February 2006 Issue | Martha R. Herbert, MD, PhD Center for Morphometric Analysis/Pediatric Neurology

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  • February 2006 Issue | Martha R. Herbert, MD, PhD Center for Morphometric Analysis/Pediatric Neurology




Welcome to Functional Medicine Update for February 2006. This is going to be an exciting issue. We are going to focus on an area of functional medicine that has great opportunity for both general learning and for specific application to a major clinical condition-autism and autistic spectrum disorder, a rapidly advancing area of concern, interest, and clinical opportunity. It is also very telling, because it represents a condition that has multiphasic inputs. It is not a single condition; it does not have a single cause; it does not have just one etiological agent. Therefore, it lends itself nicely to the functional medicine model as a general teaching tool, as well as a clinical evaluation tool.

13th International Symposium on Functional Medicine
This topic fits nicely into our preparation for the 13th International Symposium on Functional Medicine, to be held at the Tampa Marriot Waterside Hotel & Marina in Tampa, Florida on April 19-22. Please note that the symposium is being held earlier than usual this year. It has been held in May in previous years. The focus of the symposium is Managing Biotransformation: The Metabolic, Genomic and Detoxification Balance Points. This is nicely amplified and discussed in our Applying Functional Medicine in Clinical Practice training program and in our new Textbook of Functional Medicine.

We could not be happier to see the textbook hit the desks of our clinicians, practitioners, and Institute for Functional Medicine members. I hope you are as excited about it as I am. It is a culmination of a couple of years of very diligent work on the part of the IFM staff, particularly Sheila Quinn, our Senior Editor, working with David Jones, president of IFM. The quality of the work that has gone into this book on the part of the authors, the editors, the reviewers, and the graphic layout people is a tremendous representation of what we have been trying to achieve over the past 20 plus years we have been talking about functional medicine. If you have not yet seen a copy of the Textbook of Functional Medicine, it certainly should be on your list of things to read. Reading the chapters on biotransformation and detoxification would be a good way to prepare for the 13th International Symposium on Functional Medicine.

This issue is going to focus on one of the most significant debates in medicine, which has been ongoing since 1998. That is saying a lot, with all the things going on in the field of medicine, but in terms of the functional medicine model, the autistic spectrum disorder debate is at the forefront of medical controversy, medical interest, media attention, and parent activism. It has all the trappings of one of the great social issues and historical medical movements of our time. In 20, 30 or 40 years, I am sure that medical historians will write about this period with interesting color. Like all times of great paradigm changes, it is full of energy (and sometimes volatility), a lot of preconceptions and strong statements, as well as strong personalities, which makes it interesting from a humanistic perspective. It also makes it very confusing at times when trying to sort out the wheat from the chaff.

Start of the Debate–1998 Study by Andrew J. Wakefield, et al.
We are going to do our best during the course of this month’s issue of FMU to go through the debate that started with a seminal paper in 1998 that resulted in a rising tide of international controversy and interest in this area. I am talking about the paper by Andrew J. Wakefield, SH Murch, and their colleagues that came out of the Inflammatory Bowel Disease Study Group, University Department of Medicine, Royal Free Hospital & School of Medicine in London. We reviewed this article almost eight years ago in FMU. It is titled “Ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children”1 This report has generated continuous debate, as well as inquiry, discussion, invectives, and every possible kind of adjective that could be used to define human emotion. For eight years, there has been an ongoing debate about this paper and its implications to the etiology and potential treatment of autism and autistic spectrum disorder.

For those of you who may not remember the nature of this particular paper, it was a report on 12 children (mean age of six years) who were referred to a pediatric gastroenterology unit with a history of normal development, followed by a loss of acquired skills, including language, together with diarrhea and abdominal pain. This was conducted in a gastroenterology clinic setting; therefore, the principal reason for referral was digestive problems. The children underwent gastroenterological, neurological, and developmental assessment. Ileocolonoscopy, biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were also done (under sedation). Barium follow-through radiography was done where possible, and biochemical, hematological, and immunological profiles were examined. Based upon information from the parents, it was reported that the onset of behavioral symptoms was associated with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioral disorders included autism (nine), disintegrative psychosis (one), and possible post-viral or vaccinal encephalitis (two). There were no focal neurological abnormalities, and MRI and EEG tests were normal. Noted abnormal laboratory results included a significantly raised urinary methylmalonic acid, as compared with age-matched controls (p=0.003), low hemoglobin (4 children), and a low serum IgA (4 children). The researchers concluded that the gastrointestinal disease and developmental regression in this group of previously normal children was generally associated in time with a possible environmental trigger-the MMR vaccination.

Groundswell of Controversy
When this article was published, it created a groundswell of controversy. Those in support of a multifocal environmental connection to neurologic disease jumped on the bandwagon, whereas those who felt this was presumptuous and not supported by hard facts considered it an exaggeration of findings and an extrapolation beyond reason. There is something interesting about this study that I have not heard discussed much-the biochemical recognition that these children had a significant increase in urinary methylmalonic acid excretion as compared to age-matched controls. What that means to me as a clinical biochemist, and probably to all of you who are students of functional medicine, is that it may have been an indication of a functional vitamin B12 deficiency. A raised methylmalonic secretion is often coupled with elevated homocysteine-the metabolic abnormalities associated with functional B12, folate, and/or B6 deficiency. Elevated urinary methylmalonic acid could represent a functional B12 deficiency, which may track back to certain biochemical genetic markers. In other words, do these children have some form of subclinical genetic susceptibility for altered vitamin B12-dependent metabolism? Or, do they have a malabsorption problem, such as a parietal cell insufficiency of intrinsic factor secretion? Vitamin B12 is a very large nutrient that needs to be absorbed in the absence of a “helper,” which is called intrinsic factor. This raises all sorts of questions about gastrointestinal (GI) physiology, vitamin B12 absorption, and the effect B12 has on the neurological system beyond the frank immunological influence between ileal nodular hyperplasia and autistic spectrum disorder.

This is an interesting interpretation of the story: Could there be some kind of immunological event in susceptible children that modifies their gut-associated lymphoid tissue (GALT) activity that, in turn, influences inflammatory processes, lowers absorption of critical nutrients such as B12 (required for neurological function), and translates into not only elevated urinary methylmalonic acid excretion, but also the problems we see associated with autistic spectrum disorder? That is just a question, a hypothesis.

If the folate connection to neurology goes through the pathway of the folate cycle and through 5-methyltetrahydrofolate, homocysteine and, ultimately, to S-adenosylmethionine (SAM), it is possible that the combination of B12 and folate metabolism polymorphisms, coupled with immunological triggers in a child, gives rise to an overlapping series of events that could trigger certain types of neurological dysfunction.

