BRIAN H. CORCORAN, Special Master.
On July 11, 2008, R.V. and E.V. filed a petition on behalf of their minor child, L.V. seeking compensation under the National Vaccine Injury Compensation Program (the "Vaccine Program").
An entitlement hearing was held on April 13-14, 2015, and in the following months the parties submitted post-hearing briefs. Having completed my review of the evidentiary record and the parties' filings, I hereby deny Petitioners' request for compensation for the reasons stated below.
L.V. was born at term by caesarean section on March 15, 2005, at Abington Memorial Hospital in Abington, Pennsylvania, presenting with no abnormalities. Pet'rs' Ex. 1 at 7, 15-16. L.V. passed his hearing screening on March 16, 2005, and was routinely discharged on March 19, 2005. Pet'rs' Ex. 2 at 4-5, 7. Throughout the first weeks of L.V.'s life, he had red and swollen eyes with yellow drainage. Pet'rs' Ex. 3 at 5. He was ultimately diagnosed with acute nasolacrimal stenosis,
At L.V.'s second well-child appointment on May 12, 2005, he was determined to be developing appropriately for his age, and received: (a) Diphtheria, Tetanus, and acellular Pertussis ("DTaP") vaccine; (b) haemophilus influenza type B ("Hib") vaccine; (c) inactivated polio vaccine ("IPV"); and (d) pneumococcal conjugate vaccine ("PCV"). Pet'rs' Ex. 3 at 113-14. A month later, L.V. was diagnosed with onychia.
On July 22, 2005, L.V. had his third well-child visit, at which time his pediatrician, Dr. Sharon Corcoran, evaluated him as developing appropriately for his age. Pet'rs' Ex. 3 at 50-51. L.V. again received the DTaP, Hib, IPV, and PCV vaccines. Id. at 113, 114. On August 15, 2005, L.V. developed cold symptoms including a cough, as well as a possible toe infection. Id. at 54, 56, 59. L.V. was prescribed augmentin
On September 16, 2005, L.V. had his fourth well-child visit, and once again Dr. Corcoran evaluated L.V. as developing appropriately for his age. Pet'rs' Ex. 3 at 66. At this time L.V. received the DTaP, IPV, and PCV vaccines, after which he developed a localized rash. Id. at 69, 113, 114. Months later, on December 16, 2005, L.V. was again evaluated by Dr. Corcoran as developing appropriately for his age. Id. at 77.
As L.V. approached his first birthday, there remained no obvious signs of developmental problems. In February of 2006, L.V. was taken to the pediatrician because he was experiencing diarrhea, and was diagnosed with gastroenteritis.
On September 8, 2006, L.V. visited the pediatrician for a 17-18 month well-child appointment. At this visit, L.V. was assessed as having normal growth and development (including motor skills such as use of a cup and spoon), and received the hepatitis A vaccine. Pet'rs' Ex. 3 at 123-24, 194. Later that same month, the Vs also brought L.V. to Allergy and Asthma Specialists, P.C. in Flourtown, Pennsylvania, because L.V. had developed a large hive after eating blueberry yogurt and pancakes. Pet'rs' Ex. 7 at 39-40.
L.V. received the first dose of flu vaccine on November 8, 2006 (at approximately 20 months of age), and the second on December 8, 2006 (at approximately 21 months of age).
Three days after L.V. received the second flu vaccine dose, on December 11, 2006, Mrs. V phoned the pediatrician's office to report that L.V. was experiencing serious constipation "for a while," and had not had a bowel movement since December 9th. Pet'rs' Ex. 3 at 132. She reported no other problems, however. An office appointment was set for December 13, 2006. Id.
At the December 13th visit, Mrs. V again identified only constipation as the reason for the appointment. Pet'rs' Ex. 3 at 134-35. Thus, the medical records explicitly state that L.V. had not been "going regularly for 1-2 months" despite alteration of his diet. Id. In addition to the constipation, L.V. also now presented with left otitis media,
Over a week passed without any further contact with L.V.'s pediatrician. Then, on December 22, 2006, Mrs. V called Dr. Corcoran's office to report that L.V. (who had been on antibiotics to treat the ear infection for nine days) had now developed a fever of 102 degrees (which later that same day rose to 104 degrees). Pet'rs' Ex. 3 at 138-40. L.V.'s treaters prescribed augmentin and recommended an in-office visit if L.V.'s symptoms did not improve in the next few days. Id. at 138.
L.V.'s follow-up pediatric visit occurred on December 26, 2006. Pet'rs' Ex. 3 at 142-47. At this point, the Vs reported to L.V.'s treaters that he was suffering from rashes on his face, shoulders, back, and diaper area that had first become evident on December 23rd, along with a cough and runny nose. Id. at 144. The records make no mention, however, of an ongoing fever (beyond reference to the fever that the Vs reported on December 22nd), and indicate that L.V. displayed no particular distress. Dr. Corcoran diagnosed L.V. as suffering from an augmentin allergy (based upon the circumstantial link between the time that medication was started and the rash development), and he was prescribed omnicef as a substitute for augmentin. Id. at 142, 144.
Before their first visit to the pediatrician in 2007, the Vs obtained an initial early intervention assessment from Montgomery County's provider on January 17, 2007, after requesting it on January 10th. See generally Pet'rs' Ex. 13 at 1-11 and Ex. 30 at 475. The written report generated from this initial assessment (based on observation of L.V. along with parental reports) placed L.V. at eleven months for cognitive development, ten months for communication development, six months for social development, and sixteen months for fine motor/physical development. Pet'rs' Ex. 13 at 5-6. The report contains references to L.V. having lost language or expressive abilities, but notes that "he lost these abilities around 18 months." Id. at 8. In addition, other developmental problems (such as not responding to his name, or making eye contact) are noted as uncommon occurrences, rather than behaviors that abruptly ceased or regressed. See, e.g., Id. at 5 (L.V. "did not respond to his name today. Parents report that he will respond to his name 20% of the time (at best)").
L.V.'s next pediatric visit was on January 18, 2007. Pet'rs' Ex. 3 at 148-49. Although L.V. returned to Dr. Corcoran in part for a follow-up visit regarding his ear infection, the Vs also made it clear that they wished to discuss "developmental issues." Id. at 149. Specifically, the medical records from that visit note the Vs' statements that L.V. had "lost some of his language and does not make a lot of eye contact." Id. at 149. The January 18th records do not indicate when the lost language began or was first observed — nor do they make any reference to the flu vaccine or L.V.'s subsequent ear infection, brief fever, or rash as having any role in such developmental matters. However, these records substantiate that the Vs had already initiated the process for obtaining an early intervention assessment, as noted above. Id. at 149.
Dr. James Coplan, M.D., of Neurodevelopmental Pediatrics of the Main Line, P.C. in Rosemont, Pennsylvania thereafter (upon referral by Dr. Corcoran) performed another early evaluation assessment, completing his write-up of the assessment on January 23, 2007. See generally Pet'rs' Ex. 5 at 3-7. The assessment was based on both a physical examination and a medical and personal history provided by the Vs (including the January 17th early assessment report). Dr. Coplan's conclusions were discouraging: he diagnosed L.V. with autism or autism spectrum disorder ("ASD").
Dr. Coplan's assessment included some discussion of the course of L.V.'s developmental problems. He thus noted that the developmental and skills "deterioration" in a child's second year, as evidenced by L.V.'s history, occurs in 20 percent of autistic children. Pet'rs' Ex. 5 at 6. However, Dr. Coplan also proposed that despite the "striking history of developmental deterioration" at 18 months provided by the Vs' personal recollections, it was not entirely clear that L.V. was truly regressing developmentally, given other information provided by the Vs about L.V.'s earlier developmental abnormalities (such as his failure to "acquire appropriate use of `mama' and `dada'). Id. at 6. Dr. Coplan also indicated that it was unlikely the immunizations that L.V. had received played any role in his development of autism (and this record does not contain any statement from the Vs linking L.V.'s alleged regression and his receipt of the flu vaccine in November and December of 2006). Id. at 6.
The Vs later obtained a child development evaluation from Dr. Hillary Kruger, M.D., at Children's Hospital of Philadelphia ("CHOP"). See generally Pet'rs' Ex. 6. In her initial pediatric evaluation, dated May 21, 2007, Dr. Kruger concurred with the autism diagnosis proposed earlier that year by Dr. Coplan. Id. at 5. Her written report also references previous records from 2007 in which the Vs had stated to treaters that they noticed L.V.'s regression when he was 18 to 19 months old. Id. at 1.
In this action, Petitioners have alleged that L.V. experienced a dramatic developmental regression after he received the second flu vaccine. However, as the medical records contemporaneous with L.V.'s alleged regression consistently reveal, the Vs repeatedly reported to doctors that L.V.'s regression began no later than when he was 18 to 19 months old.
As noted above, the contemporaneous records from January of 2007 (when Dr. Coplan evaluated L.V. at 22 months of age) reveal that the Vs informed treaters such as Drs. Coplan and Kruger that L.V.'s developmental problems and/or regression had been evident to them since L.V. was 18 months old, or around September of 2006. Pet'rs' Ex. 5 at 3. This reported onset is repeated numerous other times in the subsequent medical record. Thus, Mrs. V informed Dr. James A. Neubrander in September of 2007 (when L.V. was almost two and a half years old) that at 19 months she noticed L.V. had lost the few words he had, lost social interest, and appeared withdrawn and irritable, and at around 20 months, L.V. lost eye contact, began constantly jumping, became increasingly irritable, and began making only a few sounds with vibrations. Pet'rs' Ex. 8 at 4. Dr. Bryan Jepson's 2008 notes corroborate the same timeframe, reporting that according to the Vs "[t]here was a regression from normal development around age 12 months in hindsight: more noticeable around 18 months" including "arm flapping, loss of contact, less socially interactive, [and] loss of his few words." Pet'rs' Ex. 10 at 5.
There are many other similar examples from the medical record. See, e.g., Pet'rs' Ex. 7 at 29-30 (January 31, 2007 visit to CHOP for genetic testing); Pet'rs' Ex. 10 at 78 (April 15, 2007 visit at Thoughtful House with Dr. Jepson); Pet'rs' Ex. 6 at 1 (May 21, 2007 visit with Dr. Kruger); Pet'rs' Ex. 9 at 6 (June 14, 2007 visit with Dr. Krigsman); Pet'rs' Ex. 8 at 3 (September 27, 2007 visit with Dr. Neubrander); Pet'rs' Ex. 8 at 32 (September 29, 2007 visit with Dr. Neubrander).
After L.V.'s initial ASD diagnosis in January of 2007, the Vs (whom the record underscores were extremely dutiful in caring for their son) explored possible explanations for L.V.'s autism, as well as treatments that would be effective under the circumstances. Eventually they became very interested in determining whether L.V.'s purported post-vaccine regression had something to do with an underlying disorder involving dysfunction (if not disease) in his mitochondria and their efficiency in producing energy.
To that end, the Vs consulted with a variety of autism specialists, some of whom were themselves exploring the links between autism and mitochondrial diseases. In May of 2007, L.V. saw Dr. Corcoran and Dr. Hilary Kruger, a developmental pediatrician, both at CHOP, who determined after genetic testing and evaluation that L.V. had no clinically significant genetic abnormalities
The Petitioners next brought L.V. to Texas specifically in search of a Defeat Autism Now ("DAN")
At the recommendation of Dr. Krigsman and other Thoughtful House practitioners, the Vs traveled to New Jersey to bring L.V. to see Dr. Neubrander, another noted DAN doctor, who L.V. first saw on September 29, 2007. Pet'rs' Ex. 8 at 1-3. Following a physical exam performed that same day, Dr. Neubrander confirmed L.V.'s autism diagnosis, and also diagnosed him with "gastroenteritis associated with autistic spectrum disorders" and nutritional deficits. Id. at 36-37.
The Vs eventually obtained treatment from Dr. Richard Frye, beginning in August of 2008, who at the time was a physician at the Child and Adolescent Neurology Clinic at the University of Texas Health Science Center in Houston, Texas. Pet'rs' Ex. 8 at 2. Petitioners learned of Dr. Frye from Dr. Krigsman, and it was Dr. Frye who first proposed to them that L.V. might have some kind of mitochondrial disease that had played a role in his ASD. Tr. at 93-94. The Vs traveled back to Texas in order to obtain Dr. Frye's services.
Dr. Frye performed testing to evaluate whether in fact L.V. displayed any of the clinical indicia necessary for a mitochondrial disease diagnosis. At L.V.'s first visit with Dr. Frye on August 1, 2008, extensive blood work was performed. Pet'rs' Ex. 11 at 3. Then, on December 3, 2008, Dr. Frye had Quest Diagnostics, Inc. perform an amino acid analysis and a comprehensive metabolic panel, intended to clarify what type of mitochondrial disorder L.V. had, if any. Id. at 17-22.
Initial test results did not suggest the existence of a specific or inherited metabolic defect, and returned an essentially normal acylcarnitine profile.
In 2009, L.V. underwent additional testing at Dr. Frye's direction, through the Mitochondrial Diagnostic Laboratory of the Medical Genetics Laboratories of the Baylor College of Medicine ("BCM") in Houston, Texas. See generally Pet'rs' Ex. 34. There, specialists performed a MitoMet oligo aCGH analysis
During the time of this testing under Dr. Frye's direction, the Vs brought L.V. back to CHOP. Pet'rs' Ex. 36 at 18. Metabolic studies of L.V. performed on August 12, 2010, "were essentially normal and were not suggestive of metabolic or mitochondrial dysfunction." Id.; Pet'rs' Ex. 26, Part 2 at 1-9. During their September 2, 2010, visit, the doctors confirmed that interpretation. Pet'rs' Ex. 36 at 18.
By the fall of 2010, the Vs sought the opinion of another specialist with views similar to Dr. Frye's regarding the possible metabolic causes of autism, Dr. Richard Kelley at the Kennedy Krieger Institute in Baltimore, Maryland. Dr. Frye had recommended in August of 2010 that Petitioners speak with Dr. Kelley (Pet'rs' Ex. 33 at 30), and (in written communication introducing the Vs to him) set forth the opinion that L.V. had a "mitochondrial complex deficiency." Pet'rs' Ex. 26 at 4. Dr. Kelley and his assistants subsequently reviewed L.V.'s lab work. Id. at 32-33. After review of the relevant results and L.V.'s history, however, Dr. Kelley expressed the belief that there were "no metabolic abnormalities," and thus nothing consistent with mitochondrial dysfunction (although he acknowledged that L.V.'s condition could be consistent with an encephalitis). Id.
