Re: http://www.dorway.com/blayautism.txt

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Excellent article. I didn't have time to read it all but, I've gotten to the part where they are explaining the glutamate receptors in further detail. miminm <mnmimi@...> wrote: I am trying to explain that my research comes from medical journals not the sensational news. I too Have approached this from a science practial based ideology.I sell nothing and I promise noting and I am very careful. I went to a nutritionist and had blood tests done. I was simply tring to show that the media swings both ways

and I don't rely on it but I will say the science is out there. the stakes are high, in the fact that ploitical factions have a great stake in the outcome. I son't do anything wacky or misguided and I do it the long and hard way using nutrition, education, and psycological approaches. Medicine is hard to trust because really they want us to take pills and go away. for me nutrition replaces pills and gets better results. (in my case) If one is allergic to food then Don't EAT IT. There is no agenda to that.The Central Role of Excitotoxicity in Autism Spectrum DisordersIntroductionIn this discussion I shall define autism spectrum disorders as a groupof disorders of higher cortical function ranging from attention deficitdisorder to full blown autism itself. Despite divisions into numerousindividually named disorders, Asperger's, high autism, attention deficithyperactivity disorder, etc, many feel that

they represent a spectrum ofrelated cognitive disorders. I do this recognizing that clinically,several may have characteristics that make them significantly differentfrom the others. Recognizing these differences, I shall discuss theirspecial physiology and biochemistry as the need arises.Recent evidence indicates that most neurological disorders, both acuteand chronic, have a common set of pathological events despite theirvarying clinical presentation.1 At the center of this process is whathas become known as excitotoxicity. Named in 1969 by Dr. Olney,excitotoxicity is a phenomenon characterized by the triggering ofneuronal excitation through over-stimulation of susceptible neurons bythe excitatory amino acids, primarily glutamate and aspartate. 2Using cloning techniques, scientists have characterized five sets ofexcitatory receptors that include NMDA, AMPA, kainate and twometabotrophic type

receptors.3 We know the most about the NMDA receptor,which controls a voltage-gated calcium channel. Clustered around thecalcium channel are various regulator receptors, including the zinc andmagnesium sites that modulate the channel, so as to prevent over-activation, and a glycine receptor which enhances the signal during NMDAreceptor activation. A phencyclidine receptor powerfully inhibits theopening of the calcium channel.Glutamate is the most abundant neurotransmitter in the central nervoussystem, yet it is also the most neurotoxic. It is for this reason thatits concentration outside the neuron is so carefully controlled. Thiscontrol is maintained by a family of glutamate transport proteins, whichattach to the transmitter soon after its release. Soon after it istransported it to a nearby astrocyte, where it is deposited.4Excess levels of glutamate, or other excitatory molecules, allow

thecalcium channel to remain open for a relatively long period of time.Calcium excess in the cytosol of the cell triggers the activation ofinducible nitric oxide synthase and protein kinase C. The iNOS producesNO in excess, which begins to accumulate within the cell. When NOcombines with the superoxide radical it forms the very destructiveperoxynitrite radical. This radical is particularly injurious to themitochondria, the chief source of energy for the neuron.5At the same time, protein kinase C then activates phospholipase A2within the neuron membrane, which brings about the release ofarachidonic acid into the cytosol. Here the arachidonic acid is acted onby two enzymes, lipoxygenase and cyclooxygenase, which produce a seriesof potentially destructive eicosanoids. Of particular concern is the COXII enzyme, which brings about the accumulation of PGE2 and PGD2, bothpro-inflammatory molecules.

Interestingly, only glutamatergic neuronscontain COX II enzymes, which are located on distal dendrites and areconcentrated in dendritic spines.6The accumulation of inflammatory eicosanoids leads to the production offree radicals, including the very destructive hydroxyl radical. As theprocess accelerates, the free radicals interact with the neuron'snumerous membrane structures, including nuclear, mitochondrial andcellular membranes. Once this process begins, a chain reaction withinthe membrane's polyunsaturated fatty acids is initiated, a process wecall lipid peroxidation.Numerous by-products are produced during lipid peroxidation, includingthe production of several aldehydic products. While the most abundant ofthese LPO products is malondialdhyde ( MDA), most destructive is aproduct called 4-hydroxynonenal.7 Recent research has shown that 4-HNEcan produce extensive damage to the cell, including

