Kottenstette v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 15-1016V

Filed: June 2, 2020

PUBLISHED

MARYELLEN KOTTENSTETTE and

NICHOLAS KOTTENSTETTE, as best Special Master Horner

friends of their daughter (CK),

Petitioner, Decision on Remand; Infantile

v. Spasms; DTaP Vaccination; Althen

Prong Two

SECRETARY OF HEALTH AND

HUMAN SERVICES,

Respondent.

John F. McHugh, Law Office of John McHugh, New York, NY, for petitioners.

Camille Michelle Collett, U.S. Department of Justice, Washington, DC for respondent.

DECISION ON REMAND1

On September 11, 2015, petitioners, Maryellen and Nicholas Kottenstette, filed a

petition under the National Childhood Vaccine Injury Act, 42 U.S.C. § 300aa-10-34

(2012), alleging that their minor daughter, C.K., suffered an encephalopathy following

several vaccinations administered on October 2, 2012.2 (ECF No. 1, pp. 1-2.)

Petitioners alleged C.K.’s encephalopathy represented a Table Injury following her

DTaP vaccination or, alternatively, that it was caused-in-fact by her October 2, 2012

DTaP vaccination. (Id. at 4-5.) However, they later pursued this case on the basis that

C.K. experienced infantile spasms caused-in-fact by her October 2, 2012 vaccinations,

including most notably her DTaP vaccination.

1 Because this decision contains a reasoned explanation for the special master’s action in this case, it will

be posted on the United States Court of Federal Claims’ website in accordance with the E-Government

Act of 2002. See 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic

Government Services). This means the decision 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 the special master, upon review, agrees that the identified material fits within this definition, it will be

redacted from public access.

2 Specifically, Diphtheria, Tetanus, and acellular Pertussis (“DTaP”), Haemophilus influenzae b (“Hib”),

inactivated polio (“IPV”), and pneumococcal conjugate (“PCV”) vaccines.

The previously-assigned special master found petitioners entitled to

compensation (2017 WL 6601878 (Fed. Cl. Spec. Mstr. Dec. 12, 2017)) and later issued

a decision awarding damages (2019 WL 2587395 (Fed. Cl. Spec. Mstr. May 29, 2019)).

Although this case was not reassigned to me until after the decision awarding damages

was issued, the prior ruling on entitlement was subsequently vacated upon respondent’s

motion for review and the case was remanded to me by the Court of Federal Claims for

further consideration of petitioners’ entitlement to compensation consistent with the

Althen test for causation-in-fact. 2020 WL 953484 (Fed. Cl. Feb. 12, 2020). For the

reasons set forth below, I conclude that petitioners are not entitled to compensation

because they have not met their burden under the second Althen prong of

demonstrating a logical sequence of cause and effect establishing that C.K.’s condition,

diagnosed as infantile spasms, was caused by vaccination.

I. Procedural History

At the initial status conference held on November 20, 2015, the special master

explained that C.K.’s injury was unlikely to represent a Table encephalopathy (see also

Section VII, below), but encouraged the parties to explore settlement based on an injury

of infantile spasms. (ECF No. 14.) Subsequently, in August of 2016, petitioners filed an

expert report opining that C.K. experienced vaccine-caused infantile spasms. (ECF No.

19; Ex. 6.) Since that time, this case has been prosecuted as involving a seizure

disorder rather than an encephalopathy. (ECF Nos. 50, 67.)

Petitioners relied on the opinion of pediatric neurologist Marcel Kinsbourne, M.D.

Dr. Kinsbourne’s curriculum vitae does not reveal any credentials specific to infantile

spasms; however, he testified that in his career he has treated “hundreds” of patients

with seizures generally and forty or more patients with infantile spasms in particular.

(Tr. 36.) Dr. Kinsbourne considers himself “largely, but not entirely” retired. (Tr. 35.)

Petitioners did not offer any opinion from an expert with qualifications specific to

immunology.

Respondent filed a responsive expert report by pediatric neurologist John

Zempel, M.D., Ph.D (neurobiology). (ECF No. 38-1; Ex. A.) Dr. Zempel is a professor

of neurology and pediatrics at Washington University and also has an active clinical

practice treating patients with intractable epilepsy wherein he estimates he treats about

10-15 cases of infantile spasms per year. (Tr. 107-09, 112-13.) Dr. Zempel agreed that

C.K. suffered infantile spasms but disputed that they were causally related to any of her

vaccinations. Respondent likewise did not offer an opinion by an immunologist.

An entitlement hearing was held on July 24, 2017. Maryellen Kottenstette, Dr.

Kinsbourne, and Dr. Zempel, all testified. (ECF No. 66, Transcript of Proceedings

(“Tr.”), 7/24/2017.) Subsequently, a ruling on entitlement was issued on December 12,

2017, finding petitioners entitled to compensation. (ECF No. 78.)

2

In her ruling, the previously-assigned special master summarized her finding as

follows:

Putting this all together, the undersigned finds that CK, even though she

received DTaP, not [DTP],3 would have qualified to have been in the

Bellman and Melchior studies4 because she had infantile spasms within a

week of pertussis vaccination and the vaccination was a trigger, according

to both the Bellman and Melchior studies, which prompted the onset of her

spasms. We are not dealing with the niceties of statistical significance in the

Vaccine Program under the guidance of the Federal Circuit’s decisions in

Knudsen, Althen, and Capizzano.5 The principle the Federal Circuit

pronounced in Knudsen, i.e., that causation can be found in vaccine cases

based on epidemiological evidence and the clinical picture regarding the

particular child without detailed medical and scientific exposition on the

biological mechanisms[,] governs the outcome of this decision.

(ECF No. 78, p. 17.)

Thereafter, the parties resolved the appropriate amount of compensation for the

damages in this case over the following year and a half. Respondent filed a proffer on

award of damages on May 29, 2019, which the special master adopted as her decision

regarding damages. (ECF Nos. 100-02.) The case was reassigned to me on June 5,

2019, and respondent filed a motion for review of the prior ruling on entitlement on June

28, 2019. (ECF Nos. 103, 107.)

On review, the Court of Federal Claims granted respondent’s motion and vacated

the ruling on entitlement in this case. (ECF No. 130.) The Court found the special

master’s reliance on the Bellman and Melchior studies to be arbitrary and capricious

and also explained that she misapplied the Federal Circuit’s Knudsen precedent and

failed to engage in a full discussion of the type of analysis dictated by the Althen

precedent.6 (Id. at 6-8.) The Court remanded the case for reconsideration under the

3“DTaP” refers to the Diphtheria Tetanus and acellular Pertussis vaccine. “DTP” refers to a different,

earlier formulation wherein whole cell pertussis was used. The distinction is further addressed below.

4Referring to: M.H. Bellman, E.M. Ross & D.L. Miller, Infantile Spasms and Pertussis Immunisation, 1

LANCET 1031 (1983) (Ex. D, Tab 1); J.C. Melchior, Infantile Spasms and Early Immunization Against

Whooping Cough, 52 ARCHIVES OF DISEASE IN CHILDHOOD 134 (1977) (Ex. D, Tab 2).

5Referring to: Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543 (Fed. Cir. 1994); Althen v. Sec’y

of Health & Human Servs., 418 F.3d 1274 (Fed. Cir. 2005); Capizzano v. Sec’y of Health & Human

Servs., 440 F.3d 1317 (Fed. Cir. 2006).

6 Notably, the special master’s ruling on entitlement did discuss a number of points from prior Federal

Circuit precedents having to do with the specifics of petitioners’ burden of proof, such as the idea that

petitioners are not required to come forward with an exact biological mechanism or that the requirement

of epidemiological studies or general acceptance in the scientific community are contrary to the Federal

Circuit’s Althen test. The remanding opinion characterized these points as “well-taken,” but concluded

that citation to these points does not substitute for the lack of an analysis consistent with the Althen test.

(ECF No. 130, p. 7.)

3

correct legal standard, also noting the intervening decision of Boatmon v. Secretary of

Health & Human Services, 941 F.3d 1351 (Fed. Cir. 2019).

Upon remand, I reviewed the entire record of this case and concluded that the

parties had a full and fair opportunity to present their respective cases.7 Moreover, the

remanding opinion did not introduce any issues into the case not previously addressed

by the parties in their written submissions. I initially issued a decision on remand

dismissing petitioners’ case on April 27, 2020. (ECF No. 132.)

Subsequently, however, petitioners moved to reopen the record on entitlement

and for reconsideration of my decision. (ECF No. 133.) Petitioners argued that they had

not had a full and fair opportunity to present their case, contending, inter alia, that the

remanding opinion had heightened their burden of proof subsequent to the close of the

record on entitlement. (Id.) I granted petitioners’ motion to the extent of withdrawing the

decision on remand to consider petitioners’ arguments; however, I denied petitioners’

request to reopen the evidentiary record and found the arguments advanced in favor of

reconsideration to be unpersuasive. (ECF No. 138.) Accordingly, I indicated that a

superseding decision pursuant to Vaccine Rule 10(e) would issue, but that the

superseding decision would not reach a conclusion different than the prior, now

withdrawn, April 27, 2020 decision on remand. (Id.)

Accordingly, the matter is again ripe for decision and, the previously-assigned

special master’s ruling on entitlement having been vacated, entitlement to

compensation in this case will now be considered in light of the guidance provided by

the remanding opinion.

II. Applicable Legal Standard

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, long-standing injury; and has

received no previous award or settlement on account of the injury. Additionally, and

most significantly, the petitioner must also establish a causal link between the

vaccination and the injury.

7 In Kreizenbeck v. Secretary of Health & Human Services, 945 F.3d 1362 (Fed. Cir. 2020), the Federal

Circuit explained that special masters have wide discretion to determine whether oral testimony is

reasonable and necessary to resolve the differences in scientific or expert opinion so long as the parties

have had a full and fair opportunity to present their case and develop a record sufficient for review. In this

case, there has already been a hearing in which expert testimony was presented; however, I was not the

special master presiding over this case at that time. Nonetheless, I have reviewed the transcript of that

hearing and determined that the testimony provided is sufficient to resolve this case. Notably, the

Kreizenbeck court explicitly rejected the argument that a special master must hear live testimony before

reaching a credibility determination regarding expert opinion. 945 F.3d at 1366.

4

Where a Table Injury claim is unavailable,8 the petitioner may gain an award by

showing that the recipient’s injury was “caused-in-fact” by the vaccination in question. §

300aa-13(a)(1)(B); § 300aa-11(c)(1)(C)(ii). In such cases, 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 v. Sec’y of Health & Human Servs., 940 F.2d 1518, 1525 (Fed. Cir. 1991).