Despite such inconclusive results, the Vs nevertheless pursued further attempts to identify the source of L.V.'s ASD. To that end, on January 21, 2011, L.V. underwent a muscle biopsy, performed to measure lactic acid
Such additional testing was performed at Dr. Frye's direction in late January of 2011, but detected no deficiencies in L.V.'s mitochondrial ETC enzymes. Pet'rs' Ex. 23 at 1-3. However, the mitochondrial DNA content analysis performed at BCM on February 7, 2011, showed that L.V.'s muscle contains approximately 189% of the mean value of the age and tissue-matched controls, suggesting a compensatory amplification of mitochondrial DNA due to some other kind of mitochondrial dysfunction. Pet'rs' Ex. 34 at 16. A follow-up ETC test performed at BCM on February 22, 2011, once again did not detect any deficiencies. Id. at 9.
In spite of such generally inconclusive data, on August 4, 2011, Dr. Frye diagnosed L.V. (who was at that time six years old) with a mitochondrial disorder. Pet'rs' Ex. 72, Part 2 at 25-26. He did so by applying criteria set forth in an article written by Morava, entitled Mitochondrial Disease Criteria, Diagnostic Applications in Children (the "Morava criteria"). Pet'rs' Ex. 41, Ref. 25 at 31 (E. Morava, et al., Mitochondrial disease criteria: Diagnostic applications in children, 67 NEUROLOGY 1823 (Nov. 2006) [hereinafter Morava]). As discussed in greater detail below, Morava set forth diagnostic guidelines for evaluating whether a child suffers from some kind of mitochondrial disease, through application of a point system for various symptoms or test results observed in the diagnosed patient. Pet'rs' Ex. 24 at 1; Tr. at 120-21, 442-44.
In a "to whom it may concern" letter dated February 29, 2012, Dr. Frye identified the specific grounds for his conclusion that L.V. suffered from a "definite" mitochondrial disease (based on application of the Morava criteria). See generally Pet'rs' Ex. 24 at 1-3. In his opinion, L.V. exhibited three clinical signs consistent with a mitochondrial disorder, including: (i) exercise intolerance, (ii) history of regression in skills, and (iii) gastrointestinal abnormalities. Id. at 1. Dr. Frye then listed three metabolic indicators (based on previous bloodwork) he found significant, including: (i) elevated lactate,
As stated above, the Vs filed this petition in 2008. On May 6, 2009, Respondent filed a statement expressing no objection to the jurisdiction and appropriateness of Petitioners proceeding within the Omnibus Autism Proceeding ("OAP").
After filing a statement of completion on September 25, 2012, Petitioners offered the expert report of Dr. Frances Kendall on August 20, 2013. ECF No. 64. On February 19, 2014, Respondent filed a Rule 4(c) Report, contending that the record failed to establish by preponderant evidence the causal connection between the flu vaccine and L.V.'s subsequent conditions, and disputing the reliability of Petitioners' medical theory. ECF No. 71. In response, Respondent filed an expert report from Dr. Bruce Cohen. ECF No. 72. The Vs then elected to file a supplemental expert report from Dr. Yuval Shafrir on December 30, 2014. ECF No. 95. With records gathering and the filing of relevant evidence and expert reports complete, a two-day entitlement hearing was set for April of 2015. (Petitioners later moved to file out of time a second supplemental expert report from Dr. Shafrir on March 17, 2015 (ECF No. 129), and I permitted them to do so.)
On January 4, 2015, Petitioners filed a second amended petition that presented facts and allegations relevant to Petitioners' claim for compensation.
On April 13-14, 2015, a two-day entitlement hearing was held. During the hearing, I heard testimony from Mrs. V; Petitioners' experts Drs. Kendall and Shafrir; and Respondent's expert Dr. Cohen. After requesting two extensions of time (ECF Nos. 147 and 152) both of which I granted, Petitioners filed their post-hearing brief on July 13, 2015. ECF No. 155. In response, Respondent then filed her post-hearing brief on September 14, 2015. ECF No. 157. Petitioners replied to Respondent's argument on October 14, 2015.
E.V., L.V.'s mother, was the only non-expert witness who testified at the entitlement hearing. See generally Tr. at 7-103. Her testimony provided some context about L.V.'s overall development — and also sought to rebut the notion, reflected in the medical records, that the Vs were aware of signs of L.V.'s regression before he received the flu vaccines in November and December 2006. In order to do so, she frequently attempted to diminish the weight to be given statements in the medical record reporting earlier onset.
Thus, Mrs. V repeatedly stressed that the first time she or her husband had observed developmental issues with L.V. was in mid-December of 2006, after he received the second dose of flu vaccine. Compare Tr. at 29, 36, 40 with Tr. at 56, 58. Some photographs of L.V. were offered to bulwark her assertions that L.V.'s pre-vaccination development was completely normal. Id. at 54-74.
More significantly, Mrs. V was unable to deny the many instances from the contemporaneous medical records in 2007 in which she and/or her husband reported to treaters evaluating L.V.'s autism that L.V. first displayed such symptoms by the time he was 18 months old. For example, on cross-examination, Respondent pointed out that the excel sheet prepared by Mrs. V documenting L.V.'s issues and presented to Dr. Neubrander at L.V.'s September 29, 2007, visit reported that at 19 months L.V. "lost a few words he had, lost social interest, seemed withdrawn, irritable." Tr. at 87-88; Pet'rs' Ex. 8 at 4. This is in apparent contradiction to Mrs. V's testimony (nearly nine years after the events in question) and her affidavit (prepared nearly three years after the vaccination), both of which maintain that L.V.'s regression manifested no sooner than 21 months, or after his receipt of the flu vaccine in December 2006. Compare Tr. at 29, 36, 40 with Tr. at 56, 58. Mrs. V had also prepared a narrative for Dr. Krigsman for L.V.'s June 2007, visit, which is similarly inconsistent with her testimony and affidavit. Id. at 90; Pet'rs' Ex 9 at 6 (reporting that L.V. "did always seem to be more difficult than other children" and that he "began flapping his arms as early as 12 to 18 months").
To the extent Mrs. V admitted that she had made such statements about the actual onset of L.V.'s ASD-related symptoms, she attempted to downplay their significance, suggesting that she and her husband had not considered L.V.'s earlier symptoms to be alarming enough to merit a medical response. Tr. at 63. This line of reasoning — that L.V.'s "real" regression began only after the second flu vaccine administration, and that any earlier signs of developmental problems were too inconclusive to meaningfully relate to the later, agreed-upon developmental difficulties L.V. experienced — was a general theme that Petitioners and their experts came back to during the hearing multiple times. See, e.g., id. at 86, 93, 152, 179-80.
Dr. Kendall offered an expert report and testimony at the entitlement hearing in support of Petitioners' theory that L.V. likely had an underlying, preexisting mitochondrial disease that was exacerbated by receipt of the flu vaccine, thereby precipitating L.V.'s autism.
Dr. Kendall graduated from UMDNJ-New Jersey Medical School in 1987 after which she completed her residency in pediatrics at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Pet'rs' Ex. 42 at 1; Tr. at 106. From 1990 to 1993 she completed two fellowships in genetics and metabolism at Children's Hospital and Harvard Medical School and Tufts University and is licensed by the American Board of Medical Genetics. Pet'rs' Ex. 42 at 1; Tr. at 106. She has worked and taught across the country in genetics and metabolism, including as Director of the Mitochondrial Disorders Program at the Children's Hospital of Boston, and written extensively, including her own reports and reviews of others, on issues of mitochondrial energy production and the errors of metabolism. Pet'rs' Ex. 42 at 6-8; Tr. at 106, 108-09. She is presently board-certified in biochemical genetics, and was previously board-certified in pediatrics. Tr. at 111. Dr. Kendall currently treats patients from all over the world "for evaluation of and management of mitochondrial disease" and estimates that since 2009 she has seen about a thousand patients, most of whom she continues to treat. Id. at 105.
Dr. Kendall's expertise thus lies in the specific field of mitochondrial disorders. Tr. at 104. She did not, however, claim expertise in autism or in immunology. Id. at 233-34. In preparing her expert opinion, Dr. Kendall reviewed the contemporaneous pediatric records, including L.V.'s various evaluations discussed above, although she admitted that certain records relevant to Dr. Frye's analysis of L.V. were not provided to her at the time of her report's preparation in July of 2013. Id. at 130, 214. Nor did Dr. Kendall ever specifically examine or evaluate L.V.; her opinion relied solely on test results performed by other treaters. Id. at 231.
Dr. Kendall characterized the diagnosis of mitochondrial disease as an "imperfect science" (tr. at 198), stating that it is "not an easy process, and it's not clean" (id. at 114), given limitations in the available tools to evaluate it, along with a general lack of a medical/scientific consensus as to the proper diagnostic criteria. Id. at 117, 119. Ultimately she embraced the Morava criteria applied by Dr. Frye in his diagnosis of L.V. Pet'rs' Ex. 10. She admitted, however, that there is actually no accepted set of criteria (based on scientific consensus) that can be used in diagnosing mitochondrial disease. Tr. at 119. In most cases, a definitive diagnosis of mitochondrial disease requires a muscle biopsy or confirmation by molecular testing aimed at looking for a possible genetic cause. Id. at 116-18, 146; Pet'rs' Ex. 41 at 9.
Dr. Kendall also acknowledged the evolving nature of the criteria (and specific tests) applied when attempting to diagnose a mitochondrial disease. Thus, Dr. Kendall noted that when the science for detecting mitochondrial diseases was less advanced, muscle biopsy tests were the "gold standard" diagnostic tool (Tr. at 241), but that more recently such tests were applied only to confirm a mitochondrial disease diagnosis (id. at 118), and that she herself rarely performs them. Id. at 119. She maintained that now there are many diagnostic tools available to test for mitochondrial disease more useful than the muscle biopsy. Id. at 118-19.
Based upon her review of the results of the many tests performed on L.V., along with his medical history, Dr. Kendall provided her opinion that the mitochondrial disease/dysfunction diagnosis for L.V., as first proposed by Dr. Frye and based upon his application of the Morava criteria, had evidentiary support. Tr. at 131-32. She acknowledged, however, that she did not accept the Morava number assigned to L.V. by Dr. Frye (nine points); rather, she would reclassify the total as six or seven,
Dr. Kendall agreed with Dr. Frye's analysis that L.V. was properly assigned three Morava "points" for clinical signs and symptoms. Thus, she found worthy of a Morava point the exercise intolerance that L.V. was reported to have displayed, pointing to his limited eye movement as evidence thereof. Tr. at 148. Yet, as Dr. Kendall acknowledged, there was little record evidence supporting this conclusion — going so far as to admit that her embrace of Dr. Frye's scoring for this Morava factor was wholly dependent on what the Vs had reported to treaters about L.V. rather than objective evidence, and that she herself did not believe based on her own review of those records that L.V. in fact had ever displayed any such weakness. Id. at 193-94, 245. She admitted the same with respect to L.V.'s purported low muscle tone (hypotonia), another factor relevant to the application of the Morava criteria (and indeed acknowledged that there were contrary reports in the medical records undermining the conclusion that L.V. displayed low muscle tone). Id. at 148, 194.
Dr. Kendall otherwise accepted the two additional points assigned by Dr. Frye in this category, based on L.V.'s alleged autistic regression (evidence of a CNS-related symptom)
Dr. Kendall did not, however, accept every aspect of Dr. Frye's application of the testing results under Morava. In particular, she substantively disagreed with Dr. Frye's point calculation with respect to the results of the enzymatic and metabolic tests. Thus, Dr. Frye gave L.V. the four point maximum under the Morava diagnostic framework for test results showing elevated lactate (two points), urinary tricarbon acid excretion (one point), and ethylmalonic aciduria (two points). Pet'rs' Ex. 24 at 1. Dr. Kendall, however, questioned the weight given by Dr. Frye to the elevated lactate finding because "it's not a true elevation from a biochemical mitochondrial perspective" and "we don't have any concurrent data to show whether it was a collection artifact." Tr. at 140. She therefore indicated that she disagreed with awarding a Morava point for the lactate results because concurrent tests of other enzyme levels (alanine to lysine ratios) did not corroborate them. Id. at 149. But she agreed with Dr. Frye that L.V. had high tricarboxylic acid excretion (tr. at 149), as well as high ethylmalonic acid levels, which (as corroborated by the fatty oxidation studies done on skin fibroblasts) were in her opinion suggestive of mitochondrial disease. Id. at 138-39. Thus she would have granted only two or three points for the test results relevant to this biomarker category.
More broadly, Dr. Kendall admitted (consistent with the manner in which she applied the Morava criteria) that any mitochondrial disease L.V. suffered from was on the mild end of the spectrum, and did not approach the severity of something like Leigh disease
Dr. Kendall also acknowledged that her opinions about Dr. Frye's diagnosis arose from her own expertise and familiarity with the Morava criteria, and that she therefore did not particularly rely on much of the independent literature filed by the Petitioners in support of their claim, noting that some of it was not pertinent to L.V.'s circumstances.
Based upon all of the above, Dr. Kendall proposed that Petitioners could meet all three of the prongs necessary to establish causation in a non-Table case under Althen v. Sec'y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). First, Dr. Kendall offered the theory that the flu vaccine could sufficiently exacerbate an underlying mitochondrial disorder, synergistically reacting with an intercurrent infection,
To support this proposition, Dr. Kendall relied on literature discussing that vaccines can act as stressors for sufferers of mitochondrial diseases (tr. at 153-60), although she admitted that only isolated cases, or incidents involving well-understood and particularly severe forms of mitochondrial diseases such as Leigh disease, supported this element of her theory. Id. at 174. She also pointed to a paper filed by Petitioners but not relied upon in her report, indicating that "the influenza virus can, via a specific mitochondrial component . . . cause a cascade of events leading to apoptosis, which is a kind of programmed cell death." Id. at 162 (citing Pet'rs' Ex. 101 (A. Tran, et al., Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation, 87(2) J. OF VIROLOGY 1049 (Jan. 2013)) [hereinafter "Tran"]). She then said that such a study made it more likely or plausible that the flu vaccine could cause an injury in a person with mitochondrial disease. Tr. at 163. Given the understanding that an infection can itself precipitate a regression or decompensation (id. at 155-56), she testified, the introduction of flu vaccine could similarly place stress on a patient with a preexisting mitochondrial disease. Id. at 165-66.
