DIMANT v. SECRETARY OF HEALTH AND HUMAN SERVICES

Opinion

In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS No. 19-461V

Filed: April 2, 2026

Special Master Horner

RON DIMANT and CHRISTINA SACZEK parents of L.D., a minor,

Petitioners,

v.

SECRETARY OF HEALTH AND HUMAN SERVICES,

Respondent.

Ronald Craig Homer, Conway, Homer, P.C., Boston, MA, for petitioners. Lauren Kells, U.S. Department of Justice, Washington, DC, for respondent.

RULING ON ENTITLEMENT1

On March 28, 2019, petitioners, Ron Dimant and Christina Saczek, filed a petition on behalf of their minor child, L.D., under the National Childhood Vaccine Injury Act, 42 U.S.C. § 300aa, et seq. (2012).2 They alleged that L.D. suffered a neurologic injury, namely Opsoclonus Myoclonus Syndrome (“OMS”), as a result of mumps-measlesrubella (“MMR”), varicella, Diphtheria-Tetanus-acellular-Pertussis (“DTaP”), and inactivated polio (“IPV”) vaccines received on April 11, 2016, and ultimately argued that the post-vaccination neurologic injury in question constituted a significant aggravation of a pre-existing OMS.3 (ECF Nos. 1, 36.) For the reasons set forth below, I conclude that petitioners are entitled to an award of compensation.

1 Because this document contains a reasoned explanation for the action taken in this case, it must be

made publicly accessible and will be posted on the United States Court of Federal Claims' website, and/or at https://www.govinfo.gov/app/collection/uscourts/national/cofc, in accordance with the E-Government Act of 2002. 44 U.S.C. § 3501 note (2018) (Federal Management and Promotion of Electronic Government Services). This means the document will be available to anyone with access to the internet. In accordance with Vaccine Rule 18(b), Petitioner has 14 days to identify and move to redact medical or other information, the disclosure of which would constitute an unwarranted invasion of privacy. If, upon review, I agree that the identified material fits within this definition, I will redact such material from public access.

2 Within this decision, all citations to § 300aa will be the relevant sections of the Vaccine Act at 42 U.S.C.

§ 300aa-10, et seq. 3 The petition itself is ambiguous with respect to a significant aggravation claim.Although petitioner’s amended petition incorporates the factual history that underlies a significant aggravation analysis, the

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I. Applicable Statutory Scheme

Under the National Vaccine Injury Compensation Program, compensation awards are made to individuals who have suffered injuries after receiving vaccines. In general, to gain an award, a petitioner must make a number of factual demonstrations, including showing that an individual received a vaccination covered by the statute; received it in the United States; suffered a serious or long-standing injury or death; and has received no previous award or settlement on account of the injury. Finally – and the key question in most cases under the Program – the petitioner must also establish a causal link between the vaccination and the injury. § 300aa-11(c)(1); § 300aa-13(a)(1).

In some cases, the petitioner may simply demonstrate the occurrence of what has been called a “Table Injury.” That is, it may be shown that the vaccine recipient suffered an injury of the type enumerated in the “Vaccine Injury Table,” corresponding to the vaccination in question, within an applicable time period following the vaccination also specified in the Table. If so, the Table Injury is presumed to have been caused by the vaccination unless it is affirmatively shown that the injury was caused by some factor other than the vaccination. § 300aa-13(a)(1)(A)-(B); § 300aa-11(c)(1)(C)(i); § 300aa-14(a). In many cases, however, the vaccine recipient may have suffered an injury not of the type covered in the Vaccine Injury Table. In such instances, an alternative means exists to demonstrate entitlement to a Program award. That is, the petitioner may gain an award by showing that the recipient’s injury was “caused-in-fact” by the vaccination in question. § 300aa-11(c)(1)(C)(ii). In such a situation, the presumptions available under the Vaccine Injury Table are inoperative. The burden is on the petitioner to introduce evidence demonstrating that the vaccination actually caused the injury in question. Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005); Hines ex rel. Sevier v. Sec’y of Health & Human Servs., 940 F.2d 1518, 1525 (Fed. Cir. 1991).

In this case, petitioners have not alleged any injury or condition listed on the Vaccine Injury Table. Therefore, petitioners must meet the burden of proof for establishing causation-in-fact.

The showing of “causation-in-fact” must satisfy the “preponderance of the evidence” standard, the same standard ordinarily used in tort litigation. § 300aa-13(a)(1)(A); see also Althen, 418 F.3d at 1278-79; Hines, 940 F.2d at 1525. Under that standard, petitioners must show that it is “more probable than not” that the vaccination was the cause of the injury. Althen, 418 F.3d at 1279. They need not show that the vaccination was the sole cause but must demonstrate that the vaccination was at least a “substantial factor” in causing the condition at issue and was a “but for” cause. Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344, 1352 (Fed. Cir. 1999).

petition did not explicitly state that L.D.’s alleged post-vaccination neurologic injury was an aggravation of her pre-existing condition. (ECF No. 36.) Instead, it was respondent’s report that first asserted that L.D.’s pre-vaccination symptoms were a part of her later diagnosed OMS. (ECF No. 40, pp. 15-16.) By the time of the hearing, the parties had stipulated in a joint pre-hearing stipulation that the appropriate framework for resolution of entitlement was whether petitioners had met the test for significant aggravation (ECF No. 90) and each party separately briefed their position with respect to that question (ECF Nos. 95-96).

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Thus, petitioners must supply “proof of a logical sequence of cause and effect showing that the vaccination was the reason for the injury.” Althen, 418 F.3d at 1278 (quoting Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992)). Ultimately, petitioners must satisfy what has come to be known as the Althen test, which requires: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of proximate temporal relationship between vaccination and injury. Id.

Additionally, where a petitioner in an off-Table case is seeking to prove that a vaccination aggravated a pre-existing injury, the petitioner must establish three further factors. See Loving v. Sec’y of Health & Human Servs., 86 Fed. Cl. 135, 144 (2009) (combining the first three Whitecotton factors for claims regarding aggravation of a Table injury with the three Althen factors for off table injury claims to create a six-part test for off-Table aggravation claims); see also W.C. v. Sec’y of Health & Human Servs., 704 F.3d 1352, 1357 (Fed. Cir. 2013) (applying the six-part Loving test). The additional Loving factors require the petitioner to demonstrate aggravation by showing: (1) the vaccinee’s condition prior to the administration of the vaccine, (2) the vaccinee’s current condition, and (3) whether the vaccinee’s current condition constitutes a “significant aggravation” of the condition prior to the vaccination. Loving, 86 Fed. Cl. at 144.

A petitioner may not receive a Vaccine Program award based solely on his or her assertions; rather, the petition must be supported by either medical records or by the opinion of a competent physician. § 300aa-13(a)(1). Medical records are generally viewed as particularly trustworthy evidence because they are created contemporaneously with the treatment of the patient. Cucuras v. Sec’y of Health & Human Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993). However, medical records and/or statements of a treating physician’s views do not per se bind the special master to adopt the conclusions of such an individual, even if they must be considered and carefully evaluated. § 300aa-13(b)(1). A petitioner may rely upon circumstantial evidence. See Althen, 418 F.3d at 1280. The Althen court noted that a petitioner need not necessarily supply evidence from medical literature supporting petitioner’s causation contention, so long as the petitioner supplies the medical opinion of an expert. Id. at 1279-80. While scientific certainty is not required, that expert’s opinion must be based on “sound and reliable” medical or scientific explanation. Boatmon v. Sec’y of Health & Human Servs., 941 F.3d 1351, 1359 (Fed. Cir. 2019).

Cases in the Vaccine Program are assigned to special masters who are responsible for “conducting all proceedings, including taking such evidence as may be appropriate, making the requisite findings of fact and conclusions of law, preparing a decision, and determining the amount of compensation, if any, to be awarded.” Vaccine Rule 3(b)(1). Special masters must ensure each party has had a “full and fair opportunity” to develop the record but are empowered to determine the format for taking evidence based on the circumstances of each case. Vaccine Rule 3(b)(2); Vaccine Rule 8(a); Vaccine Rule 8(d). Special masters are not bound by common law or statutory rules of evidence but must consider all relevant and reliable evidence in

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keeping with fundamental fairness to both parties. Vaccine Rule 8(b)(1). The special master is required to consider “all [] relevant medical and scientific evidence contained in the record,” including “any diagnosis, conclusion, medical judgment, or autopsy or coroner’s report which is contained in the record regarding the nature, causation, and aggravation of the petitioner’s illness, disability, injury, condition, or death,” as well as the “results of any diagnostic or evaluative test which are contained in the record and the summaries and conclusions.” § 300aa-13(b)(1). The special master is required to consider the entirety of the evidentiary record, draw plausible inferences, and articulate a rational basis for the decision. Winkler v. Sec’y of Health & Human Servs., 88 F.4th 958, 963 (Fed. Cir. 2023) (citing Hines, 940 F.2d at 1528).

II. Procedural History

This case was originally assigned to another special master. (ECF No. 4.) In May and July of 2019, petitioners filed medical records marked as Exhibits 1-21. (ECF Nos. 8-11, 15.) This case was subsequently reassigned to the undersigned’s docket in August of 2019. (ECF Nos. 18-19.) In the following months, petitioners continued to file medical records marked as Exhibits 22-24, 26-27. (ECF Nos. 20, 23, 28, 31.) In 2020, petitioners filed an amended petition setting out their claim, as well as L.D.’s birth certificate marked as Exhibit 28. (ECF Nos. 36-37.)

On October 6, 2020, respondent filed his Rule 4(c) Report, recommending against compensation. (ECF No. 40.) Specifically, respondent contended that petitioners had not set forth a medical theory causally connecting the subject vaccinations with L.D.’s alleged injuries. (Id. at 15-16.) Thereafter, petitioners filed an expert report by pediatric neurologist Daniel J. Bonthius, M.D., Ph.D., and accompanying medical literature. (ECF Nos. 44, 46-48; Exs. 29-57.) On November 9, 2021, respondent filed a responsive expert report by pediatric neurologist Gregory L. Holmes, M.D., and accompanying medical literature. (ECF Nos. 52, 55-58; Exs. A-B.)

Following a Rule 5 status conference on March 16, 2022 (ECF No. 60), petitioners filed a supplemental expert report by Dr. Bonthius (ECF Nos. 67, 69; Exs. 59-62), and respondent filed a supplemental expert report by Dr. Holmes, as well as an expert report by immunologist Ari J. Fried, M.D. (ECF Nos. 71-75; Exs. C-E). In December of 2023, petitioners filed an additional supplemental report by Dr. Bonthius. (ECF No. 83; Exs. 64-77.) An entitlement hearing was held on September 16, 2025. (Transcript of Proceeding (“Tr.”), at ECF No. 105.) Accordingly, this case is now ripe for resolution.

III. Factual History

a. Pre-vaccination

L.D. was born in Dallas, Texas, on April 2, 2012, without complication. (Ex. 28;

Ex. 3, p. 108; Ex. 13, p. 1469.) She was a generally healthy infant and toddler. (Ex. 2;

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Ex. 3, p. 108.) However, in November of 2015, L.D.’s parents reported that L.D. had been experiencing “balance issues” following a “head cold.” (Ex. 2, p. 5.)

On November 11, 2015, just five months prior to vaccination, then three-year-old L.D. presented to pediatric neurologist Adelaida Martinez, M.D., at Portland Hospital for Women and Children in London for evaluation of acute imbalance. (Ex. 6, p. 6.) Dr. Martinez recorded that L.D. had developed a cold while on vacation in Dallas and that her ears were blocked during the flight back to London. (Id.) Her parents noticed some instability, shakiness, and clumsiness. (Id.) They described how L.D. “would go down the stairs on her bum,” and noted that her treaters suspected cerebellitis. (Id.) Physical examination showed marked joint hypermobility (universal) with normal muscle power and deep tendon reflexes, as well as “an intention tremor with no pass pointing.” (Id.) Her Romberg test4 was negative, and she had trouble walking in a straight line. (Id.) However, she had normal eye movements and no nystagmus or titubation. (Id.) Dr. Martinez diagnosed marked joint hypermobility, intention tremor and imbalance (recent acute onset), and normal cognitive abilities. (Id. at 7.) An MRI of the head was ordered, and Dr. Martinez noted, “If she has cerebellitis and is getting better slowly, we could watch and see, but if she is not getting better soon enough, we would carry out more tests.” (Id.)

The next day, on November 12, 2015, L.D. presented to pediatric otolaryngologist David Albert, M.D. (Ex. 22, p. 4.) L.D.’s parents reported that, in retrospect, L.D. “was always a little clumsy compared [to] her siblings and did not respond to pain quite as expected.” (Id.) Dr. Albert recorded that L.D. had “developed a nasty cold in Dallas with congestion and no temperature.” (Id.) Her grandparents noticed that she was “slowing down generally and talking slowly” and, by the end of her vacation, L.D. “was beginning to walk with a rather wobbly gait.” (Id.) Dr. Albert recorded that, since returning to London, L.D.’s walking issues had progressed and were now associated with shaking hand movements. (Id.) On physical examination, Dr. Albert observed “a wide based, wobbly gait” without any falls, “pass pointing on finger/nose test but no nystagmus,” and an inability to stand on one leg or walk on the spot. (Id.)

Throughout November and December of 2015, L.D. completed additional diagnostic testing. Her lab results showed a slightly high AST, high calcium, and low, globulin, protein, cystine, and glutamic acid, but the bile acids, biotinidase, TFTs, Transferrin Isoforms, and creatinine were normal. (Ex. 6, pp. 1-5, 7.) L.D. also underwent an MRI of the brain and EEG, which were both normal. (Id. at 9-10.)

On January 4, 2016, Dr. Martinez noted that L.D. “had another acute episode of ataxia associated to a high temperature and an upper respiratory tract infection and she was ataxic for a week.” (Ex. 6, p. 7.) Dr. Martinez discussed anti-neuronal antibodies

4 Romberg test evaluates “swaying of the body or falling when standing with the feet close together and

the eyes closed.” Romberg sign, DORLAND’S MEDICAL DICTIONARY ONLINE, https://www.dorlandsonline.com/dorland/definition?id=106448 (last visited Mar. 17, 2026).

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testing and noted that they would “widen the search” in the event of another acute episode. (Id.) L.D.’s January 18, 2016 urine organic acids were essentially normal. (Ex. 3, p. 79.)

By April 11, 2016, L.D.’s pediatrician recorded that her ataxia had “fully resolved.”

(Ex. 2, p. 10.) L.D. received the subject DTaP, IPV, MMR, and varicella vaccines during a well child visit on that same date. (Id.; Ex. 1, p. 1.) At the time of vaccination, L.D. was four years old. (Ex. 2, p. 10.)

b. Post-Vaccination

However, by May 6, 2016, L.D.’s parents were reporting that L.D. was “shaking again“ and wobbly within 10 days of her vaccinations. (Ex. 2, p. 5.) They further reported drooling and possible jet lag. (Id.) L.D. returned to Dr. Martinez on May 18, 2016, and the following was recorded:

[L.D.] had been very well from January until April. She had no symptoms and no longer was ataxic. Parents were in the USA and when they flew back from the USA after having her vaccine boosters, she went back to being as imbalanced and shaky as before or worse, plus she is now drooling, is bad tempered and she has been incontinent when she gets angry. She does not shake when held, but she has intention tremor. The previous episode lasted 3 months and the current one started 4 weeks ago: it started gradually and got worse with time. The bad temper and problems with her sleep happened later. There is a video of [L.D.] back in April the 2nd on her birthday, while the family was in the USA and she had no imbalance, no intention tremor and her speech was normal. She went skiing in Utah with no problems before this second episode. Parents have been worried since, in case the transatlantic flight or the change in sleeping routine could have triggered it.

(Ex. 6, p. 7.) On physical examination, L.D. was unsteady on her feet and had intention tremor but no nystagmus. (Id.) Her speech was also slightly slurred. (Id.) Dr. Martinez suggested further testing and repeat imaging. (Id. at 7-8.)

On May 27, 2016, L.D. presented to pediatrician and pediatric infectious disease specialist J. Patrick Hieber, M.D., in Dallas. (Ex. 8, p. 1.) Dr. Hieber recorded a history of two ataxic episodes beginning in October of 2015, no remarkable illness or immunization preceding initial episodes, one hospitalization for rehydration during infancy due to viral illness, no other serious illnesses, and recent four-year-old immunizations. (Id.) On physical examination, Dr. Hieber observed mild nystagmus, ataxic gait, and poor head/trunk control. (Id. at 3.) L.D. was diagnosed in pertinent part with acute cerebellar ataxia and referred to a pediatric neurologist for further evaluation. (Id. at 3, 7, 13.)

