"Market Growth for Home Hyperbaric Treatments"
Biomedical Treatments for Neurodevelopmental, Autoimmune and other Chronic Disorders David Berger, MD Medical Director Wholistic Pediatrics Tampa, FL (813) 960-3415 www.wholisticpeds.com Autistic Spectrum Disorders ADHD Asperger’s PDD Autism Syndrome In many of our patients, there are multiple biological abnormalities Discover Magazine, 3/14/07 Intestinal Abnormal flora (dysbiosis) Abnormal permeability (leaky gut) Illeal lymphoid hyperplasia Persistent Measles virus Immune System Th1 Th2 type of WBC Low TH1 can cause susceptibility to infections, with potential increased exposure to antibiotics. – Related Yeast Overgrowth in Intestinal Tract as well as Clostridia and Parasites High TH2 can lead to inappropriate antibody formation – Auto-antibodies – Food antibodies Biochemical Abnormalities Low sulfur amino acids Low zinc levels Low selenium levels High copper to zinc ratios Low omega – 3 fatty acids High ammonia levels Abnormal methylation metabolism High microbial metabolites Elemental Toxins: Mercury, Lead, etc Robert Cade, MD, Professor, University of Florida Medical School “A gluten and casein free diet resulted in significant improvement in 81% of children with autism within three months.” Rationale for Casein/Gluten Free Diet Gluten and casein have immune, as well as neurotransmitter impacts. Many ASD children have food hypersensitivities Improper digestion leads to buildup of opiate-like peptides. These can be identified in the urine of many children with ASD. Dr Cade at UF recently injected rats with casomorphin, causing the rats to develop autistic- like behaviors DPP-IV Dipeptidyl Peptidase IV, carboxypeptidase A, and aminopeptidase are some of the main enzymes that brake down the opiate peptides. Some of the enzymes are zinc dependent, and it’s activity can be inhibited by mercury, among other things. A first generation enzyme containing DPP-IV is available from Kirkman Labs. Although for most children it can not serve as a sole replacement for the C/G free diet, giving it with these foods allow some children to take c/g foods with out negative reactions, and it can be administered in cases of accidental exposure Dr. Lewis’ book is the essential starting point for a gluten and casein free diet. Milk: It does your body good? Frank Oski - Past chairman of Johns Hopkins Department of Pediatrics and Past- President of the American Academy of Pediatrics Evaluating Children Urine and Stool Studies Thyroid profile Toxic Metals Inborn Errors of Amino Acids Fragile X, Chromosomal Analysis Metallothionein analysis RBC Fatty Acids Brain auto-antibodies Immunoglobulins, WBC activity Detoxification Metabolism Hormone Profiles Autism Speaks Launches Pediatrician Outreach Initiative to Increase Awareness about the Diagnosis and Treatment of Gastrointestinal Problems Consensus Statement Developed by Expert Panel Includes Recommendations for Care Specific to Children with Autism February 28, 2007 Abnormal Stool & Urine Findings Best, and in some cases imperative to treat these prior to starting more advanced therapies such as chelation Stool : Yeast (Candida), Parasites (Giardia, Dientameoba, and others), Malabsorption, Blood, etc. Urine : Yeast and Bacterial metabolites, abnormal Kreb’s cycle metabolites, oxalates, opiate peptides, etc Treat Stool & Urine Findings Yeast Killers: Nystatin, Diflucan, Sporonox, Uva Ursi, MCT, goldenseal, Garlic, Candex (digestive enzyme) and others. Clostridia Killers: high dose lactobacillus, Metronidazole (benzoate by compounding), Vancomycin Parasites: the ones we see most often are also sensitive to Metronidazole Benzoate, other specific natural and pharmacological agents used depending on the particular organism OAT test OAT After Culturelle and Nystatin Nicholas (8 y/o)After Culturelle and Nystatin (3 months later) Attention span has definitely improved since the last visit. getting very good reports fro the teachers more "with it", not spacey now will respond much faster when spoken to. Reading skills vastly improved, with good comprehension skills. Reading instruction manuals and understanding it. Wants to keep reading on and on. performing skills at school that he never did before. Amazing memory for spelling. Learned how to tell time. Can perform addition. less problems with interactions with his peers, but he prefers solitary play when in his house. When visiting others he will interact more. He does much better in small and quiet groups getting better balance of his body. Sulfation Sulfur is an element critical to the structure and functioning of body mechanisms. Dr. Rosemary Waring reports that most autistic children show a deficiency of sulfates in their plasma. Of the autistic children she tested, 92% had sulfate levels that were only 12% of normal Low sulfates can lead to a leaky gut, as well as a weakness in the phenolsulfotransferase (PST) system. the PST pathway is important in removing toxins A weakness in the PST system is often characterized by night sweats, red face and ears, allergies, and keratosis pilaris (red bumps on back of arms) Tx: Epsom Salt by bath or transdermal application, or oral sulfates such as glucosamine sulfate and MSM After Epsom Salt Baths Eric’s (6 y/o) Response to Epson Salt Baths •Making new statements. Becoming more creative with language. Responding to answers appropriately •still needs help focusing for long periods of time, but paying more attention •echolalia is gone •showed much more interest in presents that he received for the holidays. •getting more involved with his brother, they are fighting a bit now. Ammonia •Ammonia is a known toxin to the brain. •High enough levels can cause can cause neurological symptoms, even coma. This is usually associated with liver disease •About 5-10% of ASD patients we check have mild to moderate elevations in Ammonia levels (in the presence of normal liver tests) •Proposed mechanism: Proteins >> Amino Acids >>Ammonia >>liver fuses 2 ammonia molecules to form urea >> excreted in urine. Gut pathogens >> leaky gut. Urease enzyme made by certain