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

2. 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

3. 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.

5. HBOT and Autism

6. 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)

7. 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”

8. Effects of HBOT Patel, 2005 Skin Cell Growth and Wound Healing

9. Gionis et al., 1999 Intensive Care Med 26(3):355 Effects of HBOT

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

13. Demchenko et al., 2000 Nitric Oxide 6(4):597-608 Effects of HBOT Cerebral blood flow

14. Effects of HBOT Cerebral blood flow Demchenko et al., 2005 J Cereb Blood Flow Metab 25(10):1288-300

15. Effects of HBOT Cerebral blood flow Demchenko et al., 2005 J Cereb Blood Flow Metab 25(10):1288-300

16. Effects of HBOT Cerebral oxygenation Demchenko et al., 2005 J Cereb Blood Flow Metab 25(10):1288-300

17. Calvert et al., 2002 Effects of HBOT Hypoxia Ischemia Hypoxia Ischemia + HBOT Control Rat Brain

18. Rosenthal et al., 2003 Distribution of Ischemic Changes Effects of HBOT

19. Postischemic BBB permeability Veltkamp et al., 2005 Postischemic cerebral edema Rats 3 ATA 100% oxygen Effects of HBOT

20. “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)

21. Recent Autism Findings Autistic children compared to neurotypical controls have: –Relative cerebral hypoperfusion –Evidence of neuroinflammation –Increased excretion of porphyrins –Increased oxidative stress

22. Allen et al., 2003 fMRI Cerebellar Blood Flow and Activation Autism and Cerebral Hypoperfusion

23. Muller et al., 1999 Autism and Cerebral Hypoperfusion

24. Bruneau et al., 1992 Middle Cerebral Arteries Abnormal Vascular Response: Abnormal Vascular Response: Cerebral Hypoperfusion

25. Zilbovicius et al., 2000

26. Bitemporal hypoperfusion Boddaert et al., 2002 Autism and Cerebral Hypoperfusion

27. Bitemporal hypoperfusion Boddaert et al., 2002 Autism and Cerebral Hypoperfusion

28. Wilcox, 2002 Hypoperfusion of the prefrontal and left temporal areas worsened and became “quite profound” as the age of the autistic child increased.

29. Cerebral Hypoperfusion in Autistics 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 Wernicke Brodmann Thalamus Temporal Amygdala

30. 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

31. Mathieu et al., 2002

32. Mulligan et al., 2004 Reactive Astroglia (green) Vargas et al., 2005 Abnormal Astrocyte Vascular Control: Abnormal Astrocyte Vascular Control: Cerebral Hypoperfusion

33. 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)

34. Golden et al., 2002 BaselineMidwayEnd HBOT and Cerebral Hypoperfusion

35. Heuser, 2002 SPECT Scans in a 4 year old autistic child after 10 sessions of HBOT at 1.3 atm and 24% oxygen

36. Evidence of Neuroinflammation Vargas et al., 2005 Autism and Neuroinflammation

37. A – Normal control cerebellumB – Autistic brain with loss of Purkinje cell layer (P) and granular cell layer (G) Vargas et al., 2005 P G Autism and Neuroinflammation

38. Singh et al., 2004 Autism and Neuroinflammation

39. Vojdani et al., 2002 Autism and Neuroinflammation

40. Vojdani et al., 2004 Autism and Neuroinflammation

41. 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)

42. Saline 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 INFLAMMATION

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

44. Buchman et al., 2001 HBOT and Inflammation HBOT, 30 sessions at 100% oxygen and 2.0 ATA

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

46. 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

47. 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

48. Dennog, 1999 HBOT and Oxidative Stress

50. Antioxidants, HBOT and 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)

51. Rats 4 ATA 100% oxygen HippocampusCerebral Cortex HypothalamusCerebellum HBOT and Oxidative Stress Melatonin

52. 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

53. Thom et al. in press

54. Thom et al. in press

55. Steindler et al., 2002 HBOT and Stem Cells

56. Cerebral Hypoperfusion Oxidative Stress Neurodegenerative Disease AUTISM Summary Neuroinflammation and GI inflammation Excretion of Porphyrins

57. Cerebral Hypoperfusion Oxidative Stress Neurodegenerative Disease Summary Neuroinflammation and GI inflammation HBOT Stem Cells Excretion of Porphyrins

58. 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

59. Side effects of HBOT Barotrauma (2%) Sinus squeeze Serous otitis Claustrophobia Reversible myopia Seizures (0.01 – 0.03%)

60. Survival of Hippocampal neurons after 5 minutes of ischemia Wada et al., 2001 HBOT “Dosing”

61. HBOT and Autism