the prevention ofdephosphorylation of excessively phosphorylated tau protein,significantly interfering with microtubule function.8 It has also beenshown to inhibit glutathione reductase, which is needed to convertoxidized glutathione to its functional reduced form. 9 It has beendemonstrated that children with active autoimmune diseases havesignificantly higher blood levels of 4-HNE than controls. 10It is also known that 4-HNE can conjugate to synaptic proteins, where itimpairs the transport of both glucose and glutamate. 11 This process isespecially dangerous because several studies have shown that impairedenergy supplies markedly enhances glutamate sensitivity. In fact, undersuch conditions, even normal levels of glutamate can produceneurotoxicity. 12 Peroxynitrite, by damaging mitochondrial membranes,DNA and electron transport enzymes, can also significantly reduceneuronal energy production.

13It is known that numerous pathological events can triggerexcitotoxicity, including ischemia, hypoxia, hypoglycemia, viral andbacteriological pathogens, toxic metals, trauma, autoimmune diseases,and free radical excess. It should also be recognized that there is anintimate relationship between excitotoxicity and free radicalgeneration. Free radicals precipitate the release of glutamate in thebrain and excitotoxins trigger the productions of large amounts of freeradicals, both of the oxygen and nitrogen species.While this review of excitotoxicity is not complete it will provide thereader with a better understanding of the process.Seizures, Autism and ExcitotoxicityIt has been recognized that seizures are fairly common with several ofthe autism spectrum disorders. Approximately one third of autisticchildren have definable seizures or abnormal EEG seizure foci.14 Overtseizures are not

necessary for regression. In many cases, abnormal EEGseizure foci have been found in the absence of clinical seizures.15These abnormal seizure foci, with and without clinical seizures, areseen more commonly in autistic children who regress.Childs and Blair reported dramatic improvements after treatment withvalproic acid in a pair of autistic twin boys who were found at agethree to have absence seizures.16 The parents, on reflection, recalledsymptoms consistent with seizures occurring at age two. These boys hadsymptoms characteristic of autism, including perseverative, non-purposeful and self-stimulatory behavior, a lack of symbolic play, pooreye contact, echolalic and non-communicative speech and a lack ofresponse to discipline.In some autistic children one finds evidence of tuberous sclerosis, acondition associated with a high incidence of seizure disorders.17Approximately 25% of children with tuberous

sclerosis will be autistic.If you add pervasive developmental disorder the incidence increases to40 to 45%. Among autistic children 1 to 4% will also have tuberoussclerosis. The incidence increases to 8 to 14% in autistic children withseizures.There is evidence that seizure foci in autistic children have beengrossly underdiagnosed. In a recent study of children with LandeauKleffner syndrome (LKS) as compared to autistic children withregression, researchers using a highly sensitive magnetoencephalographictechnique ( MEG), found that out of 50 autistic children examined duringstage II sleep, 82% demonstrated eipleptiform activity in the sameregion of the brain as seen in Landeau Kleffner syndrome.18 Thedifference in the two groups was that the LKS children demonstrated noepileptiform activity outside the left intra/perisylvian area whereas75% of the regressive autistic children demonstrated

seizure foci withindependent activity, outside this area. The LKS children demonstratedpropagation of the seizure to frontal and parietal regions on occasions,which could explain associated difficulties with socialization andbehavior.During the examinations, standard EEG recordings were donesimultaneously with the magnetoencephalographic recordings. While theMEG 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 overlookedduring routine examinations. It is also possible that depth electroderecordings would detect even more abnormalities in subcortical areas,such as the amygdala and septal areas.That a persistent seizure focus discharge is pathologically damaging isgraphically shown in the case of Landeau Kleffner syndrome. In thisdisorder, a

persistent seizure focus results in a progressive loss oflanguage function and social interaction, both higher cognitivefunctions. Of particular concern is that the seizures usually occur atnighttime and are very difficult to recognize by the parents or doctors,as we have seen. Recovery of language function depends on early seizurecontrol.Another graphic demonstration of the connection between seizures,glutamate accumulation and cognitive deterioration is seen in the caseof pyrodoxine-sensitive seizure in newborns. It has been shown that inthe untreated child, CSF glutamate levels are 200X normal and seizuresare uncontrollable.19 When given an intermediate dose of 5mg/kg/BW/dayof pyrodoxine, the seizures cease, but mental deterioration continues.Glutamate levels at this dose were still 10X higher than normal. Whenusing pyrodoxine at 10 mg/kg/BW/day there were no seizures, no

