CHRISTIAN J. MORAN, Special Master.
Nancy Barclay is the mother of Matthew Ramirez, a developmentally delayed child, who is 10 years old. When he was born, Matthew 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 Na
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, Ms. Barclay alleges that the DTaP vaccine significantly aggravated Matthew's Dravet syndrome. In other words, Ms. Barclay maintains that "but for" the DTaP vaccine, Matthew would have been less delayed. She seeks compensation through the National Childhood Vaccine Injury Compensation Program, 42 U.S.C. § 300aa—10 through 34 (2006). Her primary source of evidence is the opinion of Jean-Ronel Corbier, a pediatric neurologist.
The Secretary disagrees with Ms. Barclay'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 Matthew is delayed. In their view, the SCN1A mutation was sufficient, by itself, to cause Matthew's outcome.
For the reasons discussed in more detail below in sections VI and VII, the Secretary's position is persuasive. Section VI discusses Ms. Barclay's claim that the DTaP vaccine significantly aggravated Matthew's Dravet syndrome. Ms. Barclay has failed to demonstrate that the DTaP vaccination affected Matthew in any meaningful way. Conversely, the Secretary has established that the SCN1A mutation most likely determined Matthew's outcome. Section VII reviews a separate deficit in Ms. Barclay's case: she 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.
The parties rely upon the doctors whom they retained to explain the significance of events in Matthew's life. Thus, the following sections provide some context for the opinions discussed throughout this decision.
Dr. Corbier graduated from medical school at Michigan State University. Exhibit 18 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 18 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 18 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.
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.
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.
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.
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.
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.
Since 1986, Dr. Wiznitzer has worked in Cleveland, Ohio, at Rainbow Babies & Children's Hospital as a child neurologist.
Collectively, these doctors described the relevant concepts and principles underlying 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.
Genes contain DNA. DNA is composed of sequences of four nucleotides: adenine, thymine, guanine, and cytosine.
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,
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, whether the mutation arose in a conserved region,
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.
As a fetus and shortly after birth, humans and other mammals rely on a sodium channel known as Na
A gene primarily responsible for the body's creation of the Na
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,
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 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 Na
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.
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 Na
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.
Matthew was born on November 16, 2004. Exhibit 3 at 3. Although no one knew this in 2004, Matthew was born with an abnormality in his SCN1A gene. Tr. 95 (Dr. Corbier), 263 (Dr. Raymond). The results of testing, which took place in 2009, established the foundation for the disputed issues in this case. The report from Athena Laboratories, Inc. stated: "This individual possesses a DNA sequence variant that is either a previously reported disease-associated mutation or is predicted to be a disease-associated mutation. This test result is consistent with a diagnosis of, or a predisposition to develop, SMEI or SMEB, the severe phenotypes associated with SCN1A mutations." Exhibit 13B at 8.
The SCN1A mutation did not appear to affect Matthew's initial development. At his first two well-baby visits, which occurred on November 30, 2004, and January 21, 2005, Matthew appeared well. His pediatrician did not note any concerns about his development. Exhibit 4 at 2, 4;
On March 25, 2005, Matthew had another well-baby appointment. He, again, appeared to be healthy. He received a set of vaccinations, including a second dose of the DTaP vaccine. Exhibit 4 at 2, 4.
Around 11:00 p.m., Matthew developed a fever. His mother gave him infant Motrin. Exhibit 5A at 12;
Matthew's parents brought him to a local emergency room. He had a fever on arrival and was still seizing. The doctor gave him Versed and his seizures abated within one minute. Exhibit 5A at 11, 13. The total time of Matthew's seizure was approximately 45 minutes.
After admission, doctors ordered a multitude of tests and most were negative. Among the studies that were performed on Matthew were an EEG, a CT scan of his brain, and an MRI. The EEG was normal. Exhibit 5A at 42-44. The CT was normal.
Matthew remained in the hospital from March 26, 2005, until March 29, 2005. Exhibit 5A at 18 (discharge summary). When he was discharged, Matthew was administered amoxicillin and his final diagnosis stated febrile seizures due to pneumonia. Exhibit 5A at 18.
