Transcript AUTISM ONE TORONTO Biomedical Treatments for Autism: A …

Biomedical Treatments
for Autism:
A Review.
Dr Wendy Edwards
B.Sc.N., M.D., F.R.C.P.C.
Autism is a Medical Disorder
 Not static or hard wired in the brain.
 Affects many different body systems.
Can Autism be Cured?
Autism is a chronic condition (think diabetes) that can
be treated in some (??all) cases, to varying degrees of
relief.
3 Main Areas I’ll Review:
 Immune system function and malfunction
 Biochemistry of methylation and transsulfuration
pathways (normal function and malfunction) and
oxidative stress.
 Short chain fatty acid metabolism deficiencies
(Dr. MacFabe’s work)
But what about genetic causes
for autism?
Genes
Environmental factors
Developmental stages
3 Main Areas I’ll Review:
 Immune system function and malfunction
 Biochemistry of methylation and transsulfuration
pathways (normal function and malfunction) and
oxidative stress.
 Short chain fatty acid metabolism deficiencies
(Dr. MacFabe’s work)
Abnormal Immune
System Function
 Malfunctioning immune system - one reason why many
children develop autism?
 Many studies support the fact that some children with
autism, compared to neurotypical children, have several
family members with autoimmune diseases (hence, an
inherited dysfunctional immune system is more likely).
 Genetically, is this one of the inherited features that could
lead to autism?
Abnormal Immune System Function
 Paul Ashwood, an immunologist at the MIND
Institute in California, published (2006) a review
of the studies supporting immune dysfunction in
autism.
 “Increasing research has focused on the
connections between the immune system and the
nervous system…” “successful neurodevelopment
(is) contingent upon a normal balanced immune
response.”
To understand what might be
wrong we need to understand
how a normal immune system
works.
The immune system
 System of cells and chemicals that communicate with
each other
 Provide protection from non-self or foreign invaders
 Identify invader, destroy it, clean up debris of “battle”
and heal damage to host
The immune system
 Disease is when immune system fails and too much
invader takes over, or too much damage is done to the
host while trying to fight the invader, or there is a
misfire and the host is damaged along with invader.
Abnormal Immune System Function
 One part of the immune system are T helper cells.
 Th1 cells are most effective against viruses/fungi, (often
intracellular invaders). Natural killer cells (NK) also work
against these types of invaders. They are called into action
by the Th1 cells.
 Th2 cells work by activating the B cells of the immune
system to make antibodies against foreign invaders found
outside the cell (or sometimes antibodies against the cell
itself = autoimmune disease)
So why would an abnormal system lead to
autism?
 Autistic children… Th2 activity > Th1.
 So viruses (perhaps even minute amounts in vaccines??)
and fungi will survive more easily and predominate in the
body = cell death, inflammation, a change in the bowel
flora environment, etc.
 Increased Th2 activity = the formation of antibodies that
won’t ‘‘turn off’’, causing a never ending inflammatory cycle
or…
 Resulting in the production of antibodies to self (e.g..
antibodies against brain tissue).
Abnormal Immune System Function
 Ashwood P, et. al. The immune response in autism: a
new frontier for autism research. J Leuk Biol. 2006
Jul:80;1-15
 Warren RP, et. al. Reduced natural killer cell activity
in autism. J Am Acad Child Adolesc Psychiatry. 1987
May;26(3);333-5
 Korvatska E, et. al. Genetic and immunologic
considerations in autism. Neurobiol Dis. 2002
Mar;9(2);107-25
Abnormal Immune System Function
 Gupta S, et. al. Th1 and Th2 like cytokines in CD4+
and CD8+ T cells in autism. J Neuroimmunol. 1998
May;66(1-2):143-5
 Molloy C, et. al. Elevated cytokine levels in children
with autism spectrum disorder. J Neuroimmunology.
2006;172:198-205
 Pardo CA, et. al. Immunity, neuralgia and
neuroinflammation in autism. Int Rev Psychiatry.
2005 Dec;17(6):485-95
Abnormal Immune System Function
 Comi AM, et. al. Familial clustering of autoimmune
disorders and evaluation of medical risk factors in
autism. J Child Neurol. 1999 Jun;14(6):388-94
 Sweeten TL, et. al. Increased prevalence of familial
autoimmunity in probands with pervasive
developmental disorders. Pediatrics. 2003
Nov;112(5):e420
Can we alter the immune system?