cognitivedeterioration, and glutamate levels are normal. It is interesting tonote that some reported cases of pyridoxine-dependent seizures also hadfeatures of autism.20While most cases of pyridoxine-dependent seizures are present at birth,cases have been reported that experienced their initial onset as late as14 months after birth.21 It has been suggested that pyridoxine-dependentseizures are more common than is being reported, and that neurologicaldeterioration can occur in the absence of seizures.22 A wide array ofneurological symptoms can be seen on the basis of excitotoxic lesionsproduced with this syndrome, including, visual agnosia, squint, severearticulatory apraxia, and motor delay. We also know that the excitotoxicprocess associated with this syndrome can produce physical changes inthe brain as seen on MRI and CT scans, usually with cortical andsubcortical atrophy and

progressive ventricular dilitation.23Another demonstration of the importance of glutamate in seizurepathology comes from the study by Mathern and co-workers whodemonstrated increased NMDA receptor content in cases of temporal lobeepilepsy associated with mesial hippocampal sclerosis, indicatingdentate granule cell hyperexcitability.24 Others have shown degenerationof dendritic connections in epileptic hippocampal neurons characteristicof excitotoxicity. 25 Interestingly, a recent study found that theanatomic substrate of the limbic system, which included the subiculum/CA1-CA3 area and the dentate gyrus/ CA4 area, was smaller in autisticsubjects than matched controls.26 This.It has been observed that a percentage of autistic children improve whensupplemented with zinc. It is known that the temporal lobes have thehighest zinc content in the brain and that zinc plays a major role inreducing NMDA

excitability.27 Zinc has also been found to reduce dentategranule cell hyperexcitability in epileptic humans.28It is now known from experimental studies that seizures are intimatelyconnected to the excitotoxic process.29 Not only can glutamate andaspartate precipitate seizures, especially when injected into the brain,but seizures themselves can stimulate the release of excitatory aminoacids from the brain, most likely by stimulating free radicalgeneration. Spontaneously discharging neurons, especially when theprocess is prolonged, are associated with energy loss, ischemia, andhypoxia, all of which precipitate excessive release of glutamate.There is considerable evidence that excitotoxicity is responsible formuch of the pathological damage produced by prolonged seizures.30,31This destructive process has been proposed as the mechanism for both themirror focus seen with temporal lobe seizures

and the cognitivedeterioration associated with status epilepiticus. Cytopathologicalchanges have been described in the hippocampus following prolongedseizures that closely resemble excitotoxic damage, with destruction ofneurons in the CA1 and CA3 areas, and dendritic swelling in the hilus ofthe fascia dentata, as seen with cases of autism.Recent studies have shown that ketamine, a powerful NMDA receptorantagonist, can powerfully inhibit seizures, including statusepilepticus.32 Of particular concern is the excitotoxic damage producedduring limbic status epilepticus, a common form of epilepsy seen inautism spectrum disorders, and which may explain the above mentionedlimbic atrophy in autism.33Another excitotoxic substance associated with seizures is quinolinicacid.34 This excitotoxin is important for two reasons. First, it is ametabolic product of serotonin breakdown, and second it is released

fromboth astrocytes and microglia when these cells are activated by variousstimuli. 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 glutamatecan inhibit oxidative phosphorylation. Studies using retinal cells haveshown that high concentrations of glutamate can reduce complex I, II/IIIand IV, and that this inhibition can be completely blocked by MK-801.35Several studies have shown that neuronal energy deficits dramaticallyincrease excitotoxic sensitivity, even to the point where normalconcentrations of glutamate can become excitotoxic.While glycine demonstrates inhibitory actions in the spinal cord, in thecerebrum it is excitatory. This is because it plays a major role inglutamate activation of the NMDA receptor. High concentrations ofglycine have been shown to cause

marked hyperexcitability andneurotoxicity in hippocampal brain slices.36Kainate can induce kindling, when injected into the cortex or amygdala.The kindling response can occur without initiating seizures. Kindlingwithout clinical seizures is something that has been observed in autism.Several studies have shown that kindling can produce excitotoxic lesionsin the absence of clinical seizures, again, something important toconsider in the autistic child.37While neuronal degeneration can result from elevated levels ofglutamate, a loss of dendritic connections can occur at much lowerconcentrations. There is also substantial evidence that elevated levelsof glutamate during periods of critical brain formation can result inaltered pathway development by over-stimulating growth cones.38Glutamate levels are carefully regulated during early brain formationand disruptions in glutamate levels can result in