gut pathogens >> Urease enters the bloodstream >> splits urea back to ammonia at a pace faster then urea can be formed. Connor’s original Ammonia level Connor’s ammonia after 2 capsules of alpha ketoglutaric acid •Increased speech, repeating everything •socializing better, especially with sister •Separation still a problem when school starts •When peer tantrums, Conor gets upset. He did approach a crying child instead of running away, and when sister was crying he sought help instead of withdrawing Connor After 4 capsules of Alpha Ketoglutaric Acid •No more episodes of the rapid eye blinking or enlarged pupils •interacting better with sister •less melt-downs when others tantrum •speech improving on a weekly basis sound sensitivities seem to no longer be a problem Essential Fatty Acids The Omega Factor Omega 3’s in Autism Replacing and Omega-3 deficiency (source independent) Vs. Addressing Omega deficiency and Supplementing with natural Vitamin A (Cod Liver Oil) Immunity is complex and impacts every system in the body. It isn’t surprising that it effects child behavior and development. Immune System TH1 TH2 type of WBC Viral Stimulation Inappropriate antibody formation – Auto-antibodies – Food antibodies Frequent Infections - Especially Ear Related Yeast Overgrowth in Intestinal Tract w/ Clostridia and Parasites IMMUNIZATIONS I am not suggesting that we abandon our vaccination policy I am concerned about the growing number of chronically ill children There are more children with learning disabilities and autoimmune disorders then there has ever been in the history of medicine. Concerns about Vaccines Are we unnaturally stressing underdeveloped immune systems beyond their capabilities in our effort to keep the children from becoming ill? There are inadequate safety studies for the vaccines that are currently on the market Are we giving too many vaccines over a short time span? We do not have a clear understanding of the effects of some of the vaccine components such as thimerosal, aluminum, formaldehyde, and human fetal tissue. What’s Going On? Social deficits, shyness, social withdrawal Repetitive, perseverative, stereotypic behaviors; obsessive-compulsive tendencies Irritability, aggression, temper tantrums Lacks eye contact; impaired visual fixation Loss of speech, delayed language, failure to develop speech Speech comprehension deficits Sound sensitivity; mild to profound hearing loss Abnormal touch sensations; touch aversion Flapping, myoclonal jerks, choreiform movements, circling, rocking, toe walking, unusual postures Poor concentration, attention, response inhibition Self injurious behavior, e.g. head banging ADHD traits Sleep difficulties Diarrhea; abdominal pain/discomfort, constipation ALL SIGNS AND SYMPTOMS OF… MERCURY TOXICITY MERCURY Statement:Pediatrics 2001 Jul, American Academy of Pediatrics: Committee on Environmental Health. The developing fetus and young children are thought to be disproportionately affected by mercury exposure, because many aspects of development, particularly brain maturation, can be disturbed by the presence of mercury. Minimizing mercury exposure is, therefore, essential to optimal child health…..Mercury in all of its forms is toxic to the fetus and children, and efforts should be made to reduce exposure to the extent possible to pregnant women and children as well as the general population. _______________________________________________________________ Vaccine inserts would typically say “0.01% thimerosal as a preservative”, which to anyone would sound like an extremely small amount. When called to testify in front of the Institute of Medicine, an independent group formed by our government to monitor safety issues, Dr. Neil Halsey of Johns Hopkins University, and head of the vaccine recommendation committee that reports to the CDC, went on record as saying “No one ever did the math…. No one knows what dose of mercury, if any, from vaccines is safe. We can say there is no evidence of harm but the truth is no one has looked” Mercury/Thimerosal Thimerosal is Ethylmercury, a neurotoxin Mercury was found in the blood of newborns even before Hepatitis B shot, and higher levels after the shot. • Journal of Pediatrics, May 2000 In some pre-term infants, mercury levels were 10 times that of term infants Pre-term babies are vaccinated according to chronological age, not gestational age. Mercury/Thimerosal Intrauterine sources may include: • maternal fish consumption • mercury amalgam fillings •Rhogam (given to Rh (-) mothers, no longer present) •Influenza vaccine (still present) Mercury/Thimerosal Hepatitis B vaccine was introduced in 1991- with most newborns getting the first dose before leaving the hospital Hep B vaccine had contained 12.5 mcg of thimerosal = 6.25mcg mercury EPA established the “safe limit” at 0.1 mcg/kg/day, approximately 0.4 mcg/day for an 8 pound newborn Mercury/Thimerosal Typical Thimerosal Exposure for 2 month old infant: Hep B 12.5 mcg DTaP 25 mcg Hib 25 mcg Total 62.5 mcg of which 50% is ethylmercury = 31.25mcg Total “safe” dose for 10 pound (2 month old) baby by EPA standards: 0.5 mcg. The average 2 month old received ~60x the EPA limit Mercury/Thimerosal By 6 months of age, a fully vaccinated infant would have received: – 3 DTP 75 mcg thimerosal – 3 Hib 75 mcg thimerosal – 3 Hep B 37.5 mcg thimerosal Total 187.5 mcg thimerosal 93.75 mcg mercury 1999 FDA Center for Biologics Evaluation and Research Heavy Metal Exposures After exposure to mercury, the length of time to be eliminated varies for different organs: Blood and Hair: 4-6 months Non CNS organs: several years Brain: 20 years (Boyd Haley, PhD, University of Kentucky, Dept of Chemistry) Lead typically deposits into brain and bone. After exposure to lead, within several months the blood and urine levels will be normal even if the lead is still in the bone and brain (Clarkson, 2002) Who’s looking into all of this? Boyd Haley, PhD, Department of Chemistry Chairman, University of Kentucky. Dr Haley is considered one of the leading researchers in America on Heavy Metal toxicity • He reports that