The testifying experts differed in their assessment of Matthew's health when he was leaving the hospital. Dr. Corbier opined that the March 26, 2005 seizure altered Matthew's brain. Tr. 15, 64-65. He held this opinion despite acknowledging that electroencephalogram and neuroradiological tests were normal. Tr. 97, 216. In Dr. Corbier's view, "an immature brain exposed to prolonged febrile seizure will then not have just an isolated event but will have further seizures." Tr. 99.
In contrast, Dr. Wiznitzer took these same normal test results as evidence that Matthew had returned to baseline. Tr. 423-25. Dr. Wiznitzer also emphasized that Matthew's problem was (and is) in his "wiring." As such, the March 26, 2005 seizure did not affect Matthew's brain. The "wiring" defect happened when Matthew was born with a defective SCN1A gene. Tr. 423.
On April 15, 2005, and April 25, 2005, Matthew had additional seizures. Tr. 15-16. Unlike the March 26, 2005 seizure, the April 15, 2005 seizure was unprovoked.
After the April 25, 2005 seizure, Matthew satisfied the criteria for being epileptic, which are two or more unprovoked seizures.
Following this discovery, Matthew's treating doctors diagnosed him as suffering from Dravet syndrome. Exhibit 16 at 43-44. The testifying experts all agree that Matthew suffers from Dravet syndrome. Tr. 20 (Dr. Corbier), 227 (Dr. Raymond), 446 (Dr. Wiznitzer). The question in this litigation on which the experts disagree is whether the March 25, 2005 DTaP vaccine affected Matthew's development.
Since he started having seizures, Matthew has not developed normally. Various anticonvulsant medicines have not controlled his seizures. He experiences approximately ten seizures each month. He speaks sentences that are three or four words in length. He can walk but has difficulty catching a ball. Exhibit 40 at 1-2; Tr. 18.
Ms. Barclay began this action when she filed a petition on August 14, 2007, alleging that the DTaP vaccine caused Matthew to suffer a severe seizure disorder and this seizure disorder led to developmental delays. Pet. 1-2. Ms. Barclay supported her allegations by filing some of the pertinent medical records.
In the initial status conference, held on September 20, 2007, the Secretary reported that she had informally requested additional medical records. Ms. Barclay's attorney also represented that he had sent the file to an expert for an opinion.
This expert was Marcel Kinsbourne, a pediatric neurologist. Dr. Kinsbourne summarized Matthew's medical history. Dr. Kinsbourne noted that his presentation "is consistent with the diagnosis of severe myoclonic epilepsy of infancy (SMEI) also known as Dravet's syndrome." Exhibit 9 at 2. Dr. Kinsbourne cited the National Childhood Encephalopathy Study, a study of British children who received the whole-cell diphtheria-pertussis-tetanus ("DPT") vaccine and Dr. Kinsbourne also explained why, a study involving whole-cell DTP provided meaningful information about a vaccine containing acellular pertussis.
The parties discussed Dr. Kinsbourne's report in a March 4, 2008 status conference. The Secretary requested medical records about the extent of Matthew's developmental delay and any genetic testing. Ms. Barclay's attorney represented that there had not been any genetic testing for Matthew.
The Secretary filed her report, pursuant to Vaccine Rule 4, on May 5, 2008. The Secretary reviewed the medical records and noted that although a doctor had recommended genetic testing, the exhibits did not contain the results of any genetic testing. Resp't's Rep't at 4 n.2 (citing exhibit 5 at 115, 120). The Secretary also argued that Dr. Kinsbourne's opinion was not reliable. To support her criticism of Dr. Kinsbourne, the Secretary relied upon the report of Dr. Wiznitzer.
Dr. Wiznitzer accepted the diagnosis of SMEI, although he recommended that Matthew be tested. Exhibit A at 3, 6. In Dr. Wiznitzer's view, "SMEI is genetically determined."
