A clinical approach to treating Autism

Transcription

1 A clinical approach to treating Autism Dr Nicola Antonucci, Edinburgh, 12nd June 2013

2 What is Autism? Developmental Disorder of unknown origin.

3 Autism Spectrum Disorder DMS-IV Disorder: a cluster of symptoms, there is no implication of etiology Disease: is a illness where the underlying etiology is known Ex: Mental Disorder, Mood Disorder,Depressive disorder

4 What is Autism? Genes?

5 + 78%

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7 + 78% yearly increase + 13%

8 + 13% in 50 1 in 42 1 in 37 1 in 33 1 in 29 1 in 26 1 in 23 1 in 20 1 in 18

9 What is Autism? Genes Environmenta

10 Neuroglial Activation and Neuroinflammation in the brain of patients with autism Vargas et al Annals of Neurology 2005 Jan; 57 (1): 67-81

11 Microglia: small glial cells that interact with neurons as part of normal immune defence When ACTIVATED, Microglia numbers increase and change morphology

12 Microglia: small glial cells that interact with neurons as part of normal immune defence When ACTIVATED, Microglia numbers increase and change morphology

13 Excitotoxicity

14 Excitotoxicity

15 Excitotoxicity (?)

16 TNFa, IL-1b, IL-6,INFg LPS ( Pathogenic Microrganism) Oxidative stress Activated MICROGLIA Heavy Metals

17 Excitotoxicity TNFa, IL-1b, IL-6 LPS Oxidative stress Heavy Metals

18 The Autism Mercury Hypothesis S. Bernard, A. Enyati, L. Redwood, H. Roger, T. Binstock. Autism: A Novel Form of Mercury Poisoning. Medical Hypothesis 2001;56(4): In individuals with a genetic susceptibility (such as a defect in enzymes which are responsible for clearing toxic heavy metals), prenatal and early postnatal exposure to mercury leads to neurologic damage resulting in autistic symptoms.

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20 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

21 Autism research shows: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

22 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

23 Microtubule and neurite degeneration Construction and repair of the nervous system requires the structural protein tubulin to form microtubules which support axons and neurites

24 Microtubule and neurite degeneration Mercury binds the beta-subunit of tubulin breaking the links between the tubulin subunits and disrupting this scaffolding

25 Microtubule and neurite degeneration. Mercury interferes with the ability of the tubilines to dock together.

26 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

27 Long-distance underconnectivity and local over-connectivity Provoking preferentially retraction and degeneration of large axons, Mercury is causing a lost of long-range connections in brain (underconnectivity) and a local dendritis overgrowth as compensatory mechanism The loss of asymmetry and reduced interhemispheric connectivity in adolescents with autism: A study using diffusion spectrum imaging tractography Original Research Article Fig. 2. The regions of interest (ROIs) and reconstructed callosal fiber tracts. The ROIs at the bilateral orbitofrontal lobes (yellow), bilateral inferior frontal gyri (pink), and bilateral superior temporal gyri (blue) are shown. The fiber tracts are pseudocolored threedimensionally according to the local tract orientation with respect to the image coordinates.

28 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

29 Oxidative stress and Lipid Peroxidation and low Glutatione Hg Overproduction of Reactive Oxygen Species atoms, molecule and ions with unpaired elettrons they steal elettrons from Lipid Membranes Lipid Peroxidation Lost of membrane integrity and fluidity Neurons death

30 Oxidative stress and Lipid Peroxidation and low Glutatione Hg activity of GSH-related enzymes (gluthatione peroxidase,gluthatione reductase) Inhibit the development of cerebral GSH methabolism Permanent functional deficit of GSH-related enzyme GSH

31 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

32 Microglial activation neuroinflammation and gliosis Release of pro-oxidants (ROS, NO and Superoxide) Lipid Peroxidation, protein and nucleid acids oxidated Low Glutathione > Brain Oxidative Damage Increased number of migratory astrocites and microglia (gliosis)