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 1279; Hines, 940 F.2d at 1525.

In what has become the predominant framing of this burden of proof, the Althen

court described the “causation-in-fact” standard, as follows:

Concisely stated, Althen’s burden is to show by preponderant evidence that

the vaccination brought about her injury by providing: (1) a medical theory

causally connecting the vaccination and the injury; (2) a logical sequence

of cause and effect showing that the vaccination was the reason for the

injury; and (3) a showing of proximate temporal relationship between

vaccination and injury. If Althen satisfies this burden, she is “entitled to

recover unless the [government] shows, also by a preponderance of the

evidence, that the injury was in fact caused by factors unrelated to the

vaccine.”

Althen, 418 F.3d at 1278 (citations omitted).

As the remanding order in this case indicated, the Federal Circuit most recently

interpreted this causation-in-fact standard in the Boatmon case. 941 F.3d at 1351. The

Boatmon court stressed that “[w]e have consistently rejected theories that the vaccine

only ‘likely caused’ the injury and reiterated that a ‘plausible’ or ‘possible’ causal theory

does not satisfy the standard. Id. at 1360 (citing Moberly v. Sec’y of Health & Human

Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010)). Citing to the Circuit’s prior Knudsen

decision, Boatmon explained that “[w]hile [the causation-in-fact standard] does not

8 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, and the petitioner is automatically entitled to compensation, unless it is

affirmatively shown that the injury was caused by some factor other than the vaccination. § 300aa-

13(a)(1)(A); § 300 aa-11(c)(1)(C)(i); § 300aa-14(a); § 300aa-13(a)(1)(B). In this case, although

petitioners initially included a claim of a Table encephalopathy in their petition, by the time of the

entitlement hearing they had apparently abandoned that claim. In both their pre- and post-hearing briefs,

petitioners asserted that C.K. suffered a vaccine-caused seizure disorder, which is not an injury listed on

the Vaccine Injury Table. (ECF Nos. 50, 67.) Additionally, for the reasons discussed in Section VII,

below, I have confirmed that C.K. did not experience an encephalopathy within the meaning of the

Qualifications and Aids to Interpretation governing the Table Injury of encephalopathy. Accordingly, there

is no viable Table claim as originally pled in this case.

5

require medical or scientific certainty, [a petitioner’s theory] must still be ‘sound and

reliable.’” Id. at 1359 (citing Knudsen, 35 F.3d at 548-49).

In particular, the remanding order in this case stresses that the language of the

Federal Circuit’s Knudsen decision must be understood in the context of its subsequent

Althen decision. The remanding order explained that statements in Knudsen “should

not be taken to loosen the requirements of Althen, which was decided almost 11 years

later.” (ECF No. 130, p. 8.)

III. Issues to be Decided

In this case, there is no dispute that C.K. was properly diagnosed with infantile

spasms and that it continues to be her correct diagnosis. (Tr. 54-55 (Kinsbourne), 168-

69 (Zempel).) There is also no meaningful dispute that her seizures began soon after

her October 2, 2012 vaccinations. (Tr. 38-39 (Kinsbourne), 127 (Zempel).) Rather, the

primary dispute between the parties is whether the DTaP vaccine (or any vaccine) can

cause infantile spasms in general and whether it did in this case, i.e. issues relating to

Althen prongs one and two.

In that regard, the question that has so far received the most attention in this

case, both in the initial ruling on entitlement and subsequently in the remanding opinion,

is the appropriate weight to be assigned to the above-referenced Bellman and Melchior

studies. The previously-assigned special master treated these studies as dispositive;

however, on review the Court found this to be an abuse of discretion because the

special master did not explain the basis for her inference that studies related to the DTP

vaccine could provide evidence relative to an injury from the DTaP vaccine.

Significantly, however, the prior special master’s conclusion that the Bellman and

Melchior studies were dispositive preempted further exploration of the remainder of

petitioners’ theory pursuant to the Althen test. In addition to opining that the DTP-

related studies in the record supported petitioners’ claim, petitioners’ expert also

advanced a theory based on an “immune/endocrine model of infantile spasms” whereby

he indicated that discharge of proinflammatory cytokines (specifically interleukin 1-β) as

part of the innate immune response to vaccination activates the stress system which, in

turn, releases a hormone called corticotropin-releasing hormone (“CRH”). According to

Dr. Kinsbourne, CRH is known to be epileptogenic. (Ex. 6, pp. 6-9; Tr. 41-42.)

In this decision, familiarity with the prior ruling on entitlement is assumed.

Although the previously-assigned special master ultimately relied only on part of the

expert presentations in this case, she did discuss each presentation extensively and in

full. (ECF No. 78, pp. 4-14.) Accordingly, the expert presentations will not be re-

summarized. I will first briefly discuss the injury at issue and clarify the weight and

significance of the Bellman and Melchior studies for purposes of determining entitlement

in this case. I will then apply the Althen test to petitioners’ theory of infantile spasms as

a form of CRH-induced epilepsy. In applying the Althen test in full for the first time in

this case, I find that petitioners’ proposed theory cannot be meaningfully applied to the

6

facts of this case and, contrary to the decision previously reached, I conclude that

petitioners are not entitled to compensation because they have not met their burden

under Althen prong two.

IV. C.K.’s Medical History and the Condition at Issue – Infantile Spasms

The condition at issue in this case is not interchangeable with other forms of

epilepsy or seizure activity. The condition of “infantile spasms” (also referred to as

epileptic spasms or “West Syndrome”) was first described in the 19th century. (Tallie Z.

Baram, Pathophysiology of Massive Infantile Spasms: The Putative Role of the Brain

Adrenal Axis, 33 ANN NEUROL 231 (1993) (Ex. 6-1).) The condition represents an

epileptic9 encephalopathy.10 (Tr. 126.) Outwardly, it is characterized by “repetitive

bursts of myoclonic11 jerking of the head or limbs.” (Bellman, supra, at Ex. D, Tab 1, p.

1.) However, the three cardinal features of infantile spasms, as explained by both

experts in this case, are: (1) encephalopathy; (2) epileptic spasms; and (3)

hypsarrhythmia.12 (Ex. 6, p. 2; Tr. 180-81.)

Infantile spasms typically present between three to nine months of age. (Tr.

123.) The vast majority of cases have onset within the first year of life. (Id.) There are

“some exceptions, but not many.” (Tr. 50.) In some cases, the infantile spasms result

from known structural damage in the brain, such as brain damage at birth or

encephalitis. (Tr. 49-50.) This is referred to as “symptomatic” infantile spasms. (Id.) In

contrast, cryptogenic infantile spasms, which may also be called idiopathic infantile

spasms, are instances of infantile spasms that have no identified etiology. 13 (Tr. 118-

19.)

9According to Dr. Zempel, epilepsy by definition is having more than one seizure that is unprovoked. In

most cases, it is not known why an individual seizure occurs when it does. (Tr. 137.) Pertinent to this

case, according to Dr. Zempel, C.K.’s “cluster” of seizures represents a single seizure for purposes of

assessing the presence of epilepsy. (Tr. 143.) Seizure clusters are a notable feature of infantile spasms.

(Tr. 121.)

10 Broadly speaking, encephalopathy is defined as “any degenerative disease of the brain.” (Dorland’s

Illustrated Medical Dictionary, p. 608 (33rd ed. 2019).) With regard to infantile spasms, Dr. Zempel

explained that encephalopathy can manifest with immediate signs of an altered mental state such as

sleepiness or abnormal behavior or can manifest longer term in the form of developmental regression or

stagnation. (Tr. 126-27.)

11“Myoclonus” refers to “shocklike contractions of a portion of a muscle, an entire muscle, or a group of

muscles, restricted to one area of the body or appearing synchronously or asynchronously in several

areas.” (Dorland’s, p. 1205.)

12Hypsarrhythmia is “an electroencephalographic abnormality sometimes observed in infants, with

random, high-voltage slow waves and spikes that arise from multiple foci and spread to all cortical areas.”

(Dorland’s, p. 897.)

13 I do note that in his post-hearing brief, respondent was critical of Dr. Kinsbourne for using the terms

symptomatic and cryptogenic, arguing that the terms are outdated. (ECF No. 74, pp. 14-15.)

Respondent filed literature that distinguishes between cryptogenic and idiopathic, proposing that the term

cryptogenic should be reserved for cases where an underlying neurological condition, unknown at the

time of initial presentation, is subsequently uncovered. (John P. Osborne, The Underlying Etiology of

7

C.K. was born via cesarean section on June 1, 2012, and there is nothing in her

own medical records, her mother’s preterm medical records, or her delivery records, to

suggest her infantile spasms could be symptomatic. There was some discussion during

the hearing of whether pregestational diabetes, and Ms. Kottenstette’s treatment for that

condition with Glyburide, could have contributed to C.K.’s later infantile spasms;

however, respondent’s expert would not support that contention.14 (Tr. 154-55.)

On October 2, 2012, C.K. presented for her four-month well baby check. (Ex. 2,

pp. 19-22.) No concerns were noted developmentally, neurologically, or in her motor

development. (Id.) At that time she received several vaccinations, including DTaP, Hib,

IPV, and Prevnar. (Ex. 2, p. 21.) Ms. Kottenstette likewise testified that the well-baby

check-up was uneventful. (Tr. 8.)

She explained, however, that later that evening while C.K. was nursing “her arms

went forward and her head went forward and her legs kind of came up.” (Tr. 8.) Ms.

Kottenstette explained that her husband made an after-hours call to the pediatrician’s

office and spoke with a covering pediatrician (i.e. not C.K.’s own pediatrician). (Id.)

They were advised to take C.K. to the emergency department. At first, petitioners

questioned the instruction, explaining that C.K. was not running a fever. According to

Ms. Kottenstette, “the physician said that’s exactly why you need to bring her.” (Id. at 8-

9.)

Later that night, shortly before 10:00PM, C.K. was taken to the Emergency

Department at the University of Massachusetts Children’s Medical Center. (Ex. 4.) She

was admitted status post immunizations with “abnormal arms [and] shoulder

movements multiple times this evening.” (Id. at 1.) One of these episodes, occurring at

about 8:30PM, reportedly lasted about five minutes. (Id. at 9.) The episodes did not

include eye or leg involvement. (Id. at 10.) At the time of evaluation, C.K. was not

observed to be in a postictal state. She was also negative for fevers, chills, or

fussiness. (Id. at 9.) Her initial discharge diagnoses were “rhythmic episode” and

“possible seizure.” (Id. at 5.) A referral was made for a follow up electroencephalogram

(“EEG”). (Id.)

