HOLLAND ON THE OMNIBUS AUTISM PROCEEDING: 5/30

By Mary Holland

Omnibus Autism Hearings,
Friday, May 30, 2008:  Day 15

Rebuttal Testimony of Dr. Kinsbourne
Direct Examination of Dr. Kinsbourne

Q:  [Mr. Powers] During cross-examination, you were asked about your employment status at University of Toronto.  You were asked about grounds for your termination.  What was your response at that point to the document you saw which was a grievance committee report? 
A:  I never saw the report actually; I don’t think it was a formal report.  I pointed out that some allegations were made; I filed a grievance; the grievance prevailed; they were investigated and withdrawn, and a protective order was issued.  In 30-some years, no one until this time has violated that protective order.

Q:  Did you find more available information on this?
A:  Yes.  I looked in my files and found the settlement agreement with the University.  This is the outcome of grievance proceedings.  This settlement made clear that all charges were withdrawn and that I was not terminated. 

Q:  And you stated under cross-examination that you resigned and were offered an opportunity to rejoin? 
A:  Not in this document, but yes, that’s true.

Q:  We’ll move on to Dr. Rutter’s testimony about you.  He critiques your mechanistic model of neuroinflammation and overactivation.  He seemed to suggest that your model lacks scientific rigor and scientific certainty.  How do you respond? 
A:  I have a high regard for Dr. Rutter’s work.  I was not presenting a scientific discovery that I can prove to be the case.  That’s not my role in these proceedings.  What I’m presenting is a reasonable medical mechanism by which this could have happened.  Dr. Rutter didn’t address the actual purpose and role of my proposal.  If a scientist offers a conclusion before adequate research, it’s considered speculation.  I was not drawing a conclusion; I was offering a possible mechanism. 

Q:  Is that mechanism biologically plausible in your opinion? 
A:  Yes, and it is grounded in contemporary scientific literature, as reflected in my report.  Dr. Rutter wasn’t really talking about what I was presenting.  He was saying that autistic children are overemotional.  The overarousal model had early origins in EEG studies.…
 
Q:  Is there more contemporary literature that supports your model of excess glutamate? 
A:  The hyperglutaminergic idea is not my idea; it was in the literature before I proposed it.  I can provide the court with more documentation.  My role has been to consider the role of glutamate excess and neuroinflammation and put it together with evidence of overarousal.

Q:  Do you recall Dr. Rust’s critique that the glutaminergic response does not contribute to autistic symptoms?
A:  Yes.

Q:  Let’s discuss some of the contemporary scientific literature that references this model. 
This is Dr. Ashner’s article about glutamate and methylmercury neurotoxicity.  I’d like to direct you to page 2.  What do you think is the significance of the highlighted text? 
A:  This encapsulates a major part of my proposal; in fact, it’s one of the sources for my proposal.  This is an article from 2007. 

Q:  Is this an article by Dr. Purcell and others on postmortem brain abnormalities of the glutamate neurotransmitter system in autism? 
A:  Yes. 

Q:  Please look at the highlighted section in Dr. Purcell’s paper [text not read aloud].  What is the significance of this section to your theory?
A:  GFAP is a protein released by astrocytes under stress.  The article points out that there may be reactive gliosis in response to this stress, and that that proliferation may contribute to autism.

Q:  [text shown, not read].   The paper relates to autistic symptoms related to glutamate?   
A:  Yes.  People have taken this seriously and currently are trying to determine whether drugs that block glutamate receptors might be effective for control of autistic symptoms.  There are several studies on this funded by the NIH and a foundation which is finding out whether glutamate antagonists could help autistic children.

Q:  We’ll add an exhibit discussing one of the clinical trials that you’re talking about.  Now also please describe this study.
A:  This study has been funded by the NIMH.  This drug is a glutamate blocker.  It has been shown to be effective in childhood obsessive-compulsive disorder.  People at Hopkins and the NIMH have thought it appropriate to try to lower the glutamate levels in these children.  If anybody really thought that the neuroinflammation that Vargas and Pardo found was protective, this study would never have been funded.

Q:  Glutamate plays a crucial role in excitation and may play a role in obsessive compulsive disorders.  Is this study’s statement about glutamate’s role in excitatory activity consistent with your main theme? 
A:  Yes. 

Q:  Back to Dr. Rutter and his description of your model of overactivation as being a historical relic.  Are you aware of contemporary discussion of this very theory?
A:  Yes indeed.

Q:  Does that include discussions by Dr. Casanova, one of Respondent’s witnesses, who submitted a report but didn’t testify? 
A:  Correct.

Q:  You have in front of you an article by Dr. Casanova on columnar pathology in autism.  [highlights paragraph]  In this section, is Dr. Casanova discussing the arousal model in the brain as related to ASD? 
A:  Yes, it is quite specific.

Q:  He goes on to say that the “arousal theory is of some interest because it is consistent with the reduction of inhibitory interneuronal activity.”  So the arousal theory is of enough importance for Dr. Casanova to discuss it here? 
A:  Yes.

Q:  And his discussion is on the flip side of the glutamate process, he’s talking about the inhibitory process, GABA, correct?
A:  Yes, he’s still addressing the excitation-inhibition balance. 

Q:  And this excitation-inhibition balance is a core concept in your model?
A:  Yes, and it is a core concept in brain functioning.

Q:  Is there some implication in recent science that the excitation and neuroinflammation and glial activation might be related to brain pathology? 
A:  A number of sources have raised that possibility.

Q:   Here’s an article by Dr. Courchesne,  “Autism at Beginning,” that’s been discussed a lot in these proceedings.  I’d like to have you comment on the section that says, “glial cells play key roles in brain organization during development as well as in neuroinflammatory reaction.”  The bulk of your report discusses the role of glial cells in neuroinflammatory reactions? 
A:  Yes. 

Q:  So Dr. Courchesne is acknowledging the role of glial cells in development, but he’s also saying something new – that it plays a role in organizing the brain? 
A:  Well, we knew this.  Glial cells play a scaffolding function in brain organization.

Q:  You heard testimony of neuropathologist Dr. Kemper who argue that pathological abnormalities in the brain cause neuroinflammatory responses in some cases.  Is that correct? 
A:  Correct. 

Q:  But they haven’t discussed that glial disruptions can be the cause of the underlying neuroinflammatory responses?  Did they discuss that?
A:  No.

Q:  Dr. Courchesne is saying is that excess glial activation or overproduction has the potential to produce any or all of the previously described microstructural findings?
A:  Yes.

Q:   And he argues that glial disruption can affect the physical architecture of the developing brain? 
A:  Yes.  In a manner to generate the kinds of abnormalities that have been reported.

Q:  Including the mini-column abnormalities that Dr. Casanova describes, correct?
A:  Yes.  It references Dr. Casanova’s work.

Q:  So, would you say the current scientific literature supports the notion in your report and testimony that glial activation can cause neuroinflammation leading to the symptoms of autism, and that overactivation can actually cause changes in brain structure?
A:  Yes.  There’s support for this proposition and that support is in the articles that we just took a look at. 

Q:  Dr. Rust says that in a couple of places, you misrepresented the cited articles. He said that regarding articles by Dr. Friedman and Dr. Petropolis.  We’ll take a look at those. 
A:  This is a study of the brain of individuals of ASD by MRI.  It talks about particular aspects of imaging. 

Q:  And do you recall that Dr. Rust characterized your citation as inaccurate because this article doesn’t talk directly about neural inflammation leading to the symptoms of autism? 
A:  Yes. 

Q:  You didn’t cite it for that proposition, did you? 
A:  No, I didn’t cite it for that.  [discussion of text of article]

Q:  If you recall, Dr. Kemper specifically said you were incorrect in describing edema as a consequence of neuroinflammation.  Do you remember that criticism? 
A:  Yes, I do.

Q:  And here it says that edema is characteristic of neuroinflammation? 
A:  Yes.

Objection:  Respondent’s counsel requests that the witness actually answer questions, rather than having counsel lead him through rebuttal. 

Q:  What’s the significance of this paragraph to your report?
A:  The significance is that the MRI findings are consistent with ongoing neuroinflammation, and the authors relate their findings to studies on glial activation and cytokines that have been associated with autistic disorders.

Q:  Let’s turn to page 14 of your report.  Please show the Special Masters what statement in your report you cite to this article for?   
A:  [Dr. Kinsbourne points to the sentence with the citation to the Friedman article].  I think it is an accurate reflection of the literature we just reviewed.

Q:  I want to address Dr. Kemper’s testimony.  Do you recall Dr. Kemper’s criticism of your theory?  Did he describe that edema was not characteristic of neural inflammation? 
A:  Yes.

Q:  And we just discussed the citation where you find support?   
A:  Yes. 

Q:  He did say that there was no local invasion of immune cells.  Do you believe that in the process of neuroinflammation there can be no local inflammation of immune cells? 
A:  Yes, it’s documented in the literature. 

Q:  This is Dr. Pardo’s article that’s been much discussed.  Please focus on page 6, last paragraph.  It talks about an increase in mcp1 expression. What is mcp1? 
A:  It’s a cytokine released by glial cells. 

Q:  Is this part of the inflammation process? 
A:  Yes. 

Q:  What is described as the significance of mcp1 as related to autism? 
A:  It discusses that monocytes and macrophages are attracted to the brain by mcp1. 

Q:  Do you believe that this paper is consistent with your statement that neuroinflammation is associated with the infiltration or invasion of immune cells?
A:  Yes, that’s what I was referring to.

Q:  I’m also going to refer to Dr. Vargas’s article.  [highlighted text in article]  Do you see where the authors describe a marked accumulation of perivascular macrophages and monocytes in the cerebellums of autistic individuals?
A:  Yes.  In four of the ten autistic individuals studied.  As I pointed out, these cells come from the circulation and pass through the walls of blood vessels to a perivascular location.

Q:  So do you believe that statement is consistent with your theories of neural inflammation?   
A:  Yes.

Q:  Dr. Kemper took issue with a statement at page 17 of your report.  [Highlights “The inflammation becomes chronic…”]  Dr. Kemper took issue with the idea that cells, particularly astrocytes, are dying.  He said that the Vargas folks did not find dead astrocytes, so your “friendly fire” description was inaccurate.  How would you respond? 
A:  What I was saying is there are circumstances in which astrocytes, in fact, die.  I wasn’t saying this is the case of autism.  My point in autism is there are functional abnormalities with astrocytes, and specifically they do not regulate the flow of glutamate, which in turn activates neurons that would not have been activated otherwise.  Death is not part of the model that I’m proposing, although I’m sure it can and does happen. 

Q:  Do you say anywhere that it’s a necessary part of your model that astrocytes are dying? 
A:  No, in fact, it’s a necessary part of my model that they don’t die. 

Q:  But you do say that some die, correct?
A:  Yes. 

Q:  Where is support that some astrocytes might be dying, even if you don’t find the dead cells? 
A:  …Basically, astrocytes produce a substance in the course of death and there’s evidence of this substance being present. 

Q:  What does that mean to you? 
A:  It’s a self-protecting regulating mechanism that’s present here.

Q:  Dr. Rust thought your model implausible because he didn’t understand that it could be self-regulating?  How would you respond?
A:  There are two ways of countering that.  (1) A number of articles in peer-reviewed journals have in fact found a concept of a chronic overactivated state to be a reasonable regulating concept.  (2) There are self-regulating processes in the brain to hold inflammation in check, as Dr. Rust described.  Up to a point, it’s biologically plausible that inflammation may occur but not escalate to an overwhelming state in the brain as a whole.  That must be the case because other scientists found evidence of neuroinflammation not just in children, but in adults well into their 40s.  No one argues that this inflammation just began in the 40s.  Neuroinflammation can at some low level continue for many, many years.  It implies that proinflammatory factors continue, and anti-inflammatory factors hold it at some level of check. 

Q:  Dr. Rust rejects your concept of neuroinflammation as a result of environmental factors.  Do you remember that critique?
A:  Yes.

