excitotoxicity autism disorders: Russell L. Blaylock, MD: Part 1/2:
Murray 7.10.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1010

http:www.dorway.com/blayautism.txt
The Central Role of Excitotoxicity in Autism Spectrum Disorders
Russell L. Blaylock, MD 601-982-1175 Madison, Mississippi

Introduction
In this discussion I shall define autism spectrum disorders as a group
of disorders of higher cortical function ranging from attention deficit
disorder to full blown autism itself. Despite divisions into numerous
individually named disorders, Asperger’s, high autism, attention deficit
hyperactivity disorder, etc, many feel that they represent a spectrum of
related cognitive disorders. I do this recognizing that clinically,
several may have characteristics that make them significantly different
from the others. Recognizing these differences, I shall discuss their
special physiology and biochemistry as the need arises.

Recent evidence indicates that most neurological disorders, both acute
and chronic, have a common set of pathological events despite their
varying clinical presentation. 1 At the center of this process is what
has become known as excitotoxicity. Named in 1969 by Dr. John Olney,
excitotoxicity is a phenomenon characterized by the triggering of
neuronal excitation through over-stimulation of susceptible neurons by
the excitatory amino acids, primarily glutamate and aspartate.2

Using cloning techniques, scientists have characterized five sets of
excitatory receptors that include NMDA, AMPA, kainate and two
metabotrophic type receptors.3 We know the most about the NMDA receptor,
which controls a voltage-gated calcium channel. Clustered around the
calcium channel are various regulator receptors, including the zinc and
magnesium sites that modulate the channel, so as to prevent over-
activation, and a glycine receptor which enhances the signal during NMDA
receptor activation. A phencyclidine receptor powerfully inhibits the
opening of the calcium channel.

Glutamate is the most abundant neurotransmitter in the central nervous
system, yet it is also the most neurotoxic. It is for this reason that
its concentration outside the neuron is so carefully controlled. This
control is maintained by a family of glutamate transport proteins, which
attach to the transmitter soon after its release. Soon after it is
transported it to a nearby astrocyte, where it is deposited.4

Excess levels of glutamate, or other excitatory molecules, allow the
calcium channel to remain open for a relatively long period of time.
Calcium excess in the cytosol of the cell triggers the activation of
inducible nitric oxide synthase and protein kinase C. The iNOS produces
NO in excess, which begins to accumulate within the cell. When NO
combines with the superoxide radical it forms the very destructive
peroxynitrite radical. This radical is particularly injurious to the
mitochondria, the chief source of energy for the neuron.5

At the same time, protein kinase C then activates phospholipase A2
within the neuron membrane, which brings about the release of
arachidonic acid into the cytosol. Here the arachidonic acid is acted on
by two enzymes, lipoxygenase and cyclooxygenase, which produce a series
of potentially destructive eicosanoids. Of particular concern is the COX
II enzyme, which brings about the accumulation of PGE2 and PGD2, both
pro-inflammatory molecules. Interestingly, only glutamatergic neurons
contain COX II enzymes, which are located on distal dendrites and are
concentrated in dendritic spines.6

The accumulation of inflammatory eicosanoids leads to the production of
free radicals, including the very destructive hydroxyl radical. As the
process accelerates, the free radicals interact with the neuron’s
numerous membrane structures, including nuclear, mitochondrial and
cellular membranes. Once this process begins, a chain reaction within
the membrane’s polyunsaturated fatty acids is initiated, a process we
call lipid peroxidation.

Numerous by-products are produced during lipid peroxidation, including
the production of several aldehydic products. While the most abundant of
these LPO products is malondialdhyde ( MDA), most destructive is a
product called 4-hydroxynonenal.7 Recent research has shown that 4-HNE
can produce extensive damage to the cell, including the prevention of
dephosphorylation of excessively phosphorylated tau protein,
significantly interfering with microtubule function.8 It has also been
shown to inhibit glutathione reductase, which is needed to convert
oxidized glutathione to its functional reduced form.9 It has been
demonstrated that children with active autoimmune diseases have
significantly higher blood levels of 4-HNE than controls. 10

It is also known that 4-HNE can conjugate to synaptic proteins, where it
impairs the transport of both glucose and glutamate. 11 This process is
especially dangerous because several studies have shown that impaired
energy supplies markedly enhances glutamate sensitivity. In fact, under
such conditions, even normal levels of glutamate can produce
neurotoxicity. 12 Peroxynitrite, by damaging mitochondrial membranes,
DNA and electron transport enzymes, can also significantly reduce
neuronal energy production. 13

It is known that numerous pathological events can trigger
excitotoxicity, including ischemia, hypoxia, hypoglycemia, viral and
bacteriological pathogens, toxic metals, trauma, autoimmune diseases,
and free radical excess. It should also be recognized that there is an
intimate relationship between excitotoxicity and free radical
generation. Free radicals precipitate the release of glutamate in the
brain and excitotoxins trigger the productions of large amounts of free
radicals, both of the oxygen and nitrogen species.