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A few days later, on May 31, 2016, L.D. presented to pediatric neurologist Mohsin Maqbool, M.D., for evaluation of “static encephalopathy.” (Ex. 3, p. 108.) Dr. Maqbool recorded the following history:

[L.D.] is a 4 year old girl who is being evaluated for loss of balance and coordination as well as tremors in her hands. According to history provided by biological parents and grandparents she suffered from a 10-week bout of loss of balance and tremors lasting from mid-[O]ctober to the end of December 2015. She was in England at the time and the episode started after her flight from USA to London. She was thoroughly evaluated for underlying infectious post infectious and autoimmune disorders. Her initial work up was negative and her operant diagnosis was acute cerebellar ataxia (post infectious). There is history of ‘booster shots’ before the onset of her symptoms. Her coordination worsened over a period of first four weeks after which there was a plateau. Towards the end of December 2015 a recovery was rather fa[s]ter lasting over less than 2 weeks. From January 2016 through April 2016 she was completely back to normal with complete range of her motor functions coordination stability and eye movement. Starting by the end of April was the onset of similar symptoms including worsening balance coordination, tremors that get worse when she tries to pe[r]form fine motor tasks and some unusual eye movements noted by her PCP. Family is also noticing drooling and behavioral issues including irritability and temper tantrums. . . . The common findings between the onset of two episodes are booster shots and transatlantic flight.

(Id.) Dr. Maqbool noted that L.D.’s bloodwork and imaging were unremarkable and that she retains her mental status and intelligence during episodes of imbalance. (Id.) A review of symptoms was positive for “clumsiness and involuntary movements (tremors, intention (left worse than right)).” (Id. at 108.) Physical examination revealed ataxic and unsteady gait; intention tremor of bilateral upper extremities and lower extremities with left side worse than right side; inaccurate and slow heel-to-shin and finger-to-nose test; slow and clumsy rapid alternating movements; negative Romberg test; and negative pronator drift. (Id. at 109.) Based on the history and physical examination findings, Dr. Maqbool concluded that L.D.’s diagnosis was “most consistent with Episodic Ataxia type 2.” (Id.) Dr. Maqbool detailed that, although most cases of episodic ataxia are inherited, there is a significant proportion of patients that develop a de novo mutation. (Id. at 110.) Progressive cerebellar ataxia and cerebellar degeneration were less likely due to normal brain MRI and complete remission of symptoms between January and April. (Id.) White matter disorders, brain tumor/lesions, and hydrocephalus could be ruled out based on the same findings. (Id.) Metabolic and infectious etiologies had been ruled out through extensive bloodwork, and epileptic disorders had been ruled out by normal EEG and absence of clinical seizures. (Id.) Dr. Maqbool noted that “onset of symptoms after booster shots and transatlantic flights is an example of ataxia (in particular) and ‘channleopathies’ (in general) being triggered after a stressful event,” and that L.D.’s behavioral issues were also likely reactive to the stressful situation and

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persistent symptoms. (Id.) L.D. was started on a trial of Diamox (acetazolamide),5 and genetic testing was ordered. (Id.)

A June 9, 2016 comprehensive ataxia evaluation of 42 genes known to be associated with hereditary ataxia was unremarkable. (Ex. 3, pp. 30-33.) Although the diagnosis could not be completely ruled out due to limitations of the assay, the results “did not identify mutations associated with hereditary ataxia.” (Id. at 30.) Anti-neuronal antibodies testing on June 23, 2016, was also negative. (Ex. 6, p. 23.)

L.D. presented to pediatric neurologist and epilepsy specialist Eli Heymann, M.D., at Assaf Harofeh Medical Center in Tel Aviv, Israel, on July 18, 2016. (Ex. 27, p. 2.) Dr. Heymann recorded a history of present illness and noted that, since April 16, 2016, L.D.’s ataxia had caused walking difficulties, which required support, and speech difficulties, including slow and inchoate speech. (Id. at 2-4.) On examination, Dr. Heymann observed noticeable head and body tremor, appendicular ataxia, and atactic walking, but normal eye movement and no nystagmus. (Id. at 6.) Dr. Heymann recommended further MRI to investigate “a neuroblastoma-type process” and further testing for immune-mediated cerebellar ataxia and neurotransmitters. (Id.) Dr. Heymann noted that, “[f]or the past 8 months, there was a cerebral syndrome that was started around light [upper respiratory infection], without Encephalopathy.” (Id.)

On July 24, 2015, L.D. was seen by professor B. Ben-Zev in the Pediatric Neurology Institute – Epilepsy Unit at the Edmond and Lily Safra Children’s Hospital in Tel Aviv. (Ex. 26, pp. 1-2.) Dr. Ben-Zev recorded “onset about nine months ago of subacute cerebellar ataxia following a mild febrile illness which developed, within a few days, into significant walking difficulty (despite her continuing to walk), dysarthria, and significant tremor (without clear evidence of myoclonic component and without opsoclonus eye movement).” (Id. at 1.) It was noted that L.D. was diagnosed with “post infectious cerebellitis” and recovered “spontaneously over 1.6 months, but never really recover[ed] to her prior state of health.” (Id.) Then, in April of 2016, “one week after the MMR vaccination and vaccinations against polio, pertussis, and varicella she again developed a more acute case of recurrent ataxia.” (Id.) During this episode, L.D. also experienced sleep disturbances and behavioral changes “perhaps triggered by frustration.” (Id.) Dr. Ben-Zev noted that episodic ataxia was considered, but L.D. did not respond to treatment with acetazolamide. (Id.) On examination, Dr. Ben-Zev observed abnormal eye movement (smooth pursuit problem) but no nystagmus, cerebellar dysarthria, low extremity tone but brisk reflexes, significant dysarthria, ataxic gait, tremor during movement (jerky movement but no myoclonus), and possibly increased tension in right Achilles. (Id.) Dr. Ben-Zev opined that L.D.’s presentation was consistent with acquired cerebellar ataxia without clear components of myoclonus or opsoclonus. (Id.) The differential diagnoses included immune mediated ataxia as 5 Diamox is the trademark preparation of acetazolamide, “a carbonic anhydrase inhibitor with a wide

variety of uses.” Diamox, DORLAND’S MEDICAL DICTIONARY ONLINE, https://www.dorlandsonline.com/dorland/definition?id=13759 (last visited Mar. 17, 2026); Acetazolamide, DORLAND’S MEDICAL DICTIONARY ONLINE, https://www.dorlandsonline.com/dorland/definition?id=394 (last visited Mar. 17, 2026).

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the “first choice,” but a neoplastic process still needed to be ruled out. (Id.) Dr. Ben- Zev also wanted to reinvestigate a metabolic/genetic factor for ataxia, despite noting that the possibility of finding such factor was “very low.” (Id. at 1-2.) Further labs and imaging were ordered with a plan to start a five-day course of prednisone following lumbar puncture. (Id. at 2.) Following treatment with prednisone, L.D. was to be reevaluated for consideration of immunoglobulin treatment. (Id.) A subsequent MRI of the brain showed normal myelination and no evidence of structural impairment. (Id. at 3.)

On August 15, 2016, L.D. returned for a pediatric neurology follow up with Dr.

Maqbool. (Ex. 3, p. 12.) Dr. Maqbool recorded that, since her last visit, L.D.’s ataxia had progressed over several days, plateaued over the following several weeks, and then “slightly improved (just like her prior episode by the end of 2015 that took 3 months to abate).” (Id.) However, L.D.’s symptoms did not respond to treatment with acetazolamide and meclizine, and she had not returned to her baseline from prior to the first episode or her baseline between the two prior episodes. (Id.) Dr. Maqbool recorded treater suspicion for autoimmune cerebellitis (paraneoplastic) and noted that L.D.’s testing was unremarkable. (Id.) On examination, L.D. was able to stand but was unsteady, could walk and run but was clumsy and prone to falling, and had poor fine motor skills; however, there was no evidence of nystagmus, myoclonus, or opsoclonus. (Id.) The differential diagnoses included “autoimmune/paraneoplastic spinocerebellar degeneration, neurodegenerative disorder secondary to undiagnosed/unknown genetic mutation (idiopathic spinocerebellar ataxia).” (Id.) At this point, L.D. was diagnosed with ataxia of unknown origin. (Id.) Further labs and imaging were ordered, and L.D. was started on a trial of IV steroids followed by IVIG, if needed. (Id. at 13.) A subsequent full body PET scan was normal. (Id. at 3-4.)

Later that month, on August 31, 2016, L.D. was admitted for inpatient neurology services “due to progressive loss of balance and coordination for the past 3 months.” (Ex. 3, p. 9.) Dr. Maqbool noted that L.D. “had undergone extensive evaluation for the diagnosis of her ataxia; however, all the prior diagnostic testing has returned normal.” (Id.) “[I]t was postulated based on deductions inferred from prior testing and clinical assessment that a trial of immunosuppressive therapy would be attempted in order to observe for any improvement in her coordination and gait. The working theory was based on autoimmune progressive ataxia.” (Id.) A review of symptoms was positive for poor coordination and balance and for intention tremor that is aggravated when “she tries to approach her target object.” (Id.) A physical examination showed deep tendon reflexes of 1-2+ bilaterally in upper and lower extremities and ability to get up from sitting position with minimal support; however, L.D. had slightly unstable gait with slightly parted feet when walking with variable length and arm swing and slight scissoring of her gait, which her parents described as new as of 2-3 weeks prior. (Id. at 10.) L.D. was also very irritable and fussy throughout the examination. (Id.) Dr. Maqbool assessed progressive ataxia of unknown etiology with a working diagnosis of autoimmune progressive ataxia. (Id. at 11.) L.D.’s PET scan and lumbar puncture were unrevealing. (Id.) The plan remained to start L.D. on a 5-day course of high dose steroids followed by possible IVIG administration. (Id.) Dr. Maqbool also ordered

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physical and occupational therapy evaluation and planned to follow the IV steroids with an oral taper of steroids to avoid withdrawal symptoms. (Id.)

L.D. was subsequently admitted to the Children’s Hospital at Medical City Dallas Hospital for administration of IV steroids. (Ex. 7, p. 72.) It was noted that L.D. experienced ataxia of unknown etiology in October 2015 with interval improvement; however, she “developed recurrent ataxia 1 week after 4yr vaccines were given in April 2016.” (Id.) Her April 2016 episode of ataxia had “progressively worsened and [was] accompanied by intention tremor in hands, increased clumsiness and horizontal nystagmus.” (Id.) It was noted that L.D. “seemed to be clumsy in first year of life after 1yr vaccines, now walks with assistance, but falls often” and experiences slurred speech. (Id.) Cerebellar dysfunction was noted on physical examination. (Id. at 74.) Imaging of L.D.’s thoracic, cervical, and lumbar spine was normal. (Ex. 3, pp. 1-2, 24- 25; Ex. 7, pp. 168-73.) After a steroid taper with prednisone and a 5-day course of IVIG, L.D. was discharged home on September 8, 2016, with a diagnosis of autoimmune progressive ataxia. (Ex. 7, pp. 59-63.) It was noted that L.D.’s condition had improved since admission. (Id. at 61.)

On October 17, 2016, L.D. had a follow up appointment with Dr. Maqbool. (Ex.

3, p. 102.) Dr. Maqbool recorded “significant improvement in her gait, stability and speech clarity” after a 5-day course of IVIG; however, L.D.’s balance and stability had gradually declined over the past week. (Id.) A review of symptoms was positive for clumsiness and involuntary movements, including intention tremors that affected the left side more than the right side. (Id. at 103.) Physical examination showed ataxic and unsteady gait; intention tremor in the bilateral upper and lower extremities but left side worse than right side; inaccurate and slow finger-to-nose test and heel-to-shin test; slow and clumsy rapid alternating movement; negative Romberg test; and negative pronator drift. (Id. at 104.) Dr. Maqbool assessment was “ataxia of unknown origin” but “[m]ost likely autoimmune cerebellar ataxia.” (Id.) L.D. was to receive treatment with plasmapheresis, to attend occupational and physical therapy both before and after the procedure, and to follow up in six months. (Id.)

Later that month, on October 25, 2016, L.D. was again admitted to the pediatric intensive care unit at Medical City Dallas Hospital for plasmapheresis. (Ex. 7, pp. 387- 88.) It was noted that L.D. had “developed recurrent ataxia 1 week after her 4-year vaccines which were given in April 2016” and that her ataxia had “progressively worsened and is now accompanied with intention tremors in hands, increased clumsiness and horizontal nystagmus.” (Id. at 387.) On admission, a physical examination showed L.D. to be “mildly hypertonic to her upper extremities with tremors to her forearms and hands.” (Id. at 388.) She received a half course treatment of plasmapheresis on October 26, 2016, followed by three consecutive full courses of plasmapheresis on October 27 to 29, 2016, then another treatment on October 31, 2016, and again on November 2, 2016. (Ex. 3, p. 14.) After her plasmapheresis treatment, L.D. received one treatment of IVIG. (Id.) She was discharged home “in excellent condition” on November 2, 2016. (Id.; Ex. 4, p. 3.)

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On November 3, 2016, L.D. returned to Dr. Maqbool and it was noted that L.D.

had experienced “significant improvement in her gait stability and speech” following treatment with plasmapheresis and IVIG. (Ex. 3, p. 98.) A review of symptoms was positive for clumsiness and intention tremor, as well as insomnia and temper tantrums. (Id. at 99.) On physical examination, L.D.’s gait remained unsteady and ataxic but had improved since the last examination. (Id. at 100.) Her speech clarity had also improved, though she was still exhibiting dysmetria and intention tremor. (Id.) Dr. Maqbool’s impression remained ataxia of unknown origin but likely autoimmune, and a referral to immunology was recommended to discuss long-term immunosuppression. (Id.) L.D. was to follow up in December to determine whether another course of plasmapheresis would be needed. (Id.)

However, L.D. returned to Dr. Maqbool on November 28, 2016, due to “a subacute decline in her fine motor hand use as well as gait stability over the past one to two weeks.” (Ex. 3, p. 94.) It was noted that there had been “no antecedent or preceding or concurrent sickness or vaccinations this time.” (Id.) A physical examination showed worsened gait stability since the last examination. (Id. at 96.) Additionally, L.D. exhibited dysmetria, intention tremor in the upper extremities, and dysarthric speech. (Id.) Although her gait was unstable while walking, it was noted that running was “relatively effortless for her.” (Id.) Another round of plasmapheresis was recommended. (Id. at 96-97.)

On December 5, 2016, L.D. was again admitted to the Medical City Dallas Hospital for plasmapheresis. (Ex. 7, p. 963.) She received a 5-day course of plasmapheresis (on December 5, December 6, December 7, December 10, and December 12, 2016). (Id.) After treatment, L.D. “seemed to have similar or slightly improved gross motor skills,” but her fine motor skills in her upper extremities were unchanged. (Id.) Her diagnoses on discharge were cerebellar ataxia, “likely post- vaccination cerebellar ataxia,” and “fine motor tremors-intention tremors.” (Id.)

On December 20, 2016, L.D. presented for a follow up with Dr. Maqbool. (Ex. 3, p. 90.) L.D. was two weeks out from her second plasmapheresis treatment, but “[u]nlike the last round of plasmapheresis, there [had] been no improvement in ataxia,” though her drooling and hand tremors had improved. (Id.) L.D. was referred to a neurogeneticist for second opinion due to her lack of response to plasmapheresis. (Id. at 90, 93.) It was also noted that L.D. was scheduled to see an immunologist and that her catheter needed to be flushed as a result of a clot. (Id. at 90.) Her physical examination remained the same, but her paraneoplastic panel was negative. (Id. at 92.)

A little over a month later, on January 24, 2017, L.D. returned to Dr. Maqbool due to a “significant decline in her coordination (hand use and gait) as well as nystagmus (new onset).” (Ex. 3, p. 86.) L.D. was now unable to ambulate independently. (Id. at 88.) Dr. Maqbool noted that L.D.’s condition was “[m]ost likely auto-immune cerebellar ataxia based on response to immunosuppression (IVIG and plasmapheresis)” and that L.D.’s “[w]orsening gait and new onset nystagmus indicated a decline in cerebellar function.” (Id. at 89.) An MRI of the brain with and without contrast was ordered, but

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any further plans for immunosuppression were suspended pending a neuro-genetics evaluation. (Id.) Dr. Maqbool subsequently ordered another PET scan. (Id. at 123.)

On January 26, 2017, L.D.’s father authored an email to Dr. Maqbool, stating:

[W]e are all very concerned right now . . . as [L.D.’s] condition continues to deteriorate every day . . . she is worse now than she has ever been . . . [L.D.] is no longer capable of sleeping peacefully through the night[,] which likely contributes to her frustration and the tantrums during the day . . . .

Given the rapid deterioration[] and the new symptoms[,] I was wondering whether the recent development with [L.D.]’s eyes might suggest that we should reconsider opsoclonus myoclonus syndrome (OMS) as a possible diagnosis[.] I recall during our initial consultations with neurologists in the UK and Israel that it was because nystagmus was not one of [L.D.]’s symptoms (although slightly abnormal eye movement was first reported by the Israel doctors in August, 2016) that we could be reasonably confident that neuroblastoma was not the cause of her condition [and] . . . that OMS was excluded as a possible diagnosis at that time for the same reason[] (i.e. no nystagmus).

