Transcript Slide 1

HyperAutism
Baric
Oxygen
Therapy
and
Dan Rossignol, M.D.
DAN! Physician
Clinical Assistant Professor
University of Virginia
Department of Family Medicine
Outline
• Rise in autism prevalence
• Effects of HBOT
• Recent autism findings:
– Cerebral Hypoperfusion and HBOT
– Neuroinflammation and GI Inflammation and
HBOT
– Increased excretion of porphyrins and HBOT
– Oxidative Stress and HBOT
• HBOT safety
• HBOT dosing
• HBOT case series
Prevalence of Autism
• According to the U.S. Dept. Developmental
Services, the prevalence of autism spectrum
disorders increased 556% from 1991 to 1997.
• Autism is now more common than childhood
cancer, Down’s syndrome, spina bifida or cystic
fibrosis.
• 1 in 80 boys have autism (boys are affected 4
times as often as girls).
• 1 out of 68 families will have a child with autism.
• Autism is increasing by 3.8% per year
worldwide.
Number of cases per 10,000
.
Prevalence of Autism
80
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60
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40
h
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20
a
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1965
d
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1970
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1985
f
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1990
1995
2000
2005
HBOT and Autism
HBOT Definition
• Hyperbaric oxygen therapy (HBOT)
involves inhaling 100% oxygen at greater
than 1 atmosphere absolute (ATA) in a
pressurized chamber. (Feldmeier, Undersea and
Hyperbaric Medical Society, 2003)
HBOT Approved Indications
• Air or gas embolism
• Severe anemia
• Carbon Monoxide
• Intracranial abscess
Poisoning
• Necrotizing soft tissue
• Gas gangrene
infections
• Crush injuries and
• Refractory
compartment
osteomyelitis
syndrome
• Skin flaps and grafts
• Decompression
• Delayed radiation
sickness
injury
• Wound
• Thermal
burns
The healing
use of HBOT for autism
is “off-label”
Effects
of HBOT
Skin Cell
Growth and
Wound
Healing
Patel, 2005
Effects
of HBOT
Gionis et al., 1999
Intensive Care Med 26(3):355
Sunami, et al.
Crit Care Med 2000; 28: 2831-36
Effects
of HBOT
Cerebral blood flow
Demchenko et al., 2000
Nitric Oxide 6(4):597-608
Effects
of HBOT
Cerebral blood flow
Demchenko et al., 2005
J Cereb Blood Flow Metab 25(10):1288-300
Effects
of HBOT
Cerebral blood flow
Demchenko et al., 2005
J Cereb Blood Flow Metab 25(10):1288-300
Effects
of HBOT
Cerebral oxygenation
Demchenko et al., 2005
J Cereb Blood Flow Metab 25(10):1288-300
Effects
of HBOT
Hypoxia
Ischemia
Control
Rat Brain
Hypoxia
Ischemia
+ HBOT
Calvert et al., 2002
Effects
of HBOT
Distribution of
Ischemic Changes
Rosenthal et al., 2003
Effects
of HBOT
Rats 3 ATA
100% oxygen
Postischemic BBB permeability
Postischemic cerebral edema
Veltkamp et al., 2005
“Off-label” Studied Uses of HBOT
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Cerebral Palsy (Montgomery, 1999)
Amyotrophic Lateral Sclerosis (Steele, 2004)
Complex Regional Pain Syndrome (Kiralp, 2004)
Fetal Alcohol Syndrome (Stoller, 2005)
Ischemic Brain Injury (Neubauer, 1992; Neubauer, 1998)
Traumatic Midbrain Syndrome (Holbach, 1974)
Closed Head Injury (Rockswold, 1992)
Lupus (Wallace, 1996)
Stroke (Nighoghossian, 1995)
Myocardial Infarction (Shandling, 1997)
Recent Autism Findings
• Autistic children compared to neurotypical
controls have:
– Relative cerebral hypoperfusion
– Evidence of neuroinflammation
– Increased excretion of porphyrins
– Increased oxidative stress
Autism and Cerebral Hypoperfusion
fMRI Cerebellar Blood Flow and Activation
Allen et al., 2003
Autism and Cerebral Hypoperfusion
Muller et al., 1999
Abnormal Vascular Response: Cerebral Hypoperfusion
Middle Cerebral Arteries
Bruneau et al., 1992
Zilbovicius et al., 2000
Autism and Cerebral Hypoperfusion
Bitemporal hypoperfusion
Boddaert et al., 2002
Autism and Cerebral Hypoperfusion
Bitemporal hypoperfusion
Boddaert et al., 2002
Wilcox, 2002
Hypoperfusion of the prefrontal and left temporal areas
worsened and became “quite profound” as the age of
the autistic child increased.
