A Review of Chelation Therapy in the Treatment of Autism Kelly Ann LaPietra Caldwell College

Source Identification Keywords: “chelation”, “chelation and autism” Assigned Textbooks Barnes and Noble bookstore “Special Needs Children section” Pubmed Database Academic Search Premier Database Psychinfo Database Google Scholar Google Search Engine Autism Resource Websites References cited in articles and in books

OUTLINE TOPIC: Chelation Therapy I. Introduction A. Origin of the word B. Description II. History III. Common Uses A. Unapproved B. Approved IV. Chelation & autism A. Theory B. Basis C. Contradictory evidence V. Video VI. Commonly Used Chelators A. Drug names B. Administration VII. Chelation Therapy A. Preparation B. Sample Treatment Regimen

OUTLINE A. Methods B. Provoked urine excretion test IIX. Testing A. Methods B. Provoked urine excretion test 1. Information gleaned 2. Limitations IX. Effects of Chelation Therapy A. Claimed benefit B. Side effects X. Treatment XI. A. Guidelines B. Qualifications C. End of treatment indicators D. Problems XII. Participating Doctors XIII. Research XIV. Any Evidence? XV. Points of View X. Pseudoscience

Chelation Therapy Derived from the Greek word chele, which means “claw” Named for the grabbing effect chelating agents have on metal molecules Refers to the way certain synthetic chemical and body proteins can bind metal molecules Walker, Morton. (1990). The Chelation Way. NY: Avery Publishing Group.

What is Chelation? Detoxification process by which heavy metals are pulled from tissues and made water-soluble so they can be excreted through urine or stool. Heavy metals have an affinity for the binding sites of chelators. There are many different chelating agents and are selected for use based on the metal targeted for removal. Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications.

HISTORY First introduced into medicine to cure aresenic-based poison gas that was used in WWI First chelating agent used was the organic dithiol compound dimercaprol AKA British Anti-Lewisite (BAL) Large scale lead poisoning of Navy personnel in the wake of WWII, led to the use of EDTA 1960’s DMSA began use (a modified form of BAL with less side effects) EDTA and BAL were used less after introduction of DMSA DMSA- became the mainstay for lead, arsenic, and mercury poisoning in the US Retrieved from http://research-chelation-therapy.com Lead poisoned for painting hulls of ships DMSA still today

HISTORY Former Soviet Union gave us DMPS, a mercury-chelating agent and ALA, a mercury and arsenic chelator Today DMPS remains an experimental chelator; ALA is used as a nutritional supplement EDTA approved by FDA for treating lead and heavy metal toxicity American College for the Advancement of Medicine (ACAM) began claiming the restorative effects of EDTA in the treatment of atherosclerosis 1998, Federal Trade Commission (FTC) argued against this misrepresentation, citing a lack of evidence 1999, ACAM no longer advertised this claim Retrieved from http://research-chelation-therapy.com

A Note of Caution “NOTE: Due to pharmacological property differences and mechanisms of action, each drug agent should be used as indicated by the FDA or off label usage noted. CIGNA HealthCare does not cover Chelation Therapy for the following indications because they are considered experimental, investigational or unproven!” Retrieved from www.cigna.com

What is chelation being used for? • atherosclerotic vascular diseases • coronary artery disease • reperfusion injury during coronary angioplasty or cardiopulmonary bypass surgery • progressive renal insufficiency in Type II diabetic nephropathy • Alzheimer’s disease • Parkinson’s disease • primary biliary cirrhosis • ankylosing spondylitis • autism • glioblastoma • scleroderma • porphyria • hypercholesterolemia Retrieved from www.cigna.com

Chelating Agents & the Condition they Treat Coverage Policy CIGNA HealthCare covers each respective Chelation Therapy agent as Medically necessary when it is used for its usage/FDA approved indication and associated condition as listed in the table below: DRUGS: Edetate Calcium Disodium (Calcium EDTA) (Calcium Disodium Versenate®) Succimer (DMSA) (Chemet®) CONDITION: heavy metal overload or toxicity (e.g., lead, arsenic, mercury, iron, copper, or gold) confirmed by appropriate laboratory results (e.g., blood, plasma, and/or urine) or clinical findings consistent with metal toxicity Retrieved from www.cigna.com There are several chelating agents that are dependent on the target metal, but again, for the purpose of this class, I will touch on the ones mentioned in the chelation/autism literature Remember that these are only 2 of the chelators being commonly given for tx of autism

CHELATION AND AUTISM THEORY: Children with autism carry a toxic heavy metal body burden (Bernard, S., Enayati, A., Redwood, L., Roger, H., & Binstock, T., 2001). RATIONALE FOR TX: Chelating agents will remove the offending toxins from the body and the symptoms of autism will decrease. If we are all exposed to heavy metals throughout our lives and proponents of chelation for autism claim these metals have a causal role in the onset of autism, why doesn’t everyone get autism? High exposure in infancy or “pathophysiology” that impairs their ability to excrete heavy metal toxins from their body and makes them susceptible to metal toxicity

