McGuire v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

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

NICOLETTE MCGUIRE, *

* No. 10-609V

Petitioner, * Special Master

* Christian J. Moran

*

v. * Filed: September 18, 2015

*

SECRETARY OF HEALTH * Entitlement; human

AND HUMAN SERVICES, * papillomavirus (“HPV”)

* vaccine; headaches; cytokines.

Respondent. *

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

Ronald C. Homer, Sylvia Chin-Caplan, and Meredith Daniels, Conway, Homer &

Chin-Caplan, P.C., Boston, MA, for Petitioner;

Debra A. Filteau Begley, U. S. Dep’t of Justice, Washington, DC, for Respondent.

PUBLISHED DECISION DENYING COMPENSATION1

Nicolette McGuire alleges that the human papillomavirus vaccinations she

received when she was 20 years old caused her to develop headaches, resulting in

great pain. Ms. McGuire seeks compensation pursuant to the National Childhood

Vaccine Injury Compensation Program, codified at 42 U.S.C. § 300aa–10 through

34 (2012).

To support her claim, Ms. McGuire filed her medical records. Because the

records were inconsistent about when Ms. McGuire started having significant

headaches after the vaccination, she provided her recollections during a hearing

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.

held on November 4, 2011. Revised Findings of Fact, issued October 12, 2012,

determined that Ms. McGuire started experiencing prolonged headaches on

October 25-28, 2007, and these headaches became constant approximately one

week later.2

After the Revised Findings of Fact were issued, the parties presented

opinions from experts retained for the litigation. In due course, a hearing was held

during which the four experts testified.

The undersigned has considered the entire record. After weighing the

evidence, the undersigned finds that Ms. McGuire has not met her burden of

establishing that the HPV vaccination caused her headaches. The simplest

explanation is that Ms. McGuire failed to present a reliable basis for concluding,

on a more-likely-than-not basis, that the HPV vaccination can cause headaches that

last for months and years.

The remainder of the decision elaborates on this basic finding. The

background of the experts are set forth initially because their experience provides a

context for understanding Ms. McGuire’s medical history, which is set forth in the

following section. Collectively, those sections are the foundation for the analysis

section that explains why the evidence does not preponderate in Ms. McGuire’s

favor.

Biographies

The parties rely upon the doctors whom they retained as expert witnesses to

explain the respective positions regarding Ms. McGuire’s illness. Ms. McGuire

retained Dr. Spencer Weig, an expert in child neurology, and Dr. Sahar Swidan, a

PharmD who specializes in headache treatment. The Secretary retained Dr. David

2

The parties disagreed, for a time, about the type of headache Ms. McGuire suffered.

Ms. McGuire proposed chronic daily headaches (CDH) and the Secretary proposed new daily

persistent headaches (NDPH). However, before the hearing, the parties concluded that

classifying Ms. McGuire’s headaches as either CDH or NDPH would not affect the outcome of

the claim that the HPV vaccination caused Ms. McGuire’s headaches. Resp’t’s Status Rep., filed

Mar. 11, 2015.

2

Alexander, a neurologist, and Dr. Andrew Saxon, an immunologist.3 The

following sections provide some context for the opinions discussed throughout this

decision.

Dr. Weig

Background. After completing his education in medical school in 1983, Dr.

Weig practiced pediatric neurology from 1987-2011. Tr. 174. His patients were

younger than 19 years old. Tr. 168. If a potential patient were older than 20 years,

Dr. Weig referred the person to an adult neurologist. Tr. 209.

Dr. Weig treated children with a variety of neurologic disorders. Some of

these disorders, such as acute disseminated encephalomyelitis, limbic encephalitis,

NDA receptor encephalitis, multiple sclerosis, transverse myelitis, acute

inflammatory demyelinating polyneuropathy or Guillain-Barré Syndrome, chronic

inflammatory demyelinating polyneuropathy, dermatomyositis, and myasthenia

gravis, involve the immune system. Tr. 173; exhibit 30 (Dr. Weig’s report) at 5-6.

For these patients, he sometimes, but not always, consulted a colleague who

specialized in immunology. Tr. 212. His knowledge of how diseases originate

was an essential part of his ability to practice as a pediatric neurologist. Tr. 176.

In Dr. Weig’s practice, approximately one-third of his patients suffered from

some type of headache. Tr. 148-49. For CDH, Dr. Weig cared for 20-30 people in

his practice and more during hospital rounds. Tr. 271-72. For NPDH, Dr. Weig

estimated that he saw two or three people who satisfied the formal diagnostic

criteria. Tr. 210. He most recently saw a patient suffering from CDH in May

2011, shortly before he retired. Tr. 277.

Although Dr. Weig retired from practicing pediatric neurology, he has

continued his teaching duties, which began in 1990. Currently, he advises medical

school students during rounds at a hospital. Tr. 148, 276. He does not see any

patients outside of hospital rounds. Tr. 275. To maintain his license, he attends

conferences with other doctors approximately twice per month. Annually, he

spends about 20-30 hours at these conferences. Tr. 276.

3

The Secretary retained Dr. Saxon after her original immunologist, Burton Zweiman,

died. Resp’t’s Status Rep., filed Jan. 2, 2014. At the Secretary’s suggestion, Dr. Zweiman’s

report and curriculum vitae were struck from the record. Order, issued Mar. 6, 2015.

3

Dr. Weig’s education, training, and experience qualified him as an expert in

pediatric neurology. Tr. 175-76. However, the Secretary raised two arguments

about Dr. Weig’s experience that reduced the value of his opinion. The lesser

point is Dr. Weig’s background as a pediatric neurologist does not perfectly fit Ms.

McGuire’s case because her headaches began when she was 20 years old. Tr. 165-

70. Special masters have sometimes found the differences between pediatric

neurology and adult neurology to be significant. See, e.g., Milik v. Sec'y of Health

& Human Servs., No. 01-64V, 2014 WL 6488735, at *12 (Fed. Cl. Spec. Mstr.

Oct. 29, 2014) (crediting a pediatric neurologist’s opinion regarding childhood

developmental delays), mot. for rev. denied, 121 Fed. Cl. 68 (Fed. Cl. Apr. 29,

2015); Deribeaux v. Sec'y of Health & Human Servs., No. 05-306V, 2011 WL

6935504, at *38 (Fed. Cl. Spec. Mstr. Dec. 9, 2011) (crediting a pediatric

neurologist’s interpretation of an MRI performed on a child), mot. for rev. denied,

105 Fed. Cl. 583 (Fed. Cl. 2012), aff’d, 717 F.3d 1363 (Fed. Cir. 2013). However,

the Secretary did not present any evidence, such as testimony from the neurologist

that she retained, that established CDH in the pediatric population differs from

CDH in the adult population. Thus, despite his pediatric focus, Dr. Weig’s opinion

remains relevant. See Hall v. Sec'y of Health & Human Servs., No. 02-1052V,

2009 WL 3423036, at *30 (Fed. Cl. Spec. Mstr. Oct. 6, 2009) (stating, in the

context of awarding attorneys’ fees and costs, that “the fact that someone else may

have better qualifications does not mean that [a retained doctor] was entirely

unqualified”); cf. Sullivan v. Sec'y of Health & Human Servs., No. 10-398V, 2015

WL 1404957, at *20 (Fed. Cl. Spec. Mstr. Feb. 13, 2015) (stating “the possibility

of a better study is not an effective critique of an existing, otherwise valid study”).

The Secretary’s second criticism of Dr. Weig is more meaningful. The

Secretary argued that Dr. Weig lacked the training in immunology to offer a theory

of how the HPV vaccine causes CDH via the immune system. Tr. 171-73. Dr.

Weig admitted that his formal training in immunology came in medical school

from which he graduated in 1973. Tr. 145-46, 172. He is not board-certified in

immunology. Tr. 149-50. In addition, after Dr. Weig presented his first report and

the Secretary countered with a neurologist plus an immunologist (first Dr.

Zweiman, then Dr. Saxon), Ms. McGuire announced a plan to retain an

immunologist to support Dr. Weig.4

4

Ms. McGuire did not present testimony from an actual immunologist. She presented

testimony from Dr. Swidan, whose qualifications are reviewed below.

4

Although Dr. Weig’s working knowledge of immunology suffices as a basis

to explain a general theory, Dr. Weig lacked any detailed understanding of

immunology. For example, Dr. Weig’s knowledge of the function and working of

cytokines was limited. He was unable to discuss how cytokines like tumor

necrosis factor alpha (“TNF”) are produced, stating instead that he would have to

defer to an immunologist. Tr. 279. Dr. Weig’s lack of specialization in

immunology makes his opinion on immunologic topics less valuable than the

opinion of Dr. Saxon, who is an immunologist. Locane v. Secʼy of Health &

Human Servs., 685 F.3d 1375, 1380 (Fed. Cir. 2012) (finding that special master

was not arbitrary in considering the backgrounds of experts and crediting the

expert with a more specific specialization).

Opinion. Dr. Weig expressed his opinions in four reports. Exhibits 28, 30,

37, and 40. He categorized Ms. McGuire’s headaches as chronic daily headaches.

He opined that the HPV vaccine can cause CDH by stimulating the production of

cytokines, particularly TNF. For this proposition, he relied primarily upon a paper

whose lead author is Ligia Pinto. Dr. Weig also opined that increased levels of

TNF contribute to the pathology of CDH and for this proposition, Dr. Weig

primarily relied upon a paper co-written by Todd Rozen and Sahar Swidan. In his

January 12, 2015 report, Dr. Weig expressed the opinion that expected interval

between vaccination and the onset of headaches is 5 days to 6 weeks. Dr. Weig

also defended Dr. Swidan’s qualifications.

Dr. Alexander

Background. Dr. Alexander completed medical school in 1979, and a

residency in neurology in 1983. Exhibit A, tab 1 (C.V. of Dr. Alexander). In

1984, he started private practice in Los Angeles, California. He started teaching at

UCLA in 2002, and became a full-time professor there in 2008. Tr. 304-06. He

holds board-certifications in three areas: neurology, spinal cord medicine, and

strokes. Tr. 306.

As a practicing neurologist, he has treated hundreds of patients with CDH.

Tr. 414. However, he has not diagnosed any patient with the rare form of CDH,

NDPH. Tr. 310, 404.

5

His current responsibilities include three duties. He treats patients at a

hospital with 11 beds.5 Very few of his current patients suffer from CDH. Tr. 309.

He teaches neurologic topics, particularly disorders of the spinal cord and strokes.

Tr. 313. He also has administrative responsibilities, including serving on one of

UCLA’s institutional review boards, which authorizes research projects involving

human beings. Tr. 311.

The Secretary requested that Dr. Alexander be recognized as an expert in

adult neurology. Ms. McGuire did not object. Tr. 314-15.

Although Dr. Alexander qualifies as an expert in neurology, his background

does not match the subject of Ms. McGuire’s case perfectly. She suffers from

some form of CDH and Dr. Alexander specializes in treating other neurologic

maladies that afflict adults. Thus, much like Dr. Weig, there appears to be a small,

yet noticeable, gap between the doctor’s specialty and Ms. McGuire’s illness. This

gap does not disqualify Dr. Alexander from offering a reliable opinion, but if Ms.

McGuire’s case required expertise specifically on headaches, then it was not

apparent that Dr. Alexander would be of much assistance.

Apart from the slight discordance in background, another flaw in Dr.