 Dr. M. Boris published results of his study in 2007
showing that the drug ACTOS, previously used to treat
Type II diabetes, can be used “off label” to shift the
undecided Th null cell from becoming a Th2 cell to
becoming a Th1 cell.
Can we alter the immune system?
 Initial studies were successful with MS patients. ASD
is currently being studied.
 If we could successfully alter the immune system this
would decrease viral load (increased Th1 activity) and
decrease autoimmune inflammation in the brain, GI
tract, etc. (decreased Th2 activity).
Can we alter the immune system?
 Low dose Naltrexone studies are also promising.
 Encouraging studies have been published regarding
treatment of MS, Crohn’s disease and cancer.
Can we alter the immune system?
 Naltrexone blocks endorphin receptors.
 Low doses work for few hours versus 24 hours for
standard dose.
 The body will increase endorphin levels briefly to
compensate for the blockade.
 Increased endorphin levels = switch from Th2 activity
to Th1 activity in the body.
Can we alter the immune system?
• Dr. Vojdani (Autism One Chicago 2009)
discussed the Th3 cell – which regulates
activities between Th1 and Th2 cells. These
cell numbers are low in autism.
• TGF beta is a cytokine that “regulates” also,
and is low in autism.
• Published re low natural killer cell activity
(not numbers) in autism.
So if the immune system is malfunctioning….
 Think increased survival of fungi/viruses in the GI
tract.
 Think increased survival of intracellular invaders
(?disruption of methylation cycle?)
 Think autoimmune inflammation of the GI tract ,
brain, etc.
Gastrointestinal issues
Immune System and the Gut
 Why do so many children with autism have gut issues?
Immune System and the Gut
 G.I. tract is one of the body’s first lines of defense.
 A large part of the immune system is in the G.I. tract.
If it malfunctions, toxins will survive (decreased Th1
function) or there will be overreaction to other
substances there = inflammation (increased Th2
function).
Immune System and the Gut
 Many of our children have inflammation, (due to
yeast/viral/bacterial overgrowth in the G. I. tract
and a weak immune system) = diarrhea,
constipation, pain, flatus, or bloating.
 An inflamed bowel wall will not absorb nutrients
well. Increased mucous production covers the
bowel wall cells preventing enzymes there from
doing their jobs. Foods are not well digested or
absorbed.
Immune System and the Gut
 First step I always insist upon is healing the gut!!
 Most supplements are oral so imperative that
children treated for autism have healthy guts to
absorb these.
 Treatment is: Remove (yeasts, viruses, abnormal
bacteria), replace (probiotic therapy) and avoid
(GF/CF or other diet).
Immune System and the Gut
 Valicenti-McDermott M, et. al. Frequency of
gastrointestinal symptoms in children with autistic
spectrum disorders and association with family
history of autoimmune disease. J Dev Behav
Pediatr. 2006 Apr;27(2 Suppl):S128-36
 Horvath K, et. al. Autistic disorder and
gastrointestinal disease. CurrOpin Pediatr. 2002
Oct:14(5):583-7
Immune System and the Gut
 Balzola F, et. al. Autistic enterocolitis: confirmation of
a new inflammatory bowel disease in an Italian cohort
of patients. Gastroenterology. 2005;128:Suppl.2;A-303
 Ashwood P, et. al. Immune activation of peripheral
blood and mucosal CD3+ lymphocyte cytokine profiles
in children with autism and gastrointestinal
symptoms. J Neuroimmunol. 2006 Apr;173(1-2):126-34
Immune System and the Gut
 Parracho HM, et. al. Differences between the gut
microflora of children with autistic spectrum disorders
and that of healthy children. J Med Microbiol. 2005
Oct;54(Pt 10):987-91
Brain issues
Immune System and the Brain
 PET and MRI scans have revealed many abnormalities
in the brains of children with autism, both structural
and functional.
 BUT…wide individual variation of pathology so no
quick answer to explain autism will come from here.
Immune System and the Brain
 Complex interactions between chemical signals in the
brain and the immune system.
Immune System and the Brain
 Cytokines (chemicals that communicate instructions
in the immune system) can affect cognitive and
behavioural processing in the brain. Cytokine release
from inflammation anywhere in the body can affect
the brain.
