Gram v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 15-515V

Filed: November 16, 2022

* * * * * * * * * * * * *

ELIZABETH GRAM, for and on behalf of * To Be Published

her minor daughter, A.L.M., *

*

Petitioner, * Ruling on Entitlement; Afebrile Seizures;

* Epilepsy; DTaP, Hib, MMR,

v. * Prevnar 13, Varicella Vaccines;

* Insufficient Proof of Causation.

SECRETARY OF HEALTH *

AND HUMAN SERVICES, *

*

Respondent. *

*

* * * * * * * * * * * * *

Sean Greenwood, Esq., Greenwood Law Firm, Houston, TX, for petitioner.

Christine Becer, Esq., U.S. Department of Justice, Washington, DC, for respondent.

DECISION1

Roth, Special Master:

On May 19, 2015, Elizabeth Gram (“Ms. Gram” or “petitioner”) filed a petition on behalf

of her minor child, A.L.M., for compensation under the National Vaccine Injury Compensation

Program, 42 U.S.C. §300aa-10, et seq.2 (the “Vaccine Act” or “Program”). The petition alleges

that A.L.M. received DTaP, Hib, MMR, Pneumococcal conjugate, and Varicella vaccinations on

October 25, 2012 and thereafter developed a seizure disorder. Petition at 1, ECF No. 1.

An entitlement hearing was held on November 23, 2020 via videoconferencing. Following

careful review and analysis of all the documentary evidence and testimony submitted in this case

1

This Decision has been designated “to be published,” which means I am directing it to be posted on the

Court of Federal Claims’ website, in accordance with the E-Government Act of 2002, Pub. L. No. 107-347,

116 Stat. 2899, 2913 (codified as amended at 44 U.S.C. § 3501 note (2006)). This means the Decision will

be available to anyone with access to the internet. However, the parties may object to the Decision’s

inclusion of certain kinds of confidential information. Specifically, under Vaccine Rule 18(b), each party

has fourteen days within which to 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, the whole Decision will be available to the public. 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).

by both petitioner and respondent and in accordance with the applicable legal standards, I find that

petitioner has not proffered sufficient evidence to demonstrate that the vaccinations A.L.M.

received on October 25, 2012 caused or contributed to her afebrile seizure disorder. Accordingly,

I find that petitioner is not entitled to compensation.

I. Issues to be Determined

The parties dispute whether any of the vaccines A.L.M. received on October 25, 2012 can

cause afebrile seizures and epilepsy, and, if so, whether the vaccines caused A.L.M.’s injury here.

Thus, all three Althen prongs are at issue.

II. Procedural History

Ms. Gram filed the petition on May 19, 2015, and her case was initially assigned to Special

Master Nora Beth Dorsey. Pet. Ex. 1, ECF No. 1. Petitioner filed medical records in the form of

compact discs on the following dates: July 7, 2015, March 8, 2016, and June 14, 2016. On October

21, 2015, the case was reassigned to the undersigned. ECF No. 15. Petitioner filed additional

medical records on the following dates: March 4, 2016, August 8, 2016, August 7, 2017. Pet. Ex.

13, 15, 19, and 20, ECF Nos. 23, 33, and 46.

Petitioner filed expert reports from Dr. Marcel Kinsbourne on August 8, 2016, Pet. Ex. 14,

ECF Nos. 35, 41, and 91; on March 13, 2017, Pet. Ex. 16, ECF Nos. 42 and 91; on September 7,

2017, Pet. Ex. 21, ECF. Nos. 49 and 91; and on April 16, 2018, Pet. Ex. 36, ECF Nos. 53 and 91.

Petitioner also filed expert reports from Dr. Alan Levin on September 24, 2018, Pet. Ex.

39, ECF No. 62; and on May 20, 2019, Pet. Ex. 50, ECF No. 80.

In support of petitioner’s expert reports, petitioner filed medical literature on September 7,

2017, Pet. Ex. 22-35, ECF No. 49; on April 16, 2018, Pet. Ex. 37, ECF Nos. 53 and 91; on August

17, 2018, Pet. Ex. 37 and 38, ECF No. 58; on September 24, 2018, Pet. Ex. 41-45, ECF No. 63;

on June 26, 2019, Pet. Ex. 51-55, ECF No. 81; on October 13, 2020, Pet. Ex. 58, ECF No. 100;

and November 17, 2020, Pet. Ex. 59-61, ECF No. 105.

Respondent filed expert reports from Dr. Gregory Holmes on November 8, 2016, Resp.

Ex. A, ECF No. 37; on December 29, 2017, Resp. Ex. Q, ECF No. 51; on June 15, 2018, Resp.

Ex. V, ECF No. 55; and on August 16, 2019, Resp. Ex. YY, ECF No. 82.

Respondent also filed expert reports from Dr. Christine McCusker on December 21, 2018,

Resp. Ex. Z, ECF Nos. 73 and 75; and on August 16, 2019, Resp. Ex. FFF, ECF No. 82.

In support of the expert reports, respondent filed medical literature on December 8, 2016,

Resp. Ex. C-P, ECF No. 38; on December 29, 2017, Resp. Ex. R-U, ECF No. 51; on June 15, 2018,

Resp. Ex. W-Y, ECF No. 55; on April 17, 2019, Resp. Ex. BB-XX, ECF Nos. 78 and 79; and on

August 16, 2019, Resp. Ex. ZZ, AAA-EEE, GGG, and HHH, ECF No. 82.

An entitlement hearing was held on November 23, 2020 via videoconferencing. Both

2

parties filed post-hearing briefs on March 11, 2021, and petitioner filed a reply brief on January

14, 2022. See ECF Nos. 109, 110, and 111.

This matter is now ripe for decision.

III. Relevant Medical Terminology

The following medical terms appear throughout this decision.

A seizure is defined as the sudden attack or recurrence of a disease or the single episode

of epilepsy.3 It involves a temporary, uncontrolled surge of electrical activity in the brain.4 Multiple

seizures occurring in a 24-hour period are considered a single event.5

A focal seizure, also known as a “partial” seizure, is a seizure that occurs in a specific part

of the brain, although the surge of electrical activity can move from one location to another as the

seizure intensifies.6 These seizures are most common in people with head injuries, febrile

childhood seizures, brain infections, or other conditions that affect the brain.7

A complex partial seizure is a partial seizure characterized by varying degrees of

impairment of consciousness; the person affected performs non-purposeful, repetitive movements

which they may not remember.8

A provoked seizure is a seizure that is the result of environmental stress, such as low blood

sugar, low blood sodium, fever, alcohol or drug withdrawal, or an infection that does not usually

affect the brain. 9 Tr. 141. On the other hand, an unprovoked seizure occurs without a concurrent

illness, fever, or acute brain injury.10

Epilepsy is characterized by paroxysmal transient disturbances of brain function that may

manifest as loss of consciousness, abnormal motor phenomena, sensory disturbances, or

perturbation of the autonomic nervous system.11 It is considered one of the most common nervous

system disorders.12

Mesial temporal sclerosis is scarring in the inner portions of the temporal lobe. It may be

caused by brain infection or head trauma that interrupts the flow of oxygen to the temporal lobe,

3

Dorland’s Illustrated Medical Dictionary 1660 (33rd ed. 2019) [hereinafter “Dorland’s”].

4

Cleveland Clinic, Seizure, https://my.clevelandclinic.org/health/diseases/22789-seizure.

5

Wei-Ling Lee, MD & Hian-Tat Ong, MD, Afebrile Seizures Associated with Minor Infections:

Comparison with Febrile Seizures and Unprovoked Seizures, 31 PEDIATRIC NEUROLOGY 157, 158 (2004),

filed as “Pet. Ex. 29.”

6

Cleveland Clinic, Focal Seizure, https://my.clevelandclinic.org/health/diseases/22893-focal-seizure.

7

Id.

8

Dorland’s 1660.

9

Lee & Ong, supra note 5.

10

Id.

11

Dorland’s 626.

12

Johns Hopkins Medicine, Epilepsy: Overview, https://www.hopkinsmedicine.org/health/conditions-and-

diseases/epilepsy.

3

resulting in brain cell death. It can cause a form of temporal lobe epilepsy with partial (focal)

seizures that can spread and affect other areas of the brain.13

Encephalopathy is any degenerative disease of the brain that alters brain function or

structure.14 Abnormal results from cerebrospinal fluid (“CSF”) may show encephalopathy.15

Landau-Kleffner Syndrome is an epileptic syndrome of childhood characterized by

partial or generalized seizures, psychomotor abnormalities, and aphasia progressing to mutism.16

IV. The Factual Record

A. A.L.M.’s Medical History Prior to the Vaccinations

A.L.M. was born on October 24, 2011. Pet. Ex. 14. Apart from being slightly jaundiced at

birth, A.L.M. was the product of an uncomplicated term pregnancy. Pet. Ex. 10 at 5; Pet. Ex. 14

at 3. She received a Hepatitis B vaccination on the day she was born. Pet. Ex. 10 at 7, 9. She was

discharged home with her mother on October 26, 2011. Pet. Ex. 11 at 221-37; Pet. Ex. 10 at 5-10.

A.L.M. was presented for follow up examinations of neonatal jaundice on October 27,

2012 and October 29, 2012. Pet. Ex. 11 at 196, 219-22.

A.L.M. had some feeding difficulties in the first month of life that resolved without event.

Pet. Ex. 11 at 181-82, 191-92, 194.

On November 29, 2011, at five weeks old, A.L.M. was presented to the pediatrician with

acute respiratory infection, congestion, and spitting up. Pet. Ex. 11 at 175. A.L.M. was gasping at

times, seemed unable to breathe, and had not slept well the night prior; she tested positive for

respiratory syncytial virus (“RSV”). Id. at 176-77, 179.

At a follow up examination on December 2, 2011, A.L.M.’s physician noted that she had

acute bronchiolitis due to RSV with eyes tearing, loss of appetite, ear problem, increased

congestion, and coughing. Pet Ex. 11 at 167-68, 170-72. Petitioner was instructed to use a

humidifier, saline drops, and a bulb syringe. Id. at 172. At follow up on December 8, 2011, A.L.M.

was improving with an increased appetite, but she had a raspy cry. Id. at 167.

At her two-, four-, and six-month-old well baby visits, A.L.M. was meeting all milestones.

Pet. Ex. 11 at 146-48, 151-54, 158-61. On January 13, 2012, she received Pediarix (a combination

vaccine which includes DTaP, Hepatitis B and polio) and Hib vaccinations; petitioner declined

13

Johns Hopkins Medicine, Epilepsy Causes, https://www.hopkinsmedicine.org/health/conditions-and-

diseases/epilepsy/epilepsy-causes.

14

Dorland’s 608; National Institute of Neurological Disorders and Stroke, Encephalopathy,

https://www.ninds.nih.gov/health-information/disorders/encephalopathy.

15

T. Ichiyama et al., Tumor Necrosis Factor-[alpha], interleukin-1[beta], and interleukin-6 in

Cerebrospinal Fluid from Children with Prolonged Febrile Seizures: Comparison with Acute

Encephalitis/Encephalopathy, 50 AM. ACAD. OF NEUROLOGY 407 (1998), filed as “Pet. Ex. 42.”

16

Dorland’s 1806.

4

Prevnar and Rotateq at this visit. Id. at 161. On March 6, 2012, A.L.M. received Hib, Pediarix, and

Prevnar 13 (a pneumococcal vaccine that protects against bacterium Streptococcus pneumoniae)

vaccinations. Id. at 155. On April 25, 2012, she received Pediarix and Prevnar 13. Id. at 150.

A.L.M. received all the above vaccinations without event.

On June 5, 2012, A.L.M. was presented to the pediatrician after rolling off the bed and

hitting her head on the carpeted floor. Pet. Ex. 11 at 141. Her mother reported a bump on her

forehead. Id. Petitioner also reported that A.L.M. had rolled off the bed earlier in the week as well

and was found on her belly. Id. A.L.M. cried a bit but was laughing later. Id. She had no vomiting,

was acting fine, and was using all extremities. Id. The physician noted that A.L.M. had a possible

bump on the right side of her forehead. Id. at 142.

On July 24, 2012, at her nine-month-old well baby check, A.L.M. was meeting all

milestones and had a normal checkup. Pet. Ex. 11 at 86-90, 137, 139.

On August 21, 2012, A.L.M. was presented to the emergency room (“ER”) at Memorial

Hermann Southeast Hospital (“Memorial Hermann”) with vomiting, diarrhea, and fever since the

night before. Pet. Ex. 7 at 141. An abdominal X- ray showed gaseous distention of the stomach

and portions of the small and large bowel with multiple air fluid levels on upright view. Id. at 142.

The physician noted that the findings were “not normal” and may be related to adynamic ileus or

a small bowel obstruction. Id. at 142, 145. Petitioner left with A.L.M. before the results were

discussed and before discharge papers were given. Id. at 143. The discharge notes indicated that

A.L.M. was in good and stable condition. Id.

A.L.M. was presented to the pediatrician the next day with a two-day history of vomiting,

diarrhea, and decreased appetite. Pet. Ex. 11 at 129. Petitioner advised that she took A.L.M. home

before receiving any test results from the ER because A.L.M. had a large bowel movement. Id. at

130. Petitioner also noted that A.L.M.’s diaper was dry this morning, and she seemed perkier. Id.

at 129-31. The physician’s assessment was that A.L.M. had colitis, enteritis, and gastroenteritis of

infectious origin. Id. at 129.

On October 25, 2012, at her one-year-old checkup, A.L.M. was meeting all milestones.

Pet. Ex. 11 at 120-21. At this point, she was walking 2-3 steps independently, drinking from a cup,

babbling with inflection, and playing simple games (peek-a-boo and pat-a-cake). Id. at 121.

A.L.M. received her DTaP, Hib, MMR, Prevnar 13, and Varicella vaccinations, but petitioner

declined the Influenza vaccine. Id. at 122.17

17

At the October 25, 2012 checkup, petitioner was provided with a fact sheet associated with the vaccines

A.L.M. received that day, which included in pertinent part:

A small number of children get a rash and fever 7 to 14 days after the measles-mumps-

rubella (MMR) or the varicella vaccines. The rash is usually on the main body area and

lasts 2 to 3 days. Call your healthcare provider within 24 hours if the rash lasts more than

3 days or gets itchy. Call your child’s provider immediately if the rash changes to purple

spots.

Pet. Ex. 11 at 122, 127 (emphasis in original).

5

B. A.L.M.’s Medical Records after the Vaccinations

A.L.M.’s next medical visit was on November 26, 2012, when petitioner brought her in for

“possible seizure activities.” Pet. Ex. 11 at 115-16. Petitioner reported that A.L.M. was having

staring episodes with chewing motions starting about one week prior. Id. at 116. A.L.M. was noted

to be sitting during the episodes. Id. A.L.M. reportedly had two episodes on November 25, 2016,

the day before petitioner brought her in to be seen, which also involved twitching of the left eye.

Id. She had an episode the day of the appointment with staring and movement of her tongue and

left fingers for about 4 seconds. Id. The progress notes stated that she did not drool and had no

injuries, trauma, URI symptoms, or fever. Id. The pediatrician’s assessment was “staring spell;

suspect seizure activity.” Id. The pediatrician made a referral for an electroencephalogram

(“EEG”) and a neurology appointment with Dr. Dreyer. Id. at 116, 118. A.L.M. had an EEG on

November 29, 2012 that was “normal in wake and sleep.” Id. at 238.

Petitioner telephoned the pediatrician on December 1, 2012.18 Pet. Ex. 4 at 2.

The next day, December 2, 2012, A.L.M. was presented to Texas Children’s Hospital

(“TCH”) with a history of “having sz like episodes” beginning 4-6 weeks prior. Pet. Ex. 15 at 2.

Petitioner reported that A.L.M. would stare, left eye twitching, lips smacking, and not responding

to her name during the episodes. Id. There was no associated body shaking or stiffness, but she

seemed to be losing her balance more in the past week. Id. Initially, the episodes lasted 10-15

seconds and occurred twice daily, but now lasted 30-45 seconds and occurred 4-5 times daily. Id.

Petitioner reported five episodes that day. Id. A.L.M. was otherwise healthy and meeting all

milestones. Id. Petitioner reported that A.L.M. was seen by a neurologist last week and had a 30-

minute EEG that was normal. Id. Petitioner was told to follow up with the primary care physician.

Id. A.L.M. was noted to be “negative for fever” and “positive for seizures.” Id. at 2, 3. The record

documented a “[H]istory consistent with possible complex partial seizure, asymptomatic currently.

Okay for outpatient workup.” Id. at 4. Discharge instructions were to schedule an EEG and discuss

an outpatient Magnetic Resonance Imaging (“MRI”) to be done by the primary care physician. Id.

The following morning, December 3, 2012, A.L.M. was presented to the pediatrician. Pet.

Ex. 11 at 111; Pet. Ex. 4 at 3. The pediatrician ordered an MRI without contrast and issued a

referral for Dr. Dreyer in neurology and EEG/EP. Pet. Ex. 11 at 45, 112. Petitioner was instructed

to go to the ER if A.L.M.’s condition worsened. Id. at 112.

On December 3, 2012, around 7pm, A.L.M. was presented to the ER at Memorial Hermann

for seizure onset at about 3:30pm. Pet. Ex. 7 at 157. She reportedly had three seizures that day but

was awake and alert on presentation. Id. at 157, 159. A.L.M.’s vitals were taken, and her

temperature was 98.8 degrees Fahrenheit. Id. at 157. Petitioner reported that the seizures began

one month ago and were getting worse. Id. at 171. The seizures lasted seconds with no loss of

consciousness and no confusion postictally. Id. Petitioner stated that A.L.M.’s first episode

occurred while A.L.M. was playing and crawling and then she sat up and made chewing motions

for approximately ten seconds; this occurred twice. Id. at 2. In later episodes, her left eye started

to twitch, then her eyes moved back and forth slowly from left to right; additionally, in more recent

18

The phone log does not contain any content other than a date.

6

episodes, both hands shook, and she made a chewing motion. Id. A.L.M. did not respond to her

name during the episodes. Id. After the episodes, she briefly appeared tired before returning to

baseline. Id. Petitioner reported that A.L.M. had these episodes 4 to 5 times per day. Id. A.L.M.

had an episode during this ER visit that lasted for about one minute. Id.

The notes indicated that A.L.M. was seen three days ago at TCH ER, at which time neither

an EEG or MRI was performed, and no medication was started. Pet. Ex. 7 at 2; Pet. Ex 10 at 67.

The physician noted that A.L.M. was afebrile but positive for diarrhea, which had now resolved.

