292 Autism, An Extreme Challenge For Integrative Medicine. Part I

Autism Review
Autism, An Extreme
Challenge to Integrative Medicine.
Part 1: The Knowledge Base
Parris M. Kidd, PhD
Abstract inflammation and autoimmunity. Coagulation

Autism, archetype of the autistic spectrum abnormalities have been reported. Part 2 of this
disorders (ASD), is a neurodevelopmental review will attempt to consolidate progress in
disorder characterized by socially aloof integrative management of autism, aimed at
behavior and impairment of language and improving independence and lifespan for
social interaction. Its prevalence has surged people with the disorder.
in recent years. Advanced functional brain (Altern Med Rev 2002;7(4):292-316)
imaging has confirmed pervasive neurologic
involvement. Parent involvement in autism Introduction
management has accelerated understanding
In 1943 the psychologist Leo Kanner pub-
and treatment. Often accompanied by epilepsy,
lished case histories of a childhood developmen-
cognitive deficits, or other neurologic
tal disorder he called autism. He defined three
impairment, autism manifests in the first three
symptom patterns: (1) failure to use language for
years of life and persists into adulthood. Its
communication, (2) abnormal development of
etiopathology is poorly defined but likely
social reciprocity, and (3) desire for sameness, as
multifactorial with heritability playing a major
seen in repetitive rituals or intense circumscribed
role. Prenatal toxic exposures (teratogens) are
interests.1 Autistic children seem abnormally with-
consistent with autism spectrum
drawn, almost self-occupied, and out of touch with
symptomatology. Frequent vaccinations with
reality. As a group they score significantly lower
live virus and toxic mercurial content
on measures of adaptive or life skills than the gen-
(thimerosal) are a plausible etiologic factor.
eral population.2
Autistic children frequently have abnormalities
Individuals with autism tend to have ex-
of sulfoxidation and sulfation that compromise
treme difficulty learning from experience and
liver detoxification, which may contribute to the
modifying their behavior to accommodate vary-
high body burden of xenobiotics frequently
ing situations.2 Coping with the unpredictability
found. Frequent copper-zinc imbalance implies
of the social world is especially demanding, even
metallothionein impairment that could
overwhelming, for adults with autism; associated
compound the negative impact of sulfur
anxiety exacerbates the problem.2 Adult individu-
metabolism impairments on detoxification and
als with autism have life outcomes that range from
on intestinal lining integrity. Intestinal
complete dependence to (rarely) successful em-
hyperpermeability manifests in autistic children
ployment. Most are able to benefit from structured
as dysbiosis, food intolerances, and exorphin
training programs with marked improvement in
(opioid) intoxication, most frequently from
their quality of life.3
casein and gluten. Immune system
abnormalities encompass derangement of Parris Kidd, PhD (cell biology, University of California at
antibody production, skewing of T cell subsets, Berkeley) Contributing Editor, Alternative Medicine
Review; health educator and biomedical consultant to the
aberrant cytokine profiles, and other supplement industry.
impairments consistent with chronic Correspondence address: 847 Elm Street, El Cerrito, CA
94530
Page 292 Alternative Medicine Review Volume 7, Number 4 2002

Copyright2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Review Autism
Autism has become epidemic in the in- Diagnosis, Classification, Epidemic

dustrialized societies. In the United States, autism
was relatively rare until the early 1990s, after
Prevalence
which its prevalence increased by at least double, The modern concept of autism recognizes
and more likely 3-5 times.2 Similar steep increases Kanners classic autism as autism, autistic dis-
in prevalence have been recorded in the United order or AD, and subsumes this within a broader
Kingdom.4 The gender ratio is 3-4:1 boys to girls.2 category called autistic spectrum disorders or
Since every autistic child has a major impact on ASD. For the physician these distinctions can be
the family, school system, and community, this hard to make. In this review, use of the term au-
epidemic calls for compassion, sensitivity, and tism will refer to AD and the broader category will
maximum assistance from society as a whole. be referred to as ASD, unless otherwise specified.
There is a great deal of debate in the
healthcare world over the existence of an autism Emergence of the Disorder
epidemic and the possible contributing factors. Autism begins very early in life. Almost
Parents, supported by progressive healthcare pro- all autistic patients are normal in physical appear-
fessionals, are on one side pointing at vaccines ance, but physiologic abnormalities can become
manufactured with known toxic ingredients. On evident within mere months of birth.8 The three
the other side are governmental and private orga- primary symptom patterns first defined by Kanner
nizations seemingly unwilling to institute reform. manifest by 36 months. This characteristic triad
The annual monetary cost of autism in the United may be accompanied by sensory and motor dys-
States is estimated to be $26 billion.5 functions, or by cognitive or other mental process-
From the clinical-biological perspective, ing deficits.9 Neurological abnormalities dominate
this disorder or spectrum of disorders, is extremely autism.
complex and multifaceted. Its expression, pathol- In the majority of autism cases the disor-
ogy, etiology, and management rank it among the der first becomes apparent as a parent notices the
most perplexing disorders known. Autism chal- growing child is not using words to communicate,
lenges the intellect and research skill of investi- even though the child usually can recite the al-
gators obtaining funding support to investigate it. phabet. In a minority of cases, autism appears as
Yet despite all the limitations, real progress has developmental regression: parents report their
been made within the last decade toward helping child was developing normally, then regressed
autistic people become productive members of so- occasionally abruptly in language, sociability,
ciety. and play.10 In rare cases motor skills also regress.
The Autism Research Institute, founded After a plateau that lasts for some months, devel-
by Dr. Bernard Rimland, and its Defeat Autism opment resumes, but in most cases never returns
Now! (DAN!) initiative, have successfully ad- to its previous level.
vanced medical management of autism to the de- Some autistic children make little progress
gree that some children largely recover and can throughout their life, remaining nonverbal, se-
have somewhat normal lives.6,7 Within the broader verely withdrawn, and mentally deficient, while
medical community, diagnosis and assessment others fare better, although complete recovery is
have also markedly improved, as have the pace rare.11 While 75 percent of AD cases are mentally
and intensity of research. This review (Part 1 of retarded, only 50 percent of ASD cases exhibit
2) seeks to define the features of the disorder and retardation. As many as one in 10 autistics are sa-
its core abnormalities. Part 2 will address the va- vants gifted in areas such as music, drawing,
riety of approaches to its medical management, memorization, or calculations. They have islands
along with priorities for future research. of genius in skills that require attention to detail,
memory, or computations such as calendrical cal-
culating or perfect pitch.12,13 Tentative suggestions
have been made that risk of autism may be greater
Alternative Medicine Review Volume 7, Number 4 2002 Page 293

Autism Review
Diagnosis and
Figure 1. Conceptual Interrelationships of the Autistic Classifications
Autism is diag-
Spectrum Disorders16 nosed generally at around
two years of age, when the
child should begin to par-
ticipate in organized social
activities. Social deficits
become evident when the
child is compared with
peers of the same age. The
young child with autism is
unlikely to seek out others
AUTISM when he is happy, show or
point to objects of interest,
or call his parents by name.
CHILDHOOD The child is, in a sense, ab-
DISINTEGRATIVE ASPERGER'S normally self-occupied.
DISORDER DISORDER During preschool years, re-
petitive behaviors begin to
develop. These could in-
RETT'S clude using peripheral vi-
DISORDER
sion to look at lines or
wheels, or peculiar hand and
finger movements.
From the early in-
ATYPICAL AUTISM / PDD-NOS 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
in families where one or both parents has selected autistic child is observed to be less adept at mak-
a field of interest emphasizing focus and atten- ing eye contact with another person, has poor abil-
tion to detail.14 ity to make facial expressions, and is less able to
Persons with autism have reduced life coordinate his vocalizations with his intentions,
expectancy.5 Those with the most severe mental compared to children within the normal develop-
retardation tend to die soonest. Those with mild mental range.8
or no mental retardation still die earlier than the In concept, the diagnosis of autism has not
general population, most often from seizures, ner- changed since formulated by Kanner, but there
vous system dysfunction, drowning, or suffoca- have been evolutionary changes in how the symp-
tion (all rates more than three times higher than tom patterns are interpreted and assessed. Recog-
the general population). Deaths due to epilepsy nizing that no two cases are alike, even within the
are 24 times that of background; many of the same family, it has become more useful to view
deaths by drowning involve heart attacks, perhaps autism as a spectrum of disorders, classified au-
related to adverse effects from medications. tistic spectrum disorders with Kanners classic
autism at the core (Figure 1).

Review Autism
All the autistic spectrum disorders feature was estimated at about 5 per 10,000 for AD and
deficits in communicative and social skills, but 20 per 10,000 for total ASD.21 By 1997, the preva-
they vary in symptom pervasiveness, severity, lence of autistic spectrum disorders was estimated
onset, and progression over time. For the purposes to be 40-50 per 10,000.2 In one community, Brick
of this review, the term ASD is considered syn- Township in New Jersey, the frequency of ASD
onymous with pervasive developmental disorders may have reached 1 in 150.22
(PDD). The category ASD includes at its core AD, Some experts argue that such increased
overlapping with Aspergers disorder (Aspergers prevalence of AD/ASD is only apparent because
syndrome, AS), childhood disintegrative disorder of changes in diagnostic criteria and improvements
(CDD), and Retts disorder (Retts syndrome, in early detection. But the documented minimal
RTT). All these are enveloped by pervasive de- doubling perhaps quadrupling of prevalence
velopment disorder not otherwise specified (PDD- within a little more than a decade seems too ex-
NOS, also called atypical autism).16 It is not un- treme to be attributed only to improved diagno-
common for these ASDs to occur concurrently sis.
within the same family. Sidney M. Baker, MD, and Richard A.
Kunin, MD, pioneers in autism management, have
Physical Characteristics and Co- independently listed factors that have become
more prominent in developed societies between
Morbid Conditions 1950 and 2000, and which they strongly suspect
Early reports of an association between have contributed to the autism upsurge.23,24 They
autism and epilepsy17 helped implicate biological both have identified the following factors: in-
rather than mere psychogenic factors in the etiol- creased antibiotic use; mercury exposure by in-
ogy of autism. Epilepsy may occur in up to 30 jection in infancy; increase in combined live viral
percent of individuals with autism. Although its vaccines and the numbers of vaccinations; in-
peak onset is during early adolescence, it may also creased soil depletion leading to vitamin/mineral
occur in infancy.2 Infantile spasms that involve the deficits; decreased omega-3 and -6 essential fatty
brainstem may initiate autistic symptoms. Landau- acids in the diet; and greater exposure to xenobiotic
Kleffner syndrome features epileptiform activity, toxins.
abrupt loss of language, and autistic symptoma- From 1987 to 1998, the number of chil-
tology.18 dren being treated for autism in California jumped
Epidemiological studies indicate that cur- 273 percent.25 A nationwide figure for 1991 to
rently at least 25-30 percent of people with au- 1997 was 556 percent. Whatever the limitations
tism have associated medical conditions.19 Among of the statistics in regard to determining the real
the most prevalent are sensory impairment (blind- prevalence of these disorders, the data starkly in-
ness and/or deafness), tuberous sclerosis, neurofi- dicate there is considerable need for societal at-
bromatosis, and epilepsy, all of which predomi- tention to autism. Hopefully, the most polar advo-
nate among those with the most severe mental re- cates on both sides of the prevalence debate could
tardation. Hearing loss may be more prevalent than agree on one point: that communities, schools, and
previously reported, and may be linked to abnor- the healthcare systems are being confronted with
mal brainstem auditory-evoked responsiveness.20 the challenge to raise, educate, and otherwise
manage ever-increasing numbers of children with
Rising Prevalence of Autism and profound functional impairments.
ASD
The statistics on occurrence of AD and
ASD strongly suggest these disorders have become
epidemic. From surveys conducted prior to the
1990s, nationwide prevalence in the United States

