Biomedical Treatments for Neurodevelopmental, Autoimmune and other Chronic Disorders

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Biomedical Treatments for Neurodevelopmental,
Autoimmune and other Chronic Disorders

• David Berger, MD
• Medical Director
• Wholistic Pediatrics
• Tampa, FL
• [phone]
• www.wholisticpeds.com

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Is there an Autism Epidemic?

• Before 1985, the total incidence of Autism was
  3-5 per 10,000 Births (12000-3000). Most cases
  were from acute medical problems, present since
  birth, and caused by known genetic disorders
• By 1997, the rate of autism had increased to 30
  per 10000 births (1333), with 80 regressive
  type, after a period of normal development
• In 2004, the AAP reported the incidence of ASD at
  1166
• In 2007, the CDC has revised the incidence to
  1150
• Many people refuse to call this an epidemic,
  saying that this is just due to better diagnosis
  and awareness
• The DSM-IV criteria for Autism has NOT changed
  since the early 1990s

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Autistic Spectrum Disorders

• ADHD Aspergers PDD Autism
• Syndrome
• In many of our patients, there are multiple
  biological abnormalities

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Discover Magazine, 3/14/07
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Intestinal

• Abnormal flora (dysbiosis)
• Abnormal permeability (leaky gut)
• Illeal lymphoid hyperplasia
• Persistent Measles virus

6
Immune System

• Th1 Th2 type of WBC
• Low TH1 can cause susceptibility to infections,
  with potential increased exposure to antibiotics.
• Related Yeast Overgrowth in Intestinal Tract as
  well as Clostridia and Parasites
• High TH2 can lead to inappropriate antibody
  formation
• Auto-antibodies
• Food antibodies

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Biochemical Abnormalities

• Low sulfur amino acids
• Low zinc levels
• Low selenium levels
• High copper to zinc ratios
• Low omega 3 fatty acids
• High ammonia levels
• Abnormal methylation metabolism
• High microbial metabolites
• Elemental Toxins Mercury, Lead, etc

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Robert Cade, MD, Professor, University of
Florida Medical School

• A gluten and casein free diet resulted in
  significant improvement in 81 of children with
  autism within three months.

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Rationale for Casein/Gluten Free Diet

• Gluten and casein have immune, as well as
  neurotransmitter impacts.
• Many ASD children have food hypersensitivities
• Improper digestion leads to buildup of
  opiate-like peptides. These can be identified in
  the urine of many children with ASD.
• Dr Cade at UF recently injected rats with
  casomorphin, causing the rats to develop
  autistic-like behaviors

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DPP-IV
Dipeptidyl Peptidase IV, carboxypeptidase A, and
aminopeptidase are some of the main enzymes that
brake down the opiate peptides. Some of the
enzymes are zinc dependent, and its activity
can be inhibited by mercury, among other
things. A first generation enzyme containing
DPP-IV is available from Kirkman Labs. Although
for most children it can not serve as a sole
replacement for the C/G free diet, giving it with
these foods allow some children to take c/g foods
with out negative reactions, and it can be
administered in cases of accidental exposure
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Dr. Lewis book is the essential starting point
for a gluten and casein free diet.
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Milk It does your body good?

• Frank Oski -
• Past chairman of Johns Hopkins Department of
  Pediatrics and Past-President of the American
  Academy of Pediatrics

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Causes of Autism?

• Genetic Predisposition
• Persistent measles infection in the GI Tract
• Vitamin A deficiency following Pertussis
• Metallothionein Deficiency/Dysfunction
• Mercury Poisoning
• Inadequate Detoxification
• Nutritional Deficiencies

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Evaluating Children

• Urine and Stool Studies
• Thyroid profile
• Toxic Metals
• Inborn Errors of Amino Acids
• Fragile X, Chromosomal Analysis
• Metallothionein analysis
• RBC Fatty Acids
• Brain auto-antibodies
• Immunoglobulins, WBC activity
• Detoxification Metabolism
• Hormone Profiles

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Autism Speaks Launches Pediatrician Outreach
Initiative to Increase Awareness about the
Diagnosis and Treatment of Gastrointestinal
Problems Consensus Statement Developed by Expert
Panel Includes Recommendations for Care Specific
to Children with Autism
February 28, 2007
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Abnormal Stool Urine Findings

• Best, and in some cases imperative to treat these
  prior to starting more advanced therapies such as
  chelation
• Stool Yeast (Candida), Parasites (Giardia,
  Dientameoba, and others), Malabsorption, Blood,
  etc.
• Urine Yeast and Bacterial metabolites, abnormal
  Krebs cycle metabolites, oxalates, opiate
  peptides, etc

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Treat Stool Urine Findings

• Yeast Killers Nystatin, Diflucan, Sporonox, Uva
  Ursi, MCT, goldenseal, Garlic, Candex (digestive
  enzyme) and others.
• Clostridia Killers high dose lactobacillus,
  Metronidazole (benzoate by compounding),
  Vancomycin
• Parasites the ones we see most often are also
  sensitive to Metronidazole Benzoate, other
  specific natural and pharmacological agents used
  depending on the particular organism

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OAT test
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OAT After Culturelle and Nystatin
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Nicholas (8 y/o)After Culturelle and Nystatin(3
months later)

• Attention span has definitely improved since the
  last visit.
• getting very good reports fro the teachers
• more "with it", not spacey
• now will respond much faster when spoken to.
• Reading skills vastly improved, with good
  comprehension skills. Reading instruction manuals
  and understanding it. Wants to keep reading on
  and on.
• performing skills at school that he never did
  before. Amazing memory for spelling.
• Learned how to tell time.
• Can perform addition.
• less problems with interactions with his peers,
  but he prefers solitary play when in his house.
  When visiting others he will interact more. He
  does much better in small and quiet groups
• getting better balance of his body.