While this review of excitotoxicity is not complete it will provide the
reader with a better understanding of the process.

Seizures, Autism and Excitotoxicity
It has been recognized that seizures are fairly common with several of
the autism spectrum disorders. Approximately one third of autistic
children have definable seizures or abnormal EEG seizure foci.14 Overt
seizures are not necessary for regression. In many cases, abnormal EEG
seizure foci have been found in the absence of clinical seizures.15
These abnormal seizure foci, with and without clinical seizures, are
seen more commonly in autistic children who regress.

Childs and Blair reported dramatic improvements after treatment with
valproic acid in a pair of autistic twin boys who were found at age
three to have absence seizures.16 The parents, on reflection, recalled
symptoms consistent with seizures occurring at age two. These boys had
symptoms characteristic of autism, including perseverative, non-
purposeful and self-stimulatory behavior, a lack of symbolic play, poor
eye contact, echolalic and non-communicative speech and a lack of
response to discipline.

In some autistic children one finds evidence of tuberous sclerosis, a
condition associated with a high incidence of seizure disorders.17
Approximately 25% of children with tuberous sclerosis will be autistic.
If you add pervasive developmental disorder the incidence increases to
40 to 45%. Among autistic children 1 to 4% will also have tuberous
sclerosis. The incidence increases to 8 to 14% in autistic children with
seizures.

There is evidence that seizure foci in autistic children have been
grossly underdiagnosed. In a recent study of children with Landeau
Kleffner syndrome (LKS) as compared to autistic children with
regression, researchers using a highly sensitive magnetoencephalographic
technique ( MEG), found that out of 50 autistic children examined during
stage II sleep, 82% demonstrated eipleptiform activity in the same
region of the brain as seen in Landeau Kleffner syndrome.18 The
difference in the two groups was that the LKS children demonstrated no
epileptiform activity outside the left intra/perisylvian area whereas
75% of the regressive autistic children demonstrated seizure foci with
independent activity, outside this area. The LKS children demonstrated
propagation of the seizure to frontal and parietal regions on occasions,
which could explain associated difficulties with socialization and
behavior.

During the examinations, standard EEG recordings were done
simultaneously with the magnetoencephalographic recordings. While the
MEG recordings demonstrated abnormal activity in 85% of cases combined,
the standard EEG recordings demonstrated problems in only 68% of cases.
This indicates that significant abnormalities are being overlooked
during routine examinations. It is also possible that depth electrode
recordings would detect even more abnormalities in subcortical areas,
such as the amygdala and septal areas.

That a persistent seizure focus discharge is pathologically damaging is
graphically shown in the case of Landeau Kleffner syndrome. In this
disorder, a persistent seizure focus results in a progressive loss of
language function and social interaction, both higher cognitive
functions. Of particular concern is that the seizures usually occur at
nighttime and are very difficult to recognize by the parents or doctors,
as we have seen. Recovery of language function depends on early seizure
control.

Another graphic demonstration of the connection between seizures,
glutamate accumulation and cognitive deterioration is seen in the case
of pyrodoxine-sensitive seizure in newborns. It has been shown that in
the untreated child, CSF glutamate levels are 200X normal and seizures
are uncontrollable.19 When given an intermediate dose of 5mg/kg/BW/day
of pyrodoxine, the seizures cease, but mental deterioration continues.
Glutamate levels at this dose were still 10X higher than normal. When
using pyrodoxine at 10 mg/kg/BW/day there were no seizures, no cognitive
deterioration, and glutamate levels are normal. It is interesting to
note that some reported cases of pyridoxine-dependent seizures also had
features of autism.20

While most cases of pyridoxine-dependent seizures are present at birth,
cases have been reported that experienced their initial onset as late as
14 months after birth.21 It has been suggested that pyridoxine-dependent
seizures are more common than is being reported, and that neurological
deterioration can occur in the absence of seizures.22 A wide array of
neurological symptoms can be seen on the basis of excitotoxic lesions
produced with this syndrome, including, visual agnosia, squint, severe
articulatory apraxia, and motor delay. We also know that the excitotoxic
process associated with this syndrome can produce physical changes in
the brain as seen on MRI and CT scans, usually with cortical and
subcortical atrophy and progressive ventricular dilitation.23


