VICP Registry Case Source Bundle Canonical URL: https://vicp-registry.org/case/USCOURTS-cofc-1_14-vv-00820 Package ID: USCOURTS-cofc-1_14-vv-00820 Petitioner: Victoria Mager Filed: 2014-09-05 Decided: 2023-06-20 Vaccine: HPV Vaccination date: 2012-09-11 Condition: significant aggravation of preexisting seizure disorder leading to sudden unexpected death in epilepsy (SUDEP) Outcome: compensated Award amount USD: 365593.02 AI-assisted case summary: On September 5, 2014, Michael Mager filed a petition under the National Childhood Vaccine Injury Compensation Program on behalf of his daughter, Victoria Mager, who died on January 11, 2014. The petition alleged that the human papillomavirus (HPV) vaccine administered on September 11, 2012, caused or significantly aggravated a pre-existing seizure disorder, leading to her death from Sudden Unexpected Death in Epilepsy (SUDEP). Victoria Mager was born on July 29, 1995. Her medical history prior to the HPV vaccinations was generally normal, though she experienced bed-wetting around age eight, received speech therapy, and had some reported school performance and attention issues. She received meningococcal and Tdap vaccines on September 4, 2007, and her first HPV vaccine on October 2, 2007. Approximately 43 days later, on November 14, 2007, she had a seizure, followed by another seizure four minutes later. An EEG showed epileptiform discharges indicating focal sites of cerebral hyperexcitability. She was prescribed Depakote. At a December 2007 follow-up, her parents reported possible earlier seizure episodes, and her bed-wetting had stopped after starting Depakote. A neurologist noted focal onset epilepsy by EEG and frontal lobe dysfunction. In February 2008, her parents requested she be weaned off Depakote due to side effects, and a subsequent neuropsychological evaluation noted focal language findings and a maternal family history of epilepsy. From April 2008 to October 2012, Victoria appeared to function normally, with no reported seizure activity for four years. She received her second HPV vaccination on September 11, 2012. Twenty-nine days later, on October 10, 2012, she suffered another seizure, diagnosed as a probable seizure. She reported two more seizures in October and November 2012 and was again prescribed Depakote. In January 2013, a neurologist assessed a primary generalized seizure disorder, possibly juvenile myoclonic epilepsy (JME), and switched her medication to Keppra. By July 2013, her Keppra compliance was noted as "less than ideal." On January 11, 2014, Victoria was found unresponsive and pronounced dead on arrival at a hospital. An autopsy revealed brain changes consistent with a seizure disorder, including focal subpial gliosis. The death certificate listed "seizure disorder" as the cause of death. The parties agreed Victoria had a seizure disorder that caused her death but disputed the diagnosis and vaccine causation. Petitioner's expert, Dr. Michael Shafrir, argued for autoimmune epilepsy and a challenge-rechallenge pattern, suggesting the second HPV dose aggravated her condition. Respondent's experts, Dr. Douglas Kohrman and Dr. Robert Fujinami, argued for JME, citing pre-vaccination seizure signs and lack of autoimmune markers. Special Master Christian J. Moran initially denied compensation, finding insufficient evidence of autoimmune epilepsy. The Court of Federal Claims vacated this decision, remanding for further analysis under the Althen standard. On remand, the Special Master granted entitlement, finding the second HPV dose medically acceptable within a plausible timeframe and sufficient to satisfy the challenge-rechallenge framework for significant aggravation. The Special Master rejected a molecular mimicry theory but concluded the sequence of events satisfied causation requirements. Respondent's motion for review was denied by Judge Ryan T. Holte on June 20, 2023. Judgment was entered for $365,593.02. Theory of causation field: Victoria Mager, age 17, received the second dose of the HPV vaccine on September 11, 2012. Petitioner alleged this vaccine significantly aggravated a pre-existing seizure disorder, leading to her death from SUDEP on January 11, 2014. The theory of causation relied on a challenge-rechallenge paradigm: a seizure occurred approximately 43 days after the first HPV vaccine on October 2, 2007, followed by a seizure approximately 29 days after the second HPV vaccine on September 11, 2012, after a nearly five-year seizure-free period. Petitioner's expert, Dr. Michael Shafrir (pediatric neurologist), posited autoimmune epilepsy and HPV-triggered neuroinflammation, citing WHO challenge-rechallenge causality concepts and Slade study for a 4-42 day biologically plausible window. Respondent's experts, Dr. Douglas Kohrman (pediatric epileptologist) and Dr. Robert Fujinami (immunologist), argued for juvenile myoclonic epilepsy (JME), citing pre-vaccination seizure signs, generalized seizures, medication response, lack of autoimmune markers, and timing inconsistent with vaccine-induced autoimmune causation. The Special Master initially denied compensation, finding insufficient evidence of autoimmune epilepsy. The Court of Federal Claims vacated and remanded, directing analysis under Althen. On remand, the Special Master found entitlement, accepting the challenge-rechallenge paradigm and significant aggravation, noting the 29-day interval after the second dose was medically acceptable. The Special Master found the sequence of events satisfied causation requirements, rejecting respondent's argument that death was solely due to the natural course of epilepsy. The Court of Federal Claims affirmed the entitlement ruling, awarding $365,593.02. Attorneys: Renee J. Gentry (Petitioner), Laurie Wiesner and Zoe Wade (Respondent), Special Master Christian J. Moran, Judge Ryan T. Holte. Public staged source text: ================================================================================ DOCUMENT 1: USCOURTS-cofc-1_14-vv-00820-1 Date issued/filed: 2021-08-24 Pages: 20 Docket text: PUBLIC DECISION (Originally filed: 07/29/2021) regarding 189 DECISION of Special Master. Signed by Special Master Christian J. Moran. (hh) Service on parties made. -------------------------------------------------------------------------------- Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 1 of 20 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS * * * * * * * * * * * * * * * * * * * * * MICHAEL MAGER, as parent of * VICTORIA MAGER, * * No. 14-820V * Special Master Christian J. Moran Petitioner, * * v. * Filed: July 29, 2021 * SECRETARY OF HEALTH * Entitlement; human papillomavirus AND HUMAN SERVICES, * (“HPV”) vaccine; autoimmune * epilepsy; sudden unexpected death in Respondent. * epilepsy (“SUDEP”); diagnosis. * * * * * * * * * * * * * * * * * * * * * * Renee J. Gentry, Vaccine Injury Clinic, George Washington University Law School, Washington, DC, for petitioner; Laurie Wiesner, United States Dep’t of Justice, Washington, DC, for respondent. DECISION DENYING COMPENSATION1 Michael Mager alleges that the human papillomavirus (“HPV”) vaccine his deceased daughter Victoria received on September 11, 2012, caused her to suffer autoimmune epilepsy leading to sudden unexpected death in epilepsy. He seeks compensation pursuant to the National Childhood Vaccine Injury Compensation Program. As detailed below, the undersigned finds that Mr. Mager is not entitled to compensation because based on the evidence submitted, he has not met his burden 1 The E-Government Act, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services), requires that the Court post this decision on its website. This posting will make the decision available to anyone with the internet. Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the document posted on the website. Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 2 of 20 to show that Victoria suffered from autoimmune epilepsy. Furthermore, because this is a threshold issue for which the evidence and briefing already submitted is sufficient to make a determination, a hearing is not required. I. Procedural History Represented by attorney Mark Krueger, Mr. Mager asserted that the HPV vaccination Victoria received on October 2, 2007, caused her to suffer a seizure disorder leading to her death on January 11, 2014. Pet., filed Sept. 5, 2014, at Preamble, ¶ 12. Mr. Mager filed an amended petition on November 19, 2014. He then gathered medical records, including those requested by the Secretary in advance of the Rule 4(c) report, and the record was complete on February 17, 2015. The Secretary filed his Rule 4(c) report on April 1, 2015, contesting causation and arguing that Victoria’s seizure disorder existed pre-vaccination. Resp’t’s Rep. at 8-11. Mr. Krueger withdrew from the case on May 18, 2016. Mr. Mager submitted a fact witness affidavit on July 7, 2015. Ms. Renee Gentry was substituted as counsel of record for Mr. Mager on August 3, 2016, after which the case proceeded to the expert report stage. After multiple extensions, Mr. Mager filed his first expert report from Dr. Mikovits and Dr. Ruscetti on November 17, 2016.2 The Secretary then filed responsive expert reports from Dr. Fujinami and Dr. Kohrman on March 2, 2017, and March 22, 2017, followed by supplemental expert reports from Mr. Mager on May 25, 2017; October 12, 2017; and October 27, 2017. The Secretary submitted supplemental expert reports on March 19, 2018, and Mr. Mager submitted his final supplemental expert reports on May 25, 2018. In a status conference held on June 19, 2018, the undersigned discussed the relative weaknesses of Mr. Mager’s expert reports and his attorney requested additional time to retain a pediatric neurologist to better support his claim. Mr. Mager then filed an expert report from Dr. Shafrir on October 3, 2018. In this report, Dr. Shafrir raised the potential helpfulness of obtaining the slides from Victoria Mager’s autopsy. While Mr. Mager began the process of attempting to obtain the autopsy slides and the exchange of expert reports continued, the case was referred to alternative dispute resolution (“ADR”) on January 30, 2019. However, the parties failed to reach a settlement agreement and the case was 2 Because Mr. Mager eventually chose not to rely on the opinions of Dr. Mikovits or Dr. Ruscetti, all submissions from these expert witnesses were later stricken from the record. 2 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 3 of 20 removed from ADR on March 25, 2019. Respondent then filed supplemental expert reports on April 22, 2019. Dr. Shafrir asserted a diagnosis of autoimmune epilepsy based, in part, on what he deemed neurological reactions to the vaccine that suggested underlying autoimmune encephalitis. Exhibit 55 at 18. Dr. Kohrman, however, maintained a diagnosis of juvenile myoclonic epilepsy (“JME”), based on his view that Victoria suffered pre-vaccination seizure activity, non-focal (i.e. generalized) seizures, and a lack of evidence regarding an autoimmune process in Victoria’s autopsy. Exhibit Y at 7. Dr. Fujinami agreed with the JME diagnosis, highlighting that Victoria’s seizures were not treatment resistant, as would be true of seizure activity involved in autoimmune epilepsy. Exhibit CC at 1-2. Dr. Shafrir and Dr. Kohrman both have significant experience in neurology and pediatric neurology, exhibit 56; exhibit B, though Dr. Kohrman has particularly strong experience regarding epilepsy and pediatric epilepsy, including a current board certification with the American Board of Psychiatry and Neurology with a subspecialty in epilepsy. Exhibit B at 2. Dr. Fujinami has significant experience as an immunologist. Exhibit J. After trying for an extended period to obtain the autopsy slides, Mr. Mager filed a status report on October 28, 2019, stating that a supplemental expert report from Dr. Shafrir would not be necessary. The undersigned issued an order for submissions in advance of potential adjudication on November 20, 2019. After multiple extensions, Mr. Mager filed a supplemental expert report from Dr. Shafrir on July 25, 2020, and his brief on July 27, 2020. The Secretary, again after multiple extensions, filed his supplemental expert reports from Dr. Fujinami and Dr. Kohrman, as well as his brief, on February 10, 2021. Mr. Mager filed his reply brief on March 26, 2021. With the briefing complete, this case is ripe for review. II. Standards for Adjudication Petitioners are required to establish their cases by a preponderance of the evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence standard requires a “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 v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations omitted). To receive compensation, petitioners must establish five elements. 42 U.S.C. § 300aa–11(c)(1)(A) through (E); 42 U.S.C. § 300aa–13(a)(1)(A) (authorizing special masters to award compensation when petitioners establish 3 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 4 of 20 items listed in section 11(c)(1)). To establish causation for off-Table injuries, petitioners bear a burden “to show by preponderant evidence that the vaccination brought about [the vaccinee’s] injury by providing: (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 v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). The process for finding facts in the Vaccine Program begins with analyzing the medical records, which are required to be filed with the petition. 42 U.S.C. § 300aa–11(c)(2). Medical records that are created contemporaneously with the events they describe are presumed to be accurate. Cucuras v. Sec’y of Health & Human Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993). Furthermore, as a threshold matter, a petitioner must establish she suffers from the condition for which she seeks compensation. Broekelschen v. Sec’y of Health & Human Servs., 618 F.3d 1339, 1346 (Fed. Cir. 2010). When a petitioner fails to establish her diagnosis, there is no need for an analysis pursuant to Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). Lombardi v. Sec’y of Health & Human Servs., 656 F.3d 1343, 1353 (Fed. Cir. 2011). III. Diagnostic Criteria Mr. Mager alleges that Victoria Mager suffered from autoimmune epilepsy. However, the Secretary contends that her condition was more likely indicative of JME. See exhibit A at 13-14. The difference between autoimmune epilepsy and JME affects the outcome of Mr. Mager’s case because his theory of causation relies on an autoimmune disease causing neuroinflammation. To better assess whether Mr. Mager has met his burden in establishing that Victoria suffered from autoimmune epilepsy, as well as the Secretary’s assertion of JME as the more likely diagnosis, it is necessary to set forth the diagnostic criteria for each. A. Autoimmune Epilepsy The three major indicators of autoimmune epilepsy are: (1) “demonstration of autoantibodies against neuronal components in the patient’s blood”; (2) in most patients, seizures that “may not respond to regular antiepileptic medications but respond to immunomodulatory treatment”; and (3) “occurring in relation to an autoimmune disease or autoimmune encephalitis.” Pet’r’s Br. at 9-10.3 With 3 Mr. Mager states that he gleaned these diagnostic criteria from exhibit 88 and exhibit 65 and that this specific list “does not appear” verbatim in the medical literature filed. Pet’r’s Status 4 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 5 of 20 respect to the third criterion, Mr. Mager alleges that Victoria suffered from autoimmune encephalitis. The diagnostic indicators of autoimmune encephalitis include: (1) Focal seizures, particularly focal motor and focal dyscognitive, secondary generalized seizures; (2) seizure clusters, status epilepticus; (3) seizures and epilepsy of unknown cause; (4) refractory seizures; (5) associated features of encephalopathy, movement disorders, neuropsychiatric symptoms, cognitive or memory impairment; and (6) history of autoimmune diseases (personal or family). Exhibit 65 (Suleiman) at 3.4 Focal seizures are those in which the onset in the brain is localized, while the onset of generalized seizures is not localized. Secondary generalized seizures start out localized, but then spread to both sides of the brain. Refractory are those which do not respond to anti-seizure medications. As outlined above, focal, secondary generalized, and/or refractory seizures are clinical indicators specific to autoimmune encephalitis, though both focal/secondary generalized and primary generalized seizures can occur in people with autoimmune encephalitis. Thus, while presence of a focal, secondary generalized, and/or refractory seizure would necessarily indicate autoimmune encephalitis, presence of a primary generalized seizure could indicate autoimmune encephalitis or juvenile myoclonic epilepsy because primary generalized seizures occur with both conditions. Mr. Mager points out that “it is not necessary to find each of these attributes to come to a diagnosis of autoimmune encephalitis,” id. (citing exhibit 65), “origin of seizure onset is difficult to determine with certainty,” id. at 12 (citing exhibit BB (Dr. Kohrman’s report), tab 4, at 1), and autoimmune epilepsy can occur in patients with milder presentations, see Pet’r’s Br. at 10 (citing exhibit 88). B. Juvenile Myoclonic Epilepsy In his brief, the Secretary sets out the clinical features of JME as: (1) presence of myoclonic, tonic-clonic, and/or absence seizures; (2) an average onset age of 15.1 years, although this metric is highly variable; and (3) myoclonic seizures may precede the first generalized tonic-clonic seizure by 6-12 months, although generalized tonic-clonic seizures occur as the first seizure type in Rep., filed June 17, 2021, CM/ECF No. 188. Respondent did not challenge this list as the criteria for autoimmune epilepsy in any of his briefs. Therefore, the undersigned will accept these criteria for the purposes of this decision. 4 For a more detailed analysis of the Suleiman article, see Moriarty v. Sec’y of Health & Human Servs., No. 03-2876V, 2016 WL 5390172, at *28 (Fed. Cl. Spec. Mstr. Aug. 23, 2016), vacated and remanded, 130 Fed. Cl. 573 (2017). 5 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 6 of 20 approximately one third of patients. Resp’t’s Br. at 13-14 (citing exhibit BB (Dr. Kohrman’s report)). Unlike autoimmune epilepsy, JME produces seizures that generally respond to anti-seizure medication and is characterized by the presence of primary generalized, not focal or secondary generalized, seizures. See id. at 14 (citing exhibit BB). IV. Facts Victoria Mager was born on July 29, 1995. Pet. ¶ 1. Prior to receiving the vaccination that is the subject of Mr. Mager’s claim on her behalf, Victoria suffered from enuresis, or bed wetting, at approximately eight years old. Exhibit 18 at 5. Her primary care provider also noted that she was receiving speech therapy at this time and experienced “poor performance” and “decreased attention” at school during this time. Id. Other than this, Victoria’s pre-vaccination health history appears relatively normal. On September 4, 2007, Victoria received the meningococcal and tetanus- diphtheria-acellular pertussis (“Tdap”) vaccines. Exhibit 4 at 2, 3. She then received the HPV vaccine on October 2, 2007. Id. at 2, 9. On November 14, 2007, Victoria experienced a seizure and was taken to the emergency room of Children’s Hospital of Wisconsin. Exhibit 11 at 28. In her admission notes, the description of her condition states that she experienced a seizure followed by a second seizure approximately four minutes later. Id. A head CT scan, urine toxicology screen, and chest x-ray were performed with normal results. Id. at 3-4, 13. An EEG was then performed, the results of which were “[i]ntermittent epileptiform spike & low wave discharges over the left frontal region, as well as the bifrontal region, maximal on left” and “intermittent generalized spike and slow wave discharges, maximum over left frontal region, seen predominantly during drowsiness and sleep.” Id. at 17. It was noted that these discharges “indicate focal sites of cerebral hyperexcitability which can be associated with partial seizures/epilepsy.” Id. Victoria was prescribed Depakote, an anti-seizure medication, and discharged on November 15, 2007. Id. at 38. On December 12, 2007, Victoria saw a pediatric neurologist, Dr. Sharif, for a follow-up. Dr. Sharif noted that, after she was discharged, her parents recalled and reported to Dr. Sharif in this appointment that “for a while, [Victoria] was waking up with big cuts in her tongue at least twice and also complaining of soreness after waking up and it is possible that these might have been seizures.” Exhibit 11 at 75. Victoria’s stepmother also reported that there had been no more bed wetting incidents after the prescription of Depakote between her hospital admission and this appointment. Id. Dr. Sharif noted an impression of “focal 6 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 7 of 20 onset epilepsy by EEG” and “some frontal lobe dysfunction.” Id. at 77. Dr. Sharif recommended neuropsychological testing. Id. Victoria saw another pediatric neurologist, Dr. Koehn, approximately two months later on February 21, 2008. An EEG was performed, the results of which were normal. Exhibit 6 at 22. Referring to the original abnormal EEG taken during her hospital admission, Dr. Koehn noted that “[t]he first EEG pattern could represent a fragment/a more lateralized pattern of an underlying generalized discharge or it could in fact be a focal discharge. Therefore, leaving the possibility open for this to have been a primary or secondarily generalized seizure.” Id. at 20. Victoria’s father and stepmother requested that she be weaned off Depakote, although the medication appeared to be controlling her seizure activity. They cited poor performance and difficulties focusing in school, which they thought may have been attributable to the Depakote. Id. at 24. Dr. Koehn therefore directed that she be gradually weaned off Depakote and referred her for neuropsychological testing. Id. at 28; see also Pet. ¶ 4. On April 1, 2008, Victoria underwent neuropsychological testing with Dr. Waltonen. Exhibit 6 at 6. Dr. Waltonen noted that she had “a history of some type of learning difficulty at least in the speech and language area.” Id. at 6. He also noted a family history of epilepsy and seizures on her maternal side. Id. at 2. With respect to learning and school-related difficulties, he noted that Victoria’s stepmother reported “increasing problems with doing well in school” and Victoria’s teachers indicated “problems following directions.” Id. at 1, 4. Dr. Waltonen ultimately concluded that “[o]verall, her examination does not reveal evidence of significant cognitive impairment with the exception of very focal language findings.” Id. at 6. He further recommended that “her language be looked at a bit more extensively” and, under “Plan,” noted “Refer to the school for speech and language evaluation.” Id. at 6-7. Between April 2008 and her next medical event in October 2012, Victoria appears to have been functioning normally. School records submitted from part of this time period do not indicate any abnormalities. See exhibit 83. She received a normal sports physicals and health maintenance exams on August 8, 2009, and March 2, 2012. Exhibit 10 at 15-17; exhibit 14 at 1-2. She also saw Dr. Budde for a physical exam and removal of hand warts on January 5, 2012, when she reported that she had not experienced seizure activity in four years. Exhibit 10 at 18. On September 11, 2012, she received her second HPV vaccination. Exhibit 4 at 1. Approximately one month later, she was taken to the emergency department of Theda Clark Medical Center on October 10, 2012, after suffering a seizure. Exhibit 7 at 9. Her work-up, including an EKG, was normal. Id. at 13-14. She was diagnosed with a “probable seizure” and discharged. Id. at 14. 7 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 8 of 20 She saw her primary care doctor, Dr. Budde, on November 8, 2012. Exhibit 9 at 39. At this appointment, she reported two additional seizures following her ER visit on October 19, 2012, and November 7, 2012. Id. Dr. Budde prescribed Depakote and referred her to a neurologist. Id. Victoria saw neurologist Dr. Edgar on January 14, 2013. Exhibit 9 at 24-25. An EEG was also performed. Dr. Edgar noted that the “EEG is normal during wakefulness. During sleep there is activation of infrequent potentially epileptiform activity over the left frontal and bioccipital head regions, consistent with the patient’s history of generalized seizures.” Id. at 25. Dr. Edgar’s impression was primary generalized seizure disorder and he noted “age of onset at approximately 11 years of age suggests the possibility of juvenile myoclonic epilepsy, although no myoclonic seizures are reported.” Id. at 9. He recommended Depakote but, after Victoria specified that she did not wish to remain on Depakote, Dr. Edgar directed her to begin weaning off Depakote and prescribed Keppra, a different anti- seizure medication. Id. at 8. During a follow-up appointment with Dr. Edgar on July 8, 2013, he stated that Victoria’s compliance with her Keppra prescription had been “less than ideal,” with a sub-therapeutic level of the medication in her blood documented from a test on May 30, 2013. Exhibit 9 at 3. Victoria expressed a desire to discontinue use of Keppra, but Dr. Edgar persuaded her to remain on the drug given her history of seizures. Id. at 4. Dr. Edgar noted “probable juvenile myoclonic epilepsy” at this appointment due to age of onset. Id. On January 11, 2014, Victoria was rushed to the emergency department after being discovered unresponsive at a friend’s house. Exhibit 8 at 2. She was pronounced dead upon her arrival at the ER. Id. As part of an investigation of the death by the Waukesha Police Department, a witness reported that Victoria had been “missing a lot of doses of her medication” and Mr. Mager reported that “she was having seizures more frequently.” Exhibit 13 at 2. An autopsy was performed by Dr. Okia on January 13, 2014. Exhibit 12 at 1. The findings included pulmonary edema and brain changes consistent with a seizure disorder. Exhibit 16 at 1. Sections of the brain showed focal areas of subpial gliosis. Id. at 6. Furthermore, a toxicology screen showed levels of Keppra in her blood. Exhibit 13 at 11. According to the toxicology report, regular dosing of Keppra results in 3-37 mcg/mL in the blood, with peak levels of 10-60 mcg/mL within 1.5 hours after dosage. Id. Victoria’s toxicology results revealed 26 mcg/mL of Keppra in her blood at the time of death. Id. Victoria’s death certificate listed “seizure disorder” as her cause of death. Exhibit 1 at 1. 8 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 9 of 20 V. Analysis This section will first analyze the relative qualifications of the experts, specifically Dr. Shafrir and Dr. Kohrman, as their expertise is relevant to their diverging opinions regarding Victoria’s diagnosis. Next, this section will consider whether Mr. Mager has met his burden to prove each diagnostic criterion for autoimmune epilepsy: presence of autoimmune antibodies, response to anti- seizure medications, and co-existing autoimmune disorder. Because in order to satisfy the third criterion, Mr. Mager asserts that Victoria suffered from autoimmune encephalitis, section B. includes an analysis of whether he has met his burden to show each of the six diagnostic criteria for autoimmune encephalitis. Finally, section C. discusses statements from treating doctors. A. Qualifications of Experts Because a determination regarding whether Mr. Mager has met his burden to prove Victoria suffered from autoimmune epilepsy hinges in part on the diagnostic opinions of Dr. Shafrir and Dr. Kohrman, it is helpful to compare their qualifications as a preliminary matter. Special masters may consider the relative expertise of testifying experts when weighing the value of their opinion. See Depena v. Sec’y of Health & Human Servs., No. 13-675V, 2017 WL 1075101 (Fed. Cl. Spec. Mstr. Feb. 22, 2017), mot. for rev. denied, 133 Fed. Cl. 535, 547-48 (2017), aff’d without op., 730 Fed. App’x 938 (Fed. Cir. 2018); Copenhaver v. Sec’y of Health & Human Servs., No. 13-1002V, 2016 WL 3456436 (Fed. Cl. Spec. Mstr. May 31, 2016), mot. for rev. denied, 129 Fed. Cl. 176 (2016). Though both Dr. Shafrir and Dr. Kohrman have ample experience and expertise in pediatric neurology, Dr. Kohrman has a notable special expertise in epilepsy. For example, Dr. Kohrman holds a current board certification with the American Board of Psychiatry and Neurology with a subspecialty in epilepsy. Exhibit B at 2. Dr. Shafrir’s board certifications include pediatrics, neurology, and psychiatry with a special qualification in child neurology, and clinical neurophysiology. Exhibit 56 at 2. Both experts have published in the areas of epilepsy and pediatric epilepsy. However, Dr. Kohrman’s publication history specific to issues involving pediatric epilepsy appears more extensive. See exhibit B at 3-9; exhibit 56 at 4-6. Though Dr. Shafrir’s certifications and topics of focus in his publications are certainly relevant and helpful to this case, Dr. Kohrman’s specialty in epilepsy—particularly his board certification with a subspecialty in epilepsy and focus on pediatric epilepsy—makes him particularly qualified to opine on a case in which potential diagnoses of autoimmune epilepsy or juvenile myoclonic epilepsy are at play. 9 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 10 of 20 B. Diagnosis of Autoimmune Epilepsy The three major indicators of autoimmune epilepsy are: (1) “demonstration of autoantibodies against neuronal components in the patient’s blood”; (2) in most patients, seizures that “may not respond to regular antiepileptic medications but respond to immunomodulatory treatment”; and (3) “occurring in relation to an autoimmune disease or autoimmune encephalitis.” Pet’r’s Br. at 9-10. Each of these indicators will be addressed in turn. 1. Presence of autoimmune antibodies Mr. Mager concedes, based on Dr. Shafrir’s report that, with the respect to the first element of autoimmune epilepsy, Victoria was not tested for autoimmune antibodies in her blood. Exhibit 85 at 4. Thus, there is no affirmative evidence on this point. Mr. Mager asserts potentially valid reasons why Victoria’s treating doctors may not have thought to perform tests relevant to an autoimmune epilepsy diagnosis. Specifically, he asserts that autoimmune epilepsy is a relatively “emerging field.” Pet’r’s Reply at 18. He refers vaguely to comments made by both his and respondent’s experts. However, it is unclear where these assertions regarding the emerging nature of this diagnosis are located in any of the reports. Still, even assuming this is true and that there is a valid reason for the lack of testing, a lack of evidence on this point does not help Mr. Mager’s case. While this fact is not dispositive as to the determination of whether Victoria had autoimmune epilepsy, and does not rule out autoimmune epilepsy, a lack of testing also does not provide any affirmative evidence supporting an autoimmune epilepsy diagnosis. Mr. Mager also concedes via Dr. Shafrir’s report that no autoimmune process was detected from Victoria’s autopsy. Exhibit 85 at 4. However, Dr. Shafrir in his first report pointed to the finding of gliosis in Victoria’s autopsy as an indicator of an inflammatory process. Specifically, he stated: Gliosis is typically an inflammatory mechanism which is induced by various brain insults. Although we do not have a good description of the extent, cellular components, and the localization of the gliosis in the postmortem examination of Victoria’s brain, it definitely supports an inflammatory mechanism as a cause of epilepsy. Exhibit 55 at 20. He argues that this constitutes evidence of autoimmunity because of the connection between autoimmunity and inflammatory responses. Id. at 19- 20. In response, Dr. Fujinami contended that gliosis found in Victoria’s autopsy is a “common finding in epilepsy and represents the result of a neuronal injury and cell death . . . and not an acute or chronic inflammatory process related to 10 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 11 of 20 vaccination.” Exhibit Y at 7. Mr. Mager states that medical literature relied upon by Dr. Fujinami contradicts this contention. In his reply brief, he states that astrogliosis, like that detected in Victoria’s autopsy, can indicate inflammatory attacks. Pet’r’s Reply at 19 (citing exhibit Y-15 at 8). Dr. Kohrman agrees that gliosis is a “regular finding in juvenile myoclonic epilepsy” and that the pathologist “concluded this was a typical finding in epilepsy and [Victoria] ha[d] primary generalized epilepsy.” Exhibit BB at 15. Thus, the experts dispute the significance of the gliosis finding as it pertains to evidence of autoimmunity. The connection made between the gliosis found in Victoria’s autopsy and the potential for an inflammatory response, which may indicate autoimmunity is tenuous. While there may be some chance of an inflammatory process—and thus, in Dr. Shafrir’s opinion, evidence of autoimmunity—indicated by the gliosis in Victoria’s autopsy, this does not tip the scale persuasively in the direction of an autoimmune disease, as evidenced by the conclusions of the pathologist performing the exam. It also does not provide evidence of autoimmune antibodies in Victoria’s blood, which is the actual relevant criterion in terms of testing for a diagnosis of autoimmune epilepsy. 2. Response to anti-seizure medications and refractory seizures The second clinical feature of autoimmune epilepsy is seizures that do not respond to anti-seizure medication, also called refractory seizures. See Pet’r’s Reply at 13-14. As detailed in the facts, Victoria was prescribed Depakote after her first emergency room visit in November 2007 and weaned off the medication at her father’s request starting in February 2008. She was then prescribed Keppra, another seizure medication, in November 2012 after her second emergency room visit for a seizure. She maintained the Keppra prescription until her death in January 2014. To support the contention that Victoria’s seizures were resistant to anti- seizure medication, Mr. Mager points to two particular incidents: (1) Victoria suffered a seizure the night she was discharged from the hospital in November 2007, after she had been prescribed and started on Depakote; and (2) levels commensurate with prescriptive use of Keppra were found in her blood upon her death. To the first point, while Mr. Mager did report that Victoria experienced a seizure after being discharged from the hospital, there is also evidence that, after she began taking Depakote, her seizure-related activity, such as enuresis, stopped. Exhibit 11 at 75 (report by stepmother in December 2007 appointment with Dr. 11 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 12 of 20 Sharif). Her providers, including Dr. Sharif and Dr. Koehn, recommended continuation of Depakote. At her appointment with Dr. Koehn in February 2008, she had a normal EEG and no reports of seizure activity since the night of her hospital discharge. Exhibit 6 at 20. Victoria’s parents requested that she be weaned off Depakote, however, against Dr. Koehn’s recommendations, see id. at 20-21 (noting a discussion of potential recurrent seizures if not on Depakote and recommending Keppra if seizures recur), and Victoria did not take Depakote or experience seizure activity between approximately February 2008 and October 2012 when she began to experience her second bout of seizure activity. Thus, the single seizure occurring the night of her hospital discharge after she had just begun taking Depakote does not outweigh the months of a lack of seizure activity while on Depakote, that was further supported by a normal EEG and recommendations to continue anti-seizure medication at her appointment with Dr. Koehn in late February 2008. To the second point, regarding presence of Keppra in her blood upon death, Victoria was prescribed Keppra after her seizure and hospitalization in October 2012, as an alternative to Depakote. However, multiple medical records discuss Victoria’s irregular use or lack of adherence to her Keppra prescription. After Dr. Edgar initially prescribed Keppra in January 2013, Victoria returned to him for a follow-up in July 2013. In this appointment, Dr. Edgar noted that Victoria’s compliance with her Keppra prescription had been “less than ideal,” with a sub- therapeutic level of the medication in her blood documented from a test on May 30, 2013. Exhibit 9 at 3. Based on the notes from this visit, it also appears that Victoria was generally averse to continuing her Keppra prescription, perhaps because of unwanted side effects. Id. at 4. However, Dr. Edgar persuaded her to continue with the medication in light of potential recurrent seizure activity. Though there were what appear from the toxicology report to be levels of Keppra detected in Victoria’s blood during her autopsy that were consistent with the range present as a result of normal dosing, a source noted that Victoria had been “missing a lot of doses of her medication” and Mr. Mager reported that “she was having seizures more frequently” leading up to her fatal seizure in January 2014. Exhibit 13 at 2. Thus, multiple sources of evidence show that Victoria did not take Keppra as prescribed and was having seizures leading up to her death. Because of this, the contention that levels of Keppra in her blood at death shows the presence of refractory seizures is unpersuasive, given the evidence against regular adherence to anti-seizure medication. There is no other evidence, besides these two instances which appear unpersuasive, that Victoria’s seizures were resistant to anti-seizure medications. In fact, there is some contradictory evidence from the few months when she was taking Depakote as prescribed, that this anti-seizure medication was effective in controlling her seizure activity. 