1. True Health Medical Center
Excitotoxicity in ASD
Autism ONE Conference
May 2008
Anju Usman, M. D.
True Health Medical Center
Naperville, Illinois

2. Our kids carry the burdens of a physically and emotionally toxic world!
Genetic predispositions
Mother’s Burdens
Heavy Metals
Environmental Pollutants
Electromagnetic Fields
Excess Sensory Input
Stress/Internal Conflicts
Dietary Factors
Microbial/Biofilm
Immune/Inflammatory Burden

3. Metabolic Imprint of the Body Burdens
Oxidative Stress
Thimerosal (Mercury), Arsenic, Lead, Aluminum Overload
Depletion of Antioxidants, Glutathione, and Metallothionein
Mitochondrial Dysfunction
Elevated Oxidative Stress Markers
Abnormal Ammonia, Lactic Acid, Pyruvate Acid
Low Carnitine
Impaired Detoxification
Methylation Defects
Sulfation Defects
Cysteine Deficiency
Glutathione Deficiency (GSH)
Gastrointestinal Dysfunction
Dysbiosis (Yeast, Bad Bacteria, Parasites, Virus…)
Malabsorption
Maldigestion (enzyme deficiency, IgG food sensitivities, urinary peptides)
Autistic Enterocolitis/ Lymphonodular Hyperplasia
Immune System Dysregulation/Inflammation
Proinflammatory Cytokines
Microglial Activation
Th1/ Th2 skewing
Decreased Natural Killer Cell Activity
Increased Autoimmune Markers

4. What exactly is causing my child’s symptoms that are being diagnosed as autism?
Verbal stims/ Perseverative/ Repetitive/ Has language but not motivated to use it/ Rigid behaviors/ Scripted language/ Constipated/Anxiety/OCD/ Motor Tics
Differential Diagnosis
Chronic Infections
Strep
Viruses
Glutamate
Ammonia
Mercury
Aluminum
Lead
Pesticides
Vaccine Adjuvants (viral fragments)
All of these lead to Excitotoxicity in the brain!!!!

5. Excitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
The toxicity of glutamate was then observed by D. R. Lucas and J. P. Newhouse in 1957 when the feeding of monosodium glutamate to newborn mice destroyed the neurons in the inner layers of the retina. Later, in 1969, John Olney discovered the phenomenon wasn't restricted to the retina but occurred throughout the brain and coined the term excitotoxicity.
Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is paradoxically also the major excitatory neurotransmitter in the mammalian CNS.
One of the damaging results of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium.

6. Excitotoxicity (Excess excitatory neurotransmission)
Causes brain atrophy
Neuronal loss
Brain more susceptible to Toxins
Neuroinflammation
Proinflammatory Cytokines
Increased TNF alpha
Increased IL-1, High IL-6
Upregulation of Brain Immune System
Microglial Activation
“Sickness Behavior”
Russell Blaylock, “Vaccines, Neurodevelopment, and ASD”

7. Sickness Behavior What does if feel like to be chronically sick????
Restless
Irritable
Disturbed Sleep
Fatigue
Difficulty Thinking…
Russell Blaylock, “Vaccines, Depression and Neurodegeneration”

8. Microglial Activation
RESTING MICROGLIA
Support brain growth
Protect brain cells
ACTIVATED MICROGLIA
Ready to fight foreign invader
Inflammatory cytokines
Free radicals
Lipid Peroxidation
Glutamate production
Quinolinic acid

9. Autism and the Immune system
It remains unclear how and when microglia and astroglia become activated in the brains of patients with autism. Glial responses in autism may be part of intrinsic, or primary, reactions that result from disturbances in glial function or neuronal-glial interactions during brain development. They may also be secondary, resulting from unknown disturbances (such as infections or toxins) in prenatal or postnatal CNS development. Nevertheless, the findings of this study highlight the existence of neuroimmunological processes in autism and provide a setting for new research approaches to the diagnosis and treatment of this debilitating neurological disorder.
Slides A and C, from patients with autism, show an increase in neuron-supporting cells called glia. This increase is likely a sign of a neuroimmunological response to the disorder. © 2005 Pardo et al.

10. Russell Blaylock, “Vaccines, Depression and Neurodegeneration”
Microglial Activation should only last a few days. If insults persist…. it can last years
Vaccine induced microglial activation, especially when numerous vaccines are given simultaneously, can last YEARS.
Russell Blaylock, “Vaccines, Depression and Neurodegeneration”

11. Activated Immune System
Once the system is turned on or activated the cycle persists.
This persistent immune upregulation creates autoimmunity in the body and microglial activation in the brain.

12. Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
The principle excitatory receptor, the N-Methyl-D-Aspartate (NMDA) receptor, and its associated calcium (Ca2+) permeable ion channel are activated by glutamate and co-agonist glycine.

13. Calcium Homeostasis Symptoms of abnormal Calcium homeostasis
Calcium is one of the most important 2nd messengers
Tightly regulated by stores, pumps and buffers
VGCC- Voltage Gated Calcium Channels
L type (LTCC)
CNS
Immune system
GI tract
Inner Ear
Symptoms of abnormal Calcium homeostasis
Excitation/Hyperactivity/Stimming Behaviors
Muscle Tone /Coordination Issues
GI Motility
Visual Disturbances
Auditory Sensitivity
History of Kidney Stones, Fractures, Excess Oxalates
“Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”
N.B.S. Lozac Feb. 2007

14. Effects of Abnormal Calcium Homeostasis
Neurotransmitters
Decreased Nicotinic Acetylcholine, Increased Glutamate, Decreased Dopamine
Endocrine/Hormone
Impaired Insulin, Oxytocin, Vasopressin, Melatonin, Cortisol, IGF1
Immune/Inflammatory
Microglial activation, Th2 skewing, Proinflammatory cytokines
Viral induced immune suppression
Vascular/Smooth Muscle
Gastrointestinal
Increased Gastric Acid, Abnormal Motility, Increased Insulin release, Phopholipase C
Membranes
Decreased Cholesterol
Mitochondria
Stores excess Calcium which inhibits Oxidative Phosphorylation Poor Energy Production and Elevation of ROS (reactive oxygen species)
Oxidative Stress
Cross Talk between Calcium and ROS(peroxide, nitrous oxide, superoxide)
Cause Damage to Endothelial Cells
Motor – Sensory
“Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”
N.B.S. Lozac Feb. 2007

15. Potential Biomarkers of Abnormal Calcium Homeostasis
Decreased Antioxidant Status
Elevated Pro-oxidants
Elevated extracellular and intracellular Ca+2
Elevated ionized Calcium, elevated hair Ca+2
Elevated osteocalcin
Elevated Alkaline Phosphatase (isoenzyme-bone)
High CO2
Low Vitamin D
Elevated urinary oxalates
Hypoglycemia

16. Treating Excitotoxicity
Avoid Excitotoxins/Dietary Modifications
Use Glutamate Modulators
Maximize Antioxidants
Eliminate Toxins
Treat and Identify Chronic Infections
Alkalinize the Gut
Limit excess Calcium, Ammonia, and Glutamate
Support ATP production and the Mitochondria
Provide adequate Methylation support
Natural Anti-Inflammatories

17. Avoid Excitotoxins
Substances that cause an excess of excitatory neurotransmission in the brain. The excess excitation may lead to microglial activation and chronic inflammation in the brain.
Chronic Infections
Pesticides
Heavy Metals
Glutamate/MSG
Sulfites/Hydrogen Sulfide
Nitrites
Propionates
Benzoates

18. Excitotoxic Triggers Glutamate Excess Calcium Excess Ammonia
Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
Excitotoxic Triggers
Glutamate
Monosodium Glutamate (MSG)
Hydrolyzed Protein
Modified Food Starch
Natural Flavors
Peas, Mushrooms, Tomatoes
Parmesan Cheese
Excess Protein
Excess Calcium
Excess Ammonia
Excess Sulfur/Sulfite/
Hydrogen Sulfide
Lead
Aluminum
Mercury
EMF

19. Glutamate Modulators Magnesium Antioxidants
Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
Glutamate Modulators
Magnesium
Antioxidants
Leucine, Isoleucine, and Lysine
Pycnogenol
Rosemary, Lemon Balm
Skull Cap, Chamomile
Taurine
GABA
L- Theanine
Vitamin K
Gingko biloba
Silymarin
Flavinoids (curcumin, quercetin)
Namenda (drug)
Minocycline (antibiotic)

20. Anti-oxidants
Excessive free radical formation/inadequate antioxidant status is a major pathway of excitotoxic damage. 
Various free radicals (ROS), including superoxide, peroxide, hydroxyl and peroxynitrite, are generated through the inflammatory prostaglandin/leukotriene pathways triggered by excitotoxic intracellular calcium excess. 
These free radicals can damage or destroy virtually every cellular biomolecule: proteins, fatty acids, phospholipids, glycoproteins, even DNA, leading to cell injury or death. 
Although vitamins C and E are the two most important nutritional antioxidants. Brain cells may concentrate C to levels 100 times higher than blood levels. 
Vitamin C, E, alpha-lipoic acid, Co Q10 and NADH act as a team.
One of the many ways excitotoxins damage neurons is to prevent the intracellular formation of glutathione.
The combination of E and Idebenone may provided complete antioxidant neuronal protection in spite of extremely low glutathione levels caused by glutamate excitotoxic action.