(Ex. 3, p. 122.) Although L.D. had never formally been diagnosed with opsoclonus and/or myoclonus, L.D.’s father noted that his own online research has led him to believe that “eye problems are apparently often the last of the symptoms to appear with OMS.” (Id.) He further noted that “there is recent research suggesting that viral infections and vaccinations are linked to OMS.” (Id.) L.D.’s father detailed L.D.’s symptoms and requested an opinion regarding further treatment. (Id. at 122-23.)

Dr. Maqbool responded:

In the retrospect, response to immunosuppression pointed towards an autoimmune etiology but with emergence of nystagmus/opsoclonus like eye movements; OMS is becoming “the diagnosis” especially when combined with ataxia, sleep and behavioral issues. It has been the lack of classic eye movements that misled us to think that it is autoimmune cerebellitis.

(Ex. 3, p. 123.)

On February 1, 2017, L.D. presented to pediatric neurologist and neurogenetics specialist Saima Naeem Kayani, M.D. (Ex. 13, pp. 65-72.) Dr. Kayani recorded that, at one year of age, L.D. “was felt to be clumsy which was a bit more than her baseline for an unknown duration, however it was not thought to be out of norm for a toddler.” (Id. at 65.) Then, in October of 2015, L.D. “had a 10 week period of ataxia following a viral infection and was diagnosed with cerebellar ataxia. Her symptoms completely resolved after 3 months.” (Id.) Within a week of her four-year vaccinations, L.D. experienced a recurrence of her ataxia and speech difficulties. (Id.) Although no nystagmus was

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noted at this time, L.D. did experience “a slight tracking problem.” (Id.) Dr. Kayani noted that L.D. was diagnosed with “post vaccine neurologic symptoms” by a treater in Isreal but no treatments were initiated. (Id.) Although L.D. experienced minimal change or improvement following treatment with steroids and IVIG, she experienced significant improvement after treatment with plasmapheresis. (Id.) Following a decline in her condition, L.D. received a second treatment with plasmapheresis. (Id.) Ataxiamyoclonus and opsoclonus were noted on physical examination. (Id. at 66.) Specifically, it was noted that L.D.’s opsoclonus was worse when she tried to focus on something and her ataxia was aggravated by voluntary muscle movements. (Id. at 69.) Her myoclonus was evident at rest but more prominent with movement. (Id.) Dysmetria and titubation were also observed. (Id.) L.D. required help ambulating and was visibly upset throughout the exam. (Id.) Dr. Kayani assessed opsoclonus myoclonus syndrome, an immune mediated disease. (Id.) Due to prior positive response, L.D. was to receive another course of plasmapheresis, followed by a dose of rituximab. (Id. at 70.) Dr. Kayani also ordered repeat imaging of L.D.’s brain and spine, another lumbar puncture and paraneoplastic panel, and abdominal imaging. (Id.)

L.D. was admitted to the Children’s Medical Center in Dallas for evaluation and another round of plasmapheresis. (Ex. 13, pp. 231-34.) The results of an MRI of L.D’s spinal cord and brain were normal. (Id. at 670-74.) An ultrasound of her abdomen was also unrevealing. (Id. at 674-75.) L.D. underwent a lumbar puncture on February 7, 2017. (Id. at 252-53.) Thereafter, L.D. was evaluated by a neuroimmunology fellow, Cynthia Wang, M.D., who assessed “opsoclonus-myoclonus-ataxia syndrome (OMAS) based on clinical symptoms and relapsing course, without evidence of neuroblastoma based on prior workup, with symptomatic improvement in the past with immunomodulatory therapies.” (Id. at 242.) Dr. Wang recommended a five-day course of plasmapheresis, which was initiated on February 8, 2017. (Id. at 242, 1485.) L.D. received her final round of plasmapheresis on February 16, 2017. (Id. at 421-26, 1617- 18.) After treatment with plasmapheresis, L.D.’s gait, speech, and behavior were noted to be improving. (Id. at. 228.) A PET scan on February 16, 2017, was negative for occult malignancy. (Id. at 228, 676-77.) L.D. received rituximab on February 17, 2016. (Id. at 228.) She was discharged the following day, appearing “much improved.” (Id.)

On March 2, 2017, L.D. returned to the Children’s Medical Center, complaining of bilateral hip pain with movement. (Ex. 13, p. 4280.) Her parents were concerned that this may be a side effect of her rituximab treatment; however, although rituximab is known to cause arthralgias, a neurology consultation suggested that this would be an “unusual” reaction, given the length of time (two weeks) between treatment with rituximab and onset of hip pain. (Id. at 4280, 4304-05, 4308.) It was suggested that L.D.’s hip pain could be due to her ataxic gait. (Id. at 4308.) Ultimately, the etiology of L.D.’s hip pain was unclear, despite an extensive work up. (Id. at 4295-96.) Lab results and imaging of L.D.’s hips and pelvis were unremarkable, and L.D. was subsequently discharged on March 5, 2017. (Id. at 4289-90, 4295-96.)

On March 30, 2017, nearly one-year post-vaccination, L.D. presented to pediatric neurologist Wendy Mitchell, M.D., at the Children’s Hospital of Las Angeles for a second

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opinion regarding her OMS. (Ex. 5, pp. 4-13.) Dr. Mitchel recorded a history of present illness that included an observation by L.D.’s parents that she appeared clumsier than her sibling and experienced “‘insane rages’ where she would throw temper tantrums a lot and more so than the other kids.” (Id. at 5.) L.D.’s marked balance and coordination issues began in October of 2015, and she was subsequently diagnosed with “postviral cerebellar ataxia as she may have had the sniffles prior to her symptoms.” (Id.) She “significantly improved and was close to full recovery by January 2016.” (Id.) In April of 2016, L.D. “was taken to her PCP for her 4 year old well-check exam. She received her 4 year vaccines including DTaP-IPV, MMR, Varicella. About 1 week later, she started to have coordination issues again.” (Id.) However, her symptoms during this recurrence were “10 times worse” and included significant temper tantrums, drooling, urine accidents, and frequent napping. (Id.) L.D. was also talking less and slower. (Id.) Extensive testing was unrevealing, and initial treatment with Diamox and Meclizine was unsuccessful. (Id. at 5-6, 11.) L.D. was eventually treated with a 5-day course of IV Methylprednisolone with a taper followed by a 5-day course of IVIG, but she experienced “little improvement with each treatment.” (Id. at 6.) L.D. experienced “remarkable improvement” with plasmapheresis. (Id.) “However, during plasmapheresis, she developed what [her] parents describe as ‘whole body tremors’ and ‘loss of fine motor skills’ as she was always tremulous.” (Id.) Her condition again declined after about two weeks. (Id.) “In December 2016, [L.D.] received a second course of plasmapheresis. Again, she improved. However, 2 weeks later, she declined again.” (Id.) At this point, L.D.’s parents began to notice “abnormal eye movements where her eyes would jump in different directions for very brief periods at a time.” (Id.) A third course of plasmapheresis and one dose of rituximab followed. (Id.) On examination, Dr. Mitchell observed “brief intermittent episodes of opsoclonus.” (Id. at 9.) L.D.’s speech was dysarthric, not age appropriate, slow, and had abnormal prosody. (Id.) Her gait was ataxic, wide-based, and wobbly, but she was able to walk independently. (Id. at 9-10.) Dr. Mitchell observed intermittent, full-body titubation, as well as bilateral dysmetria when reaching for objects. (Id. at 10.) Dr. Micthell opined that, although L.D.’s course was atypical given the delayed onset of opsoclonus, “she most likely does have OMS.” (Id. at 11.) Dr. Mitchell emphasized that L.D.’s “exam is significant for opsoclonus, titubation and ataxia all seen in OMS,” and emphasized the lack of a “specific work-up for neuroblastoma, which is strongly associated with OMS.” (Id. at 12.) Dr. Mitchell planned to obtain a further work-up specifically for neuroblastoma, including an MRI of the chest, abdomen, and pelvis, as well as lumbar puncture for CD19+cells and indication for further rituximab. (Id.) Dr. Mitchell recommended starting L.D. on treatment with pulse dose dexamethasone,6 prophylactic low dose antibiotics due to combination of rituximab and steroids, and gastrointestinal protection during steroid pulses. (Id.) It was further suggested that monthly IVIG may be necessary depending on whether L.D. responded to the dexamethasone pulses. (Id.)

6 Dexamethasone is a synthetic glucocorticoid that is used as an anti-inflammatory and

immunosuppressant in a wide variety of disorders. Dexamethasone, DORLAND’S MEDICAL DICTIONARY ONLINE, https://www.dorlandsonline.com/dorland/definition?id=13599 (last visited Sept. 9, 2025).

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On June 1, 2017, L.D. presented to pediatric neurologist Cheryl Hemingway, M.D., at Great Ormond Street Hospital for Children for “further opinion and management of her presumed opsoclonus-myoclonus syndrome.” (Ex. 15, pp. 8-9.) Dr. Hemingway provided a relevant medical history that included acute onset of ataxia in October of 2015, leading to a diagnosis of acute cerebellitis that was “presumed to be post viral.” (Id. at 9.) “Within six months of the first presentation, at around the time of her fourth birthday in April 2016, she was completely back to normal. She then received her booster vaccinations and within a week of this she deteriorated significantly.” (Id.) L.D. could no longer walk independently and she became dysarthric and significantly tremulous in both hands, but extensive work-up was inconclusive for diagnosis. (Id.) L.D. was still symptomatic in July of 2016, and it was suggested that she could be suffering from immune-mediated ataxia. (Id.) L.D. was treated with IV steroids, IVIG, and plasmapheresis with “some benefit.” (Id. at 9-10.) “In January 2017 opsoclonus was noted for the first time and she was diagnosed as having atypical opsoclonus- myoclonus syndrome.” (Id. at 10.) Dr. Hemingway noted that L.D. had not started dexamethasone, as prescribed by Dr. Mitchell, because testing revealed a positive QuantiFERON. (Id.) On examination, opsoclonus was elicited, but no obvious myoclonic jerks were observed. (Id.) However, “[h]er tone was significantly increased at her ankles with tight tendon Achilles and with clonus being easily elicitable.” (Id.) L.D. was drooling, dysarthric, and “had a significant tremor with titubation of her head.” (Id.) “She was grossly ataxic and although she was able to stand while supported she was not able to walk independently. She had significant dysmetria in both upper and lower limbs.” (Id.) Dr. Hemingway noted that she “was struggling to find an alternative diagnosis[ ]to Opsoclonus-myoclonus syndrome (OMS)” and that “on balance with the opsoclonus and ataxia which appears to have been at least provisionally relapsing- remitting an immune-mediated pathology must be highly likely.” (Id. at 11.) The plan was “to treat her for now as OMS and to escalate immune suppression as required,” to continue investigating whether neuroblastoma could be causing the OMS, to investigate alternative causes, and to seek further oncology and ophthalmology opinions. (Id.) L.D. was started on dexamethasone. (Id.) Subsequent MRI revealed no neuroblastoma, and anti-nuclear antibody testing was negative. (Ex. 11, p. 230; Ex. 15, p. 322.)

L.D. returned to Dr. Hemingway on June 23, 2017. (Ex. 15, p. 115.) Dr.

Hemingway recorded that “within seventy-two hours of starting on the dexamethasone [L.D.] made a significant improvement in both her speech and her mobility.” (Id. at 116.) Although it was noted that she experienced some mood changes, these symptoms resolved after discontinuing steroids and “she is significantly less impaired by her OMS.” (Id.) On examination, no opsoclonus could be elicited, she was “not as dysarthric,” no myoclonic jerks were observed, and she was independently mobile but still “quite ataxic.” (Id.) Her dysmetria and tremor were still evident but had improved since her last examination. (Id.) Although there had been some improvement, Dr. Hemingway opined that “she still remains significantly impacted by her OMS.” (Id.) Dr. Hemingway suggested repeating rituximab with simultaneous use of dexamethasone. (Id.) L.D. received a rituximab infusion on June 30, 2016. (Id. at 105.)

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By July 20, 2017, L.D.’s father was reporting that she was “making tremendous improvements, walking, jumping, leaping, babbling words, and stopped drooling.” (Ex. 3, p. 111.) However, despite her parents’ reports that L.D.’s “functional skills have improved dramatically,” it was noted, during an occupational therapy assessment the following day, that she continued to experience “poor stability and bilateral intention tremors, in line with her new diagnosis of opsoclonus-myoclonus, which is impacting her . . . functional fine motor skills.” (Ex. 20, pp. 1-2.) During a follow up appointment with Dr. Maqbool on October 25, 2017, it was noted that L.D. had experienced “marked improveme[nt] in her ataxia and incoordination” and that her mood and behavior was “tremendously better.” (Ex. 3, p. 81.) On examination, Dr. Maqbool noted a “complete resolution of dysmetria and intention tremors in upper and lower extremities,” clear speech, and stable gait for walking, running, and skipping. (Id. at 83-84.) Dr. Maqbool opined that L.D.’s diagnosis was “most likely OMS induced by vaccination.” (Id. at 84.) L.D. was to continue treating with rituximab and dexamethasone and to follow up as needed. (Id.)

On November 3, 2017, L.D. returned to Dr. Hemingway. (Ex. 15, p. 197.) L.D.

had made “remarkable progress” since July. (Id. at 198.) Dr. Hemingway recorded that, “[i]n just over five months, she has gone from being extremely symptomatic to almost back to baseline. She is able to walk and run independently, has no tremor and her mood has improved significantly. She is sleeping well and has made huge developmental progress. Her speech is showing excellent recovery . . . .” (Id.) L.D.’s examination was normal, and Dr. Hemingway noted that she had responded “well to her immune-modulating treatment.” (Id.) L.D. was to continue on dexamethasone monthly for at least the next six months. (Id.) Dr. Hemingway also noted that L.D.’s QuantiFERON had been negative and that, after nine months of treatment, Isoniazid could now be discontinued. (Id.)

On June 27, 2018, L.D. presented to pediatric neurologist Yael Hacohen, M.D., in consultation with pediatric neurologist, Ming Lim, M.D. (Ex. 15, pp. 271-72.) It was recorded that L.D. was “continuing to make a substantial recovery” and that, although she was still experiencing “some subtle difficulties,” she had been discharged from physiotherapy, occupational therapy, and speech therapy. (Id. at 272.) At this point, L.D. had been treating with dexamethasone for a year, which was the “current protocol for OMS.” (Id.) While her parents had noticed some symptoms towards the end of the month, they reported that those symptoms had resolved and that they were “not seeing any symptoms at all, including when she gets an intercurrent illness.” (Id.) On examination, L.D. had a normal gait but difficulty with tandem walking and abnormal saccade. (Id.) It was suggested that L.D. discontinue dexamethasone with the possibility of reassessment if her symptoms recurred. (Id.)

On February 1, 2019, just shy of three years post-vaccination, L.D. returned to Dr. Hemingway. (Ex. 17, pp. 1-2.) Dr. Hemingway recorded intermittent falling episodes but that L.D. was “generally doing fantastically.” (Ex. 17, p. 2.) L.D. was communicating well, her behavior was good, and she was not experiencing any episodes of OMS associated with intercurrent illness. (Id.) Her examination was

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normal with the exception of “some difficulty with tracking.” (Id.) Dr. Hemingway noted that L.D. “had made such good progress” and she remained “well despite being off all treatment.” (Id.) At this stage, Dr. Hemingway determined that “there is no further intervention, but we will continue to keep a close eye on her.” (Id.)

There are no further medical records pertaining to the diagnosis, symptoms, or treatment of L.D.’s post-vaccination condition.

IV. Summary of Expert Opinions and Qualifications

a. Petitioners’ Pediatric Neurology Expert, Daniel J. Bonthius, M.D., Ph.D.7

Dr. Bonthius provided three expert reports on petitioners’ behalf, as well as expert testimony during the entitlement hearing. (Exs. 29, 58, 63; Tr. 5-78.) Dr. Bonthius opines that L.D. suffers from relapsing-remitting OMS and that the subject vaccines likely exacerbated her condition. (Tr. 62; Ex. 29, p. 4; Ex. 58, p. 2; Ex. 63, p. 4.) OMS is a rare neurological disorder that primarily affects children and is characterized by opsoclonus, presenting as spontaneous, random, conjugate, multidirectional saccades, and myoclonus, presenting as brief, shock-like involuntary movements, as well as ataxia, tremor, titubation, developmental plateau, and behavioral changes, including irritability and sleep disturbances. (Ex. 29, p. 4 (citing Michael R. Pranzatelli & Elizabeth D. Tate, Opsoclonus Myoclonus Syndrome, in SWAIMAN’S PEDIATRIC NEUROLOGY 938 (Swaiman et al. eds., 6th ed. 2018) (Ex. 51); Josep Dalmau & Myrna R. Rosenfeld, Opsoclonus-Myoclonus Syndrome, UPTODATE (last updated Aug. 13, 2020) (Ex. 38)).) Dr. Bonthius opines that L.D. eventually exhibited all characteristics of OMS; however, the delayed onset of opsoclonus frustrated her diagnosis and treatment. (Id.) Onset of opsoclonus solidified her diagnosis and “all of her treating physicians thereafter agreed that she did have OMS.” (Id.

