Paradigm Shift in Models of Autism
(adapted from Martha Herbert, PhD)
Specificity
Local changes
Widespread insults with
local vulnerabilities
Locus
Cause
Brain based
Genetics
Systemic
Genetic susceptibilities,
environmental insults
Timing
Prenatal
Plasticity
Hardwired
Prognosis
Incurable
Triggers affecting
developmental stages
Architectural and
Metabolic changes
Treatable
Four Vicious Cycles
Food sensitivities
Malabsorption
Gut inflammation
Increased
oxidative
stress
Dysfunctional
enzymes
2
1
Abnormal intestinal permeability
Increased
damage from
toxins
Environmental
toxins
4
Impaired
detoxification
Slide courtesy of Dr. Liz Mumper
Abnormal
Methylation
biochemistry
Chronic viral
And fungal
infections
TH1 to TH2
shift
3
Increased
Autoimmunity
And allergy
TREAT AUTISM AS A MEDICAL,
NOT PSYCHIATRIC DISORDER!
There Are 5 MAJOR MECHANISMS
With Evolving Biomarkers That Give Us
Strong Clues So We Can Effectively
Oxidative Stress
Methylation & Transsulfuration
Toxins & Heavy Metals
Immune System Dysregulation
Gastrointestinal Inflammation
Cost to Benefit Comparisons Must Be Considered
Relative to Every Family’s Unique Circumstances
Relative Cost for Treatment
Examples: MB12,
Diets, Epsom salts
Examples: HBOT,
Colonoscopy, IVIG
Relative “Global” Benefits
Examples: Epsom
salts, Melatonin
Examples: MB12
HBOT, IVIG
BIOMEDICAL TREATMENT PRINCIPLES
Remove or reduce dietary stressors
Remove or reduce environmental stressors
Remove or reduce inflammation
Improve nutritional support
Improve damaged biochemistry
Improve immune function
Improve detoxification
Philosophy: “Break the Gridlock”
Referral for colonoscopy
IV
therapies
Methyl-B12
Early testing (?)
Anti-viral Tx
LDN, Actos
Treat allergies
HBOT
Diet
Supplements
“Chelation”
Heal the gut
Treat infections
Philosophy: Test only if it will affect treatment
It’s Time To Talk About What
Treatments Use Your Time
And Spend Your
Money Most Wisely!
Works
most of
the time
Works some
of the time
Works a little bit
of the time
It’s Time To Talk About What
Treatments Use Your
And Spend Your
Most Wisely!
50% to 90%
Response Rate
Methylcobalamin: SQ
Hyperbaric Oxygen
IV Chelation
Healing the Gut
Diets
Supplements
Other IV Therapies
It’s Time To Talk About What
Treatments Use Your
And Spend Your
Most Wisely!
25% to 50%
Response Rate
Non-IV chelation
Antivirals
Modified Genomics
IVIG
Glutathione, non-IV
Allergy Treatment
Melatonin
Epsom salt baths, MSM
It’s Time To Talk About What
Treatments Use Your
And
Spend Your
Most Wisely!
LDN
Actos (PPAR)
Homeopathy
Metallothionein promoter
Secretin
Sauna, e.g. FIR
“Natural chelation”
GABA
5% to 25%
L-theanine
DMAE
Response Rate
DMG
Vitamin A/Bethanecol
TTFD
Transfer factor
NAET
PANDAS
Chiari malformation
Creatine
ALA & TD-ALA
“Zeolite”
“Liver Life”
“NDF & NDF Plus”
It’s Time To Talk About Treatments That
Are New Or Being Tried In Different Ways
That May Have Promise
New and
Exciting
Times
•
•
•
•
•
•
•
•
•
•
Oxytocin
Variable
Spironolactone
Response
Thyroid
Rates
Lyme disease
Lowering testosterone
D-penicillamine
chelator
Clinicians
Minocycline
Are Not Yet
COX inhibitors
In Agreement
Stem cells
About These
“Biofilm”
Some Children
Defy the Odds
And
“Average”
Has No
Bearing On
Individuality!
A Good
Example Is
Secretin
And
Methyl-B12
The Methylation and Transsulfuration Pathways Provide the
Reduced Glutathione (GSH) to Repair Oxidative Damage.
