RULING ON ENTITLEMENT 1
NORA BETH DORSEY, Chief Special Master.
On September 24, 2012, Laura Day ("petitioner") filed a petition for compensation under the National Vaccine Injury Compensation Program ("the Program"),
Respondent recommended against awarding compensation, stating that petitioner had not presented adequate evidence that B.K.D.'s Gardasil and FluMist vaccinations caused her to suffer from NMO.
II. Factual Background
a. Summary of Relevant Facts
B.K.D. was born on August 25, 1998, in Mooresville, Indiana. Pet'r's Ex. 1 at 1. As a young child, B.K.D. enjoyed relatively good health, although she suffered from occasional ear infections and colds. Pet'r's Ex. 14 at 15. B.K.D.'s previous medical history includes symptoms of juvenile arthritis at the age of three and breaking her right wrist and the pinky finger on her right hand, for which she had surgery on September 17, 2011. Pet'r's Ex. 3 at 4; Pet'r's Ex. 4 at 5. B.K.D. was an otherwise active, healthy child who enjoyed playing competitive year-round softball. She received a physical examination at a CVS Minute Clinic in Mooresville, Indiana, on August 2, 2011, where she was cleared for participation in her school's sports programs. Pet'r's Ex. 16 at 1. The CVS nurse practitioner reported that B.K.D. "does not present apparent contraindications (including cardiovascular, musculoskeletal, and neurological) to practice and participate in [sports]."
On September 28, 2011, at the age of twelve, B.K.D. received a FluMist and a third Gardasil vaccination at the Morgan County Health Department.
On October 31, 2011, B.K.D. again presented in the emergency room at St. Francis complaining of constant diarrhea and a twelve pound weight loss over the course of the last two weeks. Pet'r's Ex. 2 at 186. She also reported a sore neck, fever, and a rash that began on or around October 27, 2011, along with irregular pupils.
After B.K.D. began complaining of leg weakness and numbness that progressively worsened, she had an MRI of her brain and spine on November 2, 2011. Pet'r's Ex. 4 at 93; Pet'r's Ex. 4 at 347. The MRI of her spine revealed findings consistent with acute disseminated encephalomyelitis ("ADEM").
B.K.D. continued to receive treatment for ADEM, including both intravenous and oral steroids and Neurontin, until she was discharged from Riley Hospital on November 9, 2011. She was immediately transferred to Inpatient Pediatric Rehabilitation Services. Pet'r's Ex. 4 at 5. After spending a week in rehabilitation, B.K.D. regained much of her strength and was able to walk short distances when using a cane.
When B.K.D. stopped taking oral steroids on December 16, 2011, her symptoms quickly worsened. On December 28, 2011, B.K.D. reported pupil irregularity, unsteady gait, right leg weakness, and back pain. She was admitted to Riley Hospital for overnight observation and was administered oral steroids. MRIs of her brain and spine were taken on December 29, 2011. The MRI of B.K.D.'s spine showed "areas of cervicothoracic cord expansion and . . . improving scattered thoracic meningeal enhancement." Pet'r's Ex. 11 at 36. However, B.K.D. continued to experience trouble walking. Pet'r's Ex. 9 at 11.
On January 5, 2011, B.K.D. again presented to the emergency room at Riley Hospital complaining of a severe headache and reporting that both of her legs felt numb, weak, and tingl
B.K.D. continued to recover until June 12, 2012, when she was again admitted to the emergency room at Riley Hospital with complaints of left hand and arm tingling, left leg weakness, and trouble running. Pet'r's Ex. 6 at 11. She also reported one episode of blurred vision in her left eye. An MRI of the brain showed no definite intracranial abnormalities, but an MRI of the spine showed extensive abnormalities from the C3 to the T6 level.
On July 10, 2012, B.K.D. followed up with Dr. David Mattson, a neurologist with expertise in the treatment of MS, at the MS Center of Indiana University. Dr. Mattson noted that B.K.D. had a long segment of spinal cord demyelination, which is another symptom consistent with a diagnosis of NMO. Dr. Mattson did not initially diagnose B.K.D. with NMO because she had not shown symptoms of optic neuritis, which is one of the disease's most prominent symptoms. Ex. 6 at 5. He recommended that B.K.D. begin using Rebif, which is commonly used to treat patients with MS, in order to facilitate long-term management of the disease.
B.K.D. has been receiving treatment at the MS Center of Indiana University. On November 12, 2012, Dr. Mattson reaffirmed a decision to continue treating B.K.D. long-term with Rebif. Pet'r's Ex. 20 at 274. Rebif prevented B.K.D. from relapsing from the end of 2012 up until December 2013, when another relapse began. Tr. 18-19. On December 4, 2013, an MRI of her brain and spine showed new lesions, and B.K.D. began another round of steroids. Pet'r's Ex. 35 at 5-6; Pet'r's Ex. 36 at 6. B.K.D. continued her visits to the MS Clinic, where her lower extremity symptoms continued and she was slowly weaned off steroids. After B.K.D. was seen at the MS Clinic on February 4, 2014, Dr. Grimes decided to switch her medication from Rebif to azathioprine in hopes of decreasing the enhancing activity in her brain and spinal cord. Pet'r's Ex. 36 at 4; Pet'r's Ex. 35 at 19.
b. Summary of Petitioner's and B.K.D.'s Testimony
Both petitioner, Laura Day, and her daughter, B.K.D., testified during the hearing on June 10, 2015. Ms. Day testified that although her daughter has never been diagnosed with rheumatoid arthritis, B.K.D. experienced aching in her legs when she was about two years old. Tr. 7. However, B.K.D. did not experience further problems after she visited a chiropractor, and she never visited a rheumatologist or had bloodwork done.
Ms. Day also testified about the ways in which her daughter's illness has impacted their family. She stated that since B.K.D.'s initial onset of NMO in September 2011, she has had to watch her daughter relearn to walk five times. Tr. 15. Ms. Day presented a clear timeline of her daughter's illness, beginning with the onset of symptoms and including B.K.D.'s second relapse of NMO in March 2012 and her third relapse in June 2012. Tr. 17-18. Ms. Day reported that after B.K.D. was diagnosed with NMO and began taking Rebif in June 2012, she enjoyed 14 months of good health and started to return to a more normal life, until her daughter's fourth relapse in December 2013. Tr. 20-21. Ms. Day described 2014 as a year of "one relapse after another," during which B.K.D. was hospitalized over ten times. Tr. 21-22. Ms. Day stated that in October 2014, B.K.D. began seeing Dr. Weinshenker, an NMO specialist at the Mayo Clinic. While her health has improved with an increase in her steroid treatment and an experimental chemotherapy drug treatment, it is still unclear whether this course of treatment will prevent further relapses of NMO. Tr. 21, 33. Additionally, Ms. Day reported that the medications used to control B.K.D.'s NMO make it difficult for her to enjoy a normal life and have caused her to gain over 120 pounds. Tr. 26.
Despite the uncertain future of her daughter's health, Ms. Day testified that B.K.D. has tried to make the most of her situation and enjoy life. Ms. Day stated that she and B.K.D. attended a prom at Riley Hospital and that B.K.D. enjoyed her sixteenth birthday party in Riley Hospital's lobby. Tr. 23, 25. B.K.D. also received a wish from the Make-A-Wish Foundation, where she, her family, and a friend traveled to California for a sightseeing trip. Tr. 28. And B.K.D.'s brother and his baseball team named one of their tournaments after B.K.D. and donated the money they raised to help pay for her treatment. Tr. 24. The family is hopeful that Dr. Weinshenker's new therapies will help B.K.D. to resume a more normal life.
In addition to petitioner's testimony, B.K.D. also testified. She described how the medications she takes for NMO make her feel tired, cause bruising in her arms, and occasionally make her sick. Tr. 41. B.K.D. testified about the difficulties of being in and out of the hospital and having to go to rehabilitation therapy to relearn how to walk. Tr. 43-44. She stated that she has had to teach herself how to walk many times, and that she has a cane, a walker, multiple leg braces, a gait belt, and two wheelchairs.
c. Procedural History
Petitioner filed this case on September 24, 2012, alleging that B.K.D. suffered from MS as a result of receiving the Gardasil and FluMist vaccinations on September 28, 2011. Petition at 1, ¶¶ 8-9. Petitioner filed the first set of medical records on November 2, 2011. Respondent addressed petitioner's claims in a report filed pursuant to Vaccine Rule 4(c), wherein respondent argued that petitioner was not entitled to compensation under the Program. Resp't's Report at 2. Respondent also asserted that petitioner had not filed a complete set of medical records or any affidavits in support of her position.
The parties also filed expert reports in support of their respective positions. On January 24, 2014, petitioner filed an expert report from neurologist Dr. Carlo Tornatore, his curriculum vitae, and several articles referenced in his report. Pet'r's Ex. 21. Dr. Tornatore concluded, "[B.K.D.] developed an HPV-induced ADEM/NMO mediated by an autoantibody to aquaporin-4."
As stipulated by the parties, there are no disputed facts in this case.
The parties agree that B.K.D.'s alleged injury is not set forth on the Vaccine Injury Table,
d. Issue to be Decided
The sole issue to be decided is whether the Gardasil and FluMist vaccinations administered to B.K.D. on September 28, 2011, were the cause of her NMO. Joint Pre-Hearing Submission at 2.
e. Neuromyelitis Optica (NMO)
NMO is a demyelinating autoimmune disorder consisting of optic neuritis and transverse myelopathy.