Autism Review
The Defining Abnormalities ability for social interactions, which typically re-
Most experts agree the neurological prob- quire flexible and immediate evaluation, then se-
lems seen in autism seem to stem, not primarily lection of appropriate responses to multidimen-
from the senses, but from interpretation of the sional information.28
world.25 When normal people view an array of The most recently favored hypothesis for
objects, for example, they infer social relationships social cognitive impairment in autism features
among the objects. Rather than see a room, they theory of mind.29 It suggests that autistics fail to
see individual details within it. Autistic people tend appreciate the representational theory of mind and
to see shapes and objects as isolated. They also instead think of mind on too literal a basis. For
have trouble interpreting faces, sometimes gaz- example, the autistic child shown a milk carton
ing at the mouth rather than the eyes, as normal filled with paper clips may conclude the carton
people usually do. The autistic child would more really was manufactured to carry paper clips. Chil-
often describe his father as a man who is tall and dren normally can correct such false beliefs by
wears glasses, rather than as his father who is kind the time they reach age four. Children with ASD
and works hard.25 typically do not pass this stage until their verbal
The ability to understand facts but not re- mental age is at least eight years.
late them to concepts is another common symp-
tom. Children with autism may learn a particular Neuropathologic Findings
task yet be unable to generalize it to other situa- Inconsistent
tions. Their difficulty in processing information To date only about 30 autopsies of autis-
on the higher levels extends to their motor activ- tic brains have been formally reported. The lim-
ity as well. They can have trouble kicking balls, ited autopsy studies have not uncovered any con-
writing, or tying shoes.25 sistent differences between autistic brains and
nonautistic brains. Microscopic pathology and
Possible Information Processing structural imaging studies have also failed to con-
Deficits firm differences. But very recently advanced func-
Several theories have been posited as to tional imaging has succeeded in defining a pat-
the processing mechanisms that may be affected tern of abnormalities in autism.
in autism. One is weak central coherence.26 Autis- Neuropathological examinations have at
tic individuals generally demonstrate remarkable one time or another pointed to possible abnormali-
skill on the Block Design subtest from the ties in the brainstem, the cerebellum, and limbic
Wechsler Performance Scale. The hypothesis is structures, including the hippocampal formation,
that autistics fail at holistic processing of an im- amygdala, septal nuclei, mammillary nuclei, and
age, instead remaining focused on its individual anterior cingulate cortex;30 however, the majority
parts. Thus on Block Design, they do not recon- of neuropathological studies have failed to con-
struct the overall form of the image and as a result firm any differences from normal brains.31
find it easier to see the component parts. Three different groups have reported ab-
An alternative to weak central coherence normalities of the cerebellum, especially loss of
has been the executive dysfunction hypothesis.27 Purkinje cells.9 Loss of cerebellar Purkinje cells
Executive functions are typically used for non- is seen frequently in seizure disorders, so it would
routine problem solving, and would include such be important to conclusively determine whether
mental operations as planning, working memory, these cells are depleted in autistic subjects with-
maintenance and shifting of attention, and inhibi- out a history of seizure disorders.
tion of inappropriate responses. Executive func- Structural magnetic resonance imaging
tion deficits could potentially explain the repeti- has failed to detect consistent changes in autism.9
tive and rigid behaviors of ASD, and the impaired In different studies, both atrophy and normal mass

Review Autism
have been reported in the

cerebellum. A few studies
reported subtle abnormali- Figure 2. Abnormally Low Blood Perfusion of the
ties in the amygdala, while Temporal Lobes in Childhood Autism, Mapped from Two
many reported normality.31 Separate Studies
As well, studies that re-
ported reductions of the hip-
pocampus, mesial temporal
lobe, or caudate nucleus in
autistic subjects have been
counterbalanced by others
that found no change.31,32
Functional brain
imaging techniques, such as
positron emission tomogra-
phy (PET), single photon
emission computed tomog-
raphy (SPECT), and func-
tional magnetic resonance
imaging (fMRI), initially
made little progress over
structural imaging. But with
the second generation of in-
strumentation has come
greatly improved resolution
and data filtering. Now two
groups have independently
reported abnormalities of
blood flow in the temporal lobes of autistic chil- In 2000, using PET imaging, Zilbovicius
dren. In addition, activation studies have revealed et al detected significant temporal hypoperfusion
abnormal patterns of cortical activation. in 21 autistic and 10 control children.34 Careful
Both PET and SPECT allow accurate data analysis confirmed that 16 of the 21 autistic
measurements of cerebral glucose metabolism children (77%) were lower than the controls; of
and/or blood flow. Measurements can be per- these, four were unilaterally affected and 12, bi-
formed at rest or during the performance of spe- lateral. These investigators then imaged another
cific sensory, motor, or cognitive tasks. The first 12 autistic children and successfully confirmed the
good functional study was published in 1995. first result. That same year Ohnishi et al published
Zilbovicius and collaborators imaged regional a SPECT study of 23 autistic and 26 control chil-
cerebral blood flow in five primary autistic children that detected significant hypoperfusion in the
dren (subjects free of epilepsy or other neurologi- fronto-temporal region.35 These two sets of results
cal complications), first at the age of 2-4 years are so closely similar they are virtually
then three years later.33 They found that perfusion superimposable on each other (Figure 2).
of the frontal lobes at the earlier age matched the The evidence is now clear that autistic
pattern of perfusion in much younger normal chil- children, free of other major neurological
dren, and concluded these children had delayed conditions, manifest abnormally low blood flow
frontal lobe metabolic maturation. in the temporal cortex. 33-35 Neurologically,
dysfunction in these regions could explain almost
all the symptoms (perceptive, emotional, and

Autism Review
cognitive) observed in primary autism. The the functional findings are consistent with autis-
temporal associative regions are highly connected tic subjects language impairment and inadequate
to the frontal and parietal lobes and the limbic and behavioral response to words.32
associated sensory systems. The temporal lobe is Boddaert and Zilbovicius also described
believed to be central to the processing of other types of activation studies with autistic chil-
numerous environmental signals, as well as for dren and adults.32 All the PET studies are consis-
the further conversion of these signals into tent with disorganized establishment of neural cir-
structured patterns of neural activity that bring cuits. Baron-Cohen and colleagues40 tested the
meaning to the world around us. social intelligence (theory of mind) of autistic
Indirect corroboration of this key finding adults. Two sets of images were presented: (1)
comes from observations that individuals with photographs of eyes, for the subject to guess
temporal lobe pathology (epilepsy, herpes simplex whether each was a man or a woman and (2) pho-
encephalitis) sometimes manifest autistic behav- tographs of people, for the subject to describe the
ior.32 In children with infantile spasms, temporal mental state of the person in the photograph. The
lobe hypometabolism is strongly associated with nonautistic control subjects activated both the
later emergence of autism symptoms.36 Similar ob- fronto-temporal neocortical regions and non-neo-
servations were made of children with tuberous cortical regions, including the amygdala, hippoc-
sclerosis and from experiments conducted with ampus, and striatum. The autistic subjects acti-
primates.32 vated the frontal neocortex less extensively, and
failed to activate the amygdala. In other studies,
Functional Imaging During Cortical autistic subjects failed to activate a cortical face
area when attempting to assess facial expressions.
Activation The amygdala and cerebellum were not activated
Activation studies measure local changes during processing of emotional facial expressions.
of cortical blood flow or blood oxygenation, re- In summary, state-of-the-art functional
flecting the variation of synaptic activity in re- brain imaging has established that autistic indi-
sponse to sensory, cognitive, or motor stimulation. viduals exhibit abnormal temporal lobe function.
PET, SPECT, and fMRI activation studies suggest Dysfunctional connections between these regions
that autistic subjects activate different brain re- and the fronto-parietal zones could explain the
gions than controls, indicating they have different cognitive abnormalities; to the limbic system, the
cerebral circuit configurations.32 Garreau et al con- emotional abnormalities; and to the auditory re-
ducted the first such SPECT study37 and found that gions, the sensory perception abnormalities. Func-
in response to auditory stimuli, autistic children tional imaging detected abnormal activation pat-
activated the right posterior associative cortex terns sufficient to suggest more or less widespread
while the control group activated the left side. disorganization of cortical networks in the autis-
Muller et al38 reported similar findings in adult tic brain.
autistic males.
An auditory activation PET study was
performed in autistic adults during passive listen-
Candidates for the Etiopathology of
ing to speech-like stimuli.39 The autistic subjects Autism
showed significantly higher activation of the right The etiopathology of AD/ASD is almost
posterior temporal lobe. Applying the same audi- surely multifactorial. Although it is probably not
tory model to children, Boddaert et al39 detected an inborn error of metabolism, a genetic suscepti-
significantly lower activation of the left temporal bility almost surely exists. During the last 40 years,
lobe. Altogether, the activation findings suggest autism has been linked with many etiologies, in-
autism is associated with abnormal activation of cluding various inborn errors; genetic abnormali-
the left temporal cortex. Since this is the region ties such as fragile X syndrome; rubella and other
thought to handle brain organization for language,