12 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 13 of 20 3. Association with autoimmune encephalitis The third and final clinical indicator of autoimmune epilepsy is association with an autoimmune disease. To this point, Mr. Mager specifically asserts that Victoria suffered concurrently from autoimmune encephalitis. The diagnostic criteria for autoimmune encephalitis are: (1) Focal seizures, particularly focal motor and focal dyscognitive, secondary generalized seizures; (2) seizure clusters, status epilepticus; (3) seizures and epilepsy of unknown cause; (4) refractory seizures; (5) associated features of encephalopathy, movement disorders, neuropsychiatric symptoms, cognitive or memory impairment; and (6) history of autoimmune diseases (personal or family). Pet’r’s Reply at 11 (citing exhibit 65). According to Mr. Mager, “It is not necessary to find each of these attributes to come to a diagnosis of autoimmune encephalitis, but ‘the suspicion of autoimmune encephalitis should be predominantly based upon clinical characteristics and supportive investigations.’” Pet’r’s Reply at 11 (quoting exhibit 65 at 1). i. Focal vs. Generalized Seizures Focal seizures, or seizures which begin in a localized part of the brain, are clinical indicators of autoimmune encephalitis. Exhibit 65 (Suleiman) at 1. Secondary generalized seizures, or seizures that start out localized and then spread to both sides of the brain, are also included as clinical indicators of autoimmune encephalitis. Id. Generalized seizures, which do not have a localized onset, however, can occur in people with autoimmune encephalitis or juvenile myoclonic epilepsy. Victoria’s EEG results indicated that her seizures were not focal or secondary generalized. To counteract this lack of evidence, Mr. Mager argues, citing respondent’s medical literature, that “EEGs of patients suffering from autoimmune epilepsy ‘may have variable findings including normal, focal, and generalized slow activity, periodic discharges, and focal epileptiform discharges.’” Id. at 12 (quoting exhibit BB, tab 4, at 1). Additionally, “in a study of children with new-onset epilepsy, over 40% of these children experienced generalized seizures.” Id. at 16 (citing exhibit 65). However, Dr. Kohrman states that “generalized discharges are the hallmark of [primary or idiopathic generalized epilepsies].” Exhibit BB at 2-3. Though the classification of Victoria’s seizures as generalized does not rule out autoimmune encephalitis, it also does not constitute affirmative evidence of 13 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 14 of 20 autoimmune encephalitis. In other words, the presence of generalized seizures could indicate either autoimmune encephalitis or juvenile myoclonic epilepsy, whereas only the presence of focal or secondary generalized seizures would point specifically to a diagnosis of autoimmune epilepsy. After factoring in Dr. Kohrman’s comment that generalized seizures are also the “hallmark” of primary or idiopathic generalized epilepsies (i.e. epilepsies without an autoimmune component), as well as the fact that Dr. Kohrman possesses superior expertise with respect to epilepsy, see supra Part V.A, this makes Mr. Mager’s argument even less persuasive. ii. Seizure Clusters, Status Epilepticus Mr. Mager states that Victoria may have suffered one seizure cluster, referring to her first hospital admission in November 2007. Pet’r’s Reply at 12-13. Specifically, he states that, after her ER visit, which was precipitated by a seizure, “she suffered a three-minute seizure followed very closely by a shorter seizure, without recovering between the two.” Id. at 13 (citing exhibit 6 at 24). It is not clear whether “status epilepticus” was applicable to this particular “cluster.” However, it also does not appear that “status epilepticus” is necessarily present in a case of autoimmune encephalitis. Id. (citing exhibit 65 at 4). Still, while this incident following Victoria’s November 2007 hospitalization could constitute a seizure cluster, it also does not provide persuasive evidence regarding this particular indicator of autoimmune encephalitis, or evidence of autoimmune encephalitis as a whole, given the inconclusiveness of a classification of this incident as a “cluster” and the fact that, if it was, it was an isolated incident. iii. Seizures of Unknown Cause It does appear that treaters in this case were not uniform in their assessment of the cause of her seizures. During her first hospitalization, it was noted that the discharges detected in her EEG “indicate focal sites of cerebral hyperexcitability which can be associated with partial seizures/epilepsy.” Exhibit 4 at 17. At her second hospitalization, the reason for her visit was noted as “probable seizure.” Exhibit 7 at 14. Dr. Sharif noted an impression of “focal onset epilepsy by EEG.” Exhibit 11 at 77. Dr. Koehn, in her assessment, elected to “leave[] the possibility open for this to have been a primary or secondarily generalized seizure.” Exhibit 6 at 20. Finally, Dr. Edgar diagnosed her with “probable juvenile myoclonic epilepsy” based on age of onset. Exhibit 9 at 4. Thus, this clinical factor does appear to be present in Victoria’s case in that no treater gave her a certain diagnosis or cause of her seizures and there is some disagreement on ultimate conclusions among treaters. However, because this factor represents a lack of information by definition, rather than information pointing specifically to a 14 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 15 of 20 diagnosis of autoimmune encephalitis, it appears to be a less persuasive indicator than some of the other factors discussed. iv. Refractory Seizures As explained above, see supra Part V.B.2, Mr. Mager has not met his burden to show that Victoria’s seizures were refractory, or in other words resistant to anti- seizure medication. v. Movement Disorders, Neuropsychiatric Symptoms, and/or Cognitive or Memory Impairment Mr. Mager asserts that Victoria experienced cognitive impairment and bases this assertion on neuropsychological testing performed by Dr. Waltonen in April 2008. Pet’r’s Reply at 14-15. Dr. Waltonen ultimately concluded that “overall, her examination does not reveal evidence of significant cognitive impairment with the exception of very focal language findings.” Exhibit 6 at 6. In his brief, Mr. Mager emphasizes the language findings as proof that the results of this testing were irregular. However, Victoria has a documented history of “some type of learning difficulty at least in the speech and language area.” Id.; see also exhibit 18 at 5 (pre-vaccination notation from a primary care provider regarding “poor performance” and “decreased attention” at school). It does not appear that the results of Dr. Waltonen’s assessment, which were very narrowly limited to language-related deficits, can rise to the level of a cognitive impairment indicative of autoimmune encephalitis, especially when these language issues existed to some degree long before her vaccination. See exhibit A at 12 (Dr. Kohrman opining that Victoria’s normal range IQ “argues against a neurodegenerative disorder as a cause for the seizures”). vi. History of Autoimmune Diseases Mr. Mager concedes that Victoria did not have any significant personal or family history of autoimmune disease. Pet’r’s Reply at 15. While, as Mr. Mager points out and as is true with the other diagnostic indicators of autoimmune encephalitis, this fact is not dispositive, the absence of a family or personal history of autoimmune disease further adds to the lack of persuasiveness with respect to the existence of autoimmune encephalitis. vii. Summary: Autoimmune Encephalitis Thus, with respect to autoimmune encephalitis, the only diagnostic criterion that Mr. Mager has met his burden to show is that Victoria’s seizures were of an unknown cause. It follows that Mr. Mager has then not met his burden in showing 15 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 16 of 20 that Victoria suffered from autoimmune encephalitis, as this is only one of six diagnostic criteria, and one that is relatively less weighty given that it by definition indicates a lack of information regarding Victoria’s condition. C. Lack of Support from Treating Doctors The opinions of treating doctors regarding the diagnosis of a petitioner’s condition are generally favored given that, having examined the petitioner, they are in the best position to opine on the petitioner’s condition. See Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006). In this case, no treating doctors diagnosed Victoria with autoimmune epilepsy. On December 12, 2007, pediatric neurologist Dr. Sharif noted an impression of “focal onset epilepsy by EEG.” Exhibit 11 at 77. On February 21, 2008, pediatric neurologist Dr. Koehn assessed her abnormal EEG during her hospitalization as indicating a possible “primary or secondarily generalized seizure,” but did not diagnose her with any specific type of epilepsy. Exhibit 6 at 20. Later, she was assessed with “probable seizure” during her hospitalization in October 2012, exhibit 4 at 14, and subsequently visited her primary care doctor who prescribed anti-seizure medication, exhibit 9 at 39. Again, no diagnoses of epilepsy were made. On January 14, 2013, neurologist Dr. Edgar noted an impression of primary generalized seizure disorder and stated: “age of onset at approximately 11 years of age suggests possibility of juvenile myoclonic epilepsy.” Exhibit 9 at 9. Dr. Edgar again noted “probable juvenile myoclonic epilepsy” at a second appointment on July 8, 2013. Id. at 4. Thus, as evidenced by these records, none of Victoria’s treating doctors diagnosed her with autoimmune epilepsy, or in fact made a definitive diagnosis at all. The closest Victoria came to receiving a diagnosis were Dr. Edgar’s impressions. However, Dr. Edgar specifically stated that he suspected probable juvenile myoclonic epilepsy, not autoimmune epilepsy. The lack of support from treating doctors regarding a diagnosis of autoimmune epilepsy is yet another factor that weighs against finding that Victoria suffered from autoimmune epilepsy. D. Conclusion: Autoimmune Epilepsy As explained above, Mr. Mager advanced the presence of autoimmune encephalitis as an associated autoimmune disease as one of three overall diagnostic indicators of the asserted diagnosis—autoimmune epilepsy. Mr. Mager has not met his burden to show either the presence of autoimmune antibodies in Victoria’s blood or that Victoria’s seizures were refractory. See supra Parts V.B.1, V.B.2. 16 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 17 of 20 Because he also could not persuasively show that Victoria suffered from autoimmune encephalitis, and therefore an associated autoimmune disease, see supra Part V.B.3, it follows that he has not shown by a preponderance of the evidence that Victoria suffered from autoimmune epilepsy. Because he has not established the threshold issue of diagnosis, it also follows that further analysis regarding causation is unnecessary. See Lombardi v. Sec’y of Health & Human Servs., 656 F.3d 1343, 1353 (Fed. Cir. 2011); Broekelschen v. Sec’y of Health & Human Servs., 618 F.3d 1339, 1346 (Fed. Cir. 2010). If an Althen analysis were performed, then one element is that Mr. Mager establish, by preponderant evidence, “a proximate temporal relationship between vaccination and injury.” Althen, 418 F.3d at 1278. Here, relying upon a post- marketing study, Slade, Mr. Mager asserts that a window of 4-42 days was “‘biologically plausible.’” Pet’r’s Br. at 45, quoting exhibit 59 (Slade) at 5. Mr. Mager further maintains that Victoria developed seizures within the appropriate time. In 2007, she received her first dose of the HPV vaccine on October 2, 2007. Exhibit 4 at 2, 9. She suffered a seizure on November 14, 2007. Exhibit 11 at 3. The interval between these events is 43 days. Five years later, Victoria received a second dose of the HPV vaccine on September 11, 2012. She then experienced a seizure on October 10, 2012. The interval between these events is 29 days. In response, the Secretary does not strenuously argue that the seizures occurred outside an expected window. Instead, the Secretary points out that “temporal proximity alone is insufficient to establish causation.” Resp’t’s Br. at 23, citing Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1323 (Fed. Cir. 2010) and Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992). The sequence of events in Victoria’s life in that she twice experienced seizures after receiving the HPV vaccine seems to underlie Mr. Mager’s good faith belief that the vaccinations harmed his daughter and, ultimately, caused her death much too soon. However, Congress has not allowed special masters to award compensation based upon a petitioner’s belief alone. 42 U.S.C. § 300aa–13(a)(1); see Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344, 1349 (Fed. Cir. 1999). Although Mr. Mager has present opinions from a qualified expert, Dr. Shafrir, his opinion that Victoria suffered autoimmune epilepsy is not persuasive for the reasons explained at length above. And, without this predicate showing, examination of Dr. Shafrir’s opinions regarding all Althen prongs is not required according to Federal Circuit precedent. 17 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 18 of 20 VI. Ruling on the Record is Appropriate Special masters may rely on accumulated knowledge in the Vaccine Program to make entitlement decisions on the papers. Thus, special masters, “based upon their accumulated expertise in the field, judg[e] the merits of individual claims.” Whitecotton v. Sec’y of Health & Human Servs., 81 F.3d 1099, 1104 (Fed. Cir. 1996) (quoting Hodges v. Sec’y of Health & Human Servs., 9 F.3d 958, 961 (Fed. Cir. 1993)). Additionally, special masters retain wide discretion in determining whether an evidentiary hearing is necessary. Kreizenbeck v. Sec’y of Health & Human Servs., 945 F.3d 1362, 1365 (Fed. Cir. 2020) (citing 42 U.S.C. § 300aa-12(d)(3)(B)(v) (“In conducting a proceeding on a petition a special master . . . may conduct such hearings as may be reasonable and necessary.”)). The special master must only determine “that the record is comprehensive and fully developed before ruling on the record.” Id. at 1366 (citing Simanski v. Sec’y of Health & Human Servs., 671 F.3d 1368, 1385 (Fed. Cir. 2012)). A hearing to determine the threshold issue of diagnosis in this case is not needed. The parties have had ample opportunity to develop their positions through submissions of evidence (primarily medical records) about Victoria, lengthy and multiple expert reports, and thorough briefing. Mr. Mager’s claim fails for reasons that a hearing could not cure given the paucity of evidence establishing a diagnosis of autoimmune epilepsy, which is essential for the remainder of Mr. Mager’s claim to proceed. He has had a full and fair opportunity to present his case. Thus, a disposition on the papers is appropriate. See Kreizenbeck, 945 F.3d at 1365. VII. Conclusion For the foregoing reasons, the undersigned finds that Mr. Mager has not met his burden to show, by a preponderance of the evidence, that Victoria suffered from autoimmune epilepsy. Therefore, Mr. Mager has not shown that the HPV vaccination caused her to suffer autoimmune epilepsy resulting in sudden unexpected death in epilepsy. Accordingly, the claim for compensation is DENIED. The Clerk’s Office is instructed to enter judgment in accord with this decision unless a motion for review is filed. Information about the submission for a motion for review, including deadlines, is presented in the Vaccine Rules, which are available through the Court’s website. 18 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 19 of 20 IT IS SO ORDERED. s/Christian J. Moran Christian J. Moran Special Master 19 Case 1:14-vv-00820-RTH Document 190 Filed 08/24/21 Page 20 of 20 Appendix of Articles Cited Barbara A. Slade et al., Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine, 302 J. Am. Med. Ass’n 750 (2009), filed as exhibit 59. Jehan Suleiman et al., The recognition and treatment of autoimmune epilepsy in children, 57 Dev. Med. & Child Neurology 431 (2015), filed as exhibit 65. Jehan Suleiman et al., Autoantibodies to neuronal antigens in children with new-onset seizures classified according to the revised ILAE organization of seizures and epilepsies, 54 Epilepsia 2091 (2013), filed as exhibit 88. Alexei Verkhratsky & Arthur Butt, General Pathophysiology of Neuroglia, in Glial Physiology and Pathophysiology 431 (2013), filed as exhibit Y, tab 15. 20 ================================================================================ DOCUMENT 2: USCOURTS-cofc-1_14-vv-00820-2 Date issued/filed: 2022-02-15 Pages: 24 Docket text: JUDGE VACCINE REPORTED OPINION: Public version of 198 Order on Motion for Review. Signed by Judge Ryan T. Holte. (rnb) Service on parties made. -------------------------------------------------------------------------------- Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 1 of 24 In the United States Court of Federal Claims No. 14-820 (Filed: 15 February 2022*) *************************************** MICHAEL MAGER, as parent of * MS. VICTORIA MAGER * * Petitioner, * Vaccine Act; Off-Table Case; * Autoimmune Epilepsy; Actual Causation; v. * Sudden Unexpected Death in Epilepsy * (“SUDEP”); Competing Diagnoses; SECRETARY OF HEALTH AND HUMAN * Human Papilloma Virus Vaccine (“HPV”). SERVICES * * Respondent. * * *************************************** Renee J. Gentry, Vaccine Injury Clinic, George Washington University Law School, of Washington, DC, for petitioner. Zoe Wade, with whom were Laurie Wiesner, Trial Attorney, Heather L. Pearlman, Deputy Director, C. Salvatore D’Alessio, Acting Director, Brian M. Boynton, Acting Assistant Attorney General, Torts Branch, Civil Division, U.S. Department of Justice, of Washington, DC, for respondent. OPINION AND ORDER HOLTE, Judge. This case involves the tragic death of a child and the government’s system for compensating vaccine-injured children—and by extension, their families. Congress designed the Vaccine Act as part of “the Nation’s efforts to protect its children by preventing disease.” Cloer v. Sec’y of Health & Hum. Servs., 654 F.3d 1322, 1325 (Fed. Cir. 2011) (quoting H.R. Rep. No. 99-908, at 4 (1986)). “[W]hile most of the Nation’s children enjoy greater benefit from immunization programs, a small but significant number have been gravely injured.” Id. “[F]or the relatively few who are injured by vaccines,” Congress noted the “opportunities for redress and restitution [were] limited, time-consuming, expensive, and often unanswered.” Id. In response, “Congress created the Vaccine Program” to “compensate injured persons quickly and fairly” for injuries “either presumed or proven to be causally connected to vaccines.” Id. This * This opinion was initially filed under seal pursuant to Vaccine Rule 18(b) of the Rules of the Court of Federal Claims. The Court provided the parties 14 days to submit proposed redactions, if any, before the opinion was released for publication. Neither party proposed redactions. This opinion is now reissued for publication in its original form. Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 2 of 24 Program “exempt[s] petitioners from the burden of proving causation” by removing “the tort requirements of demonstrating that a manufacturer was negligent or that a vaccine was defective.” Id. In short, the Act “assure[s] parents that when their children are the victims of an appropriate and rational national policy, a compassionate [g]overnment will assist them in their hour of need.” Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1364 (Fed. Cir. 2019) (Newman, J., dissenting on unrelated grounds) (quoting Sen. Edward Kennedy, S. Comm. on Labor & Human Res.). Michael Mager seeks compensation for his daughter’s seizure disorder and death, which he alleges are the result of her being vaccinated for the human papilloma virus. Ms. Mager’s first documented seizure occurred shortly after receiving the first HPV vaccine dose. The seizures subsided for several years until she received a second dose of the HPV vaccine, at which point her seizures returned and became more regular—ultimately resulting in her death. The Special Master denied Mr. Mager’s petition because, according to the Special Master, there was insufficient evidence to support a diagnosis of Autoimmune Epilepsy, which the Special Master considered to be necessary for Mr. Mager’s argument to succeed. Mr. Mager moves the Court for review of the Special Master’s decision denying his petition. According to Mr. Mager, the Special Master abused his discretion by mischaracterizing Mr. Mager’s medical theory of his daughter’s injury, failing to adhere to precedential case law when considering whether the vaccine caused her injury, and failing to consider the entirety of the evidence. For the following reasons, the Court grants petitioner’s motion, vacates the Special Master’s order, and remands this case to the Special Master for further proceedings consistent with this opinion. I. Petitioner’s Medical History and the Vaccination As the basic facts have not changed significantly, the Court’s recitation of the background facts draws from the Special Master’s Decision Denying Compensation, ECF No. 189. Ms. Mager’s health history was relatively normal before receiving the vaccination for the human papilloma virus (“HPV”).1 Ms. Mager received the vaccine on 2 October 2007. Pet. at 1, ECF No. 1. Six weeks later, Ms. Mager suffered a seizure and was taken to a nearby emergency room. Pet’r’s Ex. 11 at 28, ECF No. 9-4. The admission notes from that visit state she experienced a seizure followed by a second seizure approximately four minutes later. Id. Her head CT scan, urine toxicology screen, and chest x-ray were all normal. Id. at 3–4, 13. An electroencephalogram (“EEG”) “indicate[d] focal sites of cerebral hyperexcitability which can be associated with partial seizures/epilepsy.” Id. at 17. Ms. Mager was prescribed Depakote, an anti-seizure medication, and discharged on 15 November 2007. Id. at 38. In a follow-up visit on 12 December 2007, Ms. Mager’s physician, Dr. Shafrir, noted that her parents recalled that “for a while [after her initial seizure], [Ms. Mager] was waking up with 1 While the government argues Ms. Mager’s seizures began before she was vaccinated for the human papilloma virus, the parties agree the onset of her seizures is ambiguous and the Special Master made no finding concerning when the seizures began. Mot. for Review Oral Arg. Tr. (“Tr.”) at 20:21–22:14, ECF No. 197 (“COURT: Did the Special Master make any findings about seizures occurring before the HPV vaccine? [GOVERNMENT:] He did not. THE COURT: [Petitioner], any follow-up on that? [PETITIONER]: . . . I agree . . . .”). The only exception to Ms. Mager’s normal health was, at twelve-years-old, she required speech therapy, demonstrated “poor school performance,” “decreased attention” at school, and suffered from enuresis, or bed wetting. Pet’r’s Ex. 18 at 5, ECF No. 22-2. - 2 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 3 of 24 big cuts in her tongue at least twice and also complaining of soreness after waking up and it is possible that these might have been seizures.” Pet’r’s Ex. 11 at 75. Ms. Mager’s stepmother also reported Ms. Mager’s enuresis was resolved after she began taking her antiseizure medication, Depakote. Id. Dr. Shafrir noted the EEG indicated an impression of “focal onset epilepsy” and “some frontal lobe dysfunction,” and he recommended neuropsychological testing. Id. at 77. Approximately two months later, Ms. Mager saw another pediatric neurologist, Dr. Koehn, who ordered another EEG—the results of which were normal. Pet’r’s Ex. 6 at 22, ECF No. 8-7. Dr. Koehn noted, referring to the original abnormal EEG, that “[t]he first EEG pattern could represent a fragment/a more lateralized pattern of an underlying generalized discharge or it could in fact be a focal discharge. Therefore, leaving the possibility open for this to have been a primary or secondarily generalized seizure.” Id. at 20. Although the medication appeared to control her seizure activity, Ms. Mager’s father and stepmother noted undesirable side effects of the medication and requested she be weaned off Depakote. Id. at 24. Accordingly, Dr. Koehn agreed to gradually wean Ms. Mager from Depakote and referred her for neuropsychological testing. Id. at 28; see also Pet. at 1. Shortly after seeing Dr. Koehn, Ms. Mager saw another physician, Dr. Waltonen, for neuropsychological testing. Pet’r’s Ex. 6 at 6. Dr. Waltonen observed she had “a history of some type of learning difficulty at least in the speech and language area.” Id. He also noted Ms. Mager had a family history of epilepsy and seizures on her maternal side. Id. at 2. He noted reports of “increasing problems with doing well in school” and Ms. Mager’s teachers indicated she had “problems following directions.” Id. at 1, 4. Ultimately, Dr. Waltonen concluded that “[o]verall, her examination does not reveal evidence of significant cognitive impairment with the exception of these very focal language findings.” Id. at 6. From April 2008 to October 2012, Ms. Mager did not experience any seizure activity and appeared to function normally. Her school records did not indicate any abnormalities. See Pet’r’s Ex. 83, ECF No. 144-3. The results of sport physicals she received in August 2009 and March 2012 were normal. Pet’r’s Ex. 10 at 15–17, ECF No. 9-3; Pet’r’s Ex. 14 at 1–2, ECF No. 12-2. During a physical exam in January 2012, she reported she had not experienced seizure activity for four years. Pet’r’s Ex. 10 at 18. Ms. Mager received her second HPV vaccination on 11 September 2012. Pet’r’s Ex. 4 at 1, ECF No. 8-5. The following month, on 10 October 2012, she suffered a seizure and was taken to the emergency department of a nearby medical center. Pet’r’s Ex. 7 at 9, ECF No. 8-8. Her evaluation, which included an EKG, was normal. Id. at 13– 14. She was diagnosed with a “[p]robable seizure” and discharged. Id. at 14. In a visit with her primary care doctor the next month, she reported two additional seizures occurring on 19 October 2012 and 7 November 2012 after her ER visit. Pet’r’s Ex. 9 at 39, ECF No. 9-2. Her doctor prescribed an antiseizure medication, Depakote, and referred her to a neurologist. Id. Neurologist Dr. Edgar saw Ms. Mager a couple months later in January 2013. Pet’r’s Ex. 9 at 24–25. According to Dr. Edgar’s note, “[t]he EEG is normal during wakefulness. During sleep there is activation of infrequent potentially epileptiform activity over the left frontal and - 3 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 4 of 24 bioccipital head regions, consistent with the patient’s history of generalized seizures.” Id. at 25. Dr. Edgar believed Ms. Mager suffered from primary generalized seizure disorder, and he noted the “age of onset at approximately 11 years of age suggests the possibility of juvenile myoclonic epilepsy, although no myoclonic seizures are reported.” Id. at 31. He recommended Depakote, but due to Ms. Mager’s objections, he directed her to begin weaning off Depakote and prescribed Keppra, an alternative antiseizure medication, instead. Id. at 8. Dr. Edgar observed during a follow-up appointment in July 2013 that Ms. Mager’s compliance with her Keppra prescription was “less than ideal”; she had a sub-therapeutic level of the medication in her blood according to a test on 30 May 2013. Pet’r’s Ex. 9 at 3. Ms. Mager wanted to stop using Keppra, but Dr. Edgar persuaded her to remain on the drug given her history of seizures. Id. at 4. Due to her age at the onset of her seizure condition, Dr. Edgar again noted “probable juvenile myoclonic epilepsy.” Id. Months later, on 11 January 2014, Ms. Mager was found unresponsive at a friend’s house and was rushed to the emergency department of a nearby hospital where she was pronounced dead upon arrival. Pet’r’s Ex. 8 at 2, ECF No. 8-9. The local police department reported a witness statement that Ms. Mager had been “missing a lot of doses of her medication,” and her father reported that “she was having seizures more frequently.” Pet’r’s Ex. 13 at 2, ECF No. 9-6. According to an autopsy, Ms. Mager suffered pulmonary edema and brain changes consistent with a seizure disorder. Pet’r’s Ex. 16 at 10, ECF No. 18-2. There was subpial gliosis in sections of her brain. Id. at 16. A toxicology screen showed therapeutic levels of Keppra in her blood. Pet’r’s Ex. 13 at 11. The cause of Ms. Mager’s death was “seizure disorder” according to her death certificate. Pet’r’s Ex. 1 at 1, ECF No. 8-2. The parties agree Ms. Mager suffered from a seizure disorder that caused her death, Tr. 6:14–16, but they dispute the underlying diagnosis. Pet’r’s Prehr’g Br. at 9, ECF No. 168 (“Petitioner contends [Ms. Mager] suffered from autoimmune epilepsy that resulted in sudden unexpected death with epilepsy or SUDEP.”); Gov’t’s Prehr’g Br. at 1, ECF No. 180 (“the evidence supports that Ms. Mager most likely suffered from juvenile myoclonic epilepsy”). II. The Petition and Procedural History Before the Special Master Petitioner filed his petition alleging the HPV vaccination caused Ms. Mager to suffer a seizure disorder leading to her death on 11 January 2014. Pet. at 2. All relevant medical records were submitted, and the record was complete on 17 February 2015. See Statement of Completion, ECF No. 23. A couple months later, the Secretary filed his report contesting causation and arguing Ms. Mager’s seizure disorder preexisted her vaccination. See Resp’t’s Rule 4(c) Report, ECF No. 25. After a change in counsel and experts, and multiple extensions of time, the parties submitted their experts’ reports. See Pet’r’s Ex. 55, ECF 116-1; Gov’t’s Ex. Z, ECF No. 128-1; Gov’t’s Ex. AA, ECF No. 129-1; Pet’r’s Ex. 85, ECF No. 165-2; Gov’t’s Ex. CC, ECF No. 182-1; Gov’t’s Ex. BB, ECF No. 183-1. Petitioner’s expert, Dr. Shafrir, asserted Ms. Mager’s epilepsy was autoimmune in nature based, in part, on autoimmune reactions to the vaccine. Pet’r’s Ex. 55 at 18. Respondent’s experts, Dr. Kohrman and - 4 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 5 of 24 Dr. Fujinami, however, both stated Ms. Mager suffered from juvenile myoclonic epilepsy (“JME”). Gov’t’s Ex. Y at 7, ECF No. 95-3; Gov’t’s Ex. CC at 1–2. The Special Master ordered the parties to submit briefs in advance of potential adjudication on 20 November 2019, ECF No. 142. After multiple extensions, Mr. Mager filed a supplemental expert report from Dr. Shafrir on 25 July 2020, ECF No. 167, and his brief on 27 July 2020, ECF No. 168. The Secretary, again after multiple extensions, filed his supplemental expert reports from Dr. Fujinami and Dr. Kohrman, as well as his brief, on 10 February 2021, ECF Nos. 180–83. Mr. Mager filed his reply brief on 26 March 2021, ECF No. 186. In the interim period between the parties’ briefing and the Special Master’s decision, a significant colloquy between the Special Master and petitioner took place. The Special Master issued an order in June asking petitioner to “identify the source of the diagnostic criteria for autoimmune epilepsy listed in his [prehearing] brief.” Order at 1, ECF No. 187. Petitioner responded accordingly the next day but noted “[t]he criteria are discussed in that section solely to demonstrate that autoimmune epilepsy can present as milder epilepsy.” Status Report Re Order of June 16, 2021 (“Pl.’s Resp. to Special Master’s 16 June 2021 Questions”) at 1, ECF No. 188 (emphasis added). The Special Master then issued his decision denying compensation the following month on 29 July 2021. See Decision Den. Compensation, ECF No. 189. In his decision, the Special Master denied petitioner’s claim on the basis that there was insufficient evidence to support a diagnosis of Autoimmune Epilepsy. Id. at 16–17. A. Expert Reports In weighing the evidentiary value of the parties’ experts’ opinions, the Special Master determined petitioner’s expert, Dr. Shafrir, and the government’s expert, Dr. Kohrman, both “have ample experience and expertise in pediatric neurology[;] Dr. Kohrman has a notable special expertise in epilepsy.” Decision Den. Compensation at 9. The Special Master noted “Dr. Shafrir’s certifications and topics of focus in his publications are certainly relevant and helpful to this case,” but determined “Dr. Kohrman’s specialty in epilepsy—particularly his board certification with a subspecialty in epilepsy and focus on pediatric epilepsy—makes him particularly qualified to opine on a case in which potential diagnoses of autoimmune epilepsy or juvenile myoclonic epilepsy are at play.” Id. Dr. Shafrir, believes Ms. Mager’s seizures and death were caused by a neurological reaction to the HPV vaccination. He explains: [B]ecause of some unknown and a very rare genetic susceptibility, [Ms. Mager] had an abnormal immune reaction to the HPV vaccination which produced brain inflammation in autoimmune epilepsy. The reactivation of the autoimmune and inflammatory mechanism with the second vaccination, produced recurrence of her epilepsy with more frequent seizures. The mechanism is likely based on molecular mimicry which could be supplemented by activation of the innate immune system . . . . - 5 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 6 of 24 Pet’r’s Ex. 55 at 17. The HPV vaccine, according to Dr. Shafrir, is a uniquely potent stimulator of the immune system. Id. at 19 (“In contrast to many other vaccines, the level of antibodies produced by [sic] HPV vaccine is more than 10 to 100[-]fold higher than the level of antibodies produced by the natural infection.”). The medical literature he cites identifies examples of brain autoimmunity related to the HPV vaccination and proteins. Id. “[A]wareness of autoimmune epilepsy has dramatically increased in the last several years,” says Dr. Shafrir, to the extent that “[c]hecking autoantibodies in appropriate cases of intractable epilepsy has become the standard of care.” Id. at 18–19. Here, there is strong evidence of an autoimmune inflammatory reaction, according to Dr. Shafrir, because Ms. Mager’s autopsy report found evidence of gliosis which suggests inflammation of the brain. Id. at 20. He further reasons the occurrence and recurrence of Ms. Mager’s seizures in correlation with the HPV vaccine demonstrates it caused her seizures and death. He explains: The relationship between vaccinations and her seizures is based on a “rechallenge” test and has been performed here with another episode of seizure occurring after her second HPV vaccination but not after [other vaccinations] given before the sec- ond HPV vaccination. One has to understand that in clinical situations, such a rechallenge for any treatment, medication or immunization would suffice to confirm a causal relationship. Pet’r’s Ex. 55 at 17, ECF No. 116-1. Dr. Shafrir emphasized