Svagdis v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 15-520V

Filed: February 17, 2022

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*

A.S., a minor, by her parents, *

*

JEREMY and KIMBERLY SVAGDIS, * TO BE PUBLISHED

*

Petitioners, *

*

* Decision on Entitlement; DTaP Vaccine;

v. * IPV; Hib vaccine; Hep. B vaccine;

* Prevnar vaccine; RotaTeq vaccine;

SECRETARY OF HEALTH AND * Mitochondrial Dysfunction;

HUMAN SERVICES, *

* Encephalopathy; Infantile Spasms;

* Seizures.

Respondent. *

*

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Michael McLaren, Black McLaren, et al., PC, Memphis, TN, for Petitioners

Ronalda Kosh, U.S. Department of Justice, Washington, DC, for Respondent

DECISION ON ENTITLEMENT1

Oler, Special Master:

On May 21, 2015, A.S. and her parents, Jeremy Svagdis (“Mr. Svagdis”) and Kimberly

Svagdis (“Mrs. Svagdis”) (collectively “Petitioners”) filed a petition for compensation under the

National Vaccine Injury Compensation Program, 42 U.S.C. § 300aa-10, et seq.2 (the “Vaccine

Act” or “Program”) alleging, in part, that A.S. suffered from a significant aggravation of her

previous neurologic and/or physical impairments that were present, to a lesser extent, prior to the

allegedly causal vaccinations. Pet. at 1. For the reasons discussed in this decision, I find that

1

This Decision will be posted on the United States Court of Federal Claims’ website, in accordance with

the E-Government Act of 2002, 44 U.S.C. § 3501 (2012). This means the Decision will be available to

anyone with access to the internet. As provided in 42 U.S.C. § 300aa-12(d)(4)(B), however, the parties

may object to the Decision’s inclusion of certain kinds of confidential information. To do so, each party

may, within 14 days, request redaction “of any information furnished by that party: (1) that is a trade secret

or commercial or financial in substance and is privileged or confidential; or (2) that includes medical files

or similar files, the disclosure of which would constitute a clearly unwarranted invasion of privacy.”

Vaccine Rule 18(b). Otherwise, this Decision will be available to the public in its present form. Id.

2

National Childhood Vaccine Injury Act of 1986, Pub. L. No. 99-660, 100 Stat. 3755. Hereinafter, for ease

of citation, all “§” references to the Vaccine Act will be to the pertinent subparagraph of 42 U.S.C. § 300aa

(2012).

1

Petitioners have not demonstrated that that the vaccines A.S. received significantly aggravated her

condition.

I. Procedural History

Petitioners filed a petition on May 21, 2015, alleging that their minor daughter, A.S.,

developed infantile spasms, seizures, developmental regression/delays, epileptic encephalopathy,

and/or other neurologic and/or physical impairments and other injuries that were “caused-in-fact”

by the DTaP, IPV, Hib, Hep. B, Prevnar and/or RotaTeq vaccinations A.S. received on June 18,

2012; or in the alternative, that these vaccines significantly aggravated her underlying neurological

condition.3 Pet. at 1. ECF No. 1. A CD containing Exhibits 1-14 was received by the Clerk’s Office

on May 27, 2015. On June 15, 2015, Petitioners filed a statement of completion. ECF No. 6.

On December 10, 2015, Petitioners filed an amended petition, additional medical records,

and an amended statement of completion. ECF Nos. 11-13. The amended petition added that the

DTaP vaccine “resulted in the table injury of encephalopathy (or enc[]ephalitis) within 72 hours

of vaccination.”4 Am. Pet. at 1. Petitioners’ petition and amended petition both stated that “while

there was originally some concern about [A.S.] possibly suffering from a mitochondrial disorder,

that has since been ruled out by her current treating physicians.”5 Pet. at 4; Am. Pet. at 5.

On November 3, 2016, Petitioners filed expert reports written by Drs. Marcel Kinsbourne

and Richard Boles. Exs. 17, 30. On March 17, 2017, Respondent filed a Rule 4(c) Report and three

expert reports written by Drs. Max Wiznitzer, Christine McCusker, and Shawn McCandless. Exs.

A, C, E. On August 16, 2017, Petitioners filed an expert report from Dr. Eric Gershwin. Ex. 37.

On July 27, 2018, I held a status conference with the parties to discuss a date for an

entitlement hearing and concerns regarding Dr. Kinsbourne’s health and ability to testify at the

hearing. ECF No. 47. An entitlement hearing was set for September 5-6, 2019. See non-PDF

Scheduling Order on 8/6/2018. On September 24, 2018, Petitioners filed a status report confirming

they will rely on Dr. Kinsbourne’s expert report and testimony. ECF No. 48.

On June 17, 2019, Respondent filed three supplemental reports from Drs. Wiznitzer,

McCusker, and McCandless. Exs. G, H, I.

I held an entitlement hearing on September 5-6, 2019. On October 28, 2019, Petitioners

filed a post-hearing statement from Dr. Kinsbourne and two additional pieces of medical literature.

3

Although Petitioners initially alleged A.S.’s injuries were caused in fact by her vaccines, they exclusively

pursued a significant aggravation claim at hearing. See, e.g., Pet’rs’ Pre-Hearing Brief at 7-8. ECF No. 55;

Pet’rs’ Post-Hearing Brief at 1, 13. ECF No. 96.

4

Petitioners did not pursue this Table claim. See Joint Prehearing Submission at 2: “The parties agree that

A.S. did not suffer an acute Table encephalopathy following her June 18, 2012 vaccinations as defined by

the Vaccine Act.” ECF No. 66.

5

At the entitlement hearing, Petitioner’s theory of the case rested on the assumption that A.S. had

mitochondrial dysfunction that made her susceptible to injury from vaccination.

2

Ex. 59. On December 30, 2019, Respondent filed reports from Dr. Wiznitzer and McCandless.

Exs. N, P. On February 13, 2020, Petitioners filed a report from Dr. Kinsbourne. Ex. 62. On May

15, 2020, Respondent filed reports from Dr. Wiznitzer and McCandless. Exs. R, S.

On July 20, 2020, Petitioners filed a status report stating they did not intend to file

additional expert reports and believed the record was complete. ECF No. 93. On August 19, 2020,

Respondent filed a status report stating the record was complete. ECF No. 94.

I held a status conference on September 7, 2021 where counsel and I discussed the fact that

no post-hearing briefs had been filed. I indicated that briefing would be helpful to me, and set a

briefing schedule. ECF No. 95.

On November 7, 2021, Petitioner filed a post-hearing brief. ECF No. 96. On December 7,

2021, Respondent filed a post-hearing brief. ECF No. 97. On January 13, 2022, Petitioners filed a

status report indicating that they did not plan to file a reply brief, and that this matter was now ripe

for a decision. ECF No. 99.

II. Medical Records

A. Relevant Pre-Vaccination History

A.S. was born on December 15, 2011 with no serious complications. She was released

from Northside Hospital Forsyth the next day. Ex. 15 at 11, 21.

On December 19, 2011, A.S. had a routine check-up at Preston Ridge Pediatric Associates.

Ex. 8 at 11. A.S. had a normal neurological exam but was noted to be jaundiced and had latching

problems. Id. On January 9, 2012, A.S. returned to Preston Ridge Pediatric Associates for another

routine check-up. Id. at 8. Under current problems, A.S. was noted to have “lots of drool”, and

gurgles and spitting, but was otherwise normal. Id. at 8-9. A.S.’s weight was recorded as 10-25

percentile. Id. at 8. A.S. was scheduled for an appointment on February 13, 2012 but did not show.

On March 8, 2012, A.S. visited Preston Ridge Pediatric Associates. Ex. 8 at 6. A.S. was

three months old at this visit. Id. The pediatrician noted that A.S. was gagging on her bottle and

she had decreased consumption of Similac. Id. It was also noted that A.S. had back arching. Id.

The doctor observed a feeding and indicated “gagging at first but eventually was able to coordinate

suck/swallow/breath.” Id. A.S.’s weight was recorded as being in the tenth percentile. Id.

On April 17, 2012, A.S. returned for another pediatric visit. Ex. 8 at 5. The record noted

“difficulty with feeding with tongue thrusting/top of mouth.” Id. A.S. was in the tenth percentile

for weight. Id.

On June 18, 2012, A.S. had her six-month pediatric visit. Ex. 8 at 4 . A.S.’s weight was

recorded as “↓3%.” Id. Dr. Douglas noted that A.S. was sitting with support and was not

consistently rolling over but had in the past. Id. A.S.’s mother reported that although A.S. had

crossed her eyes before, this had become more noticeable since prior visits. Id. The doctor noted

HEENT (head, eyes, ears, nose, and throat), EXTR, NEUR abnormalities, with additional

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notations of “R eye medial gaze/poor tracking,” “strabismus6,” “↑ tone x 4 ext/feet + hands

clenched,” and “poor seated control/ ↓ upper body strength”. Id. Dr. Douglas referred A.S. to

ophthalmology and neurology for additional evaluation. A.S. received the DtaP, IPV, Hib, Hep.

B, Prevnar, and RotaTeq vaccinations during this visit. Id. at 4, 15.

B. Post-Vaccination History

On June 19, 2012, Mrs. Svagdis called Preston Ridge Pediatric Associates. Ex. 8 at 3. The

note states “parents went home and researched on internet and up all night processing.” Id.

Although they had an appointment at 9:00 that morning with Dr. Lipsky, Mrs. Svagdis indicated

she was unable to get an appointment with Dr. Schuls, a neurologist, until August. Id. The

transcriber noted “Mom requesting we call to get neurologist due to significant changes

developmentally/neuro since 4 mo. will call [illegible] to attempt help with scheduling.” Id.

On the same day, A.S. visited Dr. Steven Lipsky, an ophthalmologist, at the Thomas Eye

Group. Ex. 8 at 17. Dr. Lipsky noted that A.S. “does not fix and follow well, but when she is

attentive, she does follow.” Id. Dr. Lipsky noted that A.S.’s eyes have crossed since birth. Id. Dr.

Lipsky opined that he felt that “her developmental status is way behind and her vision may very

well be appropriate for her developmental state.” Id.

On June 20, 2012, A.S. visited Dr. Raymond Cheng, a neurologist at Child Neurology

Associates, P.C. Ex. 3 at 1-2. Dr. Cheng stated A.S. presented with crossed eyes, lethargy, and

stiffness. Id. at 1. Mrs. Svagdis informed Dr. Cheng that A.S. “always has both hands fisted,” and

“is always very stiff”. Id. Dr. Cheng also noted that in the past few weeks, there has been a

progressive worsening of the tendency to “zone out” and poor eye contact with parents when they

are talking to A.S. Id. Petitioners also informed Dr. Cheng that A.S. had poor head control,

especially when she was younger. Petitioners were also concerned “about failure to thrive because

of dropping off the growth scale.” Id. Dr. Cheng’s neurological exam found:

Bilateral poor eye contact. I was not able to get her attention and to engage. There

is a persistent prominent ATNR (asymmetrical tonic neck reflex) response with

fencing posturing. Cranial nerves show response to light, but no clear-cut focusing

on face. Gag is intact. Face is symmetric. Motor examination shows diffusely

increased tone in all four extremities with poor head control for her age. There is

also bilateral scissoring when suspended vertically. The sensory exam is intact to

pin and touch. Reflexes are also very brisk in all four extremities with upward going

toes bilaterally. She was not able to really voluntarily reach for objects.

Id. at 2. Dr. Cheng’s impression was that A.S. had “1. Spastic quadriplegia. 2. Suspected

seizures/encephalopathy. 3. Global developmental delay. 4. Failure to thrive. 5. Question of

possible etiology related to herpes. Id. Dr. Cheng directed A.S. to the emergency room to start an

evaluation. Id.

6

Strabismus is “an eye condition in which the visual axes cannot be directed at the same point of fixation

under normal conditions of seeing.” Dorland's Illustrated Medical Dictionary, (33 ed. 2019):

https://www.dorlandsonline.com/dorland/definition?id= 47369 (hereinafter “Dorland’s”).

4

On the same day, A.S. went to the Children’s Healthcare of Atlanta (CHOA) – Scottish

Rite emergency room and was seen by Dr. Gregory Melnikoff. Ex. 11 at 2184. The History of

Present Illness (HPI) section noted that

Infant has been making unusual movements since birth including staring off into

space, turning head to side and rigid extension of one arm, lasting approx. 20

seconds. Child has had problems with feeding since birth which has worsened over

the last month. Child has only gained 4 ounces in the last month.

Id. at 2184-85. All review of systems were negative. Id. at 2185. A.S. was to undergo an EEG,

MRI, labs, and subspecialty consultations. Id. at 2186.

The EEG performed on June 20, 2012 was “a normal awake and sleep EEG for age.” Ex.

11 at 2280. The history taken at the time of the EEG noted that A.S. had been tracking up until

five months of age and then began focusing less. Id. Her feedings had always been slow, “but over

the past month, patient feedings have markedly decreased.” Id.

Also on June 20, 2012, A.S. visited Dr. Barbara Bruce, a neurologist. Ex. 11 at 2192. Dr.

Bruce noted that A.S.’s active problems included abnormal eye movements, abnormal involuntary

movements, feeding difficulty in infant. Consultation requested by Dr. Rowe for evaluation of

developmental regression, possible seizures, and failure to thrive.” Id. (emphasis in original).

The HPI provided additional details concerning A.S.’s development:

It appears some concerns were raised ~2 months ago … pediatrician noted

increased tone. Patient tends to keep arms flexed and hands in clenched positions

(this has been going on for some time according to pictures mom has taken in the

past). At 5 months patient began focusing on mom’s face less. Patient has always

had difficulty supporting self when parent is holding her on hip. Head control was

better previously although it appears patient never had complete control. Three days

ago, patient had 6 month vaccinations. Mom has noticed a significant regression in

milestones since that time. Patient will not even focus on mom, her cooing has

decreased as has her appetite (previously taking 3-4 ounces per meal and now

taking < 2 ounces)… Patient is also more somnolent. Additionally patient has been

experiencing paroxysmal events concerning for seizures. Patient will grimace and

move her head/neck quickly back and forth. Patient also experiences episodes

where she chews her tongue repetitively.

Id. at 2192-93. Dr. Bruce’s impressions were that A.S. may have a metabolic/mitochondrial

disorder, neurodegenerative disorder, and leukodystrophy. Id. at 2196.

On June 22, 2012, A.S. visited Dr. Willian Meyers, a gastroenterologist, for a consultation.

Ex. 11 at 2186-87; 2188-92. Dr. Meyers noted, “No overt symptoms of reflex and normal anatomy

on UGI today. Suspect feeding decline is a component of a yet to be diagnosed neurological,

seizure, or metabolic disorder. Patient is at nutritional risk and may require long-term enteral

access to meet her nutritional needs.” Id. at 2186-87. A.S. was to be fed through a NG (nasogastric)

5

tube eight times per day. Id. at 2187. The video EEG performed on June 22-23, 2012 was normal.

Id. at 2315. A.S. was discharged on June 26, 2012. Id. at 2173.

On June 29, 2012, A.S. was seen at by Dr. Bob Bagheri at Lakeside Pediatrics for

“develop[mental] regression, hypertonia, bilat[eral] eye deviation, feeding prob. Esotropia.”7 Ex.

13 at 1, 5.

On July 9, 2012, A.S. visited Dr. Vaishali Kute at Chattahoochee Pediatrics with a chief

complaint of “developmental regression post vaccines”. Ex. 12 at 11. It was noted that A.S. had

been admitted to the hospital for:

possible seizures, pretty much non-responsive to any stimulation. Severe

developmental regression. Had routine vaccines 2d before. Got NG tube 6/22/2012.

Waiting on genetics tests results. She has made a lot of developmental progress

since the hospitalization, but not 100%. She is now in ST and PT…. Congestion

since birth. Would like ENT referral. Questions about GERD, she does not spit up,

but she is on Zantac. Occasionally stomach acid will float up into her NG tube….

Eyes were crossing before the vaccines at 6mo WC.

Id. Dr. Kute’s plan was “[a]wait report on labs ordered by geneticist. Continue PT, ST. Continue

tube feeds, F/U with GI, neurology, genetics.” Id. at 12.

On July 23, 2012, A.S. visited Dr. Kute for a weight recheck. Ex. 12 at 11. Dr. Kute noted

that A.S. was having diarrhea multiple times per day that seems to have been resolved. Id. Dr.

Kute’s assessment was that A.S. has good weight gain and she was to continue her current feeding

plan. Id.

On August 15, 2012, A.S. visited Dr. Kute for another weight recheck. Ex. 12 at 10. A.S.

had continued feeding difficulties and had thrown up the morning of the appointment. Id. A.S. was

to continue her current feeding plan and to follow up with “GI and genetics.” Id.

On August 30, 2012, A.S. returned to Dr. Kute complaining of lactose intolerance. Ex. 12

at 9. Mrs. Svagdis reported that A.S. threw up after consuming yogurt and tried soy but continued

to throw up. Id. Mrs. Svagdis also reported that A.S.’s bowel movements looked like tomato paste

but when A.S. was switched to Goodstart, she threw up twice but had normal bowel movements.

Id. Dr. Kute’s assessment was, “GER [gastroesophageal reflux], good weight gain.” Id.

On September 5, 2012, A.S. visited Dr. Kute for ear pulling and a cough. Id. at 8. Dr. Kute

diagnosed A.S. as having an upper respiratory infection. Id. at 9.

On September 17, 2012, A.S. had a routine infant/child health check with Dr. Kute. Ex. 12

at 7-8. Dr. Kute noted that A.S. had gained enough weight such that her parents were trying to

7

Esotropia is “strabismus in which there is manifest deviation of the visual axis of an eye toward that of

the other eye, resulting in diplopia.” Dorland’s. https://www.dorlandsonline.com/dorland/definition?id=

17375.

6

wean her off the feeding tube but A.S. was not tolerating solids well. Id. at 7. The records indicate

that A.S. had more energy when she ate less. Id.

On October 9, 2012, A.S. visited Dr. Meyers for feeding concerns. Ex. 11 at 1582-84.