Alexander’s presentation was a series of missteps in his reports. In his reports, Dr.

Alexander suggested that various factors other than the HPV vaccine, such as her

use of SSRI,6 oral contraceptives, and analgesics, caused Ms. McGuire’s

headaches. Exhibit A at 10-12; exhibit C at 8-9. However, in response to

information presented during cross-examination, Dr. Alexander modified or

retreated from some of his earlier written statements. Tr. 361-91. Thus, Dr.

Alexander is encouraged to use more care in how he writes his reports in the

future.

Opinion. Dr. Alexander wrote three reports. Exhibits A, C, E. A significant

topic was the assertion that Ms. McGuire’s headaches were new daily persistent

headaches. As noted in footnote 2 above, the dispute over CDH or NDPH turned

5

UCLA is building a new rehabilitative facility with 138 beds and Dr. Alexander will be

the director of that facility when it opens. Tr. 312.

6

SSRI is defined as “selective serotonin reuptake inhibitor.” Dorland’s Illustrated

Medical Dictionary 1759 (32d ed. 2012).

6

out to be academic because Ms. McGuire’s TNF theory could explain how the

HPV vaccine would cause either CDH or NDPH.

Dr. Alexander disagreed with the assertion that the HPV vaccination can

cause prolonged headaches of any type and he disagreed with the assertion that the

HPV vaccination caused Ms. McGuire’s headaches. He noted that the cause of

these headaches is unknown.

Dr. Saxon

Background. Dr. Saxon described himself as a “physician-scientist.” Tr.

567. He graduated from medical school in 1972. He completed a post-doctorate

fellowship in immunology at UCLA in 1977, and became a professor at UCLA.

While at the institution, he started the division of immunology within the

department of medicine. Tr. 577.

He is board-certified in internal medicine, immunology, and diagnostic

laboratory immunology. Tr. 569. His research has focused on immunologic

concepts and he has written nearly 200 articles that have appeared in peer-

reviewed publications. Tr. 578. In the 1970s, as part of the litigation involving the

swine flu vaccine, judges appointed him to advise them. Tr. 582, 678-79.

Dr. Saxon currently spends about 15 percent of his time on medical-legal

matters. Tr. 571. Most of his time is spent on biomedical research for companies.

Since his retirement from UCLA in 2006, he rarely sees any patients and the

patients whom he sees have severe immunologic diseases. Tr. 570.

Dr. Saxon was qualified as an expert in immunology and diagnostic

immunology. His testimony demonstrated that among the people who testified, he

was the most knowledgeable about immunology and diagnostic immunology. The

precision with which he answered questions suggested that he understood and

could explain subtle points about immunology. His presentation was thoughtful

and engaging.

The one place where Dr. Saxon arguably went awry concerns the disclosure

of his opinions. In his testimony, Dr. Saxon described how he investigated the

reference levels reported in the Rozen and Swidan article discussed below. Dr.

Saxon did not disclose his opinions in a report before trial and he should have

given Ms. McGuire’s attorney and Dr. Swidan an opportunity to prepare for this

testimony. However, Ms. McGuire did not move to strike the testimony during the

hearing and neither Ms. McGuire’s attorney nor Dr. Swidan requested an

opportunity to respond after the hearing. Thus, any procedural deficiencies

7

associated with a lack of notice are considered waived. Nevertheless, Dr. Saxon is

instructed to be mindful about the requirement to disclose opinions in advance of

the trial.

Opinion. Dr. Saxon wrote three reports. Exhibits D, F, I. The first report

was a general response to Dr. Weig’s opinion that the HPV vaccine can cause

prolonged headaches. Dr. Saxon asserted that the HPV vaccinations did not

contribute to Ms. McGuire’s headaches. Dr. Saxon addressed two aspects of Dr.

Weig’s opinion: the potential role of TNF in headaches as reported in the Rozen

and Swidan article and the HPV vaccine’s ability to prompt the production of TNF

as discussed in the Pinto article. Exhibit D.

Dr. Saxon’s next two reports addressed more narrow topics. In exhibit F, he

challenged Dr. Swidan’s qualifications to opine on immunology. This topic is

explored in more detail below. In Dr. Saxon’s last report, he responded to Dr.

Weig’s opinion regarding timing. Exhibit I.

Dr. Swidan

Background. The final expert is Dr. Swidan. Because her background is

unusual for an expert who testifies in the Vaccine Program, her education, training,

and experience is described in a bit more detail.

After starting her college education at Eastern Michigan University, Dr.

Swidan completed four years of study at the University of Michigan, where she

received a Doctorate of Pharmacy degree. Exhibit 39 (C.V.) at 1; Tr. 433. A

doctorate in pharmacy is not the same as a Ph.D. in pharmaceutical sciences. Tr.

450-52.7 In obtaining her doctorate in pharmacy, Dr. Swidan studied

pharmacology. Tr. 434. Pharmacology is “the science that deals with the origin,

nature, chemistry, effects, and uses of drugs; it includes pharmacognosy,

pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology.”

Dorland’s Illustrated Medical Dictionary 1425 (32d ed. 2012); accord Tr. 460-62.

Dr. Swidan also learned about immunology, including “antibiotics, antivirals, [and]

vaccines.” Tr. 435.

7

The Secretary’s cross-examination of Dr. Swidan brought out the distinction between a

doctorate of pharmacy and a Ph.D. in pharmacology. Ms. McGuire’s counsel’s error in

characterizing Dr. Swidan’s degree appears inadvertent. See Tr. 433-34, 449.

8

Dr. Swidan’s training to earn a doctorate in pharmacy emphasized clinical

aspects of pharmacology. (In contrast, people pursuing a Ph.D. in pharmaceutical

sciences conduct more research in laboratories.) Tr. 451. Clinical pharmacology,

in turn, concerns “help[ing] the physicians make smarter decisions about drug

therapy.” Tr. 469. Clinical pharmacologists provide this assistance by knowing

about the individual patient, confirming that the correct drug was prescribed at the

correct dose, and “monitoring for any adverse effects.” Id.

After graduating with her doctorate in pharmacy, Dr. Swidan completed a

fellowship in biopharmaceutics. Exhibit 39 at 1; Tr. 435. In that position, Dr.

Swidan designed clinical trials and wrote reports about the results. Tr. 435-37;

exhibit 39 at 11-12 (listing articles).

After Dr. Swidan completed her post-graduate training, she became the

clinical coordinator at Chelsea Community Hospital. This hospital is located in a

town of about 5,000 people and is affiliated with the larger University of Michigan

Health System. Tr. 437-38, 453. Within the Chelsea Community Hospital, an

inpatient unit treated people with head and general pain. Dr. Swidan described this

as a tertiary care center to which people with refractory headaches from around the

world are referred. Tr. 447-48.

Dr. Swidan joined the team who made daily rounds. Tr. 438. When going

on rounds, “the physicians taught more disease and diagnosis and neurological

type syndromes.” Tr. 446. As discussed during cross-examination, Dr. Swidan

worked under supervision of a doctor and could not diagnose a patient. Tr. 452,

475. On rounds, Dr. Swidan taught “the pharmacology, treatment of pain

syndromes, head pain, some of the reactions, [and] some of the

pharmocogenetics.” Tr. 446.

Dr. Swidan described “head pain and pain management” as her “clinical

interest and love.” Tr. 443. Dr. Swidan, as part of a team, has written articles and

book chapters about head pain and headache management. Tr. 445, 458; see also

exhibit 39 at 11-13. Dr. Swidan’s co-authorship of a paper about TNF and chronic

headaches led to her retention as an expert witness in this case and there is

extensive discussion about that paper in section I.B.3(a), below.

Dr. Swidan stated that she “do[es] 60 to 100 lectures a year in general

around the country and internationally in mainly pain management, head pain and

neurological conditions,” Tr. 444, although her curriculum vitae lists considerably

fewer “invited presentations.” Her curriculum vitae indicates that she has made

9

presentations to the Michigan Pharmacists’ Association about CDH and to the

American Academy of Neurology. Exhibit 39 at 6, 8; see also Tr. 543-44.

In 2007, she stopped working at Chelsea Community Hospital and opened a

business called Pharmacy Solutions. She attempts to bring her experience as a

clinical pharmacist in a hospital to a larger audience. Tr. 441.

In addition to operating Pharmacy Solutions, Dr. Swidan is also a clinical

associate professor of pharmacy at the College of Pharmacy at the University of

Michigan. Exhibit 39 at 2. Her teaching focuses on neurology and pain

management. Tr. 441-42. In the context of asking Dr. Swidan about her

responsibilities as a professor, Ms. McGuire inquired about Dr. Swidan’s teaching

about pathophysiology. Tr. 442-43.

Dr. Swidan’s knowledge about how diseases, particularly headaches, arise is

a point of particular controversy. Dr. Swidan explained that as a professor, she

teaches pharmacology students “the physiology, how does the body normally work

because it’s hard to understand what goes wrong if you don’t understand how the

body normally works.” She continued that she reviews “pathophysiology . . . what

happens to the body in disease state and then how can we treat the disease.” Tr.

443.

When Ms. McGuire attempted to build on this foundation by asking Dr.

Swidan to explain how vaccines can cause persistent headaches, the Secretary

argued that Dr. Swidan lacked the qualifications to offer an opinion about the

cause of headaches. Tr. 474-75. The Secretary maintained that although Dr.

Swidan was on a team that treated headache patients, Dr. Swidan did not have the

knowledge to comment on the cause of the headaches:

[Dr. Swidan] always makes her determination with the

assistance of a medical doctor with specialized

knowledge in the condition. And they inform her of the

diagnosis. They inform her of the pathophysiology and

then ask her for treatments -- recommendations on

treatments.

So, she constantly uses the term “we” and then she

assumes the entire knowledge of the team that she is on,

despite the fact that she plays a particular role on that

team. So, that, I think, is where we’re starting to cross

over to impute on Dr. Swidan the entire knowledge of the

10

teams that she works on, despite the fact that she doesn’t

have their qualifications or expertise. And that’s what

I’m trying… to explain there’s a difference between the

two.

Tr. 477-78.

After the Secretary raised this objection, Dr. Swidan further elaborated upon

her training and experience. She stated “it’s very important for us [professionals

with a doctor of pharmacy degree] to understand the pathophysiology” of diseases

such as asthma. Tr. 485. The Secretary did not present any testimony suggesting

that clinical pharmacists are not trained in pathophysiology.

In responding to the Secretary’s challenge to Dr. Swidan’s testimony, Ms.

McGuire asserted that Dr. Swidan is qualified to provide opinions because of her

“listening to her colleagues, from her education, her training and her background

and her specialized knowledge, and it’s based on review of the medical literature.”

Tr. 489-90. In Ms. McGuire view, the Secretary’s objection is “not a basis to

exclude her testimony, but it’s more a question of the weight that [the special

master], as a fact finder, assign to that testimony.” Tr. 490.

Dr. Swidan was permitted to present her opinions about the causes of

headaches and how a vaccination can contribute to the cause of headache. Tr. 491.

This evidentiary ruling to admit the opinion was based, in part, on her background

in headache pain. See Tr. 471.8

The Secretary’s argument regarding Dr. Swidan’s lack of qualifications

raised during the hearing echo an argument presented in a pre-hearing motion.