the importance of the relationship between the vaccination and Ms. Mager’s seizures in a supplemental report: [T]he near identical sequence of events following each of the HPV vaccinations qualify as “certain” in the causality assessment of suspected adverse drug reactions, according to the existing criteria described in [the cited medical literature] in my first report. What is crucial here is the fact that Ms. Mager could stop antiepileptic medication and remained seizure free throughout the entire period of more than three years before the second vaccination. After the second vaccination in the recurrence of the seizures, the seizures became more frequent. In part, this is a result of her lack of easy access to neurological care, insurance issues which may have affected her ability to get her medications, and general lack of compliance. According to a witness after her death, she reported that she has seizures every week. This suggests that the immune reaction to the HPV vaccine, which produced the seizures, was more severe and more prolonged after the second vaccination probably because of the presence of immunological memory. Pet’r’s Ex. 85 at 1 (citations omitted). This relationship between the vaccination and the seizures, Dr. Shafrir reasoned, “is another strong support . . . for the causal relationship between the [HPV] vaccination and [Ms. Mager’s] seizure disorder and unexpected death.” Pet’r’s Ex. 55 at 20. - 6 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 7 of 24 The government submitted reports from two experts, Dr. Kohrman and Dr. Fujinami, both of whom dispute Dr. Shafrir’s theory of autoimmune epilepsy caused by the HPV vaccine. See Gov’t’s Exs. Z, AA, BB, CC. According to Dr. Kohrman, evidence weighing against a diagnosis of autoimmune epilepsy includes: (1) treating physicians diagnosed Ms. Mager with primary generalized epilepsy; (2) evidence Ms. Mager’s seizures predated the HPV vaccine; (3) absence of history of focal clinical seizures in the medical record; (4) absence of evidence indicating an autoimmune process in the autopsy report; and (5) absence of test results indicating presence of antineuronal antibodies. Gov’t’s Ex. BB at 12. Regarding Dr. Shafrir’s emphasis on the correlation between the HPV vaccine and Ms. Mager’s seizures, Dr. Kohrman commented: Given the diagnosis of a primary generalized epilepsy, that was never adequately treated [due] to family request and behavior, and the lack of patient taking [sic] meds[,] [h]er history and clinical course cannot be considered a challenge[-]rechallenge. It was never documented medically that she was seizure[-]free prior to [sic] second vaccination. The[re] is not [sic] contemporaneous medical record of her seizures noted between July 2008 and her second vaccination. Her seizures were primarily nocturnal and she did not always recognize these according to her [f]ather. Id. (citation omitted). Ms. Mager’s diagnosis, according to Dr. Kohrman, was most likely juvenile myoclonic epilepsy (“JME”). Id. at 14. Dr. Kohrman explains: JME is an idiopathic generalized epilepsy syndrome characterized by myoclonic seizures, generalized tonic-clonic seizures, and absence seizures. It is extremely common, accounting for [twenty-six percent] of idiopathic generalized epilepsies . . . and [ten percent] of all epilepsies . . . . [T]he average age of onset is 15.1 years ([seven to twenty-eight] years) with a slight female predominance. In the classic syndrome of JME, myoclonic seizures may precede the first generalized tonic- clonic seizure . . . by [six to twelve] months, although [generalized tonic-clonic seizures] occur as the first seizure type in approximately one-third of patients. Some have proposed specific subgroups of JME separating those patients who present with typical childhood absence or juvenile absence seizures, although this is much less common than the classical presentation of JME, accounting for only [ten percent] of cases . . . . Photosensitivity is relatively common, occurring in approximately [thirty percent] of patients. Id. at 2. Dr. Kohrman reviewed Ms. Mager’s medical history and determined her diagnosis was most likely JME. Id. at 15. He pointed to her treating physician’s comment that her epilepsy was likely JME due to her age. Id. at 2, 14 (citing Pet’r’s Ex. 10 at 23). He believed her medical history also supported a diagnosis of JME; specifically, that her seizures appeared to be controlled with antiseizure medication and other evidence such as her history of tongue-biting and enuresis (which he considered to be evidence of nocturnal seizures), her family history of epilepsy, and her history of speech and learning problems. Gov’t’s Ex. BB at 2, 14. He also explained her seizures were described as generalized tonic-clonic seizures and her EEGs showed - 7 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 8 of 24 generalized epileptiform activity, both of which are consistent with a diagnosis of JME. Id. at 14. Dr. Kohrman did not believe Ms. Mager suffered from autoimmune epilepsy. Id. at 12. He repeated her treating physician’s diagnosis of primary generalized epilepsy and noted JME falls on a spectrum of primary or idiopathic generalized epilepsies. Id. at 2, 12. He also believed her seizure disorder predated her HPV vaccination and observed there was an absence of evidence of antineuronal antibodies. Id. at 12. Regarding Dr. Shafrir’s suggestion that the autopsy revealed gliosis which indicated inflammation in the brain, Dr. Kohrman explained “subpial gliosis is a regular finding in juvenile myoclonic epilepsy. The pathologist at necropsy concluded this was a typical finding in epilepsy and [Ms. Mager had] generalized epilepsy . . . .” Id. at 15. Dr. Fujinami also believed Ms. Mager suffered from JME and observed that Ms. Mager’s seizures were not resistant to antiseizure medication, as would be the case if her seizures were caused by autoimmune epilepsy. Gov’t’s Ex. CC at 1. B. The Special Master’s Decision Denying Compensation The Special Master’s analysis in terms of the diagnostic criteria for autoimmune epilepsy is clear, thorough, and well-reasoned. The Special Master began his analysis by weighing the relative qualifications of the experts, specifically Dr. Shafrir and Dr. Kohrman. Decision Den. Compensation at 9. The Special Master considered both experts to be well qualified but found “Dr. Kohrman’s specialty in epilepsy—particularly his board certification with a subspecialty in epilepsy and focus on pediatric epilepsy—makes him particularly qualified to opine on a case in which potential diagnoses of autoimmune epilepsy or juvenile myoclonic epilepsy are at play.” Id. Next, the Special Master carried out a thorough analysis applying the diagnostic criteria petitioner identified for autoimmune epilepsy to the facts of this case. He explained this was necessary “because [petitioner’s] theory of causation relies on an autoimmune disease causing neuroinflammation.”2 Id. at 4. The three diagnostic criteria the Special Master considered were: “(1) ‘demonstration of autoantibodies against neuronal components in the patient’s blood’; (2) in most patients, seizures that ‘may not respond to regular antiepileptic medications but respond to immunomodulatory treatment’; and (3) ‘occurring in relation to an autoimmune disease or autoimmune encephalitis.’” Id. at 10 (citing Pet’r’s Prehr’g Br. at 9–10, ECF No. 168). Looking at the first criterion, the presence of autoantibodies against neuronal components in the patient’s blood, the Special Master found there was “no affirmative evidence on this point.” Id. at 10. This is a key criterion because the presence of neuronal antibodies in the blood is conclusive evidence of an autoimmune reaction. Id. Unfortunately, an antibody test was not performed in this case. Decision Den. Compensation at 10. The Special Master noted 2 Petitioner admits Ms. Mager’s condition does not fit the diagnostic criteria for autoimmune epilepsy. Tr. at 34:7–20. When asked why petitioner included the diagnostic criteria for autoimmune epilepsy, counsel for petitioner explained: “I do not believe that she meets the diagnostic criteria. Neither does Dr. Shafrir, and he stated that for the most severe case. . . . [O]ften in clinical settings, you’re going to get a diagnosis that doesn’t . . . meet all the diagnostic criteria. We’ve not alleged that she meets that diagnostic criteria in this case. We are alleging . . . that she meets the general clinical definitions based on the etiology of her epilepsy.” Tr. at 34:11–20. - 8 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 9 of 24 petitioner’s “potentially valid reasons” why Ms. Mager’s treating physicians may not have thought to perform tests for autoimmune antibodies—particularly that “autoimmune epilepsy is a relatively ‘emerging field.’” Id. (citing Pet’r’s Reply to Resp’t’s Prehr’g Mem. at 18, ECF No. 186). The Special Master reasoned, however, “a lack of evidence on this point does not help Mr. Mager’s case.” Id. “While this fact is not dispositive as to the determination of whether [Ms. Mager] had autoimmune epilepsy, and does not rule out autoimmune epilepsy,” the Special Master reasoned, “a lack of testing also does not provide any affirmative evidence supporting an autoimmune epilepsy diagnosis.” Id. The Special Master considered the autopsy report’s finding of gliosis and whether it was an indicator of an inflammatory process, as Dr. Shafrir argued, but concluded the evidence was tenuous because the experts dispute its significance as it pertains to evidence of autoimmunity. Id. at 11. The Special Master cited Dr. Fujinami, who argued gliosis is a “common finding in epilepsy and represents the result of a neuronal injury and cell death . . . and not an acute or chronic inflammatory process related to vaccination,” and Dr. Kohrman who said gliosis is a “regular finding in juvenile myoclonic epilepsy.” Id. at 10–11 (citing Gov’t’s Ex. Y at 7; Gov’t’s Ex. BB at 15). Besides, the Special Master reasoned, “[i]t also does not provide evidence of autoimmune antibodies in [Ms. Mager’s] blood, which is the actual relevant criterion in terms of testing for a diagnosis of autoimmune epilepsy.” Decision Den. Compensation at 11. Thus, the Special Master concluded there was an absence of evidence indicating the presence of autoantibodies, the first criterion for a diagnosis of autoimmune epilepsy. Id. at 10. Regarding the second criterion, the Special Master found there was insufficient evidence to conclude Ms. Mager’s seizures were resistant to antiseizure medication. Id. at 12. The Special Master considered petitioner’s argument that at least two incidents demonstrated Ms. Mager’s seizures were refractory: (1) Ms. Mager suffered a seizure the night she was discharged from the hospital in November 2007 after she started taking Depakote, an antiseizure medication; and (2) Ms. Mager had a therapeutic level of antiseizure medication, Keppra, in her blood at the time of her death. Id. at 11. The Special Master was not persuaded either incident was the result of resistance to antiseizure medication. Id. at 12. In the first instance, the Special Master reasoned, Ms. Mager’s seizures and seizure-related activity (e.g., enuresis) appeared to be controlled while she continued taking Depakote. Id. at 11–12. In the second, multiple sources of evidence suggested Ms. Mager did not take her medication as prescribed in the period preceding her death. Decision Den. Compensation at 12. In sum, the Special Master found the evidence in favor of finding the petitioner satisfied the second criterion was unpersuasive. Turning to the third criterion, the Special Master carried out an extensive analysis as to whether Ms. Mager suffered from autoimmune encephalitis.3 Id. at 13. The Special Master evaluated six clinical features of autoimmune encephalitis the petitioner identified. Id. (citing Pet’r’s Reply to Resp’t’s Prehr’g Mem. at 11). Those six clinical features include: 3 At oral argument, petitioner argued: “[W]e never alleged autoimmune encephalitis. We were, again, submitting evidence showing that anything that can cause this severe a storm of autoimmune encephalitis can cause something less than that.” Tr. at 29:22–30:1. In petitioner’s prehearing reply brief, however, “[p]etitioner contends [Ms. Mager] suffered from autoimmune-triggered encephalitis, which caused her epilepsy and eventual SUDEP.” Pet’r’s Reply to Resp’t’s Prehr’g Mem. at 10. - 9 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 10 of 24 (1) Focal seizures, particularly focal motor and focal dyscognitive, secondary generalized seizures; (2) seizure clusters, status epilepticus; (3) seizures and epilepsy of unknown cause; (4) refractory seizures; (5) associated features of encephalopathy, movement disorders, neuropsychiatric symptoms, cognitive or memory impairment; and (6) history of autoimmune diseases (personal or family). Id. The Special Master found there was insufficient evidence to satisfy these criteria, except the third (i.e., seizures of unknown cause). Id. at 15–16. The Special Master summed up: [T]he only diagnostic criterion that Mr. Mager has met his burden to show is that [Ms. Mager’s] seizures were of an unknown cause. It follows that Mr. Mager has then not met his burden in showing that [Ms. Mager] suffered from autoimmune encephalitis, as this is only one of six diagnostic criteria, and one that is relatively less weighty given that it by definition indicates a lack of information regarding [Ms. Mager’s] condition. Id. III. Petitioner’s Motion for Review and Respondent’s Arguments A. Petitioner’s Arguments Petitioner alleges “[t]he Special Master abused his discretion by mischaracterizing [p]etitioner’s position with respect to diagnosis and ignoring significant points made by [p]etitioner’s expert with respect to the diagnosis and causation, to such an extent as to deny [p]etitioner his full and fair hearing.” Mot. for Review at 2, ECF No. 191. According to petitioner, the Special Master commits two errors regarding Ms. Mager’s diagnosis: (1) he conflates her diagnosis before death with her alleged injury; and (2) he focuses on the autoimmune epilepsy portion of Dr. Shafrir’s proposed causation theory and fails to consider Dr. Shafrir’s theory in its full context. Id. at 16. Petitioner argues he “is not hinging his case on a diagnosis of autoimmune epilepsy, nor did he proffer the diagnostic criteria to support a diagnosis of autoimmune epilepsy. Rather, [p]etitioner argue[s] that [Ms. Mager] experienced [sudden unexpected death with epilepsy] as a result of her epilepsy which was, yes, likely to be autoimmune in nature.” Id. at 17. Petitioner maintains his “predominant argument was that [Ms. Mager] experienced challenge/rechallenge . . . . Rechallenge is not dependent on a finding that [Ms. Mager] suffered from autoimmune epilepsy. It is dependent on [Ms. Mager] suffering an adverse event, in this case seizures, after more than one administration of a particular vaccine, e.g.[,] the HPV vaccination.” Id. While petitioner’s expert, Dr. Shafrir, testified Ms. Mager’s HPV vaccination triggered autoimmune epilepsy in Ms. Mager, petitioner argues “the complexity of her diagnosis cannot be stripped down to the three [diagnostic] criteria [for autoimmune epilepsy] as the Special Master did in this case. Particularly, when [those] criteria [are] offered to demonstrate that autoimmune epilepsy can present in a range of severity including the milder epilepsy from which [Ms. Mager] suffered.” Id. - 10 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 11 of 24 Petitioner argues the Special Master improperly failed to consider the entirety of petitioner’s claim by limiting his analysis to the diagnostic criteria for autoimmune epilepsy before dismissing the case. Id. at 18. According to petitioner, the Special Master’s reliance on Lombardi v. Sec’y of Health & Hum. Servs., 656 F.3d 1343 (Fed. Cir. 2011), and Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339 (Fed. Cir. 2010), is misplaced, and the Special Master should have analyzed the case under Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274 (Fed. Cir. 2005), and its progeny because Lombardi and Broekelschen are distinguishable. Mot. for Review at 18. Plaintiff further argues the Special Master was obliged to consider the entire record before disposing of the case due to his decision to not hold a hearing. Id. at 15. To support his proposition that the procedural posture of a case affects the Special Master’s burden to consider the evidence, petitioner cites Moriarty by Moriarty v. Sec’y of Health & Hum. Servs., 844 F.3d 1322, 1333 (Fed. Cir. 2016). Id. “In the instant matter,” petitioner argues, “the Special Master’s refusal to conduct an evidentiary hearing . . . renders it particularly important that he review the entire record . . . . If a Special Master may not, as a matter of law, decline to consider evidence on the record only because it was not discussed at hearing [as was the case in Moriarty], it is even more imperative that he consider all the evidence when he also declines to conduct a hearing.” Id. B. Respondent’s Arguments Respondent argues petitioner affirmatively articulated a causation theory that hinges on an autoimmune epilepsy diagnosis. Resp. to Mot. for Review at 10, ECF No. 193. Specifically, respondent points to petitioner’s statements that his theory of causation is a “neurological autoimmune process triggered by the HPV vaccine, causing autoimmune epilepsy[,]” and “the initial HPV vaccine dose caused [Ms. Mager’s] epilepsy and the subsequent dose aggravated that condition through a neurological autoimmune process causing autoimmune epilepsy.” Id. (quoting Pet’r’s Prehr’g Br. 16, ECF No. 168). Respondent maintains “[i]t is thus plain that petitioner’s case hinged on the argument that Ms. Mager developed autoimmune epilepsy.” Id. Respondent cites the Special Master’s decision which summarizes the experts’ opinion on Ms. Mager’s diagnosis: Dr. Shafrir asserted a diagnosis of autoimmune epilepsy based, in part, on what he deemed neurological reactions to the vaccine that suggested underlying autoimmune encephalitis. Dr. Kohrman, however, maintained a diagnosis of juvenile myoclonic epilepsy (“JME”), based on his view that [Ms. Mager] suffered pre-vaccination seizure activity, non-focal (i.e. generalized) seizures, and a lack of evidence regarding an autoimmune process in [Ms. Mager’s] autopsy. Dr. Fujinami agreed with the JME diagnosis, highlighting that [Ms. Mager’s] seizures were not treatment resistant, as would be true of seizure activity involved in autoimmune epilepsy. Id. at 11 (quoting Decision Den. Compensation at 3). Respondent further cites the Special Master’s conclusion that “[t]he difference between autoimmune epilepsy and JME . . . affects the - 11 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 12 of 24 outcome of [petitioner’s] case because his theory of causation relies on an autoimmune disease causing neuroinflammation.” Id. at 12 (quoting Decision Den. Compensation at 4). “Accordingly,” respondent argues, “it was necessary and legally correct for the Special Master to undertake a preliminary inquiry regarding whether petitioner met his burden in proving that Ms. Mager suffered from autoimmune epilepsy.” Id. Respondent argues petitioner now disavows his allegation that Ms. Mager’s seizure was caused by her autoimmune epilepsy. Resp. to Mot. for Review at 12. According to respondent, “[i]f petitioner was not relying on a diagnosis of autoimmune epilepsy, or wanted the Special Master to consider criteria from a different condition, he had plenty of chances to clarify his position. As the Special Master points out, ‘[t]he parties have had ample opportunity to develop their positions through submissions of evidence (primarily medical records) about [Ms. Mager], lengthy and multiple expert reports, and thorough briefing.’” Id. at 12 (quoting Decision Den. Compensation at 18). Regarding the Special Master’s decision to resolve the claim without an evidentiary hearing, respondent argues “[t]he Vaccine Rules explicitly authorize a special master to make findings of fact and decide a case on the basis of the written record without an evidentiary hearing.” Id. at 14 (citing VRCFC 8(d); Dickerson v. Sec’y of Dep’t of Health & Hum. Servs., 35 Fed. Cl. 593, 598 (1996); Plummer v. Sec’y of Dep’t of Health & Hum. Servs., 24 Cl. Ct. 304, 307 (1991)). Respondent cites 42 U.S.C. § 300aa-12(d)(3)B(v) (2018), which provides a special master “may conduct such hearings as may be reasonable and necessary,” (emphasis added), for supporting its argument the decision whether to hold a hearing is within the Special Master’s discretion. Id. According to respondent, the Special Master afforded petitioner a full and fair hearing: It is evident from the case record that the Special Master carefully evaluated all of the evidence and decided the case on the merits. The Special Master found that petitioner’s “claim fails for reasons that a hearing could not cure given the paucity of evidence establishing a diagnosis of autoimmune epilepsy, which is essential for the remainder of [petitioner’s] claim to proceed.” The Special Master observed, “[petitioner] has had a full and fair opportunity to present his case. Thus, a disposition on the papers is appropriate.” Id. at 15 (quoting Decision Den. Compensation at 18). Respondent further argues the Special Master’s decision to forgo an evidentiary hearing conserved judicial resources and provided a simplified process consistent with the legislative intent of the Vaccine Act. Id. IV. Legal standards A. The Court’s Standard of Review of a Special Master’s Decision The Vaccine Act provides this Court jurisdiction to review a Special Master’s decision upon timely motion of either party. See 42 U.S.C. § 300aa-12(e)(1)–(2). In reviewing the record of the proceedings before the Special Master, the Court may: (1) “uphold the findings of fact - 12 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 13 of 24 and conclusions of law of the special master and sustain the special master’s decision”; (2) “set aside any findings of fact or conclusion of law of the special master found to be arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law and issue its own findings of fact and conclusions of law”; or (3) “remand the petition to the special master for further action in accordance with the court’s direction.” § 300aa-12(e)(2). “Fact findings are reviewed . . . under the arbitrary and capricious standard; legal questions under the ‘not in accordance with law’ standard; and discretionary rulings under the abuse of discretion standard.” Saunders v. Sec’y of Dep’t of Health & Hum. Servs., 25 F.3d 1031, 1033 (Fed. Cir. 1994) (quoting Munn v. Sec’y of Dep’t of Health & Hum. Servs., 970 F.2d 863, 870 n.10 (Fed. Cir. 1992)). It is not the Court’s role “to reweigh the factual evidence, or to assess whether the special master correctly evaluated the evidence.” Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d 1357, 1360 (Fed. Cir. 2000) (quoting Munn, 970 F.2d at 871). The Court also does “not examine the probative value of the evidence or the credibility of the witnesses. These are all matters within the purview of the fact finder.” Id. (quoting Munn, 970 F.2d at 871). “Reversal is appropriate only when the special master’s decision is arbitrary, capricious, an abuse of discretion, or not in accordance with the law.” Snyder ex rel. Snyder v. Sec’y of Health & Hum. Servs., 88 Fed. Cl. 706, 718 (2009). The arbitrary and capricious standard “is a highly deferential standard of review[:] [i]f the special master has considered the relevant evidence of record, drawn plausible inferences and articulated a rational basis for the decision, reversible error will be extremely difficult to demonstrate.” Hines ex rel. Sevier v. Sec’y of Dep’t of Health & Hum. Servs., 940 F.2d 1518, 1528 (Fed. Cir. 1991). B. The Standard of Causation in Vaccine Cases “A petitioner seeking compensation under the Vaccine Act must prove by a preponderance of the evidence that the injury or death at issue was caused by a vaccine.” Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1341 (Fed. Cir. 2010) (citing 42 U.S.C. §§ 300aa-11(c)(1), 13(a)(1) (2018)). “A petitioner can show causation under the Vaccine Act in one of two ways”: (1) “by showing that she sustained an injury in association with a vaccine listed in the Vaccine Injury Table[,] . . . [i]n such a case, causation is presumed”; or (2) “if the complained-of injury is not listed in the Vaccine Injury Table . . . the petitioner may seek compensation by proving causation in fact.” Id. at 1341–42 (internal citations omitted). Vaccine cases employ a burden shifting standard: “[o]nce the petitioner has demonstrated causation, she is entitled to compensation unless the government can show by a preponderance of the evidence that the injury is due to factors unrelated to the vaccine.” Id. at 1342 (citing Doe v. Sec’y of Health & Hum. Servs., 601 F.3d 1349, 1351 (Fed. Cir. 2010); 42 U.S.C. § 300aa-13(a)(1)(B)). “When a petitioner has suffered an off-Table injury . . . [the Federal Circuit] has established the following test for showing causation in fact under the Vaccine Act:” [The petitioner’s] burden is to show by preponderant evidence that the vaccination brought about her injury by providing: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing - 13 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 14 of 24 that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury. Broekelschen, 618 F.3d at 1345 (quoting Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005)). Under the first prong of Althen, “[a] petitioner must provide a ‘reputable medical or scientific explanation’ for its theory.” Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1359 (Fed. Cir. 2019) (quoting Moberly ex rel. Moberly v. Sec’y of Health & Hum. Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010)). “While it does not require medical or scientific certainty, [the explanation] must still be ‘sound and reliable.’” Id. (quoting Knudsen ex rel. Knudsen v. Sec’y of Dep’t of Health & Hum. Servs., 35 F.3d 543, 548–49 (Fed. Cir. 1994)). Petitioners “need not produce medical literature or epidemiological evidence to establish causation under the Vaccine Act.” Andreu ex rel. Andreu v. Sec’y of Dep’t of Health & Hum. Servs., 569 F.3d 1367, 1379 (Fed. Cir. 2009). Where such evidence is introduced, it must not be viewed “through the lens of the laboratorian, but instead from the vantage point of the Vaccine Act’s preponderant evidence standard . . . .” Id. at 1380. For satisfying the second Althen prong, “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.’” Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006) (quoting Althen, 418 F.3d at 1280). Lastly, “the proximate temporal relationship prong requires preponderant proof that the onset of symptoms occurred within a timeframe for which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation-in-fact.” de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). C. The Standard for Issuing a Decision on the Papers Without a Hearing in Vaccine Cases The Court may “set aside any findings of fact or conclusion of law of the special master found to be arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law . . . .” 42 U.S.C. § 300aa-12(e)(2)(B). This is a “highly deferential standard of review.” Burns ex. rel. Burns v. Sec’y of Dep’t of Health & Hum. Servs., 3 F.3d 415, 416 (Fed. Cir. 1993) (quoting Hines ex. rel. Sevier v. Sec’y of Dep’t of Health & Hum. Servs., 940 F.2d 1518, 1528 (Fed. Cir. 1991)). The Special Master’s discretionary rulings are reviewed for abuse of discretion; such rulings “rarely come into play except where the special master excludes evidence.” Dickerson v. Sec’y of Dep’t of Health & Hum. Servs., 35 Fed. Cl. 593, 597 (1996) (citing Munn, 970 F.2d at 870 n.10). The Vaccine Act provides “a special master may conduct such hearings as may be reasonable and necessary.” 42 U.S.C. § 300aa-12(d)(3)(B)(v) (emphasis added). A “special master may decide a case on the basis of written submissions without conducting an evidentiary hearing.” VRCFC 8(d); Plummer, 24 Cl. Ct. 304. This Court has held that a special master’s discretion to hold an evidentiary hearing is tempered by the requirement that: - 14 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 15 of 24 The special master shall be responsible for conducting all proceedings, including requiring such evidence as may be appropriate, in order to prepare a decision, including findings of fact and conclusions of law . . . [and] shall determine the nature of the proceedings, with the goal of making the proceedings expeditious, flexible, and less adversarial, while at the same time affording each party a full and fair opportunity to present its case . . . . Dickerson, 35 Fed. Cl. at 598 (citing VRCFC 3(b)). Accordingly, “it is incumbent upon [a special master] to explain to the parties the evidence which is necessary and provide them a reasonable opportunity to come forward with it.” Id. V. Review of the Special Master’s Decision A. The Special Master’s Consideration of Mr. Mager’s Proposed Causation Theory Mr. Mager argues the Special Master mischaracterized his argument on causation and ignored significant points made by petitioner’s expert. Mot. for Review at 2, ECF No. 191. Petitioner acknowledges his expert believed Ms. Mager’s epilepsy was autoimmune in nature, but he contends “his argument for causation does not hinge [on] a diagnosis of autoimmune epilepsy base[d] on the diagnostic criteria presented to the Court.” Id. at 16. “In fact,” petitioner argues, “the Special Master’s reliance on that diagnostic criteria referenced in his opinion, directly contradicts [p]etitioner’s stated reason for offering the criteria.” Id. According to petitioner, he provided the diagnostic criteria “solely to demonstrate that autoimmune epilepsy can present as milder epilepsy.” Id. at 16–17 (quoting Pl.’s Resp. to Special Master’s 16 June 2021 Questions at 1, ECF No. 188). Petitioner clarifies: In other words, [p]etitioner is not hinging his case on a diagnosis of autoimmune epilepsy, nor did he proffer the diagnostic criteria to support a diagnosis of autoim- mune epilepsy. Rather, [p]etitioner argued that [Ms. Mager] experienced SUDEP as a result of her epilepsy which was, yes, likely to be autoimmune in nature. Id. Petitioner argues further the Special Master failed to address his “predominant argument,” which he summarizes as follows: [Ms. Mager] experienced challenge/rechallenge, i.e.[,] that [Ms. Mager]’s presentation meets the classic definition of challeng[e]/rechallenge, i.e.[,] “rechallenge, an adverse event that occurred after more than one administration of a particular vaccine in the same individual.” Rechallenge is not dependent on a finding that [Ms. Mager] suffered from autoimmune epilepsy. It is dependent on [Ms. Mager] suffering an adverse event, in this case seizures, after more than one administration of a particular vaccine, e.g.[,] the HPV vaccination. Id. “[T]he complexity of [Ms. Mager’s] diagnosis,” petitioner contends, “cannot be stripped down to the three criteria as the Special Master did in this case. Particularly, when that criteria is offered to demonstrate that autoimmune epilepsy can present in a range of severity including the milder epilepsy from which [Ms. Mager] suffered.” Mot. for Review at 16–17. Petitioner - 15 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 16 of 24 concludes the Special Master abused his discretion by allegedly failing to consider the entirety of petitioner’s case. Id. at 2, 16, 18. The government contended at oral argument the Special Master’s characterization of petitioner’s argument is a factual determination subject to review under the arbitrary and capricious standard. Tr. at 23:10–25:6. At the same time, the government recognized it is an exercise of discretion for a special master to exclude evidence or impose limitations on the record, and such decisions are subject to review for abuse of discretion. Tr. at 26:24–27:22 (“[GOVERNMENT]: . . . [Decisions to admit or exclude evidence] are prime examples of exercise of judicial discretion. Limitation of the record, I construe in similar terms, in terms of making decisions about what the Court will or will not consider . . . . And those are things that are within the Special Master’s discretion and, therefore, there may be instances where that discretion might be abused.”). The government also recognized it “would not necessarily be solely a factual error” for a special master to rely on a flawed characterization of petitioner’s case but struggled to identify the proper standard of review for such a scenario. Tr. at 30:19–31:9. The Court disagrees with the government’s argument that a special master’s characterization of a petitioner’s theory of causation is a factual determination. The Federal Circuit has held a special master’s rulings are subject to review for abuse of discretion if they exclude evidence or limit the record on which the special master relies. Contreras v. Sec’y of Health & Hum. Servs., 844 F.3d 1363, 1368 (Fed. Cir. 2017); Lampe v. Sec’y of Health & Hum. Servs., 42 Fed. Cl. 632, 636 (1998) (citing Saunders, 25 F.3d at 1033). In Contreras, the Federal Circuit found a special master abused his discretion by limiting his analysis to a single diagnosis even though the petitioner alleged two diagnoses and the government did not dispute the nature of the petitioner’s injury. Contreras, 844 F.3d at 1368. According to the Federal Circuit, the special master’s decision to limit his analysis to a single diagnosis improperly limited the record such that the special master did not consider evidence relevant to the spurned diagnosis. Id. at 1368–69. Thus, a special master’s characterization of a petitioner’s theory of causation is subject to review for abuse of discretion. Id. at 1368 (“We review discretionary rulings—i.e., exclusion of evidence or limitation of the record upon which the special master relies—under the abuse of discretion standard.”) (citing Munn, 970 F.2d at 870 n.10). The Court may set aside a special master’s decision for abuse of discretion “if the decision is clearly unreasonable, arbitrary, or fanciful; is based on an erroneous conclusion of law; rests on clearly erroneous fact findings; or involves a record that contains no evidence on which the [special master] could base its decision.” Cottingham ex. rel. K.C. v. Sec’y of Health & Hum. Servs., 971 F.3d 1337, 1345 (Fed. Cir. 2020) (citing In re Durance, 891 F.3d 991, 1000 (Fed. Cir. 2018)). Petitioner’s prehearing brief summarized his argument on causation as follows: Petitioner’s theory of causation is a neurological autoimmune process triggered by the HPV vaccine, causing autoimmune epilepsy, which is strongly supported by the challenge/rechallenge, . . . i.e.