Court Opinion

ID: 4666195
Source: CourtListenerOpinion
Date Created: 2021-03-09 21:01:56.938252+00
Date Added: 2024-06-11T08:02:47.290179
License: Public Domain

In the United States Court of Federal Claims
                               No. 15-1066V
                       (Originally filed: 11/13/2020) 1
                         (Re-issued: March 9, 2021)

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

KATHY CASTANEDA, on behalf of
N.A.C., a minor child,

                                                     National Childhood
                     Petitioner,                     Vaccine Injury Act, 42
                                                     U.S.C. §§ 300aa-1 to -34
v.                                                   (2018); off-table claim;
                                                     motion for review; Althen
SECRETARY OF HEALTH                                  test; burden of proof,
AND HUMAN SERVICES,                                  cytokines, PANS, blood-
                                                     brain barrier,
                     Respondent.

**********************
    Andrew D. Downing, Phoenix, AZ, for petitioner.

       Zoe Wade, Trial Attorney, U.S. Department of Justice, Civil
Division, Torts Branch, Washington, DC, with whom were Ethan P. Davis,
Acting Assistant Attorney General, C. Salvatore D’Alessio, Acting
Director, Darryl R. Wishard, Assistant Director, for Respondent.

                                   OPINION
BRUGGINK, Judge.
        Pending is petitioner’s motion for review of the Special Master’s
decision of May 18, 2020, denying compensation under the National
Childhood Vaccine Injury Act. The matter is fully briefed, and the court
finds that oral argument is unnecessary. Because the Special Master was not
arbitrary or capricious in determining that petitioner did not meet her burden

1
 This opinion was originally held for fourteen days to afford the parties an
opportunity to propose redactions of protected information. They did not
propose any redactions. The opinion thus appears in full.
of proving that the vaccines were causally connected to the injury, we deny
the motion for review.

                              BACKGROUND2

        N.A.C. was born October 9, 2007 and was largely a healthy, happy
baby. Ms. Castaneda described N.A.C. as a typical, playful, happy child and
provided a video which she said showed him in his typical pre-vaccination
state. Shortly before his fifth birthday, on September 26, 2012, N.A.C.
received four vaccines: Pentacel, MMR, Hepatitis A, and Prevnar 13. The
Washington County Health records from that visit have a box check for “no”
to the question “Is child sick today?” Pet.’s Ex. 1 at 1.

       Approximately thirty hours later, in Ms. Castaneda’s description,
N.A.C. began stomping in place, bowing, holding his arms out, and moving
his head back and forth. When she asked him to stop, the child said that he
was unable to stop and he began telling himself to stop, which his mother
described as if he were arguing with his own brain about stopping. See Tr.
15-17 (Entitlement hearing, Oct. 4, 2018). Petitioner further testified that
N.A.C.’s behavior became aggressive and he began repeatedly banging his
head on the floor. Ms. Castaneda also testified that N.A.C. began to later
exhibit OCD behavior, which is also recorded in his medical records from
doctor visits in 2012 and 2015. For instance, he would straighten all of the
labels of items in a grocery aisle or would insist on flushing the toilet three
times, crossing the threshold of a room three times, flip lights on and off three
times, etc. Id. at 18.

        According to Ms. Castaneda, N.A.C.’s behavior worsened in the 2-3
days leading up to his birthday on October 9, 2012, 13 days post-vaccination.
He had by then a terrible stutter and continued to be violent. That day the
Castanedas took N.A.C. to the emergency room at Vidant Medical Center.
The complaint for the visit said “mother stated pt has had a change in
behavior recently, mother stated recently pt has been having a twitch and will
stutter and say stop and then will run a short distance. Pt has had increased
crying.” Pet.’s Ex. 5 at 2. Paperwork from the visit also states:

2
  The background facts are drawn from the Special Master’s opinion and the
record below. They are largely not in dispute with a few noted exceptions.

                                       2
      [N.C.] is a 5 y/o male who presents today with recent behavior
      problems. Per mother, he has always been an irritable child but
      has been worse over the past few weeks. He has been fussy,
      crying more frequently, and misbehaving. He is also walking
      strangely, taking 1-2 steps then shuffling. Mother states he has
      also been leaning his head right, then left, then saying “stop.”
      She states he will do this repeatedly. Today is his birthday, and
      he was behaving normally and eating normally earlier today.
      Tonight he would not eat dinner and was spitting.

Id.

       A CT scan was performed, which came back unremarkable. The
doctor agreed that N.A.C. was having symptoms typical of Tourette’s
Syndrome, but he could not legally diagnose him in the ER. Instead, the
Castanedas would need to have N.A.C. examined by a neurologist.
According to Ms. Castaneda, when asked if the vaccine could have caused
these symptoms, the doctor responded “Yes, there’s a possibility.” Tr. 26.
On October 11, 2012, the Castanedas took N.A.C. to their family physician,
Dr. Myung Kil Jeon, who recorded that N.A.C. was having tics and
involuntary body movements and referred him to a neurologist. Pet.’s Ex.
13. Ms. Castaneda testified that Dr. Jeon told her that there was a good
possibility that the vaccines could have caused the behavior changes. Tr. 31.

