Court Opinion

ID: 6339892
Source: CourtListenerOpinion
Date Created: 2022-05-12 13:01:25.741882+00
Date Added: 2024-06-11T14:57:10.273678
License: Public Domain

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: April 19, 2022
                            *
SECRETARY OF HEALTH         *                       Remand; entitlement; human
AND HUMAN SERVICES,         *                       papillomavirus (“HPV”) vaccine;
                            *                       epilepsy; significant aggravation;
             Respondent.    *                       challenge-rechallenge; timing; death
*********************

Renee J. Gentry and Julie Kim, Vaccine Injury Clinic, George Washington
University Law School, Washington, DC, for petitioner;
Zoe Wade and Tyler King, United States Dep’t of Justice, Washington, DC, for
respondent.

           RULING FINDING ENTITLEMENT TO COMPENSATION 1

      Michael Mager alleged that the human papillomavirus (“HPV”) vaccine his
deceased daughter Victoria received on September 11, 2012, significantly
aggravated an epilepsy. He sought compensation pursuant to the National
Childhood Vaccine Injury Compensation Program.

      After a previous decision found that Victoria did not suffer from a particular
form of epilepsy, autoimmune epilepsy, the Court of Federal Claims held that this
       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 ruling on its
website. This posting will make the ruling 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.
focus on autoimmune epilepsy was erroneous. The Court, accordingly, vacated the
previous decision and remanded for an analysis of whether the 2012 vaccination
harmed Victoria.

       On remand, the parties presented testimony from three people. Mr. Mager
called Yuval Shafrir, M.D., a neurologist. The Secretary called Michael H.
Kohrman, M.D., a neurologist, and Robert S. Fujinami, Ph.D., a specialist in
immunology, although not a medical doctor. Based upon this testimony as well as
the written material, the undersigned finds that Mr. Mager is entitled to
compensation.2

I.    Facts

        Victoria’s history can be separated into three periods. These are (A) from
birth to the first dose of the HPV vaccine at age 12, (B) from the first dose of the
HPV vaccine to the second dose of the HPV vaccine approximately five years
later, (C) from the second dose of the HPV vaccine to Victoria’s death.

          A. Events and Health Before the First Dose of the HPV Vaccine on
          October 2, 2007

       Victoria Mager was born on July 29, 1995. Amend. Pet., filed Nov. 19,
2014, at ¶ 1. Victoria had a family history of epilepsy on her mother’s side. Three
cousins on her maternal line had seizures similar to the seizures that Victoria
eventually experienced. Exhibit 11 at 28, 40; exhibit 6 at 2. In addition, Victoria’s
maternal grandfather had epilepsy for which he was treated with surgery. Id. The
testifying neurologists recognize that Victoria had a family history of seizures. Tr.
218, 221 (Dr. Shafrir), 447-48 (Dr. Kohrman). In other words, she had a genetic
propensity to develop seizures. Id. at 221, 332 (both Dr. Shafrir). For Dr.
Kohrman, the family history contributes to Victoria’s relatively early onset of
juvenile myoclonic epilepsy (“JME”). Id. at 454, 502.

      An early medical record from her four-year well-child exam indicates that
Victoria’s parents had been divorced for about six months. Exhibit 18 at 19. In
this November 2, 1999 well-child exam, Victoria’s mother informed the
pediatrician, Dr. Jason Wray-Raabolle, that Victoria “does not speak much, and
others will occ[asionally] have a hard time understanding her.” Id. Dr. Wray-
Raabolle offered Victoria an evaluation by a speech therapist, but Victoria’s

      2
        The undersigned has considered all the material in the record, although this
ruling does not discuss all the material. This ruling focuses upon the evidence that
the parties have emphasized.
                                          2
mother stated that “she feel[s] her daughter is improving and does not wish to
[pursue] that at this time.” Id. at 21.

       This concern about speech recurs about one year later as part of the five-year
well-child exam. By this time, Victoria had started kindergarten. Victoria’s
mother stated others had difficulty understanding Victoria’s speech. Id. at 12
(Sept. 6, 2000).
      In another well-child exam about 18 months later, Victoria’s mother
reported that Victoria was receiving speech therapy. Exhibit 18 at 3 (Mar. 11,
2004). Victoria was in second grade, and she was earning Ds in some subjects. Id.
According to a neuropsychologist’s report created in 2008, Victoria had an
individualized education plan (“IEP”) from first to fourth grade, and an IEP in
speech and language from grades four through seven. Exhibit 6 at 1; accord Tr.
280 (Dr. Shafrir), 510 (Dr. Kohrman). However, any IEP is not among the
exhibits. Dr. Kohrman saw Victoria’s learning difficulties as consistent with JME.
Tr. 455; see also id. at 539.

       In the March 11, 2004 appointment, Victoria’s mother informed the
pediatrician that Victoria was wetting the bed. Exhibit 18 at 3. At this time,
Victoria was eight years old. A non-contemporaneous medical record indicates
that the bedwetting started when Victoria was around six years old. Exhibit 6 at 25
(Dr. Koehn’s Feb. 21, 2008 report). It appears that Victoria was placed on
Ditropan.3 In addition to the bedwetting, Victoria’s pediatrician noted that she was
receiving speech therapy and experienced “poor performance” and “decreased
attention” at school. Exhibit 18 at 5.

      Victoria was weaned off Ditropan in summer 2007, about three years after
bedwetting was first reported. See exhibit 6 at 25; exhibit 11 at 30. The records
indicate that Ditropan helped with Victoria’s bedwetting. Exhibit 6 at 25. After
stopping Ditropan, Victoria had a few episodes of bedwetting between summer and
November 2007. Id. One report states that the bedwetting
“stopped . . . completely” after Victoria began to use Depakote, an anti-seizure
medication, in November 2007. Id. When asked about these records at hearing,
Dr. Kohrman stated that the medical records indicate her bedwetting improved
with Ditropan before she received the first HPV vaccine but did not stop
completely. Tr. 515. He reasoned that the reference in the records that states the

      3
       Ditropan prevents bedwetting by relaxing the bladder, allowing it to
expand to contain more urine. Tr. 334. Ditropan is not an antiepileptic
medication. Id. at 242.
                                         3
bedwetting stopped after starting Depakote implies that Victoria was wetting the
bed, at least to some degree, until she started taking Depakote. Id. Dr. Kohrman
further reasoned that the cessation of bedwetting after taking an anti-seizure
medication indicates that the bedwetting was due to seizures. Id. at 446, 511-12,
541.

       On this point, Dr. Kohrman was persuasive. Episodes of bedwetting in a
child from age seven-years to approximately twelve-years is unusual. See Tr. 242,
329 (both Dr. Shafrir’s testimony that approximately 10% of children are wetting
the bed at age six and of this group, half stop by age seven). 4 Episodes of
bedwetting can be the only manifestation of nocturnal seizures. Exhibit H
(Margaret N. Shouse & Mark W. Mahowald, Epilepsy, Sleep, and Sleep Disorders,
in Principles and Practice of Sleep Medicine 863 (Meir H. Kryger et al. eds., 4th
ed. 2005)) at 870; see also Tr. 328 (Dr. Shafrir: bedwetting could be consistent
with a seizure), 501-02 (Dr. Kohrman: bedwetting that continues until age 13 and
is stopped after the introduction of anti-seizure medication indicates a nocturnal
seizure).

       Based in part upon this information, Dr. Kohrman opined that Victoria’s
neurologic problems started before the first HPV vaccination. Exhibit A at 11-12.
The basis is threefold. First, Victoria had problems in school. Second, Victoria
was wetting the bed. Third, Victoria was biting her tongue. The first two points
were described above. Id.; see also Tr. 445-46; Spec. Mstr. Oral Arg. Tr. 618,
citing Tr. 543 (Dr. Kohrman’s testimony).
        With respect to tongue biting, the evidence is mixed, but favors a finding
that Victoria was biting her tongue before vaccination. Some evidence supports
this finding. On November 15, 2007, a neurologist, Dr. Uzma Sharif, obtained a
history in which she recorded, “Parents have noted tongue [difficult to read].”
Exhibit 11 at 40.5 Later, when seeing the family in follow-up, Dr. Sharif
recommended that Victoria’s stepmother (Kathy Mager) keep a journal,
documenting any episodes of bedwetting, tongue biting, soreness, and wet pillow

      4
        Mr. Mager takes a statement from Dr. Kohrman about the commonness of
bedwetting in young children out of context. Pet’r’s Posthear’g Br., filed Mar. 25,
2022, at 21, quoting Tr. 501-02.
      5
        During the hearing, the undersigned asked Dr. Kohrman whether he could
read the last word and Dr. Kohrman stated he could not. Tr. 515. On redirect, the
Secretary’s attorney leadingly asked whether the word could be “lacerations.” Id.
at 543. Mr. Mager’s attorney objected, and this objection was sustained. Id.
                                         4
with saliva. Id. at 77. The November 15, 2007 history from Dr. Sharif is
consistent with a history obtained one day earlier in which a doctor recorded:
“Episodes waking up [with] cuts in mouth.” Id. at 28.

       Thus, the evidence is clear and convincing that before Victoria’s generalized
tonic-clonic seizure on November 14, 2007, she was biting her tongue. Even Dr.
Shafrir agreed on this point. He wrote: “everybody agreed that she probably had
episodes of nocturnal seizures during the previous month.” Exhibit 55 at 17;
accord Tr. 254, 262 (Dr. Shafrir’s testimony that Victoria “quite likely” had
nocturnal seizures before November 14, 2007). Mr. Mager also agrees that
Victoria bit her tongue before the generalized tonic-clonic seizure on November
14, 2007. See Pet’r’s Posthear’g Br., filed Mar. 25, 2022, at 20-21; Spec. Mstr.
Oral Arg. Tr. 627-28. The ensuing question is whether the tongue biting also
started before the October 2, 2007 vaccination.

      Two pieces of evidence support a finding that Victoria began biting her
tongue before the first vaccination. First, when Victoria went to the hospital on
November 14, 2007, in the context of explaining no history of seizures, her
stepmother informed the doctor that Victoria had
             2 questionable episode[s] of

             2 month[s] ago
             2 week[s] ago

Exhibit 11 at 30.6 An episode that occurred two months before November 14,
2007 would be approximately September 14, 2007, meaning before the
vaccination.

      Second, when the family sought care from a neurologist (Dr. Koehn) in
February 2008 (approximately three months after the tonic-clonic seizure), Mr.
Mager told this doctor “that months before this incident happened, Victoria did
complain that a couple of times she bit her tongue when she woke up in the
morning.” Exhibit 6 at 25; accord Tr. 445. Again, “months” before the November
14, 2007 tonic-clonic seizure places the onset of tongue biting before the
vaccination. See Tr. 266.

      6
         The doctor’s note regarding “month” is not clear. The number before
“month” could be a “1” or a “2.” See Tr. 266 (Dr. Shafrir, interpreting this note as
a “1”); id. at 541 (Dr. Kohrman, interpreting this note as a “2”).
                                            5
       Mr. Mager attempted to refute the accuracy of these records. Relying upon
Shapiro v. Secretary of Health & Human Services, 101 Fed. Cl. 532, 539 n.10
(2011), mot. for reconsideration denied after intervening remand, 105 Fed. Cl. 353
(2012), Mr. Mager argued a contemporaneous record cannot refer to events taking
place months earlier. Spec. Mstr. Oral Arg. Tr. 605-07; see also Pet’r’s Posthear’g
Br. at 20-21. The upshot to Mr. Mager’s argument appears to be that because
doctors first documented tongue biting months after the tongue biting reportedly
occurred, the tongue biting did not occur when the reports said it did.

      The evidence that the tongue biting started after the vaccination was created
much later in time, and, therefore, is less reliable. In 2013, a neurologist (Dr.
Edgar) obtained a history that began with Victoria experiencing her first tonic-
clonic seizure in 2006. It continues: “One month prior to the seizure event, she
awoke and had bitten her tongue. A few weeks prior to this, she had received an
HPV shot.” Exhibit 9 at 6. Dr. Shafrir relies upon this record, despite its creation
approximately five years after the events in question. Tr. 241-42, 255; cf. id. at
542 (Dr. Kohrman: a person’s memory is altered by events). While this record
provides some evidence that the HPV vaccination preceded any tongue biting, this
record carries less weight because it was created many years later. Although Mr.
Mager may be correct that Dr. Koehn’s February 21, 2008 record is not
contemporaneous with events happening in July 2007, Mr. Mager has not
persuasively justified why Dr. Edgar’s record from 2013 is more likely to be
accurate. Moreover, an additional reason for not crediting the history Dr. Edgar
obtained in 2013 is that the history is erroneous in describing Victoria’s first
seizure as occurring in 2006, when the first tonic-clonic seizure was actually in
2007. Exhibit 9 at 6. Given these inaccuracies in recollections presented in 2013
about events occurring in 2007, crediting Mr. Mager’s affidavit from July 15, 2015
(exhibit 19 at ¶¶ 4-6) is also not possible. See O’Connell v. Sec’y of Health &
Hum. Servs., 40 Fed. Cl. 891, 893, 895 (1998) (denying motion for review when a
special master declined to credit the parents’ oral testimony because the passage of
time may have tainted their memories), aff’d in unpublished op., 217 F.3d 857,
1999 WL 1039699 (Fed. Cir. 1999).

       For these reasons, 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. Tr. 265, 328 (both Dr. Shafrir).
      Consequently, preponderant evidence supports a finding that Victoria was
experiencing seizures before the vaccination. 7 This finding can be made despite

      7
        Mr. Mager argued against a finding that Victoria experienced seizures
before her first vaccination because, at least in part, there was no “clear evidence.”
                                           6
the fact that a doctor treating Victoria before the vaccination did not diagnose her
as suffering from seizures. It appears that the family did not inform the doctors
that Victoria was biting her tongue until after the tonic-clonic seizure. See exhibit
11 at 30. More importantly, a retrospective analysis is not surprising. In Dr.
Shafrir’s second report, he quoted a treatise on neurology, stating, “Patients
frequently come to medical attention only after a generalized convulsion, and the
history of earlier myoclonic jerks is often obtained retrospectively.” Exhibit 85 at
3, quoting exhibit 87 (Eliane Kobayashi et al., Juvenile Myoclonic Epilepsy, in
Epilepsy: A Comprehensive Textbook (Jerome Engel & Timothy A. Pedley eds.,
2d ed. 2008)). As Dr. Kohrman explained, this is what happened in Victoria’s
case. Tr. 457-58. Dr. Kohrman’s testimony is persuasive.

      The finding that Victoria suffered seizures before the October 2, 2007
vaccination does not alter her cause of action. Her cause of action is that a
vaccination in 2012 worsened her preexisting epilepsy. Spec. Mstr. Oral Arg. Tr.
604.
       On September 4, 2007, Victoria received the meningococcal and tetanus-
diphtheria-acellular pertussis vaccines. Exhibit 4 at 2, 3. Mr. Mager has not
asserted that either of these vaccines harmed Victoria.
       B. Events and Health from the First Dose of the HPV Vaccine (Oct.
       2, 2007) to the Second Dose of the HPV Vaccine (Sept. 11, 2012)

      Because this period encompasses approximately five years, it is further
divided into two subsections.

             1.    October 2007 to July 2008
      Victoria received the HPV vaccine on October 2, 2007. Exhibit 4 at 2, 9. In
Mr. Mager’s first affidavit, he stated that following the HPV vaccine, Victoria
experienced headaches and muscle aches. Exhibit 2 at ¶ 2.

       Approximately six weeks after the HPV vaccination, on November 14, 2007,
Victoria was attending a funeral. Exhibit 11 at 13. After the funeral while at a
restaurant, she experienced a seizure and was taken to the emergency room of
Children’s Hospital of Wisconsin. Id. at 13, 28. Her extremities shook, her eyes
rolled, her face turned blue briefly, and she was disoriented. Id. at 13. In her
admission notes, the description of her condition states that she experienced a

See, e.g., Pet’r’s Posthear’g Br. at 54-55 n.20. However, the evidentiary standard
for the finding of facts is a mere preponderance.
                                          7
seizure followed by a second seizure approximately four minutes later. Id. at 28.
A head CT scan, urine toxicology screen, and chest x-ray were performed with
normal results. Id. at 3-4, 13.