Methionine
FOLATE CYCLE
Mg
TRANSMETHYLATION
THF
B6
SAM
MS
MSR
5,10-CH2-THF
Methyl acceptor
DMG
B12
MTHFR
Methyl transferase
BHMT
Trimethylglycine
SAH
5-CH3-THF
SAHH
Zn
Homocysteine
B6
Methylated Product
(DNA, RNA, Protein,
Neurotransmittors)
Adenosine
CBS
Cystathionine
Cell membrane
B6
TRANSSULFURATION
Cysteine
Reactive Oxygen
Species:
Peroxides
Glutathione
Peroxide
GST M1
GSH
GSSG
NULL
Slide courtesy of Dr. Jill James and Dr. Jeff Bradstreet
A Power
Player
Methyl-B12
Executive
Function
Socialization
Emotion
Speech & Language
Vending Machines
of the Mind
3
CH
Phospholipids
GA
(Creatine)
Neurotransmitters
CH3
The Methyl-B12 Grandfather Clock
Pays for
education to
“make the brain
smart”
Methylation
Pays the body’s
firemen and
garbage
collectors to
“keep the body
safe, clean, and
comfy”
Transsulfuration
The
Methyl-B12
Clock
Methionine
SAM
Methyl-B12
(with Methionine
Synthase)
SAH
Homocysteine
The
Methylation
Transsulfuration
Pathways
Cysteine
Glutathione
The “Car”
at the
Crossroad is
Homocysteine
Methionine
SAM
B12
SAH
Homocysteine
Cysteine
And
Mr. Methyl B12
“Drives” the Car
Cysteine
(Not Adenosyl, Cyano, Hydroxy, or Glutathionyl B12 )
Glutathione
Methionine
SAM
Methyl-B12
Methionine
Synthase
SAH
Homocysteine
Cystathionine
B-Synthase
Homocysteine
Traffic Is Directed
By Two Enzyme
Traffic Cops
Glutathione
Executive Function
Speech & Socialization
Methionine
SAM
Methyl-B12
SAH
Hg, Pb
Heavy Metals
Toxic
Chemicals
Free Radicals
Runaway
Electrons
Infections
Glutathione
FOLIC (“FOLIAGE”) ACID CYCLE
Methionine
THF
5,10-CH2THF
1
SAM
MS
B12
MTHFR
5-CH3
THF
MTase
Cell Methylation
2
BHMT
Methylation
Potential
(SAM/SAH)
SAH
Betaine
Choline
SAHH
Adenosine
Homocysteine
1
2
Folate Cycle
Methionine Cycle
B6
CBS
Cystathionine
3
Cysteine
3
Transsulfuration
Pathway
GSH
Antioxidant
Potential
GSH/GSSH
GSSG
FOLIC (“FOLIAGE”) ACID CYCLE
Methionine
THF
5,10-CH2THF Methyl
MSticket
MTHFR
5-CH3
THF
Homocysteine
By using the methyl ticket that
was sold by Mr. MTHFR, one can
get on the MT Line and take a
train ride to make “brain things”
while “putting out fires” and
“cleaning house!”
B6
The “brain form” of methionine synthase is critically
different from the “body form” of methionine synthase
HCY Domain
SAM Domain
Cobalamin
(vitamin B12)
Cobalamin
Domain
Cap
Domain
5-methyl THF Domain
Richard Deth, PhD with JN, MD
Without the Cap or SAM domains, oxidized B12 will readily
dissociate and must be continuously replaced by more methyl-B12
IN THE CORTEX
Domain
M-BSAM
12
Methyl-B12
Is The Cobalamin
That Works Best
With Methionine
Synthase In
The Brain
HCY Domain
Cobalamin
(vitamin B12)
Cobalamin
Domain
Cap
Domain
5-methyl THF Domain
Richard Deth, PhD with JN, MD
Response Rate and Intensity
of Responses for Methyl-B12
1. Subcutaneous: Range 80% to 94%
Global responses out of 135
Average 30-45 or more!
2. Nasal: Range 25% to 60%
(most say 25% to 30%)
Far less global responsiveness
3. Transdermal: Range 5% to 8%
Minimal global responsiveness
4. Oral: Range 3% to 5%
Minimal global responsiveness
5. Sublingual: Not used; ineffective
6. TMG blocks MB12 effects because
BHMT competes with MS!
1)
2)
3)
4)
5)
6)
7)
8)
9)
MECHANISMS OF ACTION FOR HBOT
Angioneogenesis from the addition of O2.
Angioneogenesis from the removal of O2.
Increases in blood flow independent of new
blood vessel formation.
Decreasing levels of inflammatory
biochemicals.
Up-regulation of key antioxidant enzymes and
decreasing oxidative stress.
Increased oxygenation to functioning
mitochondria.
Increased production of new mitochondria
Bypassing functionally impaired hemoglobin
molecules secondary to abnormal porphyrin
production.
Improvement of the immune system and the
autoimmune system.
10) Decreasing the bacterial and yeast load
systemically and in the gastrointestinal system.