       On October 15, 2012, Mr. and Ms. Castaneda took N.A.C. to see a
children’s neurologist at the Children’s Hospital of the King’s Daughter in
Norfolk, VA, at which the Castanedas told the doctor about the tics and
violent behaviors mentioned above, such as banging his head against a wall.
The Assessment from that visit states, “I explained to the mother that I do
not think that these abnormal movements are related to the vaccines. There
was no specific data in the medical literature to support such concerns.”
Pet.’s Ex. 2 at 11. The neurologist, Dr. Miller, could not diagnose N.A.C.
with Tourette’s that day, but needed to see him over a period of time.
Petitioner recalled that Dr. Miller was surprised that N.A.C. manifested so
many symptoms all at the same time. Tr. 35.

       The Castanedas visited the pediatric neurologist again on November
9, 2012. The records from that visit indicate that N.A.C. had symptoms
consistent with Tourette’s Syndrome. Pet.’s Ex. 2 at 9. On March 11, 2013,
Dr. Miller diagnosed N.A.C. with Tourette’s syndrome. That diagnosis was
                                     3
reiterated in the records of a follow up visit on August 11, 2014. Id. at 4.
Ms. Castaneda testified that there is no family history of tics or OCD
tendencies and that previous to his vaccination N.A.C. had not been
diagnosed with OCD, tics, or any other neurological conditions. There is no
question that petitioner and her family have suffered a number of hardships
in dealing with N.A.C.’s condition thereafter.

        On September 25, 2015 Ms. Castaneda, on behalf of her minor child,
N.A.C., filed a petition seeking compensation under the National Childhood
Vaccine Injury Act. Petitioner has alleged a non-Table claim, wherein
petitioner contends that after receiving the Pentacel, MMR, Hepatitis A, and
Prevnar 13 vaccinations on September 26, 2007, N.A.C., developed Pediatric
Acute-onset Neuropsychiatric Syndrome (“PANS”). On October 4-5, 2018,
the Special Master held an entitlement hearing in Washington, DC.
Castaneda v. Sec’y of Health & Human Servs., No. 15-1066V, 2020 WL
3833076, *1 (Fed. Cl. Spec. Mstr. June 21, 2018). Medical records,
literature, and expert reports were filed before and after that hearing. During
the hearing, petitioner presented the expert testimony of Dr. Kiki Chang, and
respondent presented that of Dr. Donald Gilbert.

        Dr. Chang is a child, adolescent, and adult psychiatrist and a member
of the American Academy of Child and Adolescent Psychiatry and the
American College of Neuro-Psychopharmacology. Castaneda, 2020 WL
3833076 at *8. He was previously on the faculty of the Stanford University
Hospital and Children’s Hospital. While at Stanford, he formed the
university’s Pediatric Acute-Onset Neuropsychiatric Syndrome (“PANS”)
clinic. He organized a meeting in 2013 for researchers and experts to reach
consensus on clinical criteria for PANS, which was then achieved. He now
runs his own practice, seeing patients of all ages who present with complex
psychiatric and neuropsychiatric illnesses. He has seen between 100-200
cases of PANS over the years. He wrote a book on PANS and has over 100
peer-reviewed publications. Dr. Chang was involved in the development of
consensus criteria and treatment for children with PANS.

       Dr. Chang began by explaining how the PANS diagnosis was
developed. In the 1990s, a doctor at the National Institute of Health proposed
that a new diagnosis be assigned to children who develop certain
neuropsychiatric disorders after having been infected with the streptococcal
virus (“strep”).     Pediatric Autoimmune Neuropsychiatric Disorder
Associated with Streptococcus (“PANDAS”) was the resulting diagnosis for
children who suffer acute onset of obsessive compulsive disorder (“OCD”)
                                      4
with accompanying symptoms like motor tics, behavioral problems,
aggressiveness, depression, separation anxiety, and concentration problems
after a strep infection. Castaneda, 2020 WL 3833076 at *8. What the data
eventually showed, however, was that some children would present with an
acute onset of these symptoms without a strep infection. For this subset of
patients, the PANS diagnosis was proposed and adopted.

        For both PANS and PANDAS, Dr. Chang explained that there is a
triggering event, either known or unknown, which causes an attack on the
basal ganglia in the brain. Researchers and doctors understand the basal
ganglia as the affected area because it is where the brain “fine tunes many, if
not all, of the brain functions.” Castaneda, 2020 WL 3833076 at *8. He
recited that studies have found basal ganglia abnormalities present with
Parkinson’s and Tourette’s and that studies of the brain have shown the basal
ganglia as likewise related to OCD, attention deficit disorders, and tics.

