4. MMR and Late-Onset Autism -(Autistic Enterocolitis)

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4. MMR and Late-Onset Autism -(Autistic Enterocolitis)

A Briefing Note by Thrower

Continued from a previous post.

PART Fb - EVIDENCE TO SUGGEST THAT THERE IS A LINK

42. Paper by Kulman, Neri, Rovelli, Roselli, Lissoni and Bertolini,

Divisione di Neuropsichiatria Infantile, Ospedale S. Gerardo, Monza, Italy

This examined the role of the pineal hormone melatonin (MLT) in the

pathogenesis of autism. The study included 14 children affected by autism,

median age seven years, mostly suffering sleep disorders, and found that:

* no patients exhibited physiological MLT increase during the night

* mean serum levels of MLT observed during the night were

significantly lower in patients than controls

* there was therefore an indication of severe pineal function damage

* the absolute lack of MLT increase during the night would justify

exogenous administration of MLT as replacement hormonal therapy

43. A USA parents’ group, the Developmental Delay Registry, has

reported that of nearly 700 children aged between one and twelve that had

been surveyed in 1994:

* those that had taken more than 20 cycles of antibiotics in their

lifetime were more than 50% more likely to suffer developmental delays

* nearly 75% of the developmentally-delayed children had been reported

as developing normally in their first year of life

* developmentally-delayed children were 37% more likely to have had

three or more ear infections than non-developmentally delayed children

* developmentally-affected children were nearly four times as likely

to have had adverse reactions to immunisations

44. Other Researchers Who Believe Link Possible

Published evidence by Stratton et al ( " Adverse Events Associated With

Childhood Vaccines " , National Academy Press 1994, 64-65) states " In the

course of its review the committee encountered many gaps and limitations in

knowledge.......(including) inadequate understanding of biological

mechanisms underlying adverse events, insufficient information from case

reports and case series, inadequate size or length of follow-up of many

population-based epidemiologic studies " .

A paper published by Bitnun et al, Clinical Infectious Diseases

Journal, October 1999, confirmed the presence of measles virus in the brain

tissue of a previously-healthy 21-month-old boy, 8.5 months after he

received MMR. The child had no history of exposure to measles or if immune

deficiency. The nucleotide sequence in the nucleoprotein and fusion gene

regions was identical to that of the Moraten and Schwartz vaccine strains.

The fusion gene differed from known genotype A wild-type viruses.

45. Statement by Professor Walter O. Spitzer

Although not a study, the statement by Professor Spitzer deserves a

high profile. Professor Walter O. Spitzer, Emeritus Professor of

Epidemiology, McGill University, Montreal, stated on December 6th 2000:

" The safety of MMR has been brought into question, both in the United

Kingdom and in California. It is not possible to rule out the possibility

that excessive rates of autism occur among children immunised with MMR "

" The early epidemiological findings are worrisome. The clinical and

laboratory data strongly suggest the biological plausibility of a link

between MMR and autistic disorders "

He " ......strongly endorses immunisation as a pillar of public health

strategy for most diseases. But one should never surrender caution " .

46. Wakefield & Montgomery " Through A Glass Darkly " Paper (Look Back

At MMR Safety Trials), Journal of Adverse Drug Reactions, 2000 19(4),

265-283)

Wakefield & Montgomery reviewed following safety studies: Buynak et al

1969, Stokes et al 1971, Minekawa et al 1974, Schwartz et al 1975, Crawford

and Gremillion 1981, et al 1987.

Buynak study identified viral " interference " . Follow-up only 12 days

Stokes study revealed persistent gastrointestinal problems in US trial

children. Follow-up only 28 days. Stokes compared 228 MMR children with 106

unvaccinated controls. Data, from Philadelphia and Costa Rica and San

Salvador, was combined - serious methodological error.

Gastroenteritis significantly more common in Philadelphia vaccinees

(24%) compared with unvaccinated Philadelphia controls (5.6%). No

significant difference between vaccinated and unvaccinated in Costa Rica and

San Salvador because of high levels of gastroenteritis anyway (50% in

vaccinees, 44% in controls). Combining all the data masked these instructive

differences.

Also significant " unrelated " illness in 39% of Philadelphia vaccinees

(otitis, allergy, viral infection, abdominal pain), compared with 12.2%

controls. Relevance not seen at time.