21. Antioxidant Phytonutrients

22. Infections produce triggers that cause excitotoxicity!
Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
Infections produce triggers that cause excitotoxicity!
Viruses
Bacteria- especially Strep and Clostridia………..
Yeast
Parasites
Lyme
Mycoplasma
Chronic infections need to be effectively treated to stop persistent activation of the immune system.
Infections are common in ASD patients. These infections are often resistant to treatment. Persistent organisms often produce biofilm.
Toxic Foci include tonsils, adenoids, ears, lymph nodes, GI tract…
Some infections produce excess ammonia.

23. Keys to treating chronic infections
Identify type and location
Aggressively clean up the gut
Breakdown biofilm (diet, nutrition, and alkalinize)
Treat infections with homeopathics and natural agents if possible
Be patient
Keep ammonia levels low
Have a plan to manage die off

24. Ammonia If severely elevated rule out urea cycle disorder
Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
If severely elevated rule out urea cycle disorder
If mildly elevated consider possible causes
Dysbiosis
Recent infection
Liver stress
High protein diet or supplements
BH4 (tetrahydrobiopterin deficiency)
Symptoms
Irritability, aggression, headache, head-banging, hyperactivity
Treatment Strategies
Avoid excess protein in diet
Activated Charcoal, Fiber, Pectin, Zeolites
Yucca / Aloe
BH4
Butyrate
Ammonia RNA (Yasko)

25. Vitamin K Protocol (Catherine Tamaro)
Vit K
Vit D
Vit A
DHA
Bicarbonate
Melatonin
Avoid Calcium supplementation
This Protocol is good for addressing
excess extracellular calcium.

26. The Mitochondria is the
powerhouse of each cell.
Inside the Mitochondria,
the Citric Acid Cycle
produces ATP.
ATP is the fuel for the cell.
ATP provides energy.

27. ATP (adenosine triphosphate)
ATP is the energy "currency" of all cells, including neurons.  Each neuron must produce all the ATP it needs - there is no welfare state to take care of needy but helpless neurons. 
ATP is needed to pump glutamate out of the synaptic gap into either the glutamate-secreting neuron or into astrocytes.  ATP is needed by atrocytes to convert glutamate into glutamine. 
ATP is needed by sodium and calcium pumps to get excess sodium and calcium back out of the neuron after neuron firing. ATP is needed to maintain neuron resting electric potential, which in turn maintains the magnesium-block of the glutamate-NMDA receptor.  With enough ATP bioenergy, neurons can keep glutamate and aspartate in their proper role as neurotransmitters.
Neurons produce ATP by "burning" glucose (blood sugar) through 3 interlocking cellular cycles: the glycolytic and Krebs' cycles, and the electron transport chain, with most of the ATP coming from the electron transport chain.
Various enzyme assemblies produce ATP from glucose through these 3 cycles, with the Krebs' cycle and electron transport chain occurring inside mitochondria, the power plants of the cell.

28. Mitochondrial Support and ATP Production
The various enzyme assemblies require vitamins B1, B2, B3 (NADH), B5, biotin, and alpha-lipoic acid as coenzymes. 
Magnesium is also required by most of the glycolytic and Krebs' cycle enzymes as a mineral co-factor.
The electron transport chain especially relies on NADH and Co Q10 to generate the bulk of the cell's ATP. 
Idebenone is a synthetic variant of Co Q10 that may work better than CoQ10, especially in low oxygen conditions, to keep ATP production going in the electron transport chain. 
Acetyl l-carnitine may regenerate aging mitochondria that are suffering from a lifetime of accumulated free radical damage.
Potential Krebs Cycle Support 
Malic Acid
Fumaric Acid
Succinic Acid
Alpha Keto Glutarate (careful)

29. Methylation & Beyond...
Text

30. Methylation Support and Glutathione Production
Combination of Pfeiffer Treatment Center, Defeat Autism Now, and Yasko Approach
Understanding the underlying genetics is helpful in difficult cases
CBS status, MTHFR, MTR, MTRR and COMT are helpful for understanding methylation issues
Amino Acid testing and Cysteine, Glutathione, and Sulfate levels define picture.
Undermethylation, COMT (- -), High Histamine
Overmethylation, COMT (++), Low Histamine

