DENISE K. VOWELL, Chief Special Master.
On January 21, 2005, Laura Holt ["Ms. Holt" or "petitioner"] filed a "short-form" petition seeking compensation under the National Vaccine Injury Compensation Program, 42 U.S.C. § 300aa-10, et seq.
However, petitioner now appears to be repudiating ASD as the claimed injury, while nevertheless asserting that the neurological symptoms relied on for the ASD diagnosis constitute at least part of the compensable injury.
The amended petition in this case and petitioner's apparent disavowal of an ASD diagnosis appear to be part of the trend by some former OAP petitioners to re-characterize 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.
Prior to the hearing, petitioner filed a joint submission of the parties, listing the jurisdictional and factual issues upon which they agreed. The parties indicated that "[t]he issue to be decided is whether the vaccinations [A.H.T. received] (either alone or in combination) caused-in-fact her subsequently diagnosed developmental, neurological, or mitochondrial issues." Joint Submissions at ¶ 7. This joint submission clarifies the injuries for which compensation is sought.
Regardless of how A.H.T.'s condition is characterized, petitioner has the burden to demonstrate by preponderant evidence that a vaccine actually caused or significantly aggravated A.H.T.'s condition.
After the short-form petition was filed, A.H.T.'s case, like most other OAP cases, remained on hold until litigation in the test cases was completed.
On March 15, 2011, petitioner filed a motion to substitute Mr. Downing as her attorney of record. I granted the motion and, interpreting it as evincing petitioner's intent to proceed with her claim, I ordered her to file an amended petition that asserted the specific basis for her causation claim. Order, issued Apr. 4, 2011. Petitioner complied on September 22, 2011, filing several statements or declarations and some medical records and other evidence along with the petition. See Pet. Exs. 1-6. Over the next six months, petitioner filed additional medical records, statements and affidavits,
In July 2012, respondent filed her Rule 4(c) report; and the expert reports and accompanying medical literature from Drs. Max Wiznitzer and Shawn McCandless. See Respondent's Rule 4(c) report; Respondent's Exhibits ["Res. Exs."] A-Q. After consultation with the parties, I scheduled an entitlement hearing in Washington, D.C. from February 13-15, 2013. Order, issued Aug. 16, 2012; Pre-Hearing Order, issued Aug. 31, 2012.
Four physicians, Drs. DeMio, Kendall, McCandless, and Wiznitzer, testified in person. Petitioner, Garrick Tipton (A.H.T's father), and Mrs. Christy Holt ["Christy Holt"] (A.H.T.'s aunt) also testified in person. I heard telephonic testimony from Mrs. Mary Jo Holt Dunn (A.H.T.'s maternal grandmother), and Ms. Amy Hunter, the doula who assisted with A.H.T.'s birth.
Based on testimony at the hearing about the availability of video evidence supporting petitioner's case (see Tr. at 116, 121), I ordered petitioner to file video records of A.H.T. from birth to three years of age. Three DVDs were filed on April 4, 2013 as Pet. Tr. Ex. 3.
A.H.T. was born in 2002, following a normal pregnancy. Tr. at 11-12; Joint Submissions at ¶ 2, filed on January 22, 2013. She was delivered at home, with the assistance of a midwife, Juliet Dietsch, and doula, Amy Edwards Hunter. See Petitioner's Exhibits ["Pet. Exs"] 77, 82 (statements of Amy Edwards Hunter
At her initial visit to her pediatrician, Dr. Rhonda Buttleman, A.H.T. was alert and her physical examination was normal. Pet. Ex. 58, p. 2330.
The only two vaccinations A.H.T. ever received (two hepatitis B vaccinations) were administered before she was six weeks old. She received the first at this initial pediatric visit. Pet. Ex. 58, pp. 2313, 2326, 2330. The documentary evidence and testimony establish that, within days after the first vaccination, A.H.T. developed problems with constipation and that she cried more often and more robustly than many infants. Tr. at 22-23, 56 (Ms. Holt); 129-30 (Mr. Tipton); Pet. Exs. 52, p. 2234; 34, p. 1287. Her sleeping patterns changed and Ms. Holt testified about problems with breastfeeding. See, e.g., Tr. at 20-22, 24, 29, 32, 56, 91-92. These issues are discussed in more detail in Section V, Part B(4), below.
Mr. Tipton did not remember any specific reactions to the second vaccination. He testified that A.H.T. "continued to worsen as time went on," but stopped short of saying that she regressed or lost skills. Tr. at 131, 133. Ms. Holt also testified that A.H.T. got worse, but more as a progression of the symptoms she was already experiencing.
Over time, some of the problems that first manifested in the days and weeks after A.H.T's initial vaccination varied in intensity. The medical records and the testimony of her parents and other family members about the persistence and intensity of these problems were often in conflict with other evidence. What seems clear from the record as a whole is that A.H.T. was a difficult infant and toddler. Behavioral problems continued as she grew older, and by the time she was six years old, they accounted for most of the health care visits and support services rendered. See generally, Pet. Exs. 16 (2008 therapy records of Dr. (Ph.D.) Julie Murray, a treating psychologist); 51 (2009 neuropsychological evaluation by Dr. (Ph.D.) Andrew Jones, clinical psychologist); 38 and 54 (2009-12 records from an agency providing behavior analysis and support services); 7, p. 51 (2010 letter from psychiatrist Dr. Arehanna Barry).
Notwithstanding any temperament, sleep, feeding, and gastrointestinal issues, A.H.T. appeared to be developing normally for her first 15-17 months of life. See generally, Pet. Exs. 52, 58. She gained weight appropriately. See Pet. Ex. 58, p. 2314 (growth chart). She interacted with parents at home and caregivers at her pediatric visits. Videos of her taken at one to nine months of age show an alert and interactive infant engaged with toys, household items, and her parents. See generally Videos 1 and 2.
Neither her first pediatrician, Dr. Rhonda Buttleman, who saw her from five days to about nine months of age, nor the family practice physician, Dr. Richard Hefner,
Aside from a one-page document from Dr. James O'Dell, a naturopath who saw A.H.T. in July 2002,
Developmental problems were first noted in September 2003 at A.H.T.'s 18 month well-child visit, when Dr. Hefner observed that A.H.T. was not using two-word phrases, indicating a possible language delay. Pet. Ex. 52, p. 2226. In a history taken in May 2004, Ms. Holt reported that her concern about A.H.T.'s speech arose at about 18 months of age as well.
The remaining medical treatment and therapy records are extensive, and except when relevant to one of the issues in controversy, are not set forth in detail in this decision. In summary, A.H.T. was seen by many different health care providers, in addition to her primary care provider, Dr. Hefner. These caregivers fall into four categories: therapists addressing specific areas of developmental delay or behavior concerns; several different types of mental health specialists; at least five alternative or complementary medicine providers; and specialists who assessed or treated her for gastrointestinal, urinary, and sleep disorders. Other than Dr. Hefner and Dr. Puri and his associates, none of the health care providers treated A.H.T. over a long period of time.
Aside from the primary care records, the records from the early intervention program provide the evidence prepared closest in time to the events after A.H.T.'s initial hepatitis B vaccination. Through the early intervention program, A.H.T. received Applied Behavioral Analysis ["ABA"] therapy
She received ST with the early intervention program until she was discharged in March 2005, because early intervention services terminated at three years of age. Pet. Ex. 18, p. 184. She continued to receive ST services, according to her primary care records (see Pet. Ex. 52, p. 2219 (well-child visit at four years of age reflecting improvements with speech therapy)). There are some speech therapy records from Cardinal Hill in 2011. See, e.g., Pet. Ex. 27, pp. 606-23. According to testimony at the hearing, A.H.T. was still receiving ST services. Tr. at 117; See also Pet. Ex. 27, p. 614 (last ST record filed).
A.H.T. began receiving physical therapy ["PT"] services in March 2007, at the recommendation of Dr. Puri. Pet. Ex. 37, p. 1495. She was discharged from PT in February 2008, based on her improved functioning. Pet. Ex. 33, pp. 1285-86. She was re-evaluated in 2009 and received services again until February 2010.
Beginning in late 2010, the primary therapy for addressing A.H.T.'s continuing behavior problems was behavioral analysis and ancillary support services from Community Ties and Homeplace Support Services. These problems included defiance, temper tantrums or meltdowns, verbal aggression, and physical aggression towards property, pets, and people. Services continued at least into early 2012. See generally Pet. Exs. 38, 57.
A.H.T.'s treatment by alternative or complementary medical providers began as early as July 2004 when she saw Anne Linden Steele.
The unidentified health care provider who saw A.H.T. at Integrative Health Specialists from March-June 2005 assessed her with "candida" (yeast overgrowth), vitamin and mineral deficiency, and "metal toxicity."
A.H.T. saw three Defeat Autism Now! ["DAN!"]
In addition to treatment by the DAN! physicians, A.H.T. saw a developmental pediatrician, several pediatric neurologists,
A comprehensive neurodevelopmental evaluation was performed in early 2005 at the Weisskopf Child Evaluation Center ["Weisskopf Center"], a part of the University of Louisville School of Medicine Department of Pediatrics. Pet. Ex. 46. Doctor Gail Williams, a developmental pediatrician, diagnosed A.H.T. with a regulatory disorder
By 2007, Dr. Puri's practice seemed to have accepted a pervasive developmental disorder diagnosis, although it is unclear whether this was based on the history of the diagnosis provided by Ms. Holt or on an independent assessment of A.H.T.'s functioning. See Pet. Ex. 31, pp. 1246 (noting a previous diagnosis of "sensory integration disorder/PDD" in the history section of the office notes in 2007), 1249 (recording diagnoses of pervasive developmental disorder, sensory integration disorder, autistic disorder, and behavioral disorder later in 2007).
In February 2009, when A.H.T. was almost seven years old, Dr. Jones diagnosed her with a bipolar disorder and depression and, according to Dr. Puri, he referred A.H.T. to Dr. Barry. Pet. Exs. 31, p. 1243; 51, p. 2207. In August 2009, Dr. Puri recorded diagnoses of PDD-NOS, bipolar affective disorder, learning disability, central auditory processing disorder, and insomnia. Doctor Puri seemed particularly concerned about A.H.T.'s sleeping difficulty, since lack of sleep "can be a problem in some temperamental children like her." Pet. Ex. 31, p. 1245.
A.H.T. also received care and treatment for several medical issues not directly related to her behavior problems. She had an endoscopy and colonoscopy in the spring of 2007. Pet. Ex. 12, p. 102. She also saw a pediatric urologist in 2008 for frequent urinary tract infections ["UTI"]. Pet. Ex. 14, p. 116.
Beginning in June 2010, A.H.T. was evaluated and treated at the Behavioral Sleep Medicine Clinic, a part of the University of Louisville's Pediatric Sleep Medicine Center, where she saw Dr. (Ph.D.) Sarah Honaker, a clinical psychologist, and Dr. Vincent McCarthy. The records from this clinic reflect a significant behavioral component to A.H.T.'s widely varying sleep hours, and a great degree of difficulty in getting A.H.T.'s parents to document sleeping patterns and to implement the recommended changes.
The sleep center observations by Dr. (Ph.D.) Honaker regarding parental inconsistency in setting and enforcing bedtimes and in seeking physiological explanations for A.H.T.'s sleeping difficulties were mirrored by the behavior analysis specialists who saw her from October 2010 through at least January 2012. After several months of observation of A.H.T. and her caregivers, these analysts developed a plan to change targeted behaviors, which scripted certain daily activities and implemented a "token economy" reward system in which completion of tasks was rewarded by tokens which A.H.T. could redeem weekly for preferred activities or objects. See Pet. Ex. 38, pp. 1690-98. The records reflect numerous concerns by the analysts about A.H.T.'s parents' poor compliance with the behavior modification program.
The medical and therapy records relevant to the factual conflicts and other issues in this case are discussed in more detail below.
Five physicians offered opinions on vaccine causation and other matters in dispute. Three of the experts (Drs. Kendall, McCandless, and Wiznitzer) were well-qualified to offer expert opinions; the other two (Drs. Levinson and DeMio) had experience in treating children with autism and children with mitochondrial disorders, but are best characterized as alternative or complementary medical providers who lacked the academic background, research qualifications, or specialized training important in my assessments of the bases for and reliability of the opinions they offered.
The Federal Circuit has upheld the special masters' use of Daubert and summarized the four Daubert factors as "(1) general acceptance in the scientific community, (2) whether the theory has been subjected to peer review and publication, (3) whether the theory can and has been tested, and (4) whether the known potential rate of error is acceptable." Cedillo, 617 F.3d at 1339 (citing Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579, 593-94 (1993)); see also Andreu v. Sec'y, HHS, 569 F.3d 1367, 1379 (Fed. Cir. 2009). The Federal Circuit also approved the use of the Daubert factors in evaluating an expert's "reliability" as well as their "methodology." Cedillo, 617 F.3d at 1339.
In this case, Drs. Levinson and DeMio's status as treating physicians adds little to the reliability of their causation opinions, which largely consisted of conclusory statements. With regard to the logical connection between vaccination and injury, these particular treating physicians are no more percipient as witnesses about what actually transpired after the vaccinations than any other physician who testified in this case. Moreover, 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,
However, I have fully credited the records of the treating physicians, Drs. Buttleman and Hefner, who saw A.H.T. during her first year of life and who treated her for irritability and constipation, and diagnosed colic.
The four physicians who testified at the hearing offered opinions regarding symptoms A.H.T. allegedly displayed after the vaccinations and whether these were symptoms that suggested a mitochondrial regression had occurred. Although they were not percipient witnesses, their testimony about the likelihood of the events described is a factor in the factual findings set forth in Section V, Part C, below. The primary contributions of the experts were in explaining mitochondrial disorders, the distinction between primary mitochondrial disorders and secondary mitochondrial dysfunction, and explaining the evidence and conflicting opinions surrounding A.H.T.'s diagnosis and vaccine causation.
The witnesses' training and experience that bear on their qualifications to testify as experts and on the weight I accorded their testimony are set forth below, along with some observations and impressions regarding their testimony.
All three of petitioner's experts opined that the hepatitis B vaccination was responsible for the symptoms A.H.T. displayed after vaccination. All three stated that A.H.T. had a mitochondrial disorder or dysfunction which was aggravated by her hepatitis B vaccination, but their theories about how the vaccination did so varied considerably. Their backgrounds and qualifications were likewise quite divergent as well.
Doctor Levinson graduated from the University of Miami School of Medicine, and completed a residency in psychiatry. Pet. Ex. 60 at 2339. He did not list any publications on his CV, although the CV included a reference to his dissertation on the use of valerian root as a sleep aid. According to his CV, he has lectured on the "biomedical" treatment of autism and gastrointestinal issues in autistic patients, as well as on "detoxification" and dietary interventions. He has also appeared in several television programs on subjects as diverse as reversing aging, autism, and heavy metal poisoning. Id. at 2340-41. According to his February 2012 statement, he regularly treated patients "with mitochondrial disease, metabolic disorders, and immune-system related conditions" and "frequently lecture[d] on mitochondrial disorder[s]and the potential for environmental and biological triggers of this condition."
From the filed records, it is difficult to determine what diagnoses informed his treatment of A.H.T., as his records from 2010 and 2011 do not reflect a diagnosis. He referred A.H.T. to Dr. Shoffner for mitochondrial disorder testing about a year after Ms. Holt completed his intake form. In his February 2012 statement, Dr. Levinson mentioned his treatment of A.H.T. for a mitochondrial disorder and her improvement on such treatment, but he did not indicate the nature of the treatment, when it began, or what constituted improvement or how it differed from the treatment he provided prior to her diagnosis. See Pet. Ex. 59 at 2336-37.
His February 2012 statement was conclusory in nature. He did not explain his reasoning or point to anything that supported the opinions he expressed regarding diagnosis and causation. These were serious deficiencies, given his lack of any training in immunology, oxidative stress, or mitochondrial disorders, matters about which he opined.
Doctor DeMio testified as both treating physician and expert, although precisely what qualified him as an expert in either mitochondrial disorders or the causes of autism spectrum disorders remains elusive. He graduated from medical school at Case Western Reserve University. Pet. Ex. 63, p. 2358. He is board certified in emergency medicine. Tr. at 226. He has no formal specialized training in metabolic diseases or in any of the several areas (pediatrics, immunology, neurology, or gastroenterology), in which he proffered opinions. Tr. at 227-28. His only publications involved chapters on arthritis, gout, inflammation, and nutrition in an integrative medicine textbook. Pet. Ex. 63, p. 2360.
He did partial residencies in pathology and internal medicine, followed by a three-year residency in emergency medicine, all in the Cleveland, OH area. Tr. at 183-84. As a part of his emergency medicine residency, he received some pediatric training. Tr. at 226-27; Pet. Ex. 63, p. 2359. After completing his residency in 1989, he worked briefly in Massachusetts, before returning to Cleveland's Mount Sinai hospital as a part-time faculty member. He also worked at emergency medicine departments in two other hospitals and in their residency training programs. Tr. at 185-86. None of his appointments during this period were full-time faculty or clinical positions at any one institution. Tr. at 186-87. He also maintained a private medical practice in which he offered nutritional treatments as an alternative to drugs. Tr. at 188.
At the time of his testimony, he held no faculty appointments, although he had privileges at several hospitals. Tr. at 228. He currently treats patients with immune dysfunction, metabolic disorders, mitochondrial disorders, developmental problems, behavior and mood issues, and cognitive dysfunction diagnosed "by other people who basically aren't doing much, if any, medical treatment for them." Tr. at 188-89, 230. The majority of his patients are children with developmental disabilities, including ASD, obsessive compulsive disorder ["OCD"], attention deficit hyperactivity disorder, dyspraxia, apraxia, mitochondrial dysfunction, and mitochondrial disease. Mitochondrial dysfunction patients comprised from a quarter to a third of his patients over the last nine years. Tr. at 194-95. His clinical practice is a "cash office," which does not directly bill medical insurers for the care rendered. Tr. at 229-30.
He serves as the Chief Medical Officer of the U.S. Autism and Asperger's Association (Tr. at 190) and has assisted the Autism Research Institute with their "think tanks" and meetings (Tr. at 191). He is the founder and executive director of the American Medical Autism Board, which he described as "the board certified by medical doctors who do the kind of treatment that several of us out there are doing" (Tr. at 192), presumably referring to biomedical approaches to the treatment of autism. He acknowledged that this board is not recognized by the American Board of Medical Specialties. Tr. at 231.
Much of Dr. DeMio's testimony involved broad, general statements, even when he was discussing his own treatment of A.H.T. In describing that treatment, he used medical terminology vaguely and indiscriminately. For example, he testified regarding his treatment of A.H.T. that: "then there's methylation[
He was equally vague about how A.H.T. responded to his "biomedical" treatments. He testified that:
Tr. at 214.
To summarize, I did not find his testimony reliable in general or useful in resolving either the factual disputes or causation questions. Although Dr. DeMio had treated A.H.T.,
Doctor Kendall, a biochemical geneticist and mitochondrial disease specialist, obtained her medical degree from the New Jersey Medical School. Tr. at 291; Pet. Ex. 80 at 2504.
She has held academic appointments at both Harvard Medical School and Emory Medical School as a geneticist in the pediatrics department. Tr. at 293-94. She currently teaches and lectures at symposiums, at Emory University Nursing School, and annually at the United Mitochondrial Disease Foundation's symposium. She has a hospital appointment at Children's Healthcare of Atlanta as a clinical geneticist. Tr. at 295. However, her primary work is in an outpatient setting, in her role as President, Virtual Medical Practice, where she manages patients with a known diagnosis, evaluates patients for mitochondrial disease, and provides second opinion consultations throughout the world as the "virtual" part of the practice. Pet. Ex. 80 at 2505; Tr. at 295, 298-99. She also evaluates patients being considered for enrollment in clinical trials. Tr. at 299.