Minekawa study confirmed viral interference. Follow-up only 15 days.

Schwartz study also merged its data, so provided insufficient insight.

Follow-up only 21 days. Looked at two different populations, 282 children in

Ohio and 926 children in Santo Domingo, Dominican Republic. Merging of data

from different countries again a serious error. No data provided to permit

analysis of adverse events.

Crawford and Gremillion study of USAF recruits confirmed viral

interference. Follow-up only 19 days. Some 512 vaccinees were compared with

835 unvaccinated controls. Study noted increased fever and diarrhoea in

those that received measles and rubella vaccines simultaneously. Effect not

ADDITIVE but SYNERGISTIC - key point.

Eddes study (small UK study) 1991 compared reactions to MMR with

monovalent measles vaccine. High rates of gastrointestinal disorders (41.9%

and 37.8%). Authors dismissed these as normal background illness.

study noted diarrhoea common (26% of vaccinees). Follow-up only

21 days. Major missed opportunity of following up large cohort. (NB Dr.

, who has been so vociferous in criticising the Wakefield

findings and in defending MMR, including presentations to MP groups, was

co-author, and designed the poor 1999 , North London study)

Stokes, Schwartz, and Eddes studies were all too small or too

superficial to pick up uncommon adverse events.

Plesner et al study of gait disturbance following MMR (Acta

Paediatrica, 2000, 89, 58-63) confirmed association and indicated more

severe cerebellar ataxias following MMR may be associated with residual

cognitive deficits.

Peer review comments on Wakefield & Montgomery paper very powerful.

Peer reviewers included Dr Fletcher, former Principal Medical Officer

in Medicines Division (now MCA), who was medical assessor to Committee on

Safety of Medicines. His comments:

" Evidence on safety very thin " , and " Too few followed for sufficient

time "

" Big numbers were necessary, and computerised databases already in

place to permit this, but was not done "

" Caution should have ruled the day " , and " Should have been strong

encouragement to conduct 12-month observational study on 10,000-15,000

children " (not done)

" Granting of product licence was premature "

Wakefield paper is actually argument for vaccination - but not using

triple measles-containing vaccines. Wakefield not anti vaccination per se.

Duty is to patient. He is investigating children brought to him, not

campaigning against DoH for its own sake. He is simply relating what he is

finding.

Other background points relevant to paper:

Is already accepted by Medical Research Council that concurrent

exposure to natural (or vaccine) measles and natural mumps is a risk-factor

for inflammatory bowel disease

Also is legal precedent for triple vaccine causing autism (Lassiter

case, US, 1996). This was a DPT vaccine, but established important ruling on

probability of causation.

MCA has left itself an escape route for later: " The numbers included

in the trials, even if they were all followed up long term, would not be

sufficient to detect rare problems..... " . But what is " rare " ?

47. The Wakefield//Shattock Rebuttals - " Anything You Can Rebut,

I Can Rebut Better "

Through A Glass Darkly safety paper by Wakefield and Montgomery has

been criticised by Mike , Medical Director of Aventis Pasteur MSD, the

manufacturers of MMR.

But ’s criticisms do not themselves stand up to scrutiny, as

demonstrated below by Shattock of Sunderland University Autism Research

Unit (tel 0). The only aspects that cannot be bottomed-out by

Shattock are where the studies themselves have not been published.

maintains that observation period in trials (as reported in

paper by Stokes et al, 1971) was up to 63 days, not up to 28 as reported by

Wakefield. However, Shattock quotes Stokes study as saying " Joint

involvement was noticeably absent during six to nine week

follow-up....Present studies with queries at six to nine weeks following

vaccination did not reveal any occurrence of arthritis or arthralgia beyond

the 28-day period for close observation " . Trial therefore was 28 days, with

only queries for arthritis etc beyond this. Wakefield version therefore

correct.

maintains that " MMR I " safety was investigated in four studies

prior to licensing in US 1971 and UK 1972. Also, " MMR II " investigated by

seven studies, two of which published. Immruvax also tested in seven

studies. But Shattock: unclear whether studies are published or secret.