7 Dr. Bonthius received his medical degree and Ph.D. in neuroscience from the University of Iowa in

1990. (Ex. 30, p. 1.) From there, he completed a Fulbright Scholarship in neuroanatomy at the University of Otago in Dunedin, New Zealand, followed by a combined postdoctoral fellowship in neuroscience and residency in pediatrics at the University of Virginia, and a residency in pediatric neurology at the University of Iowa. (Id.; Ex, 29, p. 1.) Dr. Bonthius joined the faculty as pediatric neurologist at the University of Iowa College of Medicine. (Ex. 30, p. 2; Ex. 29, p. 1.) He was eventually promoted to professor with tenure of pediatrics and neurology at the University of Iowa College of Medicine. (Ex. 30, p. 2.) In 2019, Dr. Bonthius accepted a position as a professor of pediatrics at the Carolina Medical Center and Chief of the Division of Child Neurology at the Levine Children’s Hospital – Atrium Health in Charlotte, North Carolina. (Id.; Ex. 29, p. 1.) He is board certified in pediatrics, as well as psychiatry and neurology, and he maintains medical licenses in Iowa and Virginia. (Ex. 30, p. 1.) Dr. Bonthius’s research has focused on infection and inflammation in the developing brain, and he serves as Associate Editor of the Journal of Child Neurology and Child Neurology Open, in which he reviews and assigns all manuscriptions dealing with the subjects of infection and inflammation. (Ex. 29, p. 1.) He has published 71 peer reviewed articles, 102 chapters and newsletters, 89 abstracts, and 55 articles in Child Neurology Society. (Ex. 30, pp. 23-51.) Dr. Bonthius was proffered without objection as an expert in pediatric neurology with special qualifications in child neurology and neuroscience. (Tr. 9.)

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Dr. Bonthius opines that OMS is an autoimmune disease. (Ex. 29, p. 4 (citing Poonam Bhatia et al., Opsoclonus-Myoclonus-Ataxia Syndrome in Children, 269 J. NEUROLOGY 750 (2021) (Ex. 33)).) To support this contention, Dr. Bonthius points to “a combination of four facts.” (Id.) First, he notes that OMS patients often have abnormal antibodies against cellular components of the central nervous system, particularly the cerebellum. (Id.) Such antibodies may include antibodies against cerebellar Purkinje cells, cerebellar granule cells, and central nervous system synaptic proteins. (Id. (citing Anne M. Connolly et al., Serum Autoantibodies in Childhood Opsoclonus-Myoclonus Syndrome: An Analysis of Antigenic Targets in Neural Tissues, 130 J. PEDIATRICS 878 (1997) (Ex. 37); Franz Blaes et al., Surface-Binding Autoantibodies to Cerebellar Neurons in Opsoclonus Syndrome, 58 ANNALS NEUROLOGY 313 (2005) (Ex. 34); Martina Korfei et al., Functional Characterisation of Autoantibodies from Patients with Pediatric Opsoclonus–Myoclonus-Syndrome, 170 J. NEUROIMMUNOLOGY 150 (2005) (Ex. 42; see also Ex. 60)).) Although Dr. Bonthius acknowledges that “no specific pathogenic antibody has yet been identified,” he submits that “the presence of abnormal antibodies points toward an autoimmune etiology.” (Id.) Second, the chemokine receptor ligand CCL21, which balances tolerance and immune response, is expressed in abnormal levels in OMS patients and returns to normal levels when OMS patients are treated with immunosuppressants, suggesting an immune-based pathogenesis. (Id. (citing Michael R. Pranzatelli et al., CCR7 Signaling in Pediatric Opsoclonus-Myoclonus: Upregulated Serum CCL21 Expression Is Steroid-Responsive, 64 CYTOKINE 331 (2013) (Ex. 50; see also Ex. D, Tab 3)).) Relatedly, Dr. Bonthius contends that the beneficial effect of immune modulators on symptoms of OMS in general suggests that the process is autoimmune. (Id. at 5 (citing Dalmau & Rosenfeld, supra, at Ex. 38).)

Finally, Dr. Bonthius contends that evidence supports neoplasms and viral infections as triggers for OMS. (Ex. 29, pp. 4-5.) The neoplasm most commonly associated with OMS is neuroblastoma as antibodies generated in OMS patients can have antiproliferative and cytotoxic effects on neuroblastoma cells.8 (Id. (citing Blaes et al., supra, at Ex. 34; Korfei et al., supra, at Ex. 42).) Regarding viral infections, Dr. Bonthius points to evidence of multiple infections preceding onset of OMS. (Id. at 5 (citing Dalmau & Rosenfeld, supra, at Ex. 38).) Such infections include hepatitis C, Coxsackie B3, rotavirus, Epstein-Barr virus, Lyme disease, streptococcus, and mycoplasma pneumonaie. (Id. (citing Vildan Ertekin & Hüseyin Tan, Opsoclonus- Myoclonus Syndrome Attributable to Hepatitis C Infection, 42 PEDIATRIC NEUROLOGY 441 (2010) (Ex. 39); Ronald van Toorn et al., Opsoclonus-Myoclonus in an HIV-Infected Child on Antiretroviral Therapy–Possible Immune Reconstitution Inflammatory Syndrome, 9 EUR. J. PAEDIATRIC NEUROLOGY 423 (2005) (Ex. 54); Karl C. Kuban et al., Syndrome of Opsoclonus-Myoclonus Caused by Coxsackie B3 Infection, 13 ANNALS NEUROLOGY 69 (1983) (Ex. 43); K. Ki Pang et al., A Prospective Study of the Presentation and Management of Dancing Eye Syndrome/Opsoclonus-Myoclonus Syndrome in the United Kingdom, 14 EUR. J. PAEDIATRIC NEUROLOGY 156 (2010) (Ex. 46); Raj D. Sheth et al., Opsoclonus Myoclonus Syndrome Secondary to Epstein-Barr Virus Infection, 10 J. CHILD NEUROLOGY 297 (1995) (Ex. 53)).) In most cases, onset of

8 Dr. Bonthius acknowledges that, despite very extensive testing in L.D.’s case, no neuroblastoma was

uncovered. (Tr. 53.)

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OMS was within several weeks of infection, suggesting a causal association. (Id.) Thus, Dr. Bonthius opines that OMS is an autoimmune condition because it is a paraneoplastic and parainfectious process and such processes are “almost always” autoimmune in nature. (Id.)

Dr. Bonthius opines that the fact that OMS is an autoimmune disease is “key” to his argument that vaccines can trigger OMS. (Ex. 29, p. 5.) He notes that neurological disorders that are para- or post-infectious in etiology have been linked to immunizations. (Id.) By way of example, he notes that several prominent autoimmune neurological disorders, namely, Guillain-Barré syndrome (“GBS”), acute disseminated encephalomyelitis (“ADEM”), transverse myelitis (“TM”), and acute hemorrhagic leukoencephalitis, have been linked to vaccination. (Id. (citing Hugh J. Willison et al., Guillain-Barré Syndrome, 388 LANCET 717 (2016) (Ex. 57); Diederick L.H. Koelman & Farrah J. Mateen, Acute Disseminated Encephalomyelitis: Current Controversies in Diagnosis and Outcome, 262 J. NEUROLOGY 2013 (2015) (Ex. 41); N. Agmon-Levin et al., Transverse Myelitis and Vaccines: A Multi-Analysis, 18 LUPUS 1198 (2009) (Ex. 31); Kari Wellnitz et al., Fatal Acute Hemorrhagic Leukoencephalitis Following Immunization Against Human Papillomavirus in a 14-Year-Old Boy, 8 CHILD NEUROLOGY OPEN 1 (2021) (Ex. 56)); Ex. 63, p. 2 (citing Shih-Chieh Shao et al., Guillain-Barré Syndrome Associated with COVID-19 Vaccination, 27 EMERGING INFECTIOUS DISEASES 3175 (2021) (Ex. 72); Wellnitz et al., supra, at Ex. 56; F. Lapenna et al., Post-Vaccine Opsoclonus- Myoclonus Syndrome: A Case Report, 6 PARKINSONISM & RELATED DISORDERS 241 (2000) (Ex. 44; see also Ex. A, Tab 54; Ex. D, Tab 8); Fardin Nabizadeh et al., Acute Disseminated Encephalomyelitis (ADEM) Following COVID-19 Vaccination: A Systematic Review, 111 J. CLINICAL NEUROSCI. 57 (2023) (Ex. 73); Yhojan Rodríguez et al., Guillain-Barré Syndrome, Transverse Myelitis and Infectious Diseases, 15 CELLULAR & MOLECULAR IMMUNOLOGY 547 (2018) (Ex. 74)).) In none of these disorders is the precise pathophysiology completely understood; however, like in OMS, they are all believed to be immune-mediated, their etiology is believed to involve a “corrupted relationship between the immune system and the nervous system,” and their treatment involves immunosuppression. (Ex. 63, p. 2.) Notably, several vaccines, including vaccines against influenza, human papillomavirus, and rubella, have been specifically “implicated in the induction of OMS.” (Ex. 29, p. 5 (citing Lapenna et al., supra, at Ex. 44; James E. McCarthy & James Filiano, Opsoclonus Myoclonus After Human Papilloma Virus Vaccine in a Pediatric Patient, 15 PARKINSONISM & RELATED DISORDERS 792 (2009) (Ex. 45; see also Ex. D, Tab 9); Amanda L. Piquet et al., Opsoclonus- Myoclonus Syndrome Post-Vaccination and Viral Illness, 3 INT’L J. CLINICAL MED. 304 (2012) (Ex. 48; see also Ex. D, Tab 10)).) He notes that Dr. Holmes acknowledges on respondent’s behalf that “OMS can be triggered by events or conditions outside of the inherent course of the disease,” including non-infectious causes. (Ex. 58, p. 1.) In response to respondent’s experts’ reliance on a study by Dr. Pranzatelli that found OMS relapse in 159 children was related to infection in 40% of cases, to treatment tapering in 48% of cases, and to both in 12% of cases, Dr. Bonthius opines that “[j]ust because none of those 159 OMS patients had a relapse due to vaccination cannot be taken as evidence that no one with OMS has a relapse due to vaccination” and that, in a separate study, “Dr. Pranzatelli specifically designates vaccination as a potential trigger

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for OMS relapse.” (Ex. 63, p. 3 (citing Michael R. Pranzatelli et al., Demographic, Clinical, and Immunologic Features of 389 Children with Opsoclonus-Myoclonus Syndrome: A Cross-Sectional Study, FRONTIERS NEUROLOGY, Sep. 2017, at 1 (Ex. A, Tab 10; see also Ex. C, Tab 3; Ex. D, Tab 11); Michael R. Pranzatelli & Elizabeth D. Tate, Trends and Tenets in Relapsing and Progressive Opsoclonus-Myoclonus Syndrome, 38 BRAIN & DEV. 439 (2016) (Ex. A, Tab 5; see also Ex. D, Tab 12)).)

Although Dr. Bonthius acknowledges that the precise mechanism by which a vaccine can trigger OMS is unknown, he contends that “it is believed to occur through molecular mimicry, wherein certain antigens on the infecting pathogen or in the vaccine share sequence or conformational homology with endogenous human [central nervous system] proteins, leading to immune cross-reactivity.” (Ex. 29, p. 5 (citing Michael R. Pranzatelli, The Immunopharmacology of the Opsoclonus-Myoclonus Syndrome, 19 CLINICAL NEUROPHARMACOLOGY 1 (1996) (Ex. 49)); Ex. 63, p. 1.) Antibodies and other components of the immune system target central nervous system cells, rendering these cells dysfunctional and leading to neurological signs and symptoms. (Ex. 29, p. 5.) Thus, Dr. Bonthius asserts that “there is a highly plausible biological theory and strong scientific and medical support that vaccinations can induce OMS in children.” (Id. (emphasis omitted).) However, Dr. Bonthius acknowledges that, while a “variety of abnormal antibodies have been detected in OMS patients,” no specific pathogenic antibodies have been identified. (Ex. 58, p. 2 (citing Connolly et al., supra, at Ex. 37; Blaes et al., supra, at Ex. 34; Korfei et al., supra, at Ex. 60).) He clarifies that “inflammatory reactions, such as infections and immunizations, can induce exacerbations of autoimmune disorders,” regardless of whether there is evidence of shared molecular homology. (Id.) By way of example, Dr. Bonthius points to multiple sclerosis (“MS”), which has been found to be triggered by various infections despite the lack of evidence supporting shared molecular homology. (Id. (citing Marlan Marrodan et al., The Role of Infections in Multiple Sclerosis, 25 MULTIPLE SCLEROSIS J. 891 (2019) (Ex. 61)).) He asserts that his “inability to point to a specific antibody or peptide sequence simply reflects modern medicine’s limited knowledges regarding the precise pathophysiology of OMS.” (Id.) He contends that vaccination is “a far more plausible trigger” than jet lag as vaccination, which is “given for the express purpose of activating the immune system,” is “more likely to substantially impact immune function.” (Id. at 1; Ex. 63, pp. 2-3.) Jet leg, on the other hand, only affects the immune system “tangentially” by potentially altering circadian rhythms or heightening stress. (Ex. 58, p. 1; Ex. 63, p. 3.) However, he acknowledges that “[t]here has never been, nor is there ever likely to be, a controlled scientific study comparing vaccines and jet lag in their immune activation.” (Ex. 63, p. 2.)

In addition to molecular mimicry, Dr. Bonthius also proposes bystander activation and protease production as potential antigen-nonspecific mechanisms to explain how the subject vaccine could cause a relapse in OMS. (Ex. 58, p. 2.) Dr. Bonthius focuses on bystander activation, which he describes as a process by which “inflammatory environments induced by the immune response to the vaccine activate autoimmune cells in a non-specific manner.” (Id. (citing Robert S. Fujinami et al., Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and Autoimmune Disease, 19

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CLINICAL MICROBIOLOGY REVS. 80 (2006) (Ex. 59)).) He opines that L.D. likely had a genetic predisposition to OMS and that the trigger for onset of her disease may be different from the triggers related to subsequent relapses. (Tr. 28-29.) As a result, identification of a specific antigen or molecular mimic is less important in the context of a relapse than identification of an immune stimulus that could inflame an ongoing condition. (Id. at 29.) Thus, during the hearing, Dr. Bonthius clarified his opinion that molecular mimicry can explain the initial onset of OMS following the infection and bystander activation can explain the subsequent relapses following immune activation by infection and vaccination. (Id. at 68-70, 76.) He states that “[t]he important point is that inflammatory reactions, such as infections and immunizations, can induce exacerbations of autoimmune disorders.” (Ex. 58, p. 2.) He emphasizes the fact that L.D. received multiple vaccinations in April of 2016 and explains that the introduction of multiple antigens at once can lead to an aberrant immune response. (Tr. 70.)

Regarding L.D.’s condition, Dr. Bonthius opines that she had been developmentally and neurologically normal up until November 2015, when she first developed ataxia, shaking hand movements, tremor, and slowed speech. (Ex. 29, p. 6 (citing Ex. 3, pp. 35-37).) He further opines that, although she was not yet diagnosed with OMS, “it is highly likely that this was her first bout of OMS” as “all of her symptoms at that time were consistent with OMS and overlapped with the symptoms that she later acquired when she was diagnosed with OMS.” (Id.) He ultimately opines that L.D. experienced two bouts of OMS prior to the subject vaccinations: an episode in November 2015 and a second episode in January of 2016, both of which were mild, followed an infection, and lasted about a week. (Tr. 9-10, 51-52, 60-61; Ex. 29, pp. 6- 8.) Dr. Bonthius emphasizes that her symptoms had fully resolved by January 2016. (Id. at 9-10, 51; Ex. 29, pp. 6-8 (citing Ex. 2, p. 10).)

However, approximately two weeks after receiving the DTaP/IPV, MMR, and varicella vaccines on April 11, 2016, L.D. developed an acute onset of ataxia, shaking hand movements, tremor, and slowed speech. (Tr. 10-11, 49-51; Ex. 29, p. 6 (citing Ex. 2, p. 5).) Although similar in character to her prior episode, Dr. Bonthius opines that L.D.’s symptoms were “substantially more severe” in both duration and severity during her post-vaccination episode. (Tr. 51-52; Ex. 29, pp. 6, 8.) He describes her post- vaccination condition as “debilitating.” (Ex. 29, p. 7.) Her symptoms persisted for more than two years, resulting in a complete inability to walk independently and requiring several hospitalizations. (Id.) She also experienced new symptoms, including drooling, irritability, and sleep disturbances. (Id. at 6 (citing Ex. 3, pp. 36-37).) She eventually developed opsoclonus, which solidified her diagnosis of OMS. (Id. (citing Ex. 3, pp. 122-24).) Dr. Bonthius opines that prior to vaccination, L.D.’s condition persisted in a waxing and waning manner, but her symptoms worsened and her post-vaccination episode included onset of new symptoms indicative of an exacerbation. (Tr. 11-13, 17, 43.) Following her opsoclonus diagnosis, L.D. was treated with immunosuppressants that are known to be effective for OMS, and she experienced “an excellent recovery.” (Ex. 29, pp. 6-7 (citing Ex. 11, pp. 278-84).) Dr. Bonthius emphasizes that L.D. underwent extensive diagnostic testing but no alternative explanation for her condition was ever uncovered and that several different specialists evaluated L.D. and “all

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ultimately agreed that the proper diagnosis is OMS.” (Id. at 6.) Therefore, Dr. Bonthius opines that there is a logical sequence of cause and effect linking the April 11, 2016 vaccinations and an “exacerbation” of L.D.’s pre-existing OMS. (Id. at 6-7; Tr. 50-51, 60-62.)

Dr. Bonthius discusses the distinction between a relapse and an exacerbation, noting that a relapse occurs when an asymptomatic patient develops clinical disease, while an exacerbation occurs when something aggravates an ongoing disease process. (Tr. 61-62.) He agrees that both the overall course of OMS and the course of an individual relapse can be variable. (Id. at 62.) Although Dr. Bonthius acknowledges the possibility that L.D.’s post-vaccination episode could have occurred spontaneously as part of the natural course of her disease, he opines that this scenario “is less likely because both of her other episodes were triggered or occurred in association with some kind of an immune challenge” or inflammatory event. (Tr. 18, 52-53; Ex. 63, p. 3.) He opines that it is more likely that all three episodes (i.e., the two pre-vaccination episodes in November 2015 and January 2016, and the post-vaccination episode in May 2016) were triggered by inflammatory events. (Ex. 63, pp. 3-4.)

In response to discussion of L.D.’s prior vaccinations without adverse reaction, Dr. Bonthius opines that it is common for vaccines that were previously tolerated to induce inflammatory effects upon subsequent exposure. (Ex. 63, p. 3 (citing Biykem Bozkurt et al., Myocarditis with COVID-19 mRNA Vaccines, 144 CIRCULATION 471 (2021) (Ex. 76)).) The literature does not differentiate between initial vaccination and revaccination. (Id.) In response to the contention by respondent’s experts that L.D. did not display any evidence of an adverse inflammatory response following vaccination, Dr. Bonthius provides several examples of neuroimmune disorders featuring inflammation confined to the brain or peripheral nervous system that he contends are not usually “accompanied by fever, myalgia, or any other signs or symptoms in other organ systems.” (Id. at 1 (citing Michael J. Olek & Jonathan Howard, Evaluation and Diagnosis of Multiple Sclerosis in Adults, UPTODATE (last updated May 9, 2022) (Ex. 64); Eppie Yiu, Guillain-Barré Syndrome in Children: Epidemiology, Clinical Features, and Diagnosis, UPTODATE (last updated Oct. 24, 2023) (Ex. 65); Benjamin Greenberg, Transverse Myelitis, UPTODATE (last updated Feb. 14, 2023) (Ex. 66); Laura J. Balcer, Optic Neuritis, 354 N. ENG. J. MED. 1273 (2006) (Ex. 67); M. Stonehouse et al., Acute Disseminated Encephalomyelitis: Recognition in the Hands of General Paediatricians, 88 ARCHIVES DISEASE CHILD. 122 (2003) (Ex. 68); Willison et al., supra, at Ex. 57).) He thus opines that the “lack of symptoms in the periphery is not surprising or unusual for an immune-mediated neurological disorder.” (Id.) Additionally, Dr. Bonthius opines that, under the theory of molecular mimicry, “one would not expect redness, swelling, or induration at the injection site, nor would one expect fever myalgia, or any other peripheral sign, because the pathogenic antibodies are directed specifically at CNS targets.” (Id. at 1-2 (citing Burkhard Becher et al., Antigen Presentation in Autoimmunity and CNS Inflammation: How T Lymphocytes Recognize the Brain, 84 J. MOLECULAR MED. 532 (2006) (Ex. 69); Yehal Segal & Yehuda Shoenfeld, Vaccine-Inducted Autoimmunity: The Role of Molecular Mimicry and Immune Crossreaction, 14 CELLULAR & MOLECULAR IMMUNOLOGY 1 (2018) (Ex. 70)).) Accordingly, Dr. Bonthius opines that,

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“both in practice and in theory, one would not expect signs or symptoms outside of the nervous system in cases of vaccination-induced OMS.” (Id. at 2.)

Although he acknowledges that the precise timeframe between trigger and relapse in OMS is unknown, Dr. Bonthius opines that onset of L.D.’s symptoms within two weeks post-vaccination is “precisely the timing that one would expect for an immune-mediated reaction following a triggering event.” (Ex. 29, p. 7; Ex. 63, p. 2.) He notes that this timeframe is consistent with what is typical of other autoimmune neurological disorders that are known to be triggered by vaccination. (Ex. 29, p. 7; Ex. 58, p. 1; Ex. 63, p. 2 (citing Wellnitz et al., supra, at Ex. 56; Lapenna et al., supra, at Ex. 44; Daniela Pohl et al., Acute Disseminated Encephalomyelitis: Updates on an Inflammatory CNS Syndrome, 87 NEUROLOGY S38 (2016) (Ex. 75)).) Additionally, Dr. Bonthius opines that the “progression of symptoms over several weeks is precisely the clinical course that is typically seen in OMS.” (Ex. 29, p. 7 (citing Dalmau & Rosenfeld, supra, at Ex. 38).) Thus, Dr. Bonthius opines that there is a “strong and logical temporal relationship” between the subject vaccinations and the onset and progression of symptoms in this case. (Id. (emphasis omitted).)

b. Respondent’s Pediatric Neurology Expert, Gregory L. Holmes, M.D.9

Dr. Holmes provided two expert reports on respondent’s behalf, as well as expert testimony during the entitlement hearing. (Exs. A, C; Tr. 80-158.) Dr. Holmes agrees with “much of” Dr. Bonthius’s initial report; however, he disputes that the subject vaccinations significantly aggravated L.D.’s OMS. (Ex. A, p. 9.) He describes OMS as a rare neurological condition that typically occurs in children between the ages of 0.5 and 3 years and is characterized by opsoclonus (erratic saccadic intrusions), myoclonus and/or ataxia, and behavioral features with developmental plateauing, irritability, and insomnia. (Id. at 7, 11 (citing M. Kinsbourne, Myoclonic Encephalopathy of Infants, 25 J. NEUROLOGY NEUROSURGERY & PSYCHIATRY 271 (1962) (Ex. A, Tab 3); Pranzatelli et al., supra, at Ex. A, Tab 10; Michael R. Pranzatelli et al., Multifactorial Analysis of Opsoclonus-Myoclonus Syndrome Etiology (“Tumor” vs. “No Tumor”) in a Cohort of 356 9 Dr. Holmes received his medical degree from the University of Virginia School of Medicine in 1974,

before going on to complete an internship and residency in pediatrics at Yale University School of Medicine, followed by a residency in pediatric neurology at University of Virginia School of Medicine. (Ex. B, p. 1.) In 1979, Dr. Holmes accepted a teaching position at the University of Connecticut Health Center. (Id. at 2.) He was promoted to associate professor of neurology and pediatrics before moving on to the Medical College of Georgia, followed by Harvard Medical School. (Id.) While at Harvard Medical School, Dr. Holmes was elevated to professor of neurology in 1996, before accepting a position as a professor of neurology and pediatrics at Dartmouth Medical School in 2002. (Id.) Finally, in 2013, Dr. Holmes accepted his current positions as professor and Chair of neurological sciences and professor of pediatrics at Larner College of Medicine at the University of Vermont. (Id.) He is board certified in pediatrics and clinical neurophysiology, as well as psychiatry and neurology with a special competence in child neurology, and he maintains an active medical license in Vermont. (Id.; Ex. A, p. 1.) Dr. Holmes is an active clinician who evaluates and treats children with neurological disorders, and his research has focused on a wide range of topics in pediatric neurology with an emphasis on pediatric epilepsy. (Ex. A, p. 1.) He has published 317 peer reviewed articles, 142 non-peer reviewed articles, 78 book chapters, and hundreds of other scholarly publications. (Ex. B, pp. 33-110.) Dr. Holmes was proffered as an expert in neurology, pediatric neurology, and electrophysiology without objection. (Tr. 85-86.)

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US Children, PEDIATRIC BLOOD & CANCER, May 2018, at 1 (Ex. A, Tab 43; see also Ex. D, Tab 2)); Tr. 95.) OMS typically presents over a matter of days and relapses are common. (Ex. A, p. 7.) Dr. Holmes opines that L.D. met the diagnostic criteria for OMS and that she suffered from OMS prior to the subject vaccinations. (Id. at 7, 9.)

Specifically, Dr. Holmes opines that L.D. suffered a waxing and waning course that consisted of six separate episodes of OMS, two episodes prior to the subject vaccinations and four episodes post-vaccination. (Tr. 120-21.) Symptoms consistent with OMS were first documented on November 11, 2015, following an infection. (Id. at 106-07 (citing Ex. 22, pp. 5, 7-9; Ex. 6, pp. 7-9).) L.D. experienced a second episode following an upper respiratory infection in January of 2016. (Id. at 108-09 (citing Ex. 3, pp. 36-37).) Dr. Holmes agrees that the symptoms associated with L.D.’s pre- vaccination episodes of OMS were mild and had fully resolved before the subject vaccinations. (Id. at 107, 109.) However, in May of 2016, about 10 days post- vaccination, L.D. experienced a relapse in her OMS. (Id. at 110-11, 119 (citing Ex. 2, p. 5; Ex. 3, pp. 36, 110-11).) Dr. Holmes describes three additional relapses in August 2016, in October through November 2016, and in January 2017. (Id. at 112-15, 117- 21.) He describes L.D.’s development of opsoclonus in January 2017, about seven months post-vaccination, as a “major exacerbation,” though he emphasizes that L.D. developed opsoclonus in the absence of a viral or vaccine trigger and as “part of the continuum of her disease process.” (Ex. A, pp. 9-10; Tr. 118-21.) In fact, he notes that all three additional relapses occurred in the absence of vaccination. (Ex. A, p. 10; Tr. 113, 115, 117-18.) He asserts that these relapses represent the natural course of L.D.’s waxing and waning condition, which he ultimately characterizes as relapsing-remitting OMS. (Tr. 97, 121-22.)

Dr. Holmes suggests that her post-vaccination condition was merely a continuation of her pre-existing condition. (Ex. A, p. 9.) He contends that “OMS typically has a fluctuating course” and that relapse is “a fundamental problem in OMS, whether a neoplasm is found and regardless of treatment.” (Id. (citing Pranzatelli & Tate, supra, at Ex. A, Tab 5; Pike, supra, at Ex. A, Tab 6; Mitchell & Snodgrass, supra, at Ex. A, Tab 11; Brunklaus et al., supra, at Ex. A, Tab 46; Akshata Huddar et al., Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome: Experience from a Tertiary Care University Hospital, 66 NEUROLOGY INDIA 1332 (2018) (Ex. A, Tab 47)); Tr. 95-96.) He cites a retrospective study by Brunklaus et al., which found that 61% of OMS patients had a chronic-relapsing course, 32% of patients experienced several acute exacerbations, and only 7% of patients had a monophasic course. (Ex. A, p. 9 (citing Andreas Brunklaus et al., Outcome and Prognostic Features in Opsoclonus-Myoclonus Syndrome from Infancy to Adult Life, 128 PEDIATRICS e388 (2011) (Ex. A, Tab 46)).) Dr. Holmes suggests that the terms “exacerbation” and “relapse” are used interchangeably in the literature. (Tr. 87, 98, 152-54.) He explains that exacerbations increase the underlying pathology, while relapses usually occur when a patient gets worse after at least 24-72 hours of stability. (Id. at 98-99, 153.) He further explains that relapses may also occur where patients are no longer exhibiting the classic signs of OMS but are not yet fully asymptomatic due to persistent speech deficits, sleep disturbances, and behavioral problems. (Id. at 153; Ex. A, pp. 8, 10 (citing Pranzatelli & Tate, supra, at

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Ex. A, Tab 5).) Although OMS is a heterogenous disorder and relapses are variable (Ex. A, p. 8 (citing Michael Pike, Opsoclonus-Myoclonus Syndrome, 112 HANDBOOK CLINICAL NEUROLOGY 1209 (2013) (Ex. A, Tab 6)); Tr. 95-96, 99), Dr. Holmes opines that relapses typically require a trigger, which is usually a tumor, infection, or reduction/discontinuation of immunotherapy. (Tr. 122-23, 138, 144-45 (citing Pranzatelli & Tate, supra, at Ex. A, Tab 5); Ex. A, p. 10 (citing Wendy G. Mitchell & S. Robert Snodgrass, Opsoclonus-Ataxia Due to Childhood Neural Crest Tumors: A Chronic Neurologic Syndrome, 5 J. CHILD NEUROLOGY 153 (1990) (Ex. A, Tab 11)).) While Dr. Holmes asserts that relapses are usually caused by the same agent, he acknowledges that Dr. Pranzatelli has not specified that the triggers of OMS onset and relapse have to be the same. (Tr. 122-23, 138.) He instead quotes Dr. Pranzatelli’s statement that “[i]t is unclear if pathologic events that trigger OMS and those that trigger relapse are the same, and whether they both occur at the same brain locations.” (Ex. C, p. 4 (quoting Pranzatelli & Tate, supra, at Ex. A, Tab 5).) He further asserts that “if you get one relapse, you are more likely to get another relapse and another relapse.” (Tr. 96.) Ultimately, Dr. Holmes opines that distinguishing between whether L.D.’s post- vaccination episodes were relapses or exacerbations would be “splitting hairs.” (Id. at 153-54.) He describes L.D.’s post-vaccination relapses as more severe than her prior relapses and specifically notes that “she didn’t rebound like she did after her first episode.” (Id. at 99, 112.) Apart from her age at onset (3 years and 7 months), Dr. Holmes opines that L.D.’s OMS presentation was not atypical. (Id. at 106, 108.)

Dr. Holmes agrees that OMS is an autoimmune disease. (Ex. A, p. 9.) He notes that autopsy findings, though limited, demonstrate widely disseminated perivascular collections of lymphocytes, supporting an immune-mediated etiology. (Id. at 8 (citing C.A. Young et al., Opsoclonus-Myoclonus Syndrome: An Autopsy Study of Three Cases, 2 EUR. J. MED. 239 (1993) (Ex. A, Tab 7)).) Although paraneoplastic etiology can be proven in about 50% of cases, there is also evidence to support parainfectious, toxic-metabolic, and idiopathic etiologies. (Id. (citing Pranzatelli et al., supra, at Ex. A, Tab 10).) Dr. Holmes acknowledges that “reported infectious/parainfectious cases are many,” including hepatitis C, Lyme disease, herpes, Epstein-Barr virus, poststreptococcus infection, HIV, COVID-19, malaria, influenza A, tuberculosis, West Nile Virus, mumps, chikungunya and dengue virus, Coxsackie B3, salmonella, mycoplasma pneumoniae, neuroborreliosis, rotavirus, cytomegalovirus, and cryptococcosis infection.10 (Id.) However, he contends that, “[d]espite a litany of infections reported in

10 Citing Duncan Smyth et al., Post-COVID-19 Opsoclonus-Myoclonus Syndrome and Encephalopathy

Associated with Leucine-Rich Glioma-Inactivated 1 (LGI-1) Antibodies, J. NEUROLOGICAL SCIS., Sep. 2021, at 1 (Ex. A, Tab 13); Cendrine Foucard et al., Acute Cerebellar Ataxia and Myoclonus with or Without Opsoclonus: A Para-Infectious Syndrome Associated With COVID-19, 28 EUR. J. NEUROLOGY 3533 (2021) (Ex. A, Tab 14); Priyank Bharatkumar Shah & Soaham Dilip Desai, Opsoclonus Myoclonus Ataxia Syndrome in Setting of COVID-19 Infection, 96 NEUROLOGY 33 (2021) (Ex. A, Tab 15); Dana Lev et al., Opsoclonus-Myoclonus As a Presentation of Post-Malaria Neurologic Syndrome, April 2020, J. TRAVEL MED., at 1 (Ex. A, Tab 16); Eleni Papageorgiou et al., Dancing Eyes Syndrome from West Nile Virus Encephalitis, 96 POSTGRADUATE MED. J. 442 (2020) (Ex. A, Tab 17); Lokesh Saini et al., Infection- Associated Opsoclonus: A Retrospective Case Record Analysis and Review of Literature, 35 J. CHILD NEUROLOGY 480 (2020) (Ex. A, Tab 18); Ya Chen et al., Opsoclonus-Myoclonus Syndrome Associated with Herpes Simplex Virus Infection: A Case Report, 131 INT’L J. NEUROSCI. 307 (2021) (Ex. A, Tab 19); Soaham D. Desai et al., Opsoclonus Myoclonus Syndrome: A Rare Manifestation of Dengue Infection in a

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case studies, . . . no consistent pathogen has been identified.” (Id. (citing Elizabeth D. Tate et al., Neuroepidemiologic Trends in 105 US Cases of Pediatric Opsoclonus- Myoclonus Syndrome, 22 J. PEDIATRIC ONCOLOGY NURSING 8 (2005) (Ex. A, Tab 12; see also Ex. C, Tab 2)).) Notably, Dr. Holmes points to a large cohort study that failed to differentiate between OMS in groups designated as “paraneoplastic” and those designated as “para/post-infectious” or “idiopathic.” (Id. (citing Pranzatelli et al., supra, at Ex. A, Tab 43).) “Differences in the underlying pathophysiology of the two patterns of disease remain unclear and do not seem to be influenced by the presence or absence of a neoplasm.” (Id. at 9.)