What evidence are they basing this theory on? Low levels of mercury found in baby hair of children with autism compared to controls (Holmes, A. S., Blaxill, M. F., & Haley, B. E., 2003). High levels of mercury in baby teeth of children with autism compared to controls (Adams, J. B., Romdalvik, J., Sadagopa, V. M., & Legator, M. S., 2007). Higher mercury excretion after a 3-day treatment with DMSA in children with ASDs compared to controls (Bradstreet, J., Geier, D. A., Kartzinel, J. J., Adams, J. B., & Geier, M. R., 2003) We will talk about the errors of higher excretion with challenge dose of chelator

CONTRADICTORY EVIDENCE Williams, Hersh, and Sears (2008) found that there were no significant differences between mercury levels in hair of children with autism and their typically developing siblings. In 2007, Soden, Lowry, Garrison, and Wasserman found that when a 24-hr DMSA provoked excretion test was administered to children with autism there was no measurable increase in excretion of toxic metals.

VIDEO Dateline MSNBC (2006): Interview with Dr. Jim Adams http://www.youtube.com/watch?v=FHkr4l12veI http://www.youtube.com/watch?v=4eyJb-izu6M&NR=1

4 Most Commonly Used Chelators in the Treatment of Autism DMSA (dimercaptosuccinic acid)* EDTA (Calcium EDTA) * DMPS (2, 3-dimercapto-1-propanesulfonic acid) Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications. TTFD (thiamine tetrahydrofurfuryl disulfide) Lonsdale, D., Shamberger, R. J., & Aduhya, T. (2002). Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: A pilot study. Neuroendocrinological Letters, 23, 303- 308. Note that only two of these were on Cigna’s list of approved chelating agents. That is right, there are doctors who are administering unapproved chelating agents to children by compounding…

How are they administered? Orally Transdermally Intravenously Rectally (suppositories) Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications.

PREPARATION FOR CHELATION THERAPY FOR AUTISM Reduce exposure to toxins Ex. Consuming organic foods and drinking reverse osmosis water, remove mercury dental fillings, avoid pesticide use Improve levels of essential vitamins and minerals Improve glutathione levels Treat gut dysbiosis Retrieved from www.autism.com

RECOMMENDED TREATMENT REGIMEN According to the Treatment Options for Mercury/Metal Toxicity in Autism and Related Developmental Disabilities: Consensus Paper (2005), chelation treatment should be administered as follows: Oral/Rectal Suppository - 3 days of Tx, followed by 11 days off Transdermal- Tx on alternating day schedule TTFD: Oral, Transdermally, Rectal Suppository- no Tx recommendations No treatment protocol for DMPS

How are metals being tested? Hair Stools Urine Blood Baby teeth Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications. No standard way, except blood lead levels test for the presence of lead since lead exposures are usually from chronic exposure, but mercury, aluminum, arsenic more difficult Mercury and other metals have a short half life in the blood (weeks) Hair and urine are measures of excretion

PROVOKED URINE EXCRETION TEST AKA Diagnostic Chelation Challenge PROCEDURE: Levels of toxic metals are measured in the urine before the dose of chelator is administered and then urine is collected for 6-8 hours after and a sample of the accumulation of urine is tested. RISK: short-term, if any. RATIONALE: Metals tend to hide in the body and these hidden metals are not reflected by evidence- based testing methods Zhiping, Y., Wu, Q., & Fan, D. (2009). Inappropriate diagnosis and chelation treatment of alleged heavy-metal toxicity. Annals of Internal Medicine. 151, 8. Possibly pro-chelation-autism treatment’s “ruler”

1. Metal was present in the body What an Increase in Toxic Metals in Urine tells us after Administration of a Challenge Dose of Chelator 1. Metal was present in the body 2. Chelator was able to assist in excretion of metals Zhiping, Y., Wu, Q., & Fan, D. (2009). Inappropriate diagnosis and chelation treatment of alleged heavy-metal toxicity. Annals of Internal Medicine. 151, 8.

LIMITATIONS OF PROVOKED TESTING 1. No provoked excretion reference range for comparison. 2. Collecting urine for less than 24-hrs. is not representative of excretion levels. 3. Provocation has been shown to artificially increase the 24-hour average urine mercury level. Zhiping, Y., Wu, Q., & Fan, D. (2009). Inappropriate diagnosis and chelation treatment of alleged heavy-metal toxicity. Annals of Internal Medicine. 151, 8. End up comparing it against excretion of people not taking a chelator- so of course it would be higher (Consensus Paper) comparing provoked vs. unprovoked- not same thing Call for a banning of provoked testing because it promotes inappropriate testing

CLAIMED BENEFITS OF CHELATION TREATMENT FOR AUTISM Highly effective in: removing toxic metals improving glutathione normalizing platelets (a marker of inflammation) Adams, J. B., Baral, M., Geis, E., Mitchell, J., Ingram, J., Hensley, A., Zappia, I., Newmark, S., Gehn, E., Rubin, R. A., Mitchell, K., Bradstreet, J., and El-Dahr, J. (2009). Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A-Medical results. BMC Clinical Pharmacology, 9, doi:10.1186/1472-6904-9-16. Possibly beneficial in: reducing the symptoms of autism Rapid progression of language ability Improved social interaction Improved eye contact Decreased Self-stimulatory behaviors Improvement in both strength and coordinator Retrieved from www.autism.com What do you think of that claim???