Doctor Kendall's CV listed three research interests: inborn errors of metabolism; the pathophysiology of multisystem problems in disorders of mitochondrial energy production; and the efficacy of clinical treatment in disorders of mitochondrial energy production. Pet. Ex. 80 at 2505. There were eight journal articles listed as "Original Reports" on her CV, Pet. Ex. 80, but only one of them explicitly involved mitochondrial disorders. Id., p. 2509. However, she testified that her most recent publication (which did not appear on Pet. Ex. 80, her CV) was a review article on mitochondrial disease and diagnostics. Tr. at 296-97. The CV also listed "Reviews," which appeared to include book chapters and journal articles, including one on testing in mitochondrial disorders and one entitled "Bridging the Gap between ASD and Mitochondrial Disease." Pet. Ex. 80, at 2509.
Unlike Dr. DeMio, Dr. Kendall possessed the requisite qualifications to opine about mitochondrial disorders. The reliability and credibility problems posed by Dr. Kendall's testimony did not concern her qualifications to opine about mitochondrial disorders, but rather her lack of familiarity with the medical records regarding A.H.T.'s growth, development, and treatment during the relevant periods, and her evasiveness in answering my questions as well as those from opposing counsel.
Her lack of familiarity about the medical records was somewhat unusual for an expert witness testifying in the Vaccine Program. She was unsure what diagnostic criteria Dr. Shoffner used (Tr. at 324-25), although it was clearly identified in the diagnostic report. Pet. Ex. 61, pp. 2349-50. She was unable to recall when A.H.T. manifested some of the symptoms upon which the diagnosis was based. See Tr. at 310. When asked if she had reviewed A.H.T.'s medical records from her first year of life, Doctor Kendall replied that she was "assuming" that she did. Tr. at 339. She could not recall if fever was mentioned in the medical records as a symptom occurring after A.H.T.'s vaccination. Tr. at 341-42. She could not recall when A.H.T. was diagnosed with hypotonia. Tr. at 344. She could not recall when A.H.T. started having autistic-like behaviors. Tr. at 345. She could not recall when A.H.T. began displaying symptoms of dysautonomia (temperature instability),
Additionally, Dr. Kendall avoided giving straight answers to straightforward questions. When asked whether a neonate with primary mitochondrial disease would likely have normal growth and weight gain, she replied, "[t]hey can." When pressed to indicate if such growth and weight gain would be expected, she responded "it depends on the patient." She was similarly evasive in answering questions regarding motor and intellectual development in a neonate with a primary mitochondrial disease, responding again, "it depends on what their clinical presentations are." Tr. at 348. These tautological answers were not informative about what is generally or typically seen in such patients. This evasiveness, coupled with the lack of support for some aspects of her opinion, caused me to question whether her testimony was entirely reliable.
Her testimony provided details on her theory of vaccine causation that her expert report lacked. The portion of her report addressing causation (Pet. Ex. 79 at 2496-97) was very short, only about two paragraphs long, and was based on two cited journal articles, one of which was largely a case report, discussing autistic regression in children with diagnosed mitochondrial disorders. As Dr. Kendall admitted on cross examination, A.H.T. did not experience autistic regression in the classic sense of losing "speech and those type of things," and she agreed that there were many differences between the children described in the studies and A.H.T.'s presentation. Tr. at 356; 357-58.
When asked about support for specific aspects of her theory of causation, she avoided a direct answer, as exemplified by the following exchange:
Q: What other literature are you relying on for your theory?
A: As I indicated, some of the other articles that talk about temperature.
Q: Can you be more specific?
A. They are noted in some of the other articles.
Q: Nothing was filed with your report, so I'm just —
A: No, I understand. I'm just mentioning it based on the questions that you're posing, and it's coming up, so that's what I'm saying.
Q: But you did not submit anything to support your theory, is that correct?
A. I did not submit those articles, no.
Tr. at 358. She clarified that not all the articles she cited in her report were actually filed as evidence. Tr. at 360. The failure of petitioner to file supportive evidence for her opinions, particularly after Dr. McCandless challenged her reliance on other literature she claimed was supportive of her opinions (see Res. Ex. G at 4), was troubling.
With regard to A.H.T.'s symptoms after vaccination and the likelihood that they occurred as described by the witnesses, I accorded greater weight to the testimony of respondent's two experts. Both were currently board certified in pediatrics, displayed familiarity with the contemporaneous records, gave careful attention to the testimony of A.H.T.'s parents and fact witnesses, and provided reasons for their conclusions. Both Drs. Wiznitzer
Doctor McCandless holds three board certifications: pediatrics, clinical genetics, and clinical biochemical genetics. After completing medical school and a residency in pediatrics, he practiced pediatric medicine for five years. He then completed a clinical genetics residency at Case Western Reserve University in Cleveland, Ohio. Tr. at 414. This was followed by a faculty position in clinical genetics at the University of North Carolina. He later returned to Cleveland for a fellowship in clinical biochemical genetics. Tr. at 413-14.
In his current positions at Rainbow Babies and Children's Hospital and Case Medical Center, he evaluates and cares for patients who have, or are suspected to have, biochemical genetic disorders. Tr. at 414. He is also involved in outpatient care for the same disorders. He is the medical director of a Prader-Willi syndrome clinic and of the Center for Human Genetics. He diagnoses and treats children and adults with mitochondrial disorders. He has been caring for such patients for the last 17 years. Tr. at 414-16.
Doctor McCandless holds a faculty appointment at the Case Western Reserve School of Medicine, where he teaches genetics to medical students and graduate students, and serves as the director of the residency training program in medical genetics. Since 1996, his teaching has focused primarily on inborn errors of metabolism, some general genetics, and mitochondrial diseases as a part of the biochemical genetics program. He is a member of several professional societies, including the American Academy of Pediatrics, is a fellow of the American College of Medical Genetics, and a member of the board of directors for the Society for Inherited Metabolic Disorders. Tr. at 416-17. He lectures about mitochondrial disorders at the medical school, and developed the program on mitochondrial disorders for a national meeting of the American College of Medical Genetics and the Society for Inherited Metabolic Disorders joint session.
His research has focused primarily on fatty acid oxidation disorders, with fewer publications in the area of respiratory chain disorders. Tr. at 418. He is the principal site investigator for a multicenter clinical trial of coenzyme Q-10 therapy for children with mitochondrial disorders. His research laboratory uses mouse models to try to understand how mitochondrial dysfunction leads to symptoms and how to better treat those symptoms. He is involved in several clinical trials related to the treatment of urea cycle disorders and drug trials to treat phenylketonuria and other lysomal storage diseases. Tr. at 419.
Doctor McCandless has testified as an expert witness twice for plaintiffs and once for a defendant in courts other than the Vaccine Program. This was his first appearance as a witness in a Vaccine Act case. Tr. at 421-22.
Although not lengthy, his opinion (Res. Ex. G) was well-written and well-reasoned. The primary discrepancy in his opinion — stating that Dr. Shoffner diagnosed a possible, rather than a probable, mitochondrial disorder — is not inaccurate, just incomplete. Because Dr. Shoffner's records regarding A.H.T. were filed as a part of three different exhibits (Pet. Exs. 26, 47, and 61) and Dr. Shoffner apparently changed his diagnosis between August 1 and August 10, 2011, without any reference to the earlier diagnosis, much less an explanation for the change, Dr. McCandless apparently missed the later diagnosis of a probable mitochondrial disorder. I find this oversight understandable, particularly as there was no additional testing conducted by Dr. Shoffner between the two visits that would account for the change in diagnostic category.
After graduating from medical school, Dr. Wiznitzer completed a three year residency in pediatrics at what is now Cincinnati Children's Hospital, followed by a year-long fellowship in developmental pediatrics at the Cincinnati Center for Developmental Disorders. Tr. at 619. He then completed a three year fellowship in child neurology at the University of Pennsylvania and an additional two year fellowship at the National Institutes of Health on disorders of higher cortical function in children. Tr. at 619-20. He is board certified in pediatrics, neurology (with special qualifications in child neurology), and neurodevelopmental disabilities. Tr. at 620.
At the time of the hearing, he was an associate professor of pediatrics, neurology, and international health at Case Western Reserve University School of Medicine, and teaches at the nursing and medical schools. Tr. at 620-21. His primary clinical appointment is as a child neurologist at Rainbow Babies and Children's hospital. His clinical responsibilities there include services at the inpatient unit, outpatient clinical practice, the epilepsy service and teaching residents. His responsibilities also include administration of research grants, including one involving autism treatments. Tr. at 621.
He is a member of and holds positions in several relevant professional organizations, including teaching and course development as a fellow of the American Academy of Neurology ["AAN"], where he has presented courses or lectures on ADHD, autism, and pediatric behavioral neurology. He is part of an AAN task force charged with developing a position paper on interventions in autism. Tr. at 621-22. He is a member of the executive committee of the American Academy of Pediatrics ["AAP"] and serves as that organization's liaison to the executive committee of the Council on Children with Disabilities. He is a member of the autism subcommittee of the AAP and a member of various AAP working groups, including one on neuromotor examinations in children. Tr. at 622. He chairs a task force dealing with dyspraxia, a developmental coordination disorder. Tr. at 646. He is also a member of the Child Neurology Society and the International Society for Autism Research. Tr. at 622-23.
Doctor Wiznitzer is a member of the editorial boards of two professional journals. He is a peer reviewer on a regular basis for medical journals dealing with pediatrics, neurology, and other specialties. Tr. at 623. As a member of the Brighton Collaboration, an international organization dealing with vaccine safety, he has helped to develop definitions for various conditions to help in standardizing studies into adverse events after vaccination. Tr. at 623. He also develops questions for various medical certification examinations. Tr. at 624.
He has diagnosed and treated children with ASD and other developmental disabilities for about 25 years. He has conducted research into and has numerous peer reviewed publications, including journal articles, book chapters, and abstracts, on the topics of autism (including co-morbid conditions such as tuberous sclerosis), ADHD, and other developmental disabilities. Tr. at 624-25. He treats children with mitochondrial dysfunction and disorders in his clinical practice. He refers children with suspected mitochondrial disorders to the genetics department and the mitochondrial team for testing and diagnosis. Tr. at 625.
In addition to his clinical, teaching, writing, and research responsibilities, Dr. Wiznitzer devotes about four to five hours per week to litigative consultations. Although he primarily reviews cases for respondent in the Vaccine Program, he has recommended compensation in some of those cases, and has supported claims of his own patients for compensation. Tr. at 625-26. He has testified frequently on behalf of respondent in the Vaccine Program. Doctor Wiznitzer was offered as an expert in pediatric neurology and developmental disabilities, without objection. Tr. at 626-27.
Neither party filed much background information about mitochondrial disorders in general. The comprehensive literature review filed by petitioner, D. Rossignol & R. Frye, Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis, MOLEC. PSYCHIATRY, 17: 290-314 (2010), Pet. Ex. 71 [hereinafter "Rossignol & Frye, Pet. Ex. 71"], did not discuss the wide variety of mitochondrial disorders, focusing more on the co-morbidities in mitochondrial dysfunction, mitochondrial disease, and ASD, and the relative rates of various clinical findings. Some of the various clinical phenotypes, such as Alper and Leigh syndromes, were mentioned in C. Verity, et al., The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national, prospective, population-based study, DEV. MED. & CHILD NEUROL., 52: 434-40 (2010).
Mitochondrial disease can present in a wide variety of ways, according to Dr. McCandless. Tr. at 435. He added that "it has been said that mitochondrial dysfunction can cause almost any symptom in any part of the body at almost any time, which to a certain extent is true." Id. However, "mitochondrial diseases tend to present in some very characteristic ways [which are] usually related to the tissue that's most involved, and those are the tissues that use the most energy." Id. Doctor Kendall explained that "there are subtypes of mitochondrial disease that are clearly defined [that] are descriptive of a group of clinical features that are seen over and over again and often in constellation with a specific gene defect or a specific biochemical feature," but that most patients do not fall into a "well-categorized subtype." Tr. at 349. She testified that A.H.T. does not fit into one of these subtypes. Tr. at 349-50.
Initially, petitioner claimed that A.H.T. has a mitochondrial disorder, one which was "significantly aggravated" by A.H.T.'s initial hepatitis B vaccination. Petition, ¶¶ 15-16. This claim appears to have been modified by petitioner's post-hearing brief. Drawing from the headings in the brief, petitioner claims that A.H.T. has mitochondrial dysfunction (Petitioner's Post-Hearing Brief ["Pet. Br."] at 1-3), which was vaccine induced (id. at 3-10), entitling her to compensation (id. at 10-13). Likewise, Dr. Kendall's expert report claimed that A.H.T. has a mitochondrial disorder, but in questioning Dr. Kendall, petitioner's counsel primarily asked about "mitochondrial dysfunction." For example, Dr. Kendall testified that A.H.T. had probable mitochondrial dysfunction (Tr. at 328-29), but her report referred to "clinical features and biochemical and enzymatic data in support of a mitochondrial disorder." (Pet. Ex. 79 at 2497) (emphasis added).
The terms used to characterize A.H.T.'s condition varied throughout the post hearing brief, suggesting that petitioner thinks the terms mitochondrial disorder and dysfunction are interchangeable.
The most helpful information concerning the distinction between mitochondrial disorders and mitochondrial dysfunction came from Dr. McCandless. He defined primary mitochondrial disease as "a set of clinical abnormalities that directly result from mitochondrial dysfunction." Res. Ex. G at 2. In primary mitochondrial disease, there is evidence that the mitochondria do not function normally and there is a measurable clinical effect of the dysfunction. Tr. at 423, 564-66.
In testimony, Dr. Kendall defined a primary mitochondrial disorder as one "in which there is an alteration in a gene that alters a protein that is directly involved in energy production." Tr. at 396-97. In essence, she asserted that a defect in either mtDNA or nDNA is necessary to have a primary mitochondrial disorder or disease. Tr. at 397-98. Doctor McCandless agreed that the defect had to be one that "leads to a protein in the mitochondria that's not doing its job properly and that leads to the dysfunction," but he did not require that the defect be genetic. Tr. at 428. In a primary mitochondrial disorder, "the basic underlying problem is the mitochondrial structure or function is wrong from the beginning," leading to symptoms of mitochondrial disease. Tr. at 429.
According to Dr. McCandless, secondary mitochondrial defects exist when some other process causes dysfunction of the mitochondria, leading to symptoms. Tr. at 429. When dysfunction of the mitochondria is observed in a laboratory setting, there must be some evidence that the dysfunction also causes an identifiable clinical finding or symptom before the patient can be characterized as having a mitochondrial disease or disorder. Res. Ex. G at 2; Tr. at 428. In testimony, he clarified that one can infer from in vitro (laboratory) testing of tissue to what may happen in vivo, but there still must be some evidence of dysfunction in the body. This evidence may be test results or some clinical symptomology. He pointed to hypoxia or rotenone (a fish poison) as examples of an outside agent that could produce mitochondrial dysfunction. Tr. at 428-29.
Most of the few studies filed in this case focused on individuals with diagnosed mitochondrial disorders, rather than individuals with some evidence of mitochondrial dysfunction. Thus, the applicability of these studies to someone with mitochondrial dysfunction, rather than a mitochondrial disorder, is questionable. Additionally, although A.H.T. has been diagnosed with a probable mitochondrial disorder, the evidence supporting that diagnosis rests on the presence of certain symptoms, about which there are significant factual disputes. This may explain petitioner's shift in focus from mitochondrial disorder to mitochondrial dysfunction in petitioner's post hearing brief. And, as it is more difficult to establish how a vaccine can trigger a genetic condition present since birth, the focus on dysfunction rather than disorder eases, to some extent, petitioner's burden to prove that a vaccination can, more likely than not, be responsible for A.H.T.'s symptomology.
The causation theory identified in the amended petition — that mitochondrial disease can be aggravated by an outside event — builds on an observed characteristic of mitochondrial disorders that is not particularly controversial, even if it has not been well studied or documented. That is, the condition of individuals with mitochondrial disorders often worsens over time. This may occur gradually, or there may be abrupt regressions or decompensations that result in illness and/or the inability to perform motor or cognitive tasks once mastered. Pet. Ex. 79 at 2494; Res. Ex. A at 8; Res. Ex. G at 2; Tr. at 444-46, 588.
These regressions may occur without any apparent cause or may be temporally related to events such as viral or febrile illness, anesthesia, dehydration, surgery, and the use of some drugs, such as HIV medications and statins. Pet. Ex. 79 at 2494; Res. Ex. G at 4; Tr. at 392-93, 398, 572, 588-89, 608-09. Some of those who experience decompensation or regression return to baseline, some plateau, and in many, the loss of skills signals a downward spiral in the progression of mitochondrial disease. Unfortunately, many mitochondrial diseases are relentlessly progressive and ultimately fatal. Res. Ex. G at 2-3; see also Verity, Res. Ex. K at 435, 439 (noting that mortality rates of children with mitochondrial disease enrolled in this study were high, with 40 of the 112 children enrolled in the study beginning in 1997 having died by 2008).
In certain types of mitochondrial or metabolic disorders, there is a measurable physiological response that causes the decompensation. In individuals with urea cycle disorders, an illness (or dehydration due to an illness) may produce an excess of ammonia in the body, termed "hyperammonemia," resulting in a metabolic decompensation. See J. Kingsley, et al., Immunizations for Patients with Metabolic Disorders, PEDIATRICS, 118(2): e460-70 (2006), filed as Pet. Ex. 70, at e464 (hyperammonemiac states are produced by breakdown of muscle tissue during periods of anorexia, such as may be seen in ill children) [hereinafter "Kingsley, Pet. Ex. 70]; T. Morgan, et al., Vaccines are not Associated with Metabolic Events in Children with Urea Cycle Disorders, PEDIATRICS 127: e1147-53 (2011) [hereinafter "Morgan, Res. Ex. I" or the "Morgan study"] at e1148 ("children with [urea cycle disorders] are at high risk of devastating metabolic decompensation in the setting of acute childhood illnesses"). See also Tr. at 502-03 (Dr. McCandless discussing vaccinations in children with urea cycle disorders and the Morgan study).
Decompensation or regression occurs in other types of mitochondrial or metabolic disorders as well as in urea cycle disorders. A correlation has been drawn between metabolic stressors, such as illnesses and surgery, and periods of regression in these patients, based on a temporal relationship between such stressors and a regression or decline in health. This relationship has not been well documented, but it appears to be generally accepted as a causal one. Res. Ex. G at 4; Tr. at 502-03. Fever, in particular, has been recognized as a stressor that can possibly aggravate a mitochondrial disorder, although fever in the absence of an illness has not been systematically studied. Tr. at 352, 392, 572; Pet. Ex. 61, pp. 2347-48. Several of the filed medical journal articles discussed the connection between fever, febrile illness, and decompensation. However, Dr. McCandless testified that it was the underlying illness, and not merely the febrile response to it, that was responsible for the deterioration. Tr. at 512-13, 572-73.
The lack of both specificity and strength in the association between illness and decompensation or regression has contributed to the uncertainty about the causal mechanism — that is, what is it about a fever or illness that causes the loss of skills? Not all individuals with mitochondrial disorders experience periods of decompensation with such stresses, and many experience such periods of decompensation even in the absence of metabolic stress.
Both Drs. Kendall and McCandless testified about some of the theories regarding the causal mechanism for decompensation or loss of skills. Tr. at 352-53, 444-45. Petitioner's theory that a vaccine can cause onset of a dormant or underlying mitochondrial disease or cause long-lasting mitochondrial dysfunction was presented primarily by Dr. Kendall. This theory extends what is generally accepted about mitochondrial disorders in three specific ways. 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.
The medical witnesses petitioner presented did not agree on the specific nature and mechanism of the damage. During the hearing and in her post hearing brief, petitioner advanced Dr. DeMio's theory that ongoing "brain inflammation" was responsible for A.H.T.'s symptoms. The "brain inflammation" theory ostensibly incorporated most of Dr. Kendall's theory that a vaccination can trigger an underlying mitochondrial disorder, producing a loss of skills. However, Dr. DeMio 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. This theory was not explicitly argued in the post hearing brief, but petitioner quoted a portion of Dr. Levinson's statement regarding this position in her post hearing brief. Pet. Br. at 10. Each of these theories, along with some of the evidence provided by respondent, is discussed in more detail below.
Doctor Kendall's expert report provided few details on her theory of causation. The portion of Pet. Ex. 79 that addressed causation was very short, only two paragraphs long. Id. at 2497. She referenced two medical journal articles as the support for her assertions.