Infantile Spasms (West Syndrome): Information from the United Kingdom Infantile Spasms Study (UKISS)

on Contemporary Causes and their Classification, 51 EPILEPSIA 2168 (2010) (Ex. D, Tab 10, p. 3).) In

contrast, the term idiopathic should be used to indicate that no known underlying, predisposing condition

is present. (Id.) The authors acknowledged, however, that these newly proposed terms are “hardly, if

ever, used this way.” (Id.) Dr. Zempel likewise acknowledged that the older terms are “broadly . . . still in

the medical literature.” (Tr. 119.) Accordingly, for purposes of this decision, C.K.’s condition is referred to

as cryptogenic and references to cryptogenic in the medical literature are generally assumed to constitute

cases similar to C.K.’s condition unless otherwise specifically indicated. However, if one accepted the

newer terminology, and on the current record, idiopathic would be a more accurate term for C.K.’s

condition.

14However, Dr. Zempel did note that based on her age at the time of her MRI, cortical dysplasia could still

not be ruled out. (Tr. 147-49.)

8

Ms. Kottenstette explained that she called C.K.’s pediatrician’s office the next

morning and “spoke with her about what had happened, and we discussed that I should

keep an eye on her but that maybe it was a mild reaction to the vaccination or maybe it

was reflux.15 And because it had happened when I was nursing her, I – that made

sense that maybe that’s what it was.” (Tr. 9-10.) Subsequently, however, on October 6,

2012, C.K. experienced another cluster of seizures that was clearly unrelated to

nursing. (Tr. 10-11.) Ms. Kottenstette videotaped the seizures and took C.K. to Boston

Children’s Hospital. (Tr. 11.) C.K. was hospitalized at Boston Children’s from October

6 to October 10. (ECF No. 9-1; 9-2.)16

Upon admission, C.K. was noted to have experienced three prior clusters of

seizures, all of which were described similarly. (ECF No. 9-1, p. 1.) “She woke out of

sleep and suddenly had a series of jerks, demonstrated by mom as arms extended out

and jerking inward every 5 seconds for about 3-5 minutes. She seemed to be alert

throughout the entire episode. Afterwards, she was back to her baseline immediately.”

(Id.) After reviewing the video of the seizure, the admitting physician noted that C.K. “is

seen in mom’s arms, looking around and appropriately alert, with intermittent episodes

of rapid arm extension then shoulder abduction and arm jerk inwards, clinically

consistent with infantile spasms.” (Id.) C.K.’s MRI, echocardiograms, and serum

chemistries were negative, but her EEG was consistent with hypsarrhythmia and she

was referred to neurology for management of her seizures with a working diagnosis of

infantile spasms. (Id. at 3, 8.) She was started on ACTH.17 (Id.)

C.K. returned for a neurology follow-up on October 30, 2012. (ECF No. 9-1, p.

10.) Petitioners reported that C.K. experienced some improvement on the ACTH. They

reported that the frequency of her spasms increased (from two to three episodes per

day to three to five episodes per day), but the duration had decreased to about one to

two minutes. (Id.) Petitioners confirmed that there had been “no regression in [C.K.]’s

development since the spasms began.” (Id. at 11.) A second EEG did not meet the

criteria for hypsarrhythmia, but the diagnosis of infantile spasms was maintained. (Id. at

12.) Given her mild improvement with her first course of ACTH, a second course was

recommended. (Id.) C.K.’s neurological exam was significant for some mildly

increased tone in her lower extremities but was otherwise normal and non-focal. (Id.)

On November 16, 2012, C.K. had a further neurology follow-up. Her

development was still noted to be appropriate and her seizures had decreased in both

frequency and severity. (ECF No. 9-1, p. 14.) However, on January 16, 2013, it was

noted that she “now seems to be progressively encephalopathic with less movements

and arrested development with some elements concerning for regression, particularly

15This impression was later memorialized in C.K.’s medical records within the history of present illness

provided upon admission to Boston Children’s Hospital on October 6. (ECF No. 9-1, p. 1.)

16As noted in the prior ruling on entitlement, the records for Boston Children’s Hospital were

inconsistently labeled as either Exhibit 2 or Exhibit 3, accordingly they will be referenced by their docket

location instead.

17 ACTH is adrenocorticotropic hormone. It is a common treatment for infantile spasms.

9

her head control and level of interaction.” (ECF No. 9-2, p. 4.) Ms. Kottenstette

similarly explained during the hearing that C.K. declined very rapidly after her ACTH

treatment was stopped after the second round. (Tr. 19-20.)

Ms. Kottenstette testified that, although C.K.’s seizures are not consistent,

nothing has eradicated them. (Tr. 15, 17.) C.K. has developed refractory seizures,

meaning that they do not respond to medication, and she continues to experience

seizures. (ECF No. 9-1, p. 15.) This is unusual in that most children “outgrow” their

infantile spasms, leaving her in a smaller category of more severe or prolonged cases.

(Tr. 132.) Notably, however, C.K. has not developed any other form of epilepsy, which

can sometimes be a further sequela of infantile spasms. (Alexis Arzimanoglou, Renzo

Guerrini & Jean Aicardi, Infantile Spasms and Related Syndromes (3rd ed. 2004) (Ex.

D, Tab 3); Tr. 54-55.) C.K. continued “having approximately 30 seizures a day that last

between 10-30 seconds. Her seizures continue to be characterized by epileptic spasms,

primarily of the upper extremities and head drops.” (Ex. 26, p. 15.) C.K. started going

to school and has an IEP in place. (Id. at 16.) C.K. had difficulty sleeping, which her

neurologist warned may increase C.K.’s frequency of seizure clusters. (Id.)

V. Assessing the Melchior and Bellman Studies

Because C.K. developed infantile spasms within one week of her DTaP

vaccination, the prior ruling on entitlement treated two studies examining post-DPT

infantile spasms – by Melchior and Bellman respectively – as dispositive in this case.

(ECF No. 78, pp. 17-18.) On review, that was found to be error because “[t]he special

master did not explain the basis of Dr. Kinsbourne’s opinion and did not offer an

independent basis for applying the DPT-study findings to the DTaP vaccine.” (ECF No.

130, p. 6.) In light of this, separate discussion regarding the weight to be given these

two studies is warranted.

According to the literature filed in this case, a possible link between pertussis

vaccination and infantile spasms was first proposed in 1964. (Melchior, supra, at Ex. D,

Tab 2, p. 1.) However, subsequent papers suggested that the possible association was

merely a coincidence of timing. (Id.) In April of 1970, Denmark changed its

immunization schedule for pertussis vaccination. Previously, pertussis vaccine was

typically administered in Denmark as a triple combination at five, six, and 15 months of

age. After April of 1970, that schedule was advanced so that pertussis was

administered as a monovalent vaccine at five and nine weeks of age and then again at

10 months. (Id.) However, immunization against diphtheria-tetanus-polio was still given

at five, six and 15 months of age. (Id.) This provided an opportunity to examine

whether the change in the vaccine schedule would result in a statistically significant

change in the typical age of onset for infantile spasms. (Id.) J.C. Melchior published a

survey study regarding this question in the Archives of Disease in Childhood in 1977.

(Id.)

Melchior compared 113 cases of infantile spasms diagnosed between April 1 of

1970 and March 31 of 1975 to 86 cases of infantile spasms occurring from 1957 to

10

1967. (Melchior, supra, at Ex. D, Tab 2, p. 1.) Of the 113 cases from the early 1970’s,

40 were classified as cryptogenic, 60 of the subjects as symptomatic, and the remaining

13 reported as having an unclear etiology, but with immunization occurring prior to

onset. (Id. at 2.) Of those 13 subjects, six had seizures following either the first or

second dose of monovalent pertussis and seven had seizures following a combined

diphtheria, tetanus, and polio vaccination. (Id. (Table 2).) The conclusion reached by

the study was that: “A comparison of the age of onset of infantile spasms shows no

significant difference between the series of spasms before the new immunization

programme and after.” (Id. at 2.)

Moreover, it was further noted that “[o]f special interest is the occurrence of

infantile spasms in 7 children, developing within 2 weeks of the diphtheria-tetanus-polio

immunization. This seems to confirm the opinion that we are dealing mainly with a time-

coincidence and suggests that whatever immunization we administer in the age groups

between 1 and 2 months and 9 and 10 months, some children will develop neurological

disorders which are typically associated with these age groups.” (Id. at 3.) Melchior

characterized the possibility of a causal connection between pertussis vaccination and

infantile spasms as “very unlikely.” (Id. at 3.)

Despite these conclusions, Dr. Kinsbourne pointed out certain findings specific to

the DTP vaccine. He noted that the Melchior study results demonstrate that “12% of

cases of infantile spasms had onset before age 2 months when DTP had not yet been

given by then, whereas 23% began before the child was two months old when DTP had

been given at 5 weeks. There were nearly twice as many early onsets when DTP had

been administered at the earlier age.” (Ex. 6, p. 3.)

Critically, however, several prior cases in this program have addressed the

distinction between the DTP and DTaP vaccine formulations, the former utilizing whole

cell pertussis while the later uses acellular pertussis. These cases have persuasively

explained at length why findings relating to the safety of the DTP vaccine are not

applicable to the later DTaP vaccine, which was specifically developed to address

safety concerns related to the earlier, whole cell DTP formulation. See, e.g. Sharpe v.

Sec’y of Health & Human Servs., No. 14-65V, 2018 WL 7625360, at *31-32 (Fed. Cl.

Spec. Mstr. Nov. 5, 2018); Taylor v. Sec'y of Health & Human Servs., No. 05-1133V,

2012 WL 4829293, at *30 (Fed. Cl. Spec. Mstr. Sept. 20, 2012); Holmes v. Sec'y of

Health & Human Servs., No. 08-185V, 2011 WL 2600612, at *20 (Fed. Cl. Spec. Mstr.

Apr. 26, 2011); Simon v. Sec'y of Health & Human Servs., No. 05-941V, 2007 WL

1772062, at *7 (Fed. Cl. Spec. Mstr. June 1, 2007); Grace v. Sec'y of Health & Human

Servs., No. 04-[redacted], 2006 WL 3499511, at *9 (Fed. Cl. Spec. Mstr. Nov. 30,

2006). These decisions make clear that epidemiological findings relating to the safety

of DTP vaccines cannot reasonably be said to relate to the DTaP vaccine at issue in

this case.