Before the hearing, the Secretary had filed a motion to exclude Dr. Swidan’s

opinion as unreliable pursuant to Daubert. To support this motion, the Secretary

relied, in part, on an opinion from Dr. Saxon that Dr. Swidan “does not have the

required scientific expertise to address the issues at hand and failed to employ the

8

Although Dr. Swidan was admitted as an expert in pharmacology, she was not admitted

as an expert in immunology. Dr. Swidan does not have any advanced degree in immunology.

Tr. 457. She also could not respond to some questions about immunologic concepts. Tr. 458-59.

Dr. Saxon later described this knowledge as “basic” enough that a “first-year graduate student”

would have. Tr. 648. The ruling that Ms. McGuire had not shown that Dr. Swidan was qualified

in immunology did not prevent Ms. McGuire from asking Dr. Swidan any questions. Dr. Swidan

answered every question that Ms. McGuire asked. In other words, no testimony was excluded.

11

proper scientific approach and methodology in reaching her conclusions.” Exhibit

F at 1-2. While that motion was pending, the Federal Circuit indicated that a

special master should not give less weight to a person with a Ph.D. in immunology

than a person who graduated from medical school. Koehn v. Secʼy of Health &

Human Servs., 773 F.3d 1239, 1244 (Fed. Cir. 2014). In accord with Koehn, the

Secretary’s motion to exclude Dr. Swidan’s testimony was denied. Order, issued

Feb. 19, 2015.

Now, having heard Dr. Swidan’s testimony, the undersigned may comment

that Dr. Swidan’s opinion was not very helpful. Dr. Swidan delivered much less

than was promised. Ms. McGuire retained Dr. Swidan to counter the opinion of

Dr. Saxon, the immunologist whom the Secretary retained, and to present

information about the paper she co-authored with Dr. Rozen. On immunology, the

contest between Dr. Swidan and Dr. Saxon was not close. Dr. Saxon possesses

expertise in immunology, as reflected in his status as a board-certified internist,

clinical immunologist and diagnostic immunologist, that Dr. Swidan lacks. Tr.

569. Dr. Saxon explained relatively sophisticated immunologic concepts in a way

that is consistent with someone who has practiced medicine as an immunologist

and taught immunology for more than 35 years. In contrast, Dr. Swidan’s

testimony was often conclusory. The lack of support was particularly glaring when

Dr. Swidan attempted to demonstrate that her education (a Ph.D. in

pharmacology), and her experience (20 years as a clinical pharmacist) qualified her

to opine on the causes of diseases. Although Dr. Swidan and Ms. McGuire’s

attorney consistently pressed the idea that Dr. Swidan’s responsibilities as a

clinical pharmacist require her to understand the pathogenesis of diseases, they

failed to persuade me, the trier of fact, that Dr. Swidan possesses sufficient

knowledge about the causes of relevant diseases that would make her testimony

useful.9

Dr. Swidan’s relative lack of knowledge carried over to the other topic about

which she was expected to possess some mastery --- the article about TNF and

headaches. Dr. Swidan could not answer many questions about the article that she

co-authored, repeatedly saying that Dr. Rozen was responsible for that section. To

9

Given that the Secretary had filed a motion to exclude Dr. Swidan’s testimony before

the hearing, it was incumbent on Ms. McGuire’s attorney to establish a solid foundation for Dr.

Swidan’s expertise. Ms. McGuire’s attorney’s examination into Dr. Swidan’s background left

many topics unexplained.

12

some degree, Dr. Saxon’s failure to disclose his specific criticisms about the Rozen

and Swidan article in advance of the hearing placed Dr. Swidan at a disadvantage.

Nevertheless, Dr. Swidan should have been prepared to talk in-depth about the

article because (a) the article was one of the two articles most important to Ms.

McGuire’s case, and (b) Dr. Swidan was retained specifically because she co-wrote

that article.

In short, although Dr. Swidan contributed some meaningful information as

the citations to her testimony demonstrate, Dr. Swidan fell significantly short in

testifying on the topics critical to Ms. McGuire’s claim. In the future, an attorney

representing a petitioner should consider the strengths and weaknesses in Dr.

Swidan’s background before retaining her to testify in the Vaccine Program.

Opinion. Dr. Swidan wrote two reports. Exhibit 38 set forth her basic

opinion – that the HPV vaccination caused an inflammatory response in Ms.

McGuire and this inflammatory response caused her to have headaches. Dr.

Swidan emphasized the role of TNF in headaches. In her second report, Dr.

Swidan, after reviewing Dr. Saxon’s criticism of both her background and her

opinion, confirmed her opinion that the HPV vaccination caused Ms. McGuire’s

headache. Exhibit 41.

Ms. McGuire’s Medical Background

The October 12, 2012 Revised Findings of Fact resolved one critical aspect

of this case: when Ms. McGuire’s headaches began. During most of the litigation,

the details about Ms. McGuire’s headaches seemed important because Dr. Weig

stated that she suffered from NDPH and Dr. Alexander, in contrast, opined that she

suffered from CDH. Exhibit 28 (Dr. Weig); exhibit A (Dr. Alexander). However,

this dispute about diagnosis turned out to be insignificant because Ms. McGuire’s

experts presented a theory through which the HPV vaccine can cause either NDPH

or CDH. See Resp’t’s Status Rep., filed Mar. 11, 2015. Eliminating the arguments

about diagnosis simplifies Ms. McGuire’s case. Many of the details about the

quality, duration, location, and intensity of her headaches are not material.

Consequently, this decision discusses Ms. McGuire’s medical records relatively

summarily, although the medical records themselves have been reviewed

thoroughly.

Health before Vaccination

Ms. McGuire was born in 1987. Exhibit 2 at 1. Her father suffered from

cluster headaches at least once. Exhibit 4 at 1; Tr. 85, 99. Dr. Alexander asserted

13

that Ms. McGuire’s genetic background may have contributed to her headaches.

Tr. 325.

In 2003, Ms. McGuire sought treatment for a panic disorder. She was

prescribed Zoloft. Exhibit 22 at 130-31, 126; see also Tr. 34-35. Ms. McGuire

continued to take Zoloft until the summer 2004. But, after she stopped taking

Zoloft, her anxiety returned and she resumed the prescription. Exhibit 22 at 118-

22.

In August 2006, Ms. McGuire saw Robert M. Levenson, her pediatrician.

Ms. McGuire reported that she had returned from a cruise to Bermuda slightly

more than two weeks earlier. After coming home, Ms. McGuire had a sudden

onset of frontal headaches, tiredness, malaise and an achy neck and shoulders for

two weeks. Dr. Levenson prescribed Fioricet and recommended therapeutic

massages. Exhibit 1 at 107-08; see also Tr. 30-31, 54 (Ms. McGuire’s testimony

that a medical record ostensibly referring to a headache in December 2006 was

actually referring to her August 2006 headache); cf. Tr. 328-29, 370-71, 472.

Approximately one year later in August 2007, Ms. McGuire went to an

urgent care center for anxiety and panic attacks. She also reported symptoms of

depression after stopping Zoloft in January that year. The doctor prescribed

lorazepam. Exhibit 1 at 93-94.

In September 2007, Ms. McGuire was working as a medical assistant for

Harvard Vanguard Medical Associates. Exhibit 21 (employment records) at 1; see

also Tr. 9, 103 (describing duties). She was also attending nursing school in the

evening. Exhibit 20 (school records). She described herself as “healthy and

active.” Exhibit 17 (affidavit) at 1; accord Tr. 9-10.

On September 20, 2007, Ms. McGuire saw Laura Tremblay, her primary

care physician, for a complete physical examination. Ms. McGuire said that she

was having various gastrointestinal and gynecological complaints, but after Dr.

Tremblay’s review, she said all other systems were negative. At this appointment,

Ms. McGuire received the first dose of the HPV vaccine. Exhibit 1 at 88-89; see

also Tr. 36.10

10

Ms. McGuire averred that after receiving the vaccination, she left work because she felt

ill. Specifically, she had a fever and headache, was nauseated, and vomited. Exhibit 17 at 1; Tr.

(continued…)

14

Health after Vaccination

Between October 25 and October 28, 2007, Ms. McGuire began having

headaches that were initially intermittent. One week after the headaches began,

Ms. McGuire’s headaches became constant. Revised Findings, issued Oct. 12,

2012. Ms. McGuire took over-the-counter medications, which did not help.

Nonetheless, she continued to work and to attend school. Tr. 11-12.

On November 14, 2007, Ms. McGuire received the second dose of the HPV

vaccine. Exhibit 1 at 86. Approximately four months later, Ms. McGuire told her

neurologist that there “was no change in her headache after the second vaccine.”

Id. at 54; see also Tr. 73; cf. Tr. 222.11 On November 20, 2007, Ms. McGuire had

a nutrition assessment. Exhibit 1 at 86; Tr. 47.12

Ms. McGuire recalled that after having a headache for many weeks, she

became concerned that her headache had not stopped. In addition, the severity was

increasing. Tr. 14-15, 52. Therefore, on December 9, 2007, she went to seek

assistance at an urgent care facility associated with her employer, Harvard

Vanguard Medical Associates. Tr. 15. She stated that she had been having

headaches for six weeks before her appointment. Exhibit 1 at 83-84; see also Tr.

47-48. In terms of a more recent history, Ms. McGuire’s report appears to be

11, 37-39, 119. She made similar statements to doctors treating her months later. See exhibit 1

at 54 (Mar. 20, 2008); exhibit 3 at 77 (Apr. 23, 2008).

Ms. McGuire’s experts did not mention her illness on September 20, 2007. Exhibit 28

(Dr. Weig’s rep.) at 1; exhibit 38 (Dr. Swidan’s rep.) at 3. However, Dr. Swidan did briefly

testify that Ms. McGuire “was sick with a febrile illness” and that the blood-brain barrier can be

leaky in sick patients. Tr. 526.

11

Ms. McGuire testified that about a week and a half after the second dose of HPV

vaccination, her headaches changed from intermittent to constant. Tr. 13, 43-44, 91-92, 123-24.

However, her recollection is not consistent with several medical records that do not mention a

change in her headache quality or frequency after the second dose of the HPV vaccine. See

exhibit 1 at 46 (record dated May 17, 2008), 54 (record from March 20, 2008); exhibit 3 at 73-76

(record dated June 17, 2008); see also Tr. 222-24, 340-43; but see exhibit 11 at 12 (record dated

Aug. 31, 2009); Tr. 299.

12

Ms. McGuire did not discuss her headaches with the dietician. In Dr. Alexander’s

opinion, this omission is inconsistent with a claim that she was suffering from severe headaches.

Tr. 335-36, 402. In contrast, Dr. Weig did not perceive any inconsistency because people would

not normally talk to a dietician about their headaches. Tr. 423.

15

inconsistent. At one place, Ms. McGuire said that, “for the past two weeks” (that

is, starting around Thanksgiving), she was feeling frontal pressure. Exhibit 1 at 83;

see also Tr. 51-52; cf. exhibit 3 at 3 (a Dec. 23, 2007 emergency department record

suggesting frontal headaches started four weeks earlier); Tr. 60-61 (Ms. McGuire’s

testimony about the Dec. 23, 2007 record); Tr. 215. Yet, later within the same

paragraph, Ms. McGuire stated that “Symptoms have not accelerated, and there

was no change in location or quality in the past 2 weeks.” Exhibit 1 at 83; see also

Tr. 219, 337.

