       In the United States Court of Federal Claims
                              OFFICE OF SPECIAL MASTERS


*************************************
ESFANDIAR SANTINI and LAURIE        *
OMIDVAR, legal representatives of a *                    No. 06-725V
minor child, AYDIEN CLIFF OMIDVAR, *                     Special Master Christian J. Moran
                                    *
             Petitioners,           *
                                    *
v.                                  *                    Filed: December 15, 2014
                                    *
SECRETARY OF THE DEPARTMENT *                            Entitlement; significant
OF HEALTH AND HUMAN SERVICES, *                          aggravation; SCN1A mutation;
                                    *                    severity (six-month) requirement;
                    Respondent.     *                    DTaP vaccine.
*************************************

Curtis R. Webb, Twin Falls, ID, for petitioners;
Voris E. Johnson, Jr., United States Dep’t of Justice, Washington, DC, for
respondent.

       PUBLISHED DECISION DENYING COMPENSATION1

      Esfandiar Santini and Laurie Omidvar are the parents of Aydien Omidvar, a
developmentally delayed child, who is 11 years old. When he was born, Aydien
had a mutation in a gene, known as the SCN1A gene, that creates a particular type
of sodium channel. This sodium channel, which is known as Nav1.1, contributes to
preventing seizures. When Aydien was approximately four months old, he
received a set of vaccines, including a diphtheria-tetanus-acellular pertussis
(“DTaP”) vaccine. Later that day, Aydien suffered his first seizure.

       1
          The E-Government Act of 2002, Pub. L. No. 107-347, 116 Stat. 2899, 2913 (Dec. 17,
2002), requires that the Court post this decision on its website. Pursuant to Vaccine Rule 18(b),
the parties have 14 days to file a motion proposing redaction of medical information or other
information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special
master will appear in the document posted on the website.
       This first seizure is now recognized as the first manifestation of Dravet
syndrome. People suffering from Dravet syndrome typically experience various
types of seizures and developmental delay. The developmental delay can vary in
severity from mild to severe.

       Here, Mr. Santini and Ms. Omidvar allege that the DTaP vaccine
significantly aggravated Aydien’s Dravet syndrome. In other words, Mr. Santini
and Ms. Omidvar maintain that “but for” the DTaP vaccine, Aydien would have
been less delayed. They seek compensation through the National Childhood
Vaccine Injury Compensation Program, 42 U.S.C. § 300aa—10 through 34 (2006).
Their primary source of evidence is the opinion of Jean-Ronel Corbier, a pediatric
neurologist.

      The Secretary disagrees with Mr. Santini’s and Ms. Omidvar’s allegation.
The Secretary has presented opinions from Max Wiznitzer, a pediatric neurologist,
and Gerald Raymond, a neurologist and geneticist. Both Dr. Wiznitzer and Dr.
Raymond maintain that the DTaP vaccination did not affect the degree to which
Aydien is delayed. In their view, the SCN1A mutation was sufficient, by itself, to
cause Aydien’s outcome.

      For the reasons discussed in more detail below in sections VI and VII, the
Secretary’s position is persuasive. Section VI discusses Mr. Santini’s and Ms.
Omidvar’s claim that the DTaP vaccine significantly aggravated Aydien’s Dravet
syndrome. Mr. Santini’s and Ms. Omidvar have failed to demonstrate that the
DTaP vaccination affected Aydien in any meaningful way. Conversely, the
Secretary has established that the SCN1A mutation most likely determined
Aydien’s outcome. Section VII reviews a separate deficit in Mr. Santini and Ms.
Omidvar’s case: they failed to present preponderant evidence that any harm caused
by the DTaP vaccine lasted more than six months as the Vaccine Act requires.

       The simplest reason for this case’s outcome is that Dr. Wiznitzer’s and Dr.
Raymond’s opinions were more persuasive than the opinion from Dr. Corbier. Dr.
Wiznitzer and Dr. Raymond explained the relevant medical concepts and showed
how those principles were the foundations for their opinions. Dr. Corbier did not.
Dr. Wiznitzer and Dr. Raymond supported their opinions with articles from peer-
reviewed medical journals. Dr. Corbier often misinterpreted or misconstrued the
most important articles. Finally, the academic and professional backgrounds of the
Secretary’s experts made them better qualified than Dr. Corbier to discuss the
issues in the case.
                                              2
I.    Biographies of Witnesses

       The parties rely upon the doctors whom they retained to explain the
significance of events in Aydien’s life. Thus, the following sections provide some
context for the opinions discussed throughout this decision.

      A.     Dr. Corbier

      Dr. Corbier graduated from medical school at Michigan State University.
Exhibit 51 at 1. He completed his residency training also through Michigan State
University and then went to Cincinnati Children’s Hospital, and the University of
Cincinnati, to do his neurology fellowship training. Tr. 12. In 2002, Dr. Corbier
became board-certified in neurology with a special qualification in child
neurology. Exhibit 51 at 2.

       Dr. Corbier has been in clinical practice, as a full-time general pediatric
neurologist, since 2000. For six years, he practiced in Montgomery, Alabama,
before moving to Concord, North Carolina, where he has practiced since 2007. Tr.
12; exhibit 51 at 2-3. Through his practice, Dr. Corbier has “been able to see a lot
of kids with a variety of neurological problems including epilepsy, and in severe
cases, like Dravet and other conditions.” Tr. 13. Dr. Corbier has treated “a
handful” of patients with Dravet syndrome, some of whom he diagnosed himself.
Tr. 92.

       Dr. Corbier has written two self-published books about autism, but has not
written any articles published in peer-reviewed journals. Further, because Dr.
Corbier’s professional work occurs in a clinical practice, his teaching
responsibilities are limited to a small number of residents that circulate through a
clinic. Tr. 91-92.

      B.     Dr. Raymond

      Dr. Raymond graduated from medical school at the University of
Connecticut. Tr. 221. Subsequently, he completed a residency in pediatrics at
Johns Hopkins, and then went to Massachusetts General Hospital to study
neurology with an emphasis on child neurology. Id. Dr. Raymond spent a year




                                             3
abroad at the Université catholique de Louvain in Brussels, and then returned to
Massachusetts General to complete a fellowship in genetics and teratology. 2 Id.

      Dr. Raymond is board-certified in clinical genetics, as well as neurology
with a special qualification in child neurology. Tr. 223. According to Dr.
Raymond, fewer than ten other individuals hold dual certifications in these areas.
Tr. 223. Dr. Raymond has been invited to give lectures in the field of
neurogenetics, and has reviewed publications for several medical journals. Tr.
226. Further, Dr. Raymond has several of his own publications in the field of
neurogenetics. Id.

       Dr. Raymond is currently employed as a Professor of Neurology, and as
Director of Pediatric Neurology, at the University of Minnesota. Tr. 220-21. In
his position, Dr. Raymond conducts clinical research, focusing predominantly on
the interaction between neurology and genetics. Tr. 222. In the clinical side of his
practice, Dr. Raymond’s patient population is drawn from individuals who have
neurogenetic issues, including Dravet syndrome. Tr. 222-24.

       C.     Dr. Wiznitzer

       Dr. Wiznitzer graduated from medical school at Northwestern University.
Tr. 335. He completed a pediatrics residency at Cincinnati Children’s Hospital, a
developmental pediatrics fellowship at the Cincinnati Center for Developmental
Disorders, and a child neurology fellowship at the University of Pennsylvania
Children’s Hospital of Philadelphia. Tr. 336. He then finished his education with
a National Institutes of Health-funded fellowship in higher cortical functions in
children at the Albert Einstein College of Medicine in New York. Id.

       Dr. Wiznitzer is board-certified in pediatrics and neurology with special
qualification in child neurology and in neurodevelopmental disabilities. Tr. 339.
He has written approximately 60 articles published in peer-reviewed journals, and
serves on the editorial boards of the Journal of Child Neurology and Lancet
Neurology.



       2
        Teratology is “the branch of embryology and pathology which deals with abnormal
development and the production of congenital anomalies.” Dorland’s Illustrated Medical
Dictionary 1883 (32d ed. 2012).

                                                4
      Since 1986, Dr. Wiznitzer has worked in Cleveland, Ohio, at Rainbow
Babies & Children’s Hospital as a child neurologist. Id. He currently is
responsible for the outpatient practice, and also serves on the hospital’s inpatient
service. In his clinical practice, Dr. Wiznitzer commonly treats patients with
epilepsy, and has treated 6-10 children with Dravet syndrome. Tr. 342-43. Dr.
Wiznitzer is also an Associate Professor of Pediatric Neurology and International
Health at Case Western Reserve University. Tr. 338.

      Collectively, these doctors described the relevant concepts and principles
underlying Dravet syndrome.

II.   SCN1A Genes and Dravet Syndrome

        At conception, the embryo receives a set of genes from its mother and
father. Tr. 229. The set of genes may contain spontaneous mutations, meaning
that neither the mother nor father carried the particular gene. These spontaneous
mutations are said to arise de novo. See Dorland’s at 1214; Tr. 169, 240.

      Genes contain DNA. DNA is composed of sequences of four nucleotides:
adenine, thymine, guanine, and cytosine. Billups-Rothenberg, Inc. v. Assoc. Reg’l
and Univ. Pathologists, Inc., 642 F.3d 1031, 1032 (Fed. Cir. 2011). A sequence of
nucleotides in a gene is transcribed and translated by a cell to produce a chain of
amino acids. Tr. 231-33. In translation, the mRNA translates the amino acid
sequence into a protein. Tr. 234. A set of three amino acids determines the type of
protein being created. Tr. 233; see also Billups-Rothenberg, at 1032 (discussing
genes, amino acids, and proteins).

      Genes affect traits of individuals. Tr. 295. For example, eye color is
determined by genes. Tr. 154, 296. Genes are expressed at certain times in a
person’s development. The medical term for how genes are turned on/off is
methylation. Tr. 160, 294. For example, Huntington’s disease is a genetically
caused disease that appears later in life, usually during the fourth decade. Tr. 155,
158-59, 419-20, Dorland’s at 536.

       Mutations in genes can produce a variety of outcomes. Some mutations are
benign, such as when one amino acid is substituted for a similar amino acid. At
the other extreme, some genetic combinations may not be consistent with life. Tr.
284. Factors contributing to the extent to which a genetic mutation affects a
person’s health, if at all, include the type of mutation, the location of the mutation,
                                              5
whether the mutation arose in a conserved region,3 and whether the mutation was
inherited or arose de novo. Tr. 236-40 (Dr. Raymond); see also Tr. 166-69 (Dr.
Corbier).

      The brain’s development is largely determined by genes. In a child’s first
six months, neurons are growing rapidly. Tr. 157-58. Within the infant’s brain,
sodium channels evolve in the first six months of life. Humans contain a variety of
sodium channels, which are part of cells that are incorporated into different organs.
Tr. 241; Escayg at 1650; Lossin at 114.4 Sodium channels regulate electrical
excitability. Escagy at 1650. The channel is activated by membrane
depolarization resulting in increased permeability to sodium ions. Id. Later, the
sodium channel closes, decreasing the permeability of sodium ions and the
membrane returns to resting level. Id.

       As a fetus and shortly after birth, humans and other mammals rely on a
sodium channel known as Nav1.3. Tr. 362.5 At around two-to-three months of
age, a different sodium channel, Nav1.1, becomes predominant. Tr. 300; see also
Tr. 247-48. The Nav1.1 form is primarily expressed in GABAergic interneurons.
Tr. 242, 359. These neurons help maintain balance in the brain and an imbalance
can lead to seizures. Tr. 243, 247.

       A gene primarily responsible for the body’s creation of the Nav1.1 sodium
channel is known as the SCN1A gene. Tr. 51, 259. The ensuing protein has more
than 2000 amino acids. Lossin at 115. A mutation in an SCN1A gene can have a
deleterious effect on a person. Dr. Raymond and Dr. Wiznitzer, as discussed
below, opined that the SCN1A mutation in Aydien was the sole cause of his
developmental delay because the mutation prevented the creation of a properly
functioning sodium channel. Without a properly functioning sodium channel, it
was inevitable that Aydien would have seizures. While Dr. Corbier did not agree,


       3
        A conserved region is an aspect that is preserved through evolution in many species.
The repetition of genes suggests that changes are not easily tolerated. Tr. 265, 269.
       4
         This decision cites to medical articles by the last name of the first author. A full citation
is provided at the end of the decision.
       5
         The discussion about sodium channels largely relies upon Dr. Raymond because Dr.
Corbier did not know much about sodium channels. Tr. 160.

                                                      6
he still acknowledged that “SCN1A mutation is not good.” Tr. 165. Some people
with an SCN1A mutation develop Dravet syndrome.6

        Dravet syndrome is a clinical diagnosis, meaning doctors identify the illness
by how the child presents. Tr. 255, 355-57. Typical presentation includes an
onset, between four and eight months, of clonic or hemi-clonic seizures. The
initial seizure is sometimes an episode of status epilepticus. In the second or third
year of life, the seizures evolve into different types of seizures including myoclonic
seizures, absence seizures, and complex partial seizures. Although the initial
development is normal, by the time the child becomes a toddler, his or her
development stagnates. Tr. 350-51, 358. After a doctor suspects a child suffers
from Dravet syndrome, the doctor will order genetic testing to confirm. Tr. 255-56
(Dr. Raymond), 357 (Dr. Wiznitzer).

       Dravet syndrome encompasses a range of severity. Tr. 357. Particular
subtypes have been known as generalized epilepsy with febrile seizures (GEFS),
severe myoclonic epilepsy – borderline (SMEB), and severe myoclonic epilepsy in
infancy (SMEI) and these have been considered to be conditions occurring on a
spectrum. Tr. 278-79.

       To understand more about the consequence of an SCN1A mutation,
researchers have studied animals with mutations in their SCN1A gene. While
animal studies do not always inform a situation involving people, Isaac v. Sec'y of
Health & Human Servs., 108 Fed. Cl. 743, 752-53 (2013) (quoting 2011 report
from the Institute of Medicine), aff’d, 540 Fed. Appx. 999 (Fed. Cir. 2013), the
experts agreed that rodents can model the human condition with regard to an
SCN1A mutation. Tr. 110-11 (Dr. Corbier), 184 (discussion of Dr. Corbier’s
report), 208-09 (Dr. Corbier), 281-87 (Dr. Raymond). One advantage of animal
models is that they reduce the influence of any environmental factors. Tr. 318-19
(Dr. Raymond). A group of researchers led by Dr. William Catteral have used
rodents with SCN1A mutations in a series of experiments.

      The mice in these experiments are known as “knock out mice.” A portion of
the mouse’s SCN1A gene has been deleted (or knocked out). This produces a

       6
          Some SCN1A mutations are also associated with other conditions such as migraines.
Tr. 191. The difference in outcome, as discussed in the text below, depends upon factors such as
the location of the mutation and the nature of the mutation.

                                                   7
truncated mutation. Tr. 245-46, 282. The mice with this mutation display
symptoms analogous to the symptoms of some humans with Dravet syndrome.

       According to Dr. Raymond, the development of these mice is consistent with
SMEI. In one study, researchers demonstrated that heating mice to replicate a
fever provoked a seizure in genetically mutated mice only when the mice were a
certain age. Tr. 245-46; Oakley at 4. Dr. Raymond explained that the delay in
onset corresponds to the switch from Nav1.3 to Nav1.1. Tr. 247-48. Dr. Corbier
agreed. Tr. 182, 532-36.

       Another experiment discovered a different consequence of an SCN1A
mutation. Unlike the Oakley experiment in which the mice were heated to provoke
a seizure, the mice in the second experiment were not heated. They were left
alone. Without the introduction of any outside (environmental) factor, the mice
with a defective SCN1A gene had seizures spontaneously.7 Yu at 1144; Tr. 248;
see also Tr. 284-88. For the proposition that these knock out mice suffer seizures
spontaneously, other researchers have cited the Yu article. See Catarino; Escayg
(also citing Oakley), and Martin.

       Another group of researchers, who are from Japan, explored the long-term
consequence of the genetic mutation in the knock out mice. The researchers found
that the defect in the Nav1.1 “causes autistic behaviors and cognitive decline in
addition to epileptic seizures” in the knock out mice “as well as in patients with
Dravet syndrome.” Ito at 29. As discussed by Dr. Raymond, Tr. 318-19, the
researchers’ conclusion was even stronger in dismissing environmental factors.
They stated:

               Although it has been proposed that polytherapy and long-
               term use of anticonvulsants have potentials to affect the
               cognitive function and behaviors of Dravet syndrome
               patients, . . . our present results on mouse models suggest
               that the Nav1.1 haploinsufficiency is fundamentally
               responsible for the behavioral and cognitive impairments
               in Dravet syndrome patients and those impairments
               should occur in patients even without medications.


      7
          Mice that had no SCN1A gene (“null mice”) died within 15 days of birth. Yu at 1143.

                                                   8
Ito at 39. Dr. Wiznitzer interpreted this article as well as an article by Ceulemans
as showing the cause of the developmental problems is “not just the seizures
themselves. The excitation / inhibition abnormality associated with the sodium
channelopathy also impacts cognitive development in an independent manner from
the epilepsy.” Tr. 411-12.

III.   Facts8

       Aydien was born on July 6, 2003. Exhibit 1 at 1. When he was born, he
already possessed the genetic mutation that is at the center of this case. Tr. 73, 95.
Aydien’s SCN1A gene was not normal. Specifically, at codon 1756, there is
supposed to be an amino acid known as cysteine. Instead, Aydien’s gene creates a
different amino acid, known as tyrosine. Exhibit 29 at 1. At the hearing, Dr.
Raymond presented a two-dimensional image of this change. The creation of
cysteine at codon 1756 is a conserved feature. Tr. 267, 316, 391.

      When he was born, no one suspected that anything was wrong with Aydien.
His birth was not complicated. Exhibit 3. At his first visit with his pediatrician,
the pediatrician did not note any concerns. Exhibit 4 at 4 (visit on July 10, 2003).
When he was approximately seven weeks, he was described as developing well.
Exhibit 4 at 2. At his well-baby visit for two months, Aydien received a set of
vaccines without complications. Exhibit 6. During this period, Aydien’s brain was
using a fetal sodium channel, Nav1.3. Tr. 509.

       The appointment for Aydien’s four month well-baby checkup was on
November 7, 2003. The pediatrician again did not note any concerns. Aydien
received another set of vaccines, including a dose of the DTaP vaccine. Exhibit 6
at 1; see also Tr. 83 (Dr. Corbier’s description of Aydien before vaccination).

       Approximately ten hours after vaccination, Aydien had two seizures, lasting
about two minutes each. In these seizures, Aydien’s left arm jerked and then his
entire body jerked. Exhibit 8 at 1; exhibit 80A at 1, 9; exhibit 84A at 4, 8.

       A third seizure began and Aydien’s parents called 911 at 8:21 P.M. Exhibit
21 at 12. Emergency Medical Services (“EMS”) arrived, recorded that his

       8
         The parties generally accept the accuracy of medical records created close in time to the
events being memorialized. Resp’t’s Posthr’g Br., filed Nov. 22, 2013, at 1.

                                                    9
temperature was 100.8 degrees, and transported Aydien to a local hospital. Exhibit
8 at 1. While going there, EMS personnel observed continuous seizure activity for
30 minutes. Id. at 2. Two doses of Valium were needed to stop the seizure.
Exhibit 80A at 1, 9; exhibit 84A at 4, 8.

       When Aydien was in the local hospital, his temperature was 100.8 degrees.
Exhibit 80A at 9; see also Tr. 79 (Dr. Corbier’s discussion of Aydien’s
temperature). He remained in the local hospital for only two hours. During this
time, his rating on the Glasgow Coma Scale was 14-15 (maximum score is 15).
Exhibit 8 at 7. He was taken, via air ambulance, to San Diego Children’s Hospital.
Exhibit 84A at 4-10.

      On November 7, 2003, when he arrived at Children’s Hospital, his
temperature was 100.2 degrees. Exhibit 84A at 5; exhibit 9 at 2. The admitting
doctor, Natasha Fein, stated that “[t]he etiology of seizures is suspicious for
adverse side effect of immunization, despite receiving 2-month immunizations
without complications. Other possibilities include infection.” Exhibit 9 at 3.

       Aydien remained in Children’s Hospital for two days. Tests on his blood,
urine and cultures were normal. Exhibit 9 at 5-9. Tr. 102. When he was
discharged, his diagnosis was seizures due to DTaP immunization. Exhibit 10 at 1;
see also Tr. 101-02 (Dr. Corbier stating Aydien returned to baseline before he was
discharged).

       Aydien’s seizures continued. On December 3, 2003, he had a short seizure.
Exhibit 79 at 11. On December 13, 2003, and December 19, 2003, Aydien had
longer seizures lasting approximately 20 minutes and 30-60 minutes, respectively.
For the latter two seizures, Aydien was treated at Children’s Hospital. Exhibit 79
at 10-11; exhibit 48F at 150-53; exhibit 80B at 25-26; exhibit 84A at 90-96; see
also Tr. 75. A doctor at Children’s Hospital ordered an MRI. The results were
essentially normal. Exhibit 84A at 20; CH&N at 224 (testing on December 15,
2003).9

     On May 10, 2004, a neurologist saw Aydien. The doctor recorded that
Aydien was laughing, playing, and eating appropriately, despite having seizures.

       9
         “CH&N” refers to an unnumbered exhibit that Mr. Santini and Ms. Omidvar filed, on a
pro se basis, on October 20, 2006.

                                                10
Aydien was diagnosed as having epilepsy but was otherwise “developmentally
appropriate.” Exhibit 84B at 244; see also Tr. 432 (Dr. Wiznitzer’s discussion
about Aydien’s history in the first year of life).

      After another ten months of seizures during which Aydien continued to
make developmental progress, see exhibit 23 at 33, on March 14, 2005, Aydien
had an EEG. The EEG was abnormal, showing “abundant interictal epileptiform
discharges.” Exhibit 81D at 233. He was diagnosed as suffering “gross
developmental delay.” Exhibit 81A at 3; see also Tr. 76 (Dr. Corbier’s testimony
that Aydien deteriorated at about one year).

       As discussed in the procedural history, Mr. Santini and Ms. Omidvar filed
this claim in 2006. This submission led to Dr. Wiznitzer’s review of Aydien’s
medical record and his recommendation that Aydien be tested for an SCN1A
mutation. Exhibit A at 2; see also Tr. 432-35 (Dr. Wiznitzer).

        Athena Diagnostic’s testing of Aydien took place in October 2007. Exhibit
D-E. Athena Diagnostic later tested Aydien’s parents to see whether the mutation
that it had identified in Aydien was present in his parents. It was not. The final
report from Athena Diagnostic explained the significance of this information:
“[p]arental testing indicates that the amino acid variant identified in this individual
arose de novo (was not inherited). This finding is most consistent with this DNA
variant being associated with a severe phenotype (SMEI or SMEB) rather than a
mild or normal phenotype.” Exhibit 29 at 1; accord Tr. 267.

       Various pharmaceutical interventions and the placement of a vagus nerve
stimulator have failed to control these seizures. The petitioners have reported that
Aydien has approximately four seizures per week during which he loses
consciousness. He walks unsteadily and can speak approximately 50 single words.
Pet’rs’ Prehr’g Br. at 4; see also Tr. 77 (Dr. Corbier’s testimony about current
condition).

IV.   Procedural History

       Mr. Santini and Ms. Omidvar began this action when they, appearing pro se,
filed a petition on October 20, 2006. They submitted a set of medical records.
Less than one month later, Andrew W. Dodd became counsel of record for the



                                              11
petitioners and Mr. Dodd filed an amended petition on November 2, 2006.10 The
amended petition alleged that a diphtheria pertussis and tetanus vaccination, given
to Aydien, caused him to suffer an encephalopathy as defined in the Vaccine Injury
Table. Am. Pet. ¶¶ 2.h, 6.

       The Secretary reviewed the medical records about Aydien in her report
submitted pursuant to Vaccine Rule 4. The Secretary noted that the records show
that Aydien received a dose of the acellular formulation of the pertussis vaccine,
not the whole cell version. Resp’t’s Rep’t at 1 n.1; see also exhibit 5. The
Secretary argued that Aydien did not qualify as an on-Table encephalopathy
because he did not suffer a decreased level of consciousness for 24 hours. Resp’t’s
Rep’t at 11, citing exhibit 8 at 7. Thus, the petitioners would be entitled to
compensation only if they established that the DTaP vaccine was the cause in fact
of Aydien’s injury. On this point, the Secretary argued that Mr. Santini and Ms.
Omidvar had not met their burden of proof. The Secretary also proposed that a
forthcoming report would provide additional information. Id. at 15.

       On February 26, 2007, the Secretary submitted an expert report and
curriculum vitae for Max Wiznitzer, a pediatric neurologist. Dr. Wiznitzer stated
“Aydien Omidvar’s history is consistent with the diagnosis of severe myoclonic
encephalopathy of infancy (SMEI or Dravet’s syndrome).” Exhibit A at 2. He
continued, “[t]his disorder is usually caused by a mutation of the SCN1A gene . . .
and, therefore, is genetic in origin. There is no evidence that immunizations (such
as DTaP) either cause or aggravate this order.” Id. Dr. Wiznitzer recommended
genetic testing.

       After status conferences with the special master, the parties started pursuing
genetic testing. The Secretary filed the results as exhibit D on February 6, 2008.
At the ensuing status conference, the special master ordered that the Secretary file
a letter from Dr. Wiznitzer explaining the significance of those results and to state
whether she intended to obtain a report from a geneticist. Order, filed Feb. 15,
2008.

     Dr. Wiznitzer’s short letter stated that Aydien’s mutation “is consistent with
a symptomatic mutation causally related to his clinical diagnosis of [SMEI].” Dr.

       10
         Mr. Dodd represented the petitioners until he died. The petitioners’ current counsel of
record, Curtis R. Webb, became counsel of record on March 25, 2009.

                                                  12
Wiznitzer recommended testing Aydien’s parents to determine whether the
mutation rose de novo. Exhibit E at 2. In addition, the Secretary represented that
she would file a report from Dr. Raymond, a geneticist in approximately two
months.

      Dr. Raymond’s April 7, 2008 report began with a summary of Aydien’s
medical history, including the genetic mutation. Dr. Raymond provided a brief
overview of Dravet syndrome. He explained how the SCN1A gene encodes a
sodium channel. Exhibit I at 1-4.

       Dr. Raymond also discussed Aydien’s specific mutation. Dr. Raymond
expected that his mutation would cause a disease because of details about the
structure of the resulting sodium channel in Aydien. Dr. Raymond noted that
although Aydien’s parents had not been tested, he expected that Aydien’s mutation
“will be a spontaneous event without familial antecedent.” Exhibit I at 5. Dr.
Raymond concluded “Aydien Omidvar is a child who has Severe Myoclonic
Epilepsy of Infancy or Dravet syndrome secondary to a mutation in his SCN1A
gene. This is the sole cause of his epilepsy syndrome including his subsequent
developmental delay. It was not caused []or exacerbated by any of the
immunizations that he received.” Id. at 6.

       The parties discussed Dr. Raymond’s report, including his recommendation
for parental testing at the next status conference. The special master requested
more information from Dr. Raymond. In addition, the special master noted that the
issue of the SCN1A mutation was involved in other cases and proposed that the
petitioners’ attorneys work together. The special master noted a concern about
going to a hearing in which the Secretary offered the opinion of a neurogeneticist
(Dr. Raymond) and the petitioners did not. See order, filed June 12, 2008.

       Dr. Raymond’s letter addressed the need for parental testing. In his view,
even if one of Aydien’s parents had a genetic mutation, his opinion would remain
that “SMEI is a genetic disorder secondary to a defect in SCN1A and is not altered
by immunizations.” Exhibit K. Dr. Raymond also stated that “the finding of no
alteration in either of the parents would reinforce the evidence that this gene
alteration is the sole cause of SMEI.” Id.

      During a September 23, 2008 status conference, Mr. Santini and Ms.
Omidvar reported that they planned to have genetic testing done on themselves.
They filed these results on December 11, 2008. Exhibit 29.
                                           13
       As mentioned in footnote 10 above, Mr. Webb became counsel of record.
During the first status conference in which he participated, the parties discussed
whether this case should be stayed in light of the pending adjudications in Stone v.
Sec’y of Health & Human Servs., No. 04-1041V, 2010 WL 1848220 (Fed Cl.
Spec. Mstr. Apr. 15, 2010) and Hammitt v. Sec’y of Health & Human Servs., No.
07-170V, 2010 WL 3735705 (Fed. Cl. Spec. Mstr. Aug. 31, 2010).11 On
September 21, 2009, Mr. Santini and Ms. Omidvar requested a stay pending those
cases.

