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Volume 351, Number 9103 28 February 1998 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

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=0003), 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
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 63 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 45 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.
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.
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.


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