EARLY REPORT

Early report

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, andpervasive 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

Summary

Introduction

D

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 foodintolerance), were investigated. All children were admitted to theward for 1 week, accompanied by their parents.

Clinical investigations

We took histories, including details of immunisations andexposure 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 byconsultant staff (PH, MB) with HMS-4 criteria.1 Developmental
histories included a review of prospective developmental records
from parents, health visitors, and general practitioners. Fourchildren 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 weretaken from the terminal ileum; ascending, transverse,
descending, and sigmoid colons, and from the rectum. The
procedure was recorded by video or still images, and werecompared 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 compliancemade these possible), and lumbar puncture were done.

AC

Methods 12 children (mean age 6 years [range 3–10], 11boys) were referred to a paediatric gastroenterology unit
with a history of normal development followed by loss ofacquired skills, including language, together with diarrhoea
andabdominal
pain.
Childrenunderwent
gastroenterological, neurological, and developmental
assessment and review of developmental records.
Ileocolonoscopy and biopsy sampling, magnetic-resonanceimaging (MRI), electroencephalography (EEG), and lumbar
puncture were done under sedation. Barium follow-throughradiography was done where possible. Biochemical,
haematological, and immunological profiles were
examined.

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 somecases, food intolerance. We describe the clinical findings,
and gastrointestinal features of these children.

TE

Background We investigated a consecutive series ofchildren with chronic enterocolitis and regressive
developmental disorder.

ETR

Findings Onset of behavioural symptoms was associated,by the parents, with measles, mumps, and rubellavaccination in eight of the 12 children, with measles
infection in one child, and otitis media in another. All 12
children had intestinal abnormalities, ranging fromlymphoid nodular hyperplasia to aphthoid ulceration.
Histology showed patchy chronic inflammation in the colonin 11 children and reactive ileal lymphoid hyperplasia inseven, 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 agematched controls (p=0·003), low haemoglobin in fourchildren, and a low serum IgA in four children.

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Interpretation We identified associated gastrointestinal
disease and developmental regression in a group ofpreviously normal children, which was generally associatedin time with possible environmental triggers.

Lancet 1998; 351: 637–41
See Commentary page

Inflammatory Bowel Disease Study Group, University Departmentsof 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), andRadiology (A Valentine FRCR), Royal Free Hospital and School of
Medicine, London NW3 2QG, UK
Correspondence to: Dr A J Wakefield

THE LANCET • Vol 351 • February 28, 1998

Laboratory investigations
Thyroid function, serum long-chain fatty acids, andcerebrospinal-fluid lactate were measured to exclude known
causes of childhood neurodegenerative disease. Urinary
methylmalonic acid was measured in random urine samples fromeight of the 12 children and 14 age-matched and sex-matchednormal controls, by a modification of a technique described
previously.2 Chromatograms were scanned digitally on
computer, to analyse the methylmalonic-acid zones from casesand controls. Urinary methylmalonic-acid concentrations inpatients and controls were compared by a two-sample t test.
Urinary creatinine was estimated by routine spectrophotometricassay.
Children were screened for antiendomyseal antibodies andboys were screened for fragile-X if this had not been done

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EARLY REPORT

Age (years) Sex

Abnormal laboratory tests

Endoscopic findings

Histological findings

1

4

M

2

9·5

M

Hb 10·8, PCV 0·36, WBC 16·6
(neutrophilia), lymphocytes 1·8, ALP 166
Hb 10·737M

Ileum not intubated; aphthoid ulcer
in rectum
LNH of T ileum and colon; patchy loss ofvascular pattern; caecal aphthoid ulcer
LNH of T ileum

4

10

M

5

8

M

6

5

M

Platelets 480, ALP 207

7
8

3
3·5

M
F

Hb 9·4, WBC 17·2 (neutrophilia), ESR 16, IgA 0·7
IgA 0·5, IgG 7

LNH of T ileum; loss of vascular pattern inrectum
LNH of T lieum; proctitis with loss ofvascular pattern
LNH of T ileum; loss of colonic vascularpattern
LNH of T ileum
Prominent ileal lymph nodes