These are all interesting speculations, but as we move forward from the initial observation of ileal nodular hyperplasia (like mumps of the intestinal tract), ultimately being found with pervasive developmental disorder in children labeled as autism, it raises questions about what autism really is. Is it a brain disease, or is it a disseminated disorder associated with immunological imbalances that have neurological sequelae? And that leads to a further question. Could one of the potential environmental triggers in a genetically or immunologically susceptible child be something like mumps, measles, and rubella vaccination?

In public health, this question strikes terror in the hearts of people, because we have, with hard-won success, been able to immunize children and lower many of the very serious diseases that have threatened children’s lives and created huge epidemics of infant mortality, such as rubella, small pox, and diphtheria. These conditions caused serious epidemics and have resulted in the death of many tens of thousands of children. The ability to immunize against these disorders and make them virtually non-existent has been a very successful medical breakthrough. To suggest that immunization is contributing to something as severe as an autistic spectrum disorder, even in a small group of children, raises the question as to whether parents will continue to immunize their children. That has resulted in much debate and controversy. What is the risk versus the benefit? What can we say about the connection between an MMR-precipitating trigger and the ultimate expression of something called autistic spectrum disorder?

Wakefield’s 1998 paper triggered many Letters to the Editor that appeared in various journals, particularly the Lancet. In 1998, there was a plethora of letters 2 arguing that a study of only 12 children is too small to draw any kind of strong conclusions, and indicating that other studies have not corroborated these findings. And, there is evidence from epidemiological records in the UK that there was no increase in the prevalence of autism with immunization. If autism is triggered by the MMR vaccine, one should be able to track back to the 1950s when this vaccination was first routinely required in children. If there is a connection, it should be seen in an increase of autism, but that does not seem to hold true when looking at the epidemiological record.3

In the May 1998 issue of the Lancet, there was an article that talked about autism, inflammatory bowel disease, and MMR vaccination.4 Again, the discussion was about the risk/benefit and how much we can make of the Wakefield data. On behalf of the authors, Wakefield replied, saying that: yes, there are all sorts of reasons to be concerned about the methodology, whether the selection of patients was biased, whether it was a large enough sample size, and whether the data was reported correctly, but that the authors stand by the findings. Furthermore, he stated: “We recommend that pediatric gastroenterologists investigate this problem further, since it is our belief that there is both a large unmet need in the community and a possible window-of-opportunity for some children with autism.”5

We start to see a swirl of debate developing among different factions. Is the data adequate? Is it accurate? Was the study done properly? Did the investigators have a preconceived bias and pounded the data into that bias, or was it a real effect? Many Letters to the Editor in the Lancet over a period of several months debated this topic.

We begin to look at how autism and the GI tract may be interrelated. Another review of Wakefield’s work generated an interesting, critical editorial that came to the conclusion that this paper is a wakeup call.

“Wakefield, et al. are to be congratulated in opening yet another window onto the ever-broadening spectrum of gut-brain interactions. Their findings raise many challenging questions that should provoke further, much-needed research in this area, research that may provide true grounds for optimism for affected patients and their families.”6

This editorial, in response to the Wakefield work, was written by Drs. Eamonn Quigley and David Hurley from the Department of Medicine, National University of Ireland and appeared in the American Journal of Gastroenterology.

Wakefield and his colleagues continued their studies and have published more papers on this concept, with a recent (2000) report in the American Journal of Gastroenterology (a very highly respected journal), titled “Enterocolitis in children with developmental disorders.”7

The authors describe some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. This study extended the size of the previous sample to 60 affected children and 37 developmentally normal controls. Ileal nodular hyperplasia was present in 54 of 58 (93 percent) affected children, and 5 of the 35 control children (14 percent), with a statistical significant difference of p<0.001. Colonic LNH was present in 18 of 60 affected children (30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) and in 2 of 37 controls (5.4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) ileal biopsies from affected children and in 4 of 14 (29{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) with ulcerative colitis, but not in non-inflammatory bowel disease controls (p<0.01).
By extending the sample size to larger groups of children, they were able to support what they had first reported in the Lancet in 1998. They concluded that a new variant of IBD was present in the group of children with developmental disorders. That “raised the ante,” so to speak, relative to the critics who said there could be no such connection.

If it were not for the MMR vaccination connection, this would probably not be so controversial. Had Wakefield’s report just contained a discussion of ileal nodular hyperplasia and the gut/brain connection, he would have presented a striking, new view of the etiology of autistic spectrum disorder. The addition of the vaccination issue resulted in a bite that was too big for many to swallow.

Wakefield’s 2000 paper resulted in another series of commentaries in the Lancet, including one that appeared in the June 15, 2002 issue, titled “MMR vaccination, ileal lymphoid nodular hyperplasia and pervasive developmental disorder.”8 The authors of this editorial (Barbara Hendrickson and Jerry Turner from the Section of Pediatric Infectious Diseases, University of Chicago, Chicago IL) state that perhaps we are starting to develop more understanding of this issue and we should not be rejecting it out of hand. They went on to say:

“Thus, the idea of pervasive developmental disorder-associated inflammatory bowel disease deserves further consideration. In support of this hypothesis, Torrente and colleagues (again with Wakefield) have now reported that IgG and complement C1q were found deposited on the basolateral epithelium in duodenal biopsy specimens from 23 of 25 autistic children, but not in specimens in control cases.”9

The model starts to grow. There was a paper that put a negative twist on this There was a study published in The New England Journal of Medicine, titled “A population-based study of measles, mumps, and rubella vaccination and autism.”10 It was concluded that there was no correlation between the initiation of MMR and frequency changes in autism. The authors conducted a retrospective cohort study of all children born in Denmark from January 1991 through December of 1998. The cohort was selected on the basis of data from the Danish Civil Registration System, which assigns a unique identification number to every live-born infant and new resident in Denmark. MMR-vaccination status was obtained from the National Board of Health. Information on the children’s autism status was obtained from the Danish Psychiatric Central Register, which contains information on all diagnoses received by patients in psychiatric hospitals and outpatient clinics in Denmark. They obtained information on potential confounders from the Danish Medical Birth Registry, the National Hospital Registry, and Statistics Denmark. They looked at 537,303 children in the cohort; 440,655 had received the MMR vaccine. They identified 316 children with a diagnosis of autistic disorder and 422 with a diagnosis of other autistic-spectrum disorders. After adjustment for potential confounders, the relative risk of autistic disorder in the group of vaccinated children, as compared with the unvaccinated group, was 0.92, or slightly lower, and the relative risk of another autistic spectrum disorder was 0.83. The investigators concluded that there was no association between the age at the time of vaccination, the time since vaccination, or the date of vaccination and the development of autistic disorder. This study provides strong evidence against the hypothesis that MMR vaccination causes autism.