[,] “rechallenge, an adverse event that occurred after more than one administration of a particular vaccine in the same individual.” [Ms. Mager] experienced a similar adverse event after each of two administrations - 16 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 17 of 24 of her HPV vaccination. Further [Ms. Mager’s] HPV vaccination triggered an immune-mediated response that resulted in the development of her autoimmune epilepsy after her first dose, and subsequently caused the significant aggravation of her autoimmune epilepsy (characterized by recurrence of seizures, increased frequency of seizures and death from SUDEP). As it is medically most likely, the seizures she suffered after the first and the second HPV vaccination represent the same medical condition. Pet’r’s Prehr’g Br. at 16–17, ECF No. 168 (emphasis added). Notably, petitioner’s prehearing arguments mention three times that the HPV vaccine resulted in autoimmune epilepsy. Petitioner agrees Ms. Mager’s condition does not satisfy the diagnostic criteria for autoimmune epilepsy, Tr. at 34:7–20, but he argues Ms. Mager’s condition was a milder form of generalized epilepsy that was autoimmune in nature and caused by an autoimmune reaction. Tr. at 52:14– 53:2. In other words, petitioner argues Ms. Mager’s condition is not Autoimmune Epilepsy— “capital A, capital E”—as defined by the diagnostic criteria but epilepsy that is autoimmune in nature. Tr. at 108:15–109:9. The parties agreed arguendo considering petitioner’s distinction this way—i.e., Autoimmune Epilepsy being defined by the diagnostic criteria and autoimmune epilepsy being epilepsy that is autoimmune in nature—assists with discussion. Tr. at 108:19– 110:8 (“THE COURT: . . . If there is a distinction between Autoimmune Epilepsy, capital A, capital E [,] . . . and just autoimmune epilepsy, lowercase—[GOVERNMENT]: Got it.”). To support his argument, petitioner pointed to “the direct relationship with the HPV vaccination strongly supported by the challenge/rechallenge circumstances.” Pet’r’s Prehr’g Br. at 9. He also referred to “[a]dditional supporting evidence” of inflammation of the brain, which was detailed in the postmortem report. Id. Petitioner further argued the medical literature demonstrates autoimmune epilepsy can be difficult to distinguish from other types of epilepsy. For example, petitioner referred to an Australian study involving 114 patients with new onset seizures, 11 of which tested positive for one or more autoantibodies compared to three of 65 control patients. Id. at 39–40 (citing Pet’r’s Ex. 88, ECF No. 165-5). Petitioner summarized disparate data characterizing patients with and without autoantibodies and suggested this data demonstrates autoimmune epilepsy presents in various ways and can be difficult to identify. Id. at 40. Petitioner explained: Overall, there was no significant difference in the demographic or clinical pictures between the antibody positive and the antibody negative group. . . . The article does not prove that the antibodies were the cause of the epilepsy, but it is a very solid possibility . . . . Overall, [the article] shows that neuronal antibodies are relatively common in patients with new onset epilepsy, which is otherwise considered idiopathic and that the epileptic presentation is very variable. Id. at 40–41. In other words, autoimmune epilepsy can be difficult to distinguish from other types of epilepsies.4 This study, petitioner argued, also demonstrates autoimmune epilepsy can 4 While petitioner speaks of neuronal antibodies as an indicator of autoimmune epilepsy, Ms. Mager’s blood was never tested for neuronal antibodies. The Special Master recognized petitioner’s “potentially valid reasons” why - 17 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 18 of 24 present in milder epilepsy cases. Id. at 9–10. Petitioner referred to this study, along with the diagnostic criteria for autoimmune epilepsy, to support the proposition that autoimmune epilepsy can present as milder epilepsy. Pet’r’s Prehr’g Br. at 9–10. Petitioner held this position consistently throughout the prehearing proceedings.5 Before making his decision on compensation, the Special Master followed up with petitioner asking him to “identify the source of the diagnostic criteria for autoimmune epilepsy listed in his [prehearing] brief.” Order at 1, ECF No. 187. Petitioner responded accordingly but noted “[t]he criteria are discussed in that section solely to demonstrate that autoimmune epilepsy can present as milder epilepsy.” Pl.’s Resp. to Special Master’s 16 June 2021 Questions at 1. In his decision denying compensation, the Special Master acknowledged and quoted petitioner’s language identifying the source of his diagnostic criteria, Decision Den. Compensation at 4 n.3, ECF No. 189, but omitted petitioner’s clarification that “[t]he criteria are discussed solely to demonstrate that autoimmune epilepsy can present as milder epilepsy,” Pl.’s Resp. to Special Master’s 16 June 2021 Questions at 1 (emphasis added). The Special Master then proceeded to apply the diagnostic criteria to the evidence in the record despite petitioner’s clarification, ultimately concluding there was insufficient evidence to support a diagnosis of Autoimmune Epilepsy and denying petitioner’s claim on that basis. Id. at 16–17. The exchange between the Special Master and petitioner clarifying the source and purpose of the diagnostic criteria demonstrates two important points: (1) petitioner was not arguing a diagnosis of Autoimmune Epilepsy was necessary; and (2) there was a misunderstanding between petitioner and the Special Master concerning the relevance of the diagnostic criteria for autoimmune epilepsy. Counsel for the government—who also acknowledges misunderstanding the argument—recognizes the Special Master may have misunderstood petitioner’s argument. Tr. at 61:22–25 (“COURT: So is it possible the Special Master misunderstood [p]etitioner’s argument? [GOVERNMENT]: I certainly did, so certainly that’s possible.”). Petitioner’s clarification apparently did not clear up that misunderstanding since the Special Master proceeded to apply the diagnostic criteria as if it were central to his argument.6 See Decision Den. Compensation. While the Special Master’s analysis of the diagnostic criteria was careful and thorough, it was also not necessary—petitioner agrees Ms. Mager’s condition does not fit the diagnostic criteria neatly. Tr. at 34:7–20 (“I do not believe that she meets the diagnostic criteria. Neither does Dr. Shafrir . . . . We’ve not alleged that she meets that diagnostic criteria in this case.”). Petitioner argues the diagnostic criteria are a starting point but there is no requirement that they be firmly adhered to. Tr. at 37:12–38:3 (“The diagnostic criteria . . . [are] the point where you Ms. Mager’s doctors did not test her blood for neuronal antibodies, such as the emerging nature of the diagnosis. Decision Den. Compensation at 10. 5 As discussed below, petitioner maintained this position when asked to identify the source of his diagnostic criteria. He responded: “[t]he criteria are discussed in that section solely to demonstrate that autoimmune epilepsy can present as milder epilepsy.” Pl.’s Resp. to Special Master’s 16 June 2021 Questions at 1, ECF No. 188. 6 The Special Master’s apparent misunderstanding of petitioner’s argument likely could have been clarified if a hearing had been held. - 18 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 19 of 24 start. . . . And the diagnostic criteria [are] typically based on developing treatment modalities and things like that. In a clinical setting, doctors use diagnostic criteria, but they’re not married to them. . . . [Y]ou get people diagnosed all the time [who] don’t meet diagnostic criteria.”). The Vaccine Act jettisons strict adherence to diagnostic criteria for a more flexible approach to proving causality. Knudsen ex rel. Knudsen v. Sec’y of Dep’t of Health & Hum. Servs., 35 F.3d 543, 548–49 (Fed. Cir. 1994) (“Causation in fact under the Vaccine Act is thus based on the circumstances of the particular case, having no hard and fast per se scientific or medical rules. The determination of causation in fact under the Vaccine Act involves ascertaining whether a sequence of cause and effect is ‘logical’ and legally probable, not medically or scientifically certain.”) (citing Bunting v. Sec’y of Dep’t of Health & Hum. Servs., 931 F.2d 867, 873 (Fed. Cir. 1991)); Andreu ex rel. Andreu v. Sec’y of Dep’t of Health & Hum. Servs., 569 F.3d 1367, 1382 (Fed. Cir. 2009) (“[T]he function of a special master is not to ‘diagnose’ vaccine-related injuries, but instead to determine ‘based on the record evidence as a whole and the totality of the case, whether it has been shown by a preponderance of the evidence that a vaccine caused the child’s injury.’” (quoting Knudsen, 35 F.3d at 549)). In providing a thorough analysis of the diagnostic criteria, the Special Master missed the core of petitioner’s argument—the vaccine caused an autoimmune response triggering recurrence and aggravation of Ms. Mager’s epilepsy disorder. Tr. at 63:10–14. Petitioner devoted several pages of arguments in support of his theory that the HPV vaccine triggered recurrence and aggravation of Ms. Mager’s seizure disorder, see Pet’r’s Prehr’g Br. at 14–17; these arguments were unaddressed in the Special Master’s decision, Tr. 75:10–76:2 (“COURT: So explain that out more. That there was not proper weight given to challenge/rechallenge. [PETITIONER]: . . . I don’t think [the Special Master] did any analysis [in] that regard. . . . COURT: Does the [g]overnment have anything on that? [GOVERNMENT]: I don’t believe he did.”). By focusing his analysis on the diagnostic criteria for Autoimmune Epilepsy—criteria the petitioner provided only to demonstrate the breadth of severity with which autoimmune epilepsy can manifest—the Special Master did not consider petitioner’s primary argument; i.e., an autoimmune reaction to the HPV vaccine triggered recurrence and aggravation of Ms. Mager’s epilepsy disorder. The Special Master is statutorily mandated to consider all relevant medical and scientific evidence contained in the record, 42 U.S.C. § 300aa-13(b)(1); the Court therefore must find this constitutes an abuse of discretion, Contreras, 844 F.3d at 1368–69 (finding a special master committed reversible error by failing to consider relevant evidence related to the petitioner’s medical theories). B. The Special Master’s Legal Requirement, if any, to Analyze the Case Under Althen and its Progeny The parties in this case agree Ms. Mager suffered from an epileptic seizure disorder, but they dispute the underlying diagnosis of the disorder—petitioner argues autoimmune epilepsy while the government argues JME. Decision Den. Compensation at 4. In view of these competing diagnoses, the Special Master, citing Lombardi and Broekelschen, set out as a threshold matter to determine which diagnosis was correct. The Special Master found petitioner did not meet his burden to show by preponderant evidence Ms. Mager suffered from - 19 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 20 of 24 Autoimmune Epilepsy. Id. at 16–17. The Special Master considered a diagnosis of Autoimmune Epilepsy to be necessary for petitioner to succeed, so he denied the petition without analyzing whether the vaccine caused or aggravated Ms. Mager’s epilepsy disorder under Althen. Id. The Court reviews de novo the Special Master’s decision to diagnose Ms. Mager’s condition and dismiss the case without analyzing whether the HPV vaccine caused Ms. Mager’s injury under Althen. Broekelschen, 618 F.3d at 1345 (holding the Court “owe[s] no deference to the . . . special master on questions of law.”). For off-Table vaccine cases, the petitioner bears the burden of showing she “sustained, or had significantly aggravated, any illness, disability, injury, or condition not set forth in the Vaccine Injury Table . . . .” 42 U.S.C. § 300aa-11(c)(1)(C)(ii)(I). “[T]he statute places the burden on the petitioner to make a showing of at least one defined and recognized injury . . . not merely a symptom or manifestation of an unknown injury.” Lombardi v. Sec’y of Health & Hum. Servs., 656 F.3d 1343, 1353 (Fed. Cir. 2011). The Vaccine Act provides compensation for “any illness, disability, injury, or condition not set forth in the Vaccine Injury Table . . . which was caused by a [designated] vaccine . . . .” 42 U.S.C. § 300aa-11(c)(1)(C)(ii)(I) (emphasis added). A petitioner need not diagnose her injury, she must merely “show that the vaccine in question caused [her] injury—regardless of the ultimate diagnosis.” Kelley v. Sec’y of Health & Hum. Servs., 68 Fed. Cl. 84, 100 (2005) (citing 42 U.S.C. § 300aa-11(c)(1)(C)(ii)(I)). If, however, “the existence and nature of the injury itself is in dispute, it is the special master’s duty to first determine which injury was best supported by the evidence presented in the record before applying the Althen test to determine causation of that injury.” Lombardi, 656 F.3d at 1352 (citing Broekelschen, 618 F.3d at 1346). Absent a “showing of the very existence of any specific injury of which the petitioner complains, the question of causation is not reached.” Lombardi, 656 F.3d at 1353. In this case, petitioner alleges the HPV vaccine caused or aggravated Ms. Mager’s epileptic seizure disorder ultimately resulting in her death. Am. Pet. at 2, ECF No. 11; Mot. for Review at 10. Petitioner submitted evidence showing Ms. Mager indeed suffered from an epileptic seizure disorder that caused her death. The government does not dispute this. Tr. at 95:8–11. Instead, the government contends Ms. Mager’s injury could not have been caused by the vaccine because her underlying diagnosis is better diagnosed as JME. The government’s argument fails, however, because JME and autoimmune epilepsy are variants of the same disorder—i.e., a seizure disorder. Gov’t’s Prehr’g Br. at 14, ECF No. 180 (arguing Ms. Mager suffered from a generalized seizure disorder); Gov’t’s Ex. BB at 12, ECF No. 183-1 (explaining Ms. Mager was diagnosed with a primary generalized epilepsy disorder); Tr. at 95:8–11 (“COURT: . . . The Government does not disagree that [Ms. Mager] suffered from a seizure disorder. [GOVERNMENT]: No.”); Tr. at 93:12–15 (“[PETITIONER]: I mean, they’re both epilepsy and they’re both seizure disorders.”). While this case involves competing diagnoses, they are only competing in the sense that the parties dispute them—not in the sense that they are mutually exclusive. Tr. at 85:23–25 (“[GOVERNMENT]: Do I think there’s anything that would preclude her from having an autoimmune response, no.”). While autoimmune epilepsy is characterized in terms of its etiology, or causality, Tr. at 7:14–20, 40:19–22, JME is characterized in terms of its phenotype, or observable characteristics, see Gov’t’s Ex. BB at 2. Unlike the competing diagnoses in - 20 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 21 of 24 Broekelschen and Lombardi, juvenile myoclonic epilepsy is an idiopathic generalized epilepsy disorder—its cause is unknown. Gov’t’s Ex. BB at 2. The question of causation cannot turn on a diagnosis if its underlying cause is unknown, particularly when the disputed diagnoses are variants of the same disorder as they are here. Broekelschen, 618 F.3d at 1346, 1349 (holding where “the injury itself is in dispute, the proposed injuries differ significantly in their pathology, and the question of causation turns on [the] injury” it is appropriate for the special master to first determine which injury the evidence supports). The outcome in Lombardi is also distinguishable from the outcome in this case because Lombardi was “unusual in that the identification of the injury and its nature [were] in dispute.” Lombardi, 656 F.3d at 1352. In contrast, there is no dispute in this case that Ms. Mager suffered from an epileptic seizure disorder that resulted in her death. Tr. at 95:8–11. Moreover, in addition to extreme disagreement between experts,7 the Federal Circuit noted the competing conditions in Lombardi were not “so similar that doctors consider them to be conditions along a spectrum of diseases.” Lombardi, 656 F.3d at 1352. By contrast, both competing diagnoses here are variants which fit within the category of epileptic seizure disorders. Tr. at 9:2–3; 12:4– 5. Moreover, the government admits Lombardi is factually distinguishable from this case. Tr. at 91:5–8. This case is distinguishable from Broekelschen for the same reasons, but also because the parties agree Ms. Mager suffered from a seizure disorder—a fact that distinguished Broekelschen from the Federal Circuit’s precedents. Broekelschen, 618 F.3d at 1346 (distinguishing Broekelschen from Andreu because “the parties agreed that the petitioner suffered from a seizure disorder”). Further, the competing diagnoses in Broekelschen are unlike the two competing diagnoses in this case, which are both epileptic in nature and variants of the same disorder. Cf. Broekelschen, 618 F.3d at 1346. The Special Master’s inquiry into the underlying diagnosis of Ms. Mager’s seizure disorder places too much emphasis on the diagnostic criteria for autoimmune epilepsy and too little on whether she suffered an injury. See, e.g., Decision Den. Compensation at 4 (“The difference between autoimmune epilepsy and JME affects the outcome of [petitioner’s] case because his theory of causation relies on an autoimmune disease causing neuroinflammation.”). The inquiry improperly narrows the analysis on diagnostic criteria the petitioner never alleged it satisfied. By narrowly focusing on the diagnostic criteria, the Special Master denied the petitioner’s claims on grounds the petitioner never argued in making his case. Tr. 29:9–30:9 (“And in doing that, it essentially set up a strawman argument that could be knocked down. You know, we can’t defend a diagnosis that we didn’t allege.”). In doing so, the Special Master effectively abbreviated the causation analysis, which is an improper application of the Federal Circuit’s holding in Broekelschen. W.C. v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1357 7 The petitioner in Lombardi alleged she suffered from three different medical conditions: transverse myelitis, chronic fatigue syndrome, and systemic lupus erythematosus. Lombardi, 656 F.3d at 1351. The government’s experts, on the other hand, refuted the petitioner’s proposed medical conditions and proposed five others. Id. at 1352–53. Further complicating matters, the government’s expert witness testimony “refuted each of those diagnoses and proposed five other possible conditions that Lombardi may have suffered from.” Id. “In the face of such extreme disagreement among well-qualified medical experts,” the Federal Circuit reasoned, “it was appropriate for the special master to first determine what injury, if any, was supported by the evidence presented in the record before applying the Althen test to determine causation.” Id. at 1352–53. - 21 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 22 of 24 (Fed. Cir. 2013) (explaining where parties agreed on injury and “the issue [was] whether the vaccine caused [p]etitioner’s [injury], the special master should have expressly applied the analysis set forth in Althen”); Lombardi, 656 F.3d at 1358 (O’Malley, J., concurring) (expressing concern with “provid[ing] a mechanism for special masters to shortcut the causation analysis in instances where the alleged injuries can support multiple diagnoses”); see also Broekelschen, 618 F.3d at 1352 (Mayer, J., dissenting on other grounds) (“[The] approach, of first assigning a diagnosis to [petitioner’s] symptoms before applying the Althen test, is not supported by statute, caselaw, or logic, and its effect [is] to impermissibly heighten [petitioner’s] burden.”). The “existence and nature of the injury” was not in dispute, so the Special Master erred in failing to consider whether the vaccine caused Ms. Mager’s injury under Althen and its progeny. W.C., 704 F.3d at 1357 (finding the special master improperly failed to carry out analysis under Althen where parties agreed on petitioner’s injury); Contreras, 844 F.3d at 1368–69 (finding the special master erred by inquiring into petitioner’s diagnosis and failing to conduct a complete Althen analysis for all medical disorders alleged by the petitioner). For these reasons, the Court finds the Special Master must perform the requisite causation analysis under Althen and its progeny. W.C., 704 F.3d at 1357 (finding where parties agreed on injury and “the issue [was] whether the vaccine caused [p]etitioner’s [injury], the special master should have expressly applied the analysis set forth in Althen”); Contreras, 844 F.3d at 1368 (finding the special master erred in conducting a threshold inquiry into the specific diagnosis of the alleged vaccine injury). VI. Whether the Special Master is Obliged to Consider the Entire Record in View of his Decision to not Hold an Evidentiary Hearing In deciding the case on the papers without an evidentiary hearing, the Special Master reasoned “[a] hearing to determine the threshold issue of diagnosis in this case is not needed. The parties have had ample opportunity to develop their positions through submissions of evidence (primarily medical records) about [Ms. Mager], lengthy and multiple expert reports, and thorough briefing.” Decision Den. Compensation at 18. Petitioner argues, under Moriarty, the Special Master’s decision to forgo an evidentiary hearing in this case requires the Special Master to consider the entire record. Mot. for Review at 15–16. Petitioner acknowledges the Special Master is not required to conduct an evidentiary hearing but contends “[i]f a [s]pecial [m]aster may not, as a matter of law, decline to consider evidence on the record only because it was not discussed at [a] hearing it is even more imperative that he consider all the evidence when he also declines to conduct a hearing.” Id. The Court reviews discretionary rulings, such as exclusion of evidence or limitation of the record, upon which the Special Master relies under the abuse of discretion standard. Contreras, 844 F.3d at 1368. The Vaccine Rules authorize a special master to make findings of fact and decide a case based on the written record without an evidentiary hearing. See VRCFC 8(d); Plummer v. Sec’y of Dep’t of Health & Hum. Servs., 24 Cl. Ct. 304, 307 (1991). Whether to hold a hearing is a matter within a special master’s discretion. 42 U.S.C. § 300aa-12(d)(3)(B)(v) (a special master “may conduct such hearings as may be reasonable and necessary”) (emphasis added). The Vaccine Act requires a special master to consider any medical records or reports “contained in the record regarding the nature, causation, and aggravation of the petitioner’s . . . injury” as well as “all other relevant medical and scientific evidence contained in the record.” 42 U.S.C. - 22 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 23 of 24 § 300aa-13(b). The statute also requires special masters to “‘consider the entire record and the course of the injury’ when evaluating the weight to be afforded to any medical records or reports present in the record.” Moriarty by Moriarty v. Sec’y of Health & Hum. Servs., 844 F.3d 1322, 1327 (Fed. Cir. 2016) (quoting 42 U.S.C. § 300aa-13(b)). Accordingly, a special master must consider any relevant medical records or reports contained in the entire record of the case. Id. Unless the Special Master expressly indicates he did not consider certain evidence, a presumption applies that he “considered the relevant record evidence even though he does not explicitly reference such evidence in his decision.” Id. at 1328. The inquiry in this case is straightforward. The Court starts from the presumption that “a special master considered the relevant record evidence even though he does not explicitly reference such evidence in his decision.” Id. In this case, the Special Master did not expressly indicate he did not consider certain relevant evidence. See Decision Den. Compensation. Petitioner admits there is no indication in this case the Special Master failed to consider evidence relevant to a diagnosis of autoimmune epilepsy. Tr. at 35:10–23. In the absence of any indication the Special Master failed to consider any relevant evidence for a diagnosis of autoimmune epilepsy, the presumption maintains. Petitioner is correct that a special master is required to consider the entire record of the case, 42 U.S.C. § 300aa-13(b), but petitioner has not shown that the Special Master failed to consider any relevant evidence. Moreover, petitioner neglects the Federal Circuit’s emphasis on relevant evidence, Moriarty, 844 F.3d at 1327–28 (“[A] special master . . . must consider all relevant medical and scientific evidence . . . , which includes any relevant medical records or reports. . . . [T]he special master ‘shall’ consider the entire record, which includes this relevant evidence . . . .”). A special master’s burden to consider evidence contained within the record extends only to evidence relevant to the factual inquiry at hand. Moriarty, 844 F.3d at 1327–28; 42 U.S.C. § 300aa-13(b). The Federal Circuit in Moriarty found the special master in that case erred by failing to consider relevant expert testimony. Moriarty, 844 F.3d at 1328. There is no indication here that the Special Master did not consider evidence relevant to Ms. Mager’s diagnosis. To the extent the Special Master was required to consider all evidence relevant to making a factual finding on Ms. Mager’s diagnosis, the Court finds the Special Master did not err. Id. As discussed above, however, the Special Master improperly viewed the evidence through the narrow lens of diagnostic criteria rather than petitioner’s actual theory and failed to carry out a causation analysis under Althen and its progeny. The Court makes no finding regarding whether the Special Master considered all relevant evidence to that inquiry. VII. Conclusion For the above reasons, petitioner’s motion for review is GRANTED and the Special Master’s 29 July 2021 Decision Denying Compensation, ECF No. 189, is VACATED. The case is REMANDED for the Special Master to determine whether petitioner can satisfy the required - 23 - Case 1:14-vv-00820-RTH Document 202 Filed 02/15/22 Page 24 of 24 elements for an off-Table claim under Althen and its progeny, and for other proceedings consistent with this Opinion. IT IS SO ORDERED. s/ Ryan T. Holte RYAN T. HOLTE Judge - 24 - ================================================================================ DOCUMENT 3: USCOURTS-cofc-1_14-vv-00820-5 Date issued/filed: 2023-06-20 Pages: 43 Docket text: JUDGE VACCINE REPORTED OPINION: Public version of 248 Opinion and Order on Motion for Review. Signed by Judge Ryan T. Holte. (eir) Service on parties made. (Main Document 249 replaced on 7/5/2023 to add judgment language.) (dls) -------------------------------------------------------------------------------- Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 1 of 43 Corrected In the United States Court of Federal Claims No. 14-820 (Filed: 20 June 2023*) *************************************** MICHAEL MAGER, as parent of VICTORIA * MAGER, * * Petitioner, * * v. * * SECRETARY OF HEALTH AND HUMAN * SERVICES, * * Respondent. * * *************************************** Renee J. Gentry, Vaccine Injury Clinic, George Washington University Law School, of Washington, DC, for petitioner. Zoe Wade, Trial Attorney, with whom were Darryl R. Wishard, Assistant Director, Heather L. Pearlman, Deputy Director, C. Salvatore D’Alessio, Director, Torts Branch, Brian M. Boynton, Principal Deputy Assistant Attorney General, Civil Division, Department of Justice, all of Washington, DC, for respondent. OPINION AND ORDER HOLTE, Judge. “[W]hile most of the Nation’s children enjoy greater benefit from immunization programs, a small but significant number have been gravely injured.” Cloer v. Sec’y of Health & Hum. Servs., 654 F.3d 1322, 1325 (Fed. Cir. 2011) (quoting H.R. Rep. No. 99-908, at 4 (1986)). The Vaccine Act “assure[s] parents that when their children are the victims of an appropriate and rational national policy, a compassionate [g]overnment will assist them in their hour of need.” Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1364 (Fed. Cir. 2019) (Newman, J., dissenting) (quoting statement of Sen. Edward Kennedy, S. Comm. on Labor & Human Res.). The pro-petitioner Vaccine Act does not require clarity or perfection in proving a vaccine injury. Indeed, “‘[t]he purpose of the Vaccine Act’s preponderance standard is to allow *This Opinion and Order was initially filed under seal on 2 June 2023 pursuant to Vaccine Rule 18(b) of the Rules of the Court of Federal Claims (“VRCFC”). The Court provided the parties 14 days to submit proposed redactions, if any, before the Opinion and Order was released for publication. Neither party proposed redactions nor indicated there were no redactions by 16 June 2023, the 14-day deadline. This Opinion and Order is now reissued for publication in its original form. Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 2 of 43 the finding of causation in a field bereft of complete and direct proof of how vaccines affect the human body,’ even if the possible link between the vaccine and the injury is ‘hitherto unproven.’” Porter v. Sec’y of Health & Hum. Servs., 663 F.3d 1242, 1261 (Fed. Cir. 2011) (quoting Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1280 (Fed. Cir. 2005)). The current issue before the Court revolves around challenge-rechallenge—an inferred clinical determination of causality, generally accepted in the medical field and based on repeat adverse reactions to the administration of a pharmaceutical or biologic. Victoria Mager’s first observed seizure occurred shortly after receiving the first dose of the HPV vaccine. The seizures subsided for several years until Ms. Mager received a second dose of the HPV vaccine, at which point her seizures returned—ultimately resulting in her death. Petitioner proffered the challenge-rechallenge paradigm as evidence of causation, and the Special Master found Mr. Mager was entitled to compensation under the Vaccine Act. Respondent moved the Court for review of the Special Master’s Ruling Finding Entitlement alleging the Special Master erred by allowing the use of the challenge-rechallenge paradigm, among other things. The Court addresses some nuances of challenge-rechallenge as it applies to the Vaccine Act. For the following reasons, the Court denies respondent’s Motion for Review. I. Petitioner’s Medical History and the Vaccination The Court’s recitation of the background facts draws from the Special Master’s Decision Denying Compensation, ECF No. 189, the Court’s Opinion and Order granting petitioner’s 2021 Motion for Review, Mager v. Sec’y of Health & Hum. Servs., 158 Fed. Cl. 136 (2022), ECF No. 202, and the Special Master’s Ruling Finding Entitlement to Compensation (“Ruling Finding Entitlement”), ECF No. 224. Ms. Mager’s health history was relatively normal before receiving the vaccination for the human papilloma virus (“HPV”).1 Ms. Mager received the vaccine on 2 October 2007. Pet. at 1, ECF No. 1. Six weeks later, Ms. Mager suffered a seizure and was taken to a nearby emergency room. Pet’r’s Ex. 11 at 28, ECF No. 9-4. The admission notes from that visit state she experienced a seizure followed by a second seizure approximately four minutes later. Id. Her head CT scan, urine toxicology screen, and chest x-ray were all normal. Id. at 3–4, 13. An electroencephalogram (“EEG”) “indicate[d] focal sites of cerebral hyperexcitability which can be associated with partial seizures/epilepsy.” Id. at 17. Ms. Mager was prescribed Depakote, an anti-seizure medication, and discharged on 15 November 2007. Id. at 38. In a follow-up visit on 12 December 2007, Ms. Mager’s physician, Dr. Shafrir, noted that her parents recalled that “for a while [after her initial seizure], [Ms. Mager] was waking up with big cuts in her tongue at least twice and also 1 Prior to remand, “the Special Master made no finding concerning when [Ms. Mager’s] seizures began.” Mager, 158 Fed. Cl. at 2 n.1. On remand, the Special Master found the following two factors persuasive: (1) Dr. Kohrman’s testimony asserting the cessation of Ms. Mager’s enuresis upon taking anti-seizure medication was evidence of seizures occurring prior to receiving the first HPV vaccine; and (2) various medical records pointing to the existence of tongue-biting episodes prior to receiving the first HPV vaccine. Ruling Finding Entitlement at 4–6. - 2 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 3 of 43 complaining of soreness after waking up and it is possible that these might have been seizures.” Pet’r’s Ex. 11 at 75. Ms. Mager’s stepmother also reported Ms. Mager’s enuresis was resolved after she began taking her anti[-]seizure medication, Depakote. Id. Dr. Shafrir noted the EEG indicated an impression of “focal onset epilepsy” and “some frontal lobe dysfunction,” and he recommended neuropsychological testing. Id. at 77. Approximately two months later, Ms. Mager saw another pediatric neurologist, Dr. Koehn, who ordered another EEG—the results of which were normal. Pet’r’s Ex. 6 at 22, ECF No. 8-7. Dr. Koehn noted, referring to the original abnormal EEG, that “[t]he first EEG pattern could represent a fragment/a more lateralized pattern of an underlying generalized discharge or it could in fact be a focal discharge. Therefore, leaving the possibility open for this to have been a primary or secondarily generalized seizure.” Id. at 20. Although the medication appeared to control her seizure activity, Ms. Mager’s father and stepmother noted undesirable side effects of the medication and requested she be weaned off Depakote. Id. at 24. Accordingly, Dr. Koehn agreed to gradually wean Ms. Mager from Depakote and referred her for neuropsychological testing. Id. at 28; see also Pet. at 1. Shortly after seeing Dr. Koehn, Ms. Mager saw another physician, Dr. Waltonen, for neuropsychological testing. Pet’r’s Ex. 6 at 6. Dr. Waltonen observed she had “a history of some type of learning difficulty at least in the speech and language area.” Id. He also noted Ms. Mager had a family history of epilepsy and seizures on her maternal side. Id. at 2. He noted reports of “increasing problems with doing well in school” and Ms. Mager’s teachers indicated she had “problems following directions.” Id. at 1, 4. Ultimately, Dr. Waltonen concluded that “[o]verall, her examination does not reveal evidence of significant cognitive impairment with the exception of these very focal language findings.” Id. at 6. From April 2008 to October 2012, Ms. Mager did not experience any seizure activity and appeared to function normally. Her school records did not indicate any abnormalities. See Pet’r’s Ex. 83, ECF No. 144-3. The results of sport physicals she received in August 2009 and March 2012 were normal. Pet’r’s Ex. 10 at 15–17, ECF No. 9-3; Pet’r’s Ex. 14 at 1–2, ECF No. 12-2. During a physical exam in January 2012, she reported she had not experienced seizure activity for four years. Pet’r’s Ex. 10 at 18. Ms. Mager received her second HPV vaccination on 11 September 2012. Pet’r’s Ex. 4 at 1, ECF No. 8-5. The following month, on 10 October 2012, she suffered a seizure and was taken to the emergency department of a nearby medical center. Pet’r’s Ex. 7 at 9, ECF No. 8-8. Her evaluation, which included an [electrocardiogram], was normal. Id. at 13–14. She was diagnosed with a “[p]robable seizure” and discharged. Id. at 14. In a visit with her primary care doctor the next month, she reported two additional seizures occurring on 19 October 2012 and 7 November 2012 after her ER visit. Pet’r’s Ex. 9 at 39, ECF No. 9-2. Her doctor prescribed an anti[-]seizure - 3 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 4 of 43 medication, Depakote, and referred her to a neurologist. Id. Neurologist Dr. Edgar saw Ms. Mager a couple months later in January 2013. Pet’r’s Ex. 9 at 24–25. According to Dr. Edgar’s note, “[t]he EEG is normal during wakefulness. During sleep there is activation of infrequent potentially epileptiform activity over the left frontal and bioccipital head regions, consistent with the patient’s history of generalized seizures.” Id. at 25. Dr. Edgar believed Ms. Mager suffered from primary generalized seizure disorder, and he noted the “age of onset at approximately 11 years of age suggests the possibility of juvenile myoclonic epilepsy, although no myoclonic seizures are reported.” Id. at 31. He recommended Depakote, but due to Ms. Mager’s objections, he directed her to begin weaning off Depakote and prescribed Keppra, an alternative anti[-]seizure medication, instead. Id. at 8. Dr. Edgar observed during a follow-up appointment in July 2013 that Ms. Mager’s compliance with her Keppra prescription was “less than ideal”; she had a sub-therapeutic level of the medication in her blood according to a test on 30 May 2013. Pet’r’s Ex. 9 at 3. Ms. Mager wanted to stop using Keppra, but Dr. Edgar persuaded her to remain on the drug given her history of seizures. Id. at 4. Due to her age at the onset of her seizure condition, Dr. Edgar again noted “probable juvenile myoclonic epilepsy.” Id. Months later, on 11 January 2014, Ms. Mager was found unresponsive at a friend’s house and was rushed to the emergency department of a nearby hospital where she was pronounced dead upon arrival. Pet’r’s Ex. 8 at 2, ECF No. 8-9. The local police department reported a witness statement that Ms. Mager had been “missing a lot of doses of her medication,” and her father reported that “she was having seizures more frequently.” Pet’r’s Ex. 13 at 2, ECF No. 9-6. According to an autopsy, Ms. Mager suffered pulmonary edema and brain changes consistent with a seizure disorder. Pet’r’s Ex. 16 at 10, ECF No. 18-2. There was subpial gliosis in sections of her brain. Id. at 16. A toxicology screen showed therapeutic levels of Keppra in her blood. Pet’r’s Ex. 13 at 11. The cause of Ms. Mager’s death was “seizure