Petitioners reported they were able to feed A.S. approximately six ounces with a NG tube

consistently, but A.S. would pull at the tube, making feeding more difficult. Id. at 1583. Petitioners

requested a gastrostomy tube (“G-tube”) for more stable feeding. Id. Dr. Julie Glasson placed a

gastrostomy tube on the same day. Id. at 1585-86.

On October 30, 2012, GeneDx analyzed A.S.’s buccal swab sample and prepared a genetic

testing report. Ex 7 at 1-2. The testing revealed that A.S. had a NDUFA1 variant. Id. at 1. The

report noted that “the clinical significance of this variant is unknown, although it is a strong

candidate for a disease-causing mutation.” Id.

On November 9, 2012, A.S. visited Dr. Bruce for possible seizures. Ex. 11 at 1235-37. The

record noted that she is “currently having episodes where she has decreased responsiveness and

after which it may take [A.S.] several minutes to “come to.” She is also having episodes of sudden

jerking of her arms and occasional head drop.” Id. at 1235. A.S. was admitted for observation and

an EEG. Id. at 1237. An EEG performed on the same day revealed “independent left and right

occipital sharp waves. The discharges from the left occurred more frequently than the right…. This

record was moderately abnormal given the presence of spikes from the bilateral occipital region.”

Id. at 1241-42.

On November 15, 2012, A.S. saw Dr. Fran Kendall of Virtual Medical Practice, LLC, with

a chief complaint of a neurodegenerative course with loss of skills and onset of seizures, along

with feeding issues. Ex. 10 at 6-9. Dr. Kendall specializes in metabolic, mitochondrial, and

inherited genetics. Dr. Kendall “expressed considerable concern for the possibility of a Leigh

disease picture.” Id. at 8. Dr. Kendall recommended a follow-up in three months and asked that

she be given access to the results of A.S.’s genetic testing. Id. at 8-9.

On December 12, 2012, A.S. underwent an EEG. Ex. 11 at 1115-16. The impression by

the interpreting physician, Dr. Bryan Philbrook, was that this was “markedly abnormal” due to “1)

a poorly developed background for chronological age; consistent with a diffuse encephalopathy.

2) Frequent posterior spikes and slow waves bilaterally. This record was consistent with

localization related epilepsy and supports abnormalities in the posterior head regions.” Id. at 1116.

On December 18, 2012, A.S. had an MRI, which was normal. Ex. 11 at 255.

On January 3, 2013, A.S. traveled to the Cleveland Clinic Neurological Institute Epilepsy

Center and was admitted for observation. Ex. 5 at 9. Her history was taken by Dr. Julie Cernanec

and detailed as:

[A.S.] presents with developmental regression and drop attacks. Patient was born

full term with no complications and has been developing normally until 6 months

of age when she started having sudden regression of milestones after receiving her

6 month shots. No previous adverse reactions from 2 month or 4 month shots were

7

noted. According to parents, within a few hours after receiving her 6 month[] shots,

patient developed episodes of “stiffening” of both arms and legs; and was unable

to roll and babble as she was previously able to do. She also had trouble with

feeding, and per mom became as if she was a “newborn” again. They also noted

that at this time, her eyes [were] crossing and so patient was seen by ophthalmology

and neurology in Atlanta…. EEG and MRI brain also done which was allegedly

normal…. She continued to have poor feeding and was NG fed for several months.

She developed failure to thrive and G-tube was placed last October.

In November, patient was noted to have episode of flexed posturing of the arms

with blank gaze – EEG done which showed “optical seizures” and patient was

started on trileptal. She did not improve on trileptal and in mid-December started

having drop attacks. Parent provided a video which showed sudden flexed

posturing of whole body. These episodes would occur around 4-5x a day usually in

clusters and worse when waking up in the morning…. She is now having increasing

frequency of drop attacks which prompted parents to get a second opinion at CCF

[Cleveland Clinic Foundation].

Id. at 9. Dr. Cernanec suspected West syndrome, Lennox-Gastaut, or another neurometabolic

disorder. Id. at 12.

A.S. visited Dr. Elaine Wyllie who performed a video EEG. Id. at 18. She noted a modified

hypsarrhythmia pattern with multiregional and generalized sharp waves and generalized

continuous slows. Id. at 20. During A.S.’s sleep, her EEG was discontinuous and several clusters

of epileptic spasms were recorded. Id. There were also two instances of hypomotor seizures with

arrest activity and eye deviation to the left. Id.

During her stay at the Cleveland Clinic, A.S. was also seen by Dr. Timothy Moss on

January 4, 2013 for a medical genetics consult. Ex. 5 at 21. Dr. Moss informed Mr. Svagdis that

“given the diagnosis of hypsarrhythmia, the number of potential causal genes is dramatically

reduced, but still over 20. With that finding, more unlikely to be metabolic in nature, and the few

metabolic causes have already been somewhat screened for.” Id. Dr. Moss believed Rett and Rett-

like syndromes were likely given A.S.’s regression but indicated the whole exome sequencing

performed by GeneDx would have found something. Id. Dr. Moss encouraged Mr. Svagdis to

communicate the hypsarrhythmia diagnosis to GeneDx for further analysis. Id.

Dr. Wyllie assessed A.S. again on January 5, 2013. Ex. 5 at 25-26. Dr. Wyllie discussed

various treatment options with Petitioners, who chose to try Topamax for A.S.’s epilepsy. Id. at

25.

A.S. was discharged from the Cleveland Clinic on January 6, 2013 with instructions to

consult with genetics, epilepsy, and neurology experts. Ex. 5 at 33.

On January 7, 2013, A.S. visited Dr. Robert Flamini at the Atlanta Headache Specialists &

PANDA Neurology for a consultation. Ex. 2 at 26-29. Dr. Flamini’s assessment noted infantile

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spasms and developmental regression, “likely manifestation of severe underlying process yet to be

labeled.” Id. at 28.

On January 17, 2013, A.S. returned to CHOA for a “seizure disorder.” Ex. 11 at 943-52.

The medical records indicate that “Parents have not witnessed any clinical spasms for ‘a while’,

but ha[ve] been noticing child ‘crying out’ which she previously would do prior to her clinical

spasms. Continues on G-tube feeds and tolerating. No other concerns at present.” Id. at 947.

Another EEG was performed. Id. at 957. The impression from the EEG suggested global cortical

dysfunction, consistent with a diffuse encephalopathy. Id.

On January 22, 2013, A.S. returned to Dr. Flamini for a follow-up visit. Ex. 2 at 22-25.

The HPI noted that A.S. was starting to interact more with her parents and would sometimes reach

and grab things. Id. at 22. A.S. was to continue her current medication and therapy and was

recommended to undergo a longer EEG in the future. Id. at 24.

On February 11, 2013, A.S. and her parents had a genetic consultation with Dr. Vidya

Krishnamurthy, who diagnosed A.S. with a mitochondrial metabolism disorder. Ex. 7 at 60-61.

Dr. Krishnamurthy informed Petitioners that a variant of the NDUFA1 gene could cause a complex

1 deficiency and recommended Mrs. Svagdis get genetic testing done, as the gene was on the X

chromosome. Id. at 60. The records indicate that a buccal swab was done with Dr. Goldenthal

which revealed a complex IV deficiency but required retesting. Id.

On February 26, 2013, A.S returned to Dr. Flamini for a follow-up. Ex. 2 at 19-21. A.S.

was no longer experiencing spasms or hypsarrhythmia. Petitioners informed Dr. Flamini that A.S.

continued to stare off several times per day but had been more attentive to noises and changes. Id.

at 19.

On March 6, 2013, A.S. returned to Dr. Kendall for a follow-up appointment. Ex. 10 at 2-

5. Dr. Kendall discussed A.S.’s genetic testing results with Petitioners, and informed them that

while she believed A.S. had mitochondrial disease, she could not “classify her as a Leigh disease

patient given her brain MRI findings although she is very Leigh-like in regards to her significant

encephalomyopathic findings.” Id. at 4. Dr. Kendall recommended that A.S. undergo another

swallow study and undergo additional seizure disorder testing. Id.

On April 3, 2013, A.S. underwent a video EEG at PANDA Neurology. Ex. 2 at 36. The

study was abnormal due to “the presence of a persistent area of focal abnormality over the left

posterior quadrant. There are no clear epileptiform components associated with it.” Id.

On April 23, 2013, A.S. returned to PANDA Neurology for a follow-up. Ex. 2 at 16-18.

Dr. Flamini noted that Dr. Kendall diagnosed A.S. with a mitochondrial disorder. Id. at 16. A.S.

was to continue her topiramate medication and therapy. Id. at 18.

On August 2, 2013, A.S. returned to Dr. Flamini for a follow-up. Ex. 2 at 13-15. Dr. Flamini

noted no further regression and slow progression. Id. at 16. A.S. was able to hit toys and touch

objects on command and was able to roll, but was still unable to sit independently. Id.

9

On August 8, 2013, A.S. underwent another EEG at PANDA Neurology. Ex. 2 at 35. The

EEG was abnormal due to “poorly developed background for chronological age with diffuse

slowing. However, interpretation is limited by continuous myogenic artifact.” Id.

On August 21, 2013, A.S. returned to the Cleveland Clinic to see Dr. Parikh. Ex. 5 at 190-

95. Dr. Parikh’s impression noted that A.S. worsened on Trileptal but improved on TPM, which

raised questions concerning an underlying sodium channelopathy. Dr. Parikh also suggested A.S.

may have an underlying mitochondrial disorder because of A.S’s slight elevation in lactate levels.

Id. Dr. Parikh stated he could not exclude an inflammatory etiology or an underlying onset

epileptic encephalopathy condition. Id. He recommended additional genetic testing. Id. at 195.

On November 4, 2013, A.S. saw Dr. Flamini for a follow-up. Ex. 2 at 10-12. A.S. was able

to sit by herself with no support for up to a minute and was able to bring food to her mouth. Id. at

10.

On November 14, 2013, A.S. underwent a 24-hour ambulatory EEG at PANDA Neurology.

Ex. 2 at 34. The EEG recorded interictal abnormalities including diffusion background slowing

and a “single well-delineated right frontotemporal (F8/T4) spike and slow wave.” Id. Dr. Flamini

noted that clinical and neuroimaging correlation was necessary. Id.

On February 5, 2014, A.S. returned to see Dr. Flamini for a follow-up appointment. Ex. 2

at 7-9. Dr. Flamini noted that the potential mitochondrial disorder had no confirmatory findings.

Id. at 7. A.S. was able to use her hands and had been tested for Retts and atypical Retts. Id. A.S.

also had normal MTHF (5-Methyltetrahydrofolate) in her CSF. Id. He also noted that A.S. had not

experienced any clinical seizures since January 2013. Id.

On April 30, 2014, A.S. returned to the Cleveland Clinic to see Dr. Parikh. Ex. 5 at 217-

20, 236. Exome genetic testing performed at the prior visit revealed “no disease-causing mutation.”

Id. at 218. The records indicate that A.S. was clinically stable and that her general health was good.

Id. at 219.

On May 14, 2014, A.S. returned to Dr. Flamini. Ex. 2 at 4-6. Dr. Flamini noted A.S was

making progress: she was able to grab objects, play more, maintained better eye contact, and could

sit by herself. Id. at 4. The underlying diagnosis was still unknown however a genetic disorder was

still being considered. Id.

On June 5, 2014, A.S. visited Shriners Hospitals for Children for right hip dysplasia. Ex. 6

at 1-5. A.S. had rolled off a bed and onto the floor and was uncontrollably crying the next day.

On August 14, 2014, A.S. had a follow-up appointment with Dr. Flamini. Ex. 2 at 1-3. The

HPI noted:

[A.S.] returns in f/u today with remote h/o infantile spasms controlled for the last

20 months, appearing at age 11m and present for only one month which responded

to Topamax. The etiology is still unclear, has seen several physicians and has been

seen for an opinion at the Cleveland Clinic Dr. Parik [sic], who did not consider[]

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her to have a mitochondrial d/o and did not feel the NDUFA gene [] is responsible

[either]…. She continues to make slow developmental gains tested at ~10 months

overall. Makes noises, still won’t swallow and is tube fed. Motor skills including

sitting independently with lateral protective reflects, not up on all 4’s. Grabbing

things quicker PT OT ST and Vision therapy as well as massage therapy.

Id. at 1. A.S. was to continue medication and therapy. Id. at 3.

III. Petitioners’ Affidavits and Testimony

A. Affidavits of Jeremy and Kimberly Svagdis

The affidavits filed by both Petitioners are identical and will be summarized as one. Exs.

1, 14. A.S. received her vaccinations at the Forsyth County Health Department on June 18, 2012.

Id. at 1. According to Petitioners, the same day, A.S. became stiff and unresponsive to stimuli, and

was completely “out of it.” Id. Mrs. Svagdis called A.S.’s pediatrician and left a message to report

these symptoms on June 19, 2012. Id. at 2. A.S. visited Dr. Raymond Cheng on June 20, 2012 who

diagnosed her with “spastic quadriplegia and suspected seizures and encephalopathy, among other

things” and referred A.S. to Children’s Healthcare of Atlanta – Scottish Rite for further work up.

Id.

At CHOA, testing was inconclusive and A.S. was discharged on June 26, 2012 with a

working diagnosis of “abnormal eye movements, abnormal involuntary movements, and feeding

difficulty.” Exs. 1, 14 at 2-3. A.S. was then placed on a G-tube on October 9, 2012. Id. at 3. On

January 9, 2013, Petitioners took A.S. to the Cleveland Clinic for an evaluation of her neurologic

function and overall functional decline. Id. A.S. had medically refractory seizures since seven

months of age with epileptic spasms beginning in December 2012, and was ultimately diagnosed

as having infantile spasms and developmental regression. Id.

A.S. returned to the Cleveland Clinic on August 21, 2013 and visited Dr. Sumit Parikh.

Exs. 1, 14 at 3. Dr. Parikh was “unable to exclude an inflammatory etiology as a cause of her

symptoms” and the “onset of epilepsy shortly thereafter raises question of an underlying infantile

onset epileptic encephalopathy condition as well.” Id. at 3-4. According to Petitioners, there were

concerns of a mitochondrial disorder that have since been ruled out by her current treating

physicians. Id. at 4.

B. Testimony

1. Kimberly Svagdis

Mrs. Svagdis testified that she was a stay-at-home mother with A.S., and her one-year-old

sister, M.S. Tr. at 6-7. A.S. was seven years old at the time of the entitlement hearing but has

remained developmentally at around the age of six to ten months. Id. at 8. A.S. requires 24-hour

care, wheelchair assistance, and still feeds via feeding tube. Id. A.S. goes to school but has a one-

on-one nurse to take care of her needs. Id. at 11.

11

A.S. continues to see many doctors and goes to physical therapy twice per week. Tr. at 13-

14. A.S. continues to have absence seizures, where she will get quiet and stare off into the distance,

and not move. Id. at 18. Mrs. Svagdis stated these seizures occur every night and sometimes during

the day. Id. at 19-20. A.S. has been on a number of anti-seizure medications in the past but is now

only on Fycompa. Id. at 18, 20.

A.S. received her six-month vaccinations at the Forsyth Community Health Center because

Mr. Svagdis was self-employed at the time and thus the family had no health insurance. Tr. at 23.

Prior to her vaccinations, A.S. had her six-month well child visit with Dr. Elinor Douglas. Id. at

25. Mrs. Svagdis informed Dr. Douglas that A.S. crossed her eyes, but Mrs. Svagdis also had a

crossed eye so she wasn’t concerned. Id. Mrs. Svagdis also clarified that A.S. had consistently

been able to roll over, and has video of A.S. rolling over, although it was noted as inconsistent in

the medical records. Id. at 27. Mrs. Svagdis remembered leaving the six-month appointment

confused because A.S. was referred to see an ophthalmologist and neurologist. Id. at 31. As a

result, Mrs. Svagdis did some research online because she noticed A.S. was clenching more,

continued to have feeding problems, and have more severe eye crossing. She decided to call back

the following morning to get clarification and “get this going.” Id. at 34.

Between June 18, 2012 and June 20, 2012, Mrs. Svagdis noticed that A.S. was less

engaging and would become really quiet. Tr. at 40. Mrs. Svagdis stated that on June 19, 2012, she

continued to worry about A.S. and search online but was able to schedule an appointment with Dr.

Cheng the next day with help from Dr. Douglas’s office. Id. at 37-38. Mrs. Svagdis remembered

that during the appointment with Dr. Cheng, he “pointed out the hospital across the street and told

us to go there,” so they went to the Children’s Hospital of Atlanta ER. Id. at 39, 41. A.S. was

immediately given an EEG and was admitted to the hospital for the next six days. Id. Mrs. Svagdis

testified that prior to June 18, 2012, A.S. never had issues with tracking objects and that she had

not heard of the terms “spastic quadriplegia” or “suspected seizures, encephalopathy,” or that A.S.

was developmentally delayed. Id. at 44-46. Mrs. Svagdis stated that A.S.’s current issues include

global developmental delays, strabismus, mitochondrial disease/dysfunction (which some doctors

have diagnosed her with and some haven’t), epilepsy, feeding difficulties, incontinence, and hip

dysplasia. Id. at 67-68.

2. Jeremy Svagdis

Mr. Svagdis works as a telecom project manager, which involves upgrading cell phone

towers. Tr. at 71. Mr. Svagdis testified that he was the secondary caregiver to A.S. He testified

that Mrs. Svagdis stayed home to take care of A.S. and M.S. but he attempted to go to doctor

appointments with A.S. Id. at 71-72. Mr. Svagdis testified that he did not remember attending the

April 17th wellness visit but did attend the June 18th appointment. Id. at 72-73. Mr. Svagdis recalled

becoming concerned because A.S. repeatedly shook her head back and forth horizontally on June

19, 2012. Id. at 76-77. Mr. Svagdis further testified that the head shaking occurred prior to the visit

with Dr. Lipsky on June 19, 2012 and that the appointment was not significant. Id. at 77-78.