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Sulfation

• Sulfur is an element critical to the structure
  and functioning of body mechanisms.
• Dr. Rosemary Waring reports that most autistic
  children show a deficiency of sulfates in their
  plasma. Of the autistic children she tested, 92
  had sulfate levels that were only 12 of normal
• Low sulfates can lead to a leaky gut, as well as
  a weakness in the phenolsulfotransferase (PST)
  system.
• the PST pathway is important in removing toxins
• A weakness in the PST system is often
  characterized by night sweats, red face and ears,
  allergies, and keratosis pilaris (red bumps on
  back of arms)
• Tx Epsom Salt by bath or transdermal
  application, or oral sulfates such as glucosamine
  sulfate and MSM

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After Epsom Salt Baths
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Erics (6 y/o) Response to Epson Salt Baths

• Making new statements. Becoming more creative
  with language. Responding to answers
  appropriately
• still needs help focusing for long periods of
  time, but paying more attention
• echolalia is gone
• showed much more interest in presents that he
  received for the holidays.
• getting more involved with his brother, they are
  fighting a bit now.

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Ammonia

• Ammonia is a known toxin to the brain.
• High enough levels can cause can cause
  neurological symptoms, even coma. This is usually
  associated with liver disease
• About 5-10 of ASD patients we check have mild to
  moderate elevations in Ammonia levels (in the
  presence of normal liver tests)
• Proposed mechanism Proteins gtgt Amino Acids
  gtgtAmmonia gtgtliver fuses 2 ammonia molecules to
  form urea gtgt excreted in urine. Gut pathogens
  gtgt leaky gut. Urease enzyme made by certain gut
  pathogens gtgt Urease enters the bloodstream gtgt
  splits urea back to ammonia at a pace faster then
  urea can be formed.

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Connors original Ammonia level
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Connors ammonia after 2 capsules of alpha
ketoglutaric acid

• Increased speech, repeating everything
• socializing better, especially with sister
• Separation still a problem when school starts
• When peer tantrums, Conor gets upset. He did
  approach a crying child instead of running away,
  and when sister was crying he sought help instead
  of withdrawing

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Connor After 4 capsules of Alpha Ketoglutaric
Acid

• No more episodes of the rapid eye blinking or
  enlarged pupils
• interacting better with sister
• less melt-downs when others tantrum
• speech improving on a weekly basis
• sound sensitivities seem to no longer be a problem

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Essential Fatty Acids

• The Omega Factor

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Omega-3 Fatty Acid Depletion in Post-Partum Women

• After one child low DHA
• After two children lower DHA
• After three children lowest DHA
• Lactation At 16 weeks, significant decrease in
  DHA

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Omega 3s in Autism

• Replacing and Omega-3 deficiency
• (source independent)
• Vs.
• Addressing Omega deficiency and Supplementing
  with natural Vitamin A
• (Cod Liver Oil)

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Immunity is complex and impacts every system in
the body. It isnt surprising that it effects
child behavior and development.
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Immune System

• TH1 TH2 type of WBC
• Viral Stimulation
• Inappropriate antibody formation
• Auto-antibodies
• Food antibodies
• Frequent Infections - Especially Ear
• Related Yeast Overgrowth in Intestinal Tract w/
  Clostridia and Parasites

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PPARS (Peroxisome Proliferator-Activated
Receptors)

• Used in DM type II to increase insulin
  responsiveness
• 2 effect decreases Th0 moving towards Th1 and
  away from Th2.
• Boris et al at NYU studied 350 ASD children
  using ACTOS, showing significant increases in
  cognition, calmness, verbal skills and
  socialization, with decreases in aggression and
  diarrhea. 22 of these kids had hyperactivity, 9
  had periorbital edema, 34 had weight gain, 0 had
  hyperglycemia or hyperinsulinism
• Cytokines pre and post treatment have been
  measured, improvements in MBP autoantibodies and
  thyroid autoantibodies have been documented.

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IMMUNIZATIONS

• I am not suggesting that we abandon our
  vaccination policy
• I am concerned about the growing number of
  chronically ill children
• There are more children with learning
  disabilities and autoimmune disorders then there
  has ever been in the history of medicine.

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Concerns about Vaccines

• Are we unnaturally stressing underdeveloped
  immune systems beyond their capabilities in our
  effort to keep the children from becoming ill?
• There are inadequate safety studies for the
  vaccines that are currently on the market
• Are we giving too many vaccines over a short time
  span?
• We do not have a clear understanding of the
  effects of some of the vaccine components such as
  thimerosal, aluminum, formaldehyde, and human
  fetal tissue.

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Whats Going On?

• Social deficits, shyness, social withdrawal
• Repetitive, perseverative, stereotypic behaviors
  obsessive-compulsive tendencies
• Irritability, aggression, temper tantrums
• Lacks eye contact impaired visual fixation
• Loss of speech, delayed language, failure to
  develop speech
• Speech comprehension deficits
• Sound sensitivity mild to profound hearing loss
• Abnormal touch sensations touch aversion
• Flapping, myoclonal jerks, choreiform movements,
  circling, rocking, toe walking, unusual postures
• Poor concentration, attention, response
  inhibition
• Self injurious behavior, e.g. head banging
• ADHD traits
• Sleep difficulties
• Diarrhea abdominal pain/discomfort, constipation
• ALL SIGNS AND SYMPTOMS OF
• MERCURY TOXICITY

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MERCURY
StatementPediatrics 2001 Jul, American Academy
of Pediatrics Committee on Environmental Health.

The developing fetus and young children are
thought to be disproportionately affected by
mercury exposure, because many aspects of
development, particularly brain maturation, can
be disturbed by the presence of mercury.
Minimizing mercury exposure is, therefore,
essential to optimal child health..Mercury in
all of its forms is toxic to the fetus and
children, and efforts should be made to reduce
exposure to the extent possible to pregnant women
and children as well as the general
population. ______________________________________
_________________________ Vaccine inserts would
typically say 0.01 thimerosal as a
preservative, which to anyone would sound like
an extremely small amount. When called to testify
in front of the Institute of Medicine, an
independent group formed by our government to
monitor safety issues, Dr. Neil Halsey of Johns
Hopkins University, and head of the vaccine
recommendation committee that reports to the CDC,
went on record as saying No one ever did the
math. No one knows what dose of mercury, if any,
from vaccines is safe. We can say there is no
evidence of harm but the truth is no one has
looked
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Mercury/Thimerosal

• Thimerosal is Ethylmercury, a neurotoxin
• Mercury was found in the blood of newborns even
  before Hepatitis B shot, and higher levels after
  the shot.
• Journal of Pediatrics, May 2000
• In some pre-term infants, mercury levels were 10
  times that of term infants
• Pre-term babies are vaccinated according to
  chronological age, not gestational age.