Dr. Holmes opines that, regarding pathological mechanism and recurrence of relapses, OMS is most similar to relapsing-remitting MS. (Ex. C, p. 3.) He explains that MS is an inflammatory disorder of the brain and spinal cord, in which focal lymphocytic infiltration leads to damage of myelin and axons and, over time, to widespread microglial activation that is associated with extensive and chronic neurodegeneration. (Id.) This is comparable to autopsy findings in OMS patients, which demonstrate widely disseminated perivascular collections of lymphocytes, though myelin is not preferentially affected in OMS. (Id. (citing Young et al., supra, at Ex. A, Tab 7).) Similar to OMS, the specific cause of MS is unknown. (Id. (citing D.S. Goodin, The Epidemiology of Multiple Sclerosis: Insights to a Causal Cascade, 138 HANDBOOK CLINICAL NEUROLOGY 173 (2016) (Ex. C, Tab 11); Alyssa Nylander & David A. Hafler, Multiple Sclerosis, 122 J. CLINICAL INVESTIGATION 1180 (2012) (Ex. C, Tab 12)).) Dr. Holmes explains that the “most widely accepted theory” of MS involves “an inflammatory immune-mediated disorder characterized by an autoimmune response to self-antigens in a genetically susceptible individual.” (Id. (citing Nylander & Hafler, supra, at Ex. C, Tab 12).) He contends that, “[b]ecause the pathogenesis of MS is thought to involve the immune system, it has been hypothesized that a stimulus of the immune system (e.g., a vaccine)

Child, 13 J. PEDIATRIC NEUROSCI. 455 (2018) (Ex. A, Tab 20); Noella Maria Delia Pereira et al., Opsoclonus-Myoclonus-Ataxia Syndrome in an HIV-Infected Child, 10 OXFORD MED. CASE REPS. 252 (2016) (Ex. A, Tab 21); Enrique Urrea-Mendoza et al., Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS) Associated with SARS-CoV-2 Infection: Post-Infectious Neurological Complication with Benign Prognosis, 11 TREMOR & OTHER HYPERKINETIC MOVEMENTS 1 (2021) (Ex. A, Tab 22); Pauline Krug et al., Opsoclonus- Myoclonus in Children Associated or Not with Neuroblastoma, 14 EUR. J. PAEDIATRIC NEUROLOGY 400 (2010) (Ex. A, Tab 23); Mateus Santana do Rosário et al., Opsoclonus-Myoclonus-Ataxia Syndrome Associated with Chikungunya and Dengue Virus Co-Infection, 75 INT’L J. INFECTIOUS DISEASES 11 (2018) (Ex. A, Tab 24); José Renan Miranda Cavalcante-Filho et al., Kinsbourne Syndrome Associated with Cryptococcosis Infection, 47 PARKINSONISM & RELATED DISORDERS 86 (2018) (Ex. A, Tab 25); Borislav Radic et al., A Case of Adult-Onset Poststreptococcal Opsoclonus-Myoclonus Syndrome, 118 ACTA NEUROLOGICA BELGICA 541 (2018) (Ex. A, Tab 26); Akihiko Morita et al., Opsoclonus-Myoclonus Syndrome Following Influenza A Infection, 51 INTERNAL MED. 2429 (2012) (Ex. A, Tab 27); Vildan Ertekin & Hüseyin Tan, Opsoclonus-Myoclonus Syndrome Attributable to Hepatitis C Infection, 42 PEDIATRIC NEUROLOGY 441 (2010) (Ex. A, Tab 28); I. Zaganas et al., Opsoclonus-Myoclonus Syndrome Associated with Cytomegalovirus Encephalitis, 68 NEUROLOGY 1636 (2007) (Ex. A, Tab 29); L. Peter et al., Opsoclonus-Myoclonus As a Manifestation of Lyme Disease, 77 J. NEUROLOGY NEUROSURGERY & PSYCHIATRY 1090 (2006) (Ex. A, Tab 30); Marc Gibaud et al., Opsoclonus in a Child with Neuroborreliosis: Case Report and Review of the Literature, 26 ARCHIVES DE PÉDIATRIE 118 (2019) (Ex. A, Tab 31); Hiroshi Mitoma et al., Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms, 14 J. MOVEMENT DISORDERS 10 (2021) (Ex. A, Tab 32).

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may trigger the disease.” (Id.) Dr. Holmes cites several studies that have failed to show any association between vaccines and MS. (Id. (citing Alberto Ascherio et al., Hepatitis B Vaccination and the Risk of Multiple Sclerosis, 344 N. ENG. J. MED. 327 (2001) (Ex. C, Tab 13); Christina Confavreux et al., Vaccinations and the Risk of Relapse in Multiple Sclerosis, 344 N. ENG. J. MED. 319 (2001) (Ex. C, Tab 14); Miguel A. Hernán et al., Tetanus Vaccination and the Risk of Multiple Sclerosis: A Systematic Review, 67 NEUROLOGY 212 (2006) (Ex. C, Tab 15); Oliver T. Rutschmann et al., Immunization and MS: A Summary of Published Evidence and Recommendations, 59 NEUROLOGY 1837 (2002) (Ex. C, Tab 16); Frank DeStefano et al., Vaccinations and Risk of Central Nervous System Demyelinating Disease in Adults, 60 ARCHIVES NEUROLOGY 504 (2003) (Ex. C, Tab 17); Annette Langer-Gould et al., Vaccines and the Risk of Multiple Sclerosis and Other Central Nervous System Demyelinating Diseases, 71 JAMA NEUROLOGY 1506 (2014) (Ex. C, Tab 18)).) However, he notes that, as in OMS, multiple triggers can precede relapses in MS. (Id.) Although he suggests that “the identity of an antigen or infectious agent leading to the oligoclonal expansion of B and T cells is unknown” in MS (Id.), he cites a study by Lanz et al. that “convincingly provides a mechanism linking EBV with MS through molecular mimicry.” (Id. at 5 (citing Tobias V. Lanz et al., Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM, 603 NATURE 321 (2022) (Ex. C, Tab 24)).) He suggests that this study does not support that a vaccine will result in molecular mimicry as “the antigen load of EBV is considerable” and the potential for molecular mimicry resulting from “the minute amounts of antigen given as an immunization” is “dubious.” (Id.)

Dr. Holmes disputes the applicability of evidence referenced by Dr. Bonthius in support of a relationship between immunization and OMS. (Ex. A, p. 11 (discussing (Lapenna et al., supra, at Ex. A, Tab 54; McCarthy & Filiano, supra, at Ex. 45; Piquet et al., supra, at Ex. 48).) He submits that the age of onset in the patients studied “was outside the common age of onset of OMS.” (Id. (citing Pranzatelli et al., supra, at Ex. A, Tab 10; Pranzatelli et al., supra, at Ex. A, Tab 43).) He further contends that these case reports merely describe a temporal relationship without providing a pathophysiological mechanism of causation. (Id.) Moreover, these cases referenced a new onset of OMS without provided evidence to show that immunization can cause an exacerbation of OMS. (Id.)

Although Dr. Holmes credits Dr. Pranzatelli as the leading expert on the pathophysiology of pediatric OMS, he contends that “none of Dr. Pranzatelli’s publications provide any specific information regarding the relationship between immunization and OMS onset.” (Ex. C, p. 2; Tr. 91-92.) He cites two studies to support this position. In the first study, Dr. Holmes acknowledges that immunization is listed as a possible etiological factor in a series of 105 children with OMS; however, “more than 85% of the children had received immunizations . . . prior to onset of neurological problems” and only two patients received the diphtheria, pertussis, tetanus vaccine within one week of onset. (Ex. C, p. 2 (citing Tate et al., supra, at Ex. C, Tab 2).) In the second study of 159 children with OMS relapse, Dr. Pranzatelli found that relapse was linked with infection in 40% of cases, with treatment-tapering in 48% of cases, and with “both/other” in 12% of cases. (Id. (citing Pranzatelli & Tate, supra, at Ex. A, Tab 5).)

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The authors cautioned against immunization in children experiencing acute or chronic relapse and in children not yet in remission due to the risk of relapse. (Id. (citing Pranzatelli & Tate, supra, at Ex. A, Tab 5).) However, Dr. Holmes contends that “Dr. Pranzatelli does not recommend stopping immunization in children with [OMS].” (Id.) Similarly, Dr. Holmes agrees with Dr. Pranzatelli’s recommendation to screen for tumor, infection, and tapering/discontinuation of steroid treatment and states that he would not recommend vaccination while an OMS patient is undergoing immunotherapy; however, he disagrees that vaccination is a trigger for OMS exacerbation or relapse. (Tr. 137- 39.)

Dr. Holmes further asserts that the Institute of Medicine determined that “epidemiological and mechanistic evidence is inadequate to accept or reject a causal relationship between MMR and DTaP vaccines and OMS.” (Ex. C, p. 2 (citing INSTITUTE OF MEDICINE, ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY (Kathleen Stratton et al. eds., 2012) (Ex. A, Tab 59)).) He explains that, given the rarity of the condition, “no one has, or likely will ever, perform a prospective study using nonimmunized children as a control group.” (Id.) However, despite specifically noting the rarity of the condition, he contends that it is ”not surprising” that some children would be noted to experience a relapse in close temporal proximity to immunization. (Id.) He suggests that this is simply because OMS generally “occurs at an age when children are receiving many immunizations.” (Id.) However, he asserts that temporal proximity to vaccination alone is not enough to prove causation. (Id.) Moreover, Dr. Holmes opines that, in about 30% of cases, there is no identified trigger. (Tr. 144-45.)

Regarding Dr. Bonthius’s proposed theory of causation based on molecular mimicry, Dr. Holmes submits that molecular mimicry “very rarely” causes human disease. (Ex. A, p. 12 (citing N.R. Rose & I.R. Mackay, Molecular Mimicry: A Critical Look at Exemplary Instances in Human Diseases, 57 CELLULAR & MOLECULAR LIFE SCIS. 542 (2000) (Ex. A, Tab 58)).) He notes that, in order to prove a causal role for molecular mimicry, the following must be shown: (1) the peptide sequence in the vaccine that is shared with a host peptide must induce an immune response in the host tissue; (2) the immune response triggered by the vaccine must be able to cross-react with the shared host peptide; and (3) the cross-reactive immune response must be harmful. (Id. at 11-12 (citing J. Lindsay Whitton & Robert S. Fujinami, Viruses as Triggers of Autoimmunity: Facts and Fantasies, 2 CURRENT OP. MICROBIOLOGY 392 (1999) (Ex. A, Tab 57)).) In particular, Dr. Holmes points out the lack of identified sequence homology between peptides found in the brain and the vaccine and that lack of evidence to support a cross-reactive response to the peptides resulting in OMS. (Id.) Mere detection of an autoantibody or T cell is insufficient as, even when autoimmune response does occur, “it is not known if such responses are the cause of the disease, the result of the disease . . . or are completely unrelated to the disease process.” (Id. at 12.) He contends that Dr. Bonthius has not proven a pathological role for the autoantibodies elicited by the vaccine. (Id. at 10.) Autoantibodies and self-reactive T cells have been found in healthy individuals and were likely present prior to vaccination. (Id. at 10, 12.) Dr. Holmes states that it is unclear whether Dr. Bonthius “believes the autoantibodies elicited by the immunizations through the proposed mechanism of

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molecular mimicry were the same autoantibodies as those elicited by the upper respiratory infection.” (Id. at 10.) In the instant case, Dr. Holmes opines that it is “highly unlikely” that molecular mimicry played “any role in her disease process.” (Id. at 12.)

Dr. Holmes explains that the working hypothesis is that much of the damage caused by OMS is the result of neuroinflammation. (Ex. A, p. 8 (citing Pranzatelli & Tate, supra, at Ex. A, Tab 5).) He notes that, “in rare situations,” children receiving the DTaP and MMR vaccines “can have a neuroinflammatory response.” (Ex. C, pp. 1-2.) However, he submits that L.D. did not experience any signs of a significant peripheral response to vaccination, such as pain, redness, swelling or induration at the injection site, fever, myalgia, or headache, “making it highly unlikely that cytokines generated peripherally by the vaccines had any role in the pathogenesis of the condition.” (Ex. A, p. 11; Ex. C, p. 2.) Although he opines that “[i]t is difficult to understand how an immune-mediated pathophysiological mechanism would result in a relapse two weeks following the immunizations without causing any other symptoms” (Ex. C, p. 2), Dr. Holmes suggests that some OMS patients experience prodromal symptoms and that it may be unclear whether the symptoms are related to an underlying infection or the OMS itself (Tr. 104-05). Moreover, Dr. Holmes opines that, while there is evidence to support a correlation between sera CCL21 and severity/duration of OMS, “there is no evidence that cytokines are causative of OMS.” (Ex. A, p. 11 (citing Michael R. Pranzatelli et al., Cytokines, Cytokine Antagonists, and Soluble Adhesion Molecules in Pediatric OMS and Other Neuroinflammatory Disorders, 326 J. NEUROLOGICAL SCIS. 53 (2013) (Ex. A, Tab 55)).) He explains that Dr. Pranzatelli has determined that an aberrant B cell response is likely responsible for this autoimmune condition. (Ex. C, p. 2.) There is a drastic increase in B cells during neuroinflammation, and these B cells, which are shared between multiple CNS compartments and the peripheral immune response, follow chemokine gradients into the CNS. (Id.) Dr. Holmes explains that, while several chemokines are elevated in untreated OMS, “most of the pro- and anti- inflammatory cytokines were normal.” (Id. at 2-3.) Although Dr. Pranzatelli’s findings “are consistent with the CSF B cell expansion . . . and intrathecal oligoclonal band synthesis, described in pediatric OMS, and support the humoral hypothesis” of antibody-mediated disease, Dr. Holmes opines that it is unlikely that cytokines induced by the vaccine could cause a relapse. (Id. at 3 (citing M.R. Pranzatelli et al., B- and T- Cell Markers in Opsoclonus-Myoclonus Syndrome: Immunophenotyping of CSF Lymphocytes, 62 NEUROLOGY 1526 (2004) (Ex. C, Tab 6)).)

Dr. Holmes notes that evidence shows that other autoimmune diseases can be exacerbated by non-infectious causes, including stress. (Ex. A, p. 10 (citing Kaseem Sharif et al., The Role of Stress in the Mosaic of Autoimmunity: An Overlooked Association, 17 AUTOIMMUNITY REVS. 967 (2018) (Ex. A, Tab 48); C. Jane Welsh et al., Neuroimmune Interactions in a Model of Multiple Sclerosis, 1153 ANNALS N.Y. ACAD. SCI. 209 (2009) (Ex. A, Tab 49); Hanna Ilchmann-Diounou & Sandrine Menard, Psychological Stress, Intestinal Barrier Dysfunctions, and Autoimmune Disorders: An Overview, FRONTIERS IMMUNOLOGY, Aug. 2020, at 1 (Ex. A, Tab 50)).) In this case, jet lag was raised as a possible explanation for L.D.’s symptoms on May 6, 2016. (Id. (citing Ex. 2, p. 5).) Dr. Holmes explains that “patients are subjected to numerous

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physical, biological and climatic factors which can cause stress and adverse effects on general health” during long flights. (Id. (citing U. Lange, Physikalische Belastung beim Reisen, 70 ZEITSCHRIFT FÜR RHEUMATOLOGIE 299 (2011) (Ex. A, Tab 51)).) For instance, evidence has shown that circadian rhythms, which are disturbed by international flights, can play a role in the pathogenesis of MS. (Id. (citing Simone Kern et al., Clinical Relevance of Circadian Melatonin Release in Relapsing-Remitting Multiple Sclerosis, 97 J. MOLECULAR MED. 1547 (2019) (Ex. A, Tab 52); David C. Mohr, Stress and Multiple Sclerosis, 254 J. NEUROLOGY 11/65 (2007) (Ex. A, Tab 53)).) He submits that Dr. Bonthius has not provided any evidence to support his position that vaccination is more likely to substantially impact the immune system as compared to jet lag. (Ex. C, p. 4.) While Dr. Holmes suggests that “[t]he stress and circadian disruption of a transatlantic flight could have contributed to the exacerbation of [L.D.]’s condition” (Ex. A, p. 10; Tr. 141-42), he acknowledges that there is no published literature to support a relationship between jet lag or circadian disruption and onset of OMS (Tr. 140-42). Moreover, in his supplemental report, Dr. Holmes acknowledges that two-week delay between L.D.’s international flight and onset. (Ex. C, p. 4.) He ultimately asserts that “[i]t is unlikely that two weeks after the flight there would have been any residual jet lag that would trigger an exacerbation.” (Id.)