In 2002, in the journal, Alimentary Pharmacology and Therapeutics, there was another paper published by Wakefield and his group. Now, he is under tremendous pressure, as you might imagine, from all sorts of groups for his outspoken position on the correlation between MMR and autism. This paper was titled “Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.”11

In this paper, Wakefield states:

“There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin.”

Again, this suggests that autism is not just in the brain, and that it has etiological factors produced elsewhere in the body that contribute to what we see as autistic spectrum disorders and functional brain changes.

Wakefield goes on to say:

“Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.”

In the functional medicine model, we call this the 4R Program-remove, replace, reinnoculate, and repair. This GI restoration program adds back friendly biota and prebiotics, nourishing the GI mucosa, eliminating toxic or parasitic organisms, reducing food allergies, and other immune-activating substances from the diet. The first therapeutic target based on this model would be what, in functional medicine parlance, we call the 4R Program.

The second thing Wakefield talks about is anti-inflammatory and immunomodulatory therapies. These would be things that can reduce the activity of an upregulated GALT (the gut immune system) and lower immunological activity, systemic and hepatic, as well as neurologic microglial and immune inflammatory activity.

The next thing he talks about is a specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut and trying to lower the production of some of the endogenous opioid mimetics. Some of these may come from certain food families by partial hydrolysis. One family that has been implicated is dairy proteins, from which release of certain fragments may take place after partial hydrolysis of the milk proteins that have neurologic activity. Or, there may be secondary byproducts of bacterial fermentation in the gut by specific types of bacteria. Similarly, gluten has been suggested to be potentially neuroactive. This raises some questions about food types, diet types, the GI milieu, and inflammatory/anti-inflammatory balance. Perhaps these would constitute different approaches one might take toward the management of autism and autistic spectrum disorder.
Small Intestinal Enteropathy with Epithelial IgG and Complement Deposition in Children with Regressive Autism
Following up, Torrente et al. published a marvelous paper in Molecular Psychiatry.10 This was the paper referred to in the Lancet article that appears to demonstrate that IgG deposition was seen in the basal lateral epithelial surface in 23 of 25 autistic children, co-localizing with complement C1q. This was not seen in other conditions. These findings seem to demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The findings are suggestive of an autoimmune lesion. There is some kind of activity that results in the body producing an antibody to itself-to the GI and possibly to brain tissue. We have now put the autistic spectrum disorder into the family of potential autoimmune disorders.

In another issue of Molecular Psychiatry, there was a very interesting editorial by Dr. Wakefield, titled “Enterocolitis, autism and measles virus,” in which he states that, in some children, measles infection that attacks the gut mucosal immune system can induce an upregulated immunological vigilance associated with the appearance of autistic spectrum disorder12 Sometimes, we lose the sense of this story because it is so tightly tied to MMR vaccination, but actually, there may be many different triggering factors that precipitate immunological changes that are ultimately seen as autistic spectrum disorder, suggesting there is more than one cause. Yes, the MMR vaccination component is certainly worth attention, but in and of itself, it is not the whole story.

Dr. Wakefield speaks to this beautifully in another article he wrote for the Journal of Pediatric Gastroenterology and Nutrition, titled “The gut-brain axis in childhood developmental disorders.”13 In this article, he proposes that there may be multiple molecules produced through immunological activation in the intestinal lumen that can mediate what we call autism, as noted in this quote:.

“Neuroactive compounds derived from the intestinal lumen can permeate the mucosa; cross the blood-brain barrier; and cause psychiatric, cognitive, and behavioral disturbances. Indeed, this axis is critical in oral medication of psychopathology. Awareness is growing, particularly within the field of childhood developmental disorders, that in a substantial proportion of affected children, gut-brain interactions may be central to abnormal neural development and the subsequent expression of aberrant behaviors. Difficulties in accepting the biological plausibility of such a model, particularly among those whose interests have focused on primary pathogenic mechanisms operating within the central nervous system, may reflect, in part, a perceived lack of an analogous gut-brain interaction in either human or experimental models of encephalopathy. Among gastroenterologists and hepatologists, however, the evidence for such a mechanism is readily apparent. Seeking an analogy with circumstances in which clear evidence shows an influence of the gut on the normal brain, may help advance this argument. ”

“Untreated celiac disease-a aberrant immune response to dietary gliadin, is associated with intestinal mucosal inflammation, increased intestinal permeability, increased absorption and urinary excretion of neuroactive dietary peptides, autistic and psychotic behaviors, and neurological complications. The precise mechanism(s) of central nervous system sequelae has not been established, although toxicity from the gut and autoimmunity are pathogenetic forerunners.”

There is a precedent here. We can even talk about hepatic encephalopathy-a variable impairment of cerebral functioning in patients with acute or chronic liver disease-being the result of multiple biochemical influences on central neural transmitter systems. In addition to the neurotoxic effects of ammonia, we now recognize that derangements of what are called middle-molecular-weight nitrogenous molecules, such as gamma aminobutyric products, or serotonergic products, are evident with regard to hepatic encephalopathy. It should really be called gastrointestinal hepatic encephalopathy-the gut connected to the liver connected to the brain.
I am saying that there is some circumstantial evidence from other fields of medicine that indicates these mechanisms exist in human physiology. They track against specific types of neuropsychiatric disorders, and the connection with children appears to make good sense and be worthy of attention. During the course of the clinical assessment and management of children with autistic spectrum disorders, Wakefield and his group have been impressed by the improvement in symptoms and general improvement in well being after bioclearance before colonoscopy with simply the purging of gut contents.

Treatment of intestinal inflammation with 5-amino-salicylate-based compounds or a polymeric diet resulted not only in the relief of chronic constipation, but significantly improved overall function in these children. There was an elimination of certain potential reactive proteins, like casein and gluten. There was improvement in the microbial function of their gut.

In seeking to test this hypothesis (a role for intestinal Clostridial dysbiosis in autism, specifically through neurotoxic encephalopathy), Sandler et al. noted objective cognitive improvement in autistic children in an open-label study of oral vancomycin, an antibiotic that exhibits minimal systemic absorption.
“Children regressed after cessation of therapy, suggesting that any colonic dysbiosis and associated toxic sequelae probably were secondary to underlying intestinal disease, rather than the primary problem.”

It is interesting that an antibiotic that works principally in the gut could have such an effect on brain chemistry. Again, from a functional medicine model, we see the interconnectedness of the gut to the immune system to the liver to the systemic circulation to the brain and the brain’s immune system through the microglia. The failure of vancomycin to eliminate clostridial spores is also a possibility, although less likely, given the efficacy of the drug in treating Clostridia difficile. This is one approach that has been used as part of the 4R Program (ie., the remove step). By removing specific organisms through antibiotic or antimicrobial therapy, the load of potential secondary metabolites is lowered, which alters immunological function and improves neurological function.

Wakefield goes on to say:
“In summary, within the autistic spectrum, a substantial group of children have what may be primary intestinal pathology. The constellation of developmental disorder and gastrointestinal pathology (provisionally termed ‘autistic enterocolitis,’ combines the paradoxic elements of a motility disorder-esophageal reflux and constipation with spurious diarrhea-and enterocolonic mucosal inflammation, a feature more commonly associated with frank diarrhea.”

Understanding the neurochemical basis of the gut-brain interaction in autistic enterocolitis may be very important in resolving this paradox and helping to develop rational therapeutic approaches. Wakefield has continued this work. One of his papers appeared in the Journal of Clinical Immunology, titled “Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology.”14 Again, he has extended his research to more detailed work on immunity.

Allegations of Research Misconduct
An amazing thing happened in 2004. The Lancet went after Dr. Wakefield and set up an independent investigation board to examine his protocols, his methodology, his research, and his lab notebooks, to see if, in fact, they stood the test of scrutiny. Ultimately, this led to a series of statements in the Lancet, one by Dr. Wakefield in the March 6, 2004 issue, in which he expresses his rancor at such allegations of research misconduct.15 Ultimately, through several debates, that led to a position statement on the allegations published by the editors of the Lancet.16
“The evidence we have seen indicates that ethics committee approval was given for data collection from clinically indicated investigations in the children with an initially undiagnosed illness and who were described in the 1998 Lancet paper.

“As described under Allegation 1, detailed clinically appropriate investigations led to a re-evaluation of the initial diagnosis of these children, as set out in protocol 172-96.

“We do not judge that there was any intention to conceal information or deceive editors, reviewers, or readers about the ethical justification for this work and the nature of patient referral. We are pleased to have had the opportunity to clarify the scientific record over the matters raised by these serious allegations.”

In all the years I have followed this publication on a weekly basis, I consider some of these statements to be quite remarkable.

Lessons of the Research on Autism and MMR
What are the lessons of MMR and of this work, the most remarkable probable evolution of a functionally-based view of chronic disease that we have seen over the last 10 years? Ultimately, this controversy led to Dr. Wakefield’s change of professional residence. He left the Royal Free and University College Medical School in London and moved to the United States to set up his own private research institute. He continues to publish extensively. He published a paper in the Journal of Clinical Immunology, in 2004, titled “Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10.”17

Most recently, Dr. Wakefield published a paper in the European Journal of Gastroenterology and Hepatology, in which he continues to reinforce his original theme. The title of this paper is “The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder.”18

He concludes:
“Ileo-colonic LNH is a characteristic pathological finding in children with ASD and gastrointestinal symptoms, and is associated with mucosal inflammation. Differences in age at colonoscopy and diet do not account for these changes. The data support the hypothesis that LNH is a significant pathological finding in ASD children.”

We are at an interesting juncture in the evolution of this hypothesis. People have challenged that the work was not extensive enough. Dr. Wakefield responded by continuing the work and publishing it in top-flight journals. It has opened up more debate in the field. It has challenged our views, in the sense that disease of the brain is beginning to look more like a functional disorder. It is consistent with a different paradigm of medicine than that of the differential diagnosis-one of the organ-specific pathology model of disease, where multiple organ involvement across many different systems is examined. This is functional medicine, and I honor Dr. Wakefield for being such a vigilant warrior, despite the extraordinary abuse and criticism he has sustained in developing this hypothesis, and his scholarly work and commitment to excellence in getting this message better understood.

It is time for our Clinician/Researcher of the Month, who will do a good job of carrying this discussion forward


Martha R. Herbert, MD, PhD
Center for Morphometric Analysis/Pediatric Neurology
Massachusetts General Hospital-East
Bldg. 149, 13th Street; Room 6012
Charlestown, MA 02129

JB: I’ve been looking forward to this month’s interview for a long time. We are going to be talking with Dr. Martha Herbert, who is an assistant professor of neurology at Harvard Medical School and a pediatric neurologist at Massachusetts General Hospital in Boston. She is a member of the Harvard/MIT Massachusetts General Hospital Martinos Center for Biomedical Imaging. That is all very interesting, but there is something well beyond that we are going to learn about Dr. Herbert.

Jay Johnson and I have been recording FMU for almost 27 years. During that time, I can honestly say I have never read a more interesting, rich, and robust C.V. than that of Dr. Herbert. It stands alone as being the most unique C.V. I have seen over the years. She started off with a Bachelor’s in Fine Arts from the California Institute of Arts in Los Angeles. She went on to pursue a PhD in the history of consciousness, which is pretty remarkable. It gave her some very fundamental knowledge in, as Humphrey Osmond said, “understanding understanding.”

Dr. Herbert received her MD from the Columbia University College of Physicians and Surgeons. Here is a person with a Bachelor’s Degree in Fine Arts, a PhD, and after that an MD, who ends up as an intern in pediatrics, a resident in pediatrics and neurology, a pediatric neurology Fellow and ultimately, a clinical associate in neurology at Massachusetts General Hospital and Harvard Medical School. With that background comes a tremendous range of understanding, from the standpoint of philosophy, psychology, and the history of science, as well as the medical and biomedical sciences.

You might have heard Dr. Herbert give one of her many lectures. Autism is one of the areas on which she is focusing a lot of attention. Her work is ongoing at the Martinos Center for Biomedical Imaging, and her Harvard Medical School/Massachusetts General Hospital connection is focused on research devoted to the structural and functional connectivity in neurobehavioral disorders, particularly autism. She is an active member of the Defeat Autism Now (DAN) group.

I have had the privilege of reviewing a manuscript that Dr. Herbert allowed me to look at that has just been accepted for publication. Before we get into the topic at hand, I’d like to read the abstract portion of this paper. I think it defines the spectrum of discussion we will have in this month’s issue of FMU.

“Autism is defined behaviorally, as a syndrome of abnormalities involving language, social reciprocity and hyperfocus or reduced behavioral flexibility. It is clearly heterogeneous and it can be accompanied by unusual talents, as well as by impairments, but its underlying biologic and genetic basis is unknown. Autism has been modeled as a brain-based, strongly genetic disorder, but a series of emerging findings and hypotheses support a broader model of the condition as genetically influenced and systemic. These include imaging, neuropathology, and psychological evidence of pervasive (and not just specific) brain and phenotypic features; postnatal evolution and chronic persistence of brain, behavior, and tissue changes (e.g., inflammation) and physical illness symptomatology (e.g., gastrointestinal, immune, and recurring infection); overlap with other disorders; and reports of rate increases in improvement or recovery that support a role for modulation of the condition by environmental factors (e.g., exacerbation or triggering by toxins, infectious agents, or other stressors, or improvement by treatment). Modeling autism more broadly encompasses previous work, but also encourages the expansion of research and treatment to include intermediary domains of molecular and cellular mechanisms, as well as chronic tissue, metabolic and somatic changes previously addressed only to a limited degree.”19 (This paper is available from herbertbrainstudies@partners.org.)

This is probably the longest introduction I’ve ever made on FMU, Dr. Herbert, but it’s well deserved. Your background, experience, and focus on this very complex disorder all fit together. Welcome to FMU. The first question I want to ask is: How did your travels take you to this point? Your journey sounds very remarkable.

MH: Thank you. First of all, I didn’t start out as an artist. I started out as a biochemistry major in college. I went to the Bronx High School of Science and I was a “geek.” I come from a family that was very interested in social and political theory, as well as science, so I was imbued with a range of concerns. I took a journey away from science and, while I was doing that, a few things happened. When I was still in college, I got involved with some peer counseling work and became very interested in the biology of emotional catharsis. That’s what eventually led me to neurology. The other thing that happened was spending some time in Mexico working with Ivan Illich before he wrote Medical Nemesis. I stayed in touch with him and went to his medical school to work with him on the history of the body.

I also studied with a variety of complex systems thinkers. The most prominent of them was Richard Levins at the Harvard School of Public Health. I also studied with Gregory Bateson and a variety of other people. I was exposed to integrative thinking for decades and, between graduate school and medical school, I worked with a group of very reflective developmental and evolutionary biologists for a number of years doing seminars.

When I got into medicine and neurology, I thought I was going to look at the biology of emotion, but I got handed autism data. The autism data was initially frustrating and kind of dull. I was trying to do brain behavior correlations, such as which region of the brain is a different size and how that correlates with behavior. We pulled out a few things like language area asymmetry alterations. But what we found really interesting was that the brains were big and they reflected widespread, non-uniform changes. It wasn’t just in one place. You couldn’t reduce the kind of things we were coming up with to any known neuropsychological model. Parallel to that clinically, I began seeing more children. These children didn’t just have behavioral problems; they were sick.

I went to a conference in Rome in 1999 to deliver my brain behavior correlations, and there was someone there by the name of Paul Shattock. He put up a slide about abnormal urinary peptides in autism. As a pediatric neurologist, I knew something about peptides-urinary peptides reflect a metabolic abnormality. That was not what I had been told about autism. If we’re finding measures that are abnormal at that level, the thing we are looking at is a very different animal than what I had previously thought I was looking at. I had a complex biology systems background and then, I walked into a situation where I began to question something I’ve heard Sid Baker say. Do you see what you believe or do you believe what you see? I started seeing things that were different than what I had been told to believe, and I had to deal with it. That’s how I got to where I am.

JB: Through imaging, you see certain things, but what you see is obviously sifted through your belief system. Tell us what you’ve seen through your imaging studies with the autistic spectrum disorders.

Brain Volume Increase in Autism
MH: The first thing we saw was that these brains are bigger. We saw an overall volume increase, and this is the most replicated finding in autism research. I have a review of this in the October 2005 issue of Neuroscience, titled “Large brain in autism: the challenge of pervasive abnormalities.”20 We have been oriented toward looking for modular changes to explain modular behaviors, but here, we have a widespread change. We found that the largest brains existed in high-functioning autism (first identified by Pauline Filipek, who is now at the University of California Irvine), compared to controls. Low-functioning autistic brains in our sample weren’t as big as the high-functioning brains were, but they were still bigger than the brains of children with comparable mental retardation but without autism. We also found that developmental language disorder (DLD) brains were larger than normal. Nobody had ever measured the whole brain in DLD; everybody had been looking at the language areas, presuming that a language disorder is specific to language parts of the brain. We’re now finding out that even developmental language disorder is systemic. These children have a lot of non-language-related neurological problems-clumsiness, and EEG/ERP abnormalities in a variety of things, as well as a possible association with autoimmune abnormalities, in the children or their close relatives in some cases. We found that there was a tendency for the brains to be bigger, and a seemingly countervailing tendency for mental retardation to bring them down a little bit. That was the first thing.

Significance of Brain White Matter
In trying to find out what was making the brain bigger, we found that the predominant thing was the white matter. White matter makes up 30 percent of the total brain volume (cerebral white matter), but it makes up 65 percent of the volume increase. That’s interesting, because most people don’t think of white matter; they’re into neurons, and white matter is just supposed to be there to get neuron signals from one neuron to the next one. Actually, it’s not looking that way anymore. White matter has become interesting in a variety of neurodegenerative disorders, as well as in children’s disorders. The thing about the white matter was, is it all of the white matter, or is it just some of the white matter?

White Matter Parcellation
We have a technique in our laboratory called white matter parcellation. We divide the white matter into zones related to the tract architecture. This was developed for scans where you can’t see the fiber tracts, as new diffusion imaging allows you to do. We found that the white matter that was contributing to the enlargement was what we call the radiate-the outer white matter (including the “corona radiata”) tucked under the gyral folds. This predominantly includes short connections between parts of the cortex that are both close to each other and within the same hemisphere-not the longer tracts, not the corpus collosum that connects the two hemispheres, not the long tracts that go down to the body, but predominantly, the shorter corticocortical tracts. This is also the area that myelinates latest-myelination starts deeper in the brain.

We also found that the later an area myelinated, or the longer it took to myelinate, the more it tended to be larger than in the brains of the controls. We felt that we had found some sort of “archaeological footprint” of something that happens in time, which changes and becomes more intense over time.

The last thing we found was a rather large-scale shift, not away from leftward asymmetry, which was the same in comparing autism, developmental language disorder and controls; but instead an addition of a lot more areas that were rightwardly asymmetric, particularly in the higher order association areas-that is, the areas that are most highly connected up with other multiple parts of the brain. That is interesting, because other people are finding a lot of right hemisphere problems in autism. Those are the main things that we found.21 Where I’m going now is to study these findings on some other levels.

JB: The general suspicion is that the frequency of autism is increasing in our population. Is this factually correct?

Increased Incidence of Autism Linked to Geographical Toxicity
MH: I’ve been showing some slides I got from Ray Palmer, who is at the University of Texas has a paper on autism rates in Texas. They are visual slides-maps of Texas by school district. The interval from 1990 to 1993 is shown on the first map. The interval from 1998 to 2000 is reflected on the second map. There are a lot more districts in the 1998-2000 interval that show a high rate of autism. These images are very visually powerful. Then, Palmer showed the slide of the later time interval with the higher rates next to the Federal Toxic Release Inventory, followed by another map showing the distribution of total toxicity by district. The overlay was remarkable. Every time I show this slide, it’s a complete show-stopper, because you can see powerfully that the increases have occurred more frequently in the areas where there’s more toxicity. Interestingly, there was one district in southwestern Texas that had a very high rate of autism but did not overlap with any indications of high toxicity. It turns out that the oldest mercury mine in the country is located there. The last thing this paper showed was that for every 1000 pounds of airborne-released mercury (I’m talking about environmental pollution here), there was a 43 percent increase in special education rates, and a 61 increase in autism rates. This paper and these images are a potent piece of data consolidation.

My feeling is that if you look at the epidemiological studies, there are differences in methodology from one to the next, which some people use as grounds to say we “cannot be sure” what is happening. But knowing what we know from this Texas study, and what we know is going on environmentally on the planet, my position on this is that the null hypothesis cannot any longer be that nothing is happening. We can’t wait around until we’ve definitively proved there’s an epidemic and exactly what agent is causing it. We need to be incorporating hypotheses right now that address potential mechanisms that could be driving an increase like this, particularly when you see it overlaid with toxics, as was done in Palmer’s paper.

JB: What is this new term, “autistic spectrum disorder,” which seems to broaden the diagnostic criteria, and how did it arise?

Autistic Spectrum Disorder
MH: There’s been a history of trying to refine the behavioral criteria clustered together that we call autism, but even though it’s defined in relation to three behavioral domains, it’s a continuously distributed set of features. Each of the three defining domains of behavioral deficits-language, socialization, and repetitive behaviors-is continuously distributed. Autism spectrum includes conditions called pervasive developmental disorders NOS (not otherwise specified), which are basically the same thing, only milder. To be PDD-NOS rather than autistic, either you don’t meet all the criteria, or you don’t meet them by the age of three. It’s something less severe. In Asperger’s syndrome, there isn’t the language abnormality and the same language delay or impairment, although there may be unusual language. The continuous distribution of the features is a real issue. People involved in the world of genetics are trying to develop measures that deal more with continuous rather than dichotomous variables, because the dichotomous variable approach wasn’t resulting in genetic findings of significance, and it wasn’t helping with studying milder features in relatives. Geneticists are hoping that maybe they’ll get further with the continuous variables.

My problem is that if we define this autism syndrome behaviorally where you’re talking about a biological disorder-we don’t know what the biology is that is driving it, but we do know there’s a set of symptomatologies that tend to travel with it-then maybe the way we’re defining it doesn’t point to the right level at which to look at what’s going on. If these children have GI and immune problems, maybe some of the genetics are GI or immune genetics, or maybe it’s environmental vulnerability genetics-not just brain or behavior.

Autism Environmental Genomics Project
I did an autism environmental genomics project, which I’m just writing up, where I overlaid the genes from the environmental genome project from an inflammatory database (Seattle SNPs) and from the comparative toxicogenomic database, onto autism genome linkage regions. I found 135 genes with mutations in areas that change coding, and 67 of these have never been thought about before in relation to autism. Most people are looking for genes that will directly hit the central nervous system (CNS). Well, maybe the CNS is downstream. Maybe it’s systemic where lots of things are hit in parallel, or maybe cytokines in the gut go to the brain. There are a lot of possibilities, but we need to begin to collect more data that would relate to the range of possibilities that could be going on, given the clinical and epidemiological pictures, and not just assume it’s a brain disorder. That’s what I have tried to convey in my paper, “Autism: A brain disorder or a disorder that affects the brain?” the abstract of which you read at the start of this interview.

JB: Obviously, you’ve gotten everyone inspired with that last discussion. If that doesn’t raise questions and open our minds to new opportunities, nothing will. I recently heard an interview featuring Nobel Prize-winning Laureate, James Watson (the arguable dean of molecular biology). He was talking about the exciting breakthrough in discovering the gene that controls autism. As I listened to him, I asked myself how someone so astute, so erudite, and so knowledgeable, could talk about the gene for autism, but yet that’s what he was saying. I presume from your discussion that you would argue there is not a single loci, but that we’re looking at a polygenomic type of disorder?

Autism Genetics
MH: Yes. We’re looking at multiple high-frequency, low-penetrance genes. I was with Susan Santangelo last night, who has recently written quite a good review of autism genetics. She has been saying that if there were high-penetrance genes that strongly influenced autism, we would have found them by now. It doesn’t look like that’s the type of genetic abnormality going on. And today I just finished listening to Vamsi Mootha who gave Grand Rounds in my department. He received a MacArthur Foundation Award in 2004. He was talking about mitochondrial genetics, and they’re looking at diabetes type 2 as a chronic disorder. They’re looking at patterns of interactions of large numbers of genes and not individual gene changes, as you might see in a minority of disorders. Many of us think that’s the kind of thing going on in autism. You can have multiple polymorphisms in a pathway that give you vulnerability. The vulnerability would come out looking very similar. Let’s say you mess up your glutathione pathways (there’s evidence that this is going on in autism). But you wouldn’t have to do it in the same way each time.
What are the methodologies? That’s one of my problems with studying these network analyses of genomic function. I’m not sure they take into account specific environmental vulnerabilities that we know something about. That’s something I’m actively thinking about. But in one way or another, it’s not going to be one gene/one disease, and unfortunately, James Watson has said oversimplified and reductionist things like that before. I don’t think he’s oriented toward thinking about gene-environment complexity.

JB: That takes me back to your previous discussion (another blockbuster concept) about the amount of white matter in the brains of autistic children. I am reminded of one of the many articles I’ve recently seen that appeared in the Annals of Neurology in 2005, titled “Neuroglial activation and neuroinflammation in the brain of patients with autism.”22

This is work by Diana Vargas and Carlos Pardo at Johns Hopkins. They were talking about the fact that there is a hypothesis that autism is associated with a neuroinflammatory condition. Of course, the white matter of the brain has the glial cells, which is like the brain’s immune system. It puts structure and function together. Is there something you see to this connection of neuroinflammation with autism?

Neuroinflammation and Autism
MH: For those of us who were already aware of the recurrent infections in these children-the eczema, IBD, and the multiple (not always consistent, but definitely multiple) measures of inflammatory dysfunction-this paper was pivotal, because to see microglial and astroglial activation in the brains of those from five years to 44 years old, and inflammatory cytokine and chemokine profiles in both brain and CSF, says that we’re dealing with a chronic disease. The Vargas-Zimmerman-Pardo paper was a breakthrough in identifying these things in the brain and not just “peripherally.” There’s another abstract by Perry and Salomon that reports finding carboxyethylpyrrole, which is a lipid peroxidation marker, in every autistic brain they’ve cut.23 This means that what we’re looking at in autism is something different than what had been thought before, and it’s consistent with what functional medicine is about. Pardo and Vargus say that this is an innate immune reaction in the brain, whereas it’s been pointed out that there’s both innate and adaptive immune reactivity in the gut. It raises the question of interaction among multiple systems of the body. First of all, it’s a chronic disease. Second, it could be environmentally mediated. Third, it’s multi-system.

JB: That segues into what may be one of the greatest controversies in medicine, at least if you’ve followed medicine in the Lancet for the last several years. I’m talking about Andrew Wakefield’s discovery about ileal nodular hyperplasia and MMR vaccination. Do you see this emerging in the field to create some space for discussion, or has it just been rejected as being too preposterous to warrant serious evaluation?

The Vaccination Controversy
MH: I’m going to put on my sociologist’s hat here, if you don’t mind. What I see going on needs a sociological dimension to analyze it, because it’s not just about science. People who are deeply committed from a public health perspective are very concerned about reducing the proportion of the population that gets vaccinations. It’s very difficult to have a discourse in that setting about anything that may appear to undermine the legitimacy of the vaccine program. On the other hand, people involved with immunology and immunotoxicology seem to be more intrigued by the mechanisms that might interact among certain kinds of vaccine exposures and issues in other systems, such as the GI tract.

There are other considerations having to do with economics. I think one of the reasons immunology in autism isn’t further advanced is that people have been staying away from it because they don’t want to be tainted by the vaccine controversy. But now, a lot of people are finding that the immune system is an important thing to deal with in autism. In a way, the levy is down, and we have to start grappling with immune studies in autism. It’s becoming more and more acceptable to do that.

Let’s go back to our previous discussion. I’ve been hearing more and more geneticists talking about the rising rates of autism. I think there’s a kind of evolution to get space to deal with these things, but it isn’t happening in a direct, head-on way. It isn’t about getting the people who have been saying it’s really dangerous territory to do such an abrupt 180 about-face. It’s more that there’s a whole lot of circumstantial information coming out about this, showing that we need to be thinking about immune exposures in certain contexts as being the basis for chronic problems. Once you get that general framework, the vaccine issue could be a special case. As far as people got with it early on, the epidemiological data had not been sufficiently powered to exclude this kind of impact in small numbers of people, but it excludes it as a cause of the overall epidemic. Now, people are starting to get more involved in studying the level of mechanism. If we’re going to treat these children, we have to understand mechanisms. My focus has been toward getting people to gain an appreciation for the multiple types of mechanisms that could be involved in mediating these sorts of changes.

JB: You and David Ziegler, from the Brain and Cognitive Sciences, Mass Institute of Technology, published an interesting paper in NeuroToxicology on volumetric neuroimaging and low-dose early-life exposures related to these conditions, and how there may be a coupling of this pathogenesis of exposure.24 Would you tell us a little bit about that paper, because I think it bears on some of the things you’re talking about.

Autism and Rate of Toxic Exposure
MH: Most toxicological studies have been done with high-dose exposures. When you have a high-dose cytotoxic exposure, enough to directly knock off a cell, you’re going to get a hole in the brain. A few years ago, when I would discuss these things with my colleagues, they would say that autism couldn’t have anything to do with toxins, because if it did, the brains would be smaller. The brains in autism are bigger, so it’s got to be something else. But there is so much research going on now having to do with low-dose and multiple toxic exposures. Let’s talk about low-dose exposures.

At low doses, chemicals can have biomimetic effects. They can act like other signaling molecules and confuse things. If that happens during development, one could experience changes, not like a hole in the brain, but rather widely distributed, involving changes in scale and proportion. That’s the kind of thing I’ve been measuring. These changes are not hugely dramatic because, first of all, there’s not a whole lot of tolerance in the brain. You can’t wildly change the size of something in the brain without causing an enormous problem. We need to understand that when we measure volume changes in the brain, they can be subtle. I think the issue is that people have been very much involved in looking at brain behavior relationships, and they’ve assumed there’s some kind of different genetically determined developmental trajectory and that the brain tissue is basically healthy-they’ve assumed that the brain is just wired differently, or it has different neurotransmitters. If we’re now looking at chronic tissue changes, we could have altered developmental trajectories or subtle tissue changes, such as chronic mild inflammation, that could also change things at a subtle level, but wouldn’t necessarily be confined to the neural systems that govern any particular behavior. They would just be an overlap between the tissue-based pathology of inflammation or oxidative stress and the behaviorally related neural systems that happen to be in the same territory.

I don’t know whether inflammation would specifically target a certain visual or cognitive pathway. I don’t think people have looked at it that much, because for the most part, people who do neurobehavioral research haven’t been thinking about chronic brain tissue pathology.

JB: You’ve raised an interesting question. If, in fact, autism, or a variant thereof, has some neuroinflammation component, the easiest assumption might be to give these children non-steroidal antiinflammatories to treat their disease. But I don’t think the results are quite that simple.

Treating Autism with Steroids
MH: There is a history of treating autism with steroids, going back to the 1970s. Actually, there’s a reporter who’s been on a tear about autism, and he actually googled and found the first person ever diagnosed with autism by Leo Kanner at Johns Hopkins. (Kanner developed the diagnostic category.)

This individual was 71 years old. The reporter showed up on his doorstep, but he wasn’t home. When he was diagnosed back in the early 1940s, Leo Kanner told the family that autism was hopeless, and advised them to place the child with a nice family somewhere to be taken care of, and to get on with their lives, which they did. The child came back six years later at death’s door. He was taken back to Hopkins, but couldn’t be diagnosed, so he was sent home to die. Back home, a local doctor said he had juvenile rheumatoid arthritis, and advised treating it with gold salts, which they did. The juvenile rheumatoid arthritis was resolved-and at the same time, so was the autism! Therefore, the very first child ever diagnosed with autism actually turned out to have an inflammatory condition that seemed to be associated with the autistic symptomatology, in that the autism went away when the inflammatory condition went away. Of note, in a follow-up paper, Kanner noted the improvement in this patient, but attributed it to the kind care of his foster family and made no mention of the inflammatory disease or the medical intervention.

When that investigative news story came out a few months ago, there was a flurry in the community about giving our children gold salts. One of the issues (Carlos Pardo has been very concerned about this and posted cautions on his website), is what kind of inflammation is this, what is it doing, and how do you best treat it? Steroids are radical and they have side effects, but there are people who are thinking about other approaches to treating inflammation, more along functional medicine lines. In a way, the DAN group, a major proponent of such interventions, is like a sister organization to functional medicine. They do a lot of more gentle functional medicine-like interventions with these children, with a fair amount of good results.