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Mercury/Thimerosal

• Intrauterine sources may include

• maternal fish consumption
• mercury amalgam fillings
• Rhogam (given to Rh (-) mothers, no longer
  present)
• Influenza vaccine (still present)

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Mercury/Thimerosal

• Hepatitis B vaccine was introduced in 1991- with
  most newborns getting the first dose before
  leaving the hospital
• Hep B vaccine had contained 12.5 mcg of
  thimerosal 6.25mcg mercury
• EPA established the safe limit at 0.1
  mcg/kg/day, approximately 0.4 mcg/day for an 8
  pound newborn

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Mercury/Thimerosal

• Typical Thimerosal Exposure for 2 month old
  infant
• Hep B 12.5 mcg
• DTaP 25 mcg
• Hib 25 mcg
• Total 62.5 mcg
• of which 50 is ethylmercury 31.25mcg
• Total safe dose for 10 pound (2 month old) baby
  by EPA standards 0.5 mcg. The average 2 month
  old received 60x the EPA limit

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Mercury/Thimerosal

• By 6 months of age, a fully vaccinated infant
  would have received
• 3 DTP 75 mcg thimerosal
• 3 Hib 75 mcg thimerosal
• 3 Hep B 37.5 mcg thimerosal
• Total 187.5 mcg thimerosal
• 93.75 mcg mercury
• 1999 FDA Center for Biologics Evaluation and
  Research

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Mercury/Thimerosal

• Thimerosal was used as a preservative in all
  multiple dose vaccines (10 doses/vial)
• Shaken vs. Stirred
• The 10th child may receive 125-250 mcg per dose
  if the mercury has settled
• In 1999, the CDC called for Thimerosal to be
  removed from all vaccines.
• Physicians were told it is OK to use up the
  vaccines that they already have

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Heavy Metal Exposures

• After exposure to mercury, the length of time to
  be eliminated varies for different organs
• Blood and Hair 4-6 months
• Non CNS organs several years
• Brain 20 years
• (Boyd Haley, PhD, University of Kentucky, Dept of
  Chemistry)
• Lead typically deposits into brain and bone.
  After exposure to lead, within several months the
  blood and urine levels will be normal even if the
  lead is still in the bone and brain (Clarkson,
  2002)

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Whos looking into all of this?!?!?!
Mark R. Geier, MD, Ph.D. (Submitted to the
Institute of Medicine, of the US National Academy
of Sciences, January 2004

• There was a 6-fold statistically significantly (p
  lt 0.05) increased incidence rate of autism
  reported to VAERS following thimerosal-
  containing DTaP vaccines in comparison to
  thimerosal-free DTaP vaccines. (analyzing data
  comparing thimerosal vs. thim-free DTaP)
• In analyzing the Vaccine Safety Datalink In the
  group receiving a minimum of three doses of
  thimerosal-containing DTaP vaccine only in
  comparison to our group receiving a minimum of
  three doses of thimerosal-free DTaP vaccine only,
  that there was statistically significantly
  increased risk for autism (relative risk 27.6,
  attributable risk 3.81 per 10,000 children, p lt
  0.0001).
• What does the AAP conclude about Geiers
  research?
• Study Fails to Show a Connection Between
  Thimerosal and Autism from the AAP webpage,
  Posted May 16, 2003

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Whos looking into all of this?

• Boyd Haley, PhD, Department of Chemistry
  Chairman, University of Kentucky. Dr Haley is
  considered one of the leading researchers in
  America on Heavy Metal toxicity
• He reports that exposing neurons to thimerosal
  rapidly results in the stripping of tubuluin
  from the nerve axon, and also reduces the
  viability of actin. Actin and tubulin are
  proteins that are critically important for the
  growth of dendrites and to maintain the structure
  of the axon.
• On exposing neurons grown in culture for 24
  hours, then exposed to vaccines with thimerosal
  and thimerosal-free vaccines. There was
  significantly more cell death in those exposed to
  thimerosal vaccines. The most concerning part
  about this was that there was an extremely low
  amount of thimerosal used in the study, 10K less
  then the concentration found in most vaccines

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Whos looking into all of this?!?!?!

• When cultures of the same were then co-exposed to
  thimerosal and aluminum, and those cells died
  much faster then those with thimerosal alone
• The same neurons were then taken and half
  received thimerosal and estrogen, and half
  received thimerosal and testosterone. Those with
  estrogen co-administered were protected against
  thimerosal-induced neuron death. Those
  co-administered with testosterone had a very
  large increase in neuron death. This may explain
  the 51 ratio of boysgirls.
• His conclusion, as presented to the Institute of
  Medicine Immunization Safety Review committee
  To date the data has been very consistent the
  toxicity of the vaccines is primarily dependent
  on the presence of thimerosal, and in my opinion,
  thimerosal containing vaccines would be
  classified as severely toxic to numerous brain
  proteins

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Whos looking into this (cont)

• The following are excerpts from posters presented
  at the November 2002 International Meeting for
  Autism Research
• Hornig et al, Center for Immunopathogenesis and
  Infectious Diseases, Mailman School of Public
  Health, Columbia University, demonstrated that
  early postnatal administration of thimerosal
  using doses and timing that mimic the childhood
  immunization schedule induces mouse
  strain-specific effects on weight gain, locomotor
  and exploratory activity, stereotypic behaviors,
  and size of certain regions of hippocampus. SJL/J
  mice, a strain with heightened sensitivity to
  autoimmune disease, show the most prominent
  behavioral and neuropathological effects. In this
  strain, male gender is associated with a more
  severe outcome. (This associates a potential
  genetic predisposition may give way to a subset
  of subjects that are biologically susceptible to
  toxic effects on the brain.)

