Is Autism a Brain disorder or A disorder that affects the brain?

Is Autism a Brain disorder or
A disorder that affects the
brain?
Elizabeth Mumper, , MD
Medical director,
Autism Research Instititute
Founder, RIMLAND Center

The emergence of a
new autism model
•Everyone (including doctors) thinks using MODELS
•Most doctors and researchers use an older model of autism
•People using the older model often either
–Don’t know there’s a new model,
–Dismiss the new model without studying it

The emergence of a
new autism model
Older model
Genetically determined
Brain based
Hard-wired
Treatable but not
curable
Is autism a BRAIN
DISORDER?
Newer model
Environmentally triggered
Genetically influenced
Both brain and body
Metabolic abnormalities
play big role
Treatable and recovery
possible
OR is it
A DISORDER THAT
AFFECTS THE BRAIN?

Lecture Orientation
Paradigm shift: from autism as a static
encephalopathy to autisms as systems disorders
that are treatable
Basic concept: integration of the science with
clinical clues and findings to design individual
treatment plans
– Moving from the macrocosm to microcosm
– Respect for individual variation and uniqueness
– Respect for synergy of biologic systems

8 physiologic lenses
timing
memory
perception
membrane
message
detox
energy
synthesis
Courtesy Dr. Sid Baker

Concept of brain effects secondary to
pathology elsewhere in body
Gut brain axis

Vargas DL et al. Annals of
Neurology 2005:57:000
000-000
• Examine for evidence for immune activation in
brain and spinal fluid of patients with ASD and
controls
Slides courtesy Dr. Wakefield

Results
Increased activation of the brain’s resident innate immune
system - observed in post mortem tissue from autistic patients
Control ASD HLA-DR
Associated with Purkinjie cell loss in the cerebellum

CSF cytokine profile
Cytokine Fold increase p
INF-γ 232.5
0.008

Examination of CSF
Presence of inflammatory cytokines of
lymphocyte origin, but no lymphocytes
Absence of same cytokines in
brain tissue
Cytokines from somewhere else
Origins of immune activation from
somewhere else – GUT?

Analogy to celiac
Celiac Disease: primary inflammation of the intestinal
mucosa associated with a abnormal immune response to
gluten, and a wide variety of secondary neurological
complications

Changing the Environment…
Effect of emotions on
the gut
– Stress suppresses
Lactobacillus,
Bifidobacteria,
immune function
– Adrenalin stimulates
growth of gram-
negative organisms
– Anger or fear
increases Bacteroides
fragilis
Courtesy Dr. Patrick Hanaway

Shultz et al., 2008 Neuropharm 54:901-11

The Role of Infections
Infections, biofilms and other
infectious associations
with autism

Courtesy
Dr. Robyn Cosford
Otitis Media
· Prior to 1990’s –
· incidence of respiratory tract infections and otitis media
peaked at 4 to 6 years old
· (1997)
· now peak incidence between 6 and 12 months of age.
· Otitis media now said to occur in 48% children
within first 6 months
· in 79% within 1st 12 months; 91% by age 24 months
Paradise JL,. Pediatr 1997: 99:318-333
333
1989 figures:
62% of children by 12 months, 83% at age 3 years
(Teele
DW,et al J Infect Dis 1989;160:83-94).
94).

Overt Infections
Overt infection common in history of children
prior to diagnosis of autism
most common - otitis media (AOM)
recent study 206 children under age of 3 with
autism :
– average of nearly 10 bouts of AOM, received an
average of 12 courses of antibiotics
– over 1/3 all given to children under 12 months
(Fallon J. Med Hypotheses 2005)
Courtesy Robin Cosford

Infections and autism
Previously noted high correlation between
prevalence otitis media and autism
(Kontstantareas
M et al, J Autism and Dev Dis 1987)
earlier age of otitis media correlates with
more severe autism
(ibid)
increased incidence otitis media
correlated with more severe form autism
(ibid)
However more recent studies indicate no significant difference between b
incidence of OM in autistic compared to non- autistic children – ? reflection
of increased rates of OM in general community

Biofilms
OME, sinusitis associated with
persistent bacterial infection
Resistant to antibiotics (1000x)
Recently recognized that bacteria exist
in biofilms – aggregates adherent to
mucosa, surrounded by mucus slime

Non animated picture of
Biofilm/Slime!
Courtesy Anju Usman

What is Biofilm?
A collection of microbial communities
enclosed by a matrix of extracellular
polymeric substance (EPS) and separated by
a network of open water channels.
These communities adhere to manmade and
natural surfaces, such as metals and teeth,
typically at a liquid-solid interface .
Their architecture is an optimal environment
for cell-cell interactions, including the
intercellular exchange of genetic material,
communication signals, and metabolites
The matrix is composed of a negatively
charged polysaccharide substance, held
together with positively charged metal ions
(calcium, magnesium, and iron).
Staphylococcus aureus biofilm
The matrix in which microbes in a biofilm are
embedded protects them from dehydration,
phagocytosis, , antibiotics, antimicrobial
agents and the immune system.
Courtesy Anju Usman

Biofilms and Group Action
Biofilms regulated by quorum sensing ;
bacteria able to detect presence of other
bacteria
Bacteria change metabolism, produce and
excrete ‘slime’ that cements them together
Also produce toxins
Enable persistence of biofilm in various
environments where existence as separate
organisms is not viable
(Matz
C et al, PLoS ONE July 2008;3(7):e2744)

Environmental toxins
Effects on neurologic function

Concerns
US EPA estimates there are over 87,000
chemicals currently in widespread use today.
Of these 62,000 are small enough molecules to
cross cell membranes.
15,000 are produced in annual quantities of over
10,000 pounds (that’s s 5 tons/year)
Courtesy Stu Fredenfeld