Review Autism
pathogens; and many other factors.41 Genetic pre- language disorder (SPCH1). A gene, FOXP2, has
disposition, metabolic abnormalities, and abnor- been identified from this zone and is being actively
malities of the gastrointestinal, hepatic, and im- investigated.
mune systems all appear to be markedly involved.
Developmental/Teratologic
Genetic Predisposition Several lines of evidence implicate an
A solid body of evidence indicates genet- early brainstem injury in autism.44 Minor physi-
ics plays a primary role in autism, probably not as cal anomalies of the ear are found in as many as
inborn error(s) but as a strongly predisposing fac- 45 percent of autistic children, and point to a pos-
tor.42 There is compelling evidence for high, very sible insult during ear development during the lat-
likely multigenically-determined, heritability as ter part of the first month of gestation.45 Rodier
evidenced by the 50-percent concordance rate for and colleagues have developed a body of work
monozygotic twins, versus about three percent for that supports thalidomide exposure as a teratoge-
dizygotic twins.9 Further, the rate of autism among nic factor in autism. Some 30 percent of children
the siblings of an affected child is 3-6 percent, a exposed to thalidomide during neural tube closure
rate 50-100 times higher than the general popula- (days 20-24) developed autism, probably prima-
tion.43 This degree of genetic conditioning of au- rily related to brainstem damage.46 Such cases usu-
tism exceeds genetically-conditioned diseases ally display ear anomalies, including hearing loss,
such as Alzheimers, asthma, diabetes, and schizo- and Moebius syndrome (facial paralysis and a lack
phrenia. These data are also consistent with the of eye abduction). Rodier explored the mecha-
existence of multiple (probably between 3 and 20) nisms in animal models and suggested many such
susceptibility genes for autism.25,42 individuals should show brainstem abnormalities
The likelihood that autism is strongly de- at autopsy.47
termined by heredity has stimulated much recent
research. A small proportion of autistic individu- Metabolic Abnormalities
als (no more than 10-15 percent) demonstrate co- A number of inborn or acquired metabolic
morbidity with known genetic conditions includ- abnormalities may manifest as AD, ASD, or quasi-
ing tuberous sclerosis, neurofibromatosis, fragile autistic syndromes. Biochemist Jon Pangborn, also
X syndrome, and chromosomal abnormalities. As the father of an autistic child, has reviewed these
many as 25 percent of fragile X cases display au- in a compilation of the applicable biochemical
tistic-like symptoms that nonetheless are distinct assessments.48 The most prominent of the abnor-
from AD. Other X-linked gene mutations, such as malities are phenylketonuria (PKU) variants,
in the MECP2 of Retts disorder, may contribute histidinemia, adenylosuccinate lyase deficiency,
to subsets of AD. purine synthesis deficiencies, inosine phosphate
The chromosomal disorder most dehydrogenase weakness, Lesch-Nyhan Disease,
frequently found (up to 3 percent) in recent large adenosine deaminase deficiency, and ADA bind-
samples of AD has been a maternal duplication of ing protein weakness.
15q11-q13, a region on chromosome 15 linked to Pangborn is also skilled at assessing
other developmental disorders. While featuring amino acid analysis data from ASD cases with
mental retardation, these distinctly differ from AD, variable or non-inborn metabolic dysfunction. In
but a distance effect from this zone has not been a survey of 62 autistic children, he found taurine
ruled out. Several genome-wide gene screens have deficiency most predominant (62% on urinaly-
already been published on autism9 and a number sis).48 Deficiencies of lysine (59%), phenylalanine
of candidate gene regions are under scrutiny. Of (54%), and methionine (51%) were trailed by de-
these the most suspicious is a relatively large ficiencies of tyrosine, leucine, glutamine, valine,
region on chromosome 7 (7q31-35). The 7q31 and asparagine, in that order. In addition to amino
zone has been independently linked to a speech-

Autism Review
acid analyses he also strongly recommends el- their water-soluble sulfate salts for subsequent
emental analyses from red cells and hair, and liver excretion. Most of the sulfate substrate comes from
detoxification assessment using urinary caffeine, sulfoxidation of the amino acid cysteine. Sulfation
acetaminophen, and salicylate (aspirin) clearance. is important for the excretion of endogenously
Serotonin is a monoamine brain transmit- produced substances such as steroids, bile acids,
ter that is one of the earliest to appear in the de- and catecholamine neurotransmitters.51 Impaired
veloping brain. It also plays a role in regulating sulfation also seriously compromises the ability
brain development.49 Elevated blood serotonin is to excrete xenobiotics from the body.
one of the most consistent abnormalities in au- Sulfation and sulfoxidation capacities are
tism, documented in more than 20 studies to date.50 known to vary substantially among individuals,
Up to 40 percent of ASD cases feature abnormally and to be highly genetically conditioned. 52
elevated blood serotonin.50 Certain serotonin re- Sulfoxidation capacity (activity of the enzyme
ceptors may be supersensitive, which may con- cysteine dioxygenase) can be roughly determined
tribute to repetitive behaviors.49 Paradoxically, from the metabolism of the drug S-carboxymethyl-
serotonin excess can result in lowered responsive- L-cysteine (SCMC).51 About 65 percent of the
ness to serotonin, due to feedback down-regula- population test as good metabolizers of SCMC,
tion of the receptors.49 But some areas of the au- 32.5 percent as poor metabolizer,. And 2.5 per-
tistic brain can have decreased serotonin concen- cent are classed as non-metabolizers.53 Despite
trations while other areas are abnormally elevated, limitations of this specific test, it seems clear that
perhaps corresponding to abnormal development up to 2.5 percent of the general population have
of brain networks.49 genetic polymorphisms that render them virtually
Warren and Singh measured serotonin in unable to convert cysteine to inorganic sulfate.
20 autistic subjects and correlated the blood lev- Inorganic sulfate is important for many
els with genetic typing. They linked the blood se- physiological functions. The liver relies on its sul-
rotonin elevation to a combination of MHC (ma- fate pool to neutralize phenolic substances, chemi-
jor histocompatibility complex) genes on chromo- cals common in foods and contaminants (exog-
some 6, a chromosome previously linked to au- enous) and also routinely produced in the body
tism.50 The genes potentially involved are known (endogenous). Endogenous compounds that are
to regulate immunity, and are often associated with sulfated for excretion include the hormones
immune deficits and autoimmune disorders. progesterone and dehydroepiandrosterone
(DHEA), and the catechol neurotransmitters
Organ Abnormalities in Autism: dopamine and epinephrine. One exogenous sub-
strate is acetaminophen (Tylenol), an all-too-
Detoxification Impairments frequent cause of liver damage.
While there are a seemingly unending When sulfation is impaired or a high dose
number of theories seeking to explain the cause of acetaminophen is ingested, the resultant over-
of autism, one category of abnormalities occurs load can deplete glutathione stores and result in
with close to 100-percent frequency abnormal liver injury or failure. Endogenous substrate over-
liver detoxification. load, as from high estrogen during pregnancy or
from use of estrogen-containing birth control pills,
Importance of Sulfoxidation and can further reduce liver sulfation capacity.54,55
Sulfation to Health In addition to the livers heavy reliance,
The P450 detoxification system that is the gastrointestinal (GI) tract also relies on sul-
most concentrated in the liver uses sulfation as fate availability for its essential functions. The
one pathway for the detoxification of endogenous gastrointestinal mucosa must have sulfate avail-
and exogenous substances. Enzymes draw on a able in order to conduct first-pass neutraliza-
pool of sulfate to convert phenolic substances to tion of potentially toxic bacterial fermentation

Review Autism
products (e.g.,
from protein),
foodborne pheno- Table 1. Xenobiotic Overload (based on the maximum
lics, and manmade acceptable adult values) in Blood. Modified from Edelson and
xenobiotics. The Cantor. 41
mucosa presum-
ably receives most
of its sulfate sup- Xenobiotic %Children % Adult Maximum
ply from the
blood, within One or more xenobiotics 89% >100%
which sulfate
levels are homeo- Ethyl- or Methyl- benzenes 78% 111-1800%
statically con-
trolled by kidney 2- or 3- Methylpentanes 55% 106-400%
56
conservation.
Human Xylenes 44% 139-928%
studies have docu-
Toluene 17% 367-10,000%
mented inad-
equate sulfation Benzene 17% 260-1160%
capacity in some
individuals.51 The n-Heptane 17% 270-440%
model drug used
for this test is usu- Styrene 11% 200-400%
ally acetami-
nophen. Ulti- Trichloroethylene, 5% 325-1900%
mately, three mea- Chloroform, Dieldrin
sures confirm sul-
fate metabolism
abnormalities.
These are impaired sulfoxidation (from the SCMC clearance by 20 autistic children, diagnosed as AD
test), impaired sulfation (from the acetaminophen and low-functioning, against 20 age-matched
test), and an elevated cysteine-to-sulfate ratio in controls.58 Among the autistic subjects 18 of 20
the blood. To date these abnormalities are mani- were impaired, while among the controls 19 of 20
fest in rheumatoid arthritis, as well as in the neu- were normal (p value < 0.00002). In another 40
rological diseases Alzheimers, Parkinsons, mo- autistic children not directly compared, 37 of 40
tor neuron disease, and autism.57 showed a similar degree of sulfation impairment.
In total, of 60 autistic children examined, 55 were
Abnormalities of Sulfoxidation and markedly impaired (92 percent). The investiga-
Sulfation in Autism tors suggested their findings should help explain
Reduced metabolism of SCMC, impaired why many autistic children are triggered by
sulfation, and an elevated cysteine-to-sulfate ra- foodstuffs, particularly foods (e.g., bananas,
tio have been reported in autistic children by War- chocolate, cheese and other fermented products)
ing and collaborators, working in cooperation with with relatively high profiles of phenolic amines
parent groups in both the United Kingdom and such as dopamine, tyramine, and serotonin.
the United States. 57 Additional support for this interpretation
Alberti, Waring, and colleagues did a pi- came when Waring and others found that the ac-
lot study in which they measured acetaminophen tivity of phenylsulfotransferase (PST), the enzyme
catalyzing the sulfation of acetaminophen, was

Autism Review
abnormally low in autistic children as measured significantly in excess of the established adult
from the blood platelets. This was more direct acceptable maximum values, in 16 of 18 of these
proof of a systemic incapacity of autistic subjects children (Table 1).
to detoxify endogenous and exogenous phenols Subsequently this sample population was
and amines via sulfation.59 expanded to include 56 children, 43 males and 13
These systemic impairments of sulfation females, mean age 6.54 years.41 All 56 subjects
in autistics threaten the stability of the catechola- had abnormally high heavy metal burden; of these,
mine transmitter systems, the integrity of the gut 55 expressed liver detoxification malfunctions and
lining, and heighten vulnerability to foodborne or 53 had one or more toxic chemicals in excess of
pollutant xenobiotic overload. In this scenario a the adult maximum reference range.
substance as ubiquitous as pyrethrin (a common A recent review by this author explored
ingredient of pesticides) could become neurotoxic, the likelihood of linkages between the variety of
and many commonly-employed pharmaceuticals toxins extant in the modern environment and the
(including Tylenol) could switch from (appar- marked increases in childhood abnormalities.60
ent) friend to foe. Endogenously produced steroid The environment is suffused with organic pollut-
hormones could generate metabolic imbalances ants. Pesticide spraying is still routine in many
with the potential for long-term harm. Depletion school districts. Heavy metals, organohalide pes-
of the endogenous sulfate pool could limit the bio- ticides, herbicides, fumigants, and a wide range
synthesis of necessary substances such as bile ac- of aromatic and aliphatic solvents have been linked
ids (for digestion) or glycosaminoglycans (for to abnormalities in behavior, perception, cogni-
joints and connective tissues). Backed-up dopa- tion, and motor ability during early childhood.
mine and norepinephrine could auto-oxidize to Children exposed acutely or chronically to alumi-
nonspecifically reactive, free radical-type molecu- num, arsenic, cadmium, mercury, or lead are of-
lar species with great potential to damage the ner- ten left with permanent neurological sequelae.
vous system. Lead can cause developmental delay and mental
Cysteine is a known excitatory amino retardation. Studies on lead serve as a model for
acid. In that portion of the population who cannot other toxic metals, and seemingly lead toxicity has
readily transform it to sulfate, there might be real no lower threshold of damage.61
potential for cysteine to become synergistic with The typical modern home is not a clean,
exogenous excitotoxins such as excitatory food protected environment.62 Chemicals embedded in
constituents or anticholinesterase agents and other carpets and wall materials; dust, molds, germs;
neurologically-toxic insecticides, ubiquitous in the lead in paints and radon contamination; pollutants
environment. in the air, water, and foods, all can be toxic to the
Ongoing research into multiple chemical developing infant. Children are especially vulner-
sensitivity, ulcerative colitis, and non-IgE delayed able, due to their relatively immature detoxifica-
food sensitivity, suggests that impaired sulfation tion capacities. Studies of infants prenatally ex-
of ingested phenolics and phenolic food constitu- posed to mere background environmental lev-
ents may well be causally linked with intolerance els of such pollutants consistently report changes
to foods and xenobiotics.51,57,59 in neurodevelopmental parameters.63 Literally all
the residents of industrialized countries now carry
Excessive Accumulation of Xenobiotic measurable amounts of several xenobiotic pollut-
Pollutants ants in breast and other tissues.
Edelson and Cantor reported in 1988 that
a group of 20 autistic children, ages 3-12, exhibited Abnormal Metallothionein Function
abnormal liver detoxification profiles.41 Blood The healthy body carries an array of pro-
analyses for identification of specific xenobiotic teins which naturally chelate, and therefore buffer,
agents revealed toxic overload, defined as zinc, copper, and other redox-active metals.64

