# Vernacchio v. Secretary of Health and Human Services

> United States Court of Federal Claims · July 13, 2016

URL: https://www.frixlaw.com/law-library/cases/4015413

## Case

- **Court:** United States Court of Federal Claims
- **Decided:** July 13, 2016
- **Precedential status:** Published
- **Opinion:** Opinion
- **Cited by:** 0 later opinions in the Frix Law Library

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## Opinion text

In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
No. 08-504V
(To be published)

*****************************
*
R.V. and E.V., parents and natural guardians of * Special Master Corcoran
L.V., a minor, *
* Filed: February 19, 2016
Petitioners, *
* Entitlement Decision; Influenza
v. * (“Flu”) vaccine; Autism Spectrum
* Disorder (“ASD”); Mitochondrial
SECRETARY OF HEALTH AND * Disease; Autoimmune
HUMAN SERVICES, * Encephalopathy Following Fever
* or Vaccine.
*
Respondent. *
*
*****************************

Robert Joel Krakow, Law Office of Robert J. Krakow, P.C., New York, NY, for Petitioners.

Lynn Elizabeth Ricciardella, U.S. Dep’t of Justice, Washington, DC, for Respondent.

DECISION1

On July 11, 2008, R.V. and E.V. filed a petition on behalf of their minor child, L.V. seeking
compensation under the National Vaccine Injury Compensation Program (the “Vaccine
Program”).2 The Vs sought to establish that the influenza (“flu”) vaccine that L.V. received on
December 8, 2006, when he was 21 months old, caused an encephalopathy, and/or aggravated
L.V.’s alleged underlying mitochondrial disorder, resulting in L.V.’s physiological symptoms and

1
Because this decision contains a reasoned explanation for my actions in this case, I will post it on the United States
Court of Federal Claims website, in accordance with the E-Government Act of 2002, 44 U.S.C. § 3501 (2012). As
provided by 42 U.S.C. § 300aa-12(d)(4)(B), however, the parties may object to the published decision’s inclusion of
certain kinds of confidential information. Specifically, under Vaccine Rule 18(b), each party has fourteen days within
which to request redaction “of any information furnished by that party: (1) that is a trade secret or commercial or
financial in substance and is privileged or confidential; or (2) that includes medical files or similar files, the disclosure
of which would constitute a clearly unwarranted invasion of privacy.” Vaccine Rule 18(b). Otherwise, the whole
decision will be available to the public. Id.

2
The Vaccine Program comprises Part 2 of the National Childhood Vaccine Injury Act of 1986, Pub. L. No. 99-660,
100 Stat. 3758, codified as amended, 42 U.S.C. §§ 300aa-10 through 34 (2012) [hereinafter “Vaccine Act” or “the
Act”]. Individual section references hereafter will be to § 300aa of the Act.
subsequent developmental regression.

An entitlement hearing was held on April 13-14, 2015, and in the following months the
parties submitted post-hearing briefs. Having completed my review of the evidentiary record and
the parties’ filings, I hereby deny Petitioners’ request for compensation for the reasons stated
below.

I. FACTUAL BACKGROUND3

A. Birth and Early Medical History.

L.V. was born at term by caesarean section on March 15, 2005, at Abington Memorial
Hospital in Abington, Pennsylvania, presenting with no abnormalities. Pet’rs’ Ex. 1 at 7, 15-16.
L.V. passed his hearing screening on March 16, 2005, and was routinely discharged on March 19,
2005. Pet’rs’ Ex. 2 at 4-5, 7. Throughout the first weeks of L.V.’s life, he had red and swollen eyes
with yellow drainage. Pet’rs’ Ex. 3 at 5. He was ultimately diagnosed with acute nasolacrimal
stenosis,4 and then subsequently diagnosed with gastro-esophageal reflux 5 during his first well-
child appointment on March 31, 2005. Id. at 5, 25.

At L.V.’s second well-child appointment on May 12, 2005, he was determined to be
developing appropriately for his age, and received: (a) Diphtheria, Tetanus, and acellular Pertussis
(“DTaP”) vaccine; (b) haemophilus influenza type B (“Hib”) vaccine; (c) inactivated polio vaccine
(“IPV”); and (d) pneumococcal conjugate vaccine (“PCV”). Pet’rs’ Ex. 3 at 113-14. A month later,
L.V. was diagnosed with onychia.6 Id. at 37-41.

On July 22, 2005, L.V. had his third well-child visit, at which time his pediatrician, Dr.
Sharon Corcoran, evaluated him as developing appropriately for his age. Pet’rs’ Ex. 3 at 50-51.
3
The medical records in this case are particularly voluminous, and include many records pertaining to efforts to treat
L.V.’s autism (and possible causes of it) post-vaccination that only bear tangentially on the issues to be resolved in
this entitlement proceeding. Although I have reviewed the entire record, I do not discuss all such medical records in
detail, but instead focus on what both sides have identified as the most significant records relevant to the causