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Biomedical Interventions:

The Paradigm Shift For Practitioners

MINDD Sydney, Australia

August, 2011

Nancy O’Hara, MD www.ihealthnow.org

The emergence of a new autism model

•Everyone (including doctors) thinks using MODELS •Most doctors and researchers use an older model of autism •People using the older model often either

–Don’t know there’s a new model, –Dismiss the new model without studying it

The emergence of a new autism model

Older model

• Genetically determined

• Brain based

• Hard-wired

• Treatable but not curable

Newer model

• Environmentally triggered • Genetically influenced

• Both brain and body

• Metabolic abnormalities play big role

• Treatable and recovery possible

Is autism a BRAIN DISORDER?

OR is it A DISORDER THAT

AFFECTS THE BRAIN?

Genetics Don’t Cause Epidemics

• Increases Over the Past 20 Years – Autism: 6000% Increase

• 1/10,000 to 1/150 (Fombonne et al, JAACAP, 2001) • 1/91 (1/54 boys; National Children’s Health Survey, 2007)

– ADHD: 400% increase 7x increase in prescriptions (Swanson et al, Neuropsych Rev 2007)

– Asthma: 300% Increase – Allergies: 400% Increase – Diabetes: 103% Increase 5 x increase in <5 year old (Bingley, 2007)

What Is The Disease Process of Autism?

• Behavioral/Neurologic – Brain Inflammation – Dysregulated Neurotransmitters – Autonomic Dysfunction

• Gastroenterologic – Food Sensitivities – Intestinal Dysbiosis – Nutritional Deficits – Gut Inflammation

• Immune – Frequent Infections – Chronic Inflammation – Autoimmune Reactions – Environmental Allergies

• Biochemical/Metabolic – Oxidative Stress – Mitochondrial Dysfunction – Glutathione Depletion

Vicious Cycles

Gut inflammation

Abnormal intestinal permeability

Food sensitivities Malabsorption

Dysfunctional enzymes

Abnormal Methylation biochemistry

Increased oxidative

stress

Environmental toxins

Impaired detoxification

Increased damage from

toxins

TH1 to TH2 shift

Increased Autoimmunity

And allergy

Chronic viral And fungal infections

Dr Nancy O’Hara

Biomedical Overview and Updates

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History, General

• Family – – Autoimmune (Valicenti-McDermott) – GI, allergies, IDDM

• Prenatal – – Maternal amalgams/vaccines/meds/diet

• Neonatal – – Birth trauma/meds/vaccines – Hyperbilirubinemia (Croen et al, 2005, Pediatrics) – Breastfeeding/colic/reflux/sleep

• Environmental – EMF, water, mold, ticks

History, Specific

• Onset and Triggers • Diet – cravings, reactions • Stool – constipation, diarrhea, encopresis, overflow

around impacted stool • Illness/Injuries/Medications • Vaccines/Reactions • Signs/Symptoms • Questionnaire

Concept of brain effects secondary to pathology

elsewhere in body Gut brain axis

Gut inflammation

Abnormal intestinal permeability

Food sensitivities Malabsorption

The Gut- Brain Link

• Many studies have shown abnormalities: – Autistic enterocolitis (Ashwood et al, J Clin Immunol, 2003;

Balzola et al, Gastroenterology, 2005; Torrente et al, Am J Gastroenterol, 2005;)

– GI Symptoms (D’Souza et al, Pediatrics, 2006; Valicenti-McDermott et al, J Dev Behav Pediatr, 2006; Richler et al, J Autism Dev Disord, 2006)

– Intestinal Permeability (D’Eufemia et al, Acta Paediatr, 1996; Horvath et al, Curr Opin Pediatr, 2002; MacFabe et al, Am J of Biochem and Biotech, 2008)

Historical clues: gut dysfunction

• Difficulty breastfeeding • Persistent colic • Gastro-esophageal reflux • Food sensitivities • Failure to thrive • Frequent antibiotics (abnormal flora) • Abnormal posturing • Hands in pants/probing • Self injurious behavior • Poor sleep

Physical/Lab clues: Gut Dysfunction

• Abnormal Stools – Grainy (insoluble bile salts) – Diarrhea/constipation/encopresis

• Wasted buttocks • Distended abdomen/bloating/doughy • Esophagitis • Gastritis • Lymphoid nodular hyperplasia • Colitis (duodenitis/ileitis/proctitis) • Insatiable appetite

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Historical Clues & Physical Exam Pearls - Other

• Zinc Deficiency – Acne/sparse hair/psoriasis – White spots/lines on nails – Canker sores