Review Autism
group compared to healthy controls matched for

age and gender (p < 0.0001). Walsh asserts that
Table 2. Common Abnormalities 99 percent of ASD cases were affected and that
on Stool and Digestive Analysis copper:zinc imbalance leads to emotional insta-
seen in Autism bility, attention deficit and hyperactivity, neu-
rotransmitter imbalances, and impairment of hip-
pocampus and amygdala function.
1. Digestive function: Deficient Walsh also asserted that elevated toxic
chymotrypsin; fat malabsorption metals are seen in 92 percent of autism cases,
malabsorption in 85 percent, under-methylation
2. Metabolic abnormalities: in 45 percent, over-methylation in 15 percent, and
Imbalanced short-chain fatty pyrrole disorder in 20 percent of cases.65 He dis-
acids, also indicative of possible cussed in depth a number of likely pervasive con-
bacterial imbalance (dysbiosis) sequences for intestinal function, immunity, and
brain function from an overloaded or otherwise
3. Symbiotic beneficial bacteria:
Marker species of Lactobacillus
inadequate MT system examples, MTs appear
and Bifidobacterium often low or to be involved in regulating brain nerve cell growth
lacking, occasionally also E. coli and in the GI production of enzymes that digest
casein and gluten. Walsh also made available pro-
4. Bacterial imbalances: tocols aimed at MT system restoration and over-
Streptococcus species, all management of autism.
Staphylococcus species,
hemolytic E. coli, Enterobacter Organ Abnormalities:
5. Possible pathogens: Candida Gastrointestinal
excess, Blastocystis, Klebsiella, The gastrointestinal system is a central
Bacillus species, Staphylococcus source of symptom triggering in the autistic child
aureus, others and most autistic children have significant GI pa-
thology.66-69 Common symptoms include diarrhea
and/or constipation, abdominal pain, gas, bloat-
ing, and burping and gastro-esophageal reflux.
These are called metallothioneins (MTs), due to Horvath and colleagues70 found reflux esophagi-
their extraordinary metal-binding capability be- tis in 69 percent of an autistic sample, duodenal
cause of the many sulfhydryl (SH) groups they inflammation in 67 percent, low carbohydrate di-
contain. Their synthesis is inducible at the gene gesting enzymes (lactase) in 58 percent, and ab-
level, allowing some adaptation of the system to normal pancreatic response to secretin in 75 per-
increased demand. MTs are the bodys primary cent.
protection against toxic metals Hg, Pb, Cd and
exposures to heavy metals normally lead to their Stool Analysis, Digestive Function,
adaptive up-regulation. Separate MTs guard the Dysbiosis
brain and gastrointestinal tract against heavy metal Stool appearance is often abnormal in
overload. It is likely that MT impairment would ASD, and stool cultures often reveal a variety of
result in imbalances of heavy metals. abnormalities (Table 2).48,71
William Walsh, PhD, at the Pfeiffer Treat- Pathogenic organisms can directly attack
ment Center, examined 503 patients diagnosed the GI tract, but many also generate a variety of
with ASD (318 autistic disorder, 23 Aspergers, toxins (detected by urine organic acid testing) that
162 PDD with autistic features).65 He found a sig- can have systemic effects. Shaw reported finding
nificantly higher copper:zinc ratio in the ASD a wide array of abnormal organic acids in urine

Autism Review
samples from autistic children.72 In one case, a boy intestines, allowing the digestive enzymes later
with apparent regressive autism following re- secreted by the pancreas to work optimally.
peated courses of antibiotics showed abnormally Secretin therapy is under active development for
elevated levels of tartaric acid in the urine. The ASD children with GI pathology. One study found
boy responded positively to treatment with anti- 75 percent of the children had insufficient secretin
fungal medication (Nystatin) and concomitantly production.70
the urine tartaric acid level dropped. The mucus barrier may be poorly formed,
Tartaric acid is a potentially harmful ap- as when glycosaminoglycan (GAG) synthesis is
proved food additive. It can appear in the urine of impaired by metabolic sulfation defects.74 As the
autistic children at very high levels, and the source system functionally fails to cope with certain food
is unclear but Shaw suggests it could be a product constituents such as gluten, casein, or other large
of breakdown of arabinose in the gut. Arabinose proteins or carbohydrates, incompletely digested
is a sweet-tasting aldose sugar that occurs in some fragments are likely to penetrate the mucus bar-
foods, most notably apples. It has the potential to rier and reach the epithelium. There, the Gut-As-
undergo Schiff-type cross-linkage reactions with sociated Lymphoid Tissue (GALT) can be bom-
proteins and thereby disrupt function. Elevated barded with high doses of antigenic or other bio-
urine arabinose has been linked with yeast over- logically active molecules. Past this stage, unless
growth (Candida species). Shaw reported analyz- the GALT system can be protected against such
ing urine from more than 95 autistic children and inappropriate stimulation, frank inflammatory and/
20 age-matched controls and finding the mean or autoimmune damage to the GI lining is initi-
arabinose levels to be five times higher than con- ated. A vicious cycle is generated, whereby the
trols. The data presented was sketchy and no sta- linings integrity is compromised. Using a stan-
tistical analysis was performed.72 Shaw claims dard two-sugar test for intestinal permeability,
when children with abnormally high urine arabi- DEufemia67 documented abnormally increased
nose are treated with antifungal medication, the permeability in 9 of 21 (43%) autistics.
arabinose levels fall. For the autistic child with abnormal GI
Dysbiosis is an almost routine conse- permeability, clinically significant damage may be
quence of antibiotic treatment, commonly used in averted or at least minimized if a gluten-free,
young children for ear and other infections. Many casein-free diet can be implemented. Here, im-
parents have reported their healthy child became provement of symptoms following step-by-step
autistic following a course of antibiotic therapy; elimination of suspect foods is the only real test
Galland documented one instructive case history.73 of success. Improvement with a casein-free diet
A high-sugar/high-carbohydrate diet can encour- can be seen within three weeks and usually pre-
age fungal growth (Candida or other less common dicts success of a gluten-free diet, which often
species) and further contribute to the vicious cycle takes longer than three months.75
of dysbiosis.
Penetration of Opioid Stimulants; the
Intestinal Lining Abnormalities, Leaky Opioid Excess Theory
Gut Panksepp in 1979 proposed an opioid
Inborn or neonatally-acquired weaknesses excess theory of autism. Other researchers have
may predispose to gut lining dysfunction, with found opioid peptides (exorphins, derived from
subsequent impairments of digestive, absorptive, partially-digested food proteins) in the urine of
or barrier functions. Secretin is a small protein autistic individuals.48,76-78 Molecules this size do
(polypeptide) secreted by cells of the small not normally cross the gut mucosa. Reichelt and
intestine. It is a hormone whose function is to colleagues working in Norway reported signifi-
stimulate the pancreas to release bicarbonate, cantly higher levels of exorphins in urine from 315
which creates an alkaline environment in the small autistic children from eight different countries

Review Autism
compared to 143 normal children. The mean lev- intestinal pathology, 10 non-ASD children with
els were almost twice as high in the autistics (p < ileal lymphoid nodular hyperplasia (LNH), 15 with
0.001).78 Crohns disease, and 14 with ulcerative colitis.68
Another group based in the United King- Histology demonstrated lymphocytic colitis in the
dom focused their opioid investigations on pep- ASD children, albeit less severe than classical in-
tide effects on the dopamine transmitter system. flammatory bowel disease (IBD). However, base-
They examined urine from 25 autistic adults and ment membrane thickness and mucosal gamma
found abnormally high levels in 21 of them (84%) cell density were significantly increased over the
when compared to 20 healthy controls. However, other comparison groups, including IBD. Intra-
they found essentially the same pattern in indi- epithelial lymphocyte numbers and CD3, plasma
viduals with other mental handicaps, and ex- cell, and CD8 cell counts were also markedly in-
pressed doubt this finding could be specific for creased. The investigators concluded their find-
autism.79 ings pointed to a lymphocytic enterocolitis in ASD,
Reichelt et al recently updated the opioid possibly skewed in the T-helper 2 (TH2) domi-
excess theory of autism.78 They found exorphin nant (autoimmune) direction.
opioids derived from casein and gluten crossed In a recently published paper, 11 of the
the blood-brain-barrier and caused social indif- same investigators extended this line of inquiry
ference symptoms in experimental animals, as from the colon to the duodenum.69 They compared
well as inability to differentiate essential from non- duodenal biopsies in 25 children with regressive
essential stimuli. They found a peptide in urine autism to 11 with celiac disease, five with cere-
from autistics that increased platelet content of bral palsy and mental retardation, and 18 histo-
serotonin, which is also a common finding in au- logically normal controls. Histology revealed in-
tism. Altered serotonin availability has been linked creased numbers of enterocytes and Paneth cells
to insistence on sameness, reminiscent of ASD. in the autistic children. The duodenal lining also
They attempt to rationalize all the other charac- had increased lymphocyte proliferation, crypt cell
teristics of autism according to this model, sug- proliferation, and more T cells. The investigators
gesting that autism is based in a genetic error of were particularly struck by the finding of increased
peptide digestion, perhaps of the enzyme IgG deposition on the epithelial cell surfaces, ac-
diaminopeptidase IV,72 and that the brain stimu- companied by complement C1q. This novel form
lant activity of the exorphins can explain most, if of enteropathy in the regressed autistic children
not all, autism symptomatology. Further clinical was not seen in the other conditions. The research-
research will establish the relative correctness of ers believe this pattern is suggestive of auto-
this hypothesis. immune lesions and distinctive for autism.
Distinctive Enterocolitis Associated with Organ Abnormalities: Immune

