ANDREW WAKEFIELD

[Guest guest]

Writes to Irish newspaper re latest 'MMR link to autism research' the

hearing in March will be interesting !!

Dr Wakefield, whose 1998 research on the effects of MMR and its

possible links to autism sparked a massive controversy, has responded

to a recent study that claims to dismiss the link.

" Response to Baird G. et al. Measles vaccination and antibody response

in autism spectrum disorders. Archives of Disease in Childhood.

Published 5th February 2008. "

In a case-control study of 10 to 12-year-old children with either

autism, special-educational needs, or normal development, the authors

examined measles-antibody responses (plaque reduction neutralization

assay) and the presence of measles virus in peripheral blood

mononuclear cells (reverse transcriptase polymerase chain reaction).

The study apparently sought to identify autistic children relevant to

the original MMR/autism hypothesis, i.e., those who regressed and

those with bowel symptoms.

The study is severely limited by case definition in the context of the

crucial `possible enterocolitis' group. For inclusion in this group

they required the presence of two or more of the following five

current gastrointestinal symptoms:

current persistent diarrhea (defined as watery/loose stools three or

more times per day >14 days),

current persistent vomiting (occurring at least once per day, or more

than five times per week),

current weight loss,

current persistent abdominal pain (3 or more episodes [frequency not

specified by authors] severe enough to interfere with activity);

current blood in stool;

plus:

past persistent diarrhea >14 days' duration, and excluding current

constipation.

We have over the last 10 years evaluated several thousand children on

the autistic spectrum who have significant gastrointestinal symptoms.

Upper and lower endoscopy and surgical histology have identified

mucosal inflammation in excess of 80% of these children. Almost none

of these children with biopsy-proven enterocolitis would fit the

criteria set out above. Firstly, these children rarely have vomiting,

current weight loss (as opposed to failure to gain weight in an

age-appropriate manner), or passage of blood per rectum. The

requirement is thus narrowed to a child having two of two relevant

symptoms – current persistent diarrhea and current abdominal pain

according to their criteria, plus a past history of persistent

diarrhea excluding current constipation.

The requirement for the current presence of these symptoms, for 14 or

more days continuously, shows a singular lack of understanding of the

episodic, fluctuating, and alternating (e.g. diarrhea/constipation)

symptom profile experienced by these children. In our experience, ASD

children with histologic enterocolitis typically have 1 to 2 unformed

stools per day that are very malodorous and usually contain a variety

of undigested foodstuffs. This pattern alternates with that of

" constipation " in which the unformed stool is passed after many days

of no bowel movements at all, and with excessive straining. This group

is entirely overlooked by the arbitrary criteria set forth in their

paper. With respect to diarrhea and constipation, a detailed

discussion of stool pattern in these children is available1 which

further highlights the shortcomings of the above criteria.

Moreover, the interpretation of pain as a symptom in non-verbal

children, as it often manifests as self injury, aggressive outbursts,

sleep disturbances, and abnormal posturing, is notoriously difficult.

This interpretation requires an insight based upon the correlation of

symptoms, histological findings, and response of symptoms to

anti-inflammatory treatment. There is no evidence in the Baird et al.

paper that these crucial factors were taken into account. This study's

inappropriate symptom criteria would explain the discordance with

other reports that have revealed a high prevalence of significant

gastrointestinal symptoms in general autism populations2,3.

It is surprising that Dr Sullivan, a co-author on the paper, who

presumably provided the above gastroenterological criteria, was not

aware of the aforementioned limitations. In his role as a Defendant's

expert in the UK MMR litigation, he will have had access to the

clinical records of autistic children with the relevant intestinal

symptoms and biopsy-proven intestinal inflammation.

We suggest that the authors might wish to reflect on the ethical

implications of setting the bar too high for the investigation of such

children by ileo-colonoscopy, with the attendant risk of missing

symptomatic, treatable inflammation.

Since the relevant MMR/autism children are considered to be those with

regression and significant gastrointestinal symptoms, the appropriate

stratification for between-group analyses of measles virus antibody

levels has not been conducted; therefore the paper is difficult to

interpret, adding little if anything to the issue of causation.

Moreover, it is a major error to have presumed that peripheral blood

mononuclear cells are a valid `proxy' for gut mucosal lymphoid tissues

when searching for persistent viral genetic material.

A further major problem in this study is the number of children who

dropped out or who were unable to provide adequate blood samples. We

know nothing about either the 735 children who were lost at stage two,

or the 100 children for whom blood samples were not available. At the

very least, we should be told whether the children who dropped out

were likely to be representative of those who stayed in, with regard

to the key issues of interest.

For reasons that will emerge in the near future, it would be of

interest to know whether siblings of autistic children were included

in either of the two control groups. This information is not provided.

As a general observation, this paper contributes nothing to the issue

of causation, one way or another. Case definition alone is likely to

have obscured the relevant group of autistic children. The study tells

us nothing about what actually happened to the children at the time of

exposure. We are increasingly persuaded that measuring things in blood

many years down the line tells us very little about the initiating

events in what is, in effect, a static (non-progressive)

encephalopathy unlike, for example, subacute sclerosing

panencephalitis, which is a progressive measles encephalopathy. The

gut is a different matter, and analysis of mucosal tissues has been

very informative, since here, in the relevant children, active

ongoing, possibly progressive[AV1] 4, inflammation has been identified.

References.

1.Wakefield AJ. Autistic enterocolitis: is it a histopathological

entity? Histopathology 2006;50:380-384.

2.Valicenti-McDermott M, et al. Frequency of Gastrointestinal Symptoms

in Children with Autistic Spectrum Disorders and Association with

Family History of Autoimmune Disease. Developmental and Behavioral

Pediatrics. 2006;27:128-136.

3.Horvath K, and Perman JA. Autistic disorder and gastrointestinal

disease. Current Opinion in Pediatrics. 2002;14:583–587.

4.Balzola F et al. Autistic Enterocolitis in childhood: the early

evidence of the later Crohn's disease in autistic adulthood?

Gastroenterology 2007;132:suppl 2, A 660.