(Please publish?) Wakefield can only comment on what is published.

states that virologists generally accept wild measles virus

only causes persistent disease in central nervous system, as subacute

sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis

(MIBE). Wakefield maintains potential for delayed intestinal pathology has

been borne out by Fournier et al, 1968. Shattock: technology has failed to

isolate measles virus RNA in affected children, but further progress

expected.

states that mutant measles virus genetic material can persist

in tissues of apparently healthy people without causing disease (Katayama et

al, 1998). Shattock: so mutant measles can persist but vaccine strains

cannot? - challenge for evidence to substantiate this claim.

Shattock also makes points that (a) MMR test group in Stokes 1971

paper had way more GI problems than controls, ( that in Schwartz et al

paper 1975 the results of 282 children from Daytona Ohio and the 1192 from

Santo Domingo and Panama were pooled (unscientific), and © why was

gastroenteritis completely omitted from list of side effects when difference

of incidence between groups so blatant?

: " gold standard " in safety studies was placebo-controlled

crossover study of 1162 twins in Finland 1982. More detail published by

Virtanen, Peltola et al 2000. Shattock: was 1982 study published?/where? The

2000 paper was actually only published after Wakefield & Montgomery paper

submitted.

Wakefield: follow-up interval reduced from 4 weeks in initial

controlled trial to 3 weeks in subsequent trials. : insists follow-up

was up to 63 days. Shattock: observations were for 28 days. At up to 63

days, parents asked about any significant illness - side effects listed in

paper apparently excluded. No doubt Wakefield’s 28 days is right.

: later MMR II studies had observation period of 42 days.

Priorix studies had periods of 42-60 days. Shattock: where are publication

details?

: numerous post-marketing studies of MMR have been conducted and

published. Shattock: references please? Why haven’t they been quoted by DoH,

why can’t anyone find them?

Other " facts " quoted by in " Aventis Pasteur MSD - Vaccines For

Life " paper:

: " national safety regulators require all side effects to be

reported " . But this doesn’t mean they actually are, especially novel

syndrome with (up till 1998) no publicity, delayed onset, and official

refusal to count as " adverse reaction "

: " there have been over 500m doses given worldwide " . But there

are also many hundreds of thousands of cases of autism worldwide, and none

of these has been admitted by authorities to be consequence of MMR, keeping

its safety record clean.......

: " As anyone in clinical trials knows, all participants or their

parents are very carefully informed and consented " . Yes, but this wouldn’t

have covered a warning to watch out for subsequent delayed degeneration into

autism!

: " Any unusual event that occurs in that child at any time after

trial should be reported to MCA " . But this would almost certainly never have

included autism pre-1997, when very first publicity was given in Pulse

magazine and BBC Newsnight. (In Oliver Thrower case, Newsnight report 8/97

was first clue, nine years after vaccination. In his case, vaccination never

previously mentioned or considered as possibility by health professionals.

He was added to MCA database 11 years after vaccination. So much for the

value of even a 63-day trial follow-up!)

: " An unimmunised child is the infectious equivalent of a drunk

driver " . This comment is a revealing insight.

: " Giving vaccines separately would be more expensive " . More

expensive than all the extra health costs, care costs, special education

costs, special needs transport costs, lost earnings of victim, lost tax

revenues, parents’ lost earnings and taxes?

Quote from MSD product insert on MMR: " Clinical studies of 279 triple

seronegative children, 11 mths to 7 years of age, demonstrate that MMR is

highly immunogenic and generally well tolerated. " (So is just 279 the

number?)

48. UK Department of Health Repudiation of Wakefield & Montgomery

" Through A Glass Darkly " Paper

The UK DoH’s response was summarised in its press release of 21st

January 2001. The main points are set out below, with the DoH in italics,

and with my own responses following.

The claim by Wakefield & Montgomery that there was insufficient

research " is factually incorrect, as many studies recorded safety data up to

six weeks, which is standard for vaccines, and some studies recorded data

for longer - up to a year in some cases " . Yes, but autism did not form part

of this surveillance, the importance of gastrointestinal problems was not

appreciated, the reference to six weeks being " standard for vaccines " doesn’

t address the autism/gut syndrome, and very few cases indeed, in very few

studies indeed, followed up for longer than a few weeks. The syndrome was

missed.