       The testifying neurologists differed in how they assessed the funeral. Dr.
Kohrman suggested that the stress of attending a funeral for a loved one could have
provoked a seizure. Exhibit Z at 2; exhibit BB at 13; Tr. 459-60, 516-17. On the
other hand, although Dr. Shafrir agreed that stress can lead to a seizure, he asserted
that a funeral is not the type of stressful event that could lead to a seizure within
hours. Tr. 329-30.

       Dr. Shafrir identified this November 14, 2007 tonic-clonic seizure as the first
clinical manifestation of any adverse consequence to the HPV vaccination. Tr.
244. This testimony is consistent with his second report in which he asserted that
Victoria “would not have developed epilepsy [had] she not receiv[ed] the
vaccination.” Exhibit 85 at 6.

       The histories given during this hospitalization shed some light on Victoria’s
health leading up to the tonic-clonic seizure for which she was treated in the
hospital. Her father reported that Victoria was a “previously healthy [female]
[with] new onset [of seizures].” Exhibit 11 at 19; accord id. at 28 (admitting note
stating no history of seizures). Yet, at the same time, the histories also contain
details that, as discussed above, contribute to the finding that Victoria had, in fact,
had nocturnal seizures before November 14, 2007. For example, the neurology
resident or fellow documented that Victoria was having enuresis and an issue with
her tongue. Id. at 39-40.

       During her hospitalization, Victoria underwent an electroencephalogram
(“EEG”). Exhibit 11 at 16-17. The results were abnormal. Id. More specifically,
the EEG showed “[i]ntermittent epileptiform spike & slow 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 the 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. Dr. Shafrir emphasized that a
nationally renowned epileptologist interpreted this EEG as showing discharges in a
focal location, not generalized. Tr. 227, 230. Dr. Kohrman responded that a
person with primary generalized epilepsy can have intermittent focal discharges
“here-and-there, now-and-again.” Id. at 447. Dr. Kohrman also maintained that
the EEG showed a “classic” pattern for a primary generalized epilepsy. Id. at 517-
18.

                                           8
       Late in the evening of November 15, 2007, Mr. Mager requested that
Victoria be discharged from the hospital. Exhibit 11 at 36. While the doctors
agreed that Victoria could be discharged, they recommended that Victoria take
Depakote. Id. Mr. Mager agreed that Victoria would take Depakote for one
month. Id. Victoria was expected to follow up with the neurologist who saw her
in the hospital, Dr. Sharif, in about one month. See id. at 71.
        The medication the doctors prescribed for Victoria, Depakote, is primarily
given to patients with generalized epilepsy. Tr. 444-45, 463, 531 (Dr. Kohrman);
id. at 557 (Dr. Shafrir). Patients with partial epilepsy are likely to be prescribed
levetiracetam (Keppra) or oxcarbazepine (Trileptal). Tr. 463, 531 (Dr. Kohrman);
id. at 557-58 (Dr. Shafrir). The doctor’s selection of Depakote “push[ed]” Dr.
Kohrman to favor a diagnosis of primary generalized epilepsy. Id. at 519.
       The day after being discharged from the hospital, Mr. Mager observed
Victoria having a similar tonic-clonic generalized seizure while sleeping. Exhibit
6 (Dr. Koehn’s notes) at 24. This episode lasted approximately one minute and
then she was unconscious for approximately five minutes. Victoria did not
remember the event happening. Id. at 24-25.

       The follow up appointment happened as expected, on December 12, 2007.
Exhibit 11 at 75-77. Dr. Sharif noted that after Victoria 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.” Id. at 75. Victoria’s stepmother also reported that there had been
no more bedwetting incidents after the prescription of Depakote between her
hospital admission and this appointment. Id. Dr. Sharif noted an impression of
“focal onset epilepsy by EEG” and “some frontal lobe dysfunction.” Id. at 77. Dr.
Sharif recommended neuropsychological testing. Id. Dr. Sharif wrote that
Victoria might be a candidate for surgery. Id. To Dr. Shafrir, the suggestion that a
surgery might improve Victoria’s epilepsy meant that Dr. Sharif believed that
Victoria’s epilepsy was focal. Tr. 230.

       Victoria saw another pediatric neurologist, Dr. Monica Koehn,
approximately two months later on February 21, 2008. Exhibit 6 at 20. An EEG
was performed, the results of which were normal. Id. at 22; accord Tr. 231-32.
Referring to the original abnormal EEG taken during her hospital admission, Dr.
Koehn noted, “The 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.” Exhibit 6 at 20. Victoria’s father and
                                         9
stepmother requested that she be weaned off Depakote, although the medication
appeared to be controlling her seizure activity. Id. at 24, 28. 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 Amend. Pet. at ¶ 4. Victoria stopped taking Depakote in March
2008. Exhibit 6 at 9.

       On April 1, 2008, Victoria underwent neuropsychological testing with Dr.
Stuart Waltonen. Exhibit 6 at 1. 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 these 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. Dr. Kohrman indicated that the
results of the neuropsychological evaluation showed that Victoria suffered from
discrete learning problems and these discrete learning problems are consistent with
JME. Tr. 455.

      In conjunction with the neuropsychological testing, Victoria saw her
neurologist, Dr. Koehn, again. Exhibit 6 at 8. Dr. Koehn noted that discerning the
type of seizure Victoria was experiencing was difficult. Id. at 11. When asked
about Dr. Koehn’s comment, Dr. Shafrir stated that different neurologists did not
agree on whether Victoria had “generalized epilepsy, symptomatic generalized
epilepsy or partial seizure with secondary generalization.” Tr. 341-42. Dr.
Kohrman recognized that at the time of Dr. Koehn’s assessment, she had limited
information about Victoria. Thus, he would have had questions similar to the ones
Dr. Koehn raised. Id. at 521.

      Dr. Koehn planned to repeat the EEG in the summer when Victoria was not
taking Depakote. Exhibit 6 at 11. The next EEG happened on June 26, 2008. It
was normal. Id. at 13. Dr. Kohrman stated that the normalized EEG showed that
Victoria responded to Depakote. Tr. 464.8 Dr. Shafrir said that a “total

      8
        Dr. Kohrman also opined that the normal EEGs could have missed
seizures. Tr. 462.
                                         10
disappearance of all discharges” would be “quite unusual,” although it does
happen. Id. at 558.

       Dr. Koehn reviewed the EEG in an appointment on July 10, 2008. Exhibit 6
at 15-18. Dr. Koehn documented that Victoria was failing almost all her subjects
in school. Id. at 16. The neurologic exam was normal. Id. at 17-18; see also Tr.
521. Dr. Koehn recommended that Victoria continue not taking medication and
return in about one year. Exhibit 6 at 18; see also Tr. 342 (Dr. Shafrir’s agreement
that he would have recommended not continuing medication).

      Within one week of the July 10, 2008 appointment with Dr. Koehn,
Victoria’s stepmother inquired whether the HPV vaccination was related to
Victoria’s seizures. Exhibit 6 at 19 (call log). Dr. Koehn responded that the HPV
immunization was not related to the seizure. Id.

             2.    July 2008 to September 2012

      From July 2008 to September 2012, Victoria attended eighth, ninth, tenth,
and eleventh grades. While there is no academic record for Victoria in eighth
grade, see exhibit 83, her high school transcript shows her academic performance.
Exhibit 83 at 1. During these years, Victoria’s grades were mixed, including many
Cs and Ds. Id. 9

      During these four years, relatively few medical records were created. A
doctor indicated that Victoria was healthy enough to play volleyball in 2009.
Exhibit 14 at 1-2.
      Victoria established a relationship with a new doctor, Dr. David Budde, on
January 5, 2012. Dr. Budde’s history indicates that Victoria had not had any
seizures in four years. Victoria was not taking any medications. Exhibit 10 at 18.

      Victoria returned to Dr. Budde for an annual maintenance exam on March 6,
2012. Id. at 15. Dr. Budde recorded that Victoria was doing “fairly well in
school,” although there was “room for some improvement.” Id. He also noted,

      9
         Dr. Shafrir noted that after the seizures initially disappeared, Victoria
continued to have problems with learning. Tr. 238. He also opined that “it tells us
that the [vaccine] was associated with encephalopathy and was most likely the
cause of encephalopathy, the situation.” Id.; accord id. at 278. However, Dr.
Shafrir appears to overlook that Victoria had difficulties in school before the first
HPV vaccination.
                                         11
“Mother has no concerns about her.” Id. The medical record from this visit
contains no information about seizures. See id.

       Dr. Shafrir emphasized that Victoria was seizure-free for nearly five years.
During this period, she likely experienced stress and likely was deprived of sleep at
least sometimes. Tr. 215, 338. However, she did not experience seizures. This
seizure-free time helps Dr. Shafrir isolate the vaccinations as the triggers for
Victoria’s seizures.

       Dr. Kohrman had less confidence in the assertion that Victoria did not
experience seizures during these approximately five years. He noted that after her
death, Mr. Mager recounted that Victoria did not always perceive having seizures
during sleep. Tr. 491; see also exhibit 13 at 2; exhibit 16 at 3 (Mr. Mager’s report
to medical examiners). 10
      On September 11, 2012, Victoria received her second HPV vaccination.
Exhibit 4 at 1. Mr. Mager alleges that this vaccination aggravated her seizure
disorder. Amend. Pet. at ¶ 12; Spec. Mstr. Oral Arg. Tr. 605.
       C.    Events and Health from October 2012 Until January 2014

       Approximately one month after the second HPV vaccination, Victoria 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
electrocardiogram (“EKG”), was normal. Id. at 13-14. She was diagnosed with a
“probable seizure” and discharged. Id. at 14. When she was discharged, Victoria
was recommended to see a neurologist in follow-up. Id. Because Victoria already
had a seizure disorder, the doctors at the emergency room did not need to order an
EEG. Tr. 525.

      It appears that Victoria experienced two other seizures for which she did not
seek medical attention emergently. She had a seizure at school on October 19,
2012. Exhibit 9 at 6 (report to Dr. Edgar); exhibit 2 at ¶ 7 (Mr. Mager’s first
affidavit). She had a third seizure on November 7, 2012. Exhibit 9 at 39 (Dr.
Budde’s Nov. 8, 2012 report); id. at 6 (report to Dr. Edgar listing seizure on
November 8, 2012).

      10
         Dr. Kohrman also asserted, “There is no medical record during that
period.” Tr. 491. However, this assertion overlooks records from Dr. Budde. See
id. at 522-23.
                                         12
       Following a third seizure, Victoria 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 emergency room visit on October 19, 2012, and
November 7, 2012. Id. Dr. Budde recorded that although the doctors at Theda
Clark had recommended an appointment with a neurologist, Victoria had not seen
one. Id. Dr. Budde noted that Victoria “adamantly denies any drug or alcohol
use.” Id.

       Dr. Budde also stated that Victoria felt “spacy” and may have been “losing
some time during lectures or conversations that could represent absence-type
seizures.” Id. Dr. Kohrman interpreted the history of feeling “spacy” as consistent
with Victoria experiencing absence type seizures. Tr. 450. Dr. Shafrir disagreed,
stating that feeling “spacy” “is not evidence for absence.” Id. at 313.

       In the history obtained by Dr. Budde, he wrote, “Sometimes, [Victoria]
thinks she can feel them coming on as she will get an unusual sensation. She had a
cramping sensation in her calf prior to one seizure.” Exhibit 9 at 39. Dr. Shafrir
interpreted this information as an “aura.” Tr. 232, 309, 559-60. An aura, in turn,
makes the diagnosis of JME less likely. Id. In contrast, Dr. Kohrman considered
Victoria’s unusual sensation (or aura) as consistent with an absence seizure and her
cramping as a myoclonic jerk. Id. at 529, 567. At the end of the appointment, Dr.
Budde prescribed Depakote and facilitated a referral to a local neurologist, Dr.
Terence Edgar. Exhibit 9 at 39.
      Victoria saw Dr. Edgar on January 14, 2013. Exhibit 9 at 6-8. Dr. Edgar
recorded that “Mom does report occasional staring spells, but it is unclear if there
are absence seizures.” Id. at 8. Dr. Shafrir relied upon this statement to opine that
Victoria did not have absence seizures. Tr. 311-12.
       An EEG was also performed. Exhibit 9 at 24-25. 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. Shafrir
indicated that the January 2013 EEG supports a diagnosis of partial seizures with
secondary generalization. Tr. 347-48. Dr. Kohrman recognized that this EEG was
not typical for juvenile myoclonic epilepsy. Id. at 545-46.

      Dr. Edgar’s impression was a 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.”
Exhibit 9 at 8. Dr. Edgar also noted that he “inquired into the myoclonic seizures.”
Id. He recommended Depakote but, after Victoria specified that she did not wish
                                         13
to remain on Depakote, Dr. Edgar directed her to begin weaning off Depakote and
prescribed a different anti-seizure medication, Keppra. Id. at 8. Dr. Edgar
instructed Victoria to follow up in one year. Id. In Dr. Kohrman’s opinion,
Keppra was likely to be a less effective medication. Tr. 467.

       To Dr. Shafrir, Dr. Edgar’s record that Victoria did not report myoclonic
seizures was important. Victoria could not suffer from JME without having
myoclonic seizures. Tr. 232-33. Dr. Kohrman was less concerned about the lack
of reports about myoclonic seizures because myoclonic seizures can be difficult to
detect. Id. at 443, 451-52, 457-58, 496. Dr. Kohrman gave much more weight to
Dr. Edgar’s (and Dr. Koehn’s) diagnosis of primary generalized epilepsy. Id. at
496; see also exhibit A at 13.

      Victoria was supposed to have blood drawn at Berlin Hospital on March 1,
2013. However, she did not appear. Exhibit 9 at 15.

      To obtain more information, Dr. Edgar ordered additional labs. On June 18,
2013, Victoria’s stepmother told Dr. Edgar that Victoria may miss a dose of
Keppra “here and there.” Exhibit 9 at 13.

      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 subtherapeutic 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. Because Victoria was concerned about not having insurance, Dr.
Edgar gave her a three-month supply of Keppra. Id. Dr. Edgar noted “probable
juvenile myoclonic epilepsy” at this appointment due to age of onset. Id.11

       The summer of 2013 was the summer after Victoria had graduated from high
school. During her senior year, she earned a mixture of grades. Exhibit 83 at 1.
According to Victoria’s obituary, Victoria planned to enter military service.
Exhibit 110. At Waukesha County Technical College in the fall 2013, Victoria did
not earn any credits as she failed two classes and withdrew from a third. Exhibit
82 at 1.

      11
         Mr. Mager asserted that “Dr. Edgar only suggests the possibility of JME.”
Pet’r’s Posthear’g Br. at 25 (emphasis added). However, Dr. Edgar stated, “The
age of onset at 11 years of age suggests probable juvenile myoclonic epilepsy.”
Exhibit 9 at 4, 27 (emphasis added).
                                        14
       In November 2013, Victoria called Dr. Edgar’s office to say that she was
running out of medication. Exhibit 9 at 11. Due to the lack of records, Dr. Shafrir
could not comment on Victoria’s compliance with her medication in the fall 2013.
Tr. 349-50. According to an account Mr. Mager provided shortly after Victoria’s
death, she picked up more medication over the holidays. Exhibit 13 at 2. On
January 2, 2014, Kathy Mager informed Dr. Edgar’s office that Victoria intended
to transfer her care to a doctor closer to her, although the doctor was not identified.
Exhibit 9 at 9; see also Tr. 355.

       Mr. Mager told medical examiners that in November 2013, Victoria was
occasionally having seizures in her sleep unknowingly. Exhibit 13 at 2; exhibit 16
at 3; see also Tr. 354. How Mr. Mager reached this conclusion is not clear as it
appears that Mr. Mager was not living with Victoria at this time. Tr. 354.
      On January 11, 2014, after being discovered unresponsive at a friend’s
house, Victoria was rushed to the emergency department. Exhibit 8 at 1-2. She
was pronounced dead upon her arrival. Id. at 2. 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. Zelda Okia on January 13, 2014. Exhibit
12 at 1. The findings included pulmonary edema and brain changes consistent
with a seizure disorder. Id. at 2; exhibit 16 at 10. 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.; see also Tr. 302 (Dr. Shafrir: Victoria did not have low levels of medication in
her blood at the time of her death); id. at 467 (Dr. Kohrman: Keppra level of 26 is
in the middle of the therapeutic range).