exposing neurons to thimerosal rapidly results in the stripping of tubuluin from the nerve axon, and also reduces the viability of actin. Actin and tubulin are proteins that are critically important for the growth of dendrites and to maintain the structure of the axon. •On exposing neurons grown in culture for 24 hours, then exposed to vaccines with thimerosal and thimerosal-free vaccines. There was significantly more cell death in those exposed to thimerosal vaccines. The most concerning part about this was that there was an extremely low amount of thimerosal used in the study, 10K less then the concentration found in most vaccines Who’s looking into this (cont) •Holloway et al, Arizona State:Oral antibiotics have been shown in rats to increase the half-life for excretion of mercury from 10 days to over 100 days. (Doctors have been told it is OK to vaccinate children as long as they are not seriously sick, with high fevers, and there is no recommendations not to vaccinate children on antibiotics) •Holloway et all, Arizona State 2002 carried out a DMSA challenge study involving 15 children with autism and 15 typical children. The children received a single dose of meso-2,3-dimercaptosuccinic acid (DMSA), at a dose of 10 mg/kg, followed by a 10-hour urine collection. The DMSA resulted in a much greater increase in heavy metal excretion in the children with autism compared to the controls. Many of the children with autism excreted high levels of one or more heavy metals, although there was wide variation in the amount and type of metal excreted. (The data suggests that many children with autism have a greatly diminished ability to excrete heavy metals, and thus would be unusually vulnerable to exposures to those metals) Mercury Testing As there is a relative short half life of mercury in serum, blood and urine testing will often be negative if more then 6 months have passed between exposure and testing Hair tests can be falsely positive if there are metals in shampoos, conditioners, or water. Also, there is evidence that mercury levels in the hair of autistic children is less than in controls (Cave and Holmes) For me, the best test is an oral chelation challenge, extracting the heavy metal and excreting it in the urine. This can document that the metal is present, it is not being excreted under normal circumstances, AND that the chelation agent and the route of administration given works for the individual Mercury Removal: Chelation Agents EDTA, Dimercaprol (BAL), DMSA, DMPS, and DMPA all have heavy metal binding activity Marked specificity for heavy metals, but also can cause decreases in trace elements and micronutrients (and these should be tested for periodically) Mercury is essentially irreversibly bound to DMSA, so mercury is not deposited in other tissues, even the kidney. DMSA/DMPS works through increasing urinary excretion. DMSA/DMPS does not cross the blood-brain barrier, so no risk of delivering bound mercury to the brain Very low toxicity. Side effects may include anorexia, nausea, vomiting, diarrhea, rash and a transient increase in liver enzymes. There are no known adverse drug interactions with DMSA/DMPS. EDTA: disodium vs Calcium disodium. Disodium EDTA given rapidly by IV can suddenly drop serum calcium levels. Only should use CaNa2 EDTA Mercury Removal: Chelation • oral (DMPS and DMSA) • IV (DMPS and CaNa2 EDTA) • Rectal (DMPS, DMSA, CaNa2 EDTA [detoxamin]). – best to have stool passage before insertion – CaNa2 EDTA seems to cause less yeast exacerbation • TD – emu oil seems the best vehicle – seen very little benefit/movement with DMPS – seen some positive excretions with DMSA – CaNa2 very difficult to keep in suspension without precipitation Single dose chelation challenge – baseline urine taken before dose given – 8 hour urine collection regardless of type/route – empty bladder before giving dose – DMSA (oral or rectal 25mg/kg) – DMPS (3mg/kg for IV, 10mg/kg for rectal, 5-10mg/kg oral) – CaNA2 EDTA (25-50mg/kg regardless of rout, maximum of 1500mg) – May need to do more than 1 challenge with different agents/routes (DAN! 2005 Consensus Paper) Antonio (7 y/o) on first chelation challenge with DMSA Antonio, after 4 cycles of DMSA Antonio, after 8 cycles of DMSA Antonio After Chelation with DMSA Has bad gas during the DMSA days, and is moody, then this goes away when the DMSA is finished. Doing better and better in speech therapy If he does not want to do things he cries. Teachers are reporting improvements seen on a month-to-month basis More hand gesturing In a more advanced class. The mimicry behavior has stopped. At this point language is the major barrier, behaviors and stemming are under control Richard (6 y/o) on first DMSA Challenge Richard after 2 mo of DMSA Richard Before Chelation •No self help skills •No bathroom skills •No attention span •No learning anything at school Richard After Chelation •Using the bathroom appropriately •Will sit still for haircuts •Focus and attention significantly improved •Knows his letter, numbers and colors •Excelling in all areas of education except for verbal speech, though is vocalizing more then every before Baseline DMPS/Glutathione-IV DMPS/Glutathione-Rectal Urine Porphyrins Porphyrins represent a group of uniquely structured compounds that can surround different types of ions/metals. Each has a specific biological function – Hemoglobin – Myoglobin – Chlorophyll Biochemistry 101 Enzymes – the keys to life A+B 0 C 0 D A & B are substrates, the ingredients being “mixed” together 0 is the enzyme, the catalyst that makes the reaction proceed. C & D are products made by the reaction, which can then go on to be substrates (ingredients) in other reactions Some enzyme reactions can go both directions Biochemistry 101 A+B 0 C 0 D What can cause an enzyme not to work? •Not enough or particular substrate •The genes that code for the enzyme are abnormal, creating a damaged or inefficient enzyme •Something “poisons” the enzyme so it won’t work •Too much of a product (D) drives the reaction in the other direction Urine Porphyrins Certain toxins, such as