" Combined MMR vaccines had been extensively tried and tested in

Scandinavia and the USA before they were introduced in the UK in 1988 " . As a

statement, this proves nothing. The new syndrome of autistic enterocolitis

was not suspected in these countries, either, and again was missed.

" Now MMR is successfully used in over 30 European countries as well as

the USA, Canada, Australia and New Zealand " . Same comments apply.

Presumably, these other Governments are claiming that " it’s safe because it’

s used in the UK " ?

" A publication in 1988 lists 30 published studies where combined MMR

vaccines were studied and follow-up extended up to ten years " . Same comments

again apply. (See also the Wakefield//Shattock rebuttals section)

" The safety of combined MMR vaccines has been reviewed repeatedly by

the Government’s independent expert scientific advisory committees including

the Committee on Safety of Medicines and the Joint Committee on Vaccination

and Immunisation " . This is true in a literal sense, but the reviews have

been mis-designed and halfhearted or inconclusive ( " It was impossible to

prove or refute the suggested association between MMR vaccine and

autism/pervasive development disorder or inflammatory bowel disease because

of the nature of the information, the self-selection of cases and the lack

of comparators " - Committee on Safety of Medicines Report of the Working

Party on MMR Vaccine, page 12, paragraph 5.5).

One can also argue that the Committees quoted are neither independent

(see other references) nor expert in the field of gastroenterology, as

opposed to immunology. They stand to lose a great deal by a link being

exposed, both corporately and individually, and possibly financially.

" The use of MMR vaccine is also endorsed by the World Health

Organisation, the British Medical Association, the Royal College of General

Practitioners and the Royal College of Nursing. " This in itself proves

little in the context of an intense scientific debate about a new discovery

in gastroenterology. The latter institutions may come to regret their

endorsement in the fullness of time. Have their advisers read all the

evidence, on both sides, first-hand?

" By 2000, several hundred million doses will have been given

wordwide " . Yes, and there will also be several tens, or hundreds, of

thousands of cases of autism worldwide, some of which may have been

precipitated by MMR.

In short, the DoH’s rebuttal was a " non-denial denial " . It sought to

refute the Wakefield/Montgomery paper, but was almost entirely couched in

generalities. The devil is in the detail of the Wakefield/Montgomery paper.

And the DoH was unable to refute this detail - indeed, it largely avoided

addressing it at all.

49. Department of Health Re-Launch of MMR, 22/1/01

On 22/1/01, DoH launched £3m publicity campaign for MMR and rejected

Wakefield " Through A Glass Darkly " MMR safety-test paper, without:

Announcing any investigation into affected children

Any additional funding for research into causes of autism (however,

see later DoH/MRC announcement of 5th March 2001)

Any explanation as to why autism is rising so steeply in UK and around

the developed world (again, see DoH/MRC announcement of 5th March)

DoH also released 15-page paper, " Combined MMR Vaccines: Response of

the Medicines Control Agency and DoH " to attempt to refute Wakefield paper.

However, paper merely re-assembles previous studies quoted by DoH, and adds

nothing new of note.

The Chairman of the Committee on Safety of Medicines, Professor

Alasdair Breckenridge, said " MMR vaccination is very safe. There is no

question-mark whatever over its licensing " . (Breckenridge is one of the 10 -

out of 37 - members of the CSM to have no declared interests whatever).

Professor Langman, chairman of the JCVI, said " My Committee

has independently (sic) considered all the issues and reached the same

position as the Committee on Safety of Medicines " . Langman has non-current

non-personal declared links with Merck Sharpe Dohme.

The Chief Medical Officer, Professor Liam son, said " We are very

pleased to have this further confirmation from the two independent expert

committees " .

Some parents feel that, in the absence of conclusive evidence, either

way, and taking all the surrounding factors into account, the re-launch of

MMR was a serious error, leaving the authorities no escape should the test

cases win in the High Court. The Department of Health’s high-risk strategy

would, if this was the outcome, severely damage public confidence, probably

in all forms of immunisation. The repercussions for the Department, and for

child health generally, would be significant. The Department’s actions seem

to have not countenanced this potential scenario.

Note: Part G - Flawed UK Regulatory and Monitoring Systems, Part H - Various

Experiences Elsewhere, Part J - Political Initiatives, Part K - Recent &

Coming Events, all can be found at

http://www.whale.to/vaccine/thrower11.html

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