Holt v. HHS, Case No. 05-0136V (Fed. Cl. Spec. Mstr. Jun. 24, 2015) (Vowell, CSM)

Former OAP case, alleging significant aggravation of a mitochondrial disorder resulting in neurological symptoms somewhat resembling ASD.  The court noted, in an 104 page opinion, a “trend by some former OAP petitioners to recharacterize their children’s diagnoses as something other than ASD, in an attempt to render irrelevant the impressive body of evidence produced in the OAP test cases establishing that vaccines are exceedingly unlikely to be responsible for ASD.”

Presenting expert opinions for Petitioner were Fran Kendall (biochemical geneticist and mitochondrial disease specialist), Levinson (psychiatry) (did not testify due to technical difficulties), and DelMio (emergency medicine), the latter two of whom were treaters.  Although not offered as an expert, treating physician and well-known mitochondrial expert John Shoffner, MD, had diagnosed a “possible” mitochondrial disorder and later a “probable” mitochondrial disorder.

Testifying for HHS were Max Wiznitzer, MD, (pediatrics, neurology with special qualifications in child neurology, and neurodevelopmental disabilities) and Shawn McCandless (pediatrics, clinical genetics, and clinical biochemical genetics).

The infant received only two vaccines in her lifetime, the first two doses of hepatitis B vaccine, one at 5 days and one at 6 weeks.  She suffered from temperament, sleep, feeding, and gastrointestinal issues, but otherwise met developmental milestones until around 15-17 months.  It appears that around 18 months, speech concerns were first noted and the child entered early intervention and began ABA therapy.  It is not entirely clear when or if an ASD diagnosis was officially reached through traditional diagnostic methods; the child was diagnosed with a “regulatory disorder”.  Multiple therapies were tried over the ensuing years and great detail is given in the opinion to the alternative and complementary therapies received from DAN! doctors and other practitioners.  The child received IVIG although no apparent support existed in the medical records for such an intervention.  There was also much discussion of lab work done at non-mainstream labs, many of which had been discussed in the OAP.

The overall theory presented by petitioner was that A.H.T. had a febrile response to her initial hepatitis B vaccination. The fever activated an underlying mitochondrial disorder, triggering the onset of temperament changes, sleeping difficulties, problems with breastfeeding, and gastrointestinal dysfunction. Later alleged manifestations of the triggered mitochondrial dysfunction include developmental delay and behavioral problems variously diagnosed as sensory integration disorder, regulatory disorder, and ASD.

As is often the case, factual disputes were critical:  “whether A.H.T. experienced a fever after her initial vaccination; the nature and diagnostic significance of other symptoms arising after vaccination; and whether A.H.T. truly had the symptoms relied upon in diagnosing her probable mitochondrial disorder.”

It was not contested that she suffered from symptoms of irritability, crying, and constipation beginning shortly after the initial vaccination.  However, there were no contemporaneous records that supported a post-vaccination fever.  The Court found the greater weight of the evidence did not support a finding of fever. The parents had testified that there had been a fever and that there were alleged to have been numerous [non-record] calls to the pediatrician about this.  However, there was no mention of fever in the mother’s extensive journal and a post-vaccination fever was only first recorded years later, in a visit with Dr. Shoffner.  Interestingly, the court stated: “I note that petitioner, who bears the burden of proof in this off -Table case, could have asked me to compel [the pediatrician] to testify, prepare an affidavit, or answer interrogatories concerning her recollections of telephonic contact, how telephonic contacts were documented by her practice, and whether she considered the presence of fever in a neonate sufficiently serious so as to occasion an office or emergency room visit. Petitioner did not make such a request.”

There was also no record support for any symptom worsening after the second vaccine at six weeks of age.  There was no indication in the medical records of any deterioration in neurological status, plateaus in development, or the loss of developmental milestones, after either vaccine, which would logically be expected under any of the medical theories advanced.

With regard to the diagnosis of mitochondrial disease made by Dr. Shoffner, the Court closely examined the underlying test results and the scoring system used (Nijmegen).  The child had no known mutations of nDNA or mtDNA associated with mitochondrial disease (MD); only 50% of mutations are identified in MD.  Dr. McCandless opined:

[A.H.T.] has some abnormal tests pointing to [Complex I and Complex III] in the muscle biopsy. She has almost no evidence of metabolites accumulating that would be the result of dysfunction of mitochondria, and the only thing that was in any way abnormal in my opinion is that mildly elevated lactate and pyruvate, which I did not find at all compelling for mitochondrial dysfunction. I think it’s much more likely to be an artifact. So except for the two pieces of data that suggest a I [and] III defect in the biopsy, which I don’t quibble with, I think this sort of all together, just the laboratory part of it, I would say this is possibly mitochondrial disease. Mitochondrial dysfunction, possibly.