Pet. Ex. 7 at 16. She was walking, said “momma,” and knew her name. Id. at 17. There were no

developmental delays. Id. Petitioner herself was noted to have a history of febrile seizures at age

three but does not have epilepsy, and A.L.M.’s paternal half uncle has epilepsy. Pet. Ex. 7 at 17;

Pet. Ex. 10 at 82. The physician concluded that A.L.M. had an unprovoked seizure, was

developmentally normal for her age, and had multiple nonfebrile tonic and clonic seizures. Pet.

Ex. 7 at 18. There was no overt perinatal insult identified. Id.

On December 4, 2012, A.L.M. was transferred from Memorial Hermann to Children’s

Memorial Herman Hospital (“CMHH”). Pet. Ex. 7 at 175-76; Pet. Ex. 10 at 81. The same day,

petitioner called the pediatrician.19 Pet. Ex. 4 at 3. A 23-hour EEG at CMHH showed a seizure

unofficially read as temporal lobe epilepsy more prominent on left. Pet. Ex. 7 at 2-3, 21-22, 33-

34; Pet. Ex. 10 at 71-72. She also had a brain MRI, the results of which were normal. Pet. Ex. 7 at

80; Pet. Ex. 10 at 84. Complete blood count (“CBC”) results showed a right shift to be monitored

for fever or signs of infection. Pet. Ex. 7 at 18, 180-81. While in the hospital, a urine analysis was

abnormal. Id. at 182. A.L.M. had multiple seizure events during her two-day hospitalization. Pet.

Ex. 10 at 85. She was discharged on December 6, 2012 with a prescription for Keppra and

Diazepam for seizures greater than 10 minutes. Follow up was recommended. Pet. Ex. 7 at 21-22.

The diagnosis was likely temporal lobe epilepsy. Id. at 21.

Petitioner called the pediatrician on December 7, 2012 and presented that day for follow

up. Pet. Ex. 4 at 3; Pet. Ex. 11 at 108. Petitioner reported that A.L.M. was diagnosed with complex

partial seizures and prescribed Keppra; petitioner noted that A.L.M. was doing well with no

seizures since her hospital discharge the day before. Pet. Ex. 11 at 106, 108. Her neurologist at the

hospital was Dr. Butler. Id. at 109.

A.L.M. continued to do well until she reportedly had five seizures between December 25

and 26, 2012. Pet. Ex. 7 at 222-79. She was admitted to CMHH for generalized epileptic seizures.

Id. at 227. Tests performed earlier that month showed left temporal lobe epilepsy on a video-

electroencephalogram (“vEEG”) and a normal brain on the MRI. Id. at 22, 270. Her initial seizures

included staring, chewing motions, then left eye twitching; current seizures included collapsing

with more involvement of bilateral extremities lasting 1 to 1.5 minutes. Id. at 2, 210. She was on

“300 mg po BID” of Keppra daily and taking it as recommended. Id. at 225, 270. Multiple seizures

were reported with no post ictal phase. Id. at 225. She was scheduled to see Dr. Heard, a pediatric

epileptologist, on January 8, 2013. Id. at 197, 199, 272. She was discharged on December 28, 2012

with a plan to continue weaning her off Keppra and adding Trileptal. Id. at 209, 272.

19

The records only show that a call was made to the pediatrician’s office on that date.

7

A.L.M. was presented to the pediatrician on January 2, 2013 with a respiratory infection

for two days. She was noted to have complex partial epilepsy. Pet. Ex. 11 at 105. She was in the

process of weaning off Keppra and switching to Trileptal. Id. Since starting Trileptal, she had no

further seizures. Id.

A.L.M. was presented to neurologist Dr. Heard on January 8, 2013. Pet. Ex. 10 at 64.

A.L.M.’s seizures reportedly began a month prior to her first hospitalization with staring and lip

smacking which increased over the next several weeks with left eye twitching and left hand

twitching. Id. A 23-hour EEG performed during her early December hospital stay showed left

temporal epileptiform activity. MRI was normal. Id. A.L.M. was discharged from the hospital on

December 6, 2012 with a prescription for Keppra. Id. Despite the prescription, her seizures

continued, and now involved her entire body with bowel incontinence. Id. The Keppra prescription

was increased to maximum without success. Id. A.L.M. was again admitted to the hospital on

December 25, 2012, weaned off Keppra and prescribed Trileptal. Id. While being weaned from

Keppra and switched to Trileptal, A.L.M. was seizure-free for four days. Id. However, while at

Dr. Heard’s office, she had a seizure that lasted 25 seconds with a few clonic hand jerks, left eye

twitching, and blue lips and mouth. Id. at 66. The entire episode lasted 45-60 seconds. Id. A.L.M.

“spaced out” for about 5 seconds afterwards then continued eating her snack. Id. Dr. Heard

increased the Trileptal, ordered a helmet, and instructed petitioner to follow up in 1-2 months. Id.

At her 16-month-old well child visit on March 15, 2013, A.L.M. was noted to have a past

diagnosis of complex partial seizure and was taking Trileptal. Pet. Ex. 11 at 100. There were no

current health problems or concerns. Id. A.L.M. was reaching all milestones, walking

independently, and had 4-6 words. Id. Petitioner declined vaccinations. Id. at 100-01.

On the 18-month Ages & Stages Questionnaire (“ASQ”)20 petitioner noted concern about

A.L.M.’s speech delay and “the fact that seizures began within 2 weeks of 12 month vaccination.”

Pet. Ex. 2 at 6.

Over the next several months, A.L.M. was presented with multiple febrile illnesses

including: April 1, 2013 for viral gastroenteritis with a four-day fever of 102 degrees Fahrenheit,

Pet Ex. 11 at 92-93; April 12, 2013 for otitis media, URI with fever upon presentation, a “terrible”

runny nose, vomiting with cough and “banging her head on the wall” for 1-2 weeks, Pet. Ex. 11 at

84-85; and May 14, 2013 for Hand, Foot and Mouth disease with 103.2 fever. Pet. Ex. 11 at 212-

13. A.L.M. had no seizures from any of these febrile illnesses.

At her neurology visit with Dr. Heard on June 3, 2013, A.L.M.’s last seizure was noted to

be on February 4, 2013. Pet. Ex. 10 at 50. Her seizures were under control with Trileptal. Id. at 51.

A.L.M. was noted at this visit to have a speech impediment and that the left temporal lobe epilepsy

could be playing a part in her speech difficulties. Id. She was diagnosed with Landau Kleffner

syndrome, although she did not have the typical symptoms and features. Id. Dr. Heard prescribed

speech therapy, as well as Lamictal to help with A.L.M.’s language development. Id. Petitioner

was encouraged to bring A.L.M. up to date on her immunizations, but she expressed concern

“about the coincidence of seizures occurring within weeks of her 1 yr immunizations.” Id.

20

The form does not contain a date.

8

Thereafter, A.L.M. was presented for medical care on July 11, 2013 for sinusitis and

drainage and redness of her eyes without fever, Pet. Ex. 11 at 75; September 8, 2013 for periorbital

cellulitis, Pet. Ex. 11 at 24; September 9, 2013 for eye swelling, acute upper respiratory infection,

and acute otitis media, Pet. Ex. 11 at 70; and September 12, 2013 for a follow up from the last

appointment, at which time she was doing well. Pet. Ex. 11 at 66.

At her well child visit on September 16, 2013, A.L.M. had ear pulling, no fever, good

appetite and had reached all milestones appropriate for her age. Pet. Ex. 11 at 56-57. She could

run, scribble spontaneously with a crayon, had 7 to 10 words, and imitated use of objects (for

example, using a comb and a phone). Id. at 57. An M-Chat was completed with no concerns noted.

Id. at 57-58. However, speech delay was noted on ASQ survey, so petitioner was instructed to

contact Early Childhood Intervention (“ECI”) for speech services. Id. at 59. Petitioner again

declined vaccinations for A.L.M. Id.

An occupational therapist and intervention specialist performed an ECI Assessment for

A.L.M. at petitioner’s home on October 1, 2013. Pet. Ex. 10 at 17-32. The comments noted that

A.L.M. “has a diagnosis of seizure disorder, which automatically qualifies her for ECI

enrollment,” and “mom’s primary concern developmentally is communication.” Id. at 17.

At a follow up visit on October 8, 2013, Dr. Heard documented a 19-month-old whose

seizures were controlled on Trileptal; A.L.M. had not had a seizure since February 4, 2013. Pet.

Ex. 10 at 43. Petitioner reported numerous URIs and viral illnesses since starting day care in

March. Id. She was concerned about A.L.M.’s communication skills since she could only

pronounce a few words and her vocabulary was limited. Id. A.L.M. had been evaluated by a speech

therapist, but the therapy had not yet started. Id. She had a diagnosis of Landau Kleffner syndrome,

though she did not have the typical symptoms. Id. at 45. Dr. Heard again suggested that Lamictal

be started to reduce the spikes in the temporal lobe and improve neuronal development for

language; petitioner was “more amenable today to give the Lamictal a try.” Id. at 45.

Genetic testing for chromosomal microarray analysis performed on October 8, 2013 was

negative.21 Pet. Ex. 10 at 47.

On June 3, 2014, A.L.M. was presented to the pediatrician for herpangina, an infection in

the back of the throat. Pet. Ex. 11 at 52. She was a two-year-old with a three-day fever, a slight

cough the day before, and a sore throat the night prior. Id. Her current medication was listed as

Trileptal. Id. Petitioner was advised to encourage fluids and give Tylenol or ibuprofen as needed.

Id. at 53.

In October 2014, an initial evaluation at the Westwood Elementary School was performed

for an Individual Education Program (“IEP”) Report. Pet. Ex. 5 at 1. A.L.M. was nearly three years

old. Id. at 2. She attended daycare three days a week. Id. at 18, 23. Her primary disability was

“Speech Impairment” with articulation as the main concern. Id. at 5-7. Speech Language Therapy

for fourteen 30-minute sessions over nine weeks was recommended to begin on October 24, 2014.

Id. at 16. Her history was seizures controlled with medication and no seizures since February 2013.

21

The record is incomplete. The document filed contains only a description of chromosomal microarray

analysis. See Pet. Ex. 10 at 47.

9

Id. at 20. She lived with her mother, stepfather, and 12-year-old sister. Id. at 23. She was the

product of an uneventful pregnancy and delivery with normal childhood illnesses until two weeks

after her 12-month vaccinations, at which time she began having seizures. Id. at 24. She was

hospitalized and diagnosed with epilepsy, complex partial seizures with secondary generalization.

Id. Petitioner reported no issues with word development until after her seizures began, after which

time she went months without progress in her speech. Id. Petitioner believed that A.L.M.’s speech

was affected by the type of seizures she experienced. Id. at 24, 42. Her hearing, vision, and motor

skills were normal. Id. at 24. A.L.M. was well behaved and responded appropriately to discipline.

Id. The report also said that A.L.M. separated well from her mother, played by herself, and was

agreeable and happy. Id. at 25. A.L.M. scored within the average range for receptive, expressive,

and total language; further, “no concerns were raised regarding her language development.” Id.

She used primarily “d,” “t,” and “b” in substitution, placing her in the 3rd percentile below the

criteria used to determine an articulation disability. Id. at 26. Her language, voice, and fluency

skills were intact. Id. at 27.

Petitioner filed a request for exemption of vaccinations with the Texas Department of State

Health Services on October 29, 2014. Pet. Ex. 3.

At a March 26, 2015 neurology visit, A.L.M. was taking Trileptal two times daily, and was

making “good progress” in speech therapy in both her language and speech. Pet. Ex. 10 at 38. Her

last seizure was on February 4, 2013 and last EEG was in 2012. Id. at 37. Petitioner gave A.L.M.

one dose of Lamictal but stopped it because A.L.M. fell and petitioner felt that Lamictal made her

unsteady. Id. at 38, 39. She had not received vaccinations since October 2012 because petitioner

believed that the vaccines triggered her seizures. Id. at 38. A.L.M. attended daycare three days a

week and stayed with her aunt or grandmother on the other days. Id. She liked to play with dolls,

Legos, and coloring books. Id. She was affectionate and had good eye contact, with no other

behaviors suggestive of autism spectrum disorder (“ASD”). Id. The record documented onset of

seizures at 13 months of age with no trigger. She had no further seizures since February 4, 2013;

the seizure type included staring spells and lip smacking lasting 10 seconds 4-5 times a day. Id. at

39. It was also noted that her paternal half uncle has epilepsy. Id. A 23-hour EEG done on

December 4, 2012 was abnormal “due to bihemispheric multifocal independent epileptiform

discharges, more prominent in the left hemisphere, particularly the temporal area, and 1

electrographic seizure that appeared to arise from the left temporal area.” Id. at 40. Her brain MRI

done the same day was normal. Id. The assessment was a three-year-old on Trileptal, seizure free

for two years since February 2013, with speech impairment improved. Id. Before considering

weaning her off medication, the physician wanted another EEG and repeat brain MRI to evaluate

myelination. Id. at 40-41.

A chromosomal microarray analysis – HR + SNP screen performed on March 27, 2015

was normal. Pet. Ex. 6 at 1. A 23-hour video and scalp EEG done on July 5, 2015 was normal for

her age. Pet. Ex. 19 at 6. The brain MRI without contrast was performed on August 27, 2015 and

compared to the December 2012 MRI; results were negative and normal with no migrational

anomaly or focal cortical dysplasia. Id. at 107.

A.L.M.’s assessment for the 2016-2017 school year was speech impairment in the area of

articulation. Pet. Ex. 20 at 4, 26. The notes document that A.L.M. “no longer takes medication for

10

seizures. Mom reports she has been off of the medication for about a year.” Id. at 5. A.L.M. was

noted to need only speech services and could enter kindergarten with no need for accommodations.

Id. at 26.

C. Other Evidence

i. VAERS report

Two years post-vaccination, petitioner completed a VAERS report on October 15, 2014,

reporting a reaction to A.L.M.’s October 25, 2012 vaccines. Pet. Ex. 12 at 3-4. She reported that

A.L.M. suffered a rash on her neck, chest, and face on November 2, 2012. Id. In an attached

statement, petitioner reported that she called the doctor’s office and was told the rash was a normal

reaction to immunizations. Id. at 4. The rash disappeared within a few hours. Id. Within two weeks,

A.L.M. started making chewing motions with staring spells, was not reacting to her surroundings,

and was motioning as if she was rubbing something between her fingers on her left hand. Id.

A.L.M.’s physician referred her to neurologist Dr. Dreyer. A.L.M. underwent a 30-minute EEG

which was normal. Id. Petitioner reported that A.L.M.’s seizures persisted and later included eye

twitching. Id.

Petitioner took A.L.M. to TCH ER, where she was seen but discharged with a referral to

another neurologist. Pet. Ex. 12 at 4. The following day, petitioner took A.L.M. to Memorial

Hermann ER, where she was admitted and subsequently transferred to Houston Memorial

Hermann Children’s Hospital, where staff performed two EEGs, one of which showed seizure

activity. An MRI was normal. Id. A.L.M. was discharged with a diagnosis of complex partial

seizures and prescription for Keppra. Id.

A.L.M. then had an appointment with an epilepsy specialist, Dr. Heard, who diagnosed her

with complex partial seizure with secondary generalization seizures. Pet. Ex. 12 at 4. Near the end

of December 2012, A.L.M. was again admitted to the hospital where doctors switched her to

Trileptal. Id. According to petitioner, A.L.M.’s seizures were under control with Trileptal, but

A.L.M.’s pediatrician and Dr. Heard, as well as petitioner, noticed that A.L.M. was not talking. Id.

A.L.M.’s speech was evaluated, and she has been in speech therapy, which has improved her

speech. Id. Petitioner concluded her statement noting that A.L.M. was babbling and saying simple

words prior to the seizures; after the seizures began, she was quieter. Id.

ii. Additional Records from Pediatrician’s Office

Petitioner filed phone logs from the pediatrician’s office. Pet. Ex. 4. The record contains a

list of telephone calls and office visits between November 26, 2012 and September 18, 2013. Pet.

Ex. 4. The record is internally inconsistent and not all entries are contained in the pediatric medical

record. Focusing on November and December 2012, Pet. Ex. 4 reflects telephone calls with

petitioner on November 2, 2012, December 1, 2012, December 3, 2012, and December 4, 2012.

Pet. Ex. 4 at 1-3. However, Pet. Ex. 4 at 3 does not contain the telephone call on December 1, 2012

that is documented at Pet. Ex. 4 at 2. Additionally, Pet. Ex. 4 at 3 includes a telephone call on

December 4, 2012 that is not listed on Pet. Ex. 4 at 2. Further, Pet. Ex. 4 at 1 reflects a telephone

11

call on November 2, 2012, not contained in either Pet. Ex. 4 at 2 or 3. The discrepancies in the

record have not been explained.

D. Fact Witness Affidavits and Testimony

i. Affidavit and Testimony of Elizabeth Gram

Petitioner submitted her affidavit with her petition and testified at the hearing. Pet. Ex. 1.

Petitioner testified that A.L.M. was a typical, healthy baby who received all her shots with

no problem. Tr. 6-7. On October 25, 2012, she had a one-year-old checkup and received all her

vaccinations; no vaccines were declined. Tr. 7.

Petitioner testified that A.L.M. developed a rash on her neck, face, chest, and back on

November 2, 2012, one week after her October 25, 2012 vaccines. Tr. 9; but see Pet. Ex. 1 at 1,

affirming that the rash was on A.L.M.’s chest and face. She telephoned the pediatrician who said

it was a normal reaction. Tr. 9. Petitioner stated the rash was gone the next morning. Tr. 10; but

see Pet. Ex. 12 at 4, stating that the rash disappeared within a few hours. Later during the hearing,

petitioner did not remember if the rash was gone within hours or the next day. Tr. 21. Petitioner

stated she had to look at the pediatric record for the date of the phone call regarding the rash to

know that it was November 2, 2012. Tr. 21. Petitioner felt A.L.M. at the time of the rash and she

was not feverish. Tr. 21-22.

Petitioner affirmed “within days and over the next few weeks” A.L.M. began making

chewing motions and would sit up abruptly while playing or walking. Pet. Ex. 1 at 2. Petitioner

would check her mouth but find nothing. Id. Then she began rubbing her fingers together and had

eye twitching. Id. During these episodes she would stare off, not react to sound or her name, and

her eyes would slowly move back and forth. Id.

During the hearing, petitioner stated that A.L.M. started chewing and progressed to staring

spells, chewing, and rubbing of her fingers within days of the rash. Tr. at 11. The behavior started

happening more frequently and progressed to twitching, so petitioner took A.L.M. to the doctor on

November 26, 2012. Tr. at 12; Pet. Ex. 1 at 2. The record for that appointment documents that

petitioner told the doctor these episodes began a week prior to the November 26, 2012 visit.

