Healing the New Childhood Epidemics Through Biomedical Treatment and Interventions by Kenneth Bock

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AUTISM, ADHD, ASTHMA, AND ALLERGIES
Healing the New Childhood Epidemics:
Kenneth A. Bock, MD, FAAFP, FACN
Rhinebeck Health Center 108 Montgomery Street Rhinebeck, NY 12572 Phone: 845.876.7082 Fax: 845.876.4615 www.rhinebeckhealth.com www.4-AHealing.com
4-A Disorders
© K Bock, MD
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.
© K Bock, MD
Synergistic Toxicity
Pb and stress Pesticides
 Paraquat
& 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.
© K Bock, MD
Oxidative Stress in Autism
Increased levels of prooxidants

Organic toxins
Pesticides PCBs

Heavy metals
Mercury Lead

Inflammatory cytokines Promotes oxidative stress Documented by SPECT and PET scans
Hypoperfusion
 
© K Bock, MD
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
© K Bock, MD
Redox/Methylation Hypothesis of Autism
Proposes that environmental insults initiate
autism in genetically sensitive individuals by promoting cellular oxidative stress and initiating adaptive responses that include reduced methylation activity. Impaired methylation in turn leads to developmental delay and deficits in attention and neuronal synchronization that are the hallmarks of autism.
Deth et al Neurotoxicology (2007) Doi:10.1016/j.neuro.2007.09.010
© K Bock, MD
Redox/Methylation Hypothesis of Autism
Deth et al Neurotoxicology (2007) doi:10.1016/ j.neuro.2007.09.010
© K Bock, MD
Redox/Methylation Hypothesis of Autism
Deth et al Neurotoxicology (2007) doi:10.1016/ j.neuro.2007.09.010
© K Bock, MD
Potently Inhibit Activity of Methionine Synthase
Lead Mercury Thimerosal Alcohol Oxidative Stress
© K Bock, MD
Deth et al Neurotoxicology 2007
Methylation, Oxidative Stress & Polymorphisms
The level of MS inhibition and impaired methylation
depends upon the extent of oxidative stress, but also on SNPs affecting cobalamin and folate status, as well as SNPs affecting enzymes and metabolites of the methionine cycle (i.e., MTHFR, RFC, TCII).
© K Bock, MD
Deth et al Neurotoxicology 2007
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 SAH
Methylated Product 5-CH3-THF RFC Homocysteine Cystathionine CBS Cysteine GCL Glutathione GST Am J Med Genetics, 2006 Adenosine
© 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 glutathione levels Inadequate metallothionein function (Walsh)
© K Bock, MD
Impaired Detoxification
Leads to an overload of toxins in the body Excess toxins can lead to oxidative stress
and chronic inflammatory conditions
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Chronic Inflammation
Esophagitis Colitis Atopic Dermatitis Asthma Immune Inflammation Neuroinflammation
© K Bock, MD
CONCLUSION: Children with ASD had increased activation of both Th2 and Th1 arms of the adaptive immune response, with a Th2 predominance, and without the compensatory increase in the regulatory cytokine IL-10.
© K Bock, MD
PATHOGENESIS FOR PANDAS
Susceptible Host
GABHS Abnormal Immune Response
Antibiotic Prophylaxis
Immunomodulatory Treatment
CNS & Clinical Manifestations
© K Bock, MD
Adapted from SE Swedo, MD Molecular Psychiatry 2002; 7: S24-S25
Neuroinflammation and Oxidative Stress in Autism
Neuroglial activation and neuroinflammation in the brain of patients with autism
Vargas et al, 2005, Annals of Neurology
Carboxy-ethyl pyrrole staining in autism brains - dendrites: evidence of lipid peroxidation (from oxidative stress) that could impact synaptic transmission
– Perry, Salomon 2005 abstract
© K Bock, MD
ADHD
3 – 10% of American children have symptoms that
result in a diagnosis of ADHD 3.5 million children are on ADHD medications
1.5 million adults are on ADHD medications
Twice as many adults are on ADHD medications
now as compared to the year 2000 $3.1 billion was spent on ADHD drugs in 2005, almost four times as much as was spent in 2000 90% of all the ADHD drugs in the world are consumed in America
© K Bock, MD
ADHD
Genetic Risks Modified by Environmental Factors
© K Bock, MD
ADHD and D4 Dopamine Receptor
Association of ADHD with alleles of the DRD4
gene  7-repeat allele as the “risk” allele DRD4 is a receptor that interacts with methionine synthase  Therefore its activity will be affected when heavy metals act to lower GSH levels and methionine synthase activity
Swanson et al Neuropsych Rev 2007 Communication R Deth, 2007
© K Bock, MD
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Baker, SM, James, J, Milivojevich, A. Patterns of Thiol Chemistry in Autistic Children
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Changing Levels of Concern Regarding Lead
 Over time, researchers have identified health consequences
resulting from lead exposure at low levels
© K Bock, MD
Lane et al J Adolesc Health, 2007
© K Bock, MD
Braun et al Env Health Perspectives. 2006; 114:1907.
Our results further indicate that blood lead levels below the CDC action level of 10 µg/dL are associated with an increased risk for ADHD in children. This result is consistent with previous studies that have found cognitive deficits in children with blood lead levels < 10 µg/dL.
© K Bock, MD
Lower Levels of Lead Exposure
Attention deficits Lower IQ scores Difficulty regulating emotions Delinquency
© K Bock, MD
… a recent meta-analysis of double-blinded, placebo-controlled trials has shown a significant effect of AFCA [artificial food colors and other food additives] on the behavior of children with ADHD…
© K Bock, MD
McCann et al Lancet, Sept. 2007
The present findings, in combination with the replicated evidence for the AFCA effects on the behaviour of 3 year-old children lend strong support for the case that food additives exacerbate hyperactive behaviours (inattention, impulsivity and overactivity) in children at least up to middle childhood … These findings show that adverse effects are not just seen in children with extreme hyperactivity (i.e., ADHD), but can also be seen in the general population and across the range of severities of hyperactivity. Our results are consistent with those from previous studies and extend the findings to show significant effects in the general population. The effects are shown after a rigorous control of placebo effects and for children with the full range of levels of hyperactivity. We have found an adverse effect of food additives on the hyperactive behaviour of 3 year-old and 8/9 year-old children.
© K Bock, MD
McCann et al Lancet, Sept. 2007.
Are ADHD, CFS and FM Allergy Related?
 Precise etiologies have not been identified  Appear to be initiated or exacerbated by allergic
mechanisms  Emerging evidence to suggest that adverse reactions to foods or food components may be associated with behavioral disturbances that may play a role in each of these disorders  An understanding of the interactive responses involved in the neuroendocrine-immunological networks is essential for a comprehension of the pathophysiology of ADHD, CFS and FM, and the role of allergies appears to be an important triggering event in each of these disorders
Bellanti et al Allergy Asthma Proc 2005; 26(1):19-28.
© K Bock, MD
Asthma is a Th2-based Chronic Inflammatory Disorder
 Striking increase in worldwide prevalence and severity of allergic
asthma, particularly in developed countries, during the past three decades  Persistent stimulation of innate host response involving microbial pattern recognition and development of adaptive Th1 immunity antagonizes the development of Th2-dependent responses, which protect against asthma  Reduced microbial burden in the young deprives the developing immune system of microbial antigens needed to stimulate Th1 cells, and consequently favors the evolution of Th2 responses – the basis of the hygiene hypothesis.  Importance of correct balance between these two arms of the immune response  However, that is not the whole story
 