Another demonstration of the importance of glutamate in seizure
pathology comes from the study by Mathern and co-workers who
demonstrated increased NMDA receptor content in cases of temporal lobe
epilepsy associated with mesial hippocampal sclerosis, indicating
dentate granule cell hyperexcitability.24 Others have shown degeneration
of dendritic connections in epileptic hippocampal neurons characteristic
of excitotoxicity. 25 Interestingly, a recent study found that the
anatomic substrate of the limbic system, which included the subiculum/
CA1-CA3 area and the dentate gyrus/ CA4 area, was smaller in autistic
subjects than matched controls.26 This.

It has been observed that a percentage of autistic children improve when
supplemented with zinc. It is known that the temporal lobes have the
highest zinc content in the brain and that zinc plays a major role in
reducing NMDA excitability.27 Zinc has also been found to reduce dentate
granule cell hyperexcitability in epileptic humans.28

It is now known from experimental studies that seizures are intimately
connected to the excitotoxic process.29 Not only can glutamate and
aspartate precipitate seizures, especially when injected into the brain,
but seizures themselves can stimulate the release of excitatory amino
acids from the brain, most likely by stimulating free radical
generation. Spontaneously discharging neurons, especially when the
process is prolonged, are associated with energy loss, ischemia, and
hypoxia, all of which precipitate excessive release of glutamate.

There is considerable evidence that excitotoxicity is responsible for
much of the pathological damage produced by prolonged seizures.30,31
This destructive process has been proposed as the mechanism for both the
mirror focus seen with temporal lobe seizures and the cognitive
deterioration associated with status epilepiticus. Cytopathological
changes have been described in the hippocampus following prolonged
seizures that closely resemble excitotoxic damage, with destruction of
neurons in the CA1 and CA3 areas, and dendritic swelling in the hilus of
the fascia dentata, as seen with cases of autism.

Recent studies have shown that ketamine, a powerful NMDA receptor
antagonist, can powerfully inhibit seizures, including status
epilepticus.32 Of particular concern is the excitotoxic damage produced
during limbic status epilepticus, a common form of epilepsy seen in
autism spectrum disorders, and which may explain the above mentioned
limbic atrophy in autism.33

Another excitotoxic substance associated with seizures is quinolinic
acid.34 This excitotoxin is important for two reasons. First, it is a
metabolic product of serotonin breakdown, and second it is released from
both astrocytes and microglia when these cells are activated by various
stimuli. Quinolinic acid acts at the NMDA receptor and, like glutamate,
its activity can be blocked by MK-801.

There is evidence that excessive accumulation of extraneuronal glutamate
can inhibit oxidative phosphorylation. Studies using retinal cells have
shown that high concentrations of glutamate can reduce complex I, II/III
and IV, and that this inhibition can be completely blocked by MK-801.35
Several studies have shown that neuronal energy deficits dramatically
increase excitotoxic sensitivity, even to the point where normal
concentrations of glutamate can become excitotoxic.

While glycine demonstrates inhibitory actions in the spinal cord, in the
cerebrum it is excitatory. This is because it plays a major role in
glutamate activation of the NMDA receptor. High concentrations of
glycine have been shown to cause marked hyperexcitability and
neurotoxicity in hippocampal brain slices.36

Kainate can induce kindling, when injected into the cortex or amygdala.
The kindling response can occur without initiating seizures. Kindling
without clinical seizures is something that has been observed in autism.
Several studies have shown that kindling can produce excitotoxic lesions
in the absence of clinical seizures, again, something important to
consider in the autistic child.37

While neuronal degeneration can result from elevated levels of
glutamate, a loss of dendritic connections can occur at much lower
concentrations. There is also substantial evidence that elevated levels
of glutamate during periods of critical brain formation can result in
altered pathway development by over-stimulating growth cones.38
Glutamate levels are carefully regulated during early brain formation
and disruptions in glutamate levels can result in alteration leading to
either subtle or profound effects on brain function, depending on the
timing and dose. Seizures, especially when prolonged, can result in such
elevations of glutamate levels.

It is also known that ischemia and hypoxia, not uncommon in prolonged
seizures, can produce dramatic increases in glutamate levels for
prolonged periods of time. These levels could have a profound effect on
pathway formation as well as a loss of neurons, synaptic connections,
and stem cells. It is known that after age two years, the developing
brain contains more synaptic glutamate receptors than at birth, and that
the number slowly declines over the next decade.39 This makes the infant
brain especially vulnerable to excitotoxicity.

