Fw: The Reasoned MMR-Autism Debate/ DMG Letter

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The Reasoned MMR-Autism Debate/ DMG Letter

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" Healing Autism: No Finer a Cause on the Planet "

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April 20, 2001 Search www.feat.org/search/news.asp

Also: Letter on the DMG Research

The Reasoned MMR/Autism Debate

[This essay by Dr. Ken Aitken, an " Independent Consultant Child

Clinical Neuropsychologist " in Scotland, comes from a collection on the

MMR/Autism debate published in the ish Society for Autism's magazine

'In Touch'. Here is their introduction. Thanks to Bill Welsh.]

" The MMR debate is certainly heating up and whilst there is no clear

proof yet of a link between the MMR vaccination programme and autism, there

appears to be enough anecdotal evidence, coupled with preliminary findings

from a range of studies being carried out in Britain, Europe and across USA,

to suggest that there may be a connection and that administration of the

triple vaccination may be one of a number of possible environmental factors

which, when linked with a predisposition to autism, may be sufficient to

cause autism in particular children.

" Such evidence tends to stem from limited areas in terms of numbers

and methodology, and is, therefore, dismissed by the authorities as an

inadequate research base from which to draw specific final conclusions. "

Dr Ken Aitken

I would like to preface this brief contribution with a clear statement

that I am not arguing against vaccination to protect children from measles,

mumps or rubella. In my view it is important to ensure protection of

children against these diseases through vaccination. My questions concern

the evidence, or lack of it, for the safety of the live MMR vaccines which

have been used in the UK since 1988.

For anyone starting to read about the controversy over a possible link

between MMR vaccines* and autism, the initial feeling must be one of

confused and conflicting professional and public opinion.

There are several questions most people might expect to ask:

1) Is there evidence for a rise in the rate of autism, the timing of

which could be linked to the introduction of MMR vaccines ?

The rate of autism has been stable over much of the period that we

have recognised autism as a clinical disorder. From 1966 when the first,

Aberdeen based, population study of autism was reported (Rutter 1966)

through to the late 1980s (see Fombonne 1999; Gillberg & Wing 1999 for

recent reviews), the majority of studies published reported a rate of autism

somewhere in the region of 4.5 per 10,000 population, although some

estimates put the figure as high as 15 per 10,000.

When we move to the period after MMR was introduced, things become

more confused. Some people argue that there is no difference in the rate of

autism since MMR introduction and that therefore there is nothing to be

worried by (see eg. Fombonne 2001). Others argue the opposite - that there

is a real increase which is consistent with a possible problem with MMR

vaccines (eg. Rimland 1999; 2000), while a third camp seem to be arguing

that there is a real and significant increase but that it cannot be said to

result from MMR due to factors such as the apparent timing of the change in

rate ( et al 1999; Kaye, Melero-Montes & Jick 2001; Bramley, Ahmed,

Cromie: above). Practically the only view I have yet to see being argued is

that there has been a reduction in the rate of autism.

Perhaps the clearest review of the evidence to date as it pertains to

the question of possible linkage with vaccines comes from the recent

Institute of Medicine Immunization Safety Review Committee briefing paper

(Stoto, Cleary & 2001) the conclusion of which is that

'...based on the epidemiological evidence reviewed in this paper and

the opinion of the authors..., the evidence is inadequate to accept or

reject a causal relationship between MMR and autism.'

Overall, a balanced summary of the evidence shows that there is a real

rise in the reported rate of autism, but at present it is not possible on

the basis of these studies alone to identify the basis to the rise.

2) Is any increase in the rate of autism consistent with a problem

over some or all of the MMR vaccines ?

