Oxidative Stress & Autism A Paradigm for Effective Treatment

1. Oxidative Stress & AutismA Paradigm for Effective Treatment Allen T. Lewis, MD, FAAP Medical Director, Pfeiffer Treatment Center Warrenville, Illinois

2. Questions • What is autism? • How did it happen? • What can be done?

3. An Axial Approach • Axis I Clinical Disorders • Axis II Personality Disorders & Mental Retardation • Axis III General Medical Conditions • Axis IV Psychosocial & Environmental Problems • Axis V Global Assessment of Functioning

4. A Preponderance of Autisms Social interaction: • poor eye contact • inability to regulate social interaction • inability to develop age appropriate relationships Language: • delay or lack of spoken language • abnormal or absence of imitative play Symbolic or imaginative play: • rituals • repetitive mannerisms (aka “stims”) • restricted areas of interest

5. Three Strikes Drs. Hornig and Lipkin describe in animal model studies a 3 strike concept of potential cause for neurodevelopmental disorders. It is a triad of (1) genetic susceptibility in light of (2) critically timed environmental insults of (3) sufficient severity and quantity that trigger the disease process that manifests as a neurodevelopmental disorder (i.e. PDD, ASD, etc.).

6. Understanding a Disease Process What does it look like? • Diagnostic criteria • Level of functioning • Clinical manifestations What is broken? • Genetic & Epigenetic influences • Physiology/ Biochemistry • Review of systems

7. Manifestations of an Illness • Physical • Behavioral • Developmental • Neuropsychiatric

8. Mechanisms of an Illness • Organ Systems • brain, bowel, etc. • General metabolic processes • Oxidative stress & inflammation • Individual Biochemical Pathways • trace metals, methylation, pyrrole chemistry • Systemic, regional or local • global brain effects or specific regions.

9. A Biologically Impaired Brain Primary Brain Dysfunction • Abnormalities in structure and/or maturation • Genetic predisposition for Axis 1 symptoms Acquired Brain Dysfunction • Metabolic, biochemical and nutritional imbalances • Oxidative stress and Metallothionein dysfunction => Resulting in Sensory Integration Dysfunction Disorganized processing of sensory, biochemical, or neuropsychiatric signals leading to abnormal behavior, learning and development.

10. More than the Brain • Gastrointestinal • Neurologic • Immune • Autoimmune • Metabolic • Biochemical

11. Paradigm of Autism ASD is a medical illness - with a biologically impaired brain, - commonly associated with multiple medical problems and organ systems, - with genetic and acquired factors - leading to abnormal behavior, learning, and development - that is treatable.

12. Why Oxidative Stress?

13. What is Oxidative Stress? • An excess of chemical free-radicals that can damage proteins and essential fats, as well as disrupt normal cellular processes. • Oxygen free radicals are one of many free radicals that lead to oxidative damage. Nitrogen species and ionized metals are also important free radicals.

14. Consequences of Ox Stress • Inflammation • Poor immune function • Neurodegeneration • Impaired methylation and other cellular processes • Increased sensitivity to toxic influences • Depletion of glutathione and metallothionein

15. Severity of Oxidative Injury Both genetic susceptibility and the severity of the environmental insult likely determines the degree to which the injury is manifest: (1) Mild injury results in PDD or speech delay. (2) Severe injury results in lower functioning ASD or mutism.

16. Timing of Oxidative Injury • Early injury => ASD Delayed or impaired maturation resulting in immature brain cells and developmental delay • Late or cumulative injury => Alzheimer’s Disease Degeneration of mature cells and thereby loss of previously established normal brain function.

17. Evidence of Oxidative Stress

18. Vascular Damage in the Kidney Study of treatment-naive patients with autism vs. age matched controls: • Evidence of increased oxidative markers in the urine. • Evidence of oxidative damage to vascular tissues. Yao Y et al. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol. 2006 Aug;63(8):1161-4.

19. Implications of Vascular Study • Increased oxidative damage of fats, vascular tissues, and other molecules may be present in many tissues and organs of the body, i.e. brain, bowel. • Antioxidant therapy may be helpful for patients with ASD.