In that regard, however, Dr. Kinsbourne testified that efforts to eliminate whole

cell pertussis in favor of acellular pertussis are not completely effective:

11

As you know, in the acellular vaccine, the pertussis toxin is toxoided, making

– hopefully making it unable to bind to the surface of neurons and disable

the inhibitory GABA system. That’s the point of the toxoid[ing]. However,

there is literature, and I think I may have submitted some in the previous

case, the Haynes matter,18 which talks about the difficulty of toxoiding all of

the pertussis toxin . . . And that is a process which is not perfect. So, one, it

may be that the – that there is, in fact, still pertussis toxin in the vaccine, but

of course much less because of the toxoiding process . . .

(Tr. 92-93.) Accordingly, Dr. Kinsbourne testified in effect that what is true of the DTP

vaccine is also true of the later acellular formulation, but with a lower rate of reaction.

(Tr. 57.)

I am not persuaded by this logic. Even if fully crediting Dr. Kinsbourne’s

assertion that residual pertussis toxin remains in the DTaP formulation, by his own

description there remains a difference in formulation that directly implicates vaccine

safety and therefore eliminates any possibility of reasonably carrying over statistical

observations from one formulation to the other. And since the specific Melchior study

findings Dr. Kinsbourne cites are based solely on statistical observation related

specifically to incidences following DTP (as opposed to the broader conclusions that do

not support petitioners’ case), it cannot reasonably be applied in this case, especially in

light of the specific history of safety concerns with DTP and the subsequent

improvement with DTaP as discussed in the above-referenced decisions. In other

words, without more and on this record, Dr. Kinsbourne’s intimation of a meaningful

residual relationship between DTaP and infantile spasms is entirely speculative.

The subsequent Bellman study, however, presents a more complicated question.

In 1983, Bellman et al., published a further study of 269 cases of infantile spasms

reported to the National Childhood Encephalopathy Study in Great Britain. (Bellman,

supra, at Ex. D, Tab. 1, p. 1.)19 Of those, 92 were classified as symptomatic, 163 as

cryptogenic, and a further 14 as “doubtful.” (Id.) Unlike the Melchior study, Bellman

compared the immunized population to age-matched controls. (Id. at 2.) Also

18Referring to Haynes v. Secretary of Health & Human Services, No. 00-358V, a prior case before the

previously-assigned special master. In the prior decision resolving that case, the special master

discussed the Bellman and Melchior studies at length and found pursuant to an Althen analysis that a

DTaP vaccine did cause a child’s infantile spasms. 2011 WL 681066 (Fed. Cl. Spec. Mstr. Feb. 7, 2011).

During the hearing in this case, the special master explained that she disagrees with the view, as

discussed in the above-cited cases, that DTP studies are inapplicable to the later acellular formulation.

(Tr. 57.)

19Although it was petitioners who sought to rely on this study, citation is to respondent’s exhibit. Dr.

Kinsbourne cited the 1983 Bellman study in his initial report (Ex. 6, p. 3), but does not actually appear to

have included a copy of the study in his submission. Several of the articles cited in his report were

omitted, with pages inserted stating only “MISSING TO BE FILED LATER.” (See, e.g., Ex. 6, pp. 49, 85.)

Nonetheless, Dr. Zempel filed a copy of the Bellman study in support of his rebuttal.

12

significant, Bellman examined not only the DTP vaccine, but also a DT vaccine without

any pertussis at all. (Id.)

Examining the pertussis vaccine, the Bellman study found no significant

association between spasms and the administration of a pertussis vaccine in either the

prior seven days or 28 days. (Bellman, supra, at Ex. D, Tab. 1, p. 3.) However, they

did find that “a small excess in the number of cases over that expected by comparison

with controls in 7 days after immunization with both DTP and DT vaccines followed by a

corresponding deficit in the next 3 weeks suggests that, in some cases, immunization

may trigger the onset of spasms or attract attention to symptoms in children destined to

show the condition overtly within a short time.” (Id.) Thus, the Bellman study observed

a potentially vaccine-related and control-matched change in symptom presentation,

albeit a small one.20 Additionally, unlike the Melchior study, because the same

observation was made both among those receiving the DTP and DT vaccines, that

finding cannot necessarily be wholly dismissed as relating to the prior whole cell

pertussis formulation of the DTP vaccine or to pertussis at all.

Significantly, however, as between the two groups, those experiencing spasms

following the DT vaccine were much more likely to be suffering symptomatic rather than

cryptogenic infantile spasms. Only about one-third of the post-DT cases were

cryptogenic compared to two-thirds of the post-DTP cases. (Id. at 3 (Table III).) Dr.

Kinsbourne indicated that there is “quite a big difference” between symptomatic and

cryptogenic infantile spasms in that symptomatic cases have identified structural

damage in the brain. (Tr. 50.) He characterized symptomatic cases as having “extra

liability” for a vaccine reaction to occur. (Tr. 60.) Moreover, for his part, Dr. Zempel

suggested the uptick in post-vaccination onset observed in the study could be

attributable to recall bias, which was also raised by the study authors. (Tr. 161-62.)

These factors do cast doubt on the significance of the finding.

For these reasons, I assign no weight to the Melchior study. However, I give

some minimal weight to the Bellman study as evidence suggesting that onset of infantile

spasms may respond to some vaccine formulations involving tetanus and diphtheria

and not limited to DTP. However, I do not find that the Bellman study provides evidence

specific to the DTaP formulation. Nor, given the above-discussed limitations, do I find

that the Bellman study alone is sufficient to provide preponderant evidence of a medical

theory linking any vaccine to infantile spasms.

20Interestingly, Dr. Zempel filed with his report a 2004 book chapter that noted the Bellman study to be

the largest controlled study to date. (Arzimanoglou, Guerrini & Aicardi, supra, at Ex. D, Tab 3, p. 15.) Dr.

Zempel highlighted language from that chapter explaining that Bellman found the chronological

association coincidental; however, the authors also characterized the Bellman study as among studies

that “have implicated triple or quadruple immunization as an etiologic factor, with the pertussis component

usually being incriminated.” (Id.)

13

VI. Applying the Althen Test to Petitioners’ Claim

a. Althen Prong One

Petitioners’ burden under the first Althen prong is to provide, by preponderant

evidence, “a medical theory causally connecting the vaccination and the injury.” Althen,

418 F.3d at 1278. 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. However, such a theory must only be “legally probable, not medically or

scientifically certain.” Knudsen, 35 F.3d at 549. 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 v.

Sec’y of Health & Human Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009). While special

masters may apply the Daubert framework21 to assess expert reliability, special masters

are not required to apply Daubert.22 Boatmon, 941 F.3d at 1359.

In this case, petitioners’ theory seeks to causally link the DTaP vaccine to

infantile spasms. As explained above, infantile spasms represent both an epilepsy and

a coexisting encephalopathy. Significantly, however, there has been no assertion by

Dr. Kinsbourne that C.K.’s vaccinations can be directly linked to the encephalopathy

that contributes to C.K.’s infantile spasms. Rather, petitioners contend through their

expert that C.K.’s vaccination brought on the onset of her seizures, which, in turn,

brought on her condition as a whole. (ECF No. 50, pp. 1, 7; ECF No. 67, pp. 5-6.)

Thus, the initial threshold question posed by petitioners’ theory is whether vaccination

can be considered the trigger of an individual infantile spasm seizure event.23

In this regard, Dr. Kinsbourne began with the starting premise that infantile

spasms are not wholly genetic in cause, but rather among cryptogenic cases, “[i]nfantile

21When analyzing expert testimony, a Daubert analysis weighs the following factors: (1) whether a theory

or technique can be (and has been) tested; (2) whether the theory or technique has been subjected to

peer review and publication; (3) whether there is a known or potential rate of error and whether there are

standards for controlling the error; and (4) whether the theory or technique enjoys general acceptance

within a relevant scientific community. See Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579,

592-95 (1993).

22

As noted above, in Boatmon the Federal Circuit rejected “plausible” or “possible” formulations of expert

opinion. 941 F.3d at 1360. In this case, Dr. Kinsbourne in his initial report indicated alternately that his

theory is “biologically plausible” or “medically reasonable.” (Ex. 6, p. 9.) At the outset of his hearing

testimony, he again referenced what is “possible” and what “could” have happened. (Tr. 39.) However,

the special master explained that “I can only deal with probable. Possible is irrelevant.” (Tr. 37.) She

asked Dr. Kinsbourne to clarify his degree of certainty and he ultimately confirmed that regardless of his

specific phrasing he holds his opinion “to a medically reasonable degree” and that his opinion is that “the

vaccinations probably did cause the onset of her seizures.” (Tr. 39-40.)

23Dr. Kinsbourne has presented the theory of cytokine-induced seizures in prior cases to mixed results in

the recent past. Compare Jaafar v. Sec’y of Health & Human Servs., No. 15-267V, 2018 WL 4519066

(Fed. Cl. Spec. Mstr. Aug. 10, 2018) and Fuller v. Sec’y of Health & Human Servs., No. 15-1470V, 2019

WL 7576382 (Fed. Cl. Spec. Mstr. Dec. 17, 2019).

14

spasms have been linked to ‘stressors that include infections and malformation.’” (Ex.

6, p. 6.) Though he acknowledged that this is believed to be related to age-specific

hyperexcitability that constitutes a susceptibility, he further opined that the majority of

seizures are not spontaneous, but rather are provoked or triggered by stressful stimuli.

(Ex. 6, p. 6 (citing Baram and Hatalski (1998),24 Brunson (2001),25 and Dichter

(2009)26). That is, Dr. Kinsbourne proposed a “two-hit model” of epileptogenesis

wherein a susceptibility responds to a stress-related enhancement.27 (Ex. 6, pp. 6-7.)

More specifically, in 1993, Baram proposed the hypothesis that the endogenous

neuropeptide called Corticotripin-releasing hormone (“CRH”) acts as a convulsant in the

pathophysiology of infantile spasms. (Tallie Z. Baram, Pathophysiology of Massive

Infantile Spasms: Perspective on the Putative Role of the Brain Adrenal Axis, 33 ANN

NEUROL 231 (1993) (Ex. 6-1, p. 1).) This was based on a number of prior observations,

including prior evidence that adrenocorticotropic hormone (“ACTH”) and glucocorticoids

(“GCs”) have been effective treatments for infantile spasms as well as evidence from

animal studies that showed stress-related increases in CRH synthesis having an effect

on the developmental pattern of CRH gene expression. (Id. at 2-3.) Baram also

observed that a prior study had shown reduced levels of ACTH in the cerebral spinal

fluid of infants with infantile spasms. (Id. at 4.) Baram confirmed that finding in an age-

matched control study as well as a reduction in cortisol; however, no difference was

found in CRH levels.28 (Id.) Petitioners cited additional articles by Baram and Hatalski

(1998), Brunson (2001), and Dicther (2009), further advancing this hypothesis as a “final

24

Tallie Z. Baram & Carolyn G. Hatalski, Neuropeptide-mediated Excitability: A Key Triggering

Mechanism for Seizure Generation in the Developing Brain, 21 TRENDS NEUROSCI 471 (1998) (Ex. 6-2).

