Dr Nancy O’Hara Biomedical Overview and Updatesmindd.org/s/uploads/public_members/pdfs/1BiomedicalOverviewUpd… · Function in Children with Autism and Attention Deficit Hyperactive
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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
-15.0%
-10.0%
-5.0%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
2-Mar
16-M
ar
30-M
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11-M
ay
25-M
ay8-J
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22-Ju
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20-Ju
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31-A
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14-S
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28-S
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26-O
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Perc
ent I
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ase
0
2
4
6
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12
Polle
n C
ount
Percent IncreasePollen Count
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
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