disorder” according to her death certificate. Pet’r’s Ex. 1 at 1, ECF No. 8-2. The parties agree Ms. Mager suffered from a seizure disorder that caused her death, [2021 Mot. for Review Oral Arg. Tr. at] 6:14–16[, ECF No. 197], but they dispute the underlying diagnosis. Pet’r’s Prehr’g Br. at 9, ECF No. 168 (“Petitioner contends [Ms. Mager] suffered from autoimmune epilepsy that resulted in sudden unexpected death with epilepsy or SUDEP.”); Gov’t’s Prehr’g Br. at 1, ECF No. 180 (“the evidence supports that Ms. Mager most likely suffered from juvenile myoclonic epilepsy”). Mager, 158 Fed. Cl. at 140–42. - 4 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 5 of 43 II. The Petition and Procedural History Before the Special Master The procedural history before the Special Master comes primarily from the Court’s 2022 Opinion and Order granting petitioner’s 2021 Motion for Review: Petitioner filed his petition alleging the HPV vaccination caused Ms. Mager to suffer a seizure disorder leading to her death on 11 January 2014. Pet. at 2. All relevant medical records were submitted, and the record was complete on 17 February 2015. See Statement of Completion, ECF No. 23. A couple months later, the Secretary filed his report contesting causation and arguing Ms. Mager’s seizure disorder preexisted her vaccination. See Resp’t’s Rule 4(c) Report, ECF No. 25. After a change in counsel and experts, and multiple extensions of time, the parties submitted their experts’ reports. See Pet’r’s Ex. 55, ECF [No. ]116-1; Gov’t’s Ex. Z, ECF No. 128-1; Gov’t’s Ex. AA, ECF No. 129-1; Pet’r’s Ex. 85 [(“Shafrir Reply Report”)], ECF No. 165-2; Gov’t’s Ex. CC, ECF No. 182-1; Gov’t’s Ex. BB, ECF No. 183-1. Petitioner’s expert, Dr. Shafrir, asserted Ms. Mager’s epilepsy was autoimmune in nature based, in part, on autoimmune reactions to the vaccine. Pet’r’s Ex. 55 at 18. Respondent’s experts, Dr. Kohrman and Dr. Fujinami, however, both stated Ms. Mager suffered from juvenile myoclonic epilepsy (“JME”). Gov’t’s Ex. Y at 7, ECF No. 95-3; Gov’t’s Ex. CC at 1–2. The Special Master ordered the parties to submit briefs in advance of potential adjudication on 20 November 2019, ECF No. 142. After multiple extensions, Mr. Mager filed a supplemental expert report from Dr. Shafrir on 25 July 2020, ECF No. 167, and his brief on 27 July 2020 . . . . The Secretary, again after multiple extensions, filed his supplemental expert reports from Dr. Fujinami and Dr. Kohrman, as well as his brief, on 10 February 2021, ECF Nos. 180–83. Mr. Mager filed his reply brief on 26 March 2021, ECF No. 186. In the interim period between the parties’ briefing and the Special Master’s decision, a significant colloquy between the Special Master and petitioner took place. The Special Master issued an order in June asking petitioner to “identify the source of the diagnostic criteria for autoimmune epilepsy listed in his [prehearing] brief.” Order at 1, ECF No. 187. Petitioner responded accordingly the next day but noted “[t]he criteria are discussed in that section solely to demonstrate that autoimmune epilepsy can present as milder epilepsy.” Status Report Re Order of June 16, 2021 . . . at 1, ECF No. 188 (emphasis added). The Special Master then issued his decision denying compensation the following month on 29 July 2021. See Decision Den. Compensation . . . . In his decision, the Special Master denied petitioner’s claim on the basis that there was insufficient evidence to support a diagnosis of Autoimmune Epilepsy. Id. at 16–17. Mager v. Sec’y of Health & Hum. Servs., 158 Fed. Cl. 136, 142–43 (2022). On 27 August 2021, petitioner moved for review of the Special Master’s Decision - 5 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 6 of 43 Denying Compensation. See Mot. for Review (“2021 Mot. for Review”), ECF No. 191. Petitioner alleged the Special Master erred by analyzing the diagnostic criteria of autoimmune epilepsy as prerequisites to causation-in-fact. Id. at 16. Petitioner asserted his theory of causation did not hinge on the diagnostic criteria. Id. The Court granted petitioner’s Motion for Review on 21 January 2022, finding the Special Master had not analyzed petitioner’s theory of causation through the appropriate lens. Mager, 158 Fed. Cl. at 157. The Court vacated the 29 July 2021 Decision Denying Compensation and remanded the case to the Special Master to perform the causation analysis. Id. The Special Master held hearings and received briefs in March and April of 2022, heard oral arguments on 8 April 2022, and issued a ruling finding entitlement on 19 April 2022. Ruling Finding Entitlement at 1, 23. On 5 December 2022, the Special Master issued a decision awarding compensation, ECF No. 240. On 4 January 2023, respondent moved for review of the Ruling Finding Entitlement and filed a supporting memorandum. See Resp’t’s Mot. for Review, ECF No. 242; Resp’t’s Mem. in Supp. of Mot. for Review (“2023 Mot. for Review”), ECF No. 243. Petitioner filed a response to respondent’s Motion for Review on 3 February 2023. See Pet’r’s Resp. to Resp’t’s Mem. in Supp. of Mot. for Review (“Pet’r’s Resp.”), ECF No. 244. The Court heard oral argument on 4 April 2023. See 4 April 2023 Oral Arg. Tr. (“Tr.”) at 1:18, ECF No. 247. A. The Special Master’s Ruling Finding Entitlement In his Ruling Finding Entitlement, the Special Master summarized Ms. Mager’s medical records and related findings of fact. See Ruling Finding Entitlement at 2–16. The Special Master found moot the issue of Ms. Mager’s specific epilepsy diagnosis as the Court’s remand found the distinction inapplicable to petitioner’s theory of causation. Id. at 27–28. The Special Master analyzed petitioner’s claim under Loving and additionally examined whether respondent provided preponderant evidence showing Ms. Mager’s death resulted from the natural course of her underlying disorder rather than the vaccination. Id. at 28–55. 1. The Special Master’s Factual Summary Based on evidence regarding the course and timeline of her enuresis (bed-wetting) and tongue-biting episodes, the Special Master determined Ms. Mager’s seizure disorder began prior to her 2 October 2007 HPV vaccination. See id. at 3–6. The Special Master found Dr. Kohrman’s expert testimony persuasive: Dr. Kohrman presented evidence pharmacological interventions had not resolved Ms. Mager’s enuresis until she started taking anti-seizure medications. Id. at 4–6. Respondent also proffered evidence of the relatively rare incidence of enuresis among Ms. Mager’s age group. Id. at 4. In examining evidence of tongue-biting prior to the first HPV vaccination, the Special Master relied on contemporaneous medical records of the 14 November 2007 seizure referring to a history of tongue-biting episodes. Ruling Finding Entitlement at 4–5. While the Special Master considered the lack of pre-2007 medical records mentioning tongue-biting, the Special Master credited the medical records because both parties’ expert physicians testified to the commonality of retrospective symptom identification in seizure patients and petitioner himself agreed Ms. Mager experienced tongue-biting episodes prior to her 14 November 2007 seizure. Id. at 4–7. Additionally, the Special Master considered the testimony of petitioner’s expert, Dr. - 6 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 7 of 43 Shafrir, stating Ms. Mager “quite likely” had nocturnal seizures2 during the month prior to the 14 November 2007 seizure. Id. at 5. 2. The Special Master’s Summary of Procedural History In reciting the case’s procedural history, the Special Master restated several sections of expert witness reports related to petitioner’s medical theory of causation under challenge-rechallenge. Id. at 17–21. Dr. Kohrman’s report filed in response to Dr. Shafrir disputed the alleged occurrence of challenge-rechallenge. Id. at 20. The Special Master noted, “Dr. Kohrman did not address the medical theory that Dr. Shafrir had proposed to explain how a[n] HPV vaccine can aggravate a preexisting seizure disorder.” Ruling Finding Entitlement at 20. 3. The Special Master’s Analysis While acknowledging the specific diagnosis of epilepsy was no longer in dispute, the Special Master first summarized the parties’ arguments regarding the diagnosis of JME versus autoimmune epilepsy. Id. at 24–28. In his causation analysis, the Special Master addressed Loving prongs one, two, and three, then addressed proximate temporal relationship, prong six, before examining reputable medical theory, prong four, and logical sequence of events, prong five. Id. at 28–53. The Special Master reasoned his findings on proximate temporal relationship impacted the findings on reputable medical theory and logical sequence of events. Id. at 31. In analyzing Loving prongs one and two, Ms. Mager’s condition before and after vaccination, the Special Master found Ms. Mager had not experienced seizures or required seizure medications for the nearly five-year period preceding the 2012 HPV vaccination. Id. at 28. Dr. Kohrman argued Ms. Mager experienced unwitnessed seizures in her sleep during this period, but the Special Master found this contention unpersuasive against the Mager family’s history of noting and reporting signs of seizures. Id. The Special Master noted the onset of Ms. Mager’s seizure disorder prior to the 2007 HPV vaccination did not preclude petitioner’s significant aggravation claim based on the 2012 HPV vaccination. Ruling Finding Entitlement at 29. In deciding whether Ms. Mager’s change in condition was a “significant aggravation” under Loving prong three, the Special Master acknowledged “[t]his issue is close.” Id. at 29–31. The Special Master found persuasive petitioner’s characterization of Ms. Mager’s health in terms of her risk for SUDEP. Id. Petitioner asserted Ms. Mager’s seizure-free status prior to the 2012 vaccination meant she was at very little risk, if any, for SUDEP. Id. at 30. The Special Master also considered petitioner’s argument Ms. Mager’s epilepsy became “uncontrolled” after the second vaccination. Id. The Special Master noted merit in respondent’s counterarguments on Loving prong three, 2 Nocturnal seizures “can cause abnormal movement or behavior during sleep” and symptoms “may range from awakening for no clear reason, sometimes multiple times a night, to shouting, screaming and violent movements of the arms and legs.” Johns Hopkins Medicine, Nocturnal Seizures, (last visited June 1, 2023) https://www.hopkinsmedicine.org/health/conditions-and-diseases/epilepsy/nocturnal-seizures. - 7 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 8 of 43 acknowledging each of the three seizures occurring in the immediate aftermath of the 2012 vaccination “seem[ed] mild.” Id. The Special Master further contemplated Ms. Mager’s subsequent eight-month seizure-free—albeit medicated—period. Ruling Finding Entitlement at 30. The Special Master further considered respondent’s argument Ms. Mager’s epilepsy remained mild both before and after the 11 September 2012 HPV vaccination—an argument based in part on Dr. Shafrir’s own testimony. Id. The Special Master nevertheless found Ms. Mager’s change in condition—from being seizure-free and not needing medication to experiencing seizures and requiring medication—was a “significant aggravation” under Loving prong three. Id. at 30–31. The Special Master found petitioner “persuasively” met his burden of proof on Loving prong six. Id. at 37. The Special Master noted the parties’ agreement on the timeline of seizures: Ms. Mager experienced generalized tonic-clonic seizures3 occurring 43 days after the 2007 vaccination and 29 days after the 2012 vaccination. Id. at 31–32. The Special Master’s analysis centered on the contested definition of a “medically acceptable timeframe” for challenge-rechallenge under Loving prong six. Id. at 31–40. On this point, the Special Master considered evidence offered by Dr. Shafrir regarding the Slade post-marketing surveillance study, which utilized a “biologically plausible” interval for autoimmune reactions between four and 42 days after HPV vaccination. Ruling Finding Entitlement at 32–33 (citing Barbara A. Slade et al., Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine, Am. Med. Ass’n (2009)). The Special Master specifically noted respondent’s pre-hearing filings did not challenge the reasonableness of a 42-day (or 43-day) interval but rather argued temporal proximity was insufficient to establish causation. Id. at 33. Respondent’s expert Dr. Fujinami nevertheless challenged Dr. Shafrir’s proposed 42-day interval at the hearing. Id. at 34–35. The Special Master considered Dr. Fujinami’s testimony, asserting the clinical manifestations of an autoimmune reaction to a vaccination would occur within 14 days. Id. The Special Master noted Dr. Fujinami based his testimony on personal knowledge of primate studies on the subject and personal observations made while experimenting with mice. Id. The Special Master observed Dr. Fujinami did not cite specific studies. Id. Dr. Fujinami further admitted some studies have allowed for autoimmune responses more than 40 days after vaccination. Ruling Finding Entitlement at 35. The Special Master also briefly referred to the existence of testimony from Dr. Kohrman on the issue of the timeline, however, the Special Master did not address how Dr. Kohrman’s testimony on the timeline impacted his legal reasoning, if at all. Id. In further analyzing the timeline under Loving prong six, the Special Master contemplated respondent’s cross-examination of Dr. Shafrir regarding a study cited in Dr. Shafrir’s report. Id. at 33 (citing Margaret Stanley, HPV – Immune Response to Infection and Vaccination, 5 INFECTIOUS AGENTS & CANCER 19 (2010)). The study in question suggested memory B cells on rechallenge from HPV vaccination produce peak antibody levels within three to five days. Id. The Special Master remarked Dr. Shafrir could not persuasively account for why Ms. Mager’s seizures started more than three weeks after peak antibody levels and fell back 3 Generalized tonic-clonic seizures, or grand mal seizures, affect both sides of the brain and can make a person cry out, lose consciousness, fall to the ground, and have muscle jerks or spasms. CDC, Types of Seizures, (last visited June 1, 2023) https://www.cdc.gov/epilepsy/about/types-of-seizures.htm. - 8 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 9 of 43 on the Slade study. Id. The Special Master did not credit Dr. Fujinami’s opinions on the timing of clinical manifestations. Id. at 38–39. The Special Master listed three distinct reasons: (1) counter to typical Vaccine Program practice, neither respondent nor Dr. Fujinami disclosed said opinions in pre-hearing filings and reports; (2) the opinion was inconsistent with other evidence such as the Slade post-marketing study; and (3) Dr. Fujinami did not present literature supporting his opinions. Ruling Finding Entitlement at 38–39. The Special Master found petitioner advanced a medically acceptable timeframe supported by relevant literature and expert testimony, and the alleged significant aggravation occurred within said timeframe. Id. at 37–38. While noting the Slade study alone was sufficient to credit Dr. Shafrir’s opinion on timing, the Special Master cited additional support from the Vaccine Injury Table, wherein Guillain-Barre Syndrome (“GBS”) induced by the influenza vaccine had been accepted within a three to 42-day interval. Id. Addressing the timeframe of the alleged 2007 challenge event, the Special Master stated, “[w]hether 43 days after the first HPV vaccination is an appropriate temporal interval is less important because Mr. Mager’s claim is not based on the first HPV vaccination.” Id. at 37 n.24. The Special Master also cited language from the Federal Circuit cautioning against special masters setting “hard and fast deadlines.” Id. at 38 (quoting Paluck v. Sec’y of Health & Hum. Servs., 786 F.3d 1373, 1383–84 (Fed. Cir. 2015)). The Special Master held, as a matter of law, preponderant evidence of a challenge-rechallenge occurrence meets the definition of “a medical theory causally connecting the vaccination and the injury” under Althen prong one (Loving prong four). Id. at 47–48 (quoting Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005)). The Special Master cited Capizzano and James-Cornelius as support for using evidence of a challenge-rechallenge occurrence to satisfy the Loving prong four definition of a reliable medical theory. Ruling Finding Entitlement at 47–48 (citing Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317 (Fed. Cir. 2006); James-Cornelius v. Sec’y of Health & Hum. Servs., 984 F.3d 1374, 1381 (Fed. Cir. 2021)) (“[I]n evaluating whether reasonable basis supported the claims set forth in a petition, the Federal Circuit stated that ‘the occurrence of a challenge-rechallenge event . . . has been recognized as a basis for establishing causation.’”). The Special Master compared Loving prong five to “asking whether the vaccine did cause the injury” and thus reasoned “[e]vidence that a vaccine did cause an injury must imply that the vaccine can cause the injury.” Id. at 48. The Special Master determined petitioner met his burden on Loving prong four because a challenge-rechallenge occurrence can cause the alleged injury. See id. at 48–49. In support, the Special Master cited the following four evidentiary points advanced by petitioner: (1) World Health Organization literature defining “the relationship between challenge-rechallenge as an adverse reaction to a vaccine as one of certain causality,” id. at 42 (citing Pet’r’s Ex. 57 at 4, ECF No. 116-3); (2) evidence of increased incidence of epilepsy among individuals with systemic lupus erythematosus, suggesting epilepsy may sometimes have an autoimmune component, id. (citing Antonio Greco et al., Autoimmune Epilepsy, 15 Autoimmunity Revs. 221 (2016)); (3) a study showing 9–14% of epilepsy patients have detectable bloodstream levels of - 9 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 10 of 43 autoimmune antibodies, id. (citing Jehan Suleiman et al., Autoantibodies to Neuronal Antigens in Children with New-Onset Seizures, 54 Epilepsia 2091 (2013)); and (4) evidence from the Slade post-marketing study reporting “convulsions” made up “8.8% of the serious reported side effects on VAERS reports from June 2001 through December 2008,” Ruling Finding Entitlement at 42 (citing Slade, supra). The Special Master considered contrary arguments from Dr. Fujinami, who advanced studies reviewed by the World Health Organization detecting no increases in autoimmune diseases or seizures among HPV vaccinees. Id. at 45. Dr. Fujinami inferred “if the HPV vaccination could cause a dysregulated immune response, some evidence . . . would have shown up in these large studies.” Id. The Special Master took note of Dr. Fujinami’s explanation of challenge-rechallenge: “Dr. Fujinami explained how repeat vaccinations can enhance the immune response. However, the challenge-rechallenge paradigm requires appropriate timing. In this case, [Dr. Fujinami opined Ms. Mager]’s seizures occurred too long after the vaccinations to be caused by the vaccinations.” Id. (internal citations omitted). The Special Master disagreed, positing the basic chronology of Ms. Mager’s clinical course fit the framework of challenge-rechallenge. Id. at 48. The Special Master also considered petitioner’s argument distinguishing a burden to provide a “medical theory” from a requirement to provide a “biologic mechanism.” Id. at 45–46. Petitioner asserted establishing challenge-rechallenge fulfilled the requirements of a medical theory. Ruling Finding Entitlement at 46. The Special Master noted respondent “did not address” petitioner’s distinction between medical theory and biologic mechanism. Id. at 46 n.29. Petitioner also advanced alternate theories of causation apart from challenge-rechallenge, including molecular mimicry; the Special Master found these theories unpersuasive. See id. at 49–50. The Special Master found petitioner carried his burden for Loving prong five by showing an appropriate sequence of events to prove challenge-rechallenge. Id. at 52. The Special Master centered his analysis around the parties’ arguments regarding indicators of chronic neuroinflammation. Id. at 51. The Special Master noted the following opinions proffered by the parties’ expert witnesses: (1) Dr. Shafrir’s opinion the subpial gliosis found on autopsy proved chronic neuroinflammation; (2) Dr. Fujinami’s and Dr. Kohrman’s assertions seizures alone can account for the gliosis; (3) Dr. Kohrman’s argument Ms. Mager’s MRI taken after her 14 November 2007 seizure showed no indications of inflammation; (4) Dr. Kohrman’s argument Ms. Mager’s May 2012 lab results showed normal levels of white blood cells in her bloodstream; and (5) Dr. Fujinami’s opinion Ms. Mager’s seizures resulted from poor medication compliance. Id. at 51–52. Although the Special Master did not delineate which arguments were persuasive, he concluded petitioner fulfilled the requirements of Loving prong five by referring to the basic chronology of Ms. Mager’s clinical course discussed for Loving prong four. Ruling Finding Entitlement at 48–49, 52. The Special Master stated, “there is no dispute that challenge-rechallenge can show that a vaccine harmed a person and then, on re-exposure, harmed the person again. . . . Mr. Mager has shown this sequence of events for [Ms. Mager].” Id. at 52 (internal citation omitted). The Special Master also addressed the telephone statements - 10 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 11 of 43 of treating physician Dr. Koehn in July 2008 opining the HPV vaccine did not cause Ms. Mager’s seizures. Id. at 52–53. The Special Master found Dr. Koehn’s statements were based on “incomplete information” as they occurred before the 2012 rechallenge event. Id. After finding petitioner met his prima facie case, the Special Master found respondent failed to provide sufficient evidence showing the 2012 vaccination was not a significant factor in Ms. Mager’s death. Id. at 53–55. On this point, respondent’s arguments included the assertion Ms. Mager suffered from JME and a secondary argument her death was due to the natural course of her epilepsy. Id. at 53. Respondent based the JME assertion on Dr. Kohrman’s testimony showing a person with JME not taking anti-seizure medications may experience years without seizures before a sudden relapse. Ruling Finding Entitlement at 53. The Special Master found this argument had a good-faith basis but was “outweighed by the value of challenge-rechallenge.” Id. The Special Master contemplated respondent’s secondary argument, which asserted Ms. Mager’s death resulted from the following underlying factors: (1) patients with epilepsy who are not taking medications redevelop seizures unpredictably; (2) Ms. Mager was reluctant to take Depakote and had mixed compliance with Keppra; and (3) Dr. Shafrir stated Ms. Mager’s SUDEP was “not correlated to the vaccine.” Id. at 54. Petitioner responded by citing Dr. Kohrman’s characterization of Ms. Mager’s epilepsy as “uncontrolled” before her death. Id. The Special Master noted this argument did not prove the lack of control resulted from the 2012 vaccination. Id. The Special Master also considered petitioner’s clarification of Dr. Shafrir’s testimony: although Dr. Shafrir stated Ms. Mager’s SUDEP was not correlated with the vaccine, Dr. Shafrir did correlate Ms. Mager’s death with her epilepsy, which in turn related to the vaccine. Id. In his holding, the Special Master acknowledged “[t]his issue, too, is close.” Ruling Finding Entitlement at 55. The Special Master pointed out respondent’s lack of evidence regarding the general incidence of SUDEP among persons with mild epilepsy. Id. Absent such evidence, the Special Master found although respondent’s claim “seem[ed] possible,” respondent had “not established this argument by a preponderance of the evidence.” Id. Based on these findings, the Special Master concluded petitioner carried his burden of proof for an off-Table significant aggravation claim related to Ms. Mager’s 11 September 2012 HPV vaccination. Id. The Special Master issued the Ruling Finding Entitlement on 19 April 2022 and the Decision Awarding Compensation on 5 December 2022. III. Respondent’s Motion for Review and Petitioner’s Arguments On 4 January 2023, respondent moved for review of the Special Master’s Ruling Finding Entitlement of 19 April 2022. 2023 Mot. for Review at 1. Respondent asserts “the Special Master erroneously found that Ms. Mager’s waking seizure on November 14, 2007 evidenced a significant aggravation of her preexisting epilepsy, that the evidence established a medically reasonable timeframe to infer vaccine causation, and that the challenge-rechallenge paradigm satisfied petitioner’s burden under Althen prong 1 and Loving prong 4.” Id. at 2. The Court summarizes the parties’ arguments for each objection in turn. - 11 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 12 of 43 A. The Finding Ms. Mager’s 14 November 2007 Seizure Evidenced a Significant Aggravation of her Pre-Existing Epilepsy, and Established a Challenge Event Regarding the first HPV vaccination, respondent submits the “Special Master erred as a matter of law by finding Mr. Mager’s claim was not based on the first HPV vaccination, erroneously failed to create a sufficient record to permit review as required by [VRCFC] 3(b)(2), and arbitrarily and capriciously found that Ms. Mager’s November 14, 2007 seizure evidenced a significant aggravation of her pre-existing epilepsy and requisite challenge event.” Id. at 11. Respondent argues the Special Master “applied the wrong legal standard by erroneously determining that ‘Mr. Mager’s claim is not based upon the first HPV vaccination.’” Id. at 7 (quoting Ruling Finding Entitlement at 37 n.24). Respondent contends “because the claim is based on challenge-rechallenge, Ms. Mager’s first vaccination was, in fact, critical to petitioner’s causation theory.” Id. Respondent, citing Nussman v. Secretary of Health and Human Services, explains petitioner is required to establish the first HPV vaccination as a challenge event and “failure to preponderantly establish a challenge event is fatal to a claim based on a challenge-rechallenge paradigm.” Id. at 8 (citing 83 Fed. Cl. 111, 120 (2008) (Sweeney, J.) (“There can only be a rechallenge if there was an initial challenge and associated adverse reaction.”)). Respondent argues the Special Master erroneously deemphasized the events surrounding the first HPV vaccination and “failed to analyze in the first instance how Ms. Mager’s November 14, 2007 waking seizure meets the statutory definition of a ‘significant aggravation.’” 2023 Mot. for Review at 8. Respondent discusses the Special Master’s failure to address the arguments made in respondent’s briefing, specifically the argument asserting the 14 November 2007 seizure was not a significant aggravation of the epilepsy. Id. Respondent argues petitioner is required to establish a challenge event to rely on the challenge-rechallenge paradigm and has not done so here. Id. at 7–9 (citing Nussman, 83 Fed. Cl. at 120). Respondent asserts there is no evidence supporting the presumption the 2007 waking seizures were different from nocturnal seizures in severity. Id. at 9–10. Respondent consequently argues there is no evidence to support the first HPV vaccination was a challenge event, i.e., Ms. Mager’s seizures were worse after the first HPV dose. Id. Even if there was a challenge event, respondent argues, the symptoms following “nearly five years without any seizure activity[] do[] not evidence ‘a substantial deterioration’ in Ms. Mager’s health.” Id. at 11 (quoting 42 U.S.C. § 300aa-33(4)). Petitioner claims respondent “mischaracterizes the Special Master’s assertion as irrelevant,” but “the Special Master is merely stating that [p]etitioner is not claiming an independent injury from the first dose of HPV vaccination.” Pet’r’s Resp. at 14. Petitioner asserts respondent’s arguments “confuse[] petitioner’s claim of significant aggravation with the theory of causation, which is challenge-rechallenge.” Id. Petitioner explains a significant aggravation claim can be solely based on the second HPV dose, but the first vaccination is critical to the theory of causation. Id. at 14–15. Petitioner defends the Special Master’s factual analysis by pointing to: (1) the discussion of facts; (2) Ms. Mager’s health prior to and after the first vaccination; and (3) expert testimony. Id. at 15. Regarding the severity of the seizures, petitioner avers the record demonstrated significant aggravation following the first dose of the HPV vaccination. Id. at 16. B. The Finding Timing Supports Petitioner’s Theory of Challenge-Rechallenge - 12 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 13 of 43 Respondent argues the determination “the timing here supports a finding that Ms. Mager experienced a challenge event following her October 2, 2007 vaccination is also deeply flawed.” 2023 Mot. for Review at 12. Respondent asserts the Slade article, which the Special Master relied upon for a “window of plausibility,” is not “related to the alleged injury in this case.” Id. Additionally, respondent argues petitioner’s expert “had no opinion as to what made [four] to 42 days ‘biologically plausible.’” Id. Respondent also criticizes the Special Master’s citation of the Vaccine Injury Table as support for the timing. Id. at 12–13. Respondent acknowledges the Vaccine Injury Table may be helpful but argues “the Special Master did not explain how the Table timeline for onset of GBS following influenza vaccination is relevant to the development of waking seizures following an HPV vaccination.” Id. at 13. Respondent contends the Special Master did not “provide[] a rational basis for selecting a timeframe generally ascribed to the development of a peripheral demyelinating condition—GBS—as opposed to some other timeframe contained in the Vaccine Injury Table.” Id. at 14. Respondent specifically disagrees with the timing of the second HPV dose supporting a rechallenge event. 2023 Mot. for Review at 14–15. Respondent argues the review articles relied upon by petitioner’s expert were contrary to the facts, and the Special Master erred in giving the articles credence. Id. at 15. Respondent contends in a footnote the “Special Master further erred in rejecting the testimony of respondent’s expert immunologist, Dr. Fujinami, as to timing.” Id. at 15 n.4. In defending the Slade article, petitioner explains “GBS is, in fact, an autoimmune disease” and a GBS comparison is therefore applicable as evidence of the timing being “biologically plausible.” Pet’r’s Resp. at 17. Petitioner asserts while the Vaccine Injury Table is “not dispositive,” it “can be properly relied upon” as the Special Master did after citing cases using the Vaccine Injury Table as support for timing. Id. at 18. Petitioner contends the Special Master’s decision on choosing the GBS-flu vaccine temporal window was not arbitrary and capricious because “it was based on expert testimony and scientific studies” and provides “additional[] though unnecessary support.” Id. at 18–19. Petitioner argues the Special Master was allowed to extend the support timeline by one day because the Federal Circuit “has admonished special masters not to set ‘hard and fast deadlines.’” Id. at 19 (quoting Paluck v. Sec’y of Health & Hum. Servs., 786 F.3d 1373, 1383–84 (Fed. Cir. 2015)). Petitioner rebuts respondent’s implications the Special Master “failed to consider Dr. Fujinami’s testimony” and states the Special Master correctly observed neither of respondent’s experts “addressed timing in their original or supplemental reports” or rebutted the timing proposed by petitioner. Id. at 19–20. C. The Finding Challenge-Rechallenge Paradigm Satisfied Loving Prong Four Respondent asserts the Special Master “erred in finding challenge-rechallenge, by itself, satisfied petitioner’s burden to show preponderant evidence of a reliable medical theory under Loving prong 4 or Althen prong 1.” 2023 Mot. for Review at 16. Citing Capizzano, respondent argues the challenge-rechallenge paradigm is “generally proffered in the context of Althen prong 2[ (Loving prong five)].” Id. (citing Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317 (Fed. Cir. 2006)). Respondent contends the Federal Circuit “did not find challenge-rechallenge sufficient by itself to satisfy Althen prong 1[ (Loving prong four)].” Id. Respondent asserts petitioner’s theory of challenge-rechallenge does not meet “petitioner’s burden to provide a - 13 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 14 of 43 reliable medical or scientific explanation of how the vaccine can bring about the injury.” Id. at 17–18. Referring to the error in timing, respondent asserts “in order to assess whether a proposed time relationship is plausible, one must have some understanding of how the vaccine is thought to bring about the injury—that is, the proposed causal mechanism.” Id. at 18. Respondent argues petitioner’s expert did not “describe any pathology for how an HPV vaccine can significantly aggravate a seizure disorder” or a plausible timeframe, and therefore relying on the challenge-rechallenge paradigm as a reliable theory under Althen prong one or Loving prong four is erroneous. Id. at 18–19. Petitioner asserts the theory of causation is the challenge-rechallenge paradigm. Pet’r’s Resp. at 20. Petitioner emphasizes the Special Master reviewed the evidence and found petitioner met the burden to present a plausible theory. Id. Petitioner defends the Special Master’s use of Capizzano “as a starting point” and points out “the [Federal] Circuit in its de novo review accept[ed] the [s]pecial [m]aster’s finding of [p]rong 1 noting that ‘In so deciding, the chief special master relied on evidence of ‘rechallenge.’” Id. at 21 (citing Capizzano, 440 F.3d at 1322). Petitioner further notes the Federal Circuit in Capizzano allowed evidence from one prong to satisfy another prong, so the evidence proffered here for Loving prongs five and six may also support prong four. Id. at 21–22 (quoting Capizzano, 440 F.3d at 1326 (“We see no reason why evidence used to satisfy one of the Althen . . . prongs cannot overlap to satisfy another prong.”)). Petitioner also argues the Federal Circuit does not “require identification and proof of specific biological mechanisms.” Id. at 22 (quoting Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 549 (Fed. Cir. 1994)). D. Burden to Establish Ms. Mager’s Death Was the Natural Result of Her Epilepsy Respondent argues “the Special Master erroneously shifted the burden to respondent to disprove that Ms. Mager’s September 11, 2012 HPV vaccination caused her death.” 2023 Mot. for Review at 19. Respondent, referencing petitioner’s expert, asserts Ms. Mager’s death was a result of SUDEP and not correlated to the vaccination. Id. at 19–20. Respondent argues because petitioner’s expert “disavowed any relationship between Ms. Mager’s vaccinations and her SUDEP, and given the Special Master’s finding that the HPV vaccine did not cause Ms. Mager’s epilepsy, the Special Master erred in shifting the burden to respondent to establish that Ms. Mager’s death was the natural result of her epilepsy and finding respondent failed to meet the burden.” Id. at 20. Petitioner, citing Walther, explains “the burden shifts to [respondent] under the ‘factor unrelated’ inquiry to show that the pre-existing condition caused the significantly worsened condition.” Pet’r’s Resp. at 23 (citing Walther v. Sec’y of Health & Hum. Servs., 485 F.3d 1146, 1151 (Fed. Cir. 2007)). Petitioner maintains he met the burden of proof, and therefore the burden shifts “to [r]espondent to prove an alternative cause, e.g. the natural course of [Ms. Mager’s] disease, for either her epilepsy post the second vaccination or her subsequent death.” Id. Petitioner asserts the Special Master “discussed the evidence related to [Ms. Mager’s] death specifically and found the [r]espondent failed to meet [its] burden” and therefore did not err. Id. at 24 (citing Ruling Finding Entitlement at 55). - 14 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 15 of 43 IV. Legal Standards A. The Court’s Review of a Special Master’s Decision The Vaccine Act provides this court jurisdiction to review a special master’s decision upon timely motion of either party. See 42 U.S.C. § 300aa-12(e)(1)–(2). In reviewing the record of the proceedings before the Special Master, the Court may: (1) “uphold the findings of fact and conclusions of law of the special master and sustain the special master’s decision”; (2) “set aside any findings of fact or conclusion of law of the special master found to be arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law and issue its own findings of fact and conclusions of law”; or (3) “remand the petition to the special master for further action in accordance with the court’s direction.” § 300aa-12(e)(2). “Fact findings are reviewed . . . under the arbitrary and capricious standard; legal questions under the ‘not in accordance with law’ standard; and discretionary rulings under the abuse of discretion standard.” Saunders v. Sec’y of Dep’t of Health & Hum. Servs., 25 F.3d 1031, 1033 (Fed. Cir. 1994) (quoting Munn v. Sec’y of Dep’t of Health & Hum. Servs., 970 F.2d 863, 870 n.10 (Fed. Cir. 1992)). It is not the Court’s role “to reweigh the factual evidence, or to assess whether the special master correctly evaluated the evidence.” Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d 1357, 1360 (Fed. Cir. 2000) (quoting Munn, 970 F.2d at 871). The Court also does “not examine the probative value of the evidence or the credibility of the witnesses. These are all matters within the purview of the fact finder.” Id. (quoting Munn, 970 F.2d at 871). “Reversal is appropriate only when the special master’s decision is arbitrary, capricious, an abuse of discretion, or not in accordance with the law.” Snyder ex rel. Snyder v. Sec’y of Health & Hum. Servs., 88 Fed. Cl. 706, 718 (2009) (footnote omitted). The arbitrary and capricious standard “is a highly deferential standard of review[:] [i]f the special master has considered the relevant evidence of record, drawn plausible inferences and articulated a rational basis for the decision, reversible error will be extremely difficult to demonstrate.” Hines ex rel. Sevier v. Sec’y of Dep’t of Health & Hum. Servs., 940 F.2d 1518, 1528 (Fed. Cir. 1991). B. Causation in Vaccine Cases “A petitioner seeking compensation under the Vaccine Act must prove by a preponderance of the evidence that the injury or death at issue was caused by a vaccine.” Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1341 (Fed. Cir. 2010) (citing 42 U.S.C. §§ 300aa-11(c)(1), -13(a)(1)). “A petitioner can show causation under the Vaccine Act in one of two ways”: (1) “by showing that she sustained an injury in association with a vaccine listed in the Vaccine Injury Table[;] . . . [i]n such a case, causation is presumed”; or (2) “if the complained-of injury is not listed in the Vaccine Injury Table . . . the petitioner may seek compensation by proving causation in fact.” Id. at 1341–42 (internal citation omitted). Vaccine cases employ a burden shifting standard: “[o]nce the petitioner has demonstrated causation, she is entitled to compensation unless the government can show by a preponderance of the evidence that the injury is due to factors unrelated to the vaccine.” Id. at 1342 (citing Doe v. Sec’y of Health & Hum. Servs., 601 F.3d 1349, 1351 (Fed. Cir. 2010); 42 U.S.C. § 300aa-13(a)(1)(B)). - 15 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 16 of 43 “For off-table claims”—for a vaccine not included in the Vaccine Injury Table under 42 U.S.C. § 300aa-11(c)(1)(C)(i)—“that an injury was either ‘sustained, or [] significantly aggravated,’ a petitioner must show the vaccine ‘caused’ the injury or aggravation.” W.C. v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1357 (Fed. Cir. 2013) (citing 42 U.S.C. § 300aa-11(c)(1)(C)(ii)). “A petitioner must prove by preponderant evidence that the vaccination caused significant aggravation by showing:” (1) the person’s condition prior to administration of the vaccine, (2) the person’s current condition (or the condition following the vaccination if that is also pertinent), (3) whether the person’s current condition constitutes a “significant aggravation” of the person’s condition prior to vaccination, (4) a medical theory causally connecting such a significantly worsened condition to the vaccination, (5) a logical sequence of cause and effect showing that the vaccination was the reason for the significant aggravation, and (6) . . . a proximate temporal relationship between the vaccination and the significant aggravation. Id. (citing Loving ex rel. Loving v. Sec’y of Dep’t of Health & Hum. Servs., 86 Fed. Cl. 135, 144 (2009)). The Federal Circuit in W.C. espoused “[t]he Loving test combines the first three Whitecotton factors, which establish significant aggravation, with the Althen factors, which establish causation.” Id. Accordingly, the standards for assessing Althen prongs one, two, and three also apply to Loving prongs four, five, and six. Id. Under the first prong of Althen, “[a] petitioner must provide a ‘reputable medical or scientific explanation’ for its theory.” Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1359 (Fed. Cir. 2019) (quoting Moberly ex rel. Moberly v. Sec’y of Health & Hum. Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010)). “While it does not require medical or scientific certainty, [the explanation] must still be ‘sound and reliable.’” Id. (quoting Knudsen ex rel. Knudsen v. Sec’y of Dep’t of Health & Hum. Servs., 35 F.3d 543, 548–49 (Fed. Cir. 1994)). Petitioners “need not produce medical literature or epidemiological evidence to establish causation under the Vaccine Act.” Andreu ex rel. Andreu v. Sec’y of Dep’t of Health & Hum. Servs., 569 F.3d 1367, 1379 (Fed. Cir. 2009). Where such evidence is introduced, it must not be viewed “through the lens of the laboratorian, but instead from the vantage point of the Vaccine Act’s preponderant evidence standard.” Id. at 1380. For satisfying the second Althen prong, “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.’” Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006) (quoting Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1280 (Fed. Cir. 2005)). Lastly, “the proximate temporal relationship prong requires preponderant proof that the onset of symptoms occurred within a timeframe for which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation-in-fact.” de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). V. Whether the Challenge-Rechallenge Paradigm Can Establish Causation Central to the parties’ argument is the challenge-rechallenge paradigm. The parties - 16 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 17 of 43 dispute: (1) whether the challenge-rechallenge paradigm can be used as a “reliable medical theory” as Loving prong four requires; (2) the standard for establishing a challenge event as part of a logical sequence of cause-and-effect under Loving prong five; and (3) what is important in establishing a challenge event. As the parties argue about the legal standards the Special Master applied, the Court reviews de novo. See Saunders v. Sec’y of Dep’t of Health & Hum. Servs., 25 F.3d 1031, 1033 (Fed. Cir. 1994). The Court first determines if the challenge-rechallenge paradigm can be used as a “reliable medical theory.” Next, the Court determines what legal standard is applied to establish the challenge event in the challenge-rechallenge paradigm. Finally, the Court reviews caselaw from the Federal Circuit and the Court of Federal Claims where challenge-rechallenge was used in the causation-in-fact analysis. A. Whether the Challenge-Rechallenge Paradigm Can Be Used as a “Reliable Medical Theory” At oral argument, respondent attempted to distinguish Capizzano. Respondent first argued “Capizzano is not particularly . . . persuasive or doesn’t speak to the issues in this case is [sic] that contrary to the Federal Circuit’s finding, the chief special master did not analyze Althen prong three in the lower court.” Tr. at 10:1–5. Respondent also asserted Capizzano is not persuasive because the underlying theory supporting the challenge-rechallenge paradigm has been discredited by other studies cited. Tr. at 21:6–14 (“[RESPONDENT]: . . . Capizzano is ultimately not persuasive . . . because the fundamental basis for the chief special master’s decision that challenge-rechallenge was proof of causation was its very heavy reliance on the position of the Institute of Medicine. And the Institute of Medicine’s position, at that time, was . . . evidence of challenge-rechallenge was tantamount to proving causation. And that has evolved.”), 21:22–22:3 (“[RESPONDENT]: . . . [T]he Pollard and Selby study . . . was a particular case report . . . the Institute of Medicine had found that challenge/rechallenge was sufficient proof of causation that the tetanus vaccine can cause [GBS]. And that’s changed. For all the reasons that are outlined in the Issac study . . . .”). Petitioner argued challenge-rechallenge might not be accepted in the context of GBS and tetanus, but “challenge-rechallenge is commonly accepted in the medical community as evidence of causation.” Tr. at 25:5–7. Further, while the Institute of Medicine (“IOM”) requires scientific certainty, petitioner asserts scientific certainty is a higher causality burden than the causality standard required by the Vaccine Act, and therefore an IOM position is acceptable to use in the vaccine injury context. Tr. at 35:22–36:4. Additionally, respondent argued challenge-rechallenge is “only anecdotal evidence of causation” and a causal mechanism is required for a “reliable medical theory.” Tr. at 28:15–29:1 (“[PETITIONER]: [The Institute of Medicine] still look[s] at rechallenge as a strong causal relationship. [RESPONDENT]: I disagree. . . . [The 2012 IOM] describes [challenge-rechallenge] as one attribute in the evaluation of clinical evidence. But it’s treated very much like case reports . . . essentially anecdotal evidence.”). Further, respondent suggested challenge-rechallenge cannot be used without something more; there needs to a mechanism for Althen prong three. Tr. at 30:8–13 (“[RESPONDENT]: [I]t’s not just a theory has to be plausible or reliable in the abstract. To satisfy [Althen] prong one, [the theory] has to have some relationship to the case. . . . You can’t really make that assessment without something additional that would inform whether or not the onset is medically reasonable . . . .”), 29:11–30:1 (“THE - 17 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 18 of 43 COURT: So then [respondent]’s argument is that there must be an underlying mechanism to satisfy reliable medical theory? [RESPONDENT]: That’s what I think would be the most useful. I would say that there has to be something more. . . . THE COURT: . . . What’s the something more? [RESPONDENT]: . . . I would say some information about the underlying mechanism to explain whether or not the onset of the condition is medically reasonable.”). Petitioner asserted “rechallenge was such a strong proof of causality that you needn’t do anything else” and no underlying mechanism was required under Federal Circuit precedent. Tr. at 15:24–16:1. A “challenge-rechallenge” circumstance exists when a person has a reaction to one administration of a vaccine or drug and then suffers the same or worsening symptoms after an additional administration of the same vaccine or drug. The Federal Circuit recognizes the challenge-rechallenge paradigm as the basis for causation. In Capizzano, the chief special master stated, “evidence of rechallenge constituted such strong proof of causality that it is unnecessary to determine the mechanism of cause—it is understood to be occurring.” Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1322 (Fed. Cir. 2006) (internal quotations and citations omitted). The Federal Circuit reaffirmed the notion in James-Cornelius ex rel. E.J.: “the occurrence of a challenge-rechallenge event . . . has been recognized as a basis for establishing causation.” James-Cornelius ex rel. E.J. v. Sec’y of Health & Hum. Servs., 984 F.3d 1374, 1381 (Fed. Cir. 2021) (citing Capizzano, 440 F.3d at 1322). The procedural history of Capizzano is unique. At the time the special master decided Capizzano, the Court of Federal Claims recently issued Althen v. Secretary of Health and Human Services, which rejected the existing Stevens standard. Capizzano v. Sec’y of Dep’t of Health & Hum. Servs., No. 00-759V, 2004 WL 1399178, at *2 (Fed. Cl. June 8, 2004), determination sustained, 63 Fed. Cl. 227 (2004), vacated and remanded sub nom. Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317 (Fed. Cir. 2006). Recognizing Althen could affect the causation analysis, the chief special master in Capizzano ordered the parties file supplemental briefing applying this court’s legal analysis in Althen to the case. Id. While respondent is correct the procedural history of Capizzano is unique, the chief special master’s foresight in having the parties provide supplemental briefing under the now controlling causation-in-fact Althen standard makes Capizzano applicable. The issue in Capizzano at the Federal Circuit involved the special master’s requirement of one of four types of evidence, which included challenge-rechallenge evidence, to demonstrate the logical sequence of cause and effect and whether the requirement was inconsistent with Althen. Capizzano, 440 F.3d at 1322. The Federal Circuit held the special master could not require specific types of evidence, but the use of circumstantial evidence was “envisioned by the preponderance standard.” Id. at 1325 (quoting Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1280 (Fed. Cir. 2005)). Respondent argues because the petitioner in Capizzano did not proffer challenge-rechallenge, the theory was not properly analyzed; petitioner argues the distinction does not negate the use of the challenge-rechallenge paradigm as a “reliable medical theory.” Tr. at 79:4–11 (respondent), 86:9–17 (petitioner). In Capizzano, the parties presented evidence on rechallenge through experts, and the special master found the rechallenge evidence persuasive to show a reliable medical theory. See Capizzano, 2004 WL 1399178 *13–16 (finding medical literature and experts persuasive for showing rechallenge can occur). At oral - 18 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 19 of 43 argument, respondent admitted “the chief special master found [testimony] satisfied [Althen] prong one” in Capizzano. Tr. at 82:16–83:22. Indeed, the Federal Circuit acknowledged the special master “relied on evidence of ‘rechallenge’ in other injectees. . . . [which] constituted ‘such strong proof of causality that it is unnecessary to determine the mechanism of cause—it is understood to be occurring.’” Capizzano, 440 F.3d at 1322 (quoting Capizzano, 2004 WL 1399178 *16). The Federal Circuit did not find error in the use of the challenge-rechallenge paradigm as a reliable medical theory or for the proximate temporal relationship between the vaccination and injury. Id. at 1325 (“There is no dispute that the first and third prongs of Althen . . . were satisfied.”). To further support Capizzano allowing for use of the challenge-rechallenge paradigm, the Federal Circuit in James-Cornelius recognized the use of rechallenge as a form of evidence for causation. James-Cornelius, 984 F.3d at 1380 (citing Capizzano, 440 F.3d at 1322). The parties disagree on whether James-Cornelius clarifies the use of challenge-rechallenge. See Tr. at 7:23–8:4 (respondent arguing James-Cornelius is dicta), 17:11–16 (“[PETITIONER]: . . . [James-Cornelius] reiterate[s] again that a challenge/rechallenge event has been recognized as a basis for establishing causation . . . because it’s a lower standard, it doesn’t mean that rechallenge is not . . . a reliable model for causation.”). Respondent argues because the issue in James-Cornelius was about the reasonable basis standard for attorneys’ fees, James-Cornelius is dicta regarding challenge/rechallenge. Tr. at 7:23–8:4. In James-Cornelius, the Federal Circuit addressed whether there was a reasonable basis for a vaccine claim. 984 F.3d at 1379. The Federal Circuit reviewed the evidence upon which the petitioner based the claim and found the evidence, including rechallenge evidence, supported a reasonable basis. Id. at 1379–80. The Federal Circuit expressly acknowledged “‘rechallenge,’ which has been recognized as a form of causation evidence,” is acceptable evidence. Id. at 1380. Despite reasonable basis being a lower standard than preponderant evidence, the Federal Circuit’s decision provides rechallenge evidence can be used as a form of causation evidence. Id. James-Cornelius affirms Capizzano’s allowance of the challenge-rechallenge paradigm for the causation-in-fact analysis. Id.; Capizzano, 440 F.3d at 1322. Respondent’s argument challenge-rechallenge “will never be sufficient in and of itself without some explanation” is contrary to Federal Circuit precedent. Tr. at 8:12–18, 29:11–30:1 (“[RESPONDENT]: . . . [T]here has to be something more. . . . some information about the underlying mechanism to explain whether or not the onset of the condition is medically reasonable.”). Respondent, referencing Althen, explains challenge-rechallenge “is fundamentally a temporal association. And it’s well established in the law that a temporal association, in and of itself, cannot establish causation.” Tr. at 8:8–18. Respondent misunderstands Althen. In Althen, immediately prior to setting out the standard for causation-in-fact, the Federal Circuit stated: “Although probative, neither a mere showing of a proximate temporal relationship between vaccination and injury, nor a simplistic elimination of other potential causes of the injury suffices, without more, to meet the burden of showing actual causation.” Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005) (emphasis added). “[A] mere showing of a proximate temporal relationship” is different than proffering a medically acceptable theory relying on timing. Id. A petitioner alleging causation because the injury was close to the vaccination is not sufficient. A petitioner alleging causation because the injury was close to multiple instances of the vaccination and within the timeframe of when the medically acceptable - 19 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 20 of 43 theory expects to see the repeat injury may be sufficient. Id. The Federal Circuit has explained “the Althen prongs ‘must cumulatively show that the vaccination was a “but-for cause” of the harm.’” Rickett v. Sec’y of Health & Hum. Servs., 468 F. App’x 952, 957 (Fed. Cir. 2011) (citing Pafford ex rel. Pafford v. Sec’y of Health & Hum. Servs., 451 F.3d 1352, 1355 (Fed. Cir. 2006)). The Court, during oral argument, used a hypothetical to explore this point. See Tr. at 32:5–35:21. A person receiving the flu shot for the first time gets numbness in his arm five days later. Id. A numb arm close to vaccine administration is not sufficient to show causation. See Althen, 418 F.3d at 1278. The same person receives the flu shot the next year and again gets arm numbness five days later. Tr. at 32:5–35:21. Every year the person receives the flu shot, they have arm numbness until finally their arm becomes completely paralyzed after the tenth annual shot. Tr. at 32:5–35:21. Challenge-rechallenge expects to see repetitive adverse reactions after the administration of a vaccine within a certain timeframe. Althen, 418 F.3d at 1278. Paired with the clinical picture of what one would expect to see under the challenge-rechallenge paradigm, there is more than “a mere showing of a proximate temporal relationship.” Id. Respondent also points to de Bazan for requiring the disorder’s etiology—or cause. Tr. at 38:5–21; see Etiology, Webster’s Third New International Dictionary (2002) (“all of the causes of a disease or an abnormality”). The Federal Circuit in de Bazan stated, “the proximate temporal relationship prong requires preponderant proof that the onset of symptoms occurred within a timeframe for which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation-in-fact.” de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). In context, de Bazan discusses the establishment of a medically acceptable timeframe, not necessarily requiring a specific mechanism or etiology of the reliable medical theory. Id. Requiring the cause of a disorder to satisfy the three prongs of the causation-in-fact analysis is contradictory to what Althen is intended to prove—causation. Althen, 418 F.3d at 1278 (holding the three Althen prongs show “the vaccination brought about [the] injury”). The Federal Circuit conveys in de Bazan the proximate-temporal relationship must be medically acceptable and depends on the medical understanding of the underlying reliable theory because the theory affects the timeline of the onset of symptoms. 539 F.3d at 1352. Further, it is well established “to require identification and proof of specific biological mechanisms would be inconsistent with the purpose and nature of the vaccine compensation program.” Knudsen ex rel. Knudsen v. Sec’y of Dep’t of Health & Hum. Servs., 35 F.3d 543, 548–49 (Fed. Cir. 1994); see Andreu ex rel. Andreu v. Sec’y of Dep’t of Health & Hum. Servs., 569 F.3d 1367, 1379 (Fed. Cir. 2009) (stating petitioners “need not produce medical literature or epidemiological evidence to establish causation under the Vaccine Act”). Indeed, respondent acknowledges the Federal Circuit is reluctant to require an underlying mechanism. Tr. at 30:1–6 (“[RESPONDENT]: [F]rom reviewing the Federal Circuit decisions . . . the Federal Circuit is very reluctant to impose very specific requirements of what types . . . of evidence need to be presented.”). Where challenge-rechallenge is a medically acceptable theory and petitioner establishes a medically acceptable timeframe, the microscopic mechanics of the science behind the theory, though helpful at times, are not required. See de Bazan, 539 F.3d at 1352; Knudsen, 35 F.3d at 548–49. The Special Master reviewed the caselaw surrounding the challenge-rechallenge - 20 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 21 of 43 paradigm and determined challenge-rechallenge could be used as a reliable medical theory to satisfy prong four of Loving. Ruling Finding Entitlement at 47–48. The Special Master stated “the appellate authorities seem inclined to accept challenge-rechallenge as a theory,” relying on Capizzano and James-Cornelius. Id. As discussed supra, Federal Circuit caselaw supports the use of the challenge-rechallenge paradigm as a reliable medical theory, so the Special Master did not err in finding challenge-rechallenge could be used to satisfy Loving prong four. See Capizzano, 440 F.3d at 1322; James-Cornelius, 984 F.3d at 1380; Knudsen, 35 F.3d at 548–49. B. Whether the Establishment of a Challenge Event Requires the Application of Loving Prongs One, Two, and Three The parties dispute whether the Special Master applied the correct legal standard in determining a challenge event. Respondent argues the Special Master “applied the wrong legal standard by erroneously determining that ‘Mr. Mager’s claim is not based upon the first HPV vaccination.’” 2023 Mot. for Review at 7 (quoting Ruling Finding Entitlement at 37 n.24). Respondent contends “because the claim is based on challenge-rechallenge, Ms. Mager’s first vaccination was, in fact, critical to petitioner’s causation theory.” Id. Respondent, citing Nussman, explains the petitioner was required to establish the first HPV vaccination as a challenge event and “failure to preponderantly establish a challenge event is fatal to a claim based on a challenge-rechallenge paradigm.” Id. at 8 (citing Nussman v. Sec’y of Health & Hum. Servs., 83 Fed. Cl. 111, 120 (2008) (“There can only be a rechallenge if there was an initial challenge and associated adverse reaction.”)). Implied in respondent’s arguments about the Special Master applying the “wrong legal standard” is the assertion a challenge event must be established for significant aggravation. Petitioner asserts respondent’s arguments “confuse[] petitioner’s claim of significant aggravation with the theory of causation, which is challenge-rechallenge.” Pet’r’s Resp. at 14. Petitioner explains a significant aggravation claim can be solely based on the second HPV dose, but the first vaccination is critical to the theory of causation. Id. at 14–15. While respondent did not argue Loving prongs one, two, and three are the standard to establish a challenge event in briefing, at oral argument, respondent asserted the Special Master needed to apply Loving prongs one, two, and three to establish a challenge event; petitioner disagreed. Tr. at 59:5–16 (“THE COURT: You argue that for that challenge event in 2007, we should apply preponderant standard to the first three Loving factors? [RESPONDENT]: Absolutely, yes. . . . [PETITIONER]: . . . [The Special Master did] a Loving analysis of significant aggravation, but I think that’s beyond actually what petitioner’s burden is . . . .”), 47:18–48:5 (“THE COURT: . . . [W]hat requirement is there for the 2007 challenge event? [RESPONDENT]: Factors one through three, at a minimum.”). Petitioner argued the standard for establishing a challenge event is preponderance of the evidence to see if an adverse event occurred. See Tr. at 60:12–61:21. “A challenge is not the same thing as a significant aggravation,” petitioner asserted, and therefore Loving prongs one, two, and three should not be the standard for establishing a challenge event. Tr. at 60:18–22. Petitioner explained “challenge-rechallenge is not a legal term” and is distinguishable from significant aggravation, which has a statutory definition. Tr. 72:16–73:8 (“[PETITIONER]: . . . If you look at any of the general definitions of challenge-rechallenge, it simply says an adverse event.”). While a challenge event does look at the before and after to determine an adverse reaction, the challenge - 21 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 22 of 43 event does not have to meet the definition of the statute, petitioner argued. Id. Petitioner alternatively argued, if the Court finds Loving prongs one, two, and three must be applied to determine a challenge event, the Special Master analyzed the first three prongs of Loving for the challenge event. Tr. at 59:5–16 (“[PETITIONER]: I think what should be specifically looked at is the Special Master’s factual analysis.”). The Federal Circuit, in W.C. v. Secretary of Health and Human Services, affirmed the Loving framework as the correct analytical framework for off-Table significant aggravation claims. W.C. v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1357 (Fed. Cir. 2013) (citing Loving ex rel. Loving v. Sec’y of Dep’t of Health & Hum. Servs., 86 Fed. Cl. 135, 144 (2009)) (“We hold that the Loving case provides the correct framework for evaluating off-table significant aggravation claims.”). The parties agree Loving is the correct framework for significant aggravation claims. Tr. at 42:5–13 (“THE COURT: . . . [W]hat is the correct legal standard for off-Table significant aggravation claims? . . . [RESPONDENT]: [The Loving test] is what is used to analyze a significant aggravation claim.”), 44:3–5 (“THE COURT: [What is] the correct legal standard for off-Table significant aggravation claims[?] [PETITIONER]: Loving is the correct standard.”). The Loving framework, as explained by the Federal Circuit, “combines the first three Whitecotton factors, which establish significant aggravation, with the Althen factors, which establish causation.” W.C., 704 F.3d at 1357. The Federal Circuit explained “Whitecotton requires the special master to compare the injured person’s condition prior to vaccination with his or her current condition to determine whether a significant aggravation occurred.” Id. at 1356 (citing Whitecotton ex rel. Whitecotton v. Sec’y of Health & Hum. Servs., 81 F.3d 1099, 1107 (Fed. Cir. 1996)). The comparison of the two conditions is “practically inherent in the term ‘aggravation.’” Whitecotton, 81 F.3d at 1107. “Loving prong 3, like Whitecotton prong 3, only requires a comparison of a petitioner’s current, post-vaccination condition with her pre-vaccination condition.” Sharpe v. Sec’y of Health & Hum. Servs., 964 F.3d 1072, 1082 (Fed. Cir. 2020) (emphasis added). The Loving framework therefore incorporates but distinguishes significant aggravation from the theory of causation. W.C., 704 F.3d at 1356–57. While significant aggravation is critical to causation, whether an injury was significantly aggravated is distinct from whether the vaccination could and did cause the injury within a reasonable timeframe. Id. Respondent, at oral argument, agreed there is no overlap between the significant aggravation prongs and the causation prongs. Tr. at 42:14–18 (“THE COURT: . . . [I]s there overlap between the first three factors and the last three factors of Loving because of the significant aggravation? [RESPONDENT]: No.”). Accordingly, applying Loving prongs one, two, and three is not necessary to establish a challenge event. W.C., 704 F.3d at 1356–57. Pursuant to 42 U.S.C. § 300aa-13(a)(1)(A), a petitioner must demonstrate “by a preponderance of evidence the matters required in the petition.” The Federal Circuit “has made clear that the applicable level of proof is not certainty, but the traditional tort standard of ‘preponderant evidence,’” or “the existence of a fact is more probable than its nonexistence.” Moberly ex rel. Moberly v. Sec’y of Health & Hum. Servs., 592 F.3d 1315, 1322, 1322 n.2 (Fed. Cir. 2010). The parties agree petitioner must show preponderant evidence for each prong of the Loving analysis. Tr. at 54:17–24 (respondent), 57:12–23 (petitioner). Loving prong five—a logical sequence of cause and effect—therefore, must be shown by preponderant evidence. Moberly, 592 F.3d at 1322. As petitioner relies on the challenge-rechallenge paradigm for its - 22 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 23 of 43 causation theory, petitioners must show the clinical picture of the challenge-rechallenge paradigm did occur by preponderant evidence for prong five. Id. The challenge event, or an adverse reaction, only requires preponderant evidence as part of Loving prong five. Id. An adverse reaction is not the same as significant aggravation. To require petitioner to satisfy the Loving one, two, and three prongs separately by preponderant evidence instead of Loving prong five by preponderant evidence improperly raises petitioner’s burden of proof.4 See e.g., id. Further, respondent did not point to any caselaw supporting the use of Loving prongs one, two, and three for a challenge event but merely indicated no case analyzed challenge-rechallenge in the context of a significant aggravation claim. See Tr. at 50:1–20. The statute requires petitioner to prove by preponderant evidence causation, including the establishment of a challenge event after the administration of a vaccine. § 300aa-13(a)(1)(A); W.C., 704 F.3d at 1357; Sharpe, 964 F.3d at 1082; Moberly, 592 F.3d at 1322. The Court addresses infra the question of whether the record supports a challenge event. C. Challenge Events in the Federal Circuit and Court of Federal Claims Respondent argues petitioner is required to establish a challenge event to rely on the challenge-rechallenge paradigm and has not done so here. 2023 Mot. for Review at 7–9 (citing Nussman, 83 Fed. Cl. at 120). Respondent asserts there is no evidence supporting the presumption the 2007 pre-vaccination waking seizures were different from the post-vaccination nocturnal seizures in severity. Id. at 9. Respondent argues there is consequently no evidence to support the first HPV vaccination was a challenge event, i.e., Ms. Mager’s seizures were worse after the first HPV dose. Id. Discussing the severity of the seizures, petitioner avers the record demonstrated significant aggravation following the first dose of the HPV vaccination. Pet’r’s Resp. at 16. As discussed supra Section V.A, the challenge-rechallenge paradigm can be used to establish causation. To prove the logical sequence of cause-and-effect using the challenge-rechallenge paradigm, “[t]here can only be rechallenge if there was an initial challenge and associated adverse reaction.” Nussman, 83 Fed. Cl. at 120. The Court views other cases related to challenge-rechallenge as instructive. The Federal Circuit instructed special masters to fully explain and analyze findings in relation to establishing challenge and rechallenge events in Sanchez. See Sanchez ex rel. Sanchez v. Sec’y of Health & Hum. Servs., 809 F. App’x 843, 853–54 (Fed. Cir. 2020). In Sanchez, the petitioner alleged several sets of vaccinations caused a genetic condition to manifest or aggravated the underlying Leigh’s syndrome. Id. at 847. The special master denied compensation; the Court of Federal Claims sustained the decision. Id. at 850. The petitioners appealed to the Federal Circuit, arguing “the special master failed to address their ‘challenge-rechallenge’ argument, i.e., their contention that the combination of the first 4 This is not to say a full Loving analysis will never be required for a challenge event. Under these facts and because petitioner only alleges the second HPV vaccination aggravated the condition, the full Loving analysis for off-Table significant aggravation claims is not required for the initial HPV dose and challenge event. See Tr. at 157:5–11 (“[PETITIONER]: . . . Petitioner’s claim is exclusively based on the second claim for compensation, based on the second vaccine, due to statute of limitations issues.”). The Court does not opine on a circumstance where multiple doses are alleged to have aggravated a preexisting condition. - 23 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 24 of 43 vaccination in February 2009, and the second vaccination, in August 2009, triggered or aggravated [the] condition.” Id. The Federal Circuit vacated the decision and remanded the case due to a factual discrepancy. The Federal Circuit instructed the special master to revisit causation because “the challenge/rechallenge theory is not frivolous.” Id. at 854.5 The Federal Circuit in Rickett requires petitioner’s evidence to be concrete and consistent with medical records. In Rickett, the petitioner alleged the hepatitis B vaccination caused fibromyalgia. Rickett v. Sec’y of Health & Hum. Servs., 468 F. App’x 952, 954 (Fed. Cir. 2011). The chief special master found the record did not support challenge-rechallenge; the Court of Federal Claims sustained the decision. Id. at 956. Petitioner appealed to the Federal Circuit, alleging “it was error to discount . . . expert testimony and reports regarding challenge-rechallenge to the extent they were based on [petitioner’s] testimony.” Id. at 958. The Federal Circuit affirmed this court because the special master did not err in “assign[ing] less weight to [the expert]’s conclusion regarding challenge-rechallenge to the extent it hinged upon [petitioner]’s testimony that was inconsistent with the medical records.” Id. The Federal Circuit reasoned the expert, relying on the medical records, indicated evidence of “a challenge event was ‘more speculative than real.’” Id. at 955. From Rickett, a petitioner’s evidence must be concrete and consistent with medical records. Id. The Court of Federal Claims in Nussman acknowledged the importance of timing in establishing a challenge event. See Nussman, 83 Fed. Cl. at 120. In Nussman, the petitioner alleged injuries from two hepatitis B vaccinations. Id. at 112. The special master denied the petition, finding the “petitioner did not fit within the ‘challenge-rechallenge’ paradigm because [the] petitioner did not experience adverse reactions to either hepatitis B vaccination.” Id. at 116. The Court of Federal Claims agreed the petitioner’s evidence on a challenge event was minimal, and the timing of the reactions did not fit within the challenge-rechallenge paradigm. Id. at 119–20. The court sustained the special master’s denial of compensation based on the challenge-rechallenge paradigm because the petitioner had not shown, by preponderant evidence, an adverse reaction—or challenge event—to the first vaccination and therefore could not experience a rechallenge. Id. at 120 (“There can only be rechallenge if there was an initial challenge and associated adverse reaction.”). From Nussman, a challenge event must be established and supported by appropriate timing. Id. Challenge-rechallenge failed in Bast because the asserted symptoms did not meet medical standards for challenge and rechallenge events. In Bast, this court sustained the special master’s rejection of the petitioner’s rechallenge argument. [M.S.B.] ex rel. Bast