Her testimony provided some of the details that her expert report lacked. She testified that A.H.T. had an underlying mitochondrial disorder, that the hepatitis B vaccination was "an immunological trigger" for her fever (Tr. at 352), which stressed her system, "outstrip[ped] the body's ability to develop energy for functionality" and primarily led to damage to her central nervous system. (Tr. at 353).
In terms of timing, she pointed to symptoms that developed between hours to days after the vaccination. Tr. at 353-54. Her theory accounting for the observed temporal link between illnesses and deterioration or regression in mitochondrial disease was based on the increased energy demands that such illnesses or stressors place on the body and the inability of impaired or defective mitochondria to meet those increased energy demands. Brain and muscle tissue require high levels of energy, and when illness increases the demands, the supply available to brain and muscle is reduced, resulting in lost motor and cognitive skills, among other symptoms. Tr. at 301, 303-04, 352.
This theory could account for the observation in Wolf and Smeitink, Court Ex. I, at 1402, that the presenting symptom in children with mitochondrial disorders is often neuromuscular in nature. However, it does not account for deterioration observed without an identifiable triggering event.
The specific mechanism of an energy deficit to account for clinical deterioration is less well accepted than the fact that regressions do occur. See Res. Ex. G at 4 (Dr. McCandless stating that the "strength and mechanism of any such association are not at all clear"); Tr. at 556-57 (discussing Dr. Kendall's theory, another theory, and his opinion that both might contribute to diminished energy production in the mitochondria, along with other factors as yet unknown). Nevertheless, in this decision, I will assume, arguendo, that Dr. Kendall's increased energy demand mechanism is correct. The difficulty comes in finding evidence, other than her very cursory opinion and testimony (Dr. Kendall's direct examination, including establishing her qualifications to opine, encompassed only about 40 pages of testimony), to support the other contested aspects of her opinion.
Doctor Kendall was unequivocal in stating that a vaccination does not cause alteration in a "genetic blueprint" or alter "the functionality of . . . protein structure." Tr. at 334. She testified that an individual can "harbor either DNA changes or the propensity for these diseases and not exhibit them from the time of birth, for example." Tr. at 303. Although she did not explicitly testify that an external trigger is required for an underlying mitochondrial disorder to manifest, she appeared reasonably certain that A.H.T.'s disorder was so triggered. Tr. at 352-54.
Other than Dr. Kendall's opinion, there is little evidence in this record to suggest that a metabolic stressor can trigger a dormant or unrecognized mitochondrial disorder. The anecdotal evidence linking stress to a regression is based on what mitochondrial disease specialists have seen in their own patients (see, e.g., Tr. at 557), necessarily implying that the mitochondrial disorder was already diagnosed or strongly suspected (see also Verity, Res. Ex. K, at 436 (reporting that 33 of the 112 participants diagnosed with mitochondrial disease had experienced an exacerbation of their condition "in association with fever or minor illness")). Doctor McCandless testified that he could not recall any patient who was normal and then experienced a sudden decompensation ("crash and burn") due to illness. Tr. at 608-09.
Relying on the anecdotal experience of one of her patients and Pet. Exs. 68-69, Dr. Kendall claimed that an event such as an illness could trigger a previously unrecognized mitochondrial disorder. She described an asymptomatic teenager who developed symptoms of a mitochondrial disorder (progressive muscular manifestations) after a severe case of influenza. Later, genetic testing disclosed a previously unsuspected mtDNA deletion syndrome. Tr. at 302-03. However, mitochondrial disorders can manifest at virtually any point in life, as Dr. Kendall acknowledged (see Tr. at 302-03), and thus this temporal relationship could be due to coincidence alone.
The Poling case report, filed as Pet. Ex. 69, was weak support for an external event acting as the trigger for a mitochondrial disorder. Doctor Poling, the lead author of Pet. Ex. 69, wrote the report about the experience of his infant daughter.
Even though the Poling claim was compensated, a published decision in the case indicates that compensation was based on the presence of a Table injury, in which entitlement to compensation is legally presumed. Poling v. Sec'y, HHS, No. 02-1466V, 2011 WL 678559, at *1 (Fed. Cl. Spec. Mstr. Jan. 28, 2011) (fees and costs decision, noting that the case was compensated as a Table injury). Such a decision cannot be precedential under any circumstances, as decisions issued by special masters and judges of the Court of Federal Claims constitute persuasive, but not binding, authority. (Hanlon v. Sec'y, HHS, 40 Fed. Cl. 625, 630 (1998)), and certainly not in a case involving a different vaccine (one without any associated Table injury), a different clinical presentation, and different timing.
As Dr. McCandless observed, information acquired through experience in which a causal connection between two events is inferred can be misinterpreted as proof of that causal connection. Tr. at 593. See Paluck v. Sec'y, HHS, 104 Fed. Cl. 457, 475 (2012) (noting that although "case reports `do not purport to establish causation definitively, and this deficiency does indeed reduce their evidentiary value' . . . . `case reports can by their nature only present indicia of causation does not deprive them of all evidentiary weight.'" (quoting Campbell v. Sec'y, HHS, 97 Fed. Cl. 650, 668 (2011)); Bast v. Sec'y, HHS, No. 01-565V, 2012 WL 6858040, at *24, *28 (Fed. Cl. Spec. Mstr. Dec. 20, 2012), motion for rev. denied, 117 Fed. Cl. 104 (2014) (discussing the limited value of case reports); The REFERENCE MANUAL ON SCIENTIFIC EVIDENCE, Federal Judicial Center, 2011(3d ed.) at 724 (noting that in determining medical causation, case reports "are at the bottom of the evidence hierarchy," largely because they lack controls and thus do not provide the level of information or detail found in epidemiologic studies; nevertheless, they "may be the first signals of adverse events or associations that are later confirmed with larger or controlled epidemiological studies.)" Id. at 475. "[S]ome courts have suggested that attempts to infer causation from anecdotal reports are inadmissible as unsound methodology under Daubert." Id. at 217 n.14 (citing McClain v. Metabolife Int'l, Inc., 401 F.3d 1233, 1244 (1th Cir. 2005) (additional internal citations omitted).
Another study reported the "onset of clinical symptoms [seizures in both] was temporally associated with vaccination" in two of the 112 children in the study, which looked at children with severe progressive neurological impairments. Verity, Res. Ex. K (the PIND study) at 436. The authors noted that there was some evidence of a fever in one child and the other was febrile on admission and had evidence of a Norwalk viral infection at the time of onset. Id. at 436. However, the authors drew no conclusions regarding any role of vaccination, illness, or fever in the activation or triggering of the disorders.
No other evidence that illness could trigger a dormant mitochondrial disorder appears in this record.
Assuming arguendo that a dormant mitochondrial disorder can be triggered, activated, or exacerbated by illness, can a vaccine, with or without fever, perform the same function as an illness?
Doctor Kendall's opinion that a vaccination alone can exacerbate or trigger mitochondrial disease (see Tr. at 342-43 (testifying that when she was a biochemical geneticist in training, the fact that immunizations can cause "metabolic decompensations" was "pounded into us")) represents a significant extension from what is generally accepted about the causes of such decompensations.
With the exception of a brief statement about the Poling case by the CDC director (who plays no role in Vaccine Act proceedings and whose specialty as a physician was not identified) filed as Pet. Ex. 83, there was no other evidence in this record that a vaccination alone, unaccompanied by a fever, could trigger the onset of clinical symptoms of a mitochondrial disorder.
According to Dr. McCandless, there is no evidence that a mitochondrial disease or a metabolic illness can be triggered or exacerbated by the hepatitis B vaccine. Tr. at 501-02. He indicated that the possibility that one could be was a topic of discussion, referring to the Shoffner and Poling articles (Pet. Exs. 68 and 69), but that "it's not because those of us who actually do it are that worried about [it]." Tr. at 502.
Vaccination accompanied by a fever, as opposed to vaccination alone, seemed to play a more central role in Dr. Kendall's causation theory, because, as she testified, there was more support for fever causing such regressions and there was support in in vitro studies
Although this chain of events fits Dr. Kendall's theory about the role of increased energy demands, there was little evidence to support her assertion that vaccination alone could activate or worsen a mitochondrial disorder. At best, there were articles mentioning the possibility that vaccines could exacerbate disorders involving inborn errors of metabolism.
Even the support for vaccination accompanied by a fever as an aggravating event was scant. The Poling case report noted the presence of a fever. And, as the title of the Shoffner case study suggested, fever was a prominent factor in the causation analysis postulated by Dr. Shoffner. Doctor Kendall identified both of these articles as supportive of her opinion that the hepatitis B vaccine was responsible for A.H.T.'s condition. See Pet. Ex. 79 at 2497 (citing to the Shoffner and Poling articles in stating that A.H.T.'s "exposure to the [h]epatitis B vaccination aggravated a pre-existing condition with subsequent onset of clinical symptoms and regression" and noting that this process was "documented and reported by several groups, noting a precedent for this association"). I note the overlap of Dr. Shoffner as an author of both of the articles Dr. Kendall cited in support of her opinion, suggesting that the "several groups" cited were actually part of the same group.
The Shoffner article, Pet. Ex. 68, was not supportive of Dr. Kendall's opinion that a vaccine alone could trigger onset of a mitochondrial disorder. This very small study looked retrospectively at 28 patients with co-morbid diagnoses of autism and mitochondrial disease. Pet. Ex. 68 at 429. About 61% (17 of 28) of the children studied were said to have experienced an "autistic regression" ("defined as the loss of developmental skills that included speech, receptive skills, eye contact, and social interests in individuals") — a higher percentage of regression than commonly reported in those with ASD. Id. at 430. The authors also reported that 12 of the 17 children experienced an autistic regression within two weeks of a febrile episode. Id. Vaccination, without any associated fever, was not associated with regression. Id. at 431.
Doctor McCandless characterized the Shoffner study authors as saying that vaccines can cause inflammation, which in turn can cause autistic regression. Tr. at 503-04. He thought this hypothesis merited additional study, but that the Shoffner and Poling papers Dr. Kendall relied upon did not "really prove what they claim or purport to be proving. And, if you read them carefully, they're not really claiming [a causal association]." Tr. at 504.
Aside from Dr. McCandless' criticisms, I note that the Shoffner study relied upon a very small sample, making it difficult to assign it much weight.
The authors of the Shoffner study acknowledged some limitations themselves. They "did not investigate changes that could be important in the induction of regression such as dehydration, hypoglycemia, decreases in substrate ability to oxidative phosphorylation, and other metabolic abnormalities such as fatty acid oxidation dysfunction." Shoffner, Pet. Ex. 68 at 432. The authors also commented: "In our patients with mitochondrial disease and autism spectrum disorders, the vaccines did not appear related to the neurological regression." Id. Thus, this article is a thin reed upon which to hang Dr. Kendall's opinions that vaccines, with or without fever, can trigger onset of a mitochondrial disorder or cause mitochondrial dysfunction.
Moving from theory to the logical connection between vaccination and onset of A.H.T.'s symptoms, Dr. Kendall testified that A.H.T.'s irritability and inconsolability were evidence that she experienced "some encephalopathy, some altered neurological change" after the vaccination Tr. at 329-30, 334-35. She did not explain how this encephalopathy could be followed by apparently normal growth and development, with onset of behavioral symptoms many months later. On cross examination, she acknowledged that irritability and inconsolability were non-specific symptoms that could be caused by factors other than an encephalopathic event. Tr. at 336. In response to my questions, she agreed that they might represent symptoms of colic, rather than an encephalopathy reflecting some brain injury. Tr. at 383.
Her conclusion that the vaccination triggered or otherwise activated A.H.T.'s underlying mitochondrial disorder appeared to focus on the lack of any other explanation for her symptoms. When asked if A.H.T.'s "reaction to the [h]epatitis B vaccination was the triggering event for this child that caused her to become symptomatic," she testified that "certainly there does not seem to be any other mechanism in place, and what I mean by that is there's no other documented illness, there's no other documented trigger, and there certainly seems to be no period of normalcy, as was kind of explained in detail by a lot of the questions posed to [A.H.T.'s] parents and other witnesses. So, yes, it appears that that was an aggravating event for her." Tr. at 330-31. The lack of any other cause and a presence of a temporal connection are not sufficient to establish that the vaccine was responsible, either separately or together. See Lalonde, 746 F.3d at 1341 ("a temporal correlation alone is not enough to demonstrate causation") (citing Moberly, 592 F.3d at 1323); Hibbard v. Sec'y, HHS, 698 F.3d 1355, 1366 (Fed. Cir 2012) (rejecting the assertion that lack of any other identified cause can demonstrate vaccine causation, even when the vaccine in question has been associated with the injury claimed and the temporal relationship is appropriate).
Although Dr. Kendall did not specifically testify that the autistic-like symptoms and developmental delays that A.H.T. demonstrated 15-17 months after vaccination were also caused by activation of the underlying mitochondrial disorder, the last two paragraphs of her expert report so indicate. Pet. Ex. 79 at 2497; see also Tr. at 329-30. Because these symptoms occurred so long after the vaccination, they must derive from an injury that occurred shortly after the vaccination in order to find the vaccination responsible, based on her "hours to days" testimony on timing. Whether this is the result of the "activation" or triggering of the mitochondrial disorder or of some damage (see Tr. at 330) caused by the initial activation was not set forth clearly in testimony or expert report.
Appropriate timing, like the rest of Dr. Kendall's causation theory, is based on the Poling and Shoffner articles. However, there are many significant differences between the facts of A.H.T.'s case (even accepting the facts relied upon by petitioner and Dr. Kendall) and those of the Poling child and the children discussed in the Shoffner article. Not only were there differences in the timing of onset (A.H.T.'s autistic-like symptoms occurred long after the vaccination) and the strength of the mitochondrial diagnosis, both articles discussed "autistic regression," and Dr. Kendall agreed that A.H.T. did not experience an autistic regression at any point. Tr. at 350-55; see also Res. Ex. G at 2 (Dr. McCandless discussing Dr. Kendall's reliance on these two journal articles and noting that the medical records show no deterioration in A.H.T.'s neurological status, loss of developmental milestones, or any plateau in A.H.T.'s neurological development).
Petitioner's reliance on the brain inflammation theory discussed by Dr. DeMio did not become clear until late in the hearing. During his cross-examination of Dr. Wiznitzer, Mr. Downing attempted to clarify petitioner's causation theory. He initially indicated that the hepatitis B vaccine produced systemic inflammation, based on the presence of the fever. Tr. at 678-81. In response to a clarifying question by Dr. Wiznitzer, Mr. Downing indicated that brain inflammation was a necessary part of the theory. Tr. at 682. It does not appear that brain inflammation was part of Dr. Kendall's theory (or a part of the medical literature upon which Dr. Kendall's theory was based). The term "brain inflammation" was never used by Dr. Kendall in her testimony. The closest she came to talking about inflammation of any kind was in response to a question:
Tr. at 303. However, the causal mechanism she identified as causing the injury was not inflammation itself; it was inability of the defective mitochondria to cope with increased stress, causing some unspecified form of damage. Tr. at 352-53. Some of the stressors that she identified as possible triggers of a mitochondrial regression, which included surgery and certain drugs, would be unlikely causes of brain inflammation.
The `brain inflammation" theory has its roots in the testimony of Dr. DeMio, but it was not explicitly raised in his February 2012 statement. In that statement, he commented that he had treated A.H.T. for numerous medical problems, "including those of the central nervous system, metabolism, the immune system, and the gastrointestinal system." Instead of the term "brain inflammation," he opined more generally that she had "brain damage." Pet. Ex. 62 at 2356. However he did not offer any theory as to how the brain damage occurred. He merely described the temporal relationship as "an appropriate time course." Id. at 2357. In view of the alleged regression when A.H.T. was one week old and onset of ASD-type symptoms at around 18 months of age, some further explication of the lengthy temporal relationship was necessary.
Doctor DeMio's statement paid lip service to the mitochondrial disorder diagnosis by attributing improvement in the many problems he identified ("abnormally low ability to do intellectual tasks, . . . abnormal thinking . . . cannot function normally in settings with family and peers, . . . abnormal gait, . . . abnormal play and social interactions, . . . abnormal obsessions, . . . abnormal oppositionality") to the "mitochondrial treatment" she received. Pet. Ex. 62 at 2356-57 (setting out four bullet points, each concluding that some aspect of A.H.T.'s medical issues had improved with mitochondrial treatment). However, his earlier opinions and treatment of A.H.T. had focused on the inflammation caused by toxins and presumed immune issues that are central to a biomedical approach to treating autism symptoms,
Doctor DeMio likewise adopted the mitochondrial disorder diagnosis, but the adoption was perfunctory. Tr. at 217 (stating that he agreed with the diagnosis). He devoted far more of his testimony to his position that the initial vaccination caused encephalopathy and brain damage that was inflammatory in nature or immune-based. He testified: "I mean, she had brain damage, and I'm convinced there was inflammation there, and I still am because the treatment that we've done [has] been helpful for her." Tr. at 224. He stated that there was "no doubt in my mind" that A.H.T. had brain inflammation and was "close to 100-percent sure that's what happened with her. I think it's a part of her encephalopathy. She has immune dysfunction and cognitive dysfunction, and so part of that I think really speaks to that issue of inflammation at the level of the brain." Tr. at 246. He later testified that "I think she has OCD from immune dysfunction that causes autoimmunity to the brain, including brain inflammation." Tr. at 252. He added that she had metal toxicity as well, based on testing and clinical symptoms. Id. He also testified that her "immune system's pretty sick." (Tr. at 220).
Doctor McCandless took issue with the brain inflammation theory. Although the irritability A.H.T. displayed could be consistent with brain inflammation, most mitochondrial encephalopathies do not have a great deal of inflammation associated with them. Tr. at 456.
Because he did not testify, Dr. Levinson's opinions are drawn only from his February 2012 statement. His opinion, which postulated that A.H.T. had an immune and inflammatory response to the initial vaccination, producing oxidative stress on the mitochondria (Pet. Ex. 59 at 2), is not precisely the theory presented at the hearing. Nevertheless, petitioner quoted a portion of his statement in her post-hearing brief. Pet. Br. at 10.
Doctor Levinson attributed the "central nervous symptoms" A.H.T. displayed to the initial vaccination, and I have considered his opinion in my decision on causation, in spite of its similarity to the oxidative stress caused by mercury theory advanced and rejected in the Theory 2 OAP cases. See, e.g., Dwyer, 2010 WL 892250, at *115.
Like Dr. DeMio, Dr. Levinson's opinions conformed to what he was told by A.H.T.'s parents. He 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. Pet. Ex. 59 at 2337. 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." Id.
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. 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. Pet. Ex. 59 at 2337.
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 (see, e.g., Tr. at 318, 343, 352), but she never even hinted that "oxidative stress" played a role in mitochondrial disorders.
Doctor McCandless 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. Tr. at 515. 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." Tr. at 513-14.
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. Tr. at 465-66. Testing performed on A.H.T. did not disclose a Q10 deficiency. Pet. Ex. 26, pp. 522-24.
Although some of the problems with petitioner's theories are addressed above, the factual disputes in this case are so substantial that I turn first to resolving the facts in dispute before applying Althen and Pafford to determine if petitioner has met her burden to prove that A.H.T.'s hepatitis B vaccinations were the but-for cause and a substantial factor in her initial symptoms and subsequent ASD-like behaviors. Shyface, 165 F.3d at 1352-53.
The causation theories summarized above are based on certain predicate facts concerning A.H.T.'s symptoms and diagnosis. An expert's opinion is only worth as much as the facts upon which it is based. Dobrydnev v. Sec'y, HHS, 566 Fed.Appx. 976, 982-83 (Fed. Cir. 2014) (citing Brooke Group Ltd. v. Brown & Williamson Tobacco Corp., 509 U.S. 209, 242 (1993)); Fehrs v. United States, 620 F.2d 255, 265 (Ct. Cl.1980).
In this section, I set forth the evidence, identify conflicts, and make findings of fact. Where necessary, I explain the rationale for the factual findings, and discuss the effect of these factual findings on the causation opinions.
Determining what happened after A.H.T.'s vaccinations and what symptoms of a mitochondrial disorder or dysfunction that she actually displayed involves resolving the same issues present in many Vaccine Act cases: the contemporaneously created medical records differ from the testimony and affidavits of parents, family members, and others on several points.