Second, Dr. Kendall testified that in fact the medical record confirmed that L.V. had been affected by the flu vaccine as she proposed. But she was generally unable to reference evidence from that record in support of this assertion. Tr. at 178-79, 184-86. At best, Dr. Kendall vaguely cited to reports of L.V.'s loss of words or irritability, but could not recall much else. Id. at 170-72. She also admitted that the speech delay as reported by the Vs on December 13, 2006, was not itself strong proof of a dramatic, vaccine-induced regression caused by an underlying mitochondrial disease (id. at 180), and that L.V.'s constipation and related problems were ongoing, having been present prior to his receipt of the flu vaccine. Id. She further agreed that ASD features, development delays, developmental regression, and constipation are symptoms that are often seen independent of a mitochondrial disorder. Id. at 196-97. Indeed, Dr. Kendall admitted on cross-examination that, given the paucity of evidence suggesting an immediate, post-vaccination regression, her overall theory would be undermined if it were determined that L.V.'s developmental regression began before he received the flu vaccine. Id. at 184-86.
Finally, Dr. Kendall asserted that the timeframe from the December 8, 2006, administration of the second dose of flu vaccine to L.V.'s alleged developmental regression was medically acceptable. Under Dr. Kendall's proposed theory, onset of regression would occur in seven to ten days — a length of time she derived from a single piece of literature involving a retrospective study of individuals suffering from mitochondrial disease, some of whom experienced developmental regression as is alleged to have occurred with L.V. Tr. at 166-69; Pet'rs' Ex. 84 at 6 (J. Edmonds, et al., The Otolaryngological Manifestations of Mitochondrial Disease and the Risk of Neurodegeneration with Infection, 128 ARCH. OTOLARYNGOL. HEADNECK SURG. 355 (Apr. 2002) [hereinafter, "Edmonds"] (setting forth that in most patients the neurologic event occurred three to seven days after onset of infection)). Approximately one week after L.V.'s second flu vaccination, there was "some question about some neurological changes or problems or certainly by his parents' report of changes in his irritability." Tr. at 169-70. Although Dr. Kendall admitted that irritability was not particularly strong evidence of an encephalopathy, when viewed in context with L.V.'s purported subsequent skill loss, in her opinion it was proof of the existence of a "regressive encephalopathy" that was "certainly temporally related." Id. at 170-172, 176.
Dr. Shafrir is a child neurologist who graduated from the Sackler School of Medicine at the Tel Aviv University in 1982. He thereafter did residencies in pediatrics at Kaplan University and the Bellinson Medical Center in Israel. Tr. at 252-53; Pet'rs' Ex. 81 at 2. Dr. Shafrir went on to do residencies in pediatrics at North Shore University Hospital in New York, and in pediatric neurology at the Washington University Medical Center in Missouri. Tr. at 254; Pet'rs' Ex. 81 at 2. From 1992 to 2000, Dr. Shafrir worked at a number of different U.S. hospitals, but currently practices pediatric neurology in private practice affiliated with Sinai Hospital in Baltimore, Maryland. Tr. at 252. He is licensed to practice medicine in Maryland, and has board certifications in child neurology, although he has not renewed his board certification in pediatrics. Id. at 252, 322, 334. He has worked and taught across the country in pediatrics and neurology, and presently does so at the University of Maryland School of Medicine. Pet'rs' Ex. 81 at 4. He has also written extensively on issues of pediatric neurology. Id. at 4-8.
Dr. Shafrir testified as an expert in pediatric neurology. Tr. at 252. He is not an expert in immunology or mitochondrial disease, however. Id. at 268, 321, 361-62, 380. He is also not one of L.V.'s treating physicians, and has never examined L.V. himself. Id. at 404. Dr. Shafrir sees approximately 300 patients per month. Tr. at 252-54, 402. Mostly, he treats headaches and seizures, but twenty percent of his practice is developmental in nature, and approximately ten percent of his patients have an ASD diagnosis. Id. at 252-54, 402. But he does not have clinical experience studying ASDs, nor does he possess specific research experience or training in that specialty. See generally Pet'rs' Ex. 81.
Dr. Shafrir offered brief testimonial support for Dr. Kendall's theory that L.V.'s autism was related to his alleged preexisting mitochondrial disease. Tr. at 267-68, 317-18; Pet'rs' Ex. 193 at 3. The vast majority of his testimony, however, related to his own, alternative causation theory, which was somewhat confusing and extremely wide-ranging. Dr. Shafrir's opinion began with a distinction he drew between autism that proceeds on a natural course and the "regressive autism" he believes L.V. experienced. Tr. at 336. Indeed, he disputed the concept of a "natural course of autism" that would typically include a developmental regression. Id. at 329. Rather, according to Dr. Shafrir, sudden autistic regression is more likely caused by an encephalopathy. Id. at 251. He thus maintained that regressive autism — which in his view accounts for approximately thirty percent of all ASD patients, and is in some cases treatable (due to its causes) — was a form of autism, although he admitted that it does not constitute a separate clinical phenotype that is formally recognized medically. Id. at 336-37.
In Dr. Shafrir's opinion, L.V. experienced an "acute autistic regression following his second influenza immunization" (tr. at 264) at 20 months (id. at 338) which "can be best explained as an autoimmune process." Id. at 264-65, 274. He based this view on post-vaccination evidence, which he argued revealed "all the components" of autistic regression. Id. at 280. His opinion was also based on scientific articles and literature that he maintained drew a connection between the administration of the flu vaccine and L.V.'s allegedly abrupt subsequent regressive incident.
First, Dr. Shafrir testified that the flu vaccination has been demonstrated to be a cause of autoimmune encephalopathy. Tr. at 284; Pet'rs' Ex. 80 at 28. As proof, he mentioned several pieces of literature associating vaccines (and particularly the flu vaccine) with antibody-mediated autoimmune encephalitis. Tr. at 284 (citing Pet'rs' Ex. 80, Ref. 10 (J. Dalmau, Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis, 10 LANCET NEUROL 63 (Jan. 2011) [hereinafter "Dalmau"]); Pet'rs' Ex. 80, Ref. 11 (T. Hung, et al., Anti-N-methyl-D-Aspartate Receptor Encephalitis, 52 PEDIATRICS & NEUROLOGY 361 (Jan. 2011)); Pet'rs' Ex. 80, Ref. 12 (M. Kubota and Y. Takahasi, Steroid-Responsive Chronic Cerebellitis with Positive Glutamate Receptors δ2 Antibody, 23(2) J. OF CHILD NEUROLOGY 228 (Feb. 2008)); and Pet'rs' Ex. 80, Ref. 13 (J. Takanashi, et al., Late Delirious Behavior with 2009 H1N1 Influenza: Mild Autoimmune-Mediated Encephalitis? 129 PEDIATRICS 1068 (2012)). He maintained that scientific studies have plainly observed a tendency in individuals to develop autoantibodies following receipt of the flu vaccine. Pet'rs' Ex. 80 at 30 (citing Pet'rs' Ex. 80, Ref. 31 (N. Toplak, et al., Autoimmune response following annual influenza vaccination in 92 apparently healthy adults, 8 AUTOIMMUNITY REVIEWS 134 (2008)). Such autoantibodies, in turn, attack human brain tissues, resulting in an encephalopathic incident. Tr. at 208 (citing Pet'rs' Ex. 41, Ref. 26 (E. Hsiao, et al., Modeling an autism risk factor in mice leads to permanent immune dysregulation, PROC. OF THE NAT'L ACAD. OF SCI. www.pnas.org/cgi/doi/10.1073/pnas.1202556109)
For additional support, Dr. Shafrir referenced literature highlighting instances in which vaccines have been associated with negative neurologic conditions. Tr. at 287-89; Pet'rs' Ex 80, Ref. 5 (K. Lapphra, et al., Adverse Neurologic Reactions After Both Doses of Pandemic H1N1 Influenza Vaccine With Optic Neuritis and Deymyelination, 30(1) THE PED. INFECTIOUS DISEASE J. 84 (Jan. 2011) [hereinafter, "Lapphra"]). Lapphra describes a case study showing the occurrence of neurologic changes in a two-year-old Filipino boy shortly after receiving the H1N1 flu virus vaccine. Id. at 18-19. The child was diagnosed with acute disseminated encephalomyelitis ("ADEM")
Dr. Shafrir next opined that autoimmune encephalitis (as well as immune dysfunction more generally) is a recognized cause of regressive autism. Tr. at 285; Pet'rs' Ex. 80 at 30-31. As exemplifying a portion of the "accumulating evidence" that an autoimmune process can start in the brain and precipitate autism, he pointed to a series of case studies: one of which occurred in a child with Voltage-Gated Potassium Channel ["VGKC"]
However, Dr. Shafrir acknowledged limitations to the portion of his theory connecting the flu vaccine to autoimmune-mediated encephalopathies. On cross-examination, Dr. Shafrir admitted that the literature he cited (and in particular, Dalmau) observed no more than an association between the flu vaccine and encephalopathy, and thus did not support the conclusion that the flu vaccine was itself causative of any form of encephalopathy. Tr. at 366-67, 370. He also conceded that, because there is no evidence that L.V. has anti-NMDA encephalitis, anti-NMDA antibodies, or anti-VGKC encephalitis or antibodies, studies focusing on such narrow forms of autoimmune illnesses were largely inapposite. Id. Indeed, as Dr. Shafrir admitted, L.V. displayed no objective evidence of an autoimmune reaction in his brain, and no MRI findings that would be associated with an autoimmune encephalopathy. Id. at 362-63, 369, 508. Dr. Shafrir nevertheless stressed there were individual case studies where regression associated with an encephalopathic event had occurred, and that such regressions could be treated. Id. at 373-75.
To explain the biologic mechanism by which the flu vaccine could precipitate an autoimmune encephalopathy as Petitioners alleged to have happened with L.V., Dr. Shafrir proposed molecular mimicry through homology of epitopes.
In further support of his proposed molecular mimicry mechanism (and also as evidence of the pathogenic potential of the flu vaccine), Dr. Shafrir cited a Finnish study involving narcolepsy among children after receipt of the H1N1 Pandemrix flu vaccine, along with other literature addressing the same event. See, e.g., Tr. at 291; Pet'rs' Ex. 80 at 31 (citing Pet'rs' Ex. 80, Ref. 33 (A. Käll, The Pandemrix — narcolepsy tragedy: how it started and what we know today, 102 FOUNDATION ACTA PAEDIATRICA 2 (2013)); Pet'rs' Ex. 80, Ref. 34 (M. Partinen, Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination, 13 LANCET NEUROL 600 (2014));, Pet'rs' Ex. 80, Ref. 35 (M. Partinen, et al., Does autoreactivity have a role in narcolepsy?, 13 LANCET NEUROL 1072 (Nov. 2014)); and Pet'rs' Ex. 80, Ref. 36 (A. Singh, et al., Genetic association, seasonal infections and autoimmune basis of narcolepsy, 43 J. AUTOIMMUN. 26 (Jun. 2013)). However, Dr. Shafrir admitted that the formulation of the Pandemrix vaccine was not equivalent to what L.V. received (and indeed is not even administered in the U.S. (tr. at 365)), although he nevertheless maintained that, because both versions had some of the same protein sequence components, the study still had relevance to his theory. Id. at 366.
Dr. Shafrir also maintained that an individual like L.V. could be especially sensitive to stimulation by the flu vaccine given other aspects of his overall health. Tr. at 318, 380-81; Pet'rs' Ex. 190 (G. Morris, et al., The Many Roads to Mitochondrial Dysfunction in Neuroimmune and Neuropsychiatric Disorders, 13 BIOMED CENTRAL 68 (2015)). Thus, Dr. Shafrir asserted that L.V. was immunosensitive (tr. at 285-86), having obvious abnormalities in his immune system, as evidenced by his multiple, severe allergies, high erythrocyte sedimentation rate, documented IgA deficiency, and inflammatory bowel disease diagnosis. Id. at 285-86, 296; Pet'rs' Ex. 80 at 27. He emphasized that patients who are susceptible to immune abnormalities are more likely to suffer autoimmune reactions. Tr. at 323 (citing Pet'rs' Ex. 187 (Y. Takahashi, et al., Vaccination and infection as causative factors in Japanese patients with Rasmussen syndrome: Molecular mimicry and HLA class I 13(2-4) CLINICAL & DEVELOPMENTAL IMMUNOLOGY 381 (Jun.-Dec. 2006))). Individuals with allergies are also more likely to be autistic. Id. However, he admitted that he could cite no objective evidence from the record of L.V.'s purported immune-sensitivity, and that (once again) existing MRI findings did not support this aspect of his theory. Tr. at 362-63.
Based upon the above, Dr. Shafrir offered an interpretation of L.V.'s medical history aimed at demonstrating that the regression L.V. experienced appeared suddenly, after L.V.'s second flu vaccination. He maintained that the medical record showed that L.V. was developing normally until December 8th, with a sudden and severe regression thereafter, beginning within a week (or around the time of the December 13th pediatric visit). Tr. at 268-69, 339. Yet Dr. Shafrir admitted that he lacked data from the medical record that substantiated this assertion, beyond some mention of constipation and the ear infection L.V. was experiencing at the time. Id. at 342-44. He could point to little else in the record (beyond the Vs' recollections) that L.V. ever experienced anything medically dramatic, in this period or thereafter.
Dr. Shafrir also attempted to grapple with contrary evidence in the record suggesting that L.V.'s ASD symptoms were evident before he received even the first flu vaccine. Thus, he admitted that L.V.'s medical records were "all over the place," in identifying the onset of his alleged regression and/or ASD symptoms. Tr. at 328, 409. However, he posited that the Vs became "very concerned" about L.V.'s development only at 21 months, downplaying the significance of pre-vaccination evidence of developmental problems they may have observed (and reported to treaters as having occurred at 18 and 19 months — before receipt of the first dose of the flu vaccine). Id. at 277-78, 347, 387. Thus, Dr. Shafrir proposed that the Vs likely mistook normal childhood behaviors, such as flapping (which the medical records show was observed at 12 months), as the first signs of autism. Id. at 277-78, 347-58.
Dr. Shafrir similarly attempted to rebut the many instances in the medical record, beginning in January 2007, where the Vs directly informed a treater (such as Dr. Coplan) that L.V.'s developmental regression had been evident at 18 months of age rather than 21 months. Tr. at 347. To do so, he persistently relied on a pediatric well-child visit record from September 2006, which reported that L.V. was, at that time, a "normal child," as well as Mrs. V's testimony. Id. at 281. Dr. Shafrir characterized all subsequent, contrary medical records that referenced an earlier start to L.V.'s autism symptoms as "profoundly wrong." Id. at 348. But Dr. Shafrir was generally unsuccessful in his efforts to explain why such records were untrustworthy.
