A STATEMENT
BY DR SIMON MURCH
These allegations
concerning our 1998 study are
extremely serious, and clearly
require immediate clarification. I
welcome the opportunity to do so. My
comment relates to the alleged lack
of Ethical Practices Committee
approval. I refute the allegation
absolutely on the basis of extensive
documentary evidence.
The protocol for the
1998 Lancet paper was
submitted on September 16, 1996, to
what was then termed the Ethical
Practices Sub-Committee. It was
entitled “A new paediatric
syndrome: enteritis and
disintegrative disorder following
measles/rubella vaccine”. It was
signed by Andrew Wakefield as lead
investigator. Named consultants were
John Walker-Smith and myself, with
signed collaborators Peter Harvey,
for the department of neurology, and
Mark Berelowitz, for the department
of child psychiatry. The application
was initiated due to findings at
colonoscopy of two children with
behavioural disorders, which would
now be classified within the autistic
spectrum, and a history of chronic
gastrointestinal symptoms, and
recognition of a broadly similar
clinical history among other referred
patients. Specifically, for several
years previously we had looked after
an autistic child with severe
ulcerative colitis who eventually
required colectomy (not included in
the study), and the second child
colonoscoped (on September 2, 1996)
had ileitis of sufficient extent that
a diagnosis of probable Crohn’s
disease was made. Following this
diagnosis, the child had been entered
in good faith by our inflammatory
bowel diseases fellow into an ongoing
(ethically approved) study of
polymeric enteral nutrition. He had
already made remarkable symptomatic
improvement, including apparent
cognitive advance. We, thus, appeared
to be dealing with a condition of
significant severity, and had seen
clinical improvement unprecedented in
this child’s history. News of
this improvement was rapidly
disseminated among parents of
autistic children, which I believe
led to many further referrals. This
child was included in the study, with
additional investigations performed
after ethics approval was obtained.
The title of this
submitted application is a point of
contention, and should be clarified.
Having taken initial advice from our
psychiatric colleagues on the basis
of referral letters, it was
considered that these children
demonstrated a form of autism called
disintegrative disorder
(Heller’s disease). After full
psychiatric assessment of each child
seen, it was later concluded that the
more accurate description for the
submitted paper should be pervasive
developmental disorder. Our working
title for these cases had, however,
remained disintegrative disorder,
while some parents referred to their
child as autistic, and others did
not. The whole area of nomenclature
in autistic spectrum disorders was
notably difficult at that stage. As
we saw more patients, we moved
towards a more inclusive label of
autism, which was used in subsequent
correspondence after February, 1998,
to the Ethical Practices Committee.
Measles and rubella were singled out
in the application since these
conditions, but not mumps, had been
linked to autism in previous isolated
reports.
This application
(172-96) was for permission for
in-depth analysis of 25 patients,
referred either by general
practitioners or the vitamin B12 unit
at the Chelsea and Westminster
Hospital, who had been studying B12
absorption in children with
regressive neurological disorders.
The selection criteria explicit in
this application were the presence of
disintegrative disorder, symptoms and
signs suggestive of gastrointestinal
disease, and parental request for
investigation. All patients reported
met these criteria. The consultant
paediatricians responsible for the
children’s care decided on the
investigations, although advice was
taken from colleagues at other
centres. We determined that these
investigations were required
clinically, not only to characterise
gut inflammation but also to exclude
primary neurological diseases. We had
in particular taken advice for the
neurological investigations, since
some of the referrals appeared to
have suffered an encephalitic
illness, and specifically the
inclusion of lumbar puncture was
suggested to us as important for
assay of cerebrospinal fluid lactate,
to exclude mitochondrial cytopathies
that can cause both neurological
regression and bowel disease. Several
of these cases had not been
investigated to exclude a primary
cause of their regression, and we
thought it important to ensure that
we were not missing underlying
metabolic or genetic abnormality.
Proposed investigations thus included
ileocolonoscopy and upper endoscopy,
barium follow-through if ileitis was
identified, lumbar puncture (if
sufficient fluid remained after
lactate assay, serology and/or
cytokine testing would be performed),
magnetic resonance imaging of the
brain to exclude structural defects,
electroencephalography to exclude
covert epilepsy, electrophysiological
testing, and a panel of standard
laboratory tests, with isolation of
DNA for complement genotyping, since
C4 deficiency had been reported to be
an association.
The protocol was
referred back at first submission in
November, 1996, with clarifications
and amendments suggested, and was
approved in December, 1996. This
protocol formed the basis for all
children investigated in the 1998 Lancet
paper, and all were investigated.
We had no idea at the time of our
Ethical Practices Committee
application that lymphoid hyperplasia
would prove so common, although it
was a prominent part of the final
report.
It is important to
document where the protocol differed
from the submission. First, neither I
nor my fellow endoscopist, Mike
Thomson, eventually considered it
justified to perform upper
gastrointestinal endoscopy in most
patients—there was then no
published evidence of upper
gastrointestinal pathology, and we
were performing these procedures
under sedation, as was then our
practice. Getting the precise level
of sedation is not easy in children
with such behavioural difficulties,
and we felt this was not appropriate
at that time, although our policy
altered in later years. Second, in
the event, we did not continue with
this extended protocol for the full
25 patients, again because of the
clinical concerns of myself and my
colleagues, since we had found no
evidence of underlying metabolic
abnormality in any case and did not
consider that lumbar puncture of
further cases was indicated. Other
children subsequently seen were thus
not subjected to this extended
protocol, and investigated by testing
of inflammatory markers and abdominal
X-ray, with endoscopies performed if
thought clinically indicated, unless
there were clear clinical reasons to
perform additional tests.
Following the
publication of the initial report,
John Walker-Smith sought guidance
from the Ethical Practices Committee
about further investigation of future
cases, stating “I would like
formally to request Ethical Committee
approval for our clinical research
analysis of these children who we are
continuing to see by clinical
need”. In a letter to the ethics
committee, further studies were
referred to under the title
“autism and non-specific colitis
and Lymphoid Nodular
Hyperplasia” since that was the
clinical entity that the earlier
study had defined. This was reviewed
on July 22, 1998, and data collection
from clinically indicated
investigations was approved. This was
for study of subsequent patients
investigated on the basis of
gastrointestinal symptoms and initial
assessment, and in no way relevant to
the 1998 Lancet paper, which
had been conducted entirely according
to the 1996 approval. Thus, there was
no change in the name of the ethical
approval requested for the 1998
paper, as mistakenly alleged.
A local review initiated
by the Royal Free medical school in
July, 1998, confirmed that the
application had been fully considered
by the ethics committee, and that
assurance had been given that the
investigations were clinically
indicated. It was also apparent that
the continuing investigation of those
children had been reviewed by the
ethics committee in July, 1998, and
appreciated that investigation of
children seen after publication had
become less extensive, and usually
restricted to gastroenterological
testing as thought clinically
appropriate.
We contended then, and
still contend now, that these were
standard and appropriate
gastroenterological and neurological
investigations for the symptoms
reported given the current state of
knowledge at that time. Undoubtedly
we now perform endoscopy less
frequently, but that is based on
extensive experience. Similarly, a
child with coeliac disease in the
1970s would have had three diagnostic
biopsies compared to the one, or even
none, now performed.
Thus, I can confirm that
the patients presented in the Lancet
study were investigated in
accordance with the ethics committee
approval of December, 1996, and that
no attempt was made to seek
retrospective approval.
Dr Simon Murch
Senior Lecturer and
Consultant in Paediatric
Gastroenterology, Royal Free and
University College Medical School