The Court considered all of the symptoms scored under the Nijmegen criteria, and found that one point had been incorrectly assigned by Dr. Shoffner, because the records contradicted the existence of the symptom and it was based solely on parental report.  Thus, the “assessment of a possible, rather than a probable, mitochondrial disorder best fits the facts of A.H.T.’s condition [subtracting one point reduced the score on the rating scale].”

Turning to the legal analysis, the Court first noted that the testimony of Drs. DelMio and Levinson, although treating physicians, would not be afforded any additional weight because “nothing in Capizzano requires special masters to give weight to the opinions of treating doctors who espouse “junk science,” and who treat children based on unproven hypotheses, with drugs with no known efficacy against the medical conditions presented, and without test results to warrant the speculative diagnoses proffered.”

Petitioners presented three variations on a causation theory through Dr. Kendall: “First, petitioner contends that an external event can trigger onset of a mitochondrial disorder that would otherwise have remained dormant, not simply cause regressions or loss of skills in individuals with a diagnosed or, at least suspected, mitochondrial disorder. Second, petitioner claims that a vaccine, not just an illness, can exacerbate, aggravate, or trigger this onset or cause mitochondrial dysfunction. Third, petitioner claims that this aggravation can cause the manifestation of symptoms, not only shortly after vaccination, but new symptoms manifesting many months later. Petitioner attributed A.H.T.’s post vaccination irritability and constipation to aggravation of her mitochondrial disorder or causation of mitochondrial dysfunction, signaling some form of brain injury, and also contended that the behavioral symptoms and developmental delays that manifested more than 15 months later were likewise the result of this injury (emphasis supplied).”

Petitioners other two experts presented somewhat different medical theories: “Dr. DelMio also claimed that the initial insult of the hepatitis B vaccine produced inflammation in A.H.T.’s brain and this inflammation was responsible for A.H.T.’s early and later symptoms. Yet a third theory was proposed by Dr. Levinson—that A.H.T.’s symptoms were the result of oxidative stress as the result of the interaction of her underlying mitochondrial disorder and the immunological stress of the hepatitis B vaccine.”

In her analysis of the oxidative stress theory, the court wrote:

Dr. Levinson . . . opined that the hepatitis B vaccine caused A.H.T. to have a fever, that “mitochondria are the major generators of body heat” and the “inflammatory and immune response” produced by the vaccination was a “catalyst in the development of mitochondrial disorder” by virtue of the oxidative stress caused by the vaccination. He stated that “it is more likely than not that the vaccination . . . provoked an immune and inflammatory response [which] served as an environmental trigger providing excessive oxidative stress to the mitochondria. This led to [A.H.T.] manifesting central nervous system symptomology as a direct result of a vaccine induced mitochondrial dysfunction.”

Although the oxidative stress in the OAP test cases was alleged to have been caused by a mercury-based preservative in some vaccines, rather than by the vaccines themselves, the source of the stress was unimportant in the theory presented. The purported causal relationship between oxidative stress and ASD was thoroughly debunked by the true experts on oxidative stress called by respondent. See, e.g., Dwyer, 2010 WL 892250, at *115 (emphasis supplied). Doctor Levinson provided no medically or biologically plausible, much less probable, explanation of how oxidative stress could cause or trigger either an underlying mitochondrial defect or autism-like symptoms themselves. In terms of timing, he indicated that a fever could be produced “immediately following immunization,” and implied that the fever caused mitochondria to become “extremely active,” with the inflammatory and immune response to the vaccination becoming the catalyst for A.H.T.’s mitochondrial dysfunction.

Neither of the two mitochondrial disease specialists provided any real support for the oxidative stress theory. Doctor Kendall discussed oxidative phosphorylation (OXPHOS) with regard to the electron transport chain activity in the mitochondria, but she never even hinted that “oxidative stress” played a role in mitochondrial disorders.

Doctor McCandless [R’s expert] probably provided the most support for Dr. Levinson by acknowledging that fever can cause increased energy consumption, which results in “increased flux through the system,” which is one definition of oxidative stress. The other definition, increased production of reactive oxygen species, is not an effect of fever. Id. Clearly, Dr. McCandless did not accept that this increased flux of metabolites through the respiratory chain could be responsible for a mitochondrial disorder or cause mitochondrial dysfunction, as he indicated that many things cause such increased metabolic stress, including “eating a meal [and] breathing air pollution.”