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Whos looking into this (cont)

• Holloway et al, Arizona StateOral antibiotics
  have been shown in rats to increase the half-life
  for excretion of mercury from 10 days to over 100
  days. (Doctors have been told it is OK to
  vaccinate children as long as they are not
  seriously sick, with high fevers, and there is no
  recommendations not to vaccinate children on
  antibiotics)
• Holloway et all, Arizona State 2002 carried out a
  DMSA challenge study involving 15 children with
  autism and 15 typical children. The children
  received a single dose of meso-2,3-dimercaptosucci
  nic acid (DMSA), at a dose of 10 mg/kg, followed
  by a 10-hour urine collection. The DMSA resulted
  in a much greater increase in heavy metal
  excretion in the children with autism compared to
  the controls. Many of the children with autism
  excreted high levels of one or more heavy metals,
  although there was wide variation in the amount
  and type of metal excreted. (The data suggests
  that many children with autism have a greatly
  diminished ability to excrete heavy metals, and
  thus would be unusually vulnerable to exposures
  to those metals)

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Mercury Testing

• As there is a relative short half life of mercury
  in serum, blood and urine testing will often be
  negative if more then 6 months have passed
  between exposure and testing
• Hair tests can be falsely positive if there are
  metals in shampoos, conditioners, or water. Also,
  there is evidence that mercury levels in the hair
  of autistic children is less than in controls
  (Cave and Holmes)
• For me, the best test is an oral chelation
  challenge, extracting the heavy metal and
  excreting it in the urine. This can document that
  the metal is present, it is not being excreted
  under normal circumstances, AND that the
  chelation agent and the route of administration
  given works for the individual

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Mercury Removal Chelation

• Agents
• EDTA, Dimercaprol (BAL), DMSA, DMPS, and DMPA
  all have heavy metal binding activity
• Marked specificity for heavy metals, but also can
  cause decreases in trace elements and
  micronutrients (and these should be tested for
  periodically)
• Mercury is essentially irreversibly bound to
  DMSA, so mercury is not deposited in other
  tissues, even the kidney.
• DMSA/DMPS works through increasing urinary
  excretion.
• DMSA/DMPS does not cross the blood-brain barrier,
  so no risk of delivering bound mercury to the
  brain
• Very low toxicity. Side effects may include
  anorexia, nausea, vomiting, diarrhea, rash and a
  transient increase in liver enzymes.
• There are no known adverse drug interactions with
  DMSA/DMPS.
• EDTA disodium vs Calcium disodium. Disodium EDTA
  given rapidly by IV can suddenly drop serum
  calcium levels. Only should use CaNa2 EDTA

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Mercury Removal Chelation

• oral (DMPS and DMSA)
• IV (DMPS and CaNa2 EDTA)
• Rectal (DMPS, DMSA, CaNa2 EDTA detoxamin).
• best to have stool passage before insertion
• CaNa2 EDTA seems to cause less yeast exacerbation
• TD emu oil seems the best vehicle
• seen very little benefit/movement with DMPS
• seen some positive excretions with DMSA
• CaNa2 very difficult to keep in suspension
  without precipitation

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Single dose chelation challenge

• baseline urine taken before dose given
• 8 hour urine collection regardless of type/route
• empty bladder before giving dose
• DMSA (oral or rectal 25mg/kg)
• DMPS (3mg/kg for IV, 10mg/kg for rectal,
  5-10mg/kg oral)
• CaNA2 EDTA (25-50mg/kg regardless of rout,
  maximum of 1500mg)
• May need to do more than 1 challenge with
  different agents/routes
• (DAN! 2005 Consensus Paper)

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Antonio (7 y/o) on first chelation challenge with
DMSA
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Antonio, after 4 cycles of DMSA
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Antonio, after 8 cycles of DMSA
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Antonio After Chelation with DMSA Has bad gas
during the DMSA days, and is moody, then this
goes away when the DMSA is finished. Doing
better and better in speech therapy If he does
not want to do things he cries. Teachers are
reporting improvements seen on a month-to-month
basis More hand gesturing In a more advanced
class. The mimicry behavior has stopped. At this
point language is the major barrier, behaviors
and stemming are under control
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Richard (6 y/o) on first DMSA Challenge
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Richard after 2 mo of DMSA
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Richard After Chelation
Richard Before Chelation

• No self help skills
• No bathroom skills
• No attention span
• No learning anything at school

• Using the bathroom appropriately
• Will sit still for haircuts
• Focus and attention significantly improved
• Knows his letter, numbers and colors
• Excelling in all areas of education except for
  verbal speech, though is vocalizing more then
  every before

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Baseline
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DMPS/Glutathione-IV
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DMPS/Glutathione-Rectal
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Urine Porphyrins

• Porphyrins represent a group of uniquely
  structured compounds that can surround different
  types of ions/metals. Each has a specific
  biological function
• Hemoglobin
• Myoglobin
• Chlorophyll

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Biochemistry 101
Enzymes the keys to life A B 0
C 0 D A B are substrates, the
ingredients being mixed together 0 is the
enzyme, the catalyst that makes the reaction
proceed. C D are products made by the
reaction, which can then go on to be substrates
(ingredients) in other reactions Some enzyme
reactions can go both directions
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Biochemistry 101
A B 0 C 0 D
What can cause an enzyme not to work?

• Not enough or particular substrate
• The genes that code for the enzyme are abnormal,
  creating a damaged or inefficient enzyme
• Something poisons the enzyme so it wont work
• Too much of a product (D) drives the reaction in
  the other direction

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Urine Porphyrins

• Certain toxins, such as heavy metals and
  pesticides can inhibit certain enzymes in the
  heme porphyrin pathway, leading to specific
  porphyrin profiles being excreted into the urine.
  If an enzyme is inhibited, the substrate
  upstream can build up.
• Aluminum and dioxin inhibit uropophyrin
  decaboxylase.
• Mercury inhibits coproporphyrinogen oxidase.
• Lead inhibits coproporphyrinogen oxidase and
  aminolevulinic acid dehydratase.
• (Woods, 1996)
• Second urine void of the day is the best
  collection, as supplements that cause oxidation
  if mixed with the porphyrins overnight in the
  bladder can change the structure of the porphyrin
  lead to false values (Martin, 1996)

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Urine Porphyrins

• Coproporphyrin (copro) is a general marker for
  overall toxic metal burden. It is seen elevated
  in the presence of mercury, lead and arsenic
• Precoproporphyrin (preco) an atypical porphyrin
  that only appears in the presence of mercury
• Heptacarboxyporhyrin and uroporphyrin is high on
  exposure to pesticides, PCBs, arsenic and
  aluminum
• (Woods, 2005)

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Urine Porphyrins

• Children with autism have significantly higher
  levels of copro and preco porphyrins compared to
  controls (Nataf, 2006 Geier, 2006)
• Nataf also found that the severity of autistic
  symptoms correlated with the copro level, and
  that children with autism and seizures had the
  highest copro levels.
• Urine porphyrin levels decrease with chelation
  (Pingree, 2001)

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Urine Porphyrins(how/when I use the test)

• I only send to Dr Natafs lab in France. They are
  the only commercial lab that has ranges for
  children and that autistic children has been
  studied at. The large US labs are not calibrated
  to test for levels under that which is seen in
  genetic porphyrin diseases which produce much
  higher porphyrin levels
• I prefer using the chelation challenge test, as
  it also tells me if the chelation agent/route of
  administration is working, not just if the metals
  are present.
• I order this test for
• families who do not wish to expose their
  children to a chelation agent unless there is
  proof of metals.
• If chelation challenge tests are negative but we
  still suspect metals are present
• Once chelation challenge tests are negative after
  cycles of chelation, if we still suspect metals
  are present

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Overview of The Methylation / Transsulfuration
Pathway
Methionine
Protein synthesis
MAT
THF
SAM
Methylation of DNA, RNA, proteins, membrane
phospholipids, creatine, neurotransmittors
MTase
MS
BHMT
MTHFR
SAH
MB12
Betaine
AK
SAHH
Choline
AMP
5-CH3THF
Adenosine
ADA
Homocysteine
Inosine
CBS
B6
THF tetrahydrofolate BetaineTMG
Cystathionine
B6
Cysteine
Glutathione
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The Methylation / Transsulfuration Pathway
The Enzymes MS Methionine synthase MAT
Methionine adenosyltransferase MTase Methyltran
sferase MTHFR Methylenetetrahydrofolate
Reductase SAHH S-adenosylhomocysteine
Hydrolase CBS Cystathione beta
synthase BHMT betaine-homocysteine
methyltransferase
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The Methionine Cycle Remethylation of
Homocysteine
Methionine
Protein synthesis
MAT
THF
Methylation of DNA, RNA, proteins, histones,
membrane phospholipids, neurotransmitters
SAM
MTase
MS
SAH
MB12
AK
SAHH
AMP
5-CH3THF
Adenosine
ADA
Homocysteine
Inosine
THF tetrahydrofolate
79
The Methionine Cycle Remethylation of
Homocysteine
Methionine
Protein synthesis
MAT
THF
SAM
Methylation of DNA, RNA, proteins, histones,
membrane phospholipids, neurotransmitters
MTase
MS
SAH
B12
AK
SAHH
AMP
5-CH3THF
Adenosine
ADA
Homocysteine
Inosine
THF tetrahydrofolate
80
The Methionine Cycle Remethylation of
Homocysteine
Methionine
Protein synthesis
MAT
THF
SAM
Methylation of DNA, RNA, proteins, histones,
membrane phospholipids, neurotransmitters
MTase
MS
BHMT
SAH
B12
Betaine
AK
SAHH
Choline
AMP
5-CH3THF
Adenosine
ADA
Homocysteine
Inosine
Betaine TMG
81
Methionine Transsulfuration to Cysteine and
Glutathione
Methionine
Protein synthesis
MAT
THF
SAM
Methylation of DNA, RNA, proteins, membrane
phospholipids, creatine, neurotransmittors
MTase
MS
BHMT
SAH
B12
Betaine
AK
SAHH
Choline
AMP
5-CH3THF
Adenosine
ADA
Homocysteine
Inosine
CBS
B6
THF tetrahydrofolate
Cystathionine
Transsulfuration Pathway
B6
Cysteine
Glutathione
82
Effect of Oxidative Stress on Methionine
Transsulfuration
Methionine
Protein synthesis
MAT
THF
SAM
MTase
Methylation of DNA, RNA, proteins, membrane
phospholipids, creatine, neurotransmittors
MS
BHMT
SAH
B12
Betaine
SAHH
Choline
5-CH3THF
Adenosine ( AK and/or ADA)
Homocysteine
CBS
B6
THF tetrahydrofolate
Cystathionine
B6
Cysteine
GSH GSSG
83
Neurotoxicity of Thimerosal in Human Brain
Cells is Associated with Glutathione Depletion
Protective Effect of Cysteine or Glutathione
Supplementation
S. Jill James, William Slikker, Elizabeth New,
Stefanie Jernigan, Stepan Melnyk Department of
Pediatrics University of Arkansas for Medical
Sciences Little Rock, AR
84
Neurotoxicity of Thimerosal in Human Brain
Cells is Associated with Glutathione Depletion
Protective Effect of Cysteine or Glutathione
Supplementation

• WORKING HYPOTHESIS
• Ethyl mercury in Thimerosal binds to cysteine
  thiol (SH) groups on intracellular proteins and
  inactivates function.
• The cysteine-rich antioxidant, glutathione,
  binds mercury and protects essential proteins
  from functional inactivation.
• The neurotoxicity of Thimerosal is associated
  with depletion of glutathione, the major
  intracellular antioxidant.

85
VIABILITY OF GLIOBLASTOMA AND NEUROBLASTOMA CELLS
WITH INCREASING DOSE OF THIMEROSAL
Glioblastoma Cells Neuroblastoma Cells (48
hr Exposure) (3 hr Exposure)
Viability (MTT OD)
0 2.5 5 10 20
0 2.5 5 10 20
0 2.5 5 10 20
?M Thimerosal
?M Thimerosal
86
Viability of Glioblastoma cells exposed to 15 ?M
Thimerasol in the presence of GSH-ester, Cystine,
N-acetylcysteine (NAC), or Methionine
O.D. (Viability)
Control Thimerosal GSH Cystine
NAC Methionine
87
Viability of Neuroblastoma cells exposed to 15 ?M
Thimerosal Pretreated with 100 ?M GSH-ester,
Cystine, N-acetylcysteine (NAC), or Methionine
O.D. (Viability)
Control Thimerosal GSH Cystine NAC
Methionine
88
Methyl-B12, Folinic Acid, and Betaine
Supplementation in 8 Children with Autism
Injectible Methyl-B12 (75 µg/Kg b.i.d.) was given
to the 8 children who had been taking folinic and
and betaine supplements for 3-4 months Plasma
thiol profile was repeated in the 8 children
after 4 weeks of combined folinic acid, betaine,
and methyl B12
89
Transmethyation Metabolites after addition of
Methyl-B12 to Folinic Acid and Betaine
Supplementation in 8 Autistic Children
Methionine
S-Adenosylmethionine
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Adenosine
S-Adenosylhomocysteine
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Control Before Folinic
Folinic Betaine
Betaine Me-B12
90
Transsulfuration Metabolites after addition of
Methyl-B12 to Folinic Acid and Betaine
Supplementation in 8 Autistic Children
Cysteine
Homocysteine
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Cystinyl-Glycine
Total Glutathione tGSH)
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Control Before Folinic
Folinic Betaine
Betaine Me-B12
91
Glutathione Redox Potential after addition of
Methyl-B12 to Folinic Acid and Betaine
Supplementation in 8 Autistic Children
Total Glutathione (tGSH)
Oxidized Glutathione (fGSSG)
Control Before Folinic
Folinic Betaine
Betaine Me-B12
Control Before Folinic
Folinic Betaine
Betaine Me-B12
GSH/GSSG Ratio
Control Folinic
Folinic Before Betaine
Betaine Me-B12
92
So, Why is this happening?