Increased prevalence of asthma might also stem from an under-representation of regulatory T cells (T regs) Breakdown in normal regulatory networks that operate among T cells results in immunological mayhem Wahl et al
Curr Opin Immunol 2004;16:1-7.
© K Bock, MD
Factors Contributing to Increased Prevalence of Allergy
Reduction in antigenic stimulation brought about
by

Widespread vaccination  Improvements in standards of hygiene  Extensive use of antibiotics Has contributed to the dysregulation of Th2-type
responsiveness that typifies allergy Due to a deficient immunoregulatory network and/or a lack of microbial stimulation
© K Bock, MD
Prioult and Nagler-Anderson Immunol Rev 2005; 206:204-18.
© K Bock, MD
CONCLUSION: This study provides the first experimental evidence to support a role for antibiotics and fungal microbiota in promoting the development of allergic airway disease. In addition, these studies also highlight the concept that events in distal mucosal sites such as the GI tract can play an important role in regulating immune responses in the lungs.
© K Bock, MD
Infect Immun. 2004;72(9):49965003.
Recent epidemiological studies and experimental research suggest that the microbial environment and exposure to microbial products in infancy modifies immune responses and enhances the development of tolerance to ubiquitous allergens. The intestinal microflora may play a particular role in this respect, as it is the major external driving force in the maturation of the immune system after birth and animal experiments have shown it to be a prerequisite for normal development of oral tolerance. The composition of the microflora differs between healthy and allergic infants and in countries with a high and low prevalence of allergies. These differences are apparent within the first week of life, or even in the maternal vaginal flora during pregnancy and thus precede clinical symptoms. The use of live microorganisms that might be beneficial to health has a long tradition and the safety is well documented. Prospective intervention studies, in which the gut flora was modified from birth have yielded encouraging results and may suggest a new mode of primary prevention of allergy in the future.
© K Bock, MD
Asthma, Genes and Air Pollution
 Formation of ROS is a major aspect of the inflammatory
process of asthma  Oxidative stress is a key mechanism underlying the toxic effects of exposure to some types of air pollution  Key role of antioxidants in reducing the inflammatory response associated with exposure to diesel exhaust particles  People with a polymorphism at the GSTP1 locus, which codes for GST (Glutathione S-transferase), one of a family of pulmonary antioxidants, have higher rates of asthma  Asthmatics with the null genotype for GST seem more at risk of the pulmonary effects of air pollution
© K Bock, MD
McCunney J. Occup Environ Med 2005; 47(12):1285-91.
Asthma Triggers
 Allergy to indoor allergens
  