Doctor McCandless also explained that the use of coenzyme Q10, a powerful antioxidant, prescribed to treat some mitochondrial disorders, is not evidence that such disorders are caused by oxidative stress. He commented that it is rarely effective in treating mitochondrial disorder patients, other than those who have a specific Q10 deficiency. Testing performed on A.H.T. did not disclose a Q10 deficiency (internal citations omitted).

The Court’s final comments on the oxidative stress theory:

Even were I to disregard all the OAP evidence on oxidative stress, I would come to the same conclusions regarding [Dr. Levinson’s] theory. He has failed to explain how the vaccines could cause oxidative stress or to point to any evidence of oxidative injury to her brain.

The Court rejected the brain inflammation theory because “Succinctly, brain inflammation sufficient to overload the mitochondria and cause dysfunction leading to the clinical symptoms  of developmental delay and behavioral problems would require the same type of  brain damage seen in an encephalopathy, and would thus be detected on MRI.  None were.”

The Court noted that the attempt to “make this case into the Poling case” was unavailing.  In the Court’s analysis under Althen prong one, rejecting the medical theory proposed, the court held:

“the theory that a vaccine, with or without a fever, could cause onset or significant aggravation of a mitochondrial disorder was, at present, speculative. It may, at some future time, be sufficiently supported so as to constitute a reliable medical theory explaining either onset or significant aggravation of a mitochondrial disorder, but neither the Poling case study or the Shoffner paper carry sufficient indicia of reliability for me to credit Dr. Kendall’s theory. Illness may aggravate or exacerbate an extant mitochondrial disorder, but there is little evidence that illnesses can trigger an underlying genetic disease. There is no evidence, other than Dr. Kendall’s opinion, that a vaccination can do so. In the Shoffner paper, vaccination alone did not trigger a decompensation in any of the children. In the Morgan paper, the children with urea cycle disorders–those most likely to respond adversely to febrile events–did not experience more decompensations in the seven days after a variety of vaccinations than in the period more than 21 days after such vaccinations.”

Furthermore, the Court held, even if the medical theory were accepted, the facts of the case did not fit that of the Poling case:

A.H.T. did not have a Table encephalopathy or even symptoms consistent with an encephalopathy after vaccination. She did not have a fever. She did not experience an autistic regression. She did not have a DTaP or MMR vaccination, both vaccines known to provoke fever, and with associated Table injuries of encephalopathy. She did not lose skills. She had normal development for many months after the vaccination, followed by some developmental delays and the emergence of ASD-type symptoms.

I also distinguish the mitochondrial disorder claimed in the Poling case from the laboratory evidence showing moderate mitochondrial dysfunction in A.H.T. Petitioner’s conflation of the terms “mitochondrial disorder” and “mitochondrial dysfunction” raises problems with her attempts to equate A.H.T’s case with the Poling case. Doctor McCandless’ testimony that the mitochondrial dysfunction found is not the cause of A.H.T.’s speech and behavioral problems, and may even result from whatever is responsible for those symptoms or from the many drugs used to treat her further distinguishes this case from Poling (internal citations omitted).

Finally, the court emphasized that a factual finding of fever was essential to all the proffered theories and the court had rejected that factual premise.  With regard to Althen prong three, timing, the court held “It defies logic to have an encephalopathic event (or brain inflammation sufficient to cause symptoms similar to such an event), followed by normal development, and then to attribute subsequent developmental delay to that early encephalopathic event. Children with mitochondrial encephalopathies may well have delays and problems, but early onset is not followed by normal development. It is followed by progressive neurological deterioration in most cases.”

The court also indicated that the result would be the same whether the petitioner presented a theory based on a primary mitochondrial disorder/disease or mitochondrial dysfunction:

The distinction between mitochondrial disorders and mitochondrial dysfunction may relieve petitioner from the need to explain how a vaccine can affect a disorder that is purely genetic, according to her own mitochondrial expert. But, to the extent petitioner has abandoned the claim of significant aggravation of a mitochondrial disorder set forth in the petition, substituting instead a claim that the vaccine caused or aggravated mitochondrial dysfunction, the problems noted earlier remain. A.H.T. was not febrile after her vaccination, had a diagnosis that fully explained any symptoms that might have been considered neurological, and, as Dr. McCandless so persuasively opined, her clinical presentation was not consistent with the mitochondrial dysfunction seen in vitro.

The court did not apply the Loving analysis, but that would be unnecessary in light of the failure of prongs 1-3 of Althen.

As an aside, the court mentioned that case reports are at the bottom of the evidence hierarchy and that “[S]ome courts have suggested that attempts to infer causation from anecdotal reports are inadmissible as unsound methodology under Daubert (emphasis supplied).”

Vaccine Case Reviews Denial of Entitlement – Hepatitis B Vaccine, Significant Aggravation of a Mitochondrial Disorder