Advanced Treatments for Autism and Strategies for Non-Responders

1. Advanced Treatments for Autism and Strategies for Non-Responders Dan Rossignol, MD FAAFP International Child Development Resource Center 321-259-7111 www.icdrc.org Autism One Conference 2009 May 21, 2009

2. Autism Spectrum Asperger Syndrome ADHD PDD-NOS Autism Psychologically / Behaviorally defined Stereotypical behaviors Social interaction Communication Underlying pathophysiology ???

3. Inflammation: GI, Brain Toxins Impaired Glutathione / Sulphation Oxidative Stress / Mito Dysfunction

4. Autism: Regression • Seizures (language regression) • Inflammation [Connolly, 1999] • Maternal antibodies [Braunschweig, 2008] • Familial autoimmune problems • Oxidative stress [Chauhan, 2004] • Fatty acid deficiencies [Bu, 2006] • GI problems [Valicenti-McDermott, 2008] • Mitochondrial dysfunction [Poling, 2006]

5. Non-responders • Existing / ongoing toxicity • Brain inflammation / hypoperfusion • Uncontrolled Oxidative stress • Mitochondrial dysfunction • Subclinical seizure activity

6. Detoxification “Detox” • Removal of toxic substances from the body • Major function of the liver, kidneys, and gastrointestinal system • In people with kidney failure, dialysis is a form of detoxification • Impairments in detox can occur in some individuals • e.g., Acetaldehyde dehydrogenase: facial flushing with ethanol Alcohol Acetaldehyde Acetic acid

8. The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic solvents. The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. Windham et al., 2006 Environ Health Perspect 114:1438-44

9. Multivariate a posteriori models comparing children of mothers living within 500 m of field sites with the highest nonzero quartile of organochlorine poundage to those with mothers not living near field sites suggested an odds ratio for ASD of 6.1 (95% confidence interval, 2.4-15.3). Roberts et al, 2007 Environ Health Perspect 115:1482-9

10. Sources of toxins: Prenatal • Mom (good history needed): • Dietary (seafood consumption) • Thimerosal containing vaccines; Rhogam • Amalgams • Smoking • Alcohol use • Lead stored in bone • Mercury and other metals stored in tissues • Occupational exposures (dentist, etc…) • Psychological stress during pregnancy (hurricanes)

11. Sources of toxins: Postnatal • Child: • Thimerosal (flu) / aluminum from vaccines • Environmental / atmospheric • Dietary sources (arsenic, seafood) • Water ? • Household • Amalgams • Unusual: weighted vests, old bathtubs, lead weights • Phenols, food dyes, propionic acid

12. Evaluation for Toxins • Unprovoked blood and urinary heavy metal samples reflect recent exposure • Hair tests reflect metals as long as hair has been there • Chelator challenge • Urinary fractionated porphyrins • Markers of autoimmunity • Plasma sulphate / cysteine • Urinary pesticide levels • Propionic acid

13. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (p < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (p = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder. Nataf et al., 2006 Toxicol Appl Pharmacol 214(2):99-108

14. Nataf et al., 2006 Toxicol Appl Pharmacol 214(2):99-108

15. This case involves a 4 1/2-year-old boy diagnosed with autism, attention deficit hyperactivity disorder (ADHD), and an elevated blood-lead level of 42 mcg/dl. The child was treated for the elevated blood-lead with the chelating agent succimer. The parents reported a decrease in repetitive behaviors while on succimer with a regression to previous symptoms when medication was discontinued. Also seen was a decrease of hyperactive behavior while being treated with succimer. Eppright et al., 1996 Mo Med 93(3):136-8

16. Toxic Metal Treatment(off-label use) • CaNa2 EDTA: FDA approved for lead toxicity, very poor absorption orally. Usually IV or suppository. Good for lead, ok for aluminum, poor for mercury. • DMSA: FDA approved for lead intoxication. Used orally or suppository. Good for mercury and lead, poor for aluminum. • DMPS: Not licensed in the US, but can be legally imported and compounded. Typically used IV or suppository. Good for mercury, fairly poor for lead. • D-penicillamine: FDA approved for Wilson’s disease and rheumatoid arthritis. Used orally. Good chelator of mercury. Crosses blood-brain barrier. • OTC products: Typically lack efficacy studies.