 Allergy to certain seasonal fungal spores
House dust mite Cockroach
 Chronic exposure to environmental tobacco smoke  Exposure to other indoor irritants, including products of unvented
70 – 85% asthmatic populations studied have positive skin-prick tests
combustion  Outdoor air pollution

 Rhinitis/Sinusitis  Gastroesophageal reflux  Exposure to aspirin, NSAIDs, metabisulfites (in sensitive patients)  Viral infections  Bacterial Infections Nelson
 
Ozone, respirable particulates, nitrogen dioxide
 Food Allergies
© K Bock, MD
Chlamydia pneumoniae Mycoplasma pneumoniae
Clin Cornerstone 1995; 1(2):57-65
Byrd, Joad Curr Opin Pulm Med 2006; 12(1):68-74
Physical Exam
Allergic shiners Dilated pupils Keratosis pilaris Leukonychia Perianal erythema Abdominal distention/bloating Thick, protruding tongue Coarse hair Geographic tongue Focal neurologic signs
© K Bock, MD
INTEGRATIVE MEDICINE APPROACH TO CHRONIC INFLAMMATION AND OXIDATIVE STRESS
Deal with potential contributing underlying 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

© K Bock, MD
THE HEALING PROGRAM FOR THE 4-A DISORDERS
Reduce Environmental Exposures Dietary Modifications Nutritional Supplementation Detoxification Medications
© 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
© K Bock, MD
Dietary Modifications
Organic Foods Avoid refined carbs and trans fats GF/CF Avoid reactive foods
Food allergens/sensitivities  High phenolic foods Yeast-Free

Hypoglycemia Specific carbohydrate diet (SCD) Low oxalate diet (LOD)
© K Bock, MD
Diet as an Anti-inflammatory Therapy
  
Increased CD3(+)TNFα,CD3(+)IFNγ cells Fewer 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 Ashwood et al dietary and immunomodulatory therapies


© K Bock, MD
J. Clin Immunol 2004 Nov;(6)664-73.
Nutritional Supplements
General
 Minerals
Zn, Mg, Ca, Se, Cr, Mo, Fe
 Vitamins
A, C, D, E, B6, MB12
 Amino
Acids fatty acids
Targeted: Taurine, Arginine, Lysine, BCAAs, Methionine
 Essential
EPA/DHA GLA
© K Bock, MD
Nutritional Supplements
Antioxidants
Vitamin
A Vitamin C Vitamin E Selenium
© K Bock, MD
PROBIOTICS
 Bifidobacteria species:
 bifidus,
longum, infantis, breve, lactis bulgaricus, thermophilus,
 Lactobacillus species:
 acidophilus,
rhamnosus
 Saccharomyces boulardii – competes with
Candida
© K Bock, MD
Nutritional Treatment of ADHD
 ADHD – complex multidetermined disorder requires
multifactorial treatment approach  Nutritional management

Nutritional factors linked to ADHD
Food additives Refined sugars Food sensitivities/allergies EFA deficiencies
 Increasing evidence that many children with behavioral
problems are sensitive to one or more food components that can negatively impact their behavior  Individual response/individual approach  In general, diet modification plays a major role in the management of ADHD and should be considered as part of the treatment protocol Schnoll et al
© K Bock, MD
Appl Psychophysiol Biofeedback 2003; 28(1):63-75
Zinc and ADHD
 DBPC clinical trial  44 children  6 weeks – methylphenidate + zinc sulfate (15 mg
elemental zinc) methylphenidate + placebo  Results: significant improvement in parent and teacher rating scale scores with zinc sulfate
© K Bock, MD
Akhondzadeh et al BMC Psychiatry 2004; 4:9
CONCLUSIONS: These results suggest that low iron stores contribute to ADHD and that ADHD children may benefit from iron supplementation.
© K Bock, MD
Melatonin and ADHD
 Hormone that plays an important role in the
regulation of dopamine  Helpful in regulating the sleep cycle of children with ADHD  Zinc involved in the production and modulation of melatonin
© K Bock, MD
Akhondzadeh et al BMC Psychiatry 2004; 4:9
Quercetin
Flavonoid