25Kristen L. Brunson, Mariam Eghbal-Ahmadi & Tallie Z. Baram, How do the many Etiologies of West

Syndrome Lead to Excitability and Seizures? The Corticotropin Releasing Hormone Excess Hypothesis,

23 BRAIN DEV 533 (2001) (Ex. 6-4).

26Marc A. Dichter, Emerging Concepts in the Pathogenesis of Epilepsy and Epileptogenesis, 66 Arch

Neurol 443 (2009) (Ex. 6-7).

27 Notably, in Boatmon, the petitioners sought to apply a “triple risk” theory of causation relative to Sudden

Infant Death Syndrome that similarly included an underlying vulnerability. 941 F.3d at 1362-63. In that

case, petitioners’ expert assumed the presence of an underlying brain stem abnormality based on

statistical likelihood. Id. The Federal Circuit held that in the absence of actual evidence of a brain stem

abnormality, a statistical likelihood of such an underlying condition was insufficient to meet petitioners’

burden of demonstrating a logical sequence of cause and effect under Althen prong two. Unlike in

Boatmon, however, Dr. Kinsbourne clarified that he did not suggest the presence of an underlying

susceptibility as part of his affirmative opinion of cause and effect in C.K.’s case, but only as a means of

suggesting why infantile spasms are not more prevalent. (Tr. 51, 88-89.) In fact, he explicitly disclaimed

reliance on such a vulnerability, indicating that it “isn’t essential to my theory.” (Tr. 88.)

28This is significant because Baram explained that “[i]n response to a variety of stressful stimuli, the

synthesis and secretion of this neuropeptide [i.e. CRH] are increased. CRH acts on the pituitary to

promote the release of ACTH, which, in turn, enhances GC synthesis and release from the adrenal.

ACTH and GCs act via a negative feedback mechanism to suppress the synthesis and secretion of CRH.”

(Baram, supra, at Ex. 6-1, p. 3.) Accordingly, it does not appear that the findings uniformly supported the

hypothesis.

15

common pathway” that explains the diverse etiologies (i.e. multiple underlying

conditions implicated by symptomatic infantile spasms as well as unknown etiologies in

cryptogenic cases) of infantile spasms, all of which operate at a specific maturational

state present in infancy.

For his part, Dr. Zempel, though he stressed the distinction between a seizure as

a unitary event and the overall condition of epilepsy, did not dispute Dr. Kinsbourne’s

theory that a stressor can trigger a seizure generally. He agreed broadly that stress

causes an increase in cortisol (the hormone associated with fight or flight) and that

stress “changes the brain” with both short and long-term effects on the structure of the

brain.29 (Tr. 138-39.) He cautioned against thinking of stress as having a “minute-to-

minute gating of seizures,” and explained that there is much that is not known about

why stress can reduce the seizure threshold, but he did agree as a general matter that

seizures can be associated with stress, citing examples of students experiencing their

first seizures during final exams and anecdotal reports of people experiencing seizures

during extreme emotional responses.30 (Tr. 138-39.) More specifically, Dr. Zempel also

agreed that an immune response can lower the seizure threshold, noting in particular

that fever is “by far the most powerful component of the immune response that’s related

to a decrease in seizure threshold.” (Tr. 140.) He explained that “[t]here are clearly

many processes that are going on that perhaps protect or maybe bring down your

defenses at any one moment in time in terms of your propensity for having seizures.”

(Tr. 141.)

Nonetheless, Dr. Zempel also highlighted a case report by Coppola et al., which

followed three sets of identical twins. (Giangennaro Coppola et al., Case Report:

Simultaneous Onset of Infantile Spasms in Monozygotic Twins, 43 Ped Neuro 127

(2010) (Ex. E); Tr. 150-51.) These case reports noted that in each set of twins, both

twins experienced onset of infantile spasms on the same day, despite having had

relevant genetic mutations or other known predisposing factors ruled out. (Coppola et

al., supra, at Ex. E, p. 1.) The authors concluded that these case reports point “to some

genetically determined, time-dependent biological factor, apart from any environmental

influence.”31 (Id. at 4.) Dr. Zempel testified that the report “argues genetics is very

29 Baram characterized cortisol as “the major human GC.” (Baram, supra, at Ex. 6-1, p. 4.)

30He did caution, however, that “there are not detailed mechanistic studies that say stress causes this,

causes this, that then results in a seizure.” (Tr. 138.) Dr. Kinsbourne similarly noted in his initial report

that “[i]t is quite unknown how stresses interact with the momentary state of a hyperexcitable network to

reach a clinical tipping point.” (Ex. 6, p. 6.)

31 Although I agree (as Dr. Zempel testified) that the same-day onset for each pair of twins is striking, this

specific statement appears to overstate the significance of these case reports relative to environmental

factors. Upon my review of the article, it appears that these twin sets were identified years after onset

and, while evidence relating to predisposing factors such as reported family histories and APGAR scores

at delivery were explored, I see no discussion to indicate what, if any, measures the authors took to

assess the environmental factors existing at the time of onset. In that regard, these remain isolated case

reports and one must question how different the environmental influences would be as between the twins

in each set of siblings. (For example, pertinent to petitioners’ theory, one might expect that infant twin

siblings would likely receive their routine vaccinations on the same date.)

16

powerful in explaining why you have infantile spasms and secondly that it’s quite striking

that they reported these cases of siblings, identical siblings, who had almost

simultaneous onset of their infantile spasms.” (Tr. 150-51.) On subsequent

questioning, however, Dr. Zempel confirmed that, although infantile spasms “are likely

influenced by genetics,” he is not of the opinion that infantile spasms are genetically

caused. (Tr. 153-54.)

Dr. Zempel also highlighted a 2010 “Consensus Report”32 on infantile spasms

published in Epilepsia. (John M. Pellock et al., Infantile Spasms: A U.S. Consensus

Report, 51 EPILEPSIA 2175 (2010) (Ex. D, Tab 6).) That report explains that “[l]ittle is

known about the pathophysiology of [infantile spasms].” However, it also cites

approvingly to the Baram hypothesis as one of several hypotheses being explored. (Id.

at 3.) Both the Consensus Report and Dr. Zempel cautioned that the animal models

relied upon in the underlying studies have significant limitations. (Pellock et al., supra,

at Ex. D, Tab 6, p. 3; Tr. 177-79.) Nonetheless, the Consensus Report also indicated

that the nature of infantile spasms is such that “animal models are required to further

the understanding of the pathophysiology of [infantile spasms].”33 (Pellock et al., supra,

at Ex. D, Tab 6, p. 3.) In any event, that Consensus Report endorsed by Dr. Zempel

agrees that trauma, infection, and tumors are known post-natal causes of infantile

spasms. (Id. at 1.)

Accordingly, it appears on this record that Dr. Kinsbourne’s assertion that the

stress and immune responses can, in general, trigger a seizure is based on sound and

reliable science. This does not, however, specifically implicate vaccinations. Although

Dr. Kinsbourne sought in his initial report to explain how the innate immune system –

operating via proinflammatory cytokines – interacts with the production of CRH, the

contention that vaccination in itself can commence this interaction is based exclusively

on Dr. Kinsbourne’s ipse dixit.34 The articles discussed above implicate immune

32 This Consensus Report was published by 14 authors belonging to various departments of neurology

across the United States including, amongst others, John M. Pellock from the Division of Child Neurology

at Virginia Commonwealth University School of Medicine, Richard Hrachovy Peter Kellaway Section of

Neurophysiology at Baylor College of Medicine, Slomo Shinnar from the Albert Einstein College of

Medicine in New York, Tallie Z. Baram from University of California Irvine School of Medicine, David

Bettis from Pediatric Neurology of Idaho, and Dennis J. Dlugos from the Children’s Hospital of

Philadelphia.

33 Dr. Kinsbourne cited several other animal model studies not specifically discussed herein. (Ex. 6, p. 7.)

34 In his report, Dr. Kinsbourne wrote: “Spinelli et al (1992) demonstrated that interleukin-6 could enhance

production of CRH. In turn, proinflammatory cytokines are released when the innate immune system is

activated, by infections and vaccinations. Schmidt et al (1995) showed that even transient activation of

CRH production by interleukin 1 could induce long-lasting changes in hypothalamic CRH neurons,

rendering the HPA axis hyperresponsive to subsequent stimuli.” (Ex. 6, p. 7.) It does not appear that

petitioners actually filed either the Spinelli or Schmidt papers referenced in the report, but that is

ultimately immaterial. In this report, Dr. Kisnbourne does not attribute to either citation any discussion of

vaccination. His insertion of vaccination as the “in turn” vehicle for activation of proinflammatory

cytokines, which he intimates are sufficient to bring about the cited findings by Spinelli and Schmidt, are

his words alone. In and of itself, that specific statement is not controversial as a question of basic

17

response to infection, not vaccination, in the onset of infantile spams and Dr. Zempel

agreed that fever, not vaccination itself, lowers the seizure threshold. During the

hearing, Dr. Kinsbourne was directly asked if any of the literature he filed postulated

vaccination as the “second hit” in his two-hit hypothesis. He responded: “Most of the

literature speaks about infection. And the study – the animal models clearly show two-

hit – two-hit mechanisms. Whether it specifically says vaccination as a second hit I don’t

recall.” (Tr. 78.)

Upon my review, apart from the Melchior and Bellman studies discussed in

Section V, above, Dr. Kinsbourne did not purport to provide any evidence in either of his

expert reports or his hearing testimony substantiating his assertion that the DTaP

vaccine can be the beginning cause of a cascade of inflammation and stress response

leading to seizure. Moreover, weighing against that assertion, Dr. Kinsbourne

acknowledged that inflammatory cytokine production is a normal part of the vaccine

response and is necessary to the efficacy of the vaccine. (Tr. 70.) In his supplemental

report he explained that “[t]he innate immune response by [Toll-like Receptor]s,

implicating an outpouring of proinflammatory cytokines, is a necessary early stage in the

generation of adaptive immunity. It occurs without negative consequences in the vast

majority of cases.”35 (Ex. 6-A, p. 3 (emphasis added).) In fact, in his supplemental

immunology. However, juxtaposed as the link between his interpretations of the Spinelli and Schmidt

studies, it becomes an untested opinion deep-seated in advanced immunology. (In that regard, see also

footnote 35, below.) Later in the report, Dr. Kinsbourne seeks further support by discussing more broadly

that “[v]accinations activate the innate immune system, which enables adaptive immunity to develop. The

activation of Toll-like receptors (TLRs) and the release of proinflammatory cytokines is a necessary

condition for the genesis of the adaptive immunity which vaccination is intended to engender.” (Ex. 6, p.

