Autism

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Hyper-
and
Autism
Baric
Oxygen
Therapy
Dan Rossignol, M.D. DAN! Physician Clinical
Assistant Professor University of
Virginia Department of Family Medicine
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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

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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,
  Downs 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.

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HBOT and Autism
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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)

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HBOT Approved Indications

• Air or gas embolism
• Carbon Monoxide Poisoning
• Gas gangrene
• Crush injuries and compartment syndrome
• Decompression sickness
• Wound healing

• Severe anemia
• Intracranial abscess
• Necrotizing soft tissue infections
• Refractory osteomyelitis
• Skin flaps and grafts
• Delayed radiation injury
• Thermal burns

The use of HBOT for autism is off-label
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Effects of HBOT
Skin Cell Growth and Wound Healing
Patel, 2005
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Effects of HBOT
Gionis et al., 1999 Intensive Care Med 26(3)355
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Sunami, et al. Crit Care Med 2000 28 2831-36
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Effects of HBOT
Cerebral blood flow
Demchenko et al., 2000 Nitric Oxide 6(4)597-608
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Effects of HBOT
Cerebral blood flow
Demchenko et al., 2005 J Cereb Blood Flow Metab
25(10)1288-300
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Effects of HBOT
Cerebral blood flow
Demchenko et al., 2005 J Cereb Blood Flow Metab
25(10)1288-300
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Effects of HBOT
Cerebral oxygenation
Demchenko et al., 2005 J Cereb Blood Flow Metab
25(10)1288-300
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Effects of HBOT
Hypoxia Ischemia HBOT
Hypoxia Ischemia
Control Rat Brain
Calvert et al., 2002
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Effects of HBOT
Distribution of Ischemic Changes
Rosenthal et al., 2003
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Effects of HBOT
Postischemic BBB permeability
Rats 3 ATA 100 oxygen
Postischemic cerebral edema
Veltkamp et al., 2005
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Off-label Studied Uses of HBOT

• 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)

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Recent Autism Findings

• Autistic children compared to neurotypical
  controls have
• Relative cerebral hypoperfusion
• Evidence of neuroinflammation
• Increased excretion of porphyrins
• Increased oxidative stress

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Autism and Cerebral Hypoperfusion
fMRI Cerebellar Blood Flow and Activation
Allen et al., 2003
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Autism and Cerebral Hypoperfusion
Muller et al., 1999
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Abnormal Vascular Response Cerebral Hypoperfusion
Middle Cerebral Arteries
Bruneau et al., 1992
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Zilbovicius et al., 2000
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Autism and Cerebral Hypoperfusion
Bitemporal hypoperfusion
Boddaert et al., 2002
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Autism and Cerebral Hypoperfusion
Bitemporal hypoperfusion
Boddaert et al., 2002
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Wilcox, 2002
Hypoperfusion of the prefrontal and left temporal
areas worsened and became quite profound as the
age of the autistic child increased.
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Cerebral Hypoperfusion inAutistics Correlated
Clinically with

• Repetitive, self-stimulatory, and unusual
  behaviors including resistance to changes in
  routine and environment (Starkstein, 2000)
• Obsessive desire for sameness and impairments
  in communication and social interaction
  (Ohnishi, 2000)
• Impairments in processing facial expressions and
  emotions (Critchley, 2000)
• Trouble recognizing familiar faces (Pierce, 2004)
  
• Decreased language development (Wilcox, 2002) and
  auditory processing (Boddaert, 2004)
• Decreased IQ (Hashimoto, 2000)

Thalamus
Temporal
Temporal Amygdala
Wernicke Brodmann
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Diseases in which inflammation causes decreased
cerebral blood flow
Inflammation Cerebral Hypoperfusion

• Sjögrens syndrome (Lass, 2001)
• Behçets disease (Caca 2004)
• Viral encephalitis (Wakamoto, 2000 Nishikawa
  2000)
• Kawasaki disease (Ichiyama, 1998)
• Lupus (Huang, 2002 Postiglione, 1998)

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Mathieu et al., 2002
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Abnormal Astrocyte Vascular Control Cerebral
Hypoperfusion
Reactive Astroglia (green)
Mulligan et al., 2004
Vargas et al., 2005
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HBOT and Cerebral Hypoperfusion

• HBOT has been used with success clinically in
  some hypoperfusion syndromes
• Fetal alcohol syndrome (Stoller, 2005)
• Cerebral Palsy (Montgomery, 1999 Collet, 2001)
• Closed head injury (Rockswold, 1992)
• Stroke (Nighoghossian, 1995)

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HBOT and Cerebral Hypoperfusion
Baseline
Midway
End
Golden et al., 2002
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SPECT Scans in a 4 year old autistic child after
10 sessions of HBOT at 1.3 atm and 24 oxygen
Heuser, 2002
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Autism and Neuroinflammation
Evidence of Neuroinflammation
Vargas et al., 2005
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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
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Autism and Neuroinflammation
Singh et al., 2004
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Autism and Neuroinflammation
Vojdani et al., 2002
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Autism and Neuroinflammation
Vojdani et al., 2004
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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)

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Saline
Diclofenac 10 mg/kg
INFLAMMATION
HBOT and Diclofenac 10 mg/kg
Diclofenac 20 mg/kg
HBOT
HBOT and Diclofenac 20 mg/kg
Sumen et al., 2001
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HBOT and Inflammation
Weisz et al., 1997 J Clin Immuno. 17(2)154-9
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HBOT and Inflammation
HBOT, 30 sessions at 100 oxygen and 2.0 ATA
Buchman et al., 2001
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Takeshima et al., 1999 Am J Gastroenterol
94(11)3374-5
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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
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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
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HBOT and Oxidative Stress
Dennog, 1999
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HBOT and Oxidative Stress
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Antioxidants, HBOTand Oxidative Stress

• a-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)

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HBOT and Oxidative Stress
Hippocampus
Cerebral Cortex
Melatonin
Rats 4 ATA 100 oxygen
Hypothalamus
Cerebellum
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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
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Thom et al. in press
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Thom et al. in press
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HBOT and Stem Cells
Steindler et al., 2002
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Summary
Cerebral Hypoperfusion
AUTISM
Neuroinflammation and GI inflammation
Excretion of Porphyrins
Oxidative Stress
Neurodegenerative Disease
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Summary
Cerebral Hypoperfusion
Neuroinflammation and GI inflammation
Excretion of Porphyrins
Oxidative Stress
Neurodegenerative Disease
Stem Cells
HBOT
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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
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Side effects of HBOT

• Barotrauma (2)
• Sinus squeeze
• Serous otitis
• Claustrophobia
• Reversible myopia
• Seizures (0.01 0.03)

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HBOT Dosing
Survival of Hippocampal neurons after 5 minutes
of ischemia
Wada et al., 2001
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Oxygen Partial Pressures
At sea level, partial pressure air 760 mm
Air has 21 oxygen, partial pressure oxygen 160
mm
1.3 ATA 28 oxygen
1.5 ATA 100 oxygen
1.0 ATA 21 oxygen
1.3 ATA 90 oxygen
160 mm Hg Oxygen
277 mmHg Oxygen
1143 mmHg Oxygen
891 mmHg Oxygen
Arterial 100 mmHg
Arterial 177 mmHg
Arterial 1036 mmHg
Arterial 557 mmHg
Venous 39 mmHg
Venous 69 mmHg
Venous 404 mmHg
Venous 217 mmHg
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HBOT and Autism