High concentrations in fruits, such as apple peels
Shown to down-regulate inflammatory contribution
of mast cells as well as the expression of cytokines in bronchial epithelium. Has been shown in vitro to induce gene expression of TH1 cytokines in monocytes and to inhibit the TH2 cytokine IL4
Min YD, Choi CH, et al. Inflamm Res. 2007 May; 56(5): 210-5. Kandere-Grzybowska K, Kempuraj D, et al. Br J Pharmacol 2006 May; 148(2): 208-215. Nanua S, Zick SM, et al. Am J Resp Cell Mol Biol. 2006 Nov; 35(5): 602-10. Nair MP, Kandaswami C, et al. Biochem Biophys Acta. 2002 Cec
© K Bock, MD
Immunoregulatory and Anti-Inflammatory 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
© K Bock, MD
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)
© K Bock, MD
Bengmark S J Parenter Enteral Nutr 2006 Jan-Feb; 30(1):45-51.
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
© K Bock, MD
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
© K Bock, MD
Yamazaki et al Neuroscience Letters 170 (1994) 195-197
Detoxification
Methylation/Sulfation  Zinc (picolinate, monomethionine)  Methyl B12  Folinic acid/Methyltetrahydrofolate  TMG/DMG  Reduced Glutathione  N-Acetyl Cysteine (NAC)  ES (Magnesium sulfate)  Taurine  TTFD
© K Bock, MD
The findings reported in this study have largely contributed to the understanding of the subject of Pb neurotoxicity. They show that the dose response relationship might not be the major determinant of the absorption and toxicity of Pb – that even relatively low Pb levels might be potentiated by decreased thiamine and Mg levels, particularly in a predominantly carbohydrate-dependent region, where there is an increased demand for thiamine and Mg for proper carbohydrate metabolism.
© K Bock, MD
Anetor et al Biol Trace Element Research Vol. 116, 2007.
Curcumin and Lead-induced Neurotoxicity
 Animal (rat) study investigating the neuroprotective effects of
curcumin against lead-induced neurotoxicity  Results show that lead significantly increases lipid peroxidation and reduces the viability of primary hippocampal neurons in culture  This lead-induced toxicity was significantly decreased by the coincubation of the neurons with curcumin  Curcumin-treated animals had more glutathione and less had oxidized proteins in the hippocampus than those treated with lead alone Retained spatial reference memory (i.e., water maze)  Findings indicate that curcumin, a well-established dietary antioxidant, is capable of playing a major role against heavy metalinduced neurotoxicity and has neuroprotective properties
© K Bock, MD
Dairam et al J Agric Food Chem 2007; 55(3), 1039-1044.
N-Acetyl Cysteine
© K Bock, MD
NAC
 Thiol-containing
antioxidant  Free-radical scavenger  Stimulates endogenous glutathione synthesis
© K Bock, MD
Flora et al Cell Mol Biol 2004; 50: OL543-51.
GLUTATHIONE
© K Bock, MD
Enhance Glutathione
NAC Alpha Lipoic Acid Vitamin C Vitamin E Silymarin Folinic acid, TMG, Methylcobalamin TD/Nebulized Glutathione IV Glutathione
 Most
© K Bock, MD
direct and effective way
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)

© K Bock, MD
Chelators
EDTA
DMSA
© K Bock, MD
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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
© K Bock, MD
HBOT in Autism
© K Bock, MD
Rossignol and Rossignol Med. Hypotheses. 2006.
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
© K Bock, MD
Boris et al Nutr and Environ Med 2006; 15(4):1-8.
Conclusion
 The 4-A disorders are:  Linked together by the commonality of genetic vulnerability/susceptibility triggered by environmental factors – especially toxins as well as infections and allergens  Heterogeneous
Various subgroups within each diagnostic category, as well as diverse contributing etiologic factors

Treatable, remediable and in increasing numbers of children, reversible
Using biomedical treatment approaches coupled with other appropriate therapies, such as behavioral and educational interventions
 Prevention of these childhood disorders is the most
desirable outcome

This goal may prove to be the most challenging, requiring, in addition to clinicians, researchers, and parents; governmental and corporate cooperation and intervention
© K Bock, MD
© K Bock, MD
© K Bock, MD