heavy metals and pesticides can inhibit certain enzymes in the heme porphyrin pathway, leading to specific porphyrin profiles being excreted into the urine. If an enzyme is inhibited, the substrate “upstream” can build up. Aluminum and dioxin inhibit uropophyrin decaboxylase. Mercury inhibits coproporphyrinogen oxidase. Lead inhibits coproporphyrinogen oxidase and aminolevulinic acid dehydratase. (Woods, 1996) Second urine void of the day is the best collection, as supplements that cause oxidation if mixed with the porphyrins overnight in the bladder can change the structure of the porphyrin lead to false values (Martin, 1996) Urine Porphyrins Coproporphyrin (copro) is a general marker for overall toxic metal burden. It is seen elevated in the presence of mercury, lead and arsenic Precoproporphyrin (preco) – an atypical porphyrin that only appears in the presence of mercury Heptacarboxyporhyrin and uroporphyrin is high on exposure to pesticides, PCBs, arsenic and aluminum (Woods, 2005) Urine Porphyrins Children with autism have significantly higher levels of copro and preco porphyrins compared to controls (Nataf, 2006; Geier, 2006) Nataf also found that the severity of autistic symptoms correlated with the copro level, and that children with autism and seizures had the highest copro levels. Urine porphyrin levels decrease with chelation (Pingree, 2001) Urine Porphyrins (how/when I use the test) I only send to Dr Nataf’s lab in France. They are the only commercial lab that has ranges for children and that autistic children has been studied at. The large US labs are not calibrated to test for levels under that which is seen in genetic porphyrin diseases which produce much higher porphyrin levels I prefer using the chelation challenge test, as it also tells me if the chelation agent/route of administration is working, not just if the metals are present. I order this test for: – families who do not wish to expose their children to a chelation agent unless there is proof of metals. – If chelation challenge tests are negative but we still suspect metals are present – Once chelation challenge tests are negative after cycles of chelation, if we still suspect metals are present Overview of The Methylation / Transsulfuration Pathway Methionine Protein synthesis MAT THF SAM Methylation of DNA, RNA, MTase proteins, membrane MS BHMT phospholipids, creatine, MTHFR MB12 SAH neurotransmittors Betaine SAHH AK 5-CH3THF Choline Adenosine AMP Homocysteine ADA B6 CBS Inosine THF: tetrahydrofolate Betaine:TMG Cystathionine B6 Cysteine Glutathione The Methylation / Transsulfuration Pathway The Enzymes: MS: Methionine synthase MAT: Methionine adenosyltransferase MTase:Methyltransferase MTHFR: Methylenetetrahydrofolate Reductase SAHH: S-adenosylhomocysteine Hydrolase CBS: Cystathione beta synthase BHMT: betaine-homocysteine methyltransferase The Methionine Cycle: Remethylation of Homocysteine Methionine Protein synthesis MAT THF Methylation of DNA, RNA, SAM proteins, histones, MTase membrane phospholipids, MS neurotransmitters MB12 SAH SAHH AK 5-CH3THF Adenosine AMP Homocysteine ADA Inosine THF: tetrahydrofolate The Methionine Cycle: Remethylation of Homocysteine Methionine Protein synthesis MAT THF SAM Methylation of DNA, RNA, MTase proteins, histones, MS membrane phospholipids, B12 SAH neurotransmitters SAHH AK 5-CH3THF Adenosine AMP Homocysteine ADA Inosine THF: tetrahydrofolate Effect of Oxidative Stress on Methionine Transsulfuration Methionine Protein synthesis MAT THF SAM MTase Methylation of DNA, RNA, MS proteins, membrane BHMT phospholipids, creatine, B12 SAH neurotransmittors Betaine 5-CH3THF Choline SAHH Adenosine ( AK and/or ADA) Homocysteine B6 CBS THF: tetrahydrofolate Cystathionine B6 Cysteine GSH GSSG Neurotoxicity of Thimerosal in Human Brain Cells is Associated with Glutathione Depletion: Protective Effect of Cysteine or Glutathione Supplementation S. Jill James, William Slikker, Elizabeth New, Stefanie Jernigan, Stepan Melnyk Department of Pediatrics University of Arkansas for Medical Sciences Little Rock, AR Neurotoxicity of Thimerosal in Human Brain Cells is Associated with Glutathione Depletion: Protective Effect of Cysteine or Glutathione Supplementation WORKING HYPOTHESIS • Ethyl mercury in Thimerosal binds to cysteine thiol (– SH) groups on intracellular proteins and inactivates function. • The cysteine-rich antioxidant, glutathione, binds mercury and protects essential proteins from functional inactivation. • The neurotoxicity of Thimerosal is associated with depletion of glutathione, the major intracellular antioxidant. VIABILITY OF GLIOBLASTOMA AND NEUROBLASTOMA CELLS WITH INCREASING DOSE OF THIMEROSAL Viability (MTT OD) 1.2 Glioblastoma Cells Neuroblastoma Cells 0.5 (48 hr Exposure) (3 hr Exposure) 1.0 0.4 0.8 0.3 0.6 0.2 0.4 0.1 0.2 0.0 0.0 0 2.5 5 10 20 0 0 2.52.5 5 510 10 20 20 M Thimerosal M Thimerosal Viability of Glioblastoma cells exposed to 15 M Thimerasol in the presence of GSH-ester, Cystine, N- acetylcysteine (NAC), or Methionine 0.9 0.8 0.7 0.6 O.D. (Viability) 0.5 0.4 0.3 0.2 0.1 0 Control Thimerosal +GSH + Cystine +NAC + Methionine Methyl-B12, Folinic Acid, and Betaine Supplementation in 8 Children with Autism Injectible Methyl-B12 (75 µg/Kg b.i.d.) was given to the 8 children who had been taking folinic and and betaine supplements for 3-4 months Plasma thiol profile was repeated in the 8 children after 4 weeks of combined folinic acid, betaine, and methyl B12 Transmethyation Metabolites after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children Methionine S-Adenosylmethionine 50 140 40 120 100 30 80 20 60 Control Before Folinic Folinic 40 10 Control Before Folinic Folinic Betaine Betaine Betaine Betaine Me-B12 20 Me-B12 0 0 S-Adenosylhomocysteine Adenosine 0.6 40 0.5 30 0.4 0.3 20 0.2 Control Before Folinic Folinic 10 Control Before Folinic Folinic Betaine Betaine 0.1 Betaine Betaine Me-B12 Me-B12 0 0 Transsulfuration Metabolites after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children Homocysteine Cysteine 10 250 8 200 6 150 4 100 Control Before Folinic Folinic