9

6

M

10

4

M

IgG1 9·0

LNH of T ileum; patchy erythema at
hepatic flexure
LNH of T ileum and colon

11
12

6
7

M
M

Hb 11·2, IgA 0·26, IgM 3·4
IgA 0·7

Acute caecal cryptitis and chronic non-specificcolitisAcute and chronic non-specific colitis: reactive ileal
lymphoid hyperplasia
Acute and chronic non-specific colitis: reactive ileal
and colonic lymphoid hyperplasia
Chronic non-specific colitis: reactive ileal and colonic
lymphoid hyperplasia
Chronic non-specific colitis: reactive ileal lymphoid
hyperplasia
Acute and chronic non-specific colitis: reactive ileal
lymphoid hyperplasia
NormalAcute and chronic non-specific colitis: reactive ileal
lymphoid hyperplasia
Chronic non-specific colitis: reactive ileal and colonic
lymphoid hyperplasia
Chronic non-specific colitis: reactive ileal lymphoid
hyperplasia
Chronic non-specific colitis
Chronic non-specific colitis: reactive colonic
lymphoid hyperplasia

MCV 74, platelets 474, eosinophils 2·68,
IgE 114, IgG1 8·4
IgE 69, IgG1 8·25, IgG4 1·006, ALP 474, AST 50

LNH of T ileum
LNH on barium follow-through;colonoscopy normal; ileum not intubated

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Child

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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 cellvolume 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=aspartatetransaminase 5–40 U/L.

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

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 forcomparison. All tissues were assessed by three other clinical andexperimental pathologists (APD, AA, AJW).

Ethical approval and consent

Results

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

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Clinical details of the children are shown in tables 1 and
2. None had neurological abnormalities on clinicalexamination; 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 wassubsequently 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 yearof life because of wide bridging of the nose. He wasdischarged from follow-up as developmentally normal atage 1 year.
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
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Laboratory tests
All children were antiendomyseal-antibody negative andcommon enteric pathogens were not identified by culture,
microscopy, or serology. Urinary methylmalonic-acidexcretion was significantly raised in all eight children who
Metuylmalanic acid (mg/mmol) creatinine

Histology

trained at the time or because behavioural features madechildren unable to communicate symptoms.
One child (child four) had received monovalent
measles vaccine at 15 months, after which hisdevelopment slowed (confirmed by professional
assessors). No association was made with the vaccine at
this time. He received a dose of measles, mumps, andrubella vaccine at age 4·5 years, the day after which hismother described a striking deterioration in his behaviour
that she did link with the immunisation. Child ninereceived measles, mumps, and rubella vaccine at 16
months. At 18 months he developed recurrent antibioticresistant 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 behaviouralfeatures; and age of onset of both behaviour and bowel
symptoms.

AC

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.

15

10

5

p=0·0030
Patients

Controls

Figure 1: Urinary methylmalonic-acid excretion in patients andcontrols
p=Significance of mean excretion in patients compared with controls.

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EARLY REPORT

Behaviouraldiagnosis

Exposure identified
by parents or doctor

Interval from exposure to
first behavioural symptom

Features associated with
exposure12
3
4

AutismAutismAutismAutism?
Disintegrative
disorder?

MMR
MMR
MMR
MMR

Fever/delirium
Self injury
Rash and fever
Repetitive behaviour,
self injury,
loss of self-help

5Autism6

AutismNone—MMR at 16
monthsMMR

1 week2 weeks
48 h
Measles vaccine at 15 months
followed by slowing in development.
Dramatic deterioration in behaviour
immediately after MMR at 4·5 years
Self-injurious behaviour started at
18 months
1 week

7
8

MMR
MMR

24 h
2 weeks

Recurrent otitis media

11

AutismPost-vaccinial
encephalitis?
Autistic spectrum
disorderPost-viral
encephalitis?
AutismMeasles (previously
vaccinated with MMR)
MMR

12AutismNone—MMR at 15 months

10

Bowel

12 months
13 months
14 months
4·5 years

Not known
20 months
Not known
18 months

4 years
15 months

18 months

21 months
19 months

2 years
19 months

1 week (MMR 2 months previously)

Rash & convulsion; gaze
avoidance & self injury
Convulsion, gaze avoidance
Fever, convulsion, rash &diarrhoea
Disinterest; lack of play

18 months

2·5 years

24 hFever, rash & vomiting

15 months

Not known

1 weekRecurrent “viral pneumonia”
for 8 weeks following MMR

Loss of speech development anddeterioration in language skills noted
at 16 months

MMR=measles, mumps, and rubella vaccine.