       Sections of the brain showed focal areas of subpial gliosis. Exhibit 16 at 16.
Gliosis occurs when glial cells cause structural changes to the central nervous
system in response to trauma to the brain, such as seizures. Tr. 395-96. Subpial
gliosis is found in areas of the brain associated with surface pia, including the
superior temporal gyrus and inferior temporal gyrus. Id. at 479-80. All the experts
agreed that epileptic seizures can cause gliosis. Id. at 288 (Dr. Shafrir), 394-97,
415 (Dr. Fujinami). Seizures can cause gliosis with or without an inflammatory
process. Id. at 289-90.

                                          15
       Beyond those foundational points, gliosis was the topic for a great deal of
(conflicting) testimony. See Spec. Mstr. Oral Arg. Tr. 633-37. Dr. Shafrir stated
that the amount of gliosis exceeded the amount expected in a person having
infrequent seizures. The presence of this excessive gliosis, in turn, meant that
Victoria was suffering from a process other than JME. Tr. 287.

       Dr. Fujinami noted that the neuropathologist did not report gliosis around
the blood vessels in the brain. According to Dr. Fujinami, neuropathologists would
report this abnormal finding if they saw it. Tr. 388. From the lack of reporting,
Dr. Fujinami inferred that Victoria’s blood-brain barrier was intact. Id. A secure
blood-brain barrier undermines Dr. Shafrir’s theory that an antigen from the
periphery disturbed Victoria’s central nervous system. Id. at 397. On cross-
examination, Mr. Mager’s attorney ably pointed out that the record does not
contain an actual report from a neuropathologist. Id. at 412-14. Instead, the
autopsy simply states that a neuropathologist from Froedert Hospital, Dr. Cochran,
reviewed the microscopic slides of the brain. Exhibit 16 at 15. In rebuttal
testimony, Dr. Shafrir indicated that there is only one sentence in the autopsy
report about gliosis. Thus, deriving any information from it is difficult. Tr. 555-
57.

      Victoria’s death certificate listed “seizure disorder” as her cause of death.
Exhibit 1 at 1. The testifying neurologists agreed that Victoria suffered sudden
unexpected death in epilepsy (“SUDEP”) as a consequence of her epilepsy. Tr.
355 (Dr. Shafrir), 533-34 (Dr. Kohrman adding factors that placed Victoria at
greater risk for a sudden and unexpected death); see also Spec. Mstr. Oral Arg. Tr.
648-49.

II.   Procedural History
      Represented by attorney Mark Krueger, Mr. Mager alleged that a dose of the
HPV vaccine given to Victoria on September 11, 2012 “aggravated a prior seizure
disorder leading to and causing her death.” Amend. Pet. at ¶ 12. 12 He then

      12
          The original petition, which was filed roughly two months earlier, had
alleged that a dose of the HPV vaccination given on October 2, 2007 caused
Victoria’s seizure disorder. However, the statute of limitations barred proceeding
on a claim based upon the 2007 vaccination. Thus, Mr. Mager’s attorney, Mr.
Krueger, amended the petition to assert a claim that the 2012 vaccination
significantly aggravated the seizure disorder. Although the amended petition also
asserts that the 2012 vaccination caused Victoria’s seizure disorder, Victoria was
already suffering from a seizure disorder before 2012.
                                        16
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 contested Mr. Mager’s entitlement, arguing that Mr. Mager
had not established the elements for a significant aggravation claim. Resp’t’s Rep.,
filed Apr. 1, 2015, 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.

       Mr. Mager’s initial effort to obtain competent reports from experts was not
successful. After multiple extensions, Mr. Mager filed his first expert report from
Dr. Mikovits and Dr. Ruscetti on November 17, 2016. Eventually, Mr. Mager
moved to strike the reports from these partners as well as an expert report from
their colleague, Dr. Aliffe. Thus, the details of these reports from people whom
Mr. Mager retained are no longer evidence and do not need to be discussed further.
However, before Mr. Mager ceased his reliance on Drs. Mikovits, Ruscetti, and
Aliffe, the Secretary responded with reports from Dr. Fujinami and Dr. Kohrman
on March 2, 2017, and March 22, 2017. While Dr. Fujinami and Dr. Kohrman
primarily responded to opinions expressed by Drs. Mikovits, Ruscetti, and Aliffe,
Dr. Kohrman presented some opinions that remained relevant after the withdrawal
of the earlier reports. Dr. Kohrman asserted that (1) the appropriate diagnosis for
Victoria was JME, (2) Victoria’s epilepsy began when she was five years old, and
(3) Victoria’s death was not caused by the HPV vaccination and was more likely
related to Victoria’s actions before her death, such as failing to take her anti-
seizure medication, smoking, drinking beer, and staying up late. Exhibit A at 11-
13; see also exhibit Y (Dr. Kohrman’s report, dated Mar. 18, 2018) at 2, 7.

       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 support his claim better. Mr.
Mager then filed an expert report from Dr. Shafrir on October 3, 2018. The
presentation of Dr. Shafrir’s opinion essentially begins Mr. Mager’s development
of experts.

      In this report, Dr. Shafrir reviewed Victoria’s medical history in detail.
Exhibit 55 at 1-16. In the course of this summary, Dr. Shafrir raised the potential
helpfulness of obtaining the slides from Victoria Mager’s autopsy. 13 Id. at 14. Dr.

      13
         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
                                         17
Shafrir emphasized that Victoria’s case was an example of challenge-rechallenge
in that she “suffered seizures twice within 1 month of each of her HPV
vaccinations.” Id. at 16. As for how the HPV vaccination can cause seizures /
epilepsy, Dr. Shafrir stated the “mechanism is likely based on molecular mimicry
which could be supplemented by activation of the innate immune system.” Id. at
20. He asserted that “Victoria had an abnormal immune reaction to the HPV
vaccination produced brain inflammation in autoimmune epilepsy.” Id.

      In response to Dr. Shafrir, the Secretary obtained reports from the people
who had previously responded to Drs. Mikovits, Ruscetti, and Aliffe. 14 Dr.
Kohrman began, “As I have stated in my previous report Victoria had a preexisting
encephalopathy dating to first grade.” Exhibit Z at 2. Dr. Kohrman also
commented on Victoria’s activities just before she died: “when she was prescribed
meds, she did not take them regularly prior to her death per Mr. Mager’s report.
On the night she died she had stayed up until 4 am drinking beer and smoking.
Again, her death is associated with a seizure in the face of sleep deprivation.” Id.15

        Dr. Fujinami stated that Dr. Shafrir “is opining that components contained
in the vaccine caused an autoimmune epilepsy that resulted in seizures.” Exhibit
AA at 3. Dr. Fujinami questioned whether Victoria suffered an autoimmune
process because “there is no indication of autoimmune indicators being present.”
Id. Dr. Fujinami also raised doubts about molecular mimicry because one article
(Ruiz) showed that peptides from the human papillomavirus “could actually
protect from autoimmune neuroinflammation.” Id. at 3-4, citing exhibit AA, tab 5
(Pedro J. Ruiz et al., Microbial Epitopes Act as Altered Peptide Ligands to Prevent
Experimental Autoimmune Encephalomyelitis, 189 J. Experimental Med. 1275
(1999)).16
      Given that the Secretary submitted reports from Dr. Kohrman and Dr.
Fujinami, the next step was for Mr. Mager to respond. This process was delayed

failed to reach a settlement agreement and the case was removed from ADR on
March 25, 2019.
      14
         The reports from Dr. Kohrman and Dr. Fujinami also addressed the most
recent reports from Drs. Mikovits, Ruscetti, and Aliffe. But, again, these
comments are no longer relevant.
      15
           Dr. Kohrman’s response to Dr. Shafrir’s report was essentially one page.
      16
        Like Dr. Kohrman, Dr. Fujinami responded to Dr. Shafrir in essentially
one page.
                                          18
as Mr. Mager attempted to get the autopsy slides. 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. Thus, it appeared that the submission of reports from experts was
concluded.

       The undersigned issued an order for submissions in advance of potential
adjudication on November 20, 2019. This order informed the parties that the case
might be decided without a hearing. Order, issued Nov. 20, 2019, at 1. Citing
Broekelshen v. Secretary of Health & Human Services, 618 F.3d 1339, 1346 (Fed.
Cir. 2010), the undersigned directed the parties to comment upon the appropriate
diagnosis for Victoria. This discussion was requested because Dr. Kohrman
“proposed that Victoria suffered from juvenile myoclonic epilepsy. . . . While [Dr.
Shafrir] seems to be opining that Victoria suffered an encephalopathy and Victoria
suffered from an autoimmune epilepsy, not juvenile myoclonic epilepsy.” Order,
issued Nov. 20, 2019, at 5, citing exhibit A at 13 and exhibit 55 at 18-22. In this
context, the parties were instructed to identify the diagnostic criteria for any
relevant condition. The parties also were instructed to address the six Loving
factors concerning whether a vaccine significantly aggravated an underlying
condition. Id. at 6-11. The order also raised, in a separate section, the topic of
how Victoria would have been but for the vaccination. Id. at 11.

       This order prompted Mr. Mager to obtain another report from Dr. Shafrir,
which Mr. Mager filed on July 25, 2020, after receiving multiple extensions. This
new report is approximately six pages with another two pages devoted to
references. Exhibit 85. Dr. Shafrir began with the “importance of
challenge/rechallenge.” Id. at 1. Consistent with the November 20, 2019 order,
Dr. Shafrir commented upon the appropriate diagnosis. He stated that Victoria
“suffered SUDEP [sudden unexpected death in epilepsy] as a result of the acquired
autoimmune epilepsy, which was the result of her repeated HPV vaccination.” Id.
at 2. Dr. Shafrir explained why the diagnosis that Dr. Kohrman proposed, JME,
does not fit. Id. at 2-3. Rather, the “basis for the presumed autoimmune epilepsy
is the striking relationship of the seizures to the HPV immunization.” Id. at 3. Dr.
Shafrir also added approximately a dozen articles to support “the role of HPV
vaccination in Ms. Mager[’s] autoimmune epilepsy.” Id. at 4.

      Two days after filing Dr. Shafrir’s supplemental report, Mr. Mager made his
arguments. Under the topic of “diagnosis,” Mr. Mager asserted, “Petitioner
contends Victoria suffered from autoimmune epilepsy that resulted in sudden
unexpected death with epilepsy.” Pet’r’s Prehear’g Br., filed July 27, 2020, at 9.
After discrediting the diagnosis of JME, Mr. Mager contended that “Victoria’s
most likely, most appropriate diagnosis would be autoimmune epilepsy.” Id. Mr.
                                         19
Mager presented three ways in which autoimmune epilepsy is typically diagnosed.
However, Mr. Mager did not identify any evidence supporting the ways
autoimmune epilepsy is typically diagnosed. Id. at 9-10. Mr. Mager asserted, “as
demonstrated by Suleiman et al. (Exhibit 88), autoimmune epilepsy can also be
present as milder epilepsy cases.” Id. at 10.

       In introducing his analysis of the Loving factors, Mr. Mager stated,
“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.” Id. at 16. “Molecular mimicry is the most likely
mechanism” by which the HPV vaccine triggered seizures. Id. at 21. Although
Mr. Mager discussed aspects of this theory for several pages, he stated, “all of this
underpins Petitioner’s theory of causation which is based on
challenge/rechallenge.” Id. at 23. Mr. Mager added that “while he alleges the first
HPV [dose] caused Victoria’s onset of autoimmune epilepsy, his claim is for the
significant aggravation of her epilepsy (largely controlled and seizure-free for five
years) by her second dose of HPV. Petitioner is not precluded from using the first
dose of HPV vaccination as part of her challenge/rechallenge claim as she is not
claiming injury from the initial insult.” Id. at 46.

       Due to the presentation of a new report from Dr. Shafrir, the Secretary had a
chance to respond and did so by filing a report from Dr. Kohrman and a report
from Dr. Fujinami. Dr. Kohrman opined about the appropriate diagnosis. He set
forth the diagnostic criteria for JME. Exhibit BB at 2. Dr. Kohrman also defined
the diagnostic criteria for autoimmune epilepsy. Id. at 11-12. He extensively
summarized the events in Victoria’s medical history. Id. at 3-10. He concluded, as
he did in other reports, that Victoria’s seizure disorder is consistent with JME. Id.
at 14.

      Dr. Kohrman disputed the presence of challenge-rechallenge. He
maintained that Victoria’s case did not constitute an example of challenge-
rechallenge. He explained, “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 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 [the] second vaccination.” Id. at 12.

       Dr. Kohrman also maintained, as he had in previous reports, that before the
first vaccination Victoria had nocturnal seizures. Id. at 13, citing exhibit 6 at 25
and exhibit 11 at 22. Dr. Kohrman did not address the medical theory that Dr.
Shafrir had proposed to explain how a HPV vaccine can aggravate a preexisting
seizure disorder. See exhibit BB at 14.
                                         20
       In conjunction with Dr. Kohrman’s report, the Secretary also submitted a
report from Dr. Fujinami, which is essentially one and a half, single-spaced pages.
Dr. Fujinami also disputed whether Victoria’s case is an example of challenge-
rechallenge. Dr. Fujinami argued “there is no clear information linking the
occurrence of seizures to [the] HPV vaccination, let alone an enhanced immune
response occurring against the second HPV vaccination due to immunological
memory present after the first vaccination with HPV.” Exhibit CC at 1.

       While Dr. Fujinami recognized that he is not a physician, Dr. Fujinami
opined that Victoria “was not consistently taking her anti-seizure medications,
which led to the increase of seizures.” Id. He also indicated that Victoria did not
suffer from autoimmune epilepsy, which was the diagnosis given by Dr. Shafrir.
Id.

       With the reports from Dr. Kohrman and Dr. Fujinami, the Secretary also
filed his brief. A central portion of the Secretary’s argument was that Victoria did
not suffer from autoimmune epilepsy and that her diagnosis is JME. Resp’t’s
Prehear’g Br., filed Feb. 10, 2021, at 10-15. The basic diagnostic criteria,
according to the Secretary and Dr. Kohrman, came from the Higdon and Steriade
articles. Id. at 11-12, citing exhibit BB, tab 4 (Lindsay M. Higdon, Autoimmune
Epilepsy: More than Just a Paraneoplastic Syndrome, Practical Neurology, Oct.
2018) and exhibit BB, tab 5 (Claude Steriade et al., Acute Symptomatic Seizures
Secondary to Autoimmune Encephalitis and Autoimmune-Associated Epilepsy:
Conceptual Definitions, 61 Epilepsia 1341 (2020)). In his brief, the Secretary also
addressed the Loving prongs. Id. at 17-26.
       Mr. Mager replied to the Secretary’s arguments. Under the heading,
“VICTORIA’S DIAGNOSIS,” Mr. Mager asserted that “Victoria suffered from
autoimmune epilepsy, which caused SUDEP.” Pet’r’s Prehear’g Reply, filed Mar.
26, 2021, at 10. He continued, “Victoria suffered from autoimmune epilepsy based
on her well-documented systems [sic, “symptoms” might have been intended] and
the appropriate diagnostic criteria.” Id. With respect to the diagnostic criteria, it
appeared that Mr. Mager cited reference 9 in exhibit 65 multiple times. However,
that reference was not an exhibit. Mr. Mager also maintained that he satisfied the
Loving factors. Id. at 37-50.

       Because Mr. Mager had cited, but not filed, reference 9 in exhibit 65, he was
directed to file it as an exhibit. Mr. Mager was also instructed to identify “the
source of the diagnostic criteria for autoimmune epilepsy.” Order, issued June 16,
2021.

                                         21
       In response, Mr. Mager clarified that “Pet. Ex. 65. Ref. 9 . . . does not refer
to the ninth reference in Pet. Ex. 65. Rather, Pet. Ex. 65 is also Ref. 09 in Dr.
Shafrir’s first expert report, filed as Pet. Ex. 55.” Pet’r’s Status Rep., filed June 17,
2021. For the diagnostic criteria, Mr. Mager stated that “the list itself does not
appear – it was derived from Pet. Ex. 88 along with Pet. Ex. 65. The criteria are
discussed in that section solely to demonstrate that autoimmune epilepsy can
present as milder epilepsy.” Id.