Control Before Folinic Folinic 50 2 Betaine Betaine Betaine Betaine Me-B12 Me-B12 0 0 Cystinyl-Glycine 12 Total Glutathione tGSH) 70 60 10 50 8 40 6 30 4 20 Control Before Folinic Folinic Control Before Folinic Folinic 10 Betaine Betaine 2 Betaine Betaine Me-B12 Me-B12 0 0 Glutathione Redox Potential after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children Total Glutathione (tGSH) 0.8 Oxidized Glutathione (fGSSG) 12 10 0.6 8 6 0.4 4 Control Before Folinic Folinic 0.2 Control Before Folinic Folinic 2 Betaine Betaine Betaine Betaine Me-B12 Me-B12 0 0 GSH/GSSG Ratio 40 30 20 10 Control Folinic Folinic Before Betaine Betaine Me-B12 0 So, Why is this happening? Certain toxins such as mercury can inhibit the enzymes of this pathway. Dr James has looked at the DNA sequences that code for the proteins that make up these enzymes and has found that autistic children have up to 3 times as many single DNA mutations (polymorphisms, SNPs) as do children without autism We have identified these SNPs in children with other neurodevelopmental disorders OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY JAMES A. NEUBRANDER, M.D., F.A.A.E.M. EDISON, N.J. 08837 OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY Total number of children included in the data: 85 •71 males 51 males responded •14 females 12 females responded •84% males 74.1 % of the •16 % females children responded positively! OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY THE TOP TEN Symptoms Parents Reported Were Helped Most Often Language 71% Better Behavior 35% Awareness 65% More Focused 35% Cognition 52% Understanding 35% Engagement 43% Vocalization 35% Eye Contact 37% Trying“New Things” 33% OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY Side Effects Parents Reported Hyperactivity 10% Sleep Patterns Disrupted Or Worsened 6% Uncontrolled Or Unusual Laughter 3% Increased Aggression 2% Biting Objects 2% More Distractible 2% Eczematous Symptoms Worse 2% Increased Stimming 2% Silliness, Unusual And Unexplained 2% Teeth Grinding 2% Tongue Tingles 2% •All reported side effects faded upon stopping therapy • Most parents chose to resume therapy b/c benefits outweighed the side-effects Oxalates Oxalates are small carbon and oxygen containing molecules that are found in certain types of fruits and vegetables. Also most nuts and seeds have oxalates. For most people, oxalates in the diet are not absorbed in great amounts into the bloodstream. They are usually metabolized by intestinal flora and excreted in the feces. In the presence of intestinal inflammation and leaky gut, larger amounts of oxalates can get into the bloodstream and be transported to tissues Under certain conditions they can crystallize and become deposited in tissues. The crystals can grow and become stones (kidney stones are calcium oxalate) When lodged in tissues, these crystals can produce irritation and pain. Oxalates Oxalates seem to accumulate more in conditions of glutathione deficiency and oxidative stress. Vitamin B6 (pyridoxine) is a necessary cofactor for enzymes that help prevent the formation of oxalates When sulfur is deficient, it becomes extremely difficult to keep the body from making excess oxalates. High oxalates are associated with certain conditions like vulvodynia, prostatitis, irritable bowel syndrome, fibromyalgia, interstitial cystitis, and skin sensitivity. Some people may get a sense of urinary urgency and frequent urination, and sometimes the patient would have trouble urinating (Solomon, VP Foundation) High oxalates are often seen in patients with recurrent/resistant yeast infections and glycine intolerance. Testing for High Oxalates There is no perfect test right now. Urine testing is most often used. If high values are seen then this is a strong indicator, but people secrete oxalates in their urine at different times of the day (it may be most accurate to collect multiple urine specimens during the day), and relative to food intake so there can be false negatives. Great Plains Lab full organic acid test reports a spot oxalic acid value. They also report other substances that are high when there are oxalate issues: glyceric and glycolic acid Quest Labs has both random and 24 hour urine oxalate tests, both as an individual value as well as relative to oxalate. I usually get 24 hour collection with oxalate. Treating High Oxalates The low oxalate diet. Full information can be found at several sources: – Yahoo Group: Trying_Low_Oxalates – Treating High Oxalates The Low Oxalate Cookbook is published by the Vulvar Pain Foundation, contains over 250 recipes. The book has lists of foods with actual amount of oxate per serving of a food. Aim to keep oxalate intake down to under 40-60mg oxalate a day. Food Lists and summary can be found on “Medical Topics” section of my webpage Probiotics: VSL#3: 1/2 to 1 capsule daily or ¼ to ½ packet of the unflavored powder daily Reduce vitamin C to 250mg or less a day, including foods (oxalates can be converted to vitamin C) Calcium citrate supplementation - given with meals to help bind and excrete the oxalates. Elevated Male Hormones/Androgens Several studies have demonstrated that children with Autism Spectrum Disorders have elevated androgens, including testosterone, dihydrotestosterone, androstendione and DHEA (Torjman, 1997; Knickmeyer, 2005; Geier,2006) Although not exclusive, increased androgens have been associated with increased masturbation and genital rubbing, aggressiveness, hyperactivity, self-stimming, and increased body hair (legs and back), Elevations have been seen in male and female patients I use LabCorp for my testing. They have the most specific reference ranges for both sex and age of patient. Elevated Male Hormones/Androgens The enzyme that converts DHEA to DHEA-S (storage hormone) is sulfotransferase, which is glutathione dependant. When this enzyme is not working, there is a build up of DHEA which then gets sent to androstenedione and then testosterone Treating elevated Androgens Geier – Lupron. – belongs to a class of drugs called gonadotropin-releasing hormone (GnRH) agonists. – It