health research institute bringing balance to the world – one person at a time © hri/ptc 2008 –...

Health Research Institute

Bringing Balance to the World – One Person at a

Time© HRI/PTC 2008 – All Rights Reserved

Oxidative Stress & AutismA Paradigm for Effective Treatment

Allen T. Lewis, MD, FAAP Medical Director, Pfeiffer Treatment Center

Warrenville, Illinois


Bringing Balance to the World – One Person at a Time

© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Questions

• What is autism?

• How did it happen?

• What can be done?



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.).



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Manifestations of an Illness

• Physical

• Behavioral

• Developmental

• Neuropsychiatric



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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 DysfunctionDisorganized processing of sensory, biochemical, or neuropsychiatric signals leading to abnormal behavior, learning and development.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

More than the Brain

• Gastrointestinal• Neurologic• Immune• Autoimmune• Metabolic• Biochemical



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Why Oxidative Stress?



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Timing of Oxidative Injury

• Early injury => ASDDelayed 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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Evidence of Oxidative Stress



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

What can be done?



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Pieces of the Autism Puzzle

• Neurologic

• Psychiatric

• Gastrointestinal

• Immunologic

• Biochemical



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Pyrrole Disorder

Clinical Features:

• Anxiety• Fear• Mood Swings• Stress Intolerance:

Emotional, biochemical, & physical

• Misperceptions• Sensory issues:

Light, sound, and tactile

• Increased risk of PTSD related triggers

Metabolic Consequences:

• Increased oxidative stress• Vitamin B-6 Deficiency• Impaired serotonin

synthesis• Zinc deficiency• Low blood arachindonic

acid levels• Physiologic stress



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Copper Excess

Clinical Features:

• Hyperactivity• Temper Tantrums• Learning problems• Agitation• Tinnitus• Depression

(dysthymic or refractory)

• Post-partum Depression


• Increased oxidative stress• Increased inflammatory

responses and stresses• Increased Norepinephrine

effects due to increased conversion from Dopamine

• Increased strain on zinc requirements



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Zinc Deficiency

Clinical Features:

• Explosive temper• Poor memory and

mental lethargy• Poor and delayed growth• Frequent infections• Poor wound healing• Acne• Diarrhea• Hypogeusia• White spots on finger nails


• Reduced defense against oxidative stress

• Decreased GABA formation• Altered copper homeostasis• Impaired cell-mediated

immunity• Poor energy



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Low Blood Histamine

Clinical Features:

• 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


• Folate deficiency• Over-methylation• Tendency to high

dopamine, serotonin and norepinephrine



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Elevated Blood Histamine

Clinical Features:

• ADHD• OCD, perfectionism• Blank mind• Rumination• Addictive behavior• Seasonal allergies• Migraine headaches• A history of good response

to SSRI medication.


• Methyl Deficiency• Under-methylation• Low levels of dopamine and

serotonin.• Intolerance to higher doses

of folic acid.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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 functionImpaired digestive enzyme functionImpaired functioning of the Blood Brain Barrier and the

barrier function of the bowel wallImpaired or crippled protection from oxidative stress



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

Increased Oxidative Stress

Pro-oxidant Influences:

• Elevated Copper• Emotional Stress• Environmental toxins• Immune abnormalities• Physical injury

Overwhelmed Defenses:

• Glutathione Deficiency• Zinc deficiency• Impaired metallothionein

function• Selenium deficiency• Malnutrition



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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.



© H

RI/P

TC 2

008

– Al

l Rig

hts

Res

erve

d

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 [email protected]

health research institute bringing balance to the world – one person at a time © hri/ptc 2008 –...

Documents