Two general legal principles guide the resolution of conflicts between contemporaneous records and later-adduced evidence. The first is that the absence of a reference to specific symptoms in a medical record does not conclusively establish the absence of symptoms during that time frame. See, e.g., Murphy v. Sec'y, HHS, 23 Cl. Ct. 726, 733 (1991), aff'd, 968 F.2d 1226 (Fed. Cir. 1992) ("[T]he absence of a reference to a condition or circumstance is much less significant than a reference which negates the existence of the condition or circumstance" (citation omitted)).
The second principle addresses the degree of reliance commonly accorded to contemporaneous records. Special masters frequently accord more weight to contemporaneously-recorded medical symptoms than those recounted in later medical histories, affidavits, or trial testimony. "It has generally been held that oral testimony which is in conflict with contemporaneous documents is entitled to little evidentiary weight." Murphy, 23 Cl. Ct. at 733 (citation omitted); see also Cucuras v. Sec'y, HHS, 993 F.2d 1525, 1528 (Fed. Cir. 1993) (medical records are generally trustworthy evidence). Memories are generally better the closer in time to the occurrence reported and when the motivation for accurate explication of symptoms is more immediate. Reusser v. Sec'y, HHS, 28 Fed. Cl. 516, 523 (1993). Inconsistencies between testimony and contemporaneous records may be overcome by "clear, cogent, and consistent testimony" explaining the discrepancies. Stevens v. Sec'y, HHS, No. 90-221V, 1990 WL 608693, at *3 (Fed. Cl. Spec. Mstr. Dec. 21, 1990).
The factual findings set forth below are drawn from the testimony and other evidence with these legal principles in mind. For the reasons stated, I place more weight on the contemporaneously created records, medical histories, and other documents created closer in time to the events in controversy than on the testimony of A.H.T.'s family members and friends.
The facts in controversy primarily concern 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. The parties disagree whether A.H.T. had such symptoms to the requisite degree or, indeed, at all.
It is petitioner's contention 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.
I discuss the evidence regarding the early problems that are alleged to have been caused by the hepatitis B vaccination in Part B, and make factual findings in Part C. I address the mitochondrial disorder diagnosis and related factual issues in Part D, followed by the factual findings in Part E.
Petitioner and Mr. Tipton asserted that, shortly after the initial hepatitis B vaccination, A.H.T. had a fever, changed her sleeping patterns, began to arch her back and cry inconsolably, experienced constipation, and developed problems with nursing.
In contrast to Dr. Kendall's characterization of the reports of behavioral changes, both Drs. Wiznitzer and McCandless testified that a baseline for feeding and sleeping in an infant takes days to a few weeks to establish, and that the changes from the relatively calm and placid course of the first few days after birth to the much more difficult infant after the first week was part of A.H.T.'s transition from the intrauterine to the extrauterine environment, and that the changes did not constitute a regression. Tr. at 451-53, 547-49, 627-28, 652. Doctor Wiznitzer explained that a newborn's reactions to life outside the womb evolve over the first few weeks of life, and that the changes in A.H.T. were normal aspects of this transition and attributable to the colic
I first set forth the evidence supporting petitioner's claims, followed by contemporaneous documentation, histories, and medical opinions.
Both Ms. Holt and Mr. Tipton were present at the pediatric visit on April 4, 2002, when the initial hepatitis B vaccine was administered. Mr. Tipton testified that they discussed the hepatitis B vaccine with Dr. Buttleman, who told them that the vaccine was safe and that A.H.T. might run a fever, which could be treated with Tylenol. Tr. at 111.
According to Ms. Holt, A.H.T. "slept hard" the day of the vaccination, was warm to the touch
Ms. Holt testified that the day and evening of the vaccination, A.H.T. required stimulation to stay awake while nursing. She described A.H.T.'s eyes as "glazed and unfixed." Tr. at 20. The lethargy continued into the following day, when A.H.T. had several extended family members visit. Tr. at 21-22; 54, 56; 91.
A.H.T.'s parents testified that the Saturday night after the vaccination, she began frantic, inconsolable crying, with high pitched screaming that lasted the entire night, and did not stop until Sunday. Tr. at 22-23, 56. Ms. Hunter testified that Ms. Holt called her and reported the screaming, but she was not specific about when the telephone call occurred. During the telephone call, she could hear A.H.T. screaming in the background. Tr. at 145.
Mrs. Christy Holt's account differs from those of A.H.T.'s parents and grandmother. She testified that she visited A.H.T. shortly after the vaccination. In contrast to the somnolence described by A.H.T.'s parents, she described A.H.T. as very fussy and uncomfortable. Tr. at 161. She did not recall A.H.T. running a fever, but remembered that she was very upset and could not be consoled. Id. She also described a very high-pitched, loud, and constant scream (Tr. at 162).
A.H.T.'s parents and family members testified that her inconsolable crying and screaming persisted for months. Tr. at 63, 91-92, 102-03, 145. When asked if Dr. Buttleman had ever observed the inconsolable crying at an office visit, Ms. Holt indicated that car rides seemed to put A.H.T. to sleep, intimating that A.H.T. was not screaming during her office visits with Dr. Buttleman. Tr. at 82.
According to Ms. Holt and Mr. Tipton, A.H.T.'s sleep pattern never returned to the 18-20 hours per day she slept before the vaccination. Ms. Holt described A.H.T. as being awake 17-18 hours per day, with brief catnaps accounting for the remaining hours, and requiring hours of swinging and rocking to get her to sleep at all. Tr. at 24, 32; see also Tr. at 91-92 (testimony of grandmother, Mrs. Dunn, regarding poor sleep and inconsolable crying).
Ms. Holt testified that, despite thinking that something was seriously wrong on Saturday evening, they did not take A.H.T. to the emergency room because Dr. Buttleman had told them to call her before going to the emergency room.
Ms. Holt also described A.H.T. as having problems with latching on to the breast that she had not displayed prior to the vaccination. Tr. at 22-23. She explained that A.H.T. would simply mouth or gum the breast, but did not have a secure latch. Tr. at 23, 34. However, on cross-examination, Ms. Holt testified that A.H.T. was able to nurse to get the "foremilk," but had difficulty in "taking in" the "hind milk" (Tr. at 54-55), suggesting that the problem was not an inadequate latch, but perhaps the length of time nursing. She reported that between A.H.T.'s April 15 and May 9 visits to Dr. Buttleman, the problems with nursing worsened. Ms. Holt was leaking milk and A.H.T. was spitting up. Tr. at 32; see also Tr. at 33-34 (Ms. Holt describing her own training as a doula, which included observation of an appropriate latch). Ms. Hunter, the doula, described in her April 2012 affidavit that in "one of her calls," Ms. Holt reported problems with A.H.T. latching on to the breast and being "sleepy when nursing." Pet. Ex. 77, p. 2486.
Ms. Holt testified that she called Dr. Buttleman several times about these concerns. Tr. at 21, 26-27; see also Tr. at 115 (Mr. Tipton describing two calls to Dr. Buttleman). According to Ms. Holt, one of the calls took place within 24 hours of the vaccination and another occurred on April 9, 2002 (five days after the vaccination). A later call concerned a chest rash, her low grade fever, and the lack of sleeping. Tr. at 21, 27. Mr. Tipton described the initial call as occurring when they noticed the fever, shortly after the vaccination. Tr. at 112. He testified to a second call when she began screaming, which began when she awoke from the long period of sleeping after the vaccination, sometime on Saturday night. Tr. at 113, 115.
According to both parents, Dr. Buttleman recommended Tylenol during the calls. Tr. at 26, 54, 115. On one of the calls, Dr. Buttleman told them not to call unless they had taken A.H.T.'s temperature before calling her. Tr. at 54, 112. Ms. Holt also called again on April 12, primarily because A.H.T. had not had a bowel movement for a week. Tr. at 27-28. She described Dr. Buttleman as being unconcerned. Tr. at 29. This contrasts with Ms. Holt's later testimony that at the April 15 visit, Dr. Buttleman told her that she needed to know if A.H.T. went for four days without a bowel movement. Tr. at 31. It also conflicts with Ms. Holt's journal,
Ms. Holt's and Mr. Tipton's testimony about A.H.T.'s behavior after her initial vaccination tracks closely with the symptoms Dr. Levinson relied upon in his February 23, 2012 statement. See Pet. Ex. 59 at 2336-37. However, their testimony and affidavits and those of family and friends conflict with contemporaneous records and histories provided closer in time to the events in question. Medical records and Ms. Holt's journal (Pet. Ex. 6) reflect contemporaneous reports of constipation and other symptoms of colic (inconsolable crying and gas) soon after the initial vaccination, but most of the other symptoms were either not discussed at all in the journal or the medical records or mentioned in a context different from the testimony about them.
Ms. Holt's journal entries soon after A.H.T.'s birth included questions and concerns about her own condition.
The journal also reflected questions for Dr. Buttleman and summarized a telephone consultation on April 12, 2002 (eight days after the initial vaccination), but does not contain entries for any of the other telephone calls about which Mr. Tipton and Ms. Holt testified. Pet. Ex. 6, pp. 35-36. The questions included the schedule for vaccination, travel concerns, "Mylicon
The journal entries on or around April 12 reflected Ms. Holt's interest in alternative medicine and general concerns about vaccinations and other health interventions. An undated journal entry following the entry for a postpartum visit from the midwife on April 12 contained comments about specific vaccines, followed by an entry reading "delayed schedule is better" and "exemption form (religious)." The hepatitis B vaccine was not one of the vaccines mentioned.
On April 15, 2002, A.H.T. returned to Dr. Buttleman for her two to four week checkup. Listed as one of the reasons for the visit was "trouble with" bowel movements. Pet. Ex. 58, p. 2328; Tr. at 30-31. A.H.T. was taking Mylicon,
A.H.T. had her one month checkup with Dr. Buttleman on May 9, 2002. The form reflected "worried about stomach." The entry for weight is difficult to read,
Another journal entry on May 15, 2002, also reflected Ms. Holt's continuing vaccine research. Pet. Ex. 6, p. 40; see also Tr. at 62-63. Under the name "Dr. Zieve,"
A.H.T.'s two month well-child visit took place on May 30, 2002. A note at the top of the form indicates: "per parents, no vaccines at this time."
At this visit, Dr. Buttleman discussed expressing milk rather than nursing, "to try to get on schedule." Id. at 2324. This entry suggests that the problem was not nursing per se, but more that A.H.T. had not established a regular schedule for sleeping and eating.
Ms. Holt's journal does not reflect any concerns about weight gain. An undated note (which is the only note in the journal between the notes from the May 30 visit with Dr. Buttleman and a July 25 visit to the naturopathic doctor) mentioned options for treating A.H.T.'s ongoing gastrointestinal issues. The notes reflected the amount of Mylicon to use with each feeding, the possibility A.H.T. may be experiencing "heartburn type of pain," a possible switch to a soy based formula based on a milk allergy, feeding A.H.T. only every three hours, pumping and storing breast milk, and instructions to call back "next" Thursday. It indicates "doing great → stay w/Isomil[.] treat her as reflux . . . . silent reflux → doesn't always spit up[.] Zantac." Pet. Ex. 6, p. 43. Given the reference to Zantac,
A.H.T. saw Dr. O'Dell, a naturopathic physician whom Ms. Holt had previously consulted on nutritional issues, on July 25, 2002. Pet. Ex. 73; Tr. at 79. The one-page record also contains the web address for the National Vaccine Information Center (NVIC), a resource for information on vaccine refusal rights and vaccine side effects.
Ms. Holt's journal entry referencing the Dr. O'Dell visit indicated that A.H.T. "definitely" had a milk allergy, and that the hepatitis B vaccine could have "played a role" by "mess[ing] w/her liver." He apparently recommended that A.H.T. avoid all dairy, switch from a milk-based formula to a particular soy formula, and treatment with "friendly bacteria." Doctor O'Dell informed Ms. Holt that he did not vaccinate his own children. Pet. Ex. 6, pp. 44-45.
At A.H.T.'s four month checkup, which occurred four days after the appointment with Dr. O'Dell, "no complaints" was written on the form, followed by a dash and the word "stomach." The word following "stomach" is not decipherable. Doctor Buttleman discussed stretching out feedings and starting rice cereal. Pet. Ex. 58, p. 2322. A.H.T. was sleeping four to six hours at a stretch. Id., p. 2323.
In late August 2002, A.H.T. returned to Dr. Buttleman for a "problem" visit, one not associated with the regular schedule at which developmental milestones were recorded. Doctor Buttleman discussed diet and bowel movements with Ms. Holt and diagnosed A.H.T. with constipation. In addition to using glycerin suppositories, Dr. Buttleman directed Ms. Holt to "push juices." Pet. Ex. 58, p. 2321. A.H.T. weighed over 13 pounds. Id.
At A.H.T.'s six month well-child visit in early October 2002, she weighed 14 pounds, 10 ounces, more than double her birth weight.
Two entries pertaining to sleep appear in Dr. Buttleman's records in November and December 2002, when A.H.T. was about nine to ten months old. At the November visit, A.H.T. was ill with otitis media, and one of the listed symptoms was "not sleeping," but in context, it appears to refer to a symptom of illness rather than a chronic condition. Pet Ex. 58, p. 2318. The December well-child visit notes reflected a discussion about A.H.T.'s diet, a recheck for her previous otitis media, and the presence of a cough. The notes also reflect that A.H.T. was sleeping "through the night." Id., pp. 2315-16. This was her last visit to Dr. Buttleman.
In January 2003, Dr. Hefner became A.H.T.'s primary care provider. Her first documented bout of diarrhea is referenced in Dr. Hefner's notes from January 2003, in conjunction with enteritis. She was noted to have had an early history of constipation, which was described as "better." Pet. Ex. 52, p. 2233. In August 2003, he noted that A.H.T. had experienced "frequent bouts" of diarrhea, presumably referring to several visits between January and August 2003. Pet. Ex. 52, p. 2228; see Pet. Ex. 52, p. 2229-31. He recommended dietary changes. Pet. Ex. 52, p. 2228.
Video recordings document the behavior of A.H.T. and her caregivers during discrete periods of time during the first few weeks after vaccination. Although I recognize that video recordings may represent periods of "good behavior" because parents may not record the baby during more difficult times, the recordings in this case are devoid of any statements indicating the behavior recorded is unusual or atypical. Contrary to Mr. Tipton's assertions at the hearing (Tr. at 116, 121), they do not support the testimony about A.H.T.'s problem behavior in the days and weeks after vaccination.
A video clip of approximately five minutes was recorded beginning at 8:54
On Tuesday, April 9, a video of approximately six minutes documented a visit, possibly by A.H.T.'s grandmother. A.H.T. was in a bouncy seat, and was not fussing or crying. There was a background comment of "strong little girl." About eight minutes into the video, A.H.T. began to cry, but she stopped crying when she was nursed. In a short clip less than a minute long from Wednesday, April 10, someone remarked at about 5 PM that A.H.T. had been up since 2:45 PM. Video 1, at 35:03. There was no indication that this was unusual or that she was having difficulty sleeping.
The next clip was recorded on April 26, 2002. A.H.T. was in her swing, and appeared alert. Video 1, at 46:00. The next recording was from May 18, 2002, about nine days after the second vaccination. A.H.T. played in her crib, appeared alert and happy, and made sounds. Id. at 46:51. This video is consistent with Dr. Buttleman's records of A.H.T. at the two month well-child visit. Another short clip filmed about six days later showed A.H.T. playing with her father. She was alert and not crying. Id. at 50:26.
In summary, the video showed A.H.T. to be awake on Friday, April 5 and Saturday, April 6, 2002. No comments on the video suggested that these periods of wakefulness were occurring in the context of an extended hard sleep. Video records also documented periods over the next few weeks when she was awake, interactive, and not crying. Throughout the video, she appeared to behave like a normal infant, not one who had suffered an encephalopathic event.
There are no other contemporaneous records concerning A.H.T.'s condition within a few weeks of her hepatitis B vaccinations. However, there were some histories provided by A.H.T.'s parents as they sought treatment for her gastrointestinal difficulties and during early intervention evaluations that bear on the matters in controversy. I note that all these histories were given at a time after Ms. Holt's July visit to Dr. O'Dell, who had attributed A.H.T.'s symptoms to her hepatitis B vaccinations.
The history provided closest in time to the events described is from A.H.T.'s first visit to Dr. Hefner on September 11, 2002, when she was about five and one half months old. The chief complaints at this visit were listed as "difficult [bowel movements]. crys alot (sic), inconsolable, ↓ sleeping, ↓ naps, since 1 wk old." Pet. Ex. 52, p. 2234. She was reported to take four to six ounces of formula every three hours and was gaining weight. Like Dr. Buttleman, Dr. Hefner attributed A.H.T.'s symptoms to colic. Id.
Similar complaints were voiced when A.H.T. saw a pediatric gastroenterologist in October 2002 at about six months of age. The history reflected episodic "inconsolable crying" a week after birth, with difficult bowel movements beginning two-three weeks later. Poor sleep was noted, but there was no "significant arching or food refusal." Pet. Ex. 34, p. 1287.
The next histories were given after A.H.T. was referred for early intervention services in the spring of 2004. The Carriage House developmental examination contained the history that she was "unhappy since about one week of age." Pet. Ex. 39, p. 1826. Ms. Holt reported that she had attributed A.H.T.'s crying to colic at that time, but now had concerns about A.H.T.'s "emotional status." Id. The speech and language assessment contains a history of having had words "come and go" from her vocabulary "since birth." Id., p. 1823.
A history taken in May 2004 reflected that A.H.T. had problems with colic-like behavior and difficulty sleeping during her first year. She would cry "nonstop" or until she vomited. She would then become quiet and start jerking. Ms. Holt also reported a history of difficulty with bowel movements. Pet. Ex. 55, p. 2255.
Breastfeeding difficulties were also discussed, with Ms. Holt reporting that the difficulties involved "overproduction of milk" (which would account for Ms. Holt's complaints about leaking milk) and biting or yanking at the breast. Pet. Ex. 55, p. 2256. The biting and yanking complaints are consistent with a report to Anne Linden Steele in July 2004 that "nursing was awful at 2 months" (Pet. Ex. 41, p. 1832) and to an occupational therapist in September 2004 that A.H.T. "did not nurse well and would bite and yank her head to the side" but did well on the bottle (Pet. Ex. 28, p. 1088).
In an OT assessment performed in September 2004, Ms. Holt reported to the therapist that A.H.T. "screamed nonstop" during her first year of life. She also reported that at two weeks of age, she went 17 hours without sleeping, and would only sleep in her swing. Pet. Ex. 28, p. 1088. Night terrors were reported "since she was an infant." Ms. Holt indicated that, since A.H.T. was able to walk, she would get out of bed two or three times a week while screaming and would run around without acknowledging her parents' presence. At the beginning of 2004, she was sleeping 11-12 hours per day, but at the time of the assessment, A.H.T. was sleeping only three to four hours per night, and required several hours to fall asleep, in spite of the lack of a daily nap. Id. The history of biting and yanking her head during breastfeeding was repeated. Symptoms of "intestinal spasm" and reflux at two months of age were listed, and she was reportedly unable to produce bowel movements during her first year of life without rectal stimulation. Id. Although other medical records had not indicated any persistent problems with diarrhea, outside of bouts associated with an illness, Ms. Holt reported "recurrent diarrhea." Id.
A.H.T.'s first neurology evaluation took place in August 2004. A history of "screaming episodes" since she was seven days old was provided. She was also reported as waking up wild-eyed and crying in the middle of the night since she was six months of age. Reflux, constipation, and diarrhea were also reported. Pet. Ex. 40, p. 1830.
A second neurologist, Dr. Puri, noted in September 2004 that she would not go to sleep without being held or watching TV. Pet. Ex. 31, p. 1262. The clinical psychologist who tested A.H.T. for autism in October 2004 noted that during the period from August through October 2004 the family was "struggling with significant sleep disturbance" (Pet. Ex. 17, p. 144); a report borne out by the OT records (see, e.g., Pet. Ex. 55, pp. 2267, 2276, 2279). By February 2006, A.H.T.'s sleeping problems had apparently improved, as Dr. Puri noted that she had "some difficulty falling asleep," but that she remained asleep once she fell asleep. Pet. Ex. 31, p. 1254. A somewhat dissimilar history was recorded by Dr. DeMio, also in February 2006, noting that her sleep was "poor," but he also noted long sleep latency. Pet. Ex. 23, p. 243.
The first reference in the medical records to A.H.T. suffering a fever after her initial vaccination was not made until May 18, 2011, more than nine years after the vaccination.
The physicians' testimony regarding the likelihood that the symptoms after vaccination occurred as A.H.T.'s parents and other family members described focused on two symptoms: the loss of ability to latch onto the breast and the likelihood that A.H.T. experienced a febrile reaction to her initial vaccination. They also testified about whether there were alternate explanations for A.H.T.'s uncontested symptoms of irritability, crying, and constipation beginning shortly after the initial vaccination. Petitioner's position is that the post vaccination symptoms occurred as she and Mr. Tipton described, that A.H.T.'s fever was the trigger for activating an underlying mitochondrial disorder, and that the other symptoms she displayed were consistent with an encephalopathic event, if not a full-blown mitochondrial encephalopathy. Pet. Br. at 11-12.
Both Drs. DeMio and Kendall accepted the testimony provided by A.H.T.'s parents and other friends and family at face value. Assuming both the presence of fever and the loss of the ability to latch onto the breast, Dr. Kendall testified that a vaccine could cause a fever in a neonate (Tr. 343-44, 352),
Doctor DeMio believed A.H.T.'s parents were accurate historians, and that their testimony was consistent with what they reported to him at their initial visit with him in 2005. However, he was unsure if he had ever reviewed A.H.T.'s early pediatric records. Tr. at 203, 238, 244.
Doctor Wiznitzer was clearly quite skeptical about Ms. Holt's claim that A.H.T. lost the ability to latch onto the breast. He testified that the loss of this ability necessarily implied the loss of the ability to suck and thus to take in adequate nourishment. Tr. at 656-58. The testimony and other evidence that A.H.T. gained weight, maintained appropriate percentiles in weight, height, and head circumference, and produced adequate urine were, according to Dr. Wiznitzer, inconsistent with losing the ability to latch onto the breast. Tr. at 633-35, 638, 656-58. He noted that A.H.T. gained weight without unusually frequent feedings, based on the parents' reports to Dr. Buttleman of how often and how long she was nursing. Tr. 689. He believed that the difficulties Ms. Holt encountered in nursing were consistent with nursing a child with colic and a regulatory disorder. Tr. at 687-88. Rather than having an "inadequate latch," Dr. Wiznitzer attributed the problems in breastfeeding to A.H.T.'s "difficult" temperament. Tr. at 686-89.
Doctor Kendall attempted to explain how the loss of ability to latch could exist simultaneously with normal weight gain, by indicating that frequent feeding could compensate for a poor latch or other inability to feed. Tr. at 340-41. As the record is devoid of evidence that A.H.T. was being fed at more frequent intervals, her testimony on this point is not relevant. She noted a "little bit of a drop off in" A.H.T.'s weight at around four months of age. Tr. at 384. However, by that time, A.H.T. was being bottle-fed formula and Ms. Holt testified that A.H.T. did fine on the bottle. Tr. at 37, 79. Thus, this aspect of Dr. Kendall's testimony is also irrelevant.
Doctor Wiznitzer noted that the contemporaneous medical records did not reflect any report of fever after the initial hepatitis B vaccination. He found this significant, as there is a heightened degree of concern when a fever in excess of 100.4-100.6°F is present in a neonate, as it may reflect symptoms of sepsis, a serious and sometimes fatal infection in a neonate. Tr. at 629-30; Res. Ex. A at 8. He referenced two excerpts from pediatric textbooks for this assertion. See Res. Ex. D, an excerpt from the American Academy of Pediatrics' TEXTBOOK OF PEDIATRIC CARE, Ch. 181; Fever. This excerpt states:
Id. at 3 (using the CM/ECF generated page numbers). See also Res. Ex. C, a one-page excerpt from NELSON'S regarding management of acute illnesses, which states: "Many would agree that a sepsis work-up is indicated in the febrile child younger than 1 mo and possibly younger than 3 mo."
On cross examination, Dr. Wiznitzer acknowledged that fever is a common reaction to some vaccinations, but he added that there is little evidence that the hepatitis B vaccine causes fever. Tr. at 660-62. He agreed that the vaccine monograph
With regard to the other symptoms A.H.T. allegedly displayed after the initial vaccination, respondent's experts did not contest that A.H.T. experienced persistent crying, slept less, was constipated, arched her back, and had episodic jerking. All of these symptoms were reported to one of her primary care providers, the pediatric gastroenterologist she saw at about six months of age, or were otherwise reflected in Ms. Holt's journal. However, respondent did dispute that the vaccination caused these symptoms. Respondent's experts attributed the problems in breastfeeding, persistent crying, difficulty in sleeping, back arching, and constipation to the colic diagnosed by both primary care providers and the pediatric gastroenterologist. Res. Ex. A at 9, Tr. at 629, 631-32. Doctor Wiznitzer provided unrebutted testimony that the "jerking awake" that A.H.T.'s parents described is common in infants during the first few months of life. Tr. at 633. He also testified that there was no evidence of lethargy in A.H.T.'s records during the first year of her life. Tr. at 632-33. I concur with his conclusion regarding the absence from the records, notwithstanding Dr. Kendall's assertion that the records reflected lethargy.
I have carefully considered the record as a whole in arriving at the factual findings set forth below.
(a) The advent of problems with constipation and colic within a few days of the initial hepatitis B vaccination is well-established by both testimony and medical records. Problems with constipation persisted, but lessened by about six months of age.
(b) Chronic or frequent diarrhea did not occur at a point close in time to A.H.T.'s initial or second hepatitis B vaccination.
(c) A.H.T. maintained a weight curve between the 25th and 50th percentiles until nine months of age.
(d) She fell off her weight curve between nine and 18 months of age, in conjunction with several bouts of diarrhea. Her weight dropped to the 5th percentile at one year of age, but rebounded to the 20th percentile at 15 months of age.
(e) It is possible that A.H.T. developed chronic diarrhea at some point after 18 months of age, but if so, it is not documented by contemporaneous records, which reflected bouts of diarrhea in conjunction with certain types of food and some medical interventions.
(a) A.H.T. cried more often and more robustly after her initial hepatitis B vaccination than she did before it. A.H.T. was, as an infant, difficult to console.
(b) The record as a whole does not support a finding of the "non-stop" crying in the first year of her life about which her parents and family members testified.
(c) Based on her symptoms, Dr. Hefner diagnosed colic, a diagnosis also made by Dr. Stephen and Dr. Buttleman. I accept their diagnosis as correct. That diagnosis accounted for the inconsolable crying reported and observed, as well as the gastrointestinal complaints. Infants with colic cry robustly and are difficult to console.
(d) By six months of age, the colic symptoms had eased. However, A.H.T. displayed some problems involving crying, tantrums, and general unhappiness during the remainder of her first year of life and thereafter. She was resistant to efforts to get her on a regular schedule for eating.
(a) Prior to her initial vaccination at five days of age, A.H.T. likely slept much of the day, with brief periods of alertness and interaction, including periods when she nursed. The periods of sleeping prior to her vaccination may well have been 18-20 hours per day, consistent with the sleeping patterns of many neonates.
(b) The reports that A.H.T. slept nearly continuously and was difficult to rouse in the two days after her initial vaccination
(c) A.H.T. slept less after one week of age than the 18 to 20 hours per day she slept previously. However, I do not accept A.H.T.'s parents' testimony that her total sleep per day amounted to just four or five hours daily for an extended period of time.
(d) A.H.T. napped less frequently and for shorter periods of time after her initial vaccination than she did before it, and at some point during her first 18 months, she stopped napping entirely. However, the periods of unbroken sleep described in the medical records increased over time, consistent with the normal sleep patterns of infants. Contrary to A.H.T.'s parents' testimony, I find that the reports of length of sleep in Dr. Buttleman's records reflect the longest period of unbroken sleep, rather than the total amount of sleep in a day.
(e) During infancy, A.H.T. experienced difficulty in falling asleep and often slept in her swing.
(f) At six months of age, she developed night terrors. However, by nine months of age, she was sleeping through the night.
(g) At the time of her referral for early intervention services, she had poor sleep habits, delayed sleep onset, and did not nap, but she slept through the night. Additional sleeping problems developed during her early intervention therapies.
(h) Problems with sleeping may have persisted thereafter, although the records and other evidence are not clear for how long or when, or whether the problems were periodic or episodic. Sleep problems became so severe in 2010 (when A.H.T. was eight years old) that she was treated at a pediatric sleep clinic.
(a) A.H.T. breast fed well initially, but after she developed colic, breastfeeding became more difficult. Nevertheless, she took in adequate nourishment exclusively (or nearly exclusively) from breastfeeding through two months of age, as evidenced by her weight gain and place on the weight curve.
(b) A.H.T. was receiving prune juice by bottle prior to the cessation of breastfeeding. A.H.T. had no problems with bottle feeding, which likely contributed to Dr. Buttleman's suggestion that Ms. Holt feed breast milk by bottle.
(c) A.H.T. was nursing for appropriate periods and frequency as reported at well-child visits through two months of age.
(d) A.H.T. stopped nursing regularly at about two months of age, but contrary to Ms. Holt's testimony, I find that the change to bottle feeding of breast milk and then to various formulas was not due to a problem with A.H.T.'s ability to "latch on" to the breast. Rather, it represented at least three problems: getting A.H.T. on a regular schedule, overproduction of milk, and A.H.T. biting and yanking on the breast.
(e) Ms. Holt stopped breastfeeding at about two months of age and eventually switched A.H.T. to formula at around four months of age, after about two months of bottle-feeding pumped breast milk.
Unlike the crying, gastrointestinal discomfort, sleeping, and feeding issues, there are no contemporaneous records that support even part of petitioner's claims that A.H.T. developed a fever of several days duration after the initial hepatitis B vaccination. In the absence of medical or other contemporaneous records,
Ms. Holt and Mr. Tipton's testimony differed as to how high the fever was, how long it lasted, and when and how many calls were made to Dr. Buttleman.
More significantly, however, the April 12 call to Dr. Buttleman's nurse regarding constipation and colic is documented in Ms. Holt's journal, but fever was never mentioned. Additionally, in spite of Ms. Holt's testimony about her level of concern regarding the dramatic changes in A.H.T.'s behavior, there are no references to these changes in the journal, while much more mundane issues are referenced. Ms. Holt made notes about a telephonic consultation with Dr. Buttleman's office regarding constipation between the visits when A.H.T. was five days and two weeks of age, and I find it significant that no such notes were made about a fever after vaccination.
Ms. Holt's journal is reflective of a person concerned about health questions. Her actions are those of a person willing to make unconventional health care decisions, as reflected in her rejection of the recommendation to induce labor made by her obstetrician and her choice of a home birth attended by a midwife. She wrote down questions for her health care providers and advice she received. The journal reflects concerns about side effects of vaccination and even the need for vaccinations at all, but is silent about ill effects from the vaccinations A.H.T. actually received.
I thus find it unlikely that A.H.T.'s parents would have deferred to Dr. Buttleman regarding A.H.T.'s second vaccination in light of the reactions to the first vaccination that they described. This capitulation to Dr. Buttleman is even more unlikely in view of the comments in the journal and Ms. Holt's testimony that she had "researched" a number of vaccines and how to obtain vaccine exemption between the first and second hepatitis B vaccinations.
Moreover, if Dr. Buttleman had been notified, as A.H.T.'s parents testified that she was, even as late as the next well-child visit, I am confident that she would have reflected a febrile reaction in her notes and, at a minimum, included advice about how to prevent fever before the second hepatitis B vaccinations. Fever of any level in a neonate, as Dr. Wiznitzer testified and as reflected in the medical articles filed with his expert report, would be a matter of concern for a pediatrician, and a symptom warranting an office visit and possibly a sepsis workup. I find it highly unlikely that reports of a fever after vaccination in an infant less than one week old, persisting for the period described, would elicit the "wait and see" attitude attributed to Dr. Buttleman as well as the lack of documentation in the infant's records.
It is also significant that the first references to A.H.T. suffering a fever after her initial vaccination were not made until May 2010, when she had her first visit to Dr. Shoffner. References to fever also occurred in Ms. Holt's and Mr. Tipton's largely identical affidavits, filed in September 2011, shortly after A.H.T.'s diagnosis with a mitochondrial disorder. Fever appears to be significant, if not absolutely essential, to the causation theory advanced by Dr. Kendall in this case, and the facts of the Poling case and the Shoffner study (Pet. Exs. 68-69) were widely discussed.
I find that A.H.T. did not experience a fever after her initial hepatitis B vaccination.
(a) A.H.T. had essentially normal growth and development between birth and one year of age. Although at nine months of age she was not responding well to her name and may not have been using meaningful sounds, at 12 months of age, her language skills were assessed as normal.
(b) A.H.T. acquired age-appropriate cognitive and motor skills at least through 15 months of age.
(c) None of the health care providers who treated her from five days of age to 15 months of age expressed any concern about her cognitive development.
(d) At 18 months of age, she was noted by her pediatrician to lag in language acquisition.
(e) A.H.T.'s parents did not have concerns about her development until she was about 18 months of age.
There is no reliable evidence that A.H.T. experienced any reaction to her second hepatitis B vaccination. I conclude that there were no specific symptoms that worsened soon after the second vaccination.
The second factual controversy concerns the basis for A.H.T.'s diagnosis with a mitochondrial disorder in August 2011.
A.H.T. first saw Dr. Shoffner on May 18, 2011, having been referred by Dr. Levinson, to determine if her "clinical manifestations [were] related to a defect in cellular energetics or another class of metabolic disease." Pet. Ex. 47, p. 2117. The thorough diagnostic workup she received at this visit consisted of a clinical history, tests performed on blood, urine, and cerebral spinal fluid, a muscle biopsy taken to assess mitochondrial function in living and fresh frozen tissue, and DNA analysis, among others. See generally Pet. Ex. 26. The clinical history is set forth in Pet. Ex. 47, pp. 2117-24 (reflecting the history reported at the initial visit in March 2011) and in Pet. Ex. 61, pp. 2342-48 (report from the August 10, 2011 visit). Summaries of test results and the diagnostic score sheets
The records from the May 18 visit contain a number of excerpts from A.H.T.'s medical records documenting some of her symptoms. Other symptoms, such as reports of frequent fevers and respiratory infections, are reflected only by parental history, and are either in conflict with the contemporaneous records or are not supported by the medical records or other evidence.
The "Neuromuscular" section of the medical history portion of Dr. Shoffner's records included the statements that "[p]arents and records report fatigue with activity" and that A.H.T. had "[g]eneralized hypotonia." Pet. Ex. 47, p. 2120. However, the filed medical records do not document fatigue with activity or generalized hypotonia, although some reports of low muscle tone appear in the PT and OT records. Fatigue is mentioned in her records, but primarily in the context of A.H.T. reporting fatigue when she was asked to perform activities that she did not like. A physical examination of A.H.T. found normal strength and gait, no neuromuscular eye movement problems,
This record also contains the first-ever report of a fever within one to two days of the initial hepatitis B vaccination, as well as a report of frequent fevers. Pet. Ex. 47, p. 2121. The medical records pertaining to fevers, respiratory infections, fatigue, and hypotonia are discussed in more detail below, along with the expert testimony regarding them.
The history also reflects the parental report that A.H.T. did not speak her first words until 30 months of age. Id. This history conflicts with the contemporaneous records reflecting language acquisition and use when A.H.T. was 12-18 months old and Ms. Holt's earlier histories reporting no concerns about A.H.T.'s language until she was about 18 months old. At that point, the issue was that she was not using two-word phrases, not that she had failed to acquire any words at all.
Several pages of the initial consultation report include general information about genetics, ASD, and mitochondrial disorders. Pet. Ex. 47, pp. 2124-28. The section also references Dr. Shoffner's "manuscript . . . discussing the association of autistic regression in conjunction with fever" and his opinion that "fever is a significant variable associated with autistic regression in a subset of patients with autism spectrum disorders."
In general, the test results themselves are not in controversy (see, e.g., Res. Ex. G at 1-2 (Dr. McCandless commenting that the muscle biopsy results clearly show some diminution of function in the ETC); Tr. at 532, 564 (testimony that the laboratory where testing was performed had "a good reputation," and that Dr. McCandless sent cerebrospinal fluid ["CSF"] samples to it for his own patients).
The only positive result from the muscle biopsy was in the enzymology test, which measured enzyme activity in skeletal muscle. A.H.T. had evidence of moderately impaired function in Complex I and Complex III
Other tests of mitochondrial function were "unremarkable," the term this laboratory used for negative results. See id., pp. 532 (insufficient samples for testing Complexes I-IV, and Complex V measured as unremarkable); 533-34 (finding overall assembly of supercomplexes tested to be unremarkable on blue native gel analysis);
Doctor McCandless expressed some concern about whether the test really showed a defect in Complex III, or merely one in Complex I. When the activity of Complexes I and III was measured jointly to assess "supercomplex" activity, there was a diminution in activity. Tr. at 474; see also Tr. at 321 (Dr. Kendall's explanation of supercomplexes); Pet. Ex. 26, p. 564 (laboratory explanation of supercomplexes). But, when Complex III activity was measured independently, the value recorded (see Pet. Ex. 26, p. 564) was just over 50% of the mean. Tr. at 493-94. Doctor McCandless explained that because the result was 50% of normal, most practitioners would think that the level of Complex III activity was unlikely to be associated with any clinically significant dysfunction. Tr. at 495. However, Dr. Shoffner's laboratory reported the test result as abnormal, because it was outside the reference range established by his laboratory. Tr. at 494.
High resolution respirometry testing of A.H.T.'s muscle did not identify any specific abnormalities. Pet. Ex. 26, p. 565. Notes in the methodology section of this report indicated that discrepancies between enzymology (the only clearly positive test result in A.H.T.'s case) and this test are common, because they measure different aspects of mitochondrial function.
Tests on blood, urine and cerebral spinal fluid were also performed. The parties disagreed about the significance of the level of methyltetrahydrofolate found in A.H.T.'s cerebral spinal fluid.
Doctor Kendall testified that a cerebral folate deficiency "can be" a potential indicator of mitochondrial dysfunction and is seen in "some subsets of mitochondrial disease," particularly in patients with genetic defects in mtDNA. Tr. at 322-23. She added that a cerebral folate deficiency could produce such clinical symptoms as irritability, poor sleeping, seizures, and brain atrophy. Id. Doctor McCandless testified that a cerebral folate deficiency was not diagnostic of mitochondrial dysfunction because such results were seen in many neurological diseases. Tr. at 491-92. However, in his August 1 report on testing and diagnosis, Dr. Shoffner appeared to relate the cerebral folate deficiency to A.H.T.'s autism diagnosis by referencing four medical journal articles "for cerebral folate deficiency and autism." Pet. Ex. 47, p. 2111 (citations omitted). Nevertheless, his report also noted, "[c]erebral folate deficiencies have a variety of causes. The symptoms are complex and include developmental delays, autistic features, seizures, irritability, ataxia, spastic paraplegia, dykinesias, and epilepsy." Pet. Ex. 47, p. 2125 (citations omitted).
Tests other than those on muscle tissue and body fluids were performed as well during the assessment. A.H.T.'s resting metabolic rate was measured, with results at 76% of the predicted value.
There does not appear to be any dispute concerning the test result itself, but Dr. McCandless pointed out that A.H.T.'s lack of muscle mass was a factor that should be considered in the weight to give the test results. Tr. at 479. The test report reflected A.H.T.'s body mass index as 15.7, indicating that she was underweight. Pet. Ex. 26, p. 537. Being underweight or out of condition might tend toward decreased muscle mass and a finding of a decreased resting metabolic rate.
Doctor McCandless also pointed out the equivocal nature of such testing, as both low and high resting metabolic rates can be indicators of some mitochondrial diseases. Tr. at 478-79. Doctor Shoffner's report supported this testimony.
With some minor exceptions, all other tests were "unremarkable," according to Dr. Shoffner's evaluation summary.
Tr. at 500.
