AutismAutismHyper-Hyper-BaricBaricOxygenOxygenTherapyTherapy

andand

Dan Rossignol, M.D.Dan Rossignol, M.D.DAN! PhysicianDAN! Physician

Clinical Assistant ProfessorClinical Assistant ProfessorUniversity of VirginiaUniversity of Virginia

Department of Family MedicineDepartment 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.

Prevalence of Autism

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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• 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”

Effectsof HBOT

Patel, 2005

Skin CellGrowth andWoundHealing

Gionis et al., 1999Intensive Care Med 26(3):355

Effectsof HBOT

Sunami, et al.Crit Care Med 2000; 28: 2831-36

Demchenko et al., 2000Nitric Oxide 6(4):597-608

Effectsof HBOT

Cerebral blood flow

Effectsof HBOT

Cerebral blood flowDemchenko et al., 2005J Cereb Blood Flow Metab 25(10):1288-300

Effectsof HBOT

Cerebral blood flowDemchenko et al., 2005J Cereb Blood Flow Metab 25(10):1288-300

Effectsof HBOT

Cerebral oxygenationDemchenko et al., 2005J Cereb Blood Flow Metab 25(10):1288-300

Calvert et al., 2002

Effectsof HBOT

HypoxiaIschemia

HypoxiaIschemia+ HBOTControl

Rat Brain

Rosenthal et al., 2003

Distribution ofIschemic Changes

Effectsof HBOT

Postischemic BBB permeability

Veltkamp et al., 2005Postischemic cerebral edema

Rats 3 ATA100% oxygen

Effectsof HBOT

“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)

Recent Autism Findings

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

Allen et al., 2003

fMRI Cerebellar Blood Flow and Activation

Autism and Cerebral Hypoperfusion

Muller et al., 1999

Autism and Cerebral Hypoperfusion

Bruneau et al., 1992Middle Cerebral Arteries

Abnormal Vascular Response: Abnormal Vascular Response: Cerebral Hypoperfusion

Zilbovicius et al., 2000

Bitemporal hypoperfusion

Boddaert et al., 2002

Autism and Cerebral Hypoperfusion

Bitemporal hypoperfusion

Boddaert et al., 2002

Autism and Cerebral Hypoperfusion

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 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)

Temporal

WernickeBrodmann

Thalamus

TemporalAmygdala

Diseases in which inflammation causes decreased cerebral blood

flow• 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)

Inflammation: Cerebral Hypoperfusion

Mathieu et al., 2002

Mulligan et al., 2004

ReactiveAstroglia(green)

Vargas et al., 2005

Abnormal Astrocyte Vascular Control:Abnormal Astrocyte Vascular Control: Cerebral Hypoperfusion

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)

Golden et al., 2002

Baseline Midway End

HBOT and Cerebral Hypoperfusion

Heuser, 2002

SPECT Scans in a 4 year old autistic child after 10 sessions of HBOT at 1.3 atm and 24% oxygen

Evidence of Neuroinflammation

Vargas et al., 2005

Autism and Neuroinflammation

A – Normal control cerebellum B – Autistic brain with lossof Purkinje cell layer (P) andgranular cell layer (G)

Vargas et al., 2005

P

G

Autism and Neuroinflammation

Singh et al., 2004

Autism and Neuroinflammation

Vojdani et al., 2002

Autism and Neuroinflammation

Vojdani et al., 2004

Autism and Neuroinflammation

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

Diclofenac10 mg/kg

HBOT and Diclofenac10 mg/kg

HBOT Diclofenac20 mg/kg

HBOT and Diclofenac20 mg/kg

Sumen et al., 2001

INF

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ION

Weisz et al., 1997J Clin Immuno. 17(2):154-9

HBOT and Inflammation

Buchman et al., 2001

HBOT and Inflammation

HBOT, 30 sessions at 100% oxygen and 2.0 ATA

Takeshima et al., 1999Am J Gastroenterol 94(11):3374-5

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

Atmospheric Pressure of Oxygen

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

Dennog, 1999

HBOT and Oxidative Stress

HBOT and Oxidative Stress

Antioxidants, HBOTand Oxidative Stress

• 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)

Rats 4 ATA100% oxygen

HippocampusCerebral Cortex

Hypothalamus Cerebellum

HBOT and Oxidative Stress

Melatonin

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

Steindler et al., 2002

HBOT and Stem Cells

CerebralHypoperfusion

OxidativeStress

NeurodegenerativeDisease

AUTISMAUTISM

Summary

Neuroinflammationand GI inflammation

Excretionof Porphyrins

CerebralHypoperfusion

OxidativeStress

NeurodegenerativeDisease

Summary

Neuroinflammationand GI inflammation

HBOTHBOT StemCells

Excretionof Porphyrins

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

• Barotrauma (2%)

• Sinus squeeze

• Serous otitis

• Claustrophobia

• Reversible myopia

• Seizures (0.01 – 0.03%)

Survival of Hippocampal neurons after 5 minutes of ischemiaWada et al., 2001

HBOT “Dosing”

HBOT and Autism