However, at hearing, petitioner stated the episodes began a few days after the rash and that she

“misspoke or misjudged the time frame” because she had a lot going on at the time and her father

was terminally ill. Tr. at 13. A.L.M.’s physician referred her to neurologist Dr. Dreyer because her

symptoms sounded “like staring spells.” Tr. 13.

The week following the appointment, petitioner called the pediatrician to report that A.L.M.

had several episodes of “staring, lack of attention to sounds, and trembling.” Pet. Ex. 1 at 2. She

was told to take A.L.M. to the emergency room. Id. While at the TCH ER on December 3, 2012,

A.L.M. had an episode. Id.

Petitioner affirmed that A.L.M. had episodes throughout the night of December 3, 2012,

so petitioner took her to Memorial Hermann Southeast ER. Pet. Ex. 1 at 2. That evening, A.L.M.

12

was transferred by ambulance to CMHH, where she was admitted for two days. Id. The physician

ordered an EEG, which showed a seizure. Blood tests were normal. Id. A.L.M. was put on Keppra

for complex partial seizures; but, according to petitioner, the Keppra was “not working” and “had

not helped at all.” Id. at 3; Tr. 15.

Petitioner affirmed that the episodes increased over the next few weeks and A.L.M.’s whole

body would shake, her lips would turn blue, she would not respond to her name, and she would

lose bladder/bowel control. Pet. Ex. 1 at 3. Petitioner updated Dr. Grant with the Pediatric

Neurology Department at CMHH about what was happening, and he increased A.L.M.’s Keppra

dose until she reached the maximum for her age and weight. Id. Another neurologist, Dr. Heard,

examined A.L.M. later in December 2012, during which time A.L.M. had a seizure; Dr. Heard

diagnosed A.L.M. with complex partial seizures and secondary generalization. Id.

Petitioner affirmed contacting Dr. Grant on Christmas day to report that A.L.M. was having

several seizures a day over shorter timeframes and was on the maximum dose of Keppra. Pet. Ex.

1 at 3. Dr. Grant advised petitioner to take A.L.M. to the ER, have her admitted and her prescription

changed. Id. During this hospital stay, A.L.M. was weaned off Keppra and switched to Trileptal.

Id. She was discharged the following day with a diagnosis of temporal lobe seizures. Id.

Petitioner affirmed that the Trileptal lessened the frequency of A.L.M.’s seizures. Pet. Ex. 1

at 3. A.L.M. has not had a seizure since February 2013. Id.; Tr. at 17. All medication was stopped

in late 2015, after A.L.M. had another 24-hour EEG, which came back normal. Tr. at 17-18.

Petitioner stated that A.L.M. was evaluated by speech therapists in October 2013 because

her speech and language were not progressing as they should. Pet. Ex. 1 at 4; Tr. 18. At the time

of the evaluation, A.L.M. was two years old, but she had the vocabulary of a 15-month-old. Id.;

Tr. 18. She started speech therapy at age 2. Tr. at 18. Petitioner affirmed A.L.M. has delayed verbal

communication and cognitive skills and social interaction issues. Pet. Ex. 1 at 4. At hearing,

petitioner stated that A.L.M. still has articulation issues, gets frustrated, and does not handle things

emotionally well compared to petitioner’s other child. Tr. 18-19. Petitioner considered taking

A.L.M. to a child psychologist and back to speech therapy but has not done so yet. Tr. 19-20.

The undersigned questioned petitioner about various items in the VAERS report including

petitioner’s reports that (1) within hours the rash disappeared, (2) chewing motions started two

weeks after the rash, (3) the 24-day gap between the rash on November 2, 2012 and the first

doctor’s visit on November 26, and (4) the phrase “days to weeks.” Tr. 24-30. Petitioner responded

that the rash was on A.L.M.’s back, neck, face, and chest until the following morning. Tr. 9, 26-

27. After the rash, A.L.M. started with chewing motions, then staring, then hand rubbing, then

twitching, and the combination of these symptoms prompted her to take A.L.M. to the doctor on

November 26. Tr. 24-26. Her best estimate was that the chewing started within a week or two after

the November 2, 2012 rash. Tr. 27. Petitioner then stated that the chewing started within a few

days of the rash. Tr. 27. She believed the rash was on a Friday and the chewing, staring off, rubbing

fingers, and eye-twitching began within days. Tr. 25-26, 30. Petitioner stated that when she took

A.L.M. to the hospital on December 2, 2012 reporting onset of 4 to 6 weeks prior, she was referring

to the onset of the rash. Tr. 31. Petitioner confirmed that A.L.M. had no rashes prior to November

2, 2012. Tr. 31. Petitioner agreed she prepared the VAERS report and wrote that the onset of

13

chewing was approximately two weeks after the rash on November 2, 2012 then things progressed

very quickly. Tr. 32-33.

ii. Affidavit and Testimony of Lisa Spencer

Lisa Spencer is petitioner’s sister and A.L.M.’s aunt. Tr. 37. She submitted an affidavit and

testified at hearing. Pet. Ex. 17; Tr. 36-37. Around the time of her vaccinations, Ms. Spencer saw

A.L.M. 3-4 times a week. Tr. 37.

Ms. Spencer affirmed shopping at Target with petitioner and A.L.M. on November 2, 2012

when A.L.M. “broke out in a rash.” Pet. Ex. 17 at 1. She stated that petitioner called the doctor

and was told that it was a normal post-vaccine reaction but if it got worse, to take A.L.M. to the

doctor. Id. at 1-2. The rash did not get worse, and they continued shopping. Id. at 2.

At hearing, Ms. Spencer was unsure when they were at Target, but it was either on

November 7, 8, or 9. Tr. 40. She stated A.L.M. was cranky and had developed a rash on her neck

and the front and back of her body. Tr. 38. Petitioner told Ms. Spencer that A.L.M. had her shots

a week prior. Tr. 38, 48. Ms. Spencer stated that A.L.M. felt warm at the time. Tr. 39; but see Tr.

21-22, where petitioner stated at hearing that A.L.M. was not feverish at the time of the rash. Ms.

Spencer stated that petitioner called the doctor who said the rash was normal. Tr. 39.

Ms. Spencer affirmed that petitioner told her A.L.M. had started making chewing motions

with nothing in her mouth a few days after the rash. Pet. Ex. 17 at 2. Ms. Spencer then noticed that

A.L.M. would stop what she was doing, sit up and make chewing motions. Tr. 40. At the time, she

did not think it was something that required medical attention. Pet. Ex. 17 at 2. She then saw

A.L.M. rubbing her fingers together, chewing, and staring off into nothing. Id. After this started,

petitioner took A.L.M. to the doctor. Id. Ms. Spencer affirmed that she and petitioner initially

thought A.L.M. was just doing “random ‘weird’ actions all young children occasionally engage

in.” Id. When they all started happening together, they realized medical care was needed. Id.

Consistent with her affidavit, Ms. Spencer testified that she noticed a few days after the

rash that A.L.M. was making chewing motions and in a little bit of a daze; the week after the rash,

she made chewing motions at least once when petitioner dropped A.L.M. off at her house for an

hour or two. Tr. 40-41. She didn’t think much of it until it progressed where she would sit, stare,

chew, and rub her fingers. Tr. 42.

However, on cross examination, Ms. Spencer stated that she witnessed A.L.M. making

chewing motions only two days after they were in Target. Tr. 46. She then stated that the family

was all together over Thanksgiving, and A.L.M.’s chewing motions had progressed to staring and

finger rolling, which led them to take A.L.M. to the emergency room. Tr. 47. Ms. Spencer later

corrected herself, saying that this occurred on Christmas day, not Thanksgiving. Tr. 47.

Ms. Spencer testified that she has two children and never saw a rash after their vaccinations,

only fussiness and fever, which usually occurred the night of the vaccine or the next day. Tr. 47-

48. She never saw a fever from vaccines a week after vaccination. Tr. 48.

14

According to Ms. Spencer, A.L.M. still has speech issues and writes things backwards, but

she is able to understand A.L.M. because her own son has a little stutter. Tr. 43-44.

iii. Affidavit of Sherry Mathison

Sherry Mathison is petitioner’s sister who lived with petitioner from August 2012 until

January 2013. Pet. Ex. 18 at 1. She submitted an affidavit but did not testify at hearing. Id. Ms.

Mathison affirmed in August 2012, A.L.M. was a well-behaved, typical child and was speaking a

couple of words. Id.

Ms. Mathison affirmed in November 2012, A.L.M. began making chewing motions with

nothing in her mouth and would rub her hands with nothing in her hand. Pet. Ex. 18 at 2. At first,

she and petitioner did not think anything of it. Id.

According to Ms. Mathison, “eventually” A.L.M. engaged in all these behaviors at once;

she would stop what she was doing, sit down, and make chewing motions while rubbing her fingers

together. Pet. Ex. 18 at 2. She further stated that “[i]t was around this time that I also noticed that

A.L.M. stopped making an effort to speak the words she learned.” Id. At this point, petitioner

decided to take A.L.M. to the doctor. Id.

Ms. Mathison witnessed A.L.M.’s seizures on multiple occasions where A.L.M. would fall

to her left side, have body shakes, have her hands at her chest, and her lips would lose color. Pet.

Ex. 18 at 2. For an “extended period of time,” A.L.M. had several seizures a day and “we could

never take our eyes off of her because we never knew when she might have seizure (sic).” Id.

V. The Experts’ Opinions

A. Qualifications

Petitioner filed four reports from of Dr. Kinsbourne and two reports from Dr. Levin. Pet.

Ex. 14, 16, 21, 36, 5622, 39, 50.

Dr. Marcel Kinsbourne is a medical doctor who specializes in pediatric neurology. Pet. Ex.

57; Tr. 50. He graduated from Oxford University in England in 1955 with a B.M.B.Ch., the

equivalent of an American M.D. Pet. Ex. 57 at 2. Dr. Kinsbourne began practicing in the United

States as a pediatric neurologist and neuropsychologist in 1967. Id. at 3. From 1967 to 2015, Dr.

Kinsbourne served as an associate professor in pediatrics and neurology and a senior research

associate at Duke University Medical Center before holding a series of academic positions,

including professorships in pediatrics, neurology, and psychology. His clinical experience includes

serving as a senior staff physician in Ontario from 1974-1980 and a clinical associate in neurology

at Massachusetts General Hospital from 1981-1991. See Fantini v. Sec’y of Health & Human

Servs., No. 15-1332V, 2022 WL 1760730, at *5 (Fed. Cl. Spec. Mstr. May 2, 2022).

Dr. Kinsbourne’s last hospital-based neurology practice was in 1992 and he has since

retired from the active practice of neurology. He has had various appointments as a professor since

22

It appears that Pet. Ex. 16 and 56 are the same report.

15

with his last position being at the New School in New York, which ended in 2015. Pet. Ex. 57 at

4. An amended CV was filed for Dr. Kinsbourne in this case as Pet. Ex. 57. Dr. Kinsbourne is well

known to the Court having been involved in Vaccine Program cases since the inception of the

Program, although (as noted in other cases) many years have passed since he has regularly seen

patients. See, e.g., Strong v. Sec'y of Health & Human Servs., No. 15-1108V, 2018 WL 1125666,

at *6 (Fed. Cl. Spec. Mstr. Jan. 12, 2018); Pope v. Sec'y of Health & Human Servs., No. 14–078V,

2017 WL 2460503, at *8 (Fed. Cl. Spec. Mstr. May 1, 2017).

Dr. Levin graduated from the University of Illinois-Chicago Medical Center in 1964. Pet.

Ex. 40. However, he has spent most of the last 25 years since he passed the bar practicing law,

with 95% of his income related to his law practice. Tr. 109. He does other work for his wife and

Dr. Ramey, the chief epidemiologist from California researching environmentally induced

illnesses. Tr. 109-10. He is board certified in allergy, immunology, clinical pathology, and

emergency medicine. Tr. 110. Although he spends the majority of his time in the legal field, he

keeps his medical board certifications up to date, in part by routinely attending medical lectures.

Tr. 110, 126. The last time he taught medicine was 1998, though he has been giving lectures at the

VA on environmentally induced illnesses. Tr. 110-11. He still has admitting privileges at UCSF

as an attending, but the last time he treated a patient was in 1998. Tr. 111. He last published 20

years ago. Tr. 111-12. Dr. Levin derives about 20% of his income from medical-legal expert work

and conceded that his opinions are not popular in the legal system outside of the Vaccine Program.

Tr. 112.

Respondent filed four reports from Dr. Holmes and two reports from McCusker. Resp. Ex.

A, Q, V, YY, FFF, Z.

Dr. Holmes is a pediatric neurologist. Tr. 128. He earned his medical degree at the

University of Virginia, trained in pediatrics at Yale, and returned to the University of Virginia to

train in neurology with special competence in pediatric neurology. Tr. 128. He is the chairman of

the Department of Neurological Sciences at the University of Vermont. Tr. 128. He spends 50%

of his time in clinical practice primarily seeing children with epilepsy. Tr. 128-29. The other 50%

of his time is spent doing research, administrative work, and teaching. Tr. 129; Resp. Ex. B.

Dr. McCusker is a pediatric immunologist and allergist. Tr. 184. She has an undergraduate

honors degree in microbiology and immunology, a master’s degree in molecular virology, and

spent three years in a Ph.D. program studying immunology. Tr. 184. She then went to medical

school and completed training in allergy, pediatrics, and clinical immunology after medical school.

Tr. 184. She later conducted postdoctoral research in an immunology lab for another year. Tr. 184;

Resp. Ex. AA.

Dr. McCusker is currently an associate professor of pediatrics at McGill University and the

director of the Division of Pediatric, Allergy, Immunology, and Dermatology at the Montreal

Children’s Hospital and the McGill University Health Center. Tr. 185. She spends 50 percent of

her time with patients and doing clinical work and 50 percent of her time in primary research

and/or teaching and administration. Tr. 185; Resp. Ex. AA.

16

B. Causation Opinions

i. The Expert Reports

Dr. Kinsbourne opined that A.L.M.’s growth and development were normal until

November 4, 2012, when her seizures began with chewing motions then escalated thereafter. Pet.

Ex. 14 at 1-2. At 19- and 23-months of age, A.L.M. knew only a handful of words, required speech

therapy and an IEP. Id. at 3. A.L.M. has not had a seizure since February 2013. Id. at 3. He

described the onset of her seizures as “sudden and intense” in the second week following the MMR

vaccine. Pet Ex. 14 at 3. He relied on Bourgeois’ diagnostic criteria for complex partial seizures

of the temporal lobe in infants which includes: (1) predominance of behavioral arrest with possible

impairment of consciousness; (2) no identifiable aura; (3) automatisms that are discrete and mostly

orofacial; (4) more prominent convulsive activity; and (5) a longer duration (more than 1 minute).

Id.

Dr. Kinsbourne opined that A.L.M. had a hyperexcitable neural network in the left

temporal lobe, seen on the EEG as an active seizure focus in that area of the brain. Pet. Ex. 14 at

4. The localized nature of A.L.M.’s seizure activity was either due to past historical event, such as

ischemia or encephalitis, or an underlying structural abnormality. Id. The focal origin featured

abnormal connectivity between neurons, making it more likely to discharge and cause a lowered

seizure threshold. Pet. Ex. 14 at 4-5; Pet. Ex. 32.23 He explained that the propensity for seizure

activity is greater in infancy because inhibitory GABA interneurons that present later in life are

premature in infancy. Pet. Ex. 14 at 4; Pet. Ex. 27.24 These interneurons act as an excitatory

neurotransmitter, potentially feeding incipient paroxysmal discharge. Id. Dr. Kinsbourne referred

to focal cortical dysplasia as an example of a neural disorder that lowers seizure threshold. Its’

neural mechanisms “apply broadly to other epileptogenic structural anomalies of cortical neural

networks,” and greater than 24% of epilepsies are associated with cortical malformations. Id. at 5.

Genetic causes or vascular malformations, stroke, and posttraumatic scars were all ruled out in

A.L.M.’s case by an MRI and genetic testing; thus, cerebral cortical dysgenesis being the largest

diagnostic category supports his view that it is medically reasonable A.L.M.’s vaccination more

likely than not triggered her complex partial seizure disorder. Id.

However, Dr. Kinsbourne explained, cortical dysplasia alone would not be sufficient to

trigger epilepsy. Pet. Ex. 14 at 5, 6. He described a two-hit theory whereby a latent brain

abnormality exists which is then provoked by a second hit—here, the MMR vaccine. Id. at 6.

Regarding the first hit, areas of cortical dysgenesis feature microglial activation which releases

proinflammatory cytokines, including interleukin-1 beta (also referred to a “IL-1beta”, “IL-1b”, or

“IL-1β”), imposing on an already lowered seizure threshold. Id. at 7.25 Vaccinations serve as the

second hit, activating the innate immune system to release proinflammatory cytokines including

23

David A. McCormick & Diego Contreras, On the Cellular and Network Bases of Epileptic Seizures, 63

ANN. REV. PHYSIOLOGY 815 (2001), filed as “Pet. Ex. 32.”

24

Ilgam Khalilov et al., Epileptogenic Actions of GABA and Fast Oscillations in the Developing

Hippocampus, 48 NEURON 787 (2005), filed as “Pet. Ex. 27.”

25

Jieun Choi & Sookyong Koh, Role of Brain Inflammation in Epileptogenesis, 49 YONSEI MED. J. 1

(2008), filed as “Resp. Ex. J.”

17

IL-1b, which is necessary for the stimulation of an adaptive response to confer immunity.26 Id. at

6. IL-1b specifically has a “well-documented propensity to cause seizures, and seizure activity

tends to cause further release” IL-1b. Id.; Pet. Ex. 34.27 The receptor for IL-1b is expressed by

neurons in the hippocampus and other seizure-sensitive regions of the brain. Pet. Ex. 14 at 6-7.

When IL-1b binds to its receptor, it causes enhanced neuronal excitability and a decreased seizure

threshold. Id. at 7. The second hit would initiate the cycle of seizure begetting seizure, thus leading

to epilepsy. Id. at 6.

Dr. Kinsbourne posited that patients with congenital/perinatal dysplastic lesions do not

express epilepsy until later in life and if they do, it is after some trigger. Pet. Ex. 14 at 6. The

stressors, or second hit, may facilitate eventual epileptogenesis. Id. Epileptogenic focus located in

the left temporal lobe results in delays in “language comprehension skills and persisting deficits

in speech expression.” Id.

Succinctly, Dr. Kinsbourne’s theory presumes the existence of a hyperexcitable neural

network or lower-than-normal seizure threshold due to congenital or perinatal lesions on the brain

as the first hit. Pet. Ex. 14 at 7. The MMR, which released IL-1b necessary to stimulate an adaptive

immune response, triggered the hyperexcitable neural network in the temporal lobe, causing

seizure onset emanating from that area of the brain as the second hit. Id. Dr. Kinsbourne also

opined that A.L.M.’s seizures occurred in a medically reasonable time after her MMR vaccination.