While hospitalized, Ms. McGuire underwent many tests, including a lumbar

puncture and MRIs. Exhibit 1 at 72-74. After the lumbar puncture, her headaches

worsened. Id. at 73; see also Tr. 218-19 (Dr. Weig), 340 (Dr. Alexander).

For the remainder of December 2007 and continuing into January 2008, Ms.

McGuire saw many doctors for her headaches and those doctors prescribed a

variety of pharmaceuticals. The attempted interventions did not provide any

lasting relief. See exhibit 1 at 63-81; exhibit 3 at 17-18 (admission to the

emergency room), 80-81 (discharge); Tr. 16-21, 53-68.13

Throughout 2008, Ms. McGuire visited several more doctors but they did

not help alleviate her symptoms. Some of these histories indicate that Ms.

McGuire’s first HPV vaccination preceded the onset of her headaches in October

2007. However, none of these doctors stated that the vaccination caused her

headaches. See exhibit 1 at 54-55; exhibit 3 at 78-79; exhibit 5 at 2; exhibit 1 at

46-47, 36-37; exhibit 3 at 32-34; exhibit 9 at 8; exhibit 3 at 66-67; see also Pet’r’s

Preh’g Br. at 34-36 (quoting medical records).

During a hospitalization in 2008, a doctor prescribed a short course of

prednisone. Exhibit 1 at 41, 46-47; see also Tr. 196, 355, 474. Prednisone is a

“synthetic glucocorticoid… [used] as an antiinflammatory and immunosuppressant

in a wide variety of disorders.” Dorland’s at 1508. Ms. McGuire later informed

her doctors that the course of prednisone did not help her headaches and may have

made them worse. Exhibit 3 at 70 (Dr. Klein’s letter, dated July 30, 2008); exhibit

13

Ms. McGuire’s (over)use of medication likely contributed to the continuation of her

headaches. Tr. 206, 269, 322-25, 393. Because Ms. McGuire started taking medication after her

headaches became chronic, the Secretary has not argued that Ms. McGuire’s use of medication

caused her headaches. Tr. 394.

16

12 at 3 (report, dated Dec. 10, 2008); exhibit 13 at 1 (Dr. Herzog’s letter, dated

Aug. 16, 2010).

On January 15, 2009, Ms. McGuire went to the Osher Clinical Center for

Complementary and Integrated Medical Therapies, where she saw Donald Levy,

M.D. Dr. Levy stated that because Ms. McGuire “never had headaches before the

HPV vaccination,” there was a causal connection between the vaccination and the

headache. Exhibit 12 at 9; see also Tr. 191-92, 268, 411-13.

In the remainder of 2009, Ms. McGuire saw doctors less frequently. Exhibit

2 at 2; exhibit 8 at 4; exhibit 11 at 3, 12-13; exhibit 16 at 13-15.

On July 13, 2010, Ms. McGuire saw Andrew Herzog, M.D. at the

Neuroendocrine Associates at Harvard Medical School. She stated that her

headaches started “within 2 hours of the [HPV vaccine] injection.” Exhibit 13 at

12. She also said that before the vaccination, she had never had headaches. Dr.

Herzog stated that although headaches have been reported to follow HPV

vaccinations, a long-lasting headache would be unusual. He suggested an

evaluation for an immune-mediated process. Id. at 13; see also Tr. 190. However,

this investigation did not reveal any abnormalities that would cause headaches.

Exhibit 13 at 5-11; see also Tr. 266, 412-13.

Despite the continuing problems with headaches, Ms. McGuire graduated

from nursing school in December 2010. She passed her examinations in March

2011, and became a registered nurse. Exhibit 35 (Ms. McGuire’s affidavit,

describing her employment history) at 1; Tr. 22. She worked as a registered nurse

for approximately two years, but then her headaches prevented her from working.

Exhibit 35 at 2; see also Tr. 23, 107.

Standards for Adjudication

A petitioner is required to establish her case by a preponderance of the

evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence

standard requires a “trier of fact to believe that the existence of a fact is more

probable than its nonexistence before [he] may find in favor of the party who has

the burden to persuade the judge of the fact’s existence.” Moberly v. Sec’y of

Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations

omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health &

Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991).

Distinguishing between “preponderant evidence” and “medical certainty” is

important because a special master should not impose an evidentiary burden that is

17

too high. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1379-80

(Fed. Cir. 2009) (reversing special master’s decision that petitioners were not

entitled to compensation); see also Lampe v. Sec’y of Health & Human Servs., 219

F.3d 1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Human Servs., 9 F.3d

958, 961 (Fed. Cir. 1993) (disagreeing with dissenting judge’s contention that the

special master confused preponderance of the evidence with medical certainty).

The elements of Ms. McGuire’s case are set forth in the often cited passage

from the Federal Circuit’s decision in Althen: “(1) a medical theory causally

connecting the vaccination and the injury; (2) a logical sequence of cause and

effect showing that the vaccination was the reason for the injury; and (3) a showing

of a proximate temporal relationship between vaccination and injury.” Althen v.

Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005).

Analysis

The three prongs of the Althen test are evaluated in separate sections below.

The order of presentation begins with theory, which outlines petitioner’s proposed

theory and the relevant evidence and case law. The next issue is the timing and the

last factor is the “logical sequence of cause and effect.” Each section analyzes the

evidence (medical records, testimony and medical literature) in relation to the

relevant precedent.

I. Theory

The first Althen prong requires “a medical theory causally connecting the

vaccination and the injury.” 418 F.3d at1278. Because Ms. McGuire’s injury is

chronic headaches, basic information about headaches is provided as a foundation.

Against this backdrop, Ms. McGuire bears the burden of presenting a theory to

explain how the HPV vaccine can cause chronic headaches. Veryzer v. Sec'y of

Health & Human Servs., 100 Fed. Cl. 344, 355 (2011), aff'd per curiam, 475 F.

App'x 765 (Fed. Cir. 2012).

Ms. McGuire attempted to meet her burden in two ways. As explained in

section B below, Ms. McGuire presented evidence – testimony from Dr. Weig and

Dr. Swidan. In addition, as explained in section C below, Ms. McGuire presented

an argument based on a recent case from the Federal Circuit.

18

A. Overview of Primary Headaches

Medical science does not know the cause of primary headaches.14 See

exhibit 38, tab U (Rozen and Swidan) at 1053 (stating the “pathogenesis of NDPH

is unknown”), exhibit 40, tab C (Sanjay Prakash & Nilima Shah, Post‐infectious

New Daily Persistent Headache May Respond to Intravenous Methylprednisolone,

J. Headache Pain 2010; 11:59‐66) at 59 (stating that for NDPH, the

“pathophysiology is largely unknown”), Tr. 317.

However, there are some generally accepted beliefs about the pathogenesis

of primary headaches. A vastly simplified summary is that a headache begins with

some irritant to the trigeminal nerve.15 Once the trigeminal nerve is disturbed, the

body produces various substances, including calcitonin gene-related peptide

(CGRP), that perpetuate a cycle. Tr. 317-18, 476, 491-93.

Many aspects about the etiology of chronic headaches are undetermined.

For example, scientists have not identified the initial trigger (or triggers).

Scientists have recognized that infections, surgery, and stressful life events

sometimes precede the onset of chronic headaches. Exhibit 38, tab U (Rozen and

Swidan) at 1053; exhibit 40, tab C (Prakash) at 59 (abstract). However, these

preceding factors have not been determined to be causes of the headaches. Tr.

682-83 (Saxon).

In addition to the uncertainty about the cause of headaches, there are

questions about why a headache is prolonged. Commonly, headaches resolve after

a few hours and/or after medications. The headaches that Ms. McGuire suffers

differ in that they are chronic and refractory to treatment. The factor or factors

contributing to the headache’s chronicity and resistance to treatment are

undetermined. Tr. 495-96.

A current theory is that CGRP is part of a cycle with the cytokine TNF.

Cytokines are proteins that a cell releases to communicate with another cell during

14

Primary headaches are not the same as secondary headaches. Secondary headaches are

headaches associated with another disorder, such as meningitis. Tr. 153, 316, 602-03.

15

The trigeminal nerve, which is also known as the fifth cranial nerve, is a sensory nerve

for the face, teeth, mouth, and nasal cavity. It is also the motor nerve for chewing. Dorland’s at

1260; see also Dorland’s at 1246 (illustration).

19

the generation of an immune response. Dorland’s at 466; see also Tr. 179, 350,

606. Although Dr. Weig characterized TNF as a proinflammatory cytokine, Tr.

179, Dr. Saxon disagreed. Dr. Saxon asserted that TNF is used in more than 100

biologic activities. Tr. 606. Dr. Saxon supported his view that TNF is not always

a proinflammatory cytokine by pointing to the Pinto article, which is discussed in

more detail below. Tr. 631-35, citing exhibit D, tab 16 (Ligia Pinto et al., HPV-16

L1 VLP Vaccine Elicits a Broad-Spectrum of Cytokine Responses in Whole

Blood, 23 Vaccine 3555 (2005)).16

B. Evidence relating to HPV Vaccines Causing Headaches

Ms. McGuire presented testimony from Dr. Weig and Dr. Swidan that the

HPV vaccine can cause headaches. Tr. 177, 509-11. The theory Ms. McGuire

proposes seems to contain at least three distinct steps. First, the HPV vaccine

promotes the production of various cytokines, including TNF. Second, from the

body’s periphery, TNF crosses the blood brain barrier to reach the central nervous

system. Third, in the central nervous system, TNF causes inflammation producing

headaches. See Pet’r’s Preh’g Br. at 17-18.

1. Does the HPV Vaccine Promote the Production of TNF?

The first step in the petitioner’s theory is the administration of the HPV

vaccine increases the level of TNF. For this proposition, Dr. Weig and Dr. Swidan

rely upon the Pinto article. Exhibit 28 (Dr. Weig) at 4; Tr. 179, 253 (Dr. Weig),

516 (Dr. Swidan).

In the Pinto experiment, blood from women was drawn and tested to set

baseline measuring points. Then, some women received a dose of a vaccine

against some strains of the human papillomavirus (but not the same vaccine as Ms.

McGuire received) and some women received a placebo. The participants received

another dose or placebo one month later; one month after the second dose, the

researchers drew a second sample of the women’s blood. The women received a

third dose of the vaccine (or placebo) and after waiting another month, the

researchers drew a third sample. Exhibit D, tab 16 (Pinto) at 3556.

16

In addition to the literature, another reason for crediting Dr. Saxon over Dr. Weig is

that Dr. Saxon specializes in immunology. Dr. Weig stated that he would defer to an

immunologist. Tr. 279.

20

The blood samples were cultured in vitro for 24 hours and then the amount

of cytokines was measured. The testing showed that the women who received the

vaccine produced higher amounts of TNF than the women who did not. Tr. 632-41

(Dr. Saxon). This result is not surprising because the vaccine is designed to

prompt a response from the immune system. Tr. 511 (Dr. Swidan). Thus, the

Pinto experiment supports one aspect of the petitioner’s theory: HPV vaccine

elevates the amount of TNF.

However, there are two problems with how Ms. McGuire seeks to employ

the Pinto article. The first, and less significant, issue is that the Pinto experiment

was conducted in vitro, not in vivo. Tr. 258, 643. An extrapolation from a petri

dish to human beings may be reasonable, but there needs to be some basis for the

extrapolation. “As a general matter, it may be that in vitro tests are not reliably

predictive of human safety.” Bristol-Meyers Squib Co. v. Teva Pharma. USA,

Inc., 769 F.3d 1339, 1355 n.5 (Fed. Cir. 2014) (Taranto, J.) (dissenting from denial

of reh’g en banc) (citing Reference Manual on Scientific Evidence). In other

cases, special masters have commented on the problems with using in vitro studies.

See Kolakowski v. Sec'y of Health & Human Servs., No. 99-625V, 2010 WL

5672753, at *85-86 (Fed. Cl. Spec. Mstr. Nov. 23, 2010); Dwyer v. Sec'y of Health

& Human Servs., No. 03-1202V, 2010 WL 892250, at *131-32 (Fed. Cl. Spec.

Mstr. Mar. 12, 2010). Ms. McGuire did not provide a reliable reason for making a

jump of this kind.

The second and more significant issue concerns the amount of TNF

produced in the Pinto experiment. As Dr. Saxon pointed out, the Pinto authors did

not conclude that the amount of cytokine produced was pathologic. Tr. 643-44.

Some evidence regarding the amount of TNF produced as part of a normal reaction

to a vaccine compared to an adverse reaction to a vaccine would have been helpful

because Dr. Weig’s theory asserts that the HPV vaccine caused an “excessive”

amount of TNF. Tr. 281. This assertion is particularly unsupported because Dr.

Weig admitted that he did not know the amount of TNF that was required to cause

a disease. Tr. 247.

While the lack of support for Dr. Weig’s opinion is problematic for Ms.

McGuire, the Secretary introduced evidence contradicting the assertion that the

amount of cytokines produced was pathologic. This evidence was the most recent

report on vaccines and adverse reactions from the Institute of Medicine (“IOM”).

Exhibit D, tab 4 (Kathleen Stratton et al., Adverse Effects of Vaccines: Evidence

and Causality, Institute of Medicine (2012)). Due to the credentials and expertise

of the members of the Institute of Medicine, special masters have consistently

placed great weight on their reports and appellate courts have consistently found

21

the crediting of these reports not arbitrary. See Porter v. Sec'y of Health & Human

Servs., 663 F.3d 1242, 1252–54 (Fed. Cir. 1993) (2002 report); Cucuras v. Sec'y of

Health & Human Servs., 993 F.2d 1525, 1529 (Fed. Cir. 1993) (1991 report); Isaac

v. Sec'y of Health & Human Servs., 108 Fed. Cl. 743, 768–74 (2013), aff’d, 540 F.

App’x 999 (Fed. Cir. 2013) (2011 pre-publication report); Terran v. Sec’y of

Health & Human Servs., 41 Fed. Cl. 330, 337 (1998) (1991 report and different

1994 report), aff’d, 195 F.3d 1302, 1317 (Fed. Cir. 1999); Kelley v. Sec’y of

Health & Human Servs., 68 Fed. Cl. 84, 91 n.11 (2005) (1994 report); Kuperus v.

Sec’y of Health & Human Servs., No. 01–60V, 2003 WL 22912885, at *10 (Fed.

Cl. Spec. Mstr. Oct. 23, 2003) (1994 report). In its most recent report, the IOM

found “no evidence that directly or indirectly supports the oversecretion of

cytokines as an operative mechanism.” Exhibit D, tab 4 (Stratton) at 76 [pdf 3].

Ms. McGuire introduced no persuasive evidence to rebut the IOM’s conclusion

that no evidence supports a conclusion that cytokines cause a disease.

2. Does TNF Cross the Blood Brain Barrier?

Because the HPV vaccine is given intramuscularly (exhibit 19 at 2), the

initial reaction whereby the cytokine TNF is recruited occurs near the site of

injection. Exhibit 38 (Dr. Swidan’s report) at 9. To reach the brain, the TNF must

enter the bloodstream and cross the blood brain barrier. The blood brain barrier

separates the vital parts of the central nervous system from the blood and contains

anatomical and physiological components. Dorland’s at 201. The mechanism by

which TNF penetrates the blood brain barrier is unclear. Exhibit 28 (Dr. Weig’s

report) at 4.

The Secretary’s cross-examination of Dr. Swidan revealed that the crossing

of the blood brain barrier was a second step in her theory. Tr. 525-26. However,

how TNF would cross the blood brain barrier was not explained very well. Dr.

Weig admitted that TNF would not easily cross the blood brain barrier. Tr. 181.

Dr. Swidan proposed that a rise in TNF in the body’s periphery could cause

the blood brain barrier to become leaky. Tr. 562. She further asserted that the

fever Ms. McGuire experienced within two days of the vaccination was evidence

of a systemic reaction. Tr. 526.

However, the medical doctors did not agree with Dr. Swidan. Dr. Weig, as

noted above, asserted that the TNF does not easily cross the blood brain barrier.

Even after hearing Dr. Swidan’s testimony, Dr. Weig acknowledged that he did not

know whether TNF creates permeability in the blood brain barrier. Tr. 709.

22

Likewise, Dr. Saxon stated that he had never heard of a leaky blood brain barrier.

Tr. 692-93.

Whether cytokines can cross the blood brain barrier appears to be a topic on

which medical doctors, especially a neurologist like Dr. Weig, would have more

training and experience than a pharmacologist. Dr. Swidan presented no support

for her assertion that TNF can cross the blood brain barrier. Thus, her opinion on

this point lacks reliability, undermining Ms. McGuire’s proof on prong one.

3. Does TNF Contribute to Headaches?

The final step in Ms. McGuire’s theory concerns what happens after TNF

crosses the blood brain barrier and enters the central nervous system. On this

point, Dr. Weig’s and Dr. Swidan’s opinions were unclear. At times, they seemed

to suggest that TNF caused the headache. Exhibit 28 at 4 (Dr. Weig’s Rep.) (TNF

increases production of peptide (CGRP) implicated in migraine pathogenesis);

exhibit 30 at 5 (Dr. Weig’s Supp’l Rep.) (“Elevated TNF alpha appears to be a

causative agent for multiple forms of headache.”); exhibit 38 at 12 (Dr. Swidan’s

Rep.) (TNF induces CGRP, a known factor in migraine pathogenesis); Tr. 516-17

(Dr. Swidan). At other times, they seemed to suggest that TNF only made a

headache worse (either in duration or severity). Tr. 704-05 (Dr. Swidan) (TNF

“amplifies” CGRP production; Tr. 202-04 (Dr. Weig) (headaches “substantially…

worsened” after second HPV vaccine); see also Tr. 614-17 (Dr. Saxon).

Ms. McGuire’s pre-trial brief identified an article whose authors are Dr.

Rozen and Dr. Swidan as the primary basis for the theory that TNF contributes to

headaches. Pet’r’s Preh’g Br. at 26 (stating “the two articles of utmost importance

to [Ms. McGuire’s] theory [are] the Pinto article… and the Rozen and Swidan

article”). However, for the reasons explained below, Ms. McGuire’s reliance on

the Rozen and Swidan article is misplaced. Nevertheless, this problem is not fatal

to Ms. McGuire’s case because other evidence, including a study by Dr. Durham

and the testimony of Dr. Saxon, support a finding that TNF contributes to

headaches.

a) Rozen and Swidan

Background. Dr. Rozen and Dr. Swidan designed a study to determine

whether their patients with refractory headaches were experiencing inflammation.

After Dr. Rozen diagnosed the patients, he ordered a spinal tap. Dr. Rozen sent the

cerebrospinal fluid and a blood sample to a laboratory, ARUP Laboratories, for

23

testing. Dr. Rozen and Dr. Swidan were looking for evidence of pro-inflammatory

cytokines. Tr. 495-500, 527-30.

ARUP Laboratories determined the reference range for the presence of

cytokines in the blood and the reference range for the presence of cytokines in the

cerebrospinal fluid by testing 36 volunteers. For both substances, the reference

range was less than 8.2 picograms per milliliter (pg/mL). In the published article,

Dr. Rozen stated that ARUP Laboratories disclosed the reference ranges via a

“personal communication.” Exhibit 38, tab U (Todd Rozen and Sahar Swidan,

Elevation of CSF Tumor Necrosis Factor α Levels in New Daily Persistent

Headache and Treatment Refractory Chronic Migraine, 47 Headache 1050 (2007))

at 1051. Dr. Swidan testified that ARUP Laboratories provided the information

about reference ranges to Dr. Rozen only, not to her. Tr. 531-32.

Dr. Rozen and Dr. Swidan compared the amount of TNF in their 38 patients

with refractory headaches with the amount of TNF in 36 normal individuals as

determined by ARUP Laboratories. The amount of TNF in the serum was similar

in both groups. However, the cerebrospinal fluid from patients with refractory

headaches contained more TNF than the cerebrospinal fluid from volunteers at

ARUP Laboratories. Exhibit 38, tab U at 1051-52. Dr. Rozen and Dr. Swidan

wrote: “TNF [alpha] levels are elevated in various forms of [CDH].” Id. at 1053.

From this observation, Dr. Rozen and Dr. Swidan hypothesized that

“[p]ersistent elevation of TNF [alpha] could lead to persistent elevation of CGRP,

and thus daily head pain.” Id. Similarly, they asserted that “an increase in TNF

[alpha] levels in the CSF may play a true role in the pathogenesis of CDH.” Id. at

1054. If so, pharmaceuticals that inhibit the production of TNF [alpha] could have

“an important role in the treatment of NDPH and refractory chronic migraine.” Id.

at 1055. However, Dr. Rozen and Dr. Swidan cautioned that their work “is an

initial observation, which must be substantiated by future studies.” Id. at 1054.

Both Dr. Weig and Dr. Swidan relied upon the Rozen and Swidan study.

See exhibit 28 (Dr. Weig) at 3-4; exhibit 38 (Dr. Swidan) at 11.

Criticisms. Through Dr. Saxon, the Secretary raised several arguments

against the usefulness of the Rozen and Swidan article.

24

First, Dr. Saxon challenged the way ARUP Laboratories determined the

reference range for TNF in cerebrospinal fluid --- testing 36 healthy volunteers.17

A reference range is a set of values in which 95 percent of people fall. Tr. 624; see

also Dorland’s at 2021 (defining reference values). Dr. Saxon argued that a

reference range for a laboratory test should involve at least a few hundred

participants. Tr. 625-26. Dr. Saxon’s opinion was based upon his qualification as

a board-certified expert in internal medicine, clinical immunology and diagnostic

immunology. His opinion was not challenged at all.

Second, Dr. Saxon questioned the values in ARUP Laboratories’ reference

ranges for TNF in the serum and in the cerebrospinal fluid. Dr. Saxon indicated

that having the same reference range (< 8.2 pg/ML) is “most unusual.” Tr. 609-10.

In his experience, Dr. Saxon has never before encountered a pair of tests in which

the normal levels were the same in the blood and cerebrospinal fluid. Tr. 625.18

Dr. Swidan’s experience was similar. When asked whether she was aware of any

test in which the reference range was the same for CSF and serum, Dr. Swidan

answered: “I don’t know if I can answer that with my knowledge because that’s a

pathologist’s training. . . . And, so, there may be, but I do not know of any.” Tr.

535.