Table 2: Neuropsychiatric diagnosis

were tested, compared with age-matched controls(p=0·003; figure 1). Abnormal laboratory tests are shownin table 1.

15 months

Not known

Not known

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 inendoscopically normal areas of the colon. In five cases
there was focal acute inflammation with infiltration of thelamina propria by neutrophils; in three of these,
neutrophils infiltrated the caecal (figure 3) and rectalcrypt epithelium. There were no crypt abscesses.
Occasional bifid crypts were noted but overall cryptarchitecture was normal. There was no goblet-cell
depletion but occasional collections of eosinophils wereseen in the mucosa. There were no granulomata.
Parasites and organisms were not seen. None of thechanges described above were seen in any of the normal
biopsy specimens.

ET

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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 colonicand rectal mucosal abnormalities including granularity,
loss of vascular pattern, patchy erythema, lymphoidnodular hyperplasia, and in two cases, aphthoid
ulceration. Four cases showed the “red halo” sign aroundswollen caecal lymphoid follicles, an early endoscopic
feature of Crohn’s disease.3 The most striking andconsistent 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 theterminal ileum (figure 2) was seen in the seven children
whose images were available for comparison.

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9

Age at onset of first symptom
Behaviour

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Child

Histological findings
Histological findings are summarised in table 1.

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Terminal ileum A reactive lymphoid follicular hyperplasia
was present in the ileal biopsies of seven children. In eachcase, more than three expanded and confluent lymphoidfollicles with reactive germinal centres were identified
within the tissue section (figure 3). There was noneutrophil infiltrate and granulomas were not present.
Colon The lamina propria was infiltrated by mononuclear
cells (mainly lymphocytes and macrophages) in thecolonic-biopsy samples. The extent ranged in severity
from scattered focal collections of cells beneath thesurface epithelium (five cases) to diffuse infiltration of themucosa (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. Lymphoidfollicles in the vicinity of mononuclear-cell infiltrates

THE LANCET • Vol 351 • February 28, 1998

Discussion
We describe a pattern of colitis and ileal-lymphoidnodular 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 inchildren with autistic-spectrum disorders, suggests thatthe connection is real and reflects a unique disease
process.
Asperger first recorded the link between coeliac disease
and behavioural psychoses.4 Walker-Smith andcolleagues5 detected low concentrations of alpha-1
antitrypsin in children with typical autism, andD’Eufemia and colleagues6 identified abnormal intestinal
permeability, a feature of small intestinal enteropathy, in
43% of a group of autistic children with nogastrointestinal symptoms, but not in matched controls.
These studies, together with our own, including evidenceof anaemia and IgA deficiency in some children, would
support the hypothesis that the consequences of an
inflamed or dysfunctional intestine may play a part inbehavioural changes in some children.
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EARLY REPORT

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

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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.

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The “opioid excess” theory of autism, put forward firstby Panksepp and colleagues7 and later by Reichelt andcolleagues8 and Shattock and colleagues9 proposes that
autistic disorders result from the incomplete breakdown
and excessive absorption of gut-derived peptides fromfoods, including barley, rye, oats, and caesin from milk
and dairy produce. These peptides may exert centralopioid effects, directly or through the formation ofligands 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 isdeficiency of the phenyl-sulphur-transferase systems, as
described by Waring.10 The normally sulphated
glycoprotein matrix of the gut wall acts to regulate celland molecular trafficking.11 Disruption of this matrix andincreased intestinal permeability, both features ofinflammatory 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, andserotonin)12 may also contribute. Both the presence ofintestinal inflammation and absence of detectableneurological abnormality in our children are consistent
with an exogenous influence upon cerebral function.
Lucarelli’s observation that after removal of a provocative
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Figure 3: Biopsy sample from terminal ileum (top) and fromcolon (bottom)
A=child three; lymphoid hyperplasia with extensive, confluent lymphoidnodules. B=child three; dense infiltration of the lamina propria crypt
epithelium by neutrophils and mononuclear cells. Stained withhaematoxylin and eosin.