Q:  Can you explain the relevance of this [projected] table to your theory?
A:  The notion that environmental factors are significant is embodied in this sketch.  The flow chart proceeds to the outcome of a phenotype that features regression.  In the conclusions section, it shows that to the extent that the immune response is involved, it’s innate rather than adaptive. 

Q:  Have you ever implied that it’s a response of the adaptive immune system? 
A:  No. 

Q:  What immune response are you describing in your report and testimony? 
A:  The innate immune response in the body has to do with macrophages….The same thing occurs in the brain, but features microglia and astrocytes. 

Q:  Let’s look at the part of the chart that says, “the roles of neuroglial activation…”  In this sentence, there’s talk about preexisting central nervous system abnormalities, and that neuroinflammation might  maintain some of those abnormalities.
A:  Yes, it maintains them and it might initiate some of them, consistent with the Courchesne point of view. 

Q:  Dr. Kemper’s position was that the neuroinflammatory responses seen here were in response to the underlying brain pathology? 
A:  Yes.

Q:  And that’s certainly a possibility that these authors leave wide open? 
A:  Yes. 

Q:  And does it exclude the possibility that neuroinflammation might initiate some of the abnormalities in this disorder? 
A:  No, it doesn’t at all.  It might be either; it might be both; it’s uncertain.

Q:  Let’s look at the last sentence of the paper:  “Neuroglial and neuroinflammatory responses likely have polygenic and environmental bases and may have important clinical and therapeutic implications in autism.”  How does this concluding statement relate to your opinion in your testimony?
A:  I’ve been arguing that gene-environment interaction is an important factor in causing autism.  They’re saying that -- polygenic means the gene component.  Together, genes and environment may set up the neuroinflammatory responses and may in turn have important implications for autism.

Q:  Is it your opinion that the work of Drs. Vargas and Pardo supports your theory and mechanism of injury in these cases?
A:  Indeed, I base a lot of it on their work.
 

Cross-examination by Respondent’s Counsel

Q:  [Mr. Matanoski]  In the settlement that you reached with the University of Toronto, you agreed to tender your resignation as part of that settlement, isn’t that right? 
A:  No. 

Q:  In Petitioner’s Trial exhibit 12, it states that the applicant tenders his resignation from the University.

A:  There were two parts to that: there were charges, and they were quashed.  I was offered the opportunity to stay at University of Toronto, but I elected as part of my settlement to leave. 

Q:  And that is part of the settlement?  That is part of the document you have before you?  A:  Yes.

Q:  You were asked a series of questions about Dr. Kemper’s criticisms.  Did you listen to his testimony?
A:  Yes. 

Q:  Can you list what those criticisms were? 
A:  You mean the ones we just went over? 

Q:  Yes. 
A:  OK, he criticized my statements about neuroglial cells; he said there was no edema in neuroinflammation; he agreed with the microglia activation and he disagreed with the third item.

Q:  What was that?
A:  I’ve forgotten for the moment.

Q:  Even though you just talked about it? 
A:  Yes. 

Q:  Are you sure you listened to his testimony? 
A:  Yes, I’m sure I listened. 

Q:  But you can’t even recall what the third matter was that Dr. Kemper brought up?   
A:  I’m sure I’ll remember if you want to review it.

Q:  And Dr. Rust’s criticisms:  what were they?
A:  There were an awful lot.  I’ll give you a few:  my theory is unbelievably complex, awkward, totally novel -- these are my discoveries -- and I have ignored 30 years of neuroscience research; these are highlights.

Q:  Can you be more specific than that?
A:  I haven’t finished.  He criticized my description of regression as being “striking,” even though Dr. Reichler describes it as striking.  He criticized my scientific approach as speculative; he didn’t believe that regression could be interpreted as the cause of ongoing disease because in Rett’s syndrome there’s regression that is attributed to genetic causes.  He found my model of overarousal to be really a misinterpretation of behavior of autistic children under stress.  He pointed out that in calm situations, they calm down.  These are some examples.

Q:  These are pretty broad.  He criticized just about every part of your opinion?
A:  Yes, he did.

Q:  You were given an NIH study to look at, that study was for a drug safety test, wasn’t it?   
A:  It says that it will study X (inaudible) for effectiveness in autism.

Q:  Doesn’t it say it’s for an open label study to evaluate safety in children?
A:  Yes.  It had some effectiveness in OCD children and they’re evaluating it for autism.

Q:  Is the study limited to regressive autism?
A:  No, it is not. 

Q:  Your opinion, though, is limited to regressive autism?
A:  Yes.  It’s not limited just to regressive autism, but that’s what I’m testifying about.

Q:  So your mechanism isn’t applicable only to regressive autism?
A:  I don’t know; I haven’t considered it in other contexts. 

Q:  Consider it now.  Would your theory be applicable equally to other kinds of autism?
A:  I don’t know.  I would need to consider it in light of the medical evidence.

Q:  Why did you only consider it with regard to regressive autism? 
A:  Because the issues before this court have to do with possible environmental, postnatal effects, in one case the measles virus in the measles vaccine, and in the other, mercury.  When postnatal effects are being considered, then postnatal disorders, such as regressive autism, would seem to be the relevant disorders to consider in the first instance. 

Q:  It could be any kind of autism that your mechanism applies to?
A:  I’m not giving an opinion about whether or not my mechanism applies to other kinds of autism.

Q:   So you can’t say that your mechanism is limited to just regressive autism?
A:  No, I have not considered the universe of other possibilities.

Q:  Yet you would use it as part of a differential diagnosis to determine whether or not autism occurred? 
A:  I don’t use the mechanism for differential diagnosis.

Q:  But that’s how you came to your conclusion in your report?
A:  Yes.  I said that because viruses and heavy metals are possible triggers for autism, that they should be considered in a differential diagnosis. 

PETITIONERS’ OBJECTION: I’m going to object; these questions are now past sur-rebuttal.  These are way outside the rebuttal testimony this morning. 
RESPONDENT’S OBJECTION:  I withdraw the question.  I think the answer is in his report.  I think it should be clear to the court that his mechanism is not specific to mercury vaccines. 

PETITIONERS’ OBJECTION:  I object to counsel making arguments on the record to the court here on questions to the witness.

Q:  You talked a lot about glutamate excess; how do we get to that process from vaccines?  Is it the inorganic mercury in your causal mechanism? 
A:  Neuroinflammation involves a process that I explained in detail in my report and in my direct testimony, which raises the discontrol of glutatmate by its normal regulatory mechanisms.  So whatever causes neuroinflammation is apt also to cause glutamate excess.  I pointed out 3 categories of agents that cause neuroinflammation: viruses persisting in the body; heavy metals; and neurodegenerative disorders.  Among that range of causations, vaccines could play a role in two respects:  a virus, such as the measles vaccine virus, and the other, a vaccine that contains mercury as part of its chemical constitution.  It could deliver mercury to the body and the brain.

Q:  And that would be in the form of inorganic mercury?
A:  Yes. 

Q:  And the glutamate excess is built up because of inorganic mercury in the brain?
A:  One of the many possible causes of glutamate excess in the brain would be a triggering by low levels of inorganic mercury. 

Q:  And this glutamate is going to get worse as long as inorganic mercury continues to increase? 
A:  Not necessarily.

Q:  Why not?
A:  Why should it?  I never made the claim that the glutamate excess would become worse and worse.  I pointed out earlier today that there are regulatory mechanisms which can keep glutamate in check. 

Q:  What causes those regulatory mechanisms to fail? 
A:  I didn’t testify that regulatory mechanisms fail. 

Q:  If they’re in check, then there’s not excess glutamate.
A:  No, that’s not true.  You have a certain amount of excess glutamate, but it’s capped by regulatory cells.

Q:  But after that initial impact by inorganic mercury, subsequent amounts of inorganic mercury have no impact? 
A:  I didn’t say that, it might have some impact….This is a level of specificity I can’t testify to nor do I need to, to establish support for my mechanism. 

Q:  So you’re willing to say that inorganic mercury induces glutamate excess, but you’re unwilling to say what it will do after that? 
A:  As long as it stays there, it will maintain the neuroinflammation.  I have an idea about that.  Whether the neuroinflammation will get worse or get better will depends on the person…. 

Q:  Some inorganic mercury will create this excess, but you don’t know what happens after that?

PETITIONERS’ OBJECTION:  You’re asking about dosage; we didn’t consider that on rebuttal.  This was on his direct testimony; he was crossed and re-crossed on this.  This is way outside his rebuttal testimony. 

Respondent’s counsel: I don’t know why he’s telling us about neuroinflammation if he can’t tie it to inorganic mercury and explain how it works.  He admits the neuroinflammation can be tied to many factors.  If he can’t explain how he reaches his conclusion…. 

Special Master Hastings:  This is not argument. 
Special Master Campbell-Smith:   I think Dr. Kinsbourne said he would need to examine the individual, so please move to another line of questioning.

Q:  How much glutamate must be built up before you get the excitatory effect that you’re postulating?
A:  No one I know has quantified that…. 

Q:  So you’re saying that how much glutamate is necessary can’t be measured? 
A:  It can’t be measured in living humans.  There are in vitro models in which it can potentially be measured. 

Q:  Do you have any idea what the measurement of excess glutamate would be before it becomes excitotoxic?
A:  I don’t.

Q:  Can the glutamate excess that you’re postulating manifest in overexcitation in a period of a day? 
A:  I don’t know of any medical literature that can answer that question.

Q:  Can this process of glutamate excess remain latent for years? 
A:  I know of no literature which puts a time frame on this. 

Q:  You cited the Purcell paper.  That paper didn’t deal exclusively with regressive autism, did it? 
A:  It didn’t. 

Q:  In that paper the authors stated that ‘as we are examining post mortem samples, it is more likely that we are identifying secondary effects.’  This is a portion that you didn’t cite.  They’re saying these are secondary effects, not causative ones, right?
A:  Yes, correct. 

Q:  It mentioned the Casanova article; you called it important? 
A:  Yes. 

Q:  He proposes a deficit of inhibition, not an excitation?
A:  Yes. 

Q:  But that’s not what you’re postulating? 
A:  I’m postulating a change in the excitation/inhibition balance in favor of excitation…. 

Q:  How does Dr. Casanova propose in his article that the deficit of inhibition occurs? 
A:  He argues that there’s a problem with inhibitory neurons. 

Q:  So this deficit of inhibition is actually a function of brain development? 
A:  Not necessarily. 

Q:  Isn’t that what he postulates in his article? 
A:  As we have discussed, the question of brain development is an issue that is postnatal as well as prenatal. 

Q:  Doesn’t Dr. Casanova say that he believes it occurs in the prenatal period? 
A:  You may be right, but I’ll need to refer to the article. 

Q:  Would you accept that he does? 
A:  In the first trimester?  Yes.  Let me explain the relevance of Dr. Casanova’s statement to my theory.  I wasn’t referring to this article as corroborating my theory on the origin of neuroinflammation in autism.  I was pointing to the article to rebut the statement that the overactivation theory was outdated and was not to be considered.  I was showing that he’s considering it very seriously in a recent article. 

Q:  But his mechanism is prenatal in origin? 
A:  His, and others too.  Dr. Zimmerman has also taken that position.

Q:  On the Courchesne article.  You cite this for your postulate of neuroinflammation as part of the causative mechanism, however.  You omitted the other factors that these authors were looking at as possible causes? 
A:  I can’t answer that without the article. 

Q:  Prior to the neuroinflammation, they listed two other possible mechanisms:  a failure to correctly regulate the number of neurons produced during prenatal stages and the other is a delay in apoptosis so that too many neurons survive into postnatal life. 
A: Again, I’m not presenting one of a number of medically reasonable possibilities for the cause of autism.  I’m not arguing that my proposal is better or worse, or excludes other causes.  Of course it does not. 

Q:  Is this Casanova article limited to regressive autism? 
A:  No, not specifically. 

Q:  In defending your reliance on the overarousal model, you didn’t mention the Liss article which you cite in your report.  The Liss article came out in 2006; you describe overfocusing in that article.  Is that the same as overarousal?
A:  That article isn’t a neurobiological article, it’s a behavioral article.  My model does not postulate astrocytic cells as being an essential component.

