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

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

A Briefing Note by Thrower

Continued from a previous post.

PART Fa - EVIDENCE TO SUGGEST THAT THERE IS A LINK

24. Paper By Weibel, Caserta, Benor and , " Acute Encephalopathy

Followed By Permanent Brain Injury Or Death Associated With Further

Attenuated Measles Vaccines: A Review of Claims Submitted to the National

Vaccine Injury Compensation Program " , Pediatrics, Vol 101 No. 3 March 1998.

The purpose of this study was to determine any causal relationship

between acute encephalopathy and subsequent permanent brain injury or death,

following measles vaccine, mumps vaccine, rubella vaccine, MR or MMR. The

conclusion was that a causal relationship may exist as a rare complication.

The study looked at children who received the first dose of these

vaccines 1970-93 and who then developed an encephalopathy with no determined

cause within 15 days.

A total of 48 children (out of 403 claims submitted) aged 10-49 months

met the criteria. Eight had died, the remainder had mental regression and

retardation, chronic seizures, motor and sensory deficits and movement

disorders. Symptoms were clustered on days 8 and 9 after vaccination. The

clustering was accepted as suggesting a rare complication of measles

immunisation.

Of the 48, 1 child had MR, 30 had MMR, 2 had MMR plus DTP, 2 had MMR

plus haemophilus influenzae type b (Hib), 4 had MMR plus DTP plus oral polio

vaccine (OPV), 1 had MMR plus DTP plus OPV plus Hib

Two of the deaths were in previously apparently normal healthy

children, who then received MMR. Three deaths occurred 3 months to 4 years

later. One non-fatal case reviewed had eventual hyperactivity and aggressive

behaviour at age 5 years.

The authors thought that (1) the 48 cases represented under-reporting

from a passive system, but (2) most serious cases had been captured by the

system - a self-comforting point?

25. US paper, by Drs. Delgiudice-Asch (clinical instructor in

psychiatry, Mount Sinai School of Medicine) and Hollander (Seaver Autism

Research Centre)

This includes:

* the noting of the potential relevance of antimyelin autoantibodies

* reference to the work of Stubbs in the USA and the suggestion that

an inflammatory reaction in the brain may contribute to the development of

autism

* references to indirect evidence of immune activation in autism

* the reference to Singh’s finding, also in the USA, that identified

serum antibodies to myelin basic protein in 19 out of 33 autistic children,

compared with only 9% in a control group

* reference to Todd and Ciaranello’s detection of circulating

antibodies in seven out of thirteen children with autism

26. Paper, Dialysable Lymphocyte Extract In Infantile Onset Autism: A

Pilot Study, has been published (journal not identified) by Dr. H. H.

Fudenburg of the NeuroImmuno-Therapeutics Research Foundation, Spartanburg,

South Carolina.

This studied 40 infantile autistic patients ranging from 6-15 years,

of which 22 were classical infantile autism ( " true autism " , or TA) and 18

lacking one or more defects associated with infantile autism and were

therefore termed " pseudo-autism syndrome " (PAS). Medical histories focused

on possible viral infection in the mother, especially during second

trimester, whether the child had multiple infections, especially otitis

media, in the first to fifteenth month of life, and the relation of onset of

symptoms to immunisation. Results were:

* antibodies to myelin basic protein were present in 20 out of 22 TA

and 4 out of 18 PAS children

* 12/22 TA and 6/18 PAS children had a decreased response to ConA and

negative LIF response to PHA and a decrease in suppressor functional assay

(later studies showed a good correlation of the above with low levels of

CD8/CD28 and CD8/CD38 T-cells)

* 6/22 TA and 12/18 PAS children had increased toxic metal levels,

usually aluminium) and decreased levels of trace minerals necessary for a

normal immune response

* 10/22 TA and 6/18 PAS children had elevated thyroid stimulating

immunoglobin values

* titers to rubella were ten times normal in 11/22 TA and 5/18 PAS

children

* several of the children had elevated IgM levels to measles,

indicating a defect in immune regulation

Fudenberg states that:

* the very low IL-2 receptor/positive lymphocytes and the decrease in

DR+, but not IL-2 receptor+ lymphocytes, suggests incomplete activation in

the TA children, a finding seen in other autoimmune diseases; this suggests

that TA may be an autoimmune disease

* it is possible that " auto-antibodies " are directed against various

viruses and that the reaction to myelin basic protein, neuron axone

filaments, one or other receptors for neurotransmitters, represent molecular

mimicry

* TA is probably due to adverse reactions to live virus or live virus

vaccine in a genetically-predisposed individual, one whose cell-mediated arm

of his/her immune system is not yet mature, or, in a very young infant, by

transplacental IgG antibodies from a mother with high titers of antibodies

to one of the vaccine constituents, e.g. diptheria toxin

27. Unpublished paper by Dr. Vijendra Singh at the College of

Pharmacy, University of Michigan, Ann Arbor, jointly with the late Professor

Warren, Professor of Biology at the Centre for Persons with

Disabilities, Utah State University in Logan and Adjunct Professor of

Psychiatry at the University of Utah, and also Dennis Odell

This studied the immune responses to myelin basic protein, which is a

protein component of myelin. Defects in myelin would dramatically affect

brain activity. The study of 33 autistic children at or over ten years old

was compared with eighteen age-matched normal children. twenty children with

unknown-cause mental retardation and twelve children with Down syndrome were

also studied as controls, and testing for serum antibodies to MBP

undertaken:

* antibodies were found in nineteen of the 33 (58%) of autistic

children

* the corresponding level for controls was 7%, or over eight times

higher

* testing of the autistic children showed features also found in

patients with autoimmune diseases such as rheumatoid arthritis,

insulin-dependent diabetes and multiple sclerosis

* The features above included genetic predisposition, gender

imbalance (four or five times higher frequency in boys than girls), major

histocompatibility association, and immune activation.

The authors suggest that autoimmunity may be a critical factor in the

cause of autism.

They note that an essential part of the autoimmune mechanism should

involve antibody-mediated immune responses or antibodies against the brain,

and that other recent studies have found evidence of antibodies to brain

tissue antigens, such as myelin basic protein, neurofilament proteins and

serotonin receptor.

They also note that antibodies to MBP may have some pathological

relevance since abnormal cell-mediated immune response involving a soluble

factor but not antibodies to this protein has been detected by other

researchers, suggesting that autistic children develop inappropriate immune

responses to this brain protein.

They conclude that at present (1992) the relationship between

antibodies to MBP and autism was not understood, but they hypothesised that

the development of the immune response could be the basis of autoimmune

pathogenesis in some cases of autism. It was conceivable that if an

immunological assault was to occur before birth or during infancy or early

childhood, it could lead to poor myelin development or abnormal function of

the nerve fibre myelin.

28. Further unpublished US paper, from Dr. Vijendra Singh

This suggests that:

* significant number of autistic children have positive titers of

measles and/or MMR autoantibody which is associated with the presence of

myelin basic protein autoantibody

* measles-related triggered autoimmune response to myelin may play a

pathogenesis role in the cause of autism in at least a subset of cases

29. Paper by Singh, Warren, Odell, Warren and Cole, published in Brain

Behaviour 1993 March 7(1) 97-103

This investigated the possible pathological relationship between

autoimmunity and autism, reported that:

* antibodies reactive with myelin basic protein (anti-MBP) had been

investigated in the sera of autistic children

* nineteen out of 33 (58%) of sera of autistic children under or

equal to age ten were found to be positive for anti-MBP

* in controls, only eight out of 88 (9%) were positive; controls were

age-matched and included normal children and children with mental

retardation or Downs Syndrome, as well as normal adults aged 20-40.

30. Paper by Weizman, Weizman, Szekely, Livni and Wijsenbeek,

published in the American Journal of Psychiatry 1982 Nov 139 (11) 1462-5

This reported a study by macrophage migration inhibition factor test,

in seventeen autistic patients and a control group of eleven patients

suffering from other mental diseases, of cell mediated immune response to

human myelin basic protein. It found:

* of the seventeen autistic patients, thirteen demonstrated

inhibition of macrophage migration

* none of the non-autistic patients showed such a response

* the results therefore indicate the existence of a cell-mediated

immune response to brain tissues in autism

31. Paper by Drs. Gupta, Aggarwal and Heads, titled Dysregulated

Immune System in Children with Autism - Beneficial Effects of Intravenous

Immune Globulin on Autistic Characteristics, published in the Journal of

Autism and Developmental Disorders, vol. 26 no. 4 1996

This suggested a theory that high titers of rubella antibody present

in mothers of children with autism could be transplacentally transferred and

could persist in the child, and that when the child received MMR, rubella

antigen may complex with pre-existing antibodies, thereby possibly playing a

role in the pathogenesis of autistic features

32. Unpublished US paper, by Dr. Oleske and Assistant Professor Zecca,

New Jersey Medical School

This found that:

* among 16 children diagnosed with autism, there was a threefold

increase in their serum rubeola titers over the expected normal range

* the unusually high and persistent titers of anti-measles antibodies

in autistic children was statistically significant when compared with a

similar group of non-autistic subjects

* it is suggested in the paper that MMR may play a role in the

pathogenesis of autism because elevated titers of anti-measles antibodies

may signify a chronic over-activation of the immune system

33. US paper by Binstock, Researcher in Developmental and

Behavioural Neuroanatomy, IMI, Denver

This found that

* brain regions whose pre-vaccination neuronal damage had been

relatively insignificant may, via vaccine-induced clonal expansions, suffer

additional damage.......resulting in vaccination-enhanced neuropathy

presenting clinically as autism

* recent research findings are instructive regarding autistic

children for whom.......medical records show a history of infections,

antibiotic treatments, vaccinations and temporally-associated onset of

autistic traits.........

* nearly any vaccine may have the potential for inducing neuronal

damage in persons with NdEs. " (Source: Hypothesis: Infection, Antibiotics,

Vaccination-Induced Neuropathies; Mechanism Of Pathogenesis In Some Cases Of

Autism, ADHD, Tourette’s, by Theresa C. Binstock, bit.listserv.autism 3rd

January 1997)

* although presented as a hypothesis, a route is offered that

demonstrates how a small subset of susceptible infants could be affected,

that a variety of vaccines could be involved for this subset of cases, and

that prior treatment with antibiotics may play a critical role

34. Paper by Diane E. , D. E. Hussy et al, Hopkins

University, US, has established (source: Journal of Infectious Diseases, 173

(6), 1320-26, June 1996)

This found that:

* measles virus and measles vaccinations impair cell-mediated

immunity

* they also increase the likelihood of other viral infections

These researchers found that:

* of 88 children immunised at six or nine moths with Edmonston-Zagreb

or Schwarz SW6 or SW9 strain of measles vaccine, mitogen-induced

lymphoproliferation was decreased at 2 weeks in the SW9 group and at 3

months in all groups

* this was negatively correlated with measles antibody level at 3

months

CD8 T-cells, soluble CD8, neopterin and beta2-microglobulin were

increased at 2 weeks in the SW9 group

* soluble CD8 and beta2-microglobulin remained elevated at three

months

* therefore measles immunisation resulted in suppression of

lymphoproliferation, which was most evident in infants with the highest

antibody responses and most immune activation

35. Paper by P. G. Auwaerter and Diane , (source: Clinical

Immunolgy and Immunopathology, 79(2): 163-70, May 1996):

This found that:

* measles produces immune suppression which contributes to an

increased susceptibility to other infections

* high-titred measles vaccines have been linked to increased

long-term mortality among some female recipients

* vaccines can impair cell-mediated immunity by shifting cytokines

release into a Th2 pattern, thereby allowing intracellular pathogens (e.g.