• Certain toxins such as mercury can inhibit the
  enzymes of this pathway.
• Dr James has looked at the DNA sequences that
  code for the proteins that make up these enzymes
  and has found that autistic children have up to 3
  times as many single DNA mutations
  (polymorphisms, SNPs) as do children without
  autism
• We have identified these SNPs in children with
  other neurodevelopmental disorders

93
OPEN CLINICAL TRIALMETHYLCOBALAMIN STUDY
JAMES A. NEUBRANDER, M.D., F.A.A.E.M.EDISON,
N.J. 08837
94
OPEN CLINICAL TRIALMETHYLCOBALAMIN STUDY
Total number of children included in the data
85 71 males14 females 84 males16
females
51 males responded12 females responded
74.1 of the childrenresponded positively!
95
OPEN CLINICAL TRIALMETHYLCOBALAMIN STUDY
THE TOP TENSymptoms Parents Reported Were Helped
Most Often
Language 71Awareness 65Cognition
52Engagement 43Eye Contact 37
Better Behavior 35More Focused
35Understanding 35Vocalization
35TryingNew Things 33
96
OPEN CLINICAL TRIALMETHYLCOBALAMIN STUDY
Side Effects Parents Reported
Hyperactivity 10Sleep Patterns Disrupted
Or Worsened 6Uncontrolled Or Unusual Laughter
3Increased Aggression 2Biting Objects
2More Distractible 2Eczematous
Symptoms Worse 2Increased Stimming
2Silliness, Unusual And Unexplained
2Teeth Grinding 2Tongue Tingles
2

• All reported side effects faded upon stopping
  therapy
• Most parents chose to resume therapy b/c
  benefits outweighed the side-effects

97
Oxalates

• Oxalates are small carbon and oxygen containing
  molecules that are found in certain types of
  fruits and vegetables. Also most nuts and seeds
  have oxalates.
• For most people, oxalates in the diet are not
  absorbed in great amounts into the bloodstream.
  They are usually metabolized by intestinal flora
  and excreted in the feces.
• In the presence of intestinal inflammation and
  leaky gut, larger amounts of oxalates can get
  into the bloodstream and be transported to
  tissues
• Under certain conditions they can crystallize and
  become deposited in tissues. The crystals can
  grow and become stones (kidney stones are calcium
  oxalate)
• When lodged in tissues, these crystals can
  produce irritation and pain.

98
Oxalates

• Oxalates seem to accumulate more in conditions of
  glutathione deficiency and oxidative stress.
• Vitamin B6 (pyridoxine) is a necessary cofactor
  for enzymes that help prevent the formation of
  oxalates
• When sulfur is deficient, it becomes extremely
  difficult to keep the body from making excess
  oxalates.
• High oxalates are associated with certain
  conditions like vulvodynia, prostatitis,
  irritable bowel syndrome, fibromyalgia,
  interstitial cystitis, and skin sensitivity. Some
  people may get a sense of urinary urgency and
  frequent urination, and sometimes the patient
  would have trouble urinating (Solomon, VP
  Foundation)
• High oxalates are often seen in patients with
  recurrent/resistant yeast infections and glycine
  intolerance.

99
Testing for High Oxalates

• There is no perfect test right now.
• Urine testing is most often used. If high values
  are seen then this is a strong indicator, but
  people secrete oxalates in their urine at
  different times of the day (it may be most
  accurate to collect multiple urine specimens
  during the day), and relative to food intake so
  there can be false negatives.
• Great Plains Lab full organic acid test reports a
  spot oxalic acid value. They also report other
  substances that are high when there are oxalate
  issues glyceric and glycolic acid
• Quest Labs has both random and 24 hour urine
  oxalate tests, both as an individual value as
  well as relative to oxalate. I usually get 24
  hour collection with oxalate.

100
Treating High Oxalates

• The low oxalate diet. Full information can be
  found at several sources
• Yahoo Group Trying_Low_Oxalates

101
Treating High Oxalates

• The Low Oxalate Cookbook is published by the
  Vulvar Pain Foundation, contains over 250
  recipes.
• The book has lists of foods with actual amount of
  oxate per serving of a food.
• Aim to keep oxalate intake down to under 40-60mg
  oxalate a day.
• Food Lists and summary can be found on Medical
  Topics section of my webpage
• Probiotics VSL3 1/2 to 1 capsule daily or ¼
  to ½ packet of the unflavored powder daily
• Reduce vitamin C to 250mg or less a day,
  including foods (oxalates can be converted to
  vitamin C)
• Calcium citrate supplementation - given with
  meals to help bind and excrete the oxalates.

102
Elevated Male Hormones/Androgens

• Several studies have demonstrated that children
  with Autism Spectrum Disorders have elevated
  androgens, including testosterone,
  dihydrotestosterone, androstendione and DHEA
  (Torjman, 1997 Knickmeyer, 2005 Geier,2006)
• Although not exclusive, increased androgens have
  been associated with increased masturbation and
  genital rubbing, aggressiveness, hyperactivity,
  self-stimming, and increased body hair (legs and
  back),
• Elevations have been seen in male and female
  patients
• I use LabCorp for my testing. They have the most
  specific reference ranges for both sex and age of
  patient.