       The undersigned denied compensation. Decision, 2021 WL 3737056 (Fed.
Cl. Spec. Mstr. July 29, 2021). The undersigned found that there was insufficient
evidence to support a diagnosis of autoimmune epilepsy. Id. at *11. The
undersigned reasoned that Mr. Mager had not met his burden to show either the
presence of autoimmune antibodies in Victoria’s blood or that Victoria’s seizures
were refractory. Id. at *7-8, 10. Additionally, the undersigned found that Mr.
Mager did not establish that Victoria suffered from autoimmune encephalitis. Id.
at *9. Accordingly, since the undersigned found that Mr. Mager did not establish
the threshold issue of diagnosis and analysis of causation was therefore
unnecessary, compensation was denied. Id. at *11.

        Mr. Mager filed a motion for review on August 27, 2021. Mr. Mager argued
that the undersigned mischaracterized Victoria’s diagnosis. Mot. for Rev., filed
Aug. 27, 2021, at 2. He asserted that the undersigned conflated Victoria’s pre-
death diagnosis and her alleged injury and focused only on autoimmune epilepsy
with respect to Dr. Shafrir’s causation theory instead of considering the theory in
its full context. Id. at 20. Mr. Mager acknowledged that Victoria did not meet the
criteria for autoimmune epilepsy but maintained that Victoria’s epilepsy was
“autoimmune in nature.” Id. at 21.

       The Court granted Mr. Mager’s motion for review and vacated the
undersigned’s decision denying compensation. Opinion and Order, issued Jan. 21,
2022, at 2, 158 Fed. Cl. 136, 137 (2022). The Court noted that the undersigned
was thorough in explaining why Victoria did not have autoimmune epilepsy. Id. at
19, 158 Fed. Cl. at 155. However, the Court concluded that the undersigned
mischaracterized Victoria’s diagnosis and misunderstood Mr. Mager’s argument
that “the vaccine caused an autoimmune response triggered recurrence and
aggravation of [Victoria’s] epilepsy disorder.” Id. Accordingly, the case was
remanded to the undersigned to consider whether Mr. Mager can satisfy the
elements for an off-Table claim under Althen v. Secretary of Health & Human
Services, 418 F.3d 1274, 1278 (Fed. Cir. 2005). Id. at 24, 158 Fed. Cl. at 160.

                                           22
       Following the Court’s Opinion and Order, the case was promptly scheduled
for a hearing.17 The hearing was held via videoconferencing over two days, March
8-9, 2022. Dr. Shafrir, Dr. Kohrman, and Dr. Fujinami testified.

       After the hearing, the parties argued their positions in briefs, filed on an
expedited basis. Mr. Mager submitted his primary brief on March 25, 2022 and his
reply on April 5, 2022. In between, the Secretary filed his brief on April 1, 2022.
An oral argument was held on April 8, 2022.

III.   Standards for Adjudication

      A petitioner is required to establish his case 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 & Hum. Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations
omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health &
Hum. Servs., 931 F.2d 867, 873 (Fed. Cir. 1991).
      Distinguishing between “preponderant evidence” and “medical certainty” is
important because a special master should not impose an evidentiary burden that is
too high. Andreu v. Sec’y of Health & Hum. Servs., 569 F.3d 1367, 1379-80 (Fed.
Cir. 2009) (reversing a special master’s decision that petitioners were not entitled
to compensation); see also Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d
1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Hum. Servs., 9 F.3d 958, 961
(Fed. Cir. 1993) (disagreeing with the dissenting judge’s contention that the special
master confused preponderance of the evidence with medical certainty).

       As confirmed in W.C. v. Secretary of Health & Human Services, 704 F.3d
1352, 1357 (Fed. Cir. 2013), the elements of an off-Table significant aggravation
case were stated in Loving v. Secretary of Health & Human Services, 86 Fed. Cl.
135 (2009). There, the Court blended the test from Althen, which defines off-
Table causation cases, with a test from Whitecotton v. Secretary of Health &
Human Services, 81 F.3d 1099, 1107 (Fed. Cir. 1996), which concerns on-Table
significant aggravation cases. The resulting test has six components. These are:

       (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

       17
            The cooperation of the attorneys and witnesses is appreciated.
                                           23
      “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
      showing of a proximate temporal relationship between the vaccination and
      the significant aggravation.

Loving, 86 Fed. Cl. at 144.

      Additional details about how to evaluate each prong are provided in the
analysis section below.

IV.   Analysis
       The analysis consists of eight sections. The first section reviews the topic of
diagnosis, which is no longer disputed. The next six sections concern the elements
of significant aggravation set forth in Loving. Mr. Mager bears the burden of
proof on each of these six elements. The final section (section IV.H) considers
whether the Secretary has met his burden of proof in showing that Victoria’s
epilepsy followed the natural course of the disease.

       A.      Diagnosis

               1.    Procedural Aspects to Diagnosis and the Parties’ Arguments
      Among the experts testifying in this case, Dr. Kohrman presented the first
opinion regarding diagnosis. 18 He opined that Victoria suffered from juvenile
myoclonic epilepsy (“JME”). Exhibit A at 11-13.
      In response, Dr. Shafrir disagreed with the opinion that Victoria suffered
from JME. Dr. Shafrir opined that “Victoria had an abnormal immune reaction to
the HPV vaccination which produced brain inflammation in autoimmune
epilepsy.” Exhibit 55 at 20. The term “generalized epilepsy” does not appear in
Dr. Shafrir’s first report. See id. Dr. Shafrir also did not indicate that Victoria’s
epilepsy was either “mild” or “not severe.”
      Perceiving a dispute over diagnosis, the undersigned ordered the parties to
comment on the condition the HPV vaccination aggravated. Order, issued Nov.
20, 2019, at 5, citing Broekelschen, 618 F.3d at 1346. This direction was based
upon a view that Dr. Kohrman had “proposed that Victoria suffered from juvenile

      18
           The reports from an earlier set of experts were struck.
                                           24
myoclonic epilepsy . . . . While [Dr. Shafrir] seems to be opining that Victoria
suffered an encephalopathy and Victoria suffered from an autoimmune epilepsy,
not juvenile myoclonic epilepsy.” Id. The parties were also ordered to identify the
diagnostic criteria for any relevant condition.

        Mr. Mager filed a second report from Dr. Shafrir. Dr. Shafrir opined that
Victoria “suffered SUDEP as a result of the acquired autoimmune epilepsy, which
was the result of her repeated HPV vaccination.” Exhibit 85 at 2. Dr. Shafrir also
indicated that SUDEP “can occur in patients whose epilepsy is not that severe.”
Id. at 1. Dr. Shafrir, however, did not explicitly state that Victoria’s epilepsy was
either mild or not severe. Dr. Shafrir added, “The epilepsy diagnosis (not relating
to specific etiology) is either secondary generalized epilepsy or symptomatic
generalized epilepsy. The etiology of this epilepsy is autoimmune, induced by [an]
abnormal immune reaction to the HPV vaccination.” Id. at 4.

       When Mr. Mager advocated his position, he argued, “Petitioner contends
Victoria suffered from autoimmune epilepsy that resulted in sudden unexpected
death with epilepsy.” Pet’r’s Prehear’g Br., filed July 27, 2022, at 9, citing exhibit
55 (Dr. Shafrir’s first report) at 18. Mr. Mager further argued that Dr. Shafrir
“strongly disagrees” with the assertion that Victoria suffered from JME. Id. Mr.
Mager maintained that “Victoria’s most likely, most appropriate diagnosis would
be autoimmune epilepsy.” Id. Mr. Mager also presented three factors by which
autoimmune epilepsy “is typically diagnosed.” Id. at 9-10. Citing the Suleiman
article (exhibit 88), Mr. Mager asserted that “autoimmune epilepsy can also be
present as milder epilepsy cases.” Id. at 10. In this brief, Mr. Mager did not argue
that an analysis of diagnosis pursuant to Broekelschen was inappropriate. See id.

       In contrast, the Secretary explicitly argued that whether Mr. Mager had
persuasively established that Victoria suffered from JME was a fundamental point.
“As the Federal Circuit has made clear, ‘the statute places the burden on petitioner
to make a showing of at least one defined and recognized injury.’” Resp’t’s
Prehear’g Br., filed Feb. 10, 2022, at 14, quoting Lombardi v. Sec’y of Health &
Hum. Servs., 656 F.3d 1343, 1353 (Fed. Cir. 2011). The Secretary further
maintained that Victoria did not suffer from autoimmune epilepsy but rather
suffered from JME. Id. at 10-15. This position was in accord with Dr. Kohrman’s
most recent report. See exhibit BB.

      Mr. Mager quoted the portion of the Secretary’s prehearing brief that cited
Broekelschen and Lombardi. Mr. Mager argued that Lombardi was an “unusual”
case. Pet’r’s’ Prehear’g Reply, filed Mar. 26, 2021, at 10, citing Contreras v. Sec’y
of Health & Hum. Servs., 107 Fed. Cl. 280, 294 (2012). Otherwise, Mr. Mager
advanced the position that “Victoria suffered from autoimmune epilepsy.” Id. at
                                          25
10. Mr. Mager did not qualify this assertion by describing Victoria’s epilepsy as
either “mild” or “not severe.” See id. Concomitantly, Mr. Mager argued that the
Secretary “failed to show Victoria suffered from juvenile myoclonic epilepsy.” Id.
at 16 (capitalization changed without notation).

      In response to an order, Mr. Mager provided additional information
regarding the diagnostic criteria for autoimmune epilepsy. He stated that the
diagnostic criteria in his briefs were derived from two exhibits, exhibits 88 and 65.
“The criteria are discussed in that section solely to demonstrate that autoimmune
epilepsy can present as milder epilepsy.” Pet’r’s Status Rep., filed June 16, 2021.
      The undersigned found that Mr. Mager asserted that Victoria suffered from
autoimmune epilepsy and that Mr. Mager had not persuasively demonstrated that
autoimmune epilepsy was an appropriate diagnosis. Decision, issued July 29,
2021. Because this appeared to be a predicate showing, the decision found that
Mr. Mager was not entitled to compensation. The decision did not address whether
preponderant evidence supported a finding that Victoria suffered from JME. The
decision did not quote the portion of the June 16, 2021 status report in which Mr.
Mager maintained that “autoimmune epilepsy can present as milder epilepsy.”

      Mr. Mager challenged this decision by filing a motion for review. In
relevant part, he argued that Broekelschen was distinguishable because the parties
agreed that Victoria suffered from epilepsy. Pet’r’s Mot. for Rev., filed Aug. 27,
2021, at 18.
       The Secretary in turn, defended the July 29, 2021 decision. Citing
Broekelschen and Lombardi, the Secretary argued that Mr. Mager needed to show
the injury (autoimmune epilepsy) that he alleged the HPV vaccine aggravated.
Resp’t’s Resp. to Mot. for Rev., filed Sept. 24, 2021, at 6-7.

       The Court granted the motion for review. The Court found that “JME and
autoimmune epilepsy are variants of the same disorder—i.e., a seizure disorder.”
Opinion and Order, at 20, 158 Fed. Cl. at 156. Because the “‘existence and nature
of the injury’ was not in dispute,” “the Special Master erred in failing to consider
whether the vaccine caused Ms. Mager’s injury under Althen and its progeny.” Id.
at 22, 158 Fed. Cl. at 158. In terms of direction, the Court indicated that “the
Special Master must perform the requisite causation analysis under Althen and its
progeny.” Id.

       During the post-remand hearing, the parties continued to develop evidence
regarding the type of epilepsy Victoria suffered. Dr. Shafrir stated that Victoria
suffered from partial epilepsy with secondary generalizations. Tr. 296, 316; see

                                         26
also id. at 548-49 (rebuttal testimony). He also explained why, in his opinion,
Victoria did not suffer from JME. Id. at 308-14. Dr. Kohrman had the opposite
point of view. 19 He stated that Victoria suffered from JME. Id. at 443-69. Dr.
Kohrman also discussed why autoimmune epilepsy (or epilepsy with an
autoimmune basis) is not an appropriate diagnosis for Victoria. Id. at 471-91.

      After the hearing, Mr. Mager’s position matched the opinion offered by his
expert, Dr. Shafrir. Mr. Mager asserted “that as a result of the HPV vaccination
Victoria Mager developed epilepsy which is partial with secondary generalization
on an autoimmune basis.” Pet’r’s Posthear’g Br., filed Mar. 25, 2022, at 18.

             2.    Resolution

       “Upon return of its mandate, the district court cannot give relief beyond the
scope of that mandate, but it may act on matters left open by the mandate.”
Laitram Corp. v. NEC Corp., 115 F.3d 947, 951 (Fed. Cir. 1997) (quoting Caldwell
v. Puget Sound Elec. Apprenticeship & Training Tr., 824 F.2d 765, 767 (9th Cir.
1987)) (internal quotation marks omitted). Furthermore, the doctrine of the law of
the case, which precludes relitigation of issues explicitly or implicitly decided on
appeal, sheds light on implicit appellate considerations of arguments. See
Travelers Ins. Co. v. United States, 72 Fed. Cl. 316, 325 (2006) (citing W.L. Gore
& Assocs., Inc. v. Garlock, Inc., 842 F.2d 1275, 1278 (Fed. Cir. 1988)) (“The
doctrine [of the law of the case], of course, does not constrain a trial court’s
consideration of an issue that has not been considered on appeal. But the doctrine
extends to issues that were implicitly addressed.”).

      Through the parties’ briefs and oral argument, the Court understood their
competing positions. Reduced to its simple terms, Mr. Mager’s argument was that
evaluating whether Victoria suffered autoimmune epilepsy was irrelevant because
the parties agreed she had a seizure disorder and his theory for significant
aggravation was based on rechallenge. In contrast, the Secretary argued that an
Althen analysis is possible only after a determination of whether a vaccinee suffers
from a specific condition.

      The Court found Victoria had a seizure disorder. Opinion and Order at 20,
158 Fed. Cl. at 156. The Court further ruled the precise type of seizure disorder

      19
         Dr. Fujinami also expressed the opinion that Victoria suffered from JME.
Tr. 393. However, because Dr. Fujinami is not a medical doctor, his opinion
regarding diagnosis merits less weight than the opinion of a neurologist, like Dr.
Shafrir or Dr. Kohrman.
                                        27
did not matter because it found autoimmune epilepsy and juvenile myoclonic
epilepsy are on the same spectrum. Id. at 21-22, 158 Fed. Cl. at 157-58. The
Court did not remand with instructions to reevaluate whether Victoria suffered
from autoimmune epilepsy. The Court also did not remand with instructions to
determine, for the first time, whether Victoria suffered JME. The Court remanded
for a causation analysis.

       Due to this procedural posture, any questions whether Victoria suffered from
autoimmune epilepsy, JME, or partial epilepsy with secondary generalizations are
not within the scope of remand. The parties agree with this assessment. See
Pet’r’s Posthear’g Br., filed Mar. 25, 2022, at 28-29; Resp’t’s Posthear’g Br., filed
Apr. 1, 2022, at 55-56. The Court has found the operative diagnosis is “seizure
disorder.” Thus, the remainder of this discussion uses this term, although another
appropriate term might be “epilepsy.”

       B.    Loving Prong One
      The first Loving prong is to establish “the person’s condition prior to
administration of the vaccine.” Loving, 86 Fed. Cl. at 144. Here, restating the
vaccine at issue is critical.

       The operative vaccine is the second dose, which was given on September 11,
2012. Mr. Mager cannot recover compensation based upon the first dose of HPV
vaccine, given on October 2, 2007, because Victoria experienced a seizure on
November 14, 2007. This November 14, 2007 seizure occurred more than 36
months before Mr. Mager filed his petition. See 42 U.S.C. § 300aa-16(a)(2); cf.
Pet’r’s Prehear’g Br. at 46 (“Petitioner concedes that he has not alleged injury from
the first HPV vaccine . . . .”). 20

       Before this vaccine, Victoria had not suffered any seizures in nearly five
years. While Dr. Kohrman is correct that, as a matter of logic, Victoria could have
had a seizure that no one witnessed and about which Victoria herself was unaware,
Tr. 453-54, this argument does not rise to a level of preponderant proof. Victoria’s
parents appear to have brought her to doctors as needed. When the family saw a
doctor, they appeared to try to communicate information about behaviors possibly
consistent with a seizure. See Exhibit 6 at 20 (Dr. Koehn’s February 21, 2008
report); Exhibit 9 at 39 (Dr. Budde’s November 8, 2012 report). The lack of

      20
        Mr. Mager has not claimed the statute of limitations for a claim based
upon the October 2, 2007 vaccination should be equitably tolled.
                                         28
medical records reporting seizures for approximately five years tends to show that
Victoria was not having seizures, at least at the more likely than not standard.