enteric
antigenchildrenachieved
symptomatic
behavioural improvement, suggests a reversible elementin this condition.13
Despiteconsistent
gastrointestinal
findings,
behavioural changes in these children were moreheterogeneous. In some cases the onset and course of
behavioural regression was precipitous, with children
losing all communication skills over a few weeks tomonths. This regression is consistent with a disintegrative
psychosis (Heller’s disease), which typically occurs whennormally developing children show striking behaviourchanges and developmental regression, commonly inassociation with some loss of coordination and bowel or
bladder function.14 Disintegrative psychosis is typicallydescribed as occurring in children after at least 2–3 years
of apparently normal development.
Disintegrative psychosis is recognised as a sequel tomeasles encephalitis, although in most cases no cause isever 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 thanmonovalent measles vaccine) has also been implicated.
Fudenberg16 noted that for 15 of 20 autistic children, thefirst 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 andmeasles vaccination20 have both been implicated as risk

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EARLY REPORT

References
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4thedn. Washington DC, USA: American Psychiatric Association, 1994.
2 Bhatt HR, Green A, Linnell JC. A sensitive micromethod for theroutine estimations of methylmalonic acid in body fluids and tissues
using thin-layer chromatography. Clin Chem Acta 1982; 118: 311–21.
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.
4 Asperger H. Die Psychopathologie des coeliakakranken kindes. Ann
Paediatr 1961; 197: 146–51.
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.
7 Panksepp J. A neurochemical theory of autism. Trends Neurosci 1979;
2: 174–77.
8 Reichelt KL, Hole K, Hamberger A, et al. Biologically active peptidecontaining fractions in schizophrenia and childhood autism. Adv
Biochem Psychopharmacol 1993; 28: 627–43.
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.
10 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.
12 Warren RP, Singh VK. Elevated serotonin levels in autism: association
with the major histocompatibility complex. Neuropsychobiology 1996;
34: 72–75.
13 Lucarelli S, Frediani T, Zingoni AM, et al. Food allergy and infantile
autism. Panminerva Med 1995; 37: 137–41.
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.
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 tomeasles virus in tissue from patients with Crohn’s disease.
J Gastroenterol 1995; 30: 28–33.
19 Ekbom A, Wakefield AJ, Zack M, Adami H-O. Crohn’s disease
following early measles exposure. Lancet 1994; 344: 508–10.
20 Thompson N, Montgomery S, Pounder RE, Wakefield AJ. Is measles
vaccination a risk factor for inflammatory bowel diseases? Lancet 1995;
345: 1071–74.
21 Kawashima H, Mori T, Takekuma K, Hoshika A, Hata A,
Nakayama T. Polymerase chain reaction detection of thehaemagglutinin gene from an attenuated measles vaccines strain in the
peripheral mononuclear cells of children with autoimmune hepatitis.
Arch Virol 1996; 141: 877–84.
22 Wing L. Autism spectrum disorders: no evidence for or against an
increase in prevalence. BMJ 1996; 312: 327–28.
23 Miller D, Wadsworth J, Diamond J, Ross E. Measles vaccination andneurological events. Lancet 1997; 349: 730–31.
24 Warren RP, Singh VK, Cole P, et al. Increased frequency of the nullallele at the complement C4B locus in autism. Clin Exp Immunol 1991;
83: 438–40.
25 England JM, Linnell JC. Problems with the serum vitamin B12 assay.
Lancet 1980; ii: 1072–74.
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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, andrubella 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 toshow whether there is a change in incidence22 or a linkwith 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 thecontext 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 majorhistocompatibility complex, has been recorded by Warren
and colleagues.24 C4B-gene products are crucial for theactivation 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 afunctional vitamin B12 deficiency. Although vitamin B12
concentrations were normal, serum B12 is not a good
Urinarymeasureoffunctional
B12
status.25
methylmalonic-acid excretion is increased in disorders
such as Crohn’s disease, in which cobalamin excreted inbile is not reabsorbed. A similar problem may haveoccurred in the children in our study. Vitamin B12 isessential 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 childrenthat 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 thesyndrome.

Contributors

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A J Wakefield was the senior scientific investigator. S H Murch and
M A Thomson did the colonoscopies. A Anthony, A P Dhillon, andS 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 clinicalinvestigator.

Acknowledgments
This study was supported by the Special Trustees of Royal Free
Hampstead NHS Trust and the Children’s Medical Charity. We thankFrancis Moll and the nursing staff of Malcolm Ward for their patience andexpertise; the parents for providing the impetus for these studies; andPaula Domizo, Royal London NHS Trust, for providing control tissue
samples.

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