POTENTIAL SIDE EFFECTS OF CHELATION I toxic epidermal necrolysis (TEN) thrombocytopenia erythema multiforme (Stevens-Johnson syndrome) cardiac arythmias hepatic enzyme elevation hemolytic anemia neutropenia neuropathies renal dysfunction essential mineral depletion potential for medical errors death Zhiping, Y., Wu, Q., & Fan, D. (2009). Inappropriate diagnosis and chelation treatment of alleged heavy-metal toxicity. Annals of Internal Medicine. 151, 8. Retrieved from www.autism.com Metals that were settled now become unsettled and move to different areas of the body (Autism Book, Sears) Stevens Johnson- self-limited inflammatory disorder of the skin and mucous membranes- get target shaped lesions, sore throat, mucous ulcers, fever- takes weeks to resolve and require care TEN may be fatal if not recognized

POTENTIAL SIDE EFFECTS OF CHELATION II abdominal cramps various dermatological symptoms diarrhea vomiting convulsions severe constipation bowel paralysis acute toxicity allergic reactions (Freeman, 2007) brain damage (Strangle, D. E., Smith, D. R., Beaudin, S. A., Strawderman, M. S., Levitsky, D. A., & Strupp, B. J., 2007) regression in language and behavior clinical symptoms of mercury poisoning Retrieved from www.autism.com

GUIDELINES FOR CHELATION THERAPY For lead poisoning, candidates are individuals with lead levels of >45mcg/100mL in their blood-only approved standard Mineral and vitamin supplements should be given before, during, and after chelation therapy Should be done under supervision of a physician Kidney and liver function must be evaluated regularly White blood cell count must be monitored Adams, J. (2010). Chelation: Removal of toxic metals. In K. Siri & T. Lyons (Eds.), Cutting Edge Therapies for Autism (pp 74- 78). NY: Skyhorse Publishing.

QUALIFICATIONS FOR CHELATION THERAPY No standard excretion level Dr. Neubrander’s office: children’s urine excretion is categorized as in the normal, elevated, or highly elevated range, with those in the highly elevated range qualifying for chelation; based on a provoked urine test (6-8 hr. sample). R. Neubrander, personal communication, June 1, 2010 When asked if there as any quantification of that measurement, I was told, “no”. Also told not every child with autism needs it- about 4/10 in their office- office manager

END OF TREATMENT INDICATORS At least until urinary collections reveal only modest amounts of toxic metals When improvement ceases If the child shows no significant progress during therapy or if they experience regression Retrieved from www.autism.com Begin chelating with an agent that preferentially binds to a different metal than the one already chelated with Adams, J. (2010). Chelation: Removal of toxic metals. In K. Siri & T. Lyons (Eds.), Cutting Edge Therapies for Autism (pp 74- 78). NY: Skyhorse Publishing.

PROBLEMS WITH CHELATION IN CHILDREN WITH AUTISM Measures of unprovoked blood and urine reflect only acute, ongoing exposure, and are not a reflection of tissue levels or total body burden make it difficult to assess metal toxicity in the body. There are no set standards for determining what qualifies as an abnormal or dangerous level in the general population on provocation challenges. Single provocation challenge tests can be misleading in determining total body burden because of metal’s tendency to compartmentalize in the body. There are no universal standards of qualifications for chelation therapy or for treatment protocol. Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications. Stop when improvement ceases Shows no significant progress

Where can your child get chelated locally? DAN! Physicians affiliated with Autism Research Institute Directory www.autism.com New Generation Medical Doctors affiliated with Generation Rescue Directory www.generationrescue.org

HOW DO YOU BECOME… a DAN! physician? 1. Be a medical doctor 2. Sign the ARI/DAN! philosophy statement 3. Pay $250 4. Attend a professional seminar 1x/2 years Retrieved from www.autism.com A New Generation Medical Doctor? 1. Be an M.D. or D.O. 2. Share the philosophy or Autism Research Institute Retrieved from www.generationrescue.org

RESEARCH In a pilot study, Lonsdale et al. (2002) explored the effects TTFD have on children with autism. PARTICIPANTS: 10 children diagnosed with autism TREATMENT: 2x/day rectal suppository containing TTFD for 60 days MEASURE: Clinical effects-ATEC FINDINGS: Autistic spectrum symptoms improved in 8/10 children CONCLUSION: “TTFD might be valuable in the treatment of this devastating and increasingly common disease in children.”