alteration leading toeither subtle or profound effects on brain function, depending on thetiming and dose. Seizures, especially when prolonged, can result in suchelevations of glutamate levels.It is also known that ischemia and hypoxia, not uncommon in prolongedseizures, can produce dramatic increases in glutamate levels forprolonged periods of time. These levels could have a profound effect onpathway formation as well as a loss of neurons, synaptic connections,and stem cells. It is known that after age two years, the developingbrain contains more synaptic glutamate receptors than at birth, and thatthe number slowly declines over the next decade.39 This makes the infantbrain especially vulnerable to excitotoxicity.The Role of Immune StimulationIt is recognized that activation of microglia, as well as astrocytes,during immune stimulation, can elicit excitotoxicity. 40 The

mechanisminvolves a complex array of events primarily involving the release ofnumerous cytokines. It should be appreciated that microglial activationcan occur during systemic immune challenge, as with vaccination.41,42Microglial activation elicits the release of several cytokines includingTNF-alpha, IL-1ß, IL-2, IL-6 and INF-gamma.43 In addition, cytokineactivation of inflammatory eicosanoids occurs as well.44 Closely linkedto this process is the generation of numerous species of reactive oxygenand nitrogen intermediates, including superoxide, hydrogen peroxide,hydroxyl radicals, peroxynitrite and 4-hydroxynonenal. These reactiveintermediates not only damage synaptic connections, neurons, andcellular components, but also induce the release of glutamate fromsurrounding astrocytes.45Of particular interest is the recent observation that microglialactivation can also elicit the release of

glutamate and quinolinic acid,two powerful excitotoxins, from the macrophage itself.46 Interactionwith bacterial components, viruses and lipopolysacchrides can increaseglutamate release two to three-fold above basal levels.47 Likewise,dexamethasone has been shown to reduce glutamate release followingantigen exposure by 50%.48It should also be appreciated that glutamate excess, as well asdeficiency, interferes with long termed potentiation, which is criticalfor learning and memory.49 In addition, the growth and terminaldistribution of developing brain pathways are also adversely affected byexcess glutamate, especially when prolonged. Likewise, glutamatedeficiency 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 concernabout the use of L-tryptophan enhancing supplements and medications. Ofparticular concern is an imbalance between quinolinic acid andkynurenine formation, since the latter is a neuroprotectant.Another area of concern is the ability of immune microglial activationproducts to interfere with glutamate re-uptake. The glutamate transportfamily of proteins is particularly sensitive to inactivation by IL-1ß,TNF-alpha, mercury, peroxynitrite and 4-hydroxynonenal.51,52,53 Suchinterference with glutamate disposal has been associated withamyotrophic lateral sclerosis and possibly Alzheimer's syndrome.54,55All of these inhibitory factors can be seen in cases of over vaccinationand autoimmunity.Mercury is a very powerful inhibitor of GLT-1, the glutamate transportprotein, even in very small concentrations.56 Several studies have

shownthat children with autism frequently have significantly elevated mercurylevels, with vaccines often being the only source of the mercury (as thepreservative thimerosal). Mercury exposure from dental amalgam in ratsproduced significantly elevated levels of immune complexes in the renalglomeruli and vessel walls of numerous organs, including the brain.57Based on what we know about overstimulation of the immune system, withconcomitant prolonged microglial activation, removing the mercury fromvaccines, while helpful, most likely will not eliminate the problem.Vijendra Singh and co-workers have found that 84% of autistic childrenexamined demonstrated antibodies to myelin basic protein.58 Thissuggests that a state of autoimmunity to brain has occurred in theautistic child. It is known that autoimmune states are associated withhigh levels of cytokines and inflammatory mediators such as

leukotrienesand prostaglandins.59 These inflammatory mediators increase brainoxidative stress and excitotoxicity. It is interesting to note thatautoimmunity is also found in many of the adult neurodegenerativedisorders, such as Alzheimer's disease, ALS and Parkinson'sdisease.60,61,62Another possibility is the presence of a persistent virus or a stealthvirus. When the immune system has been impaired, either genetically orby exhaustion, viruses can persist in tissues for long periods oftime.63 Because the immune system is impaired, instead of killing thevirus, the activated microglia continuously release neurotoxic mediatorsand a stream of free radicals. They also stimulate the release ofglutamate and other excitotoxins, which further increases the productionof destructive reactive intermediates. The first casualty is thesynaptic connections, followed by the immature pathways forming