is used to decrease the body’s production of specific hormones, natural chemicals that influence the behavior of certain cells. Because Lupron Depot can reduce the production of both male and female hormones, it is used to treat specific conditions in men, women, and children (www.lupron.com) Bradstreet – Spironolactone, – a potassium sparing diuretic, also has action of blocking the receptor for dihydrotestosterone. – Androgen levels should not go down with this treatment, but the effects of the hormone are blocked. Treating elevated Androgens Berger (VERY NEW) – Glycyrrhizin – the active ingredient in licorice root – decreases testosterone level by inhibiting the enzyme which converts of 17-OH progesterone to DHEA (Armanini, 1999) – Inhibits the enzyme that converts Androstendiaone to Testosterone (Fukui, 2003). – High doses can affect blood pressure and fluid retention, but doses < 0.2mg/kg/d should not cause these side effects (van Gelderen, 2000). – Current trials underway. – In addition to monitoring the androgens, also monitoring cortisol, ACTH and blood pressure Serum Hormone Concentrations in Seven Men Given Licorice for Seven Days Armanini D et al. N Engl J Med 1999;341:1158 Risperdal – 1st medicine specifically approved for Autism – For use in children with aggressiveness, extreme hyperactivity – Specific weight dosing is known – Effects are immediate, often seen the first day – Pretty easy to titrate for affective dose – Pretty easy to get kids off of once the underlying reason is uncovered – Fewer incidences of side effects compared to other psychotropic drugs Vaccine Update (time permitting) Varicella / Chicken Pox Vaccine • Brand Name: Varivax • my initial concerns over long term protection • when first released, one of the main “talking points” was that each shot saved “the system” $42 . • now we are seeing failures: – Either it didn't “take” in the first place – or long term protection was not conferred • now 2nd dose is being recommended between 4-6 years old • My recommendation: as morbidity increases with age, if not with vaccine or definitive disease by age ~11, get titer to see if immune and if not, consider the vaccine Influenza Vaccine • No guarantee that the strain of flu one is exposed to is 1 of the 3 that are in the vaccine • Thimerosal-free shot now available but not guaranteed. Must view package insert • Nasal spray – now available for children 5 and older – is mercury-free – is a live virus – makes some sense, as it uses the natural lines of defense to convey immunity – Contraindicated for those who likely could benefit from it the most….those with asthma and immunodeficiency • Article at www.wholisticpeds.com HPV/Cervical Cancer/Genital Warts • Brand Name: Gardasil • Not contagious disease, except for sexual contact. Raises ethical questions. • Not protecting against all strains of HPV – protects against 70% of strains causing cervical cancer – protects against 90% of strains causing cervical warts • being recommended for females 11-26 y/o, but can be given as early as 9 y/o • for me, it is to early to assess safety, as often less common side effects are not seen until large groups of people are vaccinated such as was seen with….. Rotavirus • 1st vaccine, called RotaShield was made available in the late 1990’s deemed safe in pre market studies • Then within the first year of widespread use there were at least 100 cases of intussusception, an acute form of bowel obstruction • The vaccine was pulled in 1999 • 2006, a new, “safer” vaccine was introduced, called RotaTeq. • So far, 28 cases reported so far, about half of them occurred within 21 days of vaccination and 16 of the infants had to have surgery. • Lactobacillus has been demonstrated to significantly shorten the length of time with diarrhea (Shornikova, 1997) and frequency of stools (Van Neil, 2002) Hyperbaric Oxygen Therapy Definition – A therapeutic modality that employs the application of pressures greater than ambient atmospheric pressure, at oxygen levels greater than atmospheric oxygen (>21%) Traditional HBOT – a hard walled chamber that exposes the patient to a maximum of 3ATA (monoplace-1 patient) or 6ATA (multiplace - >1 patient) at 100% oxygen Mild HBOT (mHBOT) - a soft walled chamber that exposes the patient to a maximum of 1.3ATA and <100% oxygen Hyperbaric Oxygen Therapy Laws of Physics Henry’s Law - the amount of a gas absorbed by a liquid is in proportion to the pressure of the gas above the liquid, provided that no chemical action occurs. Boyle’s Law - at a constant temperature, the volume and the pressure of a gas are inversely proportional. In other words, a gas will compress proportionately to the amount of pressure exerted on it. Examples of these laws: – a bottle of soda – A scuba diver Hyperbaric Oxygen Therapy History In 1662, British Physician Dr. Henshaw first used compressed air in an attempt to treat pulmonary disease. His first chamber was called the “Domicilium”. Chamber pressure was either raised or lowered with organ bellows In 1879, French surgeon Fontaine created a mobile chamber. He was able to increase the amount of oxygen carried in the blood during the administration of nitrous oxide anesthesia. This prevented blood oxygen levels from decreasing, which typically happened from surgical anesthesia In 1921 Cunningham constructed a 20 meter round ball that was the largest Hyperbaric Chamber ever built. It contained a smoking lounge, dining facilities, rich carpeting, and private quarters. Hyperbaric Oxygen Therapy Cunningham’s Sanitarium -1921 Later it was scraped for metal during World War II. Hyperbaric Oxygen Therapy History In 1934, US Naval Submarine Officer, Dr. Behnke proposed using oxygen plus recompression for Decompression Sickness (the bends). This information was ignored until 1967 In 1955, Dutch thoracic surgeon, Dr. Boerma removed the red blood cells from pigs and found they could survive with oxygen dissolved in plasma by use of hyperbaric Oxygen. In 1961 Danish Dr. Brummelkamp, Published on the ability of HBOT to inhibit the growth of anaerobic bacteria - organisms