Q:  In your testimony in Cedillo, you postulated the same mechanism and described it as astrocyte death, correct? 
A:  I can’t remember.  You’d have to show me. 

Q:  And in the Snyder proceedings, you described astrocyte death occurring? 
A:  I don’t know, you’ll have to show me what I said.  I don’t remember the words. 

Q:  In support for your proposition in your report and this morning, you refer to the Ashner article as support for your model of glutamate excess.  In Ashner’s discussion, he describes an excitotoxic model.  Doesn’t he describe a process as “a vicious amplifying cycle of neurotoxic cascade”? 
A:  I can see the words [on the screen].

Q:  And if you look further, it says ‘astrocytic glutamate uptake is inhibited.’  You were using that to support the idea that not necessarily astrocyte death, but an inhibition in the astrocyte function could result in this imbalance.  Doesn’t Dr. Ashner conclude that it sets in motion “an unimpeded cytotoxic cycle”?
A:  There was a statement about where it became synchronous, and I’m trying to find it again.  I don’t see it, but indeed, the endpoint is death, but as I pointed out in the living brain, there are regulatory mechanisms that might preclude that cycle from getting out of control in this fashion. 

Q:  In your report, you discussed the Charleston article and in it, you describe it as standing for the proposal that the astrocyte population in the brain decreased significantly.  But in Vargas, the authors didn’t find astrocyte loss, right?  And in Lopez-Hurtado, they reported no astrocyte loss, isn’t that correct?   
A:  And the Charleston people didn’t report any at 12 months and 18 months; only at 6 months. 

Q:  In those articles, the astrocytes actually recovered; it was not a lasting impact?
A:  Either they recovered or there was a compensatory proliferation of astrocytes….Charleston points that out…. 

Q:  You discussed Dr. Pardo’s article.  Do you agree that Dr. Pardo is in the best position to interpret the significance of his own work?
A:  Yes, of course.

Q:  And your opinion that mercury from a vaccine as a potential cause of autism was formed during the last few months? 
A:  I have only studied it seriously during the last few months.  Before I started studying for this cycle of trials, I always considered heavy metals, but I hadn’t paid serious consideration of the issue of mercury until recently. 

Q:  When I asked you during Snyder, you said you hadn’t formed a conclusion at that point.
A:  That’s true.

Q:  This postulate that you’ve come up with, is it true you’ve never published it or subjected it to peer review?
A:  Yes.  I only came to this conclusion quite recently.   

No questions from Special Masters.

Rebuttal Testimony of Dr. Mumper 

Special Master Campbell-Smith:  During the break, counsel discussed the videos accompanying Dr. Mumper’s testimony.  Respondent’s counsel reserves the right to counter those videos with other videos, if it wishes.

Q:  [Mr. Powers]  We have you here today to respond to specific statements from Respondent’s experts on direct testimony. 
A:  I understand.

Q:  Did you listen to Dr. Rust’s testimony? 
A:  Yes, I listened and took 40 pages of notes.

Q:  Live audio or recording? 
A:  Some of both. 

Q:  Did you listen to the entirety? 
A:  Yes. 

Q:  I want to ask some questions about William Mead and Jordan King.
Do you recall some of his testimony on Rett’s syndrome testimony?  Do you have a response to that testimony?
A:  I had thought he was elaborating on Rett’s syndrome a lot in order to lay some groundwork and then some extrapolate to make specific determinations as to these two cases.  And as time went on, I had the same questions as Special Master Hastings to where it was going.  Rett’s syndrome is very well described and occurs in girls.  We know the genes involved.  At some point Dr. Rust was making an extrapolation that Rett’s has autistic type features and we can extrapolate that autism is genetic.  But to spend so much time on such a different disorder from what we’re considering was puzzling to me.  He said Rett’s is now being described in some boys. That opens the door to certain environmental causes. Because boys don’t typically get Rett’s, you have to wonder what’s going on that they are now being identified.  We know from Dr. James’ work that there are more environmental challenges for boys, especially with respect to the role of glutathione….Boys have relatively lower levels of glutathione.  Rett’s is not relevant to these particular boys.  What I understood my job to be was to generate some specific theories on these two individual boys. 

Q:  Was there anything about Rett’s Syndrome that informed your opinion in these two cases? 
A:  No. 

Q:  Dr. Rust gave testimony on William’s head size, trying to make the point that he may have had congenital autism. 
A:  He was trying to show that Will had a small head and then showed increase in head trajectory with subsequent decline.  What’s inconsistent is that his newborn head circumference was in proportion to body length and weight and was in 80-85%ile.  Dr. Rust said that birth measurement was not appropriate because of birth trauma.  I went back to the medical records. I found 3 different references:  healthy male newborn, head and neck normal.  Another: William’s head and face symmetric, normal and skin is normal.  No bruising.  Whereas I can accept in concept Dr. Rust’s observation that in certain cases newborn head circumference might not be reliable if there’s trauma, in William’s records there’s no evidence of this. 

Q:  And if there had been trauma, there would have been ample opportunity in the records to reflect that?
A:  I believe that is true.

Q:  And a reasonable physician would have made note of some as abnormal as what Dr. Rust described? 
A:  Typically, you will see physicians indicating newborn problems; these issues don’t appear.

Q:  Do you recall testimony that both William and Jordan had abnormal development prior to regression.  Do you recall Dr. Rust being able to point to any specific evidence in the medical records? 
A:  No, he talked in terms of generalities and I was struck that he was somewhat confused about the cases as he was testifying.  For example, I remember William’s sister Eleanor in all the videos, and Dr. Rust was unable to remember that William had a sister.  I’m concerned about the level of Dr. Rust’s scrutiny that he was unable to recall that, for example…. 

Q:  Dr. Rust did describe the importance of talking to the parents in assessing the onset of autism.  Do you recall that testimony?
A:  Yes, he was describing his practice in his own clinic.  What was unclear to me is how much of this history was actually performed by him and how much was by his residents. 

Q:  Do you agree in principle that a thorough parental history is important in treating autism? 
A:  Yes, I think the history from the parents is the most crucial piece of information in putting together the picture of the entire child but also with respect to his other medical problems. 

Q:  In your practice, are you the physician who conducts this interview? 
A:  Yes. 

Q:  Do you recall if Dr. Rust had ever heard the parents’ history at any point? 
A:  He had testified that he had not heard the parents’ testimony here or heard or read their testimony. 

Q:  And do you believe that testimony to be critical to diagnosing autism and to determining onset?
A:  Yes, I believe that to be very important. 

Q:  A significant part of his testimony was a critique of the care and treatment of William and Jordan in particular and of the Autism Research Institute approach in general.  Can you describe your response in general to that critique, and particularly to the idea that these treatments are not science-based? 
A:  I was disappointed with the way Dr. Rust handled that line of questioning.  These are issues that I have studied in some detail in order to figure out how to help these children, and he dismissed various interventions almost out of hand, saying things like there is no evidence that IVIG helps children with autism, stating it as if it were fact.  In reality, there is published science about that very fact.  If you want to state that, you should say it only helps certain children with autism.  The second objection is that he tended to go down this laundry list, as if Dr. Greene was trying to cure autism with these different interventions…. It’s a crucial distinction that Dr. Greene was taking care of the whole patient, addressing the specific medical problems of the child.  He was following a very rational approach given what he knew about the child and the interventions he had available to him and looking at risk/benefit ratio of those interventions with respect to the biochemistry.   

The most egregious example was Dr. Rust’s comments about Valtrex.  He said he had no idea why it would be helpful in autism.  There’s a very well established biochemical reason for this treatment.  Thirdly, if Dr. Rust didn’t know why we would use some of these things (he hadn’t heard of Eskimo oil), in a Google age, he can look it up and see that this is  an essential fatty acid and the literature points to this substance in immune regulation and to help heal the lining of the intestine and cell-to-cell communication. 

Q:  What do you believe were some of the underlying medical conditions that were being addressed by Dr. Greene’s therapies and those that you use in your own practice?  In particular, those used not to cure autism but to heal the whole patient? 
A:  I think both boys had evidence of chronic diarrhea, subtle signs of abdominal pain.  When we get a history of chronic diarrhea for as much as a year, we can’t just write it off to childhood diarrhea in a child who’s deteriorating before our eyes. 

Q:  Whether it’s curing autism or not, it is to treat a significant medical condition? 
A:  Right.  And also he addressed methylation abnormalities, which is why he’d use various vitamins, B-12 or folinic acid.  In the record, there are indications that these things helped.  When I listened to Melinda’s testimony here, she says that if she misses a day in supplements, she sees deterioration in his performance.   

Q:  Dr. Rust described these as having no basis in science? 
A:  Yes. 

Q:  I have three slides that you prepared and brought with you today. 
A:  This is the methylation that Dr. Deth talked so much about, and this is the way we teach it to doctors who are learning how to treat children with autism.  This is Dr. Jill James’s slide, and I have made some notations that are mine on the last one and I’ll clarify these. 
Slide 1:  The folate cycle.  How folate is utilized to support methylation reaction…

Slide 2:  Effect of oxidative stress on effective trans sulfuration.  Same cycle as before but what happens when children are under oxidative stress.  Glutathione in its reduced form is down (the good kind) and oxidized glutathione (the bad kind) is up. 

Q:  And your discussion is not based on your expertise as a biochemist? 
A:  No, this is based on my initial reading of Jill James’ work; my having worked with her on some research projects; and having heard her present this ten to twenty times and my having discussed it with her at conferences and using it in my clinical practice.

Slide 3:  I’ve looked at the interventions that Dr. Greene and I use to help these children. I’ve tried to put it into the context of this pathway.

Q:  You’ve got a notation on Slide 3 of “B-12 Methylcobalamin.”  What does this mean?
A:   We try to help generate methyl donors so that the methylation cycle can occur.  Jill James’ work actually looked at children, found that they had low levels of these necessary substances, and she designed nutritional interventions that would help these children make the methylation cycle work.  She gave methylcobalamin, folinic acid and TMG.  All these help that remethylation cycle take place.  She was able to do this in a lab, and published this in a peer-reviewed journal.  She was able to show the dramatic normalization of methylation levels.  And that’s why Dr. Greene chose to use folinic acid and methylcobalamin.

Q:  Is there anything else on this slide that you would like to highlight?
A:  Well, look at B6 and magnesium.  There are 22 studies in the medical literature that have shown efficacies of B6 alone or in combination that go back decades.  We can postulate that the way it works is helping the body generate cysteine.  Cysteine is necessary for detoxification and reduced glutathione.  It’s another nutritional intervention that ties specifically to this cycle. 

Q:  Can you identify any other interventions that you and Dr. Green use that are worth mention?
A:  I’ve noted DPP4 and casein-free and gluten-free.  If you’ll bear with me, I’ll take you back to the Valtrex issue….[discussion of abnormal SAM/SAW ratios; adenosine levels and Valtrex medication; we are using Valtrex to correct this cellular biochemistry.]

RESPONDENT’S OBJECTION:  This is way beyond qualified testimony on these matters.  Can we move on to something that’s case-specific rebuttal? 

Mr. Powers:  She’s explaining the science and will soon get to the particular cases.  She’s detailing her reliance, and Dr. Green’s, on the science as a clinician. 

Respondent’s Counsel:  She’s not qualified to explain how she could rely on this.  She’s a pediatrician.

Special Master:  The witness has already explained that she is giving this testimony as a clinician, not as an expert biochemist.

A:  The reason for trying to show the chemistry was Dr. Rust saying he never saw any children benefit from a casein-free gluten-free diet.  There is a subset of children who have improved, and I’m very surprised that in his population of many hundreds of children that he hasn’t seen improvement related to the diet in at least a subset. 

Q:  What is your experience as a clinician and in your network of doctors on the efficacy of the CFGF diet? 
A:  We tend to recommend the diet based on a clinical picture in which we have some history of the child craving dairy or craving gluten or deteriorating when they eat those foods.  Our best estimate is that 30% of the children will improve dramatically, 30% will have significant improvement, and 30% that won’t respond. But in this situation where the parents were reporting chronic diarrhea, I think it is an entirely reasonable thing to do. When we use these diets, we’re careful to supplement calcium.  There’s rational reason to use these diets in children with autism. 