33 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

34 Mitocondrial damage and disfunction Oxidative stress (NO, superoxide, low GSH) Lipide peroxidation

35 Mitocondrial damage and disfunction Impaired mitochondrial membrane permeability Disrupted calcum homeostasis

36 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

37 Disruption in calcium homeostasis and signaling Mercury Excessive influx of Ca++ ions in neurons from extracellular spaces from intracellular stores (endoplasmic reticulum) Lead to inflammation, oxidative stress, free radicals untill neuronal death

38 Mercury causes in the Brain: Microtubule and neurite degeneration Long-distance underconnectivity and local overconnectivity Microglial Activation Neuroinflammation and Gliosis Oxidative stress and Lipid Peroxidation and low Glutatione Mitocondrial Damage and dysfunction Disruption in calcium homeostasis and signaling Disruption of GABAergic and Glutamatergic homeostasis

39 Disruption of GABAergic and Glutamatergic homeostasis Mercury

40 Mercury is highly toxic metal, especially when metabolized into methylmercury. Adverse health effects from mercury exposure can be: developmental deficits during fetal development, attention deficit and developmental delays during childhood

41 Recent studies suggest that mercury may have no threshold below which some adverse effects do not occur.

42 U.S. EPA Reference Dose/day 0.1 µg/kg body weight/day as an exposure without recognized adverse effects. It means a blood mercury concentrations = 5.8 µg/l EPA's 2001 Reference Dose (RfD) for methylmercury was calculated to protect the developing nervous system.

43 National Health and Nutrition Examination Survey ( NHANES) Approximately 8% of women Women ranging years old Have blood mercury concentrations greater than 5.8 ug/l Based on this prevalence, it is estimated that more than 300,000 newborns each year may have increased risk of learning disabilities associated with in utero exposure to methylmercury.

44 Environmental Mercury Exposure (1991) Amalgams: 10 times more then all the other sources of HG

45 Environmental Mercury Exposure (1991) Amalgams: 10 times more then all the other sources of HG Metallic mercury vapor from amalgam fillings at a rate of 2 to 28 μg per facet surface per day, of which about 80% is absorbed

46 Are amalgams fillings safe for pregnant woman? U.S. EPA Reference Dose/day 0.1 µg/kg body weight/day Pregnant woman 50 kg Maximum 5 mcghg/day 1 Amalgam: from 2 to 28 μghg/day! 3 Amalgams: from 6 to 84 μghg/day!

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48 Hg: which source of pollution? USA coal-fired power plants 48 tonns/year It's only the 3% of the global total!

49 Hg: which source of Intoxication?

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51 How much mercury in 100 mg of FISH? SWORDFISH 99 mcg Hg SHARK 98 mcg Hg TUNA BIGEYE (Thunnus obesus) 69 mcg Hg LOBSTER 17 mcg Hg COD 11 mcg Hg TROUT 7 mcg Hg MACKEREL 5 mcg Hg SALMON 2 mcg Hg

52 Can a pregnant woman eat fish? Pregnant woman = 50 kg Maximum exposure= 5 mcg Hg a day Fresh slice Tuna 100 mg = 69 mcg! 14 times more!!!

53 EPA guidelines for pregnant: 1. Do not eat Shark, Swordfish, King Mackerel, or Tilefish You can eat up to 2 meals (total of 12 oz) of fish a week. 2. Prefer this 5 fishes low in mercury: shrimp, canned light tuna, salmon, pollock and catfish. 3. Check local advisories about the safety of fish caught in lakes, oceans, and rivers near you.

54 Can thimerusal vaccine harm children? Child of 5 kg EPA treashould: 0,5 mcg Hg / day DTP contained = 25 mcg Hg It's 50 times more!!!

55 Reduced levels of mercury in first baby haircuts of autistic children. Holmes AS, Blaxill MF, Haley BE, Int J Toxic. 2003;22(4):

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58 What is Autism? Metabolic-Toxic Encephalopaty caused by microglia activation that can occur in children with genic defects in detoxification when exposed to environmental factors such as chiefly mercury intoxication.