However, the appointment with Dr. Cheng, the following day was significant because Dr. Cheng

instructed them to go to the hospital across the street. Id. at 79. Mr. Svagdis testified there was a

rapid decline in A.S. between June 18, 2012 and June 26, 2012, which included the head shaking,

lack of eye contact and interaction. Id. at 81-82, 84.

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IV. Expert Opinions and Qualifications

A. Petitioners’ Expert: Dr. Marcel Kinsbourne

1. Qualifications

Dr. Kinsbourne received his medical degree from Oxford University in 1955. Ex. 18 at 1

(hereinafter “Kinsbourne CV”). Dr. Kinsbourne completed post-doctoral training in neurology and

pediatrics and is board certified in pediatrics. Kinsbourne CV at 1. Dr. Kinsbourne has held a

number of hospital and academic appointments. Id. at 2. He serves on numerous editorial boards,

including Brain Research, Cognitive Neuropsychiatry, Journal of Psycholinguistic Research, and

many others. Id. at 5. Dr. Kinsbourne is also part of a number of professional societies. Id. at 5-6.

Dr. Kinsbourne has published over 400 articles and books regarding pediatrics and neurology. See

id. at 7-40. Dr. Kinsbourne has not seen patients in approximately 30 years. See Berg v. Sec’y

Health & Hum. Servs., No. 16-650V, 2021 WL 6883495 (Fed. Cl. Spec. Mstr. Dec. 14, 2021)

(discussing Dr. Kinsbourne’s qualifications); Ellis v. Sec’y of Health & Hum. Servs., No. 13-336V,

2018 WL 4846547, at *25 (Fed. Cl. Spec. Mstr. Sept. 6, 2018) (same).

2. Expert Report

Dr. Kinsbourne relied on Dr. Boles’ expertise as a geneticist and mitochondrial specialist

as well as his expert report (Ex. 30) highlighting A.S.’s illness as consistent with a mitochondrial

disorder. Ex. 17 at 4 (hereinafter “First Kinsboune Rep.”). Dr. Kinsbourne based his report on the

“neurological implication of the diagnosis of a mitochondrial disorder as they apply in the case of

[A.S.].” Id. Dr. Kinsbourne also admitted that A.S. has never been given a definitive diagnosis by

treating physicians though a mitochondrial disorder has been suggested numerous times. See id.

Regarding his proposed mechanism, Dr. Kinsbourne stated “Infections and vaccinations

can trigger the production of proinflammatory cytokines such as TNF-alpha, IL-6 and IL-1 beta.

These agents in turn can cause the synthesis of reactive oxygen species (ROS) and thereby generate

oxidative stress.” Id. at 5. Oxidative stress can impair the role of mitochondria in energy

production, and can cause cell damage and cell death. Id. Dr. Kinsbourne stated “the acellular

pertussis vaccine and other vaccines activate the Toll-like receptors of the innate immune system,

leading to the release of proinflammatory cytokines.” He further stated that “the onset of [A.S.’s]

epileptic encephalopathy was abrupt, within hours of her vaccinations.” Id. at 6 Such brief intervals

are typical for pertussis vaccine encephalopathies. Thus, the onset of [A.S.]’s encephalopathy

occurred within a medically reasonable temporal interval after the vaccinations.” Id.

3. Testimony

Dr. Kinsbourne provided testimony on September 5, 2019. I recognized Dr. Kinsbourne as

an expert in neurology. Tr. at 160. He stated that his opinion does not necessarily rely on the

presence of mitochondrial dysfunction in A.S. but that the vaccinations A.S. received on June 18,

2012 triggered a “very abrupt, unexpected regression of function in A.S.” Id. at 161. Dr.

13

Kinsbourne deferred to Dr. Boles regarding whether mitochondrial dysfunction played a role in

A.S.’s condition. Id. at 162.

Dr. Kinsbourne testified that there was no evidence of epilepsy at the onset of the vaccine

injury but brain damage did occur which resulted in the later onset of infantile spams and seizures.

Tr. at 163. On the day of A.S.’s vaccinations, it was documented that A.S. required assistance to

sit up and was not consistently rolling over. Id. at 170; Ex. 8 at 4. Dr. Kinsbourne stated that this

indicated that “something is going wrong neurologically” and that per Dr. Boles’ mitochondrial

dysfunction theory, “the mitochondria are showing signs of splaying.” He testified that this shows

the vaccinations significantly aggravated a pre-existing condition. Id. at 170.

Dr. Kinsbourne clarified that the vaccination “cause[d] a scenario which made infantile

spasms more likely to happen.”, specifically that neuro intra-brain damage or encephalopathy

occurred in June and that over the next few months, A.S. developed infantile spasms. Tr. at 175-

76. The fact that A.S. had spastic quadriplegia on June 20, 2012 when Dr. Cheng examined her is

evidence of acute brain injury. Id. at 176-77.

Dr. Kinsbourne also opined that if A.S. did not have a mitochondrial disorder, he still

believed the vaccinations could have caused her injury. Tr. at 187.

4. Post-Hearing Opinion

Dr. Kinsbourne filed a post-hearing statement (Ex. 59) (hereinafter “Second Kinsbourne

Rep.”) and a supplemental report (Ex. 64) (hereinafter “Third Kinsbourne Rep.”).

Dr. Kinsbourne’s post-hearing statement addressed A.S.’s MRI and EEGs and how they

did not reveal any acute changes post-vaccination. Dr. Kinsbourne stated that because A.S. had a

mitochondrial or metabolic encephalopathy, there was no structural damage, trauma, or anoxia

that would have appeared on A.S.’s brain imaging. Second Kinsbourne Rep. at 1. Cytokine

mediated dysfunction would not necessarily result in widespread death of neurons but instead a

“functional” decline, where affected neurons underperform. Id. According to Dr. Kinsbourne, it

would take a long time for neurons to deteriorate to the extent they become visible on an MRI, but

they could be visible on more sensitive neuroimaging such as proton magnetic spectroscopy

(MRS). Id. Dr. Kinsbourne added that diagnostic criteria for mitochondrial dysfunction do not

require an abnormal MRI but are based on metabolic, genetic and histological studies. Id.

Dr. Kinsbourne’s supplemental report rebutted Drs. McCandless and Wiznitzer’s

supplemental reports (Exs. R and S). Dr. Kinsbourne specifically disagreed with Dr. Wiznitzer’s

Gropman article, arguing severity of change observed on MRI in mitochondrial patients is not

reflected in clinical practice; patients with severe mitochondrial disorders may have completely

normal brain imaging. Third Kinsbourne Rep. at 1. Neuroimaging in children is also difficult to

read/define. Id. Dr. Kinsbourne cited to the Mitochondrial Medicine Society, which included the

following as diagnostic criteria: biochemical tests in blood, urine and spinal fluid; DNA testing,

pathology and biochemical testing of tissues, and neuroimaging. Id. at 2; citing Parikh et al.,

Diagnosis and management of mitochondrial disease: a consensus statement from the

Mitochondrial Medicine Society, 17 GENET MED. 9, 698-701 (2015) (filed as Ex. 61). On the

14

neuroimaging criteria, the MMS states that “Neuroimaging cannot by itself be the absolute

criterion for disease confirmation.” Id.

B. Petitioners’ Expert: Dr. Richard Boles

Dr. Boles provided one expert report in this case and testified at the entitlement hearing.

1. Qualifications

Dr. Boles received his medical degree from UCLA in 1987. Ex. 31 (Boles CV) at 1. At the

time of the entitlement hearing, Dr. Boles was board certified in clinical biochemical genetics but

had previously been board certified in pediatrics and clinical genetics. Tr. at 88-89. Dr. Boles

taught at the Keck School of Medicine at the University of Southern California from 1993-2014

in both clinical pediatrics and pediatrics. Boles CV at 2. Dr. Boles also serves as the Director of

Genetics Research, Director of CCS Metabolic and Mitochondrial Disease Center, and Director of

Newborn Screening Program at the Children’s Hospital Los Angeles Medical Genetics. Id. at 3.

Dr. Boles has actively participated in research in the last ten years and has two patents. Id. at 6-7.

Dr. Boles has published 74 peer-reviewed articles, seven book chapters, and has been invited to

lecture both nationally and internationally. See id. at 8-13, 20-21, 21-23. I recognized Dr. Boles as

an expert in genetics and mitochondrial medicine. Tr. at 97.

2. Expert Report

Dr. Boles provided a summary of mitochondrial dysfunction and his experience in the field.

Ex. 30 (hereinafter “Boles Rep.”) at 1-3. Dr. Boles also provided a medical summary of A.S.’s

health since birth. Id. at 3-8.

Dr. Boles asserted that A.S.’s physicians believe her developmental regression began after

June 18, 2012. Boles Rep. at 8. Dr. Boles did not cite to any specific records but stated there was

“excellent contemporaneous documentation” and that “substantial neurodevelopmental issues

were noted within hours of vaccination.” He further noted that “[A.S.] was recorded to have had

an acute loss of all milestones, going from an essentially-normal 6-month old infant to the

developmental status of a newborn.” Id.

Regarding A.S.’s underlying condition, Dr. Boles stated that “multiple aspects of [A.S.]’s

case are consistent with the presence of an underlying mitochondrial dysfunction.” Boles Rep at

8. These signs include: mild neurological findings noted on the day of the third set of vaccinations,

or a mild neurological disease preceded that vaccination; acute developmental regression; seizures,

infantile spasms, central hypotonia, spastic quadriplegia, and hip dysplasia; gastrointestinal

dysmobility; a negative family history of autosomal recessive diseases. Id. at 8-9.

Dr. Boles conceded that there is “no primary (exact, underlying) molecular (DNA-based)

diagnosis in [A.S.],” however “only 25-50% of patients with mitochondrial dysfunction receive an

exact molecular diagnosis.” Boles Rep at 11. Dr. Boles additionally stated that “the precise

mechanism of vaccine-associated injury in [A.S.] is not clear at the present time, but likely involves

immune-regulated processes,” and “the general model is that a small subset of children are

15

genetically susceptible.” Id. Finally, Dr. Boles concluded, “since [A.S.]’s developmental

regression occurred shortly following vaccination, causality between her disease and the

vaccination are highly likely… It is my opinion that, to a reasonable degree of probability, that a

large degree of [A.S.]’s disease is vaccine related.” Id.

3. Testimony

Dr. Boles provided testimony regarding the function of mitochondria in a cell, its

discovery, and its importance to research as mitochondrial dysfunction “underlies a very large

amount of disease”. Tr. at 97-98. Dr. Boles then discussed how he would diagnose mitochondrial

dysfunction in children. Id. at 99-101.

Signs of mitochondrial dysfunction as it relates to A.S. include global development delay,

epilepsy, loss of milestones or regression, and GI disease. Tr. at 101-02. A.S.’s need for a feeding

tube is another sign of mitochondrial dysfunction, as is obstipation, defined by Dr. Boles as bowels

that are not moving at all. Id. at 103.

Dr. Boles noted that A.S.’s plasma lactate was mildly elevated three times in June 2012.

Id. at 106. One elevated reading is normally not a concern however it is “consistent with

mitochondrial dysfunction and suggestive thereof, but not highly specific.” Id. at 108. The lactate

levels are a part of a “constellation” of symptoms that may not be highly specific but in

combination are “highly specific for mitochondrial dysfunction.” Id. at 109. So additional to the

lactate levels, A.S.’s pyruvate, succinate, citrate, and glutarate levels were mildly or extremely

elevated. Id. at 109-12. These compounds are involved in the Krebs cycle, which is an important

cycle in the center of metabolic pathways, and important to make energy in cells. Id. at 111.

Dr. Boles additionally identified citrate synthase as “a very good indicator of mitochondrial

dysfunction.” Tr. at 114. Specifically, Dr. Boles stated that A.S.’s citrate synthase levels were

340% above normal; when levels are elevated, a patient usually has mitochondrial dysfunction and

when it’s over 200%, it’s very highly indicative. Id.

Dr. Boles additionally stated that A.S. had a buccal swab test in 2012 which was abnormal,

and further demonstrated mitochondrial dysfunction. Tr. at 115-16. The buccal swab tested for

methyltetrahydrofolate, which is low in the case of mitochondrial dysfunction. Id. at 121. The

buccal swab testing confirmed Dr. Boles’ “clinical suspicion of mitochondrial dysfunction.” Id. at

120.

Dr. Boles also discussed his interpretation of the Haas article and how his understanding

of the “red flags” of a mitochondrial disorder differ from the views of Dr. McCandless. Tr. at 123.

Encephalopathy is one of the red flags. See Haas et al., Mitochondrial Disease: A Practical

Approach for Primary Care Physicians, PEDIATRICS, 1326-33 (2007) (filed as Ex. K, Tab 2)

(hereinafter “Haas”). Dr. Boles noted that “in my mind, [A.S.] has encephalopathy. There is

neurodegeneration. Again, this patient has neurodegeneration.” Id. Dr. Boles also stated that

another red flag is “severe dysmotility…and this patient has severe dysmotility.” Id. at 123-24.

Dr. Boles acknowledged that he could not definitely say that other red flags were present in A.S.’s

case, but “the question is, how many red flags do you happen to have before it’s suspicious for

16

mitochondrial dysfunction.” Id. at 124. Ultimately, Dr. Boles concluded that the constellation of

findings, including Krebs cycle intermediates, indicate A.S. has mitochondrial dysfunction “at

more than the 50% level.” Id. at 122, 124-25. A.S.’s previous differential diagnoses included

Kearns-Sayre syndrome and Leigh-like syndrome, both of which are mitochondrial diseases,

which are a subset of mitochondrial dysfunction. Id. at 127. In further support of his point, Dr.

Boles also noted that Dr. Kendall’s buccal swab studies were noted for signs of mito-proliferation

and complex IV deficiency, which is also consistent with mitochondrial dysfunction. Id. at 129-

30.

Regarding the NDUFA1 gene, Dr. Boles stated that at the time (2013) it was considered to

be related to disease, but over time it was discovered that the gene was too common and not disease

linked, so it would be interpreted as a benign variant today. Tr. at 131.

Dr. Boles also testified that it is unclear when A.S.’s mitochondrial dysfunction began,

stating that “it’s unclear to say whether [symptoms] were present between the four and six-month

visit and they developed at some point at that time or that they had just developed in the couple

hours or so since the vaccination.” Tr. at 137. He further testified, “What we do know is that at

four months, she had a normal evaluation, and at six months, she had a mildly abnormal

evaluation.” Id.

C. Petitioners’ Expert: Dr. M. Eric Gershwin

Dr. Gershwin provided one expert report in this case (Ex. 37, hereinafter “Gershwin Rep.”)

and also testified during the entitlement hearing.

1. Qualifications

Dr. Gershwin received his medical degree from Stanford University in 1971 and is board

certified in internal medicine, rheumatology, and allergy and clinical immunology. Ex. 38

(Gershwin CV) at 1-2. He is currently the Jack and Donald Chia Professor of Medicine and a

Distinguished Professor of Medicine the University of California, Davis. Id. at 2. Dr. Gershwin

has won numerous awards including a Doctor of Philosophy Honoris Causa from the University

of Athens, for his contribution in immunology and medicine, and is the Professor Henry N. Neufeld

Memorial Award from the United States-Israel Binational Science Foundation in 2014. Id. at 1.

Dr. Gershwin has ten patents and serves as the editor-in-chief for Clinical Reviews in Allergy,

Reviews in Autoimmunity, Autoimmunity Reviews, and Journal of Autoimmunity, as well as an

ad hoc editor for numerous other publications. See id. at 5-7. Dr. Gershwin has published more

than 900 papers, 162 book chapters, and 69 books/monographs. See id. at 8-12, 13-91, 92-106.

2. Expert Report

Dr. Gershwin stated that his medical opinion was based on the assumption that A.S.

suffered from a genetic mitochondrial defect, because he agreed with Dr. McCusker “that under

normal circumstances there would not be expected to be an abnormal increase of cytokines

following vaccination.” Ex. 37 at 2 (hereinafter “Gershwin Rep.”). Because of A.S.’s genetic

mitochondrial defect, “[A.S.] would be more susceptible to cytokine production than a normal

17

child who does not have mitochondrial dysfunction.” Id. Because of mitochondrial dysfunction,

there are changes in ATP production, reactive oxygen species, calcium dysregulation, and

mitochondrial DNA damage that would make A.S.’s brain more susceptible to damage. Id.

3. Testimony

I recognized Dr. Gershwin as an expert in the field of immunology. Tr. at 199. Dr.

Gershwin testified that his opinion was “entirely dependent” on A.S. having a mitochondrial defect

or dysfunction. Tr. at 200-01. When a person is vaccinated, cytokines are produced as a part of the

innate immune response. Id. at 201. Cytokines can cross the blood-brain barrier (BBB) and some

are produced in the brain as well and will result in oxidative stress. Id. at 202. Oxidative stress is

a “noxious type of stimulation,” that “could be as simple as eating too much fat in your diet. It

releases … super-ions that punch holes in cells.” Id. Cytokines interact with mitochondria in an

inflammatory environment. Id. Mitochondrial DNA is susceptible to oxidative stress which creates

DAMPS (danger associated molecular patterns), which lead to cell death through apoptosis or

autophagy. Id. at 203. Specifically, “[w]hen the mitochondrial DNA is stressed, it’s not healthy

for cells and the cells will die or they don’t produce as much energy and that makes the cell

dysfunctional… and the lower the amount of energy, the more dysfunctional it becomes.” Id. at

204.

Dr. Gershwin stated that there were approximately 18 different antigens within the vaccines

that A.S. received. Tr. at 205-06. Those antigens released cytokines relatively quickly because she

had received two sets of vaccinations prior to her six-month vaccinations. Id. at 206. Dr. Gershwin

added that “her mitochondria are considered like a sponge [which] is abnormal. The sponge will

bend and flex and stress the mitochondrial DNA which is in it… that reduces the amount of viable

energy for that cell and the cell will be stressed and will die.” Id. Additionally, “the more times

you’re immunized, the higher the vaccine response will be.” Id. at 206-07. Dr. Gershwin testified

that interleukin-1 (IL-1) is a cytokine that is more likely to cross the BBB. Id. at 208.