• Essential Fatty Acid Deficiency – Keratosis pilaris – Dry, coarse hair

• Magnesium deficiency – Muscle twitches/tingling – Sighing – Salt craving

Gut Dysfunction

Historical and Physical Exam Clues for Dysbiosis • Parasites

– Anal itching and probing – Picking, biting, licking, grinding

• Yeast – Rash/peeling feet/ridged, discolored nails – Inflamed cheeks/red anus – Ring worm/tinea corporis or capitis

Alteration of Intestinal Function in Autism

Endoscopic examination of 36 autistics presenting intestinal symptoms showed:

• Reflux eosophagitis 69.4%

• Chronic gastritis 41.6%

• H.pylori infection 0.0%

• Chronic duodenal inflammation 66.6% » Horvath, et al

The gut in autistic children

Pathological Mucosal Alteration Observed with Autistic Subjects

• Increased size and number of lymphoid follicles particularly in ileum

• Merging of lymphoid follicles • Luminal infiltration of neutrophils, and eosinophils • Crypt cell proliferation • Ulceration of epithelium* • Thickening of basement membrane • Decreased production of brush border associated digestive

enzymes • Up-regulated Th2 and Th1 response.

All above responses are consistent with the establishment of a chronic inflammatory condition

Lab Options for Gut Issues • Urine Organic Acids Test (OATS, MAP) • Stool Microbiology • Stool Mycology • Stool Parasitology • IgG/IgE Food Panel • Celiac Panel • Fecal Fat • Breath Test for Fructose Malabsorption • Inflammatory Markers (ESR, CRP, calprotectin,…) • Ammonia - blood • IBD Serology (prometheus testing) • Endoscopy, Colonoscopy if necessary

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What To Do • Mucosal health=Promoting Immunity

• Remove stressors (e.g., allergenic foods, gluten, yeast, bacteria, parasites, clostridia)

• Supply nutrients (e.g., diet (GF/CF/SF/YF/SCD/BED/GAPS), vitamins, zinc)

• Anti-inflammatories – Ibuprofen, EFAs (1000 mg), Mesalamine, Sulfasalazine, Steroids, Minocycline, Herbs

• Supply probiotics (up to 50 bil CFU; discourage pathogens, control inflammation, encourage peristalsis)

• Encourage digestion (e.g., disscahridases, peptidases)

With Permission. Mowat AM. 2003;3:332

VICIOUS CYCLES OF INFLAMMATION

• Immune deficiency and dysfunction (ineffective or defective responses) - low IgA and IgG subclasses

• Hypersensitivity (overreaction to innocuous foreign material) – allergies, atopy

• Autoimmunity (inappropriate reaction to self) - PANDAS

• Inflammation (too robust attack on germs) - increased TNF-alpha – Esophagitis, Colitis (GI inflammation) – Atopic Dermatitis, Asthma – Neuroinflammation

TH1 to TH2 shift

Increased Autoimmunity And allergy

Chronic viral And fungal infections

The Immune- Brain Link • Many Studies have shown abnormalities:

– Immune Dysregulation (Molloy et al, J Neuroimm, 2006; Jyonouchi et al, Neuropsychobio, 2005; Gupta et al, J Autism Dev Disord, 1996)

– Autoimmunity (Zimmerman et al, Brain, Behav and Immun, 2007; Braunschweig et al, Neurotox, 2008; Singer et al, J Neuroimm, 2009)

– Immunodeficiency (Vodjani, J Neuroimm, 2008; Ferrante et al, Biomed Pharmacother, 2003; Warren et al, J Autism Dev Disord, 1986)

– Allergy/hypersensitivity (Lucarelli et al, Panminerva Med, 1995; Boris et al, J Nut & Env Med, 2004; Singh et al, J Biomed Sci, 2002)

– Neuroinflammation (Vargas et al, Annals of Neuro, 2005; Dietert et al, J Tox Envir Health B Crit Rev, 2008; Pardo, Int Rev Psychiatry, 2005; Chez et al, Ped Neuro, 2007)

Allergy Testing Figure 2

Neurobehavioral Regression in Children with Autism upon Pollen Exposure

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Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge Authors: Boris, Marvin1; Goldblatt, Allan1 Source: Journal of Nutritional & Environmental Medicine, Volume 14, Number 1, March 2004, pp. 47-54(8) Publisher:Routledge, part of the Taylor & Francis Group

Historical Clues & Physical Exam Pearls - Immune Dysregulation

• Eczema/dermatographism • Allergic shiners • Allergic rhinitis/asthma • Warts • Molluscum contagiosum • Herpes • Thrush/fungal skin infections

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Lab Clues: Immune Dysregulation

• T cell dysregulation: TH1 to TH2 shift • Decreased NK cell function • Increased TNF • Decreased IL-10, secretory IgA • Increased IgE, eosinophilia • Increased autoimmunity • Chronic viral, fungal infections • Chronic gut inflammation, intestinal permeability,

malabsorption and food sensitivities • Allergies

Immune Balance

• Cellular (T and B) • Humoral Response (Antibodies) • Cytokines (regulate initiation and maintenance of

immune response) – Th1 (IL-2, IFN) (Gupta, 1996) – Th2 (IL-4, 5, 13, TGF-beta) – Innate (TNF-alpha, IL-1, IL-6, IL-12) (Jyonouchi, 2005) – Pro-inflammatory (TNF-alpha, IL-1, IL-6) – Anti-inflammatory (TGF-beta, IL-10) – Regulatory (IL-10, IL-12, TGF-beta)

0 4 8

12 16 20 24 28 32 36

+

*

* *

Cytokine profiles in the duodenal LPL (Ashwood, 2006)

Cyt

okin

e+ C

D3

cells

(%)

IL-2 IFN g TNF a IL-4 IL-12 IL-10

Autistic Normal

Elevated Cytokine Levels in Children with ASD

• “Children with ASD had increased activation of both Th1 and Th2 arms of the adaptive immune response, with a Th2 predominance, and without the compensatory increase in the regulatory cytokine IL-10”

• DYSREGULATION! Molloy et al J Neuroimmunology 2006 March; 172: 198-205

Autoantibodies in ASD

• Maternal Antibrain Antibodies in Autism » Zimmerman et al Brain, Behavior and Immunity (2007) 21:351-

357

• Antibodies to brain proteins found in 30-37% of ASD vs 8-13% of controls

Annals of the NY Acad of Sci (2007) 1107; 92-103

• Behaviors Associated with Fever in Children with ASD – “Rapid behavioral improvements reported during fever in ASDs suggest dysfunctional neural networks and insight into neurobiological basis of potential treatments”

» Pediatrics Dec 2007; (120) e1386-e1392

BASIC INTERVENTIONS FOR IIMMUNE DYSREGULATION

• Heal the gut • Avoid what harms-casein, gluten, soy,

phenols, additives, sugar • Give what heals-antioxidants, nutrients, EFAs,

immunotherapy, HBOT • Treat underlying problems-dysbiosis,

inflammation, detoxification

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Vicious Cycles: Metabolic • Vital role of methylation

and sulfation • Downstream effects when

cycle does not function – Cannot make creatinine – Cannot make normal

neurotransmitters – Cannot control gene

expression – Cannot make cell membranes

Dysfunctional enzymes

Abnormal Methylation

biochemistry

Increased oxidative

stress

The Metabolic-Brain Link • Many studies have shown abnormalities:

– Oxidative stress (Chauhan et al, Pathophys, 2006; MacFabe et al, Behav Brain Res, 2007; Deth et al, Neurotox, 2008)

– Impaired methylation and sulphation(James et al, Am J Clin Nutr, 2004; Alberti, Biol Psychiatry, 1999; Waring, J Nutr Envir Med, 2000)

– Mitochondrial dysfunction (Oliveira et al, Dev Med Child Neurol, 2005; Rossignol et al, Am J Biochem Biotech, 2008; Gutsaeva et al, Neuroscience, 2006)

– Neurotoxicity (Rose et al, Am J Biochem Biotech, 2008; Lidsky, J Appl Res, 2005; Roberts et al, Environ, Health Perspec, 2007)

Environment Genes

Inflammation Infection

Hormones

Autism

Timing

Factors Contributing to Oxidative Stress in Autistic Children

Gut Inflammation Brain Inflammation Immune dysfunction

GIVE P5P

ADD DPPIV AVOID CASEIN

GIVE TMG

MB12 shots

Folinic acid

THTHE

THERAPEUTIC

INTERVENTIONS REDUCED

GLUTATHIONE

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Vicious Cycles: Detoxification • ASD in Relation to Distribution of

Hazardous Air Pollutants (Windham et al, Environ Health Perspec, 2006; Rauh et al, Pediatrics, 2006; Roberts et al, Environ Health Perspec, 2007)

• Reduced levels of mercury in first baby haircuts (Holmes et al, Int J Toxicol, 2003; DeSoto et al, J Child Neurol, 2008)

• Biliary mercury secretion tied to GSH (Clarkson et al, Scand J Work Environ Health, 1985)

• Environmental mercury release (Palmer et al, Health Place, 2006)

• Altered porphyrin metabolism as biomarker of mercury toxicity (Nataf et al, Toxicol Appl Pharmacol, 2006; Woods, 1996)

Environmental toxins

Impaired detoxification

Increased damage from

toxins

Texas autism rates, by school districts

1990-1993 1998-2000

Potential association between autism rates, environmental mercury other toxins in Texas

Palmer, et al., Health and Place, 12 (2006) 203–209

All Reporting Facilities, All Chemicals TRI-(1987-2002) Map shows 3,683 of 48,205 facilities reporting nationwide

Total toxicity

Autism rates

Chemicals-TRI (Toxic Release Inventory)

On average, for each 1000 lb of environmentally released mercury, there was a 43%

increase in the rate of special education services and a 61% increase in the rate of autism.