Safeguards Have Failed
CDC conducts tests every two years for evidence of
chemical exposure in Americans.
The most recent report 12/06 found the average
American now has 116 synthetic compounds in her
body
Further studies revealed these same substances were
also in human milk, placenta and umbilical cord
blood, and in the blood and body fat of newborns.
Adapted from Stu Fredenfeld

Human Health Effects of Developmental
Exposure to Environmental Toxicants
“The
brain is particularly sensitive to toxic exposures during
development, which involves a complex series of steps that
must be completed in the right sequence and at the right time.
Slight decrements in brain function may have serious
implications for social functioning and economic activities,
even in the absence of mental retardation or obvious disease.
…The
combination of several toxic chemicals, along with other
adverse factors, , such as maternal stress or decreased thyroid
function, may trigger substantial decrements in brain function
and may predispose to the development of serious
degenerative disease.”
International Conference on Fetal Programming and Developmental Toxicity
Torshavn, Faroe Islands May 20-24, 24, 2007

Concern
Any substance that is tolerated by one
individual (or fetus) would not necessarily be
tolerated by another.
Any substance that is tolerated by itself may not
be tolerated in the presence of other
substances – synergistic toxicities

Slide courtesy Dan Rossignol
Jarosinska and Gee, 2007 Int J Hyg Environ Health 210:541-46

Health Place. 2006 Jun;12(2):203-9.
Findings: For every 1000 pounds of mercury
that is emitted from Texas smokestacks there
is a 61% increase in Autism rates in that state.

EHP Vol 6, 2006: Online 21 June 2006
Autism Spectrum Disorders in Relation to
Distribution of Hazardous Air Pollutants in the
San Francisco Bay Area
Gayle C. Windham, Lixia Zhang, Robert Gunier, Lisa A. Croen, Judith K. Grether
Division of Environmental and Occupational Disease Control, California Department of
Health Services, Richmond, CA; Impact Assessment Inc, La Jolla, CA; and Kaiser
Permanente Medical Care Program Division of Research, Oakland, CA
Methods: Subjects included 284 children with ASD and 657 controls, born in 1994 in the
San Francisco Bay Area. We assigned exposure level by census tract of birth residence for
19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or
endocrine disruptors from the 1996 HAPs database.
Results: Adjusting for these three groups simultaneously led to decreased risks for the
solvents and increased risk for metals (AORs for metals: fourth quartile 1.7, 95% CI 1.0-3.0;
third quartile 1.95, 95% CI 1.2-3.1). The individual compounds that contributed most to
these associations included mercury (highest odds ratio), cadmium, nickel,
trichloroethylene, and vinyl chloride.
Conclusions: Our results suggest a potential association between autism and
estimated metal concentrations, and possibly solvents, in ambient air around the birth
residence, requiring confirmation and more refined exposure assessment in future studies.

Windham et al., 2006 Environ Health Perspect 114:1438-44

(J Pediatr 2000;136;679-81)
1 nmolar Thimerosal inactivates methionine synthase, (Waly et al Molec Psych 2004)

Slides courtesy Dan Rossignol
Westphal et al., 2000 Int Arch Occup Environ Health 73:384-88

Homozygous GSTM1 gene deletion
Klautau-Guimaraes et al., 2005 Genet Mol Biol 28(4):827-32

Genetic Finding
in Autism
MTHFR, Adenosine
Deaminase
GST M1-null
ALAD
PON-1
HLA-DR4
Clinical Result
Decreased production of glutathione
Increased susceptibility to mercury and
xenobiotic toxicity; increased body burden
of mercury
Increased susceptibility to lead toxicity;
increased body burden of lead
Increased susceptibility to pesticide toxicity
Increased allergy and intolerance to heavy
metals

Lead is far from gone
Although lead was banned from paint and phased out of
automobile fuel in 1970’s s it was certainly not removed
from the environment.
USA releases about 4000 tons of lead into the
atmosphere annually.
Primary sources are jet fuel consumption along with
industrial metal melting, auto body finishing, cement
manufacture and incineration.
Exposure to children comes from air, soil, old paint,
plumbing, and toys made with lead.
Absorption is through the skin, lungs and GI absorption.

Kimura-Kuroda 2007 Chemosphere 67(9): S412-20

Goldman, 1995 Environ Health Perspect 103(Suppl 6):13-18

Concept
Neurological Disorders may be
expressions of the impact of
environmental toxins on genetically
susceptible individuals.

The tide falls and the rocks are
discovered
Asthma
IBS
ADHD
Crohn’s
Autism
Courtesy Sid Baker

Asthma
ADHD
IBS
Crohn’s
Autism

Factors that have lowered the
tide 1950 - 2000
Antibiotics
Decrease in omega 3/omega 6 oils
Magnesium deficit (from fertilizers)
Mercury exposure by injection in infancy
Combined live viral vaccines
Increase in dietary carbohydrate load
Vitamin / mineral deficits
Toxic exposures

Conclusions
Autisms result from complex interactions
between genetic susceptibilities and
environmental triggers, modulated by
timing of events
Multiple factors may affect final common
pathways – as of 2008 chronic oxidative
stress and neuroglial activation and
neuroinflammation are paramount

Therefore, autisms are
disorders that affect the brain
There is hope, in that
associated medical disorders
have treatment options

Follow those who seek the
truth but flee from those who
have found it. Vaclav Havel
Quote used from Sid Baker’s files

A place with a heart shaped pond

Where people seek the truth but are
acutely aware of the shortcomings of current knowledge

Where children get treatment for their medical problems

Rimland Center
www.rimlandcenter.com
Recovery Initiatives and Mentoring Linking Autism Networks and Discoveries