Q:  Are you relying on any other peer-reviewed scientific literature?  Are you relying on any other compilation of literature beyond what’s in the slides? 
A:  We’re constantly upgrading our bibliographies of scientific articles.  I’m reviewing one now.  We try to look at the whole literature. 

Q:  Who’s we? 
A:  Scientists, researchers, clinicians affiliated with Autism Research Institute. 

Q:  Dr. Rust described a concern that in a lot of these care and treatments, there seems to be an absence of controlled clinical trials and an absence of double blind crossover placebo controlled studies.  He argued that your treatments and care are not based on evidence or science.  What’s your response? 
A:  We do need many, many more placebo controlled studies, but we’re very concerned about only using that model.  Our paradigm is that these children have multiple medical problems and that if you are not careful when you pick controlled trials, you may miss something that’s helpful to a subgroup.  An example of that is the secretin study.  Dr. Rust mentioned it as being evidence of its non-effectiveness.  But if you look at the Herlihy study, there were clear responders who did dramatically well, but others who didn’t.  The scientists from ARI were concerned from beginning that the population was too heterogeneous.  So, in kids with gut symptoms, there were children with dramatic responses.  If we recall from the data, William Mead’s pancreatic enzymes were shown to be dramatically low before secretin and then improved after the secretin infusion.  For Dr. Rust to paint with a broad brush based on the placebo controlled study and not to look at the symptoms of this particular child reflects a very superficial understanding of taking care of the individual patient based on individual problems. 

Q:  Are you endeavoring to conduct such controlled trials?
A:  Yes we are.

Q:  What type of trials are you planning or are underway? 
A:  We’ve submitted grants for a double blind placebo controlled crossover study of diflucan; we’ve submitted grants to NIH for chelation, using DMSA initially probably; we’re trying to do  single subject multiple baseline study; single subject, lots of initial measurements and then do different interventions.  This is used very widely in behavioral psychology; we’re trying to adapt it to the medical model.  We’re working with Ted Carr. 

Q:  I want to touch on chelation.  Do you recall Dr. Rust’s testimony that it’s potentially harmful, fatal, painful and he didn’t understand how it could have any possible efficacy to treat this disorder postulated to be related to inorganic mercury and inflammation. You recall that testimony?  How would you respond? 
A:  Chelation is a well-recognized and widely used pediatric modality for children with lead toxicity or poisoning.  Many children we treat for mercury in their chelation urines also show evidence of lead.  We think that it’s important to go after the lead.  At ARI, we’re at least as concerned about the lead as the mercury in many of these children.  Even though it’s been taken out of gas and paint, there’s lead in toys from China and elsewhere.

With regard to dangers and the fatalities, when both Dr. Green and I do chelation, it’s oral chelation, and we tend to use blood count monitoring every 4 to 8 weeks.  That’s why you saw those screens in the charts.  When IV is used, John Greene has vast amounts of experience.  The death Dr. Rust referred to resulted from pharmaceutical error where sodium EDTA, not calcium EDTA, was given to the boy who died.  We would expect that sodium EDTA would cause severe consequences.   But that does not paint all of chelation as dangerous or fatal.  That was pharmaceutical error. 

Q:  Dr. Rust also said he didn’t understand how chelation could possibly have any efficacy because chelation can’t remove inorganic mercury from the brain, crossing the blood-brain barrier?  How do you think it is that chelation could possibly assist the symptoms in the children you see?
A:  A lot of work remains to be done in this area, but we are able to mobilize mercury, lead and other toxins from where they are hiding.  Typically mercury hides in the brain, kidneys, liver and fat.  We know we’re typically not removing mercury from the brain, but by working with rest of body burden and taking off the chronic stress that mercury provides, we’re enabling cysteine regeneration and glutathione production and reducing the heavy metal burden.   It’s also entirely possible that chelation agents work as anti-oxidant agents.  We wonder if we’re achieving an antioxidant rather than a chelating effect.  We’re trying to mobilize the body’s own mechanisms, and that’s why we focus on methylation biochemistry and nutritional support and not relying just on chelation.

Q:  I want to move away from the specific treatment issues now.  Do you recall Dr. Rust’s review of the video tape?  Do you recall that upon his review, he thought both boys were abnormal before they regressed.  Do you recall him citing to any specific portion of video? 
A:  I do not recall that he did. 

Q:  Have you identified specific portions of the video that are responsive to Dr. Rust’s testimony?
A:  Yes, I did that after taking notes on his testimony. 

Q:  You reviewed the video before Dr. Rust testified? 
A:  Yes. 

Q:  And you reviewed it again after you heard Dr. Rust’s testimony? 
A:  Yes.  When I initially reviewed it, I took extensive notes as to what appeared age appropriate or not.  The second time I was looking for specific criticisms or deficits that Dr. Rust made.  The total videotape time is less than 10 minutes for each child.

Mr. Powers:  Videos will be shown.  We have an Index of video clips entered into evidence.

Special Master Campbell-Smith:  We would appreciate it if Dr. Mumper would lay some groundwork before showing the videos or subtleties may be lost.

Mr. Matanoski:  The Court requested designation of video sections in advance.  Respondent did that; Petitioners said they would rely on all videos.  Now they’ve come forward with these clips.  We reserve the right to designate or counter designate clips with other parts of the video later for your review.  We’ll rebut what we can today. 

Mr. Powers:  Petitioners didn’t designate anything earlier on because we didn’t put this in our case in chief.  These designations are in rebuttal to testimony of Respondent’s witnesses.  It’s impossible to designate ahead of time what one might use in rebuttal. 

Special Master Campbell-Smith: Dr. Mumper, please address what part of Dr. Rust’s testimony you are responding to with the video clips. 

Mr. Matanoski:  Our experts designated parts of the video records on which they would be relying in advance of their testimony.  They only referred to the parts that had been designated already.  The idea of rebuttal now, without prior designation, seems strange at this point, and that’s why we’ve asked for relief, if necessary.

Special Master Campbell-Smith:  That request has already been granted and we will allow you to add videos to counter these. 

Testimony on Videos of Jordan King

Q:  Segment 1:  Cooing:  Why is this significant in responding to Dr. Rust’s testimony? 
A:  Dr. Rust discussed non-verbal language and other measures to communicate that did not involve actual words and it was related later to the topic of word count.  This is an early language marker.  Jordan is about three months of age.  I’m showing a normal language relationship and a to and fro relationship with the mother cooing with the child…. 
[clarification on date of video; Special Master request for specificity about Dr. Rust’s testimony this is responding to]

Dr. Rust said there’s an artificial distinction between standard and regressive autism and if you asked enough question, you’d find subtle signs of abnormality.  I picked these segments to show very normal milestones for nonverbal language, gesturing, social reciprocity and appropriate toy play. 

Special Master Hastings:  Many experts here have said that when you look at videos retrospectively, you find evidence of abnormality before “regression.”  Did Dr. Rust point to specific evidence of abnormality before regression in Jordan?

A:  On the basis of my notes, I don’t have the clarity to know if that was specifically about Jordan King or not. 

Special Master Hastings:  I want to understand what point you are trying to refute here.  Mr. Powers, what are you rebutting here?

Mr. Powers:  Dr. Rust offered general testimony that in his opinion based on video review, Jordan King and William Mead were not normal prior to regression.  He did that without reference to specific frames but definitely was placing the absence of normalcy further and further back in time.  Dr. Mumper is simply offering testimony to show that Dr. Rust was either mistaken or was not looking at the appropriate signs in his review of the videos. 

Special Master Hastings:  I do remember that Dr. Rust made some general comments.

A:  I found my notes now on Dr. Rust’s specific testimony on Jordan King.  Dr. Rust’s testimony regarding loss of speech.  Also he said that Jordan didn’t want to be held.  In this video, even though  Jordan is not being held, there’s a social reciprocity that speaks to social interactions that I thought would be valuable. 

Q:  Clip #1:  showing video segment 1.
A:  Dr. Mumper notes good eye contact, social reciprocity with mother, and appropriate language for a 3-month old baby. 

Q:  Clip #2: 
This is between ages of 13 and 16 months, but I can’t tell you specifically what age.  This is a critical time when Dr. Rust is saying the child is already showing signs of autism and impairment.  I wanted to show age appropriate, normal behavior in the time in question. 

Special Master Hastings:  The time frame is 13-16 months?  Where did you get that from?  By my calculation, that would be 15-21 months.

A:  I think we’ve established that the child is older here per Special Master Hastings.

Clip shown. 
A:  Jordan is dropping the toy, looking to see where it went -- establishing object permanency.  He is processing cause and effect.  In that age range, above 16 months, he was still smiling and having social reciprocity with whoever was behind the camera.

Clip #3:  Playing the marimba: 
A:  This is the 13-16 month age range.  It shows reciprocity with another person and engaging in an age appropriate game.  He was also looking around at the videographer. 

Clip #4:  Playing with the cat:
A:  In this situation, very appropriate interaction with the animal and the grandmother. 
Again, he looked at the camera.

Clip #5: 
A:  Dr. Rust discussed inability to use gestures.  This demonstrates gesture being picked up, which emerges around 9 months as a skill.  Again, Jordan is still making eye contact with people in the scene.

Clip #6:  Dancing
A:  This shows his ability to enjoy play, interact, ability to look at person filming him; he’s very engaged. 

Clip #7:  Tool bench
A:  This video demonstrates his ability to use tools in a functional and appropriate way as opposed to lining up toys or playing inappropriately.  Maya, his sister, is in the video, so we know he’s at least 15 months old in this video.

Clip #8:  Harmonica. 
This clip shows social reciprocity with people in the room and interactive play. 

Q:  Jordan was shown being held in this clip.  Do you recall Dr. Rust saying Jordan had an “aversion to touch”? 
A:  There are many examples in the videos of him being held by grandmother, mother and father.  He’s responding to the mother, smiling brightly and interacting.  He’s also showing gestural language. 

Q:  Do you recall Dr. Rust saying Jordan had splinter skills? What was his description of splinter skills? 
A:  I think Dr. Rust was referring to musical abilities; he’s from a musical family.  I don’t see any savant musical skills here.  That was rudimentary harmonica playing.

Clip #9:  Building the marimba. 
A:  Note here Jordan’s ability to use a nail in a functional way and imitating his father and repeatedly getting nails out of the nail bag.

Q:  Did you see anything else significant? 
A:  He was looking back and forth for approval and interaction with his father.

Clip #10:  Sister
A:  There was some speculation about Jordan withdrawing at the time of the birth of his sister and not interacting socially with her.   

Special Master Hastings:  In that segment, his sister looked like a very, very young newborn.  Is that your interpretation?

A:  Yes.  My best guess on his age is that he’s 15 months at that age.  That’s all the videos we have to show looking at normal characteristics.  We have two briefs clips to show a clear contrast to what we’ve been looking at. 

Q:  I just want to note that I didn’t hear a lot of fully formed words from Jordan in these videos.  What’s your assessment of his language in the clips we’ve seen here? 
A:  I agree that we don’t hear a lot of clearly articulated words.  I did hear Mrs. King testify, and I found her to be a very reliable historian, that he showed normal language development.  In the videos, he almost always either has pacifier in his mouth or is eating something or is playing the harmonica.  I don’t have good examples on video and am relying on parental history in that domain.

Clips 11 & 12: Presentation of post-regression symptoms. 
A:  I want the Special Masters to look for a qualitative change in his facial expressions; his detachment, no social reciprocity, oversensitive to auditory stimuli and hand flapping.

Clip #11:  Hands on his Ears
Q:  Is that a behavior that you noted in multiple videos after regression? 
A:  Yes, after regression; we did not see it before.

Clip #12:  Puzzle
Q:  What’s significant here compared to pre-regression? 
A:  It shows a qualitative change in interaction with the father.  Before he’s so engaged and now he’s withdrawing.  There’s lots of hand flapping and a vacant look on his face.  He seems to have lost his higher level of toy playing ability. 