       Unlike PANDAS, with which the triggering event is strep, the
triggering event is not nearly as clear cut for PANS. A consensus for
diagnostic criteria has developed, however. At the 2013 meeting mentioned
above, it was agreed that the acuity of onset of PANS symptoms is between
48 and 72 hours, from no symptoms observed to those symptoms necessary
for a PANS diagnosis. Dr. Chang further explained that the sudden onset of
symptoms differentiated PANS from a more typical diagnoses of OCD and
Tourette’s, which have more gradual onsets. Further, in PANS diagnoses,
the primary diagnostic criterion is OCD behavior or an eating restriction.
Secondary to one or both of those symptoms, a PANS sufferer has at least
two additional symptoms: anxiety (separation or general), emotional
problems, depression, irritability, aggression, oppositional behavior,
development regression, hyperactivity, concentration deficits, hand writing
changes, memory function problems, sensory motor issues (including motor
and vocal tics), and somatic symptoms. Castaneda, 2020 WL 3833076 at
*9.

        Dr. Chang also testified that, with both PANDAS and PANS, there
are two possible mechanisms through which the disorders are developed:
autoimmune molecular mimicry and a general inflammatory reaction caused
by cytokine production. Castaneda, 2020 WL 3833076 at *8-*9. With the
first, molecular mimicry, the body creates antibodies against a particular
antigen, such as strep in the case of PANDAS, which attack tissue in the
basal ganglia. This is because the antigen is molecularly similar enough to
the brain tissue that the antibody also affects that tissue. It is unknown
                                      5
precisely how these antibodies cross the blood-brain barrier and cause the
inflammation that disrupts the brain.

       The second mechanism, the more general inflammatory response to a
trigger, is mediated by cytokines. These cells then cross the blood-brain
barrier, selectively attack the basal ganglia, and cause PANS symptoms. Dr.
Chang opined that, although he was not certain why the cytokine response
would target the basal ganglia, this area of the brain is a “ripe area due to
where it is located in the vasculature.” Tr. 120. The trigger could be an
infection, autoimmune condition, or “anything that can really cause an
inflammatory state, including a vaccination.” Id. at 122. It is this cytokine
response that Dr. Chang believes caused N.A.C.’s symptoms, which he
opined were consistent with a PANS diagnosis. He also added on cross-
examination that there is some pending research regarding PANS and a
genetic marker, which he was unsure whether N.A.C. possessed. He
nevertheless also speculated that N.A.C. likely had a genetic predisposition
for PANS. Id. at 159.

        Dr. Chang discussed four pieces of medical literature during this
testimony, which will be discussed in greater detail below. Generally,
however, one stood for the proposition that cytokine production was
responsible for tic exacerbation in children with tic disorders and Tourette’s
Syndrome. Parker Athill et al., Cytokine Correlations in Youth with Tic
Disorders, Journal of Child and Adolescent Psychopharmacology, Vol. 25,
No. 1 (2015) (“Parker Athill”) (filed as Pet.’s Ex. 25). Another study
supported the diagnostic criteria of rapid onset of OCD symptoms with
PANS. Tanya K. Murphy, et al., Characterization of the PANS Phenotype,
Journal of Child and Adolescent Psychopharmacology, Vol. 25, No. 1 (2015)
(filed as Pet.’s Ex/ 31). The third was a survey of 700 PANS-diagnosed
patients in which many reported triggering events involving inflammation,
and 300 of which mentioned vaccines as precipitating symptoms. Denise
Calaprice, et al., A Survey of PANS Characteristics and Course, Journal of
Child and Adolescent Psychopharmacology, Vol. 20, No. 20 (2017)
(“Calaprice”) (filed as Pet.’s Ex. 16). The fourth study found an increased
incidence of vaccinations in a group of children prior to a diagnosis of
anorexia. Douglas Leslie, et al., Temporal Association of Certain
Neuropsychiatric Disorders Following Vaccination in Children and
Adolescents: A Pilot Case-Control Study, Frontiers In Psychiatry (2017)
(“Leslie”) (filed as Pet.’s Ex. 36). Dr. Chang explained that this was relevant
to his opinion because anorexia is often a misdiagnosis for food restriction,
a relevant criterion for PANS.
                                      6
       Dr. Chang was unsure why N.A.C. had not experienced these
symptoms following earlier vaccinations. When asked about autism as
possible explanation for N.A.C.’s symptoms, he demurred, explaining that
the acuity of onset and multitude of symptoms are inconsistent with autism.

        Respondent’s expert, Dr. Gilbert, is a practicing physician and
professor of pediatrics and neurology. He is board certified in neurology
with a special competence in pediatric neurology. After his residency at
Johns Hopkins University, he began his current employment at Cincinnati
Children’s Hospital Medical Center. His practice focuses on movement
disorders and neuropsychiatric symptoms associated with basal ganglia and
cerebellar dysfunction. He also has a master’s degree in statistics and clinical
research design. Dr. Gilbert serves on several relevant boards and
committees involved with Tourette’s Syndrome and pediatric neurology. He
testified that he sees approximately six patients per month where PANDAS
or PANS was considered by the referring doctor or the child’s parent.

       Dr. Gilbert’s testimony agreed with Dr. Chang about the development
of the PANS diagnosis from PANDAS. He agreed that the “thunderclap
onset of severe symptoms” unrelated to strep was the distinction that brought
about PANS. Tr. 219. Other than the acuity of onset of symptoms, however,
he explained that no biological distinction between anorexia or OCD and
PANS had been identified. He disagreed, however, that PANDAS was so
uniformly thought of as separate from Tourette’s or OCD. Id. at 217-18. He
also stated that, in his opinion, neither autoimmune nor inflammatory
mechanisms had yet been identified as the cause of PANS. Id. at 219. He
further found notable that no immune-modulating response has been found
to be helpful in treating PANS. This suggested, to Dr. Gilbert, that much
remains to be shown as to whether there is a connection between an immune
response and PANS. He found little support for the idea in the Parker Athill
study cited by Dr. Chang because it found only a marginal increase in one
particular cytokine associated with tics of OCD symptoms. Id. at 224-27.

       Dr. Gilbert testified that it was unlikely that N.A.C.’s symptoms were
caused by the vaccines because the 24-hour timeframe was too short for the
severe cytokine response necessary for the symptoms suddenly observed.
Castaneda, 2020 WL 3833076 at *13. He also explained that such an
inflammatory process in the brain would cause more generalized symptoms
such as seizures and gross motor function disruption. Further, basal ganglia
disruption would generally cause other movement disorders, not so neatly
                                       7
limited to OCD or tics. He thus opined that there is currently a gap in the
theories of PANS causation. He also found the rapid onset of symptoms of
OCD to be not nearly so atypical and thus not indicative of a triggering event.

       In a supplemental report, Dr. Gilbert stated that he found it difficult to
determine whether N.A.C. had a motor tic in the video presented of the child
prior to vaccination, but he believed that N.A.C. exhibited a misuse of the
pronoun “you,” which characterizes children on the autism spectrum.
Respt.’s Ex. C at 1. He goes on to address other behavioral markers from the
video that he believes evinces early autism in N.A.C. He finishes the report
by stating that PANS is a weak diagnosis generally because the science
behind it is limited and that, in his opinion, N.A.C.’s symptoms are likely
caused by autism and not the vaccine.

       The Special Master weighed the scientific literature, the expert
testimony, and the evidence in N.A.C.’s case and found petitioner did not
meet her burden. Specifically, the Special Master found Dr. Chang was
unable to demonstrate how vaccinations trigger pathologic levels of cytokine
production. While the Special Master noted that cytokine production often
accompanies a vaccine, petitioner did not demonstrate what level of
production of cytokines would be necessary to cause the inflammatory
cascade laid out in petitioner’s theory. She noted that Dr. Chang admitted
that he did not know what level of cytokine production follows vaccinations
and did not know what levels of cytokine production accompanied N.A.C.’s
vaccination specifically.

       The Special Master was also not persuaded by Dr. Chang’s theory that
a vaccine-induced cytokine expression would lead to cytokines crossing the
blood-brain barrier, as Dr. Chang posited. Castaneda, 2020 WL 3833076 at
*28. He was unable to explain how they would cross this barrier. Nor was
he able to show that such a crossing of the blood-brain barrier by cytokines
had occurred in N.A.C.’s case. Petitioner was unable to show why the basal
ganglia specifically would be targeted by generalized, vaccine-induced
cytokine expression, and petitioner was unable to show that the basal ganglia
had been affected in N.A.C.’s case. Showing that N.A.C.’s basal ganglia had
been inflamed would have required brain-imaging to be completed close to
the time of vaccination, which did not occur. In short, according to the
Special Master, petitioner not only failed to demonstrate a generalized theory
to explain how vaccination would have resulted in PANS, but also failed to
show that any of the necessary steps actually happened in the case of N.A.C.

                                       8
       The Special Master also found significant the fact that none of
N.A.C.’s treating physicians connected his vaccines to the onset of his
symptoms. Castaneda, 2020 WL 3833076 at *29. The Special Master noted
that no diagnostic tests of N.A.C. were completed, which might have
otherwise lent support to petitioner’s theory. The Special Master considered
the fact that N.A.C. did not suffer a post-vaccine reaction, such as fever or
malaise, as further evidence that petitioner’s theory was unavailing.

        Finally, the Special Master found that petitioner did not establish a
proximate temporal relationship between vaccination and injury. Castaneda,
2020 WL 3833076 at *29. While the Special Master confirmed that the rapid
onset of symptoms, measured from the start of the symptoms, was consistent
with a diagnosis of PANS, she nonetheless noted that the acute onset of
symptoms required for a PANS diagnosis relates only to the rapidity of
symptom onset and not to the timing between the triggering event and the
onset of symptoms. Notably, the Special Master agreed with Dr. Chang that
there is no scientific consensus about the timing between a triggering event
and the onset of symptoms for PANS. Further, the government’s expert
witness, Dr. Gilbert, stated his belief that the medical cause proposed by
petitioner could not have occurred and resulted in the onset of PANS
symptoms in so short a time from the triggering event.

        In summary, the Special Master found that the medical theory
proposed by petitioner was not adequately supported by expert testimony and
was contradicted by more credible expert testimony, that the medical
literature used to support petitioner’s theory was flawed and ultimately
unreliable, and that N.A.C.’s test results, symptoms, and the opinions of
treating physicians were not consistent with petitioner’s claims. Castaneda,
2020 WL 3833076 at *29-*30. Ms. Castaneda now appeals the Special
Master’s May 18, 2020 decision denying compensation. Petitioner filed a
motion for review, pursuant to Vaccine Rule 27 on June 17, 2020. The
government responded, and petitioner sought leave to file a reply, which we
granted.