On the issue of timing, Dr. Holmes opines that “[t]he appropriate temporal window between a trigger and relapse in OMS is not known.” (Ex. C, p. 3.) He references that Vaccine Injury Table for the expected timeframe between DTaP and MMR vaccination and onset of encephalopathy/encephalitis. (Id.) He thus contends that onset within 72 hours of DTaP vaccination and/or 5-15 days of MMR vaccination is supported. (Id.) However, he notes that the Institute of Medicine “discarded” Lapenna et al., which supported onset of OMS within 15 days of MMR vaccination, as the study “did not contribute to the weight of mechanistic evidence.” (Id.)

c. Respondent’s Immunology Expert, Ari J. Fried, M.D.11

Dr. Fried provided an expert report on respondent’s behalf, as well as expert testimony during the entitlement hearing. (Ex. D; Tr. 159-202.) Dr. Fried agrees that there is immune involvement in OMS and that OMS is a neuroinflammatory disorder; however, he notes that “the designation ‘autoimmune,’ which has different implications and is not used interchangeably, is suspected, not proven.” (Ex. D, p. 3 (quoting

11 Dr. Fried received his medical degree from Chirstian-Albrechts-Universität zu Kiel, Germany in 2001.

(Ex. E, p. 1.) From there, he completed an internship and residency in pediatrics at the University of Iowa Hospital and Clinics, followed by a fellowship in allergy and immunology at Children’s Hospital Boston. (Id.) He currently works as an attending physician in the division of immunology at Boston Children’s Hospital and an instructor of pediatrics at Harvard Medical School. (Id.; Ex. D, p. 1.) Dr. Fried has also maintained a clinical practice as an allergist and immunologist at Boston’s Children’s Hospital. (Ex. D, p. 1.) He has extensive expertise in caring for children with immune diseases, including reactions to vaccines. (Id.) Dr. Fried is board certified in pediatrics, as well as allergy and immunology, and he maintains an active medical license in Massachusetts. (Id.; Ex. E, p. 4.) He has published 13 peer reviewed articles and 5 abstracts, poster presentations, and exhibits presented at professional meetings. (Ex. E, pp. 6-7.) Dr. Fried was proffered as an expert in pediatric immunology without objection. (Tr. 162.)

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Pranzatelli et al., supra, at Ex. D, Tab 2).) He opines that “OMS remains not well characterized immunologically” and disease origin is “unclear.” (Id.) He explains that, although CSF biomarkers have been identified in correlation with some degree of disease activity, they lack sensitivity and specificity, and they do not discriminate between paraneoplastic and idiopathic causes. (Id. (citing Thomas Rossor et al., Diagnosis and Management of Opsoclonus-Myoclonus-Ataxia Syndrome in Children: An International Perspective, 9 NEUROLOGY NEUROIMMUNOLOGY & NEUROINFLAMMATION e1153 (2022) (Ex. D, Tab 1)).) Relatedly, “the largest reported cohort of children with OMS failed to differentiate OMS in the group designated as ‘paraneoplastic’ from that designated as ‘para/post-infectious’ or ‘idiopathic.’” (Id. (citing Pranzatelli et al., supra, at Ex. D, Tab 2).)

Dr. Fried opines that “Dr. Pranzatelli and other leading international experts hypothesize that a tumor origin may be uniformly present in childhood OMS and that the neuroinflammatory symptoms are a consequence of that, but that in some children the tumor may spontaneously resolve before diagnosis.” (Ex. D, p. 3 (discussing Pranzatelli et al., supra, at Ex. D, Tab 2).) He acknowledges that this hypothesis is not proven, but he notes that neuroblastoma is found in 50% of cases, that neuroblastoma screening is not always comprehensive and may lead to false negatives, and that occult neuroblastoma is occasionally discovered years after OMS presentation. (Id. (citing Pranzatelli et al., supra, at Ex. D, Tab 2).) Ultimately, Dr. Fried opines that although OMS shares immune involvement with other neuroinflammatory disorders, such as ADEM, TM, GBS, and MS, “OMS has very distinct clinical features, a likely different disease origin with possible uniformly present paraneoplastic etiology, and in contrast to most of the here mentioned diseases, no specific or reliable immune biomarkers have been identified for OMS.” (Id. at 4 (citing Rossor et al., supra, at Ex. D, Tab 1; Pranzatelli et al., supra, at Ex. D, Tab 2; Elizabeth Wells et al., Neuroimmune Disorders of the Central Nervous System in Children in the Molecular Era, 14 NATURE REVS. NEUROLOGY 433 (2018) (Ex. D, Tab 7)).)

Dr. Fried agrees that Dr. Pranzatelli has shown a significant upregulation of CCL21 in serum of untreated OMS patients when compared to controls and significantly decreased levels of CCL21 after immunomodulatory treatments. (Ex. D, p. 4 (citing ref 7).) “CCL21 is a T cell attracting chemokine important for recruitment of T cells to secondary lymphoid organs promoting co-localization of naïve T cells and antigenexperienced dendritic cells . . . to facilitate T cell activation.” (Id.) However, he contends that the immune activation effect of CCL21 in OMS “remains elusive.” (Id. (citing Jay M. Lee et al., Phase I Trial of Intratumoral Injection of CCL21 Gene Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8+ T Cell Infiltration, 23 CLINICAL CANCER RES. 4556 (2017) (Ex. D, Tab 4)).) He also notes that Dr. Pranzatelli found upregulation of CCL22, a chemokine that has an immunomodulatory effect. (Id. (citing Michael R. Pranzatelli et al., CCR4 Agonists CCL22 and CCL17 are Elevated in Pediatric OMS Sera: Rapid and Selective Down- Regulation of CCL22 by ACTH or Corticosteroids, 33 J. CLINICAL IMMUNOLOGY 817 (2013) (Ex. D, Tab 5); Moritz Rapp et al., CCL22 Controls Immunity by Promoting Regulatory T Cell Communication with Dendritic Cells in Lymph Nodes, 216 J.

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EXPERIMENTAL MED. 1170 (2019) (Ex. D, Tab 6)).) Thus, Dr. Fried opines, although supportive of immune involvement, “the data do not reveal any direct link to either autoimmunity or to a vaccine triggered immune event.” (Id.)

Dr. Fried addresses the case reports cited by Dr. Bonthius. (Ex. D, p. 4 (discussing Lapenna et al., supra, at Ex. D, Tab 8; McCarthy & Filiano, supra, at Ex. D, Tab 9; Piquet et al., supra, at Ex. D, Tab 10).) He agrees with Dr. Holmes that these case reports support a temporal association but provide no mechanism or laboratory data to support a causative association. (Id.) He also points to the rarity of the condition and frequency of vaccination to suggest that a temporal association could be mere coincidence. (Id.) In one of the case reports, Dr. Fried points out the one patient had both a vaccination and viral illness prior to onset. (Id. (citing Piquet et al., supra, at Ex. D, Tab 10).) In all cited case reports, the patients were older than L.D. and older than the typical age of OMS onset. (Id. (citing Pranzatelli et al., supra, at Ex. D, Tab 11).) He cites a series of 389 patients with OMS that specifically noted OMS occurrence in adolescence is uncommon and that data on OMS in late-onset age group “are too scant to extrapolate.” (Id. (citing Pranzatelli et al., supra, at Ex. D, Tab 2).) Finally, Dr. Fried notes that the case reports discussed initial onset of OMS, rather than relapse. (Id.)

Dr. Fried next addresses Dr. Bonthius’s claim that there is a causal link between OMS relapse and vaccination. (Ex. D, p. 5.) He cites a manuscript by Dr. Pranzatelli, including various possible triggers for OMS relapse, such as infection, steroid tapering or discontinuation, immunization, and tumor. (Id. (citing Pranzatelli & Tate, supra, at Ex. D, Tab 12).) However, all potential triggers other than immunization are discussed extensively as verified by clinical observation, while immunization is neither discussed in text nor confirmed by patient data. (Id. (citing Pranzatelli & Tate, supra, at Ex. D, Tab 12).) Dr. Fried also cites the same large case series of 159 children with OMS that found relapse was related to infection in 40% of cases, to treatment-tapering in 48% of cases, and to both in 12% of case. (Id. (citing Pranzatelli & Tate, supra, at Ex. D, Tab 12; Pranzatelli et al., supra, at Ex. D, Tab 11).) Vaccination was not demonstrated as trigger for relapse in this series. (Id. (citing Pranzatelli & Tate, supra, at Ex. D, Tab 12; Pranzatelli et al., supra, at Ex. D, Tab 11).) In a cohort study of 256 children, illness was noted as a common trigger for OMS relapse and there was evidence to show that “new inflammatory disease may develop spontaneously in patients that are [in] remission.” (Id. (citing Pranzatelli et al., supra, at Ex. D, Tab 2).) A 2022 report by the international OMS study group found that OMS relapse is associated with infection and/or reduction in immunotherapy, but there was no mention of vaccination as an observed or expected trigger for relapse. (Id. (citing Rossor et al., supra, at Ex. D, Tab 1).) The report also cites a research article from 2019 that examined revaccination of children with paraneoplastic OMS and found no exacerbation after vaccination with DTaP, Tdap, hepatitis B, IPV, pneumococcal conjugate PCV7, MMRV, meningococcal MCV 4, and typhoid vaccines. (Id. (citing Ami Patel et al., Treatment and Revaccination of Children with Paraneoplastic Opsoclonus-Myoclonus-Ataxia Syndrome and Neuroblastoma: The Memorial Sloan Kettering Experience, 67 PEDIATRIC BLOOD & CANCER e28319 (2020) (Ex. D, Tab 13)).) The report concluded that, “while febrile

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illness has been associated with [OMS] exacerbation in our cohort, this was not the case with vaccines, suggesting a difference in immune system response to vaccination and infection.” (Id. (quoting Patel et al., supra, at Ex. D, Tab 13).) Therefore, Dr. Fried opines that “infection-specific immune phenomena,” which are not provoked by vaccination, likely play “an essential role” in triggering exacerbations. (Id.)

Dr. Fried ultimately agrees that bystander activation can explain how an unspecified infection could cause a relapse or exacerbation of OMS. (Tr. 176-77.) He explains that bystander activation occurs when an immune stimulant triggers an inflammatory process that can lead to disease. (Id. at 175-76.) However, he disagrees that bystander activation is a relevant mechanism for explaining how a vaccine can cause disease as the immune response to vaccination is not the same as the immune response to infection. (Id. at 177-79.) He emphasizes that “the magnitude of inflammation is much higher and therefore the chance that you would have a mechanism such as bystander activation . . . that augment[s] the immune response would be much stronger in an active infection.” (Id. at 179.)

Regarding L.D.’s presentation specifically, Dr. Fried notes that her prior episodes of OMS were likely associated with infection but that her post-vaccination relapse was not associated with any signs of adverse inflammatory response, such as fever. (Ex. D, pp. 5-6.) He further notes that L.D. received prior DTaP, IPV, MMR, and varicella vaccines without any reported adverse effects. (Id. at 6.) He also points approvingly to Dr. Holmes’s opinion that L.D.’s “waxing and waning course is typical for the natural history of this condition” and that a remitting course is the most common presentation of relapsing OMS. (Id. (citing Pranzatelli & Tate, supra, at Ex. D, Tab 12).) Accordingly, Dr. Fried opines that L.D. likely experienced two “infection-associated episodes early in her course before she developed the expected natural course of a relapsing illness.” (Id.) He concludes that L.D.’s vaccination did not aggravate her OMS. (Id.)

V. Analysis

A. Loving prongs one through three

Under the Vaccine Act, a “significant aggravation” of a condition is “any change for the worse in a preexisting condition which results in markedly greater disability, pain, or illness accompanied by substantial deterioration of health.” § 300aa-33(4). In order to assess when this has occurred, the first three Loving prongs examine (1) the vaccinee’s condition prior to the administration of the vaccine and (2) the vaccinee’s current condition, and then (3) assess whether a comparison of the pre- and post- vaccination conditions constitutes a “significant aggravation” of the condition. W.C., 704 F.3d at 1357. Although a petitioner need not prove the expected outcome of a pre- vaccination condition or that the post-vaccination condition is worse than the expected outcome, a petitioner still must show that the post-vaccination condition was affected by his vaccination. Locane v. Sec’y of Health & Human Servs., 685 F.3d 1375, 1381 (Fed. Cir. 2012); Sharpe v. Sec’y of Health & Human Servs., 964 F.3d 1072, 1082 (Fed. Cir. 2020).

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In this case, there is little to no disagreement as to the difference between L.D.’s condition pre- and post-vaccination. The course of the condition is well summarized by a chart included in Dr. Holmes’s initial report:

(Ex. A, p. 7.) In sum, both parties’ neurology experts agree that, although L.D. was not diagnosed with OMS until much later, she suffered two bouts of the condition prior to the vaccinations at issue. (Ex. 29, p. 7; Ex. A, pp. 7, 12; Tr. 9-10, 106-09, 120.) These two episodes were relatively mild and resolved in relatively short period. (Ex. 29, p. 6; Tr. 10, 51, 62, 109.) She was in a period of remission for approximately three to four months prior to vaccination and then suffered a relapse of the condition approximately two weeks post-vaccination. (Ex. 29, pp. 6-7; Ex. A, p. 10; Ex. C, p. 2; Tr. 10-11, 51, 109-10.) There is some disagreement as to whether L.D.’s post-vaccination relapse persisted in a waxing and waning fashion or whether she instead suffered multiple relapses after vaccination. (Ex. A, p. 7; Tr. 60-62, 95-122.) However, there is ultimately no dispute that L.D. suffered a relapsing course of OMS and that her post-vaccination relapse constituted an exacerbation or worsening of the condition. (Ex. 58, p. 1; Ex. A, pp. 9-11; Tr. 11-12, 17, 43, 52, 97, 99, 112, 122.)

Nonetheless, respondent argues that L.D.’s condition was not affected by her vaccination, because she simply suffered a course of relapsing-remitting OMS consistent with the natural course of such a condition. (ECF No. 95, pp. 24-25 (citing Sharpe, 964 F.3d at 1081-82); see also Locane, 685 F.3d 1375; Stone v. Sec’y of Health & Human Servs., 676 F.3d 1373, 1380 (Fed. Cir. 2012)).) This is not persuasive. Whether L.D.’s own condition was affected by her vaccinations is addressed under Loving prong five. As a general matter, however, Dr. Holmes explained that, although OMS relapses cannot be predicted, they respond to stimuli – most notably infections and withdrawing of immune modulating treatments by Dr. Holmes’s description. (Ex. A, p. 10 (citing Mitchell & Snodgrass, supra, at Ex. A, Tab 11); Ex. C, pp. 2-3 (citing Pranzatelli & Tate, supra, at Ex. A, Tab 5); Tr. 102-03, 122-23, 144.) Moreover, Dr. Holmes indicated that OMS relapses can have a cumulative effect, whereby they may

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result in progressive damage and/or may increase the risk of additional relapses. (Tr. 95-96.) Thus, while Dr. Bonthius agrees that it is possible that L.D.’s post-vaccination relapse could have occurred spontaneously as part of a relapsing course (Id. at 52-53), respondent is not persuasive in contending that the fact that L.D. suffered a relapsing- remitting course of OMS in itself indicates that her relapse was necessarily representative of the natural course of the condition.

Considering the record as a whole, and for the reasons discussed above, petitioners have met their preponderant burden of proof under Loving prongs one through three.