Id. He further stated that there was no evidence of an alternative cause. Id.

Dr. Holmes issued a responsive report in which he opined that A.L.M.’s clinical course

was consistent with idiopathic epilepsy, and her language dysfunction was indicative of the

location from where her seizures arose. Resp. Ex. A at 6. He noted that the cause of epilepsy is

unknown in approximately 55-75% of cases. Id. at 7.

Dr. Holmes agreed that vaccines are intended to activate the innate immune system and

cause the release of proinflammatory cytokines. Resp. Ex. A at 7. He disagreed that there is any

evidence that the MMR vaccine can cause an inflammatory reaction in the temporal lobe that

results in seizures and language delay. Id. Dr. Holmes added that A.L.M. had no symptoms of

inflammatory reactions after her vaccinations only a transient rash. Id. Further, she does not have

cortical dysgenesis. Clinically, her EEG and MRI showed no acute inflammatory response and

none of her treaters considered her epilepsy to be vaccine related. Id. Further, the Institute of

Medicine (“IOM”) concluded that an association between the MMR vaccine and afebrile seizures

is lacking. Id. Dr. Holmes posited that “there is no evidence to indicate the MMR vaccine results

26

Akiko Iwasaki & Ruslan Medzhitov, Toll-like Receptor Control of the Adaptive Immune Response, 5

NATURE IMMUNOLOGY 987 (2004). This article was not filed.

27

Annamaria Vezzani, PhD & Tallie Z. Baram, MD, PhD, New Roles for Interleukin-1 Beta in the

Mechanisms of Epilepsy, 7 EPILEPSY CURRENTS 45 (2007), filed as “Pet. Ex. 34.”

18

in non-febrile seizures. Id.; Resp. Ex. M;28 Resp. Ex. N;29 Resp. Ex. O.30 In conclusion, Dr. Holmes

believed that A.L.M. has “well controlled epilepsy and an expressive speech disorder.” Resp. Ex.

A at 8.

Dr. Kinsbourne responded to Dr. Holmes’ report, clarifying that his reference to cortical

dysgenesis in his first report was for illustrative purposes only. Pet. Ex. 16 at 1. He agreed that

A.L.M. does not have cortical dysgenesis. Id. He argued that his theory, which involves the release

of proinflammatory cytokines, specifically IL-1b, is a medically reasonable mechanism to show

that vaccines can cause or trigger the onset of seizures to satisfy Prong I. Id. at 2. It is well known

that vaccines produce proinflammatory cytokines necessary to achieve immunity. Id. Dr.

Kinsbourne submitted that only the MMR vaccination A.L.M. received could cause seizures in the

second week after vaccination, agreeing that the timeframe was not as plausible for the other

vaccines. Id.

Dr. Kinsbourne issued a third report addressing afebrile seizures and MMR vaccine,

asserting that seizures may occur without fever. Pet. Ex. 21 at 1, 5; Pet. Ex. 29;31 Pet. Ex. 35.32

According to Dr. Kinsbourne, while “IL-1beta also causes fever…the epileptogenic effect of IL-

beta is not mediated by its propensity also to elevate body temperature.” Id. at 5; Pet. Ex. 24.33 Dr.

Kinsbourne explained that IL-1beta is expressed in neurons in the hippocampus and other seizure-

sensitive areas of the brain and when it binds to its receptor, it causes enhanced neuronal

excitability and decreased seizure threshold. Pet. Ex. 21 at 5. The presumption that A.L.M. had a

lowered seizure threshold is required and is reasonable “since great numbers of other children who

receive [the MMR vaccine] do not have seizures.” Id.

Further, Dr. Kinsbourne submitted, “here, seizures occurred after MMR vaccination and

during the period of viremia from the attenuated live measles virus. As with mild infections, a

minority of seizures are afebrile. A substantial amount of literature documents afebrile seizures

occurring in the risk period after MMR vaccination.” Pet. Ex. 21 at 5. For example, Le Saux

reported 78 cases of new onset seizures, of which 16 were afebrile; further, there were “33 reports

of hospitalization for afebrile seizures occurring 5 to 30 days after receipt of MMR vaccine.” Pet.

Ex. 21 at 5; Pet. Ex. 31.34 Further, von Spiczak reported 44 cases of afebrile seizures, as compared

28

Robert L. Davis & William Barlow, Placing the Risk of Seizures with Pediatric Vaccines in a Clinical

Context, 5 PEDIATRIC DRUGS 717 (2003), filed as “Resp. Ex. M.”

29

William E. Barlow, PhD et al., The Risk of Seizures After Receipt of Whole-cell Pertussis or Measles,

Mumps, and Rubella Vaccine, 345 NEW ENGLAND J. OF MEDICINE 656 (2001), filed as “Resp. Ex. N.”

30

V. Demicheli et al., Vaccines for Measles, Mumps, and Rubella in Children (Review), COCHRANE

DATABASE SYST REV. (2012), filed as “Resp. Ex. O.”

31

Lee & Ong, supra note 5.

32

Ting Zhang et al., Are Afebrile Seizures Associated with Minor Infections a Single Seizure Category? A

Hospital-based Prospective Cohort Study on Outcomes of First Afebrile Seizure in Early Childhood, 55

EPILEPSIA 1001 (2014), filed as “Pet. Ex. 35.”

33

Céline M. Dubé et al., Febrile Seizures: Mechanisms and Relationship to Epilepsy, 31 BRAIN AND

DEVELOPMENT 366 (2010), filed as “Pet. Ex. 24.”

34

Nicole Le Saux, MD, et al., Decrease in Hospital Admissions for Febrile Seizures and Reports of

Hypotonic-hyporesponsive Episodes Presenting to Hospital Emergency Departments Since Switching to

Acellular Pertussis Vaccine in Canada: a Report from IMPACT, 112 PEDIATRICS 348, 351 (2003), filed as

“Pet Ex. 31.”

19

with 136 cases of febrile seizures, noting “[s]ingle afebrile seizures were reported in 44 (17.8%)

of 247 cases, including single focal seizures (n = 4), tonic seizures (n = 2), atonic seizures (n = 3),

generalized tonic-clonic seizures (n = 14), and afebrile status epilepticus (n = 6).” Pet. Ex. 21 at 5;

Pet. Ex. 33.35

Dr. Kinsbourne agreed that the IOM committee on adverse effects of vaccines by Stratton36

did not credit any of the “numerous reports of afebrile seizures related to MMR.” Pet. Ex. 21 at 5.

However, he claimed the committee “hardly credits any causal relations between any vaccine and

any adverse event, since it chose a standard of adjudication that is quite unrealistically elevated for

purposes of vaccine injury compensation proceedings.” Id.

In his second report, Dr. Holmes agreed that A.L.M. had localized epilepsy emanating from

the left hemisphere of her brain. Resp. Ex. Q at 2. He agreed that seizures arise from abnormal

brain tissue. Id. However, Dr. Holmes was unclear about petitioner’s two-hit theory, specifically,

what constituted the first hit and what the biological mechanism was for the MMR to be the second

hit. Id. He pointed out that there is no evidence that A.L.M. had any inflammatory response

following her vaccines. Id.

Dr. Holmes added that “the adjusted incidence of new-onset epilepsy in children is 44.5

cases per 100,000 persons per year with the highest incidence rates in the first year of life.” Resp.

Ex. Q at 3. Neither the Le Saux nor the von Spiczak studies relied on by Dr. Kinsbourne examined

the comparative risk of afebrile seizures in children who were not immunized. Id.; Pet. Ex. 31;37

Pet. Ex. 33.38 Dr. Holmes agreed that a small number of children have developed epilepsy after

having afebrile seizures following an MMR vaccine but submitted those children would have

likely developed epilepsy regardless. Resp. Ex. Q at 3. For this reason, neither Le Saux nor von

Spiczak were considered by the IOM in evaluating epidemiologic or mechanistic evidence related

to the MMR vaccine; the IOM ultimately concluded that an association between MMR and afebrile

seizures was lacking. Id.; Pet. Ex. 31;39 Pet. Ex. 33.40 Additionally, Dr. Holmes added, the von

Spiczak article specifically noted that “passive surveillance [is] not suitable for determining the

frequency of a particular adverse effect.” Resp. Ex. Q at 3; Pet. Ex. 33.41 In sum, Dr. Holmes

restated his opinion that A.L.M. has well controlled epilepsy and an expressive language disorder,

but disagreed her neurological condition was related to the vaccine. Resp. Ex. Q at 3.

In his fourth report and in response to questions raised by the undersigned, Dr. Kinsbourne

submitted that the exact abnormality on the brain is immaterial; what matters is that abnormal brain

tissue exists in the area from which the epilepsy is generated. Pet. Ex. 36 at 1. Dr. Kinsbourne

added, “[t]he evidence that A.L.M. had a lowered seizure threshold resides in the facts of this

case.” Id. All that is necessary is that the person’s brain tissue includes hyperexcitable neuronal

35

Sarah von Spiczak et al., A Retrospective Population-based Study on Seizures Related to Childhood

Vaccination, 52 EPILEPSIA 1506 (2011), filed as “Pet. Ex. 33.”

36

Based on review of the record, it does not appear that the Stratton et al. (2012) article was filed.

37

Le Saux et al., supra note 34.

38

von Spiczak et al., supra note 35.

39

Le Saux et al., supra note 34.

40

von Spiczak et al., supra note 35.

41

Id.

20

tissue, by virtue of which the seizure threshold is lowered; this renders the individual susceptible

to generating seizures if provoked by a triggering event, such as receiving a vaccine. Id. According

to Dr. Kinsbourne, “[t]he damage to the neural network could theoretically have been inflicted by

the vaccinations. But far more likely it was in place before the vaccination, which rendered this

susceptibility into the reality of [A.L.M.’s] seizure disorder.” Id.

Dr. Kinsbourne claimed that the Dubé and Vezzani articles support his opinion that

proinflammatory cytokines—IL-1b—can cause seizures as well as fever, though one is not

contingent on the other. Pet. Ex. 36 at 2; Pet. Ex. 38; 42 Pet. Ex. 37. 43 He further opined that a

seizure triggered by measles viremia need not be accompanied by fever. Pet. Ex. 36 at 2. Pointing

to a chart contained in the Vezzani study, Dr. Kinsbourne suggested that IL-beta generates

epileptogenesis through different pathways that can be activated in parallel, but neither of which

features fever. Id.; Pet. Ex. 37.44

Dr. Kinsbourne conceded whether she had fever or no fever and regardless of if her seizure

threshold was lowered or her neural network hyperexcitable, the vaccine would not be responsible

for A.L.M.’s seizures if it is found that her seizures had an onset in excess of two weeks after the

MMR vaccine. Pet. Ex. 36 at 2.

Dr. Holmes responded in a third report, which addressed the temporal relationship between

vaccination and symptom onset. He submitted that febrile seizures present between 7-14 days after

MMR vaccination but can range from hours to 28 days. Resp. Ex. V at 2. If the time interval

between A.L.M.’s MMR vaccine and her first seizure is found to be 31 days, then it would fall

outside of the timeframe even for MMR-induced febrile seizures. Id. However, Dr. Holmes posited

there is no biological mechanism by which the MMR vaccine can cause afebrile seizures. Id.

Further, neither Dubé nor Vezzani address vaccination-induced proinflammatory cytokines. Id. at

3; See Pet. Ex. 38;45 Pet. Ex. 37.46 He added neither Dubé nor Dr. Kinsbourne have explained how

the MMR vaccine can increase cytokines in the absence of fever and cause seizures. Resp. Ex. V

at 3.

Dr. Holmes further opined that there was no evidence either epidemiologically or

mechanistically to support Dr. Kinsbourne’s opinion that A.L.M. had “hyperexcitable neuronal

tissue,” resulting in a lower seizure threshold and rendering her susceptible to a seizure disorder

that was activated by the MMR vaccine. Resp. Ex. V at 2-3.

Petitioner’s expert Dr. Levin issued a report which also discussed the two-hit theory. Pet.

Ex. 39 at 2. Dr. Levin proposed that the first hit was from birth trauma or a genetic propensity that

42

Céline M. Dubé et al., Cytokines: A Link Between Fever and Seizures: Interleukin-1b Contributes to the

Generation of Experimental Febrile Seizures, 57 ANN. NEUROLOGY 152 (2005), filed as “Pet. Ex. 38” and

“Resp. Ex. QQ.”

43

Annamaria Vezzani et al., The Role of Cytokines in the Pathophysiology of Epilepsy, 22 BRAIN,

BEHAVIOR, & IMMUNITY 797 (2008), filed as “Pet. Ex. 37.”

44

Id. at 801.

45

Dubé et al., supra note 42.

46

Vezzani et al., supra note 43.

21

lowered seizure threshold. Id. The second hit was from “the multiple vaccinations”47 A.L.M.

received on October 25, 2012 that caused or substantially contributed to her seizures and epilepsy,

with or without fever, because “all vaccines are engineered to activate the innate immune system

and cytokine enhancement.” Id. at 1-2. The enhanced cytokine production, then caused neuronal

damage. Pet. Ex. 39 at 2. The first clinical signs of neuronal damage were the chewing motions,

staring, not reacting to sound, and rubbing of her fingers, all of which began within two weeks of

the vaccination. Id. The seizures “were simply a further indication of the progression of neuronal

damage and were noted one month later.”48 Id. A.L.M.’s rash on November 2 was an inflammatory

response caused by cytokine production evoked by vaccination. Id.

Dr. Levin opined that MMR vaccine is associated with afebrile seizures relying on Eckerle,

Weibel, and the MMR vaccine package insert. Pet. Ex. 39 at 2; Pet. Ex. 41;49 Pet. Ex. 45;50 Pet.

Ex. 43. According to Dr. Levin, peripheral vaccinations produce cytokines, which can cause both

fevers and seizures independent of one another, writing, “seizures are caused by the neuronal

damage which, in turn, is caused by the cytokines and independent of the fever.” Pet. Ex. 39 at 2;

Pet. Ex. 42.51

Dr. Levin concluded that Prong I was “clearly” established in “[t]he fact that her symptoms

began within 2 weeks of the vaccination and they all biologically plausibly related to cytokine

reactions satisfies the 1st first signs of cytokine induced neuronal damage is totally appropriate

satisfies the 2nd prong.”52 Pet. Ex. 39 at 2 (emphasis in original). Further, Dr. Levin opined that

the vaccinations received by A.L.M. on October 25, 2012 were the cause or substantial contributor

to her neurologic pathology. Id.

Dr. McCusker responded to both Drs. Kinsbourne and Levin in her first report. She

provided an in-depth explanation of how vaccines work to produce immunity and the function of

cytokines. Resp. Ex. Z. She defined cytokines as communication proteins that interact with

receptors, inducing a response that affects the behavior and the function of the recipient cell. Id. at

3. “Cytokines shape the innate and adaptive immune response and depending upon the profile and

amount of cytokines released these responses may be pro- or anti-inflammatory.” Id. Unlike

cytokines expressed in the periphery, cytokines expressed in the brain can play a distinct role in

normal brain homeostasis and are not considered “pro inflammatory.” Id. at 3-4.

47

Notably, Dr. Levin agreed with Dr. Kinsbourne that the MMR vaccine was the “lead actor[] in this

scenario, however the contribution of the other eighteen pathogen simulating antigens, DTaP, Hib, Prevnar

13 and Varicella . . . should not be ignored in this baby’s neuropathology.” Pet. Ex. 39 at 1.

48

It appears that Dr. Levin placed seizure onset approximately one month after A.L.M.’s vaccination, which

is consistent with petitioner’s VAERS report and with the medical records. However, this is inconsistent

with Dr. Kinsbourne’s proposed date of seizure onset, which was roughly ten days following A.L.M.’s

vaccination. See Tr. 54. This issue will be discussed further in Prong III.

49

Isabella Eckerle et al., Nonfebrile Seizures after Mumps, Measles, Rubella, and Varicella-Zoster Virus

Combination Vaccination with Detection of Measles Virus RNA in Serum, Throat, and Urine, 20 CLINICAL

& VACCINE IMMUNOLOGY 1094 (2013), filed as “Pet. Ex. 41.”

50

Robert E. Weibel, MD et al., Acute Encephalopathy Followed by Permanent Brain Injury or Death

Associated with Further Attenuated Measles Vaccines: A Review of Claims Submitted to the National

Vaccine Injury Compensation Program, 101 PEDIATRICS 383 (1998), filed as “Pet. Ex. 45.”

51

Ichiyama et al., supra note 15.

52

This is a direct quote, and it is unclear what this means.

22

Dr. McCusker submitted that fever, for example, is the effect of cytokines such as IL1b,

IL6 and Tumor Necrosis Factor Alpha (“TNFα”). Id. at 3. These cytokines are part of the initial

cascade of inflammation at the site of infection or trauma which is usually transient and tightly

regulated. Resp. Ex. Z at 3. Most cytokine events occur locally and do not generate significant

systemic signaling. Id. Even with live viruses, the zone of activity is primarily limited to the local

lymph nodes. Id. at 8. Further, there is no evidence that cytokines produced from a peripheral

vaccination can trigger epilepsy generally or that it did here. Id.

Dr. McCusker relied on Kashiwagi, to explain cytokine upregulation following receipt of

vaccines that is transient and tightly regulated. Resp. Ex. Z at 5; Resp. Ex. GG.53 Notably,

examination of serum cytokine levels in children within 48 hours of vaccination showed very low

amounts of IL-1b, IL6, and TNFα, suggesting that the level of cytokines produced and released by

the peripheral immune system during vaccination is not sufficient to influence the development of

cytokine-mediated changes in seizure threshold as proposed by petitioner’s experts. Resp. Ex. Z

at 5. She acknowledged that Kashiwagi did not study live viral vaccinations like the MMR vaccine,

but did study Hib, DPT, and 7-valent pneumococcal vaccines; however, studies of wild type

measles infection did not show high levels of IL-1b. Id.; Resp. Ex. GG.54

Dr. McCusker referenced Dubé to show that the cytokine levels after peripheral vaccination

showed no evidence of significant cytokine changes in the brain. Resp. Ex. Z at 7. In Dubé, large

amounts of IL-1beta were injected directly into the brains of mice. The level of cytokines necessary

to induce a lowered seizure threshold in the mice was more than 1000 times greater than that found

in the blood during actual measles infection. Id. Dr. McCusker estimated that IL-1b levels after an

attenuated strain vaccine, like MMR vaccine, would be similar to or less than the levels seen in

wild type measles infection. Id. at 5. Thus, even if peripheral IL-1b was detectable when A.L.M.

had the rash on November 2, 2012, the level would have been low. Id. Further, she claimed that

there is no evidence of sustained IL-1b in this case. Id.