The study of NMO has been greatly advanced by the Mayo Clinic's discovery of anti-immunoglobin G ("NMO-IgG") antibodies in 2006. NMO-IgG antibodies target aquaporin-4 ("AQP4"), a protein that is present in astrocytes which helps conduct water through the cell membrane.
The Vaccine Act established the Program to compensate vaccine-related injuries and deaths. 42 U.S.C. § 300aa-10(a). "Congress designed the Vaccine Program to supplement the state law civil tort system as a simple, fair and expeditious means for compensating vaccine-related injured persons. The program was established to award `vaccine-injured persons quickly, easily, and with certainty and generosity.'"
a. Standards for Adjudication
Petitioner's burden of proof is a preponderance of the evidence. 42 U.S.C. § 300aa-13(a)(1). The preponderance of the evidence standard, in turn, has been interpreted to mean that a fact is more likely than not.
b. Elements of Petitioner's Claim
When a petitioner alleges that an injury listed on the Vaccine Injury Table ("the Table") occurs within the time frame set forth in the Table, then petitioner's vaccine claim is deemed a Table claim, and a presumption of vaccine causation attaches.
Because petitioner does not allege that B.K.D. suffered a Table injury, she must prove that either the Gardasil or FluMist vaccines that B.K.D. received caused her injury. To do so, she must establish, by preponderant evidence: (1) a medical theory causally connecting the vaccine and B.K.D.'s injury ("
In determining whether petitioner is entitled to compensation, the special master shall consider all material contained in the record, § 300aa-13(b)(1), including "any . . . conclusion, [or] medical judgment . . . which is contained in the record regarding . . . causation . . . of the petitioner's illness." § 300aa-13(b)(1)(A). Thus, the undersigned must weigh the submitted evidence and the testimony of the parties' offered experts and rule in petitioner's favor when the evidence weighs in her favor.
Althen Prong One: Medical Theory of Causation
Petitioner's theory of causation need not be medically or scientifically certain,
As noted above, the sole issue to be decided in this case is whether the vaccinations that B.K.D. received caused the injuries she sustained. Petitioner must show by a preponderance of the evidence that the Gardasil and FluMist vaccinations caused B.K.D. to develop NMO.
1. Petitioner's Expert, Dr. Tornatore
Dr. Carlo Tornatore, a board certified neurologist at Georgetown University Medical Center, testified on behalf of petitioner. Dr. Tornatore received his M.D. from Georgetown University School of Medicine, and he completed his residency in the Department of Neurology at Georgetown University Hospital. Pet'r's Ex. 55 at 2. Dr. Tornatore also completed a Fellowship in Molecular Virology at the National Institutes of Health.
Dr. Tornatore is a member of the American Neurologic Association and the American Academy of Neurology, and he has published articles, book chapters, and abstracts on a range of topics in neurology and virology in several reputable medical journals.
During the hearing, Dr. Tornatore opined that he believed to a reasonable degree of medical certainty that "B.K.D.'s NMO was caused by a combination of the Gardasil and influenza vaccinations she received on September 28, 2011." Tr. 66. Dr. Tornatore proposed three possible theories, discussed in greater detail below, to explain how the vaccinations B.K.D. received could have caused her NMO. The first and petitioner's primary theory of causation proposed by Dr. Tornatore was that of molecular mimicry. Tr. 96-97;
a. Primary Theory of Causation: Molecular Mimicry
Dr. Tornatore explained molecular mimicry as the immune system's inability to distinguish between pathogen-derived antigens and self-antigens found in the tissue of the nervous system. Tr. 96-97. If both foreign antigens and self-antigens found within the body share the same epitopes,
As previously mentioned above, NMO damages the astrocytes. Pet'r's Ex. 30 at 2. AQP4 has been identified as the protein present in astrocytes which is the target for specific NMO antibodies. Tr. 65, 67. NMO is most often diagnosed by testing a person's blood serum for the presence of AQP4 antibodies, known as NMO-IgG. Pet'r's Ex. 30 at 3. Generally, when antigens are released into the body through a vaccine, a person's immune system will direct antibodies to bind to those foreign antigens and destroy them. However, in patients with NMO, NMO-IgG antibodies are triggered to attack the AQP4 proteins, which in turn destroy the astrocytes and cause swelling in the nervous system.
Dr. Tornatore cited several studies in support of his opinion that the Gardasil and FluMist vaccinations led to B.K.D.'s development of NMO via the phenomenon of molecular mimicry. Dr. Tornatore relies on a study done by Noorbakhsh et al.,
Dr. Tornatore also referenced an NMO-specific study done by Menge et al.
Table 1 Assessment of immunologic cross-reactivity between AQ4 and L1 capsid proteins of HPV
Pet'r's Ex. 31 at 2.