In addition to the emphasis on genetics, Dr. Wiznitzer challenged the potentially causal mechanisms identified by Dr. Kinsbourne. Dr. Wiznitzer disputed the reliability of the G-protein theory and the interleukin 1beta theory. He asserted that the NCES data did not assist Ms. Barclay because it studied a whole-cell pertussis vaccine, which Matthew did not receive.
Dr. Wiznitzer addressed Matthew's fever after the DTaP vaccine. In Dr. Wiznitzer's view, the cause of this fever was pneumonia. Dr. Wiznitzer opined that, in any event, the initial post-vaccination fever did not affect Matthew's development because "children with SMEI always manifest the disorder" even if they do not have a fever.
A status conference was held two days after the Secretary filed her Rule 4 report and Dr. Wiznitzer's expert report. The Secretary continued to press for the submission of additional medical records about Matthew and his development, especially the results of any genetic testing. Order, filed May 8, 2008 at 1. Ms. Barclay's counsel aptly condensed the issue: do genes make a person develop epilepsy or do genes make a person vulnerable to developing epilepsy?
Approximately 18 months passed during which Ms. Barclay filed successive motions for enlargement of time and status reports. On October 5, 2010, Ms. Barclay filed pediatric neurology records including the Athena Diagnostics Report. Exhibit 13B. As discussed throughout this decision, Athena identified a mutation in Matthew's SCN1A gene.
At the ensuing status conference, the parties discussed possible next steps. Options included obtaining a supplemental report from Dr. Kinsbourne and waiting for additional developments in other cases involving mutations in an SCN1A gene.
Again, months passed without much progress. In an August 30, 2011 status conference, the parties explored the status of the case. Ms. Barclay's counsel suggested obtaining an additional expert. To this suggestion, the Secretary's attorney stated that it was petitioner's prerogative to explore. If petitioner obtained a new expert, then the case might be worth pursuing. Ms. Barclay's attorney defined the issue as whether prolonged seizures in a child with an SCN1A mutation damage the child's brain. This issue, according to Ms. Barclay's attorney, was not presented in
Ms. Barclay filed a report from Jean-Ronel Corbier, a pediatric neurologist. In a nutshell, Dr. Corbier's opinion is that a prolonged seizure, especially a prolonged febrile seizure, can change the infant's brain. Dr. Corbier cited articles by McClelland, Dube, and Bender to support the reliability of his opinion. Exhibit 17 at 3-5.
To Dr. Corbier, the presence of a mutation in the SCN1A gene did not automatically determine that a person would suffer Dravet syndrome, as Matthew does. According to Dr. Corbier and the literature he cited, mutations in the SCN1A produce a range of outcomes. For example, some patients develop a more benign condition, generalized epilepsy with febrile seizures plus (GEFS+). Other patients develop familial hemiplegic migraines or familial autism. Dr. Corbier interpreted this spectrum of disorders as meaning that genetics are not a sufficient explanation. He asked: "[N]ow that we have identified a genetic mutation that seems very important in children with Dravet syndrome, given the wide variability in expression, what other factors including environmental ones might be present?"
The environmental factor at issue here is the DTaP vaccine. Citing McIntosh and Tro-Bauman, Dr. Corbier stated that a vaccination leads to earlier seizures. Exhibit 17 at 11, 14. An earlier seizure links to Dr. Corbier's initial point that prolonged febrile seizures damage the infant's brain.
Dr. Corbier discussed Matthew's case in light of these general principles. Dr. Corbier stated: "The presence of an SCN1A [mutation] undoubtedly represents a strong known risk factor for the development of Matthew's epilepsy and Dravet syndrome. It also made him much more sensitive to the effects of DTaP and fever given his immature brain." Exhibit 17 at 15. He continued: "Like the underlying SCN1A mutation, DTaP made as [sic] significant contribution to the development of Matthew's epilepsy and Dravet syndrome."
In the ensuing status conference, the Secretary aggressively questioned the utility of devoting more resources from the Vaccine Injury Trust Fund to this case. The Secretary stated that the undersigned special master had already determined that a prolonged seizure did not affect the child's outcome.