A third question of the ARUP Laboratories’ reference ranges concerned the

current reference ranges. Dr. Saxon stated that shortly before trial, he called

ARUP Laboratories to ask about the reference range for TNF. Tr. 688-89. ARUP

Laboratories told him that the reference range for TNF from the serum was less

than 22 pg/ML. Tr. 610, 625. Assuming that normal TNF levels are the same in

blood as they are in cerebrospinal fluid, then an expected CSF level would be 22

pg/ML. If this is also correct, then Dr. Rozen and Dr. Swidan did not discover

anything significant because the TNF level in all the patients was less than 22

pg/ML. In other words, the patients would fall within the reference range. Tr.

538, 627-28.

17

While healthy people may provide blood samples for testing routinely, healthy people

do not undergo spinal taps usually. See Tr. 550 (Dr. Swidan: “we can’t just spinal tap people

without valid reason”), 630 (Dr. Saxon wondering whether an internal review board would

approve a study subjecting healthy people to spinal taps).

18

Dr. Saxon’s background in diagnostic immunology gives him expertise in determining

whether tests have clinical value. Tr. 586-87.

25

Assessment. Overall, these criticisms diminish the reliability of the Rozen

and Swidan article.19 Before the hearing, Dr. Swidan’s authorship of this paper

was a stated basis for Ms. McGuire’s decision to retain her to testify about the

immunologic etiologies for chronic headaches. See Pet’r’s Preh’g Br. at 25 (“Dr.

Swidan’s testimony is offered as that of an expert in . . . specifically, the

aforementioned medical article she co-authored”). However, it is now evident that

Dr. Swidan’s role in conducting the experiments and preparing the results for

publication was limited. She did not communicate with ARUP Laboratories. Tr.

531-32. Therefore, she could not defend (or even explain) the lab’s reference

ranges. Her reliance on the work of Dr. Rozen underscored her relative lack of

experience.

Apart from these concerns about the foundations for the Rozen and Swidan

paper, there are additional problems. Dr. Rozen and Dr. Swidan recommended

that future studies substantiate their findings. Exhibit 38, tab U (Rozen & Swidan)

at 1054. However, neither Dr. Saxon nor Dr. Swidan was aware of any work that

also found elevations in TNF in patients’ CSF.20 Tr. 350-52, 699 (Dr. Saxon); Tr.

546 (Dr. Swidan). Thus, substantiation remains lacking.

Consistent with the lack of confirmation for the novel finding in the Rozen

and Swidan paper, the authors’ recommendation that doctors prescribe TNF

inhibitors to patients suffering from chronic headaches has not been followed. Dr.

Weig (Ms. McGuire’s expert) does not prescribe TNF inhibitors to his patients

19

Although Dr. Saxon had prepared reports addressing the Rozen and Swidan article (see

exhibit F at 8), he had not disclosed any criticism of the reference ranges from the ARUP

Laboratories. See exhibits D, F, I.

At hearing, when an expert attempts to present an opinion not disclosed before hearing,

the opposing party may seek to strike that testimony. E.g. Childers v. United States, 116 Fed. Cl.

486, 596-99 (2013) (granting motion to strike testimony). However, Ms. McGuire’s attorney did

not attempt to strike Dr. Saxon’s opinion during the hearing when any perceived prejudice could

have been mitigated. Consequently, Ms. McGuire’s failure to move to strike the testimony

constitutes a waiver of the argument that the Secretary had failed to disclose Dr. Saxon’s

opinions in advance of the hearing. See Vaccine Rule 8(f).

20

Dr. Saxon recognized that other articles published in peer-reviewed journals have cited

the Rozen and Swidan article. Tr. 698. While these sources have cited the Rozen and Swidan

article, these investigators have not independently verified that people who suffer from chronic

headaches have elevated TNF in the cerebrospinal fluid. Id.; Tr. 628.

26

with chronic headaches. Tr. 264. Dr. Alexander similarly does not prescribe TNF

inhibitors. Tr. 414.

Collectively, these factors undermine the value of the Rozen and Swidan

article. Although Ms. McGuire characterized this article as “peer-reviewed,

published, and well-accepted,” Pet’r’s Preh’g Br. at 26, Ms. McGuire did not

present any persuasive evidence that the article is “well-accepted.”21 In another

place, Ms. McGuire described the Rozen and Swidan article as “[r]eliable.” Id. at

17. But, Dr. Saxon’s testimony with respect to the reference ranges has called into

question the reliability of the findings in the Rozen and Swidan article. Dr. Swidan

could not answer these challenges.

b) Other Evidence

Although Ms. McGuire’s pre-hearing brief emphasized the Rozen and

Swidan article, this article provides very little, if any, support for the claim that

TNF contributes to headaches. The evidence that more persuasively assists Ms.

McGuire in connecting TNF and headaches comes from one of the Secretary’s

experts, Dr. Saxon.

Based primarily on experiments reported by Dr. Paul Durham (exhibit 28,

tab G (Paul Durham, Calcitonin gene‐related peptide (CGRP) and migraine, 46

Headache S3 (2006))), Dr. Saxon testified that TNF is part of an amplification

process. He stated that the irritation of the trigeminal nerve and associated

production of CGRP is the equivalent of placing a car key in the ignition and

turning it. Tr. 614. Both start a process. Dr. Saxon continued the analogy by

saying that increasing TNF is like stepping on the gas pedal. Tr. 614, 702-03.22

This testimony from Dr. Saxon is sufficient to find that Ms. McGuire has

established the third step in her three-part theory. It is more-probable-than-not that

21

Ms. McGuire’s submission of the article from the journal Headache established that it

was “published.” Although Ms. McGuire did not present any evidence that Headache subjects

articles to a peer-review process, the undersigned assumes that there was a peer-review process.

22

Dr. Weig asserted that the Perini article complements the Durham article. Tr. 183,

citing exhibit 38, tab Q (Francesco Perini et al., Plasma Cytokine levels in Migraineurs and

Controls, 45 Headache 926 (2005)). Although Dr. Saxon raised some questions about methods

of specimen collection and statistical analysis of the Perini article (Tr. 617-20), Perini still

supports an argument that elevations in TNF contribute to chronic headaches.

27

the addition of exogenously produced TNF would cause a person to suffer

headaches that are more severe or more prolonged than otherwise.23

However, Ms. McGuire’s evidence on the first two steps of her three-part

theory falls short of being persuasive. In particular, the following questions

undermine the persuasiveness of the theory causally connecting the HPV vaccine

and chronic headaches:

 Is the amount of TNF produced after vaccination an amount sufficient to

cause a disease?

 Is there a reliable basis for extrapolating the Pinto experiment from in

vitro to in vivo?

 Is there a reliable basis for finding that TNF crosses the blood brain

barrier?

On these points, Ms. McGuire has produced a measure of evidence,

consisting of the testimony of Dr. Weig and Dr. Swidan, but did not shore up their

opinions by referring to any literature. As an abstract legal principle, petitioners

may establish that they are entitled to compensation without presenting any

medical literature. Althen, 418 F.3d at 1274. “However, it should be obvious to

petitioner that a scientific theory that lacks any empirical support will have limited

persuasive force.” Caves v. Secʼy of Health & Human Servs., 100 Fed. Cl. 119,

134 (2011), aff’d per curiam, 463 F. App’x 932 (Fed. Cir. 2012). Special masters

are not required to accept the opinion of any expert, particularly one who expresses

opinions without support. Cedillo v. Secʼy of Health & Human Servs., 617 F.3d

1328, 1347-48 (Fed. Cir. 2010).

C. Argument based upon Precedent

Despite the evidentiary shortcomings in her presentation, Ms. McGuire

draws support from the Federal Circuit’s opinion in Koehn. Ms. McGuire states

23

The finding that the evidence supports Ms. McGuire’s assertions on the third step fully

makes up for any prejudice that she may have suffered with respect to the undisclosed criticisms

of the Rozen and Swidan article. Any mistakes of Ms. McGuire’s attorney in not objecting to

Dr. Saxon’s criticisms as undisclosed or in failing to request rebuttal testimony from Dr. Swidan

did not harm Ms. McGuire. Ms. McGuire achieved the result she wanted – a finding that TNF

can worsen headaches – by a different path without relying solely on the Rozen and Swidan

article.

28

that in Koehn the Federal Circuit upheld a theory that is “profoundly similar” to

her own. Ms. McGuire appears to be implying that the similarities between her

case and Koehn support a similar outcome in her case. Pet’r’s Preh’g Br. at 20.

To assess the comparability of the cases, the facts of Koehn are set forth.

In Koehn, the petitioner’s expert presented a two-step theory. The first

proposition was that inflammatory cytokines can cause systemic juvenile

idiopathic arthritis and the second proposition was that the HPV vaccine prompts

the induction of inflammatory cytokines. Koehn v. Sec'y of Health & Human

Servs., No. 11-355V, 2013 WL 3214877, at *21 (Fed. Cl. Spec. Mstr. May 30,

2013), mot. for rev. denied, 113 Fed. Cl. 757 (2013), aff’d, 773 F.3d 1239 (Fed.

Cir. 2014).

Pursuant to Terran v. Secʼy of Health & Human Servs., 195 F.3d 1302, 1316

(Fed. Cir. 1999), the undersigned special master evaluated this theory according to

the factors that the Supreme Court articulated in Daubert v. Merrell Dow Pharma.,

Inc., 509 U.S. 579 (1993), and found that the theory was not persuasive. Koehn,

2013 WL 3214877, at *22-26. Separately, the undersigned also found that the

petitioner did not establish the third prong of Althen, which concerns timing. Id. at

*26-29. The Court of Federal Claims denied a motion for review, finding that the

special master’s findings for both Althen prong 1 and Althen prong 3 were not

arbitrary. C.K. v. Sec'y of Health & Human Servs., 113 Fed. Cl. 757, 772-73

(2013). Consequently, the judgment denied the petitioner compensation.

The Federal Circuit affirmed this judgment. The basis for the affirmance

was the finding that the petitioner had failed to establish an appropriate timing.

Koehn, 773 F.3d at 1243-44. This is the holding of the Federal Circuit. Godfrey v.

Sec'y of Health & Human Servs., No. 10-565V, 2015 WL 4972882 at *4-5 (Fed.

Cl. Aug. 19, 2015) (granting motion for review for additional consideration of

Koehn).

However, with respect to Althen prong 1, the Federal Circuit panel split.

Two members stated “the Special Master committed several errors in the

assessment of the first and second Althen prongs.” Id. at 1243. The majority

expanded on their reasoning in a footnote, stating “Had the Special Master

29

properly evaluated the evidence, we believe the Special Master would have likely

found that Koehn met her burden under the first Althen prong.” Id. at 1244 n.1.24

In the case at hand, Ms. McGuire relies upon this footnote. Pet’r’s Preh’g

Br. at 19-20 n.12. However, the views of the panel majority expressed in the

footnote are dicta and do not constitute a holding requiring that all special masters

credit any theory relying upon the Pinto article. See Highmark, Inc. v. Allcare

Health Mgmt. Sys., Inc., 701 F.3d 1351, 1354 n.2 (Fed. Cir. 2012) (en banc) (per

curiam) (discussing what panel opinions constitute binding precedent); see also

Bristol-Meyers, 769 F.3d at 1353 (Taranto, J.) (dissenting from denial of reh’g en

banc) (“[S]tatements in opinions must be read in context, considering their role in

the decision and the facts of the case. Nevertheless, advocates often ignore this

principle, relying on phrases and sentences found through database word searches

without reading the whole opinion, and arguing for a precedential effect that is

unwarranted.”); Godfrey, 2015 WL 4972882 at *7 (“the circuit’s criticisms of the

special master’s decision in Koehn with regard to causation are dicta”).