v. Sec’y of Health & Hum. Servs., 117 Fed. Cl. 104, 126 (Wolski, J.), appeal dismissed sub nom. M.S.B. ex rel. Bast v. Sec’y of Health & Hum. Servs., 579 F. App’x 1001 (mem.) (Fed. Cir. 2014). The special master in Bast found the challenge-rechallenge argument was “unavailing because petitioner offered little more than her own assertions regarding the vaccine-relatedness or the prior symptoms allegedly part of the rechallenge scenario.” Id. (internal quotations omitted). Further, the record, 5 On remand, the special master again denied compensation based on the timing of the symptoms and the underlying genetic mutation. Sanchez ex rel. Sanchez v. Sec’y of Health & Hum. Servs., 34 F.4th 1350, 1353 (Fed. Cir. 2022). The Court of Federal Claims sustained the decision, and the petitioners appealed. The Federal Circuit held the special master’s factual finding was unsupported and found the petitioners “satisfied [the] burden of showing Althen prongs 2 and 3.” Id. at 1356. - 24 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 25 of 43 and specifically the expert witness, did not discuss whether the reactions following the vaccinations met “the standards for rechallenge identified by the Institute of Medicine or, indeed, anyone.” Id. at 127. This court noted, “While a rechallenge event may be strong evidence of causality, petitioner has failed to show that the [c]hief [s]pecial [m]aster’s rejection of the rechallenge contention was arbitrary and capricious.” Id. From Bast, the asserted symptoms should meet medical standards for challenge or rechallenge events. See id. The Issac decision from this court demonstrates the importance of corroborating medical evidence and expert testimony to support the logical cause and effect of challenge-rechallenge. See Isaac v. Sec’y of the Dep’t of Health & Hum. Servs., 108 Fed. Cl. 743, 777 (Smith, J.), aff’d sub nom. Isaac v. Sec’y of Health & Hum. Servs., 540 F. App’x 999 (Fed. Cir. 2013). In Isaac, this court sustained the special master’s denial of compensation after finding the expert report and testimony was insufficient to support the challenge-rechallenge paradigm. Id. at 778–79. The special master in Isaac discredited the challenge-rechallenge paradigm when the “phenomenon . . . no longer [was] accepted by scientific experts as a link between” the vaccine and the injury. Id. at 777. In Isaac, without sufficient expert testimony and corroborating medical research, the special master did not find the medical theory persuasive. Id. Similarly, the testimony of treating physicians supports a finding of the logical sequence of cause-and-effect. In Capizzano, discussed supra, the Federal Circuit remanded for the special master to consider the opinions of the treating physicians because “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.’” Capizzano, 440 F.3d at 1326 (quoting Althen, 418 F.3d at 1280). Reading the statute and applying the principles of caselaw, to establish a challenge event by preponderant evidence, a special master must look at the whole record in the totality of the case to determine if more likely than not a challenge event—an adverse reaction—existed. While there is not one fact dispositive of an adverse reaction—nor a requirement to prove a certain number of factors—certain facts may assist a special master when determining whether the challenge event was more likely than not: (1) the timing of the onset of symptoms with a timeframe medically acceptable; (2) the timing of the rechallenge event; (3) the severity of symptoms following each of the vaccinations; (4) known adverse reactions; (5) similarities in symptoms and timing after each of the vaccinations; and (6) the similarities of etiologies and nature of conditions. See Capizzano, 440 F.3d at 1326; Sanchez, 809 F. App’x at 854; Rickett, 468 F. App’x at 958; Nussman, 83 Fed. Cl. at 120; Bast, 117 Fed. Cl. at 126–27; Isaac, 108 Fed. Cl. at 777–79. As prescribed by the Vaccine Act, facts must be supported by at least medical records or medical opinion, including treating physicians and expert testimony. See Capizzano, 440 F.3d at 1326; Sanchez, 809 F. App’x at 854; Rickett, 468 F. App’x at 958; Nussman, 83 Fed. Cl. at 120; Bast, 117 Fed. Cl. at 126–27; Isaac, 108 Fed. Cl. at 777–79. At oral argument, petitioner agreed with the list of non-exclusive factors, as long as it does not elevate the burden of proof. See Tr. at 142:4–144:8. Respondent also agreed with the non-exclusive factors but acknowledged challenge-rechallenge is “fundamentally a temporal relationship.” Tr. at 144:16–17. With the listed factors derived from caselaw as a guide, the Court next reviews the Special Master’s decision to determine if the Special Master’s determination of a challenge event is arbitrary and capricious. - 25 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 26 of 43 VI. Whether the Special Master Erred in Determining Petitioner Satisfied Loving Prongs Five and Six After determining the Special Master did not err in allowing petitioner to use the challenge-rechallenge paradigm, see supra Section V, the Court reviews the Special Master’s determination of causation. While the Special Master determined the proximate temporal relationship first, the Court reviews the Special Master’s analysis of the challenge event, Loving prong five, infra Section VI.A, and then looks at the Special Master’s analysis of Loving prong six, the proximate temporal relationship, infra Section VI.B. A. Whether the Special Master Erred in Determining Petitioner Established a Challenge Event for Loving Prong Five The parties agree a challenge is an adverse reaction to a foreign antigen—in this case a vaccine—and must be established by petitioner to rely on the challenge-rechallenge paradigm. Tr. at 68:1–9 (“THE COURT: [I]n order to establish a challenge event, does there have to be an adverse reaction to a vaccination? [PETITIONER]: An adverse reaction to whatever it is, in this instance, a vaccination, yes. . . . [RESPONDENT]: Certainly. [Respondent] agrees that’s necessary.”); see 2023 Mot. for Review at 7–9 (citing Nussman v. Sec’y of Health & Hum. Servs., 83 Fed. Cl. 111, 120 (2008)). The parties, however, disagree on whether the Special Master adequately analyzed the alleged challenge event. The 2007 seizures are central to the dispute between the parties. Respondent asserts there is no evidence supporting a presumption the 2007 waking seizures were different from nocturnal seizures in severity. 2023 Mot. for Review at 9. Respondent argues there consequently is no evidence to support the first HPV vaccination was a challenge event, i.e., Ms. Mager’s seizures were worse after the first HPV dose. Id. At oral argument, respondent argued the Special Master failed to create an adequate record regarding the waking seizure of 14 November 2007 and all of respondent’s arguments, which in turn violates VRCFC 3(b)(2).6 Tr. at 155:10–14, 156:4–16 (“[RESPONDENT]: . . . [T]he argument was made in my post-hearing brief to the Court that [Dr.] Shafrir’s casting this November 14th waking seizure as being a significant aggravation was not supported by the evidence in the record. And [the Special Master] didn’t analyze it, he didn’t address it, there’s no discussion of . . . how he weighed that evidence.”). Respondent further argued the Special Master deemphasized the 2007 waking seizure because it “wasn’t part of [the] claim.” Tr. at 156:17–21 (“[RESPONDENT]: . . . I would submit that because [the Special Master] made a determination that [the 2007 waking seizure] was less significant due to the statute of limitations, that [the 2007 waking seizure] wasn’t part of [the] claim, [the Special Master] didn’t feel that he had to analyze whether or not there was a significant aggravation. . . .”). Respondent argues the 14 November 2007 seizure was important because it was not factually a challenge event. Respondent asserts, given the Special Master’s finding of a preexisting seizure disorder, there is no significant difference before and after the 14 November 6 VRCFC 3(b)(2) details the role of the special master in “creating a record sufficient to allow review of the special master’s decision.” - 26 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 27 of 43 2007 vaccination and therefore no challenge event. See Tr. at 111:14–112:8 (“THE COURT: So your argument . . . is that there’s nothing significantly different about November 14th, 2007. [RESPONDENT]: Other than the fact that she was awake, the description of the seizure from Dr. Shafrir was that this seizure was not severe, and that none of her seizures were severe. . . . There’s no way to discern that [the muscle soreness, drooling, enuresis, and tongue-biting were] not a generalized tonic-clonic seizure that she was having nocturnally. There’s no basis to infer one way or the other. . . . [T]hat is the factual problem in this case. The only difference that we know is that on the 14th of November, she was awake.”). Respondent refers to petitioner’s expert testifying the 14 November 2007 “seizure was not severe, and that none of her seizures were severe.” Id. The lack of change in severity therefore fails to establish a challenge event, according to respondent. See id. Petitioner claims respondent “mischaracterizes the Special Master’s assertion as irrelevant,” but “the Special Master is merely stating that [p]etitioner is not claiming an independent injury from the first dose of HPV vaccination.” Pet’r’s Resp. at 14. Petitioner defends the Special Master’s factual analysis by pointing to: (1) the discussion of facts; (2) Ms. Mager’s health prior to and after the first vaccination; and (3) expert testimony. Id. at 15. Regarding the severity of the seizures, petitioner avers the record demonstrated significant aggravation following the first dose of the HPV vaccination. Id. at 16; see Tr. at 157:21–159:2 (petitioner summarizing the evidence the Special Master considered). The Court reviews the Special Master’s finding the evidence supports a challenge event using the arbitrary and capricious standard because it was a finding of fact. See Saunders v. Sec’y of Dep’t of Health & Hum. Servs., 25 F.3d 1031, 1033 (Fed. Cir. 1994) (quoting Munn v. Sec’y of Dep’t of Health & Hum. Servs., 970 F.2d 863, 870 n.10 (Fed. Cir. 1992)). It is not the Court’s role “to reweigh the factual evidence[] or to assess whether the special master correctly evaluated the evidence.” Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d 1357, 1360 (Fed. Cir. 2000) (internal quotes omitted) (quoting Munn, 970 F.2d at 870 n.10). As stated supra Section V.C, to establish a challenge event by preponderant evidence, a special master must look at the whole record in the totality of the case to determine if more likely than not an adverse reaction existed. While no one fact is dispositive of an adverse reaction, certain facts may assist a special master when determining whether the challenge event was more likely than not. The Special Master reviewed the timeline based on Ms. Mager’s medical history in both his analysis and factual sections. See Ruling Finding Entitlement at 48–49; Tr. at 98:8–100:18 (petitioner explaining where the Special Master analyzed the timeline and challenge event). The Special Master laid out a chronology of events in the below table explaining Ms. Mager “experienced worse seizures within an appropriate amount of time after the vaccination to conclude that she experienced challenge-rechallenge.” Ruling Finding Entitlement at 48. Date Event Approximate onset of tongue biting, which is evidence of a seizure. In addition, 9/14/2007 by this time, [Ms. Mager] was having episodes of bedwetting. 10/2/2007 First HPV vaccination. 11/14/2007 First generalized tonic-clonic seizure. A nearly five-year period in which no seizures are reported, consistent with Dr. - 27 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 28 of 43 Shafrir’s opinion on dechallenge. 9/11/2012 Second HPV vaccination. 10/12/2012 The first of three seizures, leading to a prescription for anti-seizure medication. Id. at 48–49. The chronology begins on 14 September 2007 with observations of tongue biting and bedwetting, which the Special Master determined to be “evidence of a seizure.”7 Id. at 48. The Special Master based his factual finding on medical records and testimonies of Ms. Mager’s parents and the experts. Id. at 2–6 (“[A] preponderance of evidence supports placing the tongue biting before the vaccination. Furthermore, there is no meaningful dispute that tongue biting can be a symptom of a seizure.”). Following the 2 October 2007 vaccination, the Special Master chronologized the tonic-clonic seizure on 14 November 2007. Id. at 48. The Special Master explained Ms. Mager “experienced a seizure and was taken to the emergency room,” where she had a second seizure. Id. at 7–8. Based on the admission notes, “[h]er extremities shook, her eyes rolled, [and] her face turned blue briefly.” Ruling Finding Entitlement at 7. The Special Master observed “[t]he histories given during this hospitalization shed some light on [Ms. Mager]’s health leading up to the tonic-clonic seizure for which she was treated in the hospital.” Id. at 8. The Special Master acknowledged the medical records and testimony of Ms. Mager’s father who indicated she was a “previously healthy [female with] new onset [of seizures],” yet medical histories also indicate Ms. Mager previously had nocturnal seizures. Id. The Special Master included the fact Ms. Mager was prescribed an anti-seizure medication and recommended for a follow-up with a neurologist. Id. at 9. Based on the medical records, the Special Master indicated Ms. Mager had a “similar tonic-clonic generalized seizure while sleeping” lasting “approximately one minute and then she was unconscious for approximately five minutes.” Id. The medical records indicate Ms. Mager was weaned off her anti-seizure medication in March 2008 at the request of her parents. Id. at 9–10. The next important event on the Special Master’s timeline is the “nearly five-year period in which no seizures were reported, consistent with Dr. Shafrir’s opinion on dechallenge.” Ruling Finding Entitlement at 48. The Special Master explained Dr. Shafrir “emphasized that [Ms. Mager] was seizure-free for nearly five years. During this period, she likely experienced 7 Petitioner clarified at oral argument petitioner alleged the vaccinations caused the seizure disorder or, in the alternative, significantly aggravated the seizure disorder. Tr. at 61:23–62:5 (“THE COURT: . . . Looking at the Special Master decision, page 16, footnote 12, the Special Master states the petitioner argues ‘the 2012 vaccination significantly aggravated the seizure disorder,’ but then he also says the 2012 vaccination caused [Ms. Mager]’s seizure disorder . . . . [PETITIONER]: We were arguing [in] the alternative.”). Regardless of the theory, petitioner argued the underlying theory was the same: challenge-rechallenge. Tr. at 63:12–23 (“THE COURT: . . . [W]hat’s described in the Special Master’s footnote 12, is that just based on different theories . . . than where you’re at now? [PETITIONER]: No. . . . [I]f the Special Master found that the seizures occurred prior to 2007, then . . . it would be a significant aggravation case. If not, then it was a new onset . . . . But we were still looking at the challenge-rechallenge.”). The Special Master found the evidence “favors a finding that [Ms. Mager] was biting her tongue before vaccination” based on the statements made by Ms. Mager’s parents to the neurologist, and therefore the record was analyzed as a significant aggravation claim. Ruling Finding Entitlement at 4. Petitioner now argues only a significant aggravation claim. Tr. at 67:12–25 (“THE COURT: What the Special Master says is ‘the 2012 vaccination . . . caused the seizure disorder.’ . . . But that’s different now. . . . [PETITIONER]: Yes. Significant aggravation is what we are arguing, yes. And, again, to be clear, the 2012 [new onset argument] was simply on the placement of when [Ms. Mager’s parents] thought the tongue-biting had occurred.”). - 28 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 29 of 43 stress and likely was deprived of sleep at least sometimes. However, she did not experience seizures. This seizure-free time helps Dr. Shafrir isolate the vaccinations as the triggers for [Ms. Mager]’s seizures.” Id. at 12 (internal citation omitted). The Special Master acknowledged respondent’s expert Dr. Kohrman’s lack of confidence Ms. Mager “did not experience seizures during these approximately five years” but gave less weight to the assertion because the records from Dr. Budde—Ms. Mager’s primary care doctor at the time—did not indicate seizures. Id. at 12, 12 n.10. Review of the Special Master’s decision demonstrates the Special Master relied on medical records and the testimonies of Ms. Mager’s parents, Ms. Mager’s treating physicians, and the experts in determining an adverse reaction followed the first HPV vaccination. Indeed, because the Special Master relied heavily on medical records and testimony, it is difficult to accuse the challenge event of being “more speculative than real.” See Rickett v. Sec’y of Health & Hum. Servs., 468 F. App’x 952, 958 (Fed. Cir. 2011). Unlike Rickett, the adverse event was well-documented and consistent with the medical records. The medical records and the testimonies of parents, physicians, and experts evidence the challenge event, whereas in Rickett the challenge event was mere speculation. Id.; see Tr. at 94:8–22 (“THE COURT: . . . [W]hat separates this case from Rickett? [PETITIONER]: Well, there is no question as to the adverse event in this case. There’s no sort of amorphous presentation of a symptom. . . . [In Rickett,] the testimony was inconsistent with the medical records . . . .”). Further, unlike Sanchez, the expert’s testimony is consistent with the medical records and within an appropriate challenge-rechallenge timeline, especially as it relates to the dechallenge period. Sanchez ex rel. Sanchez v. Sec’y of Health & Hum. Servs., 809 F. App’x 843, 854 (Fed. Cir. 2020). At oral argument, respondent argued characterizing the five-year, seizure-free period could be misleading because nocturnal seizures were difficult to see. See Tr. at 153:25–155:9 (“THE COURT: . . . [W]ouldn’t the absence of seizures for five years after a short period of time with three or more instances support a challenge event? . . . [RESPONDENT]: . . . [T]he problem in terms of evaluating that is you have a chronic condition. . . . [I]t’s certainly not rare for somebody to go five years without experiencing a seizure. And then you have to add to that the fact that the seizures that she had previously been having were largely nocturnal. . . . She very well could have had nocturnal seizures . . . that just were not witnessed.”). The Special Master, however, observed the seizure-free period, likely during some time of stress and sleep deprivation, was alluded to by the medical records. Ruling Finding Entitlement at 12. The Special Master credited the medical records as accurate and the fact there was no indication of seizures during the five-year period as evidence of the seizure-free period. The iteration of facts before and after the first vaccination illustrates the Special Master distinguished the severity of the seizures before and after the first HPV vaccination. In Rickett, petitioner was reporting the same symptoms before and after the vaccination, so the timing of the symptoms did not fit into the challenge-rechallenge paradigm. Rickett, 468 F. App’x at 958. Respondent, at oral argument, questioned whether there was a change in the seizures because there was no record of frequency prior to the first vaccination. Tr. at 151:15–18. Petitioner emphasizes “the Special Master made a distinction in this case between the nocturnal tongue-biting . . . representing the onset of . . . the original seizure disorder prior to the 2007 vaccination, and the daytime generalized tonic-clonic seizure, which is a completely different - 29 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 30 of 43 type of seizure.” Tr. at 95:19–96:4. The Court agrees the record supports the Special Master’s distinction between Ms. Mager’s condition before and after the first HPV vaccination. The Special Master acknowledged the medical records and testimony indicate Ms. Mager was a “previously healthy [female with] new onset [of seizures].” Ruling Finding Entitlement at 8. After the first vaccine dose, the Special Master detailed Ms. Mager rushing to the emergency room for the first observed tonic-clonic seizure followed by a second seizure at the hospital. Id. at 7–8. Further, the treating physicians viewed the seizures differently, illustrated by prescribing anti-seizure medication and establishing routine care with a neurologist following the 14 November 2007 seizure. Id. at 9–10; see Tr. at 112:17–113:14 (“THE COURT: . . . [W]as the November 14th, 2007, generalized tonic-clonic seizure a significant event that was different than previous items in the record [like bedwetting, drooling, and tongue-biting]? [PETITIONER]: Yes . . . . THE COURT: . . . What in the record demonstrates that? [PETITIONER]: Because . . . [t]he treating doctors don’t directly relate [the bedwetting] to [the seizures]. She has generalized soreness, but . . . we don’t know what that’s from. . . . [T]he parents reported back, she had woken up a couple of mornings [having] bitten her tongue, which is . . . significantly less than having a full-on generalized tonic-clonic seizure, which . . . causes you to turn blue and need to be resuscitated. If they were the same, there’s . . . the serious issue as to whether she would have woken up . . . which she did in prior seizures.”), 120:4–121:2 (“[PETITIONER]: . . . Dr. Sharif . . . is her pediatric neurologist after she’s already been diagnosed with epilepsy. . . . That can change the entire scenario of what the seizure disorder looks like at that point . . . . [The Magers] weren’t referred to a pediatric neurologist at that point [with only tongue-biting and bedwetting]. [The Magers were referred] only after a witnessed . . . generalized tonic-clonic seizure, which is different. It’s a different type of seizure affecting a different part of the brain. . . . [Y]ou need to take into consideration that [Dr. Sharif’s records were] post-diagnosis of the epilepsy, which she hadn’t had . . . prior.”). Even with the Special Master finding the seizure disorder predated the first vaccination, the Special Master’s narrative of Ms. Mager’s condition following the first HPV vaccination tells of a change in condition. The challenge-rechallenge paradigm has a chicken-or-egg-type problem: should the challenge or rechallenge event be established first? Petitioner asserts “the challenge event comes first. . . . But you don’t know necessarily that . . . is an adverse event to a medication . . . until the dechallenge period and a rechallenge.” Tr. at 114:13–19. In other words, hindsight is used to establish the challenge event by comparing the reactions after subsequent doses of a vaccine. See also Nussman, 83 Fed. Cl. at 120 (“There can only be rechallenge if there was an initial challenge and associated adverse reaction.”). The Special Master compared the circumstances and severity of the symptoms following the first and second HPV doses. In the Special Master’s chronology, the sixth event, following the second vaccination, was “[t]he first of three seizures leading to a prescription for anti-seizure medication.” Ruling Finding Entitlement at 49. Citing medical records and testimony, the Special Master found “[i]t appear[ed] that [Ms. Mager] experienced two other seizures for which she did not seek medical attention emergently” and “reported two additional seizures following her emergency room visit.” Id. at 12–13. The similarities of symptoms in the record—mainly the occurrence of more severe seizures—following both vaccinations are indicative of the challenge-rechallenge paradigm, as the Special Master found. The challenge analysis also looks at the timing of the adverse reactions after each of the - 30 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 31 of 43 vaccinations. See Nussman, 83 Fed. Cl. at 120. The Special Master noted the period between the first HPV vaccination and seizures is 43 days; “[f]or the second HPV vaccination, the latency is 29 days.” Ruling Finding Entitlement at 31–32. Respondent acknowledged, at oral argument, the Special Master analyzed the challenge related to timing but disputed the established timeframe. See infra Section VI.B. The timing of the adverse reactions following both vaccinations supports the establishment of a challenge event. See Nussman, 83 Fed. Cl. at 120. Like in Capizzano, the Special Master also considered the testimony of medical professionals and expert witnesses. See Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006). Specific to treating physicians, the Special Master explained Dr. Sharif treated the first observed seizure as a different type of seizure, prescribing medication, and suggested Ms. Mager “might be a candidate for surgery.” Ruling Finding Entitlement at 9. The Special Master further considered the testimony of Dr. Koehn and ultimately decided “Dr. Koehn’s July 2008 statement carries less weight because Dr. Koehn expressed [his opinion the HPV vaccination was not related to the seizure] before [Ms. Mager] received her second vaccination.” Id. at 53. In summary, the Special Master performed a full, albeit segmented, analysis of the challenge event. The Special Master reviewed the medical records—which were consistent with the opinions of the treating physicians—and the testimony of expert witnesses. From his analysis of the record, the Special Master determined the 2007 HPV vaccination constituted an adverse event and consequently a challenge event when viewed in tandem with the symptoms following the 2012 HPV vaccination; the record supports the establishment of a challenge event by preponderant evidence. See Capizzano, 440 F.3d at 1326; Sanchez, 809 F. App’x at 854; Rickett, 468 F. App’x at 958; Nussman, 83 Fed. Cl. at 120; [M.S.B.] ex rel. Bast v. Sec’y of Health & Hum. Servs., 117 Fed. Cl. 104, 126–27, appeal dismissed sub nom. M.S.B. ex rel. Bast v. Sec’y of Health & Hum. Servs., 579 F. App’x 1001 (mem.) (Fed. Cir. 2014); Isaac v. Sec’y of the Dep’t of Health & Hum. Servs., 108 Fed. Cl. 743, 777–79, aff’d sub nom. Isaac v. Sec’y of Health & Hum. Servs., 540 F. App’x 999 (Fed. Cir. 2013). The Special Master did not err in finding a challenge event, nor did the Special Master violate VRCFC 3(b)(2). B. Whether the Special Master Erred in Determining Petitioner Satisfied a Proximate Temporal Relationship for Loving Prong Six The parties dispute the proximate temporal relationship established by the Slade article and supported by the Vaccine Injury Table. Respondent argues the determination “the timing here supports a finding that Ms. Mager experienced a challenge event following her October 2, 2007 vaccination is also deeply flawed.” 2023 Mot. for Review at 12. Respondent asserts the Slade article, which the Special Master relied upon for a “window of plausibility,” is not “related to the alleged injury in this case.” Id. Additionally, respondent points out petitioner’s expert “had no opinion as to what made [four] to 42 days ‘biologically plausible.’” Id. Respondent also criticizes the Special Master’s citation of the Vaccine Injury Table as support for the timing. Id. at 12–13. Respondent acknowledges the Vaccine Injury Table may be helpful but argues “the Special Master did not explain how the Table timeline for onset of GBS following influenza vaccination is relevant to the development of waking seizures following an HPV vaccination.” Id. at 13. Respondent contends the Special Master did not “provide[] a rational basis for - 31 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 32 of 43 selecting a timeframe generally ascribed to the development of a peripheral demyelinating condition—GBS—as opposed to some other timeframe contained in the Vaccine Injury Table.” Id. at 14. Respondent specifically disputes the timing of the second HPV dose supporting a rechallenge event. 2023 Mot. for Review at 14. Respondent argues the review articles relied upon by petitioner’s expert are contrary to the facts, and the Special Master erred in giving them credence. Id. at 15. Respondent asserts the “Special Master further erred in rejecting the testimony of respondent’s expert immunologist, Dr. Fujinami, as to timing.” Id. at 15 n.4. In defending the Slade article, petitioner explains “GBS is, in fact, an autoimmune disease” and a GBS comparison is therefore applicable as evidence of the timing being “biologically plausible.” Pet’r’s Resp. at 17. Petitioner asserts while the Vaccine Injury Table is “not dispositive,” it “can be properly relied upon” as the Special Master did after citing cases using the Vaccine Injury Table as support for timing. Id. at 18. Petitioner contends the Special Master’s choice of the GBS-flu vaccine temporal window was not arbitrary and capricious because “it was based on expert testimony and scientific studies” and provided “additional[] though unnecessary support.” Id. at 18–19. Petitioner argues the Special Master was allowed to extend the support timeline by one day because the Federal Circuit “has admonished special masters not to set ‘hard and fast deadlines.’” Id. at 19 (quoting Paluck v. Sec’y of Health & Hum. Servs., 786 F.3d 1373, 1383–84 (Fed. Cir. 2015)). Petitioner rebuts respondent’s implications the Special Master “failed to consider Dr. Fujinami’s testimony” and states the Special Master correctly observed neither of the respondent’s experts “addressed timing in their original or supplemental reports” or rebutted the timing proposed by petitioner. Id. At oral argument, the parties disagreed on the persuasiveness of Slade. Respondent argued Slade is unpersuasive because “Slade actually didn’t even report a single instance of a seizure following the HPV vaccination.” Tr. at 160:9–25. Respondent, however, stated, “there is reference to seizures, but there’s no timeframe of when they were reported, and it’s not clear whether or not the onset of seizures was even reported to the authors, but there’s nothing in there that would support 42 days.” Tr. at 160:20–25. Respondent argued against Slade as persuasive evidence because the study “only reference[s four to 42 days] with respect to reports in the system of transverse myelitis and [GBS],” and therefore the authors “did not in any way, shape, or form apply that medically plausible timeframe to all of the incidents that they were reporting on.” Tr. at 161:25–162:2, 162:13–15. The broad timeframe in Slade, according to respondent, does not account for Ms. Mager’s specific adverse reaction. See Tr. at 167:16–168:1. Respondent argued a generalized window of adverse reactions is not supported by law. Tr. at 167:6–15 (“[RESPONDENT]: . . . [A] general causal window of anything that’s 42 days . . . I don’t believe would satisfy Althen prong three, especially given the fact that there’s not a single report here or anywhere in the record of a seizure following a vaccination . . . .”). Petitioner asserted the Slade article is persuasive because it talks about “an autoimmune reaction to an immunization, and that’s what we’re referring to here. . . . It’s the type of reaction and how long that reaction takes.” Tr. at 165:2–6. Petitioner further said it would be impossible to have studies with an exact timeline to show causality because the Food and Drug Administration would pull the vaccine prior to such a severe result. Tr. at 165:11–25. Additionally, at oral argument, the parties contested whether the Vaccine Injury Table can be used. Petitioner clarified the Special Master did not rely entirely on the Table to establish - 32 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 33 of 43 a medically acceptable timeline; the Special Master rather used the Table as supporting evidence of the timeframe established in Slade. Petitioner explained, “The development of the timing required for an onset of an autoimmune reaction is similar . . . in both instances [because they are both autoimmune].” Tr. at 166:7–11. Dr. Shafrir, in citing the Vaccine Injury Table, pointed to “another example where that type of timing for autoimmune reaction has been accepted as medically appropriate.” Tr. at 166:12–16. Respondent argued “it’s fairly well understood . . . in the law that the petitioner cannot rely on similar conditions or timeframes within the Table to make out a causation in fact claim. . . . [I]f they can’t rely on similar conditions and timeframes, then certainly it’s not appropriate for the Special Master to rely on dissimilar injuries and dissimilar timeframes.” Tr. at 141:8–14. Respondent also emphasized the Stanley study, which spoke to the development of antibodies following the HPV vaccination, rebuts the four to 42 days timeframe. Tr. at 166:20–167:3. Loving prong six, or the proximate temporal relationship prong, “requires preponderant proof that the onset of symptoms occurred within a timeframe for which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation-in-fact.” de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). “Strong temporal evidence is even more important in cases involving contemporaneous events other than the vaccination, because the presence of multiple potential causative agents makes it difficult to attribute ‘but-for’ causation to the vaccination.” Pafford v. Sec’y of Health & Hum. Servs., 451 F.3d 1352, 1358 (Fed. Cir. 2006). As the Federal Circuit has cautioned, and as discussed supra Section V.A, an underlying biological mechanism is not required by the Vaccine Act. The Special Master first relied on the Slade article to establish a medically acceptable timeline. Ruling Finding Entitlement at 37 (citing Slade, supra, at 754). The Special Master found “persuasive evidence comes from Slade. When Slade and colleagues were attempting to discover whether the HPV vaccination caused any adverse effects, they used the period of [four] to 42 days as biologically plausible.” Id. The Special Master stated Dr. Shafrir “concluded without elaboration: ‘The timeframe of the appearance of the seizure and encephalopathy is within the range of other HPV vaccination reaction[s]. It happened twice within the same time range.’” Id. at 32. The Special Master also noted respondent’s two experts did not “question[] the timing in their responsive reports,” and respondent did not challenge the timing in pre-hearing briefing. Id. at 32–33. The Special Master explained “the Slade study, by itself, justifies crediting Dr. Shafrir’s opinion regarding timing.” Id. at 37. The objective of the Slade article was “[t]o summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of [the quadrivalent HPV vaccine (qHPV)].” Slade, supra, at 750. Slade and his contributing authors “review[ed] and describe[d] adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system. . . . Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that received public attention.” Id. Respondent asserts the study is unpersuasive because it is not specifically narrowed to Ms. Mager’s specific symptom of seizures. The fact the Slade article encompasses many adverse events does not make it unpersuasive. The parties agree challenge-rechallenge is an adverse reaction. The Slade article details the spectrum of adverse reactions. Id. The Slade article therefore encompasses the many adverse outcomes associated with a challenge-rechallenge - 33 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 34 of 43 paradigm. To require “medical literature or epidemiological evidence to establish causation” is contrary to the Vaccine Act—nonetheless to require symptom-specific medical literature. Andreu ex rel. Andreu v. Sec’y of Dep’t of Health & Hum. Servs., 569 F.3d 1367, 1379 (Fed. Cir. 2009). The timeframe relied upon in Slade is not randomly selected either. The study reviewed reactions from the HPV vaccination “[b]ased on a 6-week window of biological plausibility after immunization.” Slade, supra, at 751. Slade noted “[g]iven the association of GBS with the 1976 swine influenza vaccine and more recently with quadrivalent meningococcal conjugate vaccine, there has been concern regarding the possibility of an association between GBS and other vaccines, including qHPV.” Id. (footnote omitted). At oral argument, respondent attempted to discredit Slade because of the now discredited Pollard Selby study. See Tr. at 21:15–22:21. Petitioner argued the fact the Pollard Selby study relating to challenge-rechallenge was discredited for GBS and tetanus does not discredit the Slade article because “challenge-rechallenge is [a] completely . . . independent thing that can be applied to any medication or anything.” Tr. at 138:21–23. Respondent further did not proffer evidence rebutting the Slade article. Ruling Finding Entitlement at 32–33. Given the evidence in front of the Special Master, it was reasonable to credit the Slade article. See Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d 1357, 1360 (Fed. Cir. 2000) (quoting Munn, 970 F.2d at 870 n.10) (stating the court should not “reweigh the factual evidence[] or . . . assess whether the special master correctly evaluated the evidence”). In addressing Dr. Fujinami’s opinions regarding timing, the Special Master stated his “opinions regarding timing are not credited” because Dr. Fujinami “did not indicate that timing was a problem in his reports,” and the “lack of disclosure is inconsistent with how the Vaccine Program usually operates.” Ruling Finding Entitlement at 38–39. The Special Master gave less weight to Dr. Fujinami’s opinions because he “did not present literature supporting his position.” Id. at 39. The Special Master acknowledged literature is not required in Vaccine cases but also noted “a scientific theory that lacks any empirical support will have limited persuasive force.” Id. at 39 (quoting Caves v. Sec’y of Dep’t of Health & Hum. Servs., 100 Fed. Cl. 119, 134 (2011), aff’d sub nom. Caves v. Sec’y of Health & Hum. Servs., 463 F. App’x 932 (Fed. Cir. 2012)) (citing Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1280–81 (Fed. Cir. 2005)). The Court’s role is “not [to] reweigh the factual evidence, assess whether the special master correctly evaluated the evidence, or examine the probative value of the evidence or the credibility of the witnesses—these are all matters within the purview of the fact finder.” Porter v. Sec’y of Health & Hum. Servs., 663 F.3d 1242, 1249 (Fed. Cir. 2011). The credibility of witnesses lays squarely within the purview of the Special Master, and the Court cannot “reweigh” the credibility but can only look to see if the Special Master’s decision was arbitrary and capricious. Id. The Special Master explained Dr. Fujinami’s testimony was not credited because of procedural issues and lack of support from other sources; the Special Master’s weighing of Dr. Fujinami’s testimony was not arbitrary and capricious. See id. Respondent also argues the Special Master could not rely on the Vaccine Injury Table. The Special Master, however, did not rely on the Vaccine Injury Table to establish a timeframe - 34 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 35 of 43 but stated “the Slade study, by itself, justifies crediting Dr. Shafrir’s opinion regarding timing” and “additional support comes from the Vaccine Injury Table.” Ruling Finding Entitlement at 37. The Special Master expressly stated the Vaccine Injury Table is “additional support,” and the Court does not find the reference to the Vaccine Injury Table to be arbitrary and capricious. The Special Master found, after crediting a four to 42 day timeframe, the timeframe “may be reasonably expanded to 43 days.” Id. at 38 (citing Paluck, 786 F.3d at 1383–84). Given the Special Master found the Slade article persuasive and the onset of seizures was within the medically acceptable timeframe, the Special Master was not arbitrary and capricious to conclude petitioner satisfied Loving prong six; the Court finds no error. See Porter, 663 F.3d at 1249. VII. Whether Petitioner Showed Ms. Mager’s Death Was a Sequela of the Significantly Aggravated Seizure Disorder to Satisfy a Prima Facie Case of Causation The parties dispute whether the burden properly shifted to respondent. Hidden in respondent’s argument is the notion of requiring petitioner to prove not only the vaccination significantly aggravated the seizure disorder but also the significantly aggravated seizure disorder caused Ms. Mager’s death. The Court notes respondent’s Motion for Review dedicated a mere three paragraphs to the unrelated factor issue, much of which was block quotes from other sources. At oral argument, respondent expounded on the argument. See Tr. at 168:20– 170:1. In addressing the argument, the Court first determines if petitioner properly established the HPV vaccine was a “substantial factor” in Ms. Mager’s death, causing the burden to shift to respondent. Respondent argues “the Special Master erroneously shifted the burden to respondent to disprove . . . Ms. Mager’s September 11, 2012 HPV vaccination caused her death.” 2023 Mot. for Review at 19. Respondent, referencing petitioner’s expert, asserts Ms. Mager’s death was a result of SUDEP and not correlated to the vaccination. Id. at 20. Respondent argues because petitioner’s expert “disavowed any relationship between Ms. Mager’s vaccinations and her SUDEP, and given the Special Master’s finding that the HPV vaccine did not cause Ms. Mager’s epilepsy, the Special Master erred in shifting the burden to respondent to establish that Ms. Mager’s death was the natural result of her epilepsy and finding respondent failed to meet that burden.” Id. Petitioner, citing Walther, explains “the burden shifts to [respondent] under the ‘factor unrelated’ inquiry to show that the pre-existing condition caused the significantly worsened condition.” Pet’r’s Resp. at 23 (citing Walther v. Sec’y of Health & Hum. Servs., 485 F.3d 1146, 1151 (Fed. Cir. 2007)). Petitioner maintains he met the burden of proof, and therefore the burden “shifts to [r]espondent to prove an alternative cause, e.g. the natural course of the disease, for either [Ms. Mager’s] epilepsy post the second vaccination or her subsequent death.” Id. Petitioner asserts the Special Master “discussed the evidence related to [Ms. Mager’s] death specifically[,] found the [r]espondent failed to meet [its] burden,” and therefore did not err. Id. at 24 (citing Ruling Finding Entitlement at 55). At oral argument, respondent explained: petitioner had not met the burden of proving the vaccination caused Ms. Mager’s death, and therefore the burden should not have shifted. - 35 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 36 of 43 Respondent’s contention at oral argument centered around Dr. Shafrir’s testimony, which asserted there was no correlation between the HPV vaccine and SUDEP. Respondent consequently argued petitioner did not connect Ms. Mager’s death with the vaccination and did not meet his burden of causation. Tr. at 168:20–169:6 (“[RESPONDENT]: [A]s you say that back to me, that’s not . . . the point that I’m making. . . . [T]he point is that the death does not appear to be a consequence of the vaccination. . . . [A] death is an injury. The petitioner bears the burden of proving that the vaccine brought about the injury. . . . [I]n this case the only causal theory was challenge/rechallenge. And if you accept that theory and you accept 42 days, well, the death did not occur within 42 days. So how does the vaccine cause the death?”). Petitioner explained SUDEP is associated with epilepsy, and the vaccination significantly aggravated the epilepsy, so the death is connected to the vaccine, albeit once removed in the chain. Petitioner also asserted, from Sharpe, death is not a defense. See Tr. at 172:2–15 (“[PETITIONER]: . . . [T]he defense of a natural course of a disease[] is not a defense under the Federal Circuit’s ruling in Sharpe.”). Petitioner maintained the Special Master “found that the vaccine caused the significant aggravation of her epilepsy and that . . . resulted in her death.” Tr. at 180:16–181:4 (“[PETITIONER]: . . . [T]he significant issue is seizure-free versus ongoing seizures . . . none of the treating doctors separated . . . her death from the seizures that she had post the second vaccination. That’s the same course. THE COURT: It was all consistent. [PETITIONER]: It’s all consistent, yeah. And there’s no requirement, no burden on petitioner, to show that the death occurs within a short period of time following vaccination. You have to draw a direct line. There is a direct line. The Special Master found that the vaccine caused the significant aggravation of her epilepsy and that . . . resulted in her death.”). To successfully establish a vaccine injury claim, a petitioner must show the vaccination was the cause of the injury or death. H.L. ex rel. A.I. v. Sec’y of Health & Hum. Servs., 715 F. App’x 990, 994 (Fed. Cir. 2017) (citing Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1341 (Fed. Cir. 2010)); 42 U.S.C. § 300aa-11(c). For the Vaccine Program to compensate a petitioner, the Vaccine Act requires the petitioner, by preponderant evidence, to “demonstrate[] that the person who suffered such injury or who died . . . sustained, or had significantly aggravated, any illness, disability, injury, or condition not set forth in the Vaccine Injury Table which was caused by a vaccine.” § 300aa-11(c)(1)(C)(ii)(I). In short, to recover for significant aggravation, petitioner must prove the vaccine caused the significant aggravation of the underlying disease and death. See Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351 (Fed. Cir. 2019). Federal Circuit caselaw has long established “[r]ecovery for a death following a . . . vaccination based on a Table claim is conditioned upon the death being a sequela of an illness or condition listed in [the Vaccine Injury Table] ‘which arose within the time period prescribed’ in the Table for that illness or condition.” Hellebrand v. Sec’y of Dep’t of Health & Hum. Servs., 999 F.2d 1565, 1570 (Fed. Cir. 1993) (emphasis added). In Hellebrand, petitioner alleged a Table vaccine-related injury which ultimately resulted in sudden infant death syndrome (“SIDS”). Id. at 1566. The special master found the petitioner was not entitled to recovery, while this court determined the petitioner was entitled to recovery. Id. at 1567–69. On appeal, the Federal Circuit held the petitioner could not recover for the death of the child because the petitioner was required to show the injury occurred within the timeframe in the Table and the subsequent “death was a sequela of” the injury. Id. at 1570. - 36 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 37 of 43 The Vaccine Act allows for compensation for both Table and off-Table injuries and subsequent deaths which are caused or significantly aggravated by a vaccination. Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005) (“The Act provides for the establishment of causation in one of two ways: through a statutorily-prescribed presumption of causation upon a showing that the injury falls under the Vaccine Injury Table . . . or where the complained-of-injury is not listed in the Vaccine Injury Table . . . , by proving causation in fact . . . .”). It is therefore a natural extension of Hellebrand to require “death [to be] a sequela of” the off-Table injury for petitioner to be entitled to compensation of a death. Id.; 999 F.2d at 1570. Where the aggravated condition ultimately leads to death, petitioner must provide a link between the aggravated state and the death. Hellebrand, 999 F.2d at 1569–70; see 42 U.S.C. § 300aa-11(c)(1)(A), (c)(1)(C)(i), (c)(1)(C)(ii)(I); see also Shyface v. Sec’y, Health & Hum. Servs., 165 F.3d 1344, 1352 (Fed. Cir. 1999) (holding when an injury or death is found to have multiple causes, a petitioner need not prove the vaccination was the principle or predominant cause but only a “substantial factor” in causing the injury or death). Petitioner here alleges not only significant aggravation of the underlying seizure disorder but also the aggravation of the seizure disorder ultimately caused Ms. Mager’s death by SUDEP. Am. Pet. ⁋ 12, ECF No. 11. Petitioner therefore needed to prove SUDEP was a sequela of Ms. Mager’s off-Table aggravated seizure disorder. See Hellebrand, 999 F.2d at 1569–70; 42 U.S.C. § 300aa-11(c)(1)(A), (c)(1)(C)(i), (c)(1)(C)(ii)(I). As the Special Master did not directly address whether SUDEP was a sequela of Ms. Mager’s aggravated seizure disorder, the Court reviews the record to determine if the record supports a finding SUDEP is the sequela of Ms. Mager’s aggravated seizure disorder. To understand the application of death as a sequela of a condition, it is helpful to understand SUDEP in comparison to a directly caused vaccine injury allegation, like SIDS, where the petitioner must show the vaccinations “cause or contribute to a . . . death.” Boatmon, 941 F.3d at 1361 (affirming this court’s denial of compensation because petitioners “failed to show by a preponderance of the evidence that vaccinations cause cytokines to provoke an abnormal brainstem serotonin response or otherwise cause or contribute to a SIDS death”). SUDEP “refers to deaths in people with epilepsy that are not from injury, drowning, or other known causes. Most, but not all, cases of SUDEP happen during or right after a seizure.” CDC, Sudden Unexpected Death in Epilepsy (SUDEP), (last visited June 1, 2023) https://www.cdc.gov/epilepsy/communications/features/sudep.htm (citing Orrin Devinsky, Sudden, Unexpected Death in Epilepsy, 365 NEW ENG. J. MED. 1801–11 (2011)). SIDS, in contrast, “is defined as ‘the sudden death of an infant under one year of age which remains unexplained after a thorough case investigation’” and requires a three-factor model to be satisfied. Boatmon, 941 F.3d at 1355. For SIDS to be compensated, a petitioner must “show by a preponderance of the evidence . . . vaccinations can be exogenous stressors,” the third factor required by the SIDS model. Id. at 1362. Whereas SUDEP is a death associated with epilepsy, death from SIDS is not associated with a particular underlying condition but requires all three factors be met. In other words, SUDEP is a medically accepted consequence of epilepsy and is properly once removed from a separate factor causing the epilepsy or increasing the severity of the underlying epilepsy. Death from SUDEP can be a sequela of seizures, caused or aggravated by a vaccination. To allege a vaccination caused SIDS, death from SIDS must be directly linked - 37 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 38 of 43 to the vaccination. The government contends petitioner should be required to directly connect Ms. Mager’s HPV vaccination to her death; the Court accordingly reviews precedential SIDS caselaw to confirm the differences between a death alleged to have been directly caused by a vaccination, such as SIDS, and a death alleged to have been a sequela of a vaccination, such as SUDEP. In Boatmon, the parents of a deceased child alleged several vaccinations caused the death of their child. Id. at 1353–54. The special master relied on expert testimony positing SIDS is “multifactorial,” occurring “when: (1) an infant in a critical development period; (2) possessing an underlying vulnerability; (3) encounters an exogenous stressor.” Id. at 1355. The petitioners’ expert theorized “receiving a vaccine can be an exogenous stressor for SIDS because it[] prompts the upregulation of cytokines.” Id. at 1356. The respondent “disagreed that upper respiratory infections—and by [the expert]’s extension, vaccinations—act as neurochemical exogenous stressors.” Id. The special master nevertheless found causation based on risk factors. Id. at 1356–57 (internal citation omitted) (“On Althen prong one, the [s]pecial [m]aster adopted [the expert]’s extension of the Triple Risk Model, concluding that ‘vaccines can . . . play a critical role . . . by stimulating the production of inflammatory cytokines.’ We note for clarity that the [s]pecial [m]aster also stated that ‘I have not concluded that vaccines present a substantial risk of SIDS. In fact, the evidence is to the contrary.’”). The Court of Federal Claims reversed because the expert testimony was not supported by a sound and reliable medical theory, and the petitioners appealed. Id. at 1357–58. The Federal Circuit affirmed the decision from this court because the petitioners failed to show the vaccinations contributed to the risk of SIDS and the ultimate death from SIDS through a reliable, reputable medical theory. See id. at 1359–63. Specifically, in Boatmon, the petitioners’ theory did not properly link the vaccinations to the exogenous stressor factor of the Triple Risk Model for SIDS through a reliable or plausible medical theory.8 Id. Respondent suggests a person with an underlying seizure disorder would never be able to recover under the Vaccine Act for SUDEP because of the inherent risk of SUDEP. See Tr. at 172:25–173:11 (“[RESPONDENT]: . . . [T]he death is related to the epilepsy. And since we know that her epilepsy predates both of her vaccines, it’s not the cause of her epilepsy. If the vaccine caused her epilepsy and she would have died from epilepsy, you would see that causal 8 SIDS research supports a Triple Risk Model for factors contributing to SIDS. Boatmon, 941 F.3d at 1355–56. While the Federal Circuit credited the Triple Risk Model, the Federal Circuit did not agree with the petitioners’ extension of the theory “to include vaccination-induced cytokine activity in the list of exogenous stressors as [the expert] propose[d].” Id. at 1360. The Federal Circuit explained, “Petitioners have not shown that their theory that vaccinations can be an exogenous stressor under the Triple Risk Model of SIDS is a sound and reliable medical theory.” Id. Indeed, the Federal Circuit, after reviewing the studies proffered to support the extension of the Triple Risk Model, held the “studies do not provide support . . . because they do not show that that cytokine activity is capable of impacting the brain’s 5–HT system.” Id. at 1362. The Federal Circuit stated “[w]e have consistently rejected theories that the vaccine only ‘likely caused’ the injury and reiterated that a ‘plausible’ or ‘possible’ causal theory does not satisfy the standard.” Id. at 1360 (citing Moberly ex rel. Moberly v. Sec’y of Health & Hum. Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010)). Both the special master and the expert found the theory only “plausible,” so the Federal Circuit held “[t]he [s]pecial [m]aster erred in allowing a theory that was at best ‘plausible’ to satisfy the [p]etitioners’ burden of proof.” Id. In summary, the Federal Circuit rejected the extension of the Triple Risk Model to link the vaccinations to the death from SIDS. Id. at 1361 (“The [s]pecial [m]aster erred in adopting an unsound and unreliable theory that constitutes a significant extension of the Triple Risk Model in the absence of any indicia of reliability.”). - 38 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 39 of 43 chain. But the epilepsy . . . predates the HPV vaccine. The vaccine didn’t cause her epilepsy. And according to Dr. Shafrir, SUDEP can happen essentially anytime, anywhere, five years later, 10 years later, 20 years later, whether you have high risks, whether you take your medication, whether your seizures are controlled or uncontrolled.”). The Federal Circuit in Sharpe addressed a similar issue where the respondent argued the underlying genetic condition barred recovery.9 Sharpe, 964 F.3d at 1087. The Federal Circuit rejected the argument, reasoning: “To uphold the [s]pecial [m]aster’s finding would effectively allow the government to prevail under the ‘factor unrelated’ inquiry with mere proof of a gene mutation. As a result, children with gene mutations will be shut out from the Vaccine Injury Program. Congress did not intend such a result.” Id. Likewise, the unfortunate circumstance of having a preexisting seizure disorder and developing a seizure disorder should not bar a whole population of persons. See id. Rather, in the case where the death is unexplained but has certain risk factors, petitioner must show how the aggravated condition increases the risk of death. See Boatmon, 941 F.3d at 1359–63. Unlike Boatmon, petitioner put forth a reliable medical theory, see supra Section V, so the Court looks to whether the record supports an increased risk of SUDEP following vaccination. In the present case, like Boatmon, respondent claims petitioner did not connect the vaccination to the ultimate death of Ms. Mager. Tr. at 175:9–10 (“[RESPONDENT]: . . . [T]he death did not occur within 42 days.”). Respondent’s contention petitioner did not meet his burden of proof is based on Dr. Shafrir’s statements made during the compensation hearing. Dr. Shafrir stated: Her death may have not happened if she was able to get better treatment. Unfortunately, she kept having insurance say if she could go to the doctor and everything. So she had SUDEP. SUDEP could have occurred, could not have occurred, could have occurred after a few months with epilepsy, could have occurred after 20 years of epilepsy. So the SUDEP is not correlated to the vaccination or to anything else. SUDEP is a terrible accident or complication of having epilepsy. 8 Mar. 2022 Compensation Hr’g Tr. at 355:3–12, ECF No. 216. The case is different than Boatmon—in Boatmon, the petitioners’ theory necessitated the vaccination contributed to SIDS as the third factor exogenous stressor; Ms. Mager’s case only requires petitioner to show the vaccination aggravated the seizure disorder and the aggravated seizure disorder contributed to the risk of a seizure death—SUDEP. See Boatmon, 941 F.3d at 1359–63. Statements throughout the record, from both parties, support Ms. Mager having a higher risk of SUDEP, unlike Boatmon. Both experts agree there are several risk factors associated with SUDEP, including “convulsions at night within the previous year . . . liv[ing] alone . . . 9 Petitioner cites Sharpe as barring death as a defense. Petitioner, however, misreads Sharpe. The Federal Circuit warned in Sharpe “off-table claim[s] present[] the difficult but important task of determining whether a child’s receipt of vaccinations significantly aggravated her seizure disorder . . . . Our case law is clear that given the complexity of a significant aggravation claim, a petitioner should not be required to disprove that a pre-existing [condition] caused her significant aggravation.” 964 F.3d at 1087. The Federal Circuit held a petitioner is not required to prove the natural course of the disease during the causation-in-fact analysis. Id. Under Sharpe, it is the respondent’s burden to prove the vaccination did not aggravate the underlying disorder but rather the aggravation of the disorder and ultimate death was the natural course of the disease. - 39 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 40 of 43 using recreational drugs and alcohol . . . frequent convulsions, particularly those that occur at night,” and compliance with medication. Kohrman Expert Report at 15 (quoting study), ECF No. 183-1; see Shafrir Reply Report at 1–2 (“Ms. Mager tragically died of SUDEP . . . . SUDEP is in the phenomenon in patients with epilepsy. It can occur in patients whose epilepsy is not that severe, although the risk is increasing in more severe forms of epilepsy, in intractable epilepsy that is not responding to treatment and in patients who are not compliant with [their] medications. Ms. Mager suffered SUDEP as a result of the acquired autoimmune epilepsy, which was the result of her repeated HPV vaccination . . . .”). Dr. Kohrman, during the compensation hearing, acknowledged Ms. Mager was at “greater risk for seizure being up until 4:00 a.m. and then going to sleep. . . . [S]he was having seizures in her sleep that she didn’t recognize. . . . [S]he had an uncontrolled epilepsy. . . . [S]he had intermittent issues with adherence to her medication, all of which put her at greater risk for sudden death.” 9 Mar. 2022 Compensation Hr’g Tr. at 533:20–534:13, ECF No. 217. Dr. Shafrir acknowledged the “four major risks are nocturnal seizures, generalized seizures, poorly controlled seizures[,] and poor compliance” but “other factors [are] involved, [and] it’s very, very important to know that many patients with SUDEP have no risk factors.” 8 Mar. 2022 Compensation Hr’g Tr. at 331:20–332:4, 355:3–12. Dr. Shafrir wrote in his reply report, “SUDEP . . . can occur in patients whose epilepsy is not that severe, although the risk is increasing in more severe forms of epilepsy.” Shafrir Reply Report at 1–2 (emphasis added). The Special Master in his opinion and in the record also found Ms. Mager’s risk was higher because the underlying seizure disorder was aggravated. Ruling Finding Entitlement at 48 (Ms. Mager “experienced worse seizures within an appropriate amount of time after the vaccinations”). SUDEP, by definition, is dependent on seizing; therefore increased seizure activity would naturally increase the risk of SUDEP. See CDC, supra (defining SUDEP as “deaths in people with epilepsy that are not from injury, drowning, or other known causes. Most, but not all, cases of SUDEP happen during or right after a seizure.”) (emphasis added). The Special Master emphasized Ms. Mager’s “condition was worse than her condition before the vaccination. Before the vaccination, [Ms. Mager] had not had a seizure in approximately five years and was not taking any anti-seizure medications. Afterwards, [Ms. Mager] suffered three seizures within about one month and began taking medications.” Ruling Finding Entitlement at 30–31. The Special Master, looking at the medical records and relying on expert testimony, found the second dose of HPV increased Ms. Mager’s risk because she began seizing again. Id. at 28 (“Before this vaccine, [Ms. Mager] had not suffered any seizures in nearly five years.”); see also Shafrir Reply Report at 1–2 (“SUDEP . . . can occur in patients whose epilepsy is not that severe, although the risk is increasing in more severe forms of epilepsy . . . .”). Respondent suggested at oral argument there may have been a dechallenge period before Ms. Mager’s death. Petitioner argues the dechallenge period is not relevant because the record supports ongoing seizures after the second dose. Tr. at 179:14–23 (“[PETITIONER]: Both the father and the best friend gave reports that she was having increasing seizures leading up to her death. They did that in a report to the police immediately afterwards and . . . the Special Master didn’t credit those because they weren’t in the medical records, but [after] only one of the subsequent seizures after the second vaccination did she go to the doctor. Most epileptics don’t go to the doctor after every seizure.”). The Special Master found persuasive petitioner’s argument the change in the severity and the consistency of seizures also increased Ms. Mager’s - 40 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 41 of 43 risk for SUDEP. Ruling Finding Entitlement at 30 (“Confronting the Secretary’s arguments, Mr. Mager replied more forcefully. He answered: ‘going from seizure-free for five years, not requiring medication and not being at risk for SUDEP (without seizures, you cannot have SUDEP), to uncontrolled epilepsy, requiring medication, persistent and ongoing seizures, and ultimately death, is a change for the worse in a preexisting condition.’”); see also Shafrir Reply Report at 1–2; Kohrman Expert Report at 15. The Special Master contemplated other risk factors, including compliance with medication, in finding the aggravated seizure disorder increased SUDEP risk. The Special Master reasoned, “Dr. Shafrir testified that [Ms. Mager]’s ‘death may have not happened if she was able to get better treatment.’ A relevant factor is that [Ms. Mager] may have had poor compliance with her medication. However, according to a toxicology report, [Ms. Mager] had therapeutic levels of Keppra in her blood at the time of her death.” Ruling Finding Entitlement at 54 (internal citations omitted). The Special Master found Ms. Mager was compliant with medications, based on the autopsy report, and the break-through seizures on medication indicated more severe seizures and consequently a higher risk of SUDEP. Id. While the Special Master did not explicitly find death was the “sequela” of the significantly aggravated seizure disorder, the record and the Special Master’s findings support the vaccination increasing the risk of SUDEP; accordingly, causation was established. See Hellebrand, 999 F.2d at 1570; Shyface, 165 F.3d at 1352 (“We adopt the Restatement rule for purposes of determining vaccine injury, that an action is the ‘legal cause’ of harm if that action is a ‘substantial factor’ in bringing about the harm, and that harm would not have occurred but for the action.”). “Once a petitioner establishes her prima facie case by satisfying the Althen test, the burden then shifts to the respondent to show by a preponderance of the evidence that the injury is due to factors unrelated to the administration of the vaccine.” Deribeaux ex rel. Deribeaux v. Sec’y of Health & Hum. Servs., 717 F.3d 1363, 1367 (Fed. Cir. 2013) (citing 42 U.S.C. § 300aa–13(a)(1)(B)); see also Sharpe, 964 F.3d at 1086. VIII. Whether the Special Master Erred in Holding Respondent Failed to Prove an Unrelated Factor Under Preponderant Evidence As the Court finds no error in the Special Master’s Loving analysis and the record supports death as the sequela of the significantly aggravated seizure disorder, the burden shifts to respondent. See supra Section VII. The Court must now determine if the Special Master erred in holding respondent did not meet the burden of proof for unrelated factor. Respondent in its Motion for Review does not challenge the Special Master’s finding respondent “has not established [Ms. Mager’s death is the natural result of her epilepsy] by a preponderance of evidence.” Ruling Finding Entitlement at 55; see 2023 Mot. for Review at 19–20. Respondent instead argues an improper shift of the burden of proof, addressed by the Court supra Section VII. Finding petitioner satisfied causation, the burden properly shifted to respondent to prove Ms. Mager’s death was a natural course of the disease with preponderant evidence. See Sharpe v. Sec’y of Health & Hum. Servs., 964 F.3d 1072, 1087 (Fed. Cir. 2020). The Court reviews factual findings under the arbitrary and capricious standard, and it is - 41 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 42 of 43 not the Court’s role “to reweigh the factual evidence, or to assess whether the special master correctly evaluated the evidence.” Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d 1357, 1360 (Fed. Cir. 2000) (internal quotes omitted) (quoting Munn v. Sec’y of Dep’t of Health & Hum. Servs., 970 F.2d 863, 870 n.10 (Fed. Cir. 1992)). To meet the burden of showing an unrelated factor, “the respondent must identify a particular factor (or factors) and present sufficient evidence to establish that it was the sole substantial factor in bringing about the injury.” Deribeaux ex rel. Deribeaux v. Sec’y of Health & Hum. Servs., 717 F.3d 1363, 1367 (cleaned up) (citing de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1354 (Fed. Cir. 2008); Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005)). The “Vaccine Act requires the Secretary to establish that the factor unrelated to the vaccination is the more likely or principal cause of the injury alleged.” Deribeaux, 717 F.3d at 1369. It is well established “a special master may find that a factor other than a vaccine caused the injury in question only if that finding is supported by a preponderance of the evidence.” Stone v. Sec’y of Health & Hum. Servs., 676 F.3d 1373, 1380 (Fed. Cir. 2012) (citing Walther v. Sec’y of Health & Hum. Servs., 485 F.3d 1146, 1151 (Fed. Cir. 2007)). In Sanchez, the Federal Circuit illustrated how unrelated factors relate to significant aggravation claims. Sanchez ex rel. Sanchez v. Sec’y of Health & Hum. Servs., 34 F.4th 1350, 1356 (Fed. Cir. 2022). Sanchez involved a petitioner with Leigh’s syndrome. Id. The respondent alleged the mutation leading to Leigh’s syndrome resulted in the same progression and severity absent the vaccine. Id. at 1356. The Federal Circuit held the respondent “did not meet its burden to establish . . . Leigh’s syndrome was the result of factors unrelated to the vaccine.” Id. The Federal Circuit criticized the reference used by the respondent because it “provide[d] no information on how the subject’s disease progressed after manifestation” or what caused the syndrome to progress the way it did. Id. Indeed, the Federal Circuit explained the cited reference by stating “a single example does not establish the typical progression of a disease and is not ‘sufficient to disprove a medical theory that a vaccine can cause aggravation in some patients.’” Id. (quoting Sharpe, 964 F.3d at 1084). The Special Master noted “[t]he parties did not extensively discuss the natural course of generic epilepsy.” Ruling Finding Entitlement at 53. The Special Master, however, reviewed the arguments of respondent and petitioner to determine whether the outcome of Ms. Mager’s epilepsy was the natural course of the disease. Id. at 53–55. Respondent’s primary argument was Ms. Mager’s significant aggravation of the underlying seizure disorder was the natural course of the disease. Id. at 53. This argument, the Special Master pointed out, is “premised, at least in part, on the assertion that [Ms. Mager] suffered from juvenile myoclonic epilepsy.” Id. The Special Master credited respondent’s expert, Dr. Kohrman, stating “a person with JME and who is not taking anti-seizure medication may have years without seizures and the redevelop seizures.” Id. The Special Master, however, ultimately did not find the argument persuasive because of the Court’s determination of simply a seizure disorder. Id.; see Mager v. Sec’y of Health & Hum. Servs., 158 Fed. Cl. 136, 155–56 (2022). Respondent’s secondary argument was Ms. Mager’s “death was due to the natural course of her epilepsy.” Ruling Finding Entitlement at 53–54. The Special Master reviewed the evidence presented by respondent regarding SUDEP being the natural course of epilepsy. A key piece of evidence was compliance with medication. Respondent argued “people whose - 42 - Case 1:14-vv-00820-RTH Document 249 Filed 06/20/23 Page 43 of 43 epilepsies are controlled without medication can redevelop seizures unpredictably.” Id. at 54. The Special Master, however, noted “according to a toxicology report, [Ms. Mager] had therapeutic levels of Keppra in her blood at the time of her death.” Id. The seizures therefore should not have broken through with Ms. Mager taking medication. The Special Master acknowledged a “potentially useful piece of information would have been how often people with mild epilepsy experience SUDEP. This evidence could have informed an assessment of how [Ms. Mager]’s epilepsy, unaggravated by the second HPV vaccination, might have progressed.” Id. at 55. The Special Master concluded without evidence of how Ms. Mager’s epilepsy might have progressed, unaggravated by the HPV vaccination, respondent’s claim Ms. Mager’s “death is the natural result of her epilepsy seems possible.” Id. In this case, like Sanchez, respondent was unable to “establish the typical progression of a disease” and therefore did not provide evidence “sufficient to disprove a medical theory that a vaccine can cause aggravation in some patients.” Sanchez, 34 F.4th at 1356 (quoting Sharpe, 964 F.3d at 1084). To meet its burden, respondent was required to show by preponderant evidence SUDEP was the natural course of Ms. Mager’s disease and therefore the “sole substantial factor” in Ms. Mager’s injury; respondent did not offer evidence showing the normal course of Ms. Mager’s unaggravated seizure disorder. The Special Master, weighing all the evidence, determined there was not a preponderance of evidence shown by respondent. Ruling Finding Entitlement at 53–55. The Special Master accordingly did not err because respondent did not prove an unrelated factor by preponderant evidence. See Sanchez, 34 F.4th at 1356 (quoting Sharpe, 964 F.3d at 1084); Stone, 676 F.3d at 1380 (citing Walther, 485 F.3d at 1151); Lampe, 219 F.3d at 1360 (quoting Munn, 970 F.2d at 870 n.10). IX. Conclusion For the foregoing reasons, the Court DENIES respondent’s Motion for Review, ECF No. 242, and SUSTAINS the Special Master’s Ruling Finding Entitlement, ECF No. 224. The Court DIRECTS the Clerk to enter judgment, pursuant to the Special Master’s decision in ECF No. 240, for $365,593.02. IT IS SO ORDERED. s/ Ryan T. Holte RYAN T. HOLTE Judge - 43 -