       The stay extended while Stone and Hammitt proceeded through appellate
review. The ultimate result was the petitioners were not entitled to compensation.
The identical outcomes are not surprising because the evidence about the effects of
an SCN1A mutation largely overlapped.12 The special master found that
“respondent has demonstrated by a preponderance of the evidence that Amelia’s
SCN1A gene mutation was more likely than not the ‘but for’ and ‘substantial
factor’ that caused her Severe Myoclonic Epilepsy of Infancy or Dravet
Syndrome.” Stone, 2010 WL 1848220, at *42 (Fed. Cl. Spec. Mstr. Apr. 15,
2010). The same language concludes the special master’s decision in Hammitt,
2010 WL 3735705, at *47 (Fed. Cl. Spec. Mstr. Aug. 31, 2010).

       After an intervening remand in each case, which did not change the result,
the cases were consolidated at the Federal Circuit. The Federal Circuit upheld the
special master’s findings of fact. “In sum, because of Dr. Raymond's expert
testimony and the considerable evidentiary support for his views in the record, we
cannot conclude that the special master's conclusion that the SCN1A gene mutation
was solely responsible for Amelia [Stone’s] SMEI was arbitrary or capricious.”
Stone v. Sec'y of Health & Human Servs., 676 F.3d 1373, 1384 (Fed. Cir. 2012),
cert. denied, 133 S. Ct. 2022 (2013).

        On May 9, 2012, the case was reassigned to the undersigned special master
and a status conference was held on May 31, 2012. The status of the case as of
that date was that the most recent medical records about Aydien had been filed in
       11
            Mr. Webb represented the petitioner in Hammitt.
       12
          In Stone, the petitioners relied upon Dr. Marcel Kinsbourne, a pediatric neurologist,
and the Secretary relied upon Dr. Michael Kohrman, a pediatric neurologist, and Dr. Raymond.
2010 WL 1848220, at *2. In Hammitt, the petitioner relied upon Dr. Kinsbourne and the
Secretary relied upon Dr. Wiznitzer and Dr. Raymond. 2010 WL 3735705, at *2.

                                                   14
2006, the Secretary had filed reports from Dr. Wiznitzer and Dr. Raymond, and the
petitioners had not filed any expert reports. As an immediate step, Mr. Santini and
Ms. Omidvar planned to obtain updated medical records. They also planned to
seek a report from Jean-Ronel Corbier.

       In this status conference, Mr. Webb also proposed consolidating this case
with Barclay, No. 06-705V, another case involving a child (Matthews Ramirez)
with an SCN1A mutation. The Secretary concurred that having one hearing would
conserve resources. Following this discussion, the two cases moved in sequence
together and portions of the expert’s reports are the same in the two cases. The
petitioners in Barclay filed a report from Dr. Corbier on May 16, 2012; a similar
report from Dr. Corbier was filed in this case on January 4, 2013. Exhibit 50.

       For Aydien Omidvar, Dr. Corbier stated that the “first question is whether
that initial seizure [the seizure Aydien experienced ten hours after vaccination] had
any bearing on the subsequent severe seizure disorder that developed?” Exhibit 50
at 5. Dr. Corbier answered his question by relying upon “epidemiological and
prospective studies linking prolonged febrile seizures to subsequent temporal lobe
epilepsy.” Among the studies that Dr. Corbier cited were articles by McClelland,
Dube, and Bender.

       Dr. Corbier maintained that an SCN1A genetic mutation does not determine
the outcome. He stated that some children with an SCN1A genetic mutation do not
have Dravet syndrome. Other children with Dravet syndrome have genetic
mutations that are not from the SCN1A gene. In Dr. Corbier’s view, “the range of
mutations throughout the entire gene is so broad that the phenotype so variable that
other factors including additional genetic factors and non-genetic, environmental
factors are likely very important.” Exhibit 50 at 9, citing Gambardella.

       Dr. Corbier implicitly treated the DTaP vaccine as one environmental factor
that affected Aydien’s outcome. He concluded that “DTaP was ‘point A’ in a
complex cascade of events that led to Dravet syndrome. Due to the underlying
SCN1A mutation, DTaP caused new onset of []prolonged seizures that made a
significant contribution and was a catalyst for the development of Aydien's
epilepsy and Dravet syndrome.” Exhibit 50 at 9.

      In conjunction with petitioners’ submission of Dr. Corbier’s report, the case
was set for a hearing in June 2013. To complete the record, the Secretary filed

                                            15
reports from Dr. Raymond (exhibit S) and Dr. Wiznitzer (exhibit U), who
responded to Dr. Corbier’s December 28, 2012 report.

       Dr. Raymond’s February 11, 2013 report provided basic information about
genetics and Dravet syndrome. Dr. Raymond identified characteristics about
genetic mutations that are relevant to determining whether the mutation will cause
a disease, including whether the mutation arose de novo, what part of the sodium
channel is affected, and the type of amino acid change. Exhibit S at 7.

      Dr. Raymond discussed Dr. Corbier’s report and the articles on which Dr.
Corbier relied. Dr. Raymond extensively reviewed the McIntosh article. In Dr.
Raymond’s opinion, McIntosh and colleagues believed that “vaccination was not
playing a role in the etiology of Dravet syndrome.” Exhibit S at 10.

       Dr. Wiznitzer, too, relied upon the McIntosh article. Dr. Wiznitzer quoted
the McIntosh article as stating “outcome was not influenced by vaccination.”
Exhibit U at 3, quoting McIntosh at 592-98. The finding in McIntosh was repeated
in a study by Brunklaus. Thus, in Dr. Wiznitzer’s opinion, “[t]here is no evidence
that his immunizations caused or aggravated” Aydien’s Dravet syndrome. Exhibit
U at 4.

        In the two months immediately preceding the hearing, the parties filed
additional materials that were primarily useful for making the record in Aydien’s
case complete. For example, on April 17, 2013, Mr. Santini and Ms. Omidvar
filed a copy of a report that Dr. Corbier had originally written for the Barclay case.
Exhibit 85. In addition, they refiled certain medical records in electronic form,
replacing records that were filed in paper form originally. The parties also filed
briefs.

       The parties’ briefs accurately predicted the experts’ testimony at the hearing,
which was held on June 5-6, 2013, in Charlotte, North Carolina. Drs. Corbier,
Wiznitzer, and Raymond testified in accord with their expert reports. In the course
of the hearing, the parties stipulated that all materials should be considered part of
the record regardless of whether the particular article or report was in only either
Matthew Ramirez’s case or Aydien Omidvar’s case. Tr. 27.




                                             16
       At the end of the hearing, the parties requested an opportunity to submit
       13
briefs. Mr. Santini and Ms. Omidvar filed an initial brief, the Secretary filed one
brief, and then Mr. Santini and Ms. Omidvar filed a reply. With the submission of
the reply brief, the matter is ready for adjudication.

V.   Elements Required to Establish Entitlement to Compensation and
Standards for Adjudication

        For petitioners to be awarded compensation, the special master must find
that they established the “matters” listed in section 11(c)(1) and “there is not a
preponderance of the evidence that the illness . . . is due to factors unrelated to the
administration of the vaccine.” 42 U.S.C. § 300aa—13(a)(1). Section 11(c)(1), in
turn, lists five items in paragraphs (A) through (E). Here, the elements in
controversy correspond to paragraphs C (causation / significant aggravation) and D
(severity).

       Paragraph C requires some showing that the vaccine harmed the person. For
certain vaccines and injuries, the Vaccine Act and its associated regulations
establish a presumptive causal connection for injuries within a defined time. The
injury may be either an initial injury or the significant aggravation of a preexisting
injury. 42 U.S.C. § 300aa—11(c)(1)(C); 42 C.F.R. § 100.3. These claims are
known as “Table claims.” For cases not based upon the Vaccine Injury Table, the
petitioners are not entitled to a presumption that a vaccine caused an injury.

       Here, Mr. Santini and Ms. Omidvar are pursuing an off-Table claim that the
DTaP vaccine significantly aggravated their son’s Dravet syndrome. As confirmed
in W.C. v. Sec'y of Health & Human Servs., 704 F.3d 1352, 1357 (Fed. Cir. 2013),
the elements of an off-Table significant aggravation case were stated in Loving.
There, the Court blended the test from Althen v. Sec'y of Health & Human Servs.,
418 F.3d 1274, 1279 (Fed. Cir. 2005), which defines off-Table causation cases,
with a test from Whitecotton v. Sec'y of Health & Human Servs., 81 F.3d 1099,
1107 (Fed. Cir. 1996), which concerns on-Table significant aggravation cases. The
resultant test has six components. These are:


       13
          Mr. Santini and Ms. Omidvar also filed a motion requesting an interim award of
attorneys’ fees and costs. They were awarded, on May 24, 2013, a total of $75,097.32. 2013
WL 3117024.

                                                 17
             (1) the person's condition prior to administration of the
             vaccine, (2) the person's current condition (or the
             condition following the vaccination if that is also
             pertinent), (3) whether the person's current condition
             constitutes a “significant aggravation” of the person's
             condition prior to vaccination, (4) a medical theory
             causally connecting such a significantly worsened
             condition to the vaccination, (5) a logical sequence of
             cause and effect showing that the vaccination was the
             reason for the significant aggravation, and (6) a showing
             of a proximate temporal relationship between the
             vaccination and the significant aggravation.

Loving, 86 Fed. Cl. at 144.

       After Loving, the Federal Circuit has explained that possible alternative
causes may be considered in determining whether petitioner has presented a
persuasive claim. See Stone v. Secretary of Health & Human Servs., 676 F.3d
1373, 1380 (Fed. Cir. 2012). In context of an SCN1A case, the Federal Circuit
held that the special master did not err in finding, after considering the entire
record, that the “Secretary proved by preponderant evidence its ‘factors unrelated’
defense by showing that the gene mutations were the sole cause of the seizure
disorders.” Snyder v. Sec'y of Health & Human Servs., 553 F. App'x 994, 999
(Fed. Cir. 2014).

       If there is preponderant evidence that the vaccine caused some harm as set
forth in paragraph C of section 11(c)(1), the petitioner must also establish that the
harm was severe pursuant to paragraph D. The Vaccine Act lists three potential
avenues, and the one requirement that Mr. Santini and Ms. Omidvar could
arguably fulfill is the vaccinee “suffered the residual effects or complications of
such illness, disability, injury or condition for more than 6 months after the
administration of the vaccine.” 42 U.S.C. § 300aa—11(c)(1)(D)(i). Additional
guidance about this element is set forth in section VII below.

      The burden of proof is preponderance of the evidence. The party bearing the
burden of proof need not establish a proposition to the level of scientific certainty.
Althen, 418 F.3d at 1278; Knudsen v. Sec'y of Health & Human Servs., 35 F.3d
543, 549 (Fed. Cir. 1994).

                                             18
VI.    Significant Aggravation

       A.     Parties’ Positions

       To explain how a vaccine could change the effect of an SCN1A mutation,
Dr. Corbier presented three overlapping theories in his testimony. A first idea is
that people with an SCN1A mutation are vulnerable or susceptible to developing
an adverse reaction to the DTaP vaccine. Tr. 20, 78, 103. A second theory is that
vaccines cause Dravet syndrome to manifest earlier by bringing about seizures
before they would have occurred otherwise. Tr. 30, 104, 140. For these two
theories, Dr. Corbier relied primarily upon material relating to SCN1A mutations.
A third concept from Dr. Corbier is that the vaccines cause a more prolonged
seizure and the prolonged seizure inflicts additional damage. Tr. 32, 144. For this
theory, Dr. Corbier based much of his opinion upon HCN channels.14

       Dr. Raymond and Dr. Wiznitzer agreed only with the portion of Dr.
Corbier’s presentation concerning the onset of the first seizure. Dr. Raymond and
Dr. Wiznitzer acknowledged that the vaccination preceded the first seizure and the
vaccination, most likely, provoked a fever that triggered the first seizure. Tr. 256
(Dr. Raymond), 353 (Dr. Wiznitzer). Dr. Raymond and Dr. Wiznitzer disagreed
with the remaining portions of Dr. Corbier’s testimony. In their view, the SCN1A
mutation is the sole cause of the developmental delay. Tr. 227, 254 (Dr.
Raymond), 359, 416, 446 (Dr. Wiznitzer).

      Dr. Raymond and Dr. Wiznitzer stated vaccines did not alter the ultimate
outcome for Aydien. Tr. 254 (Dr. Raymond), 302 (Dr. Raymond discussing
Aydien Omidvar), 359 (Dr. Wiznitzer), 454 (Dr. Wiznitzer discussing Aydien
Omidvar). They provided several reasons for their opinions, including details
about genetic mutation, rodent studies, and studies on people.

       B.     Evidence regarding SCN1A Mutations

              1.      Genetic Mutation

       Dr. Raymond, the board-certified geneticist, stated practitioners look for
details about the mutation, including the nature of the mutation, whether the
       14
         In the context of evaluating Dr. Corbier’s opinion, Section IV.C. provides more
information about HCN channels.

                                                  19
mutation arose de novo, and whether the mutation is in a conserved region. Tr.
317.

       Here, Dr. Raymond discussed the details of Aydien’s mutation. Aydien has
a base pair switch. Tr. 267. Additionally, it is a missense mutation where there is
a change which alters the chemical properties. Id. Aydien’s mutation is de novo
since neither of his parents carries the gene. Id.

      Dr. Raymond’s opinion is supported by Athena. When Athena detected the
genetic mutation, the laboratory correlated the mutation with a disease, not a
normal development. Exhibit 49H. Aydien’s gene was defective, creating
incorrect wiring in his brain. Tr. 417 (Dr. Wiznitzer).

             2.    Rodent Studies

      As explained above, the rodent studies showed that mammals with a severe
SCN1A mutation will have problems. Yu, in particular, showed that even without
a fever, the mice will develop seizures. The seizures in the Yu experiment
happened spontaneously and not in response to the introduction of an outside force.
Yu at 1144.

       When Dr. Corbier was asked questions about this study, his answers were
vague and confusing. See Tr. 536-41. Dr. Corbier seemingly did not appreciate
that the Yu study contradicted his theory that an environmental factor (like a
vaccine) affects the consequence of an SCN1A mutation.

       These two points provide a strong and reliable foundation for the opinions
that genes are the sole cause of the Dravet syndrome and vaccinations do not
contribute to developmental delay. But, more evidence buttresses these
conclusions. Dr. Raymond and Dr. Wiznitzer also cited various studies on people.

             3.    People Studies

      As more has become known about SCN1A mutations and seizures in
mammals, scientists have investigated the connection between the mutation and
epilepsy. In that research, the scientists have re-opened the question of whether
vaccinations are causing epilepsy. The four important articles are by Berkovic,
McIntosh, Tro-Baumann, and Brunklaus.


                                            20
                   a)    Berkovic

       In 2006, Berkovic and colleagues were interested in explaining why
pertussis vaccination has been alleged to cause an encephalopathy that involves
seizures and intellectual impairment. The researchers postulated that in the cases
of so-called vaccine encephalopathy, the individuals could have mutations in the
SCN1A gene because of a clinical resemblance to SMEI for which such mutations
have been identified. Berkovic et al. retrospectively studied 14 patients with an
alleged encephalopathy in whom the first seizure occurred within 72 hours of
vaccination. SCN1A mutations were identified in 11 of the 14 patients. Clinical-
molecular correlation showed mutations in eight of eight cases with phenotypes of
SMEI, in three of four cases with borderline SMEI, but not in two cases with
Lennox-Gastaut syndrome.

      The researchers concluded that cases of alleged vaccine encephalopathy
could in fact be a genetically determined epileptic encephalopathy that arose de
novo. Specifically, the researchers found,

            In the presence of SCN1A mutations, vaccination can still
            be argued to be a trigger for the encephalopathy, perhaps
            via fever or an immune mechanism. [B]ut the role of
            vaccination as a significant trigger for encephalopathy is
            unlikely for several reasons. First, although vaccination
            might trigger seizures as shown by the increased risk of
            febrile seizures on the day of triple antigen or MMR
            vaccination, there is no evidence of long-term adverse
            outcomes. Second, less than half of our patients had
            documented fever with their first seizure, which indicates
            that fever is not essential. Third, our neuroimaging data
            showed no evidence of an inflammatory or destructive
            process. Finally, truncation and missense mutations
            reported in conserved parts of SCN1A have not been
            found in many hundreds of healthy patients. Thus,
            individuals with such mutations seem to develop SMEI
            or SMEB whether or not they are immunized in the first
            year of life. We do not think that avoiding vaccination,
            as a potential trigger, would prevent onset of this
            devastating disorder in patients who already harbour the
            SCN1A mutation.
                                             21
Berkovic at 491.

       The Berkovic article has been influential. For example, the undersigned
special master has previously found Dr. Raymond’s opinion that vaccinations do
not cause Dravet syndrome persuasive because, in part, it was consistent with the
scientific literature, specifically the Berkovic article. Snyder, 2011 WL 3022544,
at *5. When the case reached the Federal Circuit, the Federal Circuit ruled that
accepting Dr. Raymond’s opinion was not arbitrary because “the researchers of the
Berkovic article did not believe that ‘avoiding vaccination, as a potential trigger,
would prevent onset of this devastating disorder in patients who already harbor the
SCN1A mutation.’” Snyder, 553 Fed. Appx. at 1002. Other special masters have
also found Berkovic to be a persuasive basis for finding that the child’s SCN1A
gene mutation was the sole cause of the Dravet Syndrome. Barnette v. Sec'y of
Health & Human Servs., No. 06-868V, 2012 WL 5285414, at *11 (Fed. Cl. Spec.
Mstr. Sept. 26, 2012), mot. for rev. denied, 110 Fed. Cl. 34 (Fed. Cl. 2013);
Deribeaux v. Sec'y of Health & Human Servs., No. 05-306V, 2011 WL 6935504,
at *34 (Fed. Cl. Spec. Mstr. Dec. 9, 2011), mot. for rev. denied, 105 Fed. Cl. 583
(2012), aff’d, 717 F.3d 1363 (Fed. Cir. 2013); Stone v. Sec'y of Health & Human
Servs., No. 04-1041V, 2010 WL 1848220, at *34 (Fed. Cl. Spec. Mstr. Apr. 15,
2010), mot. for rev. denied, 99 Fed. Cl. 187, 191 (Fed. Cl. 2011), aff'd, 676 F.3d
1373 (Fed. Cir. 2012). In addition to these legal determinations, the Berkovic
article has inspired at least three other investigations about the potential link
between vaccination and Dravet syndrome.

                     b)     McIntosh

       McIntosh and colleagues were interested in explaining why pertussis
vaccination has been alleged to cause an encephalopathy that involves seizures and
intellectual disability. In 2010, McIntosh and colleagues conducted a study in
which they aimed to establish whether the apparent association of Dravet
syndrome with vaccination was a result of recall bias and, if not, whether
vaccination affected the onset or outcome of the disorder.15



       15
         Recall bias is a phenomenon in which people remember events incorrectly. The
McIntosh researchers minimized recall bias by relying upon documents. McIntosh at 593.
Dorland’s at 212.

                                                22
      The authors retrospectively studied 40 patients with Dravet syndrome, who
had mutations in the SCN1A gene, and whose first seizure was a convulsion.
McIntosh at 593-94. The authors examined medical and vaccination records to
determine whether there was an association between vaccination and onset of
seizures in these patients. Patients were separated into a vaccination-proximate
group (seizure 0-1 day from vaccination) and vaccination-distant group (seizure 2+
days after vaccination), and the authors compared clinical features, intellectual
outcome, and type of SCNIA mutation between the groups. Id. at 594. Twelve
patients were in the vaccination-proximate group and 28 patients were in the
vaccination-distant group. Id.

       The authors found “no differences in intellectual outcome, subsequent
seizure type, or mutation type between the two groups.” Id. at 592. The authors
concluded that vaccination might trigger earlier onset of Dravet syndrome in
children who, because of an SCN1A mutation, are destined to develop the disease.
Id. However, the authors found “no evidence that vaccinations before or after
disease onset affect[ed] outcome.” Id.

       Dr. Corbier interpreted McIntosh as establishing a definitive association
between Dravet syndrome and vaccination. He also emphasized that seizures
immediately after a vaccine were likely to occur at a younger age than seizures
occurring more than two days after the vaccination. Tr. 23. Dr. Corbier explained
that McIntosh did not find a recall bias. Further, Dr. Corbier disagreed with the
McIntosh conclusion that the vaccinations did not affect outcome. Dr. Corbier
contended that because the study was not designed to address outcomes, but rather
to determine if there is a relationship at all, several variables were not included,
and a proper conclusion cannot be drawn. Tr. 114.

     Dr. Raymond maintained that there was no statistically significant effect on
outcome between the vaccination-proximate and vaccination-distant groups. Tr.
322.

       Dr. Wiznitzer opined that McIntosh suggests that children with Dravet
syndrome who have an initial seizure in temporal proximity to a vaccination still
have similar clinical outcomes to children whose initial seizures are not temporally
related to vaccination. Tr. 404. Further, Dr. Wiznitzer explained that the only
significant factor was that the age of onset was earlier for individuals who received
vaccinations — but age of onset did not change the outcome. Tr. 407.

                                            23
                   c)    Tro-Baumann

        In 2011, to gain a further understanding of the relationship between Dravet
syndrome and vaccination, Blanca Tro-Baumann and colleagues conducted another
retrospective analysis of 70 patients with Dravet syndrome and SCN1A mutations.
Through examining medical records and conducting parental interviews, Tro-
Baumann et al. found that seizures following vaccinations were reported in 27
percent of these patients. Tro-Baumann at 176. In 16 percent of the 70 patients
(that is, 58 percent of all patients with seizures following vaccination) the
vaccination-related seizures represented the first clinical manifestation of the
Dravet syndrome. Id. Two-thirds of the seizures following vaccination occurred
in the context of fever. Id.

      The authors suggested that vaccination-related seizures represent a possible
presenting feature of Dravet syndrome. Tro-Baumann at 177. Furthermore, the
authors characterized an assumed causal connection between vaccine-related
seizures and Dravet syndrome as a “misinterpretation.” Id.

      Dr. Corbier interpreted Tro-Baumann as establishing a “clear connection
between Dravet and vaccination with DTP.” Tr. 22. When Dr. Corbier was
questioned about what whether “connection” meant “causation,” his answer
revealed the challenges in trying to say whether the vaccine affected the outcome.
He stated:

            Well, it depends what we mean by causation. If
            causation means an inciting factor that in the right
            condition with the right associated factors can then lead
            to a disease, then causation fits. If we mean causation
            whereby the vaccine by itself would have caused the
            Dravet, then no. So when I use the term causation, what
            I mean is that the vaccine in a patient who's very
            vulnerable because of an underlying genetic mutation,
            there's a whole series of reactions that occur due to that
            initial vaccine, or it can be a fever or a virus that then
            changes brain function and circuitry that will result in
            long-term epilepsy.

Tr. 196.

                                           24
       Moreover, Dr. Corbier contended that the article suggests that vaccines can
cause Dravet Syndrome to “occur earlier.” Tr. 30. On cross-examination, Dr.
Corbier repeated that “vaccine-related seizures . . . represent a possible presenting
feature” of Dravet syndrome. Tr. 121. When pressed to explain whether the
vaccine-related seizures were the cause of the Dravet syndrome, Dr. Corbier stated
the Tro-Baumann article showed “that we cannot ignore the role of vaccine in
being a presenting feature in many patients with Dravet syndrome, so vaccination,
with or without fever, plays an important role as a presenting feature in many
patients with Dravet.” Tr. 122.

       When Dr. Wiznitzer was questioned about Tro-Baumann, he opined that
vaccination is associated with the onset of Dravet syndrome only so far as the
vaccination causes temperature elevation, and temperature elevation, regardless of
source, can cause seizures. Tr. 398. Dr. Wiznitzer maintained that the relationship
is not a significant aggravation or a causal connection. Tr. 401.

       Dr. Raymond did not comment on Tro-Baumann beyond noting that it did
not study differences in outcomes. Tr. 333.

                    d)    Brunklaus

       In 2012, Brunklaus and colleagues examined a large cohort of patients with
SCN1A mutation-positive Dravet syndrome. They intended to identify predictors
of developmental outcome and to determine specific clinical and demographic
features. During a 5-year study of 355 patients, Brunklaus et al. collected
information about several aspects of Dravet syndrome, including epilepsy
phenotype, electroencephalography data, imaging studies, and mutation class. Id.
at 2329. They also rated each child’s developmental status. The developmental
status was classified by the referring clinician using a five-point scale. The raters
had expertise in the assessment of developmental status including rating of gross
and fine motor skills, communication and cognitive abilities, and age appropriate
adaptive behavior. Id. at 2330.

       The authors found that clinical features predicting a worse developmental
outcome included status epilepticus, interictal electroencephalography
abnormalities in the first year of life, and motor disorder. Id. at 2329. No
significant effect was seen for seizure precipitants, magnetic resonance imaging
abnormalities, or mutation class. Id.

                                             25
        Brunklaus also investigated the precipitants of seizures. The authors found
that fever or illness had precipitated the majority of seizures, one-third had no
precipitant, and vaccination triggered 7 percent of the seizures. Brunklaus at 2333.
Moreover, the authors found that vaccination-triggered seizures presented
significantly earlier than those without precipitant or with fever/illness. Id. at
2333-34. However, citing McIntosh, the authors concluded that the vaccination
itself had no effect on the developmental outcome. Id. at 2334.

       Further, the authors contend that “children carrying a SCN1A mutation are
destined to develop the disease, which in turn can be precipitated by a series of
factors such as fever/illness, vaccination or a bath.” Id. However, the nature of the
trigger has no effect on overall developmental outcome. Id. The authors
acknowledged that their understanding of the functional effect of mutations is still
unrefined, and classification models lack accuracy to reflect the true mutation
impact. Id. at 2335.

       Dr. Corbier interpreted the study as establishing a definitive link between
vaccination and the onset of Dravet syndrome and seizures. Tr. 25. Specifically,
Dr. Corbier emphasized that the study indicated that children who suffered the
onset of seizures associated with a vaccination suffered the onset of seizures at a
significantly earlier time. Tr. 26. Moreover, Dr. Corbier explained that the
Brunklaus article found that children who had status epilepticus have a worse
developmental outcome. Tr. 54.

        Dr. Raymond interpreted the Brunklaus study as finding that vaccination
itself does not affect developmental outcome. Tr. 331. However, Dr. Raymond
acknowledges that the Brunklaus study did not present their data in the published
article. Tr. 332.

      Dr. Wiznitzer explained that the Brunklaus study clearly states that the
authors looked at their data and found that vaccination does not alter
developmental outcome, a finding that confirmed the conclusion reached in
McIntosh. Tr. 406. Dr. Wiznitzer asserted that this was an independent finding by
the Brunklaus authors and was not simply a reiteration of the McIntosh finding.
Tr. 405. Furthermore, on cross-examination, Dr. Wiznitzer acknowledged that the
Brunklaus study found that the mutation class did not predict a worse outcome, and
one of the mutation classes listed was a frame shift mutation. Tr. 450.


                                            26
              4.      Assessment

      When Dr. Corbier testified in rebuttal, he recognized that this type of
mutation is severe and “explains a lot of things.” Tr. 501. But, Dr. Corbier
maintained that the genetic mutation does not explain everything. The SCN1A
mutation, in Dr. Corbier’s view, made individuals “more susceptible for
environment insults.” Id.

       An opinion that a SCN1A mutation explains almost everything, leaving
room for an environmental factor is not persuasive. As Dr. Raymond and Dr.
Wiznitzer thoroughly discussed, the nature of the genetic mutation in these
children makes the creation of a normally functioning sodium channel in the brain
impossible. Without an effective Nav1.1, controlling the flow of sodium ions in the
brain is impaired. The occurrence of seizures is inevitable. Dr. Corbier did not
rebut Dr. Raymond’s assessment that the genetic mutation was severe. Similarly,
Dr. Corbier did not answer Dr. Wiznitzer’s assertion that the problem was
defective wiring.

       Thus, there is no reliable basis for crediting Dr. Corbier’s first theory that
people with an SCN1A mutation are vulnerable to developing an adverse reaction
to the DTaP vaccine. Similarly, there is no reliable basis for crediting Dr.
Corbier’s second theory that vaccines worsen Dravet syndrome by bringing about
seizures before they would have occurred otherwise. Tr. 30, 104, 140. Although
there may be an earlier manifestation, Dr. Corbier has not demonstrated how it
affects the child’s outcome. Dr. Raymond and Dr. Wiznitzer rested their opinion
on Berkovic, McIntosh, and Brunklaus. Dr. Corbier, on the other hand, had no
support for his opinions that the vaccines change the outcome. These studies
showed that children with SCN1A mutations have consistent symptoms, regardless
of whether the initial seizure followed a seizure.

