The Broad Spectrum Of Autism Individualizing Approaches

THE BROAD SPECTRUM OF AUTISM

INDIVIDUALIZING APPROACHES ON THE ROAD TO RECOVERY

Kenneth A. Bock, MD, FAAFP, FACN, CNS Rhinebeck Health Center 108 Montgomery Street Rhinebeck, NY 12572 845.876.7082 [email protected]

www.rhinebeckhealth.com

Subgroups of ASD / “Autisms” Subgroups  GI/Gut-Brain  Allergy/Sensitivities  Immune Deficiency/Autoimmune  Infections Viral/Bacterial(Strep, Anaerobic)/Fungal/Parasitic  Metabolic

Enzyme Dysfunction Mitochondrial Dysfunction  Heavy

Metals/Chemicals  Inflammation © 2009 K. Bock, MD

Dysfunction in ASD Neurologic/Neurotoxic Gastrointestinal Metabolic Immunologic

© 2009 K. Bock, MD

Neurologic / Neurotoxic Dysfunction

Environmental Toxins Known to Cause Damage to Children’s Developing Brains and Nervous Systems Heavy Metals  Lead  Mercury  Cadmium  Arsenic Chemicals  PCBs  Chlorinated dibenzofurans  Organophosphate pesticides  Brominated flame retardants Woodruff et al Pediatrics; 2004; 113(4):1133-40.

Synergistic Toxicity Pb and stress Pesticides  Paraquat and maneb relative risk of Parkinson’s Disease Polybrominated diphenylethers

(PBDEs) and PCBs Heavy metals

Cory-Slechta DA Neurotoxicology 2005 Feb. Eriksson et al Toxicol Sci 2006 Dec; 94(2): 302-9.

Oxidative Stress in Autism Increased levels of prooxidants  Organic

toxins

Pesticides PCBs  Heavy

metals

Mercury Lead  Inflammatory

cytokines

Hypoperfusion  Promotes

oxidative stress  Documented by SPECT and PET scans Sadjel-Sulkowski et al Am J Biochem and Biotech 4(2):73-84, 2008.

Role of Oxidative Stress in Neurodegenerative Disorders ALS Parkinson’s Disease Alzheimer’s Disease Autism

© 2009 K. Bock, MD

INADEQUATE DETOXIFICATION IN AUTISM SPECTRUM DISORDERS Impaired sulfation  92%

of autistic children (Waring et al)

Decreased activity of PST

(Phenylsulfotransferase) Impaired methylation (James, Deth) Decreased reduced glutathione levels (James) Inadequate metallothionein function (Walsh)

Gastrointestinal Dysfunction

GI Symptoms Chronic diarrhea Constipation Alternating diarrhea/constipation Gas / bloating / abdominal

discomfort Apparent pain after eating Refusal to eat Awakening at night crying © 2009 K. Bock, MD

Gastrointestinal Abnormalities in Children with Autism Spectrum Disorders Gastrointestinal abnormalities  Impaired

digestion  Inflammation  Increased intestinal permeability  Altered bowel flora Fungal overgrowth / hypersensitivity Bacterial Parasites Viral  Food

allergies / sensitivities

© 2009 K. Bock, MD

Metabolic Dysfunction

Methylation Methionine

FOLATE CYCLE

TRANSMETHYLATION

THF

B6

SAM

5,10-CH2-THF

MS MSR

DMG

B12

MTHFR

Methyl acceptor

Methyl transferase

Trimethylglycine

Methylated Product (DNA, RNA, Protein, neurotransmittors)

SAH

5-CH3-THF

SAHH

Homocysteine

B6

Cell membrane

Adenosine

CBS

Cystathionine

Cysteine Reactive Oxygen Species: Peroxides

Glutathione Peroxide

Courtesy of Jill James, PhD, University of Arkansas

B6

TRANSSULFURATION

GST M1

GSH

NULL

GSSG

A Targeted Approach to Autism Genetics: Using the Metabolic Endophenotype as a Guide to Candidate Genes Methionine THF

SAM B12

5,10-CH2-THF

TC II

DMG

Methyl Acceptor

Methyltransferase

COMT

Methylated Product

MTHFR

5-CH3-THF

SAH

RFC Adenosine

Homocysteine Cystathionine CBS Cysteine GCL Glutathione

GST

Am J Med Genetics, 2006

GLUTATHIONE

Glutathione Modulation and MeHg Induced Neurotoxicity Maintenance of adequate GSH levels protects

against MeHg-induced oxidative stress in primary cell cultures of neurons and astrocytes Neurons more susceptible than astrocytes to MeHg toxicity due to decreased concentrations of GSH Modulation of GSH levels effectively change the intracellular concentration of MeHg, which in turn will alter the risk of MeHg-induced oxidative stress Supplementation with GSH precursor (NAC) protects against MeHg exposure in vitro Kaur et al Neurotoxicology 2006; 27:492-500

The relationship between GSH function and the systemic abnormalities associated with autism

Adapted from Kern and Jones, Journal of Toxicology and Environmental Health, Part B. 2006;(9):493.