The Role of Immune Stimulation
It is recognized that activation of microglia, as well as astrocytes,
during immune stimulation, can elicit excitotoxicity. 40 The mechanism
involves a complex array of events primarily involving the release of
numerous cytokines. It should be appreciated that microglial activation
can occur during systemic immune challenge, as with vaccination.41,42

Microglial activation elicits the release of several cytokines including
TNF-alpha, IL-1ß, IL-2, IL-6 and INF-gamma.43 In addition, cytokine
activation of inflammatory eicosanoids occurs as well.44 Closely linked
to this process is the generation of numerous species of reactive oxygen
and nitrogen intermediates, including superoxide, hydrogen peroxide,
hydroxyl radicals, peroxynitrite and 4-hydroxynonenal. These reactive
intermediates not only damage synaptic connections, neurons, and
cellular components, but also induce the release of glutamate from
surrounding astrocytes.45

Of particular interest is the recent observation that microglial
activation can also elicit the release of glutamate and quinolinic acid,
two powerful excitotoxins, from the macrophage itself.46 Interaction
with bacterial components, viruses and lipopolysacchrides can increase
glutamate release two to three-fold above basal levels.47 Likewise,
dexamethasone has been shown to reduce glutamate release following
antigen exposure by 50%.48

It should also be appreciated that glutamate excess, as well as
deficiency, interferes with long termed potentiation, which is critical
for learning and memory.49 In addition, the growth and terminal
distribution of developing brain pathways are also adversely affected by
excess glutamate, especially when prolonged. Likewise, glutamate
deficiency interferes with growth cone function, leading to “miswiring”
of the brain’s circuitry.

Anything that activates microglia, including viruses, ß-amyloid,
mercury, aluminum, oxidized LDL and HDL, homocysteine and excitotoxins,
can increase the accumulation of quinolinic acid.50 This raises concern
about the use of L-tryptophan enhancing supplements and medications. Of
particular concern is an imbalance between quinolinic acid and
kynurenine formation, since the latter is a neuroprotectant.

Another area of concern is the ability of immune microglial activation
products to interfere with glutamate re-uptake. The glutamate transport
family of proteins is particularly sensitive to inactivation by IL-1ß,
TNF-alpha, mercury, peroxynitrite and 4-hydroxynonenal.51,52,53 Such
interference with glutamate disposal has been associated with
amyotrophic lateral sclerosis and possibly Alzheimer’s syndrome.54,55
All of these inhibitory factors can be seen in cases of over vaccination
and autoimmunity.

Mercury is a very powerful inhibitor of GLT-1, the glutamate transport
protein, even in very small concentrations.56 Several studies have shown
that children with autism frequently have significantly elevated mercury
levels, with vaccines often being the only source of the mercury (as the
preservative thimerosal). Mercury exposure from dental amalgam in rats
produced significantly elevated levels of immune complexes in the renal
glomeruli and vessel walls of numerous organs, including the brain.57
Based on what we know about overstimulation of the immune system, with
concomitant prolonged microglial activation, removing the mercury from
vaccines, while helpful, most likely will not eliminate the problem.

Vijendra Singh and co-workers have found that 84% of autistic children
examined demonstrated antibodies to myelin basic protein.58 This
suggests that a state of autoimmunity to brain has occurred in the
autistic child. It is known that autoimmune states are associated with
high levels of cytokines and inflammatory mediators such as leukotrienes
and prostaglandins.59 These inflammatory mediators increase brain
oxidative stress and excitotoxicity. It is interesting to note that
autoimmunity is also found in many of the adult neurodegenerative
disorders, such as Alzheimer’s disease, ALS and Parkinson’s
disease.60,61,62

Another possibility is the presence of a persistent virus or a stealth
virus. When the immune system has been impaired, either genetically or
by exhaustion, viruses can persist in tissues for long periods of
time.63 Because the immune system is impaired, instead of killing the
virus, the activated microglia continuously release neurotoxic mediators
and a stream of free radicals. They also stimulate the release of
glutamate and other excitotoxins, which further increases the production
of destructive reactive intermediates. The first casualty is the
synaptic connections, followed by the immature pathways forming during
the brain growth spurt.

That the measles virus enters the brain in cases of measles
encephalomyelitis has been shown by protein sequencing.64 Viral entry
into the brain can either induce a demyelinating syndrome (subacute
sclerosing panencephalitis) or a non-demyelinating syndrome as
characterized above. Giving children live measles viruses can possibly
lead to invasion of the brain by these persistent viruses.