        Although Victoria had not had any seizures in approximately five years
before the September 11, 2012 vaccination, five years earlier she did have seizures.
As explained above in section I.A, Victoria started having manifestations of her
seizure disorder before she received the first HPV vaccination. This finding is
based upon all the evidence, including the medical records, affidavits and the
reports and testimony of Dr. Shafrir and Dr. Kohrman. Because Victoria’s seizures
started before the October 2, 2007 HPV vaccination, the first HPV vaccination did
not cause the seizure disorder. Locane v. Sec’y of Health & Hum. Servs., 685 F.3d
1375, 1381 (Fed. Cir. 2012); accord Tr. 263. But, this finding carries little
consequence to Mr. Mager’s case for two reasons. First, as noted above, the
October 2, 2007 vaccination is not the basis for Mr. Mager’s claim. Second, as
discussed more extensively below, Ms. Mager has presented the alternative
argument that the first HPV vaccination made her seizure disorder worse. See Tr.
263-64. This worsening, according to Mr. Mager, constitutes a “challenge” event
that is one part of the challenge-rechallenge paradigm.

       C.    Loving Prong Two
       The second Loving prong is to find “the person’s current condition (or the
condition following the vaccination if that is also pertinent).” Loving, 86 Fed. Cl.
at 144. After the September 11, 2012 HPV vaccination, Victoria suffered her first
seizure in approximately five years on October 10, 2012. Exhibit 7 at 9. She had
additional seizures on October 19, 2012 and November 7, 2012. Exhibit 9 at 6 (Dr.
Edgar), 39 (Dr. Budde). She was then placed on anti-seizure medications.

      Roughly 15 months after the second dose of the vaccination, Victoria died.
Exhibit 1 (death certificate). The testifying neurologists agreed that Victoria’s
death was due to SUDEP. Exhibit 85 at 2; exhibit A at 13; Tr. 355, 533-34.

       D.    Loving Prong Three

       The third Loving prong is to find “whether the person’s current condition
constitutes a ‘significant aggravation’ of the person's condition prior to
vaccination.” Loving, 86 Fed. Cl. at 144. A “significant aggravation” means “any
change for the worse in a preexisting condition which results in a markedly greater
disability, pain, or illness accompanied by substantial deterioration of health.” 42
U.S.C. § 300aa-33(4).

      Whether any worsening is due to the natural course of Victoria’s underlying
seizure disorder is not part of this analysis. Sharpe v. Sec’y of Health & Hum.
                                           29
Servs., 964 F.3d 1072 (Fed. Cir. 2020). Resolution of that issue is deferred to
section IV.H, below.

       Here, in briefs filed after the hearing, the parties contested this issue
stridently. Mr. Mager maintained that before the second HPV vaccination,
Victoria “was able to live a normal life” and was “seizure-free for almost five
years.” Pet’r’s Posthear’g Br. at 60-61. Then, after the second vaccination, she
experienced seizures “in a greater quantity, frequency, and severity.” Id. at 61.

       In contrast, the Secretary contended that Victoria “had mild epilepsy before
her September 11, 2012, vaccination, and she had mild epilepsy after her
September 11, 2012, vaccination.” Resp’t’s Posthear’g Br. at 16-17. The basis for
the Secretary’s argument regarding the “mildness” of Victoria’s epilepsy comes
from Dr. Shafrir’s testimony. Tr. 238, 344, 561. The Secretary further argued that
Victoria’s death was not due to any worsening of her epilepsy. Resp’t’s Posthear’g
Br. at 16.

        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.” Pet’r’s
Posthear’g Reply, filed Apr. 5, 2022, at 20. Mr. Mager pointed to the abnormal
EEG on January 14, 2013 as evidence that Victoria’s condition had deteriorated.
Id. at 20-21, citing exhibit 9 at 25.

      The parties amplified their positions during oral argument. Spec. Mstr. Oral
Arg. Tr. 619-20, 627-30 (Mr. Mager), 621-26, 630-31 (the Secretary).

      This issue is close. The Secretary’s argument that Victoria’s epilepsy was
mild before the September 11, 2012 vaccination and mild after the September 11,
2012 vaccination has merit. Following the vaccination, Victoria’s suffered three
seizures, but each seems mild. See exhibit 7 at 9; exhibit 9 at 39 (Dr. Budde’s
Nov. 8, 2012 report), 6. Then, she went for approximately eight months without
having more seizures when she was taking anti-seizure medications. Exhibit 9 at 3
(Dr. Edgar’s July 8, 2013 report).

      Nevertheless, the evidence preponderates in favor of finding that Victoria’s
condition was worse than her condition before the vaccination. Before the
vaccination, Victoria had not had a seizure in approximately five years and was not
taking any anti-seizure medications. Afterwards, Victoria suffered three seizures

                                         30
within about one month and began taking medications. This deterioration in health
constitutes a significant aggravation as defined in 42 U.S.C. § 300aa-33(4).

      E.     Loving Prong Six / Althen Prong Three

      The resolution of the timing prong affects the remaining two prongs. See
Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1326 (Fed. Cir.
2006). Thus, this prong is addressed before an evaluation of the theory and logical
sequence prongs.

             1.    Standards for Adjudication

      The third Althen prong, which corresponds to the sixth Loving prong,
requires the petitioner to show a “proximate temporal relationship” between the
vaccination and the alleged injury. Althen, 418 F.3d at 1281. The timing prong of
Althen contains two parts. A petitioner must establish the “timeframe for which it
is medically acceptable to infer causation” and show that the onset of the disease
occurred in this period. Shapiro, 101 Fed. Cl. at 542-43.

             2.    Parties’ Arguments
                   a)     Events in Victoria’s Life
      With respect to the question of when Victoria experienced observed
generalized tonic-clonic seizures after the vaccinations, the parties agree. Victoria
received her first HPV vaccination on October 2, 2007, and had her first tonic-
clonic seizure on November 14, 2007. Exhibit 3 (vaccination record); exhibit 11 at
13 (emergency department record). The period between these events is 43 days.
Tr. 249 (Dr. Shafrir); Pet’r’s Prehear’g Br., filed July 27, 2022, at 45. 21

      21
         One reason for finding that Victoria’s seizures started before the
vaccination was that a medical record created during her hospitalization for
November 14, 2007 generalized tonic-clonic seizure indicated that Victoria had
questionable events “2 month[s]” and “2 week[s]” earlier. Exhibit 11 at 30; see
also footnote 6 above. It seems that to be consistent, if the report of “2 months” is
credited, then the report of “2 weeks” also should be credited. And, if the report of
“2 weeks” is credited, then Victoria suffered a seizure on October 31, 2007, which
is 29 days after the October 2, 2007 vaccination. See exhibit 55 (Dr. Shafrir’s first
report) at 17 (stating that before the November 14, 2007 tonic-clonic seizure,
“there were suggestion[s] that the seizures were occurring earlier”).
       However, neither party relied upon the report of “2 weeks.” Thus, the
undersigned will not rule upon an assertion that neither party has made. See Doles
                                          31
      For the second HPV vaccination, the latency is 29 days. Tr. 280 (Dr.
Shafrir). Victoria received the second dose on September 11, 2012. Exhibit 3.
She experienced a seizure for which she sought treatment at Theda Clark on
October 10, 2012. Exhibit 7 at 9.

                   b)     Proximate Temporal Interval

      While the parties agree about this chronology, the parties question the
appropriate temporal interval. Relying on the Slade post-marketing study (exhibit
59), Dr. Shafrir asserted that Victoria’s “seizure occurred within the risk period of
42 days defined by the study.” Exhibit 55 at 18.22 Dr. Shafrir also 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 20.

       Neither Dr. Kohrman nor Dr. Fujinami questioned the timing in their
responsive reports. See exhibits Z and AA. In his first report, Dr. Fujinami noted
that nearly 90 million doses of the HPV vaccine were administered in the United
States between June 2006 and March 2016. Exhibit I at 3. Among 90 million
doses administered, he stated that “there will be overlap with individuals who will
present with seizures following vaccination.” Id. Dr. Shafrir did not expand upon
his opinion regarding timing in his rebuttal report. See exhibit 85. Likewise, the
reports from Kohrman and Dr. Fujinami, which were submitted with briefs in
advance of adjudication, did not focus on timing. See exhibits BB and CC.

      In his brief before remand, Mr. Mager relied on the Slade post-marketing
study of HPV vaccinations that showed that the median time between
immunization and onset of hypersensitivity reactions was 17 days, with a range of
8-49 days. Pet’r’s Prehear’g Br., filed Mar. 25, 2022, at 45, citing exhibit 59
(Barbara A. Slade et al., Postlicensure Safety Surveillance for Quadrivalent Human
Papillomavirus Recombinant Vaccine, Am. Med. Ass’n (2009)) at 754. He
emphasized that the Slade study described 4-42 days as “biologically plausible” for
onset of transverse myelitis and Guillain-Barré syndrome (“GBS”) following the
HPV vaccine. Id. Although Mr. Mager acknowledged that onset of autoimmune

v. Sec’y of Health & Hum. Servs., No. 17-642V, 2022 WL 1231434 (Fed. Cl. Apr.
1, 2022) (granting a motion for review when a special master accepted a theory
that petitioner did not assert).
      22
         Although Dr. Shafrir asserts that Victoria’s seizure occurred within 42
days, the seizure happened on the forty-third day after vaccination.
                                         32
disorders normally occurs within 3 weeks following the first or second HPV
vaccination, he maintained that reports of a three-week onset are “not dispositive.”
Id.

      Initially, the Secretary did not challenge whether 42 days (or 43 days) was
an appropriate temporal interval. Instead, the Secretary argued, “Even if the time
between Ms. Mager’s vaccination and the onset of her epilepsy were considered
‘medically acceptable to infer causation-in-fact,’ it is well established that temporal
proximity is insufficient to establish causation.” Resp’t’s Prehear’g Br., filed Apr.
1, 2022, at 23, citing Moberly, 592 F.3d at 1323 and Grant v. Sec’y of Health &
Hum. Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992).

       On direct examination during the hearing, Dr. Shafrir’s testimony regarding
timing was relatively brief, spanning approximately three pages. Tr. 239-42.
Again, referencing the Slade post-marketing study, Dr. Shafrir opined that the
period of 4-42 days is considered biologically plausible. Id. at 240. Dr. Shafrir
added that the Secretary has associated some injuries that occur as long as 42 days
after vaccination in the Vaccine Injury Table. Id. at 240.

       The Secretary’s cross-examination attempted to undermine Dr. Shafrir’s
opinion. Dr. Shafrir conceded that in his first report, he wrote that “the time
interval between the [first] vaccination and the seizure was longer than we
typically associate with vaccine side effects.” Tr. 250; exhibit 55 at 17. When
pressed to explain what immunologic process could be occurring 42 or 43 days
after a vaccination, Dr. Shafrir stated that he expected the adaptive immune system
(not the innate immune system) would be involved. Tr. 253, 259.

       The Secretary further probed Dr. Shafrir’s assertion that a 29-day interval
would be appropriate for a rechallenge event. Tr. 280-85. Dr. Shafrir had relied
upon a paper by Margaret Stanley that measured responses to the HPV
vaccinations. Exhibit 68 (Margaret Stanley, HPV – Immune Response to Infection
and Vaccination, 5 Infectious Agents and Cancer 19 (2010)). According to this
article, “Antigen challenge at 60 months post dose 1 with the quadrivalent vaccine
results in a rapid and robust anamnestic response with antibody levels rising within
3-5 days to levels greater than that achieved at peak in the initial immunisation
schedule[,] demonstrating the presence of reactive memory B cells.” Id. at 22.
When asked to explain why Victoria would develop seizures approximately three
and a half weeks after the antibodies peaked, Dr. Shafrir did not have a persuasive
answer. Tr. 282-84.

      Dr. Shafrir fell back to relying upon the Slade study. Tr. 284. Dr. Shafrir
indicated that these authors “state that 4 to 42 days is [a] biologically plausible
                                          33
time interval [for] the appearance of side effects of vaccination.” Id. at 285. When
pressed to say why the authors found 42 days plausible, Dr. Shafrir testified, “They
do not explain.” Id. When asked what his opinion is, Dr. Shafrir stated, “I don’t
have a strong opinion.” Id.

     Upon redirect, Dr. Shafrir was asked no questions regarding timing. See Tr.
356-57.
       The Secretary’s challenge to the appropriate temporal interval continued
through testimony from Dr. Fujinami. Tr. 400-03. Based upon the Stanley article,
Dr. Fujinami indicated that the antibody production in response to a booster dose
of the HPV vaccine “occurs within three to five days after that immunization.” Id.
at 402. Dr. Fujinami, then, reasoned that an anamnestic (or memory) response to a
booster dose should occur “within a week after receiving that HPV number 2.” Id.
at 402-03.

       Dr. Fujinami reinforced his opinion by describing what he has observed in
his experiments in mice that are induced to develop inflammation within their
central nervous systems. In those experiments, the mice develop clinical signs of
inflammation about 7-14 days after the initial immunization and then have a
“markedly shortened” response after the booster. Tr. 400. Dr. Fujinami did not
cite any studies for this proposition.

        In Dr. Fujinami’s view, the timing of what is predicted by the science does
not fit what happened to Victoria, especially for the second vaccination. The
interval between the second vaccination and the first seizure after the second
vaccination is 29 days. But, to Dr. Fujinami, this much time exceeds what should
happen in a rechallenge. Tr. 390. Thus, Victoria’s case does not fulfill the
challenge-rechallenge paradigm. Id. at 403.

       In answering cross-examination questions and questions from the
undersigned, Dr. Fujinami defended his position that any rechallenge adverse event
would happen sooner than 29 days. Dr. Fujinami stated that literature discussing
how primates respond to immunizations shows that clinical disease becomes
apparent in 7-14 days. Tr. 418.23 Because the production of antibodies is one step
in the longer process through which antibodies might cross-react and cause
damage, the undersigned asked how long the complete process would take. Dr.

      23
         While Dr. Fujinami’s testimony is not entirely clear about how many
vaccinations the animals have received, it seems that Dr. Fujinami is discussing
how animals respond to the first (or “priming”) dose. Tr. 419.
                                         34
Fujinami stated that in experimental models using mice, most mice become
paralyzed within 14 days. Id. at 420-23.

      When asked whether vaccines can cause autoimmune conditions “40-plus
days out,” Dr. Fujinami acknowledged that some studies have used that window.
However, those studies were “very generous.” Tr. 419-20.

      Dr. Fujinami’s opinion concurred with the opinion Dr. Kohrman offered
during his testimony. Dr. Kohrman stated that an injury mediated through
antibodies would occur within about 7-14 days. Tr. 471-72 (direct testimony), 535
(response to the undersigned’s question). He stated that an autoimmune reaction
past 40 days is possible, but not likely. Id. at 494 (testimony on cross-
examination).
       During Dr. Shafrir’s rebuttal testimony, he was asked to address whether
Victoria’s rechallenge event should have occurred earlier. While Dr. Shafrir stated
that he “absolutely [did not] agree with” the opinions from the Secretary’s experts,
Dr. Shafrir did not provide a persuasive explanation. See Tr. 552-54. In this
approximately two-page answer, Dr. Shafrir generally maintained that the
vaccinations worsened Victoria’s seizures. At the end of this response, Dr. Shafrir
asserted “it could have happened in six weeks,” but did not give any basis for this
assertion. Id. at 554.

      In their post-hearing briefs, the parties continued to dispute the medically
acceptable time. Mr. Mager stated that a petitioner is required to show a
“proximate temporal relationship between vaccination and injury.” Pet’r’s
Posthear’g Br. at 33. Citing Paluck v. Secretary of Health & Human Services, 786
F.3d 1373, 1383-84 (Fed. Cir. 2015), Mr. Mager further argued that deadlines
should not be “hard and fast.” Id.