                               DISCUSSION

       This court has jurisdiction to review the Special Master’s decision in
accordance with 42 U.S.C. § 300aa-12. Our review is deferential, only
setting aside decisions when they are “arbitrary, capricious, an abuse of
discretion, or otherwise not in accordance with law . . . .” Id. § 300aa-12(e).
When the Special Master has considered the relevant evidence and
                                      9
articulated a rational basis for the decision, reversible error is “extremely
difficult to demonstrate.” Hines v. Sec’y Health & Human Servs., 940 F.2d
1518, 1528 (Fed. Cir. 1991). This court does “not reweigh the factual
evidence, assess whether the special master correctly evaluated the evidence,
or examine the probative value of the evidence or the credibility of the
witnesses–these are all matters within the purview of the fact finder.” Porter
v. Sec’y of Health & Human Servs., 663 F.3d 1242, 1249 (Fed. Cir. 2011).

        A petitioner may seek compensation for “any illness, disability,
injury, or condition” sustained or significantly aggravated by a vaccine. 42
U.S.C. §§ 300aa-11(c)(1), -13(a)(1)(A).             When a petitioner seeks
compensation for an injury caused by a vaccine other than those injuries
listed on the Vaccine Injury Table, an off-table injury, petitioner must prove
causation in fact. Althen, 418 F.3d 1274, 1278 (Fed. Cir. 2005) (citing 42
U.S.C. § 300aa-13(a)(1)(A)). Petitioner must show that the vaccination
caused the injury by proving three elements by a preponderance of the
evidence: “(1) a medical theory causally connecting the vaccination and the
injury; (2) a logical sequence of cause and effect showing that the vaccination
was the reason for the injury; and (3) a showing of a proximate temporal
relationship between vaccination and injury.” Id. These three elements are
referred to, respectively, as Althen prongs I, II, and III.

        A different showing corresponds to each of the elements, but the same
evidence may be used to prove more than one element. First, petitioner must
provide a reputable medical theory that demonstrates that the vaccine can
cause the alleged injury. A petitioner is not required to submit medical
literature, propose a generally accepted theory, or demonstrate proof of
scientific certainty. See Andreu v. Sec’y of Health & Human Servs., 569 F.3d
1367, 1378 (Fed. Cir. 2009). Yet, petitioner cannot prevail merely on “a
‘plausible’ or ‘possible’ causal link between the vaccination and the injury;
he must prove his case by a preponderance of the evidence.” W.C. v. Sec’y
of Health & Human Servs., 704 F.3d 1352,1356 (Fed. Cir. 2013) (citing
Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1332 (Fed. Cir.
2010)). “[A] mere showing of a proximate temporal relationship between
vaccination and injury” is insufficient to prove actual causation. Althen, 418
F.3d at 1278.

       To demonstrate a logical sequence of cause and effect, petitioner may
use reputable medical or scientific evidence, including medical records. See
Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1326 (Fed.
Cir. 2006) (citations omitted). Additionally, the treating physician’s opinion
                                      10
is entitled to weight, particularly because it was created contemporaneously.
Id. Finally, petitioner must establish that there is a “medically-acceptable”
timeframe between the vaccination and alleged injury that is consistent with
the theory of how the vaccine could cause the injury. De Bazan v. Sec’y of
Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008).

I. Medical Theory of Causation

       We begin where the Special Master did—petitioner established that
N.A.C. had PANS. Castaneda, 2020 WL 3833076 at *22. This finding
makes irrelevant much of Dr. Gilbert’s opinions regarding the onset of
symptoms, the trustworthiness of PANS as a diagnosis, and what caused the
symptoms suffered. It does not matter whether N.A.C. exhibited signs of
being on the autism spectrum prior to the vaccinations because that does not
preclude the diagnosis reached by Dr. Chang, which was ultimately adopted
by the Special Master. What remains then is whether petitioner’s theory
meets muster under the Vaccine Act. Is it a reliable medical theory, with
evidence of cause and effect in N.A.C.’s case, and within a medically-
acceptable time frame?

       The Special Master answered each of those questions in the negative.
She synthesized Dr. Chang’s testimony and expert report into a four-step
theory of causation: 1) the vaccines caused a general (immune) inflammatory
response via the production of cytokines; 2) those cytokines increased the
blood brain barrier’s permeability and did cross the barrier; 3) once across
the barrier, the cytokines targeted the basal ganglia; and 4) caused the
symptoms of PANS. The parties largely follow that rubric in their briefing
on review, but we note that the discussion of steps three and four were
combined.