11) Decreasing the viral load found systemically
and the viral load in the gastrointestinal
mucosa.
12) Increases in the production of stem cells in the
bone marrow with transfer to the central
nervous system.
13) Direct production of stem cells by certain areas
in the brain.
14) Increased production and utilization of
serotonin.
15) The possibility that oxidation may help rid the
body of petrochemicals (theoretical only).
16) The possibility that oxidation may help rid the
body of mercury and other heavy metals
(theoretical only).
Cell Density High
Cell Density Low
Inflammatory Presence
Ann Neurol. 2005 Jan;57(1):67-81
Neuroscience Letters 241 (1998) 17–20
~3 ½ X greater than controls!
Inflammatory
Presence
Sweeten et al., 2003 Am J Psychiatry
160(9):1691-3
Connolly et al., 1999 J Pediatr 134:607-13
Oxidative Stress and HBOT
• At pressures below 2.0 atm, HBOT can
decrease oxidative stress by
increasing anti-oxidant enzyme levels
such as:
– Superoxide dismutase (SOD)
– Catalase
– Glutathione peroxidase
– Heme-oxygenase-1
• At pressures above 2.5 atm, HBOT
may actually increase oxidative stress
SPECT Scans in a 4 y.o. Autistic Child
After 10 Treatments Using 1.3 atm and 24% O2
Before
After Mild HBO
Heuser et al., 2002
Best Publications; 2002:109-15
The Results of >30,000 Hours of
HBOT Treatments Using 1.3 and 1.5 ATA
The 20 Most Common Parental Observations
1.
2.
3.
4.
5.
6.
7.
Activity: more age appropriate activity (in contrast to true
hyperactivity).
Attentive, more: “S/he’s now just ‘with us’ where before s/he wasn’t”.
Awareness: increased in general.
Bowel function: better stools, change in frequency, consistency,
character of stool; able to potty train fully or more quickly than before.
Conversational language: more free speech; interjects own words
[sounds, babble] as attempts to be part of family or therapy
interaction; speech flows more freely; longer sentences at appropriate
times.
Eye contact: improved, turns to the person who is calling or talking;
“curious” about eyes and “the meaning” of other’s eyes; holds eye
contact longer.
Feelings: more in touch with his/her own feelings; understands others
feelings or expressions; has higher highs and lower lows in a more
normal way of being.
The Results of >30,000 Hours of
HBOT Treatments Using 1.3 and 1.5 ATA
The 20 Most Common Parental Observations
8.
9.
10.
11.
12.
13.
Gestures are more appropriate; better use of body language to
communicate wants, needs, and desires; requests that you attend to
his/her emotional or physical needs.
Good days: more, better, or of a different nature and quality than
seen by family or reported by school and therapists.
Happier: a greater general sense of feeling good about his/her self
and life in general; demonstrates an attitude that says, “Something
about my life is different and better today.”
Hyperactivity: more (true hyperactivity not to be confused with a child
being more age appropriately active).
Opinions: has his/her own opinions and definitely lets you know what
they are more than ever before, e.g. s/he expresses more freely
and/or more appropriately his/her likes or dislikes, e.g. “the I don't
want to's because I'm happy doing what I'm doing and I have my
rights, you know!”, etc.
Independent: new level of self-assuredness, self-confidence,
attempting to do things on his/her own; “self perceived ‘appropriate’
anger or irritation for you not letting him/her do something he/she
feels perfectly capable of now doing on his/her own”.
The Results of >30,000 Hours of
HBOT Treatments Using 1.3 and 1.5 ATA
The 20 Most Common Parental Observations
14.
15.
16.
17.
18.
19.
20.
“Presence”: more involved; more “with it”; seems much more attune to
what is happening on a day-to-day basis and in the world aound
him/her.
Requests: makes his/her needs known to family, friends, playmates.
Self confidence: now present for the first time or greater than before
treatment; seems proud of himself/herself and his/her
accomplishments; wants and/or demands you acknowledge what s/he
has done; expects praise and “proudly glows” when it is given.
Sentence structure: longer; more complete; more complex; better
structured; uses adjectives, adverbs, prepositions, pronouns, etc.
Spontaneous speech: more frequently initiates conversation; talks
more without prompting or just echoing or repeating.
Verbalization or vocalization increasing and/or more appropriate,
"babbling" increasing; more sounds being made or attempted.
Vocabulary: knows more words ; knows words no one ever taught;
you find yourself “surprised” that s/he said such-and-such; vocabulary
is used more appropriately.
Autism rates
Potential association between autism
rates, environmental mercury other
toxins in Texas
Palmer, et al., Health and Place 2006
Jun;12(2):203-9
On average, for each 1000 lb of
environmentally released mercury, there
was a 43% increase in the rate of special
education services and a 61% increase in
the rate of autism.
Largest
Mercury
Mines
All Reporting Facilities, All Chemicals TRI-(1987-2002)
Map shows 3,683 of 48,205 facilities reporting nationwide
Total toxicity
Chemicals-TRI
Largest
Mercury
Mines
Mercury and autoimmunity: implications
for occupational and environmental
health.
Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):282-92.
Silbergeld EK, Silva IA, Nyland JF.
Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg
School of Public Health, Baltimore, MD 21205, USA.
Mercury (Hg) has long been recognized as a neurotoxicant; however,
recent work in animal models has implicated Hg as an immunotoxicant. In
particular, Hg has been shown to induce autoimmune disease in
susceptible animals with effects including overproduction of specific
autoantibodies and pathophysiologic signs of lupus-like disease. and
antinucleolar antibodies and a positive interaction between Hg and
malaria. These results suggest a new model for Hg
immunotoxicity, as a co-factor in autoimmune disease,
increasing the risks and severity of clinical disease in the
presence of other triggering events, either genetic or
acquired.
It’s Time To Get Moving
Before Time Runs Out!
•
•
•
•
•
•
•
•
Non-IV chelation
Antivirals
Modified Genomics
IVIG
Glutathione, non-IV
Allergy Treatment
Melatonin
Epsom salt baths, MSM
It’s Time To Get Moving
Before Time Runs Out!
•
•
•
•
•
•
•
Methylcobalamin: SQ
Hyperbaric Oxygen
IV Chelation
Healing the Gut
Diets
Supplements
Other IV Therapies
Healing The Gut Is
Mandatory For Success!
•
•
•
•
•
•
•
•
Major Antifungals
Minor Antifungals
Major Antibacterials
Natural Agents
Special Diets
Probiotics
Digestive Enzymes
Major Anti-inflammatories
Autistic Enterocolitis
Histopathology is Similar to Crohn’s
Lymphonodular Hyperplasia
Apthous Ulcers
Autism
Inflammatory
I.B.D.
Normal
25
20
15
10
5
0
CD3
CD4
CD8
It’s Time To Get Moving
Before Time Runs Out!
•
•
•
•
•
•
•
Organic F/V (Jim Adams et.al.)
CFGF (Karen Serousi, Lisa Lewis)
SCD (Elaine Gotschall)
Feingold
Elimination/Rotation
Candida (Crook, Truss)
Low Oxalate (Susan Owens)
It’s Time To Get Moving
Before Time Runs Out!
•
•
•
•
•
•
•
B6 & magnesium (Dr.
Bernie Rimland)
Cod liver oil
Essential fatty acids
Zinc
Other B vitamins
Other macro & trace
minerals
Amino acids
It’s Time To
Get Moving
Before Time
Runs Out!
Same Amount Of
Food
Water
The Difference
Courtesy of Don Davis,
PhD
Nutritional Value!
It’s Time To Get
Moving Before
Time Runs Out!
•
•
•
•
•
•
•
Methylcobalamin: SQ
Hyperbaric Oxygen
IV Chelation
Healing the Gut
Diets
Supplements
Other IV Therapies
It’s Time To Get Moving
Before Time Runs Out!
•
•
•
•
•
•
•
•
Non-IV chelation
Antivirals (Stan Kurtz)
Modified Genomics
IVIG
Glutathione, non-IV
Allergy Treatment
Melatonin
Epsom salt baths, MSM
It’s Time To Get Moving
Before Time Runs Out!
•
•
•
Non-IV chelation
Antivirals
Modified Genomics
(C. Schneider, A. Usman et.al.)
•
•
•
•
•
IVIG
Glutathione, non-IV
Allergy Treatment
Melatonin
Epsom salt baths, MSM
DON’T FORGET THE ON-OFF
SWITCH/DETOUR CONCEPT!
Be careful not to over-interpret SNPs!
For an enzyme to be “slowed down” is
not the same thing as the enzyme “not
working” at all.
We are dealing in “relative values”, not
absolute manifestations!
J Autism Dev Disord. 1996 Aug;26(4):439-52.
J Autism Dev Disord. 1996 Aug;26(4):439-52.
Personal communication with
Dr. Gupta: “About 1/3 of the children
improve, occasionally achieving
full recovery!”