many viruses) to be more successful

36. Paper by ez et al, (source: Proceedings of the National

Academy of Sciences, 94.8726-31 1997):

This found that:

* relative deficiency of T-helper type 1 (Th1) and cytotoxic T

lymphocyte (CTL) responses in early life is associated with an increased

susceptibility to infections by intracellular microorganisms

* this is likely to reflect a preferential polarisation of immature

CD4 T-cells towards a Th2 rather than a Th1 pattern upon immunisation with

conventional vaccines

37. Early Report by Dr. Wakefield and team, Inflammatory Bowel

Disease Study Group at the Royal Free Hospital, London

Dr. Wakefield suggested in early 1998 that there could be the

possibility of a linkage between vaccination and autism and other disorders.

Although he was not in a position at that time to present the published

evidence of comprehensive studies, his initial findings suggested that his

hypothesis was plausible. The Royal Free Hospital study found:

* that there was patchy inflammation of the colon and swelling of the

lymph glands in the last part of the small intestine in 39 out of 40

children studied that had developmental disorders. All the children had

previously gone through periods of normal development, ad most had acquired

words and social skills which were subsequently lost

* most children had suffered either diarrhoea or alternating periods

of diarrhoea or constipation, frequently associated with bloating, abdominal

pain and poor appetite, and occasionally the passing of blood

* parents reported in some cases that certain foods made their child’

s symptoms worse, and witholding those foods improved behaviour

* this implied that there could be a syndrome that linked intestinal

inflammation with developmental disorders of the autistic spectrum, and

could offer a vital clue in understanding the origins of some forms of

childhood autism

Dr. Wakefield also speculated that if the bowel was damaged during a

critical period of brain growth, an excess of peptides could gain access to

the developing brain, where these peptides may not only influence behaviour

but also brain growth and development. The disease pathway was described as

" speculative but biologically plausible " .

No evidence to contradict this hypothesis has been offered to date by

the UK Department of Health, and the Department has yet to offer evidence of

its own that degeneration into autism or the onset of inflammatory bowel

disease following vaccination is caused by some other source.

38. Letter published in The Lancet, Vol. 352, July 18th 1998, from

Drs. Sabra, Bellanti and Colon of the International Centre for

Interdisciplinary Studies of Immunology and the Department of Paediatrics,

town University Medical Centre, Washington DC

This stated that:

* in support of the findings of Dr. Wakefield are several

behavioural and clinical features known to be related to the central nervous

system, such as infantile colic and attention-deficit hyperactivity

disorder, which have been related to food allergy

* the US researchers had noted a striking appearance of

ileal-lymphoid nodular hyperplasia in patients with non-IgE-mediated food

allergy who had presented a range of conditions including asthma and

attention-deficit-hyperactivity disorder

* examination of two cases with hyperactive disorders who were

intolerant to various foods, by colonoscopy of their terminal ileum, had

produced findings match those of Wakefield et al

* ileal-lymphoid nodular hyperplasia lesions of the gastrointestinal

tract allowed the entry of antigens across the inflamed mucosa of the bowel

as a result of the reactive inflammatory response in the adjacent lymphoid

tissue of Peyer’s patches in patients with non-IgE-mediated food allergies

* the researchers proposed that similar mechanism(s) may be involved

in the pathogenesis of the central nervous system dysfunction in the

patients described by Wakefield et al

39. Dr. Edwin Cook, Director of the Laboratory of Developmental

Neuroscience, university of Chicago, in a joint paper with Courchesne, Lord,

, Yan, Lincoln Haas, Courchesne and Leventhal, published in the May 1996

edition of Molecular Psychiatry

This noted that:

* it was a well-established finding that a significant number of

people with autism have elevated levels of blood serotonin, and the

successful use of medications (potent serotonin transporter inhibitors, or

PSTIs) suggest the possibility that serotonin plays a role in autism

* the authors studied 86 people with autism and their parents to

examine whether the gene for the serotonin transporter may contribute to the

risk of autism. They found evidence of a significant relationship

* it was possible that the serotonin transporter gene HTT was serving

as a marker in linkage disequilibrium with a genomic variant which was

contributing to susceptibility to autistic disorder

* several lines of evidence suggested the serotonin transporter as

the most logical candidate gene, based on existing evidence, but many other

candidates could be considered on only slightly weaker evidence

* the short variant at the serotonin transporter locus was found to

be preferentially transmitted from parents to children with autistic

disorder, and this provides preliminary evidence that the serotonin

transporter may serve as a susceptibility locus in autistic disorder. This

finding may contribute to identification of other factors which add

additively or in a multiplicative manner

40. The late Dr. Warren, formerly Professor of Biology at Utah

State University in Logan, set out a pathogen-autoimmune hypothesis for

autism:

* some children are susceptible to an environmental pathogen,

probably a virus or bacterium, resulting from an inherited deficiency of

their immune system

* unable to clear the pathogen, the child is at higher risk for the

pathogen to damage the developing brain or trigger an autoimmune response

* the pathogen would not necessarily create gross neuronal damage,

but have more subtle effects on portions of the brain controlling behaviour

* although not a requirement, the pathogen might persist and

replicate slowly or be maintained in homeostasis by the immune system

Dr. Warren outlined the possibility of several key factors, which

included:

* exposure to a certain pathogen at a vulnerable time, i.e. at the

time the central nervous system is undergoing rapid development

* the existence of an immune susceptibility or deficiency that would

allow a pathogen to persist

* a genetic constitution that allowed certain T cells to react to the

pathogen in such a way as to cause reactivity against the central nervous

system or products of the central nervous system such as neurotransmitters

* in some cases an immune susceptibility or deficiency in the immune

system of the mother that may permit a pathogen to be present in utero or

allow an immune response within the foetus

* in some cases, a purported immune mechanism may have not caused

irreversible damage to the central nervous system but is only interfering

with brain function such as by binding to various neurotransmitters or their

receptors

41. Warren and Singh studies

In his own studies, jointly with Singh et al, published in the journal

Immunogenetics 36:203-207 of 1992, he noted that:

* of the 46 chromosones of 23 patients, 27 chromosones (58.7%) had an

extended haplotype as compared to an unrelated control group in which 33/128

(only 25.8%) of chromosones carried an extended haplotype

* the frequency of extended haplotypes on chromosones of autistic

children was much greater than that on family-parent normal chromosones, the

latter being only 30.7%

* in the initial and later studies, only eight out of 45 autistic

subjects did not have an extended haplotype, and fifteen autistic subjects

carried an extended haplotype on each of their chromosones

* also, the mothers but not the fathers of the autistic children had

an increased representation of extended haplotypes

* an additional control group of subjects with general severe

learning difficulties had a haplotype frequency of 26%, similar to that of

the earlier-mentioned unrelated controls

He noted that many normal individuals possess one or more of the above

factors, but it would only be those children that possessed all of these,

plus probably others, simultaneously, where autism would occur. He also

noted that four season-of-birth studies had found an excess of births in the

month of March, and that, if a pathogen was involved in autism, it was

conceivable that it was more prevalent during early winter so as to affect

March babies. He also noted that four to five times more boys than girls

were affected by autism, but that autoimmune diseases were often more common

in one sex, with the influence of sex hormones on immune functions

well-established. He further noted the link between genetic background and

frequency of infections:

* the products of the C4A and C4B genes are crucial to the activation

of the other vital components of complement involved in protection against

viruses, bacteria and other infectious agents

C4A proteins bind avidly to amino-rich surfaces and C4B proteins form

linkages with hydroxyl-containing carbohydrate surfaces

* deficiency in the C4 proteins especially C4B has been associated

with increased viral and bacterial infection

* inherited abnormalities of the complement C4 proteins are linked to

certain autoimmune diseases

Continued next post.

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