Dr. Gershwin confirmed that he agreed “with virtually everything Dr. McCusker wrote in

her report” and that it was a very learned and scholarly report but they “differ about the target

organ[elle]”. Tr. at 214. Dr. Gershwin further testified that he believes A.S. had an anoxic injury

in the brain from the vaccinations. Id. at 216. A.S developed cytokines as any other normal person

or toddler would post-vaccination, it was her mitochondria that could not handle the cytokines the

same way a healthy person would. Id. at 218. As a result, A.S.’s mitochondria became more

dysfunctional and produced less energy affecting the neurological system. Id. Unlike other parts

of the body, the brain does not have the ability to repair itself. Id. at 218-19. This leads to a “vicious

cycle” of mitochondrial DNA becoming damaged and releasing DAMPs and cells dying. Id. at

219.

A.S. having developmental delay before her six-month vaccinations gave us a clue that

“something [was] wrong with her to begin with” and the vaccines were an accelerator, or a “trigger

to the falling off the cliff.” Tr. at 224. Inherent in Dr. Gershwin’s proposed mechanism is that A.S.

had developmental issues prior to the vaccines and the vaccines produced oxidants that affected

her mitochondrial DNA and worsened her underlying condition. Id. at 225.

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D. Respondent’s Expert: Dr. Max Wiznitzer

1. Qualifications

Dr. Wiznitzer received his medical degree from Northwestern University in 1977 and

completed a fellowship in developmental disorders and pediatric neurology. Ex. B (hereinafter

“Wiznitzer CV”) at 1. Dr. Wiznitzer is currently an associate professor of neurology, associate

professor of international health, and professor of pediatrics at Case Western Reserve University.

Wiznitzer CV at 2. Dr. Wiznitzer is board certified in neurology with special qualification in child

neurology, neurodevelopmental disabilities, and pediatrics. Id. at 5. Dr. Wiznitzer has written more

than 60 papers, 11 book chapters, and 55 abstracts. Id. at 13-24.

2. Expert Reports

Dr. Wiznitzer submitted four expert reports in this case. Ex. A (hereinafter “First Wiznitzer

Rep.”), Ex. I (hereinafter “Second Wiznitzer Rep.”), Ex. N (hereinafter “Third Wiznitzer Rep.”),

and Ex. R (hereinafter “Fourth Wiznitzer Rep.”). Dr. Wiznitzer opined that A.S.’s history of

difficulties with feeding and her neurological examination on June 18, 2012 were not subtle

neurological problems but were representative of A.S.’s change in neurologic function. First

Wiznitzer Rep. at 18. It is Dr. Witznitzer’s opinion that Mrs. Svagdis’ phone call to Dr. Douglas

on June 19, 2012 was to discuss the well-child visit the previous day because the notes do not

report change in mental status, nor do the ophthalmology visits on June 19, 2012 and the neurology

visit on June 20, 2012 with Dr. Cheng. Id. When A.S. was admitted to CHOA, the EEG was normal

and A.S. was awake and alert. Id. According to Dr. Wiznitzer, A.S. had no acute deterioration and

when A.S. was properly fed, she showed improvement. Id. at 19.

Dr. Wiznitzer stated that “Dr. Kinsbourne’s hypothesis of a cytokine related injury to the

brain due to the effect of cytokines on mitochondria has no biologic plausibility.” First Wiznitzer

Rep. at 19. Dr. Kinsbourne relied on one article (Ex. 22), which involved an in vitro model of

microglia activation by lipopolysaccharide (LPS – which was not present in the vaccines given to

A.S.). Furthermore, there is no evidence of cytokines crossing the BBB or that A.S. had any brain

injuries, demonstrated by the MRIs taken in 2012, or that A.S.’s microglia were activated. Id. Dr.

Wiznitzer also disagreed with Dr. Kinsbourne’s opinion that A.S. had epileptic encephalopathy

within hours of her June 18, 2012 vaccinations. Id. Dr. Wiznitzer stated that A.S. had no evidence

of any seizure activity until months after her allegedly causal vaccines and a video EEG performed

in June recorded paroxysmal events that were not epileptic in nature. Id. It is Dr. Wiznitzer’s

opinion that A.S. had a history of developmental regression that predated vaccination and did not

have an acute worsening after her June 18, 2012 vaccines.

In his second report, Dr. Wiznitzer refuted Dr. Gershwin’s medical literature and how it

related to A.S. in particular. See generally Second Wiznitzer Rep. Dr. Wiznitzer opined that Dr.

Gershwin’s conclusions are not supported by the contemporaneous medical records or his cited

medical literature. Id. at 3.

3. Testimony

19

I recognized Dr. Wiznitzer as an expert in pediatrics, pediatric neurology, and

neurodevelopmental disabilities. Tr. at 256. Dr. Wiznitzer testified that after listening to

Petitioners’ testimony, his opinion remained unchanged. Tr. at 258. He testified that A.S. had

significant neurologic dysfunction predating her June 18, 2012 vaccinations and she followed the

clinical course expected from her underlying neurologic condition. Tr. at 258. At A.S.’s four-

month wellness check, her parents reported difficulty feeding, which is a neurologic issue. A.S.

specifically had issues sucking and swallowing. Id. at 260. A.S. was also thrusting her tongue,

which indicated lack of coordination in oral motor movements. Id. at 261. A.S. showed ongoing

feeding problems. She was born in the 50th percentile for weight, dropped to the 10th percentile

around two-and-a-half months, and dropped to the 3rd percentile at six months of age. Id. at 264.

This indicated a long-standing issue with obtaining adequate calories to grow. Id. A.S.’s eye

crossing also demonstrated less brain control, since eye movement is controlled by the brain. Id.

at 265.

Dr. Wiznitzer also discussed A.S.’s lack of tone, inability to sit without support, and

feet/hand clenching as concerns. Id. at 267. On June 20, 2012, A.S. was noted to have spastic

quadriplegia, which is a form of increased tone. Dr. Wiznitzer testified that “[s]pasticity is never

an acute reaction to a brain stressor.” Id. at 267-68. He made this point by discussing adult stroke

patients, who initially have low tone in the affected body parts and then two weeks later present

with spasticity. Id. at 268.

Dr. Wiznitzer reviewed the medical records from A.S.’s visit with Dr. Cheng on June 20,

2012. Tr. at 273-79. A.S. had a persistent ATNR (asymmetric tonic neck reflex), which is present

in all children at birth until about four months of age. A child cannot develop good reaching or

grabbing until the ATNR disappears since it is an unvoluntary movement of the arm when one’s

head turns. Id. at 274. A child also cannot roll well with the ATNR intact. Id. Dr. Cheng also

documented that Petitioners reported A.S. had been zoning out more over the past few weeks; she

exhibited poor eye contact and poor head control. Id. at 275. Dr. Wiznitzer believed that Dr. Cheng

was concerned about a herpes infection, which is treatable if detected early, which led to Dr.

Cheng’s urgency in ensuring that A.S. receive treatment. Id. at 276. Dr. Wiznitzer also said he

believed herpes encephalopathy was unlikely because it would have occurred soon after birth and

“is never indolent. It’s very dramatic.” Id. at 277. Based on Dr. Cheng’s evaluation, his primary

concern seemed focused on A.S.’s failure to thrive and not on an acute encephalopathy. Id. at 279.

Regarding Petitioners’ statements about A.S. “falling off a cliff,” Dr. Wiznitzer believed

these are “inaccurate representations of her clinical history.” Tr. at 280. A.S. had a history of

feeding difficulties that gradually became more obvious; the feeding inefficiency became more

apparent as the bigger an infant grows, the more food she requires to continue growing. Id.

Although Petitioners have a video of A.S. from May 2012, based on the history Petitioners

provided to Drs. Douglas and Cheng, vision deterioration occurred soon after and prior to the June

18th vaccinations. Id. at 281. Dr. Wiznitzer also reiterated that spasticity occurs over a period of a

few weeks. Id. There were no fundamental differences between A.S. from when she was observed

by Dr. Douglas on June 18, 2012 and when she was seen by Dr. Cheng on June 20, 2012. Id.

Dr. Wiznitzer next reviewed the medical records from A.S.’s six day stay at CHOA. Tr. at

284-98. If Petitioners’ experts’ theory was accurate regarding mitochondrial dysfunction, there

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would be evidence of brain cell death, and A.S.’s EEG or MRI would have been abnormal. This

was not the case. Id. at 284-87. A.S.’s head circumference also had not changed in percentile for

the first three years of her life “to any appreciable degree”; thus according to Dr. Wiznitzer, A.S.

did not suffer from an acute injury to the brain related to the vaccines. Id. at 291. A.S. was recorded

as alert and active, not encephalopathic, at the CHOA Emergency Department. Id. at 293. When

A.S. was seen by Dr. Bruce, the medical records noted that around five months, A.S. had difficulty

focusing on Mrs. Svagdis’ face.

4. Post-Hearing Reports

Dr. Wiznitzer submitted two post-hearing expert reports. In his first post-hearing report, he

responded primarily to Dr. Kinsbourne’s conclusions as to why A.S.’s MRI scans were normal.

Third Wiznitzer Rep. at 1. Dr. Wiznitzer stated that Dr. Kinsbourne was “incorrect in his

differentiation between mitochondrial encephalopathy and anoxic encephalopathy.” Id. at 2. Dr.

Wiznitzer wrote that, while both types of encephalopathy have different triggering mechanisms,

“the end result is the same”, and they would therefore show the same result on an MRI. Id.

Dr. Wiznitzer also noted that A.S.’s MRI scans used newer modalities that are more

sensitive and able to identify the brain damage from mitochondrial disorders than routine T1 and

T2 imaging. Referencing the MRI report from June 21, 2012, he noted that it “would have

identif[ied] the alleged mitochondrial dysfunction if present.” Id. at 3.

Dr, Wiznitzer also disputed Dr. Kinsbourne’s characterization of A.S.’s EEG scans, noting

that, regardless of any seizures, if A.S. suffered from a mitochondrial or metabolic encephalopathy,

her EEG scans would have been abnormal. Id. at 3. As her scans were normal, Dr. Wiznitzer stated

that this is “consistent with the conclusion that [A.S.] did not have a mitochondrial or metabolic

encephalopathy as the reason for the claimed clinical state change….” Id.

In his second post-hearing expert report, Dr. Wiznitzer commented that in his February 12,

2020 expert report, Dr. Kinsbourne “ignore[ed] the objective findings in the records that A.S. had

no clinical evidence of encephalopathy as shown on examination and on EEG at the time of her

June 20, 2012 hospital admission.” Fourth Wiznitzer Rep. at 2. Dr. Wiznitzer also restated his

conclusion that “Dr. Kinsbourne’s speculation about the presence of a mitochondrial

disorder/dysfunction and the role of neuroimaging is not supported by his references or by the

medical records.” Id.

E. Respondent’s Expert: Dr. Christine McCusker

1. Qualifications

Dr. McCusker received her medical degree from McMaster University Medical School in

1993 and completed a pediatrics residency at the Montreal Children’s Hospital and a clinical

fellowship in allergy and immunology at McGill University. Ex. D (hereinafter “McCusker CV”)

at 1-2. Dr. McCusker is board certified in pediatrics and is a fellow of the Royal College of

Physicians and Surgeons of Canada in Pediatrics and Allergy and Immunology. Id. at 2. Dr.

McCusker is an Associate Member of the Department of Medicine at McGill University and

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Research Director at the Meakins-Christie Laboratories and McGill University. Id. at 3. Dr.

McCusker also serves as the Director of Clinical Immunology Laboratory and Division Director

of Pediatric Allergy, Immunology, and Dermatology at Montreal Children’s Hospital. Id. Dr.

McCusker is an ad hoc reviewer for a number of journals including (but not limited to), Journal of

Allergy and Clinical Immunology, Journal of Rheumatology, Life Science Journal,

Immunobiology, Journal of Medical Genetics, and Pediatric Pulmonology. Id. at 14-15. Dr.

McCusker has been awarded numerous research grants and has four patents. See id. at 21-23. Dr.

McCusker has published approximately 75 papers and abstracts. See id. at 24-32.

2. Expert Reports

Dr. McCusker first defined cytokines as “small proteins released from cells in response to

specific stimuli….which shape the innate and adaptive immune response.” First McCusker Rep.

at 3-4. She noted that the “purpose of vaccination is to stimulate the development of…adaptive

immunity against pathogens in the form of antibodies and specific T cells” and that “the

magnitudes of cytokine responses induced by vaccination are much lower than in natural

infection….” Id. at 4.

Dr. McCusker also discussed recall responses, stating that “upon subsequent exposures to

the same pathogen[,] the presence of immunological memory, in the form of antibodies, results in

rapid clearance of the pathogen from the system, with only limited activation of the innate, pro-

inflammatory pathways.” Id. at 4. Dr. McCusker stated that “recall…responses to pathogens result

in greater specificity and more rapid adaptive responses to these pathogens, leading to rapid

clearance without significant or prolonged activity of the pro-inflammatory immune response.” Id.

Dr. McCusker stated that there are “no reports of fever or evidence of inflammation at the site of

vaccine” in children receiving their third set of vaccines, as in A.S.’s case. Id. at 4-5.

Dr. McCusker then discussed cytokines and vaccination, stating that in comparison to

natural infection, vaccination results in a markedly reduced activation of innate pathways. Id. at 5.

Vaccination is “predicted to activate immune responses in part through cytokine upregulation.” Id.

Citing the Kashiwagi article, Dr. McCusker noted that development of fever was independent of

the levels of the cytokines in a child’s blood, and that the data suggested that “cytokines are

produced and released by the peripheral immune system during vaccination but there is no

evidence to suggest that the levels are sufficient to influence…development of cytokine-mediated

changes in seizure thresholds….” Id. at 5. Citing several studies, Dr. McCusker concluded that

“while cytokines are released by vaccination, the levels are extremely low, even in the case of

booster vaccination.” Id. She therefore disagreed with Dr. Kinsbourne that “pro-inflammatory

cytokines released following the vaccinations [A.S.] received acted to increase[] oxidative stress

in her central nervous system leading to seizures.” Id. at 6. To support her point, Dr. McCusker

noted that A.S. showed no signs of fever, hypoxia, or trauma following her vaccinations, and she

was diagnosed with infantile spasms only several months after her vaccinations, at a time “when

any vaccination-related cytokine release would have long-since resolved.” Id.

Finally, Dr. McCusker discussed A.S.’s symptoms in the context of vaccine inducement.

Noting that A.S. eventually developed developmental delays and seizures with no defined etiology,

Dr. McCusker stated that “there is no clinical evidence that the vaccinations [A.S.] received on 06-

22

18-2012 induced significant release of proinflammatory cytokines.” Id. Although there is

experimental evidence in mice showing that cytokines can induce seizures, the levels of cytokines

required to induce these changes are “>1000X” found post-vaccination. Id. at 8. Taken altogether,

Dr. McCusker stated that there is no evidence linking vaccinations with developmental delay, even

in those children with abnormal neurological development.” Id.

In her second expert report, Dr. McCusker responded to Dr. Gershwin’s assertion that A.S.

suffered from a genetic mitochondrial defect, which led to “alterations in cell energy metabolism

[which] would influence the target tissue response to cytokines.” Second McCusker Rep. at 2. Dr.

McCusker summarized Dr. Gershwin’s theory to mean that “cytokine production following

vaccination in this context resulted in worsening inflammation, altered cellular process and

[caused] neurological decline.” Id. at 2.

Dr. McCusker then conducted a review of the literature Dr. Gershwin cited to support this

theory. She stated that “the articles submitted by Dr. Gershwin demonstrate that mitochondrial

damage can activate proinflammatory pathways resulting in the release of cytokines.”, however,

“the articles presented do not suggest that in parties with genetic mitochondrial defects, there are

any changes in target tissue responses to peripheral cytokine release as hypothesized by Dr.

Gershwin.” Id. at 4 (emphasis in original).

Dr. McCusker concluded her report by restating her conclusion from her first report, that

“there is no evidence…of a genetic mitochondrial defect in A.S. despite multiple investigations.”

Id. at 4. She also states that “even were such a defect to be found, the literature submitted by Dr.

Gershwin does not support the contention that a child with mitochondrial dysfunction will be more

susceptible to cytokine-mediated accelerated neurological decline following vaccination.” Id.

3. Testimony

I recognized Dr. McCusker as an expert in pediatrics and pediatric immunology and

allergy. Tr. at 457. Dr. McCusker testified about the immune system’s response post-vaccination.

Id. at 460-63. She then provided testimony regarding the effects of booster vaccinations. Id. at

463-66. Dr. McCusker stated that neither the adaptive nor the innate immune systems start at zero

and thus the response becomes more targeted with each subsequent booster. Id. at 464. As it relates

to A.S., if one has a mitochondrial condition, one is unlikely to generate inflammation as it is an

energy-consuming process. Id. at 468-69.

Regarding Dr. Gershwin’s theory, Dr. McCusker disagreed on a few points. Cytokines do

not have a long half-life in the body; IL-1 beta has a half-life of 19 minutes. Tr. at 473. The idea

that cytokines, which are diluted in the blood stream, circulated in sufficient amounts to cross the

blood-brain barrier and caused an abnormal response in the brain is not a viable theory. Id. at 474.

A.S. had no fever, no redness at the injection site, or anything indicating that she was experiencing

an abnormally high cytokine response. Id. Assuming that cytokines did cross the blood-brain

barrier, Dr. McCusker noted that they interact differently in the central nervous system; for,

instance IL-1 beta is involved with memory formation and the sleep cycle in the CNS. Id. at 476-

77. Dr. McCusker further noted that the mechanism proposed by Dr. Gershwin has no support in

the medical literature. Id. at 478. If cytokines did travel to the central nervous system and cause

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cell death, Dr. McCusker testified that it would be visible on an MRI or EEG as this would be a

cyclical process, where cell death causes more inflammation which causes more cell death. Id. at

481-82.

