Results tagged “autism” from Pathophilia
As just about everyone knows by now, the Special Masters of the US Court of Federal Claims handed down their decisions on Friday, which deny a causative link between the vaccine preservative thimerosal and autism in 3 test cases.
Among the many opinions rendered in the decisions from the Special Masters (see here, here, and here) are discussions of the autism studies published by Mark and David Geier—whose work has been criticized sharply and at length at this blog and in my 2009 letter to the Journal of the Neurological Sciences.
The court's Special Master George Hastings, for instance, writes in his decision re King v Secretary of Health and Human Services:
[M]ost of the epidemiologic studies that have addressed the thimerosal/autism causation issue have failed to find any association between thimerosal-containing vaccines and autism, but there have been certain exceptions. Those exceptions were studies published by the research team of Dr. Mark Geier and his son David Geier[*]...To be sure, the petitioners in this case have not cited or relied upon those Geier studies in their post-hearing briefs, because, as I will discuss below...the petitioners argue that all of the epidemiologic studies done to date are irrelevant to the petitioners' causation theory in this case. However, since I find that the epidemiologic studies are of relevance, I have found it reasonable to examine those Geier studies, to see if they afford any significant counterweight to the many contrary studies...
After careful consideration, I conclude that the Geiers' studies cannot be given any weight. A number of those studies were considered by the Institute of Medicine (IOM) committee that fully studied the entire thimerosal/autism causation issue in 2004. That committee concluded that the studies were so flawed as to be "uninterpretable," and that the studies contributed nothing meaningful ("noncontributory") concerning the causation issue...The committee noted that the studies were based on databases that themselves had "significant limitations"...and that the studies had "serious methodological problems"...or "serious methodological limitations"...The committee added that the Geiers' articles describing their analytical methods were "not transparent" and omitted "important details," so that it was impossible to evaluate the studies...Other specific deficiencies in the studies were also discussed, including the fact that the Geiers incorrectly used several epidemiologic terms and measures.
In addition, Dr. Fombonne [respondent's expert] agreed with the IOM's criticisms of the Geier studies, and testified that the Geier studies in general failed to use accepted epidemiologic methods...Dr. Rutter [respondent's expert] was critical of the Geier studies as well...Further, petitioners' own expert witness concerning epidemiology, Dr. Greenland, agreed with the criticisms of the Geier articles, acknowledging that those studies are "deficient in methodology"...And none of the expert witnesses for the petitioners vouched for the reliability of the Geier studies.
I have reviewed the published Geier studies discussed in the 2004 IOM report, and I agree with the analysis of those studies set forth in that IOM report. Further, I have reviewed the additional studies published by the Geiers since the 2004 IOM report, and find that those studies suffer from the same type of flaws as the earlier Geier studies. That view includes a study published in 2008 by the Geiers, along with Young as the third author. Two of respondent's experts, Drs. Fombonne and Rutter, testified that that 2008 study was again deeply flawed, and those experts provided a number of specific examples of deficiencies in the study...And, again, none of the petitioners' experts testified in support of that 2008 Young, Geier, and Geier study.
In summary, I conclude that all of the Geier epidemiologic studies are not reliable, and cannot be accorded any weight.
In a lengthy footnote from the decision handed down in the case of Mead v Secretary of HHS, Special Master Patricia Campbell-Smith writes,
Although the studies conducted by Dr. Mark Geier and his son purport to find an association between thimerosal-containing vaccines and autism, their studies have been criticized consistently by various reviewers, including petitioners' own expert epidemiologist, as methodologically deficient...(Dr. Rutter [characterized] the 2008 Young study—that was conducted in part by Dr. Geier and his son...as a poorly designed study for the following reasons: (1) the researchers used a "strange" study design that is both a cohort study [a controlled study] and a time-trend analysis of the available database information [an ecological study] and (2) the researchers included emotional disturbance as one of the neurodevelopmental disorders observed following exposure to thimerosal-containing vaccines even though emotional disorders are not included in any of the official psychiatric classifications systems for neurodevelopmental disorders). The undersigned has reviewed carefully the presented studies conducted by the Geiers and has considered the criticisms leveled against the Geiers' studies. Persuaded that the studies are flawed methodologically in critical respects, the undersigned, without addressing the studies in extensive detail here, declines to accord any evidentiary weight to the studies. The undersigned notes that other researchers have been unable to verify the validity of the Geiers' statistical analysis on a number of occasions and a number of courts have expressed concerns about the reliability of their work.
Campbell-Smith goes on to cite 8 court cases in which the Geiers' work was called, among other things, "unintelligible," or in which Dr. Geier's testimony was described as "not reliable."
In her decision for the third test case, Special Master Denise Vowell affords special attention to the Young, Geier, and Geier study of 2008—which was specifically pulled apart at this blog and by Epi Wonk.
The only studies demonstrating a relationship between TCVs [thimerosal-containing vaccines] and ASD [autism spectrum disorder] are those in which Dr. and Mr. Geier appear as co-authors, including the Young study published in May, 2008, and funded by the OAP PSC [Omnibus Autism Proceeding Petitioners' Steering Committee]...Because petitioners’ own expert commented that the Geier studies were not reliable as evidence... and they were thus not addressed by respondent’s experts, I do not discuss the earlier Geier studies any further. In view of the numerous criticisms of the earlier Geier studies and petitioners' own expert’s dismissal of them, I have placed no reliance on them.
The Young study was an ecological analysis using the VSD database...Doctor Greenland [petitioners' expert] did not comment on this study during his testimony, as the article was introduced after his appearance and excusal. The study found an increased risk of ASD, based on increasing exposure to TCVs. Doctor Fombonne offered several criticisms of this study. In a critique common to many of the studies performed by Dr. and Mr. Geier, Dr. Fombonne commented that the Young article did not provide the data that would allow others to verify the calculations performed.
Doctor Fombonne reproduced one chart from the article...Using the chart, he explained that the birth cohorts used in the study did not all contain the same number of individuals, with most representing 40,000 children...One birth cohort, that of children born in 1990, contains only 2,000 children...When this "outlier" is removed, the purported statistical relationship between ASD and TCVs during the first four years of the sample disappears.
Doctor Fombonne was also highly critical of the authors' addition of invented numbers to the 1995 and 1996 data from the VSD...If the adjustments are removed, there is no correlation at all between the increase in thimerosal exposure and increase in autism cases per 10,000...Doctor Fombonne commented: "It’s dishonest to impute like 45 new cases which are just invented to top up the prevalence in a way which is supportive of their hypothesis. It’s clear that these investigators have a clear track record to do with the data that supports their hypothesis. And I’ve seen that in their previous papers."
Doctor Rutter offered similar criticisms of the Young study...calling it "a poor study for several different reasons"...It began with a cohort design, but ended up being analyzed as a time trend study. That required the authors to make adjustments to the first and last cohorts. Doctor Rutter described this as "putting together chalk and cheese in the hope of gazpacho soup coming out"...The "analytic design and strategy was not a satisfactory one."
He pointed to Table 3 as a striking example of the poor design...Table 3 compares "neurodevelopmental disorders" to several control disorders, measuring the difference in rates of the disorder developing in the cohorts that received 100 micrograms more mercury. The table shows higher rate ratios for autism, ASD, ADD/ADHD, developmental or learning disorders, disturbance of emotions, and tics...Doctor Rutter called this table an example of demonstrating a statistical effect without showing a causal effect...If the neuroinflammation hypothesis is correct, it is difficult to explain how neuroinflammation causes tics or disturbance of emotions. The study reported TCV effects across a very broad range of unconnected disorders having different ages of onset, different genetic factors, and different disease courses...The broad range of effects in these diverse disorders caused Dr. Rutter to be "immediately skeptical as to what [the study] shows."
He also questioned why "disturbance of emotions" was listed in the category of neurodevelopmental disorders, noting that anyone knowledgeable about the field of neurodevelopmental disorders would not have categorized it as one, and would have placed it with the control disorders...To prove their hypothesis that increased mercury exposure causes increases in neurodevelopmental disorders but not control disorders, the authors have to demonstrate that mercury is associated with increased rates of one but not the other. If "disturbance of emotions" was properly placed with the list of control disorders, it would undercut the authors' hypothesis. Their comparison between the two groups is therefore invalid.
Vowell also comments on a reanalysis of the Young et al data by Young herself, who found no association between birth year (which was purported to be associated with exposure to TCVs) and ASD when the imputed cases were removed.
Doctor Young’s subsequently-filed letter indicated that she reanalyzed the data to respond to Dr. Fombonne's criticisms. After she removed the 1990 birth cohort (the one containing only 2,000 cases) and the notional cases for 1995 and 1996, the results for autism, ASD, and unspecified developmental disorders lost statistical significance...She nevertheless defended the use of the 1990 birth cohort and her adjustments to the numbers for 1995 and 1996.
Vowell also dismisses the study of Young et al on the basis of its funding source.
For the reasons indicated in the criticisms proffered by Drs. Fombonne and Rutter, I have accorded the Young study little weight. An additional reason for viewing this study as unreliable is the conflict of interest generated by the PSC’s funding of the study. In its opinion on remand in Daubert, the Ninth Circuit considered whether the matters an expert proposed to testify about flowed from research conducted independently of involvement in the litigation in question, noting that this factor provides objective proof that the research was conducted for scientific purposes.
Yet, despite these unequivocal, disparaging opinions on the work of Geier and Geier, they continue to find sympathetic medical publishers. Their latest article (pdf here) can be found in the Journal of Toxicology and Environmental Health, Part A, which has now published the Geiers' work on 5 occasions.
In their latest article, the Geiers (along with Janet Kern of the Genetic Consultants of Dallas) again try to link the excretion of some urinary porphyrins (their dubious pet marker for mercury toxicity) with ASD severity. The study is very similar to their previously published work in the JNS, and one wonders if there isn't substantial overlap in the study subjects (26 vs 28 children).
Despite the suspicion, the tabulated presentation of the Geiers' urinary porphyrin data in JNS (nanomoles per gram of creatinine) makes it virtually impossible to compare these numbers with their urinary porphyrin values in the latest article (which are presented in "normalized" uP levels). Similar objections can be raised of their graphed data, primarily because of differences in the presentations of the x-axes.
N.B.--The Geier studies reviewed by Special Master Hastings included the following:
That rang 12 years ago.
Yesterday, editors of The Lancet officially retracted publication of a 12-year-old debunked study that linked the MMR vaccine to autism, according to the journal's web site, numerous news sources, and countless blogs. The study is believed to be responsible for declining vaccination rates among children in the United Kingdom and the resurgence of measles.
The journal's decision comes on the heels of an announcement last week from the UK's General Medical Council, which found that 3 of the article's authors—Andrew Wakefield, John Walker-Smith, and Simon Murch—did not act in the best interests of the study's 12 pediatric enrollees. Wakefield, in particular, was cited for "callous disregard" toward his subjects, by plying them with a few pounds in exchange for blood samples at a birthday party. The GMC's report is provided courtesy of Kathleen Siedel at her neurodiversity blog.
The Council's investigation of Wakefield and others was prompted by the investigative reporting of Brian Deer from The Sunday Times. Beginning in 2004, Deer alleged that Wakefield not only held significant financial conflicts of interest, but that he actually manufactured data. Responding to Deer's initial investigation, 10 of the study's 13 authors (including Walker-Smith and Murch) retracted their "interpretation" in a letter to The Lancet.
So where does a discredited UK doctor go? Austin, Texas, evidently. Wakefield is Executive Director of The Thoughtful House Center for Children, a questionable research and treatment center for children with autism. However, Wakefield does not have a license to practice medicine in the state, according to the online database of the Texas Medical Board.
From 2002 to 2006, the prevalence of autism spectrum disorders (ASDs) increased significantly among 8-year-old American boys and girls.* This conclusion is based on a newly published, retrospective review from the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. The CDC investigators ascribe the increased prevalence of ASDs to improved recognition and documentation, but they cannot dismiss a concomitant "true" increase in ASDs.
On the basis of an examination of health and education records at 11 US sites participating in the ADDM Network, the average prevalence of ASDs among 8-year-olds in 2006 was 9.0 per 1000 children (range, 4.2-12.1), or nearly 1%. Among the 10 US sites that provided data for both 2002 and 2006, the overall prevalence of ASDs increased significantly, by 57%. This finding contrasts with a comparison of data from 2000 and 2002, which revealed no significant increase in the overall prevalence of ASDs.
Below are the tabulated prevalence values for ASD at the 10 common sites, stratified by sex, ethnicity, and IQ. These data show consistent across-the-board increases in ASD among the assessed pediatric subgroups.
|
Group |
ASD Prevalence, |
Statistically Significant Increase, % | |
|
2002 |
2006 | ||
|
Overall |
6.0 |
9.4 |
57 |
|
Boys |
9.5 |
15.2 |
60 |
|
Girls |
2.3 |
3.4 |
48 |
|
Non-Hispanic white children |
6.6 |
10.2 |
55 |
|
Non-Hispanic black children |
5.4 |
7.6 |
41 |
|
Hispanic children |
3.2 |
6.1 |
91** |
|
IQ ≤70 |
2.6 |
3.5 |
35 |
|
IQ 71-85 |
1.0 |
1.4 |
90 |
|
IQ >85 |
1.8 |
3.1 |
72 |
The CDC investigators note that the average prevalence of ASDs was higher at sites that had access to health and education records (10.0) than at sites with only health records (7.5). This observation suggests that more opportunities for ASD documentation increase the prevalence of the condition (artificially). Investigators also found that, generally, ASDs were recognized at younger ages in 2006 than in 2002. (And if I'm correctly reading the CDC data, they indicate that significantly more children with below-normal IQs are being classified as having ASDs—a phenomenon that may also explain an increased prevalence of ASDs.)
Most of the children identified as having ASDs in 2006 (70%-90%) displayed developmental problems (eg, language delay) before the age of 3 years; however, the average age at diagnosis was considerably later, at about 4½ years (suggesting lost time for crucial behavioral interventions). In 2006 assessment, most 8-year-olds with ASDs (76%-96%) were receiving special education through public-school programs, under a wide variety of rationales (eg, autism, emotional disturbance, learning disability, language impairment, etc).
The CDC advises that the ADDM Network surveillance sites were selected "on the basis of their ability to conduct active ASD records-based surveillance," and were not intended to be a nationally representative sample. However, the Network accessed the records of more than 300,000 children, representing nearly 8% of all 8-year-olds in the United States.
Data supporting the approximate 1% prevalence of ASDs include a 2007 parent survey and several contemporary international studies, says the CDC.
* ASDs are defined on the basis of documented behaviors consistent with the DSM-IV-TR criteria for autistic disorder; pervasive development disorder, not otherwise specified; and Asperger disorder. The age of 8 years is identified as a "reasonable index age at which to monitor peak prevalence for ASDs." ASD symptoms are usually observed before the age of 3 years.
** The whopping increased prevalence of ASDs in Hispanic children is attributed to the increase in the Hispanic population overall and a prevalence increase of 144% in Arizona. The other Network sites did not reveal an increased prevalence of ASD among Hispanic children.
In 2007, the Vaccine Injury Compensation Program ruled that the family of Hannah Poling, a girl who developed an autistic condition after receiving a concentrated series of vaccinations, was entitled to compensation. The prevailing explanation for Poling's brain dysfunction: Vaccine-induced immune responses exacerbated an underlying mitochondrial disorder.*
The issue of whether children with inborn errors of metabolism (IEM), like mitochondrial disorders, are more susceptible to vaccine-related adverse events was explored by combing data from the vast Northern California Kaiser Permanente electronic medical-record system. Results of the investigation were presented Friday by Kaiser physician Nicola Klein at the annual meeting of the Infectious Diseases Society of America ("Evaluating immunization rates and safety among children with inborn errors of metabolism." Abstract 187).
Klein and her colleagues found no difference in the up-to-date vaccination rates of 79 infants who had IEM and those of 1580 matched, healthy infants.** In addition, vaccination was not delayed during the first year among infants with IEM.
By using data from 322 children with IEM who received any vaccine, Klein et al also found no difference between the rates of ER visits and hospitalizations during the 30 days after vaccination and the same rates on postvax days 31-60. The rationale for the comparison was clarified by Klein at MedPage Today: "If the vaccine was causing any problems, we would expect to see them emerge right around the time of vaccination, not a month later."
MedPage Today also indicated that "children with [IEM] were not more likely than normal children to visit emergency rooms or need hospital care after vaccination"; however, this important finding (if correctly reported) was not included in the meeting abstract, nor was it elaborated by the medical news source.
* Although Poling's mother has implied that the vaccines caused the girl's mitochondrial disorder, a belief that contradicts a general understanding of inborn errors of metabolism and her neurologist father's explanation.
** Up-to-date vaccination rates were assessed at 2 years of age. Subjects were members of the Kaiser system from birth to the age of 3 years during the time period from 1990 to 2007.
HT: MedPage Today.
Update: In an e-mail, Dr. Klein confirms that her study compared ER visits and hospitalizations for the 2 time periods (within 30 days postvax and from 31 to 60 days postvax) only among children with IEM. She further advises that a comparison of ER visits and hospitalizations between healthy children and children with IEM is not appropriate, because the 2 populations are too dissimilar. Children with IEM would be expected to have "higher background rates of ER visits and hospitalizations" than healthy children.
Sometimes even Mark and David Geier can flog only a partial confession out of data.
The father-son duo, along with frequent coauthor Janet Kern, were able to publish yet another study implicating at least some kind of link between mercury (this time from maternal dental fillings) and the severity of childhood autism. But the authors missed on what would generally be construed as the primary endpoint of their study. The negative finding is buried in the latest issue of Acta Neurobiologiae Experimentalis (Warsaw), a journal with an impact factor in the 25th percentile.*
For anyone familiar with the Geiers' previous publications, there is little shock value here. Evidently the authors remain incapable of disinterest. The introduction of the article preferentially cites highly questionable data linking mercury in dental amalgam with various bodily dysfunctions generally and autism spectrum disorder (ASD) specifically. And in consistent form, the Geiers cite their own previously published data to bolster their preformed ideas.**
The study methods are vague and fraught with potential bias: They write, "The present study looked at 100 qualifying participants who were prospectively recruited from patients presenting for outpatient genetic consultations at the Genetic Centers of America." Mark Geier is president of the "Centers," which are evidently located in the basement of his residence in Silver Spring, MD. The study is also described as blinded, although it's not clear who is blinded to what. The subjects, born either from 1990 to 1999 or between 1990 and 1999, were "previously diagnosed" with autism or pervasive development delay (PDD) by a "trained professional." As far as the reader knows, this term could refer to an autism specialist, a general pediatrician, a chiropractor, a naturopath, or a plumber. The study protocol itself is described as being approved by the Institutional Review Board (IRB) of the Institute of Chronic Illnesses, another brainchild of Mark Geier. The makeup and objectivity of this IRB has been called into serious question.
The primary finding of the study was that there was no statistically significant difference between the mean number of maternal dental fillings during pregnancy and the severity of autism. After adjusting for age, sex, race, and geographic residence, mothers of children with autism (defined as "severe") had 4.6 fillings, and mothers of children with ASD (defined as "mild") had 3.1 fillings (P = .0946). (Of course, the arbitrary distinction of severe and mild autism on the basis of the prestudy diagnoses, one of which includes the term "spectrum," is highly problematic.)
Undaunted, Geier et al attempted to define a threshold number of maternal dental fillings that significantly elevated the risk of "severe" autism. After performing a "logistic regression analysis," they concluded that the odds of "severe" (vs "mild") autism more than tripled if the number of maternal dental fillings during pregnancy exceeded 5; however, the risk was only statistically significant with 8 or more fillings. The "threshold" finding is the only conclusion cited in the article's abstract.
The most profound limitation (and there are several...arguably many) of this study is the lack of any data from a control population—namely the mean number of dental fillings in mothers whose children do not have autism.
* For comparison purposes, the NEJM has an impact factor of greater than 99%.
** In the opening paragraph, Geier et al write, "As of mid-2008, the US Food and Drug Administration (FDA) has declined to classify the medical-device safety of amalgams used in dentistry [emphasis added]." Given the article's recent publication date, this statement suggests that Geier et al had been shopping this article around for some time. The FDA issued its final regulation on dental amalgam in July. The mercury component of dental amalgam was reclassified from Class I (low risk) to Class II (moderate risk).
Citalopram (Celexa; Forest), the model SSRI, is no better than placebo for improving general behavior and reducing repetitive behaviors in children with autism or related disorders.* This conclusion is based on a multicenter, NIH-sponsored 12-week trial of the antidepressant in 149 pediatric volunteers (age range, 5-17 years; mean age, 9.4 years) with at least moderate disease. Results of the study were published in the June issue of the Archives of General Psychiatry.
Rates of general improvement (measured with the Clinical Global Impressions, Improvement subscale) were similar with citalopram (32.9%) and placebo (34.2%), and scores for OCD-like behaviors were similarly reduced with either treatment. Adverse event data suggest that citalopram is more likely to be associated with undesirable behaviors—like impulsiveness, decreased concentration, hyperactivity, stereotypy, and insomnia.
The mean dosage of citalopram administered in the study was 16.5 mg/d, with a maximum dosage of 20 mg/d. (The initial starting dosage in adults is 20 mg/d, which is typically increased to a maintenance dosage of 40 mg/d.) Citalopram has not been FDA approved for use in the pediatric population, and the label includes the general "black box" for SSRIs, which warns of suicide risk in minors.
NIH = National Institutes of Health; OCD = obsessive-compulsive disorder; SSRI = selective serotonin-reuptake inhibitor.
* Including Asperger disorder and unspecified pervasive development disorder.
And not to flattering effect.
The Chicago Tribune, a high-profile newspaper with a generally less-than-stellar reputation, nevertheless gets it right with its recent coverage of the father-and-son duo Mark and David Geier and their horrifying Lupron treatment for autism.
'Miracle drug' called junk science by Trine Tsouderos
Physician team's crusade shows cracks by Steve Mills and Tom Jones
In a noteworthy side bar (A flawed rationale for treatment), data from one published study by the Geiers (which they use repeatedly to support Lupron treatment in autistic children) are found to be specious by 3 nationally recognized pediatric endrocrinologists: Paul Kaplowitz, Alan Rogol, and Peter Lee.* Specifically Dr. Rogol labels the Geiers' FSH levels "irrelevant," and states that any conclusions based on the testosterone reference range of 0-10 ng/dL are "worse than meaningless." He also concludes that some of the Geiers' pediatric subjects were too old to be diagnosed with precocious puberty.
Mark and David Geier respond that these pediatric endocrinologists are "not qualified to discuss hormone disorders in autistic children." This forehead-slapping rebuttal is made despite the fact that 1) Mark Geier has no specialized training in pediatric endocrinology and 2) David Geier possesses no more than a BA degree.
* The Geiers' 2006 Hormone Research article was scrutinized at this blog in October of 2008.
In response to my concerns regarding the recently published (online) autism-biomarker study by Geier et al in the Journal of Neurological Sciences, editor-in-chief Robert Lisak asked 2 "distinguished scientists"* to review the article, as well as my letter to the editor and the response of Geier et al. While the new reviewers did not recommend that the paper be retracted (for some inexplicable reason), they did have "significant concerns with parts of the paper," the study's methods, and the authors' interpretation, wrote Dr. Lisak.
Neither reviewer addressed my concerns about the specific metabolite values of Geier et al nor the possibility of subject overlap in a similar Neurochemical Research article; however, Reviewer #1 chided the authors for not providing norms for laboratory values, if available. Reviewer #2 expressed concerns with the authors' lack of intra-assay standards when measuring urinary porphyrins, how these values compare with those from normal controls, and sample collection (both blood and urine). Information regarding control subjects—such as the exact number, gender breakdown, and reasons for testing—were also lacking. Both reviewers stated that Geier et al should have matched subjects and controls for age and sex, when analyzing their results.
Both reviewers also suggested that Geier et al were far too eager to ascribe their results (specifically the presence of urinary porphyrin metabolites) solely to mercury toxicity. They did not consider other possibilities, such as immune conditions, infection, or exposure to other heavy metals. Geier et al did not control for these factors, Reviewer #2 noted, and concluded, "The authors are clearly not objective. They continually refer to the results as indicative of exposure to mercury...not so."
* These unnamed scientists did not originally peer review the manuscript before publication.
In an effort to initiate some kind of corrective, but arguably foolhardy, dialog with the editors of the Journal of the Neurological Sciences—who recently published an autism-biomarker study by Geier et al (see critical posts here and here, for example)—I submitted a Letter to the Editor that identified (what I believe to be) serious flaws in the published work. My letter was published online by the journal March 9 (DOI: 10.1016/j.jns.2009.02.309 [subscription required]). The response letter submitted by Geier et al was published online March 19 (DOI: 10.1016/j.jns.2009.02.305).
Without reproducing the letters, which would violate copyright, I can describe my published criticisms of the JNS article by Geier et al and the authors' responses—which, in my opinion, are compelling only in their creativity.
Criticism 1: Geier et al presented a cherry-picked introduction of published information that causally connects environmental exposure to mercury with autism, while implying support for this link from the Centers for Disease Control and Prevention.
But in their introductory discussion, Geier et al neglected to acknowledge the known pharmacokinetic differences between environmental mercury (primarily methylmercury) and ethylmercury; the growing series of epidemiologic studies that have found no association between ethylmercury-containing vaccines and the risk of autism; and authoritative statements made by the CDC, the Institute of Medicine, and the World Health Organization that deny any persuasive evidence for an autism-mercury link.
Instead of acknowledging these facts, however, Geier et al respond that my comments imply "only isolated statements by researchers associating mercury poisoning with autism." This is a different argument altogether. I don't contend that there's limited published information associating mercury exposure with autism. There's a lot of published crap out there contending all sorts of unfounded nonsense. Certainly Geier et al themselves have contributed liberally to the medical literature that attempts to link mercury exposure with autism and, unfortunately, they have found sympathetic publishers.
My point is that Geier et al refuse to acknowledge the facts raised and, specifically, the series of epidemiologic studies that negates an association between mercury exposure (whether by methylmercury or ethylmercury) and autism. Geier et al completely sidestep this criticism; but moreover, they go on to make a flabbergasting analogy between a mercury-autism relationship and a smoking-lung cancer relationship.
Criticism 2: Metabolite data (specifically for plasma cysteine, plasma oxidized glutathione [GSSG], and plasma total sulfate) of Geier et al are substantially different from values in the literature, including articles cited by the authors themselves.
In their response, Geier et al note that their values for plasma reduced glutathione (GSH) were consistent with those in the published literature. So their initial defense boils down to, "We got 1 out of 4 right." Next Geier et al note that they measured circulating free cysteine, not total cysteine—despite the fact that they cited Han et al as their assay reference, a study providing plasma cysteine values approximately one order of magnitude higher (160-360 µmol/L) than their values (eg, 17.8 µmol/L).* Geier et al go on to cite Mansoor et al (an article not mentioned in their JNS study) as a reference for their cysteine values. In this case, Mansoor et al found a mean plasma reduced cysteine value in their male controls of 14.5 µmol/L, which, in fact, is closer to the cysteine values of Geier et al.
However, Mansoor et al imply that free (ie, non-protein-bound) cysteine exists in both reduced and oxidized forms. So in this case, their mean control value for free cysteine in men would be 14.5 + 88.2, or 102.7 µmol/L. This summed value is consistent with values in other studies, which indicate that the free cysteine level in human plasma is approximately 50% of the total cysteine value and therefore remains substantially higher than the values obtained by Geier et al—for example, 112 µmol/L ± 15.2 in 13 volunteers aged 24-29 years (Guttormsen et al) and 140 µmol/L ± 21 in 10 healthy fasting subjects aged 31-52 years (Suliman et al).
Geier et al then thank me for "raising a question about the units for our [GSSG] measurement." But they claim they had prior knowledge (before submission of my letter to the JNS editor) of a typographical error and state that the units should have been µmol/L, not nmol/L.
Let me just say that this claim is—How can I put it?—very interesting. As documented at this blog, I e-mailed Henry Sershen, associate editor of Neurochemical Research on October 14, alerting him to the discrepant metabolite values of Geier et al, including those for plasma GSSG (which were similarly published in JNS—see Criticism 3):
The associate editor of Neurochemical Research, Henry Sershen, forwarded my e-mail to Mark Geier (anchor author), who reviewed the information and responded to Dr. Sershen that the published values for GSSG were consistent with those of James et al in a 2004 study (which was also cited by Geier et al). In fact, a review of this study reveals that the printed mean value for plasma GSSG in control children, 0.32 nmol/L ± 0.1 (range, 0.11-0.43 nmol/L), is very similar to the control value of Geier et al (0.35 nmol/L ± 0.05). But it is also very different from the control value published by James et al in their 2006 study, 0.24 µmol/L ± 0.1, or 240 nmol/L ± 100.
To that end, I e-mailed Dr. James asking for clarification of the plasma GSSG values in her articles, and she responded that the units in the 2004 article were incorrect and should have been µmol/L, not nmol/L. Consequently this correction negates Dr. Geier's rebuttal that his values for plasma GSSG are consistent with those of James et al.
So after defending his original GSSG units and citing James et al as a confirmatory reference (which was acknowledged to be incorrect by the lead author), Dr. Geier (as the anchor author of Geier et al) now claims that the GSSG unit notation—made in both the Neurochemical Research and JNS articles—was a typographical error.
Last, it should be noted that Geier et al, in their letter response, do not address their discrepant values for total plasma sulfate.
Criticism 3: The possibility of significant overlap between subjects in the JNS study and those in a nearly simultaneously published study by Geier et al in Neurochemical Research is raised. If overlap existed in the 2 study populations, it should have been acknowledged by the authors.
To this point, Geier et al flat out deny that their JNS data were previously published (although, they do not specifically address any overlap of subjects between the 2 studies). This claim is made despite the fact that their control metabolite values (including standard deviations) are identical between the 2 publications, and the fact that their metabolite values in Neurochemical Research (n = 38) and JNS (n = 28) are very similar.
|
Plasma Measurement |
Mean ± SD | ||
|
ASD Subjects of Geier et al |
ASD Subjects of Geier et al |
Control Values of Geier et al | |
|
Cysteine, µmol/L |
17.8 ± 9.5 |
17.8 ± 8.3 |
23.2 ± 4.2 |
|
GSSG, |
0.46 ± 0.16 |
0.48 ± 0.16 |
0.35 ± 0.05 |
|
Total sulfate, µmol/g protein |
924 ± 245 |
934 ± 252 |
1930 ± 184 |
Criticism 4: Geier et al failed to control for age-related differences in urinary porphyrin excretion, given that their subjects ranged in age from 2 to 16 years (for a rationale, see Minder and Schneider-Yin).
Geier et al rebut that I did not read "Table 1" from their study, which compared urinary porphyrins with similar mean and age ranges. They claim, therefore, that subject age should not have affected their results to any significant extent. However, Geier et al fail to note that the age ranges of these groups were still very wide—eg, 3-13 years.
Geier et al then write that 3 "independent" studies from 3 continents "have now demonstrated that porphyrinuria is concomitant with [autism spectrum disorder]." One of these studies is, not surprisingly, from Mark and David Geier, who obtained their porphyrin data from the Laboratoire Philippe Auguste. The author of another autism-porphyrin study is, in fact, at this very laboratory.
* In a previous post at this blog, the possible distinction between total cysteine values and free cysteine in the work of Geier et al was addressed.
In yet another effort to refute the shifting arguments of those who maintain that vaccines cause autism, CHOP physicians Jeffrey Gerber and Paul Offit take on the latest rant of "too many, too soon," in the February 15 issue of Clinical Infectious Diseases.
This most recently developed theory of antivaccinationists proposes that simultaneous administration of multiple vaccines somehow affects (overwhelms, weakens, etc) a child's immune system, which in turn leads to some sort of neurologic effect that triggers autism. The big problem with this theory, as Gerber and Offit rightly note, is that there is no evidence that autism is an immune-mediated (or specifically autoimmune-mediated) disease.
Their counterarguments, with respect to vaccines:
- They do not overwhelm or weaken even a new infant's immune system—which, although immature, can generate "a vast array of protective responses."
- The total immunologic load of currently recommended vaccines (14) is actually much less than that of recommended vaccines administered in 1980 (7)—all thanks to advances in protein chemistry and DNA technology.
- Vaccines actually represent a tiny fraction of the immunologic challenges (eg, all those environmental antigens running around) that a child typically encounters.
- Vaccines don't "weaken" the immune system, as evidenced by the equivalent susceptibility to infections* among vaccinated and unvaccinated children.
- Last, there are no clinical data** to support the idea that spreading out or reducing the number of childhood vaccinations reduces the incidence of autism.
* Non-vaccine preventable.
** And for good reason, because such a study would be unethical.
In yet another news story about autism and its therapy, Jane Brody of the NYT reports on the anecdotal use of a slew of unproven and potentially risky alternative therapies for the severely autistic son of a lawyer couple. Their train of interventions over the years included several dietary changes, a truckload of supplements, glutathione cream, chelation, and hyperbaric oxygen treatments.* With reference to the last invention, Brody writes about the couple's perception of its efficacy for their son.
Only well into the article does Brody allude to the unproven nature of these interventions, by introducing Dr. Michael Fitzpatrick, a general practitioner in London who also has an autistic son. Fitzpatrick is the author of MMR and Autism and the recently published Defeating Autism: A Damaging Delusion. Brody quotes Fitzpatrick, when he likens the use of alternative therapies for autism as a return to "medicine's dark ages."
And in the last 4 paragraphs of her article, Brody finally (finally) describes the use behavioral therapy for autism, a scientifically validated (but labor-intensive) approach to improve an autistic child's communication skills. Brody would have performed a greater journalistic service by describing this intervention and highlighting its benefits from the get-go.
* At least Brody didn't imply any relation between autism and the boy's vaccination status.
In 2008, the United States experienced the largest measles outbreak in more than 10 years, due to pockets of imported or importation-associated disease in unvaccinated individuals.* An August report in the MMWR indicated that more than 80% of these 131 cases were related to 7 outbreaks (≥3 cases). Fifteen individuals, including 4 children younger than 15 months of age, were hospitalized for disease.
Most important, however, is the fact that a whopping 91% of cases occurred in individuals who had not received vaccination or whose vaccination status was unknown. Among these 112 patients, 85% were eligible to receive vaccination, but 66% had declined because of "philosophical or religious beliefs." In many cases, elected exemptions are based on parents' disproven fears of the risk of autism.
In England, measles was declared endemic this year for the first time since the mid-1990s, because a critical number of parents declined vaccinations for their children. Gibraltar also experienced an unprecedented measles outbreak, which affected 1% of the population. The outbreak was blamed on the poor uptake of measles vaccination and a subsequent shortage of the vaccine.
Those most affected by the deferral of measles vaccination are immunocompromised children and children younger than 12 months of age, who rely on adequate herd immunity. It appears to be a matter of time before a measles outbreak will cause a known, severe complication of the disease, like encephalitis or death, in the United States. Such an event occurred in April in the United Kingdom.
By way of contrast, worldwide deaths due to measles dropped dramatically, according to the World Health Organisation. The plunge in measles-related deaths, from 750,000 in the year 2000 to 197,000 last year, is due to a massive, coordinated vaccination effort, the Measles Initiative. In Africa and countries of the Eastern Mediterranean region specifically, the effort resulted in a fall in measles deaths by approximately 90% during the same time period. The goal of the Measles Initiative—which is led by the American Red Cross, the CDC, the UN Foundation, UNICEF, and WHO—is to reduce the number of measles deaths worldwide by at least 90% by the year 2010.
Because the majority of measles-related deaths no longer occur in Africa, vaccination efforts are now being intensified in other regions—particularly India, where 8.5 million children do not receive their first dose of measles vaccine by 1 year of age. According to a spokesperson for the UN Foundation, the success of the campaign depends on urgently needed funds for the next 2 years.
More details can be found at the following Pathophilia links (and at links through these links):
- And the Air-Travel Risks Just Keep on Comin': This Time, Measles
- Looming Large: The Cost of Not Vaccinating
- Measles Outbreak in DuPage County, IL
- Biggest US Measles Outbreak in 10 Years
- Boo, Boo, Boo: US Measles Cases Increase
- Most US Parents Remain Sane, Vaccinate Children
- Measles Hits Gibraltar, Hard
- Global Measles Initiative a Success, but Funding Needed
* The percentage of US toddlers who received at least 1 dose of MMR vaccine (from 91.5% to 93.0%) has remained stable since 2004. Still nearly 8% of American toddlers did not receive vaccination for the disease in 2007, and geographic clusters of unimmunized children appear to account for this year's record number of cases of the highly contagious disease.
Photo of child with measles rash from the CDC.
Is up at Happy Jihad's House of Pancakes. Check out the diabolical and heavily redacted exchange between organizer and head of IL's Department of Purest Evil, Bing McGhandi (right), and the indicted gov (left)—who, like everyone else, can't pronounce "Blagojevich."
Here's news Abbott will love. Use of the anticonvulsant sodium valproate during pregnancy may increase the risk of autism spectrum disorder (ASD), according to a preliminary report in this week's Neurology. Abbott markets the proprietary form of divalproex sodium or Depakote, a 1-to-1 molar combination of sodium valproate and valproic acid. The use of Abbott's drug during pregnancy has been previously linked to an increased risk of neural tube defects in children, and prescribing information for the anticonvulsant contains a black-box warning to this effect.*
In an ongoing, prospective study of the effect of anticonvulsants during pregnancy, UK investigators detected a relatively high incidence, 1.6%, of ASD in a cohort of 632 live births, 47% of which were to women with epilepsy. Those children diagnosed with ASD were significantly more likely to have been exposed to anticonvulsants in utero (7/168), and to sodium valproate in particular. None of the children diagnosed with ASD had a family history of the disorder.
|
Anticonvulsant Exposure In Utero |
No. With ASD (%) |
|
Sodium valproate (n = 64) |
4 (6.3) |
|
Sodium valproate with lamotrigine (n = 51) |
1 (2) |
|
Phenytoin (n = 9) |
1 (11) |
|
Lamotrigine (n = 44) |
1 (2) |
|
None (n = 336) |
3 (0.9) |
The authors acknowledge the preliminary nature of their findings, and that little can be concluded from the rate of ASD in very small treatment subgroups—for instance, phenytoin-treated women. In addition, the relatively young ages of some children in the study may have limited the detection of ASD: a small percentage, 4.3%, were younger than 3 years of age.
* The risk of neural tube defects is decreased with the preconception use of folic-acid supplements.
Among those who maintain that autism is the consequence of environmental mercury poisoning, the use of "provocation" or "challenge" doses of chelators (eg, a "Kelmer challenge test") is frequently proposed as a legitimate diagnostic maneuver. For instance, Mark and David Geier implied that the urinary or fecal excretion of mercury after the administration of DMSA (succimer) or DMPS in children with autism is evidence of mercury overload. But is this conclusion valid?
Over at Quackwatch, dentist and physician Robert Baratz reminds us that, because mercury is a ubiquitous element, it will be detected in anyone's blood or urine at some low, steady-state level (eg, <10 ug/L in urine). He advises, however,
Urine mercury levels can be artificially raised by administering a mercury scavenger (chelating agent) such as DMPS or DMSA, which collect the small amounts of mercury from the body, concentrate them, and then force them to be excreted...The urine level under such circumstances is artificially raised above the steady-state level [emphasis added].
Baratz cites a 2001 study by Frumkin et al, who found no association between a history of occupational mercury exposure and the urinary excretion of mercury either before or after DMSA (10 mg/kg) in former employees at a chloralkali plant or in an unexposed control population. The investigators concluded that a DMSA chelation challenge is not a useful diagnostic test for prior mercury exposure. Baratz writes more emphatically,
The use of a chelating agent before testing—"provoked testing"—should be considered a scam. Anyone told that a urine-mercury level produced after DMPS represents a toxic state is being misled.
Baratz also maintains that mercury levels in stool or hair samples are not accurate indicators of mercury exposure, and that such tests have not been standardized.
In 2004, Archbold et al assessed the urinary excretion of mercury in 13 healthy adult volunteers with dental fillings,* before and after the administration of DMSA 30 mg/kg. These results were compared with the mercury-excretion patterns of patients who claimed to have symptoms caused by mercury-containing dental fillings (Hibberd et al. J Nutr Environ Med. 1998;8:219-231 [no PMID]).
|
Time |
Urinary Mercury, μg/L | |
|
Archbold et al |
Hibberd et al | |
|
Before chelation dose |
2.2 ± 1.9 |
5.0 ± 3.5 |
|
After chelation dose |
13.7 ± 13.6 |
13.1 ± 9.0 |
Archbold et al found that the incremental increase in mercury excretion after the DMSA challenge in asymptomatic volunteers was comparable to that in previously reported symptomatic individuals. They concluded, therefore, that the validity of a chelation challenge test is diagnostically misleading. Their results are consistent with those of Vamnes et al, who also concluded that symptomatic individuals with dental fillings could not be differentiated from asymptomatic persons on the basis of a DMPS challenge test.
In a more recent, pilot study, Soden et al did not find evidence of "an excess chelatable body burden" of arsenic, cadmium, lead, or mercury in the urine samples of 15 autistic children after provocation doses of DMSA. Their study also evaluated 5 neurotypical control children. The authors acknowledge that their study was complicated by the fact that there are no normal references for provoked levels of urinary metals—which is the crux of the problem in general when assessing the level of urinary mercury after a chelation challenge.
DMPS = 2,3-dimercapto-1-propanesulfonic acid; DMSA = dimercaptosuccinic acid.
* One excluded volunteer suffered a severe reaction to DMSA, requiring emergency care.
In a show of institutional wisdom, the NIMH recently scrapped the idea of studying chelation therapy in autistic children. The study would have been the first well-controlled trial in autistic children of the treatment, which has been used largely on the QT and based on the unfounded idea that autism is caused by environmental mercury poisoning.
Published effects of chelation in autistic individuals (according to a PubMed search) are confined to case reports and letters—which, in some instances, reveal serious adverse effects, including death, of the therapy. A recent case report from The Netherlands described the development of Stevens-Johnson syndrome with oral DMPS therapy (eg, Unithiol, Dimaval, Mercuval) in an asymptomatic 11-year-old boy exposed to mercury vapor.
In 2005, a 5-year-old autistic British boy died after undergoing chelation therapy (Na2EDTA or edatate disodium 990 mg) by IV push in the office of US physician Roy Kerry. The cause of death was cardiac death due to hypocalcemia. (Addendum: This case was presented online last month in Clinical Toxicology.) Also that year, a 2-year-old girl with lead poisoning died of chelation-induced hypocalcemia, due to the unintentional administration of Na2EDTA (Endrate; Hospira) instead of the ordered CaNa2EDTA (edatate calcium disodium or Calcium Disodium Versenate; 3M) in a Texas hospital. In 2003, a 53-year-old woman in Oregon died of cardiac arrest due to hypocalcemia after receiving an unspecified EDTA compound, 1500 mg, by IV push. The chelator, prescribed by a naturopathic physician, was intended to remove heavy metals. (These deaths were also reported in the MMWR.)
According to Brown et al (2006), CaNa2EDTA (which is a nonspecific metal chelator) and another chelator, succimer (DMSA or Chemet; Ovation), are unlikely causes of hypocalcemia. Na2EDTA, however, "should never be used for treating lead or other heavy metal poisoning in children because it induces hypocalcemia, which can lead to tetany and death." According to the prescribing information, Na2EDTA is "indicated in selected patients for the emergency treatment of hypercalcemia and for the control of ventricular arrhythmias associated with digitalis toxicity." Earlier this year, the FDA issued a public health advisory regarding confusion between Na2EDTA and CaNa2EDTA and recommended the use of newer alternatives for Na2EDTA indications.
In the 2007 case series of Mark and David Geier (which shows up in a PubMed search for trials or case reports, using the words "autism" and "chelation"), DMSA or DMPS was administered to 8 children (at 3-14 years of age), most often as "provocation" or "challenge" doses. The amounts of DMSA or DMPS administered in these cases are not specified. Three children (at 3, 5, and 5 years of age) received "therapy" or a "treatment course" with DMSA or DMPS. Dosages prescribed and the durations of therapy in these cases are also not specified by the Geiers. Chelation was most often administered orally; although a 5-year-old child received a "provocation dose" of DMSA by suppository, and a 3-year-old child and a 5-year-old child received DMPS "therapy" transdermally.
|
Subject |
Chelation Therapy |
Route of Administration | |
|
1 |
@ 5 years |
"Provocation dose" of DMPS |
Oral |
|
2 |
@ 5 years |
"Provocation dose" of DMSA "Provocation dose" of DMPS |
Suppository Oral |
|
3 |
@ 4 years @ 5 years |
DMSA "challenge" DMSA "therapy" |
Oral Not described |
|
4 |
@ 3 years @ 5 years |
"Provocation" DMSA DMPS "therapy" |
Oral Transdermal |
|
5 |
@ 5 years |
"Provocation dose" of DMSA "Provocation dose" of DMSA |
Oral Oral |
|
6 |
@ 6 years |
"Provocation dose" of DMSA |
Oral |
|
7 |
@ 14 years |
DMPS "challenge" |
Oral |
|
8 |
@ 3 years |
"Treatment course" of DMSA |
Oral |
According to the Chemet (DMSA or succimer) prescribing information, the drug "is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 μg/dL." So-called provocation or challenge doses of the drug are not described. (A PubMed search reveals articles about the provocative use of chelating agents in the setting of lead exposure only—eg, Lee et al, 1995.) The drug is administered orally and on the basis of the child's weight. A course of treatment lasts 19 days and may be repeated, depending on the blood concentration of lead. For children who cannot swallow capsules, the contents may be sprinkled on food. Although there is a lot of online discussion among autism groups about the use of DMSA as a suppository, the manufacturer evidently does not offer a suppository formulation or recommend suppository administration of the agent.
The branded forms of DMPS do not appear to have been reviewed or approved for use in the United States by the FDA. A 2004 letter from the company Heyltex (whose parent company in Germany makes Dimaval) reported cases of skin reactions to pharmacy-compounded versions of the drug for transdermal administration. Most important, the company indicated that it was unaware of any clinical data demonstrating the efficacy or safety of transdermal DMPS and recommended that the drug only be compounded for oral or injectable administration. (The absorption of transdermal DMPS has also been questioned by Orac.*) It is unclear how DMPS is obtained by US pharmacies for compounding; however, the drug may be freely available in Germany without a prescription, given its longstanding status there. (Addendum: In a 1999 issue of the Federal Register, the FDA proposed that DMPS be considered a bulk drug substance that may be used in pharmacy compounding, although the substance is not an FDA-approved drug. According to Anderson and Aaseth (2002),
DMPS is registered in Germany for treatment of mercury intoxication; however, it is not approved in the United States, so unless special permission is given by the US Food and Drug Administration, it is not lawful for physicians to use it in the United States, nor is it lawful for pharmacies to compound it. Still, DMPS is being illegally used by members of the alternative health industry to treat people allegedly suffering from mercury intoxication...)
There is no specific indication by the Geiers that treatment courses with chelation, 2 of which were administered transdermally (DMPS) and 1 of which was administered by an unidentified route (DMSA), directly affected clinical symptoms in their autistic subjects.
DMPS = 2,3-dimercapto-1-propanesulfonic acid; DMSA = dimercaptosuccinic acid; EDTA = ethylenediamine tetraacetic acid.
* The question of the absorption (and the consequent efficacy) of transdermal DMPS is especially important, because the Geiers reported "significantly elevated mercury levels" in the hair of a child who had received transdermal DMPS therapy and "significant concentrations of mercury" in the fecal sample of another child who had received transdermal DMPS therapy, suggesting that transdermal chelation promoted the excretion of mercury.
A respite from the sad chain of questionable studies on autism is provided by this week's NEJM.
Investigators from the UK and UCLA report their discovery of 9 DNA variations (ie, single-nucleotide polymorphisms, or SNPs) in specific regions of the CNTNAP2 gene,* which are associated with a particular language impairment in nonautistic children of families affected by language disorders. These SNPs were found to associate in a highly significant way with the heritable behavioral marker (or endophenotype) of nonsense-word repetition.
But what's really interesting is that these SNP regions in CNTNAP2 have also been implicated (by some of the same investigators) in language delays among children with autism (Alarcon et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82:150-159).
The NEJM authors conclude that similar DNA variations in these regions of the CNTNAP2 gene may predispose individuals to isolated language impairment, or they may contribute to the language impairment in autistic spectrum disorder. In the case of autism, other behavioral features, like impaired social interactions or repetitive behaviors (ie, stereotypy) are proposed to be caused by different genetic mechanisms.
These findings support the prevailing idea that autism, and the observed spectrum of the disorder, is the clinical manifestation of more than one complex, genetic alteration (see Happe F et al. Time to give up on a single explanation for autism. Nat Neurosci. 2006;9:1218-1220).
* CNTNAP2 encodes CASPR2, a neurexin, which is expressed in the developing human cortex. The authors identified CNTNAP2 as a target of the transcription factor FOXP2. (FOXP2 downregulates CNTNAP2 expression.) Mutations in FOXP2 are associated with speech and language disorders.
When examining the work of Mark and David Geier (and by extension, the work of their various coauthors), it becomes readily apparent that their rationales for administering Lupron and chelation therapy to children with autism are, at best, flimsy and, at worst, products of fantasy. It amounts to, in my mind, the twisted end-result of a highly convoluted, technically dense wish fulfillment that rests on these disturbing claims:
- That autism remains a consequence of mercury toxicity (despite a lack of evidence or, in fact, an abundance of contrary evidence);
- That mercury toxicity can be indirectly established by measuring certain urinary porphyrins (on the basis of rat data and a pilot study in Mexican dental workers);
- That questionable values of thiols indicate a reduced capacity to eliminate heavy metals generally and mercury specifically (on the basis of rat and crustacean data);
- That mercury is bound up with testosterone in the human body (on the basis of an in vivo condition not found in living organisms); and
- That children with autism demonstrate central precocious puberty* (in the absence of acknowledging and publicly documenting the diagnostic criteria for the condition).
At this blog, the values of some thiol levels in autistic children published by the Geiers have been questioned in a series of posts—perhaps too many (see, for example, here, here, here, here, here, here, and here). These questionable values undermine the validity of at least one of the Geiers' claims—namely, that thiol levels in autistic children (as the Geiers' indicators of a "reduced detoxification capacity") are significantly different from those in control children.
In a kind of preemptive rebuttal to this very legitimate concern, Geier et al wrote in their recently published article in the Journal of the Neurological Sciences:
It was observed, when comparing the actual numeric values from the current study with previous studies, that there were some differences in the actual values measured for the different metabolites examined. This may reflect differences in the exact methods employed in measuring various blood levels of transsulfuration metabolites [ie, thiol levels], but given the consistency observed between the studies, helps to indicate the overall validity of the observations.
In other words, Geier et al acknowledge that some of their thiol levels are inconsistent with those in other published sources—although they do not admit specifically that their values for plasma cysteine, oxidized glutathione (GSSG), and total sulfate are different by 1, 2, or 3 orders of magnitude from those in the cited literature. They also fail to note that at least 2 of their assay references provide very different values for plasma cysteine and total sulfate, respectively.
But, because Geier et al found statistical differences between autistic children and control children—like those in the work of James et al, for instance—they defend the validity of their findings. This is like saying that, although my measurements of blood pressure are 12/8 mm Hg or 1200/800 mg Hg, instead of 120/80 mm Hg, findings of statistical difference are still valid—which is, of course, rubbish.
And in cases in which the Geiers' thiol levels in autistic children fall within published reference ranges, they nevertheless appear eager to find statistical differences between these levels and those in control children—which violates the spirit of the null hypothesis. Generally such conclusions must be offered extremely cautiously and should require independent reproducibility before recommending costly diagnostic tests or therapies.
In addition, the published drawbacks of thiol testing in human plasma also raise concerns about the validity of the Geiers' conclusions. For instance, the reliability of measuring reduced glutathione (GSH) and GSSG in human plasma has been called into question. Values of these substances are relatively very low in human plasma and can vary substantially on the basis of specimen handling—for instance, they are reported to vary considerably with even minor hemolysis. One laboratory source indicates that it is not possible to distinguish between GSH and GSSG in serum or plasma, owing to their very low levels.
On a related note, there may be confusion about the presentation of values for blood GSH and those for plasma GSH in the Geiers' published work. In "A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorder," which was published in the Journal of Toxicology and Environmental Health, Part A last year, the Geiers measured blood GSH in 5 children (age range, 4-9 years) and reported values from 18 to 28 mg/dL. This range is the same range reported for plasma GSH in 10 children by the Geiers in their 2006 Hormone Research article. To aid further examination of the Geiers' published values for blood or plasma GSH, these results are tabulated along with values from other sources (including other studies written by the Geiers). (Note that values, when necessary, are converted to units of μmol/L [molecular weight of GSH = 307.43 μg/μmol].)
|
Source |
Blood GSH, |
Plasma GSH, |
|
Geier et al, 2008 (n = 28) |
— |
3.1 ± 0.53 |
|
Geier et al, 2008 (n = 38) |
— |
3.14 ± 0.56 |
|
TAP et al, 2008 (international patent application) (n = 2) |
— |
651* |
|
620-970 |
— | |
|
Geier and Geier, 2007 (n = 5) |
585-911 |
— |
|
Geier and Geier, 2007 (n = 1) |
— |
0.933 |
|
Rossi et al, 2006 |
1323-1392 |
— |
|
Geier and Geier, 2006 |
— |
585-911 |
|
James et al, 2006 (n = 80) |
— |
1.4 ± 0.5 |
|
Melnyk et al, 1999 (n = 11) |
— |
6.9 ± 0.5 |
|
Michelet et al, 1995 (n = 13) |
— |
3.57 ± 0.74 |
|
Andersson et al, 1993 |
— |
3.4 ± 0.9 |
|
Curello et al, 1987 (n = 27) |
— |
4.2 |
* This value (originally reported in mg/dL) is not specified to be from plasma in the patent application, but it is presented along with other plasma thiol levels.
The 5 blood GSH values (585-911 μmol/L) reported by the Geiers in their 2007 case series are reasonably consistent with reference values for blood GSH in the literature, and the reference value for plasma GSH in the 10-year-old boy (>2 μmol/L) is also reasonably consistent with the relevant literature (if plasma values of GSH are reliable at all). But the data also suggest that the plasma GSH values (585-911 μmol/L) reported by the Geiers in Hormone Research in 2006 and the GSH values provided in the international patent application may well be blood GSH values.
In the 2007 case series and the Hormone Research study, GSH values were measured at the dubious Great Smokies Diagnostic Laboratory, aka Genova Diagnostics in Asheville, NC. In a curious case of indirect self-reproach, Mark Geier more or less dismissed this laboratory in his recorded June 2007 speech in front of the CDC (@ the 3:26 mark on YouTube), approximately 1 year after his Hormone Research article was published and 1 month after his case series was published.
* And this is without even discussing the Geiers' use of Lupron in autistic children during timely puberty.
Along with co-applicants Mark and David Geier, TAP Pharmaceuticals* filed an international patent application (PCT/US2007/082866), "Methods of Treating Autism and Autism Spectrum Disorders," in October of last year for the use of Lupron (leuprolide acetate, a GnRH analog), with or without chelation, in children with autism. (A big discovery hat tip for finding this patent application, along with related US patent applications, goes to Kathleen Seidel of the Neurodiversity blog.) The text of this application was published in August May of this year, and treatment descriptions in 7 children can be found if the reader is willing to wade through a lot of repetitive verbiage—including a seemingly endless string of "need in the art," "known in the art," and "skilled in the art."
Essentially, the treatment "invention" of TAP and the Geiers is intended to lower elevated mercury levels in autistic children by giving the chemical castrator Lupron. The applicants base this idea on a 1968 article, which showed that mercuric chloride complexes with testosterone in a hot benzene solution, a condition not possible in living organisms. The patent idea of TAP and the Geiers is to lower testosterone in autistic children by giving them Lupron, which then supposedly frees up toxic mercury. The idea is that the freed-up mercury can then be eliminated with the aid of chelation therapy, if necessary.
However, TAP and the Geiers don't limit their endocrinologic therapy to Lupron, nor their disease targets to autism. They also include the treatment possibilities of antiandrogen hormones (eg, cyproterone [Androcur; Schering-Plough AG]) and birth control pills and propose that mercury toxicity is implicated in Alzheimer's disease, diabetes, heart disease, obesity, amyotrophic lateral sclerosis, asthma, and immune disorders.
What follows is a summary of the pediatric "examples" of TAP's and the Geiers' so-called invention. In all cases of autism, remarkable improvements in gastrointestinal symptoms (if present) and social/cognitive skills are described, sometimes within days of what are described as well-tolerated injections of Lupron.
Subject ages: Four children were of prepubertal age (two 6-year-old boys; a 7-year-old girl; and an 8-year-old boy), and 3 children were within the age range of puberty or beyond (an 11-year-old girl, an 11-year-old boy, and an 18-year-old boy).
Previous treatments: Two of the children (a 6-year-old boy and the 8-year-old boy) had undergone previous chelation therapy with DMSA for approximately 11 and 15 months, respectively. Clinical improvement is described in the case of the 8-year-old boy; the 6-year-old boy did not demonstrate improvement with chelation, according to the patent application. The 11-year-old girl received prescription amphetamines (Adderall; Shire) for the diagnosis of attention deficit hyperactivity disorder, given at the age of 5 years.
Claims of clinical signs of precocious puberty: In no case of the prepubertal or pubertal children is the Tanner stage noted in the patent application. Signs of precocious puberty in 3 of the prepubertal children are vaguely described as increased body, leg, or facial hair; masturbation; "genital development"; or "early sexual behaviors." The 11-year-old girl showed "mild signs of precocious puberty" (whatever those may be) and "fully developed pubic hair" by 8 years of age. These descriptions were presumably obtained in retrospect by history. The girl also began menstruating at the approximate age of 10 years—which is earlier than average, but not precocious.
The performance of GnRH stimulation tests in the patient examples, as recommended by the Lupron Prescribing Information, is not described by the patent applicants. Other diagnostic criteria for central precocious puberty described in the PI, including the documentation of advanced bone age and a number of baseline tests (to exclude congenital adrenal hyperplasia, a chorionic gonadotropin-secreting tumor, a steroid-secreting testicular tumor, and an intracranial [eg, pituitary] tumor), are also not documented in the application. Addendum: Head MR imaging was performed in 2 individuals; however, the timing of the imaging is not provided by the patent applicants.
Mercury assessment: Mercury levels in the absence of chelation therapy are provided only in the case of the 11-year-old boy, whose blood showed "minimal" levels of mercury (1.5 μg/L; reference range, 0.0-14.9 μg/L) and whose urine did not reveal the presence of mercury. The patent applicants claim that urinary porphyrins (specifically urophorphyrin[sic] and hexacarboxylphorphyrins[sic]) were elevated in the 11-year-old girl. Measurements of urinary porphyrins have been proposed by the Geiers to be surrogate markers for mercury toxicity in autism on the basis of a rat study.
Thiol levels: Given that the Geiers have proposed a "decreased detoxification capacity" in children with autism, defined by certain thiol levels, these metabolites were measured in 2 children. Levels of plasma cysteine and reduced glutathione (GSH) were measured during and after the 6-year-old boy's initial chelation therapy, and selected thiol levels were measured in the 8-year-old boy after his Lupron/chelation therapy. The plasma cysteine levels, although below the reference range contained in the patent application, are within the control ranges of those in the literature. In the case of plasma GSH, the levels (when converted to units of μmol/L) are orders of magnitude greater than those found in relevant medical/science articles.
|
Plasma Metabolite, μmol/L |
8-Year-Old Boy |
6-Year-Old Boy |
Patent Reference |
Literature Reference |
|
Homocysteine |
5 |
— |
Not given |
6.0 ± 1.3a |
|
Cysteineb |
226 |
212 |
255-320 |
207 ± 22a |
|
Sulfateb |
302 |
— |
302 |
369-451c |
|
Reduced GSHb |
651 |
651 |
>1041 |
2.2 ± 0.9a |
a From James et al, 2006.
b Presented by the patent applicants in units of mg/dL.
c From Chattaraj and Das, 1992.
Testosterone levels: According to the patent applicants, baseline serum testosterone levels were elevated in 2 of their subjects: a 6-year-old boy (23 ng/dL; reference range, 0-20 ng/dL) and the 7-year-old girl (18 ng/dL; reference range, 0-10 ng/dL). They also emphasize high-normal levels of serum testosterone in the 8-year-old boy (25 ng/dL; reference range, 0-25 ng/dL) and the other 6-year-old boy (20 ng/dL). Follow-up testosterone levels predictably rose and then dropped during the Lupron therapy. (According to the Lupron PI, "During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed.")
Lupron therapy: The Lupron therapy for the 7 pediatric subjects is tabulated. Therapy was not uniform and, in some cases, involved supplementation with the non-depot (subcutaneous) formulation of Lupron. The recommended starting dosage for Lupron Depot-Ped, according to the PI, is 0.3 mg/kg every 4 weeks: 7.5 mg if ≤25 kg (≤55 lb); 11.25 mg if 25-37.5 kg (55-82.5 lb); and 15 mg if >37.5 kg (>82.5 lb). How the doses of 22.5 mg IM in the cases of the 8-year-old boy and a 6-year-old boy were derived is not stated by the patent applicants. The Lupron PI also indicates that, if downregulation is not achieved (via GnRH stimulation testing and Tanner staging), the dose should be titrated upward in increments of 3.75 mg every 4 weeks.
|
Subject |
Lupron Therapy |
|
8-year-old boy |
Depot, 22.5 mg IM on 11/24/04, 1/20/05, 3/25/05, 5/25/05, and 7/14/05 |
|
6-year-old boy |
Depot 22.5 mg IM on 4/2/05, 5/21/05, and 7/9/05 |
|
6-year-old boy |
Depot 15 mg IM followed immediately by 0.2 mL (55 μg/kg) sq à gradually increased in 0.1-mL increments to final dose of 0.4 mL (83 μg/kg) sq qd |
|
7-year-old girl |
0.3 mL (55 μg/kg) sq qd à increased by using Depot 15 mg IM to a final dose of 2.0 mg/d (74 μg/kg) |
|
18-year-old boy |
Depot 15 mg IM; augmented with 0.2 mL sq qd à gradually increased in 0.1-mL increments to 0.5 mL (45 μg/kg) sq qd |
|
11-year-old boy |
Depot 15 mg IM; augmented with 0.4 mL sq qd à gradually increased in 0.1-mL increments to 0.7 mL (32 μg/kg) sq qd |
|
11-year-old girl |
Depot 15 mg IM q 28 d plus 3.5 mg sq qd |
In 5 cases, the total duration of Lupron therapy is not specified in the patent application. In the case of the 18-year-old boy, his serum testosterone level dropped from a baseline of 559 ng/dL (reference range, 241-827 ng/dL) to a follow-up level of 28 ng/dL. The serum testosterone level of the 11-year-old boy dropped from a baseline of 153 ng/dL to 35 ng/dL after "several months of treatment." Essentially both boys were subjected by the applicants to chemical castration with Lupron at the end or beginning of puberty, respectively.
The 11-year-old girl, who began menstruating at the age of 10 years, most likely underwent chemically induced menopause with her Lupron therapy. This girl was also treated with "low dose birth control pills," presumably in conjunction with her Lupron therapy. The rationale for prescribing OCPs with Lupron in the 11-year-old girl is not stated by the applicants. (I'm out of my medical territory here, but I've only heard of prescribing Lupron with OCPs in the setting of infertility therapy.)
The Lupron PI states that discontinuation of the drug, when used for central precocious puberty "should be considered before age 11 for females and age 12 for males." This recommendation is presumably to allow timely puberty to begin. In adults, Lupron is FDA indicated for the treatment of prostate cancer, endometriosis, and uterine fibroids.
Chelation therapy: Only 2 subjects, the 8-year-old boy and a 6-year-old boy underwent chelation therapy. In the case of the 6-year-old boy, chelation preceded Lupron therapy. The 8-year-old boy underwent chelation after the initiation of Lupron therapy. The rationale for starting chelation therapy before Lupron injections is not stated by the applicants.
Other hormonal therapies: In addition to the OCPs prescribed for the 11-year-old girl, the 8-year-old boy began therapy with the antiandrogen cyproterone acetate (Androcur; Schering-Plough AG) 50 mg tid between his 2nd and 3rd doses of Lupron. Cyproterone acetate was prescribed for an unspecified period of time.
TAP's name* on this international patent application, along with the Geiers, is more than just a little troubling, given that pediatric subjects were treated with the company's proprietary drug in a maverick, off-label fashion on the basis of dubious theories about autism. Moreover, this off-label treatment, with TAP's evident involvement or knowledge, was performed without clinical-trial protocols (specifically those for the protection of human subjects) being noted in the patent application. In addition, adherence to on-label treatment guidelines, as recommended by the company's prescribing information, is not described. Clearly 3 autistic pediatric patients, who were at the beginning or end of puberty, received a drug that is known to disrupt reproductive function.
DMSA = dimercaptosuccinic acid; GnRH = gonadotropin-releasing hormone.
* Given the dissolution of TAP, it's unclear whether Abbott or Takeda is now the primary applicant for this international patent. Abbott has apparently taken over the Lupron franchise.
In their recently published study in the Journal of the Neurological Sciences, Geier et al not only presented values for transsulfuration metabolites in children with autism spectrum disorder (ASD); they also measured urinary porphyrins. Their rationale for doing so was to test a pet theory that autism is due to a reduced ability to excrete environmental mercury, as a result of an innate "decreased detoxification capacity"—which is proposed to be characterized by altered levels of transsulfuration metabolites. (The questionable values for some transsulfuration metabolites presented by Geier et al in the JNS article and elsewhere have been discussed here, here, here, and here.) In addition, because investigators have not been able to consistently find elevated mercury levels in children with ASD by direct measurement, Geier et al have turned to the use of "mercury intoxication-associated urinary porphyrins" as markers of mercury toxicity (most notably from thimerosal-containing vaccines) in children with ASD. In the JNS article, they write,
[I]t was previously demonstrated that the transsulfuration pathyway products of glutathione [15] and sulfate [16] were related to mercury excretion rates, and that the heme synthesis pathway products of urinary porphyrins can provide specific profiles that reflect mercury toxicity [17].
The references cited by Geier et al in this statement are worth examining.
First, reference "15" is a 1985 article from Ballatori and Clarkson, with the relatively straightforward (if not bone-dry) title, "Biliary secretion of glutathione and of glutathione-metal complexes." This study is an examination of the excretion of methylmercury in the bile in rats, which was found by the authors to closely parallel the biliary secretion of reduced glutathione (GSH). Important pharmacokinetic differences between methylmercury and ethylmercury (which is in the vaccine preservative thimerosal) have been discussed at this blog and by many others. Also the biochemical/biophysiologic leap from rodents to humans should have been acknowledged by Geier et al.
The same criticism can be applied to the use of reference "16," a 2004 review of organ systems in the American lobster (!) that regulate and detoxify environmental heavy metals.
Reference "17" is a 1996 study by James S. Woods from the University of Washington. In rats, Woods demonstrated changes in urinary porphyrins after prolonged exposure to—again—methylmercury. Specifically levels of 4- and 5-carboxyl porphyrins and the expression of precoproporphyrin were demonstrated in the exposed animals. Woods also conducted a possibly controversial pilot study in Mexican dental workers who were exposed to mercury-containing dental amalgam. Woods showed that the excretion of mercury increased and that levels of these urinary porphyrins decreased with chelation.*
In the JNS study, Geier et al measured urinary porphyrins in their 28 subjects with ASD (age range, 2-16 years), but not in their control children—as they did when assessing transsulfuration metabolites. (The reason for not measuring urinary porphyrins in the control group is not explained by the authors.) So without a true control group, Geier et al compared urinary porphyrin values** in their 14 children with "mild" ASD (CARS score ≤38.5) with those in 14 children with "severe" ASD (CARS score ≥38.5). (It's not clear what the authors did with the kids who hit the 38.5 mark.)
Not too surprising, Geier et al claimed significant differences in urinary levels of pentacarboxyporphyin (ie, 5-carboxyl porphyrins) and precoproporphyrin (Table 2) between the mild and severe ASD groups, which would be consistent with the methylmercury rat data of Woods. The authors also ostensibly monkeyed around with the various ratios of urinary porphyrins and found other significant differences between the 2 ASD groups. Additional fiddling demonstrated relationships between the CARS score and some porphyrin ratios. These data are intended to show that the authors' surrogate markers for mercury intoxication—urinary pentacarboxyporphyin and precoproporphyrin—are associated with the severity of autism.
Last, Geier et al assessed the plasma oxidized glutathione (GSSG) levels—as a "strong indicator of cellular oxidative stress"—among ASD children with low urinary porphyrins or high urinary porphyrins and claimed significantly increased levels of plasma GSSG in subjects with high urinary pentacarboxyporphyin or precoproporphyrin levels. Again, Geier et al intended to demonstrate that their surrogate markers for mercury intoxication are associated with a reduced capacity to excrete mercury, per the GSSG level, in ASD children. The main problem with this particular finding is that the plasma GSSG values presented by Geier et al are considerably different (eg, by 3 orders of magnitude) from those published elsewhere, including references cited by the authors.
Also published data suggest that Geier et al should have controlled for age-related differences in urinary porphyrin excretion—especially given that their subjects ranged in age from 2-16 years. A 1996 study by Minder and Schneider-Yin (Age-dependent reference values of urinary porphyrins in children) found distinctive age-related changes in the urinary excretion of 3 porphyrins, which may be explained—depending on the porphyrin—by age-related changes in the physiologic development of the excretion system and heme synthesis. For instance, their data showed that the urinary excretion of coproporphyrin III decreases steadily from the age of approximately 2 years to late adolescence. In an e-mail response, lead author Elisabeth Minder stated, in reference to the JNS study by Geier et al, that "one should control the data for age."
CARS = Childhood Autism Rating Scale.
* Curiously enough, Woods is a coauthor of a 2006 JAMA article, which reported no significant differences in urinary mercury levels or neurologic function between Portuguese children who received dental amalgam and those who received a resin-based composite for routine dental work. The study's ethics were criticized in the Petition to Order Mercury Amalgam Withdrawn From Interstate Commerce. According to the JAMA article, "Urinary...porphyrins were monitored as indicators of renal responses to mercury..and will be reported separately."
** Urinary porphyrin levels from the subjects, who were recruited in Dallas, Texas, were shipped to and measured at, for some inexplicable reason, the Laboratoire Philipe Auguste in Paris. A coauthor of the JNS article is Robert Nataf from the same Paris lab. Nataf is the lead author of a retrospective 2006 study, which reported relatively elevated coproporphyrin and precoproporphyrin levels in children with autism.
Once again, more published laboratory data bolster the argument that some metabolite values presented by Mark and David Geier in their studies of control and ASD children are highly questionable—and therefore, undermine the validity of their study results and, consequently, their conclusions.
A 1999 article from Melnyk S et al (anchor author Jill James) provides mean plasma thiol levels in 11 healthy adult women (Table 3) as follows. These are contrasted with the very different levels obtained by Geier et al in 2 of their studies (all values presented here are in µmol/L [either as a range or mean value ± SD]).
|
Plasma Thiol |
Melnyk et al, |
Geier et al, |
Geier et al, |
|
Methionine |
41.1 ± 2.5 |
1.3-5.0* |
1.2-1.9* |
|
Cysteine |
227.1 ± 4.8 |
23.2 ± 4.2** |
17.8 ± 8.3** |
|
GSH |
6.9 ± 0.5 |
911-1431* |
585-911* |
|
GSSG |
1.5 ± 0.1 |
0.00035 ± 0.00005** |
0.00048 ± 0.00016** |
- In the case of plasma methionine, the published value of Melnyk et al is at least 8 times the control value of Geier et al.
- In the case of plasma cysteine, the published value of Melnyk et al is approximately 10 times the control value of Geier et al.
- In the case of GSH, the published value of Geier et al is at least 84 times that of Melnyk et al.
- In the case of GSSG, the published value of Melnyk et al is at least 3100 times that of Geier et al.
Transsulfuration metabolites in this study were measured at the Great Smokies Diagnostic Laboratory, a laboratory of dubious reputation. Methionine levels were originally presented in units of µmol/L. GSH values were originally presented in units of mg/dL (18-24 in children with ASD), which were then converted here to units of µmol/L for purposes of comparison (molecular weight of GSH, 307.43 µg/µmol).
Transsulfuration metabolites in this study were measured at Vitamin Diagnostics, Inc. Levels of GSSG were originally presented in units of nmol/L, which were converted here to units of µmol/L for purposes of comparison.
ASD = autism spectrum disorder; GSH = reduced glutathione; GSSG = oxidized glutathione.
Following an examination of questionable transsulfuration metabolite values published by Geier et al (summary table below), e-mails were sent to the editors of Neurochemical Research and the Journal of the Neurological Sciences, alerting them to the discrepancies between these data and very different values in the published literature.
|
Plasma Test |
Mean ± SD (Geier et al) |
Reference Control Values in Literature | |
|
ASD Subjects |
Controls | ||
|
Cysteine, µmol/L |
17.8 ± 8.3 |
23.2 ± 4.2 |
|
|
Oxidized glutathione (GSSG), nmol/L |
0.48 ± 0.16 |
0.35 ± 0.05 |
|
|
Total sulfate, µmol/g protein |
934 ± 252 |
1930 ± 184 |
|
The associate editor of Neurochemical Research, Henry Sershon, forwarded my e-mail to Mark Geier (anchor author), who reviewed the information and responded to Dr. Sershon that the published values for GSSG were consistent with those of James et al in a 2004 study (which was also cited by Geier et al). In fact, a review of this study reveals that the printed mean value for plasma GSSG in control children, 0.32 nmol/L ± 0.1 (range, 0.11-0.43 nmol/L), is very similar to the control value of Geier et al (0.35 nmol/L ± 0.05). But it is also very different from the control value published by James et al in their 2006 study, 0.24 µmol/L ± 0.1, or 240 nmol/L ± 100.
To that end, I e-mailed Dr. James asking for clarification of the plasma GSSG values in her articles, and she responded that the units in the 2004 article were incorrect and should have been µmol/L, not nmol/L. Consequently this correction negates Dr. Geier's rebuttal that his values for plasma GSSG are consistent with those of James et al.
Dr. James added that she rarely sees GSSG levels greater than 0.4 µmol/L [or 400 nmol/L] in control children. Others indicate that measurements of plasma glutathione, reduced and oxidized, are highly dependent on testing procedures and vary substantially with even minor hemolysis. Still others indicate that "[i]t is not possible to distinguish between oxidized and reduced glutathione in serum or plasma," owing to very low concentrations.
* Reference cited by Geier et al.
In their 2005 Medical Hypothesis article, which inspired their questionable 2006 Hormone Research study (background here), Mark and David Geier cited a 1997 French case series (really a letter to the editor by Tordjman et al in the American Journal of Psychiatry) to support their measurement of serum testosterone in children with autism. Geier and Geier wrote...
In addition, Tordjman et al have reported on a case-series of 12 prepubertal autistic children (6-10 years old) in their inpatient child psychiatry department, four of whom the researchers observed to have precocious secondary sexual characteristics (growth of pubic hair, increase of testis volume) that suggest high androgenic activity in autistic disorders.
What Tordjman et al actually did, on the basis of their observation of 4 autistic children with precocious secondary sexual characteristics in their practice, was to measure plasma testosterone and adrenal androgen (presumably DHEA or DHEA-S) in 9 pre- or postpubertal inpatients with autism and 62 matched control children. Because of the possible positive correlation between testosterone and aggression, the investigators divided the 9 autistic children into 3 groups according to their aggressive behaviors. Notably, they observed that autistic children who displayed aggression against others were less likely to demonstrate the typical core symptoms of autism (withdrawal, stereotypy, language dysfunction)—which suggests, perhaps, that these children may actually have an alternative behavioral disorder.
Three of their 9 autistic subjects had abnormally high plasma testosterone levels (Table), given the study's matched reference values. These 3 children all showed aggression against others—meaning, according to the authors, they were less likely to demonstrate typical, core autistic symptoms.
|
Patient |
Serum Testosterone, ng/mL | ||
|
Level |
Ref Mean ± SD (range) |
||
|
10-year-old boy |
0.64 |
0.06 ± 0.03 |
0.18-1.50 |
|
17-year-old boy |
8.8 |
5.51 ± 1.27 |
3.50-9.70 |
|
13-year-old girl |
0.5 |
0.12 ± 0.09 |
0.15-0.35 |
The authors noted that the 10-year-old boy exhibited pubic-hair growth, which is probably not a sign of precocious puberty in boys aged 9 years or older. The 13-year-old girl, whose serum testosterone level exceeded the reference range in the study and that provided by the University of Iowa, also demonstrated a very high level of adrenal androgen, 4.40 ng/mL, at least according to the mean level in the study's control population (mean study reference, 0.88 ng/mL ± 0.39 [range, 0.36-1.70]; U Iowa reference range for DHEA, 1.5-5.7 ng/mL).
What Geier and Geier failed to note, however, in both their Medical Hypothesis and Hormone Research articles, is that a previous study by Tordjman et al (1995) did not find elevated testosterone levels in 31 prepubertal children with autism, when compared with 12 prepubertal subjects who had mental retardation/cognitive impairment* or 10 prepubertal control subjects. The mean levels of plasma testosterone and DHEA-S in 8 postpubertal autistic children were also similar to those in 11 postpubertal normal controls. Tordjman et al concluded from this study that "altered secretion of the androgens is not a common feature of autism."
A PubMed search by this blogger failed to disclose any other studies that assessed testosterone or other androgen levels in pre- or postpubertal children with autism.
DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate.
* The study did find increased plasma DHEA-S levels in prepubertal children with cerebral palsy (among those with mental retardation/cognitive impairment).
The discovery of questionable values for transsulfuration metabolites in the recently published studies by Geier et al (in Neurochemical Research and the Journal of the Neurological Sciences) prompts further investigation into the published work of the respective lead and anchor authors, David and Mark Geier. Specifically both recent articles reference a study of the father-son duo that was published in Hormone Research in 2006.
Information in this article has been dissected in detail at the neurodiversity blog, particularly with respect to the validity of son David's academic affiliation, the curious makeup of the IRB that approved the study, and father Mark Geier's limited experience in pediatric endocrinology, to name just three.
Evidently one of the Geiers' favored hypotheses in the pathogenesis of autism concerns the nexus of transsulfuration metabolism, androgen synthesis, and mercury toxicity, and they refer to their speculation on the subject in a 2005 Medical Hypothesis article, which was used to justify the measurement of several hormone levels and transsulfuration metabolites in the Hormone Research study.
In this study, the Geiers examined 16 children (14 boys, 2 girls) with autism spectrum disorder (ASD) who presented to the Genetic Centers of America (which is evidently located at the residential address of Mark Geier, 14 Redgate Ct, Silver Spring, MD).* The children underwent clinical examination, presumably by Mark Geier, to assess traits consistent with "hyperandrogenicity." These traits included, according to the Geiers, "early growth spurt, increased body and facial hair, aggressive behavior, and early secondary sexual changes." The Geiers also measured selected hormone levels (at LabCorp, Inc) and transsulfuration metabolites (at the Great Smokies Diagnostic Laboratory) in these children. A control population was not included in the study. The serum/plasma values of the study subjects were compared with reference values from the particular laboratory used.
So, in essence, the Geiers assessed selected serum/plasma values in 16 children with ASD, from 3 to 10 years of age, whom they believed to display signs of androgen excess (in 15 of the 16 children). However, several of the clinical traits noted by the authors do not, in and of themselves, necessarily indicate endocrine abnormalities in children—including masturbation, growth spurt, and an interest in female sexual organs among boys. A 10-year-old girl is noted to exhibit body hair and sexual development, which is not unusual given the age range of normal sexual development in girls. A 4-year-old boy is noted to exhibit male-pattern baldness, a dubious proposition without further clinical information or documentation. In only one case is the Tanner stage noted by the authors (although it is not indicated whether it is in respect to pubic hair or genitalia).
The subjects of Geier and Geier were tested for "androgen metabolites," including serum testosterone (n = 16), serum/plasma DHEA (n = 11), and serum FSH (n = 14). (Although FSH has androgenic properties in males, the glycoprotein is not, despite the Geiers' description, an androgen metabolite.)
FSH: In all 16 cases, serum FSH levels were within age- and sex-dependent reference ranges of LabCorp, which are consistent with pediatric FSH levels found elsewhere (eg, Pediatric Reference Ranges). However, the authors inexplicably concluded that the mean value of FSH in the 16 children with ASD was significantly decreased (35% of the normal reference). It should be noted that in 5 of these cases, LabCorp was unable to detect FSH in serum samples, and the authors therefore assumed that the value was equal to the lowest level that could be measured by LabCorp.
Testosterone: Geier and Geier reported elevated serum testosterone levels (ng/dL) in 12 of the 16 subjects (all boys). The reference ranges provided by LabCorp are consistent with pediatric ranges provided online by the University of Iowa. Addendum: According to Kaplowitz, prepubertal testosterone levels are generally less than 30 ng/dL; although levels ranging from 11 to 30 ng/dL may represent early puberty. The testosterone levels in all subjects of Geier and Geier were 25 ng/dL or lower.
DHEA: Geier and Geier reported elevated DHEA levels (ng/dL) in 10 (8 boys, 2 girls) of 11 subjects (Table). However, when these values are compared with age-dependent reference values from the University of Iowa, instead of LabCorp values, all 11 subjects fall within normal ranges. The Iowa reference advises that DHEA values "begin to increase progressively at about six years of age prior to any physical evidence of puberty."
|
Patient No. |
Age (y) |
Sex |
Geier and Geier DHEA (ng/dL) |
LabCorp Ref (ng/dL) |
U |
|
7 |
3 |
M |
107 |
26-72 |
20-130 |
|
9 |
3 |
M |
85 |
26-72 |
20-130 |
|
4 |
4 |
M |
120 |
26-72 |
20-130 |
|
16 |
4 |
F |
94 |
19-42 |
20-130 |
|
10 |
5 |
M |
118 |
29-66 |
20-130 |
|
12 |
5 |
M |
100 |
26-72 |
20-130 |
|
13 |
7 |
M |
148 |
29-66 |
20-275 |
|
15 |
7 |
M |
67 |
29-66 |
20-275 |
|
11 |
8 |
M |
181 |
53-135 |
20-275 |
|
6 |
9 |
M |
284 |
53-135 |
31-345 |
|
8 |
10 |
F |
251 |
234-529 |
150-570 |
A summary of the Geiers' transsulfuration metabolite values is shown below (from Table 3). These values are compared with pediatric values from James et al (2006), a reference that was cited by Geier et al in their 2 recently published articles. In the cases of methionine and reduced glutathione, the values reported by the Geiers in Hormone Research (including reference values) are 1 and 2-3 orders of magnitude off, respectively, from those published in the literature.
|
Test |
Geier and Geier, |
James et al, 2006 |
|
Plasma reduced glutathione, µmol/L (n = 10, 3-9 y) |
585-911a |
2.2 ± 0.9 |
|
Plasma cysteine, µmol/L |
185-331b |
207 ± 22 |
|
Serum cystathione, µmol/L |
0.072-0.309 |
0.19 ± 0.1 |
|
Serum homocysteine, µmol/L |
2.9-9.9 |
6.0 ± 1.3 (5-15)c |
|
Plasma methionine, µmol/L |
1.2-1.9 |
28.0 ± 6.5 (6-40)c |
a Equivalent to the reported 18-28 mg/dL, given the molecular weight of reduced glutathione, 307.43 µg/µmol.
b Equivalent to the reported 2.24-4.01 mg/dL, given the molecular weight of cysteine, 121.15 µg/µmol.
c AMA reference values.
The plasma cysteine levels of 4 of 10 children were below the lower limit of the Geiers' laboratory reference range; but in all cases, they are well within the normal reference ranges provided by others in the literature (eg, see Han et al, figure 1A, along with others). In the case of serum cystathione, the values measured in the children with ASD were within the Geiers' reference ranges. Nevertheless, the Geiers went on to conclude that serum cystathione was significantly decreased in these children. In the case of serum homocysteine, 4 children demonstrated values below the lower limit of the laboratory reference range (2.9, 4.0, 4.5, 5.0 µmol/L). The University of Iowa indicates a normal value for serum homocysteine of <10 µmol/L, and the AMA provides a range of 5-15 µmol/L. An assessment of serum homocysteine levels in more than 3500 adolescent children, published in JAMA, determined a range of 0.1-25.7 µmol/L, with a median value of 4.9 µmol/L.
The conclusions offered by Geier and Geier in Hormone Research, specifically that serum FSH, cysteine, cystathione, and homocysteine levels are significantly decreased and that DHEA levels are significantly increased in their subjects with ASD, are dubious—given that these levels (in every one of their ASD subjects) were within the normal laboratory ranges used by the Geiers or, in the case of DHEA, cysteine, and homocysteine, were within the normal ranges published by other sources. (Moreover, if the Geiers were proposing a kind of precocious puberty in children with ASD, then FSH would be expected to be elevated, not decreased.) In addition, the Geiers' values for plasma reduced glutathione and methionine are suspect, given that they are at least 1 order of magnitude off those found in other sources.
In the case of serum testosterone, the individual values in the majority of Geiers' ASD subjects were outside of the normal reference ranges (However, see Addendum above). Nevertheless, because of the noted concerns regarding some laboratory values in the Hormone Research article and the very liberal conclusions that Geier and Geier make from their data, confirmation of elevated testosterone levels in children with ASD is especially needed.
DHEA = dehydroepiandrosterone; FSH = follicle-stimulating hormone.
* And is also the address of the Institute of Chronic Illness.
In July, the journal of Neurochemical Research published a study online by the father-and-son duo of Mark and David Geier (anchor and lead authors, respectively), which concludes that children with autism spectrum disorders (ASDs) "should be routinely tested to evaluate transsulfuration metabolites" and that "treatment protocols should be evaluated to potentially correct the transsulfuration abnormalities observed." These conclusions are based on the authors' determination that levels of these metabolites—as markers of oxidative stress and "decreased detoxification capacity"—in children with ASD are significantly different from those in children without ASD.
However, the references used by Geier et al to measure these metabolites don't necessarily agree with the control values they obtained (determined by the NJ-based Vitamin Diagnostics, Inc). In some cases, these discrepancies are very large and should have been noted by the authors. In other, less dramatic cases, such discrepancies between the published literature and the results of Geier et al may be the result of age-related differences in these metabolites. In other words, values in healthy adults may differ from those in healthy children. But age-related changes, if they exist,* should have been accommodated by the authors, if necessary—especially given that their subjects ranged in age from 2 to 16 years.
The following is a stepwise examination of the plasma metabolite values obtained by Geier et al in their study and those supplied by their cited references or other relevant sources.
Cysteine: Geier et al propose a statistically significant 33% reduction of plasma total cysteine (µmol/L) in their 38 children with ASD (17.8 ± 8.3 vs 23.3 ± 4.2 in 64 neurotypical controls). However, their reference for the measurement of plasma cysteine, Han et al, provides values that are much higher: from ~160 to ~360 µmol/L in 40 adults (figure 1A), about 7-15 times the mean control value obtained by Geier et al. Other references in the medical literature report mean fasting values of total cysteine in human plasma that are consistent with those of Han et al: ~250 µmol/L (Ueland); 268 µmol/L ± 25 in 10 healthy men (Andersson et al); 213.7 µmol/L ± 14.7 in 13 volunteers aged 24-29 years (Guttormsen et al); and 264 µmol/L ± 28 in 10 healthy subjects aged 31-52 years (Suliman et al).
And in a pediatric study (James et al), which is cited by Geier et al, the mean value of plasma total cysteine in 73 control children (mean age, 10.8 years ± 4.1) was 207 µmol/L ± 22 and that in 80 autistic children (mean age, 7.3 years ± 3.2) was 165 µmol/L ± 14. Very similar values of plasma total cysteine were calculated in a smaller pediatric study by James et al (also referenced by Geier et al). Mark and David Geier themselves reported a plasma cysteine range of 2.24-4.01 mg/dL in 10 boys with ASD (age range, 3-9 years), which is equivalent to 185-331 µmol/L (given the molecular weight of cysteine, 121.15 µg/µmol). Their reference range (from the Great Smokies Diagnostic Laboratory) was 2.70-4.30 mg/dL or 223-355 µmol/L.
It should be noted that Geier et al published an article in the September online issue of the Journal of Neurological Sciences, in which they appear to use laboratory data from 28 of the 38 subjects examined in the Neurochem Res study, owing to very similar mean values and standard deviations of transsulfuration metabolites (compare Table 2 in the Neurochem Res article with Table 3 in the JNS article). In addition, sections of text are almost identical between the 2 articles.
An important difference, however, in the JNS article lies in the Materials and Methods section, in which Geier et al indicate that they attempted to measure free cysteine, not total cysteine. This distinction, which is not made in the Neurochem Res article, may account for the lower cysteine values obtained by Geier et al in their subjects. Nevertheless, other studies in the literature indicate that the free cysteine value in human plasma is approximately 50% of the total cysteine value and therefore remains substantially higher than those values obtained by Geier et al—for instance, 112 µmol/L ± 15.2 in 13 volunteers aged 24-29 years (Guttormsen et al) and 140 µmol/L ± 21 in 10 healthy fasting subjects aged 31-52 years (Suliman et al).
Reduced glutathione: Geier et al propose a statistically significant 25% reduction of reduced glutathione (µmol/L) in their children with ASD (3.14 ± 0.56 vs 4.2 ± 0.72 in 120 neurotypical controls). Their reference for the measurement of reduced glutathione, Bouligand et al, reported the substance in mouse liver, not human plasma. Therefore confirmatory reference values for reduced glutathione in human plasma must be obtained from other sources. Andersson et al measured the mean value of reduced glutathione in the plasma of 10 healthy men at 3.4 µmol/L ± 0.9—a value within the standard-deviation range of the mean values obtained by Geier et al in both children with ASD and neurotypical controls. In 27 healthy men (age range, 22-34 years), Curello et al calculated a mean reduced glutathione level of 4.2 µmol/L in plasma. In 13 children aged 10-17 years, Michelet et al calculated a mean reduced glutathione level in plasma of 3.57 µmol/L ± 0.74, which did not differ significantly from values in older subjects.
James et al (again, cited by Geier et al) calculated mean reduced glutathione levels in plasma of 2.2 µmol/L ± 0.9 (73 control children; mean age, 10.8 years ± 4.1) and 1.4 µmol/L ± 0.5 (80 autistic children; mean age, 7.3 years ± 3.2). Mark and David Geier previously reported a plasma reduced glutathione range of 18-28 mg/dL in 10 boys with ASD (age range, 3-9 years), which is equivalent to the stratospheric range of 585-911 µmol/L (given the molecular weight of reduced glutathione, 307.43 µg/µmol). Their reference range (again, from the Great Smokies Diagnostic Laboratory) was 28-44 mg/dL or 911-1431 µmol/L.
Oxidized glutathione: Geier et al propose a statistically significant 37% increase in oxidized glutathione (nmol/L [not µmol/L]) in their children with ASD (0.48 ± 0.16 vs 0.35 ± 0.05 in 120 neurotypical controls). As in the case of reduced glutathione, Geier et al cite Bouligand et al as their reference, which poses the same problem previously mentioned. Williams et al found a mean, fasting plasma level of oxidized glutathione in 20 healthy adults of 1.4 µmol/L ± 0.1 or 1400 nmol/L ± 100—a value that is substantially greater than the mean values obtained by Geier et al. Curello et al reported a plasma level of 0.2 µmol/L (200 nmol/L) in volunteers, and a Chinese study determined the mean plasma level of oxidized glutathione in persons aged 20-29 years at 0.646 µmol/L ± 0.055 (646 nmol/L ± 55), with no significant differences among older age groups. James et al (cited by Geier et al) determined mean oxidized glutathione levels in plasma of 0.24 µmol/L ± 0.1 or 240 nmol/L ± 100 (73 control children; mean age, 10.8 years ± 4.1) and 0.40 µmol/L ± 0.2 or 400 nmol/L ± 200 (80 autistic children; mean age, 7.3 years ± 3.2). These reference data suggest a wide variation of levels of oxidized glutathione in plasma, from 200 to 1400 nmol/L, which are several orders of magnitude higher than those obtained by Geier et al. (Data also indicate that measurements of plasma glutathione, reduced and oxidized, are highly dependent on testing procedures and vary substantially with even minor hemolysis.)
Taurine: Geier et al propose an approximately 50% relative drop in the mean plasma taurine level (µmol/L) in their children with ASD (48.6 ± 14.0 vs 97.5 ± 8.8 in 27 neurotypical controls). Their reference for the measurement of plasma taurine, Hopkins et al (no PMID available), provides a mean taurine value of 129 µmol/L in platelet-rich plasma and a value of 84 µmol/L in platelet-poor plasma. Trautwein and Hayes calculated a normal plasma taurine level of 44 µmol/L ± 9 in fasting subjects, which is close to the mean level in the ASD subjects of Geier et al. Suliman et al calculated a mean value of 50 µmol/L ± 10 in 10 healthy fasting subjects aged 31-52 years. The AMA Manual of Style (10th ed) provides a wide reference range for plasma taurine: 24-168 µmol/L.
Total sulfate: Geier et al propose a significant 50% reduction of the mean level of plasma total sulfate (µmol per g of protein) in their children with ASD (934 ± 252 vs 1930 ± 184 in 82 neurotypical controls). Their reference for this measurement, Chattaraj and Das, provides a total sulfate range of 35.4-43.3 µg/mL or 35,400-43,300 µg/L in human serum from 6 subjects. This range is equivalent to 369-451 µmol/L, given the molecular weight of the sulfate ion, 96 daltons (µg/µmol). (The AMA reference range for total sulfate in serum is 310-990 µmol/L). To further convert this range to units used by Geier et al,** these values are divided by the normal plasma concentration of protein, 60-80 g/L, to calculate a liberal reference range for total sulfate in plasma of 4.61-7.52 µmol/g protein. This range, determined by using the values from Chattaraj and Das, is inexplicably much lower than both the neurotypical and ASD values reported by Geier et al.
Free sulfate: Geier et al propose a 66% drop in the mean level of plasma free sulfate (µmol per g protein) in their children with ASD (1.37 ± 0.48 vs 4.1 ± 0.46 in 67 neurotypical controls). The reference for this measurement, Boismenu et al, provides a range of 200-650 µmol/L from 40 human serum samples. When this range is divided by the normal plasma concentration of protein, 60-80 g/L, the calculated reference for free sulfate is 2.5-10.8 µmol/g protein. In this case, the mean value of plasma free sulfate obtained by Geier et al in their subjects with ASD is below the lower limit calculated from the cited reference.
Geier et al present metabolite values in children with or without ASD that are questionable. In particular, some values measured by Geier et al—for example, cysteine (whether total or free), oxidized glutathione, and total sulfate—are considerably different from those published elsewhere, including those values obtained or calculated from references cited by the authors. Other values from ASD or neurotypical subjects—for example, reduced glutathione and taurine—are within the reference ranges published in the literature.*** Only in the case of plasma free sulfate was the mean level in ASD subjects outside of the normal range provided by the substantiating literature.
|
Plasma Test |
Mean ± SD (Geier et al) |
Reference Values in Literature | |
|
ASD Subjects |
Controls | ||
|
Cysteine, µmol/L |
17.8 ± 8.3 |
23.2 ± 4.2 |
160-360 213 ± 14.7 264 ± 28 207 ± 22 |
|
Reduced glutathione, µmol/L |
3.14 ± 0.56 |
4.2 ± 0.72 |
3.4 ± 0.9 2.2 ± 0.9 |
|
Oxidized glutathione, nmol/L |
0.48 ± 0.16 |
0.35 ± 0.05 |
200-1400 |
|
Taurine, µmol/L |
48.6 ± 14.0 |
97.5 ± 8.8 |
84 or 129 44 ± 9 50 ± 10 24-168 |
|
Total sulfate, µmol/g protein |
934 ± 252 |
1930 ± 184 |
4.61-7.52 |
|
Free sulfate, µmol/g protein |
1.37 ± 0.48 |
4.1 ± 0.46 |
2.5-10.8 |
Before any diagnostic or treatment recommendations can be made on the basis of this study (or any study, for that matter), results must be shown to be reliably reproducible by a different set of authors using more than one experienced, reputable laboratory, and any discrepancies between control values and those in the literature must be noted and explained. It should also be determined whether tighter controls, particularly in the form of age matching between autistic and neurotypical subjects, should be performed when comparing these metabolite levels. Last, the significance of any mean values in autistic children that lie within the published reference ranges, although they may be statistically different from a given study's control values, must be considered cautiously.
* For instance, total glutathione levels, but not reduced glutathione levels, in whole blood have been noted to be lower in children than adults (see Michelet et al).
** Geier et al do not explain why they converted the values for both total and free sulfate to units expressing micromoles per g of protein.
*** Excepting the report by Mark and David Geier regarding reduced glutathione in children with ASD.
Photo: iStockPhoto
10/17/08 update: Emails have been sent to the editors of Neurochemical Research and the Journal of the Neurological Sciences, alerting them to the noted discrepancies in their peer-reviewed journals of the metabolite values of Geier et al. No responses have been received as yet. The editors may be contacted by email as follows.
Editorial Board for Neurochemical Research
Editor-in-Chief: Abel Lajtha, Nathan S. Kline Institute, Orangeburg, NY, Lajtha@NKI.RFMH.ORG
Associate Editor: Nicolas Bazan, Louisiana State University, New Orleans, nbazan@lsuhsc.edu
Associate Editor: Henry Sershen, Nathan S. Kline Institute, Orangeburg, NY, Sershen@NKI.RFMH.ORG
Editor-in-Chief: Robert P. Lisak, Wayne State University, Detroit, MI, rlisak@wayne.edu
Deputy Editor: Paula A. Dore-Duffy, Wayne State University, Detroit, MI, pdduffy@wayne.edu
Deputy Editor: Richard A. Lewis, Wayne State University, Detroit, MI, ralewis@wayne.edu
Roger Brumback, editor in chief of the Journal of Child Neurology, is not happy. Neurologist Jon Poling, the lead author of the 2006 case report in JCN, "Developmental regression and mitochondrial dysfunction in a child with autism," did not inform Brumback's editorial board that he is the father of the girl described in the report, and moreover, that he petitioned the National Vaccine Injury Compensation Program (VICP) in 2003, claiming his daughter's alleged injury (ie, autism) was due to vaccination.
In a letter published in last month's issue of the JCN (BIG HT to Kathleen Seidel at Neurodiversity), Brumback describes the authors' lack of full disclosure "an appallingly troubling issue." The JCN editors were evidently troubled enough to determine if the case report was used to support the favorable and heavily publicized VICP ruling for the Polings earlier this year (it was not), but Brumback proposes that "media linkage of the published article to the legal outcome implies scientific support from JCN for this legal opinion." He now advises:
Beginning in January 2009, statements from all authors concerning potential conflicts of interest will be published as a part of each article. However, no written statement can substitute for honesty, good faith, and integrity on the part of the authors.
In their defense, the report's coauthors Richard Frye, Andrew Zimmerman, and John Shoffner claim in a separate letter that they did not know of Poling's pending VICP claim at the time of the report's submission to JCN. (However, it is unclear, as Seidel points out, whether the coauthors became aware of Poling's claim sometime later.) The coauthors did know that the report's subject is Poling's daughter.
Poling himself acknowledges, in yet another separate letter to the JCN, that he should have declared his daughter's identity to the JCN editors, but that he withheld her name "to protect a 6-year-old child." Poling confirms that the JCN report was not used to support the VICP claim and characterizes his involvement in the case as minimal—consisting of signing a "short original petition and submitting a required sworn parental affidavit." Poling also reveals that Zimmerman submitted an expert opinion to the VICP court in December 2007 at Poling's request.
Poling further claims, "There are certainly other physicians who have chosen not to publish promising leads or discoveries involving family members, out of respect for privacy or fear of the kind of criticism our article has generated," and suggests that "the JCN explore ways to encourage these helpful contributions, even when the patient is a family member."
An alternative suggestion is to require that any physician-author recuse himself from submitting a case report of a relative to medical journals. Let more objective physicians assess and submit this information for peer review—in an effort to eliminate conflicts of interest and, most important, to ensure the privacy and appropriate care of the patient.
* Poling also presented preliminary findings in his daughter's case in June 2001 at the Johns Hopkins Neurology Grand Rounds.
If anyone doubted the intellectual limits of Jenny McCarthy, the Weiners actress, here's unmitigated proof.
In response to Amanda Peet's characterization of antivax parents as "parasites" (which is not a far-off description), McCarthy—a supporting actress in Larry the Cable Guy's Witless Protection—tells Spectrum magazine, "I am so proud to be a parasite."
In all mustered graciousness, maybe McCarthy, featured in the straight-to-video Python, got "parasite" confused with "paragon"? Paralegal? Pair of shoes?
In any case, the same smarts that led McCarthy to accept a starring role in Dirty Love has evidently resulted in an embarrassingly limited vocabulary. Perhaps Jim Carrey will pull aside his girlfriend, who bumped boobs with Pam Anderson in Scary Movie 3, and whisper something corrective in her ear. Or maybe not. After all, he delivered that tin-ear you're-getting-on-my-nerves-like-Robin-Williams performance in Horton Hears a Who!
Peet evidently apologized for using the word "parasites" to describe antivax parents. But why is an apology necessary to someone like McCarthy, a cast member of the Untitled Patricia Heaton Project, when she views the characterization as favorable? Or maybe McCarthy (aka Yvette Denslow in BASEketball) is confused about the meaning of "proud."
There's no reason to assess the removal of a substance when there's no evidence that the substance causes the disease in question.
That's pretty much the thought process of the NIMH, when it decided Wednesday to suspend a planned phase 2 study to assess mercury chelation in autism spectrum disorders (ASD). The study would have assessed the efficacy of DMSA, an oral chelating agent, or placebo to alleviate ASD symptoms in children aged 4-10 years during a 12-week period, despite the fact that mercury (from vaccines or otherwise) has not been associated epidemiologically with autism.
Also chelation is not without its hazards, owing to its ability to remove essential minerals, in addition to toxic heavy metals like mercury and lead, from the body. Moreover, in a study published last year, DMSA in rats that were not exposed to lead "produced lasting and pervasive cognitive and affective dysfunction," which was comparable to that seen with high lead exposure. Enrollees in the NIMH study would have had detectable, but not toxic, levels of mercury and lead.
HT: AP
Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure
By Paul A. Offit
328 pages
If anybody thinks Paul Offit, infectious-disease specialist at one of the nation's best pediatric hospitals, overstates the physical threats he gets from antivaccinationists, here's a sobering rebuttal: There will be no book tour for Autism's False Prophets, Offit's plain-speaking chronicle of how vaccinations have been erroneously implicated in the rise of autism. The security risk is just too high says the book's publisher, Columbia University Press.
Paul Offit has become the medical equivalent of Salman Rushdie (who went into hiding after the publication of The Satanic Verses, which prompted a fatwa from the Ayatollah Khomeini). And it's not a bad analogy, given the blind faith practiced by those who thoughtlessly adhere to and profit from, against all credible scientific evidence, the idea that vaccines are somehow responsible for a neuropsychiatric condition that is so poorly understood.
In the book's prologue, Offit—who holds a patent on a rotavirus vaccine and who vocally advocates for vaccinations in general—reveals that he gets a lot of hate mail, some of it with religious overtones. One correspondent asked, "Why did you sell your soul to the devil?" and another prays "that the love of Christ will one day flood [his] darkened heart." Offit has also received gruesome death threats ("I will hang you by your neck until you are dead!") and non-too-subtle threats toward his children. But Offit's book, most importantly, is not about Offit.
Autism's False Prophets is a systematic unpacking of the relatively short history of autism, its identification 70 years ago, its rise in frequency (which is primarily, if not exclusively, due to increased recognition), and its broad manifestations, which have driven some parents of severely affected children to the unthinkable. Other parents, desperate for treatment, have been sucked into trying one or more bogus therapies (for instance, facilitated communication), which have been hawked by one or more charlatans willing to fill the therapeutic void in allopathic medicine.
As Offit writes, some of these false prophets are credentialed; some have no medical training whatsoever. Many have been either implicitly or outrightly endorsed by the media and political figures, with no consequences for those who sow the unfounded and dangerous idea that vaccines cause autism. One of the most prominent false prophets, according to Offit, is English gastroenterologist Andrew Wakefield, who attempted to implicate the MMR vaccine as a cause of autism in the late 1990s. Wakefield's work, which received tremendous media attention, was largely funded by a personal-injury lawyer, reveals Offit, and was later discredited on charges of fraud. However, Wakefield's ideas on the dangers of the MMR vaccine contributed to England's recent measles epidemic, and astoundingly, the doctor still has his rabid supporters.
There is also the father-son duo of Mark and David Geier, who (along with others) implicate the vaccine preservative thimerosal as a cause of autism through work performed in their home-basement laboratory in Maryland. The Geiers, in particular, have migrated into shocking territory by advocating dangerous chelation therapy and chemical castration with leuprolide (Lupron; TAP) for autistic children. Offit writes how librarian and tenacious blogger Kathleen Seidel, whose child was diagnosed with a form of autism, has nearly single-handedly revealed the highly questionable nature of the Geiers' work.
Parents of autistic children, like Seidel, who refuse to neglect science or waste their time, energy, and money on unproven and far-fetched treatments, are the poorly credited heroes of the autism story. Offit reveals that he wrote Autism's False Prophets for them. However, the noise from opportunists has been cranked up by ignorant, but highly influential (and arguably financially conflicted), political figures—specifically US Congressman Dan Burton, whose grandchild was diagnosed with autism, and tort lawyer Robert F. Kennedy, Jr., a vocal proponent of the idea that thimerosal causes autism. Public figures like Burton and Kennedy have essentially ignored the series of epidemiologic studies that have exonerated vaccines as the cause of autism, mindlessly asserting that the issue should be settled in the public, instead of scientific, arena. Consequently they divert attention and funding away from credible research into the causes of autism and its treatment.
At play in this mess, Offit soundly argues, is the media's undying hunger for controversy. The idea that vaccines don't cause autism, although true and of vital public interest, isn't particularly provocative. The story's would-be title would mimic a banal headline from the parody newspaper The Onion. Moreover, science itself, which many consumers find terribly dry, isn't easily conveyed in sound bites. Case in point is the appearance of IOM president Harvey Fineberg on "Meet the Press," when he found himself contending on air (in a show of journalistic "balance") with media-savvy writer David Kirby, author of the vaccine-maligning Evidence of Harm. And if "Meet the Press" can't be counted on to provide sound information, little can be expected of Oprah.
For readers who don't believe that science is a yelling contest, the events in Autism's False Prophets—events in which self-interested figures ride roughshod all over medical evidence—will anger. Nevertheless, it is this justifiable anger that can mobilize investigations away from life-saving vaccines and onto the very elusive causes of autism.
At last count, the number of Americans who had contracted measles this year was 127. Now add 4 more cases.
This week, the CDC's MMWR reports a total of 131 cases of the highly contagious infection in 15 US states and the District of Columbia from January 1 to July 31 (Table). The overwhelming majority of these cases were imported* (13%) or linked to imported disease (76%). (It is important to note that the number of imported measles cases in the United States has not changed appreciably over the years, but that the number of importation-associated cases accounts for this year's dubious record.) A large percentage (81%) of measles cases were related to 7 outbreaks (≥3 cases). Fifteen individuals, including 4 children younger than 15 months, were hospitalized for disease; however, there have been no deaths—yet.
Most important, however, is the fact that a whopping 91% of cases occurred in individuals who had not received vaccination or whose vaccination status was unknown. Among these 112 patients, 85% were eligible to receive vaccination, but 66% had declined because of "philosophical or religious beliefs."
|
Location |
Measles Cases |
|
|
32 |
|
|
27 |
|
|
19 |
|
|
14 |
|
|
14 |
|
|
7 |
|
|
5 |
|
|
4 |
|
|
2 |
|
DC |
1 |
|
|
1 |
|
|
1 |
|
|
1 |
|
|
1 |
|
|
1 |
|
|
1 |
The MMWR highlights outbreaks in 2 locations, Washington state and Illinois, in which affected children had not been vaccinated on the basis of personal-belief exemptions. A sizable portion of these children were home schooled, which obviates the vaccination requirement for traditional-school enrollment.
In an editorial note, the CDC advises that the current national vaccination rate for measles is adequate to prevent the "sustained spread of measles," but that importation-associated outbreaks are likely to continue as long as there are geographic clusters of unvaccinated individuals. Unfortunately this information will probably be used by parents who forego vaccination to maintain their behavior.
Most affected by the deferral of measles vaccination are immunocompromised children and children younger than 12 months of age, who rely on adequate herd immunity. It appears to be a mere matter of time before a measles outbreak will cause a known, severe complication of the disease, like encephalitis or death, in the United States. Such an event has already occurred in the United Kingdom.
* Genetically or epidemiologically linked to cases in Italy, Switzerland, Belgium, India, Israel, China, Germany, Pakistan, the Philippines, and Russia.
Photo of child with measles rash from the CDC.
This may be merely an example of water seeking its own level, but World Wrestling Entertainment and Jenny McCarthy will be getting together next month on prime-time network TV* to support Generation Rescue, an organization which promotes the unfounded (and dangerous) idea that "toxins" in vaccines produce autism and other neuropsychiatric disorders in children.
I suspect between choreographed body slams, there will be no discussion of the hazards of anabolic steroids.
* NBC, to be exact.
If you're at a loss to understand the slogan of yesterday's anti-vaccination march on Washington, DC—led by Jenny McCarthy and Jim Carrey—you're not alone. The costar of Witless Protection* and the star of Horton Hears a Who! evidently want to promote "cleaner" vaccines (whatever that means—more bacteriocidal Thimerosal?). But what they really want to do is alter the current CDC-recommended schedule for vaccinating children...to God only knows what.
Orac dives into the mess and provides commentary.
*You know, the vehicle for Larry the Cable Guy.
Photo: Jenny McCarthy playing with garden hose in kiddie pool.
This post represents the fourth (and god willing, final) installment of my review of the study by Young et al, which links exposure to Thimerosal-containing vaccines with autism. Previous posts on the subject can be found here (IRB approval), here (IRB follow-up), here (article Introduction), here (Materials and Methods), and here (Results). The current post provides commentary on statements made in the article's Discussion.
The authors begin by pointing out the favorable aspects of their study.
[T]he study design...helps to strengthen the observed results. The medical conditions examined were selected a priori as biologically or not biologically plausibly linked to Hg exposure from Thimerosal-containing vaccines administered during specific exposure windows.
Not to be too snide here, but when was it decided that foregone conclusions are study strengths?
Additionally the study design also allowed us to be certain that virtually all exposures to Hg preceded the diagnoses of the diseases examined (ie, allowing for a potential cause-effect relationship between exposure and disease). This was ensured because only children receiving a vaccine by age 3 months were examined, and as Table 2 shows the median age of initial diagnosis for the conditions examined in the present study ranged from 1.7 to 6.4 years-old.
The diagnoses in question may follow vaccine exposures, but that doesn't necessarily mean their existence does. For instance, the presence of congenital anomalies (which, by definition, exist at birth) should not be affected by subsequent exposure to vaccine-related ethylmercury. However, if Young et al were consistent in their thinking, they would propose that a 100-µg increase in ethylmercury exposure somehow confers a retroactive, protective effect against congenital anomalies (with a risk reduction of ~40%).*
[T]he methods of ensuring capture of Hg exposure from Thimerosal-containing vaccines and outcomes appear to have yielded results consistent with previous studies. For example, the US CDC previously published that the overall prevalence of ASD [autism spectrum disorder] in children, born for similar birth years as examined in the present study, was 3.4 per 1000 children in the metropolitan Atlanta, Georgia area [13]. The adjusted overall prevalence of ASDs (3.67 per 1000) in the present assessment of the VSD was consistent with the previous observation made by the US CDC.
The CDC investigators examined multiple medical or educational records from 5 Atlanta-area counties and calculated a 0.34% prevalence rate for autistic disorder, pervasive developmental disorder (NOS), or Asperger disorder (per DSM-IV criteria) among children 3-10 years of age in 1996. Young et al's overall (unadjusted) prevalence rate for ASD in the VSD was 0.293%, and the adjusted prevalence rate was 0.367%, after adding approximately 206 cases (see explanation here). Calculations for the year 1996 indicate an unadjusted rate of autism (ASD data for 1996 were not provided) of 0.17% and an adjusted rate of 0.33%, after Young et al added 80 cases. So Young et al's prevalence rates are "consistent" with the CDC's (circa 1996), after their liberal imputation of autism cases.
[T]he birth cohort years examined in the VSD help to strengthen the results observed. The birth cohort years examined from 1990 through 1996 occurred many years prior to the raising of concern about potential problems with Thimerosal in childhood vaccines by the American Academy of Pediatrics and the US Public Health Service, so that their announcement to remove Thimerosal from childhood vaccines in July of 1999 should have had virtually no impact on physicians' thoughts about Thimerosal in childhood vaccines.
While the above statement is not entirely unreasonable, it doesn't acknowledge the groundswell of anti-Thimerosal sentiment from lay and fringe medical groups during the 1990s. Therefore it is possible, as suggested in a prior post, that parents within the Kaiser system requested, or even demanded, the administration of some newly available, Thimerosal-free vaccines to their children during 1997 or later.
Additionally, the years examined in the VSD help to ensure that changes in diagnostic criteria for outcomes such as autism that came into effect in 1994 would have minimally impacted the present study since most children examined were diagnosed post-1994 with autistic disorder.
"Minimally impacted" is a disingenuous conclusion, in my opinion. According to a recent post by EpiWonk, studies indicate that the rise in autism rates during the last 3 decades is an artifact due to broadened diagnostic criteria, diagnostic substitution, and the diagnosis of autism at a younger age. Moreover, there's no reason to assume that the rate of recognizing autism would have leveled off after 1994. In fact, the increasing prevalence of autism depicted by Young et al in Figure 1 is probably due to a continuing uptick in diagnostic acuity.
[A]nother significant strength of the present study stems from the trends in birth cohort Hg exposure and outcomes. As shown in Fig. 1 for autism, it was observed there were increasing/decreasing trends in exposure and outcomes across the birth cohort years examined, and that for the neurodevelopmental disorders there were significant associations between birth cohort mean Hg exposure and disease prevalence rates. It is important to note that the increasing/decreasing trends in Hg exposure were not simply the result of random yearly fluctuations in vaccine uptake rates or even simply the result of increasing exposure to vaccine antigens, but instead reflect known changes in the Hg content of the US childhood vaccine schedule...
It's difficult to understand how Young et al can so easily dismiss the idea that "the increasing/decreasing trends in Hg exposure were not simply the result of random yearly fluctations." Note that the largest difference in the average per-person ethylmercury exposure is pretty small, approximately 35 µg according to Figure 1 (~110 µg for the 1990 birth cohort and ~145 µg for 1992), which equals a little more than 1 vaccine dose. Also note that there are many ways to represent the data in Figure 1, so that the putative association between ethylmercury exposure and the prevalence of autism is less graphically compelling (see examples below).
[B]ecause of the ecological nature of the study design, we were not able to link vaccine exposures across individual patient records...
EpiWonk explains the important distinctions between an ecological, or group-level, study and an individual-level study. He argues that Young et al have committed the "ecological fallacy."
Another possible limitation of the present study was the potential for under ascertainment of a child's total Hg exposure...Other potential sources of Hg such as fish consumption or environmental exposure, while potentially significant to the risk of a child being diagnosed with a neurodevelopmental disorder, could not be examined...We believe that these other exposures to Hg should not have biased the effects observed. In actuality, such sources of Hg exposure would potentially minimize the significance of the effects observed.
Here Young et al appear to contradict themselves. If I'm reading correctly, they first state that non-vaccine sources of mercury "should not have biased" their results, but they follow with the conclusion that non-vaccine mercury would "potentially minimize" their results.
This study was also limited to a maximum of 4 years of follow-up time for the latest birth cohorts...
Young et al's highly dubious imputation of cases for later birth cohorts, owing to shorter follow-up periods, has been discussed by EpiWonk and myself.
Finally, the present study was not able to adjust for potential factors that might have resulted in vaccine avoidance but may have predisposed one towards neurodevelopmental disorders under study. Specifically, Fine and Chen reported that there are several social and medical attributes associated with avoidance or delay of vaccination and an increased risk of neurological adverse events, and that confounding of this sort is a general problem for studies of adverse reactions to prophylactic interventions, as they may be withheld from some individuals precisely because they are already at high risk of the adverse event [14]...As a result, the effects observed in the present study may represent an underestimate of the true effects of Hg exposure from Thimerosal-containing vaccines on the risk of neurodevelopmental disorders.
Not to sound like a broken record, but What the—? Young et al cite a 1992 CDC article on confounding (an issue discussed by EpiWonk here). But as far as I can tell, Young et al have taken the article's conclusion—that is, putative vaccine benefits may be observed because fewer high-risk children are vaccinated—and turned it on its head. (BTW, this phenonmenon may well explain the observed low rate ratio for congenital anomalies and increased ethylmercury exposure.)
Young et al then go on to support their findings by citing themselves (Geier and Geier) on 3