31. COMT - - Treatment approach
DAN
Methyl B12
TMG
DMG
P5P
Folinic Acid
Creatine
L Carnitine
Glutathione(GSH)
Yasko
Intrinsic B12
Nucleotides
Methylfolate
BH4
GSH(limited)
Emphasis on
Methyl Donors:
Methyl B12
SAMe
Quercetin
Gingko
Curcumin
Green Tea
Phosphatidyl Serine
Pfeiffer
Methionine/SAMe
Methyl B12
Calcium
Magnesium
P5P/B6
Zinc
Vitamin C
Phosphatidyl Serine
Avoid Methyl Consumers:
Folates
DMAE
Cyano B12
Niacinamide

32. COMT + + Treatment approach
DAN
Methyl B12
TMG
DMG
P5P
Folinic Acid
Creatine
L Carnitine
Glutathione
Yasko
Intrinsic B12
Nucleotides
Methylfolate
Hydroxy B12
Cyano B12
BH4
Limit Methyl Donors:
Methyl B12
Quercetin
Gingko
Curcumin
Green Tea
Phosphatidyl Serine
Pfeiffer
Folic Acid
Cyano B12
Niacinamide
P5P, Vit B6
Zinc, Mb, Mn
Vitamin C
DMAE/Phosphatidyl Choline
Avoid Methyl Donors:
Methyl B12
Methyl Folate
Methionine
SAMe

33. Natural Anti-inflammatory Agents
The excitotoxic process does much of its damage through initiating excessive production of prostaglandins, thromboxanes, and leukotrienes.
Inflammatory prostaglandins and thromboxanes are produced by the action of cyclooxygenase 2 (COX-2) on arachidonic acid liberated from cell membranes   Leukotrienes are produced by lipoxygenases (LOX). 
Trans-resveratrol is a powerful natural inhibitor of both COX-2 and LOX
Quercetin is a powerful LOX-inhibitor.
Boswellia is a COX-2 and LOX-inhibitor.
Curcumin (turmeric extract), rosemary extract, green tea extract, ginger and oregano are also effective natural COX-2 inhibitors. 
Glutathione is also a LOX- inhibitor and potent Antioxidant.
Antioxidants have anti-inflammatory effects.
Fat Soluble Vitamins A,D,E, and K.
Essential Fatty Acids, Omega 3 especially DHA.

34. Keys to Excess Glutamate Removal
Avoid dietary Excitotoxins will help to minimize synaptic glutamate/aspartate.
Keep neuronal ATP energy maximal by support of the Mitochondria
Avoidance of hypoglycemia
ATP Production will assist glutamate pumps to remove excess extracellular glutamate  
ATP promotes astrocyte conversion of glutamate to glutamine, the chief glutamate removal mechanism. 
ATP will also keep calcium and sodium pumps active, preventing excessive intracellular calcium build-up. Intracellular calcium excess itself promotes renewed secretion of glutamate into synapses, in a positive feedback vicious cycle.
Maintain function of the enzyme "glutamatic acid dehydrogenase (GAD)"
Helps neurons dispose of excess glutamate by converting glutamate to alpha-ketoglutarate, a Krebs' cycle fuel.
Glutamate dehydrogenase is activated by NADH, it promotes breakdown of glutamate.
Treat toxins that inhibit GAD, like aluminum, lead, mercury, and pesticides…
Consume plenty of antioxidants which aid in removal of synaptic glutamate. 
Avoid use of glutamine.  Glutamine easily passes the blood-brain barrier and enters the astrocytes and neurons, where it can be converted to glutamate. 

35. GABA/Glutamate Cycle Glutamine ADP NH3/ Ammonia ATP Amino acids p5pMg
ADP
ATP
Glutamine
Glutamic Acid
NH3/ Ammonia
GABA
Amino acids
p5p
Proline
Decarboxylase
(brain, kidney)
NAD
NADP
NADH
NADPH
AKG
Krebs/Mitochondria
Glutamic acid dehydrogenase
p5p
Succinic Acid
Krebs/Mitochondria

36. Additional Sources of Information
Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
Additional Sources of Information
Healing the New Childhood Epidemics (Autism, ADHD, Asthma and Allergies, Ken Bock MD
Autism: Effective Biomedical Treatments, Pangborn and Baker
Changing the Course of Autism, Jepson and Johnson
Excitotoxins, the Taste that Kills, Russell Blaylock MD
Envisioning a Brighter Future, Patty Lemur
Websites

37. Thank You and Never Give Up Hope.
Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols
Thank You and Never Give Up Hope.