In one study, using mice infected with hamster neurotropic measles
virus, researchers found that after seven days post-inoculation,
hippocampal brain slices produced 18X more quinolinic acid as compared
to controls.65 Three-hydroxyanthranilic acid oxygenase, an astrocytic
enzyme responsible for the production of quinolinic acid, increased its
activity 3.3 fold on the seventh post-inoculation day. Quinolinic acid
accumulation has been associated with HIV dementia as well, secondary to
its release from activated microglia. The HIV viral envelope, gp 120 and
tat proteins are neurotoxic by an excitotoxic mechanism. Blocking the
NMDA receptor prevents quinolinic acid neurotoxicity. In mice, measles
virus-induced encephalopathy associated neurotoxicity is also prevented
by MK-801, an NMDA antagonist.66

Self-limited incidences of acute encephalopathy probably occur more
often than are reported.67 This is because many pediatricians either do
not recognized subtle neurological signs or dismiss them as the result
of an overanxious mother. Chronic viral infections of the CNS,
especially by stealth viruses, with waxing and waning symptoms, are
frequently overlooked by those not trained in neurological care.

Another study raises even more concern for atypical presentations of
measles infections of the brain.68 In this study, it was found that
hamster neurotropic virus could cause a non-inflammatory encephalopathy
with degeneration of the hippocampal CA1 and CA3 regions. The
excitotoxic reaction increased several days after the inoculation. In
humans this could lead to varying degrees of memory loss and learning
difficulties, since excitotoxin damage has been shown to interfere with
long term potentiation (LTP).

Within the last decade two cases of postvaccinal parkinsonism have been
reported following inoculation for measles. One case occurred in a five-
year-old boy who developed fever and a rigid-akinetic syndrome beginning
15 days after the vaccine. 69 A follow-up report at age seven, found
that he was still suffering from parkinsonian symptoms. From these
reports one must conclude that the virus localized within the striatum,
eliciting an excitotoxic reaction of sufficient degree to produce
parkinsonian symptoms.70,71 The fact that methamphetamine induces
nigrostriatal dopaminergic toxicity by an excitotoxic mechanism
questions the wisdom of placing children with autism spectrum disorders
on such medications.72

By grouping vaccines together, especially live viral vaccines, one
increases the stress on the immune system as well as increasing
microglial activation within the brain. Not infrequently, very small
children are given multiple vaccination during a single doctor’s visit.
This can vary between three to nine vaccines at one sitting. This not
only constitutes a heavy bacterial and/or viral antigen load, but
contains powerful adjuvants to boost immunity so as to increase the
likelihood of immunization.

This has two effects. First, it overstimulates a dysfunctional immune
system, leading to immune directed damage to the nervous system. Measles
virus is known to induce autoimmune reactions to myelin basic protein.73
Second, it eventually exhaust the immune system leading to increased
susceptibility to subsequent microbial infections or chronic viral
infections. This scenario is more likely in the malnourished child,
especially with vitamin A deficiencies. Experimentally, retinoids have
been shown to significantly reduce the clinical severity of experimental
allergic encephalomyelitis.74 Early nutrition has been shown to play a
major role in immune function not only during the neonatal period, but
also throughout life.75

Experimentally, using guinea pigs and rats, excitotoxic lesions within
the hypothalamus have been shown to suppress both humoral and cell
mediated immunity.76 Excitotoxin suppression of delayed type
hypersensitivity may explain why subacute sclerosis panencephalitis is
less often seen than excitotoxic lesions not directed at myelin. These
excitotoxic-induced lesions in the hypothalamus have been shown to
produce immune dysfunctions that persist throughout life.

It has been observed that autistic children are frequently deficient in
zinc, and zinc is known to play a role in neuroprotection.77,78 Part of
the protection arises from the zinc portion of the NMDA receptor, which
inhibits receptor activation by glutamate. Zinc is also involved in
metallothionein, a protective molecule that increases with brain
inflammation and intoxications with heavy metals, especially mercury.79
Under such conditions, zinc levels in the blood are seen to fall.
Interestingly, prenatal exposure to caffeine from maternal consumption,
induces decreased fetal levels of brain zinc.80

Magnesium levels have also been reported to be low in autistic children.
Magnesium plays a major role in neuroprotection, primarily by inhibiting
NMDA activation. Magnesium also acts as an antioxidant, with low levels
being associated with doubling of free radical generation in both
epithelial cells and neurons.81 Low magnesium also lowers cellular
glutathione levels and increases excitotoxic neuronal death. Several
studies have shown that low magnesium levels dramatically increase
excitotoxicity.82

