Biomedical Treatments for Autism: A Review.

1. Biomedical Treatments for Autism:A Review. Dr Wendy Edwards B.Sc.N., M.D., F.R.C.P.C.

2. Autism is a Medical Disorder • Not static or hard wired in the brain. • Affects many different body systems.

3. Can Autism be Cured? Autism is a chronic condition (think diabetes) that can be treated in some (??all) cases, to varying degrees of relief.

5. 3 Main Areas I’ll Review: • Immune system function and malfunction • Biochemistry of methylation and transsulfuration pathways (normal function and malfunction) and oxidative stress. • Short chain fatty acid metabolism deficiencies (Dr. MacFabe’s work)

6. But what about genetic causes for autism?

8. Genes Developmental stages Environmental factors

9. 3 Main Areas I’ll Review: • Immune system function and malfunction • Biochemistry of methylation and transsulfuration pathways (normal function and malfunction) and oxidative stress. • Short chain fatty acid metabolism deficiencies (Dr. MacFabe’s work)

10. Abnormal Immune System Function • Malfunctioning immune system - one reason why many children develop autism? • Many studies support the fact that some children with autism, compared to neurotypical children, have several family members with autoimmune diseases (hence, an inherited dysfunctional immune system is more likely). • Genetically, is this one of the inherited features that could lead to autism?

11. Abnormal Immune System Function • Paul Ashwood, an immunologist at the MIND Institute in California, published (2006) a review of the studies supporting immune dysfunction in autism. • “Increasing research has focused on the connections between the immune system and the nervous system…” “successful neurodevelopment (is) contingent upon a normal balanced immune response.”

14. To understand what might be wrong we need to understand how a normal immune system works.

15. The immune system • System of cells and chemicals that communicate with each other • Provide protection from non-self or foreign invaders • Identify invader, destroy it, clean up debris of “battle” and heal damage to host

16. The immune system • Disease is when immune system fails and too much invader takes over, or too much damage is done to the host while trying to fight the invader, or there is a misfire and the host is damaged along with invader.

17. Abnormal Immune System Function • One part of the immune system are T helper cells. • Th1 cells are most effective against viruses/fungi, (often intracellular invaders). Natural killer cells (NK) also work against these types of invaders. They are called into action by the Th1 cells. • Th2 cells work by activating the B cells of the immune system to make antibodies against foreign invaders found outside the cell (or sometimes antibodies against the cell itself = autoimmune disease)

18. So why would an abnormal system lead to autism? • Autistic children… Th2 activity > Th1. • So viruses (perhaps even minute amounts in vaccines??) and fungi will survive more easily and predominate in the body = cell death, inflammation, a change in the bowel flora environment, etc. • Increased Th2 activity = the formation of antibodies that won’t ‘‘turn off’’, causing a never ending inflammatory cycle or… • Resulting in the production of antibodies to self (e.g.. antibodies against brain tissue).

19. Abnormal Immune System Function • Ashwood P, et. al. The immune response in autism: a new frontier for autism research. J Leuk Biol. 2006 Jul:80;1-15 • Warren RP, et. al. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry. 1987 May;26(3);333-5 • Korvatska E, et. al. Genetic and immunologic considerations in autism. Neurobiol Dis. 2002 Mar;9(2);107-25

20. Abnormal Immune System Function • Gupta S, et. al. Th1 and Th2 like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998 May;66(1-2):143-5 • Molloy C, et. al. Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunology. 2006;172:198-205 • Pardo CA, et. al. Immunity, neuralgia and neuroinflammation in autism. Int Rev Psychiatry. 2005 Dec;17(6):485-95

21. Abnormal Immune System Function • Comi AM, et. al. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999 Jun;14(6):388-94 • Sweeten TL, et. al. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics. 2003 Nov;112(5):e420

22. Can we alter the immune system? • Dr. M. Boris published results of his study in 2007 showing that the drug ACTOS, previously used to treat Type II diabetes, can be used “off label” to shift the undecided Th null cell from becoming a Th2 cell to becoming a Th1 cell.

23. Can we alter the immune system? • Initial studies were successful with MS patients. ASD is currently being studied. • If we could successfully alter the immune system this would decrease viral load (increased Th1 activity) and decrease autoimmune inflammation in the brain, GI tract, etc. (decreased Th2 activity).

24. Can we alter the immune system? • Low dose Naltrexone studies are also promising. • Encouraging studies have been published regarding treatment of MS, Crohn’s disease and cancer.

25. Naltrexone blocks endorphin receptors. Low doses work for few hours versus 24 hours for standard dose. The body will increase endorphin levels briefly to compensate for the blockade. Increased endorphin levels = switch from Th2 activity to Th1 activity in the body. Can we alter the immune system?