 Cytokines affect mood, sleep, appetite, and social
interaction, as well as memory and learning. (Think
autism!!)
Immune System and the Brain
 Cytokines cross the blood brain barrier and make it
more “open” and accessible for the crossing of
neurotoxins.
 Therefore, if cytokines are decreased (when
inflammation is decreased), there will be a tighter
blood brain barrier and fewer toxins reaching the
brain.
Immune system and the brain
 Conversely, neurotransmitters and neuropeptides can
affect the development of the immune system
(remember the nicotine study). This hints at a chicken
and egg question. Does an abnormal brain result in an
abnormal immune system or visa versa?
Immune System and the Brain
 Kern JK, et. al. Evidence of toxicity, oxidative stress,
and neuronal insult in autism. J Toxicol Environ
Health B Crit Rev. 2006 Nov0Dec;9(6):485-99
 Wilson CJ, et. al. Cytokines and cognition – the case
for a head to toe inflammatory paradigm. J Am
Geriatr Soc. 2002 Dec;50(12):2041-56
Immune System and the Brain
 Zhao B, et. al. Involvement of cytokines in normal
CNS development and neurological diseases: recent
progress and perspectives. J Neurosci Res. 1998 Apr
1;52(1):7-16
 Vega JA, et. al. Neurotrophins and the immune
system. J Anat. 2003 Jul;203(1):1-19
 Cook EH, et. al. Receptor inhibition by
immunoglobins: specific inhibition by autistic
children, their relatives, and control subjects. J Autism
Dev Disord. 1993 Mar;23(1):67-78
The biochemistry of
methylation and
transsulfuration
Methylation
 The methylation pathway is how your cell creates the
products it is meant to create.
 Cells in the brain, through methylation, create
neurotransmitters, RNA and DNA, proteins, etc.
 Reactive oxygen species are also created (ROS). This is
“oxidative stress”.
Transsulfuration
 This pathway creates a means to clean up the oxidative
stress, and other toxins in the cell.
 Antioxidants that you ingest can also help to do this.
Methylation/Transsulfuration
 It is possible that a gene defect can cause a problem(s)
in either of these cycles.
 Often the problems can be bypassed by “loading” the
pathway with supplements on either side of the
problem.
Methylation/Transsulfuration
 Because autism numbers continue to grow (just as
environmental toxins increase) these pathways might
be altered/halted by toxins in our bodies.
 We can support the body to rid itself of these toxins.
Methylation Pathway
 This is the top half of the diagram and represents the
well functioning cell, reusing homocysteine to make
methionine, which in turn methylates substances to
make neurotransmitters and other products that keep
the cell and body functioning.
Methionine
Folate
Cycle
Magnesium,
ATP
Folinic
SAM
B12
Folapro
Methylation of DNA,
RNA, Proteins,
Neurotransmittors...
DMG
or
TMG
SAH
Zinc
Adenosine
DPPIV
____________________________________________
Homocysteine
______________________________________
B6
Magnesium
Cystathionine
B6
Cysteine
Taurine
Glutathione
Transsulfuration Pathway
 This is the bottom half of the diagram representing a
pathway for homocysteine to be converted to
glutathione, which in turn “cleans up” the oxidative
stress and added toxins presented to the cell, therefore
keeping it healthy.
Methionine
Folate
Cycle
Magnesium,
ATP
Folinic
SAM
B12
Folapro
Methylation of DNA,
RNA, Proteins,
Neurotransmittors...
DMG
or
TMG
SAH
Zinc
Adenosine
DPPIV
____________________________________________
Homocysteine
______________________________________
B6
Magnesium
Cystathionine
B6
Cysteine
Taurine
Glutathione
Fatty Acid Metabolism
 Making energy for the cell
 Dr. MacFabe’s work.
Fatty Acid Metabolism
 Some children with autism might not metabolize a
short chain fatty acid called propionic acid (PPA)
 This could result in decreased energy to run the
normal methylation and sulfation cycles
Fatty Acid Metabolism
 PPA is found in gluten and casein (wheat and dairy
proteins)
 PPA is also made by some bacteria (clostridia species)
in the GI tract.
 If patients get better on GF/CF diet and bowel clean
up, could it be because they are now exposed to less
PPA?