      A. Vaccination Promotes the Production of Cytokines

       The Special Master found unpersuasive the first pillar on which the
petitioner’s theory is built, namely that the vaccines could have caused the
production of cytokines necessary to trigger the response posited by Dr.
Chang. It was not the question of whether vaccines can and do produce an
inflammatory reaction, including the production of cytokines, that was
troubling for the Special Master. Rather, she found that petitioner neither
established, nor attempted to establish, the level necessary to cause the
effects posited by Dr. Chang nor what N.A.C.’s cytokine levels in fact were
shortly after the vaccine.
                                     11
       The Special Master accepted as generally recognized that vaccines
stimulate cytokine production. She cited, however, five vaccine decisions in
which “general cytokine-based theories of causation [were] not persuasive.”
Castaneda, 2020 WL 3833076 at *23 (citing Zumwalt v. Sec’y of Health &
Human Servs, No. 16-994V, 2019 WL 1953739 (Fed. Cl. Spec. Mstr. Mar.
21, 2019); Namdar v. Sec’y of HHS, No. 15-1173V, 2019 WL 1160341 (Fed.
Cl. Spec. Mstr. Feb. 8, 2019); McCabe v. Sec’y of HHS, No. 13-570V, 2018
WL 3029175 (Fed. Cl. Spec. Mstr. May 17, 2018); Dean v. Sec’y of HHS,
No. 13-808V, 2017 WL 2926605 (Fed. Cl. Spec. Mstr. June 9, 2017)). The
Special Master also highlighted Dr. Chang’s inability to provide a
substantive answer when asked what level of cytokine production is usually
observed after vaccination. Without evidence of either the actual reaction or
what is expected to normally occur after vaccination, the Special Master
found the first step in the Chang theory insufficient.

        On review, petitioner argues that her burden of persuasion was not so
high. She urges that requiring such evidence—what level of cytokine
production would be pathologic—far overshoots the gatekeeping role of the
Special Master. Petitioner urges that requiring evidence of a “dose response”
is far ahead of the science in this area and is therefore impossible to prove,
akin to proving the theory to a level of certainty, which is not required under
the act. We agree in part, but nevertheless affirm the Special Master’s
conclusion.

        The Special Master was correct that no evidence was provided
regarding the level of cytokine production expected after a vaccine nor what
would be necessary to produce the effects posited by Dr. Chang. Whether
the Vaccine Act’s preponderant standard requires such precision in all cases
where a cytokine-mediated theory is offered is a different question.
Although we need not reach the question, we note that each case is to be
decided on its own facts. The precise combination of clinical, medical
literature, and expert opinion evidence varies from case to case. To cite a
number of instances, even five, in which cytokine-based theories were found
insufficient is of no note. The evidence was not uniform in each of those
cases nor does it match what was presented here. The question is whether
Ms. Castaneda’s evidence, namely Dr. Chang’s opinion, is persuasive.

       Dr. Chang started with the consensus regarding the criteria necessary
to diagnose PANS. PANS and PANDAS are distinct from syndromes
causing similar symptoms, like Tourette’s, because of the acuity of onset,
                                      12
which the record bears out here. He also explained that the consensus is that
there is a triggering event, known or unknown, prior to the sudden onset of
symptoms. Through that lens, he examined N.A.C.’s records and finds only
the vaccinations as a likely trigger. He then turned to an explanation of how
this could have occurred.

       Dr. Chang explained that there are two likely biological pathways for
a trigger that can cause PANS. As the Special Master recognized, both
experts agreed that the symptoms are likely caused by basal ganglia
disfunction based on brain imaging studies of that region and the
understanding that it is the fine-tuner of the brains outputs. The first pathway
posited by petitioner’s expert was an autoimmune reaction resulting in an
antibody that would be predisposed to selectively attack the basal ganglia
due to molecular similarity between that tissue and the antigen, which he
called “molecular mimicry.” This mechanism, he testified, was unlikely to
be involved here because of the rapid onset of symptoms after the vaccines.

       The rapidity of the onset after vaccination suggested, to Dr. Chang,
that a much faster biological mechanism must have been involved: an
autoinflammatory response. This response would produce cytokines, which
crossed into the brain, and caused an inflammatory reaction in the basal
ganglia, according to Dr. Chang. If each of those steps could have been
established with some evidence of reliable support either in the record or the
medical literature, a different result would be likely. The Special Master
found that was not the case, however.

       B. Cytokines Increase the Permeability of the Blood-Brain Barrier

        Next, the Special Master found unavailing Dr. Chang’s testimony that
cytokines can lead to increased permeability of the blood-brain barrier. He
was asked on direct whether a particular cytokine, tumor necrosis factor
alpha (“TNFa”), is “expressed after vaccination.” Tr. 123. Dr. Chang
answered in the affirmative. He was then asked whether the same
proinflammatory cytokines can “cause the blood-brain barrier to become
more permeable.” Tr. 124. He said that they can. The Special Master found
this insufficient. She noted that there was no further discussion on the point
during the hearing nor any studies or other evidence presented. Without a
more detailed explanation of how or why cytokines pass through the barrier,
the petitioner could not show with any likelihood that this would happen,
according to the Special Master.

