Healing the New

Childhood Epidemics:
AUTISM, ADHD, ASTHMA, AND ALLERGIES

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;
© K Bock, MD 113(4):1133-40.
 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
© K Bock, MD 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
© K Bock, MD 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)
© K Bock, MD Doi:10.1016/j.neuro.2007.09.010
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

Deth et al
© K Bock, MD 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).

Deth et al
© K Bock, MD Neurotoxicology 2007
 A Targeted Approach to Autism Genetics:
Using the Metabolic Endophenotype as a
Guide to Candidate Genes

Methionine

THF
SAM Methyl Acceptor
DMG
5,10-CH2-THF B12 TC II Methyltransferase COMT

MTHFR Methylated Product

5-CH3-THF SAH
RFC
Homocysteine Adenosine

Cystathionine
CBS
Cysteine
GCL
Glutathione GST Am J Med Genetics, 2006
© 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

© K Bock, MD
 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

Immunomodulatory
Treatment
GABHS

Abnormal
Immune CNS & Clinical
Response Manifestations
Antibiotic Prophylaxis

Adapted from
SE Swedo, MD
© K Bock, MD Molecular Psychiatry 2002; 7: S24-S25
 Neuroinflammation and Oxidative Stress
in Autism

Carboxy-ethyl pyrrole staining in autism

Neuroglial activation and
neuroinflammation in the brain
of patients with autism
Vargas et al, 2005, Annals of Neurology
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
© K Bock, MD Communication R Deth, 2007
 Baker, SM, James, J, Milivojevich, A.
© K Bock, MD Patterns of Thiol Chemistry in Autistic Children
© K Bock, MD
Changing Levels of Concern Regarding Lead

 Over time, researchers have identified health consequences

resulting from lead exposure at low levels

Lane et al
© K Bock, MD J Adolesc Health, 2007
 Braun et al
Env Health Perspectives.
© K Bock, MD 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…

McCann et al
© K Bock, MD
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.

McCann et al
© K Bock, MD 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
© K Bock, MD 2005; 26(1):19-28.
 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
© K Bock, MD
2004;16:1-7.
 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

Prioult and Nagler-Anderson

Immunol Rev
© K Bock, MD 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.

Infect Immun.
© K Bock, MD 2004;72(9):4996-
5003.
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

McCunney
J. Occup Environ Med
© K Bock, MD 2005; 47(12):1285-91.
 Asthma Triggers
 Allergy to indoor allergens
 House dust mite
 Cockroach
 Allergy to certain seasonal fungal spores
 70 – 85% asthmatic populations studied have positive skin-prick tests
 Chronic exposure to environmental tobacco smoke
 Exposure to other indoor irritants, including products of unvented
combustion
 Outdoor air pollution
 Ozone, respirable particulates, nitrogen dioxide
 Rhinitis/Sinusitis
 Gastroesophageal reflux
 Exposure to aspirin, NSAIDs, metabisulfites (in sensitive patients)
 Viral infections
 Bacterial Infections Nelson
 Chlamydia pneumoniae Clin Cornerstone
1995; 1(2):57-65
 Mycoplasma pneumoniae
 Food Allergies Byrd, Joad
Curr Opin Pulm Med
© K Bock, MD 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
dietary and immunomodulatory therapies Ashwood et al
J. Clin Immunol
© K Bock, MD 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
Targeted: Taurine, Arginine, Lysine, BCAAs, Methionine
 Essential fatty acids
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

 Lactobacillus species:
 acidophilus, bulgaricus, thermophilus,
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
Appl Psychophysiol Biofeedback
© K Bock, MD 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

Akhondzadeh et al
BMC Psychiatry
2004; 4:9
© K Bock, MD
 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

Akhondzadeh et al
BMC Psychiatry
© K Bock, MD 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.
© K Bock, MD 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
 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 pro-
inflammatory cytokines
 Production of adhesion molecule
expression
Ann Nutr. Metab., 1997
© K Bock, MD 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.
© K Bock, MD
 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
© K Bock, MD 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
© K Bock, MD 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.

Anetor et al
Biol Trace Element
Research
© K Bock, MD 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 co-
incubation 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 metal-
induced neurotoxicity and has neuroprotective properties
Dairam et al
J Agric Food Chem
© K Bock, MD 2007; 55(3), 1039-1044.
 N-Acetyl Cysteine

© K Bock, MD
 NAC

 Thiol-containing antioxidant
 Free-radical scavenger
 Stimulates endogenous glutathione synthesis

Flora et al
© K Bock, MD 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 direct and effective way
© 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)

© K Bock, MD
 Chelators

EDTA DMSA

© K Bock, MD
© K Bock, MD
© K Bock, MD
 Medications
 Behavioral  Anti-inflammatory
 Actos
 Atypical antipsychotics  Spironolactone
 SSRIs  Singulair
 Asachol
 GABAergic agents/mood
 Prednisone
stabilizers
 Immunomodulatory
 Stimulants  LDN
 Central-acting α-agonists  IV IG
 Anti-infective  Hormonal
 Armour Thyroid
 Antiviral  Oxytocin
 Antibacterial
 Antifungal
 Antiparasitic
© K Bock, MD
 HBOT in Autism

Rossignol and Rossignol

© K Bock, MD 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
Boris et al
© K Bock, MD 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