Ultimately, Dr. Shafrir opined that the flu vaccine was the "only obvious cause" of L.V.'s regression. Tr. at 283; Pet'rs' Ex. 80 at 31. In so determining, he rejected the possibility of some underlying genetic or other environmental explanation. Tr. at 294, 296. Indeed, Dr. Shafrir went so far as to reject genetic causes of autism in general, stating that "genetics cannot occur in epidemics." Id. at 295.
In an attempt to support Petitioners' overall burden of demonstrating a medically acceptable timeframe between vaccination and onset of L.V.'s autistic regression, Dr. Shafrir argued that there was evidentiary support from the medical record for the conclusion that a reaction occurred within five days. Tr. at 278, 280, 289-90. He based this argument in part on the fact that L.V. had already received the first dose of the flu vaccine in November, which he claimed played "an obvious role" because "[p]rimary immune reaction cannot occur in five days." Id. at 292-93. He thus differentiated these circumstances from the typical conception of "symptomatic rechallenge,"
Again, however, Dr. Shafrir had difficulty identifying record support for this aspect of his opinion. He thus admitted that he could point to very little record evidence actually establishing the profound regression he posited that L.V. had experienced in December, beyond statements contained in Dr. Coplan's assessment about behavioral and developmental changes that the Vs had observed in L.V. — records he simultaneously attacks as inaccurate or inconsistent with the Vs' view of L.V.'s history. Tr. at 343. At most, he referenced evidence of L.V.'s constipation around the time immediately after the December 8th vaccination. Id. at 344-46.
Respondent's expert, Bruce Cohen, M.D., offered testimony mostly responding to Petitioners' theory that L.V. suffered from a mitochondrial disease or disorder of some kind that related to his alleged post-vaccine developmental regression.
Dr. Cohen graduated from Albert Einstein College of Medicine of Yeshiva University in 1982 (after completing his undergraduate degree at Washington University in St. Louis). Resp't's Ex. B at 2. Dr. Cohen went on to complete a pediatric residency at Children's Hospital of Philadelphia, followed by a Pediatric Neurology Residency at the Neurological Institute of New York and Babies Hospital of Columbia Presbyterian Medical Center and a Pediatric Neuro-Oncology Fellowship at the Children's Hospital of Philadelphia. Id. Dr. Cohen is board-certified in Neurology, with Special Competence in Child Neurology, and was previously board-certified in Pediatrics. Id. at 3.
Dr. Cohen is currently the Director of Neurology at the Children's Hospital Medical Center of Akron and a Professor of Pediatrics at Northeast Ohio Medical University, where he teaches general pediatric neurology to medical students, residents, and fellows. Resp't's Ex. B at 3; Tr. at 414. He has also taught courses specifically on mitochondrial disease in symposia. Resp't's Ex. B at 5-6. He is a reviewer for several journals and on the editorial board for the Mitochondrion and the Pediatric Neurology Journal. Id. at 4. And he serves on various review committees — seven in total — including the Neurofibromatosis Consortium. Id. Dr. Cohen has written extensively on issues of mitochondrial diseases, authoring or co-authoring nearly 100 peer-reviewed articles. See generally, id. Dr. Cohen has served in many different capacities for The United Mitochondrial Disease Foundation since 1999 and served on many different committees regarding mitochondrial disease. Id. at 4-5.
Dr. Cohen has particular expertise in studying and treating mitochondrial diseases. He has been assisting with or treating patients with mitochondrial disorders or suspected mitochondrial disorders since 1994. Tr. at 415. As a child neurologist, Dr. Cohen sees adults and children with mitochondrial diseases and brain tumors. Id. at 412. Although Dr. Cohen does not diagnose ASDs, some of his patients have autism as well as suspected mitochondrial diseases. Id. at 417. He routinely diagnoses mitochondrial diseases or dysfunction in his patients, estimating that he has seen several thousand patients in which the disease was suspected, or actually diagnosed, since 1994. Id. at 416. Of the nearly 100 peer-reviewed articles he has published, approximately a fourth of them are readily discernible as dealing primarily with issues of mitochondrial dysfunction. See generally, Resp't's Ex. B.
Relying on his experience treating patients with mitochondrial diseases, Dr. Cohen formulated his opinion after reviewing L.V.'s medical records and the expert reports and journal articles filed, along with Petitioners' expert reports. Resp't's Ex. A at 4; Tr. at 423. Based on this review, Dr. Cohen opined that there is no credible evidence that L.V. has a mitochondrial illness, or that any vaccination L.V. received in any way contributed to his autism or other medical conditions. Resp't's Ex. A at 4.
Dr. Cohen began by providing an overview of mitochondria, and the function they play in the generation of energy necessary for the human body. Tr. at 424. He explained that mitochondria exist in all mammalian cells, except for mature red blood cells. Id. at 425. Mitochondria are one micron in length, or one-forty-thousandth of an inch, and have an outer membrane and an inner mitochondrial membrane. Id. The mitochondria generate energy, or adenosine triphosphate ("ATP"),
Because not all mitochondrial diseases are the same, not every patient displays the same symptoms, though there are some classic phenotypes. Tr. at 430. Mitochondrial diseases were described as early as 1930, and since that time the diagnostic criteria used to discern if an individual suffers from such a disease have been refined. Id. at 429-30. The development of genetic testing, however, has increased the surety of the diagnosis, lessening the reliance on muscle biopsies or enzymology,
Dr. Cohen discussed the differences between primary and secondary mitochondrial disease. Tr. at 434. Primary mitochondrial disease refers to those diseases that have a "known, verified genetic cause that is linked to the clinical phenotype of the patient" and "primarily affect the mitochondrial structure." Id. Although primary mitochondrial dysfunction can be most directly diagnosed by genetic testing, it can still be properly diagnosed even in the absence of such testing if the patient's symptoms match a known phenotype, such as Leigh disease. Id. at 435-36. Secondary mitochondrial disease usually involves a problem external to the mitochondria that indirectly produces metabolic dysfunction, such as a genetic defect that causes iron not to be processed properly, with the excess iron harming the mitochondria. Id. at 435-36, 595. Dr. Cohen also discussed mitochondrial dysfunction, which he defined as a "global, generic term" referring to when the mitochondria work imperfectly or are overloaded, but not necessarily as the result of disease. Id. at 435-36. Such mitochondrial dysfunction can occur in otherwise benign, everyday contexts (i.e. eating a high-fat meal). Id. at 436.
To diagnose a mitochondrial disease, Dr. Cohen proposed, a physician should begin with a patient's medical history, including a physical exam and family history. Tr. at 432. If the patient fits a known mitochondrial disease phenotype, then the physician should conduct tests of the blood, urine, and cerebral spinal fluid for indication of the mitochondrial process. Id. at 433. While some biochemical markers on their own may suggest dysfunction, Dr. Cohen proposed that review of biomarker test results should be considered collectively rather than in isolation. Id. at 461, 477. The physician should also do a functional organ test, depending on which organ(s) the physician suspects the mitochondrial disease may be affecting. Id. Other factors indicative of an ongoing disease process are evidence of too few mitochondria or (in the case of adults) too few mtDNA. Id. at 460.
A muscle biopsy with electron or light microscopy testing can also be performed to confirm the presence of a mitochondrial disease. Tr. at 452. Through electron microscopy, a piece of muscle is processed and then magnified 25 to 40,000 times. Id. at 456. In light microscopy, by contrast, a pathologist takes a piece of muscle, slices it into thin sections for staining with different stains, sometimes at different pH levels, and then looks at it under an ordinary microscope to make a diagnosis. Id. at 452-53. As science has evolved, however, the emphasis placed on the importance or meaning of certain tests used to diagnose mitochondrial disease has changed, Dr. Cohen indicated. Thus, because over the past several years genetic testing capable of reliably confirming a mitochondrial disease has become more widely available, the significance of muscle biopsies and other tests have greatly diminished. Id. at 434.
One recent piece of literature Dr. Cohen co-authored and emphasized as particularly useful in understanding what factors are most suggestive of the existence of a mitochondrial disease is R. Haas, et al., Mitochondrial Disease: A Practical Approach for Primary Care Physicians, 120 PEDIATRICS 1326 (2007), filed as Ct. Ex. 1. ECF No. 133.
Dr. Cohen provided examples of the ways in which certain nonspecific criteria (that in the past might have been given more weight in making a mitochondrial disease diagnosis) were not particularly useful in signifying the presence of the disease. Thus, Dr. Cohen noted that the gastrointestinal dysfunction commonly experienced by individuals with an ASD was not commensurate with the far more severe kind of gastrointestinal symptoms those with classic phenotypes of mitochondrial diseases experienced. Tr. at 441-44. Similarly, the level of brain injury suffered in autism was not nearly as progressively debilitating and monophasic as that experienced by someone diagnosed with Leigh disease (whose brain injuries and other symptoms would in most cases result in death — not the outcome inevitably experienced by those diagnosed with an ASD). Id. at 434, 439.
Dr. Cohen also expressed the overarching opinion that the scientific community rejects the concept (based on present science) of a link between ASDs and mitochondrial disease (even though in rare circumstances developmental regression is seen with certain mitochondrial diseases). Tr. at 437. He recalled that when he began studying mitochondrial disease, it was widely theorized that autism might be related, given similarities in how suddenly the symptoms could develop, and/or how they seemed to involve similar energy deficiencies. Id. However, as understanding of mitochondrial diseases expanded, in his view medical science was slowly reaching the conclusion that there was no such relationship, given how few of those diagnosed with autism also presented with known symptoms of a mitochondrial disease, and the lack of other links. Id. at 438.
Turning to the record herein, Dr. Cohen explained why he differed with Drs. Kendall's and Frye's mitochondrial disease diagnosis. Tr. 455-56. In Dr. Cohen's view, L.V. merited a score of zero on the Morava scale, given the minimal morphologic data, and lack of persuasive enzymology test results. Resp't's Ex. A at 12. Rather, Dr. Cohen asserted that L.V.'s medical history and clinical phenotype reflected autism without a known etiology. Tr. at 440.
In so doing, Dr. Cohen provided his own understanding of the value of the Morava criteria, especially in light of subsequent scientific thinking on the diagnosis of mitochondrial disease. Tr. at 462-63. He pointed out Dr. Kendall's concurrence that Morava had limited application as the most up-to-date criteria (in particular given the availability today of genetic testing), and that the community of mitochondrial disease-oriented specialists were generally "walking away" from its use. Id. at 463-64, 551, 567. He reiterated the general point that Morava gives too much weight to nonspecific symptoms (for example, "exercise intolerance"). Id. at 445-46. He also stressed, however, that even current clinical diagnostic criteria for evaluating whether a mitochondrial disease was present could not be applied precisely in most cases, and could accordingly result in certain test results being interpreted as abnormal when they did not in fact suggest the presence of disease. Id. at 464-65.
Dr. Cohen examined Dr. Frye's specific application of the Morava criteria in detail. Tr. at 440-41, 444. At the outset, Dr. Cohen observed that L.V.'s clinical presenting features (primarily autistic symptoms and developmental regression) were not congruent with the severe disease phenotypes displayed by children in the study used to develop the Morava criteria (such as MELAS or Leigh disease). Id. at 465-66, 603. Dr. Cohen therefore suggested that (although he did not take issue with Dr. Frye's decision to consider the possibility that L.V. had a mitochondrial disease), the diagnostic utility of the Morava criteria in this context should have been viewed with some skepticism.
Turning to the specific Morava criteria tallies, Dr. Cohen opined that the point given by both Drs. Kendall and Frye for exercise intolerance was inappropriate. Exercise intolerance seen in relation to a mitochondrial disease is typically a product of "myopathy, muscle disease, or nerve neuropathy, nerve disease, or cardiomyopathy."
Dr. Cohen also challenged the point denoted by Dr. Frye for L.V.'s ASD. Tr. at 469. In Dr. Cohen's interpretation, L.V's developmental regression was more reflective of idiopathic autism than a mitochondrial disease. Id. at 471-72. In patients with mitochondrial diseases, Dr. Cohen testified, problems in brain function are clearly demonstrated through evidence of brain atrophy, lesions in the brain, and/or lactate peaks on their MRI scans, and can result in dementia and other severe, progressive declines in function that are measurable. Id. at 575. That kind of drastic loss of cognitive skills associated with mitochondrial diseases is readily distinguishable from the loss of cognitive skills in autism, or the loss demonstrated by L.V.'s history, which Dr. Cohen argued discounted scoring it under Morava's point system. Id.
Dr. Cohen further testified that L.V. should receive a score of zero under the Morava criteria for his purported gastrointestinal symptoms. L.V.'s constipation was mild enough to be relieved by miralax, and therefore did not rise to the level of severity commonly associated with mitochondrial diseases. Tr. at 444; Resp't's Ex. A at 12. Dr. Cohen elaborated that the gastrointestinal disturbances common to ASD look markedly different from those experienced by patients with classic mitochondrial phenotypes. Tr. at 438-39. Patients with definite mitochondrial diseases, like MELAS, experience total, severe obstruction that may require exploratory surgery to find the blockage. Id. at 442. In contrast, ASD patient constipation is much less severe. Id. at 443.
With respect to the results of various lab tests performed on L.V., Dr. Cohen maintained that even though some of the results revealed abnormalities that might merit some consideration under the Morava criteria, they were either uncorroborated by other confirmatory tests or simply overwhelmed by the weight of far more persuasive evidence that in fact L.V. did not have a mitochondrial disease. Tr. at 477.
Thus, Dr. Cohen expressed the view that the results of L.V.'s laboratory tests were also not worthy of any Morava points. Tr. at 446. With respect to the lactic acid measurements, Dr. Cohen stressed that such testing is routinely prone to false elevation because "struggling" can raise the lactic acid (and struggling is far more likely when a biopsy is obtained from a child). Id. at 447. Here, Dr. Cohen proposed that the results showing elevated lactate levels were questionable for that very reason. Resp't's Ex. A at 13. Furthermore, Dr. Cohen noted that L.V.'s amino acid testing and the alanine-to-lysine ratio
As for the abnormal ethylmalonic acid and tricarboxylic acid/Krebs cycle intermediates test results, Dr. Cohen did not consider the results to be sufficiently high, or sufficiently confirmed by additional testing, therefore suggesting only that further in-depth evaluation was required to determine if there was in fact mitochondrial dysfunction. Tr. at 450, 559-60. In addition, the acylglycine test results (used to help confirm the meaningfulness of abnormal ethylmalonic acid and kreb cycle intermediates results) were normal, further diminishing the value of some of these abnormal biomarker test results. Id. at 450.