Dr. McCusker referenced the Ron-Harel and Moidunny studies to show that cytokines play

a role in normal brain function due to their function in neuroprotection and neuromodulation. Resp.

Ex. Z at 5; Resp. Ex. II;55 Resp. Ex. JJ.56 At baseline, microglial cells present in the brain release

cytokines and can increase from stressors but are involved in basic brain physiology. Resp. Ex. Z

at 5. The Li study showed that cytokines may even reduce the risk of seizure activity, concluding

that “IL-1beta, in the CNS in general, reduces rather than augments neuronal activity.” Resp. Ex.

53

Yasuyo 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 677 (2014), filed as “Resp. Ex. GG.”

54

Id.

55

Noga Ron-Harel et al., Brain Homeostasis is Maintained by ‘‘Danger’’ Signals Stimulating a Supportive

Immune Response Within the Brain’s Borders, 25 BRAIN, BEHAVIOR, & IMMUNITY 1036 (2011), filed as

“Resp. Ex. II.”

56

Shamsudheen Moidunny et al., Interleukin-6-type Cytokines in Neuroprotection and Neuromodulation:

Oncostatin M, but Not Leukemia Inhibitory Factor, Requires Neuronal Adenosine A1 Receptor Function,

114 J. OF NEUROCHEMISTRY 1667 (2010), filed as “Resp. Ex. JJ.”

23

Z at 7; Resp. Ex. RR.57 She added that Vezzani & Baram, who chemically induced seizures with

large amounts of IL-1b injected directly into the hippocampus of rats, found that IL-1b

administered peripherally had an anticonvulsant effect. Resp. Ex. Z at 8; Pet. Ex. 34.58 While

cytokines from the periphery can cross the blood brain barrier and stimulate nerve fibers in areas

of inflammation, causing upregulation in the various areas of the brain leading to sickness behavior

such as fever there is no evidence that low concentrations of peripheral cytokines result in

significant increases or overexpression of these cytokines in the brain tissue. Id. at 7.

Dr. McCusker posited that cytokines in the brain are produced in response to and serve as

the etiology for seizures not the cause of seizures as opined by Drs. Kinsbourne and Levin. Resp.

Ex. Z at 7, 8. There is no evidence to show that the peripheral release of IL-1b or other pro-

inflammatory cytokines following vaccination can cause epilepsy. Id. at 8. Dr. McCusker pointed

out that von Spiczak concluded, “the risk for epilepsies is not elevated even though epilepsy may

present with a seizure following vaccination.” Resp. Ex. Z at 8; Pet. Ex. 33.59 The authors further

stated that “[c]arefully designed studies have failed to demonstrate an association between

vaccination and adverse neurological outcome in children.” Resp. Ex. Z at 8, Pet. Ex. 33.60 Further,

the authors in Verbeek concluded that the results supported their hypothesis that predisposing

factors within the child—and not the vaccination—caused the observed neurologic deterioration.

Id.; Resp. Ex. UU.61

Dr. McCusker added that epidemiological studies demonstrate that the incidence of

epilepsy is highest in infancy and seizure onset in the first year of life most commonly occurs

before the age of 7 months. Resp. Ex. Z at 8. She also noted that onset of focal epilepsy is mainly

in infancy. Id. at 7; Resp. Ex. PP.62 Further, more than 60% of those patients with epilepsy show

no neurological deficits at the time of onset and 37% have normal MRIs. Resp. Ex. Z at 7; Resp.

Ex. PP.63 Although there is a temporal association between seizures and vaccination, the events

have yet to be etiologically linked. Resp. Ex. Z at 8-9.

Dr. McCusker noted that A.L.M. had many events since birth that activated peripheral

immunity by releasing cytokines, including an RSV infection at 5 weeks of age, vaccinations at 2,

4, 6 and 12 months of age, and gastroenteritis during the summer of 2012. Resp. Ex. Z at 4. At 12

months old, she received multiple vaccinations and experienced no fever, no evidence of

inflammation at the vaccination site reported and no sick behaviors. Id. at 5. After her subject

vaccinations, there were no symptoms of systemic cytokine activation, although she did have a

rash on November 2, 2012. Id.; see also Resp. Ex. EE.64

57

Gang Li et al., Cytokines and Epilepsy, 20 SEIZURE 249 (2011), filed as “Resp. Ex. RR.”

58

Vezzani & Baram, supra note 27.

59

von Spiczak et al., supra note 35.

60

Id. at 8.

61

Verbeek et al., Etiologies for Seizures Around the Time of Vaccination, 134 PEDIATRICS 658 (2014), filed

as “Resp. Ex. UU.”

62

Marilena Vecchi, Symptomatic and Presumed Symptomatic Focal Epilepsies in Childhood: An

Observational, Prospective Multicentre Study, 57 EPILEPSIA 1808 (2016), filed as “Resp. Ex. PP.”

63

Id.

64

Maria I. Oliveira et al., Rash After Measles Vaccination: Laboratory Analysis of Cases Reported in São

Paulo, Brazil, 36 REVISTA DE SAUDE PUBLICA 155 (2002), filed as “Resp. Ex. EE.”

24

Dr. McCusker opined that A.L.M. had a seizure disorder which manifested weeks after her

vaccination. Resp. Ex. Z at 9. Though the precise timing of onset was unclear, there is no evidence

in the medical records or medical literature to support the idea that A.L.M.’s vaccinations led to

her seizure disorder. Id. Studies show that IL-1b levels after vaccination are very low and only

small amounts are detected in patients even with wild-type measles infection when they manifest

with rash. Id. The levels required to decrease seizure threshold would be even greater than what is

detected in patients who have severe symptoms requiring hospitalization due to natural infection.

Id. Therefore, there is no evidence of a causal link between A.L.M.’s vaccination and her seizures.

Id.

Dr. Levin responded, maintaining his opinion that twenty-one separate infectious antigens

and adjuvants received caused an inflammatory response, with A.L.M.’s rash on November 2 as

consistent with a cytokine-induced inflammatory cutaneous reaction. Pet. Ex. 50 at 1.

Further, Dr. Levin maintained that fever and seizures are independent of one another. Pet.

Ex. 50 at 1. He relied on Dubé admitting that when recombinant IL-1b was administered to wild

type mice it decreased seizures but at high doses was sufficient to induce seizures in afebrile

animals. Id.; Pet. Ex. 38.65 Vezzani showed that afebrile seizures themselves led to the expression

of IL-1b in microglia, claiming that IL-1b induced by seizures may in turn exacerbate ongoing

seizures acting as its neuronal receptor. Pet. Ex. 50 at 1; Pet. Ex. 55.66 He submitted that seizures

are caused by the lowering of seizure thresholds in neurons and from edema. Pet. Ex. 50 at 2; Pet.

Ex. 52.67 He concluded that fever and seizures are caused by independent pathways with fever

caused by the interaction of endogenous and exogenous cytokines on the hypothalamus and other

portions of the brain. Pet. Ex. 50 at 2; Pet. Ex. 53.68

Dr. Levin criticized the literature relied on by Dr. McCusker referring to Kashiwagi and

Lin as “irrelevant” and “inaccurate”. Pet. Ex. 50 at 2-3; See Resp. Ex. GG,69 Resp. Ex. HH.70 He

submitted that Dr. McCusker offered Kashiwagi to show that the cytokines released by vaccines

are very low; but her interpretation was “inaccurate and unrelated to” Dubé. Pet. Ex. 50 at 2.

According to Dr. Levin, Dubé 71 identified changes in brain cells after the direct injection of

65

Dubé et al., supra note 42.

66

Annamaria Vezzani et al., Interleukin-1b Immunoreactivity and Microglia Are Enhanced in the Rat

Hippocampus by Focal Kainate Application: Functional Evidence for Enhancement of Electrographic

Seizures, 19 J. OF NEUROSCIENCE 5054 (1999), filed as “Pet. Ex. 55.”

67

Einar E. Eriksson et al., Direct Observations In Vivo on the Role of Endothelial Selectins and Alpha (4)

Integrin in Cytokine-induced Leukocyte-endothelium Interactions in the Mouse Aorta, 86 CIRCULATION

RES. 526 (2000), filed as “Pet. Ex. 52.”

68

Mihai G. Netea et al., Circulating Cytokines as Mediators of Fever, 31 CLINICAL INFECTIOUS DISEASES

178 (2000), filed as “Pet. Ex. 53.” This article discusses fever as an important part of the body’s response

to exogenous factors and the many ways and through various organs that the body can generate fever.

69

Kashiwagi et al., supra note 53.

70

Wen-Hsuan W. Lin et al., Plasma Cytokines and Chemokines in Zambian Children with Measles: Innate

Responses and Association With HIV-1 Coinfection and In-Hospital Mortality, 215 J. OF INFECTIOUS

DISEASES 830 (2017), filed as “Resp. Ex. HH.”

71

Dubé et al., supra note 42.

25

cytokines into the brain; Kashiwagi,72 on the other hand, studied peripheral blood cells, not brain

cells. Id. at 2-3. Further, Lin73 studied acute viral diseases not vaccinations. Id. at 3. Dr. Levin

concluded that Dubé74 “clearly” shows that cytokines cause seizures and fevers separately,

supporting his theory that vaccine(s) can cause an afebrile seizure. Id.

Dr. Holmes issued a report in response to Dr. Levin. Resp. Ex. YY at 2. He posited that

there was no birth trauma in this case, citing to A.L.M.’s Apgar scores, her newborn screening,

and her numerous well-child visits. Id. Dr. Holmes also stated he was unclear on what Dr. Levin

was referring to as the “first hit.” Id.

Dr. Holmes agreed that the MMR vaccine elicits an innate response, but there was no proof

that A.L.M.’s innate immune response resulted in a neurological injury as Dr. Levin suggested.

Resp. Ex. YY at 3. Dr. Holmes explained that within hours of the introduction of an antigen to the

body, an innate immune response occurs, wherein B and T cells are activated by macrophages and

dendritic cells that engulf the antigen. Id. These new antigen-presenting cells present the antigen

to T cells and then release inflammatory cytokines and chemokines that recruit, activate, and

proliferate the B and T cells. Id. Then, activated B and T cells “release inflammatory mediators

leading to the recruitment and activation of additional immune cells that further amplify the

immune response through the release of inflammatory mediators.” Id. There is no evidence in this

case that the MMR vaccine A.L.M. received resulted in her suffering from a systemic response

that caused brain damage. Id. Dr. Levin provided no support for his argument other than relying

on a transient rash. Id.

Dr. Holmes explained that children develop rashes all the time for various reasons and

some following MMR immunization. Petitioner affirmed that A.L.M.’s rash appeared a week after

her vaccinations and lasted less than an hour. Resp. Ex. YY at 3. A.L.M.’s EEG showed no acute

inflammatory brain injury. Id. According to Dr. Holmes, Dr. Levin’s opinion—that the MMR

vaccine led to “an intense release of cytokines that resulted in a transient rash and elicited brain

damage in a child who had no signs or symptoms of central nervous system disease” leading to

permanent brain injury—is “implausible from both a clinical and biological standpoint.” Id.

Dr. Holmes discussed the Weibel and Eckerle studies relied on by Dr. Levin in support of

his theory that MMR vaccine can cause afebrile seizures. Resp. Ex. YY at 4; Pet. Ex. 41;75 Pet.

Ex. 45.76 Dr. Holmes submitted that Weibel was based on passive retrospective surveillance with

no control group and discussed children who developed encephalopathy of no determined cause

within 15 days of MMR; the authors found a clustering with peak onset of cases on days 8 and 9

after immunization. Resp. Ex. YY at 4; Pet. Ex. 45.77 Here, however, A.L.M. did not develop

encephalopathy 8 or 9 days after vaccination. Resp. Ex. YY at 4. Further, Eckerle is a case study

of one child who had three generalized tonic clonic seizures 6 days after MMR/varicella vaccines.

72

Kashiwagi et al., supra note 53.

73

Lin et al., supra note 70.

74

Dubé et al., supra note 42.

75

Eckerle et al., supra note 49.

76

Weibel et al., supra note 50.

77

Id.

26

Resp. Ex. YY at 4; Pet. Ex. 41.78 The authors concluded that it was not possible to assess a causal

relationship between afebrile seizures and vaccination. Resp. Ex. YY at 4.

Dr. Holmes disagreed that A.L.M.’s neuropathology was neuronal damage caused by

cytokines enhanced by the vaccination on October 25, 2012. Resp. Ex. YY at 4. There was no

proof in the record of neuronal damage, and Dr. Levin failed to explain what he was referring to

as “obvious signs” of neuronal damage. Id. Notably, none of A.L.M.’s treaters recognized obvious

signs of neuronal damage either. Id.

Dr. Holmes further took issue with Dr. Levin’s opinion that cytokines produced from

peripheral vaccinations can cause fever and seizures independent of one another. Resp. Ex. YY at

4. He discussed the Ichiyama study relied on by Dr. Levin, noting that the study was of prolonged

febrile seizures in children with acute encephalitis/encephalopathy associated with fever. The

study did not involve vaccines at all. Id.; Pet. Ex. 42.79 Further, A.L.M. did not have febrile seizures

or encephalopathy. Resp. Ex. YY at 4. Dr. Holmes concluded that Dr. Levin’s opinion lacked any

support from the medical record or credible literature. Id.

Dr. McCusker issued a report in response to Dr. Levin, addressing A.L.M.’s rash. She

explained that the rash that develops 7-10 days after the MMR vaccination marks the body’s

clearance of the infectious virus and the end of inflammation. Resp Ex. FFF at 3; Resp. Ex. GGG.80

Evidence shows that following the resolution of the rash, the dominant active immune response is

regulatory, anti-inflammatory T cells. Id. Thus, inflammatory cytokines would not circulate after

the rash. Id. Here, if A.L.M.’s rash was vaccine related, it was an indication that the inflammation

process had ended. Id.

Dr. McCusker also explained the concept of cytokine half-life. She pointed out that the IL-

1b in serum has a half-life clearance of 19 minutes, while subcutaneous administration peaks at

one hour with a half-life of 1.59 minutes. Resp Ex. FFF at 4; Resp. Ex. HHH.81 This means that

any unused serum IL-1b would be inactivate for only 19 minutes after release. Resp Ex. FFF at 3.

Thus, based on the data, any peripherally released IL-1b that may be elevated following

vaccination has no afebrile epilepsy-causing potential. Id.

Dr. McCusker responded to Dr. Levin’s criticisms of the literature she referenced, pointing

out that Dr. Levin provided no evidence to support his opinion that brain cell cytokine levels are

significantly elevated after vaccination. Resp. Ex. FFF at 3-4; Resp. Ex. GG;82 Resp. Ex. HH.83

She noted that in Dubé, they were only able to induce afebrile seizures using high levels of IL-1b

injected directly into the animals’ brains. Id. at 4; Pet. Ex. 38.84 This does not equate to cytokines

78

Eckerle et al., supra note 49.

79

Ichiyama et al., supra note 15.

80

Diane E. Griffin, The Immune Response in Measles: Virus Control, Clearance and Protective Immunity,

8 VIRUSES 282 (2016), filed as “Resp. Ex. GGG.”

81

Shoji Kudo et al., Clearance and Tissue Distribution of Recombinant Human Interleukin Iβ in Rats, 50

CANCER RESEARCH 5751 (1990), filed as “Resp. Ex. HHH.”

82

Kashiwagi et al., supra note 53.

83

Lin et al., supra note 70.

84

Dubé et al., supra note 42.

27

generated in response to a peripheral vaccination. Resp. Ex. FFF at 4. Additionally, and contrary

to Dr. Levin’s opinion, Li showed that the cytokines released in the brain were in response to a

seizure, not the cause of the seizure. Resp. Ex. FFF at 4; Resp. Ex. RR.85

Dr. McCusker concluded that A.L.M. suffered many infections prior to the subject

vaccination that raised her proinflammatory cytokine levels as evidenced by her fevers; however,

she did not develop febrile seizures or epilepsy at those times. Resp. Ex. FFF at 3. In Dr.

McCusker’s opinion, A.L.M. developed a seizure disorder which manifested around the age of 13

months. Id. at 4. There is no evidence that the vaccines A.L.M. received on October 25, 2012

contributed to the development of her seizure disorder. Id.

ii. The Testimony of the Experts

a. Dr. Kinsbourne

At hearing, Dr. Kinsbourne explained that his two-hit theory included genetic susceptibility

as the first hit and the MMR vaccine on October 25, 2012 as the second hit triggering A.L.M.’s

seizure disorder and epilepsy. Tr. 52, 67-70, 77-78. He added that both the MMR and Varicella

vaccines being live attenuated vaccines fit the expected time frame of 5 to 15 days for the onset of

seizures and that administering the two vaccines at the same time doubles the risk of febrile

seizures. “In my mind, it says that the ability of MMR to cause seizures during the risk period, is

greater if there is varicella as well.” Tr. 52, 92-93. Dr. Kinsbourne stated that seizures can be

triggered by a lot of different stressors or traumas in the system, including vaccination—though it

is a “less prominent” cause. Tr. 79. He submitted that A.L.M.’s family history made seizures more

likely. Tr. 69-70. She had susceptibility and the vaccine triggered A.L.M.’s seizures; if not for the

vaccine, she may have never developed seizures. Tr. 82.

In Dr. Kinsbourne’s proposed theory, the first hit was structural or genetic abnormality that

existed at the location where the seizures generated from, which lowered the seizure threshold. Tr.

67-70. “Clearly, you have a lower seizure threshold if you’re actually having seizure activity.” Tr.

68. He described A.L.M.’s seizures as “central temporal seizures” emanating from the left

hemisphere at the back of the frontal lobe or the area referred to as the central fissure, which is a

cut between the frontal lobe and the other lobes. Tr. 52-53. This area is part of the motor strip

involved with movements of the face and head. Tr. 53. Thus, the seizure activity arose from the

face, eyes, mouth, and maybe swallowing. Tr. 53.

At hearing and for the first time, Dr. Kinsbourne suggested that A.L.M. may have been

having subclinical micro seizures before her vaccinations, which lowered her seizure threshold so

that the vaccines when received set off the full seizures. Tr. 69. He reasoned that in her first year

of life, A.L.M. had more than the normal amount of excitatory activity – “you can think of

subclinical seizures going on in that area.” However, it was not until the vaccination that the area

organized and caused actual seizure activity. Tr. 61. The brain is always in flux and those with a

lowered seizure threshold do not immediately express seizures; it could be days, weeks, months,

or never. Tr. 61-63. A.L.M. just happened to receive the October 25, 2012 vaccinations when she

was most vulnerable. Tr. 63.

85

Li et al., supra note 57.