LIMITATIONS Other therapies were allowed to continue Group design masks individual results No control group Employed use of hair analysis as one of its measures

RESEARCH In 2004, Dietrich et al. explored the effect DMSA would have on standardized tests of neurodevelopment at age 7 versus controls for children who presented with blood lead levels slightly below lead poisoning level. DESIGN: Randomized, double-blind placebo-controlled trial PARTICIPANTS: 780; 647 @ completion TREATMENT: 6-13 month administration of DMSA + daily vitamin or placebo FINDINGS: Blood level levels were lowered by DMSA Tx, but no benefit in cognitive, behavioral, and neuromotor endpoints

RESEARCH A controlled study by Strangle et al. (2007 ) looked at risks/benefits of succimer in the tx of lead poisoning in rats. Tx group rats exposed to neurotoxic levels of lead poisoning and then injected with succimer chelator Control group rats with no lead poisoning were injected with succimer chelator FINDINGS: 1. Learning ability returned to normal in the Tx group Matches hypothesis that lead in the brain impairs brain function 2. Test scores went down in the control group- actually doing as poorly as the lead-poisoned rats CONCLUSIONS: Chelation is an effective treatment for lead poisoning, but with no lead to pull from the control rats’ brains, the succimer started attacking the brain cells themselves. REPERCUSSIONS: In 2008, the National Institutes of Health canceled a controlled trial of succimer treatment in children with ASD because of the risk of brain damage from succimer. 1. Not surprising, but what was surprising 2.

RESEARCH In 2009, Dr. James Adams et al. published a randomized, double-blind investigation of the effect oral DMSA therapy has on children with autism. 2-part study (Part A: Medical Results, Part B: Behavioral Results) Phase 1: All 65 participants (3-8yrs old) received a round of DMSA to screen for excretion level. Those with high urinary excretion of toxic metals (49/65) were randomly assigned to either a Tx or control group. Phase 2: Tx group- 6 more rounds of DMSA therapy Control group- 6 rounds of placebo 8 children did not qualify due to low excretion; another 7 dropped out report cited unrelated reasons, 1 dropped out due to adverse reactions before phase 1 4 dropped out due to adverse effects- 2 were tx, 2 were placebo in phase 1

Randomized in double-blind manner RESEARCH Children with ASD Randomized in double-blind manner Topical Glutathione 7 days Placebo Cream Phase 1 1 round of oral DMSA 3 doses/day 1 round of oral DMSA x 3 days Metal excretors Metal excretors Phase 2 6 rounds DMSA 6 rounds of placebo NOTE: 4 discontinued study due to adverse side effects.

RESEARCH How were they measuring effects? Parental Assessments Pervasive Developmental Disorder Behavior Inventory (PDD-BI) Autism Treatment Evaluation Checklist (ATEC) Severity of Autism Scale (SAS) Parent Global Impressions (PGI) Trained Evaluator Autism Diagnostic Observation Schedule (ADOS)

RESEARCH FINDINGS: In a single round for all groups, glutathione and platelet counts were normalized-making study more a comparison of 1 vs. 7 rounds of DMSA. Those in the 7-round group continued to excrete metals (PART A). FINDINGS: The severity of autism significantly decreased during the study for both the Tx and control groups (PART B). Authors seemed thrilled that they were getting tx effects for both groups- how they took it- just a single round of DMSA decreased everyone’s symptoms- great news! DMSA is effective, but based on parent report and parents were blinded

LIMITATIONS Urine collection for only 8 hours Parents rated behavior change “Lost” placebo comparison Arbitrarily chosen level for qualification into Phase 2; above Doctor’s Data reference range- top 95% for typical children not undergoing chelation therapy Nature of group design average may not reflect the effect for any one participant Treatment and placebo group did not differ in treatment effects

SOME POINTS OF VIEW www.asatonline.org- does not endorse it, citing that it is not an evidence-based treatment for autism www.autismspeaks.org- cautions parents to research available treatments www.autismnj.org- endorses those treatments that are science-based and have proven effectiveness

American Academy of Pediatrics “Preliminary data from the Centers for Disease Control does not suggest a relationship between thimerosal-containing vaccines and ASD.180 Hair analysis is not recommended for biomonitoring, because false elevations may occur if the specimen is not carefully collected. Provocative chelation tests for mercury have not been scientifically validated and are also not recommended. Several chelating agents, including succimer, dimercaprol, d-penicillamine, and N-acetylcysteine, have been shown to accelerate mercury elimination from the body.181 However, there is no evidence that chelation therapy will improve developmental function when given to treat mercury toxicosis. Moreover, chelating agents can have significant toxicity (eg, hepatotoxicity) and precipitate allergic reaction.182 Chelation therapy is therefore not recommended for the purpose of improving neurodevelopmental function in children with ASD.” Committee on Children with Disabilities, 2001. Technical Report: The Pediatrician’s Role in the Diagnosis and Management of Autistic Spectrum Disorder in Children. Pediatrics, 107, e85.

Any Evidence? Based on the theory that autism is a result of heavy metal poisoning, but there is no clear evidence to support this assertion Diagnosis of autism is based on behavioral characteristics- Today still no commonly accepted, biological marker associated with autism No medical test to diagnose autism After chelation therapy still no biological marker we can use to see if there has been significant improvement in the child’s degree of autism Use hair analysis which is not yet accepted by the mainstream community for this application Freeman, S. K. (2007). The complete guide to autism treatments: A parent’s handbook. Lynden, WA: SKF Books.

Any Evidence? Is there scientific data published in peer-reviewed journals to suggest that chelation therapy is an effective treatment for autism? No controlled studies with outcome data regarding the effectiveness of chelation in improving symptoms of autism Claim that chelation can extract metals and repair possible damage to the brain has no supporting evidence in children with autism There is much anecdotal support in the form of parental report. Freeman, S. K. (2007). The complete guide to autism treatments: A parent’s handbook. Lynden,WA: SKF Books.