26. Can we alter the immune system? • Dr. Vojdani (Autism One Chicago 2009) discussed the Th3 cell – which regulates activities between Th1 and Th2 cells. These cell numbers are low in autism. • TGF beta is a cytokine that “regulates” also, and is low in autism. • Published re low natural killer cell activity (not numbers) in autism.

27. Think increased survival of fungi/viruses in the GI tract. Think increased survival of intracellular invaders (?disruption of methylation cycle?) Think autoimmune inflammation of the GI tract , brain, etc. So if the immune system is malfunctioning….

28. Gastrointestinal issues

29. Immune System and the Gut • Why do so many children with autism have gut issues?

30. Immune System and the Gut • G.I. tract is one of the body’s first lines of defense. • A large part of the immune system is in the G.I. tract. If it malfunctions, toxins will survive (decreased Th1 function) or there will be overreaction to other substances there = inflammation (increased Th2 function).

31. Immune System and the Gut • Many of our children have inflammation, (due to yeast/viral/bacterial overgrowth in the G. I. tract and a weak immune system) = diarrhea, constipation, pain, flatus, or bloating. • An inflamed bowel wall will not absorb nutrients well. Increased mucous production covers the bowel wall cells preventing enzymes there from doing their jobs. Foods are not well digested or absorbed.

32. Immune System and the Gut • First step I always insist upon is healing the gut!! • Most supplements are oral so imperative that children treated for autism have healthy guts to absorb these. • Treatment is: Remove (yeasts, viruses, abnormal bacteria), replace (probiotic therapy) and avoid (GF/CF or other diet).

33. Immune System and the Gut • Valicenti-McDermott M, et. al. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36 • Horvath K, et. al. Autistic disorder and gastrointestinal disease. CurrOpin Pediatr. 2002 Oct:14(5):583-7

34. Immune System and the Gut • Balzola F, et. al. Autistic enterocolitis: confirmation of a new inflammatory bowel disease in an Italian cohort of patients. Gastroenterology. 2005;128:Suppl.2;A-303 • Ashwood P, et. al. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(1-2):126-34

35. Immune System and the Gut • Parracho HM, et. al. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005 Oct;54(Pt 10):987-91

36. Brain issues

37. Immune System and the Brain • PET and MRI scans have revealed many abnormalities in the brains of children with autism, both structural and functional. • BUT…wide individual variation of pathology so no quick answer to explain autism will come from here.

38. Immune System and the Brain • Complex interactions between chemical signals in the brain and the immune system.

39. Immune System and the Brain • Cytokines (chemicals that communicate instructions in the immune system) can affect cognitive and behavioural processing in the brain. Cytokine release from inflammation anywhere in the body can affect the brain. • Cytokines affect mood, sleep, appetite, and social interaction, as well as memory and learning. (Think autism!!)

40. Immune System and the Brain • Cytokines cross the blood brain barrier and make it more “open” and accessible for the crossing of neurotoxins. • Therefore, if cytokines are decreased (when inflammation is decreased), there will be a tighter blood brain barrier and fewer toxins reaching the brain.

41. Immune system and the brain • Conversely, neurotransmitters and neuropeptides can affect the development of the immune system (remember the nicotine study). This hints at a chicken and egg question. Does an abnormal brain result in an abnormal immune system or visa versa?

42. Immune System and the Brain • Kern JK, et. al. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006 Nov0Dec;9(6):485-99 • Wilson CJ, et. al. Cytokines and cognition – the case for a head to toe inflammatory paradigm. J Am Geriatr Soc. 2002 Dec;50(12):2041-56

43. Immune System and the Brain • Zhao B, et. al. Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspectives. J Neurosci Res. 1998 Apr 1;52(1):7-16 • Vega JA, et. al. Neurotrophins and the immune system. J Anat. 2003 Jul;203(1):1-19 • Cook EH, et. al. Receptor inhibition by immunoglobins: specific inhibition by autistic children, their relatives, and control subjects. J Autism Dev Disord. 1993 Mar;23(1):67-78

44. The biochemistry of methylation and transsulfuration

45. Methylation • The methylation pathway is how your cell creates the products it is meant to create. • Cells in the brain, through methylation, create neurotransmitters, RNA and DNA, proteins, etc. • Reactive oxygen species are also created (ROS). This is “oxidative stress”.

46. Transsulfuration • This pathway creates a means to clean up the oxidative stress, and other toxins in the cell. • Antioxidants that you ingest can also help to do this.

47. Methylation/Transsulfuration • It is possible that a gene defect can cause a problem(s) in either of these cycles. • Often the problems can be bypassed by “loading” the pathway with supplements on either side of the problem.

48. Methylation/Transsulfuration • Because autism numbers continue to grow (just as environmental toxins increase) these pathways might be altered/halted by toxins in our bodies. • We can support the body to rid itself of these toxins.

49. Methylation Pathway • This is the top half of the diagram and represents the well functioning cell, reusing homocysteine to make methionine, which in turn methylates substances to make neurotransmitters and other products that keep the cell and body functioning.