The experts agreed that in the absence of an identified genetic defect affecting mitochondrial function, there are no "gold standard" tests for diagnosing mitochondrial disorders. Tr. at 323, 439; see also Pet. Ex. 26, p. 563 (report from Dr. Shoffner's laboratory stating that a single test is rarely sufficient to diagnose or exclude mitochondrial disease).
Several different scoring systems involving various diagnostic criteria are used in evaluating patients for the presence of mitochondrial disorders. Two of these, the Bernier and Nijmegen criteria, were discussed at various points during the expert testimony. See, e.g., Tr. at 324, 377-78 (Dr. Kendall discussing Bernier on cross-examination), 439 (Dr. McCandless identifying the various criteria discussed). However, regardless of the scoring system used, clinical judgment regarding the patient's presentation plays a significant role in making a diagnosis. See Tr. at 302, 409-10, 533-34. Even when genetic evidence for a mitochondrial defect is present, a patient may not display clinical symptoms, particularly if the defect is present in mtDNA.
Doctor Shoffner used the Nijmegen criteria as the basis for his diagnoses.
The clinical criteria are divided into four categories of symptoms, two of which are largely based on test results, and two of which are symptoms-based.
Scoring can be very subjective and the clinical scoring systems can be manipulated. Doctor McCandless explained that "[t]here are proposed ways of scoring the combination of clinical and biochemical findings to determine whether somebody is more or less likely to have a primary mitochondrial disease. There's [sic] lots of problems with those scoring systems." Tr. at 439. He added that "what becomes clear is that the clinical criteria are very subjective and that if you believe somebody has mitochondrial disease, you can very easily make their score give you a result that they have mitochondrial disease." Tr. at 440. Referring to a chart she supplied with her expert report (Pet. Ex. 79 at 2500), Dr. Kendall discussed the many types of symptoms that could be indicative of mitochondrial disease. Tr. at 306-08. She also testified that the various diagnostic criteria did not work with all patients. Tr. at 323-25. Nevertheless, as the Nijmegen study pointed out, diagnosis standardization is necessary in order for proper investigation and treatment protocols to be established. Wolf & Smeitink, Court Ex. I, at 1401.
According to Dr. McCandless, the biochemical criteria also present difficulties for interpretation. While less subjective than the clinical scoring, the biochemical criteria for diagnosing mitochondrial disorders are controversial and researchers have encountered problems in producing consistent and reliable diagnoses using them. Tr. at 440. Doctor McCandless testified that it was not uncommon to see "subtle abnormalities" on biochemical testing in patients who did not have a primary mitochondrial disorder. Tr. at 568.
Doctor Shoffner made two assessments of the likelihood that A.H.T. has a mitochondrial disorder. His August 1, 2011 diagnosis of a possible mitochondrial disorder is reflected in two exhibits. Pet. Exs. 26, pp. 522-82 (copy containing diagnosis and test results); 47, pp. 2109-16 (copy from Dr. Levinson's records without test results). On these score sheets, A.H.T. received 2 points for having a low resting metabolic rate and 1 point for "exercise intolerance."
In the August 10, 2011 report, which coincided with the date Dr. Shoffner met with A.H.T. and her parents for the second time, he changed his diagnosis from a possible to a probable mitochondrial disorder. See Pet. Ex. 61, pp. 2346, 2349. No explanation was offered for the change in diagnostic category in the report, and the earlier, less definitive diagnosis was not mentioned.
In the August 1 version of the report and diagnosis, Dr. Shoffner set forth his methodology for reaching the diagnosis:
Pet. Ex. 47, p. 2111. However, when he scored A.H.T.'s clinical picture and tests, he did not assign points for the blood and CSF levels of lactate and pyruvate, probably because they did not meet the criteria specified on the score sheets, which require elevated blood lactate on three occasions and an elevation in CSF lactate. See Pet. Ex. 47, p. 2112 (score sheet reflecting the requirements). A.H.T.'s CSF lactate and pyruvate were both in the normal range, although the ratio between lactate and pyruvate was elevated. Doctor Shoffner apparently thought this was significant enough to mention in his summary (quoted above), but Dr. McCandless testified that the ratio was not important so long as neither lactate nor pyruvate was elevated. Tr. at 480. On the August 1 score sheet, A.H.T. was assessed as having a possible, not a probable, mitochondrial disorder. Id.
The diagnostic change in the August 10 report was based on 1 additional point in the clinical criteria portion of the scoring system.
Scoring was otherwise the same in both reports. No additional testing or examinations between the August 1 and August 10 reports were reflected in the records.
It is difficult to determine what precipitated the increased score in the organ system involvement category. A comparison of Pet. Ex. 61 to Pet. Ex. 26 reveals several additions to the "History of Present Illness" section of the clinical history, but the additions were not identified as the reason the scoring changed and do not appear to reflect the involvement of a second organ system. Under "Neurobehavioral features," the additions were: (1) "Significant emotional lability is observed" (found in 1(e), Pet. Ex. 61, p. 2342) and (2) "Social Communication Questionnaire completed during today's clinic visit," with a note that the score "is not inconsistent with ASD" (found at 1(f), id.). "Abnormal social and emotional behavior" was added as 2(d), under the "Neuropsychological evaluation" heading. Under "Neuromuscular, Frequent Illnesses," episodic headaches and chronic pain were added as (3(d) and (e)).
Doctor McCandless did not contest the laboratory evidence of some diminution in function in Complex I and possibly some problem in supercomplex formation in A.H.T. However, he opined that A.H.T. did not have a mitochondrial disorder based on her entire clinical picture and that the dysfunction in Complex I (and possibly Complex III) was not responsible for the symptoms A.H.T. displayed. Tr. at 423.
The factual basis for concluding that A.H.T. has exercise intolerance was one of the issues raised during the hearing. See Tr. at 347-48 (cross-examination of Dr. Kendall regarding the exercise intolerance finding by Dr. Shoffner). Subtraction of the 1 point assigned for exercise intolerance would change the most recent diagnosis from "probable" to "possible." Also disputed is the involvement of the second organ system-one other than the central nervous system — with dysfunction sufficient to qualify her as having a possible or probable mitochondrial disorder diagnosis under the Nijmegen diagnostic criteria. Two possible candidate systems were discussed by the experts: gastrointestinal and autonomic. A.H.T.'s early gastrointestinal problems were discussed supra; the more recent history is set forth below. Dysfunction in the autonomic system rests on the evidence concerning whether A.H.T. truly had recurrent fevers without a concurrent illness. It is also possible that Dr. Shoffner used neuromuscular manifestations (based on the reports of "generalized hypotonia" mentioned in his reports) in concluding that A.H.T. had symptoms of a second organ system involvement, although this is less likely, as he did not assign any points for "muscle weakness" on either of the score sheets. See Pet. Exs. 47, p. 2120; 61, p. 2349.
Because Dr. Shoffner's score sheets begin with the neuromuscular manifestations, I begin there as well.
The experts often discussed resting metabolic rate, hypotonia (low muscle tone), and exercise intolerance together in their answers. Tr. at 347 (Dr. Kendall defining fatigue as an inability to do normal daily activities without feeling overwhelmingly tired, and equating fatigue with exercise intolerance); 364-65 (Dr. Kendall testifying that exercise intolerance could be determined by history, observation, or the resting metabolic rate); 541-42 (Dr. McCandless testifying that the muscle findings that are most compelling for a mitochondrial diagnosis are large group muscle weakness, excessive fatigability, muscle breakdown, or clearly reduced exercise tolerance, not the fine motor skills delay A.H.T. displayed). The explanatory materials from the Wolf & Smeitink article, Court Ex. I, define exercise intolerance as "a symptom characterized by abnormal premature fatigue/weakness/muscle aches or cramps after normal play or activities of daily living." Id., Supplementary Materials, Section A (Muscular Presentation).
This conflation by the witnesses is understandable, because the score sheets used by Dr. Shoffner (and the Nijmegen criteria upon which the score sheets are based) have some overlap. Exercise intolerance is a subcategory under "Neuromuscular manifestations." Decreased resting metabolic rate is a subcategory under the category "Metabolic and imaging studies." However, "resting metabolic rate" is "pled in the disjunctive," as the term is followed by "or abnormal exercise studies (cycle ergometry protocol)." Thus one could argue that "exercise intolerance" counts twice, both as a neuromuscular manifestation and as an abnormal test result.
It is doubtful that this result is intended, however, as the Nijmegen criteria were established to avoid overemphasizing any one symptom, test result or manifestation. Wolf & Smeitink, Court Ex. I, at 1402-03. It is impossible, based on the scoring limitations by category, to obtain a diagnosis of a "probable" mitochondrial disorder by results in one category alone.
Instead, it appears that the score was assigned based on A.H.T.'s parents' report to Dr. Shoffner that she had exercise intolerance. See Pet. Ex. 47, p. 2120 ("Parents and records report fatigue with activity"). No medical or other records reporting exercise intolerance were excerpted and included as support for this assertion, although excerpts for many other records were interspersed throughout the medical history. See generally, id., pp. 2117-22. The most recent record from the pediatric cardiologist who diagnosed A.H.T.'s heart murmur is excerpted immediately below the "parents and records" comment. This cardiologist saw A.H.T. twice, in June 2009 (Pet. Ex. 13, pp. 105-06) and in July 2010 (id., pp. 103-04). This excerpt quotes from A.H.T.'s second visit, which does not mention exercise tolerance.
However, at the initial visit, the cardiologist wrote that A.H.T. "had a normal energy level and exercise tolerance and can easily keep up with other children." Pet. Ex. 13, p. 105. Doctor McCandless commented on this record in his testimony to support his opinion that A.H.T. did not have evidence of exercise intolerance, explaining that cardiologists "know how to elicit a history of exercise intolerance or fatigue" and that this cardiologist elicited a history that A.H.T.'s exercise tolerance was normal. Tr. at 535. Either the record from this initial visit was not provided to Dr. Shoffner or he failed to read and include it in his summary of relevant medical records.
Doctor Kendall testified that she had no idea how Dr. Shoffner came to the conclusion that A.H.T. had exercise intolerance. Tr. at 364-65. She also testified that "[a]t some point in the records there were indicators as such. Otherwise I wouldn't have stated it," but she could not recall where in the records exercise intolerance was mentioned. Tr. at 348.
My review of the records failed to disclose any physician who even mentioned exercise intolerance before Dr. Shoffner did so.
When questioned about A.H.T.'s exercise intolerance at the hearing, Ms. Holt testified that she was a very hyperactive child who never took naps. Tr. at 72. She reported that A.H.T. participated in gymnastics and horseback riding. Id. She also enjoyed swimming. See Pet. Exs. 47, p. 2058 (report to Dr. Levinson that A.H.T. was swimming and hiking); 56, p. 2287 (report to neuropsychologist that she enjoyed swimming). Ms. Holt characterized her as "awake and raring to go." Tr. at 72. She was able to keep up with other children her age, but would get pale and out of sorts at points. One of the reasons her parents thought she might be bipolar is that she would sometimes have too much energy and at other times, not enough. Tr. at 72.
Doctor McCandless specifically referenced Ms. Holt's testimony about A.H.T.'s activity level as well as the dearth of evidence in the medical records about exercise intolerance when he testified that he did not see evidence of exercise intolerance. Tr. at 534-35.
The supplemental materials to Wolf & Smeitink, Court Ex. I, contain a list of candidate organ systems with qualifying symptoms under each system. The only organ system involvement even possibly applicable to A.H.T. would be the gastrointestinal system (listed in Part C, Multisystemic involvement), the autonomic nervous system (referred to in Part B, CNS [Central Nervous System] involvement,
The gastrointestinal system category in the Nijmegen supplemental materials lists five types of symptoms, chronic hepatic dysfunction, failure to thrive, pancreatic dysfunction, intestinal pseudo obstruction, and unexplained chronic diarrhea lasting longer than three weeks. Although Dr. Kendall testified that virtually any gastrointestinal problem from reflux to severe dysmotility (pseudo obstruction) would be symptomatic of a mitochondrial disorder (Tr. at 301), Dr. McCandless disagreed. He explained that the types of gastrointestinal problems seen in mitochondrial disorders are more serious than simple constipation, particularly constipation successfully treated with diet and which resolved over time. Tr. at 553-54. Based on A.H.T.'s records, none of her gastrointestinal problems appear to meet the Nijmegen criteria, supporting Dr. McCandless' testimony that A.H.T.'s gastrointestinal symptoms were not of the nature generally observed in children with mitochondrial disease or dysfunction with gastrointestinal involvement.
Gastrointestinal dysfunction is often a symptom of mitochondrial disease. However, the type and intensity of the dysfunction seen in patients with mitochondrial disease is different from the mild constipation or alternating constipation and diarrhea that A.H.T. experienced. Tr. at 569. The term "gut motility issues" can refer to "any problem with the sort of coordinated movement of the muscles in any part of the gut from the esophagus through to the anus." Tr. at 570. In contrast, "constipation" refers to problems at the end of the gut, with many possible causal factors ranging from an absence of nerve endings through dietary problems. Children with mitochondrial problems can have constipation, but by itself, constipation would not be a sign that points to a mitochondrial diagnosis. Tr. at 570-71. What is much more suggestive is a defect of motility in the small intestine or difficulty with stomach emptying. Tr. at 571.
Although there are numerous references in A.H.T.'s medical records to a history of constipation (or alternating constipation and diarrhea), her early problems were reported as "better" at her one year checkup, and there is little evidence that A.H.T. experienced continuing problems with constipation or diarrhea after about 2009. Between these periods, Ms. Holt provided historical information that A.H.T. had experienced both constipation and diarrhea on a regular basis, but there is no evidence of medical treatment for persistent diarrhea. Rather, diarrhea seemed to be either a symptom of a concurrent illness or was attributed by Ms. Holt to diet or one of the many medical interventions to which A.H.T. was subjected. There were some interventions for constipation and A.H.T. had an endoscopy and colonoscopy, but these procedures did not identify any significant problems. Other than a telephonic consultation with Dr. Buie about six months after the procedures, she did not continue to see a gastroenterologist.
By way of examples, at the January 2005 evaluation at the Weisskopf Center when A.H.T. was not quite three years of age, a history of "chronic" problems with alternating constipation and diarrhea was reported, but her bowel issues were said to have improved with institution of the GF/CF diet and use of a probiotic. Pet. Ex, 46, p. 2037. There were reports of constipation and diarrhea again when she began treatment with Dr. DeMio in the fall of 2005. See, e.g., Pet Ex. 23, pp. 236-37, 256-57, 267. An abdominal x-ray showed "moderate constipation," but no evidence of any bowel obstruction or loop distention. Pet. Ex. 42, p. 1834. Testing for parasites, occult blood, gliadin antibodies, and other possible causal agents for gastrointestinal problems were all negative. See, e.g., Pet. Exs. 24, pp. 377-79; 42, p. 1840. Doctor DeMio thought treatment with secretin and Gastrocrom helped. See, e.g., Pet. Ex. 23, p. 256.
At her initial visit with Dr. Kartzinel in June 2007, A.H.T. was reported to have chronic constipation as well as bloating, excessive gas, and crying and straining before bowel movements, and occasional incontinence. Pet. Ex. 24, pp. 464, 467. An abdominal x-ray showed evidence of mild to moderate constipation. Id., p. 401. She was prescribed Creon for constipation at some point (see id., pp. 454, 456), but it is unclear how long she took it, as at a February 2008 visit to Dr. Hefner, it was not listed as one of her medications (Pet. Ex. 52, p. 2216).
By 2009, however, there were few, if any, contemporaneous reports of constipation and diarrhea, chronic or otherwise. Doctor Puri noted she had "normal bowel and bladder function" at an annual visit in August 2009. Pet. Ex. 31, p. 1243. The initial correspondence from Ms. Holt to Dr. Levinson did not list any current medications for constipation or diarrhea, but problems with constipation and hard stools were mentioned. Pet. Ex. 47, p. 2055. Doctor Levinson's other records do not include any significant complaints regarding bowel function.
At a June 2011 visit to Dr. Puri's practice, A.H.T.'s gastrointestinal function was reported as normal, although her history of frequent urinary tract infections was noted. Pet. Ex. 31, p. 1240. A similar report was given in September 2011. Id., p. 1233.
At the time of her August 11 visit to Dr. Shoffner, A.H.T. was taking Colace, a stool softener, indicating that some mild constipation might still be a problem. Pet. Ex. 61, p. 2343. However, her diet may have contributed to the need for a stool softener, as she was reported to refuse vegetables and was resistant to drinking water or other fluids. Id. As Dr. Wiznitzer noted, both diet and temperament issues can affect constipation. Tr. at 659.
The most recent record filed (Dr. DeMio's letter and consultation notes from August 2012) reflected that A.H.T. suffered from gastrointestinal infections, but the records did not list constipation or diarrhea as symptoms. Pet. Ex. 87.
Doctor Kendall testified that A.H.T. had a history of temperature instability, which could be reflective of dysautonomia. Tr. at 308. Dysautonomia is considered a malfunction of the autonomic nervous system. DORLAND'S at 575. She described dysautonomia as "having one's thermostat broken." Tr. at 309-10. She testified that there was evidence in the records that A.H.T. had fevers of unknown origin, which she defined as fevers not associated with intercurrent illnesses, but she could not point to any particular record in which such fevers were reported. Tr. at 309.
Doctor Wiznitzer testified that his review of the medical records did not support the assertion that A.H.T. had recurrent fevers, absent those fevers connected to an intercurrent illness. Tr. at 632. My review of the medical record is in accord with Dr. Wiznitzer's.
The first reference to a fever in A.H.T.'s records is a temperature of 101.9° during a bout with otitis media when she was 15 months old. Pet. Ex. 52, p. 2231. In her initial developmental examination at Carriage House in January 2004, Ms. Holt reported that A.H.T. "was hardly ever sick," except with bowel problems. Pet. Ex. 39, p. 1825. At her evaluation by the Weisskopf Center in January 2005, her parents reported "occasional" upper respiratory infections. Pet. Ex. 46, p. 2037. Records from ST reported occasional respiratory infections in January 2005 (Pet. Ex. 18, pp. 200-01), followed by a bilateral ear infection in February 2005 (Pet. Ex. 52, pp. 2224), and MRI evidence of "sinus disease" in March 2005 (Pet. Ex. 31, p. 1273). No fevers were reported in conjunction with these illnesses.
The next report of fever is in a telephonic consultation with Dr. DeMio in November 2005, after A.H.T. began chelation therapy. Pet. Ex. 23, p. 237. In February 2006, Dr. Puri noted a history of "no fever, chills, weight fluctuation." Pet. Ex. 31, p. 1254. Doctor DeMio noted two episodes of vomiting in February 2006, one of which was accompanied by fever. Pet. Ex. 23, p. 241. He also recorded a report of a "low grade fever" in late May 2006 in conjunction with diarrhea, irritability, and a change in medication. Id., pp. 245-46. In July 2006, A.H.T. had a cough and there was a report of fever, but the temperature recorded (36° Celsius) is not febrile. Id., p. 249.
There are several reports of illnesses in 2007 without any fever. See, e.g., Pet. Ex. 23, p. 266; Pet. Ex. 52, pp. 2213 (sinus infection with no fever); 2217 (respiratory infection without fever).
In the initial history provided for Dr. Kartzinel in June 2007, the first reports of "recurrent fever" and "periodic recurrent infection" appear, but no details were provided. Pet. Ex. 24, p. 465. These reports do not appear substantiated by the foregoing medical records. Although Ms. Holt was supposed to track fevers for Dr. Kartzinel (see id, p. 467), there is no evidence she did so. Most of the entries concerning fever in the rest of Dr. Kartzinel's records document the lack of fever, rather than the presence of one (see, e.g., id., pp. 372, 454-56); see also Pet. Ex. 52, p. 2216 (no fever in presence of urinary tract infection in 2008).
A.H.T.'s parents reported to Dr. Jones, a clinical psychologist, in February 2009 a history of frequent high fevers as a baby and toddler, another report not borne out by the primary care or other records. From 2002 through 2005, there are only two medical references to the presence of a fever, and none reflecting a high fever.
