autism, an extreme challenge to integrative medicine. part...

Alternative Medicine Review ◆ Volume 7, Number 4 ◆ 2002

Autism Review

Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

AbstractAutism, archetype of the autistic spectrumdisorders (ASD), is a neurodevelopmentaldisorder characterized by socially aloofbehavior and impairment of language andsocial interaction. Its prevalence has surgedin recent years. Advanced functional brainimaging has confirmed pervasive neurologicinvolvement. Parent involvement in autismmanagement has accelerated understandingand treatment. Often accompanied by epilepsy,cognitive deficits, or other neurologicimpairment, autism manifests in the first threeyears of life and persists into adulthood. Itsetiopathology is poorly defined but likelymultifactorial with heritability playing a majorrole. Prenatal toxic exposures (teratogens) areconsistent with autism spectrumsymptomatology. Frequent vaccinations withlive virus and toxic mercurial content(thimerosal) are a plausible etiologic factor.Autistic children frequently have abnormalitiesof sulfoxidation and sulfation that compromiseliver detoxification, which may contribute to thehigh body burden of xenobiotics frequentlyfound. Frequent copper-zinc imbalance impliesmetallothionein impairment that couldcompound the negative impact of sulfurmetabolism impairments on detoxification andon intestinal lining integrity. Intestinalhyperpermeability manifests in autistic childrenas dysbiosis, food intolerances, and exorphin(opioid) intoxication, most frequently fromcasein and gluten. Immune systemabnormalities encompass derangement ofantibody production, skewing of T cell subsets,aberrant cytokine profiles, and otherimpairments consistent with chronic

Autism, An ExtremeChallenge to Integrative Medicine.

Part 1: The Knowledge BaseParris M. Kidd, PhD

Parris Kidd, PhD (cell biology, University of California atBerkeley) – Contributing Editor, Alternative MedicineReview; health educator and biomedical consultant to thesupplement industry.Correspondence address: 847 Elm Street, El Cerrito, CA94530

inflammation and autoimmunity. Coagulationabnormalities have been reported. Part 2 of thisreview will attempt to consolidate progress inintegrative management of autism, aimed atimproving independence and lifespan forpeople with the disorder.(Altern Med Rev 2002;7(4):292-316)

IntroductionIn 1943 the psychologist Leo Kanner pub-

lished case histories of a childhood developmen-tal disorder he called autism. He defined threesymptom patterns: (1) failure to use language forcommunication, (2) abnormal development ofsocial reciprocity, and (3) desire for sameness, asseen in repetitive rituals or intense circumscribedinterests.1 Autistic children seem abnormally with-drawn, almost self-occupied, and out of touch withreality. As a group they score significantly loweron measures of adaptive or life skills than the gen-eral population.2

Individuals with autism tend to have ex-treme difficulty learning from experience andmodifying their behavior to accommodate vary-ing situations.2 Coping with the unpredictabilityof the social world is especially demanding, evenoverwhelming, for adults with autism; associatedanxiety exacerbates the problem.2 Adult individu-als with autism have life outcomes that range fromcomplete dependence to (rarely) successful em-ployment. Most are able to benefit from structuredtraining programs with marked improvement intheir quality of life.3


Alternative Medicine Review ◆ Volume 7, Number 4 ◆ 2002 93

Review Autism

Autism has become epidemic in the in-dustrialized societies. In the United States, autismwas relatively rare until the early 1990s, afterwhich its prevalence increased by at least double,and more likely 3-5 times.2 Similar steep increasesin prevalence have been recorded in the UnitedKingdom.4 The gender ratio is 3-4:1 boys to girls.2

Since every autistic child has a major impact onthe family, school system, and community, thisepidemic calls for compassion, sensitivity, andmaximum assistance from society as a whole.

There is a great deal of debate in thehealthcare world over the existence of an autismepidemic and the possible contributing factors.Parents, supported by progressive healthcare pro-fessionals, are on one side pointing at vaccinesmanufactured with known toxic ingredients. Onthe other side are governmental and private orga-nizations seemingly unwilling to institute reform.The annual monetary cost of autism in the UnitedStates is estimated to be $26 billion.5

From the clinical-biological perspective,this disorder or spectrum of disorders, is extremelycomplex and multifaceted. Its expression, pathol-ogy, etiology, and management rank it among themost perplexing disorders known. Autism chal-lenges the intellect and research skill of investi-gators obtaining funding support to investigate it.Yet despite all the limitations, real progress hasbeen made within the last decade toward helpingautistic people become productive members of so-ciety.

The Autism Research Institute, foundedby Dr. Bernard Rimland, and its Defeat AutismNow! (DAN!) initiative, have successfully ad-vanced medical management of autism to the de-gree that some children largely recover and canhave somewhat normal lives.6,7 Within the broadermedical community, diagnosis and assessmenthave also markedly improved, as have the paceand intensity of research. This review (Part 1 of2) seeks to define the features of the disorder andits core abnormalities. Part 2 will address the va-riety of approaches to its medical management,along with priorities for future research.

Diagnosis, Classification, EpidemicPrevalence

The modern concept of autism recognizesKanner’s “classic autism” as autism, autistic dis-order or AD, and subsumes this within a broadercategory called autistic spectrum disorders orASD. For the physician these distinctions can behard to make. In this review, use of the term au-tism will refer to AD and the broader category willbe referred to as ASD, unless otherwise specified.

Emergence of the DisorderAutism begins very early in life. Almost

all autistic patients are normal in physical appear-ance, but physiologic abnormalities can becomeevident within mere months of birth.8 The threeprimary symptom patterns first defined by Kannermanifest by 36 months. This characteristic triadmay be accompanied by sensory and motor dys-functions, or by cognitive or other mental process-ing deficits.9 Neurological abnormalities dominateautism.

In the majority of autism cases the disor-der first becomes apparent as a parent notices thegrowing child is not using words to communicate,even though the child usually can recite the al-phabet. In a minority of cases, autism appears asdevelopmental regression: parents report theirchild was developing normally, then regressed –occasionally abruptly – in language, sociability,and play.10 In rare cases motor skills also regress.After a plateau that lasts for some months, devel-opment resumes, but in most cases never returnsto its previous level.

Some autistic children make little progressthroughout their life, remaining nonverbal, se-verely withdrawn, and mentally deficient, whileothers fare better, although complete recovery israre.11 While 75 percent of AD cases are mentallyretarded, only 50 percent of ASD cases exhibitretardation. As many as one in 10 autistics are sa-vants – gifted in areas such as music, drawing,memorization, or calculations. They have “islandsof genius” in skills that require attention to detail,memory, or computations such as calendrical cal-culating or perfect pitch.12,13 Tentative suggestionshave been made that risk of autism may be greater


Autism Review


in families where one or both parents has selecteda field of interest emphasizing focus and atten-tion to detail.14

Persons with autism have reduced lifeexpectancy.5 Those with the most severe mentalretardation tend to die soonest. Those with mildor no mental retardation still die earlier than thegeneral population, most often from seizures, ner-vous system dysfunction, drowning, or suffoca-tion (all rates more than three times higher thanthe general population). Deaths due to epilepsyare 24 times that of background; many of thedeaths by drowning involve heart attacks, perhapsrelated to adverse effects from medications.

Diagnosis andClassifications

Autism is diag-nosed generally at aroundtwo years of age, when thechild should begin to par-ticipate in organized socialactivities. Social deficitsbecome evident when thechild is compared withpeers of the same age. Theyoung child with autism isunlikely to seek out otherswhen he is happy, show orpoint to objects of interest,or call his parents by name.The child is, in a sense, ab-normally self-occupied.During preschool years, re-petitive behaviors begin todevelop. These could in-clude using peripheral vi-sion to look at lines orwheels, or peculiar hand andfinger movements.

From the early in-fant stage, children with au-tism are likely to be devel-opmentally delayed.Trained observers can de-tect movement abnormali-ties at four months.15 The

autistic child is observed to be less adept at mak-ing eye contact with another person, has poor abil-ity to make facial expressions, and is less able tocoordinate his vocalizations with his intentions,compared to children within the normal develop-mental range.8

In concept, the diagnosis of autism has notchanged since formulated by Kanner, but therehave been evolutionary changes in how the symp-tom patterns are interpreted and assessed. Recog-nizing that no two cases are alike, even within thesame family, it has become more useful to viewautism as a spectrum of disorders, classified au-tistic spectrum disorders with Kanner’s “classic”autism at the core (Figure 1).