William Mead

A:  Dr. Rust talks in his report about kids with autism being “head shy” and this comes on very early.  He talks about aversion to eye contact as a systems problem.  He also said that parents in families with autistic children tend to be rigid, aloof and hypersensitive to criticism.  Through multiple video clips, I did not find that to apply to either set of parents. 

Mr. Matanoski:  I believe those comments by Dr. Rust were general comments. 

Mr. Powers:  His comments were general, but he was applying them to the specific cases here to support his assertion that these boys manifested abnormal development before their regression.  While he did not dispute the boys’ having regressive autism, he did make a general observation that they were not normal in their development before regression.

Mr. Matanoski:  Dr. Rust did not dispute the diagnoses of regressive autism.

Mr. Powers:  He did make reference to both boys being “not normal” before the regression. 

Special Master Campbell-Smith:  I observe that he thought there could be an assumption that there were autistic symptoms before the notation in the medical records.

Clip #1:  Johnny jump up
This shows reciprocal social interaction with one of his parents.  It shows reciprocal interaction, smiling, alertness and eye contact normal for a 5 month old.

Mr. Powers:  Does it sound accurate that this was November 1998 when he was 5 months old.
A:  Yes.

Clip #2:  Pushing up.   
That demonstrates great eye contact.  It also shows a reciprocal smile, bright eyes, and laughter with the father. 

Clip #3:  Bath time
[William and sister in the bathtub]  This speaks to Dr. Rust’s testimony that autistic kids do not want to have their heads touched or hair washed.  He tolerates that from his sister and does a fair amount of babbling. 

Q:  What was significant? 
A:  He seemed to tolerate and even enjoy the head touching.  It shows reciprocal social contact and normal bathtime play.

Clip #4:  Hi Dad!
A:  This was done around the time of his first birthday.  It demonstrates words “Hi Dad!” which are two word phrases that usually comes in at 18 months, so it shows some language.  It also shows reciprocal interactions and play with the sister and parents.  Very age appropriate.  William says “Hi Dad.”

A:  The last two videos are after his regression.  The first is covering ears and hand flapping.  The second one demonstrates that he has abdominal issues. 

Clip #5:  Hands Covering Ears   
A:  This is about 27 months.  You can appreciate the deterioration of his language.  He’s reduced from “Hi Dad” at one to guttural utterances.  He has a vacant look; there’s a qualitative change in his facial expression.  He can’t imitate saying “Say cheese!”

Q:  He’s holding hands to his ears and flapping his hands? Did you see this behavior prior to 16 months of age? 
A:  No, I did not.

Clip #6:  William at the computer. 
A:  One of Dr. Green’s therapies was treatment of gut issues.  Dr. Green was criticized by Dr. Rust for addressing William’s abdominal symptoms.  This tape shows inferential evidence of abdominal pain: a distended stomach, the way he’s touching himself.  We frequently see these symptoms in autism.  We need to be open to the possibility that they are trying to communicate that their stomachs hurt in this way because they no longer have language.  He seems nonresponsive to multiple efforts by his dad to engage him; he was staring at the computer screen and not even attempting interactive play.

Q:  So based on listening to your listening to the parents’ testimony, review of the medical records and videos, do you agree or disagree with Dr. Rust’s testimony that these boys’ development was abnormal prior to regression? 
A:  I disagree with him. 

Cross-examination
 
Q:  [Mr. Johnson]  You covered a lot of ground.  I just want to check -- since you testified last, you did not become an expert in biochemistry? No. Neurology? No. Psychiatry? No. Toxicology? No. Neurotoxicology? No. Genetics?  No.

Q:  Would it be fair to say that your knowledge in those areas is based on what you’ve learned from your colleagues at the Autism Research Institute? 
A:  Yes, that’s correct, and from other literature. 

Q:  What other literature are your referring to? 
A:  We maintain bibliographies in the autism literature.  Pardo, Zimmerman, Vargas, Martha Herbert, people in Italy working on environmental issues; people at the MIND Institute… The list could go on.  We don’t limit ourselves to just what’s in our institute publications. 

Q:  Do you give more weight to your colleagues at the Institute? 
A:  That’s a fair statement, and I also give more weight to articles where I had the opportunity to discuss them with the authors. 

Q:  You were asked a number of questions about the treatment therapies that Dr. Green provided to both boys and that you use to some extent in your own practice.  One treatment was chelation.  Did you say that in your practice the main justification for chelation was targeted towards the lead? 
A:  That’s not exactly what I meant to say.  We look at various types of toxicity, and lead is very, very common.  So when we do porphyrin analyses, we look for lead and mercury.  And we have come to appreciate how much they co-exist.  And so treating lead toxicity is well within what pediatricians are familiar with, using DMSA,which was used for these boys. 

Q:  What symptoms do you rely on in treating lead toxicity for chelation therapy? 
A:  Irritability, excitability, decline in cognitive performance.  But AAP and CDC have recommended ongoing lead screening for children because it’s not prudent to rely on development of symptoms as opposed to trying to address it unsymptomatically. 

Q:  So you would require some testing of lead in the blood before you do chelation?
A:  No, the lead level in the blood only persists for a very short time.  Blood turns over every 2-3 months, so unless you get the child right after exposure, you have to rely on indirect measures. 

Q:  So blood is not reliable to test for lead body burden? 
A:  Yes.  It can only be used for acute exposure.

Q:  You agree people have died from chelation therapy?
A:  Yes. 

Q:  You mentioned one case that Dr. Rust mentioned?  That’s not the only death, is that right? 
A:  He mentioned 4 and I consulted with my colleagues and we could not find 4 cases.  We are aware of the one I mentioned, and we’re aware of another, but I’m not aware of the third or fourth.

Q:  Are you aware of one case, where a lawsuit was brought and Metametrics lab was named in that lawsuit as a defendant, and it did lab tests in both of these cases? 
A:  No, I was not aware of that.

Q:  Let’s review other therapies you discussed.  You mentioned IVIG.  How does IVIG treat persistent inorganic mercury in the brain?
A:  I’m not saying that it does.

Q:  Whether IVIG treatment is effective really doesn’t speak to the issue of whether thimerosal in vaccines contributed to autism, is that correct? 
A:  It speaks to the fact that he was treating persistent low levels of  IVIG in these children.

Q:  And that’s not consistent with inorganic mercury in the brain?
A:  Not to my knowledge.

Q:  How does Eskimo oil treat persistent inorganic mercury in the brain?
A:  I’m not aware of any studies that have assessed that specifically.   

Q:  So the effectiveness or ineffectiveness of treatment with Eskimo oil really doesn’t speak to the issue of whether thimerosal in vaccines contributes to autism?
A:  It is being used for intestinal reasons and the other reasons I discussed.

Q:  How does Valtrex treat persistent inorganic mercury in the brain? 
A:  I think that if you use Valtrex to decrease adenosine, which would then allow methylation biochemistry to proceed, the ultimate result would be an increase in glutathione, as demonstrated by Dr. James’ work.  Cysteine and glutathione are part of the integral ways to handle mercury.  Whereas John was not doing it to target inorganic mercury in the brain, that is a biologically plausible way to improve detoxification mechanisms through the body’s own capacity to remove inorganic mercury in the brain because glutathione is the main way we get rid of mercury.

Q:  What’s the primary clinical use of Valtrex? 
A:  It’s an anti-viral agent and purine analog, and that’s where it’s utility with dealing with adenosine comes in. 

Q:  It’s also used for genital herpes? 
A:  Yes, and a slew of other viruses.  I don’t know if Dr. Green was using it as an anti-viral or in its other capacity. 

Q:  Are you aware that Valtrex has never been tested in a pediatric population? 
A:   I wouldn’t be surprised because many of the drugs we use are not tested for people under age 12.  But we do have precedent for using it in standard pediatric practice in newborns, so I’m comfortable using it. 

Q:  You alluded that there are not case-controlled studies for many of these substances? A:  Yes. 

Q:  Would you be more comfortable as a pediatrician using these if there were case controlled studies?
A:  Yes, if the case controlled study took into account individual medical problems and  was not too heterogeneous a population. 

Q:  Are you testifying that your clinical experience is more reliable than a case controlled study would be? 
A:  I’m testifying that when we are treating a generation of children and are being overwhelmed by their medical problems, that we are trying to take care of individual patients.  We feel some urgency that we can’t wait 10 or 20 years.  These children seem to have a window of opportunity where, if you treat their medical problems, they get better.  With the timeline of applying for grants, getting the studies completed and analyzing the results and the meta-analyses, we’re proceeding in good faith, realizing that we don’t have good case controlled studies for all that we do.

Q:  And I’ve heard you say that ‘the child is your laboratory’?  Is the approach you just described a way of saying that?
A:  That’s a shortcut way of saying that when you’re doing interventions, the biggest outcome is how it affects the particular child.  We certainly use laboratory values in helping us assess the child, but if we are able to give Valtrex to a particular child and show that his adenosine level went from high to the normal range, that to me is more important than what happened to 20 kids who are not my patients, if it led to improvement.

Q:  So you’re willing to rely on your own clinical judgment even in the absence of  case-control studies showing that these treatments are effective? 
A:  There have been case controlled studies demonstrating efficacy for a number of these treatments.  That’s been done for B6; there are 22 studies showing efficacy.  There are studies on Omega-3s and multiple vitamins.  But much more work remains to be done. 

Q:  Are these treatments targeted at oxidative stress issues?
A:  Yes.

Q:  And that’s not specific to mercury toxicity? 
A:  Correct. 

Q:  Other things can cause oxidative stress?
A:  Correct.

Q:  Did you listen to Dr. Rutter or Dr. Lord or Dr. Fombonne? 
A:  Not to Dr. Rutter or Dr. Lord.  And I only heard part of Dr. Fombonne’s testimony yesterday. 

Q:  And you testified that you don’t diagnose children with autism? 
A:  Yes, so that there’s no question when I treat them as to their improvement that I misdiagnosed them. 

Q:  Do you know what the ADIR is?
A:  Yes, it’s the Autism Diagnostic Interview Revised.  But we do not do the intake.

Q:  Do you know what the ADOS is?
A:  Yes, the Autism Diagnostic Observation Scale.  But again, others do the diagnosis. 

Q:  Do you know whether the ADIR or ADOS have questions targeted on whether there was regression?

PETITIONERS’ OBJECTION:  This is a redo of cross-examination of this witness.  It has nothing to do with her rebuttal testimony today. 

Mr. Johnson:  Dr. Mumper commented on the videos and this goes directly to her qualifications to provide that testimony. 

Special Master:  Proceed.

A:  My memory is that the ADIR has some targeted questions about regression. 

Q:  Do you know what those questions are?
A:  No, I do not.

Q:  Do you have your own questionnaire? 
A:  Yes, we have an intake form, but it’s not standardized. 

Q:  What questions do you ask to determine if there has been a regression? 
A:  We ask about age appropriate language, social and reciprocal behaviors.  We look for meeting of milestones and a period where they lose those milestones.  The classic example is to see that the skills are obtained and then lost and a period of time of 3 months when they demonstrated a skill and lost it. 

Q:  Can you give examples of specific questions that you ask?
A:  How many words did your child have at one year?  How many words did he have at 18 months? 

Q:  Can you determine in this case that there was totally normal development based solely on your review of the medical records, is that right? 
A:  I made the judgment that up to some point, the child appeared to be normally developing on the basis of well-baby check ups, month by month, and on the basis of the videos that I was able to review.  The normal development in the videos seemed to correlate to the notes in the pediatricians’ records.  Then there was a loss of language, social reciprocity and appropriate play. 

Q:  You did not review the videos until Thursday before you testified? 
A:  Yes, I wrote my report based on the pediatric records.  At that time, I was very dependent on the medical records.

Q:  And you had not interviewed the parents? 
A:  That’s correct.

Q:  Did you hear Drs. Rutter, Lord and Fombonne all testify that parents often don’t recognize early, subtle signs of abnormal development?
A:  I did not hear their testimony, but I do know that they have written about these subtle signs.