Future Research? Strangle et al. (2007) demonstrated that it would be unethical to test effects of chelation on children in clinical studies due to the potential health risks associated with the drugs.

CONTROVERSIAL CONTROVERSIAL CONTROVERSIAL What part of using chelation in the treatment for autism is NOT experimental? From the experimental testing to the unproven high body burden of chelable metals to the unapproved treatment to the lack of clinical trials. THERE IS NOT ONE EVIDENCE-BASED LEG TO STAND ON! DO NO HARM! NOT ONLY DOES IT LACK SCIENTIFICALLY SOUND EVIDENCE, BUT IT IS A HARMFUL AND POTENTIALLY FATAL EXPERIMENT TO DO ON A CHILD!

PSEUDOSCIENCE? Promoters benefit financially or otherwise from adoption of the therapy. Authors of the studies and those with websites touting parent testimonials are the same professionals who are directly benefitting from the use of chelation therapy to treat autism. Catchy, emotionally appealing slogans are used in marketing the therapy. The two largest organizations that are promoting biomedical interventions, including metal detoxification/chelation therapy have as part of their slogans, “Autism is Reversible” (Generation Rescue) and “Autism is Treatable” (Autism Research Institute). The word, “recovery” is often used on both website. Promoters resist objective evaluation and scrutiny of the therapy by others. Maintain that their findings are accurate despite other studies showing contradictory evidence. Testimonials, anecdotes, or personal accounts are offered in support of claims about the therapy's effectiveness, but little or no objective evidence is provided. These websites are chockful of parent testimonials. Much credence is put on the Autism Research Institute’s “Parent Ratings of Behavior Effects of Biomedical Interventions” that report chelation therapy scores the highest (74%) for reports of children who “got better” and a low 3% of parent’s reporting that children “got worse.” Retrieved from www.autism.com Negative findings from scientific studies are ignored or dismissed. Despite evidence that contradicts theory, continue to argue that the theory is supported by scientific evidence.

PSEUDOSCIENCE? Critics and scientific investigators are often met with hostility, and are accused of persecuting the promoters, being "close-minded," or having some ulterior motive for "debunking" the therapy. Argue there is a cover-up by the CDC and Big Pharm to prove their theory as unsubstantiated. Rapid effects are promised. Claim in the “studies” is that children improve with only a few rounds- in 1 study 1 round was sufficient! That is a total of 3 days! Wow, that WAS easy! The "theory" behind the therapy contradicts objective knowledge (and sometimes, common sense). Autism has not been shown to be a disease that can be tested medically. Yes, it may comorbidly exist with many other medical ailments, but it itself is not diagnosed medically. Treating the disorder by medical means contradicts all that we know about autism and its diagnosis. The therapy is said to be easy to administer, requiring little training or expertise. There are many parents at home chelating their child with autism. High "success" rates are claimed. Many children are being cured of autism by chelation therapy. Almost all in the study by Adams et al. (2009) showed improvement after just 1 round of DMSA according to the authors. Use uncoventional ways to measure. Blood test won’t show these metals- do a hair test or “provoke” the toxins out

PSEUDOSCIENCE? Professionals or other people recommend them. Majority, if not all, of the people claiming that children with autism have a toxic metal body burden are the same people who are extolling the benefits of chelation. Who are these people? DOCTORS, one of the most historically trusted professions! If they are saying it, it has to be true!

Questions ?

THANK YOU

REFERENCES Adams, J. B., Romdalvik, J., Sadagopa, V. M., and Legator, M. S. (2007). Mercury, lead, and zinc in baby teeth of children with autism versus controls. Journal of Toxicology and Environmental Health, 70, 1046- 1051. Adams, J. B., Baral, M., Geis, E., Mitchell, J., Ingram, J., Hensley, A., Zappia, I., Newmark, S., Gehn, E., Rubin, R. A., Mitchell, K., Bradstreet, J., and El- Dahr, J. (2009). Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A-Medical results. BMC Clinical Pharmacology, 9, doi:10.1186/1472-6904-9-16. Adams, J. B., Baral, M., Geis, E., Mitchell, J., Ingram, J., Hensley, A., Zappia, I., Newmark, S., Gehn, E., Rubin, R. A., Mitchell, K., Bradstreet, J., and El- Dahr, J. (2009). Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part B-Behavioral results. BMC Clinical Pharmacology, 9, doi:10.1186/1472-6904-9-17.

REFERENCES Adams, J. (2010). Chelation: Removal of toxic metals. In K. Siri & T. Lyons (Eds.), Cutting edge therapies for autism (pp 74-78). NY: Skyhorse Publishing. Bernard, S., Enayati, A, Redwood, L., Roger, H., & Binstock, T. (2001). Autism: A novel form of mercury poisoning. Medical Hypotheses, 56, 462-471. Bradstreet, J., Geier, D. A., Kartzinel, J. J., Adams, J. B., and Geier, M. R. (2003). A case-control study of mercury burden in children with autistic spectrum disorders. Journal of American Physicians and Surgeons, 8, 76-79. Committee on Children with Disabilities, 2001. Technical Report: The Pediatrician’s Role in the Diagnosis and Management of Autistic Spectrum Disorder in Children. Pediatrics, 107, e85. Coplan, J. (2010). Making sense of autistic spectrum disorders: Creating the brightest future for your child with the best treatment options. NY: Bantam Books.