In summary, the Menge authors posit that the theory of humoral immunologic cross reactivity (molecular mimicry) may be the medical theory of causation of NMO following HPV vaccine. In the alternative, they suggest "induction of bystander lymphocyte activation by upregulating both the adaptive and innate immune system." Pet'r's Ex. 31 at 2. Moreover, since L1 capsid proteins
Tr. 112. Thus, as Dr. Tornatore explained, molecular mimicry can explain the development of NMO after a vaccine, but because the homology between the L1 protein and the AQP4 is limited, such an occurrence is extremely rare. Pet'r's Ex. 31 at 1-2.
Dr. Tornatore also cited several other studies which support his theory that the Gardasil and FluMist vaccinations can cause or contribute to the development of NMO. In a study by Karussis and Petrou,
Dr. Tornatore also cited to a study by Fujinami and Oldstone
In a study by Souyah et al.,
At the conclusion of his testimony during the hearing, Dr. Tornatore also referenced a study by Gautam et al.
b. Dr. Tornatore's Other Theories
i. Immune System Imbalance
Although Dr. Tornatore's primary theory for how B.K.D. developed NMO from the Gardasil and FluMist vaccines is molecular mimicry, Dr. Tornatore also proposed two other theories of causation. The first alternative theory proposed by Dr. Tornatore is that of immune system imbalance. Dr. Tornatore referenced the Noorbakhsh report for the principle that viral pathogens can disturb the balance of the immune system causing an autoimmune disorder such as NMO. The Noorbakhsh researchers note:
Pet'r's Ex. 24 at 12.
The Menge paper's authors also posit a mechanism whereby a disturbance of the balance of the immune system could lead to the development of a disorder such as NMO. The authors reported, "An alternative pathogenic concept [in the development of NMO] may be induction of bystander lymphocyte activation by upregulating both the adaptive and innate immune systems as was shown for HPV vaccines." Pet'r's Ex. 31 at 2. The authors suggest that a protein found in a vaccine could disrupt the immune system, causing it to lose its inhibitory properties and ultimately result in the development of an autoimmune disorder.
ii. Misdirected Immune Response
With respect to the second alternative theory of causation, Dr. Tornatore briefly explained that concurrent administration of the Gardasil and FluMist vaccinations could have caused a misdirected immune system response. In reference to such an immune response, Dr. Tornatore stated:
Pet'r's Ex. 21 at 14.
2. Respondent's Expert, Dr. Leist
Dr. Leist is a professor of Neurology at Thomas Jefferson University and serves as the Chief of the Clinical Neuroimmunology Division and the Director of the Comprehensive Multiple Sclerosis Center at Thomas Jefferson University Hospital. Resp't's Ex. B at 1. Dr. Leist also works as a neurology consultant at the Inglis Foundation and is the Director of the Hospital-based Neurology Infusion Service.
Dr. Leist opined that petitioner had not met her burden of presenting a preponderant medical theory causally connecting the Gardasil and FluMist vaccinations that B.K.D. received with her onset of NMO. Resp't's Ex. A at 1. Dr. Leist first testified that while molecular mimicry is a real phenomenon, it could not have led to B.K.D.'s development of NMO. Dr. Leist also testified that the co-administration of the third round of Gardasil and the FluMist vaccine could not have had any impact on the development of NMO.
a. Arguments Against Molecular Mimicry
Dr. Leist agreed that sequence homologies as described by Dr. Tornatore can be frequently found. Resp't's Ex. A at 10; Tr. 185. Dr. Leist introduced a paper by Albert and Inman
Resp't's Ex. C at 2-3. However, Dr. Leist disagreed as to the significance of sequence homologies. Citing the Kohm
Turning to petitioner's medical literature in support of molecular mimicry, Dr. Leist pointed out that the Menge study did not confirm cross reactivity on the basis of serologic testing in patients with NMO.
Moreover, Dr. Leist opined that the Menge study was not based on reliable data, as it was merely a collection of cases from the VAERS database. He argued, "[T]he Menge article is nothing but the collection of case reports" and thus its findings are not based on epidemiologic data." Tr. 214-15. In summary, Dr. Leist urged:
Dr. Leist admitted, however, that the theory that NMO could be caused by molecular mimicry is not totally implausible. He testified, "[Molecular mimicry] could be a potential theory by which one could think . . . that [NMO] . . . could be caused. [But] sequence homology, in itself, is only one of the building blocks by which ultimately the molecular mimicry would . . . generate the disease." Tr. 204. Although Dr. Leist disagreed with Dr. Tornatore that molecular mimicry was the causal mechanism of B.K.D.'s development of NMO, he nonetheless acknowledged that molecular mimicry and sequence homology are real medical phenomena. Tr. 177.