The last category — mitochondrial morphology — also received a score of zero from Dr. Cohen. Resp't's Ex. A at 10, 12. While Dr. Cohen agreed that abnormal morphology — specifically the presence of increased mitochondria with some swelling (Resp't's Ex. A at 7) — was seen on L.V.'s electron microscopy, there were "no light microscopy correlates." Id. at 13. According to Dr. Cohen, there are "well-established immunohistochemical features" that should have been seen on "light microscopy," such as ragged red fibers and COX-negative fibers, none of which were found in L.V.'s muscle biopsy. Id. Otherwise, the finding that L.V.'s electron miscroscopy results showed swollen mitochondria was more consistent with a lab error than disease, and would therefore "be a stretch" to award a point under Morava. Id. at 11; Tr. at. 451-56. If the swelling was in fact indicative of a mitochondrial disease, the patient would also display disruption in the interim crystalline structure. Tr. at 457. Moreover, the amount of cytochrome oxidase enzyme
Dr. Cohen took issue with two of the pieces of literature offered in support of Dr. Kendall's report. He dismissed her reference to the Poling article (a case report involving vaccines other than the flu vaccine) as insufficient to draw an association between vaccinations and the development of mitochondrial disorders in children with autism. Tr. at 476-77. He similarly dismissed the Shoffner article as having little bearing herein. Even if L.V. had a mitochondrial dysfunction, there is, in Dr. Cohen's opinion, no known association between the flu vaccine and aggravation of a mitochondrial disease. Id. at 479-80.
Finally, Dr. Cohen addressed some components of Dr. Shafrir's theory that L.V.'s regression was the result of an autoimmune encephalopathy. He disputed that L.V. had experienced a regressive form of autism caused by an autoimmune encephalopathy induced by the first vaccination and magnified by the second vaccination, observing that the record suggested that L.V.'s problems actually began prior to his first flu vaccination. Tr. at 482-83. Dr. Cohen also challenged the conclusion that L.V. had experienced any traumatic brain injury along the lines of an encephalopathy, noting that MRI scans of children with autoimmune encephalopathy will often show particular abnormalities absent in this case. Thus, testing of brains in cases of anti-NMDA receptor antibody autoimmune encephalopathies will often show disease in the temporal lobes or other parts of the brain. Id. at 508-09. But, as conceded by Dr. Shafrir, L.V.'s MRI showed no similar abnormalities. Id. at 363. Moreover, none of L.V.'s treaters performed the kinds of tests that Dr. Cohen would expect would be performed if anti-NMDA receptor encephalitis had been suspected (such as a spinal tap, an imaging study like a CT scan or an MRI scan, or an EEG), nor was immunoglobulin therapy
Prior to analyzing Petitioners' claims, it would be beneficial to briefly consider the two medical conditions most relevant to this case (along with relevant case law dealing with both in the Vaccine Program): ASDs and mitochondrial disorders. The summary below is derived from materials filed by both parties in this case, as well as discussions of the conditions set forth in the decisions of other special masters or the Court of Federal Claims.
Autism or ASD encompasses a group of complex neurodevelopmental disorders characterized by "self-absorption, impairment in social interaction and communication, and a restricted range of activities and interests." Dorland's at 180; see also Autism Spectrum Disorder Fact Sheet, NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKES, Oct. 7, 2015, available at http://www.ninds.nih.gov/disorders/autism/detail_autism.html (last visited Feb. 11, 2016). Children diagnosed with ASD are often reported by their parents to have displayed developmental or behavioral problems around 18 months of age, if not by the age of two, and a significant minority of children with ASD experience regression/loss of skills, including language or vocabulary. Lehner v. Sec'y of Health & Human Servs., No. 08-554V, 2015 WL 5443461, at *34-35 (Fed. Cl. Spec. Mstr. July 22, 2015) (discussing the diagnostic criteria and characteristics of ASDs).
Since the resolution of the OAP cases, there have been numerous petitions attempting to establish that a variety of vaccines cause autism or an ASD, based on causations theories highly similar to those asserted in the present action. See, e.g., Hardy v. Sec'y of Health & Human Servs., No. 08-108V, 2015 WL 7732603, at *4-5 (Fed. Cl. Spec. Mstr. Nov. 3, 2015) (petitioners failed to demonstrate that DTaP vaccine caused or significantly aggravated underlying mitochondrial disease resulting in ASD); Miller v. Sec'y of Health & Human Servs., No. 02-235V, 2015 WL 5456093 (Fed. Cl. Spec. Mstr. Aug. 18, 2015) (petitioners failed to demonstrate that several childhood vaccines caused encephalopathy or aggravated underlying mitochondrial disease/dysfunction); Lehner, 2015 WL 5443461 (petitioners failed to demonstrate that flu vaccine resulted in autoimmune encephalitis). As Special Master Hastings noted in the recent Hardy decision, however, to date every post-OAP non-Table claim
Mitochondrial disease is (as put by Dr. Kendall) a "heterogeneous group of disorders that affect the body's ability to ultimately metabolize energy through a series of complicated reactions inside the mitochondria." Tr. at 112-13. Mitochondrial disease can manifest with a multitude of symptoms, including autism or autistic features and gastrointestinal symptoms, both of which L.V. experienced. Id. at 113, 173. Classic phenotypes of mitochondrial disease are "usually progressive and multisystemic" (Haas at 1327) and progressively severe, especially in the case of infants and young children. Id. at 1329-30. But (as all experts testifying in this case agreed), it can be difficult to diagnose mitochondrial disease given the variety of possible symptoms and the lack of a reliable and agreed-upon diagnostic biomarker. Id. at 1327; Tr. at 114, 431-32. Thus, based upon up-to-date medical and scientific thinking on the topic, the clearest diagnostic evidence that an individual in fact has a mitochondrial disease is provided by genetic testing. Haas at 1327; Tr. at 433-44.
There are differences between a mitochondrial "disease," "disorder," and "dysfunction." As Dr. Kendall put it, "mitochondrial disease is a situation in which either you have definitive information that clearly states that this person has a mitochondrial disease based on laboratory and other factors," while mitochondrial dysfunction is the proper term when there is not a clear diagnosis. Tr. at 115. Dr. Cohen largely echoed this distinction, albeit by reframing the distinction as between primary and secondary mitochondrial disease (which, as Haas defines it, is the result not of a genetic mutation directly affecting the functioning of the electron transport chain, but instead reflects impairment of the oxidative phosphorylation process by an "unrelated genetic or environmental cause.") Haas at 1330; Tr. at 435-36 (characterizing the phrase "mitochondrial dysfunction" as "a very global generic term"). Ultimately, Dr. Kendall used the terms "mitochondrial disease" and "mitochondrial disorder" somewhat interchangeably, while stressing that the existence of a secondary mitochondrial disease, less severe than more classic phenotypes such as Leigh disease, was nevertheless in her opinion sufficient to make the introduction of a vaccine problematic. Tr. at 235.
The Petitioners' argument that L.V. suffered from some form of mitochondrial disease relies on a specific set of diagnostic criteria applicable to children first set forth in 2006 and referred to in this decision as the "Morava" criteria. See generally Pet'rs' Ex. 41, Ref. 25. It is uncontested that Dr. Frye's and Dr. Kendall's diagnoses of L.V. rely on application of the Morava criteria. Tr. at 120. Dr. Cohen also applied these criteria in reviewing Petitioners' arguments (although he questioned whether they have become obsolescent in light of scientific progress in understanding mitochondrial disease).
The Morava criteria include three broad categories — clinical signs and symptoms, metabolic/imaging studies, and morphology — and then, within each category, assign points to certain defined symptoms or test results as set forth on a table contained in the article in which the criteria were first proposed. Morava at 1824. Thus, one of the subcategories under the "clinical signs and symptoms" heading is "CNS presentation," which in turn sets forth ten different possible symptoms, such as seizures, developmental delay, or cortical blindness, each of which is worth a point under the proposed Morava system, with a "cap" of two points possible for this category. Id. Similarly, the metabolic/imaging studies category sets forth eleven possible test results that could merit awarding points (such as evidence of ethylmalonic aciduria or elevated lactate). Id.
Once points have been assigned, they are totaled and then compared to a range to determine the likelihood that the patient has a mitochondrial disease. A score of one means that disease is unlikely; two to four points merit a determination of "possible" mitochondrial disease; five to seven points suggest mitochondrial disease is "probable"; and eight points or more result in the determination that mitochondrial disease is definitely present. Morava at 1824 (Table). By the Morava criteria's own parameters, some symptoms are given slightly less weight than others, with certain muscle biopsy morphology results given up to four points. Id. Indeed, as the Morava authors acknowledged at the time of the article's writing, some of the criteria's utility lay in making the very determination as to whether a muscle biopsy should be performed. Id. at 1823 ("[t]he method could also be applied in children with a suspected mitochondrial disorder prior to performing a muscle biopsy").
Importantly, however, in the ten years that have passed since the publication of Morava, there has been refinement of the diagnostic tools used to make the difficult determination of whether an individual in fact suffers from a mitochondrial disease. Haas anticipated this progress,
It has become more common for Vaccine Program petitioners to assert that a particular vaccine caused, or exacerbated, a child's preexisting, often-unidentified metabolic disorder, such as a mitochondrial disease, and that the disease was affected by the vaccine in such a way as to precipitate the child's autism or ASD-like symptoms. However, to date the vast majority of petitioners have failed in establishing any of the Althen elements in support of this kind of theory, regardless of the vaccine at issue. See, e.g., Hardy, 2015 WL 7732603; R.K. v. Sec'y of Health & Human Servs, slip. op. (Fed. Cl. Spec. Mstr. Sept. 28, 2015), mot. for review den'd, ___ Fed. Cl. ___ (Dec. 18, 2015); Padmanabhan v. Sec'y of Health & Human Servs., No. 11-141V, 2015 WL 1736345 (Fed. Cl. Spec. Mstr. Mar. 26, 2015), mot. for review den'd, No. 11-141V (Fed. Cl. Aug. 6, 2015), aff'd, ___ F.3d ____, 2016 WL 463085 (Fed. Cir. 2016) (petitioners failed to demonstrate plausible causation theory in support of claim that child's preexisting mitochondrial disease was significantly aggravated by vaccines).
The only exception to the above is Paluck v. Sec'y of Health & Human Servs., 786 F.3d 1373 (Fed. Cir. 2015). There, the Federal Circuit affirmed a Court of Federal Claims' determination that a special master erred in denying compensation to petitioners claiming (in a non-Table case) that the MMR, varicella, and pneumococcal vaccines significantly aggravated their child's mitochondrial disease, resulting in severe neurodegeneration. However, that case is facially distinguishable — not only because it involved different vaccines and a more obvious immediate reaction
To receive compensation in the Vaccine Program, a petitioner must prove either: (1) that he suffered a "Table Injury" — i.e., an injury falling within the Vaccine Injury Table — corresponding to one of the vaccinations in question within a statutorily prescribed period of time or, in the alternative, (2) that his illnesses were actually caused by a vaccine (a "Non-Table Injury"). See Sections 13(a)(1)(A), 11(c)(1), and 14(a), as amended by 42 C.F.R. § 100.3; § 11(c)(1)(C)(ii)(I); see also Moberly v. Sec'y of Health & Human Servs., 592 F.3d 1315, 1321 (Fed. Cir. 2010); Capizzano v. Sec'y of Health & Human Servs., 440 F.3d 1317, 1320 (Fed. Cir. 2006).
Vaccine Program petitioners bear a "preponderance of the evidence" burden of proof. Section 13(1)(a). That is, a petitioner must offer evidence that leads the "trier of fact to believe that the existence of a fact is more probable than its nonexistence before [he] may find in favor of the party who has the burden to persuade the judge of the fact's existence." Moberly, 592 F.3d at 1322 n.2; see also Snowbank Enter. v. United States, 6 Cl. Ct. 476, 486 (1984) (mere conjecture or speculation is insufficient under a preponderance standard). Proof of medical certainty is not required. Bunting v. Sec'y of Health & Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991). In particular, a petitioner must demonstrate that the vaccine was "not only [the] but-for cause of the injury but also a substantial factor in bringing about the injury." Moberly, 592 F.3d at 1321 (quoting Shyface v. Sec'y of Health & Human Servs., 165 F.3d 1344, 1352-53 (Fed. Cir. 1999)); Pafford v. Sec'y of Health & Human Servs., 451 F.3d 1352, 1355 (Fed. Cir. 2006). A petitioner may not receive a Vaccine Program award based solely on his assertions; rather, the petition must be supported by either medical records or by the opinion of a competent physician. Section 13(a)(1).
In attempting to establish entitlement to a Vaccine Program award of compensation, a petitioner must satisfy all three of the elements established by the Federal Circuit in Althen: "(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 showing of a proximate temporal relationship between vaccination and injury." Althen, 418 F.3d at 1278.
Each of the Althen prongs requires a different showing. Under Althen prong one, petitioners must provide a "reputable medical theory," demonstrating that the vaccine received can cause the type of injury alleged. Pafford, 451 F.3d at 1355-56 (citations omitted). To satisfy this prong, petitioner's theory must be based on a "sound and reliable medical or scientific explanation." Knudsen v. Sec'y of Health & Human Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). Such a theory must only be "legally probable, not medically or scientifically certain." Knudsen, 35 F.3d at 549.
Petitioners may satisfy the first Althen prong without resort to medical literature, epidemiological studies, demonstration of a specific mechanism, or a generally accepted medical theory. Andreu v. Sec'y of Health & Human Servs., 569 F.3d 1367, 1378-79 (Fed. Cir. 2009) (citing Capizzano, 440 F.3d at 1325-26). Special masters, despite their expertise, are not empowered by statute to conclusively resolve what are essentially thorny scientific and medical questions, and thus scientific evidence offered to establish Althen prong one is viewed "not through the lens of the laboratorian, but instead from the vantage point of the Vaccine Act's preponderant evidence standard." Id. at 1380. Accordingly, special masters must take care not to increase the burden placed on petitioners in offering a scientific theory linking vaccine to injury. Contreras v. Sec'y of Health & Human Servs., 121 Fed. Cl. 230, 245 (2015) ("[p]lausibility . . . in many cases may be enough to satisfy Althen prong one" (emphasis in original)). But this does not negate or reduce a petitioner's ultimate burden to establish his entitlement to damages by preponderant evidence. W.C. v. Sec'y of Health & Human Servs., 704 F.3d 1352, 1356 (Fed. Cir. 2013) (citations omitted).
