Autism

1. Hyper- and Autism Baric Oxygen Therapy 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. 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 HBOT Approved Indications The use of HBOT for autism is “off-label”

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

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

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

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

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

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

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

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

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

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

25. Zilbovicius et al., 2000

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

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

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 inAutistics Correlated Clinically with: Thalamus • 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 Temporal Amygdala Wernicke Brodmann

30. Inflammation: Cerebral Hypoperfusion 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)

31. Mathieu et al., 2002

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

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. HBOT and Cerebral Hypoperfusion Baseline Midway End Golden et al., 2002

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

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

37. 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

38. Autism and Neuroinflammation Singh et al., 2004

39. Autism and Neuroinflammation Vojdani et al., 2002

40. Autism and Neuroinflammation Vojdani et al., 2004

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 INFLAMMATION HBOT and Diclofenac 10 mg/kg Diclofenac 20 mg/kg HBOT HBOT and Diclofenac 20 mg/kg Sumen et al., 2001

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

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

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

46. 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

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. HBOT and Oxidative Stress Dennog, 1999

49. HBOT and Oxidative Stress

50. 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)