7 (internal citations omitted).) It is evident from the face of his report that Dr. Kinsbourne is attempting to

stitch together disparate areas of investigation in the field of immunology based only on his own say-so.

35 The significance of this statement is not that Dr. Kinsbourne acknowledges the proposed negative

consequences to be rare. This program often addresses rare occurrences. Rather, this statement

highlights that Dr. Kinsbourne is relying in the first instance on a normal and expected immune reaction

within the human body. In that context, it cannot be enough for Dr. Kinsbourne to merely highlight

cytokine production by innate immunity as a process that does occur and thereby claim it to be

necessarily injurious. This has been a recurrent issue in cases within this program relative to a number of

different conditions. For example, in a case involving sensorineural hearing loss following influenza

vaccination, a special master previously and similarly explained:

the argument that cytokine upregulation can be a pathogenic mechanism unsuccessfully

attempts to leverage what is known about how vaccines generally affect the immune

system into proof that these anticipated processes can also be pathogenic. To be sure,

components of this theory are based on reliable science. Petitioner has referenced reliable

literature establishing that certain proinflammatory cytokines (including IL-6 and TNF-

alpha) have been shown to be elevated following vaccine administration (see, e.g.,

Christian at 1, 5), or that these same cytokines may play a role in the process of hearing

loss (Kuemmerle-Deschner, Pathak). But the theory lacks similar support for its connecting

proposition – that the cytokine upregulation leads to or causes hearing loss – as well as

the concept that vaccination can instigate the entire disease process. It is not enough to

note that increased numbers of inflammatory-associated cytokines have been measured

in the context of certain injuries or illnesses (or are involved in the body's reaction to those

illnesses). Dr. Axelrod does not personally have demonstrated expertise studying these

18

expert report, after being challenged regarding the lack of support for his opinion that

vaccines can cause infantile spasms, Dr. Kinsbourne conceded that “[i]t is correct that

scientific proof is lacking.” (Ex. 6, p. 1.) Consistent with this concession by Dr.

Kinsbourne, Dr. Zempel denied that vaccines are known in the medical community to be

a cause of infantile spasms. (Tr. 160.)

Nothing requires the acceptance of an expert’s conclusion “connected to existing

data only by the ipse dixit of the expert,” especially if “there is simply too great an

analytical gap between the data and the opinion proffered.” Snyder v. Sec’y of Health &

Human Servs., 88 Fed. Cl. 706, 743 (2009) (quoting Gen. Elec. Co. v. Joiner, 522 U.S.

136, 146 (1997)); see also Isaac v. Sec’y of Health & Human Servs., No. 08-601V, 2012

WL 3609993, at *17 (Fed. Cl. Spec. Mstr. July 30, 2012), mot. for rev. denied, 108 Fed.

Cl. 743 (2013), aff’d, 540 F. Appx. 999 (Fed. Cir. 2013). Important to this point is Dr.

Kinsbourne’s lack of any qualifications in immunology. This is not to say he lacks the

qualification necessary to opine in this case generally. Neither expert in this case is an

immunologist and the injury at issue is neurologic, squarely within both experts’ field

even if some of the known or suspected causes intersect with other disciplines.

Moreover, some inferences grounded in sound and reliable science may be appropriate.

However, petitioners are specifically theorizing an immunologic cause of a neurologic

condition and bear the initial burden of proof on this point. In this instance, Dr.

Kinsbourne’s lack of relevant qualification coupled with the quality of his testimony

specific to this case, leave unpersuasive his unsupported extrapolation beyond the well-

established aspects of immunology. In fact, Dr. Kinsbourne was candid in

acknowledging during the hearing that certain aspects of his theory were beyond his

expertise.36 (Tr. 96-99.)

unsupported elements of the theory, and no persuasive or reliable literature was offered

on such points.

Inamdar v. Sec’y of Health & Human Servs., No. 15-1173V, 2019 WL 1160341, at *17 (Fed. Cl. Spec.

Mstr. Feb. 8, 2019); see also Bender v. Sec’y of Health & Human Servs., 141 Fed. Cl. 262, 266 (2019)

(denying a motion for review where “[t]he Special Master found that Dr. Byers cited no evidence to

explain how the mere presence of cytokines could instigate an autoimmune process that results in a

demyelinating condition in the central nervous system (“CNS”), particularly when the vaccines were

injected in the periphery.”); McKown v. Sec’y of Health & Human Servs., No. 15-1451V, 2019 WL

4072113, at *50 (Fed. Cl. Spec. Mstr. July 15, 2019) (finding with regard to eczema that “[t]he fact that

cytokine upregulation is promoted by vaccination – a medically reliable assertion standing alone – does

not mean that this cytokine increase is definitionally harmful, especially given (as observed by Dr.

MacGinnitie) that it is difficult to establish whether certain proinflammatory cytokines are instigators or

merely mediators of a disease process begun in some other way.”); Palattao v. Sec’y of Health Human

Servs., No. 13-591V, 2019 WL 989380, *36 (Fed. Cl. Spec. Mstr. Feb. 4, 2019) (explaining that

“[p]etitioners argued that the immunologic stimulation that vaccinations generally provide (which

inherently encourage cytokine production) could result in a demyelinating condition like TM. Petitioners’

theory was rooted in the general proposition that virtually any vaccine could be pathogenic and result in

TM. See Tr. at 160. But they have offered insufficient reliable scientific or medical evidence that

addresses the specific pathogenicity of the vaccines in dispute herein, nor anything connecting vaccines

to TM based merely on their recognized pro-inflammatory capacities.”).

36During the hearing respondent’s counsel asked Dr. Kinsbourne if he was of the opinion that infantile

spasms are an autoimmune condition. He responded that by virtue of his proposed theory, they are. (Tr.

96.) In follow up, the special master questioned the accuracy of that assertion. She asked “now, what are

19

Accordingly, while I find that Dr. Kinsbourne’s broader assertion that a seizure

can be triggered by an immune-related or stress-related response to infection or trauma

is sound and reliable, the further, more specific assertion that a vaccination can itself act

as that stressor without other factors of stress or inflammation is largely unsupported on

this record. Only scant evidence from the Bellman study supports the idea that any

vaccine, let alone the DTaP vaccine particularly, can cause a temporal shift in the onset

of infantile spasms. Thus, although I accept for purposes of a theory of general

causation that vaccines can in some contexts contribute to seizures as part of a larger

immune/inflammatory process, namely where as Dr. Zempel acknowledged the vaccine

causes a seizure threshold-reducing fever and thereby results in febrile seizures, I do

not find preponderant evidence on this record that the DTaP vaccine itself can cause

seizures. Therefore, I end the Althen prong one analysis here, because this distinction

has case-dispositive implications, discussed below, for petitioners’ case under Althen

prong two.37

the cytokines attacking in particular? The brain is normal on MRI, so what substance in the body is the

cytokine attacking in order to have this autoimmune response?” (Tr. 98.) In response, Dr. Kinsbourne

testified that cytokines “increase the excitation level of neurons” and that “an excess of proinflammatory

cytokines via the microglia can cause excitotoxic damage and actually kill a neuron, or at the lower level

can excite neurons enough to cause seizure discharges.” (Tr. 98-99.) The special master sought further

clarification, asking “[i]sn’t this immune-mediated, not autoimmune?” Dr. Kinsbourne responded that he is

not aware of the distinction, adding “perhaps I should be, but I’m not.” This prompted the special master

to reconfirm Dr. Kinsbourne’s earlier acknowledgment that he is not an expert in immunology before

further suggesting “[s]o maybe you shouldn’t be answering this question.” Dr. Kinsbourne replied “[i]t

becomes more apparent now.” (Tr. 99.)

37In point of fact, the question of whether vaccination can trigger a seizure is only a threshold question

raised by petitioners’ theory. Since the condition of infantile spasms constitutes an epileptic

encephalopathy, the question of the trigger for the first seizure is not the end of the analysis. Dr. Zempel

persuasively explained that:

We have to distinguish between the process of having epilepsy, which is epileptogenesis,

and the idea that you may have a seizure, which is a unitary event. So epilepsy is when

you’ve had more than one seizure of unknown cause. So, for example, a stressor loosely

defined or a fever, more precisely defined, in general is not -- does not then lead to a

diagnosis of epilepsy unless there are seizures that occur in the absence of those

stressors. So if I get hit in the head with a baseball bat and have a seizure, that doesn’t

qualify as epilepsy.

(Tr. 141-42.) Accordingly, even if a vaccine could trigger a seizure, the next question would be what

relationship, if any, that vaccine-induced seizure has to the overall course of infantile spasms. That is,

could a single vaccine-induced seizure be theorized to represent a substantial contributing factor in

causing the condition of infantile spasms? For all the reasons discussed in Section VI(b), below, it is not

necessary to reach that question.

I do note, however, that in the course of this case, Dr. Kinsbourne at least briefly touched upon

three potential answers to that question. First, he proposed that each seizure itself has a destructive

effect on the brain, perhaps suggesting an argument that any given seizure contributes to the child’s

coexistent encephalopathy. (Tr. 48-49.) Second, he opined that the process described by his theory

results in glutaminergic and excitotoxic changes in the brain which themselves enhance susceptibility to

subsequent seizures, suggesting an argument that a first, vaccine-induced seizure has a causal

relationship to all the subsequent and cumulatively damaging seizures. (Tr. 98-99.) And finally, and most

20

b. Althen Prong Two

The second Althen prong requires preponderant evidence of a “logical sequence

of cause and effect showing that the vaccination was the reason for the injury.” Althen,

418 F.3d at 1278. This prong is sometimes referred to as the “did it cause” test; i.e., as

opposed to the question of general causation posed by the first prong, the question is

whether the vaccine (or vaccines) actually caused the alleged injury in the case at hand.

Broekelschen v. Sec’y of Health & Human Servs., 618 F.3d 1339, 1345 (Fed. Cir. 2010)

(“Because causation is relative to the injury, a petitioner must provide a reputable

medical or scientific explanation that pertains specifically to the petitioner’s case . . . .”);

Pafford v. Sec’y of Health & Human Servs., 451 F.3d at 1352, 1355-56 (Fed. Cir. 2006)

(accepting the special master’s can it/did it formulation as equivalent to Althen prongs

one and two).