28

Acknowledging that A.L.M.’s seizures were afebrile, Dr. Kinsbourne stated that febrile

and afebrile seizures are different only as a matter of degree and can be difficult to differentiate.

Tr. 65, 80. He referenced Scheffer86 to illustrate that fever is not the mechanism responsible for

triggering seizures where a lower seizure threshold exists. Tr. 59-60, Pet. Ex. 58.87 Scheffer

provided that “[v]accination triggers the onset of seizures in one-third of patients with Dravet

Syndrome, some patients do not have a fever…” Tr. 59-60; Pet. Ex. 58.88 Dravet Syndrome is a

very serious seizure disorder caused by a mutation of SCN1A. Dr. Kinsbourne agreed that A.L.M.

does not have Dravet Syndrome. Tr. 60. However, he claimed that Scheffer shows that there is a

lower seizure threshold where excitation exceeds inhibition, so it takes less to provoke a seizure.

Tr. 60-61; Pet. Ex. 58.89

Dr. Kinsbourne further stated that A.L.M.’s seizure threshold could have been so low that

her seizures began before a fever had time to elevate, relying on Scheffer and Berg. Tr. 90; Pet.

Ex. 58;90 Pet. Ex. 61.91 He submitted that A.L.M.’s seizure threshold was very low at the time of

vaccination but increased at some point in time acknowledging that her seizures have ceased. Tr.

92. He stated, “central temporal epilepsies don’t go on into adulthood.” Tr. 92.

For the second hit, Dr. Kinsbourne opined that the MMR vaccine caused an increase in

cytokines, specifically IL-1b, that triggered A.L.M.’s epilepsy. Tr. at 75. He explained that when

confronted with an infection or vaccination, the innate immune system responds by sending out

proinflammatory cytokines, IL-1b being the most important one. Tr. 56. The hypothalamus in the

brain generates fever or inflammation in response to the cytokines, and one of the potential

consequences is a seizure. Tr. 56; Pet. Ex. 37.92 Dr. Kinsbourne conceded that fever and seizures

usually go together in young children but stated there can be seizures with no fever or only a

minimal rise in fever because fevers and seizures have separate pathways. Tr. 56-57. Afebrile or

low-grade febrile seizures following cytokines are particularly likely if the seizure threshold is

already low. Tr. 57. Fever usually has nothing to do with seizure activity. Tr. 57.

Dr. Kinsbourne stated that the literature supports afebrile seizures following vaccination.

86

Dravet syndrome is a rare type of epilepsy, usually starting in the first year of life. The first manifestation

is often a seizure triggered by a high fever and lasting more than five minutes. Children with Dravet

syndrome have other symptoms, including developmental setbacks, speech and language problems, and

balance and walking issues. Cleveland Clinic, Dravet Syndrome,

https://my.clevelandclinic.org/health/diseases/22517-dravet-syndrome.

87

Counsel referenced Pet. Ex. 60, which is Fernando Cendes & Raman Sankar, Vaccinations and Febrile

Seizures, 52 EPILEPSIA 23 (2011), filed as “Pet. Ex. 60” [hereinafter “Cendes & Sankar, Vaccinations and

Febrile Seizures”]. However, Dr. Kinsbourne discussed Ingrid E. Scheffer, Vaccination Triggers, Rather

Than Causes, Seizures, 15 EPILEPSY CURRENTS 335 (2015), filed as “Pet. Ex. 58” [hereinafter “Scheffer,

Vaccination Triggers, Rather Than Causes, Seizures”].

88

Scheffer, Vaccination Triggers, Rather Than Causes, Seizures, supra note 87.

89

Id.

90

Id.

91

Anne T. Berg, PhD et al., Predictors of Recurrent Febrile Seizures: A Prospective Cohort Study, 151

ARCHIVES OF PEDIATRICS & ADOLESCENT MED. 371 (1997), filed as “Pet. Ex. 61.”

92

Vezzani et al., supra note 43 at 5.

29

Tr. 55; Pet. Ex. 33;93 Pet. Ex. 37.94 Vezzani95 shows the release of IL-1b following a precipitating

event and supports his theory. Tr. 75-76. MMR vaccine generates proinflammatory cytokines that

activate the microglial in the brain, which then generated more IL-1b. Tr. 76. This process does

not depend on the source of the IL-1b, but rather explains how the IL-1b causes seizure and fever

independently. Tr. 76.

Dr. Kinsbourne further stated that Dubé illustrates how IL-1b can generate seizures and

fever separately. Tr. 79. In Dubé, high levels of IL-1b were injected into the brains of mice to

create a predisposition, mimicking genetic susceptibility. Tr. 80. However, Dr. Kinsbourne

conceded that the levels of IL-1b injected into the mice’s brains would not be what one would

expect to see naturally occurring. Tr. 80.

Dr. Kinsbourne agreed that Le Saux and von Spiczek did not establish a causal relationship

between seizures and vaccines, stating he only referenced the studies as circumstantial evidence

that afebrile seizures are associated with vaccines. Tr. 82-83; Pet. Ex. 31;96 Pet. Ex. 33.97 He agreed

the authors in von Spiczek looked at passive surveillance in Germany but was unsure if that

surveillance process was similar to VAERS reporting in the United States. Tr. 83; Pet. Ex. 33.98

Additionally, von Spiczek studied DTP vaccine and seizures. Tr. 84; Pet. Ex. 33.99 Further, he was

unsure whether the cases of afebrile seizures included all vaccines or just MMR. Tr. 84; Pet. Ex.

33.100 His reference to Weibel, which studied encephalopathies, seizures, and other events

following the MMR vaccine, was to show that pro-inflammatory cytokines trigger a weak point in

a person. Tr. 87; Pet. Ex. 45.101

Dr. Kinsbourne stated that the MMR package insert contains afebrile seizures in the

warnings. Tr. 58-59. He explained that after marketing a vaccine, research continues and all the

reports from people who have received the vaccine are included to warn the public of what could

happen. Tr. 58-59; Pet. Ex. 43. He claimed afebrile seizures would not be listed in the warning if

they did not happen. Tr. at 59.

He agreed that the medical literature does not provide epidemiology or scientific certainty

to suggest that the cytokines elicited by MMR vaccine can induce afebrile seizures; but for a

vaccine to work, it must produce cytokines. The immune system then decides whether to mount a

febrile response or not with great individual variability in the response. Tr. 66-67. He agreed that

the literature supports an increase in febrile seizures within 6-14 days of MMR vaccine but claimed

that epidemiology does not show the rare or random events like afebrile seizures, which is why

93

von Spiczak et al., supra note 35.

94

Vezzani et al., supra note 43.

95

Id.

96

Le Saux et al., supra note 34.

97

von Spiczak et al., supra note 35. The study states “seizures may occur in temporal relationship with

vaccination and concerns of a possible connection have been raised. Carefully designed studies have failed

to show an association between vaccination and adverse neurologic outcome in children.”

98

Id.

99

Id.

100

Id.

101

Weibel et al., supra note 50.

30

the Program does not require it. Tr. 73. He stated that rarity is a matter of degree—epidemiology

has documented febrile seizures but just because it did not document afebrile seizures does not

mean those cases don’t exist. Rather, it is likely because afebrile seizures are not routinely studied.

Tr. 73-74. Dr. Kinsbourne concluded that the literature he provided was sufficient proof for the

Program. Tr. 66.

Discussing onset, Dr. Kinsbourne described the MMR vaccine as an unusual vaccine

because it takes a week or more for the virus to assemble sufficiently in the blood stream to trigger

various manifestations. Tr. 87. He opined that A.L.M.’s first seizure occurred 2-3 days after the

rash and included facial movements, based on the testimony he heard that morning. Tr. 54; 72. His

opinion on causation is based on onset within 5-15 days of the MMR vaccine. Tr. 84-85. However,

if it is found that onset was three weeks after the November 2 rash, as stated in the VAERS report

and the medical records, then he does not believe that the vaccine was the cause. Tr. 85, 91.

Dr. Kinsbourne agreed that A.L.M.’s seizures could have been coincidental, “but

statistically, experientially, to my mind anyway, if something happens during a risk period, which

we know that the risk of seizures is increased, then it’s reasonable to say in this case that is why

the seizure was generated.” Tr. 63-64. He further stated that there could have been just one seizure,

but seizures beget seizures. Tr. 64. Dr. Kinsbourne conceded that the onset of A.L.M.’s seizures

was not intense and violent as stated in his report, but rather mysterious. Tr. 89; Pet. Ex. 14 at 3.

Once controlled with Trileptal, A.L.M. had no further seizures even though she suffered from

numerous febrile illnesses thereafter. Tr. 89. A.L.M.’s improved condition was either a result of

antiseizure medication or the fact that seizure threshold generally rises as children get older and

was not unusual. Tr. 71.

b. Dr. Levin

At hearing Dr. Levin maintained his opinion that all the vaccines A.L.M. received on

October 25, 2012 caused her seizure disorder. Tr. 97. Dr. Levin agreed with Dr. Kinsbourne’s two

hit theory with the first hit being genetic propensity which included her family history but added

“the fact of the matter is that the child had had any number of traumas, including birth trauma,

which easily could be the first hit for this particular phenomena.” Tr. 105-07. Dr. Levin stated that

it was common sense that everyone has birth trauma, which “would be the first hit in terms of an

individual who is genetically susceptible to any type of disease.” Tr. 121. He later noted that

A.L.M. also had double head trauma from falling off the bed and hitting her head twice before her

vaccinations. Tr. 126-27.

Dr. Levin stated the vaccines A.L.M. received were the second hit and “… a substantial

contributor to her disease process.” Tr. 106. Further, it would be naïve to suggest that the 21

separate antigens administered to A.L.M. did not contribute to her condition and is “illogical,

unscientific, and biologically ridiculous to give children all these vaccines at the same time.” Tr.

97-98. Dr. Levin claimed that adverse reactions to vaccines are “very, very common and much

more common that most people would like to think,” and that it is not the vaccines but the manner

in which they are given that increases the possibility of adverse reactions. Tr. 106. Here, 21

antigens were given at one time, “expecting them not to have an adverse reaction, that’s–that’s

ridiculous.” Tr. at 106.

31

According to Dr. Levin, vaccines cause the production of cytokines and cytokines cause

both fever and seizures, but the two are independent of one another. Tr.96; 98-103. Dr. Levin relied

on Dubé stating “…injection of lypopolysaccharides causes fever and also cytokine production

but that the causation is independent of one another” and “the fevers and the seizures are not related

and the mechanism of action is different.” Dr. Levin concluded that Dubé proved that high levels

of lypopolysaccharides evokes cytokines which then cause seizures independent of fever. Tr. 99-

100; Pet. Ex. 38.102 He quoted Dubé stating, “’Interestingly, nonfebrile seizures themselves led to

the expression of IL-1b in microglia, suggesting that IL-1b induced seizures may, in turn,

exacerbate ongoing seizures, apparently acting in its neuronal receptor.’” Tr. 100; Pet. Ex. 38.103

He stated:

[It] means that the lypopolysaccharides induced IL-1b–which is normal, which

everybody knows—and that the IL-1b induced both fever and seizures, but

sometimes it evokes only seizures, and that—we know that because Merck, Sharp

& Dohme talks about it, and they’re a billion dollar company and they have

certainly investigated it.

Tr. 101. The fact that the studies involved injection of “high levels” of lypopolysaccharides

into the animals’ brains did not alter his opinion. Tr. 99; Pet. Ex. 38.104

I expressed my confusion, stating that my understanding of that quote was that the seizures

themselves led to the expression of IL-1b in the microglia of the brain. In other words, that the

seizure itself generated IL-1b, not the other way around. Tr. 101; Pet. Ex. 38.105 Dr. Levin agreed.

Tr. 101. I then asked how IL-1b generated the seizure, to which he responded, “Look at Figure

1…Doesn’t that mean that cytokines cause seizures?” Tr. 101; Pet. Ex. 38.106 Further discussion

of Figure 1 ensued, with Dr. Levin stating, “The arrow points from cytokines to fever or the arrow

points from cytokines to seizures, and then—and they are related, but the fact of the matter is that

this particular article says that cytokines cause seizures independent of fever.” Tr. 103. Dr. Levin

was redirected by petitioner’s counsel, who asked if Dubé was “suggesting that the IL-1b induced

by seizures may in turn exacerbate ongoing seizures.” Tr. 104; Pet. Ex. 38.107 While agreeing that

was accurate, Dr. Levin added that cytokines could cause seizures independent of fever, based not

only on Dubé but also on “any number of articles showing that cytokines cause seizures and the

mechanism by which they do, and I believe I cited many of them in my report.” Tr. 104.

Respondent’s counsel asked Dr. Levin why A.L.M. did not have any seizures following

her other vaccinations. He replied that “you have to be appropriately susceptible at a specific time”

to have a seizure. Tr. 121. Further, “…disease is a function of the exposure to an etiologic agent

and the appropriately susceptible host, and at the time that she was getting vaccinated before, she

just was not appropriately susceptible.” Tr. 122.

102

Dubé et al., supra note 42.

103

Id.

104

Id. at Figure 1.

105

Id.

106

Id.

107

Id.

32

Dr. Levin discussed the medical literature he claimed supported his opinion that MMR

vaccine can cause afebrile seizures. Tr. 96-97. He stated that the Ichiyama study showed that

“cytokines lead to neuronal damage, which can lead to seizures independent of whether a patient

has fever.” Tr. 118, 122; Pet. Ex. 39 at 2; Pet. Ex. 42.108 He conceded that Ichiyama compared

febrile seizures to acute encephalitis and encephalopathy and did not address afebrile seizures. Tr.

119; Pet. Ex. 42.109 He stated that Eriksson stood for the proposition that seizures are the result of

a reduction of endothelial cell integrity, causing edema and lowering seizure threshold. Tr. 122;

Pet. Ex. 52.110 He conceded that the Eriksson article made no mention of the word “seizure” or

“epilepsy” and discussed endothelial cells found in the blood vessels of mouse aorta. Tr. 122-123;

Pet. Ex. 52.111 He discussed the Eckerle and Weibel articles. Tr. 112-13; Pet. Ex. 39; Pet. Ex. 41;112

Pet. Ex. 45.113 He confirmed that Eckerle discussed one case report but stated that other patients

were discussed in Table 1. Tr. 113; Pet. Ex. 41.114 He further acknowledged that Eckerle cautioned

that it was not possible to assess a causal relationship between nonfebrile seizures and vaccinations

based on the cases reviewed but added that the study was from 2013. Tr. 114; Pet. Ex. 41.115 He

acknowledged that Weibel studied whether a causal relationship existed between the attenuated

MMR vaccine and encephalopathy of undetermined cause with permanent brain injury or death

15 days after the first dose claiming that A.L.M. “technically” had encephalopathy and concluding

that “[c]onvulsive disorder is an encephalopathy.”116 Tr. 114-15; Pet. Ex. 45.117 He agreed that the

Weibel study was “hampered by a lack of background encephalopathic rates in unvaccinated

children” and expressed difficulty studying the relationship between MMR and encephalopathy.

Tr. 115; Pet. Ex. 45.118

In response to questions asked of him about the Kashiwagi119 and Lin120 articles referenced

by Dr. McCusker showing that the level of cytokines released after vaccination is very low, he

retorted that the fact remains that cytokines are released, and genetic propensity makes individuals

respond to cytokines adversely at different times. Tr. 104-05. Cytokines can cause seizures when

people are susceptible, which is what happened to A.L.M. Tr. 105.

Dr. Levin stated that the package insert for the MMR vaccine supported his opinion that

the MMR vaccine is associated with afebrile seizures, pointing out that afebrile seizures are listed

under “Adverse Reactions”. According to Dr. Levin, this listing is a “definite indication of

108

Ichiyama et al., supra note 15.

109

Id.

110

Eriksson et al., supra note 67.

111

Id.

112

Eckerle et al., supra note 49.

113

Weibel et al., supra note 50.

114

Eckerle et al., supra note 49.

115

Id.

116

It is important to note that Dr. Levin is the only expert who reached this conclusion. See Resp. Ex. YY

at 4, where Dr. Holmes stated that A.L.M. did not have encephalopathy; Tr. 81-82, where Dr. Kinsbourne

agreed that A.L.M. did not have an epileptic encephalopathy.

117

Weibel et al., supra note 50.

118

Id.

119

Kashiwagi et al., supra note 53.

120

Lin et al., supra note 70.

33

biological plausibility . . . Merck, Sharp & Dohme would not put it in there if it were not

biologically plausible.” Tr. 97, 115-17; Pet. Ex. 43 at 7. He acknowledged the package insert also

contained the statement that adverse reactions were listed “without regard to causality.” Tr. 116.

When I asked him whether the package insert listed all complaints received after marketing

irrespective of causation, Tr. 116-17, he responded as an attorney and a doctor:

I can tell you Merck, Sharp & Dohme know what they’re doing and wouldn’t put

it in their package inserts unless it was biologically plausible. And I’m sorry, but I

have been an attorney and a physician, and you’ve only been an attorney, so that

you don’t necessarily understand what’s going on in medicine, and that’s why we

have a major problem in medicine. Tr. 117-18.

Dr. Levin stated, “in the appropriately susceptible host, any vaccine can cause seizures.”

Tr. 119. A.L.M. received 21 antigens—three from the MMR vaccine and 18 from the other

vaccinations, all of which have been documented to trigger seizures by the same mechanism

proposed in this case. Vaccines cause the release of cytokines and cytokines cause afebrile

seizures. Tr. 119-21. Though he did not submit any literature discussing the 18 other antigens, he

stated “most of [the package inserts] talk about seizures.”121 Tr. 120. He further stated, “In

medicine, the human animal responds in a uniform way to any number of different etiologic

agents…the basic biology of the disease process is the same.” Tr. 120.

Based on that morning’s testimony, Dr. Levin stated that the temporal relationship between

A.L.M.’s vaccines and the afebrile seizures 10-14 days later122 was medically reasonable and

“biologically plausible” with “no other confounding factors making it more probable than not that

that vaccine caused the disease process”, and but for the vaccines, A.L. M would not have had a

seizure disorder. Tr. 107-08. He seemed to suggest his opinion might be different “if she had a

head trauma.” Tr. 108; but see Tr. 126. He was “aware that [A.L.M.] fell off a bed twice, that her

mother brought her in to the doctor’s office because she had fallen off a bed and hit her head

twice.” Nonetheless, based on the medical literature, medical records, testimony of the petitioner,

biological plausibility, and the absence of confounding factors, Dr. Levin opined that the vaccines

A.L.M. received caused or were the substantial contributing factor of her CNS abnormalities. Tr.

96.

c. Dr. Holmes

In Dr. Holmes’ opinion, A.L.M. followed a typical course for epilepsy. Tr. 141.