The second Althen prong requires proof of a logical sequence of cause and effect, usually supported by facts derived from a petitioner's medical records. Althen, 418 F.3d at 1278; Andreu, 569 F.3d at 1375-77; Capizzano, 440 F.3d at 1326; Grant v. Sec'y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992). In establishing that a vaccine "did cause" injury, the opinions and views of the injured party's treating physicians are entitled to some weight. Andreu, 569 F.3d at 1367; Capizzano, 440 F.3d at 1326 ("medical records and medical opinion testimony are favored in vaccine cases, as treating physicians are likely to be in the best position to determine whether a `logical sequence of cause and effect show[s] that the vaccination was the reason for the injury'") (quoting Althen, 418 F.3d at 1280). Medical records are generally viewed as particularly trustworthy evidence, since they are created contemporaneously with the treatment of the patient. Cucuras v. Sec'y of Health & Human Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993).
However, medical records and/or statements of a treating physician's views do not per se bind the special master to adopt the conclusions of such an individual, even if they must be considered and carefully evaluated. Section 13(b)(1) (providing that "[a]ny such diagnosis, conclusion, judgment, test result, report, or summary shall not be binding on the special master or court"); Snyder v. Sec'y of Health & Human Servs., 88 Fed. Cl. 706, 746 n.67 (2009) ("there is nothing . . . that mandates that the testimony of a treating physician is sacrosanct—that it must be accepted in its entirety and cannot be rebutted"). As with expert testimony offered to establish a theory of causation, the opinions or diagnoses of treating physicians are only as trustworthy as the reasonableness of their suppositions or bases. The views of treating physicians should also be weighed against other, contrary evidence also present in the record — including conflicting opinions among such individuals. Hibbard v. Sec'y of Health & Human Servs., 100 Fed. Cl. 742, 749 (2011) (not arbitrary or capricious for special master to weigh competing treating physicians' conclusions against each other), aff'd, 698 F.3d 1355 (Fed. Cir. 2012); Caves v. Sec'y of Dep't of Health & Human Servs., 100 Fed. Cl. 119, 136 (2011), aff'd, 463 F. App'x 932 (Fed. Cir. 2012); Veryzer v. Sec'y of Health & Human Servs., No. 06-522V, 2011 WL 1935813, at *17 (Fed. Cl. Spec. Mstr. Apr. 29, 2011).
The third Althen prong requires establishing a "proximate temporal relationship" between the vaccination and the injury alleged. Althen, 418 F.3d at 1281. That term has been equated to the phrase "medically-acceptable temporal relationship." Id. A petitioner must offer "preponderant proof that the onset of symptoms occurred within a timeframe which, given the medical understanding of the disorder's etiology, it is medically acceptable to infer causation." Bazan v. Sec'y of Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for what is a medically acceptable timeframe must also coincide with the theory of how the relevant vaccine can cause an injury (Althen prong one's requirement). Id. at 1352; Shapiro v. Sec'y of Health & Human Servs., 101 Fed. Cl. 532, 542 (2011), recons. den'd after remand, 105 Fed. Cl. 353 (2012), aff'd mem., 2013 WL 1896173 (Fed. Cir. 2013); Koehn v. Sec'y of Health & Human Servs., No. 11-355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for review den'd (Fed. Cl. Dec. 3, 2013), aff'd, 773 F.3d 1239 (Fed. Cir. 2014).
In this matter, besides arguing that the flu vaccine caused L.V.'s autism and/or autistic regression, Petitioners also offer a parallel theory that the flu vaccine significantly aggravated a preexisting condition in L.V. — his purported mitochondrial disease. Where a petitioner so alleges, the Althen test is expanded, as a petitioner has additional evidentiary burdens to satisfy. See generally Loving v. Sec'y of Health & Human Servs., 86 Fed. Cl. 135, 144 (2009). In Loving, the Court of Federal Claims combined the Althen test with the test from Whitecotton v. Sec'y of Health & Human Servs., 81 F.3d 1099, 1107 (Fed.Cir.1996), which related to on-Table significant aggravation cases. The resultant "significant aggravation" test has six components, which are:
Loving, 86 Fed. Cl. at 144; see also W.C. v. Sec'y of Health & Human Servs., 704 F.3d 1352, 1357 (Fed. Cir. 2013) (holding that "the Loving case provides the correct framework for evaluating off-table significant aggravation claims"). In effect, the last three prongs of the Loving test correspond to the three Althen prongs.
The process for making determinations in Vaccine Program cases regarding factual issues begins with consideration of the medical records. Section 11(c)(2). The special master is required to consider "all [] relevant medical and scientific evidence contained in the record," including "any diagnosis, conclusion, medical judgment, or autopsy or coroner's report which is contained in the record regarding the nature, causation, and aggravation of the petitioner's illness, disability, injury, condition, or death," as well as "the results of any diagnostic or evaluative test which are contained in the record and the summaries and conclusions." Section 13(b)(1)(A). The special master is then required to weigh the evidence presented, including contemporaneous medical records and testimony. See Burns v. Sec'y of Health & Human Servs., 3 F.3d 415, 417 (Fed. Cir. 1993) (it is within the special master's discretion to determine whether to afford greater weight to contemporaneous medical records than to other evidence, such as oral testimony surrounding the events in question that was given at a later date, provided that such a determination is evidenced by a rational determination).
Medical records that are created contemporaneously with the events they describe are presumed to be accurate and "complete" (i.e., presenting all relevant information on a patient's health problems). Cucuras, 993 F.2d at 1528; Doe/70 v. Sec'y of Health & Human Servs., 95 Fed. Cl. 598, 608 (2010) ("[g]iven the inconsistencies between petitioner's testimony and his contemporaneous medical records, the special master's decision to rely on petitioner's medical records was rational and consistent with applicable law"), aff'd, Rickett v. Sec'y of Health & Human Servs., 468 F. App'x 952 (Fed. Cir. 2011) (non-precedential opinion). This presumption is based on the linked propositions that (i) sick people visit medical professionals; (ii) sick people honestly report their health problems to those professionals; and (iii) medical professionals record what they are told or observe when examining their patients in as accurate a manner as possible, so that they are aware of enough relevant facts to make appropriate treatment decisions. Sanchez v. Sec'y of Health & Human Servs., No. 11-685V, 2013 WL 1880825, at *2 (Fed. Cl. Spec. Mstr. Apr. 10, 2013); Cucuras v. Sec'y of Health & Human Servs., 26 Cl. Ct. 537, 543 (1992), aff'd, 993 F.2d 1525 (Fed. Cir. 1993) ("[i]t strains reason to conclude that petitioners would fail to accurately report the onset of their daughter's symptoms. It is equally unlikely that pediatric neurologists, who are trained in taking medical histories concerning the onset of neurologically significant symptoms, would consistently but erroneously report the onset of seizures a week after they in fact occurred").
Accordingly, if the medical records are clear, consistent, and complete, then they should be afforded substantial weight. Lowrie v. Sec'y of Health & Human Servs., No. 03-1585V, 2005 WL 6117475, at *20 (Fed. Cl. Spec. Mstr. Dec. 12, 2005). Indeed, contemporaneously medical records are generally found to be deserving of greater evidentiary weight than oral testimony — especially where such testimony conflicts with the record evidence. Cucuras, 993 F.2d at 1528; see also Murphy v. Sec'y of Health & Human Servs., 23 Cl. Ct. 726, 733 (1991), aff'd, 968 F.2d 1226 (Fed. Cir.), cert. den'd, Murphy v. Sullivan, 506 U.S. 974 (1992) (citing United States v. United States Gypsum Co., 333 U.S. 364, 396 (1947) ("[i]t has generally been held that oral testimony which is in conflict with contemporaneous documents is entitled to little evidentiary weight.")).
However, there are situations in which compelling oral testimony may be more persuasive than written records, such as where records are deemed to be incomplete or inaccurate. Campbell v. Sec'y of Health & Human Servs., 69 Fed. Cl. 775, 779 (2006) ("like any norm based upon common sense and experience, this rule should not be treated as an absolute and must yield where the factual predicates for its application are weak or lacking"); Lowrie, 2005 WL 6117475, at *19 ("[w]ritten records which are, themselves, inconsistent, should be accorded less deference than those which are internally consistent") (quoting Murphy v. Sec'y of Health & Human Servs., 23 Cl. Ct. 726, 733 (1991), aff'd per curiam, 968 F.2d 1226 (Fed. Cir. 1992)). Ultimately, a determination regarding a witness's credibility is needed when determining the weight that such testimony should be afforded. Andreu, 569 F.3d at 1379; Bradley v. Sec'y of Health & Human Servs., 991 F.2d 1570, 1575 (Fed. Cir. 1993).
When witness testimony is offered to overcome the presumption of accuracy afforded to contemporaneous medical records, such testimony must be "consistent, clear, cogent, and compelling." Sanchez, 2013 WL 1880825, at *3 (citing Blutstein v. Sec'y of Health & Human Servs., No. 90-2808V, 1998 WL 408611, at *5 (Fed. Cl. Spec. Mstr. June 30, 1998)). In determining the accuracy and completeness of medical records, the Court of Federal Claims has listed four possible explanations for inconsistencies between contemporaneously created medical records and later testimony: (1) a person's failure to recount to the medical professional everything that happened during the relevant time period; (2) the medical professional's failure to document everything reported to her or him; (3) a person's faulty recollection of the events when presenting testimony; or (4) a person's purposeful recounting of symptoms that did not exist. La Londe v. Sec'y Health & Human Servs., 110 Fed. Cl. 184, 203-04 (2013), aff'd, 2014 WL 1258137 (Fed. Cir. Mar. 28, 2014). In making a determination regarding whether to afford greater weight to contemporaneous medical records or other evidence, such as testimony at hearing, there must be evidence that this decision was the result of a rational determination. Burns, 3 F.3d at 417.
Establishing a sound and reliable medical theory often requires a petitioner to present expert testimony in support of his claim. Lampe v. Sec'y of Health & Human Servs., 219 F.3d 1357, 1361 (Fed. Cir. 2000). Vaccine Program expert testimony is usually evaluated according to the factors for analyzing scientific reliability set forth in Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579, 594-96 (1993). See Cedillo v. Sec'y of Health & Human Servs., 617 F.3d 1328, 1339 (Fed. Cir. 2010) (citing Terran v. Sec'y of Health & Human Servs., 195 F.3d 1302, 1316 (Fed. Cir. 1999)). "The Daubert factors for analyzing the reliability of testimony are: (1) whether a theory or technique can be (and has been) tested; (2) whether the theory or technique has been subjected to peer review and publication; (3) whether there is a known or potential rate of error and whether there are standards for controlling the error; and (4) whether the theory or technique enjoys general acceptance within a relevant scientific community." Terran, 195 F.3d at 1316 n.2 (citing Daubert, 509 U.S. at 592-95).
The Daubert factors play a slightly different role in Vaccine Program cases than they do when applied in other federal judicial fora (such as the district courts). Daubert factors are usually employed by judges (in the performance of their evidentiary gatekeeper roles) to exclude evidence that is unreliable and/or could confuse a jury. In Vaccine Program cases, by contrast, these factors are used in the weighing of the reliability of scientific evidence proffered. Davis v. Sec'y of Health & Human Servs., 94 Fed. Cl. 53, 66-67 (2010) ("uniquely in this Circuit, the Daubert factors have been employed also as an acceptable evidentiary-gauging tool with respect to persuasiveness of expert testimony already admitted"). The flexible use of the Daubert factors to evaluate the persuasiveness of expert testimony has routinely been upheld. See, e.g., Snyder, 88 Fed. Cl. at 742-45. In this matter (as in numerous other Vaccine Program cases), Daubert has not been employed at the threshold, to determine what evidence should be admitted, but instead to determine whether expert testimony offered is reliable and/or persuasive.
Respondent frequently offers one or more experts of her own in order to rebut petitioner's case. Where both sides offer expert testimony, a special master's decision may be "based on the credibility of the experts and the relative persuasiveness of their competing theories." Broekelschen v. Sec'y of Health & Human Servs., 618 F.3d 1339, 1347 (Fed. Cir. 2010) (citing Lampe, 219 F.3d at 1362). However, nothing requires the acceptance of an expert's conclusion "connected to existing data only by the ipse dixit of the expert," especially if "there is simply too great an analytical gap between the data and the opinion proffered." Snyder, 88 Fed. Cl. at 743 (quoting Gen. Elec. Co. v. Joiner, 522 U.S. 146 (1997)); see also Isaac v. Sec'y of Health & Human Servs., No. 08-601V, 2012 WL 3609993, at *17 (Fed. Cl. Spec. Mstr. July 30, 2012), mot. for review den'd, 108 Fed. Cl. 743 (2013), aff'd, 540 Fed. App'x 999 (Fed. Cir. 2013) (citing Cedillo, 617 F.3d at 1339). Weighing the relative persuasiveness of competing expert testimony, based on a particular expert's credibility, is part of the overall reliability analysis to which special masters must subject expert testimony in Vaccine Program cases. Moberly, 592 F.3d at 1325-26 ("[a]ssessments as to the reliability of expert testimony often turn on credibility determinations"); see also Porter v. Sec'y of Health & Human Servs., 663 F.3d 1242, 1250 (Fed. Cir. 2011) ("this court has unambiguously explained that special masters are expected to consider the credibility of expert witnesses in evaluating petitions for compensation under the Vaccine Act").
In determining whether a particular expert's testimony was reliable or credible, I may consider whether the expert is offering an opinion that exceeds the expert's training or competence. Walton v. Sec'y of Health & Human Servs., No. 04-503V, 2007 WL 1467307, at *17-18 (Fed. Cl. Spec. Mstr. Apr. 30, 2007) (otolaryngologist not well suited to testify about disciplines other than her own specialty). While (in keeping with the liberality with which evidence offered in Vaccine Program cases is treated) I heard and have considered all of the testimony of the experts offered at the entitlement hearing, I may properly evaluate, and give appropriate weight to, whether certain testimony is beyond a particular expert's purview. See e.g., King v. Sec'y of Health & Human Servs., No. 03-584V, 2010 WL 892296, at *78-79 (Fed. Cl. Spec. Mstr. Mar. 12, 2010) (petitioner's expert far less qualified to offer opinion on general causation issues pertaining to autism than specific issues pertaining to the petitioner's actual medical history, given the nature of the expert's qualifications). The mere fact that a person dons a "white lab coat," so to speak, and then offers an expert opinion does not imbue that opinion with automatic legitimacy.