REFERENCES Dietrich, K. N., Ware, J. H., Salganik, M, Radcliffe, J., Rogan, W. J., Rhoads, G. G., Fay, M. E., Davoli, C. T., Denckla, M. B., Bornschein, R. L., Schwarz, D., Dockery, D. W., Adubato, S., & Jones, R. L. (2004). Effect of chelation therapy on the neuropsychological and behavioral development of lead- exposed children after school entry. Pediatrics, 114, 19-26. Freeman, S. K. (2007). The complete guide to autism treatments: A parent’s handbook. Lynden, WA: SKF Books. Holmes, A. S., Blaxill, M. F., and Haley, B. E. (2003). Reduced levels of mercury in first baby haircuts of autistic children. Internal Journal of Toxicology, 22, 277-285. Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications. Lonsdale, D., Shamberger, R. J., & Audhya, T. (2002). Neuroloendocrinology Letters, 23, 303-308.

REFERENCES R. Neubrander, personal communication, June 1, 2010 Soden, S., Lowry, J. A., Garrison, C. B., & Wasserman, G. S. (2007). 24- Hour provoked urine excretion test for heavy metals in children with autism and typically developing controls, a pilot study. Clinical Toxicology. 45, 476-483. doi: 10.1080/15563650701338195. Strangle, D. E., Smith, D. R., Beaudin, S. A., Strawderman, M. S., Levitsky, D. A., & Strupp, B. J. (2007). Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure. Environmental Health Perspectives, 115, 2, 201-209. Walker, Morton. (1990). The Chelation Way. NY: Avery Publishing Group. Williams, P. G., Hersh, J. H., Allard, A., & Sears, L. L. (2008). A controlled study of mercury levels in hair samples of children with autism as compared to their typically developing siblings. Research in Autism Spectrum Disorders, 2, 1 170-175. doi: 10.1016/j. rasd. 2007.05.001

REFERENCES Zhiping, Y., Wu, Q., & Fan, D. (2009). Inappropriate diagnosis and chelation treatment of alleged heavy-metal toxicity. Annals of Internal Medicine, 151, 8. http://research-chelation-therapy.com www.cigna.com www.autism.com www.generationrescue.org www.youtube.com www.autismnj.org www.autismspeaks.org www.asatonline.org

RESEARCH Autism: A Novel Form of Mercury Poisoning Bernard, et al. Hypothesized that the regressive form of autism represents another form of mercury poisoning based on similarity between traits of mercury poisoning and autism and physiological abnormalities + the known exposure to mercury in vaccines

RESEARCH In 2007, a pilot study was conducted by that in 24-Hour provoked urine excretion test for heavy metals in children with autism and typically developing controls, a pilot study (2007) QUESTION POSED: Does a proportion of children with autism have an excess chelatable body burden of arsenic, cadmium, lead, or mercury? FINDINGS: DMSA provoked excretion testing did not produce evidence of an excess chelatable body burden among the autistic participants in this study. The data presents no justification for chelation therapy for the participants. CONCLUSIONS:NO DEFINITIVE EVIDENCE TO SUPPORT LIKELIHOOD THAT CHILDREN WITH A. ARE AT INCREASED RISK OF A CHELATABLE HEAVY METAL BODY BURDEN WITH THE POSSIBLE EXCEPTION OF CHILDREN WITH PICA OR MOUTHING BEHAVIORS SECONDARY TO AUTISM

RESEARCH Reduced Levels of Mercury in First Baby Haircuts of Autistic Children Holmes, et al. FINDINGS: found children with autism had less mercury in their hair than age and gender-matched controls IMPLICATIONS: children with autism may have impaired detoxification capacity and if reduced overall mercury elimination is related to hair elimination, then autistic infants will retain significantly higher levels of mercury in tissue, including the brain, than normal infants

RESEARCH Williams, et al. -blind study Found no significant differences between mercury levels in hair of 15 children with autism and those of the hair of their typically developing siblings Question the theory that mercury toxicity causes autism and points to difficulty in quantifying chronic mercury exposure through currently available laboratory measures

Even if the claims that mercury causes ASD and that chelation helps are both true (and at present there is very contradictory support for and against these hypotheses), somewhere there has to be a tipping point between the risks of mercury exposure and the risk of brain damage from succimer, itself. If the child’s mercury is not high enough, the succimer will go after the child’s brain instead Coplan

Disclaimer I could talk for a whole semester on the theory behind these interventions and whether they have a leg to stand on and THEN whether the intervention proposed is effective at treating autism, but for the purpose of this class I will just inform you of the theory behind the rationale and then speak to the tx’s effectiveness in treating the symptoms of autism Neither of these two txs are to be used in a vacuum- proponents of both call for multiple txs- making anecdotal report for these treatments in the autism community even less credible

A Review of Hyperbaric Oxygen Therapy in the Treatment of Autism Kelly Ann LaPietra Caldwell College