MITOCHONDRIAL DYSFUNCTION Mercury leads to:  Uncoupling

of oxidative phosphorylation

Impaired mitochondrial energy generation Increased oxyradical formation

© 2009 K. Bock, MD

LAB CLUES TO MITOCHONDRIAL DYSFUNCTION  Chem Profile

Decreased CO2  Increased AST, CK (Poling et al, 2006) 

 Increased serum lactate, alanine, ammonia  Decreased free and total carnitine levels (Filipek et al, 2004)  Decreased glutathione  Increased lipid peroxides  Abnormal metabolites on UOAT  Muscle biopsy © 2009 K. Bock, MD

Immunologic Dysfunction

Immune Balance The key to normal immune system

function depends upon balanced immune system responses. Cellular response T

and B cells

Humoral response  Antibodies

© 2009 K. Bock, MD

Cytokines Small peptides secreted by a variety of

cells which regulate both initiation and maintenance of the immune response through a complex network

© 2009 K. Bock, MD

IL-12 (Macrophages)

IL-4 (Other T Cells)

Naïve T Cell IL-2

X INF-γ

TH1

IL-2 IFN- γ

X IL-4

TH2

IL-4 IL-5 IL-9

IL-10 IL-13

Immune Dysregulation in ASD Deficiency / dysfunction Hypersensitivity / allergy Autoimmunity Inflammation © 2009 K. Bock, MD

Increased Inflammation is Frequently Seen in Children with Autism Over-active innate inflammatory responses,

especially increased pro-inflammatory cytokines such as TNF-α, are consistent findings.

Immune system over-activation, especially the

innate immune system (although the adaptive immune system appears to be dysregulated as well) with evidence of immune inflammation, neuroinflammation and GI tract inflammation in many of these children.

© 2009 K. Bock, MD

PATHOGENESIS FOR PANDAS Susceptible Host

Immunomodulatory Treatment

GABHS Abnormal Immune Response

CNS & Clinical Manifestations

Antibiotic Prophylaxis Adapted from SE Swedo, MD Molecular Psychiatry 2002; 7: S24-S25

Integrative/Functional Medicine Approach to Chronic Inflammation and Oxidative Stress Deal with potential underlying

contributing factors

Infections, Toxins (heavy metals/chemicals), Allergens  GI issues 

Dysbiosis Intestinal hyperpermeability Food allergies/sensitivities

Environmental allergies/sensitivities  Nutritional deficiencies/imbalances  Hormonal imbalances  Immunological imbalances 

© 2009 K. Bock, MD

The Healing Program for Autism Spectrum Disorders Reduce Environmental Exposures Dietary Modifications Nutritional Supplementation Detoxification Medications

© 2009 K. Bock, MD

First and Foremost Reduce toxic exposures (as much as possible)  As in chicken, pressure treated wood  Hg in fish, emissions, vaccinations  Pb in water, soil, dust  Chemicals – multiple types Treat underlying infections  Gut  Sinuses  Fungal, Viral, Bacterial, Parasitic Avoid allergens  Foods  Environmental controls © 2009 K. Bock, MD

Dietary Modifications

Dietary Modifications Organic Foods Avoid refined carbohydrates/trans fats GF/CF Avoid reactive foods

Food allergens/sensitivities  High phenolic foods Yeast-Free 

Hypoglycemia Specific carbohydrate diet (SCD) Low oxalate diet (LOD) © 2009 K. Bock, MD

Diet as an Anti-inflammatory Therapy  Increased  Fewer

CD3(+)TNFα,CD3(+)IFNγ cells

CD3(+)IL-10 cells

 Significantly

greater proportion of CD3(+) TNFα(+) cells in colonic mucosa in those ASD children with no dietary exclusion compared with those on a gluten and/or casein free diet

 Consistent

profile of increased pro-inflammatory cytokines and decreased regulatory activities

 Further

evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and Ashwood et al immunomodulatory therapies J. Clin Immunol 2004 Nov;(6)664-73

Nutritional Supplements

Nutritional Supplements General  Minerals

Zn, Mg, Ca, Se, Cr, Mo, Fe

 Vitamins

A, C, D, E, B6, MB12

 Amino

Acids

Targeted: Taurine, Arginine, Lysine, BCAAs, Methionine

 Essential

fatty acids

EPA/DHA GLA

© 2009 K. Bock, MD

Nutritional Supplements Antioxidants Vitamin

A Vitamin C Vitamin E Selenium

© 2009 K. Bock, MD

Autism and Vitamin D Calcitrol (activated vitamin D) down-regulates

production of inflammatory cytokines in the brain (cytokines that have been associated with autism) Consumption of vitamin D-containing fish during pregnancy reduces autistic symptoms in offspring Autism is more common in:  Areas of impaired UVB penetration  Poleward latitudes  Urban areas  Areas with high pollution and high precipitation Cannell JJ Med Hypotheses 2008;70(4):750-9