that live where there is low or no oxygen, such as gangrene or tetanus. In June 2006 Tampa Pediatrician David Berger obtained his first mHBOT chamber, getting a second one the month later. The world has never been the same since. Hyperbaric Oxygen Therapy Official Medical Indications • Air or Gas Embolism • Exceptional Blood Loss • Carbon Monoxide (Anemia) Poisoning and Smoke • Necrotizing Soft Tissue Inhalation Infections • Carbon Monoxide • Osteomyelitis Poisoning Complicated (Refractory) by Cyanide Poisoning • Radiation Tissue • Clostridial Myonecrosis Damage (Gas Gangrene) (Osteoradionecrosis) • Crush Injury, • Skin Grafts and Flaps Compartment (Compromised) Syndrome, and other • Thermal Burns Acute Traumatic Ischemias • Decompression Sickness (the "Bends") • Enhancement of Healing in Selected Problem Wounds Hyperbaric Oxygen Therapy Proposed Mechanisms of Action • Correct Cerebral hypoperfusion (low blood flow) • Correct Cerebral Hypoxia (low oxygen levels) • Decrease Neuroinflammation • Decrease Intestinal Inflammation • Improve Immune Function • Reduce Oxidative Stress • Correct Neurotransmitter Abnormalities • Treat Intestinal Dysbiosis Rossignol DA, Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism. Med Hypotheses (2006) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Rossignol DA, Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism. Med Hypotheses (2006) • Differing levels of pressure and oxygen were used in the various studies that are discussed • Some may be at pressures that are not being recommended for children with Neurodevelomental disorders Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Cerebral Hypoperfusion and Hypoxia in Autism • Multiple studies have shown hypoperfusion to areas of the brain of children with autism, especially the temporal lobes. (Rye, 1999; Zilbovicius, 2000; Ohnishi, 2000) • The low blood flow was more profound the older a child is. (Wilcox, 2002) • Autistic children often do not increase their cerebral blood flow when doing tasks and when listening and trying to speak, as seen in neurotypical children. (Critchley 2000, Allen 2003). • Decreased blood flow to the thalamus as seen on SPECT scans has been associated with repetitive and self-stimming behaviors (Starkstein, 2000) • Decreased blood flow to Wernicke’s and Brodmann’s areas (speech areas of the brain) has been associated with decreased auditory processing (Bodaert, 2002) and language development (Wilcox, 2002) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Treating Hypoperfusion with HBOT • HBOT may overcome the effects of the hypoperfusion by providing the brain with more oxygen (Sheffield, 1976; Neubauer, 1998) • HBOT may increase new blood vessel growth (Al-Waili, 2006) • Hypoperfusion may be due to inflammation. Inflamed vascular cells can lead to diminished blood flow, and inflammation in tissue prevents maximal uptake of oxygen by cells • HBOT can increase the distance that Oxygen can travel between cells (Williams, 1997) • Increased blood flow to the brain also means increased blood flow from the brain, potentially increasing the flow of toxins away from the brain. This could bring a synergistic effect with chelation. SPECT Scans in a 4 year old autistic child after 10 dives mHBOT at 1.3 atm and 24% oxygen Before After Mild HBO Heuser et al., 2002 Best Publications; 2002:109-15 Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Neuroinflammation and Autism • Of recent, several studies have demonstrated evidence that children with autism have increased neuroinflammation. • Increased inflammatory cells and pro- inflammatory chemical mediators (cytokines) have been found in the CSF of Autistic Children (Weizman, 1982; Vargas, 2005). • Increased brain auto-antibodies have been demonstrated in children with Autism (Connolly, 1999; Singh, 1997; Vojdani, 2002; Singer, 2006) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Gastrointestinal Inflammation and Autism • A subset of children with Autism have demonstratable inflammation of their stomach, small intestine and colon (Furlano, 2001; Uhlmann, 2002; Balzola, 2005; Wakefield, 2005) • Both inflammatory cell and cytokines (TNF-ά, IL-1Β, IL-6) have been seen in increased amounts in the gastrointestinal lining in some children with Autism (Jyonouchi, 2001; Ashwood, 2003 & 2004) • Many children with autism have increased serum antibodies directed against casein and gluten based peptides (Vojdani, 2003; & 2004) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Treating Inflammation with HBOT • HBOT had been demonstrated to have anti-inflammatory affects on tissues (Al-Waili, 2006) • HBOT can decrease the production of the cyctokines that are pro-inflammatory such as IL-6 and IL-1(Weisz, 1997) and TNF-ά, (Yang, 2006) • HBOT can increase the production of cytokines that decrease inflammation such as IL-10 (Buras, 2006) • HBOT has been shown in animal studies to reduce symptoms and inflammation of arthritis (Warren, 1979) and peritonitis (Tokar, 2003) • There is evidence that HBOT can facilitate remission for non-responsive Crohn’s Disease (Brady, 1989; Columbel, 1995) and Ulcerative Colitis (Buchman, 2001; Gurbuz, 2003) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Abnormal Immune Function and Autism • 5% of Children with Autism have low serum IgA levels (Gupta, 1996) • Compared to typical children, many Autistic children have elevated IgE levels (Gupta, 1996; Lucarelli, 1995) • Some children with Autism have reduced levels of T-helper cells (Warren, 1986) • Some children with Autism have decreased lymphocyte activity/responsiveness (Stubbs, 1977) • Warren (1987) demonstrated decreased Natural Killer Cells in Autistic Children compared to controls Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Treating Immune Abnormalities with HBOT • In patients with MS, HBOT significantly increased the production in total an helper T- Lymphocyte levels as well as IgA serum levels (Nyland, 1989) • In patients with atopic dermatitis, HBOT decreased IGE levels as well as symptoms (Olszanski, 1992). • In mice studies, Lymphocyte activity