Source Identification Keywords: “chelation”, “chelation and autism”, “hyperbaric oxygen therapy”, “hyperbaric oxygen therapy and autism” Assigned Textbooks Barnes and Noble bookstore “Special Needs Children section” Pubmed Database Academic Search Premier Database Psychinfo Database Google Scholar Google Search Engine Autism Resource Websites References cited in articles and in books

OUTLINE

What is Hyperbaric Oxygen Therapy? Hyperbaric oxygen therapy involves breathing up to 100% oxygen at greater than 1 atmosphere (ATA) in a pressurized chamber. Hyperoxia- an increased level of oxygen in the tissues of the body (Coplan) Explain that at sea level air breathed is 1 ATA; most clinical applications are between 1.3- 3, but for autism we will talk about is at the low to mild pressure end

3 factors that are varied to achieve tx protocols and clinical results for children with autism 1. how much pressure is applied (1.3-1.75) 2. how strong oxygen concentration is (24%-100%) 3. how long tx session lasts (1-1.5 hrs. per dive) Neubrander

History of Hyperbaric Oxygen Therapy 1783 French physician Caillens- first to use oxygen as remedy 1930-40’s oxygen tolerance limits were established for divers- basis for oxygen recompression tables used today Borema, “Father of Modern Hyperbaric Medicine”- late 50’s removed all red cells from pigs, with only plasma remaining, living under hyperbaric conditions First Hyperbaric Oxygen Therapy textbook published by Davis and Hunt (1977)

Uses for Hyperbaric Oxygen Therapy Wound healing (Coplan) Carbon monoxide poisoning Decompression sickness (Jepson) Burns Gas gangrene Exceptional blood loss (Lerman)

HBOT AND AUTISM THEORY: some children with autism have hypoxia, gut inflammation, compromised immune function RATIONALE FOR TX: providing an elevated level of oxygen to the tissues in a pressurized chamber will decrease core symptoms of autism. (2002) Heuser published SPECT scan results from a 4-yr. old with autism post-HBOT Include what he found

What evidence are they basing this theory on?

Lerman reports such nerurological abnormalities have been verified and no controlled studies have been conducted on the behavioral outcomes of HBOT with this population

CLAIMED BENEFITS OF HBOT FOR AUTISM Relieves hypoxia Lowers the presence of anaerobic gut bacteria Decreases inflammation Improves immune function Lowers oxidative stress Increases glutathione levels (Jepson) Improves symptoms of autism (Rossignol 2006)

Dr. Neubrander’s PREDICTED OUTCOMES Only mild or mild to moderate responses within first 40 hr set Recommended to continue for several cycles- most powerful tx to induce language, increase awareness and cognition, and allow more normal socialization and emotional responses Better with pre-tx adjunct therapies including, methyl-B12 shots and supplements

POTENTIAL SIDE EFFECTS OF HBOT Increases oxidative stress which potentially can cause brain damage Triggers cell death by a process known as apotosis Leads to Alzheimer’s disease-related changes in the brain Death (Coplan) Death (cite) Increased oxidative stress Barotruma Sinus squeeze Serous otitis Claustrophobia Reversible myopia Seizures Oxygen toxicity (Lerman) Aspiration (Lerman)

Variations in Protocol Pressure used (1.1-2.8 ATA) 100% oxygen vs. oxygen concentrator Length of session (between 60-90min.) Number of sessions per day (1-2) Time elapsed between sessions (2-12hrs.) Number of treatment hours per treatment set (40-90hrs.) Q. What is the right recipe? A. No one knows right now.

GUIDELINES FOR HBOT Requires a medical doctor’s prescription Remember it is a drug therapy- too little may not be effective, but too much is toxic

Where can you go for a dive? Many clinics No hospitals- not an approved indication for HBOT Dr. Neubrander, Edison, NJ- home rental Can purchase via (put price)

RESEARCH Rossignol (2007) first prospective study of HBOT with autism The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: An open label pilot study PURPOSE: 1. Measure the effects of HBOT on oxidative stress markers 2. Measure the impact of HBOT on an inflammatory marker 3. Examine the changes in clinical symptoms, as rated by parents or caregivers, after tx with HBOT 4. Evaluate the safety of HBOT, used at 1.3 and 24% oxygen and 1.5 ATA and 100% oxygen Open study- no placebo control group

Rossignol (2007) FINDINGS: Not significantly associated with increased intracellular oxidative stress Improved inflammation HBOT was safely administered to all participants and all finished 40 dives without any major adverse events

RESEARCH Rossignol (2007) LIMITATIONS: Clinical outcomes were based on parent-ratings Parents were not blind No placebo-control group Small sample size Parents may have been bias Can’t rule out confounding variables Small size may not be generalizable

RESEARCH Rossignol et al. 2006 67 medical hypotheses PURPOSE: on 6 children with autism Study Design: Retrospective pilot study FINDINGS: showed modest behavioral improvements, especially in the younger patients, according to parent assessment using various behavior scales 40 1 hr. sessions @ 1.3 ATA and 28-30% oxygen over 3 mos.