45.0%
12
Neurobehavioral Regression in Children with Autism and ADHD upon
Pollen Exposure
40.0%
10
35.0%
30.0%
8
20.0%
6
15.0%
Percent Increase
Pollen Count
10.0%
4
5.0%
0.0%
-10.0%
ct
26
-O
ct
12
-O
ep
28
-S
ep
ug
14
-S
31
-A
ug
17
-A
ug
3A
ul
20
-J
ul
6J
un
22
-J
un
8J
ay
ay
25
-M
pr
11
-M
27
-A
pr
13
-A
ar
ar
30
-M
-5.0%
16
-M
2M
ar
2
0
Pollen Count
25.0%
Allergy Profile
This is very
uncommon
FAP from IML, GPL
This is very
common!
Many food reactions but
most with low titers
Most often secondary to
intestinal permeability
It’s Time To Get Moving
Before Time Runs Out!
An opiate antagonist that
affects immunomodulation•
and mood when used in low•
doses. There is initial
•
endorphin inhibition followed
•
by a reactive “endorphin rush”
which seems to normalize
immune responses. •
•
•
LDN (McCandless)
Actos -- PPAR
(Boris/Goldblatt)
Homeopathy
Metallothionein
promoter (Walsh)
Secretin
Sauna, e.g. FIR
“Natural chelation”
It’s Time To Get Moving
Before Time Runs Out!
•
PPAR agonist which
•
downregulates inflammation
by decreasing NF-kappa B.
•
It also has a regulatory effect
on about 150 “immune
•
regulator” genes.
•
•
•
LDN (McCandless)
Actos -- PPAR
(Boris/Goldblatt)
Homeopathy
Metallothionein
promoter (Walsh)
Secretin
Sauna, e.g. FIR
“Natural chelation”
It’s Time To Get Moving
Before Time Runs Out!
•
•
LDN (McCandless)
Actos -- PPAR
(Boris/Goldblatt)
•
A neuropeptide and GI •
hormone. How it works
in the brain is unknown
•
but in the gut it may
stimulate motility and •
•
deliver bicarbonate.
Homeopathy
Metallothionein
promoter (Walsh)
Secretin
Sauna, e.g. FIR
“Natural chelation”
It’s Time To Get Moving
Before Time Runs Out!
•
•
PANDAS (Swedo)
Chiari malformation
(Boris, Goldblatt, Feldstein)
•
•
•
•
•
•
Creatine (Green)
ALA & TD-ALA
“Zeolite”
“Liver Life”
“NDF & NDF Plus”
Many, many more
It’s Time To Get Moving
Before Time Runs Out!
•
A neuropeptide involved•
in communication and •
interpreting social cues •
that has been found to be•
low in the brain in several
•
studies of autistic
•
individuals.
•
•
•
•
Oxytocin (Rossignol, Bradstreet)
Spironolactone (Rossignol, Bradstreet)
Thyroid (Cave, Neubrander, et.al.)
Lyme disease (Kuchera, Freidenfeld)
Lowering testosterone (Geirs)
D-penicillamine chelator
(Boris/Goldblatt)
Minocycline (Jyonouchi)
COX inhibitors (Boris/Goldblatt)
Singulair (montelukast)
“Biofilm” (Usman)
Stem cells (Morales, Neubrander)
It’s Time To Get Moving
Before Time Runs Out!
•
Downregulates MCP-1
•
which is high in the brain
in some children with •
autism (Vargas, 2005) •
and also downregulates •
•
inflammation in general.
•
•
•
•
•
Oxytocin (Rossignol, Bradstreet)
Spironolactone (Rossignol, Bradstreet)
Thyroid (Cave, Neubrander, et.al.)
Lyme disease (Kuchera, Freidenfeld)
Lowering testosterone (Geirs)
D-penicillamine chelator
(Boris/Goldblatt)
Minocycline (Jyonouchi)
COX inhibitors (Boris/Goldblatt)
Singulair (montelukast)
“Biofilm” (Usman)
Stem cells (Morales, Neubrander)
Spironolactone: Safety and Tolerability
• Spironolactone is also commonly prescribed as
an adjunct in the treatment of precocious
puberty.
• In a six year study using spironolactone in 10
boys (ages 2.3 to 5.6 years) with precocious
puberty, no serious side-effects were noted
despite relatively high doses of spironolactone
(average 5.7 mg/kg/day).
• No change in electrolytes were noted.
• 50% of aggressive boys had significant
reduction in negative symptoms.
J Clin Endocrinol Metab. 1999 Jan;84(1):175-8.
Now’s The Time To Study The
Hundreds Of Biomedical Treatments
That Have The Potential To Augment
All The Other Standard Educational
And Behavioral Treatments That
You Are Already Using Because They
Work To Some Degree
Most Of The Time!
You Can Bet On It!