59 History Case Maternal Dental Amalgams Dental Amalgam in the child Fish Consumption Occupational Exposure Use of medicine which contain Thimerousal (Rogam, Lantigen B) Vaccination during pregnancy (Flu vaccines)

60 Sign and Symptom Delay of motor milestones Fine and gross motor skill imparment Hypotonia Toe walking Hypersalivation and scialorrea Seizures Skin Marmorada Pink Nails

61 Biomarkers of Oxidative Stress Plasma level of Gluthatione reduced (GSH) Plasma level of Gluthatione oxidated (GSSG) Cysteine Methionine Homocisteine Urinary 8- hydroxyguanosine Urinary Isoprostane

62 Neurochem Res Feb;34(2): Epub 2008 Jul 9.

63 Biomarkers of Mithocondrial Deficit AST/ALT < 2 Ammonia Lactate Pyruvate Acyl-Carnitine panel Alanin/Lisin <2,5 CK

64 Biomarkers of Intoxication Urinary Porphyrin Red Blood Cell test Challenge Test (after administration of chelator) Blood Mercury Hair Toxic Mineral

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67 Angelo 30 mo Diagnosys of PDD of Autism Spectrum Gastrointestinal Issues since 8 mo (costipation) Severe Asthma Delaly in walking (20 mo) Never talk Lost of contact and stimming at 15 mo Fine Motor skill Issues

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73 Biomedical Center for Autism Research and Treatment Bari Italy Rate of Abnormal Porphyrins in ASD Period of observation: N. patients = 210 M:F= 3,5:1 Age Range: 2-28 aa Philippe Auguste Lab: 67,6% +

74 Chelation Therapy DMSA DMPS CaEDTA Penicillamine

75 DMPS 2,3-Dimercapto-1-propanesulfonic acid Dimaval IV is used in Germany Expecially for mercury, also for lead, cadmium, silver, tin, and arsenic. Could slowly lower methylmercury in the brain Oral: 1-2 mg/kg, 3x/day (total dose 3-5 mg/kg/day) for 3 days on and 11 days off, Rectal:10 mg/kg, 1x/day for 3 days on and 11 days off. Other option: IV, Trandermal, Side effect: increase intestinal disbyosis (overgrowth yeast/bacteria). Possible allergic dermatological reactions

76 DMSA Meso-2,3-dimercaptosuccinic acid Approved in the 1960 s by FDA for chelation Effective at removing lead, mercury, arsenic, tin, nickel, and antimony. Do not penetrate the blood-brain barrier. Oral DMSA (10 mg/kg-dose, 3x/day, for 3 days on and 11 days off) Rectal DMSA (25mg / kg once day for 3 day on and 1 days off) Side effect: increase intestinal disbyosis (overgrowth yeast/bacteria).

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79 CaEDTA ethylenediaminetetraacetic acid, Approved by U.S FDA and European Union Very specific for lead, and less for mercury Only IV therapy (20-50 mg/kg a day) once a week No orally or rectal absorption (only 5%) No problem with intestinal dysbiosis

80 Reduction of Toxic Exposure: Avoidance of mercury-silver dental amalgams Avoid swimming pool Avoidance of fish consumption Purified water to drink and to cook Organic foods or extensive washing of the surfaces of fruits and vegetables.

81 Angelo now is 4 yo He is able to talk (even if simple sentences) Not anymore episode of Atsma No GI symptoms Cognitive Abilities Improved More connected with the world and people

82 Conclusion Toxic Encephalopaty is a plausible clinical diagnosys covered by the unuseful label Autism Chelation therapy is: still considered the most effective treatment for Autism It's safe Need more large and accurate reaserches to be accepted

83 dr Nicola Antonucci Psichiatrist Biomedical Center for Autism Research and Treatment