In this case, when asked for the basis of his opinion that C.K.’s own vaccination

caused her infantile spasms, Dr. Kinsbourne initially explained that his opinion was

based on the apparent temporal association and offered no other evidence of cause

and effect explaining C.K.’s own condition. (Tr. 38-40.) Pressed further, he indicated

that the fact that C.K. experienced a clear and decisive onset of not just one seizure, but

a cluster of seizures, suggested that a definite event happened to trigger those

seizures.38 (Tr. 44-45.) On later cross-examination, however, Dr. Kinsbourne again

indicated that his opinion was based exclusively on a temporal association: “I’m offering

this as a reasonable medical mechanism. I’m not offering it as scientific certainty. It is

reasonable to suppose that when the onset of the seizure disorder is within hours of a

vaccination that the – and when the vaccination is known to produce proinflammatory

cytokines, which are known to have an excitatory or even repligenic property that the –

that property of the cytokines was involved in the onset of the seizure disorder.” (Tr.

73.)

fully addressed, Dr. Kinsbourne opined that the timing of onset of infantile spasms dictates, or at least

influences, the severity of the sequela. Accordingly, he opined that by triggering the first seizure earlier in

life, a vaccination can advance the onset of infantile spasms and necessarily make the condition worse

than it otherwise would have been. (Tr. 52-53, 58-59.)

Dr. Zempel disputed that the timing of onset dictates prognosis. He acknowledged that in general

there is a tendency for more severe cases to manifest earlier, but he explained that those cases tend to

be instances of symptomatic infantile spasms. He indicated that more than anything else the underlying

cause of the infantile spasms determines outcome. (Tr. 130-34.) His testimony regarding the impact of

seizures, however, was more nuanced. Dr. Zempel cautioned that infantile spasms encompass both a

seizure disorder and an encephalopathy and that “[t]he key characteristic [of infantile spasms] is that the

encephalopathy is out of proportion to the expected cause of problems by the seizures.” (Tr. 127-28.) He

further explained that seizures in infantile spasms are treated less aggressively than other types of

seizure activity. (Tr. 127-28.) However, when directly asked by the special master whether in cases of

infantile spasms it is the seizure activity or the encephalopathy that damages the brain, he responded “I

think it’s both.” (Tr. 127.) He also testified that “[i]f you’ve had a meningitis or encephalitis or an infection

or particularly prenatal infections . . . it’s like a chicken-or-the-egg issue in many cases. You know, these

infections may cause developmental genetic changes that involve genes.” (Tr. 153-54.)

38 Dr. Zempel testified, however, that seizure clusters are a common presentation that distinguishes

infantile spasms from other forms of epilepsy. (Tr. 120-21.)

21

This type of mere suspicion of a temporal relationship is not sufficient to

establish causation. “When a petitioner relies upon proof of causation in fact rather

than proof of a Table Injury, a proximate temporal association alone does not suffice to

show a causal link between the vaccination and the injury . . . A reputable medical or

scientific explanation must support this logical sequence of cause and effect.” Grant v.

Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992) (citing 42

U.S.C. § 300aa–13(a)(1)). There is some inconclusive suggestion in the record of this

case that the course of C.K.’s infantile spasms responded to treatment with ACTH.

(ECF No. 9, pp. 11-13; Tr. 12; Ex. 6, p. 6; Ex. A, p. 5.) As noted above, Dr. Kinsbourne

cited the efficacy of ACTH treatment for infantile spasms as supportive of the

hypothesis that seizures may have a stress hormone-related pathophysiology. (Ex. 6,

p. 6.) However, even if I were to accept this as some limited evidence that C.K.’s initial

seizures were triggered or mediated by a stress hormone, this relates only to the

broadest aspect of Dr. Kinsbourne’s theory and, without more, does not implicate C.K.’s

vaccination(s) as a relevant stress event. Consistent with Dr. Kinsbourne’s above-cited

testimony, I can find no other evidence in the record supporting the assertion that C.K.’s

DTaP vaccine, or any other vaccine, did cause her infantile spasms.

As described above in reference to petitioners’ theory, Dr. Kinsbourne

acknowledged that inflammatory cytokine production is a normal part of the vaccine

response and is necessary to the efficacy of the vaccine and “occurs without negative

consequences in the vast majority of cases.” (Tr. 70; Ex. 6, p. 3.) In that regard, Dr.

Zempel suggested that evidence of inflammation, such as MRI findings or fever, would

be expected if excessive or abnormal cytokine inflammation were the cause of C.K.’s

condition. (Tr. 173-75.) Moreover, as Dr. Zempel explained, fever is “by far the most

powerful component of the immune response that’s related to a decrease in seizure

threshold.” (Tr. 140.) However, at the time she first presented with symptoms later

diagnosed as infantile spasms, C.K. was observed to be alert and active. She was also

negative for fevers, chills, or fussiness. (Ex. 4, p. 9-10.) Ms. Kottenstette also

confirmed in her testimony that C.K. was afebrile at the time of onset. (Tr. 8-9.)

Dr. Kinsbourne disagreed with the suggestion that cytokine inflammation would

necessarily manifest clinically beyond C.K.’s seizures. (Tr. 99-100.) Asked if there is

otherwise any evidence to suggest C.K. had a cytokine reaction, he indicated that

“[t]here is nothing in her personal file that deals with this matter. It was not investigated.

It would take – it’s not a routine investigation that’s usually done.” (Tr. 100.)

Unfortunately, however, even accepting this at face value, this leaves petitioners with

only a circular argument – the seizures themselves are advanced as the only available

evidence of the alleged, underlying inflammation that is argued to be the manner by

which the vaccine can be shown to have caused the seizures.39

39Additionally, the reasonable limits of the clinical investigation in C.K.’s case cut both ways. Dr. Zempel

observed that additional imaging would be necessary to completely rule out cortical dysplasia, which may

not have been visible on C.K.’s MRI at the time. (Tr. 147-48.) This condition is not typically visible on

MRI until about 24-40 months of age. (Tr. 148; Pellock et al., supra, at Ex. D, Tab 6, p. 5.)

22

In contrast, where Dr. Kinsbourne’s theory was previously accepted, there were

complex, febrile seizures involved, which were outwardly suggestive of an inflammatory

reaction and significant enough to be identified as the catalyst for more seizures. Fuller

v. Sec’y of Health & Human Servs., No. 15-1470V, 2019 WL 7576382 (Fed. Cl. Spec.

Mstr. Dec. 17, 2019). These factors are not present in this case. In this case, there is

no evidence that C.K.’s seizures were focal, complex, or febrile. (Tr. 55, 146, Ex. 4, pp.

9-10; ECF No. 9, p. 1.) And, although infantile spasms can secondarily lead to other

forms of epilepsy (Arzimanoglou, Guerrini & Aicardi, supra, at Ex. D, Tab 3, p. 27-28),

petitioners contend that cryptogenic infantile spasms, rather than any other form of

epilepsy, remained the correct diagnosis at the time of the hearing.40 (Tr. 54-55.)

Additionally, there is not preponderant evidence from any of C.K.’s treating

physicians attributing her condition of infantile spams to her vaccination. Following her

initial emergency department presentation, Dr. Catherine Riordan, C.K.’s pediatrician,

suggested in follow-up the possibility that C.K. was experiencing a mild vaccine

reaction; however, the basis for that opinion was not explained. (Tr. 9-10; ECF No. 9-1,

p. 1.) Moreover, at the time, it appears that Dr. Riordan may not even have recognized

C.K.’s convulsions as seizures or, at the very least, was not yet committed to that

diagnosis. Ms. Kottenstette testified that she was initially told that “maybe it was a mild

reaction to the vaccination or maybe it was reflux.” (Tr. 9-10.) C.K.’s discharge

diagnoses from the night prior had been “rhythmic episode” and “possible seizure.” (Ex.

4, p. 5 (emphasis added).) In that regard, Dr. Zempel testified that one of the difficulties

in diagnosing infantile spasms “is that it can be very complicated in the beginning when

the spasms are much more subtle to really understand what they are.” (Tr. 124.) He

noted that early seizures can be mistaken for reflux, twitches, or myoclonus. (Tr. 125.)

This lack of outward clinical evidence implicating C.K.’s vaccination as a cause of

her seizures presents an especially challenging obstacle for petitioners in this case,

because both experts otherwise agree that infantile spasms have a known, age-related

onset even without any known or well-established trigger. As noted above, Dr. Zempel

testified that infantile spasms typically present between three to nine months of age. (Tr.

123.) The vast majority have onset within the first year of life. (Id.) Dr. Kinsbourne

agreed, noting that there are “some exceptions, but not many.” (Tr. 50.) Moreover, Dr.

Kinsbourne suggested in his initial report that this onset relates to “an age specific

hyperexcitable network.” (Ex. 6, p. 6 (quoting Frances Jensen, Relationship Between

Encephalopathy and Abnormal Neuronal Activity in the Developing Brain, 49 ACADEMIC

PRESS 23 (2002) (Ex. 6-12)).) Having suffered onset of her infantile spasms following

her four-month well exam, C.K. was squarely within this age range. Accordingly, the

evidence of record not only fails to present affirmative evidence of a logical sequence of

40At the hearing, Dr. Kinsbourne testified that he had personally observed C.K. seizing the night before.

(Tr. 54.) The special master asked “So is it your testimony that she doesn’t have partial complex or any

other seizures; she still has infantile spasms?” He answered “I specifically looked for any other seizure

type, and I asked the parents. And I didn’t locate any.” (Tr. 54-55.)

23

cause and effect linking vaccination to injury, it also suggests there is reason to doubt

the significance of the apparent temporality.41

Nonetheless, Dr. Kinsbourne opined that C.K. was not preordained to experience

infantile spasms, and had she not had a trigger (her vaccines in this case), she would

have had an opportunity to exit the apparent age-related risk window. (Tr. 52-53.) Dr.

Kinsbourne did not agree that everyone who develops epilepsy is predisposed to it,

noting, for example, that some epilepsies follow head trauma. (Tr. 75.) In his initial

report, however, he explained this point in greater detail and revealed why this line of

reasoning does not support petitioners’ claim. He wrote:

Would [C.K.] not have developed infantile spasms at all but for the four-

months vaccinations? Would she necessarily have encountered another

stress capable of triggering infantile spasms in the remaining temporal

window of susceptibility up to the age of eight months? It is quite unknown

how stresses interact with the momentary state of a hyperexcitable network

to reach a clinical tipping point. At this time, this question is unanswerable.