                                      13
        She further credited Dr. Gilbert’s testimony that, before the barrier
could be transgressed, the very tight cellular junctions of that structure would
have to be loosened. Dr. Gilbert found it implausible that this process, along
with the rest of Dr. Chang’s steps, could occur in a period as short as 24
hours. Tr. 228. Lastly, the Special Master cited a similar case in which the
TNFa cytokine had been posited as the brain invader: McGuire v. Secretary
of Health and Human Services. In McGuire, a different Special Master ruled
against the petitioner’s claim that a vaccine caused her to suffer chronic
headaches because, inter alia, the pharmacologist who testified regarding
TNFa crossing the blood-brain barrier did not explain how this occurred. No.
10-609V, 2015 WL 6150598 (Fed. Cl. Spec. Mstr. Sept. 18, 2015) (also of
critical importance was the testimony of a neurologist who opined that TNFa
does not easily cross the barrier).

        We find two errors in the Special Master’s holding on this step, but
they are ultimately harmless. As pointed out in petitioner’s memorandum on
review, the Special Master was wrong when she stated that there was “no
literature filed in support of the proposition,” Castaneda, 2020 WL 3833076
at *24. Dr. Gilbert’s own work, the Martino article, states that “an increase
in TNFa would increase the permeability of the blood-brain barrier.”
Martino at 10 (Pet.’s Ex. 44). In fact, Dr. Gilbert and colleagues go on to
state that such changes “may lead to an enhanced autoimmue response and
even greater dopamine release in the basal ganglia which in turn contribute
to the clinical symptoms of [Tourette’s] and related disorders,” which
parallels much of Dr. Chang’s opinion.3 Id. The second error was faulting
the theory due to a lack of explanation of how cytokines might cross the
barrier, as in McGuire. Here, Dr. Chang testified, and Dr. Gilbert et al. wrote
that the TNFa cytokine does in fact increase the permeability of the blood
brain barrier. Further explication of precisely how this is accomplished is
not required. Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543, 549
(Fed. Cir. 1994) (“to require proof of specific biological mechanisms would
be inconsistent with the purpose and nature of the vaccine program”).

       Ultimately, we agree with Special Master on the point regarding this
step, however, because Dr. Chang did not explain why this would happen in
such a short period of time. He was neither asked nor otherwise opined on
the matter. The Special Master was within her rights to credit the testimony

3
  We note, however, in the Martino article, the statement quoted above was
in reference to a process kicked off by an immune response to a strep
infection rather than a vaccine.
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of Dr. Gilbert on the point, who discredited the plausibility of that occurring
in the time allotted in the circumstances of petitioner’s injury. Here we find
this missing link decisive.
        C. The Cytokines Target the Basal Ganglia and Cause PANS

  The final two steps of Dr. Chang’s theory were considered together. The
Special Master found insufficient evidence “that rapid cytokine cascade and
generalized inflammatory response to vaccinations is a likely mechanism by
which targeted basal ganglia dysfunction can result.” Castaneda, 2020 WL
3833076 at *25. Although she noted that a general link between
inflammation and pediatric psychiatric disorders had been observed in
medical literature, she found that petitioner had not shown that this sort of
generalized reaction to a vaccine would result in the “targeted dysfunction
observed in disorders of the basal ganglia.” Id. She further found
unanswered the question of why this inflammatory process would only target
the brain regions necessary to cause the symptoms experienced by N.A.C.
She agreed with Dr. Gilbert that, when an inflammatory reaction targets the
brain (an encephalitis), the symptoms are more generalized, such as seizures,
which indicates a wider reaction across the brain. See Tr. 366.

       Dealing with the study cited by petitioner on this point, the Special
Master found that the relationship found in the Parker-Athill article between
TNFa and symptom expression in individuals with tic disorders, like
Tourette’s, was based on too small a sample to extrapolate a solid correlation
from the findings. She also correctly noted that this study, even if fully
credited, only showed a relationship between tic exacerbation and the
cytokine level, not that the cytokine caused the symptom. Likewise, a survey
of PANS patients who reported flare-ups following flu vaccinations was
found unpersuasive because it relied on self-reported data and was not
specific regarding the dose, the temporal interval between vaccine and
symptom, nor whether the symptoms were chronic, i.e., unlikely to have been
caused by the recent flu vaccine. See Calaprice at 1.

       The temporal relationship between receiving a vaccine and the onset
of neuropsychiatric disorders reported in the Leslie study was criticized by
the Special Master and Dr. Gilbert as the product of insufficiently qualified
authors and because the study found correlation between presumably non-
vaccine caused injuries, such as broken bones, and the vaccines.
Quoting Dr. Gilbert, the Special Master thus dismissed the findings regarding
tics and OCD as “statistical noise.” Castaneda, 2020 WL 3833076 at * 26
(quoting Tr. 247).
                                      15
       Lastly, the article that Dr. Gilbert co-authored, Martino, which
petitioner cited as support for her theory generally, was discounted because
the hypothesis that tics and obsessive behaviors might be “directly or
indirectly precipitated by cytokines” was merely that, a hypothesis. Pet.’s
Ex. 44 at 9. Because the study also noted that “clear evidence of cytokine-
induced neural dysfunction in [Tourete’s Syndrom] is lacking and should be
further addressed in future studies,” the Special Master found that, by itself,
the study was insufficient to push petitioner past her evidentiary burden. In
sum, the Special Master found that the role of cytokines in these disorders
was being investigated and that the evidence available was short of a “sound
and reliable theory.” Castaneda, 2020 WL 3833076 at *26. The Special
Master thus found that petitioner had failed to establish the first prong of
Althen.