In March 2010, at eight years of age, A.H.T. experienced a febrile illness with a high fever, reportedly peaking at 105.2°. The highest temperature recorded by medical personnel at the emergency room was 103.6°. A.H.T.'s temperature declined to normal several hours after her arrival and the administration of Motrin and Tylenol. Pet. Exs. 37, pp. 1333-36 (emergency room records reflecting temperatures, a urinary tract infection, cough and congestion, and "stomach flu") and 52, p. 2212 (Dr. Hefner's records from four days later diagnosing a viral syndrome).
Although there are later reports of "recurrent fevers since infancy" (see Pet. Ex. 31, p. 1240 (in June 2011)) and recurrent fevers of 105+ (see Pet. Ex. 47, p. 2055 (in May 2010)), these histories appear to suffer from the same lack of support as the initial report to Dr. Katzinel in 2007.
The Supplemental Materials, Part A, reflect that mitochondrial disease can manifest with muscular signs and symptoms. Exercise intolerance, one of the muscular symptoms listed, was discussed above. Most of the other listed signs and symptoms are clearly inapplicable to A.H.T. Although 1 point may be assigned for reduced muscle power, the specified manifestations do not apply to A.H.T. Reduced muscle power is defined as "Gowers sign or absent or bad head control or delayed motor milestones . . . or muscular hypotonia."
Doctor Shoffner did not assign any points on the diagnostic score sheet for hypotonia, but he commented on A.H.T.'s "generalized hypotonia" in his diagnostic reports.
The medical and treatment records are in conflict regarding whether A.H.T. had hypotonia. Additionally, there is a dispute concerning the nature of any hypotonia or muscle weakness she may have displayed, with Dr. Kendall testifying that hypotonia in general would constitute a symptom of a mitochondrial disorder and Dr. Wiznitzer and Dr. McCandless opining that the descriptions of A.H.T.'s therapists suggested that she had centralized or brain-based hypotonia, not the muscle weakness seen in mitochondrial disorders. Tr. at 303, 310, 344 (Dr. Kendall), 455, 538-41 (Dr. McCandless), and 582, 585-87 (Dr. Wiznitzer); see also Supplemental Materials, Part A (reference to "muscular" hypotonia).
Children with mitochondrial encephalopathies presenting in the neonatal period are profoundly hypotonic; Dr. McCandless described them as "very, very floppy." Tr. at 455. None of A.H.T.'s early pediatric records reflect any concern about her tone. According to Dr. Wiznitzer, her gross motor development was normal and there were no references to problems with truncal or extremity tone in her pediatric records. Tr. at 645. She reached motor milestones at appropriate times, according to her pediatric records. See generally Pet. Exs. 52, 58; see also Tr. at 645 (testimony that the medical records documented good head control and normal achievement of motor milestones). Doctor Shoffner recorded milestone achievements (other than language acquisition) at times consistent with the early pediatric records. Pet. Ex. 61, pp. 2342-43. As Dr. McCandless testified, primary care physicians are often the first to note generalized hypotonia, and even inexperienced parents or grandparents may report that the infant does not feel "right" when an infant is hypotonic. Tr. at 586. No such reports were made by A.H.T.'s caregivers or parents. Doctors McCandless and Wiznitzer noted that both her medical records during the first year of her life and her parents' descriptions of how A.H.T. appeared in infancy were not consistent with hypotonia. Tr. at 611-12, 644-49. Doctor McCandless commented that in A.H.T.'s first year, her back arching would be evidence of increased tone, not low tone. Tr. at 540.
Slightly diminished muscle tone was first noted by an occupational therapist in May 2004. Pet. Ex. 55, p. 2256. However, neither of the first two neurologists she saw that year commented on any reduced tone. Although he did not comment specifically on A.H.T.'s tone, Dr. McKiernan found normal, symmetric reflexes (Pet. Ex. 40, p. 1830) and Dr. Puri found normal muscle strength (Pet. Ex. 31, p. 1264.). However, in between these two neurology visits, decreased truncal and upper extremity tone were noted at another occupational therapy assessment. Pet. Ex. 28, p. 1090. The developmental pediatrician at the Weisskopf Center recorded low muscle tone, but it was not clear whether this represented her own observation or was simply part of a summary of the evaluation team's findings. Pet. Ex. 46, pp. 2037-38.
Therapists targeted fine and gross motor skills and motor planning over the next several years. See, e.g., records from the Weisskopf Center, Pet. Ex. 46, pp. 2047 (noting the OT therapy planned), 2038 (noting fine motor and adaptive skill deficits and decreased muscle tone). However, Dr. Puri and his associates continued to find normal muscle tone, strength and bulk (Pet. Ex. 31, p. 1261); no focal motor weakness but some mildly decreased coordination (id., p. 1258); normal muscle strength, bulk and tone and normal reflexes (id., pp. 1252, 1255); normal bulk, strength and tone, with reflexes slightly brisk (id., p. 1249). Based on the varying order in which these neuromuscular findings are listed in Dr. Puri's records, it does not appear that they were part of a pre-configured form or document, and are thus more likely to represent actual observations by pediatric neurologists observing A.H.T. over time.
A physical therapy evaluation in March 2007 showed that A.H.T., who was then about five years old, was functioning about six months to a year below the typical five year old. Pet. Ex. 37, p. 1495. A PT assessment a few months later listed diagnoses of hypotonia, lack of coordination, motor coordination disorder, muscle weakness, and pronated feet. The evaluator noted that her muscle tone was "slightly low," affecting her posture. She had functional strength in her arms, but slightly decreased strength in her abdominal muscles. She also had decreased motor planning skills and bilateral coordination difficulties. Pet. Ex. 33, p. 1282. Five months later (in February 2008), she was discharged from physical therapy because she scored in the 25th to 50th percentiles on the Peabody motor scales. Her muscle tone remained slightly low, but she had increased her strength in shoulders, arms, and core. Id., p. 1286. In October 2008, Dr. Murray noted that A.H.T. had made great strides in improving her fine and gross motor abilities. Pet. Ex. 16, p. 142.
In September 2009, A.H.T. was re-evaluated for PT services. Her mother reported that she had been discharged from PT in the spring of 2008 "because she could not focus enough to make progress" (Pet. Ex. 37, p. 1356), a report different from the reason reported by the therapist at the time of discharge (Pet. Ex. 33, p. 1286). At the re-evaluation, she was found to have good motor planning, but "mildly low" muscle tone throughout her trunk and lower extremities. Pet. Ex. 37, p. 1357. She continued to receive PT services until February 2010, when she was discharged as having reached her maximal level, although there was still some weakness in core muscles. The therapist noted that Ms. Holt remained concerned about A.H.T.'s endurance and coordination. However, she could perform 30 minutes of aerobic activity, and the therapist suggested she should participate in extracurricular activities involving physical movement. Id., pp. 1362-63.
Thereafter, records from various therapists continued to reflect low muscle tone or mild hypotonia. See, e.g., Pet. Ex. 28, p. 1080. However, through August and November 2011, her neurologist continued to find her tone and strength normal. Pet. Ex. 31, pp. 1234, 1238.
The conflict between therapists and neurologists with regard to hypotonia can be resolved best by Dr. Wiznitzer's explanation of the difference between brain-based hypotonia and muscle-based hypotonia. He testified that A.H.T. has a developmental coordination disorder, a condition often associated with mild hypotonia that is brain-based, not muscle-based. Children with brain-based hypotonia have normal strength and intact reflexes (which A.H.T. demonstrated on physical examination by Dr. Puri and his associates). A child with a primary muscle disorder will have a correlation between strength and tone — the weaker the strength level, the lower the tone. Central, or brain-based, hypotonia is not correlated with mitochondrial disorders, as it has nothing to do with energy load or energy reserves. Tr. at 645-49.
This "brain based" hypotonia appears consistent with the first description of hypotonia by a physician. In early 2005, Dr. Williams, the developmental pediatrician at the Weiskopff Center, diagnosed A.H.T. with "central nervous system dysfunction" as manifested by her toe-walking and decreased tone. Pet. Ex. 46, p. 2038.
In summary, Dr. Shoffner relied upon parental reports for many of the clinical criteria in diagnosing A.H.T. with a probable mitochondrial disorder. That reliance was misplaced, as the medical records do not support many of the conditions Dr. Shoffner recorded as existing. Doctor McCandless pointed out why he came to different conclusions regarding A.H.T.'s clinical symptoms: an expert reviewing records in preparation for an expert report and testimony has the luxury of devoting considerable time to a comprehensive review that a busy clinician would not have. Tr. at 545-46. My own review of the records comports with the testimony of Drs. Wiznitzer and McCandless in most respects.
Doctor Kendall opined that A.H.T. had symptoms consistent with a mitochondrial disorder and agreed with Dr. Shoffner's diagnosis. Doctor DeMio also agreed with the mitochondrial disorder diagnosis. Tr. at 217.
Referring to the chart in her report (Pet. Ex. 79 at 2500), Dr. Kendall testified that A.H.T. had evidence of central nervous system involvement in her developmental delays and autistic features (Tr. at 307), evidence of peripheral nerve involvement in her dysautonomia as manifested by temperature instability (Tr. at 308-09); evidence of muscle system involvement in her history of hypotonia, constipation, and possibly in oculomotor dysfunction (Tr. at 310-12); and systemic involvement based on her fatigue (Tr. at 312-13). She testified that these symptoms could be seen in mitochondrial dysfunction. Tr. at 330. However, A.H.T.'s medical records did not provide supportive evidence that she actually had many of the symptoms relied upon, or that she experienced symptoms of the requisite degree.
Separate from the problems in the scoring system discussed above and from Dr. Kendall's list of mitochondrial disorder symptoms A.H.T. purportedly displayed, respondent's experts had a more basic and fundamental disagreement with Dr. Shoffner's diagnostic conclusions and the opinions of Drs. Kendall and DeMio. They opined that A.H.T. simply did not fit the picture of a child with a mitochondrial disorder, based on her presentation in the neonatal period, her pattern of meeting motor and other milestones in infancy, and the specific developmental delays and behavior problems she displayed in the remainder of her childhood.
Doctor McCandless provided numerous reasons to conclude that A.H.T. did not have a primary mitochondrial disorder and that A.H.T.'s clinical presentation was unrelated to any mitochondrial dysfunction. Tr. at 423. Doctor Wiznitzer supported Dr. McCandless' observations and opinions. In addition, he cogently explained why Dr. DeMio's brain inflammation theory did not fit the facts.
Although Dr. Kendall opined that A.H.T. had a mitochondrial disorder which was aggravated by her hepatitis B vaccination to produce an "encephalopathic picture" (Tr. at 335), she never precisely stated in testimony or her report that A.H.T. had a "mitochondrial encephalopathy." Nevertheless, that was the clear import of her testimony that A.H.T.'s underlying mitochondrial disorder was aggravated by the hepatitis B vaccination, producing encephalopathic symptoms beginning shortly after the vaccination was administered. Both of respondent's experts opined that A.H.T. did not have a mitochondrial encephalopathy.
In describing his own experiences with patients who presented in early infancy with significant mitochondrial dysfunction and disease, Dr. McCandless testified that every baby he had treated "was critically ill," hospitalized in intensive care, and often on life support. Tr. at 443-44. He stated that a "baby who's encephalopathic from mitochondrial dysfunction at day five of life" would be unlikely to survive at home. Tr. at 453-54, 455-56. Doctor Wiznitzer presented very similar testimony. Tr. at 682-84.
In Dr. McCandless' experience, a neonatal or early presentation of mitochondrial disease leads to a progressive deterioration, with a "universally bad" outcome. Tr. at 445. In a case of neonatal onset, a child would be unlikely to have a period of normalcy for five days and then "crash and burn." If A.H.T. had experienced a mitochondrial encephalopathy, he would expect her to have "profound hypotonia," with extremely floppy muscles. Tr. at 455.
Even based on the symptoms described by her parents, A.H.T.'s condition did not approach the severity described by Dr. McCandless. Doctor Kendall never described what she would expect to find in a neonate presenting with the first symptoms of an underlying mitochondrial disorder; it was one of the many questions about typical presentations that she dodged. Tr. at 348-49.
A child who experienced an encephalopathy within a week of birth would not present as normal to a pediatrician a week or two later and at subsequent visits. A.H.T. would have demonstrated a change in mental status, diminished oral intake, and significant hypotonia, and her irritability would have been noted by the physician during well-child visits. Instead, A.H.T.'s records, both from Dr. Buttleman and Dr. Hefner, indicate that she was alert and behaving normally for her age. Tr. at 636-37. Had there been an insult to the brain in the neonatal period sufficient to produce developmental delays a few years later, the records would have reflected some impairment in her development within a few months of the vaccination, with delays in motor development, adaptive skills, and early communication. Instead, the records reflected basically normal development during this period. Tr. at 637.
Brain damage, inflammatory or otherwise, sufficient to cause encephalopathic symptoms would be observable on neuroimaging. A.H.T.'s March 2005 MRI did not demonstrate an acute insult. At a minimum, atrophy would have been present, and evidence of scarring or abnormal signaling in the white matter and basal ganglia would likely be present. None of these problems were seen on this MRI. Tr. at 642-43. According to Dr. Wiznitzer, petitioner's theory of a systemic inflammatory response to the initial vaccination causing brain inflammation, followed by normal development, and then subsequent developmental delay, was biologically implausible. Tr. at 680-82. Doctor Kendall testified that a neonate with a primary mitochondrial disease could have a normal MRI (Tr. at 349). However, she did not say that this would be likely; did not specifically address whether a neonate with a mitochondrial encephalopathy could have a normal MRI; or whether it was likely that brain inflammation would be seen on an MRI.
Although one decompensation or regression in the presence of a febrile illness does not necessarily imply that a child with a mitochondrial disorder will have a similar experience with other illnesses, Dr. McCandless pointed out that A.H.T. apparently never again reacted to a fever or a febrile illness the way she purportedly did with the hepatitis B vaccination. He pointed to the lengthy gastrointestinal illness A.H.T. experienced in January 2003 (see Pet. Ex. 52, p. 2233). A.H.T., who had been at approximately the 25th percentile on the weight chart at about nine months of age (Pet. Ex. 58, p. 2314), dropped to the 5th percentile at one year of age (Pet. Ex. 52, p. 2232). This type of illness was, according to Dr. McCandless, the type most likely to cause a child with a mitochondrial disorder to decompensate. Tr. at 597. Yet, A.H.T. weathered this gastrointestinal illness and an ear infection with fever at 15 months of age (Pet. Ex. 52, p. 2231) with no apparent health or neurological impact.
Based on petitioner's claim that A.H.T. was encephalopathic shortly after the vaccination, both Drs. Wiznitzer and McCandless testified there would have been altered brain function and severe neurological changes to cause the encephalopathy. Tr. at 454, 683-84. It would be extremely unlikely for a neonate to thereafter have essentially normal development, meeting milestones in many areas and, in particular, in gross and fine motor skills. Doctor McCandless was aware of "no credible reports" of a period of normal development after a severe encephalopathy. Tr. at 454. As he explained, "the pattern and the arc of the clinical findings is, in my opinion, not consistent with a significant mitochondrial encephalopathy." Id.
The MRI performed when A.H.T. was three years old (Pet. Ex. 31, p. 1273) was normal, and thus belied the existence of the type of brain injury caused by either a mitochondrial encephalopathy or the brain inflammation Dr. DeMio insisted was present. In a "hit from mitochondrial disease to the brain," Dr. McCandless would expect to see atrophy on the brain on MRI later in life. Tr. at 455. Neither Drs. Kendall nor DeMio offered any testimony countering Dr. McCandless's expectation that an MRI would reveal such encephalopathic symptoms.
Moreover, A.H.T.'s clinical course from the days after the vaccination through the time of the hearing was not what would be expected in a child with a mitochondrial disorder. As Dr. McCandless noted, there was no indication in the medical records of any deterioration in neurological status, plateaus in development, or the loss of developmental milestones. Res. Ex. G at 2.
Developmental delay, which A.H.T. has, can certainly be a part of the mitochondrial disease picture, but many children have delayed development without having a mitochondrial disease. There are certain types of developmental delay that are more characteristic of children with mitochondrial disease, such as global developmental delay and hypotonia involving both gross and fine motor delay. Tr. at 582-83. A.H.T. did not have global developmental delay; she had very specific delays in speech and language, which might be seen in mitochondrial disease, but not typically. Tr. at 583. Doctor McCandless also opined that A.H.T.'s central nervous system abnormalities were not "the typical ones we see in patients with confirmed mitochondrial disease." Tr. at 536. Isolated speech delay is not "specific or even highly suggestive of mitochondrial disease." Tr. at 538. He also noted that isolated speech delay was not particularly indicative of mitochondrial disorders, although dysarthria, a defect in the way that muscles control speech, is much more common than a simple delay. Id.
The major problem respondent's experts expressed with finding that A.H.T. has a primary mitochondrial disorder is the presence or absence of the symptoms used in diagnosing such a disorder. Tr. at 569-71. Doctor McCandless found inadequate evidence of a mitochondrial disorder. He acknowledged that A.H.T. had evidence of mitochondrial dysfunction on the laboratory tests, but thought that the laboratory findings alone were not sufficient to conclude that they were responsible for her clinical symptoms. He indicated that they could be reflective of whatever neurological process caused her clinical symptoms rather than the cause of the symptoms. Tr. at 566-67; Res. Ex. G at 2. That is, the mitochondrial dysfunction found is not the cause of A.H.T.'s speech and behavioral problems, and may even result from them or the drugs used to treat them. Tr. at 565, 567-69.
Late in the hearing, petitioner's counsel appeared to disavow Dr. Kendall's testimony about A.H.T. experiencing an encephalopathic event after vaccination. He explained that petitioner was not relying on the theory that the vaccination caused an encephalopathy, but rather that A.H.T. "had an inflammatory antigenic response and now has identified mitochondrial dysfunction." Tr. at 679. In response to a colloquy with Dr. Wiznitzer, Mr. Downing clarified that this inflammatory response was a systemic inflammation, causing brain inflammation as well. Tr. at 680-82.
Doctor McCandless noted that inflammation was not a component of mitochondrial dysfunction (Tr. at 557-58), but Dr. Wiznitzer primarily addressed this theory, which appeared to be based on Dr. DeMio's testimony. 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. Tr. at 680-84.
Doctor Kendall testified that the efficacy of treatment for a mitochondrial disorder would support the diagnosis as being correct. Tr. at 328. Her testimony also suggested that lack of improvement might cause doubts about the validity of the diagnosis: "If they don't [improve] or worsen, then you're probably looking at something different or potentially at least." Id. She stopped short, however, of opining that A.H.T. experienced improvement with her mitochondrial treatment.
Doctors DeMio and Levinson attempted to fill that gap, opining that A.H.T.'s condition improved after institution of treatment. Tr. at 213-14 (Dr. DeMio); Pet. Ex. 59 at 2337 (noting that since he began treating A.H.T., he recorded "improvement in language, sensory issues, behavior and motor skills."). Neither pointed to any objective evidence of improvement. Moreover, A.H.T.'s parents also testified that she had improved since mitochondrial treatment had begun. Tr. at 47 (Ms. Holt) (remarking that as a result of treatment, "we have seen an incredible difference . . . . she is more engaged socially"); 117 (Mr. Tipton) (stating that after treatment for a mitochondrial disorder "[s]he's a new child. It helped.").
Doctor McCandless opined that a therapeutic response to mitochondrial disease therapy would not be evidence that the person treated had a mitochondrial disease.
He illustrated his testimony by showing where coenzyme Q10 is involved in the ETC function, thus explaining why it would be unlikely to help in a Complex I or III defect. Tr. at 466. He also noted that A.H.T. had no evidence of a coenzyme Q10 deficiency. Tr. at 490.
Some people with mitochondrial disease have low carnitine, and treatment with carnitine supplements is prescribed. Tr. at 469. However, A.H.T. had no objective evidence of a carnitine deficiency. Tr. at 490 (Dr. McCandless reviewing laboratory reports and testifying that A.H.T.'s carnitine level was "completely normal").
The therapy records provide evidence of A.H.T.'s condition before and after the mitochondrial disease treatment prescribed by Dr. Shoffner was initiated in mid-August, 2011.