Distinguishing seizures from epilepsy, Dr. Holmes defined an epileptic seizure as a disorder of the

brain that results in behavioral changes due to excessive or synchronous neuronal activity. Tr. 129.

With epilepsy, there is an enduring propensity to have epileptic seizures which often includes

neurobiological, cognitive, and behavioral problems, thus making it a condition much more than

just seizures. Tr. 129-30. The current definition of epilepsy has changed from two or more

unprovoked seizures to one unprovoked seizure and the propensity for recurrent seizures. Tr. 130.

121

Dr. Levin did not specify whether the package inserts mention afebrile seizures.

This statement conflicts with Dr. Levin’s earlier statement in his expert report, which stated that seizure

122

onset was noted to be approximately one month following A.L.M.’s vaccination. See Pet. Ex. 39 at 2.

34

Dr. Holmes described a provoked seizure as one caused by some sort of environmental

stress like low blood sugar, a hit to the head, a drop in blood sodium, being over hydrated, and

most commonly, fever. Tr. 141. Provoked seizures are not the same as epilepsy because in a

provoked seizure, the seizures stop once the stressor is removed. Tr. 141.

Dr. Holmes explained that a seizure can be triggered in a patient with epilepsy. The

literature shows that while the word “trigger” can have many meanings, it often refers to someone

who already has epilepsy and something triggers a seizure. Tr. 141-42. In this way, it acts like a

provoked seizure. Tr. 142. Triggers can include missed medication, fever, sleep deprivation, stress,

and alcohol. Tr. 141-43. Triggers cannot cause epilepsy or damage. Triggers merely bring out the

seizure in someone already predisposed to seizures, who has a lowered seizure threshold, or

already diagnosed epilepsy. Tr. 144, 167. The majority of genetic epilepsies and seizures occur

spontaneously with no trigger. Tr. 138, 144, 167.

Dr. Holmes stated that epilepsy can occur at any age, although it is much more common in

children, and seizures come and go at certain ages based on the developmental stage of the brain.

Tr. 131. Epilepsy is “time-based” and “age-based” on clinical and EEG manifestations. Tr. 131.

Risk factors for epilepsy include a hypoxic-ischemic encephalopathy at birth, stroke, a history of

encephalitis, meningitis, trauma, congenital brain abnormalities, and genetic or neurometabolic

disorders. Tr. 132. Immunizations are not a known risk factor or cause of epilepsy. Tr. 132. Where

no cause is found, the epilepsy is referred to as idiopathic, which normally refers to a genetic

abnormality even if no specific gene is found. Tr. 134. This is particularly true when there is a

family history of seizures. Tr. 134. About 50% of epilepsy has no definitive etiology, though the

number is going down, with better MRIs capable of finding structural abnormalities and advances

in gene sequencing. Tr. 135-36. Most children outgrow their epilepsy and are considered in

remission, like A.L.M. who had no further seizures after weaning from medication. Tr. 133.

Dr. Holmes described febrile and afebrile seizures, explaining that febrile seizures are

common and occur in about 1.5 percent of children under age 6. Tr. 170. The brain is always

changing and is more excitable in children. Tr. 138-39. Febrile seizures vary in severity based on

age. Tr. 139. A fever that causes a seizure in a young child will often not do the same in a 15-year-

old. Tr. 139. Epilepsy, on the other hand, occurs in 0.5-1 percent of patients over the course of a

lifetime. Tr. 170. Thus, when comparing the number of people with febrile seizures to the number

of people with afebrile seizures or epilepsy, there will be “more people with afebrile seizures or

epilepsy” because it is seen throughout patients’ lives. Tr. 170.

Dr. Holmes stated febrile seizures and epilepsy are related “in some conditions.” Tr. 151.

He agreed with Dr. Kinsbourne’s definition of febrile status epilepticus, which involves continuous

seizure activity in excess of 30 minutes with high fever causing cerebral edema in the temporal

lobe. Tr. 151-52. When the edema subsides, these children develop mesial temporal sclerosis and

can develop a chronic epileptic condition. Tr. 152. Febrile status epilepticus is deemed acquired

epilepsy due to the injury to the brain caused by the high fever and the constant seizure activity.

Tr. 152. This is a very different from a simple febrile seizure. Tr. 151-52.

Dr. Holmes agreed that A.L.M. has epilepsy and disagreed that any of her vaccinations on

October 25, 2012 caused or contributed to her epilepsy. Tr. 129. Dr. Holmes stated that he and his

35

colleagues studied the “double hit theory,” or “two-hit theory” referred to by Drs. Kinsbourne and

Levin. Tr. 153. In Dr. Holmes’s study, a toxin was administered to animals to induce very long

status epilepticus seizures, which led to intense seizures and cell injury to the brain. Tr. 153.

Several weeks later, different types of seizures were induced, causing cognitive difficulties and a

lower seizure threshold than if there had only been one insult. Tr. 153. The purpose of the study

was to see if a child with a serious brain injury would benefit from intervention before there was

a second hit, but the hypothesis did not “pan out in clinical practice.” Tr. 154. He stated that the

brain injury targeted in the study had to include destructive lesions that lead to the child’s

development of epilepsy. Tr. 154. This double hit theory does not apply to A.L.M., who did not

have a destructive brain injury. Tr. 154.

Dr. Holmes agreed that A.L.M. had abnormal neuronal tissue at the location of the brain

where the seizures emanated from and that she had a genetic predisposition to seizures based on

family history, which could have lowered her seizure threshold. Tr. 155; 171. But a genetic

propensity is not an injury per se. Rather, it means that there is a lower seizure threshold, making

a person more likely than someone else to have a seizure. Tr. 142, 156. He agreed that a lower

seizure threshold and seizures with a mild fever are more likely when there is a family history of

febrile seizures. Tr. 142-43. But “no one’s ever talked about genetic susceptibility being” the first

hit, other than Dr. Kinsbourne. Tr. 154, 171. Further, Dr. Holmes disagreed that birth is a first hit,

stating “that just makes no sense whatsoever.” Tr. 157.

Dr. Holmes agreed if he was to assume those elements constitute “first hit,” then an

infection or vaccination which causes a fever could be the trigger—or second hit—that causes a

seizure. Tr. 171, 176-77. However, he stated that the MMR vaccine could not cause afebrile

seizures, so under the circumstances the MMR vaccine is not the second hit. Tr. 156, 173. Dr.

Holmes agreed that the MMR vaccine causes an increase in cytokines, but that does not lead to an

increase of cytokines in the brain, which is his problem with petitioner’s theory in this case. Tr.

166. MMR vaccine can cause febrile—not afebrile—seizures in a person who has a lower seizure

threshold. Tr. 166.

Dr. Holmes stated that vaccines can cause fever and the fever can provoke a seizure. Tr.

151, 168. Further, the MMR vaccine can cause febrile seizures within 14 days of vaccination and

DTaP can cause febrile seizures within a couple of days of vaccination. Tr. 146. However, large

studies with proper control groups have found no indication that either MMR or DTaP can cause

recurrent afebrile seizures or epilepsy. Tr. 146. Further, the IOM conducted a rigorous review and

did not find strong evidence for afebrile seizures following vaccination. Tr. 146. Still further, there

is no support that any vaccines cause epilepsy. Tr. 146, 152. In Dr. Holmes’s opinion ,A.L.M.

would have gone on to have the identical course she experienced with or without the vaccine. Tr.

155-56.

Dr. Holmes further explained that fever can provoke a seizure, but the seizure is not

necessarily related to the etiology of the fever. The outcome of a seizure provoked by fever is the

same with and without a vaccine. Tr. 151. Dr. Holmes expressed confusion regarding Drs.

Kinsbourne and Levin’s opinion that seizures and fevers have two different pathways; vaccines

can cause fever and fever can cause seizures; vaccines do not and cannot cause seizures without

fever. Tr. 177-178. With the MMR vaccine, “…the reason you have seizures – you only have

36

febrile seizures with MMR because you have a fever caused by the MMR vaccine 10 to 14 days

after the MMR, and that leads to the seizure.” Tr. 181.

He conceded there exists one exception where vaccination may cause an afebrile seizure

and that is in children with Dravet Syndrome and the seizure occurs immediately with the event,

not 15 days later. Tr. 144-45, 167-68, 181-82. In these children, the afebrile seizure that occurs is

considered a stress reaction and does not alter the syndrome. Tr. 145, 181-82. These same children

often do not have a seizure with a subsequent vaccine. Tr. 145.

Dr. Holmes disagreed that giving several vaccines at the same time makes any difference

as no vaccine has been shown to cause epilepsy. Tr. 160.

Dr. Holmes placed little importance on the rash A.L.M. reportedly developed 5-7 days after

the MMR vaccine because rashes are common in young children and the rash disappeared quickly.

Tr. 158-59. Dr. Holmes agreed with A.L.M.’s pediatrician that a rash was a normal reaction to

vaccination. Tr. 173.

Dr. Holmes also noted that besides the transient rash A.L.M., had no sick behaviors, fever

or signs of an inflammatory reaction that could cause brain damage and seizures. Tr. 159, 172-73.

Further, if A.L.M. had inflammation of the brain which would involve a breakdown of the blood

brain barrier, the MRIs, even those performed in 2012-2013, would have shown it. Tr. 164.

However, A.L.M.’s MRIs were normal. Tr. 164-65. If there was something on her brain that was

not initially picked up, it would have still been present on the subsequent MRI performed in 2015,

but that MRI was normal as well. Tr. 164-65. Medication does not improve MRI results, although

it may improve EEG findings. Tr. 165.

Dr. Holmes explained that EEG testing is the best at determining seizure activity. In a child,

seizure severity may change due to evolving brain physiology as they get older. Tr. 140. An EEG

will display spikes and sharp waves that indicate that a group of neurons is hyperexcitable, which

in turn indicates that the child has not yet gone into remission. Tr. 140. If a child is on medication,

an EEG is done to see if the medication can be stopped. Tr. 140. Most of the time the child is fine,

but there are rare occasions where the medication is suppressing the seizures, so seizures return

when the child is weaned off the medication. Tr. 140-41. Thus, it is not unusual that A.L.M.’s

epilepsy went into remission as she got older, as evidenced by her normal EEG. Tr. 138-141.

To further support his opinion that the onset of A.L.M.’s epilepsy was related to the

individual genetic propensity and timing, not the vaccines, Dr. Holmes pointed out that A.L.M.

had many febrile illnesses before her vaccines and many illnesses in the months after her vaccines

with high fevers but no seizures. Tr. 161. “I would argue that the vaccines had nothing to do with

when her epilepsy emerged. I would argue that it was due to that stage of brain development, that

it had nothing to do with any of the vaccines she had before.” Tr. 161.

Dr. Holmes expressed his respect for Dr. Kinsbourne but disagreed that the studies Dr.

Kinsbourne relied on provided any support for a vaccine causing an afebrile seizure. Tr. 168-69.

Dr. Holmes again noted the exception for children with Dravet Syndrome having afebrile seizures

in DTaP studies and as discussed in the studies submitted by Dr. Kinsbourne. Tr. 169, 175-76.

37

Cendes addressed Dravet Syndrome and the development of seizures within 2 days of DTaP

vaccination. Tr. 147-48; Pet. Ex. 60.123 The authors found that children with and without Dravet

Syndrome developed seizures at the same rate and only 30-40% had seizures accompanied by

fever. Tr. 148; Pet. Ex. 60.124 These findings are evidence that the seizures were a stress response,

rather than an immune response. Tr. 148, 178-79. Further, the seizures following DTaP occurred

within 24 hours of vaccination not 10-14 days later, whether febrile or afebrile. Tr. 148; Pet. Ex.

60.125 When MMR was studied, children with Dravet Syndrome had the same risk of seizures as

the general population within 10-14 days following vaccination. Tr. 149. Fever was not discussed

in the article. Tr. 149; Pet. Ex. 60.126 Dr. Holmes added that the Dravet Syndrome studies also

showed that the DTaP vaccine does not cause epilepsy; rather, the vaccine brought on the seizures

earlier due to the underlying seizure disorder. Tr. 178. Other than this sole exception, a fever is

required for a vaccine to cause a seizure, according to Dr. Holmes.127 Tr. 178-79.

Dr. Holmes agreed that the Le Saux and von Spiczak studies involved afebrile seizures but

were of limited value because they had no control group, and it was unclear how the data was

entered. Tr. 149-150, Pet. Ex. 31; 128 Pet. Ex. 33.129 Dr. Holmes disagreed that the Scheffer article

supported the notion that afebrile seizures are caused by the MMR vaccine. Tr. 150; Pet. Ex. 58.130

Scheffer was a review of the Verbeek study on the etiology of seizures around the time of

vaccination which did not conclude that the MMR vaccine led to afebrile seizures. Tr. 15; Pet. Ex.

58.131

Dr. Holmes offered to go through each study relied on by Dr. Kinsbourne, but petitioner’s

counsel did not accept. Tr. 169-70. Dr. Holmes added, in addition to the IOM study, many review

studies including a review by Cochrane showed no relationship between vaccines and afebrile

seizures. Tr. 169-170; Resp. Ex. O.132 Dr. Holmes added that the studies he relied on used a control

group, “rigorously follow[ed] the patients for adverse events,” and found no evidence that the

MMR vaccine caused afebrile seizures. Tr. 176. Dr. Holmes maintained that if a seizure were to

follow a vaccine, it would be because the vaccine “causes a fever, and the fever would cause the

seizure. It’s not anything beyond that.” Tr. 176-77.

Dr. Holmes discussed the MMR vaccine package insert, noting his involvement with drug

studies and explaining that package inserts contain anything that is reported following the

marketing of a drug. Tr. 157-58; Pet. Ex. 43. Dr. Holmes does not dispute that the MMR vaccine

can cause febrile seizures; but the fact that afebrile seizures is contained in the package insert list

of adverse reactions is not an indication that the MMR vaccine can cause afebrile seizures. Tr. 158.

123

Cendes & Sankar, Vaccinations and Febrile Seizures, supra note 87.

124

Id.

125

Id.

126

Id.

127

Dr. Holmes pointed out a potential caveat to this statement: the old whole cell pertussis vaccine, which

A.L.M. did not receive. Tr. 179.

128

Le Saux et al., supra note 34.

129

von Spiczak et al., supra note 35.

130

Scheffer, supra note 87.

131

Id.

132

Demicheli et al., supra note 30. This is the article that Dr. Holmes referred to as the “Cochrane Review.”

38

Dr. Holmes stated, “[T]here’s a lot of things that were reported on that sheet there that I [sic] have

not been subsequently shown to be associated with MMR. It’s probably the worst thing you can

use to try to come up with a scientific or medical decision.” Tr. 158. He does not read package

inserts to make any medical decisions because what is contained therein is only what someone

reported—not evidence of causation stating that “. . . of our levels of evidence, I would put

[package inserts] below the lowest level you could possibly have. Having it on the package insert

means nothing except that someone reported it.” Tr. 172.

Dr. Holmes could not put a timeframe on the onset of afebrile seizures following MMR

vaccine because there is no data supporting the notion that the MMR vaccine can cause afebrile

seizures. Tr. 156. He assumes the timeframe for an afebrile seizure would be consistent with what

is expected for febrile seizures—within 10-14 days—though it is difficult to extrapolate due to the

lack of data. Tr. 156-57. He also assumed that any time past 14 days would be too far removed to

consider the afebrile seizure to be related to vaccination. Tr. 157. Dr. Holmes stated after hearing

the testimony of petitioner and her sister A.L.M.’s seizure onset was roughly 10 days after the

MMR vaccination, which is within the accepted range for MMR to cause febrile seizures but not

afebrile seizures. Tr. 174.

In summary, Dr. Holmes stated that A.L.M.’s seizures occurred simply because she has

epilepsy. Tr. 162. Genetic epilepsies start at different times because they begin spontaneously and

unrelated to vaccination; otherwise, all genetic epilepsies would begin in the first few years of life.

Tr. 161. Further, genetic epilepsy is not related to fever. Tr. 162. According to Dr. Holmes,

[n]ot all epilepsy is initiated with a provoked—I can’t emphasize that enough. I

mean, 99 percent –98 percent of our patients that have epilepsy, it’s not provoked

by fever, immunizations, anything. It just occurs. They have a neurological

condition called epilepsy, and it’s a fundamental problem with the brain, and the

immunization has nothing to do with it . . . I can’t stress that enough . . . not all

epilepsy begins with febrile seizures or immunization. Ninety-nine percent of it

does not. There’s no relationship.

Tr. 161-62.

Dr. Holmes stated that given A.L.M.’s history of high fevers and illnesses before and after

her vaccinations that were not followed by seizures, the vaccines given on October 25, 2012 were

merely coincident with the onset of seizures. Tr. 163. Children can have seizures or develop

epilepsy at any time, and the MMR vaccine is not a trigger for afebrile seizures. Tr. 173. “…I

certainly don’t believe that if she had an afebrile seizure, that caused her to have epilepsy…that

she would not have had epilepsy if it wasn’t for that afebrile seizure. So, no, I don’t buy that at

all.” Tr. 173.

As to alternative cause, Dr. Holmes agreed with A.L.M.’s treating physicians that her

seizures were idiopathic and that she had genetic epilepsy based on her family history and her

clinical course. Tr. 174-75. Succinctly stated, “A.L.M. had a genetic epilepsy that was treated

effectively and went into remission and is now doing well. There is no reason whatsoever to

implicate any vaccine to her clinical course.” Tr. 159-160.

39

d. Dr. McCusker

Dr. McCusker explained that, at baseline, the immune system is always releasing low levels

of cytokines into peripheral circulation. Tr. 187. Cytokines are small molecules of protein released

by one cell to another with a receptor telling it what to do. Tr. 186-87. There is a difference between

cytokines in peripheral circulation and cytokines in the brain. Tr. 188. Cytokine response in the

peripheral immune system is tightly regulated with inflammation and counter-inflammation

cytokines that turn down the immune response. Tr. 189-190. IL-1b is a preformed pro-

inflammatory cytokine waiting to be activated and released when there is a threat. Tr. 190. Its role

is to bring immune system cells to the area of inflammation to deal with the threat. Tr. 190.

Immediately upon activation and release of IL-1b, a decoy receptor (IL-1r) is synthesized and

released to shut down the threat. Tr. 190. Studies post-vaccination show low levels of IL-1b

because “it is not a cytokine that circulates at any great levels in general, even in significant

infections, even in patients who have very high fever.” Tr. 190-91.

Dr. McCusker explained that in a steady state, brain tissue cells (glial cells and microglia)

synthesize and release cytokines in the brain, which are used as neurotransmitters in the central

nervous system (“CNS”) to communicate pieces of information from one neuronal cell to another.

