How TACA Helps Families

› Adopt a Family
› Family Scholarship Program
› AutismCares Family Support Awards
› Parent-to-Parent Mentoring

Year-round assistance to families in great need.



Just for FUN – once a month

 

Come join your TACA friends at PUMP IT UP in Huntington Beach, Rancho Cucamonga and Sorrento Valley for some good ol’ family fun! See schedule

DAN! Conference Notes

(Defeat Autism NOW)
Dates: October 5,6,7, 2001

General overview: 1,200 parents and doctors at the conference this year. Note, due to September 11th, there was approximately 300 people who cancelled and did not attend the conference.

ALSO NOTE: These notes were typed by kjorn@thundersnow.com, a parent named Karen. I went to type up my extensive notes and she published her notes on GFCF KIDS. I saw no reason to retype my notes!!

A conference syllabus or video/audio tapes are available via www.autism.com/ari

ExtraDAN: What's In and What's Out

What's IN                                                         What's OUT

------------------------------------------------------------------------------

• New DAN protocal                                 Old DAN protocol
• New DAN dr. list                                   Old DAN dr. list
• probiotics generously                             probiotics sometimes
• enzymes all the time, any diet                 enzymes are snake oil
• GFCF diet for a time                               GFCF diet for life
• EPA fatty acids                                     DHA fatty acids
• Parents' opinions/evalutions                    "experts'" opinions/evaluations
• Child is best lab                                     labs are best labs
• minimal specific testing                            $$$$ of testing for all
• targeted minimum supplements                  handfuls of supplements for all
• Many subgroups of AS                             A few subgroups of AS

More specifically on these later, but this gets to the point.

Finding A DAN! Doctor:

DAN doctors – There will be a new format for selecting DAN doctors and putting their name on the ARI list. Before, a person with no experience in AS therapy could simply attend one DAN conference and  they were on the list. This gave the following result on the system (I heard the following descriptions, select the one you like best):

• a. not adequate
• b. needs to be reevaluated
• c. didn't work out
• d. dismal failure
• e. I would have been better off using the Yellow Pages

The DAN people say they will try to use a different criteria so the DAN list will be far more useful. This will include adding things such as the doctors' specialties, interests, geographic region, and

if they are taking new patients in person, by phone consultation, or not at all. Hopefully, this will be more meaningful to both the parents and the doctors.

If anyone has any other suggestions that would help the DAN folks make the list more useful for everyone, now would be a great time to submit those ideas to the ARI site. They are really trying to make it a quality, effective resource. It would be great to let them know what you like see and what they are doing already that is working well. They are quite short-handed with doctors getting into this area.

so, 2 points:

1. If you haven't found a DAN doctor yet, don't worry that you are substantially missing something. There are only a very few who are  very knowledgeable, and most of them are not taking new patients anyway.

2. If you met with a DAN doctor and had a not-so-great experience, you may want to give it another look in a few months with the new selection system.

Dr. Amy Holmes was taking names of the "new" DAN doctors and whether they were even taking patients or not (some on the previous list were only into research). She said to give her a day or two to get it finished and it will be on the ARI site and/or her site (does anyone know the url? I can look for it later).

I just looked and it is not up now. Check either of the following links in the following days:

• www.autism.com/ari/contents.html#icbr (ARI home page)
• www.autism.com/ari/danlist.html (ARI DAN dr. list)

They also said they are quite short on knowledgeable people, and if you can not get in to see someone good, find a local agreeable doctor of some kind (ped, neuro, development specialist, anyone) who will work with you. They can order the protocol (make sure you ask for and

get the NEW one), and you and the doc can do it together. They said they will make an effort to assist local doctors under these conditions and this was a good alternative. They realize the entire thing is in flux, treatments are still as little chaotic, and really are trying to meet the great need. Amy Holmes outlined her chelation protocal (see notes below.)

GENERAL COMMENTS ABOUT CONFERENCE:  PARENTS RULE

The parents are proving to be more accurate in terms of evaluation and selecting therapies for their children. Almost every parent I talked to at the breaks, lunches, and sessions said they definitely got the most practical help and best ideas from other parents. This was from message boards and support groups mainly (I asked). They read, they searched the internet, they posted, they replied, they researched, and, a very interesting point here, THEY SQUEAKED. Moms

and dads (mostly moms) said they had to:

• argue and push and squeak with the schools
• badger and fuss and squeak with the manufacturers' of supplements,
• foods and other products
• whine and complain and squeak with the therapists (OTs, speech,
• ABA, etc)
• pester and demand and squeak with their doctors (DAN doctors,
• pediatricians, neurologists, dentists, etc.)
• squeak, squeak, SQUEAK!

And this is how they got results. Most parents didn't hide that they were sick and tired of it, but this is what was required to assist their kids, relatives, and themselves. A couple people said they

found a gem of a doctor who would work with them – and the rest of us would be so envious. [I was fortunate to have a wonderful neurologist until she retired.] Almost every parent/adult to the man related all the stupid stuff they had been told over the years, and the runaround they got, and the walls they had to bust through in trying to find appropriate treatments.

Several companies [more than 6] of commercial supplements, lab testing, and therapies admitted they changed their focus abruptly based on parent feedback (enzymes were one of these). Of course, this is basic business and marketing – supply and demand. So what I got out of it is, parents…..SQUEAK, and keep squeaking and squeaking. Squeak to the supplement companies and vendors, squeak to the therapists, squeak to the researchers, squeak to everyone. Then

research it all for yourself. A couple companies said they did in fact sit up and take notice when parents started flooding them with emails and phone calls and pushing back and demanding answers, not just passively believing all the marketing, or the idea that "we know best because we are the experts and you are the lowly unknowledgeable parent." [My paraphrase.]

Dr. Holmes said the effective stuff, including changes in treatments and public policies (vaccines), are driven and fueled by BAMs – Bunch of Angry Moms! Along with the angry dads and doctors. So if someone feels they are having to push a great deal, you are not imagining this or being overly fussy. Just think BAM.

Hyperactivity Notes:

Hyperactivity – almost all the treatments stated increased hyperactivity in people where the treatment improved overall health and/or eventually produced positive results. In general, hyperactivity = improvement. This was seen very commonly with enzyme therapy, chelation, GFCF diet, many supplements, and bug treatments. This has come up often on the enzyme board and so I was particularly interested in this. Also, it was also common enough to see a little

regressive behavior WITH positive improvements. With chelation and bug treatment (and we can toss in enzymes here as well), as long as you are seeing positive improvements along with the awful stuff, this is generally good and will resolve itself with time. If you see regressive behavior not accompanies with some positives, then it is probably best to stop. If you see positive improvement without regressive behavior, thank your lucky stars and enjoy it.

Stimming – A parent asked, "My son has improved dramatically with several interventions, to the point he is indistinguishable from others…but he is stimming more than ever. Why and what do I do?" The answer (one possibility) was that the stimming is now a neurological response. The reaction pathway is etched in the brain. You need "redirect" or "create" a new neurological response pathway. This is how of sensory integration therapy works. Sensory therapy strives

to build more appropriate pathways using certain repeated sensory stimulas. This process is effective but can be slow. It was suggested this could be speeded up by supplementing with something???

Die-off reactions can be lessened considerably using activated charcoal. This is cheap, safe and works well. Consider this whenever a therapy is used which may contribute to die-off (chelation, anti-fungals, enzymes, diet change, supplements). Activated charcoal – your local health food store carries it, safe, cheap, effective.

Omega-3/ Metallathionein (Pfeiffer)/Vaccines – General Findings at DAN! Conference:

Omega-3 fatty acids are shown to be very important and effective in a treatment program for many people with neurological conditions. There are studies where it made significant differences in ADD, depression, bipolar, epilepsy, etc. So why not autism? It is being tried with good results in some. Most people on the traditional American diet are quite low in omega-3 fatty acids, if not outright deficient. DHA is not proving to be a key element. EPA is the key element. EPA.

Hands-down, use OmegaBrite for school age kids and adults. If a younger child will not take it, use Coromega because it is good quality and tastes decent. Coromega does contain vanillin which is an artificial flavor, if this is a concern.  [My note: people with phenol intolerance very often have problems with artificial additives.] Flax seed was "okay" but not as good with some side-effects which may be a concern. Skip the algae, seaweed, kelp, etc because humans don't metabolize it well and there are contamination concerns. Consume the fish/ fish oil because the fish metabolizes it right, and then humans can metabolize it from the fish [know your place on the food chain]. EPA – OmegaBrite. www.omegabrite.com. This is the recommendation of the presenter, but you probably want to look into this yourself.

-------------------------------

The metallothionein research by Pfieffer. Good, exciting stuff. But as with all therapies / interventions with children with autism:  NOT ALL THERAPIES WORK FOR ALL CHILDREN!  Basically, it shows too much copper via some pathways I will specify in another post on this presentation, with too low of zinc. So, add more zinc. A lot more zinc. They said like 150-200 mg of zinc. I have always been told not to go over 100 mg of zinc for an adult, but  these are the numbers said more than once. Please look into this more before buying a truckload of zinc. How to correct the metallothionein problem? It will vary for each individual and isn't completely worked

out at this time. It does involve cleaning up the gut for starters. And add more zinc. Drs. Holmes and El-Dahl will be updating their protocol to incorporate new metallothionein/mercury information. This will be on their site shortly.

----------------------------

There was some significantly positive new developments and statements on the mercury/vaccine issue that several of the doctors testified this summer for. Sorry, I did not understand them entirely except that it was a significant victory for the home team. Please refer to the web sites of Dr. Amy Holmes, Dr. Jeff Bradstreet, Dr. Andrew Wakefield or ARI for more information. Basically, they concluded that someone approving mercury in thimersol in vaccines made a big

mistake, there was a bit of a cover-up, and research on the matter is valid and needs to be funded.

Karyn Seroussi: The Gluten Free /Casein Free Diet

[Karyn did have slides but they are not in the conference book. The description on GFCF diet from the ANDI site is in the book. I am probably missing some of the slide info, maybe someone else can fill in any holes. Kd.]

Your pediatrician may say the only treatment is behavior modification. Just because a treatment is not proven does not mean it doesn't work. GFCF diet must be done right. Only some treatments will work well with only certain subgroups. Some kids are not only behaviorally a problem but are physically ill as well. As long as the person isn't mentally retarded what could possibly wrong? Chronic diarrhea as well as ear infections are associated with milk. She talked about the opiate research by Dr. Paul Shattock and Dr. Karl Reichelt and the opiate effects theory. The opioid activity is lost if the food is fully digested. The opiod peptides are a problem only when the food is partially digested. Lots of theories but no one is sure what causes this (insufficient digestion). Just something happens in the body which allows incomplete digestion.

She discussed what a leaky gut was: cells of the gut wall are compromised. It is common but is rarely tested for. A leaky gut allows for the passage of bacteria, toxins and food. Vitamins and

minerals pass too quickly to be absorbed, and all this sets the stage for multiple food allergies.

Karyn Seroussi said, "It is my hope that someday we will be able to go off the diet, but we will do it if necessary." She said her son is bugging her to let him off the diet and have other stuff. Also, a

second book/volume of Special Diets for Special Kids will be out in a few weeks. [I think she meant this will be a second book of completely new GFCF recipes, not just a new printing or update of the previous book.]

She there is a pattern of autistic excretions: not all kids respond to diet or gastro problems, but a lot do. About 1/3. Autism diagnosis is based on behavior at this time. Although people get there by different routes, the diagnosis comes from observable behavior. At this point we just don't know what to do for which subgroups.

Some problems come from the thinking this is a food allergy, or a hard-wired genetic disability. These factors may not cause autism but do cause extra symptoms. There are three different ways to have a problem with milk or wheat

1. True Allergy - Usually IgE mediated, sinuses, hives, breathing, allergy shots.

2. Food Intolerance - Usually IgG mediated, discomfort, GI distress, other symptoms

3. "Peptidurea" - leaky gut, proteins don't fully break down, opiate peptides in bloodstream affect brain.

Oddly enough, many autistics have all three of these things. There is overlap. Karyn's son has a true allergy to wheat, but not to milk. Karyn said that if your doctor, teacher, or someone else is not very receptive to the diet, you can state the following:

"Although autism has been considered to be untreatable, early studies in Europe have shown that SOME forms of autism are metabolic – and caused by the inability to break down certain proteins. Removing these proteins has shown dramatic improvement in ONE subgroup of children with autism. Children like mine do not have the luxury of waiting for the results of double-blind, placebo studies. Since it appears to be a safe intervention, I would like to experiment with

removing three proteins from my child's diet, and I would really appreciate your support." 

A child who is in pain screams. Having autism does not cause screaming. Maybe milk masks the pain. Maybe pain from a fecal impaction. Some of these kids are in real pain. No clear cut way to

tell which kids will reaction to environment insults.

Reasons given why someone can't go on diet:

1. The kids are picky, picky, picky. – worse reason of all because it indicates a problem/addiction.

Just say "no" to pizza. Living with the diet is hard. Living with a child with autism is harder. At least the diet gets easier. If you have an older child, there are other considerations. A younger child should try it. Do not know which kids won't respond.

Commercially available testing is not reliable enough. At least 2/3’s show improvement, some dramatically. The kids most likely to respond:

• Early excessive antibiotic use
• Late onset autism after normal development
• Insensitivity to pain
• Constipation or diarrhea
• Very limited diet.

and then she said "however Lisa Lewis' child had none of this."

Natural gut "flora" keeps yeast in check. Healthy immune sytem maintains balance.

Antibiotics can throw off this balance. When thrown off, yeast proliferates. Excessive yeast waste products may be absorbed from the gut & wreak havoc on the central nervous system (CNS).

A pattern emerges:

• A child is genetically predisposed to improper immune response.
• Some load triggers abnormal immune response.
• Child is ill may take antibiotics.
• Candida overgrowth causes gut damage.

Some kids will swing to other foods once the "fix" has been eliminated. Karyn's son took a few years to really expand his diet. He would go through periods of refusing something he previously ate without problem.

Little kids like little foods – less sugar, stevia. Do what is necessary at the beginning to get them on the diet – worry about balance nutrition later. The important point is that they get the peptides out first. So if they will only eat chips and GFCF crackers, let them.

Prepackaged foods are expensive, but handy in the beginning. Mixes are easier than baking from scratch, but are more economical that buying prepared commercially prepared. [She was making the point of the trade-offs between convenience and expense.] GFCF foods may still have gobs of sugar/fat/additives and preservatives, so just be aware of this and keep an eye on the entire diet over the long run.

How long must I do this diet? We are not sure…we need to understand underlying mechanism better. In one out of five cases, the child never gets worse going off the diet (no enzymes). About 4 out of 5 times, the child will regress after a while. A couple of times, Karyn's son ate something inappropriate and did not react. Maybe her son's gut has healed? She is not sure but does not intend to challenge it completely at this time. Her son asked when he can go off the diet.

There is a HUGE difference between being GFCF 98% and GFCF 100%. For gluten reactions give – digestive enzymes, alka-seltzer gold, activated charcoal, benadryl (but don't use all the time) [alka seltzer gold and benadryl are not to be used long term. Pepcid AC wasn't mentioned].

Families of children with autism seem to be immune challenged families…so a better diet can help the entire family. Milk can be very good for people without this problem, but not for this particular group.

Keep utensils separate and clean. Being 100% GFCF means all contamination including preparation surfaces, utensils, skin care, cleaning supplies, etc. If you touch a spoon from something not GFCF into something GFCF, you have contaminated the entire pot.

Siblings may respond as well: Feingold program is very helpful. Overlapping spectrum disorders [don't know what this refers to, sorry, I think like a relative has ADD] Never to late to try – many people write saying they see amazing differences even into their twenties.

Eliminate one thing at a time. Then look at yeast? or phenols? Karyn has been able to rotate things back in such as soy, chocolate and corn. Corn was the third worse offending food for her son. She is being cautious though, but it is getting better, and he can have more and more of previously offending foods.

Digestive enzymes (only showed EnzymAid, SerenAid - nothing on Peptizyde).  Absolutely keep a bottle of digestive enzymes in the house. Be committed. Don't give poison along with the antidote. You can certainly give the enzymes at every meal and see if it helps.

When is it OK to quit? If you are really doing it right…do it for 3 months (although some

say 6-12 months for adequate test period). Give a big glass of milk and see what happens. If nothing happens, go on to next thing [that is, leave the diet behind as a "tried this"]. You can send your food diary or foodlist to ANDI or the gfcfdiet.com site and someone will check it to see it they find something you did not know about (or maybe a product that was okay before, has been changed).

She said she is looking forward to the day the DAN conference is obsolete. Every subtype of autism is treatable but more work needs to be done. GF CF Vendors @ DAN!

Several presenters said doing the GFCF diet was a first step for everyone. At least try eliminating casein for 3 weeks, and gluten for 3 months, and look for improvement. The Gfcfdiet.com Group had a booth and I got a change to look at the Starter Pack which includes a lot of information on the diet, 3 week menu, shopping lists and other stuff. It certainly would have helped me when I attempted it. My opinion is that it is well worth the money. You can see a list of the contents at their site www.gfcfdiet.com. The regular list moderators Judy deHart and Cara Lewis were not able to make it and so some of the California GFCF group were at the booth. Even though they were there at the last minute, they were very helpful and gave good guidance to those considering the diet, new to the diet, and on the diet asking about questionable foods (okay, I admit I was eavesdropping). I didn't hear any pushyness or things suggesting the parents "just weren't doing it right." That line always bugs me. They also had a new Cookbook and a Parents / Professional Resource booklet, among other things. Karyn Seroussi was with the ANDI booth right next to them. The ANDI booth had examples of their newsletter and explained about the organization. www.autismndi.com/ They were not hiding the fact it is very difficult but said there were many resources for assistance. There is also a program where you can find people in your local area to help you on the GFCF diet.

Ms. Roben's booth was giving out gummi samples and goodie bags. The gummi's were intensely fruity...really fruity. They do have artifical colors so that is out for us, but the taste was good. There were sample's of Darifree vanilla and chocolate drink. Definitely better than most soy and rice drinks (except Almond Breeze Chocolate, we like that). The bag has a sample of the gummi's, gorilla munch cereal, a 100% fruit strip chewy (which had no artificials and was

very good and fruity), pretzels and a couple other things I just can't remember. www.missroben.com

For the next two booths, let me preface this by saying in general I do not like GF baked goods. Out of about 80 GFCF foods I have tried, I can list all of the ones I like on one hand, so I am not the best judge on this, and please get other opinions. This may be helpful if you have a very picky child. Ener-G Foods makes GFCF baked goods and other things. They had samples of two new breads, a raisin bread and a 6-grain bread, and vanilla cookies (when I passed by).  I didn't

like any of it because it had a slimy, gritty aftertaste that is characteristic of many GF breads. BUT, if you are looking for a GF raisin bread (with golden raisins) or a new flavor of bread, please do look into these. They are two new varieties. In health food stores and www.ener-g.com.

Jay Bigam at Kinnikinnick had a great job. He just handed out samples of about 20 different things all day but wasn't taking orders. People were always there. I REALLY DID LIKE the ginger snap cookies, and another cookie there, as well as the three flavors of donuts. Although I really don't like GF bread, their bread was the best I have ever tasted. The hot dog buns were a good texture and consistency for hot dogs (no aftertaste), and could be used for a bunch of other things. That would be my choice for sandwich bread...like a longer sub sandwich. That could go well in a kid's lunch box. Kinnikinnick is all GF but only SOME is CF, so do check your items carefully. I am thinking Jay only had GFCF there because he knows of the GFCF diet. The stictly GFCF line is called Alta. There are some yeast free, egg free and sugar free things too.

www.kinnikinnick.com . If for some reason I HAD to be exclusively GF, I would just order from them and call it a day. Now, to count the GF things I like, I will need at least two hands.

I did not get to the Glutino booth (sorry). I probably missed something else - check the DAN list of exhibitors. www.glutino.com

Special Foods. www.specialfoods.com  Talked to them a little...the foods are very unique and expensive.

Before I left home, my husband and I were betting if the conference would serve GFCF food or not. We bet not. We were right. Breakfast was provided each day. Piles of wheat bagels with assorted cream cheeses. Coffee with cream, whole milk, and skim milk. If any of the other meals were GFCF I had a touch time telling. I joked with the GFCF food vendors that at least the conference organizers could have let them put out a table of GFCF bagels with a sign "provided by..." I said this was a conference that was promoting the GFCF diet as a first and important step. Both Ener-G Foods and Kinnikinnick said their companies would have donated food for FREE! Any amount... for FREE. Since some of the parents are on the diet with their kids or for themselves, they were asking where they could get something to eat. I was happy with the selection but did find it ironic. This may be something to mention to the DAN folks if you are interested in having some GFCF selections next time.

The conference does take a ton of work and it did go quite smoothly and was FULL of information. They did a good job.

Dr. Jane El-Dahr Discussion on TH1/TH2 Inbalance & Immunologic Issues in Autism

[Dr. El-Dahr had one presentation for the parent session (this one) and one for the general session. My laptop was recharging and so my notes by hand were slow…and I got a bit lost halfway through. But her slides contained a lot of the information and it is included here.

The numbers are the slide numbers so you will know when a new slide was up. There is some good stuff on allergies vs intolerances and how o handle them. Kd.]

Jane El-Dahr, MD

Head, Section of Pediatric Allergy/Immunology/Rheumatology Tulane Medical Center, New Orleans, LA

2. Immune mechanisms – She showed a diagram illustrating the relationship of antibodies and antigens and interferons. [sorry but I couldn't follow it and she was going fast – it looked like a football play with all the arrows going everywhere]

3. The interactions involve the following systems:

• Immune
• Endocrine
• Neurologic
• Gut

4. Neuroendocrine Interactions – another diagrams and more arrows

5. The Immune System

This is the body's defense system, guarding against foreign invaders. She said she will use the military model as an analogy.

6. Innate and Acquired Immunity

[another diagram – I think I can re-create this one]

 

                        Innate immunity

            _________________|_____________

            |                |              |

Physical barriers          Cells       Chemical barriers

            |               |                    |

         Skin, mucous   [ PMN's          ]  pH, lipids, enzymes, etc.

          membranes     [ monocytes      ]

         |------------ [ Macrophages,    ] -------------| 

         |             [ eosinophilis, NK cells ]       |

Cytokines|                 /                \           |   Cytokines

         |           Antibodies          Cytokines      |

         |               /                    \         |

         |----------B cells              T Cells--------|

                        |__________________|  

                                 |

                         Acquired Immunity

 

7. Innate (no memory required)

• nonspecific and primitive: weapons (swords, guns, grenades).
• Reacts the same way every time – does not get smarter with each skirmish.
• Wite blood cells of many types. Act the same against a splinter or bacteria to destroy the "invader"
• Inflammation in autism may originate

8. Innate (no memory required)

• Physical and chemical barriers: like armor or shield
• skin
• mucous membranes
• high pH
• cough reflex

9 Complement (innate)

• Proteins which complement the other parts of the immune system.
• Complicated interactive mechanism needed to efficiently clear infections or immune complexes
• Problems would predispose to recurrent infections or autoimmune disease
• Found to be defective in some children with autism by Warren

10. Antigen Presenting Cells

• Scout for invaders; capture and hold foreigners until the commanders or troups arrive; jailors of POW camps
• Sometimes kills germ without waiting
• Types: macrophage, microglia – brain, follicular dendritic cells – lymph nodes (cells in small intestine where Dr. Wakefiled has found measles)

11. Adaptive – Acquired (memory)

• Highly specific for individual pathogens.
• Has memory of previous encounters and initiates a stronger attack if another skirmish occurs
• Discriminates between "self" and "non-self" so does not engage in friendly fire
• Lymphocytes are the commanders; their products are crucial to this process

12. B Lymphocytes

• B cells: in charge of making different types of immunoglobulins or antibodies – small specific proteins that bind to invaders, marking them for death.
• Immunoglobulins/Antibodies (also known as humoral immunity) are the troops and come in 4 types:

13. Immunoglobulin types

• IgA: Admiral; the navy, cruising mucosal (wet) surfaces as first line of defese. In tears, saliva, respiratory secretions, GI tract. (Low in a large subset of children with autism)
• Low IgA predisposes someone to autoimmune diseases and GI infections (rotavirus, giardia, etc.)

14. Immunoglobulin – IgA

• IgA deficiency: <10; low: 10-normal range
• By age 5, about half of low values normalize in typical children.
• IgA1 in bloodstream, fairly constant.
  • IgA2 in GI secretions, variable, not easy to measure accurately.
  • High fecal levels probably consistent with abnormal GI flora.

15. Immunoglobulin – IgM

• IgM: Marines; small but rapidly deployed force who will hold things at bay until the main troops arrive.
• Generally normal to high in children with autism.

16. Immunoglobulin – IgG

• IgG: General; the army – large force, takes longer to muster but once there, remains a long time to ensure control; if called for a second encounter, much bigger response. Composed of 4 subclasses. (IgG and IgG subclasses may be high or low in autism.)

17. Treatment: Low IgG

• IVIG 400 mg/kg q 4 weeks as replacement dose.
• Dr. Sudhir Gupta found improvement in autistic symptoms in some children. (Gupta Set all, Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disor 1996; 26:439-452) Continue for 6-

18 months.

• DBPC study by Dr. Gupta, results not yet published

18. Immunoglobulin – IgE

• IgE: too Eager; designed to kill parasites but causes allergy or hypersensitivity; over-reacts to innocuous agents – rogue warriors. (Often high in children with autism)
• Children with autism seem to have TH2 predominance with tendency to have elevated levels of IgE.

19. Allergy – IgE

• IgE allergy usually manifests as eczema, hives, rhinitis, conjunctivitis, or asthma; sometimes as vomiting and diarrhea.
• Total IgE <20, unlikely to find specific allergies; >100, very likely to find; 20-100, search if symptomatic.

20. IgE – Indoor Allergens

• If IgE is elevated or if having symptoms, send RAST IgE for avoidable things: dust mites, cat, dog
• Dust mite avoidance: zip-up covers for pillows, mattress, and box spring on bed(s). Pillow covers at Kmart, Wal-Mart; vinyl zip covers with washable mattress pad OK for bed.
• Animal allergies: Pet out of house > out of bedroom, HEPA filter for bedroom, use denaturant on carpets. [She said it is best to keep the pet out of the house, but if that is not always possible, please at least keep the pet out of the person's bedroom]

21. IgE – Outdoor allergens

• If IgE is high or if the child has significant seasonal symptoms, send "local" IgE inhalant panel – available from all major labs
• If not local panel not available, ask for 2-3 trees, 2-3 grasses, ragweed mix, alternaria, cladosporium, and aspergillus in addition to the indoor allergens (mites, cat, dog)

22. IgE- Antihistamines

• Antihistamines are worth trying and may have efficacy in decreasing core autistic symptoms. (Niaprazine in the treatment of autistic disorder. Rossi PG, Posar A, Parmeggiani A, Pipitone E, D'Agata M, J Child Neurol 1999;14:8 547-50). Try less-sedating/non-sedating ones first:
• Claritin (loratidine) syrup: Does not cross Blood/Brain Barrier, does not cause sedation
• Zyrtec (cetirizine) syrup: Is somewhat sedating (does cross BBB) so give at bedtime.

23. IgE – Food

• If child has atopic dermatitis/eczema, primary foods to measure IgE RAST against are milk, wheat, egg white, soy, peanut, shrimp, fish (trout and codfish).
• Peanut/nut and shellfish/fish IgE allergies are rarely outgrown, egg/soy are if avoided for more than one year
• Gluten/casein intolerance (lack of normal digestion causing opioids to accumulate or autoimmune reaction) is NOT IgE mediated.

24. IgE – Food

• Positive IgE to foods indicates that the child is allergic but does not always mean that there will be symptoms when the food is consumed – eliminate for at least 10-14 days, then challenge for 3 consecutive days.
• Parents are to watch for worsening of symptoms when the food is reintroduced, not improvements when the foods in avoided

25. Gluten and Casein tests

• No problem-free test is currently available for gluten/casein opioids. IgE of IgG Abs do not address this aspect of food intolerance- If possible, check for celiac disease – predisposes to GI cancers – BEFORE avoiding gluten: Celiac disease is diagnosed with IgA Abs. Must know if child is IgA deficient to interpret; IgA deficiency increases risk. Very small chance of this being present.

26. Allergy/Intolerance – IgG

• If gut is permeable so food leaks into the bloodstream, IgG to foods will be made since they are foreign proteins.
• Everyone has IgG Abs to a few foods; children with autism have them to lots of foods, indicative of increased intestinal permeability and a TH2 shift in the immune system.
• If the food is avoided, the levels will drop or disappear. Half-life of IgG is about 24 days.

27. IgG Food RAST

• Pinpoint suspect foods for elimination and challenge – if gut heals, likely food will be tolerated later. Don't assume food must be avoided forever.
• Probably best to wait until on gf/cf diet to get clearer picture. Once the inflammation from those foods has calmed down, gut may be less leaky and other foods less of a problem.

28. IgG Food RAST

• Remember foods can cause problems without antibodies being produced. Consider elimination/challenge with corn and soy.
• Individual food IgG tests available from all major laboratories; children who only eat a few things don't need to be tested against 100 foods.

29. T Lymphocytes

• T cells: CD4 (helpers) commanders
• TH1 – viral infections, fungal infections
• TH2 – Immunoglobulins, allergy

30. T Lymphocytes

• T cells: CD8 - Cytotoxic T cells, kill viruses and fungi with other cells: CIA CD16/56 – Natural killer cells, kill cells infected with virus: RAMBO (often low in activity/numbers in autism)

31. Cytokines: cellular messenger

• Th1 (viral, fungal, infection): IFN-gamma, IL-2, TNF. Helps T cells. Activates cytotoxic T cells, NK cells, macrophages – CELLULAR IMMUNITY
• Th2 (immunoglobuin, allergy): IL-4, IL-5, IL-10, IL-13. Helps B cells. Directs antibody production – HUMORAL.

32. Th1 and Th2 Balance

• Need both to work in balance; there should be feedback between them to maintain this. children with autism are often shifted towards Th2 (allergy) and away from Th1 (viral/fungal killing). This leaves them predisposed to viral and candidal infections and autoimmunity.

33. Th1 and Th2 – diagram on these two

34. Inflammation

• Repair mechanism in response to tissue damage (protective) or damage from allergy (destructive); acute or chronic.
• Chemical weapons – kill the target, but the surrounding area gets hit also.
• Phagocytes (jailors) release prostaglandins, kinins, leukotrienes; cause leakage from blood vessels, coagulation; neutrophils brought in to clean up.

35. Inflammatory Cytokines

• Dr. H. Jyonouchi, Univer. Of Minnesota, studied children with regressive autism and found extrememly increased levels of the inflammatory cytokine TNF-alpha.
• Other cytokines were highly variable but many differences from control children were demonstrated.
• Research tools only at this point.

36. Treatment – Inflammation

• Nonsteroidal anti-inflammatories: Ibuprofen, Naproxen, COX-2 inhibitors (Vioxx, Celebrex)
• Leukotriene blockers: Montelukast (Singulair), Zafirlukast (Accolate).
• Steroids: Prednisone.
• Specific cytokine blockers: anti-TNF, others being developed

37. MHC or HLA (self-recognition)

• Inherited markers of self; on outside of many cells so recognize "self" as OK.
• Military insignia – branch of armed service, division, battalion, company; mane tags at a reunion.
• Certain MHC types over represented in autism – related to autoimmunity?                              

38. Apoptosis

• Programmed cell death; cellular suicide – kamakazis
• Cells die without inflammation.
• Cell surface market called Fas or CD95. needed for cell to undergo this process.
• TNF-alpha or cytotoxic T cells give "suicide signal" to the targeted cells.

39. Immunopathology

• Immune deficiency/dysfunction: defective or ineffective response.
• Hypersensitivity: overactive response, out of proportion to potential damage.
• Autoimmunity: Inappropriate reaction towards self.
• Dysregulation in children with autism leads to all three problems.

40. Vaccine Titers

• Check IgG antibodies to rubeola (measles), mumps, and rubella so that a vaccine waiver can be written certifying adequate protection which is life-long once present.
• DO NOT BOOST THESE CHILDREN WITH MMR!!!

41. Vaccine Titers – High

• Vaccine titers are standardized for "protection" ONLY; how high is too high is essentially unknown. Normal post-vaccination titers are usually many many times above the protective level listed.
• Check IgG to tetanus, diptheria, hepatitis B surface antibody, H. flu, polio if evaluation immune function. Pertussis IgG antibodies not standardized; protective levels unknown.

42. Autoimmunity

• Loss of ability to tell self from non-self.
• Thought to be genetically susceptible individual plus environmental trigger.
• Molecular mimicry – foreign antigen so similar to "self" that body gets confused.
• Cell breaks open, spilling contents OR substance bind to something in or on the cell; in either case, body doesn't think it has seen this before and reacts as though it is completely foreign and must be destroyed.

43. Molecular mimicry

• [slide showing sequence similarities between microbial proteins and human host proteins – very technical, I didn't follow it, but shows there are similarities]

44. Autoimmunity

• Genetic predisposition/MHC marker important.
• Can be caused by T cells losing tolerance with cytokine dysregulation or by B cells making auto-antibodies.
• Can be localized to a single organ (anti-brain Abs, anti-thyroid Abs) or systemic with multiple different types of auto-antibodies.

45. Autoimmunity and Autism

• Family histories of autoimmune disease, expecially in mother (rheumatoid arthritis, lupus, IDDM)
• ANAs, IDDM, anti-thyroid antibodies sometimes present in children with autism – rarely looked for.

46. Autoimmunity and Autism

• Many kinds of anti-brain antibodies found: against MBP and against NAFP and GFAP
• [some journal references here]

47. Autoimmunity and Autism

• Many kinds of anti-brain antibodies found: against temporal lobe (IgG and IgM) and against serotonin receptors {two journal references here]

48. Autoantibodies

• Available through Specialty Labs 800-421-4449, www.specialtylabs.com: Anti-Myelin Basic Protein (MBP) Antuoantibodies (#1056), Anti-neurolfilament autoantibodies (#1052).
• V.K. Singh at Utah State does anti-MBP and anti-NAFP antibodies:
• singhvk@c...;435-797-7193. Also will measure anti-serotonin Abs and anti-measles Abs. Research only so not covered by insurance.

49. Autoimmunity and Autism

• Simon Murch MD: IgG antoantibodies in the small intestine with crypt cell proliferation; colon with CD8 T cell infiltration [reference here] -MHC types predisposing to autoimmunity over represented but genetics complicated [reference here]

50. Immunity/Autoimmunity: ASD Tendency towards:

• Increased Th2
• High IgE
• Low IgA
• IgE and IgG to foods
• Leaky, permeable gut

51. Immunity/Autoimmunity: ASD

• Th1 low with impaired ability to control viruses and yeast
• Decreased NK (natural killer) cell activity
• Autoantibodies with production of multiple kinds of anti-brain antibodies (and others?)
• Altered CD95-mediated apoptosis?

52. Immunity/Autoimmunity: ASD

• Inactivated DPP IV, causing opioids (?)
• Zinc deficiency
• Genetic predisposition
• Responds to IVIG
• Immune Dysregulation and Autoimmunity are hallmarks

53. Immunity/Autoimmunity: Hg

Mercury – Immune dysregulation and Autoimmunity are hallmarks;

• Th2 predominance with high IgE
• Alters immune response to foods; IgE and IgG Abs made
• Increases gut permeability, damages intestinal mucosa

54. Immunity/Autoimmunity: Hg

• Th1 low with impaired ability to control viruses and yeast
• Decreases NK cell activity
• Induces autoantibodies with production of multiple kinds of anti-brain antibodies and others [reference here] -alters CD95-mediated apoptosis

55. Immunity/Autoimmunity: Hg

• May inactivate DPP IV, causing opioids
• causes zinc deficiency
• depends on complex genetics
• Responds to IVIG [reference here]

56. Mercury effects on CNS

• Impairs motor planning
• Decreases facial recognition
• Blurred vision, constricted visual fields
• Causes insomnia, irritability, tantrums, excitability, social withdrawal, anxiety, difficulty verbalizing, altered taste, sensory disturbances or mouth

57. Mercury effects on CNS

• Slows reaction time (physical and mental)
• Impairs short-tem memory
• Causes difficulty with concentration
• Alters EEG, especially temporal lobes
• depletes intracellular glutathione
• modifies muscarinic cholinergic receptors

58. Mercury effects on CNS

• Disrupts neuronal migration
• Interferes with microtubule formation, mimicking a mitochondrial disorder
• Affects hippocampus, cerebellum, other
• symptoms of neurotoxicity delayed –Most toxic to infants and males (doesn't this all sound familiar???)

59. Treatment – Autoimmunity

• Oral tolerance for anti-MBP: Sphingolin one capsule in the am on empty stomach Correct dosage not established. Mad cow risk: Ecological Formulas (1-800-888-4585).
• Oral steroids – daily or pulse dose weekly. Many side effects, although pulse dosing decreases them.

60. Treatment – Autoimmunity

• High (Immunomodulatory/autoimmune) dose IVIG: Bradstreeet/El-Dahr, presented at the International Symposium on Autism,  Arnhem, Netherlands, 12/99 and Irvine, CA 6/00: 1-1.5 gm/kg (max 2) every 4-6 wks effective in the majority of children with anti-MBP Abs in
• improving at least one DSMIV category. Used for severe children otherwise unresponsive with (+) brain Abs, immune dysfunction, seizures. Stop if no significant improvement after 3 treatments.
• Dr. Gupta currently using 800 mg/kg.

61. Treatment – GI issues

• For low IgA, chronic diarrhea or constipation, consider probiotics. Make sure casein free.
• Kirkman's acidophilus/mixed probiotics certified casein free (1-800-245-8282, www.kirkmanlabs.com)
• Culturelle aka Lactobacillus GG best studied in infectious or post-antibiotic diarrhea and food allergy (1-888-828-4242 for local availability, or 1-800-877-2447 Vitamin Research) [www.vrp.com]

62. Treatment – GI issues

• Colostrum – Kirkman's is the only one known to be as casein free as possible – others contain casein despite claims. [none are completely casein free – companies can "claim" anything] Use more than directed at first if tolerated. Oral human Immunoglobulin (Baygam) being studied. Survives in GI tract, contains antibodies to all common human pathogens. Transfer Factor

63. Treatment – Viral

• Consider trial of Valtrex for herpes virus. HHV-6 response to this not clear. Would not continue long term unless child responding.
• Oral IFN-alpha proposed as anti-measles agent. Studied in the Phillipines during measles outbreak, shortened course of symptoms. [reference here]
• 64. Future Directions
• If heavy metal toxicity/mercury is the root of the immunologic disturbances, this will need to be addressed before immunomodulatory therapies are efficacious in the long term.
• Controlled trials to pinpoint which subgroups will respond to various therapies are critical.

65. Immune mechanisms – diagram here – same slide as Slide 2.

66. Disclaimers

• These guidelines are my personal opinions and do not represent official recommendations or beliefs or Tulane University.
• I have no financial relationship with any companies or products discussed.

Woody McGinnis, MD - Physical Health in Autism and How to Improve It.

[This is the same presentation given in the Spring DAN Conference. The slides/visuals are at www.up-to-date.com/atlanta/McGinnis.htm. I checked and they are the same ones in conference book I have. The text from the conference book and basically what Dr. McGinnis said are below. Between the slides and the text, you get more information than what he actually had time to verbalize. Kd.]

This is dedicated to Irene (Vicky) Calquhoun (1920-2000)

[Her picture is on Slide 1 of Dr. McGinnis' talk] As true discoverer in the parental tradition, Vicky reported fatty acid deficiency in hyperactive children twenty years ago. Thousands of families report benefits from zinc, evening primrose oil, and food avoidance espoused by the Hyperactive Children's Support Group.

Gastrointestinal pathology, sub-optimal nutrient status, food intolerance, chronic infections and toxic accumulations typify children with autistic symptoms. Laboratory testing and clinical

observation complement empiric treatment of these physical problems, often with substantial improvement in behavior.

From the DAN perspective, autism and ADHD occur as a result of underlying physical problems. We recognize that these physical problems ware multiple and variable amount children. We find that many of the physical problems are identifiable within our current technology and that nutrition ins central to treatment and complimentary to other modalities.

Clinical treatment is years ahead of research science in this area. Published outcome studies exist for some of our treatments (Vitamin B6 and magnesium, gluten/casein-free diet), while other useful interventions are based primarily on outcome reports from parents and clinicians. Research science can help us measure these outcomes and elucidate mechanism, especially when multiple interventions are involved.

Current thinking about autism and ADHD necessarily converges on the gut. MOST children with autism HAVE SIGNIFICANT GUT DISEASE.

Gut Problems Seen in Autism

1. Inflammation of the entire alimentary canal is common in autism. Horvath found esophagitis and duodenitis in about seventy-percent of children with autism, and Wakefield found enterocolitis and lymphyonodular hyperphasia (LLNH) in about ninety-percent of the regressed autistic subgroup. Chronic inflammation implies ongoing oxidative stressing the gastrointestinal tissue.

Consistent with the physical pathology, functional gut problems abound. Low intestinal digestive enzyme activity in about sixty percent of autistics is reported, and this is understandable in the

contest of gut disease, since these enzymes are made in the intestinal brush border. A mlabasorbing, leaky, protein-losing autistic gu is documented in the literature, and IgG food intolerance and steatorrhea is found by clinicians in the majority of children with autism. Abdominal pain, chronic diarrhea, constipation or alternating diarrhea and constipation are common in autism, and well documented.

2. Suboptimal nutrient status, microbial overgrowth, food allergens, and toxins all cause inflammation of the gut. In promoting gut inflammations, these factors have additive, inter-related effects. Mercury and cadmium bind avidly to gut membrane and are notoriously caustic to gut mucosa. Mucosal degradation is accompanied by microbial overgrowth and production of microbial toxins. Increasing toxin accumulation can affect immune function, permeability, digestion and assimilation of nutrients, and further erode microbial balance.

3 Results of gut injury:

• Suboptimal nutrient status due to impaired digestion and assimilation.
• Excess circulating peptides due to impaired brush-border and paneth cell peptidase production.
• IgG food allergy due to increased intestinal permeability.
• Increased production of toxins cush as organic acids due to local immune disruption.
• Increased uptake of toxins due to increased permeability.

4. But mucosa is especially sensitive to oxidative stress via the production of superoxide and hydroxyl radicals, as demonstrable in dischemia/reperfusion studies showing stomach and intestinal ulceration under conditions of stress. Inflammation from microbial infection, food allergy, endogenous and exogenous toxins, and suboptimal nutrient status means less resistance to oxidative stress in the sensitive gut tissue. Gastrointestinal autoimmunity should not be overlooked as a possible contributor to chronic inflammation in the gut, especially in the contest of heavy metals, which are highly oxidative by nature.

Factors Which Aggravate Oxidative Stress in the Gut

1. Microbial overgrowth: protozoal, bacterial, fungal, viral and consider chlamydia and mycoplasma.

2. Low immune-boosting nutritional factors: especially Zn, B6,Vitamin A and GLA.

3. Compromised immune function with low IgA, C4b, NK- and T-cell activity, more infections and more antibiotics.

4. Inadequate anti-oxidant nutrients with low vitamin C, vitamin A, Zn, Se, and glutathione-supporting methionine, vitamin B6, Mg, and lipoic acid. Uric acid plays a key anti-oxidant role in the plasma, and low levels seen in autism may be a reflectin of exidizing stress. [glutathione, lipoic acid, glutathione-reductase, and superoxide dismutase levels would be of interest in autism).

5. Endogenous toxins: Organic acids (exmpale: arabinose from yeast or maldigestion forms pentosidine cross linkages to block B6, biotin and lipoic acid; tartaric from yeast blocks Krebs Cycle); Pyrroles (Mauve Factor) blocks p450, heme synthesis, extremely reactive.

6. Exogenous toxic load: Pica of contaminated soils and objects, toxicants in food and water, insecticides, PCB's organic solvents, food dyes, excitotoxic flavor-enhancers, and NSAIDs.

7. Floral-derangement: Antibiotic-altered flora eliminate less heavy metal in feces, concentrate greater metals in tissue; suckling detoxification is much weaker than weaned state, probably due to flora; lactobacilli induce IgA and may be key to detox capability. There is ample suggestion of significant derangement of the autistic flora, but no formal study.

Current Nutritional Data

Pilot Study: Nutritional Status of children with autism DAN Think-Tank 2000 Phoenix AZ

Most children with autism demonstrate:

- Poor B6-binding, with low or low-normal intracellular magnesium

• Low intracellular zinc
• Low serum Vitamin A
• Low biotic, B1, B3 and B5 function on microbiological assay
• Low urinary vitamin C
• Low RBCm membrane EPA (derivative omega-3)
• Low RBC membrane GLA and DGLA (derivative omega-6)
• Elevated RBC membrane archidonic acid (inflammatory)
• Low taurine

• Elevated casomorfine and gliadomorfine
• Elevated urinary yeast metabolites
• Elevated IgG to milk
• Floral imbalance

• Many children with autism demostrate:
• Low serum selenium (50%0)
• Low folate and B12 on microbiological assay
• Elevated RBC membrane trans fatty acids
• IgG to grains
• Elevated urinary bacterial metabolites (50%)
• Overly acidic stool

Warning reports low blood sulfate and high urinary sulfate loss (and proteinuria) in most children with autism. For a review of the published studies on the nutritional status of autistic and ADHD children refer to www.autism.com/mcginnis

Current Successful Gut-related Interventions

1. Gluten/Casein-free diets: Key peptidase is produced by the intestinal membrane.

2. Anti-viral agents and IV gamma globulin: May affect chronic intestinal infection.

3. Digestive Enzymes: Multiple choices, including special peptidase and prescription microencapsulated forms.

4. Floral Remediation: antifungal, antibacterial and regular probiotic are mainstay treatment.

5. Secretin: Produced by the small intestine, stimulates digestive enzymes, trophic and stimulates blood flow to the intestine, triggers digestive juices from the pancrease, increases immune levels in bile.

6. Cod liver oil: vitamin A supports gastrointestinal membranes and mucin production. EPA in cod liver oil is anti-inflammatory.

7. Bethanecol: Stimulates all-important acid production by the stomach, tightens astroesophageal sphincter to stop reflux espohagitis, stimulates digestive enzymes, trophy to pancrease, stomach, small and large bowel mucosa, stimulates definsins release by paneth cells for local immunity, promotes ordered peristalsis.

8. DMSA and Lipoic Acid: Remove heavy metals, which have particularly high affinity for intestine. Mercuric cation at nanomolar concentrations completely inhibits activation of B6 in the intestinal mucosa. Floral alterations may affect heavy metal recirculation and heavy metal levels in the lumen may affect floral composition.

9. Zinc: Last line of defense in protection of cell membrane sulfhydryls from oxidation; inhibits bacterial lipase; lessens intestinal permeability; increases intestinal PGE1 for immune function. Necessary for stomach acid production and vitamin A metabolism.

Strategy: Assure Generous Levels of the Key Nutrients

1. Vitamin B6: Pyridoxal-5-phosphate is activated form.

2. Magnesium: glycinate form most absorbable.

3. Zinc: Picolinate form most absorbable. Dose away from minerals and food which block absorption. Balance with manganese. Warts, stretch marks, flecks subside.

4. Calcium: Assure RDA of about one gram daily plus some require extra.

5. Selenium: Doses up to 200 mcg daily as anti-oxidant and to bind mercury.

6. Vitamin A: Cod liver oil for all behavioral children unless allergic to cod.

7. Vitamin C: Twice-daily dosing rationale; also helps regularize bowel movement.

8. Vitamin E: Important chain-breaking anti-oxidant.

9. Fish Oil: Quiet inflammation with EPA. High EPA/DHA preparations available.

10. Evening Primrose Oil: Good for the gut, growth and immunity. Particularly Important for Immunity: Zn, Vitamin A, GLA

Management of Nutrition and Gut

History and physical: Dry skin, hair, allergies, thirst, frequent infections and dyspraxia suggest fatty acids; nail flecks and lighter hair for low zinc; indirect gaze for vitamin A; rashes and

carbohydrate cravings for fungal overgrowths: abnormal stool consistency and frequency; response to food challenges

Laboratory: Select sensitive lab measurement for nutritional assessment, such as RBC (intracellular) mineral levels, RBC-membrane fatty acids, functional vitamin assay; for key nutrients, treat low-normal lab ranges and do follow-up studies to verify correction.

Newer testing modalities such as IgG food allergy blood testing and urinary organic acids are useful.

1. Routine chemistry profile, thyroid, complete blood count and urinalysis

2. Stool studies: culture and sensistivity, parasitology, steatocrit

3. Urinary organic acids

4. Urinary pyrroles: Elevation in twenty-five percent implies primary Zn and B6 need. Off Zn and B6 prior to collection

5. Urinary peptides: Or, empiric trial gluten/casein-free

6. IgG blood test for food allergies

7. RBC mineral levels

8. Sensitive vitamin assay

9. RBC membrane fatty acids

10. Amino acid levels: methionine, taurine, and glutamine very important

11. Heavy metals levels and MELISA for allergic reactivity to metals

Treatment Guidelines

1. Principle: If rationale exists for an intervention, continue it unless there is a reason to stop or change it. Nutrients, floral remediation, digestive enzymes and detoxification take time to work

and they work together.

2. Combination formulations can be beneficial.

3. Tailored nutritional programs: Include B6 (P5P) and magnesium, zinc, calcium, vitamin C, vitamin E, selenium, cod liver oil and fatty acids. Add one nutrient at a time, sometimes trying lower doses. In the allergy-prone child, start with fish-oil, then balance with evening primrose oil.

4. Assure anti-oxidant coverage before administering oils: Zinc and biotin co-factors for conversion of GLA from EPO.

5. Effective levels of anti-oxidant nutrients

6. Reduce over-all oxidative stress, which is additive.: Avoid exposure to classical allergens such as pets and pollens as associated with hay fever and asthma.

7. Floral remediation: anti-parasitics, nystatin and other anti-fungals and regular probiotics are key. Lactobaccillus GG especially effective for clostridia. Some stool overgrowths may require specific antibiotics; antibiotics generally should be avoided to promote healthy flora.

8. Address food intolerance: Avoid aggravating foods to halt IgG (and IgE) reactivity to food antigens which keeps the bowel inflamed. Gastrocrom, quercitin, EPA (fish oil), vitamins C and E all quiet inflammation.

9. Digestive enzymes with all meals and snacks.

10. Avoid NSAIDS (non-steroidal anti-inflammatory medication) to lessen leaky gut.

11. Glutamine as nutrient for the enterocyte.

12. Decrease toxic burden: Organic food free of insecticides, antibiotics, flavor enhancers, artificial sweeteners, colors, and preservatives. Purified water, clean home and school environments. Assure bowel regularity (fiber, magnesium citrate, vitamin C, bethanecol) to reduce toxins. The autistic child should eat regularly, several meals per day.

13.Detoxification with DMSA/lipoic acid: precede by nutritional and gut enhancement. Floral influence on metals retention may be significant. Fluctuations in dysbiosis may be related to changes in heavy metals levels.

14. Outcomes: children with autism respond to improved nutrient status and reduction of microbial overgrowths, aggravating food antigens, ingested toxins and gastrointestinal tissue and reduce inflammation.

Future Directions

Stool mercury levels, or differences in species of mercury in stool are of interest and stool mercury levels are relatively inexpensive. Mercury metabolism and sulfate reduction in the gut flora may be linked, maybe even via mucin degradation. Mercury metabolism in the gut may generate toxic sulfides. Antibiotic exposure may select mercury-resistant flora with detrimental mercury-metabolizing traits. Common mercury methylators include condida, staph, strep and E. coli. Mercury volatilizers may emerge after antibiotic exposure.

Small Bower Overgrowth (SBO), for which either stasis or LNH are risk factors, is diagnosed by hydrogen breath-test, which presents a practical challenge in children with autism. SBO may be diagnosable by other means in autism. Microbial action could produce toxic bile acids metabolites in the feces of children with autism. One known bile metabolite, lithocholic acid, is highly toxic in animals, has not been assayed in autism. Subgroups of children with autism should be evaluated for excess fecal d-lactate production.

About half of incinerator and fossil-fuel mercury fall-out is in salt form, for which gut ha very high binding affinity. This form of inorganic mercury as well as cadmium are concentrated in effluent

sludge, used to fertilize food crops. Intestinal biopsy may demonstrate higher mercury or cadmium levels in autism, particularly recent regressions.

There is strong logic for development of a good sequestrant to bind heavy metal in the gut of children with autism.

William Walsh - Pfeiffer Institute  Is a Not-for-Profit out-patient organization.

They treat patients who come with a diagnosis of behavior, ADD, autism – mainly deal with chemical imbalances. They deal a lot with methylation disorders. And Essential Fatty acids. These are very individualized treatments. The weapons they use are nutrients, amino acids, vitamins, minerals. Look for chemicals to form in the body. He said when traditional medical doctors, ask what the Pfieffer Institute is doing, he said the traditional doctors are looking for traditional meds. When Dr. Walsh gets to the part about vitamins, minerals, and nutrition, the medical doctors tend to tune out at that point.

Where do neurotransmitters come from? The brain is a chemical factory. The body creates all the chemicals. They know where in the brain these are produced. Nutrients are the raw materials…vitamins, minerals, amino acids. Getting the wrong ones to the brain in the wrong quantities can cause problems. They deal with balancing the brain chemistry. Takes various populations and studies their chemistry – have an extensive chemistry.

They have taken the data base of behavior disorders and they fall into 4 major chemical classification. 5 major types of depression for example.

Slide 1. Year 2001 discovery: Metallothionein (MT) Dysfunction in Autism

• Absence of Cu, Zn Regulation in Blood
• MT Proteins Responsible for Cu, Zn Regulation
• MT Dysfunction consistent with Classic Autism Symptoms

Notes: MT Dysfunction occurs in almost all autists. They looked through their database of patients that clearly were diagnosed with some form of autism and did not have another co-existing diagnosis.

The remaining 503 patients comprised the test population for this study.

Slide 2. Abnormal Metal-metabolism throughout the autism spectrum

•           Autistic Disorder (318)
•           PDD with Autistic Features (162)
•           Asperger's Disorder (23)

>The incidence and severity of metal imbalances were very similar across these autism phenotypes.

3. Test Population

The test subjects were selected from a pool of 705 patients previously diagnosed with an autistic-spectrum disorder. Using DSM-IV subjects with questionable diagnoses, and patents with co-morbidity for seizures, depression, schizophrenia, serious head injury, Tourette's Syndrome, . and birth anoxia were excluded (deprived of oxygen).

4. Abnormal Metal-metabolism Observed in Test Subjects

• extremely disordered levels of Cu and Zn, indicating absence of blood homeostasis for these metals in 428 subjects (85%),
• moderately disordered Cu/Zn levels despite ongoing zinc therapy in 41 subjects (8%)
• Severe pyrrole disorder in an additional 30 subjects (6%) indicating severe zinc depletion
• only 4 of the 503 autism-spectrum patients did not exhibit a serious metal-metabolism disorder.
• >These data strongly suggest a universal metallothionein protein dysfunction in autism-spectrum patients

5. showed a line graph showing that the Cu/Zn rations in autists were clearly higher than NT control group.

6. Experimental Results and Statistical Analysis

The mean Cu/Zn ration for autism spectrum patients was 1.63 and for controls 1.15. The controls were matched for age and gender. Notes: Extremely disordered levels of Cu and Zn, indicating absence of blood homeostasis for these metals in 428 subjects (85%)

7. graph showing the amount of excessive unbound CU in 100% of autistics (number of individuals in sample = 22). Notes: Moderately disordered Cu/Zn levels despite ongoing zinc

therapy in 41 subjects (8%) Sever pyrrole disorder in an additional 30 subjects (6%), indicating

severe zinc depletion, Only 4 of the 503 autism-spectrum patients did not exhibit a serious

metal-metabolism disorder. Found a lot of unbound copper in the plasma – this is usually managed by MT. The level of unbound copper was 4 times larger in the blood of autistics.

8. Primary Functions of Metallothionein

• Development of brain neurons
• Cell transciption
• Homeostatic control of Zn and Cu
• Detoxification of heavy metals
• Maturation of the GI tract
• Powerful antioxidant
• Immune Function
• Delivery of Zn to cells

Notes: When mercury binds to MT it leaves the body easily. It is a marvelous antioxidant in the body – when MT is down, the radicals are loose.

9. A recipe for Autism

• genetic impairment of MT functioning – not so much one defective gene, but one of several genetic causes that disables MT because many things must come together to get MT to function properly. Any one of those many things can cause problems.
• environmental insults(s) which disables MT

10. Possible Causes of MT Dysfunction

• genetic MT defect
• genetic disorder which disable MT
• environmental insult which disables MT

11. Genetic Impairment of MT Function

• Tenuous MT Support for Neuronal Development
• Hypersensitivity to mercury, lead, and cadmium
• hypersensitivity to infections and vaccines

12. Environmental Insults Disable MT

• Incomplete  Maturation of Brain and GI Tract
• Build Up of Toxic Metals - Hg Pd, Cd, etc.
• Cu overload & Zn Depletion
• Impaired Hippocampal Function
• Weakened Immune Function
• > Restoration of MT function may be blocked by excessive build-up of copper and toxic metals
• It does look like this MT dysfunction can be restored.

13. The MT Protein Family

• Mt-I and MT-II are present in all cells throughout the brain and periphery
• MT-III is a neuronal growth-inhibition factor found primarily in the brain
• MT-IV is found primarily in epithelia of skin and GI tract.

14. Human MT

• Family of cysteine-rich proteins
• Short linear arrays of sixty-one to sixty-eight amino acids
• S configuration with extraordinary metal-binding capability
• Induced by Zn, Cu, toxic metals, physical trauma, and emotional stress

15. Expected Consequences of MT Dysfunction

(list of what you would expect to see with MT dysfunction)

• Hypersensitivity to HG, PB, and other toxic metals
• Zn depletion and Cu overload
• Hypersensitivity to vaccines
• Incomplete breakdown of casein and gluten
• Intestinal inflammation, diarrhea, and yeast overgrowth
• Reduced stomach acid and diminished secretin release
• Tendency for seizures, anxiety, and emotional meltdowns
• MT kills candida (so overgrowth is common when MT is stopped)
• Higher vulnerability for males than females (because hormones factor into this somehow and boys have more of one type than girls)

16. Detoxification of Toxic Metals

• Mt is the body's primary protection against toxic metals: MT is a "magnet" for mercury, lead, cadmium, etc.
• Intestinal MT provides a barrier to absorption of ingested toxic metals
• MT in periphery and brain sequesters and deactivates toxic metals. Notes: 95% of mercury is grabbed by MT right off and MT grabs other remaining metals at blood-brain barrier

17. MT Dysfunction causes Cu/Zn Imbalance

• Tendency for rages and emotional meltdowns
• ADHD is associated with Cu/Zn imbalances
• Impaired hippocampus and amygdala functioning which causes emotional memory and socialization deficits. Amygdala – when not functioning, they will not initiate social approach, ritualistic behavior, hard time interpreting facial expressions.
• Dopamine/norepinephrine imbalance – Cu is involved in this conversion
• > Normalizing Cu and Zn levels in blood is an important component of autism therapy. One nice thing is we can normalize the amounts of copper/zinc

18. MT and Immune Functions

• Deletion of MT compromises in-utero development of thymic and lymphoid tissue
• MT depletion reduces production of T cells, IL-2, thymulin, NK cells, etc.
• MT knockout mice exhibit severely weakened immunity – when MT is taken out of mice they have extraordinary weakened immunity

19. MT Impact on Casein and Gluten

• Casein/gluten peptides are broken down by Zinc dependent enzymes (carboxypeptidase A, aminopeptidase, etc ); MT dysfunction is associated with sever zinc depletion and reduced production of these enzymes.  Diminished MT in GI tract results in increased levels of unbound
• mercury, lead, cadmium, etc. which can disable enzymes that break down casein and gluten.
• >Correction of MT disorder may eliminate need for a casein/gluten free diet.

20. Role of MT 1 and MT 2 in intestinal mucosa

• Barrier to penetration of Hg, Pb, and Cd into the blood stream
• Regulation of copper absorption
• Combats inflammation
• Kills candida. – MT helps prevent yeast overgrowth
• >Normalization of MT may eliminate tendency for intestinal inflammation, leaky gut, and yeast overgrowth in autism.

21. Impact of  MT-IV Dysfunction

• Reduced production of stomach acid
• --incomplete food processing in stomach
• --Impaired secretin signaling
• --reduced amounts of gastrin, carbonate, etc.
• Sensitivity to taste and food texture
• Skin sensitivity

22. MT dysfunction and seizures

• MT knockout mice exhibit high incidence of seizure
• Zn released by hippocampal MT-1 decreases seizure activity

23. Explanation of higher autism incidence in males

• MT synthesis is enhanced by estrogen and progesterone, especially during early development.
• Females have higher estrogen and progesterone level than males
• Therefore, females are better protected against environmental insults which can trigger autism

24. Genetic Aspects of autism

• Strong genetic predisposition in autism
• --Higher concordance in siblings
• --60% concordance in identical twins
• Influence of Environmental Factors
• --Identical twin concordance not 100%
• --Dramatic differences in identical twins
• >This suggests that the cause of autism is a genetic predisposition followed by an environmental insult during early development.

25. Metallothionein Theory of Autism

• Genetic MT dysfunction results in hypersensitivity to toxic metals and viruses.
• Environmental insults during early development provoke autism: In utero insults results in autism at birth; early childhood insults provoke regressive autism.
• >After age 3, the brain and GI tract have matured to the point that environmental insults can no longer provoke autism.

26. The Onset of Autism

• Genetic weakness in MT system – not a defect, a weakness
• Environmental Insult disables MT
• --Toxic Metal Poisoning
• --Viral Assault
• --Zinc Depletion
• Temporary Disruption of Neuronal Development : Brain, GI tract

27. Timing of Environmental insults in important

In-utero  - autism evident at birth, greater severity of symptoms, mental retardation often present

After Birth – Regressive autism, symptoms depend on developmental stage during insult

>After age 3, the brain and GI tract have matured to the point that environmental insults can no longer provoke autism.

28. Severity of these insults in important – when in the developmental development did this happen. - Example: MT disruption during development of speech center

Mild insult – speech delay       Severe Insult – Autism

29. There is a biochemical aftermath and a physical aftermath. The Biochemical Aftermath

• Disabled MT system
• Copper overload
• Toxic metal overload
• Zinc depletion
• Neuro-transmitter imbalances

***Each of these biochemical conditions may be correctable

30. Physical Aftermath

• Incomplete maturation of brain
• High incidence of GI tract problems
• Compromised immune function
• Disruption of hippocampus/amygdala functioning
• ***Each of these conditions may be treatable

He sensory integration therapy showers the impulses trying to develop new brain cells and develop neural connections. It can be very effective, but often slow. They would like to find a way to speed this process up.

31. Autism Prevention Steps

•           Prenatal Avoidance of environmental Insults: Toxic metals, Vaccines, Medications, Dental procedures involving amalgams
•           -Early infant screening for Autism predispositions: Genetic screening, MT protein testing, Testing of Cu, Zn, ceuloplasmin
•           Avoidance of Environmental Insults in Autism-Prone children – amalgams, fish, Flu shots during pregnancy
• >They are trying to get some commercial tests so screening can be done.

32. Biochemistry of Metalothionein

• Induction of thionein
• Proloading with zinc assisted by Glutathione SH (need 7 zincs/MT)
• GSH/GSSH redox couple enables Zn delivery and /or sequestering of toxic metals
• MT activity enhanced by Zn, GSH, Se, Genistein, Biochanin, Vitamins,A, C and E.

33. A Lesson From Wilson's Disease

• Wilson's disease is copper overload disease which disables MT
• Two-phase treatment is effective

Step 1: removal of excess Cu

Step 2: long-term maintenance using Zn therapy – in Autism need to remove all metals.

>Autism therapy requires removal of Cu and toxic metals

34. Autism Treatment Protocol

• GI tract therapies: Clean up the gut first – GFCF diet, probiotics, secretin, digestive enzymes, dysbiosis treatment, etc.
• Biochemistry Balancing: Methylation, trace metals, pyrroles, essential fatty acids, etc.
• 15% are over methylated –need folic acid, 45% are undermethylate – need eSam?
• Removal of Toxic Metals & Excess Copper
• MT promotion Supplements.

35. MT promotion therapy

Step 1: Removal of excess copper and toxic metals

• give nutrients which promote MT function
• use clathrating agents –  binds copper and nothing else
• Tetrathiolmolydate
• Chelation agents ?

Step 2: Long-term maintenance

• MT promotion formulation (Zinc plus others)
• Minimization of toxic exposures

36. MT Promotion Agents

Primary: Zn, Glutathione, Nacetyl Cysteine, Selenium Secondary: P-5-P, Vitamins A, C, D, E, Genistein, Biochanin A, Glucocorticoids

> the Pfieffer Treatment Center is developing & testing supplement combinations and dosages aimed at maximum MT promotion. Notes: They are going to do studies to determine best protocol.

37. Potential Benefits of MT Promtion therapy

• Reduced tendency for intestinal inflammation, leaky gut, yeast overgrowth, and casein/gluten sensitivity
• Improved hippocampus and amygdala function which may enhance behavior control and learning
• Improved ability to develop new brain cells and neuronal connections
• Protection against future toxic-metal exposures

38. Conclusions

• MT dysfunction may be primary cause of autism
• Autism prevention may be possible by improved prenatal care & early-infant screening for MT dysfunction
• MT promotion therapy is highly promising for autism-spectrum patients

Q&A

Question from parent about birth control pills.

Answer: Copper overload moms are intolerant to estrogen – no birth control pills.

MT can hold 13 coppers or 7 Zincs

Question: Does use of copper plumbing hurt? What about other environmental damage?

Answer: Bottled water for all autistic patients. In swimming pools – don't use copper sulfate for algae cleaning, there are other things to use.

Question: How long does correction take?

Answer: Takes 60-90 days to correct copper/zinc balance in AD/HD and this may be longer or more involved in autism. Can get bad reaction in the beginning because the copper is released too fast. Zinc citrate is great. Bioavailable forms – zinc picolinate is good for bad guts, or zinc sulfate. Zinc acetate is good. To determine the Cu/Zn you need to do the plasma cerolum (?) Methylation disorders are easy to diagnose in adults without autism – 75% of undermethylated have seasonal allergies, overmethylated have high food sensitivities. Hard to diagnose for autists because they don't verbalize well.

Question: What is a clatherating agent?

Answer: Clatherating agent is something that sort of swallows an atom – not something that binds, but catches the atom in the lattice. Example: Copper in tetrathiomolybdate

Further information on this research is at the web site: http://www.hriptc.org/main_research.html

Protocol for Autism Spectrum: www.hriptc.org/autism_protocol.htm

The Role of Secretin in Autism

Slide 1: Repligen's Goal:

To develop safe and effective drugs for debilitating pediatric disorders through modern biotechnology

• Secretin for Autism
• Uridine for mitochondrial disease
• CTLA4 for metabolic & immune disorders

Notes: Best interval 3 weeks. No predictive markers success (sorry no way to tell who is a good

candidate for secretin). Stool calprotectin and chymotrypsis levels are not predictive markers, but the research supports the "clean the gut" prerequisite. Secretin is a neuro-transmitter with direct effects on the brain.

Slide 2. Approaches to Autism Therapy

A. Treat the Causes of Autism

• Gene therapy
• Stem cell therapy

B. Treat the Symptoms of Autism:

• Social: modulate levels of neurotransmitters
• Behavior: hyperactivity, aggression
• Other: nutrition, GI, sleep, immune system

Notes: A theory from Bill Walsh Evidence: copper/Zinc ratios are off

Hypothesis: Disorder involving the function of MT

Critiques: Copper is an "acute phase reactant" i.e. levels change in response to metabolic changes such as inflammation or hormone treatment – both of which raise copper levels.

When your inflammation rises your iron level falls and copper level rises

A theory from Paul Shattock

Epidemiology: Epidemic based on good data

Genetics: Load the gun, environment pulls the trigger.

Triggers: infections, vaccines, pesticides, dietary changes, dysbiosis, heav metals, pansticizyer (?), additives to food

Beta-endophin effects map against autistic behavior

Hypothesis: peptide mimicry of neurotransmitter, peptides result from imperfect digestion.

A theory of Sulfation: touches on effects of mercury, detoxification, integrity of gut, function of certain hormones.

A theory from IAG a compound found in Gulf war Syndrome and Autism Immunizations: Regressive subset, Friendly, thirsty, flat footed,

3. Autism has Diverse Presentation

• Variable symptoms, IQ
• Multiple brain regions identified
• Seizures in 30%
• Blood serotonin elevated in 35%
• GI symptoms in 40-50%

Diverse Biology = Multiple Approaches

Notes: Talked that there were several theories on the cause of Autism, the treatment of autism, but the "autistic" population is so diverse, that multiple approaches may be used and are helpful.

4. Reasonable Expectations [of any treatment/drug]

• Meaningful improvement in at least one of the major symptoms of autism
• Works in at least 10% of patients: 10% ASD = more patients than CF or leukemia
• Toxicity has been evaluated in ASD patients and pediatric animals No drug meets "reasonable expectations" yet

5. Phase 2 Clinical Trial of Secretin - [text slide]

6. Secretin

• Natural hormone: stimulates the pancreas
• Porcine secretin approved as a diagnostic
• Activity in autism detected in 1996 following a GI exam of an autistic child
• -diarrhea resolved
• -imitation of simple words
• -improved task focus

7. Secretin – anecdotal Observations

Secretin used "off label" in > 2,000 children with autism. Some parents & doctors reported:

• eye contact, social interaction
• some language gains
• physiological changes: diet, GI, sleep
• effect lasts 3-5 weeks
• few side-effects: hyperactivity?

Notes: off-label means it is being used for some other purpose than what is stated on the label. Hyperactivity was seen the most, but whether this was interpreted to be positive or negative was debatable.

8. FDA Clinical Trial Process

• Phase 1 – Establish safety: 10-30 patients, single dose
• Phase 2 – Establish dosing and endpoints: 50-200 patients, multiple doses, dose levels
• Phase 3 – Statistical proof of efficacy: 100-2,000 patients, full dosing regimen

Only one Phase 2 completed in autism. Notes: These are the phases of the FDA clinical trial procedure. Only one Phase 2 has been done in autism.

9. Phase 2 Clinical Trial Questions - 1

Is there a subset of patients who can be defined by symptoms or biochemical markers?

[text slide only]

10. Secretin Phase 2 Clinical Trial Inclusion Criteria

• age of 3.0-6.9 years
• gastrointestinal symptoms
• moderate to severe autims
• no functional language

Notes: He did not specify the same GI symptoms for all the children in the trial, just that they had some known GI problem

11. Phase 2 Clinical Trial Questions - 2

What is the best way to measure changes in social interactions, speech and behavior?

[text slide]

12. Showed a slide with a before and after picture of a boy. The first shot was the boy looking "blankly" out into space, the second was the same boy later actively looking and smiling at the camera. How do we measure "connectedness"? He talked about this aspect being hard to quantify and measure.

13. Measurement of Symptom Changes

• global assessment vs. specific symptoms
• parent vs clinician as an information source
• social vs behavior vs communication
• how to avoid a large placebo effect?

Notes: He talked about how to set up criteria for evaluating and rating changes in symptoms. Was the parent more accurate than the clinician? Should we go for social or behavioral or communication more? How are these things to be measured and compared?

14. Comparison of Assessment Tools

• Childhood Autism Rating Scale (CARS)
• Gilliam Autism Rating Scale (GARS)
• Autism Diagnostic Observation Schedule (ADOS)
• Clinical Global Impression of Change: Parent (CGI-P) versus Rater (CGI-R)
• MacArthur Communication Development Inventory

Notes: These are some of the assessment tools already used. They were trying to determine which if not all would be best in determining results.

15. Secretin Phase 2 Clinical Trial

• Double-blind, placebo-controlled
• 126 patients evaluated at 5 US centers
• 3 doses of secretin or placebo at 3 week intervals
• 66 patients received secretin, 60 patients received placebo

16. Autism Diagnostic Tools

• Childhood Autism Rating Scale (CARS): psychologist rates 14 symptoms on severity compared to a NT child; there is low test retest stability = random results.
• Gilliam Autism Rating Scale (GARS): Parent checklist rates severity of 56 symptoms; two administrations prior to dosing = highly variable results particularly in social domain

17. Statistics

• "Statistically significant" means there is a 95% probability that the difference between drug (or treatment) and placebo is due to activity of the drug and not random variation in symptoms
• p = .10 means 90% confidence the difference is due to the treatment, called a trend
• p = .05 means 95% confidence the difference is due to the treatment, called significant
• p = .01 means 99% confidence the difference is due to the treatment
• Statistical confidence is proportional to size of treatment effect AND number of patients
• (that is, the larger the sample size the more accurate this "confidence" will be)

18. Evaluation of Symptoms – 1 Clinical Global Impression of Change

• Independent evaluations by Rater & Parent (they used this rating scale)
• 1 = vary much improved
• 2 = much improved
• 3 = minimal improvement
• 4 = no change
• 5 = minimal worsening
• 6 = much worse
• 7 = very much worse

- FDA required assessment for depression, Alzheimer's, schizophrenia, OCD (this assessment scale is common and was used for the conditions listed)

19-23. Clinical Global Impression All 126 Patients

Notes: He showed a series of slides with bar charts showing that the parents rating was much more accurate that the expert raters (professionals representing doctors in this area). He said often it is said that parents are hopeful for their children and this skews their observations and reports, but that parents would be hopeful whether their child received the secretin or the placebo. They found that the observed changes in the children by the parents were far

more accurate than the observed changes in the children than the raters. Most probably because the parents know their children's behavior and are around them all day whereas the professional would only be seeing the child for minutes at a time. From this they learned that the parents were a very reliable source of information and would provide the most accurate ratings to be used in official clinical trials. He made a HUGE point about this.

P = 0.22 for the raters

P = 0.02 for the parents

24. Evaluation of Symptoms – 2

Autism Diagnostic Observation Schedule

• this is the "gold standard" diagnosis of autism
• evaluates social and communicative skills in a series of structured activities
• there are four modules which are adjusted for child's skill level

25. ADOS-Social Changes

[showed a chart with little dots on it I didn't understand. Sorry. The point was to show that some of the patients responded positively to secretin with a confidence rate of p = 0.12 for these results]

26. Language Assessment

slide showing a book saying User's Guide and Technical Manual on the cover. This is used to evaluate language.

27. Evaluation of Symptoms – 3

The MacArthur Communicative Development Inventory measures

• words & gestures module: designed to assess emergent language, typical of 8-16 months
• vocabulary inventory of 396 words
• determines words understood and words used

28. MacArthur Language Inventory

Notes: showed bar graph. Using this measure, the number of new words used by the children in the trial with secretin increased: expressive language with a confidence of p = 0.16 and receptive language with a confidence of p = 0.15

29. Evaluation of Symptoms – 4 GI Symptom Score

Notes: graph showing some decrease in GI symptoms for both the placebo and secretin, with no numeric values or labels. Not sure what it represented except they did make an effort to quantify and measure all these things.

30. Secretin Phase 2 Clinical Trial – Subset analysis

• improvement not correlated with GI symptom severity at baseline (shown in previous slide)
• improvements not confined to patients with diarrhea
• improvements not correlated with age Notes: they tried to break out subsets of children based on particular criteria to see if there was a pattern, and did not find any on the GI symptoms

31. Secretin Phase 2 Clinical Trial – Biological analysis

• chymotrypsis in stool: pancreatic enzyme released by secretin; this is a marker of "pancreatic insufficiency"
• Calprotectin in stool: neutrophil anti-microbial protein; this is a marker of intestinal inflammation, "colitis"

32. Secretin Phase 2 Clinical Trial – Biological analysis

• Chymotrypsis: 29% of patients had low levels
• Calprotectin: 26% of patients had elevated levels
• 64 patients with normal levels of both proteins

Patients with abnormal levels had highly variable symptoms

Notes: They tried to find particular markers to better determine who would be a better candidate for success with secretin – looking for patterns – but did not find goods ones here

33-35. showed 3 slides with charts on Clinical Global Impressions among those patients with Normal Calpro and Chymo.

36. Symptom Assessment Summary of All patients vs the Normal Calpro/chymo Patients

This showed when all the patients were rated with statistical confidence,:

• the parents came in at 98%,
• the raters were 78%,
• the ADOS Social test was 88%
• MCDI was 85%
• When the Normal Calprotectin, Chymotrypsis patients were evaluated:
• The parents came in at 99.9%
• the raters were 98%,
• the ADOS Social test was 99%
• MCDI was 98%

This showed that the parents were consistently accurate, but the other methods was only accurate with a certain subgroup of the patients.

37. Responder analysis: Normal Chymo/Calpro

slide showing data, don't remember what it was supposed to show

38. Secretin Safety.

39. Secretin Safety Phase 2 Extension Study

• All 124 patients have the option to receive 6 additional doses of secretin at 3 week intervals
• Continued surveillance for adverse events, blood chemistries, antibody formation
• retest patients with ADOS

40. Secretin Phase 2 Summary

(these are the things they accomplished with this first clinical study

• Identified biomarkers for patient selection
• Identified behavioral assessment tools which capture secretin effect
• established statistically significant drug effect on social and communicative symptoms
• established safety profile consistent with chronic dosing

41. Phase 1 Trials of Secretin

(these are the things they needed to look at with the next clinical study)

• small number of subjects
• single dose protocol
• diverse patient population: level of function, IQ, age, diagnosis, other symptoms (GI, seizures)
• Inadequate assessment tools: designed for diagnosis, not stable for test-retest, insensitive to change
• calculation and design efforts, bias (need to account for these)

42. Phase 1: Thoms Rehabilitation Hospital (this is the second study)

28 secretin and 29 placebo patients; 33% PDD

• age 3-14 years
• all function levels; ?% with GI symptoms
• one dose: evaluations at days 0, 1, 7, 14, 28
• autism behavior checklist

All patients substantially improved on day 1. There was no difference between secretin and placebo.

43. NIH Autism Coordinating Committee

Psychopharmacology Working Group

• The appropriate length of a trial will vary depending on the target and goals of the treatment, but generally should be longer than the few weeks or months usually reported in the literature.
• Studies should use narrower age ranges or stratify on age to prevent the clouding of results by developmental differences. www.nimh.nih.gov/research/autismworkshop.cfm

44. Language Assessment

showed covers of two manuals for evaluating language. The MCDI is for 8-16 months,

The PLS is for 0-7 years

45. Meta-analysis of Phase 1 trials

text slide: "There are significantly more "responders" in the secretin groups than in the placebo groups.

46. Next Step: Phase 3 Clinical Trials (this is what is being planned)

• up to 200 patients at 10-12 sites
• GI positive and GI negative patients
• longer dosing period
• additional bioprofiling
• 10-12 clinical sites

47.  Neurobiology of Secretin [text slide]

48. Effect of Secretin on Body Temperature

Two diagrams showing that body temperature increased after a first and second dose of secretin to just under 99 degrees and stayed elevated over time.

49. Brain Activation in Rats

showed a slide of a rats brain were the site in the brain activated by secretin is located. There is a definite region to look at.

50. Secretin Stimulates the Vagus Nerve

When secretin is added, it stimulates this nerve which sends a signal to the brain, which activates this particular region in the brain which sends response signals to the gut. (I think I got that right.)

51. Brain Anatomy

showed slide labeling the parts of the brain

52. Secretin Activates the Amygdala in Rates

showed slide with 8 photos or rat brain where the region was activated and where it wasn't

53. Function of the Amygdala region in the brain

• face recognition
• emotion
• fear, anxiety, stress response
• control of autonomic nervous system: body temperature, digestion and GI function, sensory input (taste, pressure), cardiac and pulmonary function

54. Does Secretin Act Directly on the Brain?

• secretin receptors in the brain
• secretin crosses the BBB in mice
• secretin activates the brain in rats

55. GI Symptoms in Autims:

Gut-Brain or Brain –Gut? Genetics/Environmental Insult leads to neural dysfunction which leads

to either autism or GI symptoms.  Notes: He said the question is does the gut activity affect the brain, or does the brain activity affect the gut (primarily)

56. diagnostic Secretin Products

• porcine secretin approved for in vivo diagnosis of pancreatic disease, Ferring withdrew product in 1998
• Repligen licensed synthetic products: Porcine – approvable letter November 2000, Human – NDA submitted Q2 2001
• FDA requested more QC data (quality control data)

57. BioProfiling in Autism [text slide]

58. BioProfiling: Systematic assessment of biomarkers (they can look at these potential markers)

• genetics: HOX A1, reelin
• Proteins: immune – interleukins, TNF, ACTH; endocrine – oxytocin, GH
• Metabolites: > 200 amino acid, metals, purines, neuroltransmitters, etc.

59. Why Do BioProfiling?

- It is a research tool to identify subsets of patients with similar disease characteristics

• gives laboratory confirmation of clinical observations
• may suggest new interventions
• may provide evidence of treatment effects

60. Secretin Phase 2 Clinical Trial: 1,250 Biological Samples

Collected from Highly Characterized Patients.  Notes: They are going to collect blood, urine, and stool samples are regular intervals during the patients' treatment with secreting to assist in bioprofiling.

61. BioProfiling in Autism: Initial Results from the Phase 2 Patients

• Urine: Opioid Peptides, Uric acid, 7-methyl Xanthine
• Blood: Cytokines, Zinc
• Stool: Calprotectin, chymotrypsin

62. Opioid Peptides in Urine

• these are small peptides derived from casein (dairy) or gluten (wheat) having opioid activity
• Hypothesis: incomplete digestion leads to opioids in gut; peptides cross gut into blood and urine; peptides cross the blood-brain-barrier

63. Opioid Peptides in Urine

• analyzed for three casomorphins and gliadomorphin by HPLC-MS
• No opioid peptides detected (<10ng/ml) in pre-treatment samples from 120 patients
• previously used HPLC-UV methods may identify "false positives"
• food intolerances may have immune or metabolic basis

64. Uric Acid (Urate)

• urate is the end product of purine metabolism which is excreted into the urine
• urine levels elevated in diseases of purine metabolism (Lesch-Nyhan)
• urate was reported to be elevated in 20% of ASD urine by Mary Coleman in 1976
• several patients treated with uridine

65. Uric Acid in Phase 2 Samples

showed a bar graph  - not sure what the point was

66. "Purine Autism"

text slide saying: Does elevated urate define a set of patients with a common biological defect? If so, can uridine therapy improve symptoms?

67-68. [This next series of slides was presented as one text slide and one bar chart showing the text] Immune Cytokines in Serum

• IFN-gamma, TNF-a, IL-2, IL-4, IL-5, IL-9, IL-10
• measured before and 4 weeks after dosing 17 out of 126 patients with elevated IFN-g 5 out of 126 patients with less than 3 elevated cytokines no relationship to symptoms, GI, age no effect of secretin on cytokine levels

69-70. Zinc

• early patients had low serum zinc levels
• zinc deficiency can lead to diarrhea
• reasonable to consider a role of the pancrease in zinc absorption  form food
• many biological processes are zinc dependent

71-73. Calprotectin

• anti-microbial protein release by neutrophils (a type of white blood cell)
• not degraded in the gut; detected in stool
• used to monitor gut inflammation in Crohn's disease, ulcerative colitis, etc.
• first used in ASD by Wakefield, et al
• 26% of Phase 2 patients showed abnormally high calprotectin at baseline: > 75 ug/gm

74-75. Chymotrypsin

• enzymes released by pancreas in response to secretin/CCK as food enters the intestine
• measured in stool as a marker for "pancreatic insufficiency"
• 29% of patients showed low chymotrypsis at baseline: <8 units/gm

76-79. Pancreatic Insufficiency in autism?

• low chymotrypsis is an indicator of pancreatic insufficiency BUT
• All 36 patients with low chymotrypsin had normal levels of SIRT (serum immunoreactive trypsinogen)
• 20 patients with low chymotrypsin has normal levels of elastase Low chymotrypsin may be a result of degradation due to increased transit time or altered gut flora

80. BioProfiling Summary

• opioid peptides – none detected
• uric acid – 25% have elevated uric acid7-methyl Xanthine – 40% have no 7-MX in urine
• Cytokines – 5% have elevated cytokines Zinc – no abnormal values Calprotectin – 26% have elevated values Chymotrypsin – 29% have depressed levels Calpro & Chymo unrelated to GI severity or diet

81. Acknowledgements

[lots of references]

82. www.repligen.com

Notes on Supplements:

This is general commentary I derived from the talks. People have mentioned hyperactivity as a negative sometimes when they start ezymes. This is also characteristic of beginning the GFCF diet. Several presenters mentioned this when starting any of several supplements. Glutamine was mentioned as being quite good for gut healing. However, if you see the hyper/negative behavior, then stop immediately. Go back to focusing on general nutrition and more gut healing first with a nutritious diet, probiotics and enzymes. Then later resume the glutamine.

Dr. Walsh said the same when trying to add zinc to balance the excessive copper. If a person reacts badly to the zinc, back off on the dose and go slower. This indicates the copper is being dumped into the body too quickly and the body cannot detox fast enough.

We see the same with epsom salts. Sometimes the child will react  badly to a epsom salt bath, so lower the amount of salts and continue and the child will improve.

Dr. Baker said it also happens commonly with yeast treatments. The child may become hysterical while "on" the treatment but this is the yeast die-off/toxin reactions. He said one client went through three rounds of outlandish bad behavior. They also saw this accompanied by

improvements so they continued. Eventually the yeast was in balance and the child showed remarkable improvement.

Dr. Holmes said the same with chelation. Look for negative behavior with the "on" cycles. If the negative behavior continues through to the "off" cycles, then you have a bug problem and need to stop chelation and deal with that first. If is it just during the "on cycles, it indicates detox of metals.

So this seems to be a very common part of the healing process. I just wanted to throw this out because it is always worrisome to see someone going through a bad time. It seems to be a tricky issue when starting a therapy of evaluating if it is a true intolerance and should be stopped, or withdrawal/die-off/detox and should be continued? The general consensus seems to be 1) back off and go slower if possible, or 2) let the bad stuff run a few days and see if the negative behavior improves after time. After a few days, stop and re-evaluate.

Dr. Amy Holmes – Chelation / Treatments for Metal Toxicity

(former oncologist – mom of autistic child) [Dr. Holmes had one talk during the parents session and one during the general session which were similar. The slides in the general session were the same as the previous one. I have combined the information from both below, plus a little further explanation from her site because it explains parts better than I could. Karen.

Slide 1. Heavy Metal Toxicity is AS – Mercury Toxicity

Slide 2. Nationwide Statistics (US)

• School Year 97-98 vs. 98-99
• Children ages 6 – 21
• Category                               Percent Increase
• All disabilities                       2.6%          
• Specific learning disabilities         2.3%   
• Speech impairments                     1.0%  
• Severe emotional disturbance           1.9%              
• AUTISM                                 26%        

Slide 3. Current Autism Incidence Rate

• 1 in 250 kids have AS
• 1 out of 150 boys AS

Slide 4. Better Diagnosis? Probably not Notes: Is this increase due to better diagnostic tools or doctors diagnosing autism better? Very doubtful. The is a behavioral diagnosis, and the definition has not changed. It is not very believable that doctors were so incompetent until 10-12 years ago

that they could not diagnose very well and then all of a sudden they became much more capable.

Slide 5. Causes of the Autism Epidemic – (can't refute the fact that it is an epidemic)

• genetics plus
• environmental factors

Slide 6. Autism: A Novel Form of Mercury Poisoning.  Authors: Bernard, Enayati, Binstock, Roger, Redwood Medical Hypothesis 2001          Available on ARI Website: www.autism.com/ari

Notes: the current paper on this is located at the above url. The symptoms are very similar.    

Slide 7. Autism = Mercury Poisoning (at least in many cases)

Slides 8-10. Sources of Mercury Exposure

• Water - ionized (Hg++), poorly absorbed
• Fish/seafood - methylmercury
• Dental amalgams - vapor (Hg-0m mercury)            
• Contact lens solution - thimerosal*
• RhoGam injections - Rh-negative moms
• Some childhood vaccines – thimerol: only some vaccines contain this, not all Vaccines that contain mercury now are the DPT, Hib routine use since late 1980s The Hep B has been mandatory in infants since 1991 – why this is, cannot understand. Unless mom has had hep B there is not way the fetus can get it until he turns into an idiot teenager and does dumb things (sex for AIDS, hep B, etc). The Hep B is the only one given within a day of birth. There is no point in this. Mother may receive RhoGam injection during pregnancy and this can be problematic – currenctly the RhoGam from Bayer is the safe one.

Slide 11. Infant Mercury Exposure Via Vaccination (US), CBER, 1999*

By age 6 months, a fully vaccinated infant has received:

• 3    DPT     75 mcg mercury   
• 3    Hib      75 mcg 
• 3    Hep B 37.5 mcg               
• TOTAL    187.5 mcg mercury  

*FDA Center for Biologics Evaluation and Research

Slide 12. An exposure of 187.5 mcg mercury in 6 months exceeds the EPA safe limit. This is what a fully immunized body gets.

Slide 13. graphic slide showing the sharp increase in autism rates correlates with the increase in vaccinations for infants escalating from 1989 through the 1990s. CA is the only state that has mandatory reported autism and PDD. This may be why the numbers are so high for CA, the other states may not be reporting all cases as promptly.

Slide 14. Historical Precedent Exists for mass poisoning of infants. Text: Those who do not remember the past are condemned to repeat it. Notes: There is a historic precedent of mass poisoning of infants involving mercury.

Slide 15. Pink Disease

• Common in children in 1890-1950s
• Pink cheeks and nose, painful pink hands
• Mystery solved 1945
• --Calomel teething powders – has mercury
• Delayed onset
• Only 1 affected for every 500 exposed

Notes: Pink disease was common in the early part of the last century. The symptoms were very common to autism and had delayed onset. It was discovered that calomel teething powders contained mercury. This powder was to put on infants' gums to numb the pain of teething. Once the teething powder was eliminated, Pink Disease went away.

Slide 16. Pink Disease

• Apathy
• Lost play
• Sound/light sensitivity
• Aversion to touch
• Head-banging
• Insomnia
• Repetitive rocking
• Repetitive hand-rubbing
• Poor muscle tone
• Seizures
• Infections

Notes: These are the common symptoms of Pink Disease. Sound familiar?!

Slide 17. Sources and Forms of Brain Mercury

diagram showing sources of mercury entering the body (vapor from teeth, vaccines, fish)

Notes: Mercury can move into the brain regardless of the source. Once it is converted to Hg++, it will not leave and it very difficult to remove.

Slides 18-19. Mercury likes to attach to sulfhydryl groups in proteins. When it binds to two sites, we call this "tighly-bound" mercury.

Slide 20. Proteins Bound to Mercury

• can be enzymes or structural proteins
• both are inhibited when bound to mercury
• loss of enzyme function
• loss of structural integrity

Notes: Whatever type of proteins they are, when mercury binds to them it inhibits their activity. These can be enzymes or structural proteins.

Slide 21. Slide showing loss of enzyme activity when mercury was added

Slides 22-24. Slides showing loss of protein activity when different vaccines were tested. Showed that enzyme activity was greatly decreased with the addition of thimerosal. Notes: A person may have cravings for salty and vinegar/sour foods because these are two of the pathways out of 5 that are not inhibited by heavy metals.

Slide 25. Conclusions

• Thimerosal inhibits both tubulin and actin viability, plus the activity of several other enzymes, at concentrations similar to observed with mercury.
• Vaccines containing thimerosal are solutions of extreme toxicity. This toxicity is most likely due to the synergistic effects of the other chemicals in the vaccine mixture.

Slide 26. Conclusions

• Thimerosal is the major toxic component of most vaccines.
• Thimerosal is a more potent inhibitor of many metabolic enzymes than is mercuric chloride.
• Due to synergistic toxicity, thimerosal exposure through vaccines with aluminum should be considered quite capable of causing severe neurological and systemic damage.

Slide 27. Why only some children?

• Most get about the same mercury exposure
• Only 1 out of 250 are autistic
• Why?

Notes: So what does this affect only some children…why are not all children who receive these vaccines affected?

Slide 28. The Answer: Genetics!

Slide 29. Predisposing Factors Under Investigation

• metallothionein
• apolipoprotein E

Notes: There is some genetic factor which makes some children more susceptible to begin with. These are two of the factors currently under investigation.

Slides 30-31. Metallothionein Functions

• Sequesters metals 
• Regulates copper-zinc balance
• Larger detox role (quenches nitric oxide) 
• Familial variability   
• Induced by zinc                                                                   

Notes: These are the main functions of Metallothionein in the body. It needs zinc to function most of the time. Reference: Dr. William Walsh

Slide 32. Metallothionien Dysfunction

• Abnormal copper:zinc ratio
• Impaired detoxification of heavy metals
• Impaired neuronal development
• Immature GI tract

Notes: These are common results of MT dysfunction.

Slide 33. Copper:Zinc Ratios

• Normal – 0.7 to 1
• ADD 1.2
• ADHD 1.4
• Autism 1.7 or greater

Note: These are the ratios of copper:zinc found by Dr. Walsh. The highest ever seen was 4.0

Slide 34. Role of vaccinations

• MMR
• Which vaccines and when?

Notes: Which vaccines may be contributing to the problems? Is timing an issue?

Slide 35. MMR

• Regressive autism reported after MMR
• Linked with various bowel symptoms
• Endoscopy – ileal lymphonoldular hyperplasia (autistic enterocolitis)
• Vaccine-strain measles virus demonstrated in intestinal lymph nodes

Notes: These things are found happening after MMR.

Slides 36-37. MMR and Mercury Toxicity

• Mercury is known to impair cell-mediated immunity
• Unable to clear viral infections
• Persistent measles infection
• Leaky gut
• Final insult in some children?

Notes: Something in the MMR is directly impacting brain enzymes but  right now we don't know what it is.

Slide 38. Reasonable Vaccine Recommendations

Notes: What is a reasonable vaccine schedule? The current one is not reasonable.

• All vaccines thimerosal free
• Hib
• DtaP – the one by Smith-Kline-Beachum is the only safe one to be giving when child starts walking outside
• measles monovalent – a very serious disease - when the child is 2 years
• Mumps monovalent (?)  - mumps in childhood is nothing, disease is more tolerable and you get life long immunity. If a boy gets this after puberty, there is a 50% chance of being sterile.
• rubella monovalent (?) - for boys no, for girl when young -Others? No reason for hepatitis before puberty - personal opinion

Slide 39. Testing for Mercury Toxicity

• not straightforward
• clears quickly from biological samples – blood clear 4-6 months after exposure
• must test for known effects on certain processes

Notes: Testing for mercury toxicity is not straightforward because it clears quickly from blood and urine samples. So we need to run a test for something that we know that mercury affects.

Slide 40. Lab tests for Mercury toxicity – in handout.

• Urine organic acid tests          
• Fractionated urine porphyrins – currently no commercial labs runs this test
• Immune system tests            
• Specific esoteric tests           

Note – The hair test is a good screen for other heavy metals, just not mercury.        

Slide 41. Urine Organic Acid and Amino Acid Tests

• Indications of mitochondrial dysfunction
• --uncoupling of oxidative phosphorylation: elevated fatty acid metabolites, elevated lactate, elevated hydroxymethylglutarate             
• --multiple partial blocks in Krebs cycle    
• Elevated 3-methyl histidine     
• Elevated sarcosine                                                                             

Slide 42. Fractionated Urine Porphyrins

no commercial labs runs this test

• elevated coproporphyrin
• elevated precoproporphyrin

[I don't know what this was in reference to]

Slide 43. Immune System Tests

• Elevated total IgE (over 300)
• Low CD8+ T cells   
• Low NK cells          
• anti-MBP antibodies               
• anti-NAFP antibodies             
• high CD3+CD26+ cells (?)      

Slide 44. Esoteric Blood Test

• Low superoxide dismutase     
• Low reduced glutathione         
• Low glutathione peroxidase
• Elevated lipid peroxides         
• Elevated platelet serotonin

Slide 45. Esoteric Urine Tests

• Elevated pyroglutamate - glutathione depletion        
• Elevated vanilmandelate - epinephrine, norepinephrine breakdown
• Elevated homovanillate - dopamine breakdown                                       

Notes: She looks for glutathione depletion and evidence of sulfate-wasting in urine.

Slide 46. Evidence of Sulfate-Wasting in Urine

Low plasma sulfate with normal urinary sulfate to creatinine ratio.

Slide 47. Lab Abnormalities NOT Found Unless Exposure was Recent

• high blood mercury
• high hair mercury
• high packed RBC mercury
• high urine mercury

Notes: Tests are VERY different from lead. Abnormal mercury will be found if the exposure was very recent, otherwise mercury content will not show up. The hair, blood and urine clear very quickly. The liver, kidney, lining of the gut, and  non central nervous system organs clear more slowly – several years. Mercury in the brain clears very slowly with a half-life estimated to be 20 years (so it is there to stay, unless you go get it).

Slide 48. Mercury Kinetics (after end of exposure)

• blood, hair rapidly cleared – 4 to 6 months
• non-CNS organs clear more slowly – several years
• brain mercury very slowly removed – half-life about 20 years

Slide 49. Mercury Removal

• Stop big sources of mercury exposure
• Clear out body mercury (this may be unnecessary with small amounts)
• Clear out tightly-bound mercury, including mercury in brain
• Appropriate nutritional support: determined by testing, particular attention to antioxidants

Slide 50. Stop Exposure to Mercury

• Remove all amalgam fillings
• Stop fish/seafood intake
• Use only thimerosal-free vaccines
• Watch for other thimerosal exposure

Slide 51. Step 1

Clear out any loose Mercury

• use DMSA alone

*This step may not be necessary

Notes: DMSA does not cross the blood-brain barrier, therefore the only mercury (or any other metals) pulled out with DMSA (with or without glycine) are coming only from non-brain organs. While it is very interesting to see how much mercury our children have managed to store in liver, kidney, intestines, and so forth, the amounts removed will have little impact on the child's brain functioning. For this reason, we do not really care how much mercury or other metals come

out of non-brain locations. The only issue while using DMSA alone is that the non-brain mercury is gone BEFORE adding lipoic acid. All we want is a "clean" body before adding lipoic acid because we do not want to give lipoic acid any chance to move body (non-brain) mercury up into the brain.

Slide 52. Step 1

• DMSA – max dose 10mg/kg three times a day for 3 days, off 11 days, repeat
• Add glycine to each dose of DMSA
• Test urine mercury after 2 to 5 rounds

Notes: Testing During Step 1 (DMSA alone): DMSA almost exclusively dumps metals into urine. We have a few choices about testing urine to determine when all or most non-brain mercury has been removed:

Option 1. Test urine on every cycle - this option is strictly for those who are REALLY curious about what metals are contained in the child, but not in brain, and are also extremely rich. The cost of this option excludes most of us parents.

Option 2. Do four 2-week cycles of DMSA (3 days on/11 days off OR 7 days on/7 days off). Then test urine on the 5th 2-week cycle, on either Day 2 or Day 3 of the cycle. If the amount of mercury excreted on the 5th cycle is very low, then we know the body (not brain) is "clean", and then we can add lipoic acid with complete safety. This option is the most popular among parents.

Option 3. Do at least eight (preferably ten or twelve) 2-week cycles of DMSA (with or without glycine). This option is reserved only for  those children who are very uncooperative with urine collections.  After eight 2-week cycles, 95% of all children have excreted virtually all non-brain mercury. After twelve 2-week cycles, 99% have "clean" bodies.

The urine test to check for excreted metals is the Urine Toxic Elements test done by Doctor's Data Lab [call Trudy at 225 767-7433]. They would like at least a 6-hour collection, but a longer collection is even better.  The bladder is a great storage place for urine, so first morning urine is at least a 6-hour collection, probably longer. For those not-yet potty-trained, urine collection bags are the best option.

Note regarding other metals besides mercury: DMSA will pull out most heavy metals, some better than others. If the child shows a large amount of some metals like lead or tin, it is very advisable to continue on DMSA alone (with or without glycine) until these metals are no longer being excreted in huge quantities. And we may accelerate the schedule from 3 days on/11 days off to something like 5 days on/ 9 days off or even 7 days on/7 days off. The reason for this is that these other metals (lead and tin most notably) really slow down Step 2 to the extent that they may even double the time required in this later step. The quicker we can get rid of these "other" metals, the faster Step 2 will go.

Slides 53-54. Showed 2 slides showing test results of patient where metal is coming out.

Slide 55. Step 2

• DMSA + lipoic acid (LA)
• Add glycine to each dose (she said this is optional, that often she forgets this entirely)
• DMSA:LA ratio from 2:1 to 6:1
• Test stool mercury every 4 to 6 months: hair test may be better for some (child must be chelating consistently for at least 2 months prior to hair specimen collection)

Notes: Sustained "regressions" once Lipoic Acid is Added is almost ALWAYS due to overgrowth of some unfriendly organism in colon – as body dumps mercury and it is going out the body, it encourages the growth of the bad flora. Any other cause(s) extremely rare.

Testing During Step 2 (DMSA plus lipoic acid)

While DMSA causes mainly urinary excretion of metals, lipoic acid excretes metals into bile - bile goes into stool. So lipoic acid does most of its metal excretion via stool. Once we add lipoic acid, we usually do not see any mercury come out in urine, except in some very young children (4 or less) unless we happen to get lucky  (urine become "hit-or-miss" detecting metals once lipoic acid is added).

The best test for mercury excretion on Step 2 (DMSA plus lipoic acid) is the Fecal Metals test also done by Doctor's Data Lab. The procedure is to collect stool on Day 4 or Day 5 that would be the 1st or 2nd day after a 3-day cycle of DMSA plus lipoic acid). While the stool test is the best test for metal excretion on Step 2, there are (or can be) a few problems:

1. Child does not "go" on either of the preferred days.

2. Child flushes the specimen down the toilet.

3. Child's stool transit time is so different from average that even though you collect on one of the "preferred" days, that day was not the "preferred" day for your child - the mercury came out either a couple days earlier or a week later, and we missed it totally. To complicate matters even further, it is impossible to tell what your child's stool transit time actually is, even if they appear to be "regular".

4. Lipoic acid is so involved with another metal (especially antimony and arsenic) that it latched on to these metals, ignoring mercury at least on this cycle. Remember, there is always competition for binding sites on both DMSA and lipoic acid between the metals, and there is also a "pecking order" of metal preference for both of these substances, for instance, lipoic acid prefers arsenic over mercury, so if there is a lot of arsenic around, mercury will be ignored. See note below about lipoic acid and other metals.

Despite the above listed problems with the stool test, for about 80% of the children so far, the stool test has been excellent - a large amount of mercury is detected in stool, and everyone is happy (there is nothing better than seeing a huge "dump" of mercury coming out in

stool!!). For the children for whom the stool test is not the best test (at least one of the above reasons), a reasonable but not very satisfying compromise is serial hair tests. The hair test will give us a rough indication of how much mercury is being mobilized, and will usually give us a good indication when to stop treatment. It is a compromise at best because:

1. We have already "flushed" the body with DMSA (with or without glycine) already, so the only mercury that is reflected in hair is a tiny amount mobilized from brain each cycle.

2. We are using an on/off schedule with DMSA plus lipoic acid. The only times metals are actually being pulled are on the "on" days. Nothing is being pulled out on the "off" days. Hair represents an average of both on and off days, so the amount shown in hair is much less than is being mobilized "on cycle". For this reason, hair always gives what appear to be very tiny quantities of all metals - and this is very unsatisfying for all involved (no immediate gratification!). But, if your child is one of the unlucky 20% who have no success for whatever reason with the stool test, we have no other choice but to use the hair test. There is one very important thing regarding the

hair test (if we have to use it) - the child must be chelating consistently for at least 2 months prior to collection of the hair sample, or else the amounts of metals reflected in the hair will be even

lower than expected false low results. Whatever test you choose for your child on Step 2,

testing every 4 to 6 months is probably best, unless you are extremely curious (and very rich!).

To obtain either the Fecal Metals or hair test kits, call Trudy (225 -767-7433) and tell her which kit you want or she will mail it to you.

Note regarding lipoic acid and other metals: Lipoic acid does cross the blood-brain barrier and will latch on to whatever heavy metals are in the brain and bring them out. It will either (usually) dump

these metals directly into stool via bile or pass them on to DMSA, in which case they will be excreted via urine.

Lipoic acid has a "pecking order" of metal preference. While it does latch on to mercury quite well, there are at least two other metals it prefers over mercury - arsenic and antimony. In fact, the best-known chelator of arsenic is lipoic acid. If there is a lot of arsenic or antimony (or some other metal lipoic acid likes a lot), lipoic acid will preferentially chelate this metal first. Eventually,

once the more-preferred metals are gone, mercury will be picked by lipoic acid. Regardless, getting rid of these other metals is very desirable. Do not be surprised if you see a huge amount of arsenic coming out on the first few Fecal Metal tests.

Slide 56. Showed test results after DMSA+LA with metals coming out.

Slide 57. Common Side Effects

• Worse behavior initially
• Diarrhea
• Headache
• Fatigue
• Overgrowth of intestinal yeast and Clostridium with lipoic acid (this can occur as the metals pass through the gut, you may need to stop chelating and treat the gut bug problem)

Slide 58. Worse Behavior

Whatever the child does that REALLY bugs the parent will get worse. It may include stimming, aggressions, hyperactivity. You should expect this to be worse on the "on" cycles and get better on the "off" cycles. If you see any sustained "regression" on DMSA alone and it is not related to an/off cycles, this is usually related to mineral deficiencies being "unmasked." You need to call the treating physician at this point.

Slide 59. Uncommon Side Effects

• Abnormal blood counts
• Mineral problems
• Seizures?
• MUST monitor with routine tests!!!

Slides 60-63. tables showing fecal test results removal of metals. In particular there was no fecal mercury on DMSA or LA alone. The combination of the two resulted in a lot of mercury being withdrawn.

Slide 64. Excretion of Mercury Using DMSA/LA

• Once no more mercury is excreted in urine on DMSA alone, adding lipoic acid causes fecal excretion of mercury
• Neither DMSA alone nor lipoic acid alone results in any fecal excretion of mercury
• Lipoic acid seems to "need" DMSA, perhaps for activation into the dihydro-form

Slide 65. Age Effect on Mercury Excretion

Table with results of fecal mercury from DMSA+LA showing much mercury removed from a 2 yr old, less removed from an 8 yr old, and hardly any being removed from a 17 yr old Notes: She said she thinks it is always good to try, but they are not seeing much metal removal from teens and they are not sure why.

Slides 66-67. Early Results

Amount of improvement from kids chelating based on 152 children – DMSA + LA 6 months

Ages 1-5     (66 kids) 36 marked improvement, 39 moderate, 15 slight,   9 none

Ages 6-12   (55 kids) 15 marked improvement, 35 moderate, 36 slight, 15 none

Ages 13-17 (24 kids)   0 marked improvement, 17 moderate, 54 slight, 29none

Ages 18+    (  7 kids)   0 marked improvement, 14 moderate, 14 slight, 71 none

Notes: This shows that the younger the child the better the results.

Slide 68. Rapid Responders (based on very early observations)

• younger children
• those with history of normal development followed by regression (this is true for all age groups)

Notes: She stressed that this is what they see now but it is subject to change at any moment because they are so early into the process and there is a lot more to learn. Maybe there is some little key they haven't found yet for the older kids so don't lose hope.

Slide 69. Pleasant Surprises with Removal of Mercury

• CNS autoantibodies have disappeared
• Symptoms and laboratory evidence of IgE-mediated allergies have disappeared.

Notes: These are things they see regularly but were surprised to find with chelation. The central nervous system AA disappeared and some allergies left.

Slide 70. Effects on Other Areas (Totally Unknown)

• Chronic viral infections Maybe we shall see
• Gluten/casein-free diet
• Gut bugs

Notes: They do not know how chelation will affect these areas in general, although any particular inidividual may see positive results. Gluten/casein diet…if it is working just stay with it…it is too early to say conclusively about the effects of continuing it or discontinuing it.

Slide 71. Conclusions

• Autism may represent fetal/infantile mercury toxicity in susceptible individuals
• Chronic viral infections may be due to inhibition of cell-mediated immunity

Slide 72. Conclustions

• Significant improvements have occurred with mercury and other heavy metal removal (based on the early data)
• Rapidity/duration of treatment seem to be dependent on age and developmental history
• Ultimate outcome is unknown but looks promising.

Notes: This is VERY early data, too early to make many conclusions, but it looks like a very promising approach. It appears to be working well in many children. The age and developmental history are very important. We are actively looking at several new related areas.

Additional information from Dr. Holmes' site:

Safety Testing

These tests do not show anything regarding how much mercury is being removed. They are strictly safety tests to make absolutely sure that DMSA (with or without lipoic acid) is not adversely affecting your child.  They are absolutely required and are of utmost importance.

Every 2 to 3 months:

1. CBC with differential counts (blood counts)

2. Liver function tests (hepatic panel)

3. Chem 7 (serum electrolytes plus creatinine)

Every 6 months:

RBC Essential Elements (intracellular trace minerals)

We used to check serum copper and plasma zinc every 2 to 3 months (along with the first 3 tests listed), but these two tests have presented some major problems because of the way our bodies excrete heavy metals with the aid of DMSA with or without lipoic acid. There is a step in heavy metal excretion that involves intracellular transport of the heavy metal inside red blood cells - this is necessary, and without this step, the metal would never be excreted. Unfortunately, while inside the red blood cell, the heavy metal displaces certain trace minerals (zinc is the most popular to be displaced) outside the cell into the serum/plasma. This results in high plasma zinc readings, leading us to erroneously conclude that we are giving the child too much zinc. The place zinc is used (as a component of many enzymes) is inside the cell, not in the plasma. So

what is important is the intracellular concentration of zinc, not the plasma zinc level. And the same is true for all of the other trace minerals, including copper.

The RBC Essential Elements test is run by only a handful of labs - we greatly prefer MetaMetrix because of the quality of the test and it is also not terribly expensive like some other labs. This is a blood test and the blood for this test can be drawn at the same time as the every 2 to 3 month tests by the same lab that does these other tests for you (any local lab), but the lab must send the specimen to MetaMetrix properly processed. It makes it much easier for whatever local lab you choose and for you to bring the RBC Essential Elements kit with you to the lab with your child, so there is no confusion on the lab's part about what needs to be done. When it is time to have

this test done on your child (every 6 months), please call Trudy (225 767-7433) and tell her you want the RBC Essential Elements test kit - I will also send you a prescription that you take with the kit to the lab of your choice requesting this test be drawn and mailed.We realize this is very inconvenient, but is unfortunately very necessary for complete safety during treatment.

1. Expect your child's behavior to get worse during the first few cycles of both DMSA alone and DMSA/ALA. This is an effect of moving metals around and out of the body and is expected to occur.

2. Other common side effects of DMSA include diarrhea in 15%, some nausea, very stinky gas, and possibly breaking out in a fine red bumpy rash that may or may not itch (this is called a mercury rash and is not dangerous - if it itches, use Benadryl cream or oral Benadryl). Side effects of lipoic acid include light sensitivity and the development of red rings around the eyes - looks like raccoon eyes, except red not black. Lipoic acid also causes euphoria in some child will like it, you will not!

3. Uncommon side effects include a drop in blood counts and a temporary increase in liver enzymes. This is why we test blood counts, liver and electrolytes/kidney every 2 to 3 months while on DMSA with or with out lipoic acid.

4. There is a theoretical possibility that by removing mercury from the brain, the membrane potentials of the brain cells may change enough to induce seizure activity. So far, with hundreds of children under treatment, including many with seizure disorders, this has not been a problem. Chances are, if we were able to remove every molecule of mercury all at once, induction of seizures would occur, but since we are only able to remove a tiny amount each cycle, that is probably why we have had no problem with seizures at all.

5. Take all of the supplements listed in your child's support protocol every day. The only exception to this rule is that if your child is taking oral glutathione, do not give this on the days he/she is on DMSA.

6. Encourage your child to drink a lot of fluids on the days on DMSA and DMSA/ALA. Three to four 8-ounce glasses of fluids per day should be more than enough.

7. It is very important to avoid known sources of mercury both during chelation and after it is over. These include:

a. Thimerosal-containing vaccines*

b. Fish and seafood**

c. Amalgam (metal) fillings. If your child ever needs to have fillings put in his/her teeth, ask the dentist to use white composite material instead. If your child already has amalgam ("silver")

fillings in his teeth, these MUST be replaced with either white composite fillings or stainless steel caps PRIOR to beginning DMSA. For future reference, stainless steel caps are fine and braces are fine - anything that does not contain mercury is fine.

7. Urine and stool will smell like sulfur on DMSA. This is normal.

*Every commonly given vaccine has at least one brand that is thimerosal-free. By 2002, all US vaccines will be thimerosol-free (according to the FDA and CDC). **To be on the completely safe side, most parents have made a new rule of the house - no fish, no seafood. If your child needs to have a note for the school cafeteria stating "no fish/no seafood", I will be more than happy to write one for you.

Do not expect to see any behavioral improvements on Step 1. If any occur, they are most likely due to the elimination of heavy metals other than mercury. Do not expect to see any improvements from the elimination of mercury until 2 to 3 months into Step 2 of the chelation protocol. Usually, younger children respond faster than older children, but this is not always the case. The timing of the response is dependent on many factors including exactly how fast the

mercury is being removed from the brain, how fast any damage that is being repaired is actually being repaired, and so forth. There is a lot of individual variation in rapidity of response.

Most Common Order of Improvements - usually starts 2 to 4 months into Step 2 (DMSA + LA):

1.  eye contact

2.  interaction with significant others

3. receptive language

4. expressive language

5. pronunciation - improvements in apraxia/dyspraxia

6. stimming/ stereotypical behaviors

7. other problem behaviors

None of these happen overnight, but you should notice slow steady improvements, usually in the order listed over several months, depending on the child's initial level of functioning and his individual response to treatment.

Problems Encountered in Step 1 (DMSA alone with or without glycine) It is extremely common to see regressions in behavior, learning, attention, and so forth around the days on DMSA - this is normal and is expected to occur. If you notice a continued regression in anything that is not related to the DMSA cycles in timing (like is happening all the time), then that is not normal. Invariably, problems like this encountered on DMSA alone are related to either minerals (usually magnesium deficiciency) or taurine deficiency or something similar. If this occurs with your child, do the following:

1. Call us and tell us exactly what is happening

2.  If he/she is already on a multimineral supplement, increase the dose. If he/she is not, get him/her on one ASAP, add additional magnesium, either via magnesium sulfate cream or oral magnesium glycinate. Same with Taurine.

Problems Encountered in Step 2 (DMSA plus Lipoic Acid)

If the regressions in behavior, etc are only occurring around the "on" days, then this is normal and expected to occur. But, if there is EVER a continued regression (or even a plateau in progress)

at any time during Step 2, the major cause (so far, at least 95% of kids) is overgrowth of some unfriendly bug in the gut that is producing toxins that influence behavior, learning, attention, stools

and even sleeping. The reason is simple - lipoic acid ends up dumping mercury into stool (this is obviously good because it is on its way out of the body). But, while mercury is in the intestines, it impedes intestinal defenses allowing all sorts of unfriendly toxin-producing bugs to overgrow, even in children who never had any bad bug problems in the intestines before.

If at any time during Step 2 (DMSA plus lipoic acid), you notice a continued regression unrelated to on/off cycles or even a plateau in progress, we MUST check for bugs SAP. This entails both:

1. Stool micro (alone or with parasitology if we even remotely suspect parasites in your child)

2. Either urine organic acid test (if your insurance paid at least 50% of the cost of this test before) or just the dysbiosis section of this test (if the insurance did not pay at least 50% of the OAT

above - no insurance will pay for just a section of the test). Call Trudy (225 767-7433) immediately and tell her which tests you want to run. She will send them to you ASAP.

These two tests together will give us a complete "bug picture". The stool culture will only grow out aerobic (will grow in the presence of oxygen) organisms, and the urine test will check markers put out by anaerobic organisms (cannot grow on culture). Almost invariably, this has been THE major reason for any regression or plateau on Step 2. Once the bugs have been eradicated, the progress resumes, and everyone (child, parent, doctor) is much better.

Of course, if any problem arises during the course of treatment in any area, please E-mail us or call Trudy. We may not be able to fix everything, but if we don't know about what is going on, we can't help much at all!

If possible, to help us keep track of progress and any problems encountered, once every 3 to 6 months, please send (mail, fax, E-mail, etc) us the following info:

1. Repeat ATEC reports (can fill out online on ARI web site) - we want results

2.  The ARI's Mercury Detoxification Progress tracking sheet (also online at ARI)

3. Any re-evaluations you have done through county early intervention/pupil appraisal teams, or even private developmental psychologists/pediatricians, speech therapists, and other people like this.

4. A list of exactly what medications and supplements he/she is currently on with dosages.

This will help us help you take the best care of your child, and will also aid the ARI/DAN group in assessing treatments. Also, anything else new that you want to try let us know, especially if it works!

If your child demonstrates any signs of central nervous system (brain) mercury toxicity, then eventually, we will end up adding lipoic acid to get rid of mercury and other divalent metals in the brain. Lipoic acid mostly dumps mercury into stool (via bile). That is good because it will be leaving the body, but while mercury is in the intestines, it impedes normal intestinal defenses, and this can allow all sorts of unfriendly organisms to overgrow, especially some yeast and Clostridia. One can usually tell if this has occurred because usually it is manifested by some continued regression or a plateau in progress. But, there are some children who show no obvious behavioral signs of a bad gut bug overgrowth problem at all (like my son). If we start Step 2 of mercury removal (DMSA plus lipoic acid) and all is getting better for a while, then you start noticing a continued regression in behavior, learning, attention, stools or sleeping behavior, that is our clue that we need to check for bad bugs ASAP. Once the offending organisms are eliminated, then progress (behavioral, learning, attention, etc) resumes. If your child is one like mine who demonstrates no obvious regressions with even the world's worst gut bugs growing wild, then we may have to resort to checking for bugs periodically just to be on the safe side. One thing is definitely known about some of these bugs - they "mask" progress very well, and may lead us to believe that the treatment isn't helping when it actually is. The strange part about many of these children who end up growing all sorts of unfriendly bugs on lipoic were the same children who had no gut bug problems at all when we started DMSA/LA. The only good part of this whole scenario is that at least it tells you beyond any doubt that you are dumping organic mercury from the brain into the gut!

Dr. Andrew Stoll talk - Omega 3 Essential Fatty Acids

Side 1. Andrew Stoll – Omega 3 Fatty Acids in Autism Psychopharmacology Research Laboratory McLean Hospital, Harvard Medical School

Notes: Decades ago, many arthritics could get relief from essential fatty acid and cod liver oil. Omega 3 EFA will be a key piece to AS.  Omega 3s are needed for every system in the body and are key to many areas such as ADD, depression, schizophrenia,…It used to be fish oils were called snake oils.

Slide 2. Autism Defined

• Autism is a biological syndrome, at least partially genetically based.
• Autism may be more than 1 disorder.
• 80% of kids with autism also exhibit learning disabilities.
• Concept of autism still evolving.
• Autism is a "spectrum disorder"
• More adults are being diagnosed with "autism spectrum disorder"

Notes: Autism is a biological syndrome, at least partially genetically based _ genetic subtypes

Autism may be more than 1 disorder – a new lingo is that people are on spectrum disorder

80% of kids with autism also exhibit learning disabilities

Slide 3. Autism: Differential Diagnosis

• Asperger syndrome
• Rett's disorder
• Childhood disintegrative disorder
• PDD-NOS
• Childhood psychotic disorders
• General medical conditions

Notes: There are many variations in each of these.

Slide 4. Autism Co-morbidity

• Biopolar disorder
• Major depression
• Seizure disorders
• Obsessive-compulsive disorder
• Motor tics
• Learning disability
• Dyslexia
• Tuberous schlerosis

Notes: Many of the symptoms have a nutritional basis. The parents must bring the information to the doctors. You will need to be in charge.

Slide 5. Autism: The Opioid Theory

• Early exposure to exogenous quasi-opioids
• Source is incompletely digested gluten or casein, which form opioid-like peptides in the gut
• Genetic vulnerability vs acquired forms (such as candidiasis)
• Failure of:
• --–Intestinal enzymes (peptidases
• ----Mucosal barrier (defective sulphation)
• ----Blood-brain barrier

Notes: The opioid theory makes good sense for many cases, definitely not all

[his slide included 2 references]

Slide 6. Autism: Inflammatory Bowel Theory

• High rates of inflammatory bowel disease are observed in autism
• Lymphoid hyperplasia (at the ileo-cecal junction)
• Biopsy revealed measles or mumps infection
• 1/3 cases occurred immediately after immunization
• The proportion of patients with an inflammatory gastrointestinal process as the etiology of their autism is unknown.[includes 2 references]

Slide 7. Autism: Secretin Theory

• Pancreatic enzyme that activates peptidase
• Supportive open-label case reports
• The Allopathic medical establishment rejects the use of secretin in autism
• Despite 5 negative placebo-controlled trials (some highly flawed), secretin remains highly popular
• Future studies should focus on possible sub-groups that are responsive to secretin.

[includes 2 references]

Slide 8. Autism: The Amygdala Theory

• The amygdala is a limbic system brain structure involved in "social intelligence, aggression, and other behavioral processes
• The Kluver-Bucy syndrome (bilateral amygdala destruction in animals) resembles some behaviors seen in childhood autism
• Functional MRI studies reveal lack of appropriate amygdala activation in children with autism, when trying to determine the emotions in photographs of human faces

Notes: Secretin interacts with receptors in this area of the brain.

[includes 1 reference]

Brain Imaging Findings

Slide 9. Autism Brain Imaging Findings

• Studies limited by small sample sizes and lack of replication
• 2 replicable findings:
• --enlarged temporoparietal regions: These regions are important for auditory processing, recognition of emotions in others and many other functions.
• --Reduced size of posterior corpus callosum: Impairs communication between left and right brain.[includes 1 reference]

Slide 10. Omega3 Deficiency in Autism: Indirect Evidence

• Reduced frequency and shorter duration of breastfeeding in children with autism compared to their normal siblings [two references for this]
• Abnormal heart rate variability [1 reference]
• High rates of stereotyped behaviors in omega-3 deficient rhesus monkeys [1 reference]

Notes: We need the official studies, but ok to keep using it (omega-3 fatty acids) in the meantime until they get around to the studies.

Slide 11. Evidence for Omega Deficiency in Autism

• High rate of inflammatory bowel disease.
• Supportive open-label data
• Increasing prevalence of autism over time??
• Are cross-national rates of autism negatively correlated with fish consumption??

Needed: 1) Double-blind, placebo controlled studies. And 2) Oral vs IV

Notes: Countries that have diets higher in Omega 3s such as eating a large amount of fish, have lower rates of depression and other disorders. The increase in autism spectrum in our country may be related to our diet.

Slide 12. Eicosapentanoic acid (EPA 20:5:n3)

Major Omega-3 Fatty Acid in Fish Oil

Notes: This slide showed the structure of EPA. It said the multiple double-bonds produce a kinked and flexible molecule and the first double-bond begins at 3rd carbon from methyl (end of the fatty acid chain). He said that having double-bonds keeps the molecule flexible and this keeps it fluid in the body under different conditions. Notes: What is an Omega 3 fatty acid? Poly means many double bonds. The multiple double-bonds produce a kinked and flexible molecule. Lard or solids have no double bond. The liquid oils will be liquid at room temperature (in your body). Flax Seed Oil = EPA. DHA had the focus for a long period of time – it is in breastmilk – but it is proving to not be effective in working in clinical trials with depression, bipolar, etc. has much slower turnover in the body

Slide 13. Eicosapentanoic acid

Many possible mechanisms of action

• Alteration in eicosanoid and cytokine pathways
• Reduction of abnormal signal transduction
• Alternatin in membrane order ("fluidity")
• Altered receptor function
• Pan-agonists at nuclear receptors (PPAR)

Notes: Many doctors need double-blind data to feel that this approach is reasonable.

They pursued EPA as an alternative to lithium, depokate…which saved lives before but came at a high cost. They have learned more about the pathways and science has improved.

Slide 14. Signal Transduction

• The receptor is the door to the cell
• The neurotransmitter knocks on the door

-Signal transduction converts and amplifies this extracellular membrane event into useful information within the cell Notes: Use EPA and has rapid turnover in the body

Slide 15. Omega-3 Fatty Acids in Bipolar Disorder: Study Design

• Double-blind placebo-controlled 4-month trial
• N=30 bipolar outpatients (mostly Type I)
• All subjects had mania/hypomania within past 1 year
• Randomized to 9.6 g/day omega-3 vs placebo (olive oil)
• Concomitant meds left unchanged-N=8 entered study on no other drug therapy
• Main outcome measures:
• --Recurrence or lack or response
• --SCID Stutus at end of trial

Notes: Bipolar Disorder:

½ got omega 3 and ½ got olive oil. Doing a perfect study is very difficult – fish oil smells so people

would know they did not have olive oil. One person's cat attacked when the supplement was brought out.

Slides 16-17. Two line graphs showing the results.

Notes: The omega 3 patients did great, 12 out of 14 did response to the treatment. The olive oil patients dropped especially by the second month. Because the placebos were dropping out at such a rate, by the fourth month they stopped instead of going on to the 9 month target date because they were running out of placebos. The response shown gave results stronger than lithium and deprokate, but these results may not replicate as dramatically. Omega 3 are anti-

psychotic agents. At the moment, these should not be relied upon exclusively – but used as an adjunct therapy. They found that it is EPA and not DHA that is helpful.

Slide 18. Omega-3 Fatty Acids in Unipolar Depression

Evidence

1.  4 studies reported lower blood omega-3 fatty acids (usually EPA) in patients with major depression.

2. Epidemiological evidence pints to lack of omega-3 fatty acids as world-wide risk factor for depression.

3. The neurochemical effects of omega-3 depletion are consistent with models of depression.

4. Abnormalities in the omega-3 dependant eicosanoid and cytokine pathways are present during major depression.

5. Open-label case series reporting antidepressant effects.

6.  Double-blind data reporting the antidepressant effects of fish oil in bipolar disorder.

7. Reduced rates of seasonal mood shifts in Iceland and Japan.

Slide 19. Evidence for Omega 3 Depletion in Western Diet

• Rates of major depression & cardiovascular disease inversely correlated with fish consumption.
• Outcome in schizophrenia better in high fish consuming nations.
• The increased incidence of major depression in the 20th century is directly correlated to a drop in omega-3 consumption.

[included 4 references]

Notes: Schizophrenia patients in other countries did much better than in the US because of their diet. Also correlates well with depression in other countries – the more fish one eats the less depression there is. Post-partum depression – also a strong reaction because women give omega 3s to baby through the placenta

Slides 20-21. Two graphs showing data supporting points in previous slide.

Slide 22. Omega-3 Fatty Acid Depletion in Post-partum Women

After 1 child: low DHA

After 2 children: Lower DHA

After 3 children: Lowest DHA

Triplets > twins

Triplets

Lactation: At 16 weeks, decreased DHA

Notes: Shows that the Omega-3 are depleted with child bearing and the number of children.

Slide 23. Picture of Eskimo ice fishing.

Notes: Because fish has mercury you need to get omega 3 from other sources.

Slide 24. 5 pictures of phytoplankton (algae)

Notes: Fish do not make omega 3 they get it from the phytoplankton they eat through the food chain. So try to eat the other sources directly.

Slide 25. Natural Sources of Omega-3 Fatty Acids

Slide 26. Fish with High Omega-3 Content

Chart showing quantities of DHA and EPA in different fish Omega-3 content of fish varies geographically and from year to year due to climatic effects of algae and other factors.

[included 1 reference]

Slide 27. Terrestrial Sources of Omega-3 Fatty Acids

• Fish with high omega 3 content – fish sources will vary
• Perilla Oil
• Chia
• Borage seed oil
• Flax seed oil good but there are some drawbacks
• Wild game because they eat wild food – not grain fed
• Seaweed has DHA and EPA but not a good source and can have heavy metals
• Omega 3 Eggs available in grocery, they are fed a special feed to increase fatty acid content

Slide 28. Effect of Regional Diet on Mercury Levels Among Greenlander Graphs showing that in North Greenland where there is high local fish consumption they have a much higher level of mercury in the system than Greenlanders living in Denmark where there is less fish consumption.

Slide 29. Palmitic Acid

• a saturated fat
• need a little bit but don't eat a lot
• no double bonds makes it a rigid solid that does not function well in cells

Palmitic acid is an 18 carbon saturated fat. Note that the lack of double bonds produces a straight chain molecule. This straight chain structure is rigid, which is why palmitic acid and other saturated fats (such as lard) are solid at room temperature (a high melting point). In contrast, the multiple double bonds in polyunsaturated fats, such as the omega-3 fatty acids, produce a very flexible molecule, which is liquid oil) at room temperature (low melting point).

Slide 30. Alpha-linolenic acid

• –double bonds helps keep it a liquid

An 18 carbon omega-3 fatty acid with 3 double bonds. Alpha-linolenic acid is found in flaxseed and other plant oils. Note how just 3 double-bonds alters the chemical structure, making alpha-linolenic acid much more highly folded than an 18 carbon saturated fat.

Slide 31. EPA

EPA is a 20 carbon omega-3 fatty acid with 5 double-bonds. Note the highly kinked structure of this polyunsaturated fat, which is found in high concentration in certain fish oils. EPA directly competes with its omega-6 counterpart, arachadonic acid, in many biochemical pathways. Arachadonic acid is converted into highly inflammatory compounds (eicosanoids), which are crucial in certain conditions, but if arachadonic acid activity is unchecked, the inflammatory

process can lead to many different disease states. EPA forms only mildly inflammatory compounds. These weaker EPA eicosanoids, along with EPA's inhibition of arachadonic acid Conversion into the highly inflammatory eicosanoids produces many health benefits, including reduced rates of heart attack, less inflammatory disease, such as rheumatoid arthritis, and reduced depressive illnesses.

Slide 32. DHA

DHA is a 22 carbon omega-3 fatty acid with 6 double bonds. Certain fish oils are rich in DHA. Note the markedly kinked chemical structure, which is characteristic of highly polyunsaturated fatty acids. DHA is crucial for neurological and visual development in the human fetus and newborn, and it found in high concentration in the brain throughout life.

Slide 33. Arachidonic acid

Arachidonic acid is 20 carbon omega-6 fatty acid with 4 double bonds. Omega-6 fats are polyunsaturated with the first double-bond beginning with the 6th carbon atom from the methyl end of the molecule.

Slide 34. Oleic acid

Oleic acid is an 18 carbon fat of the omega-9 class, because the first and only double bond begins at the 9th carbon from the methyl end of the molecule. It is considered monounsaturated because it has only one carbon double-bond. Note that one double-bond between the 9th and 10th carbon atoms produces a slight kink in the chemical structure.

Slides 35-36. diagrams showing the essential fatty acid metabolism

Omega-6 is LA goes to GLS goes to AA

Omega-3 is ALA goes to EPA goes to DHA  In order of carbon chain length and number of double bonds

Slide 37. Graphs showing the results demonstrate that EPA and DHA supplementation alters brain structure, and supports the hypothesis that omega-3s "fluidize" neuronal cell membranes.

Notes: These things really do change your body chemistry. Fat content in the brain affects the water flow in the brain and function – affects how stiff or fluid your membranes are.

Slide 38. Omega-3 Fatty Acids: Dosing Controversy

Replacing an omega-3 deficiency (low dose) vs Pharmacological effect (high dose)

Notes: He thinks it is both.

Slide 39. Omega-3 Fatty Acids (Fish oil)

Advantages:

• Double-blind, placebo-controlled data (N-30) in bipolar disorder.
• well tolerated
• health benefits
• patient acceptance
• no weight gain - because they turn on fat metabolism systems
• Highly concentrated forms now available

Drawbacks:

• More efficacy data needed
• High-doses required
• Most currently available fish oils inadequate in potency
• GI distress at high doses – some comment on bleeding but only a few isolated cases, nausea and diarrhea passes with time – side affects
• Fishy aftertaste which may be due to rancidity of fatty acids through oxidation
• Theoretical risk of increased bleeding

Usage Guide: 2-5 grams of omega-3 (EPA+DHA BID

Caution: anticoagulants or high-dose ASA or NSAID

Note: Drug companies cannot patent these things – marketing, research money, blah, blah, and that is why the natural substances are not popular. Most fish oil is squished fish in a bottle – can go rancid easily. Go with better quality oils. Any fish oil has been distilled or concentrated to over 50% purity is pretty safe. Contact the company and ask about the mercury and heavy metal content. If they will not tell you, don't use that company

Slide 40. Flax Oil (alpha-linolenic acid_

Advantages:

• More palatable than fish oil
• Native flax oil more concentrated than native fish oil
• May be used in recipes (but not as a frying oil)

Drawbacks:

• No controlled data in neuropyschiatric disorders
• May cause more manic switch than fish oil
• Limited conversion to longer chain omega-3

Usage: 1 tablespoon (~7 g of ALA) qd-TID or use capsules. Omega-3 dosage with flax oil should be the same or higher as that used for fish oid, due to the incomplete conversion of ALA to EPA.

Slide 41. Potential Adverse Effects: Fish oil

• Gastrointestinal disturbance (benign and generally only seen at high dosage levels)
• Fishy aftertaste (repeat) (due to rancidity of fatty acids through oxidation)
• Hypervitamosis A (only if high-dose cod liver oil used)
• Imparied platelet function (theoretical risk of bleeding oly; weaker than aspirin)
• Contamination with heavy metals, or organochlorine compounds

Slide 42.  Ideal Characteristics of a Fish Oil Supplement

• Maximum concentration (>90% now available)
• No heavy metal or organic carcinogens
• No fishy aftertaste, smell, or "repeat"

(these unpleasant features can be prevented by encapsulating under nitrogen to minimize oxidation)

• EPA>DHA

Slide 43. Usage Guide

• Fish oil preferred to flaxseed oil at this time.
• Usual dosage range: 1.5-10 g/d (3-5 g/d typical) omega-3 fatty acids (EPA or EPA+DHA)
• Read labels carefully. Brands differe widely in omega-3 content (listed by serving size, not per capsules)
• BID schedule optimal (qd, TID also ok)
• Food increases omega-3 absorption.
• Highest content of EPA desirable
• Antioxidants (such as vitamins C&E, etc) may prevent in vivo degradation of omega-3s
• If GI is upset: Divide dose, ginger root, Daikon radish
• Caution: Xenical; anticoagulants or high-dose NSAID?

Notes: 2-5 grams of omega-3 once or twice daily, either EPA or EPA+DHA, start low and go slow.  few problems with Flax seed oil – prostate cancer. Flax Oil – is good inside the food such as baking or pancakes, not for frying.

Slide 44. Phases of Medical Research

There are two ways things happen in science: 1) Scientific hypothesis or 2) clinical observation. both go to preliminary open-label or uncontrolled trial. Then go to Preliminary controlled study, and then to Definitive controlled study.

Slide 45. The Importance of Preliminary "Open-label" or Uncontrolled

Studies

• "Open-label" means both the patient and clinician/researcher know that the patient is receiveing the "active" drug.
• This is where major discoveries are made
• Inexpensive
• Huge, double-blind, placebo-controlled studies are crucial for confirmation of initial findings

Notes: Most things in this area start by observation – what parents notice or doctors notice from subsequent patients. If something is harmless why not use it.

Slide 46. The Pitfalls of Prelijminary "Open-label" or Uncontrolled

Studies

• The observations may be the results of the "placebo effect"
• Many sources of bias can distort the results
• Must not over-interpret open-label trials

Slide 47. Many Sources of Bias Can Distort the Results

• Placebo effect
• Lack of systematic diagnosis
• Not counting "drop-outs"
• Unconscious or conscious fudging of the results
• --The researcher wants the treatment to work
• --The participant wants to please the researcher

Slide 48. The Importance of Scientifically Controlled Research

• Evaluates preliminary uncontrolled findings
• Permits other researchers to replicate methods
• Permits patients, families, and clinicians to evaluate the merits and drawbacks of a new treatment
• Permits insurance companies, the FDA, and other regulatory agencies to evaluate the merits and drawbacks of a new treatment

Slide 49. Omega-3s in Autism: A Research Agenda

Eventually you need controlled research

• Well designed placebo-controlled clinical trials
• Must answer the following questions:
• --What is the best route of administration? Oral or IV
• --What is the most effective omega-3? EPA, DHA, ALA, or some combination?
• --What is the optimal dosage?
• Funding sources
• --The most difficult challenge

Notes: He said that eventually well designed studies are necessary and must include looking at and trying to answer the questions listed. Funding is difficult because it involved diet and nutrition.

Slide 50. Omega-3 Fatty Acids in Autism: Unanswered Questions

• Are omega-3s truly effective in autism?
• If so, which omega-3s is the active component (EPA, DHA, ALA or all 3?)
• What is the proper dosage?
• Oral vs IV?
• Are there biological markers that will predict omega-3 response?
• Are there subtypes of autism that preferentially respond to omega-3s?

Slides 51-52. He recommends Coromega for younger kids and Omegabrite for older people. These are safe bets. Showed book cover and web site for Omegabrite and the book The Omega-3 Connection by Andrew Stoll.

PAGE OPTIONS

• Printer Friendly Page