A.H.T.'s behavior (including her sleeping patterns) were out of control at the time she began receiving behavior support therapy in December 2010, after nearly two months of observation and analysis of her behavior and interactions with parents and others. Pet. Ex. 38, pp. 1709-13 (summary, background information, and intervention plan). A.H.T., who was then eight years old, was presenting what were termed "challenging behaviors," including tantrums, escaping from caregivers when outside the home (termed "elopement" by the behavioral analysts), and both physical and verbal aggression. Id., p. 1750
These terms, however, do not adequately capture the nature of A.H.T.'s behavior. She ordered adults to be quiet and to leave, called them names, and talked about urination, defecation, and vomiting multiple times daily. See, e.g., Pet. Ex. 38, pp. 1691, 1751, 1764, 1799. She interrupted adult conversations frequently. See, e.g., Pet. Exs. 7, p. 57; 38, p. 1691. She threw coins, toys, towels, glassware, bicycles, and furniture during tantrums. See, e.g., Pet. Exs. 27, p. 585; 38, pp. 1765, 1792. She hit adults and other children. See, e.g., Pet. Exs. 38, pp. 1754-55; 57, p. 2293. She hit and kicked the family dogs, as well as hitting them with towels, pillows, and stuffed animals, and grabbed the dogs' genitals. See, e.g., Pet. Ex. 38, pp. 1751, 1778, 1793.
A.H.T. presented behavior problems in other therapy sessions as well as at home, prior to initiating mitochondrial disease treatment.
A.H.T.'s behavior improved while receiving behavioral support services, particularly after her parents began more consistent compliance with the program's methodology,
A.H.T. also received ST services before and after beginning mitochondrial therapy, but there are only a few filed ST records from periods after the mitochondrial therapy began. Pet. Ex. 27, pp. 607, 614 (ST records from late August and early September 2011). Nevertheless, earlier ST records show progress in speech and both good and bad days in terms of behavior during therapy. See, e.g., id., pp. 588-89, 607-11, 614, 616. More than a year after beginning mitochondrial therapy, Dr. DeMio's records reflect speech and behavior issues that were very similar to those she displayed before the mitochondrial therapy was initiated.
On August 17, 2011, a week after A.H.T.'s diagnosis, Dr. Levinson recorded that A.H.T. was sleeping better, her speech was easier and more age-appropriate, and she had improved "processing speed and fluency" according to Ms. Holt, but she was cranky and dystonic. Pet. Ex. 47, pp. 2056-57. At this telephone consultation,
The record from the next consultation with Dr. Levinson, held on October 26, 2011, began with a report by her parents that A.H.T.'s language was "phenomenal" with an improvement in expressive language with more age-appropriate speech, but only limited improvement in receptive language. Pet. Ex. 47, p. 2058. Her behavior was "[m]ore compliant and appropriate," she was "dealing with structure better," was limited in aggression toward animals and only rarely was aggressive toward Ms. Holt. Her tactile defensiveness regarding clothing was notably decreased. She continued to have problems with lying and impulsivity, but both were reduced. Id. By report, her handwriting, a fine motor skill, continued to improve, and a notation reflected that A.H.T. was swimming and hiking. Id. Additionally, the speech therapy records also reflected an improvement, but not one described as "phenomenal." Pet. Ex. 27, p. 614.
A.H.T. was seen by psychotherapist Heather Bass for three sessions in November and December 2011 for complaints of anxiety related to a motor vehicle accident. Her parents reported that the anxiety was overwhelming and disruptive to her functioning. They were seeking help for her "aggressive and out of control behaviors" at home and with the behaviorist. Doctor (Psy.D.) Bass described her as friendly, cooperative and playful in their first two sessions, but A.H.T. presented as socially and emotionally delayed. She had difficulty maintaining a mutual conversation. A.H.T.'s anxiety appeared to focus on medical procedures after the accident, but she refused to discuss any details. During the third session, she was slightly agitated, and became distressed, more agitated, and uncooperative after the session ended. She refused to leave the office with her babysitter and demanded that her mother come and pick her up. Pet. Ex. 44, p. 1878.
The behavioral support records are the most compelling evidence of the lack of therapeutic effects of the mitochondrial therapy as they involved a systematic comparison of the frequency of problem behaviors before and after the treatment began. Without complete speech therapy records (only two were filed after beginning mitochondrial therapy), it is difficult to find objective evidence of improvement in her language ability. Moreover, even if the records demonstrated improvement, I note that A.H.T. continued to make progress in language while in speech therapy prior to beginning mitochondrial therapy. The records available show she was meeting goals set during therapy before August 2011.
There is no reliable evidence that A.H.T. had problems with temperature regulation or that she experienced high fevers not associated with an illness. She was seen by a health care provider for only one fever of 105° and that fever was associated with an illness. The records from this emergency room visit in 2010 do not reflect that such fevers were common, had occurred in the past, or had occurred without an accompanying illness. The histories in records of recurrent high fevers were not supported by any records of treatment for such fevers or attempts to acertain a cause for recurrent high fevers, and contradicted histories provided earlier.
It is unlikely that A.H.T. experienced frequent respiratory infections as an infant, toddler, or older child. Her parents reported that she was generally healthy as an infant when she was first evaluated for developmental delays, and her medical records support that she was not often ill as an infant. The extensive therapy and medical records do not reflect missed therapy sessions due to illnesses and show only occasional upper respiratory illness visits. The behavioral analysts visited A.H.T. regularly at home for more than a year, and their records do not reflect any recurrent or frequent illnesses of any type.
A.H.T. did not have generalized hypotonia. Reports of low tone or hypotonia appear in some therapy records, but no neurologist ever diagnosed generalized hypotonia or low muscle tone. She did have some mild brain-based hypotonia, but not the muscle-based form seen in mitochondrial disease. She was not a floppy baby. She had normal strength and reflexes on nearly every examination performed. No concerns about her motor development were expressed by anyone until A.H.T. was evaluated by therapists in May-June 2004.
There is no reliable evidence that A.H.T. had exercise intolerance or fatigue that interfered with activities of daily living. Prior to her diagnosis by Dr. Shoffner, A.H.T. was assessed by a pediatric cardiologist who found no history of exercise intolerance. According to her therapists, she could perform 30 minutes of aerobic exercise. Her failures to perform tasks in therapy or chores or schoolwork at home were behavioral in nature, not grounded in muscle weakness or excessive fatigue.
There is no evidence that A.H.T. ever experienced an autistic regression and no reliable evidence that she lost skills of any type that she had once displayed.
A.H.T.'s trajectory in the areas of developmental delay (motor skills and speech) does not appear to have been altered by her mitochondrial disease treatment. Her behavioral problems were not affected by that treatment.
The gastrointestinal problems A.H.T. displayed were not those typically seen in children with mitochondrial disorders. There is no evidence that she had diarrhea persisting longer than three weeks at a time. She was never diagnosed with or even evaluated for pseudo obstruction. There were frequent reports of constipation and some of diarrhea during the time frame when A.H.T. was being treated by Dr. DeMio, but it is difficult to determine whether either or both gastrointestinal conditions were adversely affected by the many treatments prescribed. By about nine years of age, A.H.T. appeared to have normal gastrointestinal function, as she was no longer taking medications targeting either constipation or diarrhea and reports to her neurologist reflected normal bowel function.
A.H.T. had developmental delay in specific areas of development, primarily in speech, fine motor skills, and visual motor coordination. She was not globally delayed. She has normal or near normal intelligence.
A.H.T.'s resting metabolic rate of 76% was below the reference range of 85-115% of the expected norm. Doctor Shoffner properly assigned points on the Nijmegen scale for this result. However, two alternate explanations for A.H.T.'s lower rate were present: A.H.T. was underweight and she had a relatively sedentary lifestyle.
A.H.T. did not experience an encephalopathy after her hepatitis B vaccination. Although there is some conflicting evidence, specifically Dr. Kendall's opinion, her opinion was not strong and was based on some symptoms (fever, lethargy, and extended somnolence) for which there is no reliable evidence. Even Dr. Kendall acknowledged that the irritability she relied upon could have been caused by the colic diagnosed by A.H.T.'s treating physicians. A.H.T. did not have the neurological and developmental sequelae that would be expected after an encephalopathic event capable of leading to developmental delays and behavioral problems months later.
Although A.H.T. likely experienced some immunological and possibly inflammatory response to her initial hepatitis B vaccination, it is highly unlikely that this response included brain inflammation. The evidence that she did so rests primarily on Dr. DeMio's opinion,
Doctor McCandless' questioned Dr. Shoffner's conclusion that A.H.T. had exercise intolerance. Based on the assessment by A.H.T.'s therapist that she was capable of performing 30 minutes of aerobic exercise, and her pediatric cardiologist that she had no history of exercise intolerance, and the lack of any objective evidence that she could not perform activities of daily living due to fatigue, I conclude that the 1 point assigned on both the August 1 and August 10 score sheets should be subtracted.
Additionally, there was inadequate evidence of the involvement of a second organ system in A.H.T.'s clinical presentation meeting the requirements specified in the Supplemental Materials for the Nijmegen criteria. A.H.T.'s gastrointestinal symptoms and neuromuscular problems did not fit these requirements. Thus, I find that the August 1 assessment of a possible, rather than a probable, mitochondrial disorder best fits the facts of A.H.T.'s condition.
When a petitioner alleges an off-Table injury, eligibility for compensation is established when, by a preponderance of the evidence, petitioner demonstrates that she received, in the United States, a vaccine set forth on the Vaccine Injury Table ["Table"] and sustained an illness, disability, injury, or condition caused by the vaccine or experienced a significant aggravation of a preexisting condition. She must also demonstrate that the condition has persisted for more than six months. Vaccine Act litigation rarely concerns whether the vaccine appears on the Table, the situs for administration, or whether the symptoms have persisted for the requisite time. In most Vaccine Act litigation, the issue to be resolved by the special master is whether the injury alleged was caused by the vaccine.
To establish legal cause in an off-Table case, Vaccine Act, a petitioner must establish each of the three Althen factors by preponderant evidence: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a proximate temporal relationship between vaccination and injury. Althen v. Sec'y, HHS, 418 F.3d 1274, 1278 (Fed. Cir. 2005); see de Bazan v. Sec'y, HHS, 539 F.3d 1347, 1351-52 (Fed. Cir. 2008); Caves, 100 Fed. Cl. at 132 (specifying that each Althen factor must be established by preponderant evidence), aff. per curiam, 463 Fed. Appx. 932, 2012 WL 858402 (Fed. Cir. 2012). The applicable level of proof is the "traditional tort standard of `preponderant evidence.'" Moberly v. Sec'y, HHS, 592 F.3d 1315, 1322 (Fed. Cir. 2010) (citing de Bazan, 539 F.3d at 1351; Pafford v. Sec'y, HHS, 451 F.3d 1352, 1355 (Fed. Cir. 2006); Capizzano v. Sec'y, HHS, 440 F.3d 1317, 1320 (Fed. Cir. 2006); Althen, 418 F.3d at 1278). The preponderance standard "requires the trier of fact to believe that the existence of a fact is more probable than its nonexistence." In re Winship, 397 U.S. 358, 371 (1970) (Harlan, J., concurring) (internal quotation and citation omitted).
Another formulation of the causation requirement in off-Table cases is the "Can it cause?" and "Did it cause?" inquiries used in toxic tort litigation. These queries are also referred to as issues of general and specific causation. Prong 1 of Althen has been characterized as an alternative formulation of the "Can it cause?" or general causation query. Prong 2 of Althen, the requirement for a logical sequence of cause and effect between the vaccine and the injury, has been characterized as addressing the "Did it cause?" or specific causation query. See Pafford v. Sec'y, HHS, No. 01-165V, 2004 WL 1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004), aff'd, 64 Fed. Cl. 19 (2005), aff'd, 451 F.3d 1352. The third Althen factor is subsumed into the other inquiries. Even if a particular vaccine has been causally associated with an injury, petitioner must still establish facts and circumstances that make it more likely than not that this vaccine caused his particular injury. Timing may be one of those circumstances.
Whether a case is analyzed under Althen or the "Can it cause?" formulation, petitioners are not required to establish identification and proof of specific biological mechanisms, as "the purpose of the Vaccine Act's preponderance standard is to allow the finding of causation in a field bereft of complete and direct proof of how vaccines affect the human body." Althen, 418 F.3d at 1280. The petitioner need not show that the vaccination was the sole cause, or even the predominant cause, of the injury or condition; showing that the vaccination was a "substantial factor" in causing the condition and was a "but for" cause are sufficient for recovery. Shyface, 165 F.3d at 1352; see also Pafford, 451 F.3d at 1355 (petitioner must establish that a vaccination was a substantial factor and that harm would not have occurred in the absence of vaccination). Petitioners cannot be required to show "epidemiologic studies, rechallenge, the presence of pathological markers or genetic disposition, or general acceptance in the scientific or medical communities to establish a logical sequence of cause and effect." Capizzano, 440 F.3d at 1325. Causation is determined on a case by case basis, with "no hard and fast per se scientific or medical rules." Knudsen v. Sec'y, HHS, 35 F.3d 543, 548 (Fed. Cir. 1994). Close calls regarding causation must be resolved in favor of the petitioner. Althen, 418 F.3d at 1280; but see Knudsen, 35 F.3d at 550 (when evidence is in equipoise, the party with the burden of proof fails to meet that burden).
By specifying petitioners' burden of proof in off-Table cases as a preponderance of the evidence, directing special masters to consider the evidence as a whole, and stating that special masters are not bound by any "diagnosis, conclusion, judgment, test result, report, or summary" contained in the record (§ 13(b)(1)), Congress contemplated that special masters would weigh and evaluate opposing expert opinions in determining whether petitioners have met their burden of proof.
In summary, special masters decide questions of credibility, plausibility, probability, and reliability, and ultimately determine to which side the balance of the evidence is tipped. See Pafford, 451 F.3d at 1359. Bearing all these legal standards in mind, I analyze the evidence against the standards established.
In essence, petitioner has attempted to make this case into the Poling case. In her post-hearing brief at n.1, she commented on the similarities between A.H.T. and the Poling child, claiming that A.H.T.'s post-vaccination history is "surprisingly similar" to that of the Poling case. There are more differences than similarities.
Petitioner's causation claim was sometimes based on the theory supplied by the Shoffner paper and sometimes on a theory unsupported by anything other than Dr. DeMio's opinion on brain inflammation and brain damage. Doctor McCandless thought the theory discussed in the Shoffner paper (and, to some extent, the Morgan paper, Res. Ex. I) merited additional study, but he was clear that 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.
Even if I found the theory to be reliable rather than speculative, it would not help petitioner in this case. In spite of herculean efforts to make A.H.T.'s presentation look like that of the Poling child, the facts are such that, as Dr. Wiznitzer remarked, "[i]t doesn't fit." Tr. at 637. 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. Poling, Pet. Ex. 69, at 3; see Pet. Ex. 79 at 2497. 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. Tr. at 565-69; Res. Ex. G at 2.
Moreover, Dr. Kendall's theory appears to rely heavily, if not exclusively, on the presence of a fever, and Dr. DeMio's theory on fever as evidence of a systemic inflammatory event. I have carefully considered all of the evidence in reaching the conclusion that A.H.T. did not have a fever after her initial hepatitis B vaccination. Thus the predicate fact upon which the theories are based is not present. This lack of a logical connection between the theories and the facts is essentially insurmountable.
Timing is problematic as well. 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 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.
In discussing the scientific and medical issues in this case, I have occasionally referenced the OAP test cases. I have also done so in commenting on Dr. Levinson's "oxidative stress" theory. By joining the OAP, the evidentiary record in this case encompasses the OAP evidence. Even were I to disregard all the OAP evidence on oxidative stress, I would come to the same conclusions regarding his 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. Doctor Kendall's theory is speculative and supported by little more than her ipse dixit. To the extent there is any support for the proposition that vaccines and fever can trigger a mitochondrial disease or cause mitochondrial dysfunction, the facts of this case do not fit her theory. There was no fever, and many of the other symptoms she attributed to a mitochondrial disorder were not present. A.H.T.'s mitochondrial disorder diagnosis was much less definitive than she presented it to be. She did not persuasively connect the laboratory evidence of mitochondrial dysfunction discovered years after the vaccinations were administered to the symptoms A.H.T. displayed post-vaccination or the behavioral symptoms that manifested with speech delay many months later. Doctor DeMio's theory has even less support. There is no evidence that A.H.T. had brain inflammation, much less that it could produce the symptoms he attributed to such inflammation, and in the manner in which they actually presented.
A.H.T.'s problems are profound, and will no doubt continue to affect her life and the lives of her parents. I have nothing but sympathy for their experiences, but I cannot decide this or any other case based on sentiment. Unfortunately, this case does not present the "close call" in which the balance of the evidence might be tipped toward petitioner.
Petitioner has failed to produce preponderant evidence that the hepatitis B vaccinations A.H.T. received can or did cause or significantly aggravate the conditions from which she suffers. Accordingly, the petition for compensation is DENIED. The clerk is directed to enter judgment accordingly.
Autism General Order #1, 2002 WL 31696785 (Fed. Cl. Spec. Mstr. July 3, 2002), Exhibit A, Master Autism Petition for Vaccine Compensation at 2. In filing a short-form petition, petitioner joined the Omnibus Autism Program ["OAP"]. A more detailed discussion of the OAP and the effects of joining it can be found in the OAP test case decisions. See, e.g., Dwyer v. Sec'y, HHS, No. 03-1202V, 2010 WL 892250, at *3 (Fed. Cl. Spec. Mstr. Mar. 12, 2010).
Id., pp. 144-45 (emphasis original).
In a Program where Daubert is not used to exclude evidence or experts, causation of rare conditions is often alleged, and there is little evidence on general and specific causation other than opinions. Special masters often discuss the evidence filed and relied upon by a party as a part of their statutory mandate to consider the record as a whole. They may accept less definitive epidemiology as some support for a causation opinion, but rarely does a special master rely upon epidemiology alone. Evidence from small studies may be the only evidence available to support or undercut an opinion on causation. When there is no support for a causation theory other than the expert's own ipse dixit, a judge in another court may refuse to admit the testimony (Joiner, 522 U.S. at 146) (citing Daubert, 509 U.S. at 589), but a special master is not similarly constrained by the federal rules of evidence. In the OAP test cases, the special masters heard evidence from the petitioners on theories that other state and federal courts refused to admit, based on Daubert and Frye v. United States, 293 F. 1013 (D.C. Cir. 1923). See Blackwell v. Wyeth, 971 A.2d 235 (2009); Doe v. Ortho-Clinical Diagnostics, Inc. 440 F.Supp.2d 465 (M.D. N.C. 2006); Redfoot v. B.F. Ascher & Co., No. C 05-2045 PJH, 2007 WL 1593239 (N.D. Cal. June 1, 2007).
I emphasize that I am not requiring epidemiological evidence in this (or any other) case, but I must consider the epidemiological evidence the parties filed as part of the statutory requirement to consider the evidence as a whole. When two well-qualified experts testify contradictory to one another on vaccine causation, support (or lack thereof) in the scientific literature is one factor identified in Daubert itself as a matter to consider in deciding if the expert testimony is reliable. Daubert, 509 U.S. at 596; see also Caves v. Sec'y, HHS, 100 Fed. Cl. 119, 133-34 (2011) (an expert may testify without medical literature support the opinion, but such experts are rarely persuasive)
Wolf & Smeitink proposed and tested new mitochondrial disease diagnostic criteria (abbreviated in the study as "MDC") for diagnosing ETC disorders in infants and children. They found that the MDC/Nijmegen criteria, which use "more precise definition of clinical and metabolic items and the independent scoring of muscle biochemical investigations" to be accurate in identifying infants and children with ETC disorders. The authors noted that the previously proposed modified adult criteria for diagnosing children had no clear definitions for the various clinical and laboratory findings. Wolf & Smeitink, Court Ex. I, at 1402. The authors concluded that splitting the diagnostic criteria into two subsets, general (which included the clinical, metabolic, imaging, and pathologic criteria) and biochemical (which included the results of muscle biopsies testing ETC function), enhanced diagnostic confidence. Id. at 1402 (Abstract). The authors recommended a "careful clinical and metabolic workup" before scheduling a muscle biopsy, indicating that the clinical criteria should be evaluated for evidence of mitochondrial disease before performing a muscle biopsy. Id. at 1404.