and lymphocyte counts were increased by HBOT (Lee, 1993&1994) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Increased Oxidative Stress and Autism • Many children with Autism show the presence of increased oxidative stress/free radicals • They have lower levels of glutathione (James, 2004) • Increased RBC nitric oxide has been seen in some Autistic children. This is a free radical and is a neurotoxin. (Sogut, 2003) • Children with Autism demonstrate increased markers of oxidative stress and lipid peroxidation such as malondialdehyde (Chauhan, 2004) • Children with Autism often have decreased activity of the enzymes that produce antioxidants such as glutathione peroxidase and superoxide dismutase (Yorbik, 2002) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Treating Oxidative Stress with HBOT • There has been concern that HBOT could, thought increased production of reactive oxygen species, increase oxidative stress, and that taking alpha-liopic acid (an antioxidant) could ameliorate this problem (Alleva, 2005). • In animal studies, there is evidence that oxidative stress is less of a concern at pressures < 2.0 ATA (Wada, 2001). • Other animal studies have shown that at < 2.0 ATA, HBOT may reduce oxidative stress by decreasing the peroxidation of lipids (Ozden, 2004, Kudchakar, 2000). • In other animal studies, HBOT has been demonstrated to increase superoxide dismutase (Gregorevic, 2001) and glutathione peroxidase (Gulec, 2004) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Abnormalities in Neurotransmitters and Autism • Serotonin levels man be lower in children with autism (Chugani, 1999; Connors, 2006) • Compared to controls, children with Autism have lower plasma tryptophan levels. Tryptophan is the amino acid precursor of serotonin. • Tryptophan uptake into brain cells was decreased in children with Autism compared to controls when studies with PET scans (Chugani, 1999) • Some children with Autism may have increased dopamine activity (Gillberg, 1997) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Correcting Neurotransmitter Abnormalities with HBOT • Serotonin uptake by endothelial cells of the lung has been shown to be reduced [the same mechanism as SSRIs] when HBOT was used (Fisher, 1980; Block, 1981) • Following brain injury, HBOT was demonstrated to decrease dopamine release (Yang, 2002) • Oxygen alone, without increased pressure, may decrease brain extracellular dopamine levels (Adachi, 2001) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Intestinal Dysbiosis and Autism • Overgrowth of certain abnormal bacteria, and in particular clostridia (anaerobic) bacteria, have been seen in many children with autism compared to controls (Feingold, 2002; Song, 2004; Parracho, 2005) • An increased clostridial byproduct (HPHPA) is often seen on urine organic acid testing of children with Autism. • Improvements in Autistic symptoms have been demonstrated in serial blinded psychological evaluations after the administration of oral Vancomycin (Sandler, 2000) • Intestinal overgrowth of yeast, viruses and parasites have been documented in children with Autism (Cave, 2001) Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Treating Intestinal Dysbiosis with HBOT • HBOT has been shown to decrease levels of atypical bacteria overgrowth in the distal ileum (Akin, 2001). • HBOT has been demonstrated to be able to kill many different types of bacteria, including clostridia (Gotleib, 1971;Unsworth, 1984) • Phagocytes, white blood cells that engulf bacteria, depend on oxygen to kill the bacteria (Babior, 1978). Killing of Staph Aureus by these leukocytes is enhanced by HBOT (Mader, 1980) Hyperbaric Oxygen Therapy Hard vs. Soft Chamber • Cost: Hard chamber dives cost 2-6x that of mHBOT • Time to depressurize if need to get out quickly. The higher the pressure, the longer it takes to depressurize • Oxygen Dangers/Flammability/fire and building codes • Oxygen Delivery – 100% in Hard Chamber. In most units, no special masks or tubes are needed. Compliance may be easier with the Hard Chamber – 24 – 40% in mHBOT depending on how O2 is delivered • Breaks vs. no breaks in therapy • Accessibility/home use approval • Is more better? • Some may respond to hard but not soft (often see 1.75ATA used for ASD, never more than 2.0ATA) – certain conditions such as crush injuries, CP, anaerobic bone infections Hyperbaric Oxygen Therapy And Seizure Risk • There is a known entity called Oxygen seizures. • Incidence of seizures has never been reported with pressures <2.0ATA for 1 hour or less • Davis (1989): In chart review, Overall incidence of seizures was 0.01%, looking at 1505 patients who did a total of 52,700 dives. 5 patients developed seizures, all recovered completely. Hyperbaric Oxygen Therapy Hyperbaric Oxygen Therapy Hyperbaric Oxygen Therapy Our Proposed Study This would be the first University based, placebo-controlled, blinded study ever performed using HBOT on children with Autism Joint project between Wholistic Pediatrics and USF Child Psychiatry, Child Neurology and Child Development teams Hyperbaric Oxygen Therapy Our Proposed Study Subjects: – Children with formal diagnosis of Autism – Selecting kids that have not done any biomedical/dietary interventions, only educational interventions – Only educational changes allowed during treatment period – 10 children to receive treatment, 10 placebo. Will cross- over the placebo group. – 6-8 year old – Must be able to comply with use of non-rebreather mask Hyperbaric Oxygen Therapy Our Proposed Study Outcome measures: • ADOS • full neuropsychological evaluation • Single subject design – since multiple N=1 • GI checklist Will do evaluations at: 3 months prior to starting mHBOT The week before starting mHBOT (to determine what a typical 3 months bring in terms of symptom changes) At the end of 3 months of dives 3 months after dives start Also will take selected data during 1-2 week intervals during the dive phase for the single subject design The Bottom Line: We Need More Research! ----The Bottom Line----The Bottom Line----The Bottom Line----The Bottom Line---