It has been shown that low magnesium plays a major role in
encephalopathy associated with deficiency of thiamin and other “B”
vitamins.83 In this study, rats made deficient only in thiamine or the
other B-vitamins developed mild cytotoxic changes in their pontine
tegmentum. Yet, when made hypomagnesmic the lesions were profoundly
worsened. Hypomagnesmia has also been shown to inhibit GABA responses
as well, which would increase cortical excitability.84

One of the principle cytokines released with microglial activation is
tumor necrosis factor-alpha. While under normal conditions TNF-alpha
acts as a neuroprotectant, it can also enhance excitotoxicity both by
increasing reactive oxygen and nitrogen intermediates and by inhibiting
glutamate re-uptake. TNF-alpha has been found to be elevated in several
of the neurodegenerative disorders and with EAE.85

Cytokines have been shown to play a major role in neurodevelpment. For
example, IL-1ß, IL-6 and TNF-alpha at physiological concentrations can
effect the survival of both dopaminergic and sertonergic neurons in the
embryo.86 At higher concentrations these cytokines significantly reduce
the survival of the dopaminergic neurons, but not the sertonergic
neurons.

Recently Petitto and co-workers demonstrated, by using IL-2 knockout
mice, that IL-2 was essential for the development and regulation of
hippocampal neurons involved in spatial memory and learning.87 Likewise,
IL-1 has been shown to have tropic functions within the brain.88,89 At
higher concentrations, both IL-2 and IL-1ß have been shown to be
cytodestructive, primarily by increasing free radical generation and
blocking glutamate re-uptake.90

Besides increasing neuronal destruction through immune enhancement of
excitotoxicity, viruses can also enhance excitotoxicity by inhibiting
mitochondrial enzyme function. The polio virus, for example, has been
shown to impair oxidative phosphorylation by inhibiting complex II of
the electron transport chain.91 As stated, reductions in mitochondrial
function significantly increase excitotoxity.

Sytemic cytokines can also have effects on the nervous system, since
they may enter by way of the circumventricular organs and through the
impaired BBB.92 Cytokines can also interact with endothelial cells
triggering the release of neuroactive substances within the brain and by
altering the permeability of the blood-brain barrier. Innterleukin-2 has
been shown to cause leaking of brain capillaries, leading to cerebral
edema in cases of glioma patients treated with this cytokine. `

Cognitive impairments have been attributed to IL-2 and TNF infusions in
humans. SPECT scans have demonstrated frontal lobe perfusion defects in
these patients, which were suspected to be caused by changes in
hypothalamic and/or frontal subcortical function.93

Treatment of patients with a variety of cytokines has demonstrated a
two-phase effect, acute and chronic. The chronic phase, occurring after
two weeks, is often characterized by psychomotor, cognitive and
psychiatric abnormalities. Interferon-alpha infusions, even at low-
doses, are also associated with numerous cognitive and psychological
effects, including decreased attention span, an inability to
concentrate, impaired short-tern memory, and hesitation of speech. Such
patients often suddenly stop speaking and stare out into space. On rare
occasions patients will progress to dementia. Many of these reactions
are reminiscent of autism behavior.

One set of symptoms associated with interferon-alpha use, that are also
similar to that seen in autism, include uncontrollable overreaction to
minor frustration, marked irritability, and a short temper.94 Even
months later, such patients may become severely agitated, abusive, and
withdrawn.

Both interleukin - 1 and 2 infusions are associated with mental changes,
including delusions, disorientation and seizures.95,96 There is evidence
that IFN-alpha can enhance spontaneous activity in neurons in the
cerebral, hippocampal and cerebellar cortices that can last several
hours following a single exposure.97 It is not clear if this is a direct
effect of interferon or if it is acting through enhanced glutamate
release.

Most of these clinical studies were on adult patients receiving
therapeutic doses of cytokines to treat either viral illnesses or
cancer. They demonstrate that peripherally administered cytokines can
have a profound effect on CNS function. In the infant, with an immature
brain undergoing rapid developmental changes, the neurotoxic effects of
the cytokines would be expected to be more profound. Also, because most
of the cytokines would be derived from activated microglia within the
brain, smaller concentrations would be expected to have a greater effect
than systemically administered cytokines.