Q:  Do you disagree with their testimony that parents often overlook subtle signs?
A:  I think there are certainly cases where parents overlook subtle signs.  If there are subtle signs I missed on these videos, I would be open to learing that from colleagues.  The fundamental issue, though is, do these kids look abnormal from birth and on an abnormal trajectory or do they look normal and then something happens that interferes with that?

Q:  You testified that you did not see evidence on the videos of Jordan King not wanting to be held? 
A:  I saw a number of cases where he was being held.  There were a couple examples where he did try to get out of the parents’ arms.  I was pointing out that the “all or nothing” situation did not exist. 

Q:  Do you agree there are notations in the medical records of his mother indicating that he did not like being held as an infant? 
A:  Yes. 

Q:  [Mr. Johnson cited two examples from the records indicating that Jordan didn’t like to be held.]
A:  Yes, these examples are in the record.

Q:  You testified that you don’t typically use videos in your own practice? 
A:  Correct. 

Q:   You don’t have time to do so? 
A:   Right. 

Q:  When were you first asked by counsel to go through the videos and identify clips that show normal development? 
A:  About two weeks after the DAN! conference, which would put it in the third week of April.

Q:  And you didn’t view the videos at that time?  Because you saw them the Thursday before you testified? 
A:  There was a Saturday morning when I spent a great deal of time looking at them, but I can’t really recall when that was.  I can only recall that it was some point after our Defeat Autism Now! conference in early April. 

Q:  Do you have notes on your review of the videos? 
A:  I have two sets of notes: from the first review before I testified and then again for this rebuttal testimony. 

Q:  Was it communicated to you that Petitioners were asked to designate portions of the videos as normal developments when you first reviewed the videos? 
A:  I may have misunderstood that; I did not realize that I had to provide that ahead of time. 

Q:  Were you ever presented with a copy of Respondent’s video designations? 
A:  No.

Special Masters

Special Master Hastings:  According to your report, Jordan received the thimerosal in question at birth, 2, 4, and 6 months.  By the time he was 7 months old, he received 127.5 mgs of ethyl mercury? 
A:  Yes. 

Q:  Is the timing of the onset of Jordan’s symptoms crucial to your ultimate opinion?  You’ve indicated that you think it’s probable that the thimerosal contributed to Jordan’s autism.  Would it matter if the first symptoms occurred at 18 months or 13 months or 9 months?  Would it matter to your opinion?
A:  It really doesn’t matter to me.  The crucial thing here is that mercury can be latent for a period of months before it manifests.  The classic example of that is the lab researcher who got two drops of mercury on her gloved hand, seemed fine for three or four months, but then got dramatically sick and ultimately died.  The concept of it being there and not causing overt symptoms for a while is entirely consistent with what I believe to be the case here.  For me, the crucial thing is more that he seemed to be developing normally and then he had autistic symptoms.  Whether those started at 15 months, 18 months, 20 months or 22 months doesn’t really change my mind about the plausibility that thimerosal was a contributing factor. 

Q:  It wouldn’t change, if it occurred even earlier than that, say at 13 months?
A:  Right, because his first exposure was a hepatitis B vaccine at birth, so his initial exposure was quite early on.  It’s difficult to put a timeline on his overt symptoms. 

Special Master Campbell-Smith:  I have questions.  Would that same observation apply to the Mead case?
A:  Yes.

Q:  You had indicated that there were three record citations of normal head size at birth. I only heard 2. 
A:  The second one I cited did not have an exhibit number, so I will turn that over to the court.  The third one is on the same page as the second one.

Q:  I recall from your testimony that you look for deviations from the standard that would cause you to be concerned about head size.  Dr. Rust gave testimony said it really didn’t matter what birth head size was; he looked for trends.  Do you think that is an invalid way?
A:  No, I agree completely with him that trends are important.  Also, I’m open to the possibility that any isolated point is an error.  So when I heard him postulate an error, I went to check the records….The trend he’s looking for is a low head size that goes up and then goes down.  That has been classically described in many different cases.  I was just pointing out that we didn’t seem to have that model in William Mead.  And if we’re going to throw away that first measurement, because it was high, it would be nice to have more than just speculation that it might have been wrong.  It just seems like from the records we really don’t have reason to think that his head was not that size at birth.  But I agree that trends are important, much more so than individual numbers. 

Q:  And you don’t think that trend exists in William Mead? 
A:  For me, that’s an unanswered question.  We have evidence that he started out with a growth percentile for his head that was normal for his body size.  He did have some elevations at the 4, 6, and 9 month check-ups, and it then comes down above the 50th percentile.  It is a little bit of a trend.  I just don’t want to leave out the possibility that initially, he was already at a high point.

That concludes Petitioners’ presentation of rebuttal witnesses. 

[Petitioner puts a letter into evidence from Dr. Young and she is ready to testify in July regarding Dr. Fombonne’s testimony about the new Young/Geier study.]

Rebuttal Examination of Dr. Fombonne

Q:  Dr. Mumper discussed various treatments that Jordan King and William Mead received for autism and other related medical issues.  Are those treatment recommended by the majority of autism experts? 
A:  None of them are recommended by the mainstream. 

Q:  Is there evidence as to efficacy of those treatments? 
A:  No, that is one of the reasons why they are not recommended.  There are no published studies that suggest that they would change the course of autism. 

Q:  Are any of those treatments dangerous? 
A:  Yes.  Although parents think they are innocuous, some can be detrimental to the health of the child:  chelation, vitamin B12, B6 can lead to neural toxicity; children on the casein free and gluten free diet have not done better.

Q:  Are there standards that are used before treatment is recommended? 
A:  Yes, the goal is to rely on evidence from randomized double blind placebo controlled clinical trials.

Q:  Do you have experience with such trials?
A:  Yes, I started my career working on randomized clinical trials.  I have tested the efficacy of a language based treatment in children.  It’s an intervention everybody likes, but when we looked at the results, there was no difference between the two treatment groups.  Our experience as clinicians and parents can be misleading.  The field of autism research is replete with interventions and treatments for the last 30 or 40 years that were disappointing when put to the test of clinical trials.  An example is the secretin study.

Q:  Is that the secretin study you’re referring to? 
A:  Yes, parents worldwide wanted to have secretin used on their children.  The NIH funded 3 separate clinical trials, and there was absolutely no advantage of secretin over placebo.  That resolved the question.  But for five or six years, practitioners and parents believed in the efficacy.  Clinical experience is in no way a measure of efficacy, including mine. 

Q:  Dr. Mumper also described IVIG treatment and took issue with Dr. Rust’s criticism of it.  Do you have experience with IVIG treatment?
A:  Yes.  We did publish a small study of about 20 children in the immunology department at the time when this treatment became very fashionable.  As a routine treatment, it has no place in the treatment of autism, unless you have a documented immunological deficit.

Q:  Dr. Mumper also discussed single subject baseline studies.  Do you have experience of single subject baseline studies? 
A:  Yes.  Often you want to have randomized clinical trials, but if we can’t, we can assess efficacy of intervention in one subject.  So you set a child’s baseline of behavior by measuring things at various points of time.  That’s the way to observe over time before, during and after treatment in a more rigorous way and it allows one to draw some meaningful inferences….   

Q:  I would like to discuss the videos of Jordan King’s and William Mead’s allegedly normal development.  Before we begin, do you have any comments about Dr. Mumper’s methodology, about how she assessed the videos? 
A:  Yes.  Some of her comments were not supported by what was on the video.  We need to assess the quality of behavior, not just whether it’s there or not.  Social reciprocity, for example:  does the child initiate or respond?  That’s the quality we need to evaluate.  The same for the quality of babble.  What is the intent?  Is there really a conversation?  You need to assess these qualities.  Otherwise, it can be misleading. 

We’re going to present some clips and comment on them in a different way.  I also want to correct something that Dr. Mumper said about object permanency, when he dropped a toy and looked to see what happened to it.  That has nothing to do with object permanency….

Q:  Any other comments?
A:  The debate was whether there is evidence of abnormal development before the regression or was the child developing normally up to the regression.  Dr. Mumper should know that we in the field do not think we can detect abnormalities in most children before the age of 12 months.  Her showing clips of earlier ages are not informative at all.  It’s documented in so many studies.  There are ongoing prospective studies of siblings of already diagnosed children.  As high as 15% will later develop autism.  Therefore, we are able to observe prospectively the abnormal development in order to identify the first signs of what will become autism in some of them.  We don’t find much with standardized procedures before the age of 10-12 months.  It is usually around the age of 12 months we start to see social abnormalities.  So using clips up to that age is not evidence of anything.

Jordan King

Clip #4:  Playing with Cat  (13-16 months old)
A:  This is an example of an observation that would fool many people who don’t look at the right things.  It’s natural.  I want to draw attention to the amount of vocalization in the clip and how he interacts with the adults who are around him. Does he produce any vocalization or any gestures?  Does he interact with them?  He doesn’t really look at his parents or grandmother.  He will follow the cat.  His mother touches him, and he doesn’t really give eye contact.  There is no babble, no vocalization at all.  It’s a small thing, but I want to remind you here that the father wrote that “he was never a babbler.”  In all the videos of Jordan King, I’ve never heard one word.  When there are vocalizations, they usually are not socially directed; there is no intent. 

Clip #5: 
You will see partial gesture.  What matters is the quality and spontaneity of gesture.  He is responding to an initiation by an adult.  Even then his response is partial.  What is important for us is to look at the spontaneity.  This is not spontaneous.  She engages him and then he responds. 

Clip #9: Building the marimba 
Yes, he’s building with his father.  He’s interested in toys or musical objects, but let’s look at the amount of vocalization to direct attention of his father to what he’s doing.  There’s no social interchange.  The quality is not there.  He’s remarkably quiet.  He does not initiate interaction with his dad.  No words heard at all. 

Q:  Dr. Mumper said he’s seeking approval from his father in this clip? 
A:  No, I don’t see that.  This is subtle, but the pattern is consistent across all the videos I’ve seen.  There is no vocalization. 

Another clip:  January – June
A:  Jason has a pacifier, but the thing to look at is the mother.  She calls him; he never orients to her at all, despite her calling him.  He’s manipulating toys, but you sense that he’s following his own agenda and in his own world.

Special Master Hastings:  What age is Jordan? 
A: Before 18 months. 

[Video plays on Respondent’s computer, but not court’s computer.  So will be submitted later.]

Q:  Would you describe why you selected this? 
A:  It’s a video of him playing alone, manipulating objects of different kinds.  His mother is filming and trying to engage him and at no point in time does he orient toward his mother as you would expect.  As he moves into the second year of life, eye contact is slowly disappearing and engagement, too.  It’s true that at 9 months he was very engaged, but there is a gradual onset of autistic symptoms.  I want to reemphasize his father’s description and my own observation; he’s remarkably quiet.  He may have had a word or two, but this is not a child who has developed language; for me that is very clear. 

Special Master Hastings:  About the segment you were just describing.  What was the time frame? 
A:  About 15 months.  I want to show clips from before 18 months.

Q:  The reason that you’re concluding it’s 15 months is because it came off a particular tape? 
A:  Yes, the tape is from 1999, from January to June.  And in that tape, it’s in the early part of the tape.  I don’t think I could come up with a precise date, but it’s probably around that time. 

Q:  You’re surmising this from the position on the tape?
A:  Yes.  But it’s the consistency of observation before the 18 month mark that I’m pointing to.

Q:  Let me ask one more question about Jordan King.  Do you recall how much video of him you saw, total? 
A:  Probably 10-15 hours. 

Q:  And how much of that was the pre-18 month period, roughly?
A:  I couldn’t say. 

Q:  Half or at least a substantial portion? 
A:  Probably half of it or more. 

William Mead

Q:  Do you have any general comments about William Mead before we look at specific clips? 
A:  Yes.  All clips which have been presented are from birth to 12 months.  For the reasons I’ve discussed before, I don’t think this is very informative for our debate.   
We’ll show a clip at about 15 months that shows abnormal signs before the alleged regression at 18 months.  It’s highly inconsistent in the medical record when the regression occurred.  I know his father dates it to 18 months, but the medical records were based on the contemporary records, so it’s difficult to know when the loss occurred.