If Dr. Gershwin’s mechanism were accurate, when A.S. contracted an upper respiratory

tract infection in September 2012, one would expect a similar response as A.S. had physical

symptoms and cytokines were activated as an immune response, however A.S. had no neurological

changes. Tr. at 483-84. Dr. McCusker ultimately testified that A.S.’s regression would have been

the same without the vaccinations. Id. at 492.

F. Respondent’s Expert: Dr. Shawn McCandless

1. Qualifications

Dr. McCandless received his medical degree from Temple University in 1988 and

completed a residency in medical genetics and a fellowship in biochemical genetics. Ex. F

(hereinafter “McCandless CV”) at 1. Dr. McCandless is an associate professor of Genetics,

Pediatrics, and Pathology at Case Western Reserve University and is board certified in pediatrics,

clinical genetics, and clinical biochemical genetics. Id. Dr. McCandless serves as the Director of

the Center for Human Genetics at Case Western Reserve University and University Hospital of

Cleveland Case Medical Center; Residency Director of the Case Medical Center, Department of

Genetics; Medical Director of the Prader-Willi Syndrome Clinic; and Associate Director of the

Center for Inherited Disorders of Energy Metabolism. Id. at 2. Dr. McCandless is an ad hoc

reviewer for a number of journals (including but not limited to), Genetics in Medicine, Pediatrics,

The American Journal of Medical Genetics, Human Molecular Genetics, and more. Id. at 2-3. Dr.

McCandless has published approximately 50 peer-reviewed papers and abstracts. Id. at 5-6, 10-

11.

Dr. McCandless now works at the University of Colorado School of Medicine and

Children’s Hospital Colorado where he is the section head for Genetics and Metabolism in the

Department of Pediatrics. Ex. H at 1. During the course of his career, he has treated approximately

100 children and adults with clinically confirmed mitochondrial disorders. Tr. at 329. He has

evaluated laboratory testing of 300-500 individuals for mitochondrial disease. Id. I recognized Dr.

McCandless as an expert in pediatrics, genetics, pediatric metabolic disease (including

mitochondrial disorders), and biochemical genetic testing. Id. at 331.

2. Expert Reports

Dr. McCandless filed four reports in this case, two of which were filed after the entitlement

hearing. Ex. E (hereinafter “First McCandless Rep.”), Ex. H (hereinafter “Second McCandless

Rep.”), Ex. P (hereinafter “Third McCandless Rep.”), and Ex. S (hereinafter “Fourth McCandless

Rep.”). Dr. McCandless also testified at the entitlement hearing.

In his first report, Dr. McCandless summarized A.S.’s current condition as a “child who

had subtle, but clear, developmental issues identified from early in life, well before her 6-month

immunizations were given on June 18, 2012.” First McCandless Rep. at 3. To support this

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contention, Dr. McCandless stated that “before she was given the 6-month immunizations, her

pediatrician was concerned enough to recommend evaluation by a neurologist and

ophthalmologist.” Id.

Dr. McCandless defined a “primary mitochondrial disorder” as “a constellation of

symptoms that have their direct cause due to inadequacy of the mitochondrial energy producing

process.” First McCandless Rep. at 3. Citing Haas; Smeitnik et al., Mitochondrial medicine: A

metabolic perspective on the pathology of oxidative phosphorylation disorders, 3 CELL

METABOLISM, 9-13 (2006) (filed as Ex. K, Tab 5). Dr. McCandless noted that there are a variety

of “red-flag” symptoms and laboratory findings that are typically suggestive of mitochondrial

disorder. The diagnosis of primary mitochondrial disease therefore requires a combination of

“appropriate clinical findings and suggestive laboratory abnormalities.” Id. Dr. McCandless stated

that, “the more specific and persisting the findings are, both clinical and laboratory, the more

convincing the argument for primary mitochondrial disease.” Id.

Based on the records provided, Dr. McCandless concluded that “there is not persuasive

evidence” that A.S. suffered from a primary mitochondrial disorder. Id.at 5. He reviewed the list

of symptoms from the Haas article and concluded that A.S. lacked any clear ‘red-flag’ symptom

of mitochondrial disease. Id. at 5. Dr. McCandless did not see “evidence in the record of an acute

encephalopathy or severe dysmotility that would be strongly suggestive of a primary mitochondrial

disorder.” Id. He did not see suggestive biochemical markers of mitochondrial dysfunction in any

of A.S.’s tests. Id.

Dr. McCandless then disagreed with Dr. Boles’ assertion that A.S. suffered from elevations

in her lactic acid. Id. at 5. Dr. McCandless stated that the values found were “trivially above the

upper end of the reference interval” and in his experience, were “related to difficulty with obtaining

free flowing blood samples from children and use of a torniquet” rather than to a mitochondrial

disease. Id. In his lab, Dr. McCandless uses a “cut-off” value of >150% of the upper reference

interval to avoid “over or inappropriate diagnosis of primary mitochondrial disease.” Id. He also

disagreed with Dr. Boles that a physician independently diagnosed significant developmental

regression in A.S., stating that “any reference to an association between regression and vaccination

in the records was based on the parent’s report, well after the events transpired.” Id. Furthermore,

he disagreed with Dr. Boles that A.S. “fell off a cliff” stating “there was not documentation of an

acute loss of all milestones”, stating that based on the records, it was clear that A.S. “was not a

normal 6-month old.” Id. Dr. McCandless also disagreed with Dr. Boles that “gastrointestinal

dysmotility at different levels is common in patients with mitochondrial dysfunction/disorders” Id.

at 7.

Dr. McCandless also refuted the assertion that the molecular test results were supportive

of primary mitochondrial disease. First McCandless Rep. at 5. He stated that the NDUFA1 variant

identified is present in A.S.’s father, who does not suffer from mitochondrial disease. The gene is

on the X chromosome and “it is a generally accepted principal of clinical genetics that an X

chromosome variant that does not cause disease in a male is not a reasonable explanation for

disease in a female.” Id. Dr. McCandless also downplayed the importance of the buccal swab

analysis stating that the test is “still in a research state…and has not yet been completely

established nor replicated.” Id. at 6. He stated that the test “should not be considered clinically

25

diagnostic [and that] is strongly emphasized by both the performing scientist and the interpreting

physician in the report.” Id.

Dr. McCandless concluded his report by stating that A.S. “had neurodevelopmental

abnormalities apparent in the first few months of life, she does not have sufficient findings to

confirm a diagnosis of primary mitochondrial disease”, and that he found “no compelling evidence

that the vaccines she received contributed to her severe neurological disorder.” Id. at 10.

In Dr. McCandless’ second expert report, he rebutted Dr. Gershwin’s assertion that A.S.

suffered from a genetic mitochondrial defect which led to alterations in cell energy metabolism,

which in turn influenced the target tissue response to cytokines. Second McCandless Rep. at 2.

Dr. McCandless understood Dr. Gershwin’s theory to be that “cytokine production following

vaccination in … resulted in worsening inflammation, altered cellular process and neurological

decline.” Id. Dr. McCandless conducted a review of the literature submitted by Dr. Gershwin to

support this point. He concluded that none of the literature submitted suggested that in patients

with genetic mitochondrial defects, there are changes in target tissue responses to peripheral

cytokine release. He noted that much of the literature focuses on the role of mitochondrial products

in the activation and release of cytokines not in response to peripheral cytokines such as those

present systemically, “albeit in minimal amounts” following vaccination. Id. at 4.

Dr. McCandless concluded his expert report by stating that the records provide no evidence

that A.S. suffers from a genetic mitochondrial defect, and, even if she did, the literature Dr.

Gershwin provided “does not support the contention that a child with mitochondrial dysfunction

will be more susceptible to cytokine-mediated accelerated neurological decline following

vaccination.” Second McCandless Rep. at 5.

3. Testimony

I recognized Dr. McCandless as an expert in pediatrics, genetics, and pediatric metabolic

disease, including mitochondrial disorders, and biochemical genetic testing. Tr. at 331. Dr.

McCandless testified that he did not believe that “compelling or convincing evidence” existed to

demonstrate that A.S. suffered from a mitochondrial dysfunction, and “there’s certainly not a

diagnosis of mitochondrial disease.” Tr. at 332.

Dr. McCandless explained the difference between mitochondrial dysfunction and

mitochondrial disease is that mitochondrial disease is “generally accepted to be a constellation of

signs and symptoms that are caused by a defect in one component of mitochondrial energy

metabolism,” Tr. at 333. He clarified this to mean that “when we talk about mitochondrial disease

or primary mitochondrial diseases, that means a defect in one component of the electron transport

chain or multiple components of the electron transport chain that…is the primary cause of the signs

and symptoms that the patient is dealing with.” Id.

Mitochondrial dysfunction, on the other hand, is used to “reflect abnormalities in

laboratory testing that suggest that the mitochondrial electron transport chain is not functioning

normally. It is agnostic to the cause of that dysfunction.” Tr. at 333. He clarified this to mean that

mitochondrial dysfunction “refers to laboratory findings that are suggestive of an alteration in the

26

function of that electron transport chain in the mitochondria.” Id. at 334. Dr. McCandless explained

that “if you can find a genetic change or clinical findings that are completely consistent with the

laboratory findings in someone that has laboratory evidence of mitochondria dysfunction, you can

make a diagnosis of primary mitochondrial disease.” Id. at 333. The fundamental question to

differentiate the two is if someone is discussing “dysfunction in any enzyme found in the

mitochondria,” they mean mitochondrial dysfunction, but if they specifically mean “dysfunction

of the electron transport chain”, they are talking about mitochondrial disease. Id. at 333-34.

Dr. McCandless next discussed the question as to whether A.S. “fell off a cliff” as far as

her status following vaccinations. Tr. at 335. He disagreed with this point stating that “there are a

number of entries in the contemporaneous medical records that indicate that there was a gradually

evolving picture of neurologic dysfunction in A.S.” Id. Dr. McCandless stated that the “concept

that there was an acute change…is primarily based on the history as the parents described it to

various providers.” Id. As evidence, Dr. McCandless pointed to the fact that A.S. was eating very

little for a child her age at her four-month visit. Id. at 337. Furthermore, at her six-month visit, she

was eating even less than she was at the four-month visit. Id. Finally, Dr. McCandless pointed to

the fact that A.S. rolled at two months as evidence of likely neurological dysfunction because at

that age, “if there’s an abnormality or an asymmetry of the tone in the arms or spasticity in the

arms…when a child tries to push up, he may have one arm that pushes more than the other, and

the baby just kind of flips over from stomach to back.” Id. at 340. Dr. McCandless couched this

opinion by saying he would defer to the neurologist about how specific or sensitive that particular

finding is.” Id. at 341.

Based on A.S.’s reduced caloric intake, Dr. McCandless opined it was extremely unlikely

she was suffering from a mitochondrial dysfunction. Tr. at 337. Dr. McCandless noted that because

A.S. continued to gain weight, this meant that her mitochondria were “working very efficiently to

extract every bit of energy she can from the food she’s taking in.” Id. at 339.

Following this, Dr. McCandless testified that he disagreed with Dr. Boles opinion that A.S.,

“more likely than not, had a mitochondrial dysfunction.” Id. at 341. He agreed with Dr. Boles that

there are no “gold standard” tests that can definitively show mitochondrial dysfunction. Id. at 342.

He testified that there are several different types of tests that try to show mitochondrial dysfunction,

but “molecular testing…is the closest we have to a gold standard.” Id. at 343. If “you find a genetic

change that is consistent, that’s been seen many times before in mitochondrial disease, you can be

confident that that’s the diagnosis….” Id.

Turning his focus to A.S.’s lab reports, Dr. McCandless noted that, although Dr. Boles

stated that A.S.’s plasma lactate was “mildly elevated,” there are very few mitochondrial experts

in the world who would consider those significantly elevated lactate values.” Tr. at 345. Patients

with a diagnosis of mitochondrial disease had lactate levels “at least 150 percent of the upper limit

of normal of the range.” Id. at 347. Dr. McCandless indicated that none of A.S.’s molecular testing

showed mitochondrial dysfunction, much less mitochondrial disease. Id. at 346-47. Dr.

McCandless also testified that A.S.’s testing for urine organic acids was not “specific or even

highly suggestive of mitochondrial dysfunction. Id. at 350. He noted that the two markers that

were important in this testing were 3-methylglutaric acid, and 3-methylglutaconic acid, and neither

one was elevated in A.S.’s sample. Id. at 352. He further stated that “the things Dr. Boles pointed

27

to in his sample as indicative of mitochondrial disease are not indicative of mitochondrial

disease…they are normal variants.” Id.

Dr. McCandless also took issue with Dr. Boles’ assertion that the pattern of the plasma

acylcarnitines in A.S. was highly suggestive of mitochondrial disorder. Tr. at 352-53. Dr.

McCandless noted that firstly, acylcarnitine analysis “is not generally thought to be highly

informative for mitochondrial disorders.” Id. at 353. Secondly, even if it were, the pattern seen in

A.S. is not the typical pattern seen in patients with mitochondrial disorders. Id. Rather, this is the

pattern seen in patients who are taking supplemental carnitine, which A.S. was. Id. at 353-54. Dr.

McCandless testified that as a result of the supplemental carnitine, A.S. had extra carnitine in the

mitochondria. Id. at 354. Dr. McCandless noted that if Dr. Boles only measured acylcarnitines in

patients on carnitine, he would see this pattern in all patients he believed to have mitochondrial

disease. Id. at 355. In relation to A.S.’s case, Dr. McCandless noted that on June 22, 2012, when

A.S. was allegedly at her sickest, her “acetyl, C3, C4OH, they are all completely normal. So if

those are indicative of mitochondrial dysfunction, why would they not be elevated when this child

is supposedly the sickest she has ever been because of mitochondrial dysfunction?” Id. at 357.

Dr. McCandless next commented on the electron transport chain analysis performed from

a buccal swab which allegedly revealed “mitochondrial proliferation and complex IV deficiency.”

Tr. at 358. Dr. McCandless first stated that this “is not a test that is widely accepted by

mitochondrial experts as having significant value.” Id. at 389-59. The test is “relatively new” and

the single publication in the literature describing the test “doesn’t provide the validation data that

laboratory would need for proposing a diagnostic test.” Id. at 359. In particular, Dr. McCandless

stated that the test lacks sensitivity and specificity. Id. He stated that the test lacks sensitivity

because “in the paper they suggest it’s about 70 or 80 percent sensitive…so it may contribute some

information but it’s certainly not a diagnostic test” and it lacks specificity because the positive

predictive value (what percentage of positive tests are false positives) is not known for this test.”

Id. at 360. Ultimately, Dr. McCandless testified that the samples are not reliable because too much

about the validity of the test is unknown. Id.

Dr. McCandless then testified that he disagreed with Dr. Gershwin’s assertion that “there’s

something special about [A.S.’s] mitochondrial DNA…[and] people that already have decreased

mitochondrial function are going to be at higher risk from…cytokines.” Tr. at 366. Dr. McCandless

stated that A.S.’s entire mitochondrial DNA has been sequenced and found to be normal, except

“two variants that are not known to be completely normal, except that they both occur…in some

number of normal people in the population.” Id.

Finally, Dr. McCandless stated that he found “no compelling clinical findings that pointed

to mitochondrial disease.” Tr. at 371. The only test that possibly pointed to mitochondrial disease

is the buccal swab, and in Dr. McCandless opinion, this test is not “a particularly good test.” Id.

Dr. McCandless also highlighted two additional pieces of evidence regarding the absence of

mitochondrial disease. First, none of her medical records refer to mitochondrial disease over the

last two years, and she is not on treatment for it. Secondly, a neurologist placed her on valproic

acid, which, if given to a patient with mitochondrial disease, would cause liver failure. Id. at 372-

73.

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4. Post-Hearing Reports

In his third expert report, Dr. McCandless refuted Dr. Kinsbourne’s explanation as to why

A.S.’s MRI scans did not show evidence of injury typically seen in mitochondrial disease. Third

McCandless Rep. at 1. Dr. McCandless characterized Dr. Kinsbourne’s theory as saying that if

A.S. had primary mitochondrial dysfunction, Dr. Kinsbourne would expect to see different injuries

on an MRI than those expected with anoxia/hypoxia. Id.

Dr. Kinsbourne opined that A.S. “fell off a cliff” following her June 18, 2012, vaccines.

Id. Dr. McCandless pointed out that “if that were the case, that there was an acute and severe

failure of mitochondrial function, one would reasonably expect to see MRI changes.” Id. He went

on to say that while “their absence does not rule out mitochondrial disease, [] it certainly

undermines the “falling off the cliff” argument.” Id.

Dr. McCandless also addressed Dr. Kinsbourne’s claim that “the absence of MRI changes

in the presence of objective major clinical/behavioral regression is further evidence for a metabolic

cause, such as a mitochondrial insufficiency.” First McCandless Rep. at 1. To rebut this argument,

Dr. McCandless pointed out that mitochondrial diseases associated with regression typically are

associated with MRI changes, and the absence of evidence of injury on an MRI scan undercuts the

argument that A.S. suffers from a mitochondrial disease. Id. at 1-2.

In his fourth expert report, Dr. McCandless restated his conclusion that A.S. did not suffer

from mitochondrial disease, but that “the most likely explanation for [A.S.]’s neurodevelopmental

disorder is that there is a genetic variant that we currently don’t have the ability to recognize that

explains her altered brain development.” Fourth McCandless Rep. at 2. He also reiterated that an

MRI scan can contribute information regarding a potential mitochondrial disorder, but it’s simply

one of many possible sources. Id. at 1-2.

V. Applicable Law

A. Petitioner’s Burden in Vaccine Program Cases

Under the Vaccine Act, when a petitioner suffers an alleged injury that is not listed in the

Vaccine Injury Table, a petitioner may demonstrate that he suffered an “off-Table” injury.

§ 11(c)(1)(C)(ii).

In attempting to establish entitlement to a Vaccine Program award of compensation for a

off-Table claim, a petitioner must satisfy all three of the elements established by the Federal Circuit

in Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274 (Fed. Cir. 2005). Althen requires that

petitioner establish by preponderant evidence that the vaccination he received caused his injury

“by providing: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical

sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a

showing of a proximate temporal relationship between vaccination and injury.” Id. at 1278.