duringthe brain growth spurt.That the measles virus enters the brain in cases of measlesencephalomyelitis has been shown by protein sequencing.64 Viral entryinto the brain can either induce a demyelinating syndrome (subacutesclerosing panencephalitis) or a non-demyelinating syndrome ascharacterized above. Giving children live measles viruses can possiblylead to invasion of the brain by these persistent viruses.In one study, using mice infected with hamster neurotropic measlesvirus, researchers found that after seven days post-inoculation,hippocampal brain slices produced 18X more quinolinic acid as comparedto controls.65 Three-hydroxyanthranilic acid oxygenase, an astrocyticenzyme responsible for the production of quinolinic acid, increased itsactivity 3.3 fold on the seventh post-inoculation day. Quinolinic acidaccumulation has been associated with HIV dementia as well, secondary toits

release from activated microglia. The HIV viral envelope, gp 120 andtat proteins are neurotoxic by an excitotoxic mechanism. Blocking theNMDA receptor prevents quinolinic acid neurotoxicity. In mice, measlesvirus-induced encephalopathy associated neurotoxicity is also preventedby MK-801, an NMDA antagonist.66Self-limited incidences of acute encephalopathy probably occur moreoften than are reported.67 This is because many pediatricians either donot recognized subtle neurological signs or dismiss them as the resultof an overanxious mother. Chronic viral infections of the CNS,especially by stealth viruses, with waxing and waning symptoms, arefrequently overlooked by those not trained in neurological care.Another study raises even more concern for atypical presentations ofmeasles infections of the brain.68 In this study, it was found thathamster neurotropic virus could cause a non-inflammatory

encephalopathywith degeneration of the hippocampal CA1 and CA3 regions. Theexcitotoxic reaction increased several days after the inoculation. Inhumans this could lead to varying degrees of memory loss and learningdifficulties, since excitotoxin damage has been shown to interfere withlong term potentiation (LTP).Within the last decade two cases of postvaccinal parkinsonism have beenreported following inoculation for measles. One case occurred in a five-year-old boy who developed fever and a rigid-akinetic syndrome beginning15 days after the vaccine. 69 A follow-up report at age seven, foundthat he was still suffering from parkinsonian symptoms. From thesereports one must conclude that the virus localized within the striatum,eliciting an excitotoxic reaction of sufficient degree to produceparkinsonian symptoms.70,71 The fact that methamphetamine inducesnigrostriatal dopaminergic toxicity

by an excitotoxic mechanismquestions the wisdom of placing children with autism spectrum disorderson such medications.72By grouping vaccines together, especially live viral vaccines, oneincreases the stress on the immune system as well as increasingmicroglial activation within the brain. Not infrequently, very smallchildren are given multiple vaccination during a single doctor's visit.This can vary between three to nine vaccines at one sitting. This notonly constitutes a heavy bacterial and/or viral antigen load, butcontains powerful adjuvants to boost immunity so as to increase thelikelihood of immunization.This has two effects. First, it overstimulates a dysfunctional immunesystem, leading to immune directed damage to the nervous system. Measlesvirus is known to induce autoimmune reactions to myelin basic protein.73Second, it eventually exhaust the immune system leading to

increasedsusceptibility to subsequent microbial infections or chronic viralinfections. This scenario is more likely in the malnourished child,especially with vitamin A deficiencies. Experimentally, retinoids havebeen shown to significantly reduce the clinical severity of experimentalallergic encephalomyelitis.74 Early nutrition has been shown to play amajor role in immune function not only during the neonatal period, butalso throughout life.75Experimentally, using guinea pigs and rats, excitotoxic lesions withinthe hypothalamus have been shown to suppress both humoral and cellmediated immunity.76 Excitotoxin suppression of delayed typehypersensitivity may explain why subacute sclerosis panencephalitis isless often seen than excitotoxic lesions not directed at myelin. Theseexcitotoxic-induced lesions in the hypothalamus have been shown toproduce immune dysfunctions that persist throughout