Finally, one problem frequently found in autistic children is an
overgrowth of various fungal species, most often Candidia albicans,
secondary to either the frequent use of broad-spectrum antibiotics or
associated with immune depression. While concern with several of the
organic acids released by the yeast organism is legitimate, and have
been shown to have a profound effect on neurological function, of equal
concern is immune activation of microglia in the brain secondary to
systemic Candidia infection, or even infiltration of the brain itself. A
recent study has shown that the Candidia organism can penetrate the BBB
by budding and developing pseudohyphae inside human microvascular
endothelial cells.98

Conclusion
Epidemiological studies have shown that from 1960 until 1978, the
incidence of autism was fairly stable nationwide, at about 100 to 200
new cases per year. Following the introduction of the MMR vaccine for
the widespread inoculation of young children, the incidence of autism
increased dramatically, and has continued to increase, with 1944 cases
being reported in 1999 alone. In California there has been a 273%
increase in severe autism cases over the past eleven years.

While purely genetic disorders can explain a small subset of cases, most
appear to involve children who are healthy until they receive their
vaccination. Several of the vaccines are suspect, especially the MMR,
DPT and HepB vaccines. Dr. Benard Rimland has pointed out that before
the introduction of MMR vaccine, most autism cases occurred at birth.
Yet, after MMR vaccine introduction most new cases were occurring around
age 15 months, when the MMR vaccine was usually given. This does not
exclude the possibility of pre-existing, genetic related immune defects
that are triggered by the immunizations.

Today, children are being given 33 doses of 10 types of vaccines before
the age of five years. This represents a tremendous antigenic load for
an immature immune system to deal with, especially when given so close
together. Until recently, children were not only receiving a massive
antigenic load but they were also exposed to very high concentrations of
mercury. A child receiving all of their vaccinations often received as
much as 62.5ug of mercury per visit, 100 times the exposure allowed by
the EPA as safe for an infant.

The oral polio vaccine and the measles vaccine were found to contain
contaminant live viruses, which have been shown to disseminate to other
organs, including the nervous system.99 The oral live polio vaccine has
been shown to contain numerous pathogenic viruses, including HHV-6 SV-40
and possibly SIV. There is serious concern that stealth viruses may have
infected millions of unsuspecting people due to contaminated vaccines.

The mechanism by which vaccinations and/or other antigenic loads can
precipitate the autistic syndrome is unknown. But we know that immune
activation of the brain, especially when intense and prolonged, can
precipitate the release of excitotoxins from astrocytes and
microglia.100 Excitotoxicity is now known to be a major mechanism of
neural destruction in cases of viral infections of the brain. Even
without direct viral invasion, as seen in AIDS, immune activation can
trigger the release of the excitotoxins quinolinic acid and glutamate.

Chronic elevations of glutamate during critical brain growth periods can
result in the development of faulty neural pathway circuitry, which can
have profound effects on complex higher cortical functions as well as
hypothalamic functions. Even transient interference during the period of
rapid brain growth, can result in the apoptotic death of millions of
developing neurons, and the loss of billions of synaptic connections.101
It should be appreciated that destruction of synaptic connection and
dendrites can occur in the absence of neuron death itself, which means
that it can occur at much lower levels of glutamate and aspartate,
especially when antioxidant levels, cellular energy generation and/or
magnesium levels are low.102

Intimately connected with excitotoxicity is free radical generation,
including numerous oxygen and nitrogen intermediates. Peroxynitrite, a
nitrogen intermediate derived from a union of nitric oxide and
superoxide, is especially damaging to the mitochondria, leading to a
loss of energy production. Low brain energy levels, no matter the cause,
results in a dramatic increase in sensitivity to excitotoxicity. Both
glutamate and reactive intermediates can induce microglial activation,
leading to a release of inflammatory cytokines, lipid peroxidation
products, inhibition of glutamate re-uptake, and eventual apoptosis and
necrosis reactions.

Glutamate excess has been shown to lead to glutathione depletion
secondary to inhibition of cystine entry into the astrocyte (by way of
its effects on the cystine transport xc system).103 A recent study
indicates that glutathione may not only function as an antioxidant, but
may act as a neuromodulator and neurotransmitter as well.104 As a
neuromodulator, glutathione has been shown to down-regulate the
excitotoxic NMDA receptor, thus blocking excitotoxicity.105

In addition, as stated, clinical seizures occur in approximately one
third of autistic children. Excitotoxicity is intimately connected to
seizures and explains the neural damage seen when they are prolonged or
repeated. Less well appreciated is the fact that chronic seizure foci,
even in the absence of clinical seizures, can produce significant neural
damage by an excitotoxic mechanism. While the immature brain is less
susceptible to neuron death than the mature brain, seizures in the
developing brain result in irreversible changes in neuronal
connectivity.106 A recent study found that repeated seizures during
early life resulted in persistent changes in the CA1 pyramidal neurons
in the hippocampus, which is related to observed behavioral changes.107

Mercury exposure is also intimately related to neonatal seizures. A
recent study found that maternal exposure to mercury during pregnancy
significantly increases epileptogenecity in the offspring.108 This is
of special importance in women having dental amalgam, particularly if
this amalgam is disturbed during the pregnancy.