        Mr. Mager argued that Dr. Fujinami’s testimony that an immune-driven
reaction should take place within approximately two weeks was not persuasive for
several reasons. First, Dr. Fujinami did not disclose this opinion in reports before
the hearing. Second, Dr. Fujinami’s opinion is not consistent with other evidence.
The primary inconsistent evidence is the Slade post-marketing study. Pet’r’s
Posthear’g Br. at 34, 53. The only other article cited in connection with the timing
aspect is exhibit 70 (Britain Baker et al., The Safety of Human Papilloma Virus-
Blockers and the Risk of Triggering Autoimmune Diseases, 14 Expert Opinion on
Drug Safety 1387 (2015)). While this article states the manifestation of symptoms
of autoimmunity “normally occurred within the first 3 weeks and following the
first or second vaccine injections,” exhibit 70 (Baker) at 3, Mr. Mager argues that
this statement is “not dispositive.” Pet’r’s Posthear’g Br. at 34, 53. However, Mr.
                                         35
Mager did not cite any evidence regarding an expert’s view of Baker and it appears
that no expert testified about Baker. See Resp’t’s Posthear’g Br. at 30. Although
Dr. Shafrir referenced the Vaccine Injury Table during his testimony (Tr. 295), Mr.
Mager did not cite it in his brief as being inconsistent with Dr. Fujinami’s opinion.

       Mr. Mager’s third reason for not crediting Dr. Fujinami’s opinion is that his
opinion is based upon animal models, not people. Pet’r’s Posthear’g Br. at 35, 52.
In this context, Mr. Mager questions the usefulness of Dr. Fujinami’s opinion
because Dr. Fujinami is not a medical doctor. Id. at 35 n.8.

       In contrast, the Secretary argued that Mr. Mager’s showing regarding timing
was not persuasive. Resp’t’s Posthear’g Br. at 27-37, 53-55. The Secretary
maintained that “the injuries and time frames set forth in the Vaccine Injury Table
have no bearing on this case.” Id. at 27. Later, the Secretary expanded this
argument by citing cases in which special masters have rejected the appropriate
temporal interval when the injury occurred around the forty-second day after
vaccination. Id. at 36-37. The Secretary further argued that the Slade post-
marketing study was not persuasive because, in part, “the authors did not explain
what made 4 to 42 days plausible for the onset of GBS or transverse myelitis.” Id.
at 28. In this regard, the Secretary emphasized that when asked why the Slade
authors selected this time, Dr. Shafrir did not “supply any basis for his conclusion
that 42 days is medically reasonable.” Id. at 29, citing Tr. 285. In addition, the
Secretary questioned the usefulness of exhibit 70 (Baker), noting that it evaluated a
variety of sources including the Vaccine Adverse Event Report System. Id. at 30.
Finally, the Secretary argued that Mr. Mager’s “exclusive reliance on challenge-
rechallenge, without providing any medical theory . . . renders Dr. Shafrir’s
testimony concerning timing both unreliable and unpersuasive.” Id. at 27.

       Beyond attacking Dr. Shafrir’s opinion regarding timing, the Secretary also
defended Dr. Fujinami’s view. Procedurally, the Secretary maintained that he
could not disclose any opinion from Dr. Fujinami before the hearing because Dr.
Shafrir had not disclosed his opinion regarding timing before the hearing. Resp’t’s
Posthear’g Br. at 32-33. Substantively, the Secretary maintained that Dr.
Fujinami’s experience, including his hypothesis about molecular mimicry being
involved in autoimmune disease and work with animal models for epilepsy, made
him more qualified than Dr. Shafrir regarding the timeframe for an autoimmune
reaction. Id. at 33.

       In his post-hearing reply, Mr. Mager again relied on the Slade study, stating
that the study establishes 4-42 days as an appropriate time interval between HPV
vaccination and onset of symptoms. Pet’r’s Posthear’g Br. at 11, citing Tr. 253;
exhibit 59 (Slade) at 754. Mr. Mager also reiterated his assertion that the
                                         36
conclusion in the Baker article that the manifestation of symptoms typically occurs
within three weeks after HPV vaccination is “not dispositive.” Id. Mr. Mager
further stated that although he is not alleging a Table injury, the 2-42-day
timeframe contained in the Vaccine Injury Table helps establish a medically
acceptable time interval. Id. at 12 n.7. Mr. Mager again argued that appropriate
time intervals should not be “hard and fast,” and conceded that there “is no
definitive timeframe for onset” in this case. Id. at 13.

             3.    Resolution

       Mr. Mager has met his burden. He has persuasively shown that two
questions should be answered in his favor. The first (and less important) question
is whether 43 days is an appropriate inference for which to infer the first HPV
vaccination in 2007 worsened Victoria’s preexisting seizure disorder. 24 The
second question is whether 29 days is an appropriate interval to infer the 2012
vaccination significantly aggravated a quiescent seizure disorder. On these similar
questions, 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 4 to 42 days as biologically plausible. Exhibit 59 at
754.

       While the Slade study, by itself, justifies crediting Dr. Shafrir’s opinion
regarding timing, some additional support comes from the Vaccine Injury Table.
In recommending an association between the flu vaccine and GBS, a peripheral
nerve disease, the Secretary “propose[d] an onset interval of 3-42 days.” National
Vaccine Injury Compensation Program: Revisions to the Vaccine Injury Table, 80
Fed. Reg. 45,132, 45,146 (proposed July 29, 2015) (codified at 42 C.F.R. pt.
100.3). Special masters have relied upon the Secretary’s acceptance of 42 days for
flu vaccine-GBS to find an appropriate temporal relationship in other
circumstances in some cases. See Mason v. Sec’y of Health & Hum. Servs., No.
17-1383V, 2022 WL 600415, at *25 (Fed. Cl. Spec. Mstr. Feb. 4, 2022) (“[T]he
fact that Table claims reflect the Government’s reasoned interpretation of
persuasive medical science thinking on a causation theory means they can at least
be considered in deciding non-Table claims.”); Randolph v. Sec’y of Health &
Hum. Servs., No. 15-146V, 2021 WL 5816271, at *20 (Fed. Cl. Spec. Mstr. Nov.
12, 2021) (“[T]he GBS ‘template’ is useful in evaluating Petitioner’s success in
meeting this Althen prong.”). In doing so, special masters have not violated the

      24
          Whether 43 days after the first HPV vaccination is an appropriate
temporal interval is less important because Mr. Mager’s claim is not based upon
the first HPV vaccination.
                                         37
Federal Circuit’s direction that “[s]imple similarity to conditions or time periods
listed in the Table is not sufficient evidence of causation; evidence in the form of
scientific studies or expert medical testimony is necessary to demonstrate causation
for such a petitioner.” Grant, 956 F.2d at 1148, cited in Resp’t’s Posthear’g Br. at
27. Here, Mr. Mager has advanced “scientific studies” (the Slade study) and
“expert medical testimony” from Dr. Shafrir.

       On the other hand, as the Secretary argues, special masters have not
universally and uncritically transferred times listed on the Table to cases involving
off-Table injuries. See Resp’t’s Posthear’g Br. at 36, citing Greene v. Sec’y of
Health & Hum. Servs., 146 Fed. Cl. 655, 661 (2020) (denying a motion for review
of a decision in which the special master found that 41 days was not a medically
reasonable interval); Nussman v. Sec’y of Health & Hum. Servs., 83 Fed. Cl. 111,
123 (2008) (denying motion for review of a decision in which the special master
found that an appropriate time for the hepatitis B vaccine to cause seizures was 30
days). Those cases undermine, but do not eliminate, the value of the Vaccine
Injury Table as supporting Dr. Shafrir’s opinion.

       From Slade’s recognition of 4 to 42 days as biologically plausible, it is a
short step of just one additional day to 43 days, which is the amount of time
between Victoria’s first HPV vaccination and her first generalized tonic-clonic
seizure. The Federal Circuit has admonished special masters not to set “hard and
fast deadlines.” Paluck, 786 F.3d at 1383-84. Thus, the amount of time from
Slade may be reasonably expanded to 43 days.
      Dr. Fujinami’s opinions regarding timing are not credited. First, Dr.
Fujinami did not indicate that timing was a problem in his reports. Exhibit I, X,
AA, CC.25 Likewise, the Secretary did not warn that he disputed the timing. See
Resp’t’s Prehear’g Br., filed Feb. 10, 2021, at 22-23.26 This lack of disclosure is

      25
         At best, in response to the (now withdrawn) report from Dr. Mikovits and
Dr. Ruscetti, Dr. Fujinami addressed the amount of time for a reaction involving
histidine. Exhibit I at 4. But, Dr. Shafrir has not put forward a theory based upon
histidine.
      26
          The Secretary’s excuses regarding the nondisclosure of Dr. Fujinami’s
opinions are not persuasive. First, the Secretary stated that until Dr. Shafrir
testified, Dr. Fujinami did not know when Dr. Shafrir believed Victoria’s first
seizure occurred. Resp’t’s Posthear’g Br. at 32. However, Dr. Shafrir linked the
first HPV vaccination to Victoria’s generalized tonic-clonic seizure on November
14, 2007. See exhibit 55 at 3, 16-17. Second, the Secretary stated that he did not
know that Mr. Mager was putting forward 4 to 42 days as a medically reasonable
                                         38
inconsistent with how the Vaccine Program usually operates. If Mr. Mager had
objected to Dr. Fujinami’s testimony that an adverse reaction would have occurred
within about two weeks, the undersigned most likely would have sustained the
objection and struck Dr. Fujinami’s testimony. See Simanski v. Sec’y of Health &
Hum. Servs., 671 F.3d 1368, 1382 (Fed. Cir. 2012).

      Apart from the lack of disclosure, Dr. Fujinami’s testimony suffers because
he did not present literature supporting his position. Although literature is not
required, Althen, 418 F.3d at 1280-81, “a scientific theory that lacks any empirical
support will have limited persuasive force.” Caves v. Sec’y of Health & Hum.
Servs., 100 Fed. Cl. 119, 134 (2011), aff’d without opinion, 463 F. App’x 932
(Fed. Cir. 2012). Similarly, the Federal Circuit has recommended that petitioners
support expert opinions with medical literature. LaLonde v. Sec’y of Health &
Hum. Servs., 746 F.3d 1334, 1341 (Fed. Cir. 2014). This same principle should
govern the analysis of opinions that respondent presents. 27
      The Secretary’s argument that establishing an appropriate temporal interval
requires a medical theory has support from case law. See Bazan v. Sec’y of Health
& Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008) (stating that the petitioner
must offer a medically acceptable timeframe that coincides with the medical theory
of causation under Althen prong one); see also Shapiro, 101 Fed. Cl. at 542. As
discussed in section IV.F below, Mr. Mager’s medical theory for causation is based
on challenge-rechallenge. Since Mr. Mager has established that Victoria’s

time until Mr. Mager presented exhibits 59 and 70 in his prehearing brief. Resp’t’s
Posthear’g Br. at 33. This point is accepted. But, the Secretary did have a chance
to respond to the materials presented in Mr. Mager’s prehearing brief. With this
opportunity, the Secretary presented another report from Dr. Fujinami that did not
address timing. See exhibit CC.
      27
         On the other hand, in future cases the undersigned might find a properly
disclosed and well-supported opinion from Dr. Fujinami persuasive. In
determining whether an amount of time is medically appropriate for an inference
of causation, the undersigned has considered animal models that attempt to
replicate disorders in a person's central nervous system. Contreras v. Sec’y of
Health & Human Servs., No. 05-626V, 2012 WL 1441315, at *9-13 (Fed. Cl.
Spec. Mstr. Apr. 5, 2012) (lengthy discussion of the time for molecular mimicry),
mot. for rev. denied in relevant part after intervening proceedings, 121 Fed. Cl.
230, 246-47 (2015), vacated on other grounds and remanded, 844 F.3d 1363 (Fed.
Cir. 2017).
                                         39
challenge event and rechallenge event occurred within a medically acceptable
timeframe, the timing is supported by the medical theory.

      Accordingly, for these reasons, Mr. Mager has met his burden of proof
regarding Loving prong six. Victoria experienced an aggravation of her
preexisting seizure disorder for which she was not taking medications within an
appropriate time after the second dose of the HPV vaccination. She also
experienced a worsening of her epilepsy after the first dose of the HPV vaccination
within a medically appropriate time.

      F.    Loving Prong Four / Althen Prong One

            1.     Standards for Adjudication
       The first Althen prong requires the petitioner to provide a “sound and
reliable” medical theory demonstrating that the vaccine can cause the alleged
injury. Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1359 (Fed.
Cir. 2019) (quoting Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 548
(Fed. Cir. 1994)). The petitioner must also offer “a reputable or scientific
explanation that pertains specifically to [his] case.” Moberly, 592 F.3d at 1322.
The petitioner “need not produce medical literature or epidemiologic evidence” to
support his theory. Andreu, 596 F.3d 1367, 1379. A petitioner satisfies his burden
under prong one when his expert “present[s] a ‘biologically plausible’ theory.”
See id. at 1375; see also J. v. Sec’y of Health & Hum. Servs., 155 Fed. Cl. 20, 42-
43 (2021).
            2.     Procedural History and Parties’ Arguments
       In Dr. Shafrir’s first report, he opined that the first HPV vaccination can
produce an immune-mediated response, resulting in the development of
autoimmune epilepsy. See exhibit 55 at 18, 20. Dr. Shafrir further explained that
the second dose leads to an enhanced immune response. See id. at 20. Because
Victoria experienced seizures after the first and second doses of the HPV vaccine
(and no seizures for nearly five years between vaccinations), Dr. Shafrir opined
Victoria’s case qualifies as an example of challenge-rechallenge. Id. at 17.

       Dr. Shafrir also put forward “[m]echanisms by which Gardasil can produce
an autoimmune disease.” Exhibit 55 at 19. The most developed mechanism was
molecular mimicry, although Dr. Shafrir listed epitope spreading, bystander
activation, and polyclonal activation. Id.; see also id. at 20 (“The mechanism is
likely based on molecular mimicry . . . .”).

                                        40
       The response to Dr. Shafrir’s theory came from Dr. Fujinami.28 In response
to Dr. Shafrir’s opinion that the HPV vaccine can cause brain inflammation, Dr.
Fujinami relied on a study of mice that were injected with peptides, which showed
that the “injection of peptides from HPV could actually protect from autoimmune
neuroinflammation.” Exhibit AA at 3-4, citing exhibit AA, tab 5 (Ruiz).

       In addition, in Dr. Fujinami’s report that preceded Dr. Shafrir’s first report,
Dr. Fujinami cited studies about the safety of the HPV vaccine. Dr. Fujinami
referenced an article from the Centers for Disease Control and Prevention, which
discusses studies from 2012 and 2014. Exhibit I, citing exhibit V (Ctrs. for
Disease Control & Prevention, HPV Vaccine Is Safe – (Gardasil) (2016)) at 2.
Both studies found that women and girls who received the HPV vaccine “were not
more likely to develop autoimmune disorders than those who were unvaccinated.”
Exhibit V at 2. Dr. Fujinami discussed the studies at the hearing, testifying that
“they found no autoimmune signal or . . . association with autoimmune disease.”
Tr. 375. He added, “there was no indication that there’s an increase in seizures in
the individuals who were vaccinated with HPV.” Id.

       Dr. Fujinami also relied on a study that found “no safety signals with respect
to autoimmune, neurological, and venous thromboembolic events” among about
one million HPV vaccine recipients between ages 10 and 17. Exhibit K (Lisen
Arnheim-Dahlstrom et al., Autoimmune, Neurological, and Venous
Thromboembolic Adverse Events After Immunisation of Adolescent Girls with
Quadrivalent Human Papillomavirus Vaccine in Denmark and Sweden, 347 BMJ
5906 (2013)) at 5.
      Dr. Shafrir’s second report was similar to his first report. He emphasized the
“importance of challenge/rechallenge.” Exhibit 85 at 1. Dr. Shafrir referenced a
study of autoimmune encephalitis in children, which reported that out of 48
patients with autoimmune encephalitis, three patients received a recent HPV
vaccination. Id. at 4, citing exhibit 95 (Yael Hacohen et al., Paediatric
Autoimmune Encephalopathies, 84 J. Neurology, Neurosurgery, & Psychiatry 748
(2012)). He also cited a series of articles in which the authors reported people
developed autoimmune diseases after a HPV vaccination. Id. at 4-5.

      Another study that examined patients with encephalopathy following the
HPV vaccination concluded that the patients’ responsiveness to immunotherapy
suggested an autoimmune mechanism. See exhibit 105 (M. Ando & N. Belonguel,

       Dr. Kohrman’s report did not meaningfully address the theory by which
      28

the HPV vaccine can cause or aggravate seizures. See exhibit Z.
                                          41
Autoimmune Disorders, 381 J. Neurological Sci. 530 (2017)). However, the
authors acknowledged that they could not establish a “direct relationship” between
the neurological symptoms and the HPV vaccine. Id.