       C.     Analogy to HCN channels

       To support the theory that “seizures beget seizures,” Dr. Corbier relies upon
articles by McClelland, Dube, Bender, Brewster, Chen, and Jung, and also testified
about them individually. Tr. 32-48.16 Some of these articles present results of


       16
          Dr. Corbier appeared to know relatively less about HCN channels than the Secretary’s
experts. For example, Dr. Corbier did not know whether a test could detect defects in HCN
                                                 27
experiments and some of these articles are review articles that summarize
experiments conducted elsewhere. In the articles that reported the results of an
experiment, the researchers were generally exploring a hypothesis that febrile
seizures lead to long-term epilepsy because the febrile seizures damage an HCN
channel. See Tr. 552.

       The HCN channels are located in the hippocampal region. Tr. 132, 382 (Dr.
Wiznitzer’s discussion of 2001 Chen). HCN channels are ion channels, which
allow substances such as sodium and potassium to enter and to exit the cell
membrane. Tr. 363. The purpose of HCN channels is to balance and polarize the
cell to limit the cell’s excitability. Tr. 364.

     After a summary about each article, Dr. Corbier was asked about their
combined teaching. He stated:

              I think taken collectively, these articles show that we
              have an explanation for prolonged febrile seizures
              causing permanent changes, permanent epileptic changes
              in a brain that may start out normal, for example, Dravet
              patients. We know that before six months, before they
              start having seizures, they appear normal. They don't
              have seizures. They have a prolonged febrile event or a
              prolonged febrile seizure. Something changes. They
              develop epilepsy, so this can explain why and how a
              prolonged febrile seizure vis-a-vis these HCN channels
              can result in these long-term changes.

Tr. 50. Dr. Corbier also opined about these studies’ relevance:

              They're relevant because we have to have a mechanism,
              we have to have an explanation to show why. Even if
              you have an important mutation such as SCN1A
              mutation, the changes from a SCN1A mutation that lead
              to refractory epilepsy do not occur in a vacuum. There



channels and he did not know how a defect in an HCN channel would be observable in a clinical
setting. Tr. 138.

                                                 28
              needs to be an explanation from going from no seizures
              to very refractory seizures unresponsive to medication.

Tr. 51.

       Dr. Corbier’s logic is flawed in many respects. First, he states that
something alters “a brain that may start out normal, for example, Dravet patients.”
Tr. 50. It is not correct to say that these children’s brains “start[ed] out normal.”
Dr. Corbier recognized that “these kids probably come into the world with that
SCN1A mutation.” Tr. 41. Although Dr. Corbier qualified his answer by using
the term “probably,” he later agreed that Aydien was born with the SCN1A
mutation. Tr. 94-95.

       The second error in Dr. Corbier’s assessment relates to the first. Dr. Corbier
asserted that “the changes from a SCN1A mutation that lead to refractory epilepsy
do not occur in a vacuum.” Tr. 51. There is not a vacuum. The seizures and
attendant developmental delays begin after the switch from Nav1.3 to Nav1.1. See
Brewster at 4597; Tr. 137.

       Third, HCN channels are not sodium channels. Tr. 363 (Dr. Wiznitzer).
HCN channels regulate the excitability and inhabitability in the cell. Tr. 364.
HCN channels involve not only sodium ions, which cause the cell to be
hyperpolarized, but also involve potassium ions. Id. “The HCN channel is not the
same thing as an SCN1A channel. It’s built differently. It has different
components. It has different genes. It probably has different transcriptional
regulation.” Tr. 470. When Dr. Corbier was asked to comment upon the
similarities and differences as part of his rebuttal testimony, he did not address the
question very well, beginning his answer “I don’t claim to be an expert in
channelopathies.” Tr. 524. Dr. Corbier’s non-answer left unrebutted Dr.
Wiznitzer’s assertion that “You’re dealing with two different creatures here. So I
think you can’t take the leap from one to the other.” Tr. 471.

      Fourth, the consequence of a problem in an HCN channel may be temporal
lobe epilepsy.17 But temporal lobe epilepsy is not the same as Dravet syndrome.

       17
          The text uses the conditional terminology “may be” because the connection between
HCN channels and temporal lobe epilepsy is not established. Tr. 516-19 (Dr. Corbier’s
discussion of Bender), 526-27 (Dr. Corbier).

                                                 29
Tr. 367-68, 372, 385; see also Tr. 498-99 (movement disorders seen in Dravet
syndrome do not originate in the hippocampal region).

      D.     Synopsis

       All these reasons contribute to a finding that Dr. Corbier was not persuasive
in his opinion that vaccinations affected Aydien’s outcome. The flip side of this
coin is that Dr. Raymond and Dr. Wiznitzer were persuasive in opining that the
SCN1A mutation was the sole cause. Consequently, Mr. Santini and Ms. Omidvar
have failed to establish the first prong of Althen and the Secretary has established
an alternative factor.

       Although this resolution means that Mr. Santini and Ms. Omidvar cannot be
awarded compensation, there is a second aspect to their case. Whether Aydien
suffered a severe injury due to the vaccine is discussed below.

VII. Severity of Injury

      A.     Legal Principles

      Another way of evaluating an alleged effect of vaccination on Aydien is to
consider how he would be if he had not received a vaccination. In a variety of
contexts, the Federal Circuit has held that the person claiming compensation for
another’s injury must establish a “but for” model. E.g. Nycal Offshore Dev. Corp.
v. United States, 743 F.3d 837, 844 (Fed. Cir. 2014) (oil and gas leases); Kellogg
Brown & Root Servs., Inc. v. United States, 728 F.3d 1348, 1371 (Fed. Cir. 2013)
(government counterclaim pursuant to anti-kick back act), reh’g denied, 2014 WL
1284763 (Fed. Cir. March 28, 2014). Consistent with common law principles, the
Federal Circuit has also held that petitioners in the Vaccine Program have the
burden to show “but for” the vaccine, they would not have suffered an injury.
Shyface v. Sec'y of Health & Human Servs., 165 F.3d 1344, 1352 (Fed. Cir. 1999).
Pursuant to the Vaccine Act, the injury suffered must be severe, such as lasting
more than six months. 42 U.S.C. § 300aa—11(c)(1)(D).

       In the context of a cause of action alleging a vaccine caused a discrete
injury, the “but for” world is readily identified. Petitioners maintain that but for a
vaccine, they would not have suffered any injury. However, Mr. Santini and Ms.
Omidvar in the case at hand are not proceeding on an initial-onset claim. They are


                                             30
instead pursuing a cause of action that the vaccines significantly aggravated
Aydien’s underlying disorder.

       In significant aggravation cases, constructing a hypothetical scenario without
the vaccination is more challenging. Because the physiologic basis for the disease
existed before vaccination, petitioners must present some persuasive evidence
about the natural or expected course of the disease. From this benchmark,
petitioners should show their outcome is worse than what would normally occur.
Locane v. Sec'y of Health & Human Servs., 99 Fed. Cl. 715, 731-32 (2011), aff’d,
685 F.3d 1375 (Fed. Cir. 2012); Loving v. Sec'y of Health & Human Servs., No.
02-469V, 2009 WL 3094883, at *11-12 (Fed. Cl. Spec. Mstr. July 30, 2009),
clarified on denial of reconsideration, 2010 WL 1076124 (Fed. Cl. Spec. Mstr.
March 2, 2010).

       In the cases involving an SCN1A mutation, the petitioners’ inability to
explain how the children would have fared without the vaccination was one reason
the petitioners were not compensated. Harris, 2011 WL 2446321 at *33; Snyder,
2011 WL 3022544, at *34. The Federal Circuit specifically ruled that these
findings were not arbitrary and capricious. Snyder, 553 Fed. Appx. at 999, 1003;
cf. Deribeaux, 717 F.3d at 1369 (ruling the special master was not arbitrary in
finding the SCN1A mutation to be the sole cause of the child’s injuries).

      B.     Assessment of Evidence

       For the case at hand, Mr. Santini and Ms. Omidvar’s proof again falters.
They failed to establish Aydien would be different today if he had not received the
DTaP vaccination. They have not demonstrated any sequela to his initial seizure
after which he returned to his baseline. Mr. Santini and Ms. Omidvar also have not
established any change in outcome.

       All experts agree that there is a causal relationship between the vaccinations
and the initial seizure. More specifically, the DTaP vaccine prompted a fever and
fever, in children with an SCN1A mutation, can prompt a seizure. The Secretary’s
experts conceded this point without dispute. Tr. 320 (Dr. Raymond), 448 (Dr.
Wiznitzer).

       A fever and an associated seizure, however, do not meet the Vaccine Act’s
severity requirement. Following the seizures, Aydien remained in the hospital for
less than four days. Exhibit 84A at 4-9. He underwent various tests including an
                                            31
EEG and an MRI. The results of these tests were normal. Exhibit 84A at 8,
CH&N Recs. at 224. Upon discharge, Aydien was said to be in good condition.
Exhibit 84A at 9; see also Tr. 144, 423, 427, 437. Consequently, Mr. Santini and
Ms. Omidvar cannot receive compensation for just the initial fever and initial
seizure. Therefore, Mr. Santini and Ms. Omidvar must look to Aydien’s outcome
after the initial presentation.

       Mr. Santini and Ms. Omidvar have not demonstrated Aydien would have
been worse. Dr. Corbier, on cross-examination, was asked if Aydien did not have
his initial seizure, how would he be today? Dr. Corbier responded: “the simple
answer is I don’t know.” He elaborated: “I can take an educated guess that if he
did have seizures, it would have occurred later on.” Tr. 104. In the subsequent
discussion, Dr. Corbier suggested that Aydien may not have had any seizures.
When questioned about the basis for this possibility, Dr. Corbier answered:

                  Is it possible that he could go without seizure
            despite the fact that he has an SCN1A mutation disease
            producing type of mutation? The answer is maybe.