Before the Secretary filed her expert reports, Ms. Barclay submitted a supplemental report from Dr. Corbier. This supplemental report discussed whether pneumonia could have caused Matthew's initial post-vaccination fever. In Dr. Corbier's view, the seizure caused the pneumonia. Exhibit 38.
The Secretary procured two reports — an initial report from Dr. Raymond, and a supplemental report from Dr. Wiznitzer. Dr. Raymond provided a basic explanation for how SCN1A genes lead to the production of a sodium channel. When a defect in the genes causes an alteration in the normal structure of the sodium channel, the sodium channel does not function properly. Exhibit I at 3-6. Dr. Raymond stated that "it is very clear that based on the present animal investigations, that there is no need to invoke environmental modifiers to explain disease onset or progression."
In addition, Dr. Raymond disagreed with much of Dr. Corbier's opinion. Most notably, Dr. Raymond questioned the accuracy of Dr. Corbier's assertion that an earlier onset of Dravet syndrome caused a worse outcome. Dr. Raymond's opinion was that the onset did not affect the outcome and he cited articles by McIntosh, Tro-Baumann, and Brunklaus.
Dr. Raymond's conclusion supported the Secretary's position that compensation should not be awarded to Ms. Barclay. Dr. Raymond said that: "Matthew is a child with severe myoclonic epilepsy of infancy and developmental delays diagnosed as Dravet syndrome secondary to a mutation in his SCN1A gene. This is the sole cause of his epilepsy condition. It was not caused []or exacerbated by any of the immunizations that he received."
Dr. Wiznitzer reached the same conclusion. He stated that the finding of a mutation in Matthew's SCN1A gene "leads to the conclusion that Matthew Ramirez's SCN1A mutation by itself explains and caused his clinical neurological disorder — Dravet syndrome." Exhibit K at 2. Like Dr. Raymond, Dr. Wiznitzer stated that the onset of seizures did not affect the outcome. Dr. Wiznitzer relied upon the McIntosh, Brunklaus, and Ragona studies.
A status conference followed the submission of these two reports. Ms. Barclay indicated that he did not intend to call Dr. Kinsbourne to testify. Instead, Ms. Barclay wanted to obtain a second supplemental report from Dr. Corbier. In this same status conference, the parties discussed consolidating this case with
Ms. Barclay filed the second supplemental report from Dr. Corbier on April 4, 2013, as exhibit 39. The basic thrust of this report was to emphasize the contributions from environmental factors. He stated "the general discovery of an SCN1A mutation and its impact on the sodium channel in epileptic patients can explain why patients with Dravet syndrome can be so vulnerable to certain triggers, among which is the DTaP vaccination." Exhibit 39 at 4.
In conjunction with that report, Ms. Barclay presented her pre-hearing brief. Ms. Barclay's pre-hearing brief was tightly focused. Preliminarily, Ms. Barclay categorized her case as one presenting "an off-Table (cause-in-fact) significant aggravation claim." Pet'r's Prehr'g Br., filed Apr. 22, 2013, at 3. As informed by Dr. Corbier's reports, Ms. Barclay presented the theory on which she was proceeding. He argued that the DTaP vaccine can cause the onset of seizures in children with an SCN1A mutation. He also argued that the outcome for Matthew was worse than it would have been otherwise because Matthew had a prolonged seizure and had status epilepticus.
The Secretary responded in her pre-trial brief. The Secretary agreed that Ms. Barclay presented a claim that the DTaP vaccine significantly aggravated Matthew's condition and, thus, she was required to fulfill the elements set forth in
The Secretary, however, challenged other parts of Ms. Barclay's case. The Secretary maintained that the "petitioner will be unable to produce reliable scientific evidence demonstrating Matthew's initial, prolonged seizure caused any brain damage or caused him to suffer a worse developmental outcome."
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.
At the end of the hearing, the parties requested an opportunity to submit briefs.
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, Ms. Barclay is pursuing an off-Table claim that the DTaP vaccine significantly aggravated her son's Dravet syndrome. As confirmed in
After
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 Ms. Barclay 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;
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.