Two studies - the study by Brent and colleagues from the Royal

Free Hospital (, , Farrington, Petropoulos, Favot-Mayaud, Li &

Waight 1999) and the more recent General Practice Research Database (GPRD)

study (Kaye, Melero-Montes & Jick 2001) show a significant recent increase

in the rate of diagnosis of autism, however, both papers conclude that the

rise is independent of MMR usage. Various arguments are advanced by these

authors and other to account for the apparent rise:

i) There is a trend towards earlier diagnosis which would inflate the

apparent figures: But The recent Kaye et al paper, however, indicates a

fairly stable age at diagnosis over the time in question of around 4.6 years

ii) There have been changes in diagnostic criteria which would

increase the numbers of autistic spectrum disorder children identified: But

studies such as the recent Center for Disease Control Survey in Brick

Township http://www.cdc.gov/nceh/cddh/dd/brick.htm), which reported an

autistic disorder rate of 40 per 10,000, and the CHAT survey in South London

(30.8 per 10,000) demonstrate exceptionally high rates of autistic

disorder - a change in the rate of core autistic diagnosis on the ICD and

DSM systems, not an increase due to the incorporation of broader categories

such as Asperger's syndrome.

iii) There is increasing professional and parental awareness leading

to the detection of more cases: There has definitely been a heightened

awareness in both the public and clinical professionals. Some increase is

likely to be the result of improved training and media coverage.

iv) Lastly, that 'environmental factors not yet identified' may be

important:

But Surely one environmental factor which has yet to receive full scientific

scrutiny and concerning which there is mounting public concern and

professional uncertainty is the possible role of MMR vaccines. The role of a

number of viruses in the pathogenesis of autism is known and accepted -

Cytomegalovirus, HIV, rubella and Haemophilus influenza for example. We also

have animal viral models of autism - Borna virus being one such case.

A further factor which has not been taken into account in looking at

the data in these two papers is the introduction and subsequent withdrawal

of two MMR vaccines which would have resulted in a higher rate of more

severe problems over the period from 1988-1992. Without knowing the

proportions of children who were given these as opposed to the MMR-II

vaccine it is difficult to tell whether 'diagnostic overshadowing' (where a

more severe problem - epilepsy, meningitis... is diagnosed instead of rather

than as well as autism) could have masked initial increases.

Historically, the typical pattern of presentation for an autistic

child was that as early as information was available, there were, albeit

sometimes subtle, developmental differences from normally developing

children (see eg: Teitelbaum, Teitelbaum , Nye, Fryman & Maurer 1998).

Typically differences only gave rise to parental concern somewhere in the

middle of the second year of life, when deficits in language and

socialisation became more apparent.

Recent studies are finding a very different picture. The CHAT

(Checklist for Autism in Toddlers) study (Baird, Charman, Baron-Cohen, ,

Swettenham, Wheelwright & Drew 2000) surveyed 16,235 live births over a one

year period from 10 Health Districts in South East Thames Health Region,

virtually all of whom would have received MMR vaccine. In this study, while

the expected number of autistic children could be identified on features

such as poor eye contact, lack of fantasy play and lack of protodeclarative

pointing at a year and a half (N = 10), on follow-up it transpired that four

times as many children (a further 40) who were subsequently diagnosed

autistic were found to have been developing well at 18 months as assessed on

the CHAT but subsequently to have regressed and been diagnosed autistic.

A balanced summary of the above evidence again demonstrates a real

rise in the rate of autism. I would suggest that with the limited analysis

of data on vaccination practice, the Royal Free and GPRD papers cannot rule

out a significant vaccine effect. The change in pattern of presentation

shown in the CHAT study would lend support to a 'new environmental factor'

being the most likely basis to the rise, which could indeed prove to be MMR

vaccines.

3) Is any link between MMR and autism biologically plausible?

If we suspend judgement over the state of the epidemiological

evidence, are there any mechanisms by which an attenuated trivalent vaccine

such as MMR could cause a neurodevelopmental problem like autism ?

there are several mechanisms which could be viewed as, possibly

interacting, biologically plausible mechanisms :

1) An autoimmune reaction - this would be where the body's immune

system raises antibodies to a vaccine virus, and those antibodies go on to

directly affect the functioning of the central nervous system. A parallel

can be drawn with a disorder known as PANDAs where a movement disorder

(Sydenham's chorea) occurs after a Streptococcal infection and is completely

cured by a technique which removes the antibodies from the patients

bloodstream.