      In conjunction with Dr. Shafrir’s second report, Mr. Mager presented written
arguments. As a prong-one causation theory, Mr. Mager advanced challenge-
rechallenge. See Pet’r’s Prehear’g Br. at 19, 23-24; see also exhibit 55 at 17, 20;
exhibit 85 at 1. Mr. Mager heavily relied on literature by the World Health
Organization (“WHO”), which “defines the relationship between challenge-
rechallenge as an adverse reaction to a vaccine as one of certain causality.” Pet’r’s
Prehear’g Br. at 24, citing exhibit 57 (World Health Org., Pharmacovigilance
Guidelines) at 4.

       Mr. Mager argued that “epilepsy can have an immunological mechanism.”
Pet’r’s Prehear’g Br. at 21. To support this theory, Mr. Mager noted that “epilepsy
is more common in patients with systemic lupus erythematosus (SLE) who have
antiphospholipid antibodies, and it is possible that these antibodies can lead to
immune-mediated cortical damage.” Id., citing exhibit 64 (Antonio Greco et al.,
Autoimmune Epilepsy, 15 Autoimmunity Revs. 221 (2016)). He added that
“autoimmune antibodies are detected in 9-14% of patients with epilepsy.” Id.,
citing exhibit 64 at 2 and exhibit 88 (Jehan Suleiman et al., Autoantibodies to
Neuronal Antigens in Children with New-Onset Seizures, 54 Epilepsia 2091
(2013)).
      Mr. Mager relied on the Slade post-marketing study of the HPV vaccine.
See Pet’r’s Prehear’g Br. at 23, 26, citing exhibit 59 (Slade). The study reports that
convulsions made up 8.8% of the serious reported side effects on VAERS reports
from June 2001 through December 2008. Exhibit 59 at 752.

       Mr. Mager claimed that molecular mimicry was the most probable biological
mechanism by which the HPV vaccine can cause epilepsy that is autoimmune in
nature. See Pet’r’s Prehear’g Br. at 21; Pet’r’s Prehear’g Reply at 31. Mr. Mager
explained that molecular mimicry “is the cross-reactivity between a foreign-
antigen . . . and self-antigens, which induces a break in self-tolerance of the amino
acids of the human cells and leads to the immune system attacking its owner’s
body.” Pet’r’s Prehear’g Br. at 21, citing exhibit 74 (Nancy Agmon-Levin et al.,
Vaccines and Autoimmunity, 5 Rheumatology 648 (2009)) at 3. Mr. Mager
elaborated that the HPV vaccine “contains viral sequences in L1 protein that are
similar to several human proteins integral in regulating immune and neurological
function, which set off an autoimmune action triggering [Victoria’s] epileptic
seizures.” Id. at 23.

                                         42
       To support the theory of molecular mimicry, Mr. Mager relied on articles
that discuss risks of cross-reactivity with the HPV vaccine. See Pet’r’s Prehear’g
Br. at 23, citing exhibit 72 (Darja Kanduc, Quantifying the Possible Cross-
Reactivity Risk of an HPV16 Vaccine, 8 J. Experimental Therapeutics & Oncology
65 (2009)) and exhibit 73 (Darja Kanduc & Yehuda Shoenfeld, From HBV to
HPV: Designing Vaccines for Extensive and Intensive Vaccination Campaigns
Worldwide, 11 Autoimmunity Revs. 1054 (2016)). Mr. Mager argued that the
articles support the theory of molecular mimicry “by demonstrating six and seven
amino acid homologies between the L1 capsid protein of the different strains of
HPV included in the Gardasil [vaccine] and human proteins.” Id. Mr. Mager
added that “the authors identified homologies of the viral vaccine protein and 2
human proteins, the dysfunction of which can cause seizures – calcium sensing
reception (CASRO) and perforin (PERF).” Id. Additionally, Mr. Mager argued
that this theory is further supported by challenge-rechallenge. See id.
       Mr. Mager also referenced a study documenting autoimmune neuromyotonia
following the HPV vaccination. See Pet’r’s Prehear’g Br. at 20, 43, citing exhibit
107 (Chiara Cerami et al., Autoimmune Neuromyotonia Following Human
Papillomavirus Vaccination, Muscle & Nerve, Mar. 2013). Mr. Mager asserted
that this study shows that the HPV vaccine can cause brain inflammation and
autoimmune neurological conditions. Pet’r’s Prehear’g Br. at 20.

       With a second chance to address to Dr. Shafrir’s theory, Dr. Fujinami
responded more directly. He disagreed with Mr. Mager’s challenge-rechallenge
theory, stating that “there is no clear information linking the occurrence of seizures
to [the] HPV vaccination, let alone an enhanced immune response occurring
against the second HPV vaccination due to immunological memory present after
the first vaccination with HPV.” Exhibit CC at 1. Dr. Fujinami also pointed out
that Dr. Shafrir had not addressed the study (Ruiz) “where mimicking
immunologic epitopes presented in alum [were] reported to protect against
neuroinflammation.” Id. As to the series of articles that Dr. Shafrir cited, Dr.
Fujinami asserted that exhibits 96-108 “are a compilation of case reports . . . and
do not relate to seizures/epilepsy let alone autoimmune epilepsy.” Id. at 2.

       With evidence from Dr. Fujinami, the Secretary disputed Mr. Mager’s
theory that the HPV vaccine can cause an autoimmune disease. See Resp’t’s
Prehear’g Br. at 19. Citing Dr. Fujinami’s report, the Secretary asserted, “There is
no evidence that HPV DNA fragments lead to an immune-mediated response and
that aluminum at the injection site can cause an autoimmune syndrome.” Resp’t’s
Prehear’g Br. at 19, citing exhibit I at 3.

                                         43
      The July 29, 2021 Decision did not address any theory by which a HPV
vaccine can cause or aggravate autoimmune epilepsy because it found that Mr.
Mager had not established that Victoria suffered from autoimmune epilepsy.

       In light of the lack of discussion of a theory or mechanism connecting a
HPV vaccine to seizures, the parties’ briefs supporting and opposing Mr. Mager’s
motion for review did not discuss this aspect of the case in any detail. Mr. Mager
contended that his “predominant argument was that Victoria experienced
challenge/rechallenge.” Pet’r’s Mot. for Rev., filed Aug. 27, 2021, at 21. He
further argued, “Rechallenge is not dependent on a finding that Victoria suffered
from autoimmune epilepsy.” Id.

       The Secretary disagreed with this proposition. Shortly after quoting this
portion of Mr. Mager’s brief, the Secretary argued that “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.” Resp’t’s Resp. to Mot. for Rev., filed Sept. 24, 2021, at 17.

      The Court ruled that the approach in the July 27, 2021 Decision was flawed.
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.” Opinion and Order at 19, 158 Fed. Cl. at 155.
The Court required the special master to “perform the requisite causation analysis
under Althen and its progeny.” Id. at 22, 158 Fed. Cl. at 158.

       In the hearing, Dr. Shafrir and Dr. Fujinami largely testified in accord with
the reports they authored. Dr. Shafrir emphasized challenge-rechallenge. He
discussed the WHO guidelines, stating that Victoria “clearly meets the criteria for
certain side effects caused by the vaccine.” Tr. 216. He also reviewed the events
in Victoria’s life in an attempt to show her history fits the challenge-rechallenge
paradigm. Id. at 214-19. Dr. Shafrir also explained that the five-year period of
seizure freedom between vaccinations qualifies as a “dechallenge” event, further
evidence supporting challenge-rechallenge. Tr. 216-17, 273. On cross-
examination, the Secretary questioned whether Dr. Shafrir possessed enough
information about Victoria to fulfill the WHO guidelines. These guidelines
indicate that an adverse event must take place within a “plausible time.” Exhibit
57 at 4; accord Tr. 244, 259. But, by the intimations in his attorney’s questions,
the Secretary seemed to suggest that the time of events in Victoria’s case was not
appropriate. See Tr. 259.

      When asked about potential biologic mechanisms by which the HPV vaccine
can cause or aggravate seizures, Dr. Shafrir stated that molecular mimicry is one
                                         44
potential mechanism. Tr. 223. He repeated this point on cross-examination,
stating that his opinion regarding molecular mimicry is “not a definite
certainty . . . . I suggest this is possible, molecular mimicry.” Id. at 247. He added
other potential mechanisms included a cytokine-driven response, an innocent
bystander in the brain’s immune system, and “epitope spread.” Id. at 247-49.
Among these possible theories, the evidence for molecular mimicry “is a little bit
stronger than for the other mechanisms.” Id. at 249.

      Dr. Fujinami’s testimony addressed Dr. Shafrir’s testimony. Dr. Fujinami
explained how repeat vaccinations can enhance the immune response. Tr. 400.
However, the challenge-rechallenge paradigm requires appropriate timing. Id. at
403. In this case, Victoria’s seizures occurred too long after the vaccinations to be
caused by the vaccinations. Id.

        Dr. Fujinami also opined that the HPV vaccine has not been shown to
increase the incidence of different autoimmune diseases. For example, Dr.
Fujinami discussed a short publication from the WHO (exhibit U) that reviewed
studies with hundreds of thousands or million participants. These studies did not
detect an increase in autoimmune diseases generally and, in some investigations,
the authors did not find an increased incidence in seizures specifically. Tr. 371-75.
These studies, to Dr. Fujinami, undermined Dr. Shafrir’s opinion because if the
HPV vaccination could cause a dysregulated immune response, some evidence of
that dysregulated immune response would have shown up in these large studies.
Id. at 372.

        With respect to the possible mechanisms, Dr. Fujinami stated that he did not
agree with Dr. Shafrir. For example, on molecular mimicry, Dr. Fujinami pointed
out that Dr. Shafrir had not identified what portion of the HPV vaccine would
cross-react with a body part leading to epilepsy. Tr. 367. Dr. Fujinami elaborated
on his written report’s discussion of the Ruiz article to maintain that that the use of
a weak adjuvant, like alum, protects against developing an autoimmune reaction.
Id. at 367-71, 377-78.

       Dr. Fujinami also explained why other potential mechanisms, such as a
cytokine-driven reaction, epitope spreading, or bystander activation were not
likely. Tr. 365-66, 388-91. His direct testimony concluded with a statement that
there is “no connection” between the HPV vaccination and epilepsy. Id. at 403.

      After the evidence was completed, Mr. Mager argued his case. He
recognized that Althen requires a petitioner to provide “a medical theory
connecting the vaccination to the injury.” Pet’r’s Posthear’g Br., filed Mar. 25,
2022, at 30. However, this “medical theory” differs from a biologic mechanism,
                                          45
which is not an element of petitioner’s case. Id., citing Knudsen, 35 F.3d at 549
and Simanski, 671 F.3d at 1384.

        Mr. Mager further argued that establishing challenge-rechallenge satisfies
petitioner’s obligation to provide a medical theory. Pet’r’s Posthear’g Br. at 31-32;
Pet’r’s Posthear’g Reply, filed Apr. 5, 2022, at 3. A large portion of Mr. Mager’s
argument under the “Althen prong 1” header consists of contending that Victoria
fulfills the challenge-rechallenge paradigm. See Pet’r’s Posthear’g Br. at 37-44.

       Beyond challenge-rechallenge, Mr. Mager repeated some of his arguments
from his prehearing brief. He again asserted, “Molecular mimicry is the most
likely mechanism by which Victoria suffered seizures.” Pet’r’s Posthear’g Br. at
45. Mr. Mager did not raise a theory based on cytokines, epitope spreading, or
bystander activation in this brief.

      The Secretary disagreed with Mr. Mager’s arguments regarding Loving
prong four / Althen prong one. On the question of whether invoking the challenge-
rechallenge paradigm fulfills the requirement to present a medical theory, the
Secretary asserted that Mr. Mager “has not cited any authority in the Vaccine
Program that has held that asserting challenge-rechallenge obviates a petitioner’s
burden to offer reliable evidence of a scientific theory causally connecting the
vaccination and the injury.” Resp’t’s Posthear’g Br., filed Apr. 1, 2022, at 17-18.
The Secretary also argued that evidence for Victoria experiencing challenge-
rechallenge was lacking, primarily due to the problems with timing. See id. at 20-
21, 27-34.
        As to the potential theories, the Secretary commented that Mr. Mager “made
clear his intent to rely exclusively on the challenge-rechallenge paradigm, and
elected not to advance any other medical theories of causation.” Resp’t’s
Posthear’g Br. at 22, citing Pet’r’s Posthear’g Br. at 32-33; accord id. at 21 (Mr.
Mager “has declined to endorse any causal theory beyond the challenge-
rechallenge paradigm.”). 29 The Secretary, thus, made “a truncated response” to
questions regarding the plausibility of the different theories Dr. Shafrir mentioned.
Id. at 24-25. In conjunction with this response, the Secretary argued, “Several
epidemiological studies have demonstrated the absence of increased risk of
seizures or epilepsy following HPV vaccination.” Id. at 25.

      29
        The Secretary did not address Mr. Mager’s attempt to distinguish a theory
from a mechanism.
                                         46
             3.     Resolution
       Mr. Mager appears to attempt to satisfy Loving prong four in two respects.
First, he offers the challenge-rechallenge paradigm. Second, he offers a
hodgepodge of theories, such as molecular mimicry. The former is persuasive and
the latter is not.

                    a)     Challenge-Rechallenge
       Whether invoking the challenge-rechallenge paradigm constitutes a “theory”
depends, at least in part, on the meaning of the phrase “a medical theory causally
connecting the vaccination and the injury” from Althen, 418 F.3d at 1278. The
interpretation of a case is a question of law, which appellate authorities review de
novo. Alcon Research Ltd. v. Barr Laboratories, Inc., 745 F.3d 1180, 1190 (Fed.
Cir. 2014); Toro Co. v. White Consolidated Industries, Inc., 383 F.3d 1326, 1330
(Fed. Cir. 2004).

      Here, there appears to be no controlling precedent that answered the specific
question of whether challenge-rechallenge constitutes a theory. However, the
appellate authorities seem inclined to accept challenge-rechallenge as a theory.

       In assessing challenge-rechallenge, a starting point is Capizzano. In the
special master’s underlying decision, he found that the hepatitis B vaccine can
cause rheumatoid arthritis. Thus, he effectively found that the petitioner had met
her burden regarding the first Althen prong. Capizzano, 440 F.3d at 1325. Thus,
as the Secretary argues, the Federal Circuit “did not discuss whether the challenge-
rechallenge paradigm is sufficient by itself to satisfy Althen prong 1.” Resp’t’s
Posthear’g Br. at 18. 30 For the issue that the Federal Circuit did confront, whether
the petitioner had met her burden of proof on prong two, the Federal Circuit
recognized that challenge-rechallenge evidence could be probative of causation.
Capizzano, 440 F.3d at 1327.

       Subsequently, in 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.”
James-Cornelius v. Sec’y of Health & Hum. Servs., 984 F.3d 1374, 1381 (Fed. Cir.
2021) (citing Capizzano, 440 F.3d at 1322). While the sentence in James-

      30
        This lack of analysis from the Federal Circuit on prong one, in turn,
allowed for a different finding on prong one based upon different evidence. See
Bean-Sasser v. Sec’y of Health & Hum. Servs., 127 Fed. Cl. 161, 167-68 (2016).
                                          47
Cornelius does not specify whether the challenge-rechallenge occurrence is part of
Althen prong one or Althen prong two, that analytic structure does not matter.

       Althen prong two has been likened to asking whether the vaccine did cause
the injury. Evidence that a vaccine did cause an injury must imply that the vaccine
can cause the injury. “When a treating physician concludes that an injury or illness
was caused by a vaccine, that conclusion is circumstantial evidence that the
vaccine did in fact cause that injury or illness.” Caves, 100 Fed. Cl. at 136.

      Thus, the undersigned holds that persuasive proof that a vaccinee
experienced challenge-rechallenge satisfies a petitioner’s burden to present a
theory causally connecting a vaccine to an injury. See Waterman v. Sec’y of
Health & Hum. Servs., No. 13-44V, 2016 WL 761173, at *7-8 (Fed. Cl. Spec.
Mstr. Feb. 5, 2016) (ruling finding entitlement to compensation based, in part, on
the special master’s finding that the petitioner demonstrated challenge-
rechallenge).

      The ensuing question, then, is whether Mr. Mager has shown with
preponderant evidence that Victoria experienced challenge-rechallenge. The short
answer is yes.