20. WBC/Leukocyte Study Study of treatment-naive patients with autism vs. age matched control: • Increased oxidative stress in the white blood cell (WBC). • Increased inflammation. • Decreased immune function. • Significant disturbance in methylation. Suh J et al. Altered Sulfur Amino Acid Metabolism in Immune Cells of Children Diagnosed with Autism. Am J Biochem Biotechnol. 2008 4(2); 105-113.

21. Implications of WBC Study • Similar disturbances in cellular function extend beyond the kidney to another tissue. • Oxidative stress plays an important role in the disruption of normal cellular processes. • Biochemical abnormalities exist in autism.

22. Neuroinflammation Study of autism and control brain tissue for evidence of immune-mediated differences. • Evidence of active neuroinflammation of the cerebral cortex, white matter and cerebellum of autism brain tissue. • Evidence of a proinflammatory response in the cerebrospinal fluid of patients with autism. Vargas D et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 57 (1); 67-81.

23. Oxidative Injured Brain Study of autism brain samples for evidence of oxidative injury in comparison to control brain samples. • Direct evidence of oxidative damage was found in all samples of autism brain and in no control sample. Evans T el at. The Autistic Phenotype Exhibits a remarkably Localized Modification of Brain Protein by Products of Free Radical-Induced Lipid Oxidation. Am J Biochem Biotechnol 2008. 4(2); 61-72.

24. Implications of Ox Brain Injury • Oxidative injury of proteins in the brain would likely be associated with neurologic abnormalities. • Oxidative injury of brain tissue likely plays a role in autism. • A better understanding of oxidative injury in the brain and other tissues is needed and would likely lead to improvements in the treatment of autism.

25. What can be done?

26. Goals of Treatment • Identification of broken systems. • Restoration of normal function. • Protection from re-injury. • Promotion of normal physical, emotional, and mental health. • Thereby, establish more normal learning and development.

27. Pieces of the Autism Puzzle • Neurologic • Psychiatric • Gastrointestinal • Immunologic • Biochemical

28. Nutrients and Neurotransmission The Brain is a Chemical Factory • Zinc is required for GABA synthesis • Vitamin B6 is required for Serotonin (5-HT) synthesis • Copper (Cu++) is a cofactor in the conversion of Dopamine (DA) to Norepinephrine (NE) • The Methyl:Folate ratio impacts the levels of Dopamine, Norepinephrine and Serotonin

29. Biochemical Individuality Matters Due to genetics and epigenetic influences individuals may be • deficient in several nutrients, as well as • overloaded in others. Multiple vitamins are rarely effective, as they may • contribute to nutrient excess for those with pre-existing overload (i.e. copper, folate) and/or • induce another nutrient imbalance.

30. Targeted Treatment with Nutrients • Genetic nutrient deficiency may require many times the RDA to achieve normalization/optimization. • Genetic overloads may require biochemical therapy to eliminate the nutrient excess. • Treatment focuses on correcting specific imbalances that manifest with specific clinical symptoms.

31. Differential Diagnosis of Biochemistry • Pyrrole Disorder • Disordered Metal Metabolism - Copper Excess - Zinc Deficiency • Folic Acid-responsive Methylation (aka Low Histamine) • Methionine-responsive Methylation (aka High Histamine) • Metallothionein dysfunction

32. Pyrrole Disorder Clinical Features: Metabolic Consequences: Increased oxidative stress Vitamin B-6 Deficiency Impaired serotonin synthesis Zinc deficiency Low blood arachindonic acid levels Physiologic stress • Anxiety • Fear • Mood Swings • Stress Intolerance: Emotional, biochemical, & physical • Misperceptions • Sensory issues: Light, sound, and tactile • Increased risk of PTSD related triggers

33. Copper Excess Clinical Features: Metabolic Consequences: Increased oxidative stress Increased inflammatory responses and stresses Increased Norepinephrine effects due to increased conversion from Dopamine Increased strain on zinc requirements • Hyperactivity • Temper Tantrums • Learning problems • Agitation • Tinnitus • Depression (dysthymic or refractory) • Post-partum Depression