RESEARCH Rossignol et al. 2006 67 medical hypotheses LIMITATIONS: based on parent report not blind no placebo group allowed participants to continue with other treatments and add new ones during the time of the study

RESEARCH Granpeesheh, D. et al. Randomized trial of hyperbaric oxygen therapy for children with autism. PURPOSE: to test the hypothesis that HBOT would have a beneficial effect on ASD symptoms in the context of a double-blind placebo-controlled trial INDEPENDENT VARIABLE: 24% oxygen at 1.3 ATA DEPENDENT VARIABLE: direct observational measures of behaviors symptomatic of autism and standardized psychological assessments FINDINGS: there were no differences detected between HBOT and placebo groups across any of the outcomes

RESEARCH Granpeesheh, D. LIMITATIONS:

RESEARCH Lerman et al. Using behavior analysis to examine the outcomes of unproven therapies: An evaluation of hyperbaric oxygen therapy for children with autism Purpose: to conduct a systematic evaluation of HBOT with children who were attending a day program for children with autism Design: multiple-baseline across participants Findings: HBOT did not improve task engagement or decrease problem behavior beyond that provided by ongoing behavior analytic services. Also not associated with changes in spontaneous communication for 2/3 participants. Conclusion: The effects of HBOT were not worth the price.

RESEARCH Lerman et al. (continued) LIMITATIONS: Small sample size, 1 participant dropped out after 27 due to a non-related ear infection Only tested at 88% oxygen at 1.3 ATA, 40 dives at 60 minutes each Along with HBOT, 60-minutes of access to preferred items was added to their day A different combination of pressure and oxygen may yield different results as might number of dives and length of dives 60 min of preferred may have confounded- should have given 60 min of preferred before tx began

RESEARCH Rossignol et al. First randomized controlled trial of HBOT 62 children either received HBOT or placebo treatment Authors used 3 scales- the Aberrant Behavior Checklist (ABC), the Autism Treatment Evaluation Checklist (ATEC), and the Clinical Global Impression (CGI) as outcome measures. Found differences in favor of the HBOT group for one of six subscales on the ABC, 1/5 on the ATEC, and 3/18 on the CGI, but even those few beneficial results were inconsistent- while eye contact and receptive language were improved on the CGI post-tx, social awareness, social interaction, and speech/language were not Authors completely disregard the research showing oxygen toxicity to the developing brain, asserting that it is generally regarded as safe on the basis of a single paper TAKEN FROM COPLAN BUT WILL CITE ROSSIGNOL

FUTURE RESEARCH More controlled research with randomized participants with autism More controlled experimentation with magnitude and duration of independent variables Replication, replication, replication

Even if you are convinced that the exposure to increased oxygen levels is effective in the treatment of ASD, and the risks of brain damage from oxygen are exaggerated, you may be surprised to learn that breathing oxygen from a mask can achieve the same increase in brain oxygen levels as going into a tank at a fraction of the cost- smells like quackery Coplan

Questions ?

THANK YOU

REFERENCES Jepson, B. (2007). Changing the course of autism: A scientific approach for parents and physicians. Boulder, CO: Sentient Publications. Coplan, J. (2010). Making sense of autistic spectrum disorders: Creating the brightest future for your child with the best treatment options. NY: Bantam Books. Freeman, S. K. (2007). The complete guide to autism treatments: A parent’s handbook. Lynden, WA: SKF Books.

REFERENCES Siri, K., and Lyons, T. (2010). Cutting-edge therapies for autism: 2010-2011. NY: Skyhorse Publishing. Rossignol, D. A., Rossignol, L. W., Smith, S., Schneider, C., Logerquist, S., Usman, A., Neubrander, J. Madren, E. M., Hintz, G., Grushkin, B., & Mumper, E. A. (2009). Hyperbaric treatment for children with autism: A multicenter, randomized, double- blind, controlled trial. BMC Pediatrics. 9:21 doi: 10.1186/1471-2431-9-21

REFERENCES

REFERENCES Strangle, D. E., Smith, D. R., Beaudin, S. A., Strawderman, M. S., Levitsky, D. A., & Strupp, B. J. (2007). Succimer chelation improves learning, attention, and arousal regulation in lead- exposed rats but produces lasting cognitive impairment in the absence of lead exposure. Environmental Health Perspectives, 115, 2, 201- 209. Williams, P. G., Hersh, J. H., Allard, A., & Sears, L. L. (2008). A controlled study of mercury levels in hair samples of children with autism as compared to their typically developing siblings. Research in Autism Spectrum Disorders, 2, 1 170-175. doi: 10.1016/j. rasd. 2007.05.001

REFERENCES

Even if your child has proven metal toxicity, chelation is just one of the ones to address the problem (list ways- change diet, environment, add supplements, etc.)- many things you can do before you do that

Approved Indications DRUG: Edetate Calcium Disodium (Calcium EDTA) (Calcium Disodium Versenate®) USAGE/APPROVED FDA INDICATION: Edetate calcium disodium is indicated for the reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric populations and adults. Chelation therapy should not replace effective measures to eliminate or reduce further exposure to lead. www.cigna.com This is direct quote- figure out how to do it or paraphrase

Approved Indications DRUG: Succimer (DMSA) (Chemet®) USAGE/APPROVED FDA INDICATION: Lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL www.cigna.com