Autism Dysfunction
In 1998, Wakefield and collaborators in There is substantial evidence to suggest
the United Kingdom reported finding measles vi- the immune system plays an important role in the
rus antigens in the intestinal linings of children pathogenesis of autism.66,80,81 All the arms of im-
with autism. They tentatively linked the presence munity are abnormal, and some or all of the ab-
of this antigen to recent measles-mumps-rubella normalities may have a genetic basis.82
(MMR) vaccination.66 This sparked a torrent of Cell-mediated immunity is often
criticism. In 2001 their team of 12 researchers re- abnormal in autism. Abnormalities of
ported on a blinded comparison among 21 con- macrophages, B cells, T cells, and natural killer
secutively evaluated autistic children with bowel (NK) cells have been reported.81 NK cell numbers
disorders (manifesting as abdominal pain with are decreased in approximately 40 percent of these
constipation or diarrhea), eight children without children 83 and CD4+ T cells decreased in

Autism Review
approximately 35 percent.81 Among 20 autistic proinflammatory cytokines (interleukin-1,

children examined in detail by Guptas group, 13 interleukin-6) compared with control children.
of them (65%) had CD4+ helper cells shifted In the Jyonouchi study a majority of the
away from TH1 towards TH2. This generally ASD children (40/71, 56%) and their siblings pro-
indicates a skewing of immune system balance duced abnormally high amounts of TNF- upon
toward autoimmunity. Warrens group had similar physiologic stimulation (Figure 3). A minority of
findings.84 Both findings should be replicated with the ASD children (7/71, 10%) produced abnor-
larger samples. However, the collective data is mally low amounts of TNF-a after stimulation.
strongly consistent with a likelihood of Another 13 percent (9/71) had apparent
autoimmune abnormality in at least a subset of poor regulation of TNF- in that they produced
ASD patients. normal amounts of the TNF- cytokine but ab-
Turning to humoral immunity, serum im- normally low amounts of sTNFRII, a cytokine that
munoglobulin classes and subclasses are often al- normally helps counter-regulate TNF-. In total
tered.81 Complement deficiencies are sometimes 79 percent exhibited aberrant TNF- characteris-
found, especially of the C4B complement pro- tics and 83 percent overproduced one or more of
tein;85 which apparently have a genetic basis.82,86 three proinflammatory cytokines. The investiga-
The healthy digestive tract is coated with tors concluded that a majority of their ASD chil-
mucus that carries high levels of immunoglobulin dren exhibited excessive or poorly regulated in-
A (IgA). Quantitatively, IgA is the most promi- nate immune responses. The study data also indi-
nent immunoglobulin in the body and its rate of cate seemingly healthy siblings may share this ten-
synthesis exceeds that of all the other immuno- dency yet not become autistic.92
globulins combined.87 Warren and collaborators One useful indicator of increased activity
found decreased serum IgA in 8 of 40 (20%) indi- of TNF- and other proinflammatory cytokines
viduals with autism.88 IgA deficiency predisposes is urinary pterin levels (neopterin and biopterin).
to autoimmune disease. These are also predictably raised by autoimmune
The literature suggests that at least a sub- activation in the body. Messahel et al93 analyzed
set, perhaps 35-45 percent, of the autistic popula- urine from 14 AD children, 21 siblings, and 16
tion has pervasive problems with immunity.89 controls. They found significant elevation of both
Autoantibodies to brain have been reported from substances in autistic children, and intermediate
autistic children,90 as well as antibodies directed elevation in their siblings. Their results also con-
against specific neural self-antigens. Guptas firmed that as AD children get older their pterins
group reported finding anti-MBP (myelin basic may be less elevated. These findings were taken
protein) and anti-NAFP (neuron-axon filament to indicate that autoimmune activation may be a
protein) in 50-70 percent of their patients.81,91 In contributing factor in typical or classic autism,
1991, Singh et al reported cytokine and other ab- shared to some degree by nonautistic siblings.
normalities suggestive of autoimmunity. Detractors of this line of investigation ar-
Later research substantiates that cytokine gue autism cannot be inflammatory because char-
profiles can be off-balance in autism. In a small acteristic cellular infiltrates are not found in the
sample Guptas group found tumor necrosis fac- brain, and cannot be autoimmune because demy-
tor-alpha (TNF-), a potent proinflammatory elination has not been found in the brain.94 Actu-
cytokine, was significantly increased.91 In 2001, ally, there are published case reports of demyeli-
Jyonouchi and collaborators reported testing 71 nation in autism, and Burger and Warren87 empha-
ASD children aged 2-14 years and comparing size that many different inflammation-related
them with healthy siblings and other controls.92 mechanisms can be triggered or modulated by
They found 27 of the ASD children (38%) had autoantibodies to damage the autistic brain.
significantly higher levels of TNF- and other

Review Autism
The data on
abnormal immune sys-
tem involvement in Figure 3. TNF- levels Produced by PBMCs
autism is fragmented but
substantial. Further stud- (peripheral blood mononuclear cells) from ASD
ies are needed to clarify Children, Developmentally Normal Healthy Siblings,
the potential etiological and Control Children
contributions from im-
munogenetics, cytokine
imbalances specific to 7000
Medium only LPS (0.1 g/ml)
the brain, and autoim-
mune potential from 6000
autoantibodies against
brain biomolecules. Bet-
ter understanding should 5000
TNF - [pg/ml]
lead to strategies for re-

building or rebalancing 4000
the immune system
3000
Coagulation
Abnormalities
An increasing 2000
number of integrative
physicians report find- 1000
ing coagulation abnor-
malities in their autistic
patients. According to 0
ASD Control Sibling ASD Control Sibling
Jeff Bradstreet, MD and
Jerry Kartzinel, MD,
Many autistic children 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
(and their family mem-
bers) show significant
abnormalities in blood
coagulation. 95 They then adhere to the linings of the capillaries and
suggest lack of oxygenation due to compromised other small vessels to occlude blood flow through
blood supply stemming from coagulation might them.97 Richard Kunin, MD, has also reported
explain some of the symptomatology seen in au- clotting abnormalities in autistic patients. 24
tism. A laboratory panel known as ISAC (Immune Treatment with heparin will usually normalize the
System Activation of Coagulation) may be useful coagulation parameters.
for assessment purposes.96 They also have found
vasospasm to be prevalent in autistic patients. Do Vaccines Cause Autism?
Carol Ann Ryser, MD, has had substantial The issue of whether vaccinations cause
clinical experience with this phenomenon in or contribute to autism is one of the most
chronic fatigue patients, and reports similar controversial and contentious in this field. Those
findings in autism patients. She suggests who advocate a connection note that sharp
inflammation can trigger the conversion of increases in autism prevalence in California
circulating fibrinogen to fibrin deposits, which

Autism Review
(which has 10 percent of the U. S. population) and Transfer of Measles from Vaccine to
the United Kingdom roughly parallel increases in Recipient?
the number of vaccinations given to children until Many parents of autistic children and a
the age of two (currently as many as 32 different number of medical experts believe the MMR vac-
vaccinations are given). They also claim parallels cine is the culprit behind autism. In one in six chil-
with the introduction of the MMR vaccine. dren it causes fever 7-12 days following immuni-
In California a sharp rise in autism began zation, and one in 3,000 develop febrile seizures.98
to be evident in the mid-1980s. A statewide study Thrombocytopenia occurs in one child per 30,000.
published in 1999 reported a 273-346 percent in- Sensory-neural hearing loss and gait disturbance
crease during the period from 1987-1998, depend- has been associated with use of attenuated live
ing on whether the classic Kanner-type diagno- measles vaccine as found in the MMR; joint ar-
sis or the more inclusive autistic spectrum di- thralgia or arthritis has been linked to the rubella
agnosis was applied.4 Rimland makes the point component.99
that when reporting and publication delays are A possible mechanism to connect the
taken into consideration, the reported rise from MMR vaccine with autism was advocated by
1987 may actually have begun as much as five Wakefield and his colleagues in 1998.100 They re-
years earlier, possibly around 1982. This would ported on 12 children who had undergone autis-
place the rise much more proximate to 1978, the tic-type regression soon after they received the
year the MMR vaccine was introduced into Cali- MMR vaccine. These children had gastrointesti-
fornia on a large scale.4 nal symptoms, such as diarrhea and abdominal
Introduction of the MMR vaccine into pain, and histopathological exam of the intestinal
California is also linked to an important change lining seemed to reveal the presence of measles
in the pattern of onset of autism. According to data virus. The cases were classed as a possibly new,
on many thousands of cases, collected since 1965 inflammatory bowel syndrome, and tentatively
by the Autism Research Institute of California, linked to acquisition of measles virus from the
prior to the early 1980s the majority of autism MMR vaccine (albeit attenuated and having mini-
cases had onset at birth. Since that period far more mal infectivity). Another group confirmed the
cases of autism began to manifest around 18 measles strain DNA was consistent with vaccine
months, the time after birth when most children being the source.101
receive the MMR vaccine.4 This study came under sharp criticism on
Contemporary vaccination programs in- many points, including its lack of rigorous con-
volve more than 30 inoculations administered to trols. Nonetheless, its findings were provocative.
the child between the ages of 12 and 24 months.42 Many critics totally dismissed this study, but in
Thus a large number of foreign proteins are intro- 2002 Korvatska and collaborators wrote of the
duced, sometimes as three different attenuated MMR vaccine, ...it is difficult to believe that ex-
viruses in one vaccine (as with MMR). Often there posure to a vaccine may be more severe than to
may be insufficient time between vaccinations for the virus itself. There is still a possibility of unac-
the childs immune response to return to baseline. counted interactions between the three related at-
Side effects of these vaccinations include allergic tenuated viruses during simultaneous infection.42
reactions, autoimmunity, and rarely, full develop-
ment of clinical viral disease (from infection by MMR Vaccine Safety Remains Unproven
attenuated viral particles of the vaccine).42 Some of the defenders of MMR vaccine
were perhaps uninformed that this vaccine was
never subjected to adequate safety assessment
prior 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 any to deny possible connections, uncanny similarities
case, the usual design of prelicensure vaccine tri- exist between the known patterns of mercurys
als fails to generate data on rare reactions (i.e., toxicity to children and those of autism.
less than one per 1,000 doses), reactions with de-
layed onset (i.e., 30 days or more after vaccina- Close Parallels in Mercury and Autism
tions), or reactions in subpopulations. 102 Symptomatologies
Postlicensure evaluation of vaccine safety (after Early in the twentieth century, mercury
it has gone into use) is the only option. was used as a constituent of teething lotions and
However postlicensure reporting of ad- diaper powders. A disease called acrodynia ap-
verse vaccine events has little practical useful- peared in young children and was christened pink
ness.102 It relies on passive reporting a clinician disease because it turned the facial skin pink and
must voluntarily decide to submit a report. Un- simulated blushing. After a long process of denial
der-reporting of such single case events is believed and obfuscation, mercury was confirmed respon-
to be notoriously widespread. Adequately de- sible for pink disease.103 Other information on
signed, prospective studies intended to pursue a mercury toxicity patterns comes from victims of
link between the MMR (or any vaccine) and an mercury-contaminated fish (Japan-Minamata dis-
adverse event pattern are practically nonexistent. ease), grain (Iraq, Guatemala, Russia), or from
Some experts have decried efforts by con- more individualized instances as with Mad
cerned observers to criticize the use of MMR, Hatters disease (named so because beaver hat
sometimes alluding to victimization of the per- makers used mercury in the processing).104-106 The
tussis vaccine in the 1970s. Wakefield made the symptom patterns of these conditions overlap with
important point that the pertussis vaccine did cause those that characterize autism, as summarized in
neurological problems, to the extent of at least 80- two pages of detailed comparisons painstakingly
percent disablement, in about 900 children. Large compiled by Bernard and her colleagues.107
financial compensations were legally assessed100 Scrutinizing these tables of detailed com-
that provided impetus to replace the particular parisons, even the most skeptical and rigorous
vaccine formulation with a safer version. Oppo- observer would be struck by the close resem-
nents of the current MMR vaccine suggest it could blances. The psychiatric and physical disturbances,
be made safer in its triple form, or else split into speech and language deficits, sensory abnormali-
its three components to be given in three sepa- ties, motor disorders, and cognitive impairments
rately spaced shots. of autism, all resemble mercury poisoning. The
Adding to the biological possibilities of similarities continue when looking at the most
vaccine damage comes a toxic possibility the unusual behaviors, for example, movement dis-
deliberate inclusion of toxic mercury in many of turbances that are worse on the right side of the
them. body; over- or under-reaction to sound; and the
flapping motions, originally thought so unique to
A Likely Mercury Connection with autism that they were recommended as a diagnos-
Autism tic marker for the disorder.107
During the same period that autism rates Moving from the clinical expression of
were showing a steep rise, many vaccines autism to its known biological features, again the
(although not the MMR) carried the toxic metal parallels with mercury poisoning are remarkable.
mercury. The vaccine makers chose as a The biochemical abnormalities of autism,
preservative thimerosal, which contains the highly including low glutathione and sulfate levels,
toxic compound ethylmercury. In recent years an abnormal antioxidant enzyme activity,
outcry from parents resulted in reformulation of mitochondrial dysfunctions, and disruptions of
most (although not all) vaccines to exclude purine and pyrimidine metabolism, are all
thimerosal. Although influential parties continue paralleled by mercury toxicity.107 The immune
system parallels include greater propensity to

