Oxidative Stress & Autism A Paradigm For Effective Treatment

Oxidative Stress & Autism
A Paradigm for Effective Treatment
Allen T. Lewis, MD, FAAP

Medical Director, Pfeiffer Treatment Center
Warrenville, Illinois
Health Research
Institute
Bringing Balance to the
World – One Person at a
Time
© HRI/PTC 2008 – All Rights Reserved
Questions
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Institute
• What is autism?
• How did it happen?

• What can be done?
Bringing Balance to the World – One Person

An Axial Approach
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Institute
• 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

A Preponderance of Autisms
Health Research
Institute
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

Three Strikes
Health Research
Institute
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.).

Understanding a Disease Process
Health Research
Institute
What does it look like?

• Diagnostic criteria
• Level of functioning
• Clinical manifestations
What is broken?
• Genetic & Epigenetic influences

• Physiology/ Biochemistry
• Review of systems

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

Mechanisms of an Illness
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• 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.

A Biologically Impaired Brain
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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.

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

Paradigm of Autism
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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.

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Institute
Why Oxidative Stress?


What is Oxidative Stress?
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• 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.

Consequences of Ox Stress
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Institute
• Inflammation
• Poor immune function
• Neurodegeneration
• Impaired methylation and other cellular
processes
• Increased sensitivity to toxic influences

• Depletion of glutathione and metallothionein

Severity of Oxidative Injury
Health Research
Institute
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.

Timing of Oxidative Injury
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• 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.

Health Research
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Evidence of Oxidative Stress


Vascular Damage in the Kidney
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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.

Implications of Vascular Study
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Institute
• 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.

WBC/Leukocyte Study
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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.

Implications of WBC Study
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• 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.

Neuroinflammation
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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.

Oxidative Injured Brain
Health Research
Institute
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.

Implications of Ox Brain Injury
Health Research
Institute
• 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.

Health Research
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What can be done?


Goals of Treatment
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Institute
• 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.

Pieces of the Autism Puzzle
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Institute
• Neurologic
• Psychiatric
• Gastrointestinal
•
Immunologic
• Biochemical

Health Research
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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

Health Research
Institute
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.

Health Research
Institute
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.

Health Research
Institute
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

Pyrrole Disorder
Health Research
Institute
Clinical Features: Metabolic Consequences:

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

Copper Excess
Health Research
Institute
• Hyperactivity • Increased oxidative stress

• Temper Tantrums • Increased inflammatory
• Learning problems responses and stresses
• Agitation • Increased Norepinephrine
• effects due to increased
Tinnitus
conversion from Dopamine
• Depression
• Increased strain on zinc
(dysthymic or refractory)
requirements
• Post-partum Depression

Zinc Deficiency
Health Research
Institute

• Explosive temper • Reduced defense against
• Poor memory and oxidative stress
mental lethargy • Decreased GABA formation
• Poor and delayed growth • Altered copper homeostasis
• Frequent infections • Impaired cell-mediated
immunity
• Poor wound healing

• • Poor energy
Acne
• Diarrhea
• Hypogeusia
• White spots on finger nails

Low Blood Histamine
Health Research
Institute

• Generalized anxiety • Folate deficiency
• Depression • Over-methylation
• Panic • Tendency to high
• Agitation & paranoia dopamine, serotonin and
• norepinephrine
Racing thoughts
• Underachievement
• Good response to
benzodiazepine medication
• History of significant side
effects with SSRI or anti-
histaminic medications

Elevated Blood Histamine
Health Research
Institute

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

Metallothionein
Health Research
Institute
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.

Metallothionein Dysfunction
Health Research
Institute
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.

MT Dysfunction in Autism
Health Research
Institute
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

Increased Oxidative Stress
Health Research
Institute
Pro-oxidant Influences: Overwhelmed Defenses:

• Elevated Copper • Glutathione Deficiency
• Emotional Stress • Zinc deficiency
• Environmental toxins • Impaired metallothionein
• Immune abnormalities function
• Physical injury • Selenium deficiency
• Malnutrition

Pfeiffer Research on ASD
Health Research
Institute
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

Pfeiffer Assessment
Health Research
Institute
• 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.

Health Research
Institute
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

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Institute
PTC Locations

Oxidative Stress & Autism A Paradigm For Effective Treatment

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Oxidative Stress & Autism

A Paradigm for Effective Treatment

Allen T. Lewis, MD, FAAP

• How did it happen?

• What can be done?

Bringing Balance to the World – One Person

• Axis I Clinical Disorders

Bringing Balance to the World – One Person

Symbolic or imaginative play:

Bringing Balance to the World – One Person

Drs. Hornig and Lipkin describe in animal model

(3) sufficient severity and quantity that trigger

Bringing Balance to the World – One Person

What does it look like?

• Genetic & Epigenetic influences

Bringing Balance to the World – One Person

Bringing Balance to the World – One Person

• General metabolic processes

• Individual Biochemical Pathways

• trace metals, methylation, pyrrole chemistry

• Systemic, regional or local

Bringing Balance to the World – One Person

Primary Brain Dysfunction

Acquired Brain Dysfunction

=> Resulting in Sensory Integration Dysfunction

Bringing Balance to the World – One Person

Bringing Balance to the World – One Person

ASD is a medical illness

- leading to abnormal behavior, learning,

Bringing Balance to the World – One Person

Why Oxidative Stress?

Bringing Balance to the World – One Person

• An excess of chemical free-radicals that can

• Oxygen free radicals are one of many free radicals

that lead to oxidative damage. Nitrogen species

Bringing Balance to the World – One Person

• Increased sensitivity to toxic influences

Bringing Balance to the World – One Person

Both genetic susceptibility and the severity of the

Bringing Balance to the World – One Person

• Early injury => ASD

• Late or cumulative injury => Alzheimer’s Disease

Degeneration of mature cells and thereby loss

Bringing Balance to the World – One Person

Evidence of Oxidative Stress

Bringing Balance to the World – One Person

Study of treatment-naive patients with

Yao Y et al. Altered vascular phenotype in autism: correlation with

Bringing Balance to the World – One Person

• Increased oxidative damage of fats,

• Antioxidant therapy may be helpful for

Bringing Balance to the World – One Person

Study of treatment-naive patients with

• Significant disturbance in methylation.

Suh J et al. Altered Sulfur Amino Acid Metabolism in Immune

Bringing Balance to the World – One Person

• Similar disturbances in cellular function

Bringing Balance to the World – One Person

Study of autism and control brain tissue for

cerebrospinal fluid of patients with autism.

Bringing Balance to the World – One Person

Study of autism brain samples for evidence