34. Zinc Deficiency Clinical Features: Metabolic Consequences: Reduced defense against oxidative stress Decreased GABA formation Altered copper homeostasis Impaired cell-mediated immunity Poor energy • Explosive temper • Poor memory and mental lethargy • Poor and delayed growth • Frequent infections • Poor wound healing • Acne • Diarrhea • Hypogeusia • White spots on finger nails

35. Low Blood Histamine Clinical Features: Metabolic Consequences: Folate deficiency Over-methylation Tendency to high dopamine, serotonin and norepinephrine • Generalized anxiety • Depression • Panic • Agitation & paranoia • Racing thoughts • Underachievement • Good response to benzodiazepine medication • History of significant side effects with SSRI or anti-histaminic medications

36. Elevated Blood Histamine Clinical Features: Metabolic Consequences: Methyl Deficiency Under-methylation Low levels of dopamine and serotonin. Intolerance to higher doses of folic acid. • ADHD • OCD, perfectionism • Blank mind • Rumination • Addictive behavior • Seasonal allergies • Migraine headaches • A history of good response to SSRI medication.

37. Metallothionein Short, linear, cysteine-rich proteins present in all tissues of the body that are required for trace metal metabolism and other functions: • MT I & II are present in all tissues and regulate zinc and copper; thereby cell transcription, immune function and more. Furthermore, MT I & II are in high concentrations in the intestinal and blood-brain barriers protecting the body and brain from penetration of toxic metals. • MT III is present mainly in the brain and acts as a neuronal-growth-inhibitory factor in the development, organization, and apoptosis of brain cells. • MT IV is present primarily in the GI tract and regulates stomach acid pH, and taste/texture discrimination by the tongue.

38. Metallothionein Dysfunction Disturbances in zinc and copper are directly related to MT dysfunction. Quantitative depletion: Zinc is one of the primary inducers of MT; therefore, zinc depletion leads to lower levels of MT, decreased zinc transport and zinc delivery to target tissues. Functional Impairment: Excess copper displaces zinc from MT and thereby reduces zinc availability to tissues.

39. MT Dysfunction in Autism Brain Structure and Function • impaired pruning during development • impaired functioning in tissues with high MT concentrations - Purkinjie cells, hippocampus, amygdala, pineal body and inferior olives. Impaired immune modulation and T cell function Impaired digestive enzyme function Impaired functioning of the Blood Brain Barrier and the barrier function of the bowel wall Impaired or crippled protection from oxidative stress

40. Increased Oxidative Stress Pro-oxidant Influences: Overwhelmed Defenses: Glutathione Deficiency Zinc deficiency Impaired metallothionein function Selenium deficiency Malnutrition • Elevated Copper • Emotional Stress • Environmental toxins • Immune abnormalities • Physical injury

41. Pfeiffer Research on ASD The Pfeiffer Treatment Center has evaluated approximately 20,000 patients, 5,500 with ASD, since 1989. Analysis of this data has shown: • Undermethylation in Autism, 1999. • Elevated copper/zinc in autism, 2000 • Elevated unbound copper in autism, 2001 • Metallothionein deficiency in autism, 2001 & 2003 • Confirmation of these biochemical imbalances in treatment-naïve patients with autism, 2003 • Oxidative Stress in Autism, 2006 & 2008

42. Pfeiffer Assessment • Comprehensive medical evaluation focusing on the differential diagnosis of biochemistry and associated medical conditions. • Thorough laboratory assessment of biochemistry and other conditions if needed. • Development of individualized nutrient program to address biochemical needs. • Monitoring of response to treatment and reassessment every 6-12 months.

43. Contact Information Allen T. Lewis, MD, FAAP Medical Director Pfeiffer Treatment Center 630-505-0300 4575 Weaver Parkway 630-836-0667 (fax) Warrenville, IL 60555 info@hriptc.org

44. PTC Locations