Autism Review
allergies and asthma and autoimmune health issues, conceded an autism link with mer-
overactivation with skewing toward TH2 cury is biologically plausible, and recommended
imbalance and reduced NK cell function. that thimerosal be removed from vaccines.111
The brain and other central nervous sys-
tem similarities between ASD and mercury toxic- Autistic Children Have Impaired
ity include dysfunction in the amygdala, hippoc- Capacity to Detoxify Mercury
ampus, basal ganglia, and cerebral cortex; destruc- Almost 100 percent of autistic children
tion of neurons from the cerebellum; and brainstem show impaired liver detoxification. Many also
abnormalities. Demyelination is evident in both have poor metallothionein status, therefore low-
conditions. The brains electrical patterns are simi- ered capacity to neutralize mercury and other
larly abnormal, with epileptiform and subtle, low heavy metals. Mercury is a powerful oxidant with
amplitude seizure activities. partial free radical character; it depletes cellular
antioxidants, especially glutathione, the core in-
Temporal Connections Between tracellular protectant.112 The P450 detoxifying
Mercurial Vaccines and Autism enzymes of the liver rely heavily on adequate
In most children affected by autism, symp- availability of glutathione.
toms become noticeable between four and 18 Mercury is also a potent poison to many
months after birth.77 Vaccines containing thime- enzyme systems, especially those that rely on sulf-
rosal with a 50-percent content of ethylmercury hydryl groups for their catalytic activity.106 AT-
typically were given in repeated administrations Pases, ion transport enzymes crucial to cell-level
that began at infancy and continued until 12-18 homeostasis, are highly vulnerable. Mercury binds
months of age. Mercury toxicity typically begins tightly with selenoproteins glutathione peroxi-
gradually, first as sensory- and motor-related prob- dases and other selenium-dependent enzymes
lems, then as speech and hearing deficits, then thereby endangering antioxidant defense. Mercury
progresses into the full panoply of impairments. also has other potentially toxic effects, such as
Mercury was introduced into vaccines in inducing autoantibodies to myelin and other cell
the 1930s, which is approximately when the first constituents, and poisoning mitochondria.112 In
cases of autism were recorded. Between 1970 and fact, mercury is one of the most potent toxins
1990 autism incidence doubled, from one in 2,000 known, involving virtually every known pathway
to one in 1,000, coinciding with the rise of the for inhibition.
DPT vaccines packing thimerosal. In the late
1980s and early 1990s, two new thimerosal vac- New Study Establishes Thimerosal
cines, the HIB (Haemophilus Influenzae Type B) Mercury Link with Cell Killing112
and Hepatitis B, were added to the schedule; per- A new study just being published (August
haps coincidentally, this was about the time the 2002) makes a definitive, mechanistic link be-
sharp increase in autism began.108 Some vaccines tween thimerosal and cell damage or death in the
also contain aluminum,109 which could compound exposed individual. Makani, Gupta, and col-
mercurys toxicity. leagues subjected cultured human T cells (Jurkat)
In the State of California, there is a close to thimerosal. They found thimerosals mercury
correlation between increased autism from the late ingredient (ethylmercury) specifically caused
1980s onward and cumulative mercury exposure apoptosis of these cells. The cells became depleted
through multiple vaccinations.110 The U.S. Cen- of the core antioxidant glutathione, their mitochon-
ters for Disease Control, recipient of public trust dria became decompensated, and the cells died.
for prevention of disease, has admitted that cu- The exposure levels at which thimerosal killed
mulative mercury exposure to children through these human immune cells were low and well
vaccination exceeds known safe exposure lev- within the ranges likely attained in vaccinated
els.108,111 In late 2001, the prestigious Institute of children.
Medicine, which advises the United States on

Review Autism
Skeptics of the mercury theory of autism tative feedback from parents on a variety of drugs,
sometimes inquire, with nearly all U.S. children nutrients, and other treatments. The various treat-
being immunized, why only a few would develop ments were scored, then ranked in terms of the
autism. The experiences with acrodynia/pink dis- ratio of number of autistic children helped to the
ease and other human models of mercury intoxi- number made worse. The first such ranking, from
cation illustrate that the effects of mercury are 318 parent questionnaires, scored vitamin B6 and
highly variable (1,000-10,000-fold) in its effects magnesium as having the best benefit-to-harm
on the individual. Acrodynia, for example, af- ratio.
flicted only one in 500 among children who re- In 1968 the ICBR began to conduct pro-
ceived similar, comparatively low mercury expo- spective studies of vitamin therapy for autism. The
sures.106 Mercury seems to strike harder at certain first study employed large doses of vitamin B6,
genotypes that have higher propensity to autoim- niacinamide, pantothenic acid, and vitamin C, the
mune disorders, of which autism seems to be one four treatments ranked most favorably by the par-
example. Also, low-dose mercury exposure dam- ents.114 Treating 200 children over four months, it
ages far more boys than girls, consistent with the yielded significantly positive results, with vitamin
gender imbalance of autism.113 B6 appearing to provide the most benefit. Subse-
quent trials by the ICBR and other parties found
Parent-Driven Progress in Autism vitamin B6 and magnesium made a particularly
beneficial combination, with no adverse effects.
Management The ICBR has since evolved into the Autism Re-
Following the first definitive report on search Institute (ARI).6 The ARI now has the larg-
autism by Kanner in 1943,1 research on the disor- est database in the world on autism, with upward
der was largely descriptive: symptoms were cata- of 34,000 cases.12 Parents participate in the ARI
logued with efforts made to pinpoint the brain ar- at every level, including research and publication
eas and functions that might be affected. Drugs in peer-reviewed journals.
that had been developed for other applications In 1995 the ARI initiated another break-
were tested for symptom reduction, with little suc- through in autism research and medical manage-
cess. For decades little progress was made, until ment. A conference was convened at which 30
1967 when Bernard Rimland, PhD, founded the scientists and physicians specializing in autism
Institute for Child Behavior Research (ICBR).114 founded Defeat Autism Now! (DAN!). Since then
As a father of an autistic child, Rimland several other conferences have been held, with
understood the need for immediate assistance to consensus reports published, periodic physician
individuals with the disorder. He intensively stud- training manuals, and a manual on biomedical
ied the scientific literature and used the Institute assessment options.7 As with the original ICBR
as an international clearinghouse for information and ARI, the activities of DAN! have once again
on autistic children. He solicited information and sparked further advances in diagnosis and treat-
case reports from parents, who are on the front ment of autism.
lines of the battle against autism; and from health In 1997, the U.S. National Institutes of
professionals, some who also had children with Health (NIH) began a five-year, $42-million net-
autism. Soon the ICBR was able to help parents work of collaborative research programs for au-
to help their children. Drugs did little to help, but tism. In September 2001, construction began on a
intensive, carefully planned, highly structured $39-million state-of-the-art comprehensive clinic
behavior modification did help.114 and research center to diagnose, treat, and study
By 1987 the ICBR had in its data bank children with autism. Located at the University of
detailed case history information on 9,600 autis- California at Davis, it is largely a product of par-
tic children from 40 countries, gleaned from hun- ent advocacy.25 At parents insistence, all the com-
dreds of professionals.114 They had collected more prehensive raw data generated at this facility
than 3,500 completed questionnaires with quanti- Medical Investigation of Neurodevelopmental