Palmer et al. Health & Place 12 (2006) 203–209

United Nations Environment Program Global Mercury Assessment, 2002

Diagnostic Lab Findings

• General Screen – Urinalysis – CBC; ESR or CRP – Chem Screen – liver and kidney function – Thyroid – including antibodies – Iron , ferritin – Zinc (plasma or PRBC) – Mitochondrial markers (ammonia , lactate, carnitine,

acylcarnitine, CK, amino acids) – Immune markers (Ig, C3D, strep pneumococcal

serotypes)

Diagnostic Lab Findings - Other • Methylmalonic acid (MMA) • Vitamin A (retinol) • Vitamin D (25 OH) • ASO, antiDNAse • Viral titers and vaccine titers (immunocompetency and not

viral persistence) • Autoantibodies (thyroid, endovasculature, brain) • Lyme testing • Lead (ongoing exposure) • Testosterone • Fasting lipid profile

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Diagnostic Lab Testing Primary /Initial

• Urine metabolic analysis/organic acids (G, GP, MM) • Comprehensive digestive stool analysis (G, DD) • IgG food antibodies including antigliadin Ab (Alletess,

Immuno, MM, G) • Porphyrin (MM) • Neopterin (urine immune marker) • 8-OHG (marker of RNA oxidation) • Cysteine (plasma)

Diagnostic Lab Testing - Secondary

• Natural Killer Cell Activity; T cell counts • Urine/Hair/Fecal metals (DD, G, MM) • Urine/RBC minerals (DD, G, MM) • Plasma amino acids (MM) • Plasma fatty acids (MM, G) • Genetic Testing (Genomics – G, IT)

• Breast is BEST! • Production of beneficial Bifidobacter • DHA rich

• Delay introduction of solid foods • Minimizing or avoiding wheat, milk, and foods first degree

relatives are sensitive to • Best first foods – avocado, fruits and vegetables

• Support flora with probiotics • Infants with a family history of atopic allergy who received a

Lactobacillus probiotic had a 50% in atopy @ 2yo

How does it all fit? Fostering A Healthy Environment

Where to Begin • Build a Foundation • Treat constipation • Diet

– GF/CF/SF/YF/SCD/BED/GAPS/LOD – The China Study (T.Colin Campbell)

• Basic Nutritional Changes – Fresh, unprocessed, unrefined, organic, whole foods – Varied and rotational – Non allergenic (crave that which most sensitive to) – Protein (every 4-5 hours) – Avoid excitotoxins (caffeine, MSG, dyes); phenolics (grapes,

strawberries) – Juicing; raw foods; fermented foods (kefir); good fats – Organic (especially pears, apples, peppers, celery, strawberries,

cherries, grapes, spinach, lettuce, potatoes, rice and chicken)

Remove and Avoid Toxicities www.cpsc.gov

www.atsdr.cdc.gov

• Eliminate toxins in food, water, environment • Filter water, use air purifier/ionizer • Avoid

– Plastics/phthalates (#3,6,7) – Pesticides, chemicals – Flame retardants – Lead painted toys, jewelry – Mercury containing fish, amalgams, vaccines, factories,

crematoriums – Acetaminophen (Schultz et al, Autism, 2008)

Replenish Nutrients • Good Flora (probiotics) • Enzymes (Kirkman, Houston) • Nutrients (MVI; Adams et al, 2004)

– Mg/B6 (Mousain-Bosc et al, 2006) – B12 (Nakano et al, 2005) – Folate (Ramaekers et al, 2007) – Ascorbic acid (Dolske et al, 1993)

• Essential fatty acids (Amminger et al, 2007) • Anti-Glutamates (pycnogenol (Trebaticka et al. 2006),

chamomile, taurine, GABA)

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Basic biomedical interventions

• HEAL THE GUT – Treat dysbiosis – Treat constipation – Decrease inflammation

• Avoid what harms – Gluten? Casein? – Additives? Toxins?

• Give what heals – Nutrients – Probiotics – Omega 3 EFAs

• FIX METABOLIC PROBLEMS – Methylcobalamin – Folinic acid – B6 & Magnesium – Glutathione, NAC – Anti-inflammatories – Detoxification

How to develop treatment plans?

• Begin with considering the individual history of your patient

• Test hypotheses about underlying problems by looking for physical exam clues and laboratory data

• Figure out if they are getting something they should not or if they are not getting what they need

• See treatments as clinical trials with an N of one