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