Autism Review
Disorders (MIND) Institute will be shared with this review will cover the current state of the art in
autism investigators around the world. autism treatment, which is consolidating into a
model of integrative medical management.
Conclusion
Until recently autism has been a puzzling References
disorder with a limited knowledge base and, as a 1. Kanner L. Autistic disturbances of affective
consequence, its management was largely empiri- contact. Nervous Child 1943;2:217-250.
cal. But now signs have emerged that point toward 2. Bryson SE, Smith IM. Epidemiology of
a possible pattern for this disorder. Hypofunctioning autism: prevalence, associated characteristics,
of the brains temporal lobe regions, leading to com- and implications for research and service
delivery. Ment Retard Dev Disabil Res Rev
promise of this regions networking with other re- 1998;4:97-103.
gions, can account for the core neurological symp-
3. Persson B. Brief report: A longitudinal study
tomatology. Pervasive detoxification impairments, of quality of life and independence among
documented in a high percentage of children with adult men with autism. J Autism Dev Disord
the disorder, are consistent with the abnormally high 2000;30:61-66.
xenobiotic load they carry and their heightened 4. Rimland B. The autism epidemic, vaccina-
susceptibility to mercury, aluminum, and other toxic tions, and mercury. J Nutr Environ Med
metals. Poor systemic detoxification performance 2000;10:261-266.
may account for the apparent abnormal autoim- 5. Shavelle RM, Strauss DJ, Pickett J. Causes of
mune tendency in this population. death in autism. J Autism Dev Disord
2000;31:569-576.
The autistic child may be a casualty of the
6. Autism Research Institute (ARI), 4182 Adams
toxicity of modern society. Potential triggering fac-
Avenue, San Diego, CA 92116, USA; 2002.
tors such as antibiotic overdosing, overvaccination, www.autismresearchinstitute.com
and prenatal xenobiotic overload could interact with 7. DAN! (Defeat Autism Now!). Conference
each other and with a high heritability component proceedings, consensus reports, medical
to account for the development of dysbiosis, leaky assessment protocols. Autism Research
gut, and other GI abnormalities known to fuel sys- Institute, San Diego, CA 92116, USA; 2002.
temic autoimmune reactivity. These and other trig- www.autismresearchinstitute.com
gers are so broadly threatening to human metabo- 8. Hashimoto T, Tayama M, Murakawa K, et al.
lism that they could also account for virtually all Development of the brainstem and cerebellum
in autistic patients. J Autism Dev Disord
the other abnormalities seen in autistic spectrum 1995;25:1-18.
disorders. Whether any one cause of autism will
9. Lord C, Cook EH, Leventhal BL, Amaral DG.
be established remains an open question; as the Autism spectrum disorders. Neuron
research deepens the theory of opioid excess will 2000;28:355-363.
compete with other theories. 10. Tuchman RF, Rapin I, Shinnar S. Autistic and
Much new research needs to be conducted dysphasic children. I: Clinical characteristics.
on autism before this putative pattern can be fully Pediatrics 1991;88:1211-1218.
confirmed. Many parents feel they cannot afford 11. Cohen DJ, Volkmar FR. Handbook of Autism
to wait for the normally snails-paced progression and Pervasive Developmental Disorders. New
of good science. Thus (to their credit) they are driv- York: Wiley; 1997.
ing the pace of research into this devastating disor- 12. Treffert DA, Wallace GL. Islands of genius.
Artistic brilliance and a dazzling memory can
der. The limited, fragmentary data of today could
sometimes accompany autism and other
soon become a body of knowledge that would al- developmental disorders. Sci Am 2002;286:76-
low for fuller confidence in detailed management 85.
protocols. Crucial challenges, such as a better neu- 13. Prior M, Ozonoff S. Psychological factors in
rological grounding of the disorders subtypes, autism. In: Volkmar FR, ed. Autism and
could be overcome within a few years. Part 2 of Pervasive Developmental Disorders. Cam-
bridge: Cambridge University Press; 1998.

Review Autism
14. Baron-Cohen S, Bolton P, Whellwright S. 30. Kemper TL, Bauman M. Neuropathology of

Autism occurs more often in families of infantile autism. J Neuropathol Exp Neurol
physicists, engineers, and mathematicians. 1998;57:645-652.
Autism 1995;2:296-301. 31. Sweeten TL, Posey DJ, Shekhar A, McDougle
15. Teitelbaum P, Teitelbaum O, Nye J, et al. CJ. The amygdala and related structures in the
Movement analysis in infancy may be useful pathophysiology of autism. Pharmacol
for early diagnosis of autism. Proc Natl Acad Biochem Behav 2002;71:449-455.
Sci U S A 1998;95:13982-13987. 32. Boddaert N, Zilbovicius M. Functional
16. Lord C, Risi S. Frameworks and methods in neuroimaging and childhood autism. Pediatr
diagnosing autism spectrum disorders. Ment Radiol 2002;32:1-7.
Retard Dev Disabil Res Rev 1998;4:90-96. 33. Zilbovicius M, Garreau B, Samson Y, et al.
17. Rutter M, Greenfeld D, Lockyer L. A five to Delayed maturation of the frontal cortex in
fifteen year follow-up study of infantile childhood autism. Am J Psychiatry
psychosis. II. Social and behavioural outcome. 1995;152:248-252.
Br J Psychiatry 1967;113:1183-1199. 34. Zilbovicius M, Boddaert N, Belin P, et al.
18. Dennis M. Acquired disorders of language in Temporal lobe dysfunction in childhood
children. In: Feinberg TE, Farah MJ, eds. autism: a PET study. Positron emission
Behavioral Neurology and Neuropsychology. tomography. Am J Psychiatry 2000;157:1988-
New York: McGraw-Hill; 1996. 1993.
19. Coleman M, Gillberg C. The Biology of the 35. Ohnishi T, Matsuda H, Hashimoto T, et al.
Autistic Syndromes. New York: Praeger; 1985. Abnormal regional cerebral blood flow in
20. Klin A. Auditory brainstem responses in childhood autism. Brain 2000;123:1838-1844.
autism: brainstem dysfunction or peripheral 36. Chugani HT, Da Silva E, Chugani DC.
hearing loss? J Autism Dev Disord Infantile spasms: III. Prognostic implications
1993;23:15-35. of bitemporal hypometabolism on positron
21. Fombonne E. The epidemiology of autism: a emission tomography. Ann Neurol
review. Psychol Med 1999;29:769-786. 1996;39:643-649.
22. London E. CDC findings in Brick township: 37. Garreau B, Zilbovicius M, Guerin P, et al.
autism spectrum disorders 1 per 150 children. Effects of auditory stimulation on regional
Naritive 2000;Summer:16-17. cerebral blood flow in autistic children. Dev
Brain Dysfunct 1994;7:119-128.
23. Baker SM. Clinical strategies in autism. In:
Rimland B, ed. DAN! (Defeat Autism Now!) 38. Muller RA, Behen ME, Rothermel RD, et al.
Spring 2002 Conference Practitioner Training. Brain mapping of language and auditory
San Diego, CA: Autism Research Institute; perception in high-functioning autistic adults:
2002. www.autismresearchinstitute.com a PET study. J Autism Dev Disord 1999;29:19-
31.
24. Kunin RA. Personal communication. San
Francisco, CA: Medical Practice; 2002. 39. Boddaert N, Belin P, Poline JB, et al. Temporal
lobe dysfunction in childhood autism: a PET
25. Stokstad E. Development. New hints into the auditory activation study (Abstract). Pediatr
biological basis of autism. Science Radiol 2001;31:S3.
2001;294:34-37.
40. Baron-Cohen S, Ring HA, Wheelwright S, et
26. Frith U, Happe F. Autism: beyond theory of al. Social intelligence in the normal and
mind. Cognition 1994;50:115-132. autistic brain: an fMRI study. Eur J Neurosci
27. Russell J. How executive disorders can bring 1999;11:1891-1898.
about an inadequate theory of mind. In: 41. Edelson SB, Cantor DS. Autism: xenobiotic
Russell J, ed. Autism as an Executive Disorder. influences. Toxicol Ind Health 1998;14:799-
Oxford: Oxford University Press; 1997.
811.
28. Bennetto L, Pennington BF, Rogers SJ. Intact 42. Korvatska E, Van de Water J, Anders TF,
and impaired memory functions in autism. Gershwin ME. Genetic and immunologic
Child Dev 1996;67:1816-1835.
considerations in autism. Neurobiol Dis
29. Baron-Cohen S, Leslie AM, Frith U. Does the 2002;9:107-125.
autistic child have a theory of mind?
Cognition 1985;21:37-46.

Autism Review
43. Rutter M. The Emanuel Miller Memorial 57. OReilly BA, Waring RH. Enzyme and sulphur
Lecture 1998. Autism: Two-way interplay oxidation deficiencies in autistic children with
between research and clinical work. J Child known food/chemical intolerances. J Orthomol
Psychol Psychiatry 1999;40:169-188. Med 1993;8:198-200.
44. Rimland B. Infantile Autism. New York: 58. Alberti A, Pirrone P, Elia M, et al. Sulphation
Appleton-Century-Crofts; 1964. deficit in low-functioning autistic children: a
45. Rodier PM, Bryson SE, Welch JP. Minor pilot study. Biol Psychiatry 1999;46:420-424.
malformations and physical measurements in 59. Waring RH. Biochemical parameters in autistic
autism: data from Nova Scotia. Teratology children. Dev Brain Dysfunc 1997;10:40-43.
1997;55:319-325. 60. Kidd PM. Attention deficit/hyperactivity
46. Stromland K, Miller MT. Thalidomide disorder (ADHD) in children: rationale for its
embryopathy: revisited 27 years later. Acta integrative management. Altern Med Rev
Ophthalmol 1993;71:238-245. 2000;5:402-428.
47. Rodier PM. The early origins of autism. Sci 61. Schwartz J. Low-level lead exposure and
Am 2000;282:56-63. childrens IQ: a meta-analysis and search for a
48. Pangborn JB, Baker SM. Biomedical Assess- threshold. Environ Res 1994;65:42-55.
ment Options for Children with Autism and 62. Rapp DJ. Is This Your Childs World? New
Related Problems. San Diego, CA: Autism York, NY: Bantam Books; 1996.
Research Institute; 2001. 63. Colborn T, Dumanoski D, Myers JP. Our
www.autismresearchinstitute.com Stolen Future: Are We Threatening Our
49. Whitaker-Azmitia PM. Serotonin and brain Fertility, Intelligence, and Survival? New
development: role in human developmental York, NY: Plume/Penguin Books; 1997.
diseases. Brain Res Bull 2001;56:479-485. 64. Deneke SM. Thiol-based antioxidants. Curr
50. Warren RP, Singh VK. Elevated serotonin Top Cell Regul 2000;36:151-180.
levels in autism: association with the major 65. Walsh W. Metallothionein promotion therapy
histocompatibility complex. in autism spectrum disorders. In: Rimland B,
Neuropsychobiology 1996;34:72-75. ed. DAN! (Defeat Autism Now!) Spring 2002
51. McFadden SA. Phenotypic variation in Conference Practitioner Training. San Diego,
xenobiotic metabolism and adverse environ- CA: Autism Research Institute; 2002.
mental response: focus on sulfur-dependent www.autismresearchinstitute.com
detoxification pathways. Toxicology 66. Wakefield AJ, Murch SH, Anthony A, et al.
1996;111:43-65. Ileal-lymphoid-nodular hyperplasia, non-
52. Mitchell SC, Waring RH. Variation in the S- specific colitis, and pervasive developmental
oxidation of cysteine derivatives. In: Kalow W, disorder in children. Lancet 1998;351:637-
ed. Pharmacogenetics of Drug Metabolism. 641.
New York: Pergamon Press;1992. 67. DEufemia P, Celli M, Finocchiaro R, et al.
53. Mitchell SC, Waring RH. The deficiency of Abnormal intestinal permeability in children
sulfoxidation of S-carboxymethyl-L-cysteine. with autism. Acta Paediatr 1996;85:1076-
Pharmacol Ther 1989;43:237-249. 1079.
54. Davies MH, Ngong JM, Yucesoy M, et al. The 68. Furlano RI, Anthony A, Day R, et al. Colonic
adverse influence of pregnancy upon CD8 and gamma delta T-cell infiltration with
sulphation: a clue to the pathogenesis of epithelial damage in children with autism. J
intrahepatic cholestasis of pregnancy? J Pediatr 2001;138:366-372.
Hepatol 1994;21:1127-1134. 69. Torrente F, Ashwood P, Day R, et al. Small
55. Davies MH, Klovrza L, Waring RH, Elias E. intestinal enteropathy with epithelial IgG and
Plasma cysteine and sulphate levels in patients complement deposition in children with
with cirrhosis of the liver. Clin Sci regressive autism. Mol Psychiatry 2002;7:375-
1994;87:357-362. 382.
56. Levy G. Sulfate conjugation in drug metabo- 70. Horvath K, Papadimitriou JC, Rabsztyn A, et
lism: role of inorganic sulfate. Fed Proc al. Gastrointestinal abnormalities in children
1986;45:2235-2240. with autistic disorder. J Pediatr 1999;135:559-
563.