17. Typically Used Doses • CaEDTA: 10-50 mg/kg • DMPS: 2-3 mg/kg (2 mg IV, 3 mg supp.) • DMSA • Oral: 10 mg/kg tid x 3 days / 11 days off • Suppository: 10-20 mg/kg, 2-3 x per week • D-penicillamine: 5-15 mg/kg/day oral

18. Other IV Therapies • Glutathione: 200-1200 mg • N-Acetylcysteine: 200-600 mg • Vitamin C: 2,000-4,000 mg • Other vitamins/minerals

19. Brown et al., 2006 Pediatrics 118(2):e534-6

20. Possible Side-Effects of Chelators • Depressed white blood cell (WBC) count • Elevated liver function tests (LFTs) • Depletion of vitamins and minerals • Dysbiosis • Behavioral changes (stimming, hyperactive, irritability) • Allergic reaction / rash • Anaphylaxis • Use only under physician supervision

21. Laboratory monitoring • Initially, and generally every 2-3 months (unless problem identified): • Complete blood count (CBC) • CMP (liver enzymes, renal function) • Mineral stores (red blood cell elements) • Iron storage • Cysteine / sulphate • Thyroid function • Provoked urine toxic metals • GI testing as indicated (OAT, stool culture)

22. 4 yo boy with autism • Had regression and lost words • Now speaks 20-30 words • Stimming: mild • Social interaction: poor • Hyperactivity: moderate • GI: loose BM

23. Previous UTM after oral DMSA

24. Labs • CMP, TSH, ferritin, testosterone, lactic acid, ammonia normal • CBC shows mild anemia • Cysteine 0.44 (ref 0.61-1.16) • Sulfate 3.9 (ref 3.0-5.9)

26. UTM after DMSA suppository (20 mg/kg)

27. Immune Dysregulation • Deficiencies or dysfunctions: ineffective or defective immune response(s) • Hypersensitivity: over-reaction to innocuous foreign substances • Autoimmunity: inappropriate reaction to self, loss of self-recognition • Inflammation: damage to normal tissue (“bystander effect”) from over-reaction by immune system 1 2 3 4

28. Immune System Evaluation • A child with autism who has recurrent infections deserves an immune evaluation for immunodeficiency. • A child with autism who has eczema, chronic nasal symptoms, asthma, significant GI symptoms, or recurrent respiratory infections deserves an allergy evaluation for IgE inhalant and food allergies.

29. Boris et al., 2004 J Nutr Environ Med 14(1):47-54

30. Autism and Neuroinflammation Over 4X Over 4X Vargas et al., 2005 Ann Neurol 57(1):67-81

31. Autism and Neuroinflammation Perivascular macrophages and microglia Vargas et al., 2005 Ann Neurol 57(1):67-81

32. Autism Control Connolly et al., 1999 J Pediatr 134:607-13

33. Messahel et al., 1998 Neurosci Letters 241:17-20

35. in vivo vasoconstriction Ming et al., 2005 Prostaglandins Leukot Essent Fatty Acids 73(5):379-84

37. Other tests • C-reactive protein / Sed rate • Platelet count • GI: fecal calprotectin / lactoferrin • Inflammatory comorbidities: • Eczema • Asthma • Allergies

38. Propionic acid (PPA) is a short chain fatty acid, a metabolic end-product of enteric bacteria in the gut, and a common food preservative. Recent evidence indicates that PPA can cause behavioral abnormalities and a neuroinflammatory response in rats. These findings suggest that PPA can change both brain and behavior in the laboratory rat in a manner that is consistent with symptoms of human ASD. Shultz et al., 2008 Neuropharmacology 54(6):901-11