life.It has been observed that autistic children are frequently deficient inzinc, and zinc is known to play a role in neuroprotection.77,78 Part ofthe protection arises from the zinc portion of the NMDA receptor, whichinhibits receptor activation by glutamate. Zinc is also involved inmetallothionein, a protective molecule that increases with braininflammation and intoxications with heavy metals, especially mercury.79Under 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.80Magnesium levels have also been reported to be low in autistic children.Magnesium plays a major role in neuroprotection, primarily by inhibitingNMDA activation. Magnesium also acts as an antioxidant, with low levelsbeing associated with doubling of free radical generation in

bothepithelial cells and neurons.81 Low magnesium also lowers cellularglutathione levels and increases excitotoxic neuronal death. Severalstudies have shown that low magnesium levels dramatically increaseexcitotoxicity.82It has been shown that low magnesium plays a major role inencephalopathy associated with deficiency of thiamin and other "B"vitamins.83 In this study, rats made deficient only in thiamine or theother B-vitamins developed mild cytotoxic changes in their pontinetegmentum. Yet, when made hypomagnesmic the lesions were profoundlyworsened. Hypomagnesmia has also been shown to inhibit GABA responsesas well, which would increase cortical excitability.84One of the principle cytokines released with microglial activation istumor necrosis factor-alpha. While under normal conditions TNF-alphaacts as a neuroprotectant, it can also enhance excitotoxicity both byincreasing reactive oxygen and

nitrogen intermediates and by inhibitingglutamate re-uptake. TNF-alpha has been found to be elevated in severalof the neurodegenerative disorders and with EAE.85Cytokines have been shown to play a major role in neurodevelpment. Forexample, IL-1ß, IL-6 and TNF-alpha at physiological concentrations caneffect the survival of both dopaminergic and sertonergic neurons in theembryo.86 At higher concentrations these cytokines significantly reducethe survival of the dopaminergic neurons, but not the sertonergicneurons.Recently Petitto and co-workers demonstrated, by using IL-2 knockoutmice, that IL-2 was essential for the development and regulation ofhippocampal neurons involved in spatial memory and learning.87 Likewise,IL-1 has been shown to have tropic functions within the brain.88,89 Athigher concentrations, both IL-2 and IL-1ß have been shown to becytodestructive, primarily by increasing free

radical generation andblocking glutamate re-uptake.90Besides increasing neuronal destruction through immune enhancement ofexcitotoxicity, viruses can also enhance excitotoxicity by inhibitingmitochondrial enzyme function. The polio virus, for example, has beenshown to impair oxidative phosphorylation by inhibiting complex II ofthe electron transport chain.91 As stated, reductions in mitochondrialfunction significantly increase excitotoxity.Sytemic cytokines can also have effects on the nervous system, sincethey may enter by way of the circumventricular organs and through theimpaired BBB.92 Cytokines can also interact with endothelial cellstriggering the release of neuroactive substances within the brain and byaltering the permeability of the blood-brain barrier. Innterleukin-2 hasbeen shown to cause leaking of brain capillaries, leading to cerebraledema in cases of glioma patients treated with

this cytokine. `Cognitive impairments have been attributed to IL-2 and TNF infusions inhumans. SPECT scans have demonstrated frontal lobe perfusion defects inthese patients, which were suspected to be caused by changes inhypothalamic and/or frontal subcortical function.93Treatment of patients with a variety of cytokines has demonstrated atwo-phase effect, acute and chronic. The chronic phase, occurring aftertwo weeks, is often characterized by psychomotor, cognitive andpsychiatric abnormalities. Interferon-alpha infusions, even at low-doses, are also associated with numerous cognitive and psychologicaleffects, including decreased attention span, an inability toconcentrate, impaired short-tern memory, and hesitation of speech. Suchpatients often suddenly stop speaking and stare out into space. On rareoccasions patients will progress to dementia. Many of these reactionsare reminiscent of

autism behavior.One set of symptoms associated with interferon-alpha use, that are alsosimilar to that seen in autism, include uncontrollable overreaction tominor frustration, marked irritability, and a short temper.94 Evenmonths later, such patients may become severely agitated, abusive, andwithdrawn.Both interleukin - 1 and 2 infusions are associated with mental changes,including delusions, disorientation and seizures.95,96 There is evidencethat IFN-alpha can enhance spontaneous activity in neurons in thecerebral, hippocampal and cerebellar cortices that can last severalhours following a single exposure.97 It is not clear if this is a directeffect of interferon or if it is acting through enhanced glutamaterelease.Most of these clinical studies were on adult patients receivingtherapeutic doses of cytokines to treat either viral illnesses orcancer. They demonstrate that