Even if the footnote in Koehn were not dicta, however, it is unclear whether

the views of the panel majority in that case could determine the outcome in Ms.

McGuire’s case. A “special master’s task is to make a factual determination of

causation based on the evidence in a particular case. A study of many individual

cases may be useful evidence as to causation, but it does not compel the finder of

fact to find causation in a particular case.” Lampe v. Secʼy of Health & Human

Servs., 219 F.3d 1357, 1366 (Fed. Cir. 2000). The mandate to consider the

evidence in each case carries particular force because the evidence in Koehn differs

from the evidence in this case.

Concededly, Ms. McGuire’s theory shares the basic structure of the theory

advanced in Koehn: the HPV vaccine induces the production of cytokines and the

produced cytokines cause a disease. But, the theory in Ms. McGuire’s case adds

the step of crossing the blood brain barrier. The blood brain barrier is not trivial.

In evaluating a theory, special masters may consider whether petitioners have

presented a reliable basis for finding that a vaccine, which is administered in the

body’s periphery, can cause adverse effects in the part of the body protected by the

blood brain barrier. See Moberly, 592 F.3d at 1324; Taylor v. Secʼy of Health &

24

The remaining member of the panel did not believe that the errors regarding prong 1

and prong 2 presented “adequate grounds for reversal given the highly deferential standard of

review.” Koehn, 773 F.3d at 1245 (Moore, J., concurring).

30

Human Servs., 108 Fed. Cl. 807, 819 (Fed. Cl. 2013) (denying motion for review

because, in part, petitioner failed to present evidence of a breach in the blood brain

barrier).

In addition, the evidence surrounding the theory in Ms. McGuire’s case

differs from the evidence surrounding the theory in Koehn. For example, in this

case, the Secretary presented the 2012 IOM report that found no evidence that

cytokines cause a disease. Exhibit D, tab 4 (Stratton) at 76 [pdf 3]. This evidence

was not offered in Koehn.

Another difference between Ms. McGuire’s case and Koehn is the disease

afflicting the petitioner. In Koehn, the disease was a form of arthritis. Here, the

disease is chronic headaches. While in Koehn two members of the Federal Circuit

appeared to conclude that the petitioner’s evidence supported a finding that

cytokines cause a type of arthritis, their conclusion would not necessarily mean

that cytokines can cause headaches.

In this case, a finding that the HPV vaccine can cause chronic headaches

depends upon the evidence introduced in this case. Althen, 418 F.3d at 1281. For

the reasons discussed above, the Secretary has controverted Ms. McGuire’s

evidence to such a degree that the evidence does not preponderate in Ms.

McGuire’s favor on this point.

II. Timing

Although timing is the third factor from Althen, it is easier to assess the

evidence immediately after the discussion of the theory. The causal theory largely

influences the amount of time that is consistent with an inference of causation.

Langland v. Secʼy of Health & Human Servs., 109 Fed. Cl. 421, 434 (2013).

As part of her case-in-chief, the petitioner bears the burden of establishing

that the onset of her disease occurred within an acceptable time. Bazan v. Sec’y of

Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). This formulation

implies that the third prong from Althen actually contains two parts. First, there

must be a showing that a range of time is “acceptable” to infer causation. Second,

there must be a showing that the petitioner’s disease arose in this acceptable time.

Shapiro v. Secʼy of Health & Human Servs., 101 Fed. Cl. 532, 542-43 (2011),

recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012), aff’d per

curiam, 503 F. App’x 952 (Fed. Cir. 2013).

31

For Ms. McGuire, there is no dispute about the second part of the third

prong. The time when her headaches arose was determined in the Revised

Findings: sometime between October 25 and October 28, 2007. Because she

received the first dose of the HPV vaccine on September 20, 2007, the interval

between vaccination and onset of headaches for Ms. McGuire is 35 to 38 days.

Consequently, her burden is to establish that approximately 38 days is an

acceptable period for inferring causation.

With respect to the first part of the timing prong, the parties presented

relatively little evidence. Actually, Ms. McGuire failed to present any opinion

from Dr. Weig regarding the appropriate temporal interval until after an order

directed her to review Dr. Weig’s first two reports. Order, issued Dec. 15, 2014.

His ensuing written opinion regarding the appropriate temporal relationship relied

upon a 1994 report from the Institute of Medicine. Exhibit 40 at 1. In his oral

testimony, Dr. Weig again cited the 1994 IOM report and the Prakash and Shaw

article. Tr. 199-202.

The 1994 IOM report found that acute disseminated encephalomyelitis

(ADEM) and Guillain-Barré syndrome (GBS) “generally occur after an interval of

5 days to 6 weeks following . . . injection of antigen.” Exhibit 40, tab B (Kathleen

Stratton et al., Adverse Events Associated with Childhood Vaccines: Evidence on

Causality, Institute of Medicine (1994)) at 47. ADEM and GBS are demyelinating

conditions. Tr. 265. Special masters have found the period of 5 days to 6 weeks is

an acceptable interval for diseases mediated through an autoimmune process such

as molecular mimicry. Lilly v. Secʼy of Health & Human Servs., No. 09-31V,

2009 WL 3320518, at *3 (Fed. Cl. Spec. Mstr. Sept. 28, 2009).

A problem for Ms. McGuire is that she did not present any evidence that

suggests the time for a demyelinating disease matches the time for cytokines to

produce headaches. Dr. Weig conceded that TNF is “not [causing] an autoimmune

attack in the way that that term is typically used, which would mean like an attack

to destroy . . . cells or myelin.” Tr. 283. An admission that the process Dr. Weig

has advanced involving TNF differs from the process of demyelination essentially

makes an analogy to the 1994 IOM unpersuasive.

As discussed in the preceding section, Dr. Weig’s theory contains at least

three steps, beginning with the production of TNF in response to the vaccine.

However, even for this foundational step, Dr. Weig did not know how long the

body takes to produce pathogenic levels of cytokines. Tr. 265. Dr. Weig’s

inability even to estimate the time required casts doubt on his opinion regarding

timing.

32

Dr. Swidan provided little assistance. She asserted that TNF in the serum

might remain elevated during a chronic migraine attack. Tr. 546. But, in the

Rozen and Swidan experiment, the TNF levels in serum was the same in controls

and in people suffering headaches. The more meaningful substance is the

cerebrospinal fluid. See Tr. 462 (Dr. Swidan noting that pharmacologists study

whether a substance crosses the blood brain barrier). For the cerebrospinal fluid,

Dr. Swidan acknowledged that there are no studies measuring TNF in the

cerebrospinal fluid during a chronic migraine. Tr. 546. In addition, Dr. Swidan

did not provide any testimony about the time required to produce TNF initially.

Questions were also posed to Dr. Saxon about the duration of cytokines. He

stated that on the intracellular level, which is the relevant metric, most cytokines

“work in minutes” and they last for hours. Tr. 690-91. If Dr. Saxon is correct,

then Ms. McGuire would need to show that the short duration of cytokines is

consistent with an onset of her headaches approximately 35 days later. See Koehn,

773 F.3d at 1244 (holding that special master was not erroneous in finding that a

cytokine-driven reaction would not explain an onset approximately 60 days

later).25

In commenting upon the appropriate temporal relationship, Dr. Saxon

emphasized the weakness in the underlying theory. Dr. Saxon stated that Dr.

Weig’s theory for how the HPV vaccine can cause headaches “doesn’t fit with any

logic principles.” “[B]ecause [the theory] doesn’t fit an immunologic paradigm,”

“you don’t need immunologic time frames.” Tr. 645.

This criticism fits. Dr. Weig offered a theory involving cytokines, but his

testimony revealed that he did not know the time needed to produce cytokines or

the duration of cytokines. Therefore, Dr. Weig could not persuasively offer an

explanation of the temporal interval that would be appropriate. His resort to the

1994 IOM appears to be a desperate reach for a straw. Ms. McGuire has not

established the temporal interval between the HPV vaccination and the onset of

25

As discussed in section I.C. above, the Federal Circuit’s holding in Koehn was to rule

the special master’s analysis on timing was not arbitrary or capricious. Ms. McGuire would have

been better served to pay attention to this analysis because the latency between the vaccination

and the onset of headaches was multiple weeks, which is similar to the period of latency for

arthritis in Koehn.

If Ms. McGuire’s reliance on Koehn to establish prong one were correct, then it would

seem to follow that Ms. McGuire would also be bound by Koehn on prong three.

33

chronic headaches that is appropriate for causation. Therefore, she has not

established Althen prong three.

III. Logical Sequence of Cause of Effect

Because Ms. McGuire has not presented a persuasive theory explaining how

the HPV vaccine can cause chronic headaches (prong 1) and she has not

established the appropriate temporal relationship (prong 3), it follows, as a matter

of logic, that she cannot establish “a logical sequence of events” beginning with

the vaccination and ending with her chronic headaches. Caves, 100 Fed. Cl. at

134. Nevertheless, the evidence most closely related to this prong is also discussed

to demonstrate that the entire record has been considered.

The Federal Circuit has identified several factors that may be probative with

respect to the petitioner's burden on the second prong. These include, among other

things, the opinions of a petitioner's treating physicians, expert testimony,

challenge-rechallenge, and pathological markers. See Capizzano, 440 F.3d at

1322.

A. Treating Doctors

The order for briefs before hearing instructed Ms. McGuire to identify

statements of treating doctors in which they expressed an opinion that the HPV

vaccine caused Ms. McGuire’s headaches. Order, issued Jan. 15, 2015. In

response, Ms. McGuire identified seven doctors. Pet’r’s Preh’g Br. at 34-36.

However, as Ms. McGuire conceded during the pre-trial conference, in most of the

quoted passages, the doctor is presenting only a chronological account of events.

A sequence is not the same as a statement of causation. Cedillo v. Secʼy of Health

& Human Servs., 617 F.3d 1328, 1347-48 (2010); La Londe v. Secʼy of Health &

Human Servs., 110 Fed. Cl. 184, 206 (2013), aff’d on other ground, 746 F.3d 1334

(Fed. Cir. 2014); Langland v. Sec'y of Health & Human Servs., 109 Fed. Cl. 421,

439 (2013) (stating that the special master was not arbitrary in finding that the

records from treating doctors “reflect no more than intake histories or temporal

associations”); Caves, 100 Fed. Cl. at 127.

When these reports are set aside, Ms. McGuire is left with few useful

statements from treating doctors. The potentially most useful statement comes

from Dr. Herzog, the endocrinologist who saw Ms. McGuire nearly three years

after the HPV vaccination. Dr. Herzog stated that “headache is reported as quite

common after [Gardasil] vaccination (11-12%) but long lasting headache is

unusual. . . . In the absence of response to standard migraine and muscle tension

34

headache treatments, the possibility of an immunologically mediated process could

be considered.” Exhibit 13 at 13.

On its face, Dr. Herzog’s report that he could consider an immune mediated

process a “possibility” does not satisfy the preponderant evidence standard.

Paterek v. Secʼy of Health & Human Servs., 527 F. App’x 875, 879 (Fed. Cir.

2013). In addition, as Dr. Weig acknowledged on cross-examination, Dr. Herzog

looked for evidence of immune-mediated diseases such as lupus that could have

caused headaches as a consequence of that disease but did not find any evidence of

an immune-mediated process. Tr. 267. Thus, Dr. Herzog’s report does not lend

much assistance to the theory that the HPV vaccine caused Ms. McGuire’s primary

headaches.