A number of recent papers point to autoimmune problems in autism. This

view suggests a number of novel approaches to therapy which have some

preliminary evidence of positive effects (Gupta 2000).

2) A gastrointestinal dysfunction - where interference with intestinal

function leads to alteration to endogenous opiate systems or to food related

opiate-like substances passing into the bloodstream, reaching the brain and

causing autistic-like behaviour. The 'opioid hypothesis' (Panksepp 1979)

receives support from a range of studies. The endoscopic research published

to date demonstrates abnormalities of both the oesophagus (Horvath,

Papadimitriou, Rabsztyn, Drachenberg & Tildon 1999) and the intestine

(Wakefield, , Murch, Thomson, Montgomery, Davies, O'Leary, Berelowitz

& - 2000).

3) A direct viral infection of the Central Nervous System - although

evidence for this mechanism is more limited, to date three deaths from

chronic measles infection of the nervous system (Subacute Sclerosing

Panencephalitis) have been reported within the group of children whose

families are pursuing litigation in the UK.

In summary, three biological mechanisms, in concert, in some

combination, or individually, could provide biologically plausible routes by

which a form of autism may be brought about through MMR vaccine exposure.

As far as I am aware, despite repeated rebuttal of the possibility

that MMR could be a causal / contributory factor to the rise in the rate of

autism, no properly articulated adequate alternative hypotheses have been

put forward to explain the rise in the rate of diagnosed autism.

'When you have eliminated the impossible, whatever remains, however

improbable, must be the truth.'

Arthur Conan Doyle, The Sign of Four, (1890)

4) Is current reassurance given on the basis that sufficient

appropriate research has been carried out to look into these issues or that

little research has been carried out ?

As I stated above, the conclusion of the Institute of Medicine

Immunization Safety Review Committee briefing paper was that appropriate

research to effectively address the issues has yet to be carried out. The

systems currently in place rely on passive surveillance for acute reactions

(voluntary reporting of short term severe reactions to vaccine

administration). Such systems are inadequate to monitor possible reactions

which are insidious in onset and only clearly identified typically many

months or even longer after the vaccine event.

Absence of evidence and evidence of absence are two wildly different

things - we cannot reassure people that there is not a problem when there is

no adequate research evidence - often we are 'reassured' by statements like

'I know of no evidence that...' when what is needed is reassurance on the

basis that 'the research evidence proves beyond reasonable doubt that ... is

not the case'. If there is a paucity of evidence with which to reassure,

such systematic research needs to be commissioned. I fear that the

biological plausibility of such a mechanism has so far escaped those who

have developed our current models of surveillance.

* It is only fair and reasonable to note that three MMR vaccines were

originally licensed and in use in the UK over the period 1988-1992 and that

two of these vaccines (which contained a different, Urabe, strain of mumps

vaccine) were subsequently withdrawn because of unacceptable levels of acute

side effects such as aseptic meningitis.

References

Baird G., Charman T., Baron-Cohen S., A., Swettenham J., Wheelwright S.

& Drew A. (2000) A screening instrument for autism at 18 months of age: A

6-year follow-up study. Journal of the American Academy of Child and

Adolescent Psychiatry, 39, 694-702.

Bramley C., Ahmed S. & Cromie D. (2001) MMR a safe and effective

vaccine. In Touch, this issue.

Fombonne E. (1999) The epidemiology of autism: a review.

Psychological Medicine, 29, 769-786.

Fombonne E. (2001) Commentary: Is There an Epidemic of Autism ?

Pediatrics, 107, 411-412.

Gillberg C. & Wing L. (1999) Autism: not an extremely rare

disorder. Acta Psychiatrica Scandinavica, 99, 399-406.

Gupta S. (2000) Immunological Treatments for Autism. Journal of

Autism and Developmental Disorders, 30 (5), 475-479.

Horvath K., Papadimitriou J.C., Rabsztyn A., Drachenberg C., Tildon

J.T. (1999) Gastrointestinal abnormalities in children with autistic

disorder. Journal of Pediatrics. 135(5), 559-563.