B. Loving prong four

Petitioners’ burden under the first Althen prong/fourth Loving prong is to provide, by preponderant evidence, “a medical theory causally connecting the vaccination and the injury.” Althen, 418 F.3d at 1278. Such a theory must only be “legally probable, not medically or scientifically certain.” Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543, 548-49 (Fed. Cir. 1994). Moreover, scientific evidence offered to establish Althen prong one is viewed “not through the lens of the laboratorian, but instead from the vantage point of the Vaccine Act’s preponderant evidence standard.” Andreu ex rel. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009). However, to satisfy this prong, petitioners’ theory must be based on a “sound and reliable medical or scientific explanation.” Knudsen, 35 F.3d at 548; Boatmon, 941 F.3d at 1359. Petitioners’ burden under Loving prong four varies from their burden under Althen prong one in that a significant aggravation claim requires petitioners only to show that the vaccine at issue can worsen the condition at issue, rather than being its cause. Sharpe, 964 F.3d at 1083 (explaining that “[u]nder Loving prong 4, a petitioner need only provide a ‘medical theory causally connecting [petitioner’s] significantly worsened condition to the vaccination’” (second alteration in original) (quoting Loving, 86 Fed. Cl. 144)).

The parties’ experts devoted significant attention to debating whether vaccinations can be implicated as a cause of OMS based on molecular mimicry. However, under Loving prong four, the question is not whether vaccinations can initially cause OMS, but rather whether they can cause a relapse. Although petitioners have preponderantly demonstrated that OMS is an autoimmune and post-infectious condition, it is not necessary to resolve whether molecular mimicry is implicated in order to determine that vaccine can cause a relapse of the condition.12

12 It is worth noting, however, that in three prior cases, petitioners have been found entitled to

compensation for OMS initially caused by vaccinations that are also at issue in this case. Mulvaney v. Sec’y of Health & Human Servs., No. 05-556V, 2006 WL 2438454 (Fed. Cl. Spec. Mstr. July 26, 2006) (finding MMR vaccine was substantial contributing factor in development of OMS); Butland v. Sec’y of Health & Human Servs., No. 07-111V, 2009 WL 1949059 (Fed. Cl. Spec. Mstr. June 19, 2009) (finding MMR and varicella vaccines caused OMS); Doe 79 v. Sec’y of Health & Human Servs., No. [redacted] V, 2010 WL 3034528 (Fed. Cl. Spec. Mstr. July 20, 2010) (finding DTaP vaccine caused OMS in combination with neuroblastoma); see also Tosches ex rel. Tosches v. Sec’y of Health & Human Servs., No. 06-192, 2008 WL 440285 (Fed. Cl. Spec. Mstr. Jan. 31, 2008) (finding under Althen prong one that

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In his second report, Dr. Bonthius opined that, apart from molecular mimicry, other relevant mechanisms “include ‘bystander activation,’ in which inflammatory environments induced by the immune response to the vaccine activate autoimmune cells in a non-specific manner . . . . The important point is that inflammatory reactions, such as infections and immunizations, can induce exacerbations of autoimmune disorders.” (Ex. 58, p. 2.) During the hearing, respondent’s immunology expert, Dr. Fried, agreed that bystander activation, as cited by Dr. Bonthius, is the likely mechanism by which infections are implicated as causes of relapses. (Tr. 176.) However, he disagreed that this can be extended to vaccinations, as the immune response to vaccination is meaningfully different than the immune response to infection. (Id. at 177-79.)

Importantly, however, Dr. Fried introduced into the record of this case a paper by Rosser et al., regarding the diagnosis and management of OMS. (Rossor et al., supra, at Ex. D, Tab 1.) Dr. Fried endorsed this paper as the work of an international group of OMS specialists. (Tr. 167.) Among the recommendations in this paper is the following:

Although most experts agree that immunizing patients with [OMS] while on treatment should be avoided, there is no consensus on when to reimmunize or commence catch-up immunization in patients after treatment is complete. Several issues need to be considered: (1) the risk of reactivation of [OMS] symptoms due to nonspecific immune stimulation by vaccination; (2) the risk of preventable illnesses; and (3) the ability of patients to mount an immune response after [OMS] treatment.

(Rossor et al., supra, at Ex. D, Tab 1, p. 11.) While this paper does go on to discuss significant limitations in the data available to support this recommendation, effectively suggesting the recommendation is made out of an abundance of caution, the fact of the recommendation itself is significant evidence supportive of Dr. Bonthius’s opinion that vaccines can cause OMS relapses via bystander activation.

Indeed, Dr. Holmes had previously opined on respondent’s behalf that “an aberrant B cell response is likely responsible for the autoimmune disorder. B cells, which are sparse in number in the healthy brain, increase drastically during neuroinflammation.” (Ex. C, p. 2.) Citing the fact that the Vaccine Injury Table includes encephalopathy following both pertussis-containing and MMR vaccines, “in rare situations, children receiving [these] vaccines can have a neuroinflammatory response.” (Id. at 1-2.) In that regard, both parties’ experts have relied heavily on multiple publications by OMS researchers Pranzatelli and Tate spanning decades. (Pranzatelli, supra, at Ex. 49; Pranzatelli et al., supra, at Ex. 50; Pranzatelli & Tate, supra, at Ex. 51; Pranzatelli & Tate, Ex. A, Tab 5; Michael R. Pranzatelli, The Neurobiology of the Opsoclonus-Myoclonus Syndrome, 15 CLINICAL NEUROPHARMACOLOGY 186 (1992) (Ex.

the DTaP vaccine can cause OMS, but denying compensation for reasons related to Althen prong two). L.D. received at one time all three of the vaccines previously at issue in these prior cases.

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A, Tab 8); Pranzatelli et al., supra, at Ex. A, Tab 10; Tate et al., supra, at Ex. A, Tab 12; Pranzatelli et al., supra, at Ex. A, Tab 43; Pranzatelli et al., supra, at Ex. A, Tab 55; Pranzatelli et al., supra, at Ex. D, Tab 5.) Drs. Bonthius and Holmes both confirmed during the hearing that they consider Dr. Pranzatelli a reputable and leading authority on OMS. (Tr. 33, 91-92.) Dr. Pranzatelli has repeatedly cited immunizations as among the potential triggers of OMS or OMS relapse. (Pranzatelli, supra, at Ex. 49, pp. 18-20; Pranzatelli & Tate, supra, at Ex. 51, pp. 6-7; Pranzatelli & Tate, Ex. A, Tab 5, pp. 3, 6.)

Most recently, in 2015, Dr. Pranzatelli, who died in 2018, published a paper regarding trends and tenets in relapsing and progressive OMS. (Pranzatelli & Tate, supra, at Ex. A, Tab. 5.) That paper indicates that questioning whether an OMS relapse was caused by immunization should be part of the treatment protocol for relapse. It includes the following flowchart:

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(Id. at 3 fig. 1.) According to Dr. Pranzatelli, “[a] trigger usually can be found and should be mitigated, whether it is an infection, steroid tapering, immunization, or a combination of factors, or involves a search for previously undetected neuroblastoma.” (Id.) During the hearing, Dr. Holmes confirmed that he agreed with Dr. Pranzatelli’s recommendation to screen for infection, discontinuation of medication, and tumors, but withholds his agreement only as to vaccination. (Tr. 137-39.)

Respondent’s experts have reasonably observed that there is very little data directly supporting the medical community’s concern regarding the ability of vaccinations to potentially trigger OMS relapses. However, as noted above, petitioners’

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theory must only be “legally probable, not medically or scientifically certain.” Knudsen, 35 F.3d at 548-49. Considering the record as a whole, there is preponderant evidence that the relevant medical community considers vaccination to carry a risk of relapse of OMS and petitioners’ have therefore preponderantly established that the vaccinations L.D. received can cause a significant aggravation of OMS. Respondent’s experts’ opinions to the contrary are better characterized as a search for scientific certainty.

Considering the record as a whole, and for the reasons discussed above, petitioners have met their preponderant burden of proof under Loving prong four.

C. Loving prong five

The second Althen prong/fifth Loving prong requires proof of a logical sequence of cause and effect showing that the vaccine was the reason for the injury, usually supported by facts derived from the medical records. Althen, 418 F.3d at 1278; Andreu, 569 F.3d at 1375-77; Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006); Grant, 956 F.2d at 1148. However, medical records and/or statements of a treating physician do not per se bind the special master to adopt the conclusions of such an individual, even if they must be considered and carefully evaluated. See § 300aa-13(b)(1) (providing that “[a]ny such diagnosis, conclusion, judgment, test result, report, or summary shall not be binding on the special master or court”); Snyder v. Sec’y of Health & Human Servs., 88 Fed. Cl. 706, 745 n.67 (2009) (stating that “there is nothing . . . that mandates that the testimony of a treating physician is sacrosanct – that it must be accepted in its entirety and cannot be rebutted”). The special master is required to consider all the relevant evidence of record, draw plausible inferences, and articulate a rational basis for the decision. Winkler v. Sec’y of Health & Human Servs., 88 F.4th 958, 963 (Fed. Cir. 2023) (citing Hines, 940 F.2d at 1528).

In this case, the availability of any relevant treating physician opinion is hampered by the fact that L.D. was not diagnosed with OMS until well after the onset of the OMS relapse at issue. The treating physicians cannot reasonably have been expected to recognize the likelihood that L.D.’s OMS relapse was vaccine caused when they did not even appreciate at the time that it was an OMS relapse. Nonetheless, Dr. Maqbool eventually opined that L.D.’s diagnosis was “most likely OMS induced by vaccination.” (Ex. 3, p. 84.) But in any event, petitioners’ assertion of a logical sequence of cause and effect is supported by Dr. Bonthius’s expert medical opinion. Dr. Bonthius has the requisite qualifications and experience to render such an opinion. In particular, Dr. Bonthius stressed Dr. Pranzatelli’s explanation that for OMS relapses, “[a] trigger usually can be found and should be mitigated.” (Ex. 63, p. 3 (discussing Pranzatelli & Tate, supra, at Ex. A, Tab 5, p. 3, fig. 1); Tr. 77-78.) Such an assessment is generally based on clinical history, rather than objective indicators. (Pranzatelli & Tate, supra, at Ex. A, Tab 5, pp. 2-3; Tr. 77.) In this case, the clinical history implicates the vaccinations. Dr. Bonthius stressed that, had L.D.’s OMS diagnosis been known at the time she received the vaccinations, the relevant guidance to the medical community would have suggested that she should not have received the vaccinations. (Tr. 36-37

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(citing Pranzatelli & Tate, supra, at Ex. 51, pp. 6-7).)13 Thus, Dr. Bonthius reasonably opines that L.D.’s vaccinations more likely than not were a trigger of her relapse.

Respondent’s experts raise four primary reasons for doubting that L.D.’s relapse was related to her vaccinations, none of which are persuasive. First, as already addresssed under Loving prong three, they contend that the relapsing-remitting nature of L.D.’s condition is explanation enough. Second, they note that L.D. did not experience any symptoms of a vaccine reaction, such as fever. Third, Dr. Holmes suggests that L.D.’s relapse may have alternatively been explained by jet lag. And, fourth, they assert that L.D. did not experience relapses after other vaccine doses.

While Dr. Bonthius acknowledged that it is possible that L.D.’s relapse would have occurred regardless of the vaccination (Tr. 52-53), Dr. Holmes undermined his opinion that the relapse is explained by the natural course of the condition by initially positing that it may have occurred in response to jet lag. (Ex. A, p. 10.) Although Dr. Holmes is correct that the course of relapsing-remitting OMS cannot necessarily be predicted, he agreed that individual relapses can respond to specific triggers and, apart from his skepticism regarding the role of L.D.’s vaccinations, suggested that he would otherwise embrace the possibility that L.D.’s own relapse was related to a stressor, namely jet lag. (Id.) As acknowledged by respondent (ECF No. 95, pp. 24-25), petitioners are not obligated to prove that L.D.’s ultimate outcome is worse than would otherwise have been expected given her condition. They are only obligated to prove that the vaccinations affected the condition. Sharpe, 964 F.3d at 1081-82.

Nor have respondent’s experts substantiated that outward clinical indicators of a vaccine reaction would be necessary for L.D.’s vaccinations to be the trigger of her relapse. For example, the literature indicates that when OMS relapses are caused by infection, the relapse can actually precede any overt signs of infection. (Pranzatelli & Tate, supra, Ex. A, Tab 5, p. 4.) Dr. Holmes noted that OMS relapses can often have prodromal symptoms that appear consistent with the symptoms of infection; however, it is ambiguous whether these prodromal symptoms are due to the infection or to the relapse itself. (Tr. 104-05.)

Yet, despite raising the issue of an alternative trigger for L.D.’s relapse, Dr.

Holmes is also not persuasive in that assessment. Citing multiple sclerosis as analogous, Dr. Holmes suggested that physical stress and sleep disruption, as can be seen in jet lag, can have immunologic consequences and, thereby, could be a factor contributing to the onset of an OMS relapse. (Ex. A, p. 10.) However, during the hearing, he acknowledged that there is no direct evidence to support the application of this concept to OMS. (Tr. 140-42.) Moreover, in his second report, he conceded that “[i]t is unlikely that two weeks after the flight there would have been any residual jet lag that would trigger an exacerbation.” (Ex. C, p. 4.) And, in any event, the medical

13 Specifically: “During the acute phase of OMS, immunizations may trigger disease exacerbation or

relapse. The conservate recommendation of the NPMC has been to withhold immunizations for 2 years after cessation of immunotherapy and relapse, and then cautiously reintroduce as singlet vaccinations of killed viruses at 6-month intervals.” (Pranzatelli & Tate, supra, at Ex. 51, pp. 6-7.)

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literature indicates that potential relapse triggers may operate in combination. (Pranzatelli & Tate, supra, Ex. A, Tab 5, p. 3, fig. 1.) Thus, even if jet lag were accepted as a contributing factor, this would not necessarily exonerate the vaccinations occurring at about the same time. Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344, 1352-53 (Fed. Cir. 1999) (explaining that petitioners may be found entitled to compensation where concurrent forces lead to a single harm so long as the vaccination is a substantial contributing factor and a but for harm).

Finally, while respondent’s experts note that L.D. otherwise received the other doses of vaccine without experiencing any relapse, this fact standing alone is not necessarily significant. As explained under Loving prong four, petitioners have established that vaccines can potentially cause an inflammatory response that interacts with the ongoing B cell immune response that otherwise propagates the OMS. In this case, however, the other uneventful vaccinations cited by respondent’s experts occurred before the initial onset of L.D.’s OMS. (Compare Ex. 1 (noting L.D.’s most recent vaccinations, prior to the subject vaccinations, were a flu vaccine received in November of 2014 and DTaP, varicella, and MMR vaccinations received in September of 2013), with Tr. 120 (Dr. Holmes testifying that “possible initial onset” of L.D.’s OMS was not until November of 2015).) This meaningfully distinguishes the vaccinations at issue from the other uneventful vaccinations.

Considering the record as a whole, and for the reasons discussed above, petitioners have met their preponderant burden of proof under Loving prong five.

D. Loving prong six

The third Althen prong/sixth Loving prong requires establishing a “proximate temporal relationship” between the vaccination and the injury alleged. Althen, 418 F.3d at 1281. That term has been equated to the phrase “medically-acceptable temporal relationship.” Id. A petitioner must offer “preponderant proof that the onset of symptoms occurred within a timeframe for which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for what is a medically acceptable timeframe must also coincide with the theory of how the relevant vaccine can cause an injury. Id.; Shapiro v. Sec’y of Health & Human Servs., 101 Fed. Cl. 532, 542 (2011), mot. for recons. denied after remand, 105 Fed. Cl. 353 (2012), aff’d per curiam, 503 F. App’x 952 (Fed. Cir. 2013); Koehn v. Sec’y of Health & Human Servs., No. 11-355V, 2013 WL 3214877, at *26 (Fed. Cl. Spec. Mstr. May 30, 2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2014).

Dr. Bonthius opined on petitioners’ behalf that assessment of the appropriate timing for an OMS relapse should be viewed in comparison to other autoimmune neurologic conditions, such as GBS. (Ex. 29, p. 7.) He opined that a one-to-three-week latency would be appropriate. (Tr. 49-50.) On respondent’s behalf, Dr. Holmes approached the appropriate timing differently. He cited the timing for Table encephalopathies following pertussis and MMR vaccines as instructive. (Ex. C, pp. 1-2;

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Tr. 128-29.) Pertinent to this case, the Table period for a post-MMR encephalopathy – L.D. received an MMR vaccine – is 5 to 15 days. 42 C.F.R. § 100.3(a)(III). In this case, there is no dispute that the onset of L.D.’s OMS relapse occurred approximately two weeks post-vaccination. (Ex. 29, p. 7; Ex. A, p. 10; Ex. C, p. 2; Tr. 109-10, 129.) Thus, the timing of onset is appropriate under either expert’s understanding.

Considering the record as a whole, and for the reasons discussed above, petitioners have met their preponderant burden of proof under Loving prong six.

VI. Conclusion

For all the reasons discussed above and after weighing the record evidence within the context of this program, I find that petitioners have preponderantly shown that L.D. experienced a significant aggravation of her relapsing-remitting OMS as a result of the vaccinations that she received on April 11, 2016. A separate damages order will be issued.

IT IS SO ORDERED.

s/Daniel T. Horner Daniel T. Horner Special Master