Tr. 188-89. Cytokines in the CNS are released in response to trauma, like brain injury, stroke, CNS

infection, or seizures. Tr. 192. IL-1b in the CNS has been shown to regulate sleep and IL-6 has

been shown to play a part in short- and long-term memory. Tr. 189. Both IL-1b and IL-6 are

involved in brain recovery from trauma and in pruning the neurons for learning and cognition. Tr.

189. Cytokines in the brain have specific tasks and roles in the CNS, depending on how they are

released. Tr. 189.

Dr. McCusker noted although the CNS and the peripheral immune system connect, the

connection is tightly regulated, and the process is different for each. Tr. 192, 207. A danger signal

to the cytokines in the periphery creates inflammation, a danger signal to the cytokines in the CNS

causes them to set up pathways and make responses. Tr. 207-08. Though the blood brain barrier is

not complete, meaning cytokines can pass and bind to receptors in the CNS as an alert that

something is going on, the cytokine stops there and cannot flood the CNS. Tr. 206. In other words,

low level circulating peripheral cytokines do not have unfettered access to the CNS but can

influence cytokine expression in the brain as communication molecules by stimulating the vagus

nerve up to the hypothalamus to produce fever to fight infection. Tr. 192, 205-06. Fever occurs

when a combination of IL-1b and/or IL-6 and/or TNFα is released at the site of an immune

response. Tr. 192. For example, when a vaccine is administered in the arm or leg, IL-1b is released

to the draining lymph nodes triggering nerve endings that signal up to the hypothalamus through

the vagus nerve to increase body temperature. Tr. 193. Fever is one of the protective mechanisms

against certain microbes that do not like to replicate at high temperatures. Tr. 193. The increased

body temperature slows down the replication of the microbe and gives the immune system an

opportunity to get ahead of the microbial assault. Tr. 193. The IL-1b from the periphery that

triggered the “fever event” is not found in the brain, it is found in the lymph node and triggers a

nerve signal up to the hypothalamus to increase body temperature to meet the threat. Tr. 193-94.

The trigger is specific to the area involved in temperature regulation—the hypothalamus—not the

entire brain. Tr. 193.

40

Dr. McCusker referenced Kashiwagi to show that the presence of IL-1b in the brain does

not cause fever. Tr. 194-95; Resp. Ex. GG.133 Rather,

…you get that immune response going on in the lymph node, and that sends a signal

up to the brain. Now, the degree of fever, how high the fever goes, how fast it goes

up…are factors that lead to febrile seizures…it’s the fever that is inducing those

seizures. It’s not that IL-1b, in the brain, is inducing those seizures, and that’s really

a key element here, because we know from the febrile seizure story that circulating

IL-1b is actually. . . undetectable in the Kashiwagi articles.

Tr. 195-96. In summary, the circulating cytokines signal from the lymph node to the brain at the

hypothalamus to change the body temperature and the rise in temperature leads to the seizure. Tr.

196-98; Resp. Ex. GG.134

Dr. McCusker discussed the literature relied on by Dr. Kinsbourne, noting that in Dubé

large amounts of IL-1b were injected directly into the brains of the animals but hyperthermia also

needed to be induced to result in seizures. Tr. 194-95, 208; Pet. Ex. 38.135 Dubé also showed that

IL-1b sits in the CNS all the time communicating and damage in the CNS from a CNS infection,

trauma, or post-seizure event increases the cytokines in the brain cells, not in the periphery. Tr.

208, 210; Pet. Ex. 38.136 Li and Vezzani discussed chronic epilepsy in animals and showed that

cytokines released after brain trauma, damage, or inflammation act to repair damage, but if the

seizures or trauma continues, it will significantly lower the seizure threshold over time. Tr. 211;

Resp. Ex. RR;137 Resp. Ex. SS.138 Therefore, in the CNS “. . . you have your trauma, you have

your seizure. The seizure causes damage, the damage releases IL-1b. The IL-1b tries to contain

the damage, the damage is not contained, but now the IL-1b is still being produced…now it’s

acting to change the seizure threshold within the animals.” Tr. 211-12, Resp. Ex. RR;139 Resp. Ex.

SS.140 In the animal models where the IL-1b was injected systemically similar to circulating

cytokines, there was an anti-convulsant effect as opposed to a pro-convulsant. Tr. 204. Thus, “if

you had this increase in peripheral IL-1b, mimicking what they did in the animals, and you had a

patient who had a predisposition to developing seizures,” the circulating IL-1b in the periphery

would actually lower the risk of seizures rather than increase it, suggesting that the release of

regulatory molecules immediately after the release of cytokines causes a net decrease in functional

IL-1b. Tr. 204-05. This, Dr. McCusker stated, is one of her problems with petitioner’s theory. Tr.

212.

133

Kashiwagi et al., supra note 53.

134

Id.

135

Dubé et al., supra note 42.

136

Id.

137

Li et al., supra note 57.

138

Annamaria Vezzani et al., Powerful Anticonvulsant Action of IL-1 Receptor Antagonist on Intracerebral

Injection and Astrocytic Overexpression in Mice, 97 PROCEEDINGS OF THE NAT’L ACAD. OF SCIENCES

11,534 (2000), filed as “Resp. Ex. SS.”

139

Li et al., supra note 57.

140

Vezzani et al., supra note 138.

41

Another problem with petitioner’s theory is that the half-life for active peripherally

circulating IL-1b has been shown in studies to be 19 minutes, after which they start to lose their

activity significantly. Tr. 215; Resp. Ex. HHH.141 There are no cytokines present two weeks or

even five days after vaccination. Tr. 229. Petitioner’s theory revolves around a cytokine-mediated

lowering of seizure threshold, which would have occurred immediately after vaccination if it

occurred at all. Tr. 229. Therefore, the vaccine cannot be responsible here because, at the earliest,

the seizures occurred approximately two weeks after vaccination. Tr. 229.

Dr. McCusker discussed A.L.M.’s rash on November 2, noting the difference between live

and killed vaccines and the body’s reaction to both. Tr. 199-200. In killed vaccines, all cytokines,

not just IL-1b, are transiently elevated to a level just high enough to kick off an inflammatory

event. The inflammatory event is localized in the draining lymph nodes close to the vaccination

site for the first two to three days, then the immune response circulates beyond the lymph nodes.

Tr. 200. In a live attenuated vaccine, the virus needs time to replicate so the response is not strong

in the first several days. Tr. 200-01. As the virus starts replicating, the immune system turns on

regulatory T cells, which causes a rash if any to occur 7-10 days after the MMR vaccine. Tr. 201,

227. Lin studied wild type measles infection with a co-infection of HIV-1 and found increases in

IL-1b in the peripheral blood at the time the rash started but maxing out at a very low level. Tr.

202-03; Resp. Ex. HH.142 IL-1b levels would be the same or even lower with the vaccine. Tr. 203.

Griffin showed that the rash following wild measles infection signaled the end of the immune

response, indicating that the virus is under control. Tr. 201, 226-27; Resp. Ex. GGG;143 see also

Resp. Ex. EE.144 Accordingly, if A.L.M.’s rash was a measles rash and the literature is correct, the

rash would have signaled the completion of the inflammatory process, after which point cytokines

were no longer active. Tr. 227, 229. Even if A.L.M. had a low-grade fever when she developed

the rash, the cytokine level in the periphery would still be low. Tr. 214-15. For that reason, Dr.

McCusker was unable to “connect the dots” for petitioner’s theory in this case. Tr. 214-15.

Dr. McCusker stated that the MMR vaccine can cause fever and the fever can cause a

seizure, but the degree of fever necessary to cause a seizure would also cause other symptoms. Tr.

218. Further, the mechanism for febrile and afebrile seizures is different and a predisposition,

trauma, stroke, meningitis, or encephalitis is required for an afebrile seizure. Tr. 222-23. A.L.M.

had afebrile seizures which then disappeared and were not exacerbated by subsequent febrile

events or infections. Tr. 219. Dr. McCusker stated that if the hypothesis is that the MMR vaccine

raised the IL-1b to a high enough level to lower the seizure threshold, then she would have

expected that A.L.M.’s subsequent fevers and infections would lead to the same sequence of

events. Tr. 219. However, that was not the case here. Tr. 219.

Dr. McCusker disagreed that A.L.M. was having mini seizures prior to her vaccinations,

causing her brain to release IL-1b and lowering her seizure threshold. Tr. 213. Even assuming that

she was having mini seizures, Dr. McCusker claimed that A.L.M.’s receipt of MMR and Varicella,

two live attenuated vaccines, would not “throw the IL-1b over the top,” adding that vaccination

alone is “not sufficient to trigger a seizure [even] in a predisposed host.” Tr. 223. The IL-1b levels

141

Kudo et al., supra note 81.

142

Lin et al., supra note 70.

143

Griffin, supra note 80.

144

Oliveira et al., supra note 64.

42

produced by vaccines are “infinitesimally lower than” what is necessary to induce seizures. Tr.

213. Perhaps this would be a persuasive theory if high enough amounts of cytokines were injected

directly into A.L.M.’s lateral ventricles. Tr. 236. The data suggests that elevating IL-1b in the

periphery increases seizure threshold and patients are less likely to seize in that context, so “it goes

against [petitioner’s] hypothesis.” Tr. 236, 246-48. Further, Dr. McCusker stated that if she were

to assume that A.L.M. was having micro seizures and that IL-1b was sufficient to induce seizures,

then the onset of seizures would have occurred quickly after the DTaP vaccine because it would

have produced a larger cytokine release, according to Kashiwagi. Tr. 213-14; Resp. Ex. GG.145 Dr.

McCusker detailed the sickness behaviors associated with high level of cytokines, noting that

A.L.M. was asymptomatic, had afebrile seizures, and demonstrated no symptoms indicative of

high levels of circulating cytokines. Tr. 214, 237-38. Finally, there is no evidence in the record

that A.L.M. was having micro or mini seizures. Tr. 250.

Petitioner’s counsel then suggested that perhaps A.L.M.’s innate immune system was not

working correctly, as evidenced by A.L.M.’s genetic predisposition to seizures. Tr. 236-37. Dr.

McCusker stated what counsel was suggesting was a disease called periodic fever syndrome in the

IL-1b or TNF-alpha pathways which results in high fevers without provocation. Tr. 237. There is

no evidence in the record suggesting that A.L.M. suffered from this disease or a defect in her IL-

1b regulatory pathway. Tr. 237. Any fevers A.L.M. suffered prior to her vaccinations were from

normal febrile illnesses and not indicative of periodic fever syndrome. Tr. 237.

Dr. McCusker was asked if the receipt of 8 vaccines would constitute sufficient stress to

cause a seizure. Tr. 232. She explained that she believed the reference by Dr. Holmes to stress was

an immediate stressful event such as a blood draw or needle in a child with a seizure predisposition

who then had a vasovagal response or a seizure when they saw the needle, for example. Tr. 232-

33. Vaccinations activate the immune system, and the activation leads to a cascade of events, but

whether that cascade is sufficient to cause seizures is another issue. Tr. 233.

Dr. McCusker referenced large trials involving thousands of vaccines given to children in

A.L.M.’s age group that showed a background rate of seizure disorder onset within 10, 30, or 60

days of vaccinations. Tr. 220-21; see Resp. Ex. M;146 Resp. Ex. N.147 The trials did not implicate

vaccines and demonstrated that seizures would still occur in these children, even without

vaccination. Tr. 220-21. The link to vaccines was only temporal. Tr. 220-221. Based in part on

these results, Dr. McCusker argued that A.L.M.’s clinical course was entirely consistent with

“what happens when children develop seizure disorders.” Tr. 221.

Dr. McCusker discussed the package insert for the MMR vaccine, stating that the

information is dictated by the FDA, not the vaccine manufacturer. Tr. 230; Pet. Ex. 43. Like Dr.

Holmes, she stated that all reports during clinical trials and post-marketing are included in the

insert according to the rules, but it is not an indication of causation. Tr. 230. For example, there is

nothing in MMR vaccine that would cause pneumonia, but if there were reports of pneumonia

during the clinical trials or post-marketing period, pneumonia would be listed in the package insert.

Tr. 230-31.

145

Kashiwagi et al., supra note 53.

146

Davis & Barlow, supra note 28.

147

Barlow et al., supra note 29.

43

Dr. McCusker stated that the mechanism proposed in this case makes no biological sense;

it relies on IL-1b but does not link the increase of IL-1b following vaccination to the seizure

disorder A.L.M. subsequently presented with. Tr. 221. Petitioner failed to explain how a normal

immune response to the MMRV could generate an inflammatory event that led to a change in the

predisposition of her CNS. Tr. 224. Research shows that the only way that change occurs is by

injecting high levels of cytokines directly into the ventricles of animals, moments before

hypothermia, a stimulus for seizures, was introduced. Tr. 224. The stimulus must be introduced

immediately after injecting high levels of cytokines because, after twenty minutes, the cytokines

are gone. Tr. 224. From “a mechanistic standpoint, I can’t put A and B together.” Tr. 224. Also,

with a cytokine level high enough to cause seizures, one would not expect to see a healthy child.

Tr. 225. Rather, the child would be experiencing a cytokine storm, which causes marrow and

kidney failure and a decrease in white blood cells. Tr. 225. A.L.M. did not “fit the picture of child

with rampant circulation of cytokines.” Tr. 225.

Dr. McCusker aptly posed the question, getting at the heart of this matter, “other than timing,

is there anything that says the vaccine could cause or did cause this seizure disorder in this child?”

Tr. 220. Like Dr. Holmes, she opined that the seizures would have manifested in A.L.M. regardless

of vaccination and the timing is a mere coincidence. Tr. 220.

VI. Applicable Law

A. Legal Standard Regarding Causation

The Vaccine Act provides two avenues for petitioners to receive compensation. First, a

petitioner may demonstrate a “Table” injury—i.e., an injury listed on the Vaccine Injury Table

that occurred within the provided time period. § 11(c)(1)(C)(i). “In such a case, causation is

presumed.” Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1320 (Fed. Cir. 2006);

see § 13(a)(1)(B). Second, where the alleged injury is not listed on the Vaccine Injury Table, a

petitioner may demonstrate an “off-Table” injury, which requires that the petitioner “prove by a

preponderance of the evidence that the vaccine at issue caused the injury.” Capizzano, 440 F.3d at

1320; see § 11(c)(1)(C)(ii). Initially, a petitioner must provide evidence that he or she suffered, or

continues to suffer, from a definitive injury. Broekelschen v. Sec’y of Health & Human Servs., 618

F.3d 1339, 1346 (Fed. Cir. 2010). A petitioner need not show that the vaccination was the sole

cause, or even the predominant cause, of the alleged injury; showing that the vaccination was a

“substantial factor” and a “but for” cause of the injury is sufficient for recovery. See Pafford v.

Sec’y of Health & Human Servs., 451 F.3d 1352, 1355 (Fed. Cir. 2006); Shyface v. Sec’y of Health

& Human Servs., 165 F.3d 1344, 1352 (Fed. Cir. 1999).148

To prove causation for an “off-Table” injury, petitioners must satisfy the three-pronged test

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

148

The Vaccine Act also requires petitioners to show by preponderant evidence the vaccinee suffered from

the “residual effects or complications” of the alleged vaccine-related injury for more than six months, died

from the alleged vaccine-related injury, or required inpatient hospitalization and surgical intervention as a

result of the alleged vaccine-related injury. § 11(c)(1)(D). It is undisputed that this requirement is satisfied

in this case.

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requires that petitioners show by preponderant evidence that a vaccination petitioner received

caused his or her injury “by providing: (1) a medical theory causally connecting the vaccination

and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the

reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination

and injury.” Id. at 1278. Together, these prongs must show “that the vaccine was ‘not only a but-

for cause of the injury but also a substantial factor in bringing about the injury.’” Stone v. Sec’y of

Health & Human Servs., 676 F.3d 1373, 1379 (Fed. Cir. 2012) (quoting Shyface, 165 F.3d at 1352-

53). Causation is determined on a case-by-case basis, with “no hard and fast per se scientific or

medical rules.” Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543, 548 (Fed. Cir. 1994).

Petitioners are not required to identify “specific biological mechanisms” to establish causation,

nor are they required to present “epidemiologic studies, rechallenge, the presence of pathological

markers or genetic disposition, or general acceptance in the scientific or medical communities.”

Capizzano, 440 F.3d at 1325 (quoting Althen, 418 F.3d at 1280). “[C]lose calls regarding causation

are resolved in favor of injured claimants.” Althen, 418 F.3d at 1280.

Each of the Althen prongs requires a different showing. The first Althen prong requires

petitioner to provide a sound and reliable medical theory demonstrating that the vaccines received

can cause the type of injury alleged. Pafford, 451 F.3d at 1355-56 (citation omitted); Knudsen, 35

F.3d at 548. This theory need only be “legally probable, not medically or scientifically certain.”

Pafford, 451 F.3d at 1380 (emphasis omitted) (quoting Knudsen, 35 F.3d at 548). Scientific

evidence offered to establish Althen prong one is viewed “not through the lens of the laboratorian,

but instead from the vantage point of the Vaccine Act's preponderant evidence standard.” Andreu

v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009). 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 & Human Servs., 121 Fed. Cl. 230,

245 (2015) (“[p]lausibility . . . in many cases may be enough to satisfy Althen prong one”

(emphasis in original)). But this does not negate or reduce a petitioner's ultimate burden to

establish his entitlement to damages by preponderant evidence. W.C. v. Sec'y of Health & Human

Servs., 704 F.3d 1352, 1356 (Fed. Cir. 2013) (citations omitted). Nonetheless, although petitioners

cannot be required to show “epidemiologic studies, rechallenge, the presence of pathological

markers or genetic disposition, or general acceptance in the scientific or medical communities to

establish a logical sequence of cause and effect” (Capizzano, 440 F.3d at 1325), the special master

may consider and evaluate such evidence when filed. Andreu, 569 F.3d at 1379 (Special masters

may consider medical literature and epidemiological evidence, when it is submitted, in “reaching

an informed judgment as to whether a particular vaccine likely caused a particular injury.”).

Further, “petitioners [must] proffer trustworthy testimony from experts who can find support for

their theories in medical literature.” LaLonde v. Sec’y of Health & Human Servs., 746 F.3d 1334,

1341 (Fed. Cir. 2014).

The second Althen prong requires proof of a “logical sequence of cause and effect.”

Capizzano, 440 F.3d at 1326 (quoting Althen, 418 F.3d at 1278). In other words, even if the

vaccinations can cause the injury, petitioner must show “that it did so in [this] particular case.”

Hodges v. Sec’y of Health & Human Servs., 9 F.3d 958, 962 n.4 (Fed. Cir. 1993) (citation omitted).

A sound and reliable “medical or scientific explanation must support this logical sequence of cause

and effect,” id. at 961 (citation omitted), and “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

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was the reason for the injury,” Paluck v. Sec

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