Both of the Petitioners' causation theories depend on evidentiary fact-findings in their favor — either that L.V. had a specific, preexisting mitochondrial disorder, or that he experienced an autoimmune encephalopathy that in turn produced a dramatic, post-vaccination regression. It is logical to first determine if the evidence supports either requested finding before considering if the Althen prongs can be satisfied. Broekelschen, 618 F.3d at 1346 (when an injury or diagnosis is disputed, and "the proposed injuries differ significantly in their pathology," the special master may "first find which of [the] diagnoses was best supported by the evidence presented in the record before applying the Althen test so that the special master could subsequently determine causation relative to the injury").
Neither expert accepted Dr. Frye's diagnosis that L.V. had a "definite" mitochondrial disease under the Morava criteria, so the primary fact issue posed at trial was whether the evidence established a "probable" disease. Resolving this issue required weighing the testimony of Dr. Kendall
Dr. Cohen's opinion, however, in light of the relevant facts gleaned from the medical records as well as its logic, was the more persuasive of the two. In particular (and although Dr. Cohen did directly grapple with Petitioners' argument that L.V.'s test results and other symptoms met the Morava criteria for diagnosis), his underlying point — that the Morava criteria have been supplanted by more precise diagnostic guidelines, and are therefore not a reliable basis for assessing whether a child has a mitochondrial disease — had considerable force and was unrebutted by Petitioners.
As Dr. Cohen established, Morava's point system, despite its seeming structure, is imprecise, giving too much weight to nonspecific findings, such as exercise intolerance or gastrointestinal problems, and equating them with "red flag" evidence that is closely linked with well-recognized phenotypes of mitochondrial diseases. Petitioners have thus relied on an outdated diagnostic toolset, since current science and medical knowledge (which has made more definitive tests like genetic testing possible) has cast doubt on the significance of certain criteria previously considered important. Thus, even if the Morava criteria were correctly applied under the circumstances to reach the tentative conclusion that L.V. had some mitochondrial disease (subject to a muscle biopsy — one of the possible uses for the criteria, as the article itself indicates (Morava at 1823)), it is evident today that overreliance upon it is inadvisable.
I therefore do not accept Petitioners' assertions that the determination that L.V. had a mitochondrial disease is simply a matter of deciding if Morava's point system is satisfied by the evidence. Rather, I find persuasive Dr. Cohen's testimony that, based on the more up-to-date diagnostic guidelines that differentiate nonspecific symptoms
Regardless of the above, even if I simply apply the Morava criteria mechanically to the various test results and other factors in light of it (but based on each expert's interpretation of those results), I still conclude that the evidence does not preponderate in L.V.'s favor. It is undisputed by both testifying experts that neither genetic testing nor L.V.'s lactate levels were supportive of a mitochondrial disease. See, e.g., tr. at 140. Dr. Cohen also persuasively testified to the diminished value of the nonspecific criteria for which Dr. Frye awarded Morava points, such as L.V.'s ongoing constipation, since they did not amount to the kind of more telling, serious indicia that would suggest to most treaters that an individual actually had a mitochondrial disease. Id. at 566-67 ("[c]onstipation is common in autism. The constipation doesn't rise to the level that we see it in mitochondrial disease"). And Dr. Kendall admitted that other nonspecific findings, such as exercise intolerance, that were the basis for Morava points had little support in the medical record. Id. at 193-94, 245.
The remaining Morava points awarded by Dr. Kendall are based on a mix of biochemical marker and morphology test results. But, as Dr. Cohen established, those findings were either not supportive of the diagnosis, inconclusive in light of subsequent tests (or a failure to repeat an abnormal finding), or could reasonably be interpreted as normal. Dr. Cohen was steadfast in denying the significance of the morphology findings (as observed in the microscopy evaluations of L.V.'s muscle tissue samples), such as the increased mtDNA (which is not associated with pediatric mitochondrial disease in any event) or swollen mitochondria. Tr. at 555-58. He acknowledged that some other biomarker tests (the urinary tricarboxylic acid and ethymalonic aciduria findings) produced elevated results, but convincingly testified that they were insufficiently high to warrant any additional points. Id. at 559, 563.
Drs. Frye's and Kendall's reliance on L.V.'s ASD and related regression as worthy of a Morava point is especially troubling given the undisputed medical record. Dr. Kendall readily acknowledged that L.V. does not have a primary mitochondrial disease, given the lack of severity of other symptoms. Tr. at 237-38. She also struggled to point to evidence from the same record of any dramatic signs of regression post-vaccination, and could identify little to nothing from L.V.'s earlier medical history that evidenced the condition pre-vaccination. Id. at 246-49. And yet, as Dr. Cohen noted, it is only the most severe phenotypes of mitochondrial disease that are associated with the kind of sudden and dramatic decompensations that would establish the existence of the disease. L.V.'s mitochondrial disease was, by contrast, (and as Dr. Kendall admitted), mild — but that cannot be squared with the concept that it nevertheless produced a dramatic change in L.V.
In concluding as I do, I am not attempting to diagnose L.V. myself (an act well outside the purview of my function herein). Rather, I am weighing the sufficiency of the evidence presented from a legal standpoint — and finding that such evidence does not make it "more likely than not" that L.V. suffered from a mitochondrial disease of any kind. I have given consideration to the treatment evidence from Dr. Frye upon which the Petitioners rely. But as noted above, a treater's opinion need not be accepted at face value, but is subject to weighing against the other evidence in the case. Snyder, 88 Fed. Cl. at 746 n.67. Dr. Frye's conclusions (which were arrived at four to five years ago, and well after the vaccination event in question) are undermined not merely by Dr. Cohen's more persuasive interpretation of the relevant test results, but also by the fact that none of L.V.'s immediate treaters (who were present contemporaneously when L.V.'s developmental regression is alleged to have occurred, and therefore better positioned to observe his symptoms) ever opined that L.V. suffered from a mitochondrial disease or dysfunction, whether before or after he received the flu vaccine. Indeed, Dr. Kelley (to whom the Vs were referred by Dr. Frye) reviewed many of those same test results upon which Dr. Frye based his diagnosis, but offered the conclusion that L.V. likely did not have a mitochondrial disease. Pet'rs' Ex. 26 at 32-33; Tr. at 202-04.
Petitioners offered a second causation theory in this case: that L.V.'s receipt of the flu vaccine precipitated an encephalopathy that resulted in the regression and other ASD symptoms he experienced. As discussed below (in the section on the Althen prongs), there are strong reasons to find this theory wanting. But independent of the theory's scientific plausibility, the facts from the medical records do not support the conclusion that L.V. did experience the encephalopathy necessary under this theory.
The medical records from December 2006 and January 2007 are directly relevant to this part of the Petitioners' case. They plainly demonstrate that on December 13, 2016 — five days after L.V.'s receipt of the second dose of flu vaccine — Mrs. V brought L.V. back to the pediatrician, primarily to treat his ongoing constipation. No mention was made of the second vaccination, let alone any of the kind of symptoms that might be expected if L.V. was suffering a reaction to it (in particular, fever). Pet'rs' Ex. 3 at 134-35. The records from this visit also set forth the fact that he was at that time apparently suffering from an ear infection, but do not note any fever associated with it. Id.
Significantly, the December 13th records contain the first obvious reference to any developmental problems (specifically, speech delay), but provide no detail about whether they had just recently been observed (as opposed to something noticed before). Pet'rs' Ex. 3 at 135. But speech delay is not itself congruent with the severe regressive occurrence alleged in this case — especially given the absence of evidence of any other kind of medically-concerning reaction to the vaccine received less than a week earlier, such as a high fever. And the probative value of the timing of this reported speech delay is further diminished by later, particularly persuasive contemporaneous evidence (beginning in January 2007) that the Vs repeatedly told treaters that they had observed the start of L.V.'s developmental plateau or regression before he was 22 months old. See, e.g., Pet'rs' Ex. 13 at 8 and Ex. 5 at 4.
The next most significant contemporaneous records relevant to the encephalopathy-related assertions are from December 22 and 26, 2006. These detail treatment of L.V.'s ongoing ear infection, and establish that (several days after the start of the infection) he did eventually develop a fever over 100 degrees, going as high as 104 degrees. Pet'rs' Ex. 3 at 138-40. However, the fever does not appear to have been persistent, and by December 26, 2006, the records merely note a rash, suggesting that in the ensuing period the fever had resolved. Id. at 144. Certainly the records do not reflect L.V.'s hospitalization in this period, or any other truly catastrophic reaction requiring emergency intervention; rather, they establish the Vs' diligence in attending to L.V.'s care over the holidays by reporting his fever and other ear infection symptoms to their primary care pediatrician. And there are no further records of L.V. seeing the pediatrician until several weeks later, in January — by which time the Vs had already begun the process of having L.V. professionally evaluated for his developmental problems. Such evidence does not support the contention that L.V. experienced an encephalopathy.
For purposes of comparison, it is instructive to consider the facts of the Poling and Wright cases, where petitioners successfully established (or settled) Table claim
Petitioners have offered little else to prove that an encephalopathy in fact occurred. An encephalopathy can often be corroborated after the fact, through an MRI, direct evidence of inflammation, or testing demonstrating the presence of certain antibodies associated with autoimmune reactions affecting the brain — but as both of Petitioners' experts admitted, there is no such evidence in this case. Tr. at 201-02, 362-64. And no treaters who saw L.V. at the relevant time opined otherwise. The overall factual record (as Dr. Cohen proposed, based on his review of L.V.'s treatment history and in light of his experience as a pediatric neurologist) does not support the conclusion that L.V. experienced any encephalopathy of the sort that would prompt the dramatic regression alleged by Petitioners. Id. at 508-14.
Petitioners' claim depends upon my finding that L.V. either had a mitochondrial disease or experienced a post-vaccination encephalopathic regression, so my contrary factual conclusions are fatal to their case. Yet review of the three Althen prongs for establishing a non-Table causation case reveals that Petitioners could not otherwise prevail on their claim due to evidentiary failures independent of my fact-findings set forth above.
The greatest deficiency in the Petitioners' case is that they have not established by preponderant evidence that the flu vaccine did in fact cause L.V.'s regression — whether directly (by precipitating an encephalopathy that then resulted in a dramatic developmental regression) or indirectly (by impacting L.V.'s preexisting mitochondrial disease, which in turn precipitated the purported regression). Rather, the overall record suggests that any loss of skills or language L.V. suffered likely began before his receipt of the second flu vaccine. The records otherwise do not reveal a dramatic drop-off in skills after the December 8th vaccination, let alone an encephalopathic incident of sufficient magnitude to produce regression.
I find especially probative the numerous occasions on which the Vs reported to ASD specialist treaters that they were aware of L.V.'s problems at 16-18 months, well before he received even the first flu vaccine. The presumption of the accuracy of statements contained in contemporaneous medical records is based on the reasonable belief that individuals attempt to tell treaters as much of the truth about an illness as they can, in the expectation that doing so increases the likelihood of effective treatment. Capizzano, 440 F.3d at 1326; Sanchez, 2013 WL 1880825, at *2. It is proper to give such records more weight than subsequent testimony attempting to rebut the statements that is otherwise not sufficiently compelling. Cucuras, 993 F.2d at 1528; Sanchez, 2013 WL 1880825, at *3.
Admittedly, L.V.'s pediatric records before November 2006 say little about developmental problems, as the Petitioners stress. Petitioners have also identified occasional inconsistencies between those records and subsequent autism/developmental evaluation records.
In addition, as discussed above, the evidence pertaining directly to L.V.'s post-vaccination health and developmental condition similarly does not suggest that he experienced an immediate, dramatic change that was vaccine-related, even if some of his developmental problems became more evident after December 8th. The weight of the evidence does not support the conclusion that the second dose of the flu vaccine caused L.V. to react in the manner that the literature suggests a person experiencing an immune-mediated encephalopathic event would, and that could in turn precipitate developmental regression. No evidence was offered to suggest that the flu vaccine was causally related to L.V.'s ear infection, or that the infection was not the source of the fever he subsequently experienced. L.V.'s most immediate post-vaccination illness was constipation (something he had suffered from previously), followed by an ear infection that did not result in fever until almost two weeks after the second flu vaccine dose, and which was successfully treated without hospitalization. The medical records do not corroborate Petitioners' allegations that L.V. experienced an autoimmune reaction from the flu vaccine — as Petitioners' experts admitted. Tr. at 362 (Dr. Shafrir admitting on cross-examination as to the absence of "objective evidence in the record of an immune reaction in L.V.'s brain to the flu vaccine").
This is far from a case in which a sudden, dramatic developmental regression is evident — or where a vaccine has a demonstrable, severe physiological effect on an individual which in turn could theoretically be connected to the subsequent regression into an ASD. Instead, the facts are consistent with a more typical ASD presentation — when, over time, parents become aware that a variety of smaller developmental missteps, setbacks, or plateaus in their child's development have significance.
Neither theory proposed by Petitioners was sufficiently grounded in relevant science to constitute a reliable theory in satisfaction of the first Althen prong.
a.
Instead, Dr. Kendall's testimony on the flu vaccine's causation role primarily relied on case studies (one of which was merely a description of the facts from Poling) that are limited in probative value since they describe only unrepresentative outlier instances that ultimately assume, without direct study or evidence, that vaccination could precipitate a chain of events resulting in regression. The Shoffner article, for example, involved a retrospective chart review of 28 individuals diagnosed with both mitochondrial disease and an ASD. Nearly a third of the studied individuals (17 of 28) experienced developmental regression, and nearly 71 percent of that subset regressed after fever (although the fevers' extent and duration were unknown, as the study relied wholly on parental reports of fever rather than clinically-confirmed data, making that variable unreliable scientifically). But as noted above, the applicability of a study involving high fever as the immediate proximate factor in causing regression is greatly diminished in a case in which evidence of a similarly prolonged, medically-concerning fever is lacking. Nor did Dr. Kendall link Shoffner's findings to additional literature suggesting any vaccine's propensity to cause the kind of fever necessary to precipitate the decompensation observed in Shoffner. Indeed — the article's authors explicitly recognized that their study found no relationship between vaccination and the observed regression. Shoffner at 432 ("the vaccines did not appear related to the neurologic regression"). Such literature may suggest to a scientist an avenue for further study but does not substantiate Petitioners' causation theory.
Thus, Dr. Kendall generally failed to provide reliable evidence plausibly linking the flu vaccine to regression in individuals with mitochondrial diseases. Petitioners offered no other testimony from a qualified immunologist on the topic (the kind of expert best suited to opining on the biologic capabilities or functioning of a vaccine generally).
Petitioners attempted to fill this evidentiary hole with literature — voluminous amounts, much of which was only glancingly referenced during the hearing. See generally Pet'rs' Exs. 101-05 and 113-16; Tr. at 153-68. Dr. Kendall was asked at certain points in her testimony to comment on some of this additional literature. However, in some cases, she was unfamiliar with the cited article (tr. at 164), whereas in other cases she did nothing more than repeat the article's findings and then attempt to relate them to her opinion, rather than demonstrate how her opinion actually arose from or relied upon their findings.
Such literature formed a patchwork theory, attempting to analogize disparate circumstances to the present. At best, some of the medical/scientific evidence offered in this case suggests that children suffering from the most severe phenotypes of mitochondrial disease (e.g., Leigh disease or MELAS) might experience a dramatic regression in development, as one facet of a progressively worsening condition that could result in death, but without any relationship to vaccination. Tr. at 601-04. L.V.'s condition, by contrast, while surely lamentable, is unquestionably not characterized by that degree of severity, as Dr. Kendall acknowledged. Id. at 237. There was also evidence offered suggesting that many individuals with ASDs also experience mitochondrial diseases or lesser dysfunction. In contrast, Dr. Cohen forcefully testified that the notion that there is a possible pathogenic relationship between autism and mitochondrial disease has (at least to date) not been sufficiently substantiated by science (and which he personally doubts based on his own experience). Id. at 437-39. At bottom, Petitioners failed to offer a reliable theory that such individuals would ever experience a dramatic developmental regression of the kind alleged to have happened to L.V. as a result of the flu vaccine's effects on the body.
b. Autoimmune Encephalopathy Theory — Petitioners' second causation theory — that the flu vaccine can precipitate an autoimmune encephalopathy resulting in regression — is similarly weak.
Petitioners could not offer direct evidentiary support establishing the flu vaccine's capacity to function as alleged, in this or other analogous circumstances. Instead, they sought to prove their theory with even more attenuated circumstantial evidence, pointing to studies involving the impact of different vaccines, or different formulations of the flu vaccine not used in the U.S., such as Pandemrix. Tr. at 288-92, 363-71, 373-81. They also invoked studies and literature involving brain-centered injuries (as the brain is the likely locus of where a neurologic change resulting in regression would occur) resulting from autoimmune diseases that L.V. unquestionably did not have, such as anti-NMDA encephalitis or other neurodegenerative conditions. Such conditions, more often than not, had been induced by wild virus infections (which were not established by the Petitioners to be comparable in impact to a vaccine simply because they contain the same viral protein chains). Petitioners otherwise invoked individual case studies (Poling, for example, or the incident discussed in Lapphra) that are facially distinguishable and otherwise not particularly reliable evidence.
As noted above, Vaccine Program petitioners are not required to prove their causation theories to a degree of scientific certainty, nor must they offer a particular kind of evidence (such as epidemiologic studies). But that does not relieve Petitioners of the obligation to offer proof of their theory that corresponds to facts of their claim. Moberly, 592 F.3d 1315, 1322 (Fed. Cir. 2010) (a petitioner must "provide a reputable medical or scientific explanation that pertains specifically to the petitioner's case" (emphasis added)). Petitioners here have instead offered a strung-together chain of a few individual patient case reports (which "are not, in general, strong evidence of causation" (Raymo v. Sec'y of Health & Human Servs., No. 11-0654V, 2014 WL 1092274, at *21 (Fed. Cl. Spec. Mstr. Feb. 24, 2014)), along with scientific or medical articles that themselves do not stand for the principle for which they are cited or are factually inapposite. Similarly, their autoimmune encephalopathy theory makes analogies to different illnesses or vaccines, but without literature or scientific support for the validity of those analogies.
A qualified expert could conceivably tie together such diffuse scientific and medical literature through the force and persuasiveness of his testimony and explanations. Dr. Shafrir is not that expert. He is not an immunologist, does not specialize in the study of autoimmune diseases let alone degenerative encephalopathies precipitated by autoimmunity, is not notably experienced in treating autoimmune-mediated illness, and has no background studying the effect of vaccines on individuals (other than the experience he may have gained either treating patients who he believes were so affected, or through his participation as an expert witness in other Program cases). His broad, multidisciplinary testimony required him to step well outside the bounds of his actual expertise. Although I have nevertheless considered his testimony carefully, it is reasonable to afford it significantly less weight under such circumstances. Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1317 (9th Cir. 1995) ("[o]ne very significant fact to consider is whether the experts are proposing to testify about matters growing naturally and directly out of research they have conducted independent of the litigation, or whether they have developed their opinions expressly for purposes of testifying").
My reaction to the overall ineffective and unpersuasive nature of this second causation theory should also be placed in context of other Vaccine Program cases in which the same theory was advanced. Dr. Shafrir has asserted a similar causation theory in other cases involving claims about vaccines and autism. See, e.g., Lehner, 2015 WL 5443461. In fact, he relied on much of the same literature in Lehner as he does in the present case, particularly in discussing molecular mimicry and anti-NMDA encephalitis, and its relationship to developmental or neurologic regression. Id. at *47-48. Former Chief Special Master Vowell concluded in Lehner, however, that "[t]his evidence fails to demonstrate that Dr. Shafrir's theory has sufficient indicia of reliability to be persuasive," and therefore "Dr. Shafrir's opinions are wishful thinking premised on unverified and unsupported assumptions." Id. at *45-47. Based upon my review of the record, and having heard Dr. Shafrir testify in this case, I concur with such statements entirely.
As noted above, the facts support the conclusion that L.V.'s developmental problems were more likely than not evident before he received the second flu vaccine, given the numerous instances in which the Vs so told various ASD specialists. It is reasonable to infer that the Vs would not have repeatedly done so in error. Cucuras, 26 Cl. Ct. at 543. In addition, the Petitioners and their experts have acknowledged that the Vs perceived developmental problems in L.V. earlier than December 8th, and their efforts at hearing to distinguish between pre- and post-vaccination problems as qualitatively different were not successful. There is also little to no evidence of any identifiable reaction to the second flu dose, or evidence that it synergistically reacted with L.V.'s ear infection. Finally Petitioners' experts did not offer persuasive causation theories, thus dooming their ability to place onset within the context of those theories.
I have great sympathy for the Vs and the suffering they have experienced in their loving care of L.V., and I do not question their sincerity in proceeding with this claim. But the factual record does not support their contention that L.V. suffered from a mitochondrial disease or experienced an autoimmune encephalopathy, that the flu vaccine had a causal connection to L.V.'s developmental regression and subsequent ASD diagnosis, or that the vaccine could produce the kind of regression or ASD symptoms L.V. experienced. The desire to find some explanation for L.V.'s condition is understandable — but the arguments presented herein purporting to provide that explanation are not enough to meet the standards for an entitlement award in the Vaccine Program.
I therefore DENY an entitlement award in this case. I instruct the Clerk of Court to enter judgment dismissing the case unless a motion for review is filed.
The Petitioners' Steering Committee chose six test cases to present two different theories regarding autism causation. The first theory alleged that the measles portion of the measles, mumps, rubella ("MMR") vaccine precipitated autism, or, in the alternative, that MMR plus thimerosal-containing vaccines caused autism, while the second theory alleged that the mercury contained in thimerosal-containing vaccines could affect an infant's brain, leading to autism.
The first theory was rejected in three test case decisions, all of which were subsequently affirmed. See generally Cedillo v. Sec'y of Health & Human Servs., No. 98-916V, 2009 WL 331968 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for review den'd, 89 Fed. Cl. 158 (2009), aff'd, 617 F.3d 1328 (Fed. Cir. 2010); Hazlehurst v. Sec'y of Health & Human Servs., No. 03-654V, 2009 WL 332306 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for review den'd, 88 Fed. Cl. 473 (2009), aff'd, 605 F.3d 1343 (Fed. Cir. 2010); Snyder v. Sec'y of Health & Human Servs., No. 01-162V, 2009 WL 332044 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), aff'd, 88 Fed. Cl. 706 (2009). The second theory was similarly rejected. Dwyer v. Sec'y of Health & Human Servs., No. 03-1202V, 2010 WL 892250 (Fed. Cl. Spec. Mstr. Mar. 12, 2010); King v. Sec'y of Health & Human Servs., No. 03-584V, 2010 WL 892296 (Fed. Cl. Spec. Mstr. Mar. 12, 2010); Mead v. Sec'y of Health & Human Servs., No. 03-215V, 2010 WL 892248 (Fed. Cl. Spec. Mstr. Mar. 12, 2010).
Ultimately a total of eleven lengthy decisions by special masters, the judges of the U.S. Court of Federal Claims, and the panels of the U.S. Court of Appeals for the Federal Circuit, unanimously rejected petitioners' claims. These decisions found no persuasive evidence that the MMR vaccine or thimerosal-containing vaccines caused autism. The OAP proceedings concluded in 2010.
Moreover, Petitioners exaggerate the extent to which Respondent actually conceded the Paluck causation theory. Although Respondent's expert in Paluck admitted, during the initial hearing and while under cross-examination, that the theory had plausibility, Respondent never formally agreed that Petitioner had established this particular Althen prong. In addition (as observed by the special master presiding over the case, after it was remanded to him the first time), Respondent effectively dropped the issue entirely (perhaps discouraged from further litigating it after the Court of Federal Claims' first remand, in which the Court strongly indicated its view that the evidence presented was sufficient to satisfy the "can cause" first Althen prong). Paluck v. Sec'y of Health & Human Servs., No. 07-889V, 2013 WL 2453747, at *42 (Fed. Cl. Spec. Mstr. May 10, 2013), mot. for review granted, 113 Fed. Cl. 210 (2013), aff'd, 786 F.3d 1373 (Fed. Cir. 2015) (Paluck special master noting that even though Respondent had not made an "outright concession" of petitioners' theory, she "did not present any substantive argument regarding prong one of Althen in any of her post-remand briefs"). Although an unrebutted evidentiary showing, and/or admission by a witness, may constitute a "concession" within that single case for purposes of determining whether a petitioner has met his "can cause" causation burden, such an occurrence cannot be expanded to mean that the Respondent has accepted the scientific or medical plausibility of the same theory applied to different fact patterns.
Petitioners' significant aggravation theory would, however, still founder on the third Loving prong even had they established that L.V. suffered from the milder form of mitochondrial disease proposed by Dr. Kendall. The Petitioners and their experts offered little reliable or persuasive evidence that L.V.'s post-vaccine developmental and behavioral changes were more severe than what a similarly-situated child would experience without vaccination. Indeed — the Petitioners point to L.V.'s ASD symptoms (under Morava) as evidence of his mitochondrial disease, based upon Morava's assumption that developmental problems are associated with mitochondrial dysfunction (even in the absence of vaccination). But if so, this renders it difficult to determine whether L.V. was really worse off post-vaccination than he would have been otherwise, and Petitioners' conclusory argument that this was nevertheless the case is inadequate to establish preponderant proof of this third Loving factor. See Broussard-Pacot v. Sec'y of Health & Human Servs., No. 09-107V, 2012 WL 5357478, at *19 (Fed. Cl. Spec. Mstr. Sept. 4, 2012) (petitioners' claim of significant aggravation of preexisting seizure disorder was inadequately "developed or substantiated," because it lacked medical support that child's development would have been different but for the vaccines).
There is other evidence, moreover, suggesting that Dr. Coplan's January 2007 assessment about L.V.'s self-feeding capabilities was closer to the truth than the September 2006 pediatric record. Thus, in the January 17, 2007, early intervention assessment performed by Montgomery County (before the Vs informed Dr. Corcoran of their intent to seek early intervention for L.V. and were referred to Dr. Coplan), in the section entitled "Adaptive Development," which asks for a statement on the assessed child's "self-help skills such as feeding," the treater (Dr. Beth Appelbaum) recorded the Vs' statement to her that L.V. "will bring a spoonful of food to his mouth once Mom has scooped the food." Pet'rs' Ex. 13 at 7 (emphasis added). This statement (which permits the inference that L.V.'s feeding skills were in fact developmentally behind) is consistent with Dr. Coplan's similar statement.
These purportedly inconsistent views of Dr. Cohen (to the extent they are considered his actual views, rather than statements in an article he now claims to have disavowed at time of publication) must also be considered in light of his other, unrebutted testimony that earlier in his study of mitochondrial diseases, he had considered the possibility of a relationship between autism and such diseases, but later rejected the connection. Tr. at 438-39. This, plus the fact that Weissman was written approximately eight years ago, greatly diminishes the significance of Petitioners' suggestion that Dr. Cohen has conceded that a vaccine could have any causal role in precipitating regression or other ASD-like behavioral or developmental problems in children with mitochondrial diseases.
In the same vein, the Petitioners briefly questioned Dr. Kendall about another article (Pet'rs' Ex. 114, N. Klein, et al., 12 Evaluation of Immunization Rates and Safety Among Children with Inborn Errors of Metabolism, PEDIATRICS 1139-46 (2011) [hereinafter, Klein]) ostensibly supporting the proposition that "stressors" could precipitate illness in children suffering from mitochondrial diseases. Tr. at 159-60. Klein presented a retrospective epidemiologic study of a population of immunized children, including a small percentage known to have inborn errors of metabolism ("IEM"). But the article merely concluded that although "the most vulnerable" children demonstrated increased hospitalization rates two weeks after vaccination, "vaccinating children with IEMs with routinely recommended vaccines does not seem to put them at increased risk of adverse effects." Klein at 1146. Citing such an article as support for the notion that the flu vaccine in this case could have plausibly harmed a child in L.V.'s circumstances (because it is always possible even if the vaccine in most cases is not contraindicated for children with metabolic disorders, such as a mitochondrial disease) is no more helpful to the Petitioners' case than citing the broadly true, but (from an evidentiary standpoint) irrelevant, fact that the Vaccine Program itself often awards compensation to injured parties even though the relevant vaccine is safe for the vast majority of individuals.