Under the first prong of Althen, petitioners must provide a “reputable medical theory,”

demonstrating that the vaccine received can cause the type of injury alleged. Pafford, 451 F.3d at

29

1355-56 (citations omitted). To satisfy this prong, a petitioner’s theory must be based on a “sound

and reliable medical or scientific explanation.” Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d

543, 548 (Fed. Cir. 1994). Proof that the proffered medical theory is reasonable, plausible, or

possible does not satisfy a petitioner’s burden. Boatmon v. Sec’y of Health & Hum. Servs., 941

F.3d 1351, 1359-60 (Fed. Cir. Nov. 7, 2019).

Petitioners may satisfy the first Althen prong without resort to medical literature,

epidemiological studies, demonstration of a specific mechanism, or a generally accepted medical

theory. Andreu v. Sec’y of Health & Hum. Servs., 569 F.3d 1367, 1378-79 (Fed. Cir. 2009) (citing

Capizzano, 440 F.3d at 1325-26). However, special masters are “entitled to require some indicia

of reliability to support the assertion of the expert witness.” Boatmon, 941 F.3d at 1360, quoting

Moberly, 592 F.3d at 1324. Special Masters, despite their expertise, are not empowered by statute

to conclusively resolve what are complex scientific and medical questions, and thus scientific

evidence offered to establish Althen prong one is viewed “not through the lens of the laboratorian,

but instead from the vantage point of the Vaccine Act’s preponderant evidence standard.” Id. at

1380. Accordingly, special masters must take care not to increase the burden placed on petitioners

in offering a scientific theory linking vaccine to injury. Contreras v. Sec’y of Health & Hum.

Servs., 121 Fed. Cl. 230, 245 (2015), vacated on other grounds, 844 F.3d 1363 (Fed. Cir. 2017);

see also Hock v. Sec’y of Health & Hum. Servs., No. 17-168V, 2020 U.S. Claims LEXIS 2202 at

*52 (Fed. Cl. Spec. Mstr. Sept. 30, 2020).

The second Althen prong requires proof of a logical sequence of cause and effect, usually

supported by facts derived from a petitioner’s medical records. Althen, 418 F.3d at 1278; Andreu,

569 F.3d at 1375-77; Capizzano, 440 F.3d at 1326 (“medical records and medical opinion

testimony are favored in vaccine cases, as treating physicians are likely to be in the best position

to determine whether a ‘logical sequence of cause-and-effect show[s] that the vaccination was the

reason for the injury’”) (quoting Althen, 418 F.3d at 1280). Medical records are generally viewed

as particularly trustworthy evidence, since they are created contemporaneously with the treatment

of the patient. Cucuras v. Sec’y of Health & Hum. Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993).

However, medical records and/or statements of a treating physician’s views do not per se

bind the special master to adopt the conclusions of such an individual, even if they must be

considered and carefully evaluated. Section 13(b)(1) (providing that “[a]ny such diagnosis,

conclusion, judgment, test result, report, or summary shall not be binding on the special master or

court”). As with expert testimony offered to establish a theory of causation, the opinions or

diagnoses of treating physicians are only as trustworthy as the reasonableness of their suppositions

or bases. The views of treating physicians should also be weighed against other, contrary evidence

also present in the record. Hibbard v. Sec’y of Health & Hum. Servs., 100 Fed. Cl. 742, 749 (2011),

aff’d, 698 F.3d 1355 (Fed. Cir. 2012); Caves v. Sec’y of Health & Hum. Servs., No. 06-522V, 2011

WL 1935813, at *17 (Fed. Cl. Spec. Mstr. Apr. 29, 2011), mot. for review den’d, 100 Fed. Cl. 344,

356 (2011), aff’d without opinion, 475 Fed. App’x 765 (Fed. Cir. 2012).

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

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understanding of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan

v. Sec’y of Health & Hum. 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 &

Hum. Servs., 101 Fed. Cl. 532, 542 (2011), recons. den’d after remand, 105 Fed. Cl. 353 (2012),

aff’d mem., 503 F. App’x 952 (Fed. Cir. 2013); Koehn v. Sec’y of Health & Hum. Servs., No. 11-

355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for review den’d (Fed. Cl.

Dec. 3, 2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2014).

In the present case, Petitioners allege that A.S. suffered an off-table significant aggravation

of her pre-existing neurological condition as a result of receiving the DTaP, IPV, Hib, Hep. B,

Prevnar and/or RotaTeq vaccinations on June 18, 2012. Amended Pet. at 2.

The Vaccine Act defines significant aggravation as “any change for the worse in a

preexisting condition which results in markedly greater disability, pain, or illness accompanied by

substantial deterioration of health.” § 300aa-33(4). In Loving, the United States Court of Federal

Claims established the governing six-part test for off-Table significant aggravations. Petitioner

must prove by a preponderance of the evidence:

(1) The person’s condition prior to administration of the vaccine, (2) the person’s

current condition (or the condition following the vaccination if that is also

pertinent), (3) whether the person’s current condition constitutes a ‘significant

aggravation’ of the person’s condition prior to vaccination, (4) a medical theory

causally connecting such a significant worsened condition to the vaccination, (5) a

logical sequence of cause and effect showing that the vaccination was the reason

for the significant aggravation, and (6) a showing of a proximate temporal

relationship between the vaccination and the significant aggravation.

Loving v. Sec’y of Health & Hum. Servs., 86 Fed. Cl. 135, 144 (2009); see also W.C. v. Sec’y of

Health & Human Servs., 704 F.3d 1352, 1357 (Fed. Cir. 2013) (adopting this as the proper legal

standard for significant aggravation claims brought under the Vaccine Act). Loving prongs four,

five, and six are derived from the Federal Circuit’s test for off-Table actual causation cases. Althen

v. Sec’y of Health & Hum. Servs., 17 F.3d 374 (Fed. Cir. 1994).

In Sharpe, the Federal Circuit clarified the Loving prongs and what is required by

petitioners to successfully demonstrate a causation-in-fact significant aggravation claim. Sharpe

v. Sec’y of Health & Hum. Servs., 964 F.3d 1072 (Fed. Cir. 2020). Loving prong three only requires

a comparison of a petitioner’s current, post-vaccination condition with her pre-existing pre-

vaccination condition. Sharpe at 1082; Whitecotton v. Sec’y of Health & Hum. Servs., 81 F.3d

1099 (Fed. Cir. 1996). A petitioner is not required to demonstrate an expected outcome or that her

post-vaccination condition was worse than such an expected outcome. Sharpe at 1081.

Under Loving prong four, a petitioner need only provide a “medical theory causally

connecting [petitioner’s] significantly worsened condition to the vaccination.” Sharpe at 1083; see

also Loving, 86 Fed. Cl. at 144. In other words, petitioner is required to present a medically reliable

theory demonstrating that a vaccine “can cause a significant worsening” of the condition. Sharpe

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at 1083 (citing to Pafford ex. rel. Pafford v. Sec’y of Health & Hum. Servs., 451 F.3d 1352, 1356-

57 (Fed. Cir. 2006). A petitioner may be able to establish a prima facie case under Loving prong

four without eliminating a pre-existing condition as the cause of her significantly aggravated

injury. Id.; citing Walther v. Sec’y of Health & Hum. Servs., 485 F. 3d 1146, 1151 (Fed. Cir. 2007)

(noting that “the government bears the burden of establishing alterative causation. . . . once

petitioner has established a prima facie case”).

Loving prong five requires a petitioner to show “a logical sequence of cause and effect

showing that the vaccination was the reason for the significant aggravation.” Loving, 86 Fed. Cl.

at 144. In other words, petitioner must show that the vaccinations “did” cause a worsening of

[petitioner’s underlying disorder]. Id.

In determining whether a petitioner is entitled to compensation, a special master must

consider the entire record and is not bound by any particular piece of evidence. § 13(b)(1) (stating

that a special master is not bound by any “diagnosis, conclusion, judgment, test result, report, or

summary” contained in the record). Furthermore, a petitioner is not required to present medical

literature or epidemiological evidence to establish any Althen prong. The special master essentially

must weigh and evaluate opposing evidence in deciding whether a petitioner has met their burden

of proof. Andreu v. Sec’y of Health & Hum. Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009); see also

Grant v. Sec’y of Health & Hum. Servs., 956 F.2d 1144, 1149 (Fed. Cir. 1992).

B. Law Governing Analysis of Fact Evidence

The process for making factual determinations in Vaccine Program cases begins with

analyzing the medical records, which are required to be filed with the petition. Section 11(c)(2).

The special master is required to consider “all [] relevant medical and scientific evidence contained

in the record,” including “any diagnosis, conclusion, medical judgment, or autopsy or coroner’s

report which is contained in the record regarding the nature, causation, and aggravation of the

petitioner’s illness, disability, injury, condition, or death,” as well as the “results of any diagnostic

or evaluative test which are contained in the record and the summaries and conclusions.” Section

13(b)(1)(A). The special master is then required to weigh the evidence presented, including

contemporaneous medical records and testimony. See Burns v. Sec’y of Health & Hum. Servs., 3

F.3d 413, 417 (Fed. Cir. 1993) (it is within the special master’s discretion to determine whether to

afford greater weight to contemporaneous medical records than to other evidence, such as oral

testimony surrounding the events in question that was given at a later date, provided that such

determination is evidenced by a rational determination).

Medical records created contemporaneously with the events they describe are generally

trustworthy because they “contain information supplied to or by health professionals to facilitate

diagnosis and treatment of medical conditions,” where “accuracy has an extra premium.” Kirby v.

Sec’y of Health & Hum. Servs., 997 F.3d 1378 (Fed. Cir. 2021) citing Cucuras, 993 F.2d at 1528.

This presumption is based on the linked proposition that (i) sick people visit medical professionals;

(ii) sick people honestly report their health problems to those professionals; and (iii) medical

professionals record what they are told or observe when examining their patients in as accurate a

manner as possible, so that they are aware of enough relevant facts to make appropriate treatment

decisions. Sanchez v. Sec’y of Health & Hum. Servs., No. 11-685V, 2013 WL 1880825 at *2 (Fed.

32

Cl. Spec. Mstr. Apr. 10, 2013) mot. for rev. denied, 142 Fed. Cl. 247, 251-52 (2019), vacated on

other grounds and remanded, 809 Fed. Appx. 843 (Fed. Cir. Apr. 7, 2020).

Accordingly, if the medical records are clear, consistent, and complete, then they should

be afforded substantial weight. Lowrie v. Sec’y of Health & Hum. Servs., No. 03-1585V, 2005 WL

6117475 at *20 (Fed. Cl. Spec. Mstr. Dec. 12, 2005). Indeed, contemporaneous medical records

are generally found to be deserving of greater evidentiary weight than oral testimony -- especially

where such testimony conflicts with the record evidence. Cucuras, 993 F.2d at 1528; see also

Murphy v. Sec’y of Health & Hum. Servs., 23 Cl. Ct. 726, 733 (1991), aff’d per curiam, 968 F.2d

1226 (Fed. Cir. 1992), cert. den’d, Murphy v. Sullivan, 506 U.S. 974 (1992) (citing United States

v. U.S. Gypsum Co., 333 U.S. 364, 396 (1947) (“[i]t has generally been held that oral testimony

which is in conflict with contemporaneous documents is entitled to little evidentiary weight.”)).

However, there are situations in which compelling oral testimony may be more persuasive

than written records, such as where records are deemed to be incomplete or inaccurate. Campbell

v. Sec’y of Health & Hum. Servs., 69 Fed. Cl. 775, 779 (2006) (“like any norm based upon common

sense and experience, this rule should not be treated as an absolute and must yield where the factual

predicates for its application are weak or lacking”); Lowrie, 2005 WL 6117475 at *19 (“[w]ritten

records which are, themselves, inconsistent, should be accorded less deference than those which

are internally consistent”) (quoting Murphy, 23 Cl. Ct. at 733)). Ultimately, a determination

regarding a witness’s credibility is needed when determining the weight that such testimony should

be afforded. Andreu, 569 F.3d at 1379; Bradley v. Sec’y of Health & Hum. Servs., 991 F.2d 1570,

1575 (Fed. Cir. 1993).

When witness testimony is offered to overcome the presumption of accuracy afforded to

contemporaneous medical records, such testimony must be “consistent, clear, cogent and

compelling.” Sanchez, 2013 WL 1880825 at *3 (citing Blutstein v. Sec’y of Health & Hum. Servs.,

No. 90-2808V, 1998 WL 408611 at *5 (Fed. Cl. Spec. Mstr. June 30, 1998)). In determining the

accuracy and completeness of medical records, the Court of Federal Claims has listed four possible

explanations for inconsistencies between contemporaneously created medical records and later

testimony: (1) a person’s failure to recount to the medical professional everything that happened

during the relevant time period; (2) the medical professional’s failure to document everything

reported to her or him; (3) a person’s faulty recollection of the events when presenting testimony;

or (4) a person’s purposeful recounting of symptoms that did not exist. LaLonde v. Sec’y of Health

& Hum. Servs., 110 Fed. Cl. 184, 203-04 (2013), aff’d, 746 F.3d 1334 (Fed. Cir. 2014). In making

a determination regarding whether to afford greater weight to contemporaneous medical records

or other evidence, such as testimony at hearing, there must be evidence that this decision was the

result of a rational determination. Burns, 3 F.3d at 417.

C. Analysis of Expert Testimony

Establishing a sound and reliable medical theory connecting the vaccine to the injury often

requires petitioners to present expert testimony in support of their claim. Lampe v. Sec’y of Health

& Hum. Servs., 219 F.3d 1357, 1361 (Fed. Cir. 2000). Vaccine Program expert testimony is usually

evaluated according to the factors for analyzing scientific reliability set forth in Daubert v. Merrell

Dow Pharm., Inc., 509 U.S. 579, 594-96 (1993). See Cedillo v. Sec’y of Health & Hum. Servs.,

33

617 F.3d 1328, 1339 (Fed. Cir. 2010) (citing Terran v. Sec’y of Health & Hum. Servs., 195 F.3d

1302, 1316 (Fed. Cir. 1999). “The Daubert factors for analyzing the reliability of testimony are:

(1) whether a theory or technique can be (and has been) tested; (2) whether the theory or technique

has been subjected to peer review and publication; (3) whether there is a known or potential rate

of error and whether there are standards for controlling the error; and (4) whether the theory or

technique enjoys general acceptance within a relevant scientific community.” Terran, 195 F.3d at

1316 n.2 (citing Daubert, 509 U.S. at 592-95).

The Daubert factors play a slightly different role in Vaccine Program cases than they do

when applied in other federal judicial fora. Daubert factors are employed by judges to exclude

evidence that is unreliable and potentially confusing to a jury. In Vaccine Program cases, these

factors are used in the weighing of the reliability of scientific evidence. Davis v. Sec’y of Health

& Hum. Servs., 94 Fed. Cl. 53, 66-67 (2010) (“uniquely in this Circuit, the Daubert factors have

been employed also as an acceptable evidentiary-gauging tool with respect to persuasiveness of

expert testimony already admitted”).

Respondent frequently offers one or more experts of his own in order to rebut petitioners’

case. Where both sides offer expert testimony, a special master’s decision may be “based on the

credibility of the experts and the relative persuasiveness of their competing theories.”

Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1347 (Fed. Cir. 2010) (citing

Lampe, 219 F.3d at 1362). However, nothing requires the acceptance of an expert’s conclusion

“connected to existing data only by the ipse dixit of the expert,” especially if “there is simply too

great an analytical gap between the data and the opinion proffered.” Snyder, 88 Fed. Cl. at 743

(quoting Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997)). A “special master is entitled to

require some indicia of reliability to support the assertion of the expert witness.” Moberly, 592

F.3d at 1324. Weighing the relative persuasiveness of competing expert testimony, based on a

particular expert’s credibility, is part of the overall reliability analysis to which special masters

must subject expert testimony in Vaccine Program cases. Id. at 1325-26 (“[a]ssessments as to the

reliability of expert testimony often turn on credibility determinations”).

D. Consideration of Medical Literature

Although this decision discusses some but not all of the medical literature in detail, I

reviewed and considered all of the medical records and literature submitted in this matter. See

Moriarty v. Sec’y of Health & Hum. Servs., 844 F.3d 1322, 1328 (Fed. Cir. 2016) (“We generally

presume that a special master considered the relevant record evidence even though [s]he does not

explicitly reference such evidence in h[er] decision.”); Simanski v. Sec’y of Health & Hum. Servs.,

115 Fed. Cl. 407, 436 (2014) (“[A] Special Master is ‘not required to discuss every piece of

evidence or testimony in her decision.’” (citation omitted)), aff’d, 601 F. App’x 982 (Fed. Cir.

2015).

VI. Analysis

Petitioners summarized their theory of the case as follows: “[A.S.] faced an increased

sensitivity to vaccination-related neurologic disease in June 2012 because of her mitochondrial

dysfunction.” Pet’r’s Post Hearing Brief at 8. “Her innate immune response produced a cytokine

34

[response] significant enough to create overwhelming oxidative stress due to mitochondrial

dysfunction, with the stress causing cell injury leading to a rapid, “precipitous” deterioration.” Id.

at 9. “The vaccines interacted with her dysfunctional mitochondria and accelerated any preexisting

or ongoing process in [A.S.].” Id. at 10. I will first discuss whether A.S. suffers from mitochondrial

dysfunction, and will then turn to an analysis of each of the Loving prongs.

A. Petitioner has not Presented Preponderant Evidence that A.S. Suffers from

Mitochondrial Dysfunction

Dr. McCandless defined primary mitochondrial disorder as “a constellation of symptoms

that have their direct cause due to inadequacy of the mitochondrial energy producing process.”

First McCandless Rep. at 4; Tr. at 333. In primary mitochondrial disease, the mitochondria do not

function normally in a clinically measurable way. Id.; see also Holt v. Sec’y Health & Hum. Servs.,

No. 05–0136V, 2015 WL 4381588, at *23 (Fed. Cl. Spec. Mstr. June 24, 2015) (discussing the

distinction between mitochondrial disease and mitochondrial dysfunction).

Mitochondrial dysfunction, on the other hand, is a term used to describe “abnormalities in

laboratory testing that suggest that the mitochondrial electron transport chain is not functioning

normally.” Tr. at 333. As Dr. Boles described, “the mitochondria are not working right.” Id. at 92.

Importantly, this abnormal function is “agnostic [as] to … cause.” Id. at 333. Thus, in secondary

mitochondrial dysfunction, the cause of this improper functioning rests outside of the

mitochondria. Id. at 93. “[M]itochondrial disease is a subset of mitochondrial dysfunction.” Id. at

125-26.

By way of example, Dr. Boles explained that type 2 diabetes is, in large part, due to

mitochondrial dysfunction. Tr. at 99. However, that does not mean that people with type II diabetes

have mitochondrial disease. Id. at 98-99.

Dr. Boles opined that A.S. suffers from mitochondrial dysfunction. He testified that his

confidence regarding this opinion is “in the 90 percent range.” Tr. at 124-25. With respect to

mitochondrial disease, Dr. Boles opined that “I am not saying that [A.S.] is more than 50 percent

or 90 percent likely to have mitochondrial disease. I don’t know. [A.S.] may or may not have

mitochondrial disease. My best guess would be 50/50.” Id. at 126.

Haas describes mitochondrial disease as “not a single entity but, rather, a heterogeneous

group of disorders characterized by impaired energy production due to genetically based oxidative

phosphorylation dysfunction.” Hass’s purpose was to facilitate the clinical recognition of

mitochondrial disease. Haas at 1326.

Haas listed several “red-flag” symptoms for primary mitochondrial disease.

35

Haas at 1327, Table 1. According to Haas, “[t]hese red flag features warrant the initiation of a

baseline diagnostic evaluation for mitochondrial disease.” Haas at 1327. According to Dr. Boles,

A.S. displayed several of these red flags, to include a recurrent encephalopathy,

neurodegeneration, and severe gastrointestinal dysmotility. Tr. at 123.

With respect to a recurrent encephalopathy, Dr. Boles testified that “[e]ncephalopathy just

means that the brain is not working right. This patient certainly, in my mind, has encephalopathy.”

Tr. at 123. Dr. McCandless noted that physicians who want to confirm a diagnosis of primary

mitochondrial disorder will interpret some of Haas’s red flags more broadly. By way of example,

he noted that “‘encephalopathy’ is a broad term that can include many variations of altered levels

of consciousness or brain dysfunction, or it can be applied quite specifically to individuals with an

acute, or sub-acute, marked alteration in level of consciousness that is unexplained by other causes,

such as seizures.” First McCandless Rep. at 4-5. Given the broad definition of the term, A.S., by

virtue of experiencing seizures, suffered from recurrent encephalopathy. However, such a broad

application does little to advance Petitioners’ position that A.S. suffers from mitochondrial

dysfunction.

With respect to whether A.S. had neurodegeneration, Dr. Boles testified that “There is

neurodegeneration. Again, this patient has neurodegeneration.” Id. He did not provide any

36

additional information. Degeneration is defined as “deterioration; change from a higher to a lower

form; especially change of tissue to a less functionally active form.”8 Again, given the broad nature

of this definition, I agree with Dr. Boles that A.S. had neurodegeneration.

Finally, concerning severe gastrointestinal dysmotility, Dr. Boles opined that the fact that

A.S. needed a feeding tube and also at times experienced obstipation suggests that she had severe

gastrointestinal dysmotility. Tr. at 123-24. Dr. Boles testified that “[o]bstipation means that the

bowels are not just moving slowly, but basically they’re not moving at all, they’re plugged up.

That’s a serious medical problem and a red flag for mitochondrial dysfunction.” Tr. at 103. A.S.

did suffer from periodic obstipation and did require the placement of a feeding tube, however, it

is not clear that this constitutes severe gastrointestinal dysmotility. Dr. Wiznitzer testified that

obstipation is “very common in my patients like A.S. who basically don't move, who are not as

active as they should be. You need to maintain … normal, regular activity in order to actually have

good bowel function.” Tr. at 298. Dr. McCandless agreed, noting that “Chronic constipation with

leakage of watery stool is extremely common in individuals with severe brain abnormalities of any

cause.” First McCandless Rep. at 8. Accordingly, even assuming that A.S. did experience severe

gastric dysmotility, this does not suggest mitochondrial dysfunction.

With respect to each of the red flags listed in the Haas article, Dr. McCandless testified:

“When I look through this list, I don't really see a single thing on the list of cardinal findings, of

red flag findings, that A.S. has.” Tr. at 370.

Haas also noted that “there are a multitude of nonspecific symptoms that frequently occur

in children with mitochondrial disease but have a broad differential diagnosis, and more often lead

to other clear diagnoses.”9 Haas at 1327. With respect to these nonspecific symptoms, Dr.

McCandless opined that A.S. experienced failure to thrive, infantile spasms, intractable epilepsy,

and chronic unexplained constipation or diarrhea. Tr. at 371. He went on to note that “Seizures,

intellectual disability, poor feeding and constipation are all extremely common findings in children

with brain abnormalities for any reason, and they are in no way specific or strongly suggestive of

primary mitochondrial disease in this child.” First McCandless Rep. at 6.

Dr. McCandless also noted that A.S.’s growth suggests that she does not have

mitochondrial dysfunction. He testified as follows:

8

Dorland's, www.dorlandsonline.com/dorland/definition? id=12929 (last accessed February 2, 2022).

9

This list of nonspecific findings includes: failure to thrive, short stature, intrauterine growth retardation,

microcephaly, hypotonia, infantile spasms, intractable epilepsy, unexplained movement disorder, hearing

loss, axonal neuropathy, status epilepticus with an additional red flag or nonspecific feature, coma,

ototoxicity to certain medications, tachycardia, optic nerve hypoplasia, pigmentary retinopathy, chronic or

cyclic vomiting, chronic unexplained constipation or diarrhea, symmetric lipomatosis, hypothyroidism,

hypoparathyroidism, idiopathic growth hormone deficiency, renal tubular dysfunction, nephrotic

syndrome, unexplained basal ganglia lesions, unexplained central nervous system atrophy, unexplained

leukodystrophy, sudden infant death syndrome, multigenerational maternal inheritance pattern of migraine

headaches, depression, or anxiety disorder. Haas at 1328.

37

[I]f you have significant mitochondrial dysfunction, by definition, you have a

decrease in the efficiency of utilizing the energy you're taking in from the food you

eat, and the fact that A.S. continued to gain weight in spite of the fact that she was

at this point taking in less than the minimum expected amount of calories to support

growth and development suggests that she was using those calories very efficiently.

She just wasn't able to get enough of them in because of her neurological

dysfunction.

Tr. at 338. This point strengthens Dr. McCandless’ overall opinion that A.S.’s clinical picture is

not consistent with mitochondrial dysfunction. In analyzing the Haas article, I find that while A.S.

does have some findings that can be associated with mitochondrial disease or dysfunction, her

overall clinical picture, discussed in more detail below does not support this diagnosis.

In addition to his testimony concerning the Haas article, Dr. Boles also spent a significant

portion of his testimony discussing A.S.’s blood and urine testing.

1. Blood, Urine, and CSF Testing do not Support Mitochondrial Dysfunction in A.S.

Dr. Boles opined that A.S.’s abnormal blood and urine testing results constituted a

constellation of findings that when considered in their totality, were “highly specific for

mitochondrial dysfunction.” Tr. at 109. As discussed in more detail below, I do not agree with Dr.

Boles’ conclusion.

a. Plasma Lactate

Dr. Boles noted that A.S.’s plasma lactate levels were mildly elevated three times in June

of 2012 (18.8, 19.5 and 22.3 mg/dl (normal <18)). Boles Rep. at 7; Tr. at 106; see Ex. 5 at 192. He

testified that one elevation would not be concerning, but three elevated levels are “consistent with

mitochondrial dysfunction and suggestive thereof.” Tr. at 108. Dr. Boles further testified that “I

could only find three elevated -- I could only find three lactate determinations in the chart and all

three of them were elevated.” Id. In fact, A.S.’s plasma lactate levels were measured in the normal

range at 9mg/dL in January of 2013. Ex. 11 at 946; Ex. 5 at 192. The record in this case is devoid

of any explanation of this normal plasma lactate level and how it relates to mitochondrial

dysfunction in A.S.

Dr. McCandless disagreed with Dr. Boles’ testimony concerning the significance of A.S.’s

mildly elevated plasma lactate levels. He stated that standard practice in a children’s hospital is to

use a tourniquet to draw blood. Tr. at 346. This procedure results in “trivial elevations of lactate”

as seen in A.S.’s case. Id. at 345. Dr. McCandless testified further on this point:

In our clinical practice in Cleveland, we did an extensive analysis of lactate values,

comparing them to patients that eventually ended up with a diagnosis of

mitochondrial disease and those who did not. What we found is the patients that

ended up with a diagnosis of mitochondrial disease … -- that the lactates were

elevated, but they were at least 150 percent of the upper limit of normal of … the

reference range for that laboratory. And so our practice there … was that we did

38

not consider a lactate significantly elevated as being informative for mitochondrial

disease unless it was greater than 150 percent of the upper limit of normal in that

laboratory.

Tr. at 346.

I note that an article filed by Petitioners supports the point that A.S.’s plasma lactate levels

were not abnormally elevated so as to raise a concern for mitochondrial dysfunction. See Edmonds

et al., The Otolaryngological Manifestations of Mitochondrial Disease & the Risk of

Neurodegeneration with Infection, 128 ARCHIVES OF OTOLARYNGOLOGY–HEAD & NECK

SURGERY 355-62 (2002) (filed as Ex. 24) (hereinafter “Edmonds”). The Edmonds article evaluated

40 patients with mitochondrial disease. In order to be enrolled in the study, patients had to meet

two requirements: 1) lactic acid levels in the blood or CSF of 30 mg/dL or greater; and 2) an

objective defect in the mtDNA or oxidative phosphorylation. Edmonds at 356. A.S. met neither of

these requirements. With respect to plasma lactate levels, none of A.S’s levels exceeded 30 mg/dL.

While this point is not dispositive on the question of whether A.S. has mitochondrial dysfunction,

it does constitute further evidence suggesting she does not. I find that Dr. McCandless is persuasive

on this point, and that A.S.’s mildly elevated plasma lactate levels are not consistent with

mitochondrial dysfunction, but instead likely represent mildly elevated levels that result from the

use of a tourniquet.

b. Urine Organic Acids

Dr. Boles discussed the urine organic acids, noting that on June 25, 2012 these levels were

read as “non-specific.” He noted however, that “there were several elevations, including in

pyruvate 75 (normal 0-34), succinate 127 (normal 18-79…), citrate 1696 (75-667…), suberic 3 (0-

2 …), and glutarate 4 (0-2…).” Boles Rep. at 7-8; Ex. 11 at 1937.

In discussing pyruvate, Dr. Boles noted that A.S.’s pyruvate level was 75, where the normal

range is between zero to 34. Tr. at 110. Based on this, he stated that A.S.’s pyruvate level was

approximately double the upper limit of normal. Id. Dr. Boles further opined as follows: “I would

consider that elevated pyruvate to be a fairly good indicator of mitochondrial dysfunction, not

proof in itself, but an important part of the constellation that I’m building to suggest that the

entirety of the symptoms and signs suggest mitochondrial dysfunction.” Tr. at 110.

Dr. McCandless disagreed. He opined that A.S.’s pyruvate did not reach a level suggestive

of mitochondrial disease or dysfunction. Tr. at 346-47. He noted that “very few metabolic

specialists even think about the measurement of pyruvate in urine organic acids.” Id. at 350. Dr.

McCandless again provided persuasive testimony based on his experience running a laboratory.

He testified as follows:

And when you do the urine organic acid test, one of the things you do in preparing

the samples, you add a very strong base solution to the sample, and it totally screws

up the relationship of the lactate and pyruvate. So to say that there's a modest

elevation of pyruvate means nothing in the urine organic acid, and anyone who runs

39

a urine organic acid laboratory knows this. So the pyruvate is just -- it's just not

meaningful.

Tr. at 350-51.

Dr. McCandless also discussed several other organic acids that were mildly increased, to

include oxalic acid and fluorophenylacetic acid, glycine and hexanoylglycine. He noted that these

levels may be related to overgrowth of gut bacteria, which he described as “a common thing that

one sees in people with neurologic disorders who have constipation.” Tr. at 347.

With respect to glutaric acid, which Dr. Boles noted as elevated in his report (tested at 4

with a normal range of 0-2), Dr. McCandless again opined that this result was not significant. “I'll

tell you, as someone who has done this test in the lab for almost 20 years, there is no difference

between four and two in these numbers. They are the same. That is not a significant difference.

And to try to interpret this lab to that degree of specificity is a gross overcall.” Tr. at 349.

Dr. Boles highlighted A.S.’s succinate level, which was 127 where the normal range

extends up to 79. Tr. at 110. Dr. Boles opined that this level shows an abnormal and fatty acid

metabolism. Id. In disagreeing with Dr. Boles, Dr. McCandless testified as follows: “Succinic acid

is well known to go up and down and to be often very elevated. It can be elevated in people that

have mitochondrial disease, but it's usually markedly elevated. It's one of the largest peaks on the

chromatogram, and that is not the case in this sample.” Id. at 351.

Dr. Boles discussed suberic acid in his report and at hearing, noting that it was mildly

elevated. Tr. at 111. Dr. McCandless testified that “it's well documented in the literature, since the

late 1980s, that suberic acid is a commonly seen finding in children that are on special formulas,

like that have medium chain fats in them, or when children are fasting. So suberic acid is typically

a marker for fasting.” Id. at 352.

Dr. McCandless additionally noted that A.S. did not have elevated levels of 3-

methylglutaric acid (3MG) or 3-methylglutaconic acid, which are generally elevated in individuals

with mitochondrial dysfunction. Tr. at 352.

In sum, while some of A.S.’s urine organic acid levels were elevated, Dr. McCandless

persuasively explained that these elevations did not support that A.S. suffers from mitochondrial

dysfunction.

c. Plasma Acylcarnitines

A.S.’s October 24, 2013 testing revealed mild elevations in C2, a fatty acid called

acetylcarnitine (21.54, normal 2.79-16.23), C3DC, C4OH, and C5OH metabolites. Ex. 2 at 41.

With respect to these numbers, Dr. Boles opined that “while there are various reasons why those

metabolites can be elevated, the constellation of all of those metabolites being elevated, in my

mind, strongly suggests mitochondrial dysfunction.” Tr. at 113.

40

Dr. McCandless opined that analysis of acylcarnitine is not especially informative

concerning mitochondrial disorders. Tr. at 353. He further stated “[t]his is the pattern we see in

the lab every day on patients who are taking supplemental carnitine.” Id. At the time of this test,

A.S. was in fact taking supplemental carnitine. See Ex. 2 at 11.

Dr. McCandless also made the compelling point that during A.S.’s initial hospital

admission on June 22, 2012, when she was at her sickest, her acylcarnitine levels were normal.

See Ex. 11 at 2362. This same test measured her total carnitine at 46, which is below the reference

interval, but according to Dr. McCandless “well within the normal range.” Tr. at 357; Ex. 11 at

2364. He testified that “[i]ndividuals who are sick, who are acutely ill or just not feeding very well,

their carnitine will always be low. I don't consider a total carnitine significantly low until it's below

15 or 20.” Tr. at 357.

d. Methyltetrahydrofolate

Dr. Boles noted that A.S.’s methyltetrahydrofolate level was in the low end of normal (41)

when tested on November 4, 2013; normal range is between 40-197. Tr. at 120. Dr. Boles testified

that “[t]he methyltetrahydrofolate is low or low normal in many cases of mitochondrial

dysfunction. However, it is nonspecific and it is simply one of many different indications in terms

that there might be mitochondrial dysfunction in this patient.” Tr. at 121.

Dr. McCandless disagreed with Dr. Boles, and noted that although people with

mitochondrial disease can have low methyltetrahydrofolate levels, this particular test will also

return low in people that have seizures. Tr. at 365. He testified that “almost -- every sample I've

ever sent for that test, that is low, and that's because we do the test in people with seizures, and it's

well known that that test will be low in people that have seizures.” Id. A.S. was experiencing

seizures at the time this test was performed. Because of that, Dr. McCandless opined that the low

result was not indicative of mitochondrial dysfunction or disease. Id.

Ultimately, I do not find that A.S.’s plasma lactate, urine organic acid, acetylcarnitine, or

methyltetrahydrofolate levels are indicative of mitochondrial disease or dysfunction. In arriving at

this determination, I have credited the opinion of Dr. McCandless over that of Dr. Boles.

2. Buccal Swab Testing Does Provide Some Minimal Support for Mitochondrial

Dysfunction in A.S.

The results of buccal swab testing received on November 27, 2012 note that “A.S. may

have a significant deficiency in the respiratory complex IV activity of the bucca mitochondria.”

Ex. 7 at 35. Dr. Boles testified that buccal swab testing is the gold standard for diagnosing

mitochondrial dysfunction and that these results “prove[] mitochondrial dysfunction in this child.”

Tr. at 113, 114.

Dr. McCandless disagreed with Dr. Boles and testified that buccal swab testing is not

“widely accepted by mitochondrial experts as having significant value.” Tr. at 358. One reason for

this is the lack of published data that show how stable the mitochondrial enzymes are after a saliva

sample is collected and then shipped to the laboratory. Tr. at 360.

41

Dr. McCandless further noted that there is only one piece of medical literature on this

testing, and the article was written by the inventor of the test. Id. Importantly, the literature does

not provide the validation data that, according to Dr. McCandless, “a laboratory would need for

proposing a diagnostic test.” Id. at 359.

Dr. McCandless additionally criticized the test due to its lack of specificity. He indicated

that he can't find that the specificity of the test has ever been published. In terms of the significance

of this lack of specificity, he testified as follows:

When you're looking for a diagnosis and you do a test, most of the people you do

your test on are going to be normal … it looks positive even though they don't have

the disease -- and you do that test thousands of times, and most of the people that

you do the test on don't have the disease, what that means is that most of the positive

tests will be false-positives. So a test like this cannot be used for diagnostic

purposes until that … positive predictive value of the test is known and published,

and that is not known for this test.

Tr. at 359-60.

Dr. McCandless also discussed the particulars of A.S.’s sample. He testified that there is a

normal range of protein you should see in a buccal swab sample. This range is between 350 to

1000 micrograms. Tr. at 361. A.S.’s sample had 160 micrograms of protein, which “means every

value in that sample should be questioned even more carefully.” Id. In the testing process, the

citrate synthase is divided by the protein measurement. Id. at 362. Dr. McCandless noted that “if

the protein measurement you're using is outside the control range, it means that you're amplifying

the inherent error in the measurement.” Id.

Ultimately, Dr. McCandless opined that the buccal swab test is like a screening test and

can constitute “an indicator that you should consider doing more testing.” Tr. at 361. I find Dr.

McCandless to be persuasive on this point. A.S.’s buccal swab testing constituted some evidence

suggesting further inquiry into whether A.S. had mitochondrial dysfunction was appropriate.

Standing on its own, it does not preponderantly establish that A.S. did have such dysfunction.

3. A.S.’s Mitochondrial DNA Sequence does not Support Mitochondrial Dysfunction

In his report, Dr. Boles stated that A.S.’s mitochondrial DNA sequence was read as normal,

but he opined that “there are two rare variants that cannot be said to be either definitely “benign”

or “disease related,” and thus are better defined as “variants of uncertain significance”: 5298A>G,

p.Ile277Val in the ND2 gene (present in 4/6391 people), and 5913G>A, Asp4Asn in the CO1 gene

(present in 27/6391 people).” Boles Rep. at 8. At hearing, Dr. Boles testified that over time it was

discovered that the NDUFA1 variant was too common and not disease linked, so it would be

interpreted as a benign variant today. Tr. at 131.

42

Dr. McCandless opined that neither molecular variant in A.S.’s mitochondrial DNA is

likely associated with mitochondrial disease. Dr. McCandless stated that the NDUFA1 variant is

present in A.S.’s father, who is unaffected by it. Dr. McCandless further explained that “this gene

is on the X chromosome, of which males have only one copy, and females two. It is a generally

accepted principal of clinical genetics that an X chromosome variant that does not cause disease

in a male is not a reasonable explanation for disease in a female.” First McCandless Rep. at 5.

Further, after they issued their report, the laboratory that did the testing discovered that this variant

was benign. Tr. at 369.

Dr. McCandless noted that her other variant involves a gene “that if you have both copies

broken causes a condition called methylmalonic acidemia. She does not have methylmalonic

acidemia. Her metabolites … very clearly prove that.” Tr. at 367.

Ultimately, we know A.S.’s mitochondrial DNA sequence, and this information does not

support mitochondrial dysfunction in A.S.

4. MRI Imaging does not Support Mitochondrial Dysfunction in A.S.

Dr. McCandless opined that if there “was an acute and severe failure of mitochondrial

function, one would reasonably expect to see MRI changes.” Third McCandless Rep. at 2. A.S.’s

MRIs from June 21, 2012, January 18, 2013, and December 18, 2013 showed no evidence of

parenchymal abnormality. See Ex. 11 at 2328; 255, 976. Dr. McCandless opined that the lack of

findings on MRI does not, standing alone, rule out mitochondrial dysfunction; however, it

constitutes “one more argument against that diagnosis.” Third McCandless Rep. at 2. Dr. Wiznitzer

agreed, stating “[t]he normal MRI and EEG findings during her June 2012 hospital admission are

consistent with the conclusion that she did not have an acute encephalopathy with impairment of

consciousness and that her neurological dysfunction was not caused by mitochondrial

dysfunction.” Third Wiznitzer Rep. at 4.

In an article filed by Petitioners, Dr. Andrea Gropman discussed neuroimaging in cases of

mitochondrial disease. She noted that “common patterns of brain MR imaging can be identified in

patients with mitochondrial disorders.” Andrea L. Gropman, Neuroimaging in Mitochondrial

Disorders, 10 NEUROTHERAPEUTICS 273-85, 284 (2013) (filed as Ex. 60) (hereinafter “Gropman”).

This article supports Respondent’s position that regression caused by mitochondrial disease should

be visible on MRI. The fact that A.S.’s MRIs were normal is further evidence that she did not have

a mitochondrial dysfunction.

5. A.S.’s Treating Physicians

Several of A.S.’s treating physicians questioned whether A.S. had mitochondrial

dysfunction. For example, Dr. Fran Kendall noted at an appointment on March 6, 2013 that “the

NDUFA-1 variant is likely the cause of her issues.” Ex. 10 at 4. At the time of this appointment,

Dr. Kendall did not know that the NDUFA-1 variant was benign. The fact that one premise of Dr.

Kendall’s opinion was incorrect undercuts the weight that I have afforded it. In addition, citing to

the buccal swab test results, Dr. Kendall stated that “buccal swab mito enzyme screening studies

were notable for signs of mito proliferation and complex IV deficiency.” Id. For the reasons

43

discussed earlier in this decision, I do not find this opinion regarding buccal swab testing to be

persuasive.

On February 11, 2013, A.S. and her parents had a genetic consultation with Dr. Vidya

Krishnamurthy, who assessed A.S. with a mitochondrial metabolism disorder. Ex. 7 at 60-61. Like

Dr. Kendall, Dr. Krishnamurthy also based his assessment on an incorrect interpretation of the

NDUFA1 variant. He further noted that buccal swab testing “showed complex IV deficiency but

needs to be retested.” Id. at 60.

Although Drs. Kendall and Krishnamurthy both considered that A.S. suffered from

mitochondrial dysfunction, neither provided an updated opinion once the NDUFA1 variant was

identified as benign. Further, in examining A.S.’s more recent medical records, her treating doctors

do not refer to mitochondrial disease. A.S. is no longer receiving carnitine treatment for

mitochondrial diseases. This suggests her treating doctors do not believe she suffers from that

condition.

Additionally, Dr. McCandless noted that her neurologist, Dr. Nayak, treated A.S. with

valproic acid. See Ex. 53 at 194. He testified that “[n]o neurologist that I know, no respectable

neurologist, would ever put a patient they believed has mitochondrial disease on Depakote, on

valproic acid, because that is a known danger … that is well known to cause liver failure in kids

with mitochondrial dysfunction.” Tr. at 372-73. The fact that Dr. Nayak treated A.S. with valproic

acid is strong evidence of his belief that she did not suffer from mitochondrial dysfunction.

In evaluating the evidence on this issue, to include the medical records, the testing results,

and the expert opinions, I find that Petitioners have not presented preponderant evidence that A.S.

suffers from mitochondrial disease or dysfunction.

B. Loving Prong One: A.S.’s Condition Prior to the June 18, 2012 Vaccinations

Prior to the June 18, 2012 vaccinations, A.S. was experiencing a severe neurologic

dysfunction such that the evening after her six-month well visit, Petitioners were “up all night

processing” and researching on the internet. Ex. 8 at 3. A.S. was not taking in enough calories,

likely due to an underlying neurologic issue which resulted in tongue thrusting. Ex. 8 at 5; Tr. at

261. Since birth, she had taken up to one hour to feed. Ex. 11 at 2188. She had lost the ability to

consistently roll over. Ex. 8 at 4. She was “always stiff” and exhibited foot and hand clenching.

Id.; Ex. 3 at 1. At five months of age, she began focusing on Mrs. Svagdis’ face less. She displayed

decreased eye contact and an increased progressive tendency to zone out. Ex. 3 at 1.

C. Loving Prong Two: A.S.’s Condition after the June 18, 2012 Vaccinations

After her June 18, 2012 vaccinations, Petitioners followed the recommendation Dr.

Douglas made during the six-month well visit and scheduled an appointment with a neurologist.

Dr. Cheng evaluated A.S. on June 20, 2012 and told Petitioners “there’s a hospital right there, walk

over there, go now, it would be faster than an ambulance.” Tr. at 37. A.S. was admitted to CHOA.

She continued a downward trend in calorie consumption, consuming under two ounces while

feeding. She had an NG tube placed on June 22, 2012. After that, her “[d]isposition and interaction

44

[] markedly improved on full feeds.” Ex. 11 at 2264. EEGs on June 20 and June 22, 2012 were

normal.

A.S. was admitted to CHOA in November of 2012 and had an abnormal EEG. She was

found to be “at risk of having recurrent unprovoked seizures.” Ex. 11 at 1234. As a result, she was

started on Trileptal. Id. A.S. began having paroxysmal episodes in November of 2012. Ex. 11 at

1235-37. She developed infantile spasms in December of 2012, which were well controlled with

Topamax.

As of August 14, 2014, when she was approximately 32 months of age, A.S.’s development

was tested at about the 10 month level. During this visit, Dr. Flamini noted that A.S. “makes noises,

still won’t swallow and is tube fed.” She was noted to be “sitting independently with lateral

protective reflexes, not up on all 4’s.” Ex. 2 at 1. Her condition at the time of the entitlement

hearing remained substantially the same as what Dr. Flamini observed in August of 2014. See Tr.

at 55.

D. Loving Prong Three: Did A.S. Experience a Significant Aggravation of her

Condition?

A.S.’s deterioration is consistent with the Vaccine Act’s definition of significant

aggravation resulting in markedly greater disability, pain, or illness accompanied by substantial

deterioration of health. § 33(4). Therefore, this leaves the question of whether that significant

aggravation was vaccine-related.

E. Loving Prong Four/Althen Prong One: Petitioners have not Established a Reliable

and Reputable Theory Concerning How the Vaccinations A.S. Received Can

Cause the Significant Aggravation of A.S.’s Underlying Neurologic Condition

Under Loving prong four/Althen prong one, the causation theory must relate to the injury

alleged. Thus, petitioners must provide a “reputable” medical or scientific explanation,

demonstrating that the vaccine received can cause the type of injury alleged. Pafford, 451 F.3d at

1355-56. The theory must be based on a “sound and reliable medical or scientific explanation.”

Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). It must only be

“legally probable, not medically or scientifically certain.” Id. at 549.

Petitioner’s theory that the vaccines A.S. received “can cause” a significant aggravation of

her pre-existing condition can be summarized as follows: A.S. has an underlying mitochondrial

dysfunction; vaccination caused cytokine production; these cytokines crossed the blood-brain

barrier and were produced at a high enough level to result in overwhelming oxidative stress;

because mitochondrial DNA are particularly susceptible to oxidative stress, this stress resulted in

cell death, which in turn caused progressive insults to the brain. See Pet’r’s Post Hearing Brief at

9. The vaccines ultimately caused “neuro intra-brain damage or encephalopathy” that eventually

resulted in infantile spasms (approximately five months later). Tr. at 175-76. (Dr. Kinsbourne

testified that “In this case, there was no evidence of epilepsy at the onset of the vaccine injury.

However, the brain damage that resulted from it in the longer term did result in seizures and

specifically in infantile spasms.”) Tr. at 163.

45

Other Vaccine Program cases have considered and rejected this theory. See Kreizenbeck v.

Sec’y of Health & Hum. Servs., No. 08-209V, 2018 WL 3679843, at *31 (Fed. Cl. Spec. Mstr.

June 22, 2018) (finding Dr. Kinsbourne's opinion regarding the ability of vaccines to

cause oxidative stress and ensuing immune dysfunction to be “weakly grounded in reliable

science.”); Pope v. Sec’y of Health & Hum. Servs., No. 14-078V, 2017 WL 2460503, at *20 (Fed.

Cl. Spec. Mstr. May 1, 2017) (finding that petitioners did not offer a reliable causation theory that

vaccines could precipitate an encephalopathic event in a person with mitochondrial dysfunction

resulting in developmental regression); Miller v. Sec'y of Health & Human Servs., No. 02-235V,

2015 WL 5456093 (Fed. Cl. Spec. Mstr. Aug. 18, 2015) (concluding that petitioners failed to

demonstrate that several childhood vaccines caused encephalopathy or aggravated

underlying mitochondrial disease/dysfunction).

At the outset, I note that several studies have documented the safety of vaccines in

individuals with mitochondrial enzyme deficiencies. See Morgan, et al., Vaccines Are Not

Associated With Metabolic Events in Children With Urea Cycle Disorders, 127 PEDIATRICS 5,

1147-53 (2011) (filed as Ex. K, Tab 4); Klein, et al., Evaluation of Immunization Rates and Safety

Among Children With Inborn Errors of Metabolism, 127 PEDIATRICS 5, 1139-46 (2011) (filed as

Ex. K, Tab 3); Barshop & Summar, Attitudes regarding vaccination among practitioners of

clinical biochemical genetics, 95 MOLECULAR GENETICS AND METABOLISM 1-2 (2008) (filed as

Ex. K, Tab 1). These studies support the point that even if A.S. did suffer from an underlying

mitochondrial disorder, this condition did not make her more susceptible to vaccine-induced

injury.10

It is important to note that Petitioner’s expert immunologist linked his causation opinion to

the existence of A.S.’s underlying mitochondrial dysfunction. Dr. Gershwin testified at hearing as

follows: “[I]f it turns out that A.S. does not have a mitochondrial defect, then my plausible -- what

I think are plausible explanations of what happened would not be offered in this courtroom.” Tr.

at 200. Because I have found that A.S. does not have mitochondrial dysfunction, this portion of

Petitioners’ theory is unsupported. Several other components of Petitioners’ theory are also

unsupported.

10

Although not discussed by any expert in the case, I also considered the case report filed by Petitioners

involving Hannah Poling. See Jon S. Poling et al., Developmental Regression and Mitochondrial

Dysfunction in a Child With Autism, 21(2) J. CHILD NEUROLOGY 170 (2006) (filed as Ex. 27) (hereinafter

“Poling”). The case report noted: “This patient exemplifies important questions about mitochondrial

function in autism and developmental regression.... If such [mitochondrial] dysfunction is present at the

time of infections and immunizations in young children, the added oxidative stresses from immune

activation on cellular energy metabolism are likely to be especially critical for the central nervous system,

which is highly dependent on mitochondrial function. Young children who have dysfunctional cellular

energy metabolism therefore might be more prone to undergo autistic regression between 18 and 30 months

of age if they also have infections or immunizations at the same time. Although patterns of regression can

be genetically and prenatally determined, it is possible that underlying mitochondrial dysfunction can either

exacerbate or affect the severity of regression.” In the case report, Poling questions whether vaccination

triggers autistic regression in children with underlying mitochondrial dysfunction. I find that this single

case report does not demonstrate that this occurs in cases of autism and does not speak to any other

conditions.

46

1. There is not Preponderant Evidence that Cytokines Resulting from Vaccination

Would be Produced at High Enough Levels to Cause the Damage Alleged

It is well established in the Vaccine Program that vaccination does promote the production

of cytokines. However, Dr. McCusker noted that post-vaccination cytokines are produced at an

extremely low level. First McCusker Rep. at 6. She persuasively opined that “[t]here is no evidence

that low levels of peripheral cytokines released during vaccination result in pathological increases

in CNS [central nervous system] cytokines.” Id. at 7.

Dr. McKusker cited Kashiwagi et al. as support for this point. Kashiwagi et al., Production

of inflammatory cytokines in response to diphtheria-pertussis-tetanus (DPT), haemophilus

influenzae type b (Hib), and 7-valent pneumococcal (PCV7) vaccines, 10 HUMAN VACCINES &

IMMUNOTHERAPEUTICS 3, 677–85 (2014) (filed as Ex. J, Tab 8) (hereinafter “Kashiwagi”).

Kashiwagi examined the cytokine production in children after vaccination by measuring specific

cytokine levels in serum. They demonstrated that IL1β , IL6, and TNFα were all detected at low

levels. According to Dr. McCusker, “These data suggest that cytokines are produced and released

by the peripheral immune system during vaccination but there is no evidence to suggest that the

levels are sufficient to influence the development of cytokine-mediated changes in seizure

thresholds as hypothesized by Petitioner’s Expert.” First McCusker Rep. at 6.

Dr. Kinsbourne referenced Dubé et al. in support of his opinion. See Dubé et al.,

Interleukin-1β Contributes to the Generation of Experimental Febrile Seizures, 57 ANN NEUROL.

1, 152-55 (2005) (filed as Ex. 17) (hereinafter “Dubé”). Dubé examined the role of IL1β in febrile

seizures, specifically whether the infusion of IL1β into the lateral cerebral ventricles of mice would

lower the seizure threshold. Dr. Kinsbourne noted that this study showed that IL1β injected into

normal mice caused seizures, and that mice lacking the IL1β receptor were resistant to seizures.

First Kinsbourne Rep. at 6. According to Dr. Kinsbourne, “[t]his work made it clear that an

etiologic agent can provoke seizures regardless of whether a febrile reaction occurred.” Id. While

Dr. McCusker acknowledged that extremely high dose cytokine levels infused directly into the

brain may lower the seizure threshold in mice, she emphasized the significance of the fact that “the

amounts of cytokines required to induce this lowering of seizure thresholds in mice were more

than 1000X greater than those found post vaccination in humans.” First McCusker Rep. at 6. Dr.

McCusker persuasively opined that vaccination does not result in significant cytokine changes in

the brain. Accordingly, the Dubé article does little to advance Petitioners’ position.

Ultimately, I am not convinced that cytokines produced following vaccination can result

in the neurologic damage in the manner alleged in this case.

2. There is not Preponderant Evidence that a Mitochondrial Disorder Would Cause

Mitochondria to Aberrantly Respond to Cytokines Resulting in Cell Death

Dr. Gershwin opined that because of her genetic mitochondrial defect, “[A.S.] would be

more susceptible to cytokine production than a normal child who does not have mitochondrial

dysfunction.” Gershwin Rep. at 2. He opined that “in the presence of mitochondrial dysfunction,

which will lead to alteration in ATP production, increased production of reactive oxygen species,

47

calcium dysregulation, and mitochondrial DNA damage, then her brain would be more susceptible

to d

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