      The Secretary’s argument against challenge-rechallenge is that the timing
does not fit. See Resp’t’s Posthear’g Br. at 19-22; Spec. Mstr. Oral Arg. Tr. 660.
However, for reasons explained in section IV.E, above, Mr. Mager has met his
burden regarding timing.
      The basic chronology shows how Victoria experienced worse seizures
within an appropriate amount of time after the vaccinations to conclude that she
experienced challenge-rechallenge.

 Date             Event

                  Approximate onset of tongue biting, which is evidence of a
 9/14/2007        seizure. In addition, by this time, Victoria 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. Shafrir’s opinion on dechallenge.

                                        48
 9/11/2012         Second HPV vaccination.

                   The first of three seizures, leading to a prescription for anti-
 10/12/2012
                   seizure medication.

      Accordingly, Mr. Mager has met his burden on Loving prong four (Althen
prong one) due to the preponderant proof of challenge-rechallenge.

                    b)    Other Theories
       As noted previously, whether a demonstration of challenge-rechallenge
satisfies an obligation to present a medical theory causally connecting the vaccine
with the injury has not been directly addressed by an appellate authority. To avoid
the need for a potential remand, the undersigned discusses Mr. Mager’s alternative
methods for establishing Loving prong four.

       Mr. Mager’s evidence as to how the HPV vaccine can aggravate a
preexisting seizure disorder is not persuasive. Among the different theories Mr.
Mager advanced, Mr. Mager identified molecular mimicry as “most likely.”
Pet’r’s Posthear’g Br. at 45. However, Mr. Mager has not shown that Dr. Shafrir’s
opinion how the HPV vaccine can cause (or aggravate) seizures is reliable.

      Mr. Mager has shown that the HPV vaccine prompts human beings to
produce an immune response, including the production of antibodies. Exhibit 68.
Mr. Mager has also shown that portions of a vaccine might resemble (or mimic)
portions of human tissue. See exhibit 74.

        But, Mr. Mager has not persuasively linked the production of antibodies to
the development of epilepsy. While Dr. Shafrir stated that antibodies are “known”
to cause autoimmune epilepsy, Tr. 224, Dr. Shafrir later retreated from this
statement. The presence of antibodies in patients with epilepsy was not
statistically different from the presence of antibodies in controls. Id. at 305-07
(discussion of exhibit 88 (Suleiman)). Furthermore, while Mr. Mager cites to a
series of articles, Pet’r’s Posthear’g Br. at 46, he elicited no significant testimony
about those articles. The lack of testimony is not surprising as those articles
discuss conditions other than epilepsy. See exhibit CC (Dr. Fujinami’s report) at
1-2. While the undersigned has considered those articles, Mr. Mager has not
persuasively shown how they are relevant to the theory.

                                          49
      On cross-examination, Dr. Shafrir testified “molecular mimicry is a
possibility.” Tr. 245.31 This description is apt. A theory that is “possible” does
not meet a petitioner’s burden of proof. Moberly, 592 F.3d at 1322.

      As for the remaining theories, Mr. Mager has done even less to support
them. For example, although the Secretary elicited testimony from Dr. Shafrir
about cytokines, bystander activation, and epitope spreading, Tr. 247-49, Mr.
Mager did not advance those theories. Neither “cytokine” nor “bystander” nor
“epitope spreading” appears in Mr. Mager’s post-hearing brief. In any event, Dr.
Fujinami easily and persuasively demonstrated weaknesses in Dr. Shafrir’s
testimony. Id. at 365-71, 386-98.

       In conjunction with this testimony, Dr. Fujinami discussed epidemiological
studies, which his earlier reports had cited. Tr. 365-77. These studies did not
detect any increase in various diseases after HPV vaccination. 32 For a lengthy
discussion of the value of epidemiologic studies in the Vaccine Program, see Tullio
v. Sec’y of Health & Human Servs., No. 15-51V, 2019 WL 7580149, at *5-8 (Fed.
Cl. Spec. Mstr. Dec. 19, 2019), mot. for rev. denied, 149 Fed. Cl. 448, 475 (2020).
      Consequently, if challenge-rechallenge were not a way to satisfy the
requirement to present a theory, then Mr. Mager would not have met his burden of
proof regarding Loving prong four (corresponding to Althen prong one).

      31
         The transcript may contain an error at this point. The entire sentence as
transcribed reads: “Differently molecular mimicry is a possibility.” Dr. Shafrir
may have actually stated “Definitely molecular mimicry is a possibility.”
Regardless of the first word, Dr. Shafrir said “molecular mimicry is a possibility.”
      32
        Studies included exhibit U (World Health Org., 89 Weekly
Epidemiological Record 53 (2014)); exhibit M (C. Chao et al., Surveillance of
Autoimmune Conditions Following Routine Use of Quadrivalent Human
Papillomavirus Vaccine, 271 J. Internal Med. 193 (2011)); exhibit V (Ctrs. for
Disease Control & Prevention, HPV Vaccine Is Safe – (Gardasil) (2016)); exhibit
AA, tab 5 (Pedro J. Ruiz et al., Microbial Epitopes Act as Altered Peptide Ligands
to Prevent Experimental Autoimmune Encephalomyelitis, 189 J. Experimental
Med. 1275 (1999)).
                                         50
       G.    Loving Prong Five / Althen Prong Two
             1.    Standards for Adjudication

       The second Althen prong requires a petitioner to show a logical sequence of
cause and effect usually supported by the medical records. Althen, 418 F.3d at
1278; Capizzano, 440 F.3d at 1326. The Federal Circuit has instructed special
masters to consider carefully the views of a treating doctor, “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, 440 F.3d at 1326.

             2.    Parties’ Arguments
        In briefing before remand, Mr. Mager argued that Victoria experienced
challenge-rechallenge, meaning she experienced seizures following both HPV
vaccinations. Pet’r’s Prehear’g Br. at 44. Mr. Mager further explained that she
experienced a five-year period of seizure freedom in between in her first and
second HPV vaccinations. Id. Mr. Mager argued that challenge-rechallenge
supports a logical sequence of cause and effect. See id. Dr. Shafrir wrote in his
first report, “Victoria’s immune system ha[d] been primed and then reactivated for
[a] more pronounced immune reaction to the vaccine.” Exhibit 55 at 20.

      Additionally, with respect to prong two, Dr. Shafrir opined in his
supplemental report that the subpial gliosis found in Victoria’s autopsy suggests
chronic brain inflammation. Exhibit 85 at 4. This is consistent with Dr. Shafrir’s
testimony during the hearing. Tr. 287.

       Dr. Shafrir opined in his supplemental report that the finding of subpial
gliosis in Victoria’s autopsy indicated that she likely had chronic
neuroinflammation. Exhibit 85 at 4. Dr. Shafrir reiterated this opinion at the
hearing. Tr. 287. He elaborated that neuroinflammation can cause gliosis. Id. at
289.
       Conversely, the Secretary argued that the record does not support a logical
sequence of cause and effect because there is “no indication ‘of autoimmune
indicators being present.’” Resp’t’s Prehear’g Br. at 21, citing exhibit AA at 3.
Both Dr. Fujinami and Dr. Kohrman addressed Dr. Shafrir’s opinion regarding
subpial gliosis and chronic brain inflammation in their reports. See exhibit A at
14; exhibit AA at 4. Dr. Fujinami stated that “just the act of having seizures can
cause gliosis.” Exhibit AA at 4. He added, “One does not have to hypothesize that
[the] HPV vaccination causes gliosis when individuals with epilepsy already have

                                         51
gliosis.” Id. Dr. Fujinami reiterated his opinion that seizures can cause gliosis
during the hearing. Tr. 394.

       Dr. Kohrman opined that the finding of gliosis in Victoria’s temporal lobe
was caused by her seizures. Exhibit A at 14. He stated, “There was no evidence of
acute or chronic inflammation documented at the time of autopsy.” Id. He noted
that Victoria’s lab work on May 30, 2012, showed a normal white blood cell count
and “the eosinophils and basophils were only slightly [above] the upper limits of
normal.” Id.; see also exhibit 9 at 21-22. Dr. Kohrman asserted that these results
do not suggest inflammation in the central nervous system. Exhibit A at 14. He
added that Victoria’s MRI after her first seizure was normal and did not show any
flair changes, which would have been indicative of inflammation. Id. at 12. This
was consistent with Dr. Kohrman’s testimony at the hearing.
        Dr. Kohrman also disputed Dr. Shafrir’s theory regarding brain
inflammation. In his first report, Dr. Kohrman stated that Victoria’s “MRI shortly
after [her] first seizure was normal with no evidence of changes on flair studies.
Flair changes are sensitive to blood brain barrier breakdown that can be associated
with brain inflammation.” Exhibit A at 12. Similarly, at the hearing, Dr. Kohrman
testified, “I would expect [Victoria’s] MRI to have shown [flair] and T2 changes,
none of which were present.” Tr. 482. He characterized flair and T2 changes as
“the hallmark of inflammation.” Id. During his rebuttal testimony, Dr. Shafrir
agreed with Dr. Kohrman that if Victoria’s seizures were caused by
neuroinflammation, her MRI would have shown flair and T2 changes. Id. at 562-
63.
        Dr. Fujinami also argued that Victoria’s seizures were more likely the result
of poor compliance with her anti-seizure medication. Exhibit CC at 1. Dr.
Fujinami referenced an article about JME, which states that JME patients can
control their seizures with “relatively low doses of appropriate anticonvulsants.”
Id., citing exhibit 86 (James Selph, Juvenile Myoclonic Epilepsy, Medscape (June
24, 2016)) at 3.

             3.    Resolution
      Here, there is no dispute that challenge-rechallenge can show that a vaccine
harmed a person and then, on re-exposure, harmed the person again. Capizzano,
440 F.3d at 1322. As explained in the previous section, Mr. Mager has shown this
sequence of events for Victoria. Thus, an inference of causation is appropriate.
      Capizzano also teaches that the views of treating doctors merit
consideration. 440 F.3d at 1326. Here, the most direct statement from a treating

                                         52
doctor came from Dr. Koehn in July 2008. In an exchange of telephone messages
with Victoria’s stepmother, Dr. Koehn communicated that the HPV vaccination
was not related to the seizure. Exhibit 6 at 19 (call log). This statement, however,
does not dictate a finding against Mr. Mager because any statement from a treating
doctor does not bind a special master. 42 U.S.C. § 300aa-13(b)(1); see also Snyder
v. Sec’y of Health & Hum. Servs., 88 Fed. Cl. 706, 745 n.67 (2009). Dr. Koehn’s
July 2008 statement carries less weight because Dr. Koehn expressed this opinion
before Victoria received her second HPV vaccination. Thus, in a way, Dr.
Koehn’s opinion was based upon incomplete information.

      Accordingly, Mr. Mager has met his burden of proof for Loving prong five.

       H.    Natural Course of Underlying Disorder
       Mr. Mager has demonstrated a prima facie case that the 2012 vaccination
significantly aggravated Victoria’s preexisting epilepsy. He is entitled to
compensation unless the Secretary can show some other factor caused Victoria’s
injury. 42 U.S.C. § 300aa-13(a)(1)(B). For a significant aggravation case, the
Secretary bears the burden of showing that the vaccinee’s post-vaccination
condition was consistent with the natural course of the vaccinee’s preexisting
problem.

       Here, the Secretary has not carried his burden. The Secretary’s argument
seems premised, at least in part, on an assertion that Victoria suffered from
juvenile myoclonic epilepsy. See Resp’t’s Prehear’g Br. at 25; Resp’t’s Posthear’g
Br. at 60; Spec. Mstr. Oral Arg. Tr. 688-89. This argument is difficult to credit
after the Court determined that the relevant condition is simply epilepsy. See
Resp’t’s Posthear’g Br. at 55-56.

       The parties did not extensively discuss the natural course of generic epilepsy
in their briefs and the evidence on this point seems paltry. Through Dr. Kohrman,
the Secretary persuasively showed that a person with JME and who is not taking
anti-seizure medication may have years without seizures and then redevelop
seizures. Tr. 456, discussing exhibit BB-2 (Iris E. Martinez-Juarez et al., Juvenile
Myoclonic Epilepsy Subsyndromes: Family Studies and Long-Term Follow-Up,
129 Brain 1269 (2006)), 466, 489-90. Thus, the Secretary possessed a good-faith
basis for arguing that Victoria’s course was coincident to, and not aggravated by,
the two HPV vaccinations. This argument, however, is outweighed by the value of
challenge-rechallenge.

       A secondary argument from the Secretary is that Victoria’s death was due to
the natural course of her epilepsy. See Resp’t’s Posthear’g Br. at 15-17. Several

                                         53
points underlie this argument. First, as found in section I.A above, Victoria
suffered from seizures before the initial dose of the HPV vaccination. Thus, the
HPV vaccination did not cause her epilepsy. Second, people whose epilepsies are
controlled without medication can redevelop seizures unpredictably. See exhibit F
(Julia Hofler et al., Seizure Outcome in 175 Patients with Juvenile Myoclonic
Epilepsy – A Long-Term Observational Study, 108 Epilepsy Rsch. 1817 (2014)) at
1820 (observing that 16 out of 175 JME patients experienced two years of seizure
freedom without taking antiepileptic medications); see also Tr. 492 (Dr.
Kohrman’s testimony that periods of seizure freedom are common in patients with
JME). Third, Victoria had “reluctance to remain on Depakote (an effective
treatment for her generalized seizures)” and she “lack[ed] compliance with Keppra
(a less effective treatment for generalized seizures).” Resp’t’s Posthear’g Br. at 16.

       To this list, the Secretary added testimony from Dr. Shafrir. Dr. Shafrir
stated that risk factors for sudden unexplained death in epilepsy (“SUDEP”)
include nocturnal seizures, generalized seizures, poorly controlled seizures, and
poor compliance. Tr. 331-32. But, regardless of risk factors, “SUDEP could have
occurred after a few months with epilepsy, could have occurred after 20 years of
epilepsy.” Id. at 355. To Dr. Shafrir, Victoria’s “SUDEP is not correlated to the
vaccine or anything else.” Tr. 355. The Secretary emphasizes Dr. Shafrir’s “not
correlated” comment. Resp’t’s Posthear’g Br. at 16-17.

        Mr. Mager’s response is to cite Dr. Kohrman’s testimony that before
Victoria’s death, her epilepsy was “uncontrolled.” Pet’r’s Posthear’g Reply at 19,
citing Tr. 534. However, characterizing Victoria’s epilepsy in the months before
her death in January 2014 as “uncontrolled” does not mean that the vaccination
approximately one year earlier made the seizures uncontrolled. Dr. Shafrir
testified that Victoria’s “death may have not happened if she was able to get better
treatment.” Tr. 355. A relevant factor is that Victoria may have had poor
compliance with her medication. See exhibit 13 at 2 (witness report that Victoria
had been missing doses of her medication prior to her death). However, according
to a toxicology report, Victoria had therapeutic levels of Keppra in her blood at the
time of her death. Id. at 11; Tr. 302 (Dr. Shafrir), 467 (Dr. Kohrman).

      Mr. Mager further maintained that although Dr. Shafrir did not correlate
Victoria’s death with the HPV vaccination, he correlated her death with epilepsy.
Spec. Mstr. Oral Arg. Tr. 647. Mr. Mager argued, SUDEP “is directly related to
[Victoria’s] seizures,” and her seizures were “directly related to the vaccine.” Id.
He added that Victoria’s epilepsy was uncontrolled after her second HPV
vaccination, and her resulting condition cannot be separated from her subsequent
death. Id. at 672-74.

                                         54
       This issue, too, is close. 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 Victoria’s epilepsy, unaggravated by
the second HPV vaccination, might have progressed.
      Without this evidence, the claim that Victoria’s death is the natural result of
her epilepsy seems possible. But, the Secretary has not established this argument
by a preponderance of the evidence.

V.    Conclusion

      Accordingly, Mr. Mager has established that the September 11, 2012 HPV
vaccination significantly aggravated Victoria’s epilepsy and caused her death.
Therefore, he is entitled to compensation under the Vaccine Act. Pursuant to
Vaccine Rule 28.1(a), the Clerk is directed to notify the Court of this decision.

       An order regarding damages will be issued shortly.

      IT IS SO ORDERED.

                                                     s/Christian J. Moran
                                                     Christian J. Moran
                                                     Special Master

                                         55