Dr. Leist also referenced findings from the Institute of Medicine's Committee to Review Adverse Effects of Vaccines
Furthermore, Dr. Leist disputed the relevance of the medical literature on which Dr. Tornatore relied to support his opinions.
Dr. Leist also opined that Dr. Tornatore's reference to the Schonberger et al. study
b. Arguments Against Petitioner's Alternative Theories
With respect to Dr. Tornatore's theory that the Gardasil and FluMist vaccinations caused an imbalance of B.K.D.'s immune system, Dr. Leist stated that the Noorbakhsh study which Dr. Tornatore referenced in support of this second theory was not applicable to B.K.D.'s situation because it focused on ADEM, rather than NMO. Resp't's Ex. A at 10. Specifically with respect to the Noorbakhsh study, Dr. Leist opined, "It is my opinion that [B.K.D.] did not suffer from ADEM . . . [This article] is therefore not related to this case."
Dr. Leist's also addressed Dr. Tornatore's third causative theory regarding the co-administration of the Gardasil and FluMist vaccinations causing B.K.D. to experience a misdirected immune response.
3. Evaluation of the Evidence
The undersigned evaluates the parties' respective experts' opinions based on the record as a whole.
The undersigned finds that there is preponderant evidence in the record to demonstrate that the Gardasil and FluMist vaccinations led to B.K.D.'s development of NMO through the mechanism of molecular mimicry. In support of his theory, Dr. Tornatore used the Menge study to show that there is sequence homology between HPV types 16 and 18 and AQP4. Pet'r's Ex. 31 at 2 (referencing Table 1); Tr. 111. This sequence homology demonstrates the potential for cross-reactivity to occur. Pet'r's Ex. 31 at 2.
Dr. Leist testified that if frequently occurring short sequence homologies were sufficient to induce an autoimmune reaction, then there would be a high incidence of autoimmune disorders in the general population. Tr. 180. However, Dr. Leist did not address Dr. Tornatore's explanation of why people only rarely develop autoimmune disorders due to sequence homology that then results in molecular mimicry. According to Dr. Tornatore, "[It is] possible that [a person] could be vaccinated and have antibodies to L1 but [that] those antibodies are not directed against these little fragments [on the HPV antigen] . . . Some people are going to develop immunity to different parts of the L1 molecule . . . that [will] never . . . cross-react with aquaporin-4." Tr. 112.
In addition to his opinion that the sequence similarity between L1 and AQP4 was sufficient to induce cross-reactivity and cause B.K.D. to develop NMO, Dr. Tornatore cited studies by Karussis and Petrou, Gautam, and Fujinami & Oldstone demonstrating that the sequence similarity between L1 and AQP4 is sufficient to induce cross reactivity. Pet'r's Ex. 42 at 2 (assessing the incidence of NMO after HPV vaccination and concluding that there was a possibility of cross-reactivity between L1 and AQP4); Pet'r's Ex. 40 at 3 (finding that "it is conceivable that a pathogen with homology to self proteins at only a few residues may trigger autoimmune disease"); Pet'r's Ex. 28 at 3-4 (addressing whether the sequence similarity is sufficient to induce cross-reactivity between L1 and AQP4); Tr. 116.
Therefore, the undersigned finds that petitioner has provided preponderant evidence that the Gardasil and FluMist vaccinations can cause NMO via molecular mimicry. Accordingly, petitioner has satisfied
Althen Prong Two: Logical Sequence of Cause and Effect
1. Petitioner's Expert, Dr. Tornatore
a. Logical Sequence of Cause and Effect
Dr. Tornatore opines that there is a logical sequence of cause and effect between the Gardasil and FluMist vaccinations B.K.D. received and her subsequent development of NMO. Pet'r's Ex. 21 at 10-11; Tr. 127-30. Dr. Tornatore discussed the onset of B.K.D.'s NMO in three phases. In phase one, B.K.D. received two previous Gardasil vaccinations in January and May 2011. Dr. Tornatore explained that B.K.D.'s immune system would have responded to the antigens found in these first two Gardasil vaccinations. Pet'r's Ex. 21 at 11. However, Dr. Tornatore clarified that these first two Gardasil vaccinations did not lead to the development of NMO because the antibody titers that developed as a result of the vaccine were too low and thus the immune response was not sufficient to lead to the onset of NMO symptoms. Tr. 128.
After B.K.D. received the third Gardasil vaccination on September 28, 2011, Dr. Tornatore explained that her immune system developed an immediate response to the HPV antigens. During this immune response, autoimmune antibodies were directed to the L1 protein found in the HPV vaccine, and those antibodies "very quickly [found] the homology in aquaporin-4 in the nervous system, and so those antibodies hone[d] in on that area, and then they start[ed] to cause inflammation . . . initially in the lower thoracic [area]." Tr. 128. The immune system's timely response to the HPV antigens thus resulted in B.K.D.'s initial symptom onset of abdominal pain on October 1, 2011. Tr. 128; Pet'r's Ex. 21 at 11.