39. The authors describe a child whose language and behavior regressed at 22 months and in whom pervasive developmental disorder was later diagnosed. At 6 years, he displayed a profound receptive-expressive aphasia accompanied by behavioral disturbances characterized by hyperactivity, impaired social interactions, tantrums, gestural stereotypies, and echolalia. Corticosteroid treatment resulted in amelioration of language abilities and behavior. Stefanatos et al., 1995 J Am Acad Child Adolesc Psychiatry 34(8):1107-11

40. Previously developmentally normal, he had symptoms of autism with rapid regression in developmental milestones coincident with the onset of lymphoproliferation and autoimmune hemolytic anemia. Low-dose steroid therapy induced early and complete remission in the ALPS phenotype. There was subjective improvement, followed by objective improvement in speech and developmental milestones. We propose that autism may be part of the autoimmune disease spectrum of ALPS in this child. Shenoy et al., 2000 J Pediatr 136(5):682-7

41. A prospective study was done with 44 children with language regression and abnormal Digitrace 24 EEG epileptiform activity in sleep. All the patients were treated with a form of Depakote or Depakene for 8 to 12 weeks and were reassessed with a 24-hour EEG before the addition of weekly bolus high-dose prednisone or methylprednisolone (10 mg/kg/wk). Results of poststeroid add-on treatment were available for 25 cases. Of these patients, EEG showed further improvement in 60% (n = 15), with no improvement seen in 40% (n = 10). Clinical speech data showed the combination of Depakote/Depakene and pulse dose steroid treatment yielding improvement in 82% (n=36). Side effects were unremarkable with no cushingoid complications even after 18 months of therapy. Chez et al., 1998 Annals Neurology 44(3):539

42. A total of 25 children (average age 7.9 +/- 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients. Boris et al., 2007 J Neuroinflammation 4:3

43. Children with autism have a significantly reduced level of plasma IgG (5.39+/-0.29 mg/mL) compared to the TD (7.72+/-0.28 mg/mL; P<0.001) and DD children (8.23+/-0.49 mg/mL; P<0.001). Children with autism also had a reduced level of plasma IgM (0.670.06mg/mL) compared to TD (0.79+/-0.05 mg/mL; P<0.05). Ig levels were negatively correlated with ABC scores for all children (IgG: r=-0.334, P<0.0001; IgM: r=-0.167, P=0.0285). Heuer et al., 2008 Autism Res 1(5):275-283

44. Gupta et al., 1996 J Autism Dev Disord 26(4):439-52

45. In documented autistic children, 400mg/kg IVIG was administered each month for 6 months. Baseline and monthly Aberrant Behavior Checklists were completed on each child in order to measure the child’s response to IVIG. The participants’ overall aberrant behaviors decreased substantially soon after receiving their first dose of IVIG. Further analysis of the total scores revealed decreases in hyperactivity, inappropriate speech, irritability, lethargy and stereotypy. However, 22 of the 26 children regressed to their pre-IVIG status within 2–4 months of discontinuing the IVIG. Boris et al., 2006 J Nut Environ Med 15(4):1-8

46. Naltrexone increased T-helper cells and decreased T-suppressor cells in children with autism. Scifo et al., 1996 Ann Ist Super Sanita 32(3):351-9

47. Bradstreet et al., 2007 Med Hypotheses 68(5):979-87

48. Anti-inflammatories:Typical doses Prednisone: 1-2 mg/kg/day tapered unless using high-dose protocol Spironolactone: 2-3 mg/kg/day target Actos: 15-60 mg/day Singulair: 4-10 mg/day Minocycline: 50-100 mg bid IVIG: 400-800 mg/kg once a month

49. Wilson et al., 2006 Brain Res 1098:126-8

50. 5 yo girl with autism • On supplements including antioxidants, MB12, GFCF diet • Urinary neopterin is very elevated • Mildly elevated platelet count • Porphyrins mildly elevated • History of eczema