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 Matthew. Tr. 254 (Dr. Raymond), 302 (Dr. Raymond discussing Matthew Ramirez), 359 (Dr. Wiznitzer), 454 (Dr. Wiznitzer discussing Matthew Ramirez). They provided several reasons for their opinions, including details about genetic mutation, rodent studies, and studies on people.
Dr. Raymond, the board-certified geneticist, stated practitioners look for details about the mutation, including the nature of the mutation, whether the mutation arose de novo, and whether the mutation is in a conserved region. Tr. 317.
Here, Dr. Raymond discussed the details of Matthew's mutation. Matthew has a 10 base pair deletion that arose de novo. Tr. 259. The mutation was in a conserved region. Tr. 317.
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 13B. Matthew's gene was defective, creating incorrect wiring in his brain. Tr. 417 (Dr. Wiznitzer).
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.
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.
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.
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,
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.
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.
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.
The authors found "no differences in intellectual outcome, subsequent seizure type, or mutation type between the two groups."
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.
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.
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."
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:
Tr. 196.
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.
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.
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.
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.
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."
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.
When Dr. Corbier testified in rebuttal, he recognized that Matthew Ramirez's 10 base pair mutation was severe and "explains a lot of things." Tr. 501. But, Dr. Corbier maintained the genetic mutation does not explain everything. The mutation, in Dr. Corbier's view, made Matthew Ramirez "more susceptible to environmental insults."
An opinion that a 10 base pair mutation explains
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.
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.
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:
Tr. 50. Dr. Corbier also opined about these studies' relevance:
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 Matthew 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 Na
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.
Fourth, the consequence of a problem in an HCN channel may be temporal lobe epilepsy.
All these reasons contribute to a finding that Dr. Corbier was not persuasive in his opinion that vaccinations affected Matthew'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, Ms. Barclay has failed to establish the first prong of Althen and the Secretary has established an alternative factor.
Although this resolution means that Ms. Barclay cannot be awarded compensation, there is a second aspect to her case. Whether Matthew suffered a severe injury due to the vaccine is discussed below.
Another way of evaluating an alleged effect of vaccination on Matthew 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.
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, Ms. Barclay in the case at hand is not proceeding on an initial-onset claim. She is instead pursuing a cause of action that the vaccines significantly aggravated Matthew'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.
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.
For the case at hand, Ms. Barclay's proof again falters. She has failed to establish Matthew would be different today if he had not received the DTaP vaccination. She has not demonstrated any sequela to his initial seizure after which he returned to his baseline. Ms. Barclay also has 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, Matthew remained in the hospital for less than four days. Exhibit 5 at 13. He underwent various tests including an EEG and an MRI. The results of these tests were normal. Exhibit 5 at 21-22, exhibit 6 at 23. Upon discharge, Matthew was said to be in good condition. Exhibit 5 at 18;
Ms. Barclay has not demonstrated Matthew would have been worse. Dr. Corbier, on cross-examination, was asked if Matthew Ramirez 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 Matthew Ramirez may not have had any seizures. When questioned about the basis for this possibility, Dr. Corbier answered:
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 Matthew 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 Matthew Ramirez (who did not receive the vaccination) and the real Matthew Ramirez (who did receive the vaccination), Dr. Corbier was asked about this topic again. But, once more, he could say only that the seizures occurred earlier. He could not say that the earlier onset affected his 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. 19-20 (Matthew Ramirez), 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 Na
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, Brunklaus, and Ragona). 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 Matthew Ramirez would be the same even if he did not receive the vaccine. The vaccination did not affect or contribute to his developmental delay. Ms. Barclay has failed to meet her burden of establishing, by preponderant evidence, that he suffered an injury for more than six months.
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
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.
Dravet syndrome has interfered with Matthew's development since its manifestation following the March 25, 2005 DTaP vaccination. The timing of events (in that Matthew 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 Matthew's Dravet syndrome. It is more likely than not that Matthew would be the same today whether he received the vaccination or not. Ms. Barclay has failed to demonstrate that she is entitled to compensation from the Vaccine Program. Consequently, the Clerk's Office is instructed to enter judgment in accord with this decision.