AUTISM

CHILDHOODDISINTEGRATIVE

DISORDER

RETT'SDISORDER

ASPERGER'SDISORDER

ATYPICAL AUTISM / PDD-NOS

Figure 1. Conceptual Interrelationships of the AutisticSpectrum Disorders16

Alternative Medicine Review ◆ Volume 7, Number 4 ◆ 2002 Page 295

Review Autism


All the autistic spectrum disorders featuredeficits in communicative and social skills, butthey vary in symptom pervasiveness, severity,onset, and progression over time. For the purposesof this review, the term ASD is considered syn-onymous with pervasive developmental disorders(PDD). The category ASD includes at its core AD,overlapping with Asperger’s disorder (Asperger’ssyndrome, AS), childhood disintegrative disorder(CDD), and Rett’s disorder (Rett’s syndrome,RTT). All these are enveloped by pervasive de-velopment disorder not otherwise specified (PDD-NOS, also called atypical autism).16 It is not un-common for these ASDs to occur concurrentlywithin the same family.

Physical Characteristics and Co-Morbid Conditions

Early reports of an association betweenautism and epilepsy17 helped implicate biologicalrather than mere psychogenic factors in the etiol-ogy of autism. Epilepsy may occur in up to 30percent of individuals with autism. Although itspeak onset is during early adolescence, it may alsooccur in infancy.2 Infantile spasms that involve thebrainstem may initiate autistic symptoms. Landau-Kleffner syndrome features epileptiform activity,abrupt loss of language, and autistic symptoma-tology.18

Epidemiological studies indicate that cur-rently at least 25-30 percent of people with au-tism have associated medical conditions.19 Amongthe most prevalent are sensory impairment (blind-ness and/or deafness), tuberous sclerosis, neurofi-bromatosis, and epilepsy, all of which predomi-nate among those with the most severe mental re-tardation. Hearing loss may be more prevalent thanpreviously reported, and may be linked to abnor-mal brainstem auditory-evoked responsiveness.20

Rising Prevalence of Autism andASD

The statistics on occurrence of AD andASD strongly suggest these disorders have becomeepidemic. From surveys conducted prior to the1990s, nationwide prevalence in the United States

was estimated at about 5 per 10,000 for AD and20 per 10,000 for total ASD.21 By 1997, the preva-lence of autistic spectrum disorders was estimatedto be 40-50 per 10,000.2 In one community, BrickTownship in New Jersey, the frequency of ASDmay have reached 1 in 150.22

Some experts argue that such increasedprevalence of AD/ASD is only apparent becauseof changes in diagnostic criteria and improvementsin early detection. But the documented minimaldoubling – perhaps quadrupling – of prevalencewithin a little more than a decade seems too ex-treme to be attributed only to improved diagno-sis.

Sidney M. Baker, MD, and Richard A.Kunin, MD, pioneers in autism management, haveindependently listed factors that have becomemore prominent in “developed” societies between1950 and 2000, and which they strongly suspecthave contributed to the autism upsurge.23,24 Theyboth have identified the following factors: in-creased antibiotic use; mercury exposure by in-jection in infancy; increase in combined live viralvaccines and the numbers of vaccinations; in-creased soil depletion leading to vitamin/mineraldeficits; decreased omega-3 and -6 essential fattyacids in the diet; and greater exposure to xenobiotictoxins.

From 1987 to 1998, the number of chil-dren being treated for autism in California jumped273 percent.25 A nationwide figure for 1991 to1997 was 556 percent. Whatever the limitationsof the statistics in regard to determining the realprevalence of these disorders, the data starkly in-dicate there is considerable need for societal at-tention to autism. Hopefully, the most polar advo-cates on both sides of the prevalence debate couldagree on one point: that communities, schools, andthe healthcare systems are being confronted withthe challenge to raise, educate, and otherwisemanage ever-increasing numbers of children withprofound functional impairments.


Autism Review


The Defining AbnormalitiesMost experts agree the neurological prob-

lems seen in autism seem to stem, not primarilyfrom the senses, but from interpretation of theworld.25 When normal people view an array ofobjects, for example, they infer social relationshipsamong the objects. Rather than see a room, theysee individual details within it. Autistic people tendto see shapes and objects as isolated. They alsohave trouble interpreting faces, sometimes gaz-ing at the mouth rather than the eyes, as normalpeople usually do. The autistic child would moreoften describe his father as a man who is tall andwears glasses, rather than as his father who is kindand works hard.25

The ability to understand facts but not re-late them to concepts is another common symp-tom. Children with autism may learn a particulartask yet be unable to generalize it to other situa-tions. Their difficulty in processing informationon the higher levels extends to their motor activ-ity as well. They can have trouble kicking balls,writing, or tying shoes.25

Possible Information ProcessingDeficits

Several theories have been posited as tothe processing mechanisms that may be affectedin autism. One is weak central coherence.26 Autis-tic individuals generally demonstrate remarkableskill on the Block Design subtest from theWechsler Performance Scale. The hypothesis isthat autistics fail at holistic processing of an im-age, instead remaining focused on its individualparts. Thus on Block Design, they do not recon-struct the overall form of the image and as a resultfind it easier to see the component parts.

An alternative to weak central coherencehas been the executive dysfunction hypothesis.27

Executive functions are typically used for non-routine problem solving, and would include suchmental operations as planning, working memory,maintenance and shifting of attention, and inhibi-tion of inappropriate responses. Executive func-tion deficits could potentially explain the repeti-tive and rigid behaviors of ASD, and the impaired

ability for social interactions, which typically re-quire flexible and immediate evaluation, then se-lection of appropriate responses to multidimen-sional information.28

The most recently favored hypothesis forsocial cognitive impairment in autism featurestheory of mind.29 It suggests that autistics fail toappreciate the representational theory of mind andinstead think of mind on too literal a basis. Forexample, the autistic child shown a milk cartonfilled with paper clips may conclude the cartonreally was manufactured to carry paper clips. Chil-dren normally can correct such “false beliefs” bythe time they reach age four. Children with ASDtypically do not pass this stage until their verbalmental age is at least eight years.

Neuropathologic FindingsInconsistent

To date only about 30 autopsies of autis-tic brains have been formally reported. The lim-ited autopsy studies have not uncovered any con-sistent differences between autistic brains andnonautistic brains. Microscopic pathology andstructural imaging studies have also failed to con-firm differences. But very recently advanced func-tional imaging has succeeded in defining a pat-tern of abnormalities in autism.

Neuropathological examinations have atone time or another pointed to possible abnormali-ties in the brainstem, the cerebellum, and limbicstructures, including the hippocampal formation,amygdala, septal nuclei, mammillary nuclei, andanterior cingulate cortex;30 however, the majorityof neuropathological studies have failed to con-firm any differences from normal brains.31

Three different groups have reported ab-normalities of the cerebellum, especially loss ofPurkinje cells.9 Loss of cerebellar Purkinje cellsis seen frequently in seizure disorders, so it wouldbe important to conclusively determine whetherthese cells are depleted in autistic subjects with-out a history of seizure disorders.

Structural magnetic resonance imaginghas failed to detect consistent changes in autism.9

In different studies, both atrophy and normal mass


Review Autism


have been reported in thecerebellum. A few studiesreported subtle abnormali-ties in the amygdala, whilemany reported normality.31

As well, studies that re-ported reductions of the hip-pocampus, mesial temporallobe, or caudate nucleus inautistic subjects have beencounterbalanced by othersthat found no change.31,32

Functional brainimaging techniques, such aspositron emission tomogra-phy (PET), single photonemission computed tomog-raphy (SPECT), and func-tional magnetic resonanceimaging (fMRI), initiallymade little progress overstructural imaging. But withthe second generation of in-strumentation has comegreatly improved resolutionand data filtering. Now twogroups have independentlyreported abnormalities ofblood flow in the temporal lobes of autistic chil-dren. In addition, activation studies have revealedabnormal patterns of cortical activation.

Both PET and SPECT allow accuratemeasurements of cerebral glucose metabolismand/or blood flow. Measurements can be per-formed at rest or during the performance of spe-cific sensory, motor, or cognitive tasks. The firstgood functional study was published in 1995.Zilbovicius and collaborators imaged regionalcerebral blood flow in five “primary” autistic chil-dren (subjects free of epilepsy or other neurologi-cal complications), first at the age of 2-4 yearsthen three years later.33 They found that perfusionof the frontal lobes at the earlier age matched thepattern of perfusion in much younger normal chil-dren, and concluded these children had delayedfrontal lobe metabolic maturation.

In 2000, using PET imaging, Zilboviciuset al detected significant temporal hypoperfusionin 21 autistic and 10 control children.34 Carefuldata analysis confirmed that 16 of the 21 autisticchildren (77%) were lower than the controls; ofthese, four were unilaterally affected and 12, bi-lateral. These investigators then imaged another12 autistic children and successfully confirmed thefirst result. That same year Ohnishi et al publisheda SPECT study of 23 autistic and 26 control chil-dren that detected significant hypoperfusion in thefronto-temporal region.35 These two sets of resultsare so closely similar they are virtuallysuperimposable on each other (Figure 2).

The evidence is now clear that autisticchildren, free of other major neurologicalconditions, manifest abnormally low blood flowin the temporal cortex.33-35 Neurologically,dysfunction in these regions could explain almostall the symptoms (perceptive, emotional, and

Figure 2. Abnormally Low Blood Perfusion of theTemporal Lobes in Childhood Autism, Mapped from TwoSeparate Studies


Autism Review


cognitive) observed in primary autism. Thetemporal associative regions are highly connectedto the frontal and parietal lobes and the limbic andassociated sensory systems. The temporal lobe isbelieved to be central to the processing ofnumerous environmental signals, as well as forthe further conversion of these signals intostructured patterns of neural activity that bringmeaning to the world around us.

Indirect corroboration of this key findingcomes from observations that individuals withtemporal lobe pathology (epilepsy, herpes simplexencephalitis) sometimes manifest autistic behav-ior.32 In children with infantile spasms, temporallobe hypometabolism is strongly associated withlater emergence of autism symptoms.36 Similar ob-servations were made of children with tuberoussclerosis and from experiments conducted withprimates.32

Functional Imaging During CorticalActivation

Activation studies measure local changesof cortical blood flow or blood oxygenation, re-flecting the variation of synaptic activity in re-sponse to sensory, cognitive, or motor stimulation.PET, SPECT, and fMRI activation studies suggestthat autistic subjects activate different brain re-gions than controls, indicating they have differentcerebral circuit configurations.32 Garreau et al con-ducted the first such SPECT study37 and found thatin response to auditory stimuli, autistic childrenactivated the right posterior associative cortexwhile the control group activated the left side.Muller et al38 reported similar findings in adultautistic males.

An auditory activation PET study wasperformed in autistic adults during passive listen-ing to speech-like stimuli.39 The autistic subjectsshowed significantly higher activation of the rightposterior temporal lobe. Applying the same audi-tory model to children, Boddaert et al39 detectedsignificantly lower activation of the left temporallobe. Altogether, the activation findings suggestautism is associated with abnormal activation ofthe left temporal cortex. Since this is the regionthought to handle brain organization for language,

the functional findings are consistent with autis-tic subjects’ language impairment and inadequatebehavioral response to words.32

Boddaert and Zilbovicius also describedother types of activation studies with autistic chil-dren and adults.32 All the PET studies are consis-tent with disorganized establishment of neural cir-cuits. Baron-Cohen and colleagues40 tested thesocial intelligence (theory of mind) of autisticadults. Two sets of images were presented: (1)photographs of eyes, for the subject to guesswhether each was a man or a woman and (2) pho-tographs of people, for the subject to describe themental state of the person in the photograph. Thenonautistic control subjects activated both thefronto-temporal neocortical regions and non-neo-cortical regions, including the amygdala, hippoc-ampus, and striatum. The autistic subjects acti-vated the frontal neocortex less extensively, andfailed to activate the amygdala. In other studies,autistic subjects failed to activate a cortical facearea when attempting to assess facial expressions.The amygdala and cerebellum were not activatedduring processing of emotional facial expressions.

In summary, state-of-the-art functionalbrain imaging has established that autistic indi-viduals exhibit abnormal temporal lobe function.Dysfunctional connections between these regionsand the fronto-parietal zones could explain thecognitive abnormalities; to the limbic system, theemotional abnormalities; and to the auditory re-gions, the sensory perception abnormalities. Func-tional imaging detected abnormal activation pat-terns sufficient to suggest more or less widespreaddisorganization of cortical networks in the autis-tic brain.

Candidates for the Etiopathology ofAutism

The etiopathology of AD/ASD is almostsurely multifactorial. Although it is probably notan inborn error of metabolism, a genetic suscepti-bility almost surely exists. During the last 40 years,autism has been linked with many etiologies, in-cluding various inborn errors; genetic abnormali-ties such as fragile X syndrome; rubella and other


Review Autism


pathogens; and many other factors.41 Genetic pre-disposition, metabolic abnormalities, and abnor-malities of the gastrointestinal, hepatic, and im-mune systems all appear to be markedly involved.

Genetic PredispositionA solid body of evidence indicates genet-

ics plays a primary role in autism, probably not asinborn error(s) but as a strongly predisposing fac-tor.42 There is compelling evidence for high, verylikely multigenically-determined, heritability asevidenced by the 50-percent concordance rate formonozygotic twins, versus about three percent fordizygotic twins.9 Further, the rate of autism amongthe siblings of an affected child is 3-6 percent, arate 50-100 times higher than the general popula-tion.43 This degree of genetic conditioning of au-tism exceeds genetically-conditioned diseasessuch as Alzheimer’s, asthma, diabetes, and schizo-phrenia. These data are also consistent with theexistence of multiple (probably between 3 and 20)susceptibility genes for autism.25,42

The likelihood that autism is strongly de-termined by heredity has stimulated much recentresearch. A small proportion of autistic individu-als (no more than 10-15 percent) demonstrate co-morbidity with known genetic conditions includ-ing tuberous sclerosis, neurofibromatosis, fragileX syndrome, and chromosomal abnormalities. Asmany as 25 percent of fragile X cases display au-tistic-like symptoms that nonetheless are distinctfrom AD. Other X-linked gene mutations, such asin the MECP2 of Rett’s disorder, may contributeto subsets of AD.

The chromosomal disorder mostfrequently found (up to 3 percent) in recent largesamples of AD has been a maternal duplication of15q11-q13, a region on chromosome 15 linked toother developmental disorders. While featuringmental retardation, these distinctly differ from AD,but a distance effect from this zone has not beenruled out. Several genome-wide gene screens havealready been published on autism9 and a numberof candidate gene regions are under scrutiny. Ofthese the most suspicious is a relatively largeregion on chromosome 7 (7q31-35). The 7q31zone has been independently linked to a speech-

language disorder (SPCH1). A gene, FOXP2, hasbeen identified from this zone and is being activelyinvestigated.

Developmental/TeratologicSeveral lines of evidence implicate an

early brainstem injury in autism.44 Minor physi-cal anomalies of the ear are found in as many as45 percent of autistic children, and point to a pos-sible insult during ear development during the lat-ter part of the first month of gestation.45 Rodierand colleagues have developed a body of workthat supports thalidomide exposure as a teratoge-nic factor in autism. Some 30 percent of childrenexposed to thalidomide during neural tube closure(days 20-24) developed autism, probably prima-rily related to brainstem damage.46 Such cases usu-ally display ear anomalies, including hearing loss,and Moebius syndrome (facial paralysis and a lackof eye abduction). Rodier explored the mecha-nisms in animal models and suggested many suchindividuals should show brainstem abnormalitiesat autopsy.47

Metabolic AbnormalitiesA number of inborn or acquired metabolic

abnormalities may manifest as AD, ASD, or quasi-autistic syndromes. Biochemist Jon Pangborn, alsothe father of an autistic child, has reviewed thesein a compilation of the applicable biochemicalassessments.48 The most prominent of the abnor-malities are phenylketonuria (PKU) variants,histidinemia, adenylosuccinate lyase deficiency,purine synthesis deficiencies, inosine phosphatedehydrogenase weakness, Lesch-Nyhan Disease,adenosine deaminase deficiency, and ADA bind-ing protein weakness.

Pangborn is also skilled at assessingamino acid analysis data from ASD cases withvariable or non-inborn metabolic dysfunction. Ina survey of 62 autistic children, he found taurinedeficiency most predominant (62% on urinaly-sis).48 Deficiencies of lysine (59%), phenylalanine(54%), and methionine (51%) were trailed by de-ficiencies of tyrosine, leucine, glutamine, valine,and asparagine, in that order. In addition to amino


Autism Review


acid analyses he also strongly recommends el-emental analyses from red cells and hair, and liverdetoxification assessment using urinary caffeine,acetaminophen, and salicylate (aspirin) clearance.