And now for some specifics….
 Or…where can you start with biomedical treatment for
your child?
7th rung
Heal the Damaged G.I. Tract
 Deal with inflammation
Diet – GF/CF or SCD. Remove foods that may trigger
immune system reactions and result in bowel
inflammation. You are also removing foods that
contain excess PPA by doing this.
Heal the Damaged G.I. Tract

Deal with overgrowth of unwanted
bacteria, fungi (yeasts) and viruses.
Heal the Damaged G.I. Tract
Probiotics:
At least twice a day, taken
with meals
Antiyeast meds:
Nystatin, Diflucan,
Sporonox.
Antiyeast naturals :
Oregano oil, garlic,
caprylic acid, cranberry,
grapefruit seed extract,
therapeutic enzymes.
Heal the Damaged G.I. Tract
Antiviral meds:
Amphotericin B,
Valtrex
Antiviral naturals:
Olive leaf extract,
grapefruit seed
extract, therapeutic
enzymes.
Heal the Damaged G.I. Tract
Antimicrobial meds:
Flagyl, Gentamycin,
paramomycin.
Antimicrobial naturals:
Oregano oil, garlic,
grapefruit seed
extract.
Heal the Damaged G.I. Tract
 Deal with poor nutrition due to inflammation in
G.I. tract
Vitamin and mineral supplements – ASD plex is
great - everything is in it BUT unpalatable.
SuperNuThera is good - might need to add extra
zinc and magnesium to the schedule.
.
Heal the Damaged G.I. Tract
 Support adequate digestion
Digestive enzymes with DPP4 are important. The
enzymes ensure that the food is broken down so less
likely to cause an immune system reaction. DPP4 also
works in the methylation cycle. DPP4 is made in the
gut (to digest gluten and casein), but if the gut is
swollen and contains excess mucous, its production
may be faulty. Giving it is an insurance policy!
Support the Immune System
 Low dose Naltrexone
Used as a cream (give at night). The temporary blockage of
opioid/endorphin receptors by Naltrexone causes the brain
to release more endorphins. Endorphins act like cytokines,
communicating with the immune system and repairing the
abnormal Th1 to Th2 ratio.
 Actos (on prescription)
Decreases autoimmune disease process by inhibiting the
factor which drives null cell to become Th2 cell.
Support the Immune System
 Ambrotose/Glyconutrients
Essential carbohydrates, aid immune system
in recognizing self as self, therefore avoiding
autoimmune inflammatory processes. Dr.
Vojdany supports use for immune system
health.
 Omega 3 fatty acids
EPA modulates the immune system by
changing the production of cytokines. It can
shift the immune system response from proinflammatory to anti-inflammatory.
Support Methylation Pathways
Refer back to the Methylation Pathway picture and
you will see that all these things can help/support
this process.
Methylcobalamin (MB12 )
TMG or DMG
Folinic Acid
Folapro
Magnesium
Zinc
DPP4
Support Transsulfuration Pathway
Refer back to the sulfuration pathway picture…
Vitamin B6
Magnesium
Taurine
Impaired transsulfuration and oxidative stress in autistic children:
Improvement with targeted nutritional intervention
S. Jill James, PhD.
Deal with Oxidative Stress
 Use antioxidants
Vitamin C (works well together with E)
Taurine, a direct antioxidant in itself and
also supports vitamins A and E by ensuring
bile salt absorption.
Selenium is a good antioxidant.
Deal with Oxidative Stress
 Support the production of Glutathione.
Magnesium and B6 support this in cells.
Milk thistle supports liver health, and the
liver cells produce most of the body’s
cysteine for conversion to glutathione in
the brain cells.
Oral glutathione is useless. IV glutathione
will not work on a long term basis.
Glutathione has to be made inside the cell,
we can’t put it in there!
Deal with Oxidative Stress
 Support the production of Glutathione.
Consider the use of OSR. This provides a means of
giving sulphate intracellularly. Sulphate can “clean up”
toxins in the cell, therefore leaving cell glutathione to
deal with oxidative stress more efficiently.
Detoxification
 Support liver detox (the body’s detoxifier)
Phase I of liver detox (oxidation) can be a
problem if it is in overdrive. It makes substances
“more toxic” for later conjugation. Exposure to
chemicals/toxins in the environment is more
dangerous if this is happening.