Clip #3: 
A:  Dr. Mumper used this to indicate that William is not hypersensitive to having his head being touched.  He does look at the camera with a smile throughout.  I want to draw your attention to the amount of spontaneous vocalization and babble and the extent to which he relates to his sister.  You’ll see, he doesn’t make eye contact with her at all.  Again, he seems to be engaging his father but his spontaneous vocalization -- there is not much.  I didn’t hear any spontaneous babble coming out of him.  It’s a kind of observation which is very technical.  But it’s of note.  Also, there are some unusual movements in the midline that are noticeable.

Another clip: 
A:  Dr. Mumper presented a clip speaking of social reciprocity, saying William was playing with his sister.  He’s actually not playing with his sister.  They’re in the scene together….There’s no reciprocal play.  It’s misconstrued to say there’s reciprocal play. 

Clip we’ll see now: [technical problems; not shown and will be submitted later]
A:  No reciprocal interactions between him and his sister.  July 18, 1999.  He’s 14.5 months.  Evaluate how much language he has and how much vocalization he has and his gesture.  His father tries to get him to wave his hands, but he can’t replicate that.  His sister does it, but he cannot copy her. 

At 14.5 months, William has no words.  On all the tapes, I’ve heard “Hi Dad” and “MacCheese;”  these are not two word phrases.  These are the only word utterances presented on the tapes.  Other than that, at that age, he’s not babbling, he’s not communicative, he’s not gesturing, he cannot copy a gesture, he cannot respond to his dad, he doesn’t play reciprocally with his sister.  It would be obvious to anyone who knows a child of 15 months.    

Q:  There’s been a lot of discussion about the age of onset of regression in these little boys.  Do you have any comments about that?
A:  As I said, the video exercise clearly shows to me that both boys were not normal in their development prior to loss of skills at 18 months of age.  I think maybe there is inconsistency of reports about when exactly they lost skills.  I don’t dispute that they lost skills.  That’s fair.  Those children do have regression of language.  That usually happens with language at the very beginning stages of development.  William has no language.  If he had language, he would have phrases, about 60 words.  The loss would be dramatic.  It would send the parents into the emergency room. 

Q:  Is there any evidence that William experienced such a dramatic loss? 
A:  No.  It’s obvious to me that he had no language skills or vocalization that would be normal in a 15 month old.  Had he lost 60 words at 18 months that would have been followed by some medical consultation.  It’s hard to retrospectively time the regression. 

It’s very clear to me that William did not have the language, vocalization or gesturing at 15 months of the kind that you would expect for a typical 15 month old.  In his case, there was a progressive, gradual onset of autistic symptoms.  It didn’t happen overnight.

Q:  Would you say the same for Jordan King?
A:  Yes.  Very much so.

Rebuttal Cross Examination of Dr. Fombonne 

Q:  [Mr. Powers]  I’ll be brief.  You mentioned in your earlier testimony today about the  treatments these boys received.  There is no evidence that the medical care these boys received caused them any harm, is there? 
A:  No. 

Q:  And it’s fair to say that the parents and the treating physician, Dr. Green, both report improvements.  I’m not asking you to attribute it to anything, but the parents and the treating physician both noted improvements, correct? 
A:  Yes, but can I comment on the meaning of this improvement? 

Q:  No, that wasn’t my question. 

Q:  Is it your testimony that both boys actually did regress? 
A:  Yes, I think they lost skills.  Yes, absolutely. 

Q:  And they lost skills in all three domains relevant to an autism diagnosis?
A:  I cannot assess that based on the records or videos; it’s not clear. 

Q:  We heard testimony that Dr. Rust agreed that both these boys were diagnosed with regressive autism?
A:  I disagree.  Regressive autism is not a diagnosis. 

Q:  Do you agree with Dr. Rust’s characterization that these boys experienced autistic regression? 
A:  Yes.

Q:  In your descriptions of William Mead, you sometimes said your views were “your interpretive spin.”  Is that correct? 
A:  The clips in a very young child are very difficult to interpret.  We do not see abnormality usually before 12 months.  I’m cautious of what kind of inferences I can draw. 

Q:  Is it fair to say that any analysis of these tapes is going to be somewhat subjective? 
A:  No, it would not be true for video clips when the child is older….   

Q:  At what point in a child’s life can video analysis move from the realm of “interpretative spin” into the realm of objective analysis? 
A:  Starting at the age of 10-12 months. 

Q:  When you say these boys are abnormal, do you mean that they were in the bottom 2½ percent in their age cohort in any particular domain ?
A:  In which domain? 

Q:  In any of the domains. 
A:  I cannot answer that based on the evidence I have. 

Q:  I ask because I understand that there’s always a bell curve and a median.  Two standard deviations are usually used to measure “abnormal.”  Can you tell the Special Masters whether Jordan King or William Mead in their overall development were in the bottom 2 ½ percent of their age cohort?
A:  Probably in terms of language, you’d have to use a standardized test of language development….

Q:  Are they at the bottom in social reciprocity in the first year of life?
A:  The only measure would be pretty unreliable.

Q:  So you don’t know if they were in the bottom 2 ½ ? 
A:  For language, yes and for gestures as well. 

Q:  So you do not disagree that both these boys experienced an autistic regression, correct?
A:  No.

Re-direct Rebuttal Examination of Dr Fombonne

Q:  When you review a videotape, what skills do you apply to review the videotape? 
A:  My observations and my vast clinical experience.  Being trained to measure with the ADOS, we develop particular accuracy….

Q:  Dr. Mumper used videotapes today to demonstrate typicality or normalcy.  Are video tapes a good source to show typical behavior?  Do clinicians use videos to diagnose autism or to show that a child is developing normally?
A:  No.  Tapes are used for research but not for clinical practice…. 

[Petitioners’ fairness objection that Dr. Deth was unable to give rebuttal testimony Thursday]

Rebuttal Testimony of Respondent’s Expert Dr. Johnson
Direct Examination 

Q:  Are you a neurotoxicologist? 
A:  Yes. 

Q:  Dr. Kinsbourne emphasized this morning that he was putting forth a hypothesis or model that could explain how TCVs cause autism.  What is the scientific community’s definition of hypothesis or model? 
A:  Hypothesis is when you put together certain ideas or aspects from the literature that you think might be right.  99% of the time, it could be completely wrong and if you’re lucky, you might be correct.  A model is similar in meaning. 

Q:  Both hypothesis and model would certainly require testing before any real credence could be given to them? 
A:  Yes.

Q:  Do you think Dr. Kinsbourne’s idea is a hypothesis?
A:  Absolutely.

Q:  Do you think this would  rise to the level of “more likely than not” true?
A:  Absolutely not.  It’s at the lowest level.

Q:  Does current research indicate that neuroinflammation plays a role in neurodegenerative disease? 
A:  Yes, neuroinflammation is involved in Parkinson’s, Huntington’s, Alzheimer’s, ALS. 

Q:  And you study these diseases, correct?
A:  Yes, in my laboratory and academic practice.

Q:  Does current research indicate that neuroinflammation plays a causal role in these neurodegenerative diseases?
A:  Generally, the concept is that the neuroinflammation, astrogliosis and microglial activation are part of the progression of the pathology of the disease.  They are seen more as an outcome than a cause.

Q:  Does treatment of symptoms implicate a cause of a disease?
A:  Absolutely not.  A key example is Alzheimer’s.  A lot of the symptoms are from the loss of the neurotransmitters.  Drugs we use increase the level of this neurotransmitter.  So the patient gets better, but the process that’s killing the cells continues unabated.  But there’s no causal association between treating symptoms and what’s causing the disease.

Q:  Dr. Kinsbourne discussed the Lopez-Hurtado paper this morning and you discussed it previously.  Did you identify a fairly significant methodological flaw used by those authors? 
A:  Yes, there is a significant issue I have with this paper.  They do a lot of statistical analysis in this paper comparing samples, but that cannot be done.  They’ve counted the density of neurons in one brain….These are numbers for one person.  You cannot generate a standard deviation in one individual.  Basically n=1; there is nothing about four different brains.   So the statistical analysis is really invalid. 

Q:  They use standard deviation but they shouldn’t have?
A:  They shouldn’t have.

Q:  What’s the effect if you take out the standard deviation? 
A:  The main difference between a normal and an autistic patient is the baseline where they start, not the rate of change….What was laid down developmentally seems to account for the differences across age. 

Q:  Dr. Kinsbourne also discussed astrocytic function.  Do you study this?
A:  Yes.

Q:  Have you published on this? 
A:  Yes. 

Q:  How many papers in the last 3 years? 
A:  More than 10. 

Q:  If astrocytes are unable to mop up glutamate, what happens? 
A:  Well, the glutamate will interact with the neurons, causing excitotoxicity, and eventually the neurons will die.   

Q:  Dr. Kinsbourne discussed the Purcell article.  In autistic brains, is there evidence of increased glutamate transporters?
A:  Yes, absolutely.  This paper does micro-array analysis.  It’s a fancy way of PCR.  They identified some candidate genes that are different between autistic and control brains.…In both situations, the glutamate transporters on the astrocytes were significantly increased in autistic patients.  To me, that suggests that autistic patients have greater capability to deal with excess glutamate than control patients. [reviews chart in paper] 

Q:  If you have chronic glutamate excess, would you expect the process to be neurodegenerative?
A:  Yes.

Q:  Dr. Kinsbourne also talked about Dr. Ashner’s work.  Are you familiar with that?
A:  Yes, I’ve read his work and I know him.

Q:  In this paper, what was the dose necessary to get astrocytic dysfunction? 
A:  It’s all in the micromolar range, so very high; much higher than in TCVs and a different kind of mercury….

Q:  Do you agree that once triggered, as Dr. Ashner says, a vicious cytotoxic cycle ensues? 
A:  Yes, I completely agree with that.

Q:  Is the concept that once you trigger astrocytic dysfunction, you do get this vicious cytotoxic cycle, is this well accepted in the scientific community? 
A:  Yes, I would say it’s very well accepted in the scientific community that deals with this kind of process. 

Cross Examination of Dr. Johnson

Q:  [Mr. Powers]  The Purcell paper ultimately concluded that the glutamate levels  in the autistic brain should be investigated.  That’s 2001.  Is that correct? 
A:  Yes.  I’m not saying glutamate shouldn’t be investigated in autism; it should be investigated in all these diseases as it’s implicated in the pathogenic process.

Q:  And the Purcell investigators concluded that the blockage of glutamate receptors might improve symptoms in autism?
A:  I don’t know that there’s been any evidence showing that in autistic patients.  I know in some of the other diseases, there’s some evidence that it might have some effect.

Q:  And in the Pardo and Vargas work, they do  report chronic and ongoing inflammation of the brain, correct? 
A:  They show astroglial and microglial activation in post mortem brains of autistic patients.  That doesn’t mean it’s ongoing; it means it’s there at the time of death.

Q:  And that’s across a wide range of ages? 
A:  Yes. 

Q:  7-44 years old? 
A:  Right. 

Q:  And in those brains, this point of massive neuronal death had not been reached, correct? 
A:  I’d have to go back and look, but I don’t think there was massive neuronal death. 

Special Masters

Special Master Vowell:  You said chronic glutamate excess would lead to the killing of neurons.  Is there any particular reason you say that?  You didn’t give a reason.
A:  We use it to kill cells all the time.  There is a lot of evidence in Parkinson’s and other types of disease that this chronic glutamate factor, and astrocytic dysfunction, is a major cause of neuron death.  There is evidence out there, like in ALS…

Rebuttal Testimony of Respondent’s Expert Dr. Jeffrey Brent
Direct Examination

Q: [Ms. Renzi] You heard testimony that an essential part of Dr. Kinsbourne’s model is that methylmercury decreases glutamate uptake in astrocytes.  Is that correct?
A:  Yes, I did hear that testimony.