Serotonin is a monoamine brain transmit-ter that is one of the earliest to appear in the de-veloping brain. It also plays a role in regulatingbrain development.49 Elevated blood serotonin isone of the most consistent abnormalities in au-tism, documented in more than 20 studies to date.50

Up to 40 percent of ASD cases feature abnormallyelevated blood serotonin.50 Certain serotonin re-ceptors may be supersensitive, which may con-tribute to repetitive behaviors.49 Paradoxically,serotonin excess can result in lowered responsive-ness to serotonin, due to feedback down-regula-tion of the receptors.49 But some areas of the au-tistic brain can have decreased serotonin concen-trations while other areas are abnormally elevated,perhaps corresponding to abnormal developmentof brain networks.49

Warren and Singh measured serotonin in20 autistic subjects and correlated the blood lev-els with genetic typing. They linked the blood se-rotonin elevation to a combination of MHC (ma-jor histocompatibility complex) genes on chromo-some 6, a chromosome previously linked to au-tism.50 The genes potentially involved are knownto regulate immunity, and are often associated withimmune deficits and autoimmune disorders.

Organ Abnormalities in Autism:Detoxification Impairments

While there are a seemingly unendingnumber of theories seeking to explain the causeof autism, one category of abnormalities occurswith close to 100-percent frequency – abnormalliver detoxification.

Importance of Sulfoxidation andSulfation to Health

The P450 detoxification system that ismost concentrated in the liver uses sulfation asone pathway for the detoxification of endogenousand exogenous substances. Enzymes draw on apool of sulfate to convert phenolic substances to

their water-soluble sulfate salts for subsequentexcretion. Most of the sulfate substrate comes fromsulfoxidation of the amino acid cysteine. Sulfationis important for the excretion of endogenouslyproduced substances such as steroids, bile acids,and catecholamine neurotransmitters.51 Impairedsulfation also seriously compromises the abilityto excrete xenobiotics from the body.

Sulfation and sulfoxidation capacities areknown to vary substantially among individuals,and to be highly genetically conditioned.52

Sulfoxidation capacity (activity of the enzymecysteine dioxygenase) can be roughly determinedfrom the metabolism of the drug S-carboxymethyl-L-cysteine (SCMC).51 About 65 percent of thepopulation test as “good metabolizers” of SCMC,32.5 percent as “poor metabolizer,.” And 2.5 per-cent are classed as “non-metabolizers.”53 Despitelimitations of this specific test, it seems clear thatup to 2.5 percent of the general population havegenetic polymorphisms that render them virtuallyunable to convert cysteine to inorganic sulfate.

Inorganic sulfate is important for manyphysiological functions. The liver relies on its sul-fate pool to neutralize phenolic substances, chemi-cals common in foods and contaminants (exog-enous) and also routinely produced in the body(endogenous). Endogenous compounds that aresulfated for excretion include the hormonesprogesterone and dehydroepiandrosterone(DHEA), and the catechol neurotransmittersdopamine and epinephrine. One exogenous sub-strate is acetaminophen (Tylenol®), an all-too-frequent cause of liver damage.

When sulfation is impaired or a high doseof acetaminophen is ingested, the resultant over-load can deplete glutathione stores and result inliver injury or failure. Endogenous substrate over-load, as from high estrogen during pregnancy orfrom use of estrogen-containing birth control pills,can further reduce liver sulfation capacity.54,55

In addition to the liver’s heavy reliance,the gastrointestinal (GI) tract also relies on sul-fate availability for its essential functions. Thegastrointestinal mucosa must have sulfate avail-able in order to conduct “first-pass” neutraliza-tion of potentially toxic bacterial fermentation


Review Autism


products (e.g.,from protein),foodborne pheno-lics, and manmadexenobiotics. Themucosa presum-ably receives mostof its sulfate sup-ply from theblood, withinwhich sulfatelevels are homeo-statically con-trolled by kidneyconservation.56

H u m a nstudies have docu-mented inad-equate sulfationcapacity in someindividuals.51 Themodel drug usedfor this test is usu-ally acetami-nophen. Ulti-mately, three mea-sures confirm sul-fate metabolismabnorma l i t i e s .These are impaired sulfoxidation (from the SCMCtest), impaired sulfation (from the acetaminophentest), and an elevated cysteine-to-sulfate ratio inthe blood. To date these abnormalities are mani-fest in rheumatoid arthritis, as well as in the neu-rological diseases Alzheimer’s, Parkinson’s, mo-tor neuron disease, and autism.57

Abnormalities of Sulfoxidation andSulfation in Autism

Reduced metabolism of SCMC, impairedsulfation, and an elevated cysteine-to-sulfate ra-tio have been reported in autistic children by War-ing and collaborators, working in cooperation withparent groups in both the United Kingdom andthe United States.57

Alberti, Waring, and colleagues did a pi-lot study in which they measured acetaminophen

clearance by 20 autistic children, diagnosed as ADand “low-functioning,” against 20 age-matchedcontrols.58 Among the autistic subjects 18 of 20were impaired, while among the controls 19 of 20were normal (p value < 0.00002). In another 40autistic children not directly compared, 37 of 40showed a similar degree of sulfation impairment.In total, of 60 autistic children examined, 55 weremarkedly impaired (92 percent). The investiga-tors suggested their findings should help explainwhy many autistic children are “triggered” byfoodstuffs, particularly foods (e.g., bananas,chocolate, cheese and other fermented products)with relatively high profiles of phenolic aminessuch as dopamine, tyramine, and serotonin.

Additional support for this interpretationcame when Waring and others found that the ac-tivity of phenylsulfotransferase (PST), the enzymecatalyzing the sulfation of acetaminophen, was

Table 1. Xenobiotic Overload (based on the maximumacceptable adult values) in Blood. Modified from Edelson andCantor. 41

%Children % Adult Maximum

89% >100%

78% 111-1800%

55% 106-400%

44% 139-928%

17% 367-10,000%

17% 260-1160%

17% 270-440%

11% 200-400%

5% 325-1900%

Xenobiotic

One or more xenobiotics Ethyl- or Methyl- benzenes 2- or 3- Methylpentanes

Xylenes

Toluene

Benzene

n-Heptane

Styrene

Trichloroethylene, Chloroform, Dieldrin


Autism Review


abnormally low in autistic children as measuredfrom the blood platelets. This was more directproof of a systemic incapacity of autistic subjectsto detoxify endogenous and exogenous phenolsand amines via sulfation.59

These systemic impairments of sulfationin autistics threaten the stability of the catechola-mine transmitter systems, the integrity of the gutlining, and heighten vulnerability to foodborne orpollutant xenobiotic overload. In this scenario asubstance as ubiquitous as pyrethrin (a commoningredient of pesticides) could become neurotoxic,and many commonly-employed pharmaceuticals(including Tylenol®) could switch from (appar-ent) friend to foe. Endogenously produced steroidhormones could generate metabolic imbalanceswith the potential for long-term harm. Depletionof the endogenous sulfate pool could limit the bio-synthesis of necessary substances such as bile ac-ids (for digestion) or glycosaminoglycans (forjoints and connective tissues). Backed-up dopa-mine and norepinephrine could auto-oxidize tononspecifically reactive, free radical-type molecu-lar species with great potential to damage the ner-vous system.

Cysteine is a known excitatory aminoacid. In that portion of the population who cannotreadily transform it to sulfate, there might be realpotential for cysteine to become synergistic withexogenous excitotoxins such as excitatory foodconstituents or anticholinesterase agents and otherneurologically-toxic insecticides, ubiquitous in theenvironment.

Ongoing research into multiple chemicalsensitivity, ulcerative colitis, and non-IgE delayedfood sensitivity, suggests that impaired sulfationof ingested phenolics and phenolic food constitu-ents may well be causally linked with intoleranceto foods and xenobiotics.51,57,59

Excessive Accumulation of XenobioticPollutants

Edelson and Cantor reported in 1988 thata group of 20 autistic children, ages 3-12, exhibitedabnormal liver detoxification profiles.41 Bloodanalyses for identification of specific xenobioticagents revealed toxic overload, defined as

significantly in excess of the established adultacceptable maximum values, in 16 of 18 of thesechildren (Table 1).

Subsequently this sample population wasexpanded to include 56 children, 43 males and 13females, mean age 6.54 years.41 All 56 subjectshad abnormally high heavy metal burden; of these,55 expressed liver detoxification malfunctions and53 had one or more toxic chemicals in excess ofthe adult maximum reference range.

A recent review by this author exploredthe likelihood of linkages between the variety oftoxins extant in the modern environment and themarked increases in childhood abnormalities.60

The environment is suffused with organic pollut-ants. Pesticide spraying is still routine in manyschool districts. Heavy metals, organohalide pes-ticides, herbicides, fumigants, and a wide rangeof aromatic and aliphatic solvents have been linkedto abnormalities in behavior, perception, cogni-tion, and motor ability during early childhood.Children exposed acutely or chronically to alumi-num, arsenic, cadmium, mercury, or lead are of-ten left with permanent neurological sequelae.Lead can cause developmental delay and mentalretardation. Studies on lead serve as a model forother toxic metals, and seemingly lead toxicity hasno lower threshold of damage.61

The typical modern home is not a clean,protected environment.62 Chemicals embedded incarpets and wall materials; dust, molds, germs;lead in paints and radon contamination; pollutantsin the air, water, and foods, all can be toxic to thedeveloping infant. Children are especially vulner-able, due to their relatively immature detoxifica-tion capacities. Studies of infants prenatally ex-posed to mere “background” environmental lev-els of such pollutants consistently report changesin neurodevelopmental parameters.63 Literally allthe residents of industrialized countries now carrymeasurable amounts of several xenobiotic pollut-ants in breast and other tissues.

Abnormal Metallothionein FunctionThe healthy body carries an array of pro-

teins which naturally chelate, and therefore buffer,zinc, copper, and other redox-active metals.64


Review Autism


These are called metallothioneins (MTs), due totheir extraordinary metal-binding capability be-cause of the many sulfhydryl (—SH) groups theycontain. Their synthesis is inducible at the genelevel, allowing some adaptation of the system toincreased demand. MTs are the body’s primaryprotection against toxic metals – Hg, Pb, Cd – andexposures to heavy metals normally lead to theiradaptive up-regulation. Separate MTs guard thebrain and gastrointestinal tract against heavy metaloverload. It is likely that MT impairment wouldresult in imbalances of heavy metals.

William Walsh, PhD, at the Pfeiffer Treat-ment Center, examined 503 patients diagnosedwith ASD (318 autistic disorder, 23 Asperger’s,162 PDD with autistic features).65 He found a sig-nificantly higher copper:zinc ratio in the ASD

group compared to healthy controls matched forage and gender (p < 0.0001). Walsh asserts that99 percent of ASD cases were affected and thatcopper:zinc imbalance leads to emotional insta-bility, attention deficit and hyperactivity, neu-rotransmitter imbalances, and impairment of hip-pocampus and amygdala function.

Walsh also asserted that elevated toxicmetals are seen in 92 percent of autism cases,malabsorption in 85 percent, under-methylationin 45 percent, over-methylation in 15 percent, andpyrrole disorder in 20 percent of cases.65 He dis-cussed in depth a number of likely pervasive con-sequences for intestinal function, immunity, andbrain function from an overloaded or otherwiseinadequate MT system – examples, MTs appearto be involved in regulating brain nerve cell growthand in the GI production of enzymes that digestcasein and gluten. Walsh also made available pro-tocols aimed at MT system restoration and over-all management of autism.

Organ Abnormalities:Gastrointestinal

The gastrointestinal system is a centralsource of symptom triggering in the autistic childand most autistic children have significant GI pa-thology.66-69 Common symptoms include diarrheaand/or constipation, abdominal pain, gas, bloat-ing, and burping and gastro-esophageal reflux.Horvath and colleagues70 found reflux esophagi-tis in 69 percent of an autistic sample, duodenalinflammation in 67 percent, low carbohydrate di-gesting enzymes (lactase) in 58 percent, and ab-normal pancreatic response to secretin in 75 per-cent.

Stool Analysis, Digestive Function,Dysbiosis

Stool appearance is often abnormal inASD, and stool cultures often reveal a variety ofabnormalities (Table 2).48,71

Pathogenic organisms can directly attackthe GI tract, but many also generate a variety oftoxins (detected by urine organic acid testing) thatcan have systemic effects. Shaw reported findinga wide array of abnormal organic acids in urine

Table 2. Common Abnormalitieson Stool and Digestive Analysisseen in Autism

1. Digestive function: Deficient chymotrypsin; fat malabsorption

2. Metabolic abnormalities: Imbalanced short-chain fatty acids, also indicative of possible bacterial imbalance (dysbiosis)

3. Symbiotic beneficial bacteria: Marker species of Lactobacillus and Bifidobacterium often low or lacking, occasionally also E. coli 4. Bacterial imbalances: Streptococcus species, Staphylococcus species, hemolytic E. coli, Enterobacter

5. Possible pathogens: Candida excess, Blastocystis, Klebsiella, Bacillus species, Staphylococcus aureus, others


Autism Review


samples from autistic children.72 In one case, a boywith apparent regressive autism following re-peated courses of antibiotics showed abnormallyelevated levels of tartaric acid in the urine. Theboy responded positively to treatment with anti-fungal medication (Nystatin) and concomitantlythe urine tartaric acid level dropped.

Tartaric acid is a potentially harmful ap-proved food additive. It can appear in the urine ofautistic children at very high levels, and the sourceis unclear but Shaw suggests it could be a productof breakdown of arabinose in the gut. Arabinoseis a sweet-tasting aldose sugar that occurs in somefoods, most notably apples. It has the potential toundergo Schiff-type cross-linkage reactions withproteins and thereby disrupt function. Elevatedurine arabinose has been linked with yeast over-growth (Candida species). Shaw reported analyz-ing urine from more than 95 autistic children and20 age-matched controls and finding the meanarabinose levels to be five times higher than con-trols. The data presented was sketchy and no sta-tistical analysis was performed.72 Shaw claimswhen children with abnormally high urine arabi-nose are treated with antifungal medication, thearabinose levels fall.

Dysbiosis is an almost routine conse-quence of antibiotic treatment, commonly used inyoung children for ear and other infections. Manyparents have reported their healthy child becameautistic following a course of antibiotic therapy;Galland documented one instructive case history.73

A high-sugar/high-carbohydrate diet can encour-age fungal growth (Candida or other less commonspecies) and further contribute to the vicious cycleof dysbiosis.

Intestinal Lining Abnormalities, LeakyGut

Inborn or neonatally-acquired weaknessesmay predispose to gut lining dysfunction, withsubsequent impairments of digestive, absorptive,or barrier functions. Secretin is a small protein(polypeptide) secreted by cells of the smallintestine. It is a hormone whose function is tostimulate the pancreas to release bicarbonate,which creates an alkaline environment in the small

intestines, allowing the digestive enzymes latersecreted by the pancreas to work optimally.Secretin therapy is under active development forASD children with GI pathology. One study found75 percent of the children had insufficient secretinproduction.70

The mucus barrier may be poorly formed,as when glycosaminoglycan (GAG) synthesis isimpaired by metabolic sulfation defects.74 As thesystem functionally fails to cope with certain foodconstituents such as gluten, casein, or other largeproteins or carbohydrates, incompletely digestedfragments are likely to penetrate the mucus bar-rier and reach the epithelium. There, the Gut-As-sociated Lymphoid Tissue (GALT) can be bom-barded with high doses of antigenic or other bio-logically active molecules. Past this stage, unlessthe GALT system can be protected against suchinappropriate stimulation, frank inflammatory and/or autoimmune damage to the GI lining is initi-ated. A vicious cycle is generated, whereby thelining’s integrity is compromised. Using a stan-dard two-sugar test for intestinal permeability,D’Eufemia67 documented abnormally increasedpermeability in 9 of 21 (43%) autistics.

For the autistic child with abnormal GIpermeability, clinically significant damage may beaverted or at least minimized if a gluten-free,casein-free diet can be implemented. Here, im-provement of symptoms following step-by-stepelimination of suspect foods is the only real testof success. Improvement with a casein-free dietcan be seen within three weeks and usually pre-dicts success of a gluten-free diet, which oftentakes longer than three months.75

Penetration of Opioid Stimulants; theOpioid Excess Theory

Panksepp in 1979 proposed an “opioidexcess” theory of autism. Other researchers havefound opioid peptides (“exorphins,” derived frompartially-digested food proteins) in the urine ofautistic individuals.48,76-78 Molecules this size donot normally cross the gut mucosa. Reichelt andcolleagues working in Norway reported signifi-cantly higher levels of exorphins in urine from 315autistic children from eight different countries


Review Autism


compared to 143 normal children. The mean lev-els were almost twice as high in the autistics (p <0.001).78

Another group based in the United King-dom focused their opioid investigations on pep-tide effects on the dopamine transmitter system.They examined urine from 25 autistic adults andfound abnormally high levels in 21 of them (84%)when compared to 20 healthy controls. However,they found essentially the same pattern in indi-viduals with other mental handicaps, and ex-pressed doubt this finding could be specific forautism.79

Reichelt et al recently updated the opioidexcess theory of autism.78 They found exorphinopioids derived from casein and gluten crossedthe blood-brain-barrier and caused “social indif-ference” symptoms in experimental animals, aswell as inability to differentiate essential from non-essential stimuli. They found a peptide in urinefrom autistics that increased platelet content ofserotonin, which is also a common finding in au-tism. Altered serotonin availability has been linkedto “insistence on sameness,” reminiscent of ASD.They attempt to rationalize all the other charac-teristics of autism according to this model, sug-gesting that autism is based in a genetic error ofpeptide digestion, perhaps of the enzymediaminopeptidase IV,72 and that the brain stimu-lant activity of the exorphins can explain most, ifnot all, autism symptomatology. Further clinicalresearch will establish the relative correctness ofthis hypothesis.

Distinctive Enterocolitis Associated withAutism

In 1998, Wakefield and collaborators inthe United Kingdom reported finding measles vi-rus antigens in the intestinal linings of childrenwith autism. They tentatively linked the presenceof this antigen to recent measles-mumps-rubella(MMR) vaccination.66 This sparked a torrent ofcriticism. In 2001 their team of 12 researchers re-ported on a blinded comparison among 21 con-secutively evaluated autistic children with boweldisorders (manifesting as abdominal pain withconstipation or diarrhea), eight children without

intestinal pathology, 10 non-ASD children withileal lymphoid nodular hyperplasia (LNH), 15 withCrohn’s disease, and 14 with ulcerative colitis.68

Histology demonstrated lymphocytic colitis in theASD children, albeit less severe than classical in-flammatory bowel disease (IBD). However, base-ment membrane thickness and mucosal gammacell density were significantly increased over theother comparison groups, including IBD. Intra-epithelial lymphocyte numbers and CD3, plasmacell, and CD8 cell counts were also markedly in-creased. The investigators concluded their find-ings pointed to a lymphocytic enterocolitis in ASD,possibly skewed in the T-helper 2 (TH2) domi-nant (autoimmune) direction.

In a recently published paper, 11 of thesame investigators extended this line of inquiryfrom the colon to the duodenum.69 They comparedduodenal biopsies in 25 children with regressiveautism to 11 with celiac disease, five with cere-bral palsy and mental retardation, and 18 histo-logically normal controls. Histology revealed in-creased numbers of enterocytes and Paneth cellsin the autistic children. The duodenal lining alsohad increased lymphocyte proliferation, crypt cellproliferation, and more T cells. The investigatorswere particularly struck by the finding of increasedIgG deposition on the epithelial cell surfaces, ac-companied by complement C1q. This novel formof enteropathy in the regressed autistic childrenwas not seen in the other conditions. The research-ers believe this pattern is suggestive of auto-immune lesions and distinctive for autism.

Organ Abnormalities: ImmuneDysfunction

There is substantial evidence to suggestthe immune system plays an important role in thepathogenesis of autism.66,80,81 All the arms of im-munity are abnormal, and some or all of the ab-normalities may have a genetic basis.82

Cell-mediated immunity is oftenabnormal in autism. Abnormalities ofmacrophages, B cells, T cells, and natural killer(NK) cells have been reported.81 NK cell numbersare decreased in approximately 40 percent of thesechildren83 and CD4+ T cells decreased in


Autism Review


approximately 35 percent.81 Among 20 autisticchildren examined in detail by Gupta’s group, 13of them (65%) had CD4+ “helper” cells shiftedaway from TH1 towards TH2. This generallyindicates a skewing of immune system balancetoward autoimmunity. Warren’s group had similarfindings.84 Both findings should be replicated withlarger samples. However, the collective data isstrongly consistent with a likelihood ofautoimmune abnormality in at least a subset ofASD patients.

Turning to humoral immunity, serum im-munoglobulin classes and subclasses are often al-tered.81 Complement deficiencies are sometimesfound, especially of the C4B complement pro-tein;85 which apparently have a genetic basis.82,86

The healthy digestive tract is coated withmucus that carries high levels of immunoglobulinA (IgA). Quantitatively, IgA is the most promi-nent immunoglobulin in the body and its rate ofsynthesis exceeds that of all the other immuno-globulins combined.87 Warren and collaboratorsfound decreased serum IgA in 8 of 40 (20%) indi-viduals with autism.88 IgA deficiency predisposesto autoimmune disease.

The literature suggests that at least a sub-set, perhaps 35-45 percent, of the autistic popula-tion has pervasive problems with immunity.89

Autoantibodies to brain have been reported fromautistic children,90 as well as antibodies directedagainst specific neural self-antigens. Gupta’sgroup reported finding anti-MBP (myelin basicprotein) and anti-NAFP (neuron-axon filamentprotein) in 50-70 percent of their patients.81,91 In1991, Singh et al reported cytokine and other ab-normalities suggestive of autoimmunity.

Later research substantiates that cytokineprofiles can be off-balance in autism. In a smallsample Gupta’s group found tumor necrosis fac-tor-alpha (TNF-α), a potent proinflammatorycytokine, was significantly increased.91 In 2001,Jyonouchi and collaborators reported testing 71ASD children aged 2-14 years and comparingthem with healthy siblings and other controls.92

They found 27 of the ASD children (38%) hadsignificantly higher levels of TNF-α and other

proinflammatory cytokines (interleukin-1β,interleukin-6) compared with control children.

In the Jyonouchi study a majority of theASD children (40/71, 56%) and their siblings pro-duced abnormally high amounts of TNF-α uponphysiologic stimulation (Figure 3). A minority ofthe ASD children (7/71, 10%) produced abnor-mally low amounts of TNF-a after stimulation.

Another 13 percent (9/71) had apparentpoor regulation of TNF-α in that they producednormal amounts of the TNF-α cytokine but ab-normally low amounts of sTNFRII, a cytokine thatnormally helps counter-regulate TNF-α. In total79 percent exhibited aberrant TNF-α characteris-tics and 83 percent overproduced one or more ofthree proinflammatory cytokines. The investiga-tors concluded that a majority of their ASD chil-dren exhibited excessive or poorly regulated in-nate immune responses. The study data also indi-cate seemingly healthy siblings may share this ten-dency yet not become autistic.92

One useful indicator of increased activityof TNF-α and other proinflammatory cytokinesis urinary pterin levels (neopterin and biopterin).These are also predictably raised by autoimmuneactivation in the body. Messahel et al93 analyzedurine from 14 AD children, 21 siblings, and 16controls. They found significant elevation of bothsubstances in autistic children, and intermediateelevation in their siblings. Their results also con-firmed that as AD children get older their pterinsmay be less elevated. These findings were takento indicate that autoimmune activation may be acontributing factor in typical or “classic” autism,shared to some degree by nonautistic siblings.

Detractors of this line of investigation ar-gue autism cannot be inflammatory because char-acteristic cellular infiltrates are not found in thebrain, and cannot be autoimmune because demy-elination has not been found in the brain.94 Actu-ally, there are published case reports of demyeli-nation in autism, and Burger and Warren87 empha-size that many different inflammation-relatedmechanisms can be triggered or modulated byautoantibodies to damage the autistic brain.


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The data onabnormal immune sys-tem involvement inautism is fragmented butsubstantial. Further stud-ies are needed to clarifythe potential etiologicalcontributions from im-munogenetics, cytokineimbalances specific tothe brain, and autoim-mune potential fromautoantibodies againstbrain biomolecules. Bet-ter understanding shouldlead to strategies for re-building or rebalancingthe immune system

CoagulationAbnormalities

An increasingnumber of integrativephysicians report find-ing coagulation abnor-malities in their autisticpatients. According toJeff Bradstreet, MD andJerry Kartzinel, MD,“Many autistic children(and their family mem-bers) show significantabnormalities in bloodcoagulation.”95 Theysuggest lack of oxygenation due to compromisedblood supply stemming from coagulation mightexplain some of the symptomatology seen in au-tism. A laboratory panel known as ISAC (ImmuneSystem Activation of Coagulation) may be usefulfor assessment purposes.96 They also have foundvasospasm to be prevalent in autistic patients.

Carol Ann Ryser, MD, has had substantialclinical experience with this phenomenon inchronic fatigue patients, and reports similarfindings in autism patients. She suggestsinflammation can trigger the conversion ofcirculating fibrinogen to fibrin deposits, which

then adhere to the linings of the capillaries andother small vessels to occlude blood flow throughthem.97 Richard Kunin, MD, has also reportedclotting abnormalities in autistic patients.24

Treatment with heparin will usually normalize thecoagulation parameters.

Do Vaccines Cause Autism?The issue of whether vaccinations cause

or contribute to autism is one of the mostcontroversial and contentious in this field. Thosewho advocate a connection note that sharpincreases in autism prevalence in California

Figure 3. TNF-α levels Produced by PBMCs(peripheral blood mononuclear cells) from ASDChildren, Developmentally Normal Healthy Siblings,and Control Children

7000

6000

5000

4000

3000

2000

1000

0

Medium only LPS (0.1 µg/ml)

TN

F -

α [p

g/m

l]

ASD Control Sibling ASD Control Sibling

Left, at baseline. Right, following stimulation with lipopolysaccharide (LPS). Horizontal bars represent median values. (*) Significantly higher than controls (p < 0.001). From Jyonouchi et al.92


Autism Review


(which has 10 percent of the U. S. population) andthe United Kingdom roughly parallel increases inthe number of vaccinations given to children untilthe age of two (currently as many as 32 differentvaccinations are given). They also claim parallelswith the introduction of the MMR vaccine.

In California a sharp rise in autism beganto be evident in the mid-1980s. A statewide studypublished in 1999 reported a 273-346 percent in-crease during the period from 1987-1998, depend-ing on whether the “classic” Kanner-type diagno-sis or the more inclusive “autistic spectrum” di-agnosis was applied.4 Rimland makes the pointthat when reporting and publication delays aretaken into consideration, the reported rise from1987 may actually have begun as much as fiveyears earlier, possibly around 1982. This wouldplace the rise much more proximate to 1978, theyear the MMR vaccine was introduced into Cali-fornia on a large scale.4

Introduction of the MMR vaccine intoCalifornia is also linked to an important changein the pattern of onset of autism. According to dataon many thousands of cases, collected since 1965by the Autism Research Institute of California,prior to the early 1980s the majority of autismcases had onset at birth. Since that period far morecases of autism began to manifest around 18months, the time after birth when most childrenreceive the MMR vaccine.4

Contemporary vaccination programs in-volve more than 30 inoculations administered tothe child between the ages of 12 and 24 months.42

Thus a large number of foreign proteins are intro-duced, sometimes as three different attenuatedviruses in one vaccine (as with MMR). Often theremay be insufficient time between vaccinations forthe child’s immune response to return to baseline.Side effects of these vaccinations include allergicreactions, autoimmunity, and rarely, full develop-ment of clinical viral disease (from infection byattenuated viral particles of the vaccine).42

Transfer of Measles from Vaccine toRecipient?

Many parents of autistic children and anumber of medical experts believe the MMR vac-cine is the culprit behind autism. In one in six chil-dren it causes fever 7-12 days following immuni-zation, and one in 3,000 develop febrile seizures.98

Thrombocytopenia occurs in one child per 30,000.Sensory-neural hearing loss and gait disturbancehas been associated with use of attenuated livemeasles vaccine as found in the MMR; joint ar-thralgia or arthritis has been linked to the rubellacomponent.99

A possible mechanism to connect theMMR vaccine with autism was advocated byWakefield and his colleagues in 1998.100 They re-ported on 12 children who had undergone autis-tic-type regression soon after they received theMMR vaccine. These children had gastrointesti-nal symptoms, such as diarrhea and abdominalpain, and histopathological exam of the intestinallining seemed to reveal the presence of measlesvirus. The cases were classed as a possibly new,inflammatory bowel syndrome, and tentativelylinked to acquisition of measles virus from theMMR vaccine (albeit attenuated and having mini-mal infectivity). Another group confirmed themeasles strain DNA was consistent with vaccinebeing the source.101

This study came under sharp criticism onmany points, including its lack of rigorous con-trols. Nonetheless, its findings were provocative.Many critics totally dismissed this study, but in2002 Korvatska and collaborators wrote of theMMR vaccine, “...it is difficult to believe that ex-posure to a vaccine may be more severe than tothe virus itself. There is still a possibility of unac-counted interactions between the three related at-tenuated viruses during simultaneous infection.”42

MMR Vaccine Safety Remains UnprovenSome of the defenders of MMR vaccine

were perhaps uninformed that this vaccine wasnever subjected to adequate safety assessmentprior to being released for use in large popula-tions of children. In a letter to the journal Lancet,Wakefield stated that the entire MMR prelicensure


Review Autism


safety testing lasted only three weeks.100 In anycase, the usual design of prelicensure vaccine tri-als fails to generate data on rare reactions (i.e.,less than one per 1,000 doses), reactions with de-layed onset (i.e., 30 days or more after vaccina-tions), or reactions in subpopulations.102

Postlicensure evaluation of vaccine safety (afterit has gone into use) is the only option.

However postlicensure reporting of ad-verse vaccine events has little practical useful-ness.102 It relies on passive reporting – a clinicianmust voluntarily decide to submit a report. Un-der-reporting of such single case events is believedto be notoriously widespread. Adequately de-signed, prospective studies intended to pursue alink between the MMR (or any vaccine) and anadverse event pattern are practically nonexistent.

Some experts have decried efforts by con-cerned observers to criticize the use of MMR,sometimes alluding to “victimization” of the per-tussis vaccine in the 1970s. Wakefield made theimportant point that the pertussis vaccine did causeneurological problems, to the extent of at least 80-percent disablement, in about 900 children. Largefinancial compensations were legally assessed100

that provided impetus to replace the particularvaccine formulation with a safer version. Oppo-nents of the current MMR vaccine suggest it couldbe made safer in its triple form, or else split intoits three components to be given in three sepa-rately spaced shots.

Adding to the biological possibilities ofvaccine damage comes a toxic possibility – thedeliberate inclusion of toxic mercury in many ofthem.

A Likely Mercury Connection withAutism

During the same period that autism rateswere showing a steep rise, many vaccines(although not the MMR) carried the toxic metalmercury. The vaccine makers chose as apreservative thimerosal, which contains the highlytoxic compound ethylmercury. In recent years anoutcry from parents resulted in reformulation ofmost (although not all) vaccines to excludethimerosal. Although influential parties continue

to deny possible connections, uncanny similaritiesexist between the known patterns of mercury’stoxicity to children and those of autism.

Close Parallels in Mercury and AutismSymptomatologies

Early in the twentieth century, mercurywas used as a constituent of teething lotions anddiaper powders. A disease called acrodynia ap-peared in young children and was christened “pinkdisease” because it turned the facial skin pink andsimulated blushing. After a long process of denialand obfuscation, mercury was confirmed respon-sible for pink disease.103 Other information onmercury toxicity patterns comes from victims ofmercury-contaminated fish (Japan-Minamata dis-ease), grain (Iraq, Guatemala, Russia), or frommore individualized instances as with MadHatter’s disease (named so because beaver hatmakers used mercury in the processing).104-106 Thesymptom patterns of these conditions overlap withthose that characterize autism, as summarized intwo pages of detailed comparisons painstakinglycompiled by Bernard and her colleagues.107

Scrutinizing these tables of detailed com-parisons, even the most skeptical and rigorousobserver would be struck by the close resem-blances. The psychiatric and physical disturbances,speech and language deficits, sensory abnormali-ties, motor disorders, and cognitive impairmentsof autism, all resemble mercury poisoning. Thesimilarities continue when looking at the mostunusual behaviors, for example, movement dis-turbances that are worse on the right side of thebody; over- or under-reaction to sound; and theflapping motions, originally thought so unique toautism that they were recommended as a diagnos-tic marker for the disorder.107

Moving from the clinical expression ofautism to its known biological features, again theparallels with mercury poisoning are remarkable.The biochemical abnormalities of autism,including low glutathione and sulfate levels,abnormal antioxidant enzyme activity,mitochondrial dysfunctions, and disruptions ofpurine and pyrimidine metabolism, are allparalleled by mercury toxicity.107 The immunesystem parallels include greater propensity to


Autism Review


allergies and asthma and autoimmuneoveractivation with skewing toward TH2imbalance and reduced NK cell function.

The brain and other central nervous sys-tem similarities between ASD and mercury toxic-ity include dysfunction in the amygdala, hippoc-ampus, basal ganglia, and cerebral cortex; destruc-tion of neurons from the cerebellum; and brainstemabnormalities. Demyelination is evident in bothconditions. The brain’s electrical patterns are simi-larly abnormal, with epileptiform and subtle, lowamplitude seizure activities.

Temporal Connections BetweenMercurial Vaccines and Autism

In most children affected by autism, symp-toms become noticeable between four and 18months after birth.77 Vaccines containing thime-rosal with a 50-percent content of ethylmercurytypically were given in repeated administrationsthat began at infancy and continued until 12-18months of age. Mercury toxicity typically beginsgradually, first as sensory- and motor-related prob-lems, then as speech and hearing deficits, thenprogresses into the full panoply of impairments.

Mercury was introduced into vaccines inthe 1930s, which is approximately when the firstcases of autism were recorded. Between 1970 and1990 autism incidence doubled, from one in 2,000to one in 1,000, coinciding with the rise of theDPT vaccines packing thimerosal. In the late1980s and early 1990s, two new thimerosal vac-cines, the HIB (Haemophilus Influenzae Type B)and Hepatitis B, were added to the schedule; per-haps coincidentally, this was about the time thesharp increase in autism began.108 Some vaccinesalso contain aluminum,109 which could compoundmercury’s toxicity.

In the State of California, there is a closecorrelation between increased autism from the late1980s onward and cumulative mercury exposurethrough multiple vaccinations.110 The U.S. Cen-ters for Disease Control, recipient of public trustfor prevention of disease, has admitted that cu-mulative mercury exposure to children throughvaccination exceeds known “safe” exposure lev-els.108,111 In late 2001, the prestigious Institute ofMedicine, which advises the United States on

health issues, conceded an autism link with mer-cury is “biologically plausible,” and recommendedthat thimerosal be removed from vaccines.111

Autistic Children Have ImpairedCapacity to Detoxify Mercury

Almost 100 percent of autistic childrenshow impaired liver detoxification. Many alsohave poor metallothionein status, therefore low-ered capacity to neutralize mercury and otherheavy metals. Mercury is a powerful oxidant withpartial free radical character; it depletes cellularantioxidants, especially glutathione, the core in-tracellular protectant.112 The P450 detoxifyingenzymes of the liver rely heavily on adequateavailability of glutathione.

Mercury is also a potent poison to manyenzyme systems, especially those that rely on sulf-hydryl groups for their catalytic activity.106 AT-Pases, ion transport enzymes crucial to cell-levelhomeostasis, are highly vulnerable. Mercury bindstightly with selenoproteins – glutathione peroxi-dases and other selenium-dependent enzymes –thereby endangering antioxidant defense. Mercuryalso has other potentially toxic effects, such asinducing autoantibodies to myelin and other cellconstituents, and poisoning mitochondria.112 Infact, mercury is one of the most potent toxinsknown, involving virtually every known pathwayfor inhibition.

New Study Establishes ThimerosalMercury Link with Cell Killing112

A new study just being published (August2002) makes a definitive, mechanistic link be-tween thimerosal and cell damage or death in theexposed individual. Makani, Gupta, and col-leagues subjected cultured human T cells (Jurkat)to thimerosal. They found thimerosal’s mercuryingredient (ethylmercury) specifically causedapoptosis of these cells. The cells became depletedof the core antioxidant glutathione, their mitochon-dria became decompensated, and the cells died.The exposure levels at which thimerosal killedthese human immune cells were low and wellwithin the ranges likely attained in vaccinatedchildren.


Review Autism


Skeptics of the mercury theory of autismsometimes inquire, with nearly all U.S. childrenbeing immunized, why only a few would developautism. The experiences with acrodynia/pink dis-ease and other human models of mercury intoxi-cation illustrate that the effects of mercury arehighly variable (1,000-10,000-fold) in its effectson the individual. Acrodynia, for example, af-flicted only one in 500 among children who re-ceived similar, comparatively low mercury expo-sures.106 Mercury seems to strike harder at certaingenotypes that have higher propensity to autoim-mune disorders, of which autism seems to be oneexample. Also, low-dose mercury exposure dam-ages far more boys than girls, consistent with thegender imbalance of autism.113

Parent-Driven Progress in AutismManagement

Following the first definitive report onautism by Kanner in 1943,1 research on the disor-der was largely descriptive: symptoms were cata-logued with efforts made to pinpoint the brain ar-eas and functions that might be affected. Drugsthat had been developed for other applicationswere tested for symptom reduction, with little suc-cess. For decades little progress was made, until1967 when Bernard Rimland, PhD, founded theInstitute for Child Behavior Research (ICBR).114

As a father of an autistic child, Rimlandunderstood the need for immediate assistance toindividuals with the disorder. He intensively stud-ied the scientific literature and used the Instituteas an international clearinghouse for informationon autistic children. He solicited information andcase reports from parents, who are on the frontlines of the battle against autism; and from healthprofessionals, some who also had children withautism. Soon the ICBR was able to help parentsto help their children. Drugs did little to help, butintensive, carefully planned, highly structuredbehavior modification did help.114

By 1987 the ICBR had in its data bankdetailed case history information on 9,600 autis-tic children from 40 countries, gleaned from hun-dreds of professionals.114 They had collected morethan 3,500 completed questionnaires with quanti-

tative feedback from parents on a variety of drugs,nutrients, and other treatments. The various treat-ments were scored, then ranked in terms of theratio of number of autistic children helped to thenumber made worse. The first such ranking, from318 parent questionnaires, scored vitamin B6 andmagnesium as having the best “benefit-to-harm”ratio.

In 1968 the ICBR began to conduct pro-spective studies of vitamin therapy for autism. Thefirst study employed large doses of vitamin B6,niacinamide, pantothenic acid, and vitamin C, thefour treatments ranked most favorably by the par-ents.114 Treating 200 children over four months, ityielded significantly positive results, with vitaminB6 appearing to provide the most benefit. Subse-quent trials by the ICBR and other parties foundvitamin B6 and magnesium made a particularlybeneficial combination, with no adverse effects.The ICBR has since evolved into the Autism Re-search Institute (ARI).6 The ARI now has the larg-est database in the world on autism, with upwardof 34,000 cases.12 Parents participate in the ARIat every level, including research and publicationin peer-reviewed journals.

In 1995 the ARI initiated another break-through in autism research and medical manage-ment. A conference was convened at which 30scientists and physicians specializing in autismfounded Defeat Autism Now! (DAN!). Since thenseveral other conferences have been held, withconsensus reports published, periodic physiciantraining manuals, and a manual on biomedicalassessment options.7 As with the original ICBRand ARI, the activities of DAN! have once againsparked further advances in diagnosis and treat-ment of autism.

In 1997, the U.S. National Institutes ofHealth (NIH) began a five-year, $42-million net-work of collaborative research programs for au-tism. In September 2001, construction began on a$39-million state-of-the-art comprehensive clinicand research center to diagnose, treat, and studychildren with autism. Located at the University ofCalifornia at Davis, it is largely a product of par-ent advocacy.25 At parents’ insistence, all the com-prehensive raw data generated at this facility –Medical Investigation of Neurodevelopmental


Autism Review


Disorders (MIND) Institute – will be shared withautism investigators around the world.

ConclusionUntil recently autism has been a puzzling

disorder with a limited knowledge base and, as aconsequence, its management was largely empiri-cal. But now signs have emerged that point towarda possible pattern for this disorder. Hypofunctioningof the brain’s temporal lobe regions, leading to com-promise of this region’s networking with other re-gions, can account for the core neurological symp-tomatology. Pervasive detoxification impairments,documented in a high percentage of children withthe disorder, are consistent with the abnormally highxenobiotic load they carry and their heightenedsusceptibility to mercury, aluminum, and other toxicmetals. Poor systemic detoxification performancemay account for the apparent abnormal autoim-mune tendency in this population.

The autistic child may be a casualty of thetoxicity of modern society. Potential triggering fac-tors such as antibiotic overdosing, overvaccination,and prenatal xenobiotic overload could interact witheach other and with a high heritability componentto account for the development of dysbiosis, leakygut, and other GI abnormalities known to fuel sys-temic autoimmune reactivity. These and other trig-gers are so broadly threatening to human metabo-lism that they could also account for virtually allthe other abnormalities seen in autistic spectrumdisorders. Whether any one “cause” of autism willbe established remains an open question; as theresearch deepens the theory of opioid excess willcompete with other theories.

Much new research needs to be conductedon autism before this putative pattern can be fullyconfirmed. Many parents feel they cannot affordto wait for the normally snail’s-paced progressionof good science. Thus (to their credit) they are driv-ing the pace of research into this devastating disor-der. The limited, fragmentary data of today couldsoon become a body of knowledge that would al-low for fuller confidence in detailed managementprotocols. Crucial challenges, such as a better neu-rological grounding of the disorder’s subtypes,could be overcome within a few years. Part 2 of

this review will cover the current state of the art inautism treatment, which is consolidating into amodel of integrative medical management.

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