peripherally administered cytokines canhave a profound effect on CNS function. In the infant, with an immaturebrain undergoing rapid developmental changes, the neurotoxic effects ofthe cytokines would be expected to be more profound. Also, because mostof the cytokines would be derived from activated microglia within thebrain, smaller concentrations would be expected to have a greater effectthan systemically administered cytokines.Finally, one problem frequently found in autistic children is anovergrowth of various fungal species, most often Candidia albicans,secondary to either the frequent use of broad-spectrum antibiotics orassociated with immune depression. While concern with several of theorganic acids released by the yeast organism is legitimate, and havebeen shown to have a profound effect on neurological function, of equalconcern is immune activation of microglia in the brain secondary

tosystemic Candidia infection, or even infiltration of the brain itself. Arecent study has shown that the Candidia organism can penetrate the BBBby budding and developing pseudohyphae inside human microvascularendothelial cells.98ConclusionEpidemiological studies have shown that from 1960 until 1978, theincidence of autism was fairly stable nationwide, at about 100 to 200new cases per year. Following the introduction of the MMR vaccine forthe widespread inoculation of young children, the incidence of autismincreased dramatically, and has continued to increase, with 1944 casesbeing 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, mostappear to involve children who are healthy until they receive theirvaccination. Several of the vaccines are suspect,

especially the MMR,DPT and HepB vaccines. Dr. Benard Rimland has pointed out that beforethe introduction of MMR vaccine, most autism cases occurred at birth.Yet, after MMR vaccine introduction most new cases were occurring aroundage 15 months, when the MMR vaccine was usually given. This does notexclude the possibility of pre-existing, genetic related immune defectsthat are triggered by the immunizations.Today, children are being given 33 doses of 10 types of vaccines beforethe age of five years. This represents a tremendous antigenic load foran immature immune system to deal with, especially when given so closetogether. Until recently, children were not only receiving a massiveantigenic load but they were also exposed to very high concentrations ofmercury. A child receiving all of their vaccinations often received asmuch as 62.5ug of mercury per visit, 100 times the exposure allowed bythe EPA as

safe for an infant.The oral polio vaccine and the measles vaccine were found to containcontaminant live viruses, which have been shown to disseminate to otherorgans, including the nervous system.99 The oral live polio vaccine hasbeen shown to contain numerous pathogenic viruses, including HHV-6 SV-40and possibly SIV. There is serious concern that stealth viruses may haveinfected millions of unsuspecting people due to contaminated vaccines.The mechanism by which vaccinations and/or other antigenic loads canprecipitate the autistic syndrome is unknown. But we know that immuneactivation of the brain, especially when intense and prolonged, canprecipitate the release of excitotoxins from astrocytes andmicroglia.100 Excitotoxicity is now known to be a major mechanism ofneural destruction in cases of viral infections of the brain. Evenwithout direct viral invasion, as seen in AIDS, immune activation

cantrigger the release of the excitotoxins quinolinic acid and glutamate.Chronic elevations of glutamate during critical brain growth periods canresult in the development of faulty neural pathway circuitry, which canhave profound effects on complex higher cortical functions as well ashypothalamic functions. Even transient interference during the period ofrapid brain growth, can result in the apoptotic death of millions ofdeveloping neurons, and the loss of billions of synaptic connections.101It should be appreciated that destruction of synaptic connection anddendrites can occur in the absence of neuron death itself, which meansthat it can occur at much lower levels of glutamate and aspartate,especially when antioxidant levels, cellular energy generation and/ormagnesium levels are low.102Intimately connected with excitotoxicity is free radical generation,including numerous oxygen and

nitrogen intermediates. Peroxynitrite, anitrogen intermediate derived from a union of nitric oxide andsuperoxide, is especially damaging to the mitochondria, leading to aloss of energy production. Low brain energy levels, no matter the cause,results in a dramatic increase in sensitivity to excitotoxicity. Bothglutamate and reactive intermediates can induce microglial activation,leading to a release of inflammatory cytokines, lipid peroxidationproducts, inhibition of glutamate re-uptake, and eventual apoptosis andnecrosis reactions.Glutamate excess has been shown to lead to glutathione depletionsecondary to inhibition of cystine entry into the astrocyte (by way ofits effects on the cystine transport xc system).103 A recent studyindicates that glutathione may not only function as an antioxidant, butmay act as a neuromodulator and neurotransmitter as well.104 As aneuromodulator, glutathione has been