Of special concern as well is the recent discovery that glutamate, by
activating the NMDA receptors on the BBB can disrupt the barrier,
leading to free access of blood-born toxins to the CNS.109 In addition,
free radicals themselves have been shown to open the BBB.110 Gupta and
co-workers have shown that the developing BBB is highly vulnerable to
single or repeated exposure of certain pesticides, and that the effect
persist even after the offending agent is removed.111 It has been
demonstrated that by blocking the NMDA receptor, one can significantly
reduce neurovascular dysfunction seen with experimental allergic
encephalomyelitis.112

It has been shown that humans develop the highest blood levels of
glutamate of all known animals tested following MSG exposure.113 The
immature brain is especially vulnerable to food-born excitotoxins, being
4X more sensitive than the adult brain.114 An explanation for this
hypersensitivity of the immature brain lies in the observation that
during brain development the NMDA receptor is more sensitive to
glutamate and less responsive to magnesium protection.115 Food additive
excitotoxins are found in virtually all process foods, with very high
levels in many junk foods and diet foods.116 These are the types of
foods often eaten in large quantities by children, but especially
autistic children.

With this knowledge of the central role played by excitotoxicity in the
autistic syndrome, numerous options will be available for treatment.
Many of the diets now being proposed for autistic children emphasize the
elimination of foods that are known to be exceedingly high in
excitotoxin additives, even though they are being eliminated for other
reasons. They are also low in sugar. Autistic children have a high
incidence of reactive hypoglycemia, which increases their risk of
seizures and excitotoxicity. There is some evidence that Candidia
infections may also increase the incidence and severity of hypoglycemia
in autistic children.117

Many of the vitamins used to treat autism are antioxidants, which as we
have seen, can significantly reduce excitotoxicity, as well as protect
against the harmful effects of free radicals. Experimentally, vitamins E
can completely abolish glutamate excitotoxicity in vitro. Metabolic
stimulants also greatly reduce excitotoxicity. Thiamine, pyridoxine and
nicotinamide have been shown to significantly reduce glutamate toxicity
in vitro.118

Vitamin B6 can dramatically lower blood and tissue glutamate levels and
raise seizure thresholds. In addition, along with folate and vitamin
B12, it reduces homocysteine levels. While homocysteine is a marker for
deficiencies of methionine metabolism, it is also metabolized into two
very powerful excitotoxins, homocysteic acid and homocysteine sulfinic
acid. Methylcobalamin is a glutamate receptor blocker as well.119
Pyridoxine’s ability to powerfully inhibit excitotoxity at least
partially explains the often dramatic results reported by Bernard
Rimland in treating autistic children with high dose
pyridoxine/magnesium combinations.120

Magnesium and Zinc also powerfully inhibit excitotoxicity as well as act
as co-factors in numerous enzymes systems, including energy generation.
Low magnesium is associated with dramatic increases in free radical
generation as well as glutathione depletion. High glutamate levels have
also been shown to deplete cellular glutathione. Glutathione is vital
since it is one of the few antioxidant molecules known to neutralize 4-
hydroxynonenal and mercury. In addition, both malate and pyruvate
protect against glutamate-mediated excitotoxicity.121

Of great interest is the use of selected flavonoids as antioxidants,
anti-inflammatories and antimicrobals. The flavonoids are more powerful
and versatile as antioxidants than are the vitamins.122 In addition,
flavonoids have been shown to have effects on multiple enzyme systems,
including protein kinase C, phospholipase A2, COX and LOX enzymes, iNOS,
Na+/K+ ATPase, mitochondrial energy production, as well as cytokine
production, all of which may be beneficial in protecting the brain.

It should be pointed out that enrichment of the autistic child’s
environment is also critical. Saari and co-workers have shown that
enriched environments can override some of the problems produced by
neonatal exposure to monosodium glutamate.123

Despite the central role played by excitotoxicity, it should be
remembered that numerous other mechanism are at play as well, as
detailed by William Shaw, Bernard Rimland and others. As a multifaceted
disorder, autism requires a multifaceted approach, one that should
include protection against excitotoxicity.
[Part 2/2, References:
excitotoxicity autism disorders: Russell L. Blaylock, MD: Part 2/2,
References: Murray 7.10.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1011
************************************************************************