Pervasive developmental disorder (PDD) is an umbrella term used to
describe a group of disorders, including autistic disorder, which
involve delayed development of communication and social-interaction
skills and particular behavioural abnormalities.1 Although
both genetic factors and environmental insults have been implicated in
the pathogenesis of PDD, the underlying causes remain poorly
understood. Some children with PDD present with regression in
abilities at age 1-2 years, which has raised concern about
environmental exposure during this period. An atypical immune response
to measles-mumps-rubella (MMR) vaccine has been suggested as a
possible precipitating factor.2,3 Due to the potentially
serious public-health implications, this hypothesis has evoked
considerable debate, including US congressional hearings. Moreover,
organisations including the WHO and the American Academy of Pediatrics
have issued statements on this issue.4-7 The widely-held
conclusion is that available data do not support a link between MMR
vaccine and PDD.
Andrew Wakefield and colleagues have raised the possibility that a
subset of children with PDD, particularly those with a history of
developmental regression and chronic gastrointestinal symptoms, have a
dysregulated immune response to measles antigen associated with
intestinal abnormalities.2,3,8 In 1998 Wakefield's group
reported on a group of children with PDD and other psychiatric and
neurological disorders referred to a gastroenterology clinic for
evaluation of a range of chronic gastrointestinal symptoms, including
abdominal pain, bloating, and diarrhoea.3 12 children were
evaluated, and, strikingly, 11 had ileal lymphoid hyperplasia without
granulomas.3 A subsequent study by this group noted ileal
lymphoid nodular hyperplasia in 93% of affected children compared with
14% of control children.2 A possible link between ileal
lymphoid nodular hyperplasia and MMR vaccination was suggested in
these reports based on a temporal association between the
administration of vaccine and the onset of symptoms in many cases.2,3
A potentially important sample bias in these investigations is that
patients were identified because of referral to a gastroenterology
clinic. Of interest would be evaluation of PDD patients with and
without gastrointestinal symptoms to determine if features such as a
history of developmental regression are more common among those
patients with PDD found to have ileal lymphoid nodular hyperplasia.
In a new report by V Uhlmann and colleagues (including Wakefield),
intestinal tissues of children with PDD and histologically confirmed
ileal lymphoid nodular hyperplasia were assessed.8 Using
RT-PCR the investigators identified fragments of measles-virus
nucleocapsid fusion-protein, and haemaglutinin DNA in 75 of the 91
study subjects.8 By contrast, RT-PCR for measles virus DNA
was positive in only 5 of 70 patients in a heterogeneous control
group. Hybridisation of PCR products with probes to fusion protein and
haemaglutinin DNA was demonstrated in 4 of the 75 patients, but
sequence specificity was not confirmed in any case. Results such as
these must be interpreted with caution. For example, amplification of
human DNA sequences by papillomavirus primers has been reported,
leading to the development of methods for verifying the identity of
PCR products.9,10 Nonetheless, even if measles virus DNA is
assumed to be present in the tissues evaluated, the significance of
the observation remains debatable.
Similar studies have reported detection of viruses, including
herpesvirus DNA11 and measles virus DNA,12,13 in
diseases that also manifest intestinal lymphoid hyperplasia, such as
ulcerative colitis and Crohn's disease. Thus the clinical importance
of finding sequences of measles nucleic acid in patients with PDD and
ileal lymphoid hyperplasia is unclear. One attractive alternative
explanation is that lymphoid hyperplasia is associated with the
presence of increased amounts of many antigens and DNA sequences with
resultant increases in the detection of cross-reacting antigens and
DNA sequences. Consistent with this hypothesis, a
measles-virus-related antigen, which is derived from host rather than
viral protein, has been reported in patients with a broad spectrum of
colitides.14
Wakefield and co-workers have suggested that the pattern of normal
behavioural development followed by regression shortly after measles
vaccination leading to the diagnosis of PDD is particularly
meaningful.2,3,8 However, one study has reported that the
age at which parents first noticed symptoms was no different for
autistic children with or without a history of regression.15
In addition, age of presentation was no different in a sample of
autistic children before and after MMR vaccine was introduced.15
The frequency of gastrointestinal complaints seemed similar among
autistic children with or without a history of regression.15
In view of the close temporal association between the age at which MMR
vaccine is given and the age at which symptoms typically are
recognised in children with PDD, the chance occurrence of cases where
MMR vaccination immediately precedes the presentation of PDD is
predictable.
Although the causes of PDD are likely to be heterogeneous, the
overlap in symptoms among different PDD diagnoses suggests shared
underlying factors. In addition, the commonality of some
neurotransmitters to the brain and intestine (such as vasoactive
intestinal peptide), plus the observation of altered secretin-stimulation
responses in PDD patients,16 indicates that a disturbance
of the brain-gut axis in PDD patients is biologically plausible.
Although far from universal, gastrointestinal complaints appear to be
increased among children with PDD compared with the general
population.16 Nonetheless, the intestinal complaints of
these children are often not investigated by endoscopy, so the
existence of a distinct variant of inflammatory bowel disease among
children with PDD may not be widely appreciated.
Thus the idea of a PDD-associated inflammatory bowel disease
deserves further consideration. In support of this hypothesis,
Torrente and colleagues (again with Wakefield) have now reported that
IgG and complement C1q were found deposited on the basolateral
epithelial in duodenal biopsy specimens from 23 of 25 autistic
children, but not in specimens from control cases.17
However, at present, conclusions about a causative association between
PDD, intestinal disease, and MMR vaccination are speculative.
*Barbara A Hendrickson, Jerrold R Turner
*Section of Pediatric Infectious Diseases and Department of
Pathology, University of Chicago, Chicago, IL 60637, USA (e-mail:bhendric@peds.bsd.uchicago.edu)
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