The Broad Spectrum of Autism Individualizing Approaches

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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 kbock@rhinebeckhealth.com
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 cytokines
Mercury Lead
 Inflammatory
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
FOLATE CYCLE
B6
5,10-CH2-THF THF SAM
MS MSR DMG Methyl acceptor
Methionine
TRANSMETHYLATION
B12
Methyl transferase
SAH
SAHH
MTHFR
5-CH3-THF
Trimethylglycine
Methylated Product (DNA, RNA, Protein, neurotransmittors)
Homocysteine
B6
CBS
Adenosine
Cell membrane
Cystathionine
Cysteine
Reactive Oxygen Species: Peroxides Glutathione Peroxide
B6
TRANSSULFURATION
GST M1
GSH
NULL
GSSG
Courtesy of Jill James, PhD, University of Arkansas
A Targeted Approach to Autism Genetics: Using the Metabolic Endophenotype as a Guide to Candidate Genes
Methionine THF 5,10-CH2-THF
MTHFR
SAM B12
TC II DMG
Methyl Acceptor COMT
Methyltransferase
Methylated Product 5-CH3-THF RFC Homocysteine Cystathionine CBS Cysteine GCL Glutathione GST Am J Med Genetics, 2006 Adenosine SAH
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)
Naïve T Cell
IL-2
IL-4 (Other T Cells)
X
INF-γ
X
IL-4
TH1
TH2
IL-2 IFN- γ
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. 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.
Immune system over-activation, especially the
© 2009 K. Bock, MD
PATHOGENESIS FOR PANDAS
Susceptible Host
GABHS Abnormal Immune Response
Antibiotic Prophylaxis
Immunomodulatory Treatment
CNS & Clinical Manifestations
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 profile of increased pro-inflammatory cytokines and decreased regulatory activities 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
 Consistent  Further
Nutritional Supplements
Nutritional Supplements
General
 Minerals  Vitamins  Amino
Zn, Mg, Ca, Se, Cr, Mo, Fe
A, C, D, E, B6, MB12 Targeted: Taurine, Arginine, Lysine, BCAAs, Methionine EPA/DHA GLA
Acids
 Essential
fatty acids
© 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
Thiols
a free metal ion into a ring structure, thereby neutralizing its reactive state compounds which contain a sulfhydryl group (-SH) attached to a carbon atom (Ethylenediaminetetraacetic acid)
 Organic
Pharmaceutical chelators
 EDTA  DMSA
(Dimercaptosuccinic acid)  DMPS (Dimercaptopropane sulfonate)
© 2009 K. Bock, MD
CaEDTA
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 Antiviral Antibacterial Antifungal Antiparasitic
 Anti-infective
   
 Anti-inflammatory  Actos  Spironolactone  Singulair  Asachol  Prednisone  Immunomodulatory  LDN  IV IG  Hormonal  Armour Thyroid  Oxytocin
© 2009 K. Bock, MD
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 kbock@rhinebeckhealth.com
www.rhinebeckhealth.com