After Dr. Herzog’s report, Dr. Levy’s 2009 report received the most

attention at the hearing. To recap, Dr. Levy practices alternative medicine and he

saw Ms. McGuire on January 15, 2009, which was approximately two years after

her headaches became permanent. According to the history Dr. Levy received,

Ms. McGuire “never had headaches before the HPV vaccination.” Exhibit 12 at 5.

He stated that “It seems reasonable that there is a causal connection. Headache is a

known side effect of HPV vaccine but studies show its frequency is similar in

controls and vaccinees.” Id.26 He recommended various non-traditional

interventions.

An initial problem with Dr. Levy’s report is that the history he obtained is

not accurate. Before the vaccination, Ms. McGuire did have at least one headache.

See Tr. 412-13. An incorrect history may lead a doctor to incorrect reasoning. See

Paterek, 527 F. App’x at 884 (holding that special master was not arbitrary in

rejecting the opinion of a doctor who obtained an inaccurate history).

Another issue is that Dr. Levy practices, according to Dr. Weig, “alternative

medicine.” Tr. 268. No information suggests that Dr. Levy has sufficient

expertise in either immunology or neurology to explain in a reliable fashion how

the vaccine can lead to headaches. See Tr. 268-69.

26

Dr. Levy took the additional step of postulating that the immune system, including

“proinflammatory cytokines,” might affect the “trigemino-vascular system.” He cited three

articles. Exhibit 12 at 5. However, neither party submitted those articles.

35

These two points weaken the value of Dr. Levy’s opinion that there is a

causal connection between the HPV vaccination and Ms. McGuire’s headaches. In

addition, Dr. Levy’s statement must be considered in the context of the many other

doctors who knew Ms. McGuire received the first dose of her HPV vaccination

before she started having recurring headaches in October 2007, but did not suggest

that the vaccination caused the headaches. See 42 U.S.C. § 300aa–13(a)(1)

(stating that special master must consider the record as a whole). From this

perspective, Dr. Levy’s opinion appears to be one not shared by his colleagues in

the medical profession.

B. Rechallenge

The Federal Circuit recognizes “rechallenge” as a factor that may be relevant

to considering whether a logical sequence of events supports the claim that a

vaccine caused an injury. Capizzano, 440 F.3d at 1322 (finding that a re-challenge

means “a patient who had an adverse reaction to a vaccine suffers worsened

symptoms after an additional injection of the vaccine”); see also Tr. 650.

In accord with the Federal Circuit’s instruction regarding rechallenge,

petitioners who demonstrate rechallenge may prevail in the Vaccine Program. Hall

v. Sec'y of Health & Human Servs., No. 02-1052V, 2007 WL 3120284, at *7-8

(Fed. Cl. Spec. Mstr. Sept. 12, 2007). However, petitioners must actually establish

that they fulfill the challenge-rechallenge paradigm. Shapiro v. Sec'y of Health &

Human Servs., No. 99-552V, 2012 WL 273686, at *12 (Fed. Cl. Spec. Mstr. Jan.

10, 2012), recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012),

aff’d per curiam, 503 F. App’x 952 (Fed. Cir. 2013); Nussman v. Sec'y of Health

& Human Servs., No. 99-500V, 2008 WL 449656, at *9-10 (Fed. Cl. Spec. Mstr.

Jan. 31, 2008), mot. for rev. denied, 83 Fed. Cl. 111 (2008).

The reverse of challenge-rechallenge is challenge-dechallenge.

“Dechallenge” refers to a situation in which removing the agent that supposedly

incites an adverse reaction leads to an improvement. Rider v. Sandoz Pharm.

Corp., 295 F.3d 1194, 1199-200 (11th Cir. 2002); Glastetter v. Novartis Pharm.

Corp., 252 F.3d 986, 990 (8th Cir. 2001). If removing the allegedly harm-causing

agent does not help, then the agent may not have actually caused the injury.

In this case, Ms. McGuire claims “challenge-rechallenge” and, at the same

time, the Secretary has invoked “challenge-dechallenge.” These disparate

arguments are based upon different aspects of Ms. McGuire’s medical history.

36

A succinct chronology to highlight only the events relevant to the challenge-

rechallenge-dechallenge arguments begins with Ms. McGuire’s receipt of the first

dose of the HPV on September 20, 2007. Exhibit 1 at 88-89. Her headaches began

between October 25 and October 28, 2007, and became constant one week later.

Revised Findings, issued Oct. 12, 2012. On November 14, 2007, Ms. McGuire

received the second dose of the HPV vaccine. Exhibit 1 at 86. The parties do not

dispute these events.

The parties, however, contest the next event in this sequence. To support

her argument in support of rechallenge, Ms. McGuire asserts that approximately

two weeks after receiving the second dose, her headaches became worse. See Tr.

204-05 (Dr. Weig’s testimony).27 The Secretary does not agree with the contention

that Ms. McGuire’s headaches worsened about two weeks after the second dose.

See Tr. 416-18 (Dr. Alexander). Different portions of the medical records support

each party’s interpretation. See exhibit 1 at 80 (Ms. McGuire reported on

December 10, 2007, that “her headache has progressively worsened”); exhibit 1 at

54 (Ms. McGuire told her neurologist on March 20, 2008, that there “was no

change in her headache after the second vaccine.”)

Determining whether Ms. McGuire’s headaches truly worsened at the end of

November or beginning of December 2007 is not necessary for this decision. Even

if her headaches did worsen, the worsening would not necessarily be a result of the

November 14, 2007 vaccination. This is because for CDH, “there are good times

and there are bad times.” Tr. 417. In other words, the severity of the headaches

fluctuates for a variety of unknown reasons. Thus, the possibility of worsening

does not point, even on a more-likely-than-not standard, to the vaccine as the cause

of any worsening. Thus, Ms. McGuire’s reliance on the challenge-rechallenge

theory is not persuasive.

This leaves the Secretary’s challenge-dechallenge argument. Ms. McGuire

and her experts maintain that the HPV vaccine provoked the production of an

excessive amount of TNF, which, in turn, caused the headache. Part of Ms.

McGuire’s support for the assertion that high amounts of TNF cause headaches is

the Prakash and Shaw study, which reported that people with headaches who

27

Although Ms. McGuire presented the challenge-rechallenge argument through Dr.

Weig, Ms. McGuire did not raise this contention in her pre-trial brief.

37

received high doses of steroids, which counter the production of TNF, improved.

Exhibit 40 (Dr. Weig report) at 1; Pet’r’s Preh’g Br. at 18.

From this foundation, the Secretary argues that Ms. McGuire does not fulfill

the challenge-dechallenge paradigm. See Resp’t’s Preh’g Br. at 22-23. In May

2008, Ms. McGuire received a course of steroids. Exhibit 1 at 41, 46-47.

However, the steroids either did not affect Ms. McGuire or they made her worse.

Exhibit 12 at 3; exhibit 13 at 1; exhibit 3 at 66, 70-71. Dr. Saxon and the

Secretary, thus, conclude that the lack of improvement indicates that TNF was not

responsible for Ms. McGuire’s headaches. Exhibit D at 11, Resp’t’s Preh’g Br. at

23.

Ms. McGuire effectively rebutted the Secretary’s reliance on challenge-

dechallenge. She showed that the amount of steroids used in the Prakash and Shaw

study exceeded by a large margin the amount of steroids prescribed to Ms.

McGuire. Tr. 196-98. Whether a stronger dose of steroids could have improved

Ms. McGuire’s headaches is uncertain and the dosages used by Prakash and Shaw

are not typically prescribed. Tr. 687.

Overall, neither Ms. McGuire’s challenge-rechallenge argument nor the

Secretary’s challenge-dechallenge is particularly persuasive.

C. Expected Response

A final way to consider whether Ms. McGuire presented preponderant

evidence that the sequence of events logically points to the vaccine as the cause for

her headaches is to evaluate whether she responded in a way predicted by her

expert’s theory. Both the Federal Circuit and the Court of Federal Claims have

accepted this method of analysis. Hibbard v. Secʼy of Health & Human Servs.,

698 F.3d 1355, 1364 (Fed. Cir. 2012); Dodd v. Secʼy of Health & Human Servs.,

114 Fed. Cl. 43, 57 (2013) (special master did not err in finding that the facts of the

vaccinee’s injury did not fit the theory offered by the petitioner); La Londe v.

Secʼy of Health & Human Servs., 110 Fed. Cl. 184, 205 (2013) (special master did

not err in rejecting the petitioner’s argument regarding prong 2 when the medical

records did not support the theory being offered), aff’d, 746 F.3d 1334 (Fed. Cir.

2014).

Here, Dr. Weig wrote that the vaccinations produced “a state of chronic

CNS inflammation with resulting headache.” Exhibit 28 at 4; accord Tr. 246.

People suffering from inflammation in their brains – as the term inflammation is

usually used – have “confusion, seizures, aphasia, coma, cranial nerve palsies, CSF

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pleocytosis, or systemic signs of inflammatory disease with fevers, elevated

sedimentation rate.” Exhibit A (Dr. Alexander’s report) at 12-13. Furthermore,

inflammation would be evident on MRIs and CT scans. Dr. Alexander was quite

blunt in rejecting Dr. Weig’s assertion that Ms. McGuire had inflammation in her

central nervous system. Dr. Alexander stated that “there is not a shred of evidence

that she has chronic CNS inflammation producing headaches.” Id. at 12. At the

hearing, Dr. Weig, essentially, agreed that Ms. McGuire did not have any of the

signs or symptoms of CNS inflammation as conventionally understood. See Tr.

178, 246, 289, 708-09. In his rebuttal testimony, Dr. Weig acknowledged that his

use of the term “inflammation” “would not correspond to the standard definition of

the term . . . in the general medical community.” Tr. 708.

Rather, Dr. Weig introduced a concept that was not discussed in his reports.

He stated that Ms. McGuire suffered from “sterile inflammation.” Tr. 177. Dr.

Weig said that “sterile” means “there’s no evidence of inflammatory cells in the

spinal fluid.” Tr. 177-78. Dr. Saxon clarified that Dr. Weig’s “sterile

inflammation” occurs at the molecular level. Tr. 604.

It would help a petitioner to show “evidence in the record suggesting that the

proposed mechanism was at work” in her case. Moberly, 592 F.3d at 1324. But,

this type of showing appears not to be possible because doctors do not routinely

order cerebrospinal fluid to be tested for TNF. See exhibit 30 (Dr. Weig) at 5; Tr.

550. Thus, Ms. McGuire is unable to present any evidence that she reacted in a

way that Dr. Weig’s theory would predict.

Overall, Ms. McGuire’s evidence regarding prong 2 was not of sufficient

quality or persuasiveness to compensate for the deficiencies in prongs 1 and 3.

Taken as a whole, Ms. McGuire did not meet her burden of proof on this prong.

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Conclusion

Ms. McGuire claimed that the HPV vaccine caused her to suffer headaches

and presented evidence, including opinions from Dr. Weig and Dr. Swidan, to

support her allegation. However, the evidence does not preponderate in her favor.

The Clerk’s Office is instructed to enter judgment in accord with this

decision.

IT IS SO ORDERED.

s/ Christian J. Moran

Christian J. Moran

Special Master

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