103
Elevated Male Hormones/Androgens
The enzyme that converts DHEA to DHEA-S (storage
hormone) is sulfotransferase, which is
glutathione dependant. When this enzyme is not
working, there is a build up of DHEA which then
gets sent to androstenedione and then testosterone
104
Treating elevated Androgens

• Geier Lupron.
• belongs to a class of drugs called
  gonadotropin-releasing hormone (GnRH) agonists.
• It is used to decrease the bodys production of
  specific hormones, natural chemicals that
  influence the behavior of certain cells. Because
  Lupron Depot can reduce the production of both
  male and female hormones, it is used to treat
  specific conditions in men, women, and children
  (www.lupron.com)
• Bradstreet Spironolactone,
• a potassium sparing diuretic, also has action of
  blocking the receptor for dihydrotestosterone.
• Androgen levels should not go down with this
  treatment, but the effects of the hormone are
  blocked.

105
Treating elevated Androgens

• Berger (VERY NEW)
• Glycyrrhizin the active ingredient in licorice
  root
• decreases testosterone level by inhibiting the
  enzyme which converts of 17-OH progesterone to
  DHEA (Armanini, 1999)
• Inhibits the enzyme that converts Androstendiaone
  to Testosterone (Fukui, 2003).
• High doses can affect blood pressure and fluid
  retention, but doses lt 0.2mg/kg/d should not
  cause these side effects (van Gelderen, 2000).
• Current trials underway.
• In addition to monitoring the androgens, also
  monitoring cortisol, ACTH and blood pressure

106
Serum Hormone Concentrations in Seven Men Given
Licorice for Seven Days
Armanini D et al. N Engl J Med 19993411158
107
Risperdal

• 1st medicine specifically approved for Autism
• For use in children with aggressiveness, extreme
  hyperactivity
• Specific weight dosing is known
• Effects are immediate, often seen the first day
• Pretty easy to titrate for affective dose
• Pretty easy to get kids off of once the
  underlying reason is uncovered
• Fewer incidences of side effects compared to
  other psychotropic drugs

108
Vaccine Update(time permitting)
109
Varicella / Chicken Pox Vaccine

• Brand Name Varivax
• my initial concerns over long term protection
• when first released, one of the main talking
  points was that each shot saved the system 42
  .
• now we are seeing failures
• Either it didn't take in the first place
• or long term protection was not conferred
• now 2nd dose is being recommended between 4-6
  years old
• My recommendation as morbidity increases with
  age, if not with vaccine or definitive disease by
  age 11, get titer to see if immune and if not,
  consider the vaccine

110
Influenza Vaccine

• No guarantee that the strain of flu one is
  exposed to is 1 of the 3 that are in the vaccine
• Thimerosal-free shot now available but not
  guaranteed. Must view package insert
• Nasal spray
• now available for children 5 and older
• is mercury-free
• is a live virus
• makes some sense, as it uses the natural lines of
  defense to convey immunity
• Contraindicated for those who likely could
  benefit from it the most.those with asthma and
  immunodeficiency
• Article at www.wholisticpeds.com

111
HPV/Cervical Cancer/Genital Warts

• Brand Name Gardasil
• Not contagious disease, except for sexual
  contact. Raises ethical questions.
• Not protecting against all strains of HPV
• protects against 70 of strains causing cervical
  cancer
• protects against 90 of strains causing cervical
  warts
• being recommended for females 11-26 y/o, but can
  be given as early as 9 y/o
• for me, it is to early to assess safety, as often
  less common side effects are not seen until large
  groups of people are vaccinated such as was seen
  with..

112
Rotavirus

• 1st vaccine, called RotaShield was made available
  in the late 1990s deemed safe in pre market
  studies
• Then within the first year of widespread use
  there were at least 100 cases of intussusception,
  an acute form of bowel obstruction
• The vaccine was pulled in 1999
• 2006, a new, safer vaccine was introduced,
  called RotaTeq.
• So far, 28 cases reported so far, about half of
  them occurred within 21 days of vaccination and
  16 of the infants had to have surgery.
• Lactobacillus has been demonstrated to
  significantly shorten the length of time with
  diarrhea (Shornikova, 1997) and frequency of
  stools (Van Neil, 2002)

113
Hyperbaric Oxygen Therapy

• Definition A therapeutic modality that employs
  the application of pressures greater than ambient
  atmospheric pressure, at oxygen levels greater
  than atmospheric oxygen (gt21)
• Traditional HBOT a hard walled chamber that
  exposes the patient to a maximum of 3ATA
  (monoplace-1 patient) or 6ATA (multiplace - gt1
  patient) at 100 oxygen
• Mild HBOT (mHBOT) - a soft walled chamber that
  exposes the patient to a maximum of 1.3ATA and
  lt100 oxygen

114
Hyperbaric Oxygen TherapyLaws of Physics

• Henrys Law - the amount of a gas absorbed by a
  liquid is in proportion to the pressure of the
  gas above the liquid, provided that no chemical
  action occurs.
• Boyles Law - at a constant temperature, the
  volume and the pressure of a gas are inversely
  proportional. In other words, a gas will compress
  proportionately to the amount of pressure exerted
  on it.
• Examples of these laws
• a bottle of soda
• A scuba diver

115
Hyperbaric Oxygen TherapyHistory

• In 1662, British Physician Dr. Henshaw first used
  compressed air in an attempt to treat pulmonary
  disease. His first chamber was called the
  Domicilium. Chamber pressure was either raised
  or lowered with organ bellows
• In 1879, French surgeon Fontaine created a mobile
  chamber. He was able to increase the amount of
  oxygen carried in the blood during the
  administration of nitrous oxide anesthesia. This
  prevented blood oxygen levels from decreasing,
  which typically happened from surgical
  anesthesia
• In 1921 Cunningham constructed a 20 meter round
  ball that was the largest Hyperbaric Chamber ever
  built. It contained a smoking lounge, dining
  facilities, rich carpeting, and private quarters.

116
Hyperbaric Oxygen TherapyCunninghams Sanitarium
-1921

• Later it was scraped for metal during World War
  II.