Review Autism
71. Great Smokies Diagnostic Laboratory. 83. Warren RP, Foster A, Margaretten NC.
Comprehensive Digestive Stool Analysis Reduced natural killer cell activity in autism. J
(CDSA). Asheville, NC: Great Smokies Am Acad Child Adolesc Psychiatry
Diagnostic Laboratory; 2002. www.gsdl.com 1987;26:333-335.
72. Shaw W, ed. Biological Treatments for Autism 84. Warren RP, Margaretten NC, Pace NC, Foster
and PDD. Lenexa, KS: The Great Plains A. Immune abnormalities in patients with
Laboratory, Inc.; 2002. autism. J Autism Dev Disord 1986;16:189-197.
www.greatplainslaboratory.com 85. Warren RP, Burger RA, Odell D, et al. De-
73. Galland L. Superimmunity for Kids. New York, creased plasma concentrations of the C4B
NY: Copestone Press/Dell; 1998. complement protein in autism. Arch Pediatr
74. Waring RW. Autism, sulphonation and Adolesc Med 1994;148:180-183.
cytokines. In: Rimland B, ed. DAN! (Defeat 86. Warren RP, Singh VK, Cole P, et al. Possible
Autism Now!) Spring 2002 Conference association of the extended MHC haplotype
Practitioner Training. San Diego, CA: Autism B44-SC30-DR4 with autism. Immunogenetics
Research Institute; 2002. 1992;36:203-207.
www.autismresearchinstitute.com 87. Burger RA, Warren RP. Possible immunoge-
75. Seroussi K. Following a different path. A netic basis for autism. Ment Retard Dev
childs documented recovery from autism. In: Disabil Res Rev 1998;4:137-141.
Shaw D, ed. Biological Treatments for Autism 88. Warren RP, Odell JD, Warren WL, et al. Brief
and PDD. Lenexa, KS: The Great Plains report: immunoglobulin A deficiency in a
Laboratory, Inc.; 2002. subset of autistic subjects. J Autism Dev
www.greatplainslaboratory.com Disord 1997;27:187-192.
76. Panksepp J. A neurochemical theory of autism. 89. Singh VK, Warren RP, Odell JD, Cole P.
TINS (Trends Neurochem Sci) 1979;July:174- Changes of soluble interleukin-2, interleukin-2
177. receptor, T8 antigen, and interleukin-1 in the
77. Gillberg C, Coleman M. The Biology of the serum of autistic children. Clin Immunol
Autistic Syndromes. London: Mac Keith Immunopathol 1991;61:448-455.
Press;1992. 90. Singh VK, Fudenberg HH, Emerson D,
78. Reichelt KL, Knivsberg AM. Can the patho- Coleman M. Immunodiagnosis and immuno-
physiology of autism be explained by discov- therapy in autistic children. Ann N Y Acad Sci
ered urine peptides? In: Rimland B, ed. DAN! 1988;540:602-604.
(Defeat Autism Now!) Spring 2002 Conference 91. Gupta S, Aggarwal S, Heads C. Dysregulated
Practitioner Training. San Diego, CA: Autism immune system in children with autism:
Research Institute; 2002. beneficial effects of intravenous immune
www.autismresearchinstitute.com globulin on autistic characteristics. J Autism
79. Shattock P, Kennedy A, Rowell F, et al. Role Dev Disord 1996;26:439-452.
of neuropeptides in autism and their relation- 92. Jyonouchi H, Sun S, Le H. Proinflammatory
ships with classical neurotransmitters. Brain and regulatory cytokine production associated
Dysfunct 1990;3:328-345. with innate and adaptive immune responses in
80. Bock KA. Integrative approach to autism children with autism spectrum disorders and
spectrum disorders. In: Rimland B, ed. DAN! developmental regression. J Neuroimmunol
(Defeat Autism Now!) Spring 2002 Conference 2001;120:170-179.
Practitioner Training. San Diego, CA: Autism 93. Messahel S, Pheasant AE, Pall H, et al.
Research Institute; 2002. Urinary levels of neopterin and biopterin in
www.autismresearchinstitute.com autism. Neurosci Lett 1998;241:17-20.
81. Gupta S. Immunological treatments for autism. 94. Zimmerman AW. Commentary: immunological
J Autism Dev Disord 2000;30:475-479. treatments for autism: in search of reasons for
82. Warren RP, Singh VK, Cole P, et al. Increased promising approaches. J Autism Dev Disorder
frequency of the null allele at the complement 2000;30:481-484.
C4b locus in autism. Clin Exp Immunol
1991;83:438-440.

Autism Review
95. Bradstreet J, Kartzinel J. Biological interven- 109. Yokel RA, McNamara PJ. Aluminum
tions in the treatment of autism and PDD. In: toxicokinetics: an updated minireview. J
Rimland B, ed. DAN! (Defeat Autism Now!) Pharmacol Toxicol 2001;88:159-167.
Fall 2001 Conference. San Diego, CA: Autism 110. Blaxill M, quoted in Holmes, A. Heavy metal
Research Institute; 2001. toxicity in autistic spectrum disorders. Mer-
www.autismresearchinstitute.com cury. In: Rimland B, ed. DAN! (Defeat Autism
96. Hemex Laboratories. ISAC (Immune System Now!) Fall 2001 Conference. San Diego, CA:
Activation of Coagulation) Panel. Phoenix, Autism Research Institute; 2001.
CA: Hemex Laboratories; 2002. www.autismresearchinstitute.com
www.hemex.com 111. Rimland B. 1. Institute of Medicine now says
97. Ryser CA, MD. Personal communication. autism-mercury link biologically plausible;
Kansas City, MO: Health Centers of America; 2. Centers for Disease Control (CDC) kept
2002. evidence secret. San Diego, CA: Autism
98. Duclos P, Ward BJ. Measles vaccines: a review Research Institute, Autism Res Review Interna-
of adverse events. Drug Saf 1998;19:435-454. tional; 2001. www.autismresearchinstitute.com
99. Shoenfeld Y, Aron-Maor A. Vaccination and 112. Makani S, Gollapudi S, Yel L, et al. Biochemi-
autoimmunity vaccinosis: a dangerous cal and molecular basis of thimerosal-induced
liaison? J Autoimmun 2000;14:1-10. apoptosis in T cells. Genes and Immunity
2002; in press (August).
100. Wakefield AJ. Letter to the editor. Lancet
1998;351:908. 113. Grandjean P, Weihe P, White RF, Debes F.
Cognitive performance of children prenatally
101. Kawashima H, Mori T, Kashiwagi Y, et al. exposed to safe levels of methylmercury.
Detection and sequencing of measles virus
Environ Res 1998;77:165-172.
from peripheral mononuclear cells from
patients with inflammatory bowel disease. Dig 114. Rimland B. Controversies in the treatment of
Dis Sci 2000;45:723-729. autistic children: vitamin and drug therapy. J
Child Neurol 1988;3:S68-S72.
102. Chen RT, DeStefano F, Pless R, et al. Chal-
lenges and controversies in immunization
safety. Infect Dis Clin North Am 2001;15:21-
39.
103. Warkany J, Hubbard DH. Acrodynia and
mercury. J Pediatr 1953;42:365-386.
104. Amin-Zaki L, Majeed MA, Elhassani SB, et al.
Prenatal methylmercury poisoning. Clinical
observations over five years. Am J Dis Child
1979;133:172-177.
105. OCarroll RE, Masterson G, Dougall N, et al.
The neuropsychiatric sequelae of mercury
poisoning. The Mad Hatters disease revisited.
Br J Psychiatry 1995;167:95-98.
106. Clarkson TW. The toxicology of mercury. Crit
Rev Clin Lab Sci 1997;34:369-403.
107. Bernard S, Enayati A, Redwood L, et al.
Autism: a novel form of mercury poisoning.
Med Hypotheses 2001;56:462-471.
108. Holmes A. Heavy metal toxicity in autistic
spectrum disorders. Mercury. In: Rimland B,
ed. DAN! (Defeat Autism Now!) Fall 2001
Conference. San Diego, CA: Autism Research
Institute; 2001.
www.autismresearchinstitute.com


292 Autism, An Extreme Challenge For Integrative Medicine. Part I

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

292 Autism, An Extreme Challenge For Integrative Medicine. Part I

Enviado por

Direitos autorais:

Formatos disponíveis

Autism Review

Abstract inflammation and autoimmunity. Coagulation

Page 292 Alternative Medicine Review Volume 7, Number 4 2002

Autism has become epidemic in the in- Diagnosis, Classification, Epidemic

Alternative Medicine Review Volume 7, Number 4 2002 Page 293

Page 294 Alternative Medicine Review Volume 7, Number 4 2002

Alternative Medicine Review Volume 7, Number 4 2002 Page 295

Page 296 Alternative Medicine Review Volume 7, Number 4 2002

have been reported in the

Alternative Medicine Review Volume 7, Number 4 2002 Page 297

Page 298 Alternative Medicine Review Volume 7, Number 4 2002

Alternative Medicine Review Volume 7, Number 4 2002 Page 299

Page 300 Alternative Medicine Review Volume 7, Number 4 2002

Alternative Medicine Review Volume 7, Number 4 2002 Page 301

Page 302 Alternative Medicine Review Volume 7, Number 4 2002

group compared to healthy controls matched for

Alternative Medicine Review Volume 7, Number 4 2002 Page 303

Page 304 Alternative Medicine Review Volume 7, Number 4 2002

Distinctive Enterocolitis Associated with Organ Abnormalities: Immune

Alternative Medicine Review Volume 7, Number 4 2002 Page 305

approximately 35 percent.81 Among 20 autistic proinflammatory cytokines (interleukin-1,

Page 306 Alternative Medicine Review Volume 7, Number 4 2002

lead to strategies for re-

Alternative Medicine Review Volume 7, Number 4 2002 Page 307

Page 308 Alternative Medicine Review Volume 7, Number 4 2002

Alternative Medicine Review Volume 7, Number 4 2002 Page 309

Page 310 Alternative Medicine Review Volume 7, Number 4 2002

Alternative Medicine Review Volume 7, Number 4 2002 Page 311

Page 312 Alternative Medicine Review Volume 7, Number 4 2002

14. Baron-Cohen S, Bolton P, Whellwright S. 30. Kemper TL, Bauman M. Neuropathology of

Alternative Medicine Review Volume 7, Number 4 2002 Page 313

Page 314 Alternative Medicine Review Volume 7, Number 4 2002

Alternative Medicine Review Volume 7, Number 4 2002 Page 315

Page 316 Alternative Medicine Review Volume 7, Number 4 2002

Você também pode gostar