Immunoregulatory and AntiInflammatory Effects of Ω-3 EFAs Dietary fish oil reduces:  MHC class II expression and antigen presentation  Production of pro-inflammatory cytokines (IL1, IL6, TNF)  The response to endotoxin and proinflammatory cytokines  Production of adhesion molecule expression Ann Nutr. Metab., 1997 Braz J. Med. Biol. Res., 1998

Curcumin Component of turmeric Nontoxic Antioxidant activity Inhibits mediators of inflammation  NFκB  Cyclooxygenase-2

(COX-2)  Lipoxygenase (LOX)  Inducible nitric oxide synthase (iNOS) Bengmark S J Parenter Enteral Nutr 2006 Jan-Feb; 30(1):45-51

Baker, SM, James, J, Milivojevich, A. Patterns of Thiol Chemistry in Autistic Children

CH3 B12 Neuroprotective effect  Enhanced

methylation

Phosphatidyl choline formation in membrane phospholipids  May

mimic effects of nerve growth factor (NGF)  Reduction of homocysteine concentration  Prevention of NO toxicity Protects neurons against NMDA receptor-mediated glutamate toxicity Akaike et al Eur Jour Pharm 241 (1993) 1-6

CH3 B12 Coenzyme in synthesizing methionine from

homocysteine via transfer of methyl group Promotes RNA synthesis Promotes protein synthesis Motoneurons  Schwann cells 

May act on both motoneurons and Schwann

cells to promote axonal regeneration

Yamazaki et al Neuroscience Letters 170 (1994) 195-197

Gastrointestinal Treatment Modalities Gastrointestinal abnormalities  Treat

inflammation  Treat dysbiosis (fungal,anaerobic)  Restore bowel flora  Restore and maintain intestinal wall integrity  Digestive enzymes

© 2009 K. Bock, MD

Detoxification

Detoxification General  Exogenous

Heavy metals Chemicals  Endogenous

Metabolites  

Bacterial/Fungal Ammonia

Glutamate Gastrointestinal  Essential to deal with constipation (if it is present) Liver © 2009 K. Bock, MD

Detoxification Methylation/Sulfation  Zinc

(picolinate, monomethionine)  Methyl B12  Folinic acid/Methyltetrahydrofolate  TMG/DMG  Reduced Glutathione  N-Acetyl Cysteine (NAC)  ES (Magnesium sulfate)  Taurine  TTFD

© 2009 K. Bock, MD

ENHANCE GLUTATHIONE NAC Alpha Lipoic Acid Vitamin C Vitamin E Silymarin Curcumin Folinic acid, TMG, Methylcobalamin TD/Nebulized Glutathione IV Glutathione  Most

direct and effective way

© 2009 K. Bock, MD

Heavy Metal Detoxification: CHELATION THERAPY Chelators  Bind

a free metal ion into a ring structure, thereby neutralizing its reactive state

Thiols

 Organic

compounds which contain a sulfhydryl group (-SH) attached to a carbon atom

Pharmaceutical chelators  EDTA

(Ethylenediaminetetraacetic acid)

CaEDTA

 DMSA

(Dimercaptosuccinic acid)  DMPS (Dimercaptopropane sulfonate) © 2009 K. Bock, MD

Heavy Metal Detoxification: CHELATION THERAPY  Nutritional considerations  Mineral

status Zinc/copper Magnesium  ES

baths/cream

Selenium Chromium Manganese  Fungal dysbiosis © 2009 K. Bock, MD

Medications

Medications  Behavioral     

Atypical antipsychotics SSRIs GABAergic agents/mood stabilizers Stimulants Central-acting α-agonists

 Anti-infective    

Antiviral Antibacterial Antifungal Antiparasitic

© 2009 K. Bock, MD

 Anti-inflammatory  Actos  Spironolactone  Singulair  Asachol  Prednisone  Immunomodulatory  LDN  IV IG  Hormonal  Armour Thyroid  Oxytocin

IV IG in Children with Autism IV IG is used in the treatment of immunological

diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles and neuromuscular junction Minimal risks Certain subset of autistic children might benefit 

Immune deficiency Low immunoglobulin levels



Increased autoantibodies Anti-MBP Anti-thyroid Anti-DNase B and anti-streptolysin O Boris et al Nutr and Environ Med 2006; 15(4):1-8

HBOT in Autism

Rossignol and Rossignol Med. Hypotheses. 2006

Conclusions: Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.

THE BROAD SPECTRUM OF AUTISM

INDIVIDUALIZING APPROACHES ON THE ROAD TO RECOVERY

Kenneth A. Bock, MD, FAAFP, FACN, CNS Rhinebeck Health Center 108 Montgomery Street Rhinebeck, NY 12572 845.876.7082 [email protected]

www.rhinebeckhealth.com