117
Hyperbaric Oxygen TherapyHistory

• In 1934, US Naval Submarine Officer, Dr. Behnke
  proposed using oxygen plus recompression for
  Decompression Sickness (the bends). This
  information was ignored until 1967
• In 1955, Dutch thoracic surgeon, Dr. Boerma
  removed the red blood cells from pigs and found
  they could survive with oxygen dissolved in
  plasma by use of hyperbaric Oxygen.
• In 1961 Danish Dr. Brummelkamp, Published on the
  ability of HBOT to inhibit the growth of
  anaerobic bacteria - organisms that live where
  there is low or no oxygen, such as gangrene or
  tetanus.
• In June 2006 Tampa Pediatrician David Berger
  obtained his first mHBOT chamber, getting a
  second one the month later. The world has never
  been the same since.

118
Hyperbaric Oxygen TherapyOfficial Medical
Indications

• Air or Gas Embolism
• Carbon Monoxide Poisoning and Smoke Inhalation
• Carbon Monoxide Poisoning Complicated by Cyanide
  Poisoning
• Clostridial Myonecrosis (Gas Gangrene)
• Crush Injury, Compartment Syndrome, and other
  Acute Traumatic Ischemias
• Decompression Sickness (the "Bends")
• Enhancement of Healing in Selected Problem Wounds

• Exceptional Blood Loss (Anemia)
• Necrotizing Soft Tissue Infections
• Osteomyelitis (Refractory)
• Radiation Tissue Damage (Osteoradionecrosis)
• Skin Grafts and Flaps (Compromised)
• Thermal Burns

119
Hyperbaric Oxygen TherapyProposed Mechanisms of
Action

• Correct Cerebral hypoperfusion (low blood flow)
• Correct Cerebral Hypoxia (low oxygen levels)
• Decrease Neuroinflammation
• Decrease Intestinal Inflammation
• Improve Immune Function
• Reduce Oxidative Stress
• Correct Neurotransmitter Abnormalities
• Treat Intestinal Dysbiosis
• Rossignol DA, Hyperbaric oxygen therapy might
  improve certain pathophysiological findings in
  autism. Med Hypotheses (2006)

120
Hyperbaric Oxygen TherapyProposed Mechanisms of
ActionRossignol DA, Hyperbaric oxygen therapy
might improve certain pathophysiological findings
in autism. Med Hypotheses (2006)

• Differing levels of pressure and oxygen were used
  in the various studies that are discussed
• Some may be at pressures that are not being
  recommended for children with Neurodevelomental
  disorders

121
Hyperbaric Oxygen TherapyProposed Mechanisms of
Action

• Cerebral Hypoperfusion and Hypoxia in Autism
• Multiple studies have shown hypoperfusion to
  areas of the brain of children with autism,
  especially the temporal lobes. (Rye, 1999
  Zilbovicius, 2000 Ohnishi, 2000)
• The low blood flow was more profound the older a
  child is. (Wilcox, 2002)
• Autistic children often do not increase their
  cerebral blood flow when doing tasks and when
  listening and trying to speak, as seen in
  neurotypical children. (Critchley 2000, Allen
  2003).
• Decreased blood flow to the thalamus as seen on
  SPECT scans has been associated with repetitive
  and self-stimming behaviors (Starkstein, 2000)
• Decreased blood flow to Wernickes and Brodmanns
  areas (speech areas of the brain) has been
  associated with decreased auditory processing
  (Bodaert, 2002) and language development
  (Wilcox, 2002)

122
Hyperbaric Oxygen TherapyProposed Mechanisms of
Action

• Treating Hypoperfusion with HBOT
• HBOT may overcome the effects of the
  hypoperfusion by providing the brain with more
  oxygen (Sheffield, 1976 Neubauer, 1998)
• HBOT may increase new blood vessel growth
  (Al-Waili, 2006)
• Hypoperfusion may be due to inflammation.
  Inflamed vascular cells can lead to diminished
  blood flow, and inflammation in tissue prevents
  maximal uptake of oxygen by cells
• HBOT can increase the distance that Oxygen can
  travel between cells (Williams, 1997)
• Increased blood flow to the brain also means
  increased blood flow from the brain, potentially
  increasing the flow of toxins away from the
  brain. This could bring a synergistic effect with
  chelation.

123
SPECT Scans in a 4 year old autistic child after
10 dives mHBOT at 1.3 atm and 24 oxygen
Before
After Mild HBO
Heuser et al., 2002 Best Publications 2002109-15
124
HBOT 1.3 ATA, 24 Oxygen 4 year old child Before
and after 40 dives
125
Hyperbaric Oxygen TherapyProposed Mechanisms of
Action

• Neuroinflammation and Autism
• Of recent, several studies have demonstrated
  evidence that children with autism have increased
  neuroinflammation.
• Increased inflammatory cells and pro-
  inflammatory chemical mediators (cytokines) have
  been found in the CSF of Autistic Children
  (Weizman, 1982 Vargas, 2005).
• Increased brain auto-antibodies have been
  demonstrated in children with Autism (Connolly,
  1999 Singh, 1997 Vojdani, 2002 Singer, 2006)

126
Hyperbaric Oxygen TherapyProposed Mechanisms of
Action

• Gastrointestinal Inflammation and Autism
• A subset of children with Autism have
  demonstratable inflammation of their stomach,
  small intestine and colon (Furlano, 2001
  Uhlmann, 2002 Balzola, 2005 Wakefield, 2005)
• Both inflammatory cell and cytokines (TNF-?,
  IL-1?, IL-6) have been seen in increased amounts
  in the gastrointestinal lining in some children
  with Autism (Jyonouchi, 2001 Ashwood, 2003
  2004)
• Many children with autism have increased serum
  antibodies directed against casein and gluten
  based peptides (Vojdani, 2003 2004)

127
Hyperbaric Oxygen TherapyProposed Mechanisms of
Action

• Treating Inflammation with HBOT
• HBOT had been demonstrated to have
  anti-inflammatory affects on tissues (Al-Waili,
  2006)
• HBOT can decrease the production of the
  cyctokines that are pro-inflammatory such as IL-6
  and IL-1(Weisz, 1997) and TNF-?, (Yang, 2006)
• HBOT can increase the production of cytokines
  that decrease inflammation such as IL-10 (Buras,
  2006)
• HBOT has been shown in animal studies to reduce
  symptoms and inflammation of arthritis (Warren,
  1979) and peritonitis (Tokar, 2003)
• There is evidence that HBOT can facilitate
  remission for non-responsive Crohns Disease
  (Brady, 1989 Columbel, 1995) and Ulcerative
  Colitis (Buchman, 2001 Gurbuz, 2003)