In phase two of his causation theory, Dr. Tornatore detailed the progression of B.K.D.'s symptoms. Pet'r's Ex. 2 at 176. He explained that B.K.D.'s abdominal pain was caused by inflammation of her spinal cord. Pet'r's Ex. 21 at 11. Dr. Tornatore stated:
Pet'r's Ex. 21 at 11. Dr. Tornatore's testimony connected B.K.D.'s NMO symptom onset approximately three days after receiving the Gardasil and FluMist vaccinations with the clinical symptoms of abdominal pain and generalized aches that she reported experiencing at that time.
In the third phase of his theory, Dr. Tornatore reported that three and a half weeks after receiving the vaccinations, B.K.D. developed inflammation in her spinal cord, which resulted in weakness in her lower extremities. Pet'r's Ex. 21 at 11. Dr. Tornatore opined that this acute inflammation is reflected in B.K.D.'s November 2, 2011 spinal MRI.
Although Dr. Tornatore spent a great deal of time during the hearing discussing how the Gardasil vaccination caused B.K.D.'s NMO, he also discussed how the FluMist vaccination could have created the immune response. Dr. Tornatore testified, "And the same thing . . . [goes for] the FluMist [vaccination] . . . the antigens on that virus may trigger the immune system, and that then causes the inflammation in the spinal cord, and then . . . [you] release antigens, you have epitope spreading,
b. B.K.D.'s Genetic Predisposition to Autoimmune Disorders
Dr. Tornatore also discussed how B.K.D.'s family history of autoimmunity may have predisposed her to develop an autoimmune disease from a vaccination. Tr. 131. The medical record documents that several of B.K.D.'s family members have suffered from autoimmune disorders. B.K.D.'s paternal grandmother suffered from rheumatoid arthritis and Graves' disease,
Thus, Dr. Tornatore explained that because several other people in B.K.D.'s immediate family have experienced issues with autoimmune disorders, it is likely that B.K.D. would be more likely to develop an autoimmune disorder than the average person. In conclusion, Dr. Tornatore summarized, "[T]he . . . FluMist, in combination with the Gardasil, in the right timing, with the third dose of Gardasil, in the right person, with the right genetic background, [it] may have been [a] perfect storm that . . . then caused the NMO to develop." Tr. 130-31.
2. Respondent's Expert, Dr. Leist
While Dr. Leist agreed with Dr. Tornatore that B.K.D. suffers from NMO, he argued that NMO is an idiopathic disorder.
Dr. Leist referenced a paper by McKeon et al.,
3. Evaluation of the Evidence
Dr. Tornatore's opinion regarding a logical sequence of cause and effect is pursuasive and is supported by B.K.D.'s medical records. Dr. Tornatore opined that the Gardasil and FluMist vaccinations B.K.D. received on September 28, 2011, initiated a brisk immune response to specific antigens found in the Gardasil vaccine through the process of molecular mimicry. Petr's Ex. 21 at 11. Dr. Tornatore noted, "[O]ne of the most interesting pieces of information regarding the timing of [B.K.D.'s] symptom onset is her MRIs of the brain and spine done November 2, 2011, which correlate precisely with her symptoms." Pet'r's Ex. 21 at 14. Dr. Tornatore opined that B.K.D.'s spinal MRI on November 2, 2011, showed an area of inflammation in the spinal cord from T9 to T12, consistent with B.K.D.'s complaints of "band-like" abdominal pain in early October. Pet'r's Ex. 21 at 14; Tr. 89. The inflammation of the thoracic spinal cord caused B.K.D.'s abdominal discomfort and the back pain. Tr. 94.
B.K.D.'s MRI of her spine on November 2, 2011, showed a relatively new inflammation of her upper cervical spine, which would explain why she began experiencing head and neck pain as well as leg weakness on October 31, 2011. Tr. 89-90; Pet'r's Ex. 2 at 190; Pet'r's Ex. 4 at 11, 13. Dr. Tornatore summarized, "[B.K.D.'s] MRI[s] [are] a beautiful, beautiful ability for us to look back in time" and see a clinical picture of the onset and progression of [B.K.D.'s] NMO after she received the Gardasil and FluMist vaccinations. Tr. 91.
