular hyperplasia and non-specific colitis have so far escaped explanation and have evaded pathogenetic definition.

In support of the findings of Wakefield et al are several behavioural and clinical features known to be related to the central nervous system (CNS), such as migraine,2 infantile colic,3 abdominal epilepsy,4 allergic-tension-fatigue syndrome, and attention-deficit-hyperactivity disorder,5 which have been related to food allergy, although the precise relation is still unclear. IgE-mediated food allergy is plainly not the only mechanism of tissue injury, and these specific disorders could involve other mechanisms.

A major investigative effort of our laboratories has been directed to the study of food allergy and the immunological involvement of the gut as a central focus for injury of other target organs (skin, lungs, and gastrointestinal tract). We have noted a striking appearance of ileal-lymphoid-nodular hyperplasia in patients with non-IgE-mediated food allergy who present with asthma, atopic dermatitis, and attention-deficit-hyperactivity disorder. We have also studied two patients with this hyperactive disorder who were allergic to various foods, and our findings obtained by colonoscopy of their terminal ileum, shown in the figure, match with those reported by Wakefield and co-workers.

Endoscopic view of terminal ileum in child with attention-deficit-hyperactive disorder  

Greatly enlarged lymphoid nodules in both fields of view.

In our study, ileal-lymphoid-nodular hyperplasia is the hallmark lesion of the gastrointestinal tract, which allows entry of antigens across the inflamed mucosa of the bowel as a result of the reactive inflammatory response in the adjacent lymphoid tissue of Peyer's patches in patients with non-IgE-mediated food allergy. We propose that similar mechanism(s) may be involved in the pathogenesis of the CNS dysfunction in the patients described by Wakefield and co-workers.1

Although Wakefield's study, which suggests a connection between the CNS and the gut in patients previously immunised with measles, mumps, and rubella vaccine, did not prove an association, it has stimulated further discussion and opened unanticipated lines of investigation concerning the role of ileal-lymphoid-nodular hyperplasia as a predictive marker of gastrointestinal inflammation responsible for immunologically mediated tissue injury in other target organs sites.

*Aderbal Sabra, Joseph A Bellanti, Angel R Colón

*International Center for Interdisciplinary Studies of Immunology, and Department of Pediatrics, Georgetown University Medical Center, Washington, DC 20007, USA

1 Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.  Lancet  1998; 351: 637­41. [Text]

2 Egger G, Carter CM, Wilson J, Turner MW, Soothill JF. Is migraine food allergy? Lancet 1983 ii: 865­69.

3 Hewson P, Oberklaid F, Menahen S. Infant colic, distress and crying.  Clin Pediatr  1987; 26: 69­76. [PubMed]

4 Senanayake N. "Eating epilepsy"--a reappraisal.  Epilepsy Res  1990; 5: 74­79. [PubMed]

5 Egger G, Stolla A, McEven L. Controlled trial of hyposensitization in children with food induced hypercinetic syndrome.  Lancet  1992; 339: 1150­53. [PubMed]