Kaye J.A., Melero-Montes M.del Mar & Jick H. (2001) Mumps measles

and rubella vaccine and the incidence of autism recorded by general

practitioners: a time trend analysis. British Medical Journal, 322, 17th

February.

Panksepp J. (1979) A Neurochemical Theory of Autism. Trends in the

Neurosciences, 2, 174-177.

Rimland B. (1999) The Autism Explosion

http://www.autism.com/ari/editorials/explosion.html

Rimland B. (2000) The autism increase: research needed on the vaccine

connection http://www.autism.com/ari/editorials/autismincrease.html

Rutter M. (1966) Behavioural and cognitive characteristics of a

series of psychotic children, pp51-81 in: J.Wing (Ed.) Early Childhood

Autism.

Stoto M.A., Cleary S.D. & V.B. (2001) Epidemiologic Studies

of MMR Vaccine and Autism, Commissioned Background Paper, Institute of

Medicine Immunization Safety Review Committee, Feb 23rd (this paper is

available as a downloadable file from the Institute of Medicine Website).

B., E., Farrington C.P., Petropoulos M.C., Favot-Mayaud

I., Li J. & Waight P.A. (1999) Autism and measles, mumps, and rubella

vaccine: no epidemiological evidence for a causal association. Lancet. 353

(9169) : 2026-2029.

Teitelbaum P., Teitelbaum O., Nye J., Fryman J. & Maurer R.G. (1998)

Movement analysis in infancy may be useful for early diagnosis in autism.

Proceedings of the National Academy of Science, USA, 95, 13982-13987

Wakefield A.J., A., Murch S.H., Thomson M., Montgomery S.M.,

Davies S., O'Leary J.J., Berelowitz M., - J.A. (2000)

Enterocolitis in children with developmental disorders. American Journal of

Gastroenterology, 95 (9), 2285-2295.

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Letter on the DMG Research

Dear Dr. Kern,

Your recent DMG/autism study is exciting; and the fact that there are

two DMG-responding subgroups is very important, noting the abstract's

description:

" Some children appeared to respond positively to the dimethylglycine,

and there was a smaller proportion of negative changes in the

dimethylglycine group... "

This finding stands in stark contrast to the article's conclusion,

which offers:

" ...the quantitative changes in the dimethylglycine behavioral

assessments were not significantly different from what was observed among

children who received placebo. "

The existence of subgroups in autism is so very important, and your

study illustrates i) that a treatment that is effective in one subgroup may

be contra-indicated in another subgroup; and (ii) that if the word " autism "

is used as a single concept (lacking subgroup effects), then a conclusion

can be misleading.

I would hope that ASD children who would improve with DMG are not

denied the behavioral and cognitive benefits that would ensue from DMG, just

as ASD children who would experience a DMG-related regression ought not be

given DMG.

Jon Pangborn is an amino-acids expert who is associated with the lab

" Doctors Data " . At two conferences, he has presented amino-acid profiles of

ASD children and has identified why some ASD children improve when receiving

DMG and why some deteriorate. These differing responses can be deduced by

the child's amino-acid profile -- which, increasingly, many parents are

purchasing as part of their ASD child's biomedical portrait.

Separately, I will send you Dr. Pangborn's contact information, in

case you wish further insights into the amino acid portraits that correspond

to DMG's positive and negative-responders within the autism-spectrum

population.

Thnx again for the important DMG study, and I hope that

pediatricians -- in the busy lives -- don't miss the fact that, for an ASD

subgroup, DMG is beneficial.

Sincerely,

Binstock Researcher in Developmental & Behavioral Neuroanatomy

[see abstract in April 14, FEAT Daily newsletter. 1: J Child Neurol

2001 Mar;16(3):169-73 Effectiveness of N,N-dimethylglycine in autism and

pervasive developmental disorder. Kern JK, VS, Cauller PL, Kendall

PR, Mehta PJ, Dodd M. PMID: 11305684.]

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