Dr. Leist agreed with B.K.D.'s diagnosis of NMO, but he opined that the vaccinations she received on September 28, 2011, could not have caused the initial symptoms of NMO that she developed three days later. Resp't's Ex. A at 7-8. In refutation of Dr. Tornatore's theory of causation, Dr. Leist stated that the precise cause of NMO is unknown. Tr. 187. Dr. Leist suggested that BKD's NMO was an "underlying condition [that] was already ongoing . . ." and could have been due to a genetic predisposition to autoimmune disorders. Tr. 225; Resp't's Ex. A at 9-10. Dr. Leist did not refute the interpretation of B.K.D.'s MRIs by Dr. Tornatore. Instead, he focused on the fact that NMO is currently classified as an idiopathic disorder. Tr. 188-89. Dr. Leist also emphasized, "[B.K.D.] may carry a diagnosis of juvenile rheumatoid arthritis, an autoimmune condition." Resp't's Ex. A at 9.
Both experts agree that BKD may have been predisposed to developing autoimmune disease. Dr. Tornatore stated:
For all of the reasons stated above, the undersigned finds that petitioner has shown by preponderant evidence a logical sequence of cause and effect that B.K.D.'s HPV and flu vaccinations caused her to develop NMO. Thus petitioner has satisfied her burden under
Althen Prong Three: Timing
1. Petitioner's Expert, Dr. Tornatore
a. Sufficient Period of Time Between Vaccination and Onset of NMO
The medical records demonstrate that three days after B.K.D. received the Gardasil and FluMist vaccinations, she began experiencing symptoms consistent with the initial onset of NMO, including abdominal pain, lack of bowel movement, and generalized aches. Pet'r's Ex. 2 at 178.
Although the IOM study shows a lag phase beginning at four to 10 days, Dr. Tornatore stated that because B.K.D. had received two prior Gardasil vaccinations, her immune system's primary response to the HPV antigens was much faster. Tr. 134. In fact, the IOM study reports, "Due to the development of memory B and T cells during the primary immune response, the latency between subsequent exposure to the antigen and development of the immune response will usually be shorter. The lag phase is generally one to three days." Pet'r's Ex. 47 at 2. Dr. Tornatore opined that because B.K.D. had twice been exposed to the HPV antigens, her immune response to the third vaccination was more immediate, making the latency phase much shorter and causing her to develop symptoms of NMO after three days. Tr. 135.
Dr. Tornatore also cited a study by Tenembaum et al.
Dr. Tornatore also referenced a study published by the Risk Interval Working Group of the Clinical Immunization Safety Assessment Network ("the Risk Interval Working Group")
Pet'r's Ex. 46 at 4;
In summary, Dr. Tornatore testified that NMO could occur three days after vaccination, and he provided medical literature to support his position.
b. Treating Physicians
Dr. Mattson and Dr. Golomb, two of B.K.D.'s treating physicians, also noted a temporal association between B.K.D.'s receipt of the Gardasil and FluMist vaccinations and her onset of NMO. After reviewing B.K.D.'s November 2, 2011 MRI results, Dr. Golomb noted that B.K.D.'s symptoms began shortly after her receipt of the Gardasil and FluMist vaccinations. Pet'r's Ex. 4 at 123. Additionally, after Dr. Mattson confirmed that B.K.D. tested positive for the NMO-IgG antibody, he noted, "[B.K.D.] has had an October 2011 episode, [about] a week after vaccinations, involving numbness and tingling with right leg weakness  [and] gait deterioration . . ." Pet'r's Ex. 6 at 13.
2. Respondent's Expert, Dr. Leist
a. Insufficient Period of Time Between Vaccination and NMO
Dr. Leist disagreed with Dr. Tornatore that B.K.D. could have developed NMO three days after receiving the Gardasil and FluMist vaccinations. Dr. Leist described the immune response that invades the central nervous system as a "multistep process" which could not be accomplished in such a short time interval.
Furthermore, Dr. Leist disputed the relevance of some of the medical literature referenced by Dr. Tornatore regarding an appropriate onset, including the Tenembaum article regarding the onset of post-vaccine ADEM. Dr. Leist commented, "Tenembaum et al. reported in the series of 84 children with ADEM that symptoms arose two to 30 (mean 12.1) days after a preceding event in 74 % of the cases. However, their evaluation of the potential causes did not go beyond temporality." Resp't's Ex. A at 11 (referencing Pet'r's Ex. 25 at 1). Also, as mentioned above, Dr. Leist also stated that because B.K.D. did not suffer from ADEM, the Tenembaum study was not applicable to her case. Resp't's Ex. A. at 12.
Additionally, Dr. Leist opined that the study done by the Risk Interval Working Group measuring risk intervals for immunization safety research was insufficient proof of the two to 42 day risk interval. Dr. Leist stated that although the researchers calculated a plausible secondary risk interval of two to 42 days, there was insufficient data to support this position. The Risk Interval Working Group reported:
Pet'r's Ex. 46 at 3. Accordingly, Dr. Leist stated that the results of the Risk Interval Working Group's study actually showed that the potential risk interval of three days was highly implausible, given that there were only two studies that explicitly indicated symptom onset. Finally, Dr. Leist pointed out that the Risk Interval Working Group's study does not reflect the CDC's official position on vaccine risk intervals, despite the fact that an individual CDC employee was part of the research team. Tr. 192-93.