JB: That leads us to the end of this extraordinary journey. What does the clinician do, considering the complex state of understanding on this topic? Things seem to be changing. What is the logical thing to do? Are there evaluating methodologies for managing these children?

Assessment and Treatment of Autism
MH: It’s basically a functional medicine type of assessment, but in a pediatric setting. To zoom in from 50,000 feet, you’d want to take care of predominant biomedical imbalances in inflammatory oxidative stress and other pathways, and you need to do behavioral intervention with these children, because they need a lot of reinforcement and systems remapping to function. That’s the outermost level. In order to figure out which kind of problem is predominant, you need to do further studies and history-taking.

On any clinic day, I’ll have some children with diarrhea and other children with no diarrhea; some with regression, some with no regression; some who had 30 ear infections, and others who had none. You need to go through that with some kind of cultivation of biochemistry and immunology, and sort out what the most likely initial target would be that would give you leverage. Also, you can’t just do one thing at a time. There are a lot of things going on that are mutually co-modulating and mutually reinforcing. If they were mutually reinforcing in a bad way, you’d want your treatments to be mutually reinforcing in a good way.

Beyond that, there’s a lot of material on line for the functional medicine approach at the Autism Research Institute. Hopefully, there will be more and more material coming along that will reflect some kind of integration of behavioral and biomedical approaches. There’s a textbook, published by the Organization for Autism Research (OAR) on evolutionary approaches to neurodevelopmental disorders, which does some integration of behavioral and biomedical approaches (Neurobehavioral Disorders of Childhood: An Evolutionary Perspective.25) Hopefully, we’ll see more of that.

JB: That was a brilliant answer. Just last week, I saw an interesting paper that speaks to what you’re talking about with regard to a broad-based approach that’s individualized to the patient. It was a discussion about methylene tetrahydrofolate polymorphisms and their relationship to autism, again, perhaps implicating folic acid in some of these conditions as another thing to be considered.26 Then, of course, there’s Mary Megson’s work on the cod liver oil/vitamin A connection to autism. It seems as if this is an ever-advancing opportunity for developing integrative therapies that are personalized to the individual patient.

Dr. Herbert, I can’t tell you how much we appreciate this interview. It has been an extraordinary journey in sharing your wisdom. We wish you the very best as you continue your work, and we hope we can check back in with you. This clearly is one of the great stories in 21st century medicine.

MH: Thank you for all your help. I’ve learned a lot from you and your work in functional medicine.

Microcurrent Therapy

I would like to conclude this month’s FMU with one other topic. This comes as a consequence of a follow-up with a previous FMU Clinician of the Month, Dr. Carolyn McMakin, and the work she has done on microcurrent therapy. She has been developing this approach and using it to treat low-back myofascial pain, as well as a variety of other pain-related and immunological-related dysfunctions. A very novel study of her work has been published, which is quite exciting.27 It ties into what we were just talking about-cytokines and immunological imbalance, and how they ultimately end up influencing function.

Dr. McMakin was able to demonstrate that microcurrent therapy had a very dramatic effect on cytokine production, and that this production showed a reduction in proinflammatory cytokines within just a few minutes after therapy. This was work done by measuring cytokines and blood spots taken by finger-stick from patients before and after intervention with microcurrent therapy. It indicated that the immunological system, the regulator of inflammation, is actually changed by this energy-medicine concept. Therefore, it opens up multiple ways that we might approach inflammatory conditions resulting from sequelae related to organ-specific pathologies.

I find this a very interesting contribution to our understanding. We are starting to see that the immunologically imbalanced individual may present with many different disease forms. We have been speaking principally in this issue of FMU about the conditions of autism and autistic spectrum disorder, but it is not too far a reach to say that there are many other conditions, such as fibromyalgia syndrome and chronic fatigue syndrome, that also have immune, endocrine, and neurological components associated with inflammation.

We might cluster all of these under the category of autoimmune-like disorders-the body becoming allergic to itself. That would be the gross way of describing it, but perhaps it is not allergic to itself; perhaps it is responding in a way that is designed to be there for molecules in the body that have been modified by oxidative injury, glycation, or by some kind of post-translational effect that makes them into foreign molecules to which the body’s immune system responds. It may be that many of the chronic age-related diseases have their roots in the immune response of the body, which collects injury along the road of life. In children with autism or autistic spectrum disorder, it is possible that these injuries occur very early, perhaps even in utero. At the molecular level, these injuries may activate, modulate, or modify the function of the immune system in individuals with unique genetic characteristics. Post-natal environmental exposures may serve as triggers that lead to the alteration of these mediators that are ultimately immune-modulating and inflammatory-initiating substances with specific tissue focus.

The report by Dr. McMakin-that that the modulation of inflammatory mediators, like cytokines, neurotransmitters, or endorphins, can occur as a consequence of long-wave length, low-energy radiation-indicates that there may be specific patterns, frequencies, or energy pathways that regulate many immunological functions, opening up new doors for potential therapy beyond just that of biochemical or medical interventions.

We are at the threshold of a very extraordinary revolution in thinking about the etiology of chronic disease, how the environment is translated through the immune system into inflammation, and what the therapeutic tools are that may modulate gene expression, post-translational effects, and ultimately immune regulation. I believe that sometime in the future, we will look back on these past 20 years and say that the techniques used for immunological regulation were very primitive. As we move forward, we will use things like gut signaling and modulation of environment input that will lead to both the prevention and treatment of many problematic disorders of today, such as autistic spectrum disorder.

Thanks for being with us. We will see you in March.


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15 A statement by Dr. Andrew Wakefield. Lancet; 2004;363:823.

16 A statement by the editors of The Lancet. Lancet. 2004;363:820-821.

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21 Herbert MR, Ziegler DA, Makris N, et al. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol. 2004;55:530-540.

22 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67-81.

23 Perry G, Nunomuria A, Harris P, Siedlak S, Smith M, Salomon R. 2005. Is autism disease of oxidative stress? Oxidative Stress in Autism Symoposium New York State Institute for Basic Research in Developmental Disabilities, Staten Island NY, pg 15.

24 Herbert MR, Ziegler DA. Volumetric neuroimaging and low-dose early-life exposures: loose coupling of pathogenesis-brain-behavior links. NeuroToxicol. 2005; 26(4):565-572.

25 Melillo R, Leisman G. Neurobehavioral Disorders of Childhood: An Evolutionary Perspective. New York, NY; Springer Science & Business Media: 2004.

26 James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80:1611-1617.

27 McMakin CR. Microcurrent therapy: a novel treatment method for chronic low back myofascial pain. J Bodywork Movement Therapies. 2004;8:143-153.

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