Q:  Can that have any relevance to the effects of thimerosal-containing vaccines? 
A:  Absolutely not.  That process of glutamate uptake by astrocytes and the effects of mercurial compounds have been extremely well studied.  Dr. Ashner has demonstrated that mercurial compounds at sufficient doses will inhibit glutamate uptake.  When Dr. Kinsbourne presented his hypothesis, he was asked if doses that would do that have any relevance to the doses in vaccines; he stated that he’s not a toxicologist and he would defer.  But the issue of dose here is critical.  If you look at the work of Ashner….

Q:  And this would be different from the work that Dr. Kinsbourne presented…

PETITIONERS’ OBJECTION:  A discussion of dose was part of Dr. Kinsbourne’s direct testimony, not his rebuttal testimony.   

Mr. Matanoski:  Dr. Kinsbourne was talking about astrocytes at length this morning.  This is about the astrocyte malfunction argument, including reference specifically to the work of Dr. Ashner to tie astrocyte malfunction to mercury. 

Special Master Campbell-Smith:  Dr. Brent, are you referring to the testimony you heard earlier today?
A:  Yes.  I’m specifically referring to issues of glutamate uptake by astrocytes that Dr. Kinsbourne referred to this morning. 

Special Master:  I’ll allow the question.

Q:  [Ms. Renzi]:  Is this is another of Dr. Ashner’s article?   
A:  That’s correct. 

Q:  And we’re looking specifically at Figure 2. 
A:  That’s correct.  And this is the actual data on the effects of methylmercury on glutamate uptake.  Ethylmercury has not been studied in this regard.  So everything we’re inferring is based on data from methylmercury.  [discusses chart]  Two micromolar of inorganic mercury is required to reduce glutamate uptake in the astrocytes.   To put this value in context, the normal amount of mercury in the brain is in nanomolar, which is 1,000 times less.

Q:  [Ms. Renzi shows a different slide] And there are toxic levels of mercury in the brain in developmental studies, and you referred to this in your direct testimony?
A:  Yes.  And I just want to put this concentration of 400 parts per billion level necessary to inhibit glutamate uptake in the context of what’s actually seen.  The amount of mercury in the brain in the general population is in the low parts per billion, anything from 2 to 3 to 40 or so.  The Seychelles study population had amounts in their brains at 100-200 parts per billion without any adverse effects.  Clearly, the amount of inorganic mercury that is necessary to inhibit glutamate uptake in the astrocytes, that we saw in the Ashner study at 400 parts per billion, is far above the amount that people normally have in their brains.  Therefore this could not possibly be related to anything from a vaccine, where the extra burden in the brain was an extra 2 or 3 parts per billion.  Again, the Ashner study was an in vitro study.  [technical discussion of in vitro conditions]  The amount of mercury necessary to cause this astrocyte effect is vastly, vastly greater than what could be generated by a vaccine and far above what would be seen in normal human experience.   

Q:  We heard Dr. Mumper’s testimony that she wasn’t sure how Dr. Rust gets information from his patients.  You do regularly see patients regularly, right? 
A:  Yes.

Q:  You practice in a university setting? 
A:  Yes, and a private practice as well. 

Q:  How do you take histories on the patients that you see?
A:  I’ve twice heard Dr. Mumper testify that academic physicians don’t take histories.  I take very extensive histories, and I don’t think I’m different from any of my colleagues.  I teach medical students that 90% of what you learn about a patient comes from the history.  It’s an extremely important component of patient assessment.  I usually schedule 2 hours for an initial consultation, of which 1.5 hours is spent taking the history.  I think it’s important that we dissuade the listeners from any misconception that it’s only doctors like Dr. Mumper who take histories.  I was frankly a little offended by that.   

Q:  You see autistic children in your practice? 
A:  Yes.

Q:  Are their histories any less thorough?
A:  Their histories are very thorough.  It’s a slow history from the family.  Often they have many questions they found on the internet about alternative treatments that we’ve heard about here; they tend to be very long discussions.

Q:  We’ve heard Dr. Mumper and Dr. Kinsbourne talk about chelation.  As a toxicologist, did you see any reason for chelation to remove the mercury from either of Jordan King or William Mead? 
A:  Absolutely not.  [slide]  The normal pattern for assessing mercury is that if we take a urine sample for mercury, and we simply collect it from a patient, there are validated reference ranges.  We will have a normal mercury excretion.  If we take a normal person and add a chelator, you will have a greater amount of excretion, often out of the normal reference range.  Our gold standard test for assessing mercury toxicity is an unprovoked urine mercury concentration.  There is no test in medicine that is more valid for assessing mercury toxicity than an unprovoked mercury concentration.

Below, you see the results for Jordan King and William Mead for unprovoked urine concentrations in the normal range.  On the other hand, they had been chelated, and the justification for that chelation are provoked urine samples.  Well, you’re supposed to have increased urine mercury with provoked samples.  There is absolutely no indication that suggests that there is any mercury effect in these children, and there is absolutely no reason to chelate them for any mercury-related reason. 

Q:  Dr. Mumper also testified to increased lead levels in children, and chelation may help that.  Is there any scientific or medical basis for that statement? 
A:  It is true that chelation therapy is the appropriate therapy for lead toxicity.  The records do not reflect, however, lead toxicity in the case of the children here.  Neither of them had elevated blood lead levels.  Blood tests are the gold standard for lead toxicity.  Blood tests would be elevated for years if there’s lead toxicity, contrary to testimony given earlier.  It equilibrates with the tissue, and if there’s high tissue levels, there will be high blood levels. 

Q:  So you disagree with Dr. Mumper that blood tests would only test for acute toxicity?  A:  That’s absolutely wrong.  There was absolutely no basis for chelation based on lead effects.

Q:  Is there any other accepted test for measuring lead toxicity? 
A:  Blood is the gold standard, and there are no other accepted tests that give lead levels.

Special Master Vowell:  Q:   I want to follow up and ask about the mercury levels post-chelation.  Was there anything about the levels you observed, about the levels post chelation, in the medical records? Were these extraordinarily high levels? 
A:  No, you always expect to see levels in the urine bump after chelation.  It would happen for any one of us.  There are no validated reference ranges post-chelation, that’s why they’re not used.  In fact, if you look at these two children, they had mild increases in urine lead excretion, as I recall.  They were nothing different than what you would normally expect to see.
 
Q:  And you have chelated a number of children? 
A:  Yes. 

Q:  And in your experience, there’s nothing extraordinary even in the absence of a standard?
A:  Well, in truth, we don’t follow urine lead levels, because blood is the correct level. 
So, I can’t speak to my own experience.  But I have had a number of patients come to me with lab results from Doctor’s Data who have had chelation, and they always have elevated urine levels, and I say let’s get a blood sample.  And so far, 100% of the time, they’ve been normal.

Q:  Let’s go back to mercury, though.  Are the post-chelation mercury levels in either of these two boys in excess of what you would see?  I understand there are no reference ranges?

A:  No standard references.  You do tend to see increases.  They’ve had some minor increases over the non-provoked.  Certainly not dramatic.  Certainly well within the range of what you would expect to see.  If you look at the studies I mentioned on chelators, if you look at the normal controls, you’d see increases post-chelation.  It’s a moderate increase, and it’s not particularly different than what we saw in these children.

Q: [Ms. Renzi]  You said you’ve chelated children; for mercury or lead? 
A:  Both actually. 

Q:  Why for mercury?
A:  The most common and most dramatic experience for me is that I live in Colorado, and people are still prospecting for gold, extracting gold from ore using liquid mercury.  Then they’ll heat the mercury in their house.  A tremendous amount will get into the air.  I have had a number of families that have become profoundly mercury poisoned.  They’ve been in the ICU, had ventilators. 

Q:  So when Dr. Mumper says that the chelators mobilized mercury and led to beneficial changes, do you agree? 
A:  No.  You would expect higher levels; it tells you nothing about mobilizing stores of heavy metals in the body. 

Q:  Dr. Mumper also talked about supplements to increase glutathione to treat mercury toxicity.  Do you agree that that therapy is warranted? 
A:  Supplemental glutathione to treat mercury toxicity has no validity at all.  We have very, very, very large amounts of glutathione in our bodies; huge amounts of glutathione, and glutathione is never limiting in terms of being able to handle heavy metals.  It’s a defense that’s been put into humans and animals, and it works extremely well.  There’s no way that some small additional amount of glutathione on top of the already very, very large stores that we have can make the slightest difference. 

Rebuttal Cross Examination of Dr. Brent
 
Q:  [Mr. Powers]  You were talking about Dr. Ashner’s paper on glutamate uptake.  This was an experiment on in vitro rat cells, correct? 
A:  Yes. 

Q:  And there’s some evidence, we’ve heard testimony, that human cells are often more sensitive than rat cells.  Is that correct?
A: I don’t know of any data of human cells being more sensitive to inhibition of glutamate uptake than rat cells.

Q:  Can you describe a human model that parallels what Dr. Ashner did on rat cells? 
A:  If there was a very good human model that could be used, Dr. Ashner would be using a human model, not a rat model…. It very hard to have cultured human neurons… 

Q:  And this an in vitro experiment with isolated rat astrocytes?
A:  Yes.

Q:  And since it’s an isolated culture, it would not have microglia? 
A:  Yes.

Q:    You understand, of course, that Dr. Kinsbourne’s hypothesis is based on the idea that microglial activation releases proinflammatory cytokines that harm astrocytes, correct?  So there’s nothing about this Petri dish, absent microglia, that is at all relevant to Dr. Kinsbourne’s position that it’s the reactive oxygen species and proinflammatory cytokines released by microglia that harm the astrocytes, correct?

A:  This is the data that exists about mercurial effects of astrocyte glutamate uptake.  I don’t know of any data that exist for the complex scenario that you are describing in your question.  However, clearly, if you look at the data cited by Dr. Kinsbourne, for showing that mercury inhibits uptake of glutamate, this is the data and that’s why I’ve referred to it. 

Q:  And Dr. Kinsbourne was also citing the Vargas and Pardo papers and evidence of inflammation that involves proinflammatory cytokines and their effect on astrocytes, correct?
A:  I don’t recall him citing anything that shows that proinflammatory cytokines alter astrocyte glutamate uptake in response to mercury.

Q:  And when Mr. Williams cross examined you, you testified that you are not a neuroimmunologist, and you did not comment on those papers on cross, correct?
A:  Mostly correct.  I don’t think we were discussing neuroimmunology.  This is not an immunological question.

Q:  But the inflammatory response is an immunologic process, and Dr. Kinsbourne posits that it’s initiated by microglia, and it’s impossible for the Ashner paper to address this because there were no microglia in the Petri dish with the rat brain cells.
A:  That’s true.

Mary Holland teaches at New York University Law School and may be contacted HERE. Thank you to A-CHAMP for providing this important service. A-CHAMP, Advocates for Children’s Health Affected by Mercury Poisoning, is a national, non-partisan political action organization formed by parents in support of children with neurodevelopmental and communication disorders.

Comments

[Mary Holland]

Thank you all for your kind comments. It does take time and patience to prepare these transcript-like reports. I am delighted to know that you find them useful. I want you to be able to make your own judgments about how things are going, and the best way to do that is to give you what is very close to the actual text.

[Michael A. Chernoff]

Mary & Kent, thank you so much for working so hard on this matter. God has a place for you!

Michael A. Chernoff, for Alexander and so many Others

[Theresa Cedillo]

Thank you so much Mary for the time you have put in to the omnibus proceedings. It is truly appreciated.

Theresa Cedillo

[Rolf Hazlehurst]

Mary, thank you very much for the incredible amount of time and effort, which you must have spent in covering the Omnibus Autism Proceeding. You did a great job!

[Kelli Ann Davis]

I officially nominate Mary Holland for the She-Totally-Rocks big, gold star award!

Anyone who has the patience and finger power to wipe these babies out at the speed in which she's done deserves it.

You and Kent are "da team"

Hoo Yaah (Did I get that right Ang?)

[Twyla]

Thank you, Mary -- very, very interesting.