        To support Dr. Chang’s causal theory, petitioner cites a survey by Dr.
Calaprice and a study by Dr. Leckman. But these articles were considered
in great detail by the Special Master and found to be flawed, unpersuasive,
and ultimately not supportive of petitioner’s case. Even petitioner noted that
Leckman did not provide more than a temporal link between vaccines and
symptoms: “preliminary epidemiologic evidence that the onset of some
pediatric-onset neuropsychiatric disorders, including AN, OCD, anxiety
disorders, and tic disorders, may be temporally related to prior vaccinations.”
MFR at 17, 23 (quoting Pet.’s Ex. 36 at 6). This is well short of providing a
reliable theory or even filling in the blanks left in Dr. Chang’s theory.
Calaprice provided only a correlation in blood serum levels of TNFa and
symptoms. Although relevant in a very general sense, this provides no
evidence that cytokines have crossed the blood brain barrier and are
selectively attacking the basal ganglia. Likewise, the Special Master was not
irrational in her weighing of the probative value of the Parker Athill article.

        We agree with the Special Master that Dr. Chang’s opinion and the
literature cited by petitioner are short of supporting the final two steps in Dr.
Chang’s theory. The only bridge offered by Dr. Chang was a genetic
susceptibility. That possibility was purely hypothetical and almost entirely
unexplored in his testimony and expert reports. He testified to one yet
unpublished study regarding a particular gene expression that might be
relevant. That is not reliable evidence and the Special Master did not err in
declining to rely on it to bridge any of the gaps in petitioner’s theory. We
also find no error in the Special Master’s reliance on Dr. Gilbert’s critique
that a generalized inflammatory response caused by invading cytokines in
                                       16
the brain ought to have caused more generalized symptoms. This cast
significant doubt on steps three and four in Dr. Chang’s theory. The Special
Master was neither arbitrary nor capricious in rejecting them.

II. A Logical Sequence of Cause and Effect

        On the question of whether petitioner had established by preponderant
evidence that there was a logical chain of cause and effect between the
vaccine and PANS, the Special Master began that, since she found no
medically reliable theory of caution, no cause and effect could be found
either. But even assuming a theory was posited and accepted for how the
vaccines caused PANS, the Special Master found insufficient proof that it
did in fact happen in this case. She cited the lack of a similar or same
diagnosis by the child’s treating physicians. Further, the lack of immune
testing and brain imaging of N.A.C. was problematic for the petitioner, in the
Special Master’s view because, as Dr. Chang admitted, he could not know
for a fact whether there was inflammation in the child’s basal ganglia or
whether there were elevated cytokine levels that might have caused it.
Finally, there was no evidence in the medical records presented that N.A.C.
experienced any reaction to the vaccine. The Special Master noted the
absence of a fever or any malaise, which she would have expected to see had
N.A.C. experienced a negative reaction to the vaccines he received.
Castaneda, 2020 WL 3833076 at *29.

        Although we agree with petitioner that medical records are not
dispositive on the question, and we find that the Special Master’s own
opinion regarding the absence of an immune response after vaccination is
irrelevant, we need not reach the question of whether there was error that
prejudiced petitioner as to this prong of the test. Had petitioner provided a
reliable explanation of how the vaccine caused PANS in the time period she
posited, the fact that no doctor diagnosed PANS prior to Dr. Chang would be
largely immaterial. Also immaterial would have been the lack of a fever
experienced by N.A.C. after receiving the vaccine. The Special Master cited
no record evidence for why that should be dispositive of the issue. Had the
first prong of causation been met, reversal would have been merited for
reconsideration of the logical connection between the vaccine and the injury.

III. Proximate Temporal Relationship

       Lastly, the Special Master found that Ms. Castaneda had not
established a timeframe in which it was “medically acceptable to infer
                                     17
causation.” Castaneda, 2020 WL 3833076 at *30. The 30-hour onset of
N.A.C.’s symptoms was inconclusive in the Special Master’s view because
she found Dr. Chang’s opinion on the matter unclear and inconclusive.
Although we think that the record is clear enough that Dr. Chang’s testimony
regarding the onset of PANDAS symptoms after strep infection was meant
as a contrast to his opinion regarding onset after a vaccine-triggered event,
her more general holding that Dr. Chang had not explained why a rapid
cytokine response could cause PANS in only a day was rational. Dr. Chang’s
testimony regarding the acuity of onset, as argued in petitioner’s papers, was
not directly on point. It went to the issue of why a PANS diagnosis rather
than how fast vaccine ought to have caused the onset of those symptoms.
The Special Master’s view on this point was neither arbitrary nor irrational.

                              CONCLUSION

       Although the Special Master appears to have required more than is
required by the Vaccine Act on some of the finer points, we find those errors
harmless. The conclusion reached was not contrary to law and not irrational.
Accordingly, we deny petitioner’s motion for review. The Clerk of Court is
directed to enter judgment accordingly.

                                                 s/Eric G. Bruggink
                                                 ERIC G. BRUGGINK
                                                 Senior Judge

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