Consider the use of non toxic house cleansers,
organic pesticides, etc. at home to avoid this
situation. Also consider eating organically grown
foods.
Detoxification
 Support liver detox (the body’s detoxifier)
Phase II of liver detox (conjugation) involves
several different pathways.
One is the use of glutathione, another is the
use of the sulfation pathway that requires
sulphate to work. Consider use of OSR to get
sulphate into the body or Epsom Salt baths for
absorption of magnesium sulphate.
Chelation
 The removal of heavy metals.
This can be done by IV, orally, rectally or
transdermally.
Agents include: EDTA, DMSA, DMPS, TTFD,
Glutathione.
Moving metals can lead to renewed GI
problems (yeast overgrowth) so timing is
important.
Do we need to do this?? Can the body do
this by itself, if healthy immune system
and normal biochemistry.
Consider OSR
 Dr. Boyd Haley has created an FDA approved
“supplement” to help with detox in a safe, yet
“round about manner”.
 His product consists of sulphate that can “mop
up” toxins intracellularly therefore allowing cell
glutathione levels to recover, increase and deal
with oxidative stress.
Consider OSR
• Molybdenum supplements may aid in body’s own
sulphate creation and therefore synergistically aid in
OSR’s “clean up”.
Increase Cell Energy
 A cell needs energy (ATP) to be able to function
properly (methylation/sulfuration).
 Dr. MacFabe’s research suggests that there may be
an impairment of the cell to use available energy
sources (short chain fatty acids).
 Giving coenzyme Q10, acetyl L’Carnitine, and
Omega 3 fatty acids may help to increase cell
energy.
Pliable cell wall (OMEGA 3)
SCFA/PPA
“The Bouncer” is CARNITINE
Efficient burn in
mitochondria
(CoQ10)
The value of Carnitine
 Recently published Italian studies (Pochini) have
shown (in vitro) that beta lactam antibiotics
inhibit the mitochondrial carnitine transporter.
 Cephalosporins especially caused irreversible
inhibition after prolonged exposure.
 PEDIATRICS 2007 – documented reports of
children with encephalopathy/seizures post long
term courses of antibiotics.
Use Omega 3 Fatty Acids
 Important for neurotransmitter function.
 Important for cell membrane fluidity and for
repair (post oxidative stress).
 Important for enzyme regulation.
 Important for gene expression.
Use Omega 3 Fatty Acids
 DHA is predominant in the brain and linked to
auditory and visual processing systems.
 EPA modulates the immune system by changing the
production of cytokines from pro inflammatory to anti
inflammatory.
Give Zinc
 Found in many physiological processes including
digestion, immune system function and methylation.
 Runs the enzyme process that converts B6 to its active
form (P5P).
 Helps reverse the high copper to zinc ratio found in
most autistics.
Give Zinc
 Give zinc at night away from meals and other
supplements that contain minerals.
 All forms of zinc are helpful but avoid zinc sulfate
which can upset the stomach.
 Most children do well with a dose of 15 to 30 mg/day.
Consider Melatonin
 Can help with onset and maintenance of sleep.
 Start with a dose of 3 mg. If this is effective often a
lower dose will work just as well.
 Liquid melatonin takes effect more quickly.
Consider Melatonin
 Melatonin up regulates the enzyme that converts B6 to
its active form (P5P).
 Melatonin acts as an antioxidant.
Resources to help you get started….
Each child’s situation and needs are unique. There are
many good books available to teach parents and
doctors how to understand and use supplements
effectively.
:
Please consider reading:
Changing the Course of Autism
by Dr. Bryan Jepson.
Autism: Effective Biomedical Treatments
by Drs. Sid Baker and Jon Pangborn.
Children with Starving Brains
by Dr. Jaquelyn McCandless.
Why do I believe in this???
Aerodynamically, the bumble bee shouldn't be able to fly, but
the bumble bee doesn't know it so it goes on flying anyway.
Mary Kay Ash
We have ideas – about what our
children can do. About how we can
help them. Should we give up on
those ideas?
Like stones
rolling down
hills, fair ideas
reach their
objectives despite
all obstacles and
barriers. It may
be possible to
speed or hinder
them, but
impossible to
stop them.
Jose Marti
Thank you