But any claim that she was “predestined” to suffer from this disease to this

degree (or at all) would be speculation. Predestination is not provided for in

medical science. At the very least, the vaccine injury deprived her of the

chance to emerge unscathed from the temporal window of risk.

(Ex. 6, p. 6. (emphasis added).) Having acknowledged himself that the question is

unanswerable due to the limits of our understanding of how stress interacts with the

body to reach a clinical “tipping point” – that is, that he cannot affirmatively say that C.K.

could have exited the risk window “but for” these vaccinations – he attributes

speculation only to the presumed counterpoint. However, petitioners must initially come

forward with evidence showing a logical sequence of cause and effect demonstrating

that the vaccination did cause C.K.’s injury. Absent that showing, the significance of the

temporal relationship remains unsubstantiated regardless of whether I accept that the

infantile spasms would have inevitably occurred anyway.

Finally, Dr. Kinsbourne also devoted much of his presentation to opining that,

statistically speaking, if C.K. had experienced seizures later in life, they would not have

taken as damaging a form, since the most severe epilepsies develop in the first year of

life. (Tr. 59, 76.) However, this point goes to the further consideration of whether one

vaccine-induced seizure led to further sequela and contributed significantly to C.K.’s

41 In their post-hearing brief, petitioners argue that Dr. Zempel conceded that DTaP can cause seizures

“in a few cases.” (ECF No. 67, p. 7 (citing Tr. 136).) This is incorrect. Dr. Zempel did not agree that

DTaP can cause seizures in a few cases. He agreed that the authors of the Melchior paper made that

assertion. (Tr. 135-36.) However, for the reasons discussed in Section V, above, I am assigning no

weight to the Melchior study. Moreover, Dr. Zempel’s testimony was clear that his opinion is that the age-

specific onset of infantile spasms “complicates whether there is a causal relationship because temporal

correlation does not imply causation. And simply by the tens of millions of people who obtain routine

vaccinations as part of their medical care by necessity, a small number of children who are going to

present with infantile spasms have those spasms present in a time period around the time where they got

vaccinations.” (Tr. 134.)

24

overall condition. Absent a demonstration that any one seizure was triggered by her

vaccination in the first place, this line of reasoning is moot.42

For these reasons, I find that petitioners have not satisfied Althen prong two.

c. Althen Prong Three

The third Althen prong requires establishing a “proximate temporal relationship”

between the vaccination and the injury alleged. Althen, 418 F.3d at 1281. That term

has been equated to the phrase “medically-acceptable temporal relationship.” Id. A

petitioner must offer “preponderant proof that the onset of symptoms occurred within a

timeframe which, given the medical understanding of the disorder's etiology, it is

medically acceptable to infer causation.” Bazan v. Sec'y of Health & Human Servs., 539

F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for what is a medically acceptable

timeframe must also coincide with the theory of how the relevant vaccine can cause an

injury (Althen prong one's requirement). Id. at 1352; Shapiro v. Sec'y of Health &

Human Servs., 101 Fed. Cl. 532, 542 (2011), recons. den'd after remand, 105 Fed. Cl.

353 (2012), aff'd mem., 503 Fed. Appx. 952 (Fed. Cir. 2013); Koehn v. Sec'y of Health

& Human Servs., No. 11–355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013),

mot. for review den'd (Fed. Cl. Dec. 3, 2013), aff'd, 773 F.3d 1239 (Fed. Cir. 2014).

Both Dr. Kinsbourne and Dr. Zempel explained that it is very difficult to determine

the true onset of infantile spasms. (Tr. 70, 124-25.) Many families recognize early

signs only in hindsight. (Tr. 125.) In this case, however, both experts reasonably

assumed that onset occurred approximately ten hours following C.K.’s October 2, 2012

vaccinations. (Tr. 38-39, 127.) This is the point at which C.K.’s family first became

concerned and, as Dr. Zempel described it, “whether something was going on before

that is unknowable at this point.” (Tr. 127.) Although he suggested that insidious onset

is more common, Dr. Zempel characterized an abrupt onset as “not an atypical case

either” and explained that he takes the abrupt onset suggested by the medical records

“at face value.” (Tr. 170.)

Dr. Kinsbourne, while acknowledging he is not an immunologist, indicated that,

based on his review of relevant literature, the innate immune response he cites as part

of his theory would occur “very fast, as a matter of hours.”43 (Tr. 62-63.) When asked

whether onset of infantile spasms within one day of vaccination was medically

reasonable in light of Dr. Kinsbourne’s opinion that C.K.’s injury was brought about by

her innate immune reaction, Dr. Zempel declined to answer. (Tr. 170-71.) He stressed

42Notably, this also is not uncontested. Dr. Zempel disagreed that age of onset is related to outcome.

(Tr. 131-33.) He also disagreed with the assertion that, but for the timing of her onset, C.K. was

necessarily positioned for an optimal recovery. (Tr. 165-68.)

43According to the literature filed in this case, and as the term “trigger” may suggest, the time from stress

event to seizure is rapid (within minutes). (Baram & Hatalski, supra, at Ex. 6-2, p. 2.) Accordingly, the

overall temporal relationship at issue is largely determined by the innate immune reaction cited by Dr.

Kinsbourne as inciting the stress event rather than by the endocrine aspects of the theory.

25

that he is not an immunologic expert and indicated that since he disagreed that vaccine-

causation is even possible, he could not identify what would be medically reasonable. 44

(Id.)

For purposes of this decision, since it is unrebutted, I accept Dr. Kinsbourne’s

opinion that onset of seizures within ten hours of vaccination is medically reasonable in

light of his proposed theory. In a prior case, Dr. Kinsbourne explained in greater detail

that his theory expects seizures to occur within three days of vaccination, a period that

is consistent with the time-frame identified for onset of a Table encephalopathy (which

may include seizures) following DTaP vaccination. Fuller, 2019 WL 7576382, *7; 42

C.F.R. § 100.3. In that prior case, Dr. Kinsbourne cited literature illustrating that among

Vaccine Adverse Event Reports with a known interval between vaccination and seizure,

one third (11 out of 33) experienced seizures on the same day as vaccination. Fuller,

2019 WL 7576382, *7 (citing M. Miles Braun et al., Infant Immunization with Acellular

Pertussis Vaccines in the United States: Assessment of the First Two Years’ Data from

the Vaccine Adverse Event Reporting System (VAERS), 106 PEDIATRICS 1 (2000)).

Notably, this is also consistent with the observations in the Bellman study that onset of

infantile spasms following DTP vaccination was reported to be as little as less than 24

hours and that there was a reported increase in incidences of infantile spasms within

seven days of both DTP and DT vaccination.45 (Bellman, supra, at Ex. D, Tab 1, p. 2.)

For these reasons, I find that petitioners have satisfied Althen prong three.

VII. Table Encephalopathy

Petitioners initially pled this case as a Table encephalopathy. (ECF No. 1.)

Additionally, both experts in this case have explained that the cardinal characteristics of

infantile spasms include the presence of an encephalopathy. (Ex. 6, p. 2; Tr. 180-81.)

Accordingly, in the interest of completeness, I note that the Qualifications and Aids to

Interpretation for a Table encephalopathy require, within 72 hours of vaccination, an

acute encephalopathy which, following a seizure, presents as “a significantly decreased

44Although I appreciate the logic behind Dr. Zempel’s answer, especially in light of my discussion with

regard to Althen prong one, I do not find this testimony to be fully satisfactory in the context of this case.

Dr. Kinsbourne’s explanation of his theory should have been sufficient for Dr. Zempel to engage with the

theory’s underpinnings notwithstanding his ultimate disagreement. That is, Dr. Zempel would not have

had to concede the validity of the theory to raise additional faults related to timing if he had identified any.

Accordingly, the true significance of Dr. Zempel’s testimony appears to be that he does not have the

immunological background necessary to refute Dr. Kinsbourne’s assertion. Similarly, in his expert report,

Dr. Zempel asserted that Dr. Kinsbourne’s opinion that a one-day onset is consistent with an innate

immune response was “not ‘medically reasonable’” based only on the fact that Dr. Kinsbourne did not

provide a specific citation for that assertion. He did not offer any explanation for why Dr. Kinsbourne may

be incorrect.

45 I stress that for all the reasons discussed in Section V, above, the Bellman study does not provide

evidence that the DTaP vaccine can cause infantile spasms; however, I did find that it provided some

minimal evidence that the DTP and DT vaccines triggered seizures in some children later diagnosed with

infantile spasms. Accordingly, it does provide some evidence relating to the expected temporal

relationship between seizures and vaccines generally.

26

level of consciousness that lasts at least 24 hours and cannot be attributed to a postictal

state—from a seizure or a medication.” 42 C.F.R. § 100.3(b)(2)(i)(2). Upon my review

of the complete record, there is not preponderant evidence that C.K. experienced an

acute encephalopathy consistent with the requirements of the Vaccine Injury Table. In

particular, Dr. Zempel persuasively explained:

[T]he encephalopathy associated with infantile spasms is that the child isn’t

right. They’re sleeping too much; they’re not reacting normally. The

testimony I heard was that it took many weeks for – for the medical

caregivers to really notice that an encephalopathy or developmental detail

or stagnation had occurred, most prominently after withdrawal of the ACTH.

So I think there are some children who have immediate signs that they’re

just not right associated with the seizures. Many children have the epileptic

spasms preceding the development of this longer – longer range

developmental delay or developmental stagnation.

(Tr. 126-27.)

VIII. Conclusion

It is readily apparent that C.K. and her family have experienced a tragedy. My

sympathies extend to them all. However, in light of the above-discussed legal

standards that must be applied in this and in all cases in this program, I cannot

conclude that C.K.’s infantile spasms were vaccine-caused. Although the onset of

C.K.’s infantile spasms appears temporally related to her vaccination, there is not

preponderant evidence that the vaccination did cause her condition. Unfortunately, for

all of the reasons discussed above, I must therefore conclude that petitioners are not

entitled to compensation and this case is DISMISSED.

Pursuant to Vaccine Rule 28.1(a), the clerk of court is directed to notify the

assigned judge of the filing of this decision on remand. In the absence of a motion for

review filed pursuant to RCFC Appendix B, the clerk of the court is directed to enter

judgment accordingly.46

IT IS SO ORDERED.

s/Daniel T. Horner

Daniel T. Horner

Special Master

46Entry of judgment can be expedited by each party’s filing of a notice renouncing the right to seek

review. Vaccine Rule 11(a).

27