Transcript Bringing Balance to the World – One Person at a Time

Oxidative Stress & Autism
A Paradigm for Effective Treatment
Allen T. Lewis, MD, FAAP
Medical Director, Pfeiffer Treatment Center
Warrenville, Illinois
Health Research Institute
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One Person at a Time
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Questions
• What is autism?
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• How did it happen?
• What can be done?
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An Axial Approach
• Axis I
• Axis II
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• Axis III
• Axis IV
• Axis V
Clinical Disorders
Personality Disorders &
Mental Retardation
General Medical Conditions
Psychosocial &
Environmental Problems
Global Assessment of Functioning
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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
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Symbolic or imaginative play:
• rituals
• repetitive mannerisms (aka “stims”)
• restricted areas of interest
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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.).
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Understanding a Disease Process
What does it look like?
• Diagnostic criteria
• Level of functioning
• Clinical manifestations
What is broken?
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• Genetic & Epigenetic influences
• Physiology/ Biochemistry
• Review of systems
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Manifestations of an Illness
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• Physical
• Behavioral
• Developmental
• Neuropsychiatric
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Mechanisms of an Illness
• Organ Systems
• brain, bowel, etc.
• General metabolic processes
• Oxidative stress & inflammation
• Individual Biochemical Pathways
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• trace metals, methylation, pyrrole chemistry
• Systemic, regional or local
• global brain effects or specific regions.
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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
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=> Resulting in Sensory Integration Dysfunction
Disorganized processing of sensory, biochemical, or
neuropsychiatric signals leading to abnormal behavior,
learning and development.
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More than the Brain
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Gastrointestinal
Neurologic
Immune
Autoimmune
Metabolic
Biochemical
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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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Why Oxidative Stress?
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What is Oxidative Stress?
• An excess of chemical free-radicals that can
damage proteins and essential fats, as well as
disrupt normal cellular processes.
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• Oxygen free radicals are one of many free radicals
that lead to oxidative damage. Nitrogen species
and ionized metals are also important free radicals.
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Consequences of Ox Stress
• Inflammation
• Poor immune function
• Neurodegeneration
• Impaired methylation and other cellular
processes
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• Increased sensitivity to toxic influences
• Depletion of glutathione and metallothionein
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Severity of Oxidative Injury
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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.
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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
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Degeneration of mature cells and thereby loss
of previously established normal brain function.
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Evidence of Oxidative Stress
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Vascular Damage in the Kidney
Study of treatment-naive patients with
autism vs. age matched controls:
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• 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.
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Implications of Vascular Study
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• 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.
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WBC/Leukocyte Study
Study of treatment-naive patients with
autism vs. age matched control:
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• 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.
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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.
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Neuroinflammation
Study of autism and control brain tissue for
evidence of immune-mediated differences.
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• 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.
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Oxidative Injured Brain
Study of autism brain samples for evidence
of oxidative injury in comparison to control
brain samples.
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• 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.
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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.
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What can be done?
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Goals of Treatment
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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.
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Pieces of the Autism Puzzle
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Neurologic
Psychiatric
Gastrointestinal
Immunologic
Biochemical
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Nutrients and Neurotransmission
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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
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Biochemical Individuality Matters
Due to genetics and epigenetic influences
individuals may be
- deficient in several nutrients, as well as
- overloaded in others.
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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.
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Targeted Treatment with Nutrients
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Genetic nutrient deficiency may require many times
the RDA to achieve normalization/optimization.
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• Genetic overloads may require biochemical therapy
to eliminate the nutrient excess.
• Treatment focuses on correcting specific
imbalances that manifest with specific clinical
symptoms.
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Differential Diagnosis of Biochemistry
• Pyrrole Disorder
• Disordered Metal Metabolism
- Copper Excess
- Zinc Deficiency
• Folic Acid-responsive Methylation
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(aka Low Histamine)
• Methionine-responsive Methylation
(aka High Histamine)
• Metallothionein dysfunction
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Pyrrole Disorder
Clinical Features:
Metabolic Consequences:
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• 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
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• Misperceptions
• Sensory issues:
Light, sound, and tactile
• Increased risk of PTSD
related triggers
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Copper Excess
Clinical Features:
Metabolic Consequences:
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• 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
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(dysthymic or refractory)
• Post-partum Depression
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Zinc Deficiency
Clinical Features:
Metabolic Consequences:
• 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
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Low Blood Histamine
Clinical Features:
Metabolic Consequences:
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• 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 antihistaminic medications
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Elevated Blood Histamine
Clinical Features:
Metabolic Consequences:
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• 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.
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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.
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• MT III is present mainly in the brain and acts as a neuronalgrowth-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.
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Metallothionein Dysfunction
Disturbances in zinc and copper are directly related
to MT dysfunction.
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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.
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MT Dysfunction in Autism
Brain Structure and Function
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• 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
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Increased Oxidative Stress
Pro-oxidant Influences:
Overwhelmed Defenses:
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• Glutathione Deficiency
• Zinc deficiency
• Impaired metallothionein
function
• Selenium deficiency
• Malnutrition
Elevated Copper
Emotional Stress
Environmental toxins
Immune abnormalities
Physical injury
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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:
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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 treatmentnaïve patients with autism, 2003
– Oxidative Stress in Autism, 2006 & 2008
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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.
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Contact Information
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Allen T. Lewis, MD, FAAP
Medical Director
Pfeiffer Treatment Center
4575 Weaver Parkway
630-505-0300
630-836-0667 (fax)
Warrenville, IL 60555
[email protected]
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PTC Locations
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