Dr. Mumper is a general pediatrician with experience in the medical education of Family Practice residents. She is an associate professor of clinical pediatrics at the University of Virginia and CEO of Advocates for Children. Her research involves clinical problems and immune abnormalities in autistic children with abnormal intestinal biopsies.
All of my slides are in print version in your handout, but I am a medical educator, and I like to use a lot of visual images. So the first image I'm going to give you is of a spider web. When you take a closer look, you notice things about this web that you might not have ever known were there before. And then you look at the center of the web. Much of what we do as clinicians is to try to look at the incredible intricacy that our children present to us, and try to figure out how all the pieces fit together. You cannot pluck one string of this web without affecting the rest.
What I'd like to do today is to try to integrate this science with clinical clues and explain the findings we use to design individual treatment plans for these children. We're going to move from the macrocosm to the microcosm. I have come to have a tremendous respect for individual variation in our patients, and, even more, a respect for the synergy of biological systems. I'm going to use a lot of case histories of patients from my practice. (All of these families have consented.)
I want to tell you a little bit about the gut study to which Dr. Wakefield was referring. We are looking at kids with autism and gut disease, and it's a community-based collaboration between a pediatric gastroenterologist, a couple of clinicians, and a pathologist. Our samples will be analyzed by a lab that is independent of any that Dr. Wakefield has used before. Because of potential financial conflicts of interest, we are financed on a very small budget by families of children affected by autism. The donors have no influence in the execution or design of the study. The cost of the lab analysis of the samples will be borne by the lab performing the tests. I also want to acknowledge my colleague Ari Vojdani of Immunosciences Lab in California, who has generously donated over a hundred thousand dollars for the lab tests so that we can look at the immune systems of these children and correlate them with the gut disease.
We're looking at 30 autistic patients and 30 controls. These samples will eventually be examined for genomic measles virus and avian retrovirus by a technique called RT-PCR. Our inclusion criteria for these children were that they had to be developmentally normal at one year, suffer a regression after MMR vaccine, and have a confirmed diagnosis of autism or Asperger's syndrome.
This is the gut in autistic children as demonstrated by the folks at the Royal Free Hospital, London, showing the lymphoid nodular hyperplasia that Dr. Wakefield was describing earlier, and the aphthous ulceration that he was describing as presented here. I want to show you my pictures, which look identical. So in a community hospital with a community pediatric gastroenterologist and a community pathologist, we are confirming the gross and histological findings that Dr. Wakefield first described in 1998.
This is a normal-looking specimen, and, for your purposes, I just want you to notice that there is a lot of white here. It is not the dense inflammatory infiltrate with all these dense purple cells that we see on this other slide. This is an example of chronic inflammation. You can see distortion of the crypts with the crooked appearance of what was so perfectly oval in the first slide. This slide shows that there's essentially an explosion of pus here as a result of very chronic inflammation. This was published in 1998.
In our studies in Virginia, we see the same kinds of pathologies when we look at our findings. We see very frequent esophagitis. We see lots of gastritis. The stomachs of some of the children are normal, but many of the kids have a lot of lymphoid nodular hyperplasia and duodenitis. In the ileum we see very frequent lymphoid nodular hyperplasia or frequent ileitis. In the colon we sometimes see lymphoid nodular hyperplasia throughout, and I'll show you some of these kids later. And in the rectum sometimes we see bad cases of proctitis.
In the first dozen or so cases that we examined, we only had one child that supposedly had normal histology. And, in fact, if you read the fine print, it said that there was a mild increase in intra-epithelial lymphocytes. This actually confirmed another finding that has been published by Dr. Wakefield and his colleagues. If you look on the right side of the chart you'll see "increase in intra-epithelial lymphocytes" in the autistic patients versus controls or even children with inflammatory bowel diseases such as Crohn's or ulcerative colitis. So even in our so-called normal case, everything I've seen has been consistent with Dr. Wakefield's work.
First, I want to talk about the central role of the gut. This is what I see when I'm in the clinic: a child comes in, and I look at his or her body and try to figure out what's going on inside. In this child his abdomen is a little protuberant but not as dramatic as we usually see. This slide shows one bowel movement from this child. The child has what we call a megacolon, and these are some close-ups of the large caliber stools that this child is passing. Now ordinarily small intestines look beautiful (as in this slide) with a velvety surface, which gives you a lot of area for absorption. In our patients, we frequently see the same kind of pathology that was originally described at the Royal Free; this is a patient that has lymphoid nodular hyperplasia and lots of inflammation. In fact, he had the finding first described at the Royal Free in his ileum, in his cecum, his entire colon (all three parts), and his rectum.
This is a patient who had a regression temporally associated with the MMR vaccine. However, just because the regression followed the vaccine, it doesn't prove causation. He actually has done extremely well since then; he has had language acquisition, and lots of behavioral improvements with nutritional supplements and gut rehabilitation. One of the things that brought about a marked improvement was taking gluten out of his diet. For those of you who might think that changing the diet couldn't really have profound medical effects, the little girl on the left has a gluten intolerance and the picture on the right was taken after only ten weeks of gluten restriction. You can see this makes a huge difference for the vulnerable kids.
Part of what we try to do in the clinic on a day-to-day basis is to look at a number of things like food allergies, abnormal flora, yeast, problems with parasites, or the fact that the villi that are supposed to be absorbing nutrients are blocked by these constipated stools. We try to fix that by removing the offenders that are causing the damage, re-inoculating with good flora, and repairing the children nutritionally on a day-to-day basis. I'm going to give you this mother's daily routine for achieving that end:
I am the first to admit that I probably could not do, day after day, what I ask the parents of autistic children to do. Her regimen was quite complex as you can see. Some of you might say, "How could nutritional therapy make such a big difference for a child?" Dr. Usman was the first person who taught me about biotin deficiency. The child in the top frame had a specific deficiency of biotin. He developed dermatitis in perianal, perioral, and eyelid areas along with some thinning of hair. Look how dramatically better the child was after only four days of having this crucial nutrient supplied to him. The difference can be phenomenal.
The second thing I want to talk about is the impact of genetic susceptibility. You've heard two lectures now that have talked about this in some detail, but I want to give you the clinical piece. This is a copy of the same diagram that you were shown before, demonstrating the central role of glutathione down here at the bottom. I had a patient named Nathan who first came to me as a four year old who was just coming in for a check-up. He had delayed toileting. His preschool had noticed things like sensory overload, lack of empathy, and a lot of anxiety symptoms. The school consultant was concerned that he might have Asperger's. Dr. Greenspan, whose work I respect greatly, diagnosed him with a static encephalopathy with regulatory disorder, motor problems, and sensory dysfunction. He received standard immunizations but did not get the Hepatitis B vaccine at birth. (One thing I am proud of in our community is that the local pediatricians decided that universal Hepatitis B vaccine at birth did not seem like a good idea. So when much of the rest of the country was doing the Hep B vaccine at birth, we were waiting.) But he still received cumulatively a huge load of thimerosal—187 mcg--by one year of age, when he got an MMR. In fact, he actually got two MMRs: one at 12 months, the same day he was given another vaccine that had 12.5 micrograms of thimerosal, and then, because his first immunization was overlooked, at 15 months he was given another MMR. This shows his first MMR on his growth chart. He had a little bit of a flat line afterwards and was able to regain in the ensuing months. Now, I want to show you the genetics and why that was not a good thing for this particular child. There are a number of enzymes that are dysfunctional in autism and the single nucleotide polymorphisms (SNPs) that you heard about earlier have an impact on the function of these enzymes. Having certain SNPs, which Allan Goldblatt described, would make Nathan uniquely vulnerable to potential bad reactions to such a heavy vaccine load.
For example, he had a problem with something called catecholamine O methyltransferase (COMT), which is responsible for breaking down neurotransmitters. He received the dysfunctional form of the gene from both of his parents (he was homozygous). When that happens, the children tend to have a four-fold decrease in the enzyme activity. He also had another abnormality in his glutathione pathway, having to do with enzymes that would help him break down toxins, and so this function was very poor. Then when you look at the methylenetetrahydrofolate reductase (MTHFR) and the related enzymes like the MTRR that Dr. Bradstreet was talking about earlier, you can see that he was very vulnerable genetically. We've talked about MTHFR before. This child inherited the ineffective SNP from both of his parents for methionine synthase and MTHFR.
Next I want to look at the clinical effects of the environmental toxins Dr. El-Dahr and Dr. Haley talked about. We use a lot of historical clues. As Dr. Wakefield mentioned, when first meeting a patient it is important to take a very thorough history. One of the things that we look for is potential historical clues of toxicity. For instance, let's look at arsenic. Arsenic is in rice to prevent rats from eating it when it's being shipped. Many of you are aware of tin being in dental amalgams and in toothpaste, and a lot of people now know, I think, about aluminum being in cookware. I did not know that nickel was in cocoa. Most people know that lead is in paints and ceramics and pewter -- especially from third world countries. Antimony is a particularly sad story to me. This is another example of the law of unintended consequences. Flame-retardant sleepwear was one of those things that seemed like a good idea at the time, and clearly it would help if the child was trapped in a burning building. But one of the things that happen when incontinent children urinate in their flame-retardant PJ's is that it makes the antimony more toxic. So heavy metal toxicity symptoms clinically are very similar to what I see on a day-to-day basis in my patients: apathy, poor muscle tone, insomnia, problems with sound, light, and tactile sensitivity. They rock. They hand-rub. They head-bang. They have mood swings, meltdowns, tremors, and clumsiness.
Here we see a urine metabolic analysis, which shows that this child is not utilizing methylated B12 or folate efficiently, nor does he have sufficient glutathione. So we were able to target an intervention for Nathan based on these very predictable results based on what we now know about his genomics.
In terms of detoxification profiles and problems, as Dr. El-Dahr says, this is not just mercury. I see a lot of kids with arsenic or aluminum or tin coming out. There was titanium in this particular child, but I have not seen that very often.
The next thing I want to talk about is the clinical effects of the kind of immune dysregulation that Dr. El-Dahr mentioned. This is a patient who is 15 now. He is non-verbal and he stims on a little plastic turtle that he carries around. He had normal development in infancy, but he did have a seizure at one year with no known fever or precipitants. After his MMR, he started having a lot of stimming and flapping, but at that point he was still talking. Then he received a booster immunization at which time he had status epilepticus and lost all his speech within two weeks. He has not talked again since. He developed chronic diarrhea as well as yeast infections.
Eczema is one of the clinical findings that I use as a clue to immune dysregulation, and a very high percentage of my patients with autism have eczema. This is a little girl who has infantile atopic dermatitis, also known as eczema, and that's a sign that I can look at on the skin to tell me that this child has a dysregulation in the Th2 immune status. Another clinical example of what shows up in impaired natural killer (NK) cell function is oral thrush, which is common in newborns, but you should not have oral thrush when you are two or three or five years old or have diaper rashes like this after the age of one. Such rashes are common in early infancy when you're in diapers, but as your immune system matures, you should no longer present like that.
What I frequently see in my patients with autism is this kind of oral candidiasis, even in the teenagers. Dylan, who I mentioned before, had chronic gastritis. He had terrible reflux esophagitis, and he had lymphoid nodular hyperplasia, the finding that was first documented by the Royal Free Hospital, in his ileum and his cecum. When we looked at his immunology profile, he had elevated antibodies to caseomorphin, which is essentially looking at the breakdown products from milk, and he had elevated IgG rubeola antibodies. Rubeola is the medical term for measles. He had elevated myelin basic protein antibodies, which Dr. El-Dahr just taught you about, and he had decreased NK cell activity. Now, this chart is looking at six different clinics across the country. It shows the NK cell activity of 252 children. My patients are shown in the bar graph labeled EM. At the time, my patients seemed to have fewer abnormalities because unbeknownst to Dr. Vojdani, I had sent him some controls in that sample. So I actually think this makes our science more credible since my numbers were lower than my five colleagues because my controls came back as not having abnormal NK cell function. Once we took out my controls and looked at my data, 66 % of my patients also had decreased NK cell activity. If you'll notice on the previous bar graph, that was entirely consistent with what the other five investigators were seeing. So we are seeing in the range of 60 to 69 % of patients with autism having decreased NK cell activity. When I looked at the rest of those immune profiles, 100% of those patients with poor NK cell activity had antibodies against caseomorphin, milk protein, wheat protein, or some combination of those three. All except one of those patients with poor NK cell functions had antibodies against serotonin, somatostatin, secretin, or some combination of those three. I did have two patients that had super-normal NK cell activity, but look how low most of my patients are, in terms of their NK cell functions--it is dismal.
Again, remember everything is interconnected. We know from the same study that kids with poor NK cell function have the lowest glutathione. There's a linear correlation here. So poor NK cell function and poor glutathione levels go together. Again, Dr. Vojdani has shown that over half of children with autistic spectrum disorders have poor NK cell activity, replicating the work of many scientists who have shown the same thing before, and that there is a linear association between poor NK cell activity and glutathione.
The last thing that I want to look at is the integration of metabolic intervention with treatment for gut disease and immune dysregulation, and how the two tie together. I want to tell you about Mitchell. Mitchell is a 16-year-old patient of mine whose infancy was marked by multiple episodes of otitis (ear infections) and purulent rhinitis. He took multiple courses of antibiotics, and he had normal development up until just around 18 months of age. He had had bad reactions to DPT and MMR and a really high fever. He screamed continually for 24 hours. I asked him verbally when I first met him, "What can doctors like me do to help kids like you?" He typed out on his Alpha Smart, "I want you to keep working as hard as you can so that I can talk some day." These kids are "in there." I am convinced that a vast majority of them understand every word I say.
Mitchell, whose biopsy I'll show you in a minute, had mild chronic gastritis. He had erosive esophagitis, and he had lymphoid nodular hyperplasia, as documented at the Royal Free, in his ileum, cecum, and ascending, transverse, and descending colon, as well as his rectosigmoid. This is what his esophagus looked like. When Mitchell came to me he had not slept through the night for four years. He had erosive esophagitis which must have been agonizing. After one week of treatment with the classic GI medications that we use for esophagitis, he started sleeping through the night. He had been in agony. This is his ileum, again, showing lymphoid nodular hyperplasia. We looked for evidence of immune dysregulation and some of the things that we saw are listed here and in your handout (increased IgE, autoimmunity markers, abnormal NK cell function, IgA deficiency, lymphopenia, and T cell abnormalities). When we looked at Mitchell, he had elevated caseomorphin. He had IgA deficiency. IgA is the part of your immune system that's in the mucus in your mouth and in your nose, and it's supposed to try and keep you from getting ear infections and respiratory infections. The vast majority of my patients who are not actually IgA deficient are in the lowest 25th percentile for IgA. He also had decreased NK cell activity. Because of his severe esophagitis and some of his GI problems, he ended up having what's called a Nissen fundoplication, which is a surgical procedure. Post-op he developed a sub-diaphragmatic abscess and one pint of pus was surgically removed from this boy. This is something that in pediatrics we do not typically see except in patients who have conditions like AIDS or cancer. He had to have a PIC line inserted, he was given IV antibiotics for two weeks and he had recurring fevers and GI symptoms. I am very worried that this child is like the ghost of Christmas future and that because of his severe immune dysregulation, he's showing us what can happen as time goes on with this population. Clinically he reminds me of kids with AIDS. I happened to take care of one of the first four cases of AIDS that was described in the state of Virginia from the time the little girl was in the neonatal intensive care unit until she died at the age of 11. She had transfusion-acquired AIDS. I am very worried that Mitchell and similar patients may turn out to have what I have conceptualized as a measles virus-acquired immunodeficiency syndrome. His mother was taking care of him once when he had a draining otitis. She got some of the pus from his ear on her face and developed this horrible cellulitis. This picture is actually of her in her recovery phase. At one point her eyes were swollen shut.
So here we can see some ways that these hypotheses can be integrated. We know that ethyl mercury has effects on immune function and intestinal integrity. We know these kids have poor NK cell function, which can predispose them to difficulty with live viral vaccines. We know it's correlated with glutathione depletion, and we have described a new variant of inflammatory bowel disease. There are cellular consequences of reduced methylation capacity: reduced DNA methylation, altered activity and function of proteins, decreased catecholamine-O-methyltransferase activity (altered neurotransmitter function), and reduced membrane phosphotidylcholine synthesis (altered membrane fluidity and signaling). This is the paradigm I spent a lot of the last year trying to study in order to help these children, and my colleagues each have contributed parts to this diagram. We do not have to do that today. I'm going to give you a couple of mnemonics to walk you through the biochemistry.
Methylation is a crucial biochemical crossroads. Methyl groups consist of a carbon and 3 hydrogen atoms. This is a picture of a cowgirl I dubbed Methyl, who drives a pick-up truck. Think of her CB radio call letters as CH3. Methyl groups like to be picked up, just like Methyl the cowgirl who drives the pick-up truck. As carbon groups move from one compound to another, it changes their biochemical identity and function.
You have heard a lot about glutathione today. Think of glutathione as a working woman who has many responsibilities and multi-tasks. She keeps her family healthy (proper immune function), cleans up after her kids (detoxification) and still makes time to exercise her gluteal muscles (a mnemonic to help you remember GLUTathione).
Folic acid was named for the Latin word for leaf, and looks leafy on a microscopic level. It's excellent for repairing DNA injured by oxidative stress, it helps you hang on to your electrons, and it's used in growth, regeneration, and repair.
Lots of different factors contribute to oxidative stress—radiation, drugs, pollution, poor diet, infection, stress, aging, and injury trauma. This all leads to the loss of glutathione, and cellular aging, disease, and death. Those of us who do this work spend a lot of our day treating oxidative stress.
I want to close with the case of a child named Townsend. This is a child who was born healthy, had colic, lots of fever and swelling after his vaccines, and hives after he got his immunizations. He went on to regress into autism. The thing that really kicked him over the edge seemed to be his pre-kindergarten booster vaccinations. He had started doing better developmentally and then he was "never the same again" after he received MMR, DPT, and IPV on the same day. Physicians, please do not give the second MMR at kindergarten to children in the autism spectrum. In this country it is given to every child because five percent of the kids do not develop enough antibodies after one dose. This shows the challenge/re-challenge phenomenon, where if you give autistic patients the second MMR, there's an increase in acute inflammation and epithelial changes in a significant number of patients versus controls. I recommend that you consider preloading prior to vaccines with certain things like vitamin A and other antioxidants. Please do not give live viral vaccines when the children are sick or on antibiotics or have diarrhea. Townsend had poor NK cell activity, lots of abnormal antibodies and abnormal methylation and folation pathways, as well as low glutathione. This is what he looked like at endoscopy: lymphoid nodular hyperplasia and submucosal hemorrhages.
This is what I want you to remember: when he was in his autistic regression and when the parents were being advised to institutionalize him, he was thought to have an IQ of 60. Dr. Megson, my colleague in Virginia, recovered him largely through interventions on his gut, and by putting him on a gluten-free/casein-free diet. When he was tested again, his IQ went up to 150. He says that he wants to grow up and help the other children who have "supersonic hearing and rainbows in their eyes", which is how he describes the hyperacusis of his autistic regression and his perceptual visual deficits. My take-home message today is: Care for the child. The children are sick. Believe the family. The family will tell you the clues about how to take care of these children if you listen and respect the synergy of biologic systems.