shown to down-regulate theexcitotoxic NMDA receptor, thus blocking excitotoxicity.105In addition, as stated, clinical seizures occur in approximately onethird of autistic children. Excitotoxicity is intimately connected toseizures and explains the neural damage seen when they are prolonged orrepeated. Less well appreciated is the fact that chronic seizure foci,even in the absence of clinical seizures, can produce significant neuraldamage by an excitotoxic mechanism. While the immature brain is lesssusceptible to neuron death than the mature brain, seizures in thedeveloping brain result in irreversible changes in neuronalconnectivity.106 A recent study found that repeated seizures duringearly life resulted in persistent changes in the CA1 pyramidal neuronsin the hippocampus, which is related to observed behavioral changes.107Mercury exposure is also intimately related to neonatal seizures.

Arecent study found that maternal exposure to mercury during pregnancysignificantly increases epileptogenecity in the offspring.108 This isof special importance in women having dental amalgam, particularly ifthis amalgam is disturbed during the pregnancy.Of special concern as well is the recent discovery that glutamate, byactivating 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 andco-workers have shown that the developing BBB is highly vulnerable tosingle or repeated exposure of certain pesticides, and that the effectpersist even after the offending agent is removed.111 It has beendemonstrated that by blocking the NMDA receptor, one can significantlyreduce neurovascular dysfunction seen with experimental allergicencephalomyelitis.112It has been shown

that humans develop the highest blood levels ofglutamate of all known animals tested following MSG exposure.113 Theimmature brain is especially vulnerable to food-born excitotoxins, being4X more sensitive than the adult brain.114 An explanation for thishypersensitivity of the immature brain lies in the observation thatduring brain development the NMDA receptor is more sensitive toglutamate and less responsive to magnesium protection.115 Food additiveexcitotoxins are found in virtually all process foods, with very highlevels in many junk foods and diet foods.116 These are the types offoods often eaten in large quantities by children, but especiallyautistic children.With this knowledge of the central role played by excitotoxicity in theautistic syndrome, numerous options will be available for treatment.Many of the diets now being proposed for autistic children emphasize theelimination of foods that

are known to be exceedingly high inexcitotoxin additives, even though they are being eliminated for otherreasons. They are also low in sugar. Autistic children have a highincidence of reactive hypoglycemia, which increases their risk ofseizures and excitotoxicity. There is some evidence that Candidiainfections may also increase the incidence and severity of hypoglycemiain autistic children.117Many of the vitamins used to treat autism are antioxidants, which as wehave seen, can significantly reduce excitotoxicity, as well as protectagainst the harmful effects of free radicals. Experimentally, vitamins Ecan completely abolish glutamate excitotoxicity in vitro. Metabolicstimulants also greatly reduce excitotoxicity. Thiamine, pyridoxine andnicotinamide have been shown to significantly reduce glutamate toxicityin vitro.118Vitamin B6 can dramatically lower blood and tissue glutamate levels

andraise seizure thresholds. In addition, along with folate and vitaminB12, it reduces homocysteine levels. While homocysteine is a marker fordeficiencies of methionine metabolism, it is also metabolized into twovery powerful excitotoxins, homocysteic acid and homocysteine sulfinicacid. Methylcobalamin is a glutamate receptor blocker as well.119Pyridoxine's ability to powerfully inhibit excitotoxity at leastpartially explains the often dramatic results reported by BernardRimland in treating autistic children with high dosepyridoxine/magnesium combinations.120Magnesium and Zinc also powerfully inhibit excitotoxicity as well as actas co-factors in numerous enzymes systems, including energy generation.Low magnesium is associated with dramatic increases in free radicalgeneration as well as glutathione depletion. High glutamate levels havealso been shown to deplete cellular glutathione.

Glutathione is vitalsince it is one of the few antioxidant molecules known to neutralize 4-hydroxynonenal and mercury. In addition, both malate and pyruvateprotect against glutamate-mediated excitotoxicity.121Of great interest is the use of selected flavonoids as antioxidants,anti-inflammatories and antimicrobals. The flavonoids are more powerfuland 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 cytokineproduction, all of which may be beneficial in protecting the brain.It should be pointed out that enrichment of the autistic child'senvironment is also critical. Saari and co-workers have shown thatenriched environments can override some of the problems produced byneonatal exposure

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