Cerebral Hypoperfusion in
Autistics Correlated Clinically with:
Thalamus –
Repetitive, self-stimulatory, and unusual
behaviors including resistance to changes in
routine and environment (Starkstein, 2000)
Temporal – “Obsessive desire for sameness” and
“impairments in communication and social
Temporal
interaction” (Ohnishi, 2000)
Amygdala
– Impairments in processing facial expressions
and emotions (Critchley, 2000)
Wernicke – Trouble recognizing familiar faces (Pierce, 2004)
Brodmann
– Decreased language development (Wilcox, 2002)
and auditory processing (Boddaert, 2004)
Inflammation: Cerebral Hypoperfusion
Diseases in which inflammation
causes decreased cerebral blood
flow
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Sjögren’s syndrome (Lass, 2001)
Behçet’s disease (Caca 2004)
Viral encephalitis (Wakamoto, 2000; Nishikawa 2000)
Kawasaki disease (Ichiyama, 1998)
Lupus (Huang, 2002; Postiglione, 1998)
Mathieu et al., 2002
Abnormal Astrocyte Vascular Control: Cerebral Hypoperfusion
Reactive
Astroglia
(green)
Mulligan et al., 2004
Vargas et al., 2005
HBOT and Cerebral Hypoperfusion
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HBOT has been used with success
clinically in some hypoperfusion
syndromes:
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Fetal alcohol syndrome (Stoller, 2005)
Cerebral Palsy (Montgomery, 1999; Collet, 2001)
Closed head injury (Rockswold, 1992)
Stroke (Nighoghossian, 1995)
HBOT and Cerebral Hypoperfusion
Baseline
Midway
End
Golden et al., 2002
SPECT Scans in a 4 year old autistic child
after 10 sessions of HBOT at 1.3 atm and 24% oxygen
Heuser, 2002
Autism and Neuroinflammation
Evidence of Neuroinflammation
Vargas et al., 2005
Autism and Neuroinflammation
P
G
A – Normal control cerebellum
B – Autistic brain with loss
of Purkinje cell layer (P) and
granular cell layer (G)
Vargas et al., 2005
Autism and Neuroinflammation
Singh et al., 2004
Autism and Neuroinflammation
Vojdani et al., 2002
Autism and Neuroinflammation
Vojdani et al., 2004
HBOT and Inflammation
• Inflammation in Autistic Children
– Multiple studies reveal that autistic individuals
have evidence of neuroinflammation and
gastrointestinal inflammation
– In several studies, HBOT has been shown to
have potent anti-inflammatory effects (Akin, 2002;
Luongo, 1998; Sumen, 2001)
Saline
INFLAMMATION
Diclofenac
10 mg/kg
HBOT and Diclofenac
10 mg/kg
HBOT
Diclofenac
20 mg/kg
HBOT and Diclofenac
20 mg/kg
Sumen et al., 2001
HBOT and Inflammation
Weisz et al., 1997
J Clin Immuno. 17(2):154-9
HBOT and Inflammation
HBOT, 30 sessions at 100% oxygen and 2.0 ATA
Buchman et al., 2001
Takeshima et al., 1999
Am J Gastroenterol 94(11):3374-5
Atmospheric Pressure of Oxygen
Room Air 160 mmHg
Lung Capillaries 100 mmHg
Leaving Heart 85 mmHg
Peripheral Arterioles 70 mmHg
Organ Capillaries 50 mmHg
Cells 1-10 mmHg
Mitochondria 0.5 mmHg
(0.3% of inhaled oxygen)
Mitochondria is the final
site of heme production
Autism and Oxidative Stress
Total glutathione levels were 46% lower and
oxidized glutathione was 72% higher in autistic
children compared to typical controls.
James, 2004
HBOT and Oxidative Stress
Dennog, 1999
HBOT and Oxidative Stress
Antioxidants, HBOT
and Oxidative Stress
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α-lipoic acid (Alleva, 2005)
N-acetylcysteine (Yu, 2005; Pelaia, 1995)
Vitamin E (Hollis, 1992)
Riboflavin (Boadi, 1991)
Selenium (Hollis, 1992; Boadi, 1991)
Glutathione (Weber, 1990)
Melatonin (Pablos, 1997)
HBOT and Oxidative Stress
Cerebral Cortex
Hippocampus
Hypothalamus
Cerebellum
Melatonin
Rats 4 ATA
100% oxygen
HBOT and Stem Cells
In humans, HBOT at 2.0 ATA and 100% oxygen for
2 hours per treatment for 20 treatments doubled the
number of circulating stem cells
Thom et al.
in press
Thom et al.
in press
Thom et al.
in press
HBOT and Stem Cells
Steindler et al., 2002
Summary
Cerebral
Hypoperfusion
AUTISM
Neuroinflammation
and GI inflammation
Excretion
of Porphyrins
Oxidative
Stress
Neurodegenerative
Disease
Summary
Cerebral
Hypoperfusion
Neuroinflammation
and GI inflammation
Excretion
of Porphyrins
Oxidative
Stress
HBOT
Stem
Cells
Neurodegenerative
Disease
HBOT Safety at 1.3 ATA
• 111 children; 54 received HBOT at 1.3 atm
and 40 treatments over 2 months:
– 12 children had problems with their ears
– No other safety issues noted
Collet et al., 2001
Side effects of HBOT
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Barotrauma (2%)
Sinus squeeze
Serous otitis
Claustrophobia
Reversible myopia
Seizures (0.01 – 0.03%)
HBOT “Dosing”
Survival of Hippocampal neurons after 5 minutes of ischemia
Wada et al., 2001
HBOT and Autism