                  I can’t say for sure. I don’t have any evidence to
            back me up, but I don’t see why not. . . .

                   [B]ut if we’re able to control all of the potential
            triggers, could we be left without a seizure disorder?
            Perhaps.

Tr. 107-08. Because Dr. Corbier’s answer suggested that triggers were not needed,
he was asked more questions about this point. Dr. Corbier stated “this is a
question, the answer of which I don’t know based on not seeing any particular
study designed to address that particular question. [B]ut at least hypothetically,
you know, I don’t see why not.” Tr. 109.

       Later, Dr. Corbier was again asked to differentiate Aydien from what
happens in Dravet syndrome generally. But, Dr. Corbier did not provide any
meaningful information. Tr. 142-43. Because Dr. Corbier did not explain his
opinion regarding the difference between a hypothetical Aydien Omidvar (who did
not receive the vaccination) and the real Aydien Omidvar (who did receive the
vaccination), Dr. Corbier was asked about this topic again. But, once more, he

                                             32
could say only that the seizures occurred earlier. He could not say that the earlier
onset affected Aydien’s longer term outcome. Tr. 185-91.

       These vague responses largely undermined the value of Dr. Corbier’s earlier
testimony, on direct examination, that the children at issue in the consolidated
cases were worse after the vaccination. Tr. 77 (Aydien). In the sense that the
children had seizures, they were worse. But this conclusion is too facile. It
ignores the role the mutation plays and the natural course of Dravet syndrome.

      The opinions from Dr. Raymond and Dr. Wiznitzer that the mutation
determined the children’s outcome were much more persuasive. In their view, the
vaccinations did not affect the Dravet syndrome. Tr. 263 (Dr. Raymond on
Matthew Ramirez), 270 (Dr. Raymond on Aydien), 319 (Dr. Raymond on Aydien),
423 (Dr. Wiznitzer on Matthew), 454 (Dr. Wiznitzer on both). Dr. Raymond and
Dr. Wiznitzer based their opinions that the gene caused the developmental delay on
biology. As explained above, neither child can produce a normally functioning
Nav1.1.

       The medical literature also supports the opinion that vaccinations did not
affect the outcome. Tr. 302-06 (Dr. Raymond citing McIntosh), 439 (Dr.
Wiznitzer citing McIntosh, and Brunklaus). For example, Brunklaus and
colleagues studied more than 300 cases with an SCN1A mutation. They attempted
to determine whether different variables accounted for the range of developmental
outcomes in patients with Dravet syndrome. The authors concluded that their
finding “supports the argument that children carrying a SCN1A mutation are
destined to develop the disease, which in turn can be precipitated by a series of
factors such as fever/illness, vaccination or a bath. However, the nature of the
trigger has no effect on overall developmental outcome and thus does not seem to
be responsible for the subsequent encephalopathy.” Brunklaus at 2334. In
addition to their own data, Brunklaus and colleagues cited the articles by Tro-
Baumann, Berkovic and McIntosh. When asked about this passage from the
Brunklaus article, Dr. Corbier said “I don’t see proof.” Dr. Corbier’s assessment
of Brunklaus is not credible.

       Overall, the evidence overwhelmingly demonstrated that Aydien would be
the same even if he did not receive the vaccine. The vaccination did not affect or
contribute to his developmental delay. Mr. Santini and Ms. Omidvar have failed to
meet their burden of establishing, by preponderant evidence, that he suffered an
injury for more than six months.
                                            33
VIII. Additional Comments

        The results in the case at bar match the results in previous cases involving an
SCN1A mutation. The identical outcome is not surprising because human biology
has not changed. The SCN1A genes still largely control the creation of Na v1.1.
Furthermore, the evidence is largely the same. Dr. Raymond and Dr. Wiznitzer
testified in previous cases. They cited to the same articles, such as Oakley and Yu.
The newer articles such as Brunklaus reinforce the opinions of Dr. Raymond and
Dr. Wiznitzer.

       Potential petitioners who intend to claim a vaccine injured a child with an
SCN1A mutation should consider carefully whether there is a reasonable basis for
their claims. Special masters have consistently credited evidence that the gene is
the sole cause of developmental problems.18 An expert’s opinion that a vaccine
can trigger an initial seizure in a child with an SCN1A mutation has been
insufficient to demonstrate that the vaccine caused a subsequent seizure disorder in
such a child, at least in the absence of evidence regarding a difference in the
ultimate outcome. Against this backdrop, future claims involving an SCN1A
mutation may lack a reasonable basis.

IX.    Conclusion

      Dravet syndrome has interfered with Aydien’s development since its
manifestation following the November 7, 2003 DTaP vaccination. The timing of
events (in that Aydien experienced his first seizure within one day of the
vaccination) understandably led to a hypothesis that the vaccination contributed to
the Dravet syndrome.

       However, scientific research, as Dr. Raymond and Dr. Wiznitzer ably
explained, has shown that a genetic mutation caused Aydien’s Dravet syndrome. It
is more likely than not that Aydien would be the same today whether he received
the vaccination or not. Mr. Santini and Ms. Omidvar have failed to demonstrate
that they are entitled to compensation from the Vaccine Program. Consequently,
the Clerk’s Office is instructed to enter judgment in accord with this decision.
       18
         The list of final opinions in other SCN1A cases includes: Snyder, 553 Fed. Appx. 994;
Deribeaux, 717 F.3d 1363; Stone, 676 F.3d 1373; Barnette v. Sec’y of Health & Human Servs.,
110 Fed. Cl. 34 (2013); and Waters v. Sec'y of Health & Human Servs., No. 08-76V, 2014 WL
300936 (Fed. Cl. Spec. Mstr. Jan. 7, 2014).

                                                 34
IT IS SO ORDERED.

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




                    35
                   Appendix: Full Citation for Journal Articles

                          Title                               Exhibit in     Exhibit in
                                                               Barclay         Santini
Alex C. Bender et al., SCN1A mutations in Dravet             K3            53; W.2; U.6
syndrome: impact of interneuron dysfunction on neural
networks and cognitive outcome, 23 Epilepsy Behav.
177 (2012).
Samuel F. Berkovic et al., De-novo mutations of the          20            54; C
sodium channel gene SCN1A in alleged vaccine
encephalopathy: a retrospective study, 5 Lancet
Neurology 488 (2006).
Amy Brewster et al., Developmental febrile seizures          42            86a
modulate hippocampal gene expression of
hyperpolarization-activated-channels in an isoform-and
cell-specific manner, 22(11) J. Neuroscience 4591
(2002).
A. Brunklaus et al., Prognostic, clinical and demographic    I34; K6       S.1; U.4
features in SCN1A mutation-positive Dravet syndrome,
135 Brain 2329 (2012).
Claudia B. Catarino et al., Dravet syndrome as epileptic     I28; K1       55; U.1
encephalopathy: evidence form long-term course and
neuropathy,134 Brain 2982 (2011).
Kang Chen et al., Persistently modified h-channels after     43            88
complex febrile seizures convert the seizure-induced
enhancement of inhibition to hyperexcitabilty,7(3) Nat.
Med. 331(2001).
Berten Ceulemans, Overall management of patients with        K4            U.7
Dravet syndrome, 53(Supp. 2) Devel. Med. Child
Neurology 19 (2011).
Celine M. Dube et al., Febrile seizures: Mechanism and       25            59
relationship to epilepsy, 31 Brain & Devel. 366 (2009).
Andrew Escayg and Alan L. Godin, Sodium channel              I10           S.8
SCN1A and epilepsy: Mutations and mechanism, 51(9)
Epilepsia 1650 (2010).
Dale C. Hesdorffer et al., Design and phenomenology of       I26
the FEBSTAT study, 53(9) Epilepsia 1471 (2012).
Susumu Ito et al., Mouse with Na v 1.1 haploinsufficiency,   I15           S.13
a model for Dravet syndrome, exhibits lowered
sociability and learning impairment, 49 Neurobiology of
                         Title                              Exhibit in     Exhibit in
                                                             Barclay        Santini
Disease 29 (2013).
Sangwook Jung et al., Progressive dendritic HCN            45            89
channelopathy during epileptogeneiss in the rat
pilocarpine model of epilepsy, 27 (47) J. Neuroscience
13012 (2007).
Christoph Lossin, A catalog of SCN1A variants, 31(2)       I29           62
Brain Dev. 114 (2009).
Melinda S. Martin et al., The voltage-gated sodium         I22           S.19
channel Scn8a is a genetic modifier of severe myoclonic
epilepsy of infancy,16(23) Hum. Mol. Genet. 2892
(2007).
Shawn McCelland et al., Epileptogenesis after prolonged    I25           U.2
febrile seizures: Mechanism, biomarkers and therapeutic
opportunities, 497(3) Neuroscience Letters 155 (2011).
Anne M. McIntosh et al., Effects on vaccination on onset   I32; K5       66; S.24; U.3
and outcome of Dravet syndrome: a retrospective study,
9 Lancet Neurology 592 (2010).
John C. Oakley et al., Temperature -and age-dependent      I9; K2        69; S.7; U.5
seizures in a mouse model of severe myoclonic epilepsy
in infancy, 106 Proc. Nat’l Acad. Sci. USA 3994 (2009).
Francesca Ragona et al., Cognitive development in          K8
Dravet syndrome: A retrospective, multicenter study of
26 patients, 52(2) Epilepsia 386 (2011).
Blanca Tro-Baumann et al., A retrospective study of the    I33           73
relation between vaccination and occurrence of seizures
in Dravet syndrome, 52(1) Epilepsia 175 (2011).
Frank H. Yu et al., Reduced sodium current in              I11           S.9
GABAergic interneurons in a mouse model of severe
myoclonic epilepsy in infancy, 9(9) Nat. Neuroscience
1142 (2006).