Dr. Leist referenced medical literature by Mannara et al.
Dr. Leist stated, "This work shows that even when a preformed immune response is present there is a delay in the occurrence of neurologic symptoms." Resp't's Ex. A at 11. Dr. Leist compared B.K.D.'s three day symptom onset with the results from the Mannara study to conclude that the symptoms B.K.D. developed on October 1, 2011, could not have been caused by her Gardasil and FluMist vaccinations. Resp't's Ex. A at 11; Tr. 196.
3. Evaluation of the Evidence
The undersigned finds that the onset of B.K.D.'s NMO occurred on October 1, 2011, when she began complaining of back and abdominal pain. Prior to that date, B.K.D. had no history of NMO or an NMO spectrum disorder, nor had she ever experienced any serious neurological problems. Petitioner has presented preponderant evidence showing that in rare cases, a person's immune response after receiving a vaccination can be as short as three days, especially if the body is already primed with the specific viral antigens.
Dr. Tornatore opined that a three day time frame from vaccination to the onset of NMO symptoms is medically acceptable given the process of molecular mimicry. The medical literature supports Dr. Tornatore's opinion that a person can quickly develop an immune response after a vaccination, especially if there have been previous exposures to the same viral antigens. Tr. 135;
Dr. Tornatore's theory that molecular mimicry resulted in B.K.D.'s development of NMO after three days also fits within the second risk interval time frame as established by the Risk Interval Working Group. The Risk Interval Working Group observed that while the primary risk interval for studying adverse reactions to vaccines is approximately five to 28 days, two to 42 days was "biologically plausible" as a secondary risk interval. Pet'r's Ex. 46 at 4. Moreover, while Dr. Leist opined that such intervals are merely suggested for the study of post-vaccinal neurological disorders, the undersigned finds these suggested intervals persuasive.
Dr. Liest stated that three days was an insufficient time period between vaccination and NMO symptom onset to preponderantly prove a temporal relationship between vaccination and injury in B.K.D.'s case. However, the undersigned notes that Dr. Leist did not sufficiently address Dr. Tornatore's point that B.K.D.'s immune response had been primed by two earlier doses of the Gardasil vaccination. Dr. Liest simply stated that "even in a situation where there has been a priming occurring by prior exposure, a representation of the same antigen, if we purport that this causes the disease, will still take time . . . [and] 72 hours . . . is too short." Tr. 196. Respondent did not adequately address petitioner's argument that the previous receipt of multiple doses of the same viral antigen could speed up the body's immune response.
Moreover, while Dr. Leist cited medical literature in support of his opinion that three days is an insufficient time period by which a person might normally develop NMO in response to a vaccine, the undersigned finds petitioner's evidence more persuasive. Dr. Leist stated that the Mannara study regarding the development of post-viral encephalomyelitis in mice demonstrates that three days is an insufficient time period for a person to develop visible symptoms of NMO after receiving a vaccine. Tr. 195; Resp't's Ex. H at 2. Dr. Leist highlighted the Mannara researchers' findings that mice injected with activated EAE T cells first exhibited motor symptoms of EAE seven days after vaccination to support his opinion that B.K.D. could not have developed NMO from a vaccine after three days. Resp't's Ex. H at 2; Tr. 195-96.
However, Dr. Tornatore pointed out how the Mannara article could be construed to support petitioner's position, because the mice showed non-motor signs of EAE after two days. Resp't's Ex. H at 2. Similarly, B.K.D. showed non-motoric signs of NMO three days after her vaccinations. Tr. 234. Dr. Tornatore argued, "[T]his paper . . . demonstrates that within two days, you can have evidence of an adverse response from a vaccination." Tr. 234.
Two of B.K.D.'s treating physicians documented a temporal association between the vaccines and the onset of illness. Dr. Golomb, one of B.K.D.'s treating physicians at Riley Hospital, reviewed B.K.D.'s November 2, 2012 MRI results with an ADEM expert and noted in B.K.D.'s file that she received the Gardasil and FluMist vaccinations on Thursday
In June 2012, after B.K.D. experienced several recurring episodes of what was thought to be ADEM, she followed up with Dr. Mattson at the MS Center of Indiana University, where it was first postulated that she suffered from NMO.
The undersigned is persuaded by Dr. Tornatore's argument that B.K.D. could have developed symptoms of NMO three days after receiving the Gardasil and FluMist vaccinations, and petitioner has demonstrated that this three day time frame is medically appropriate. Therefore, petitioner has satisfied her burden of presenting preponderant evidence of
For the reasons discussed above, the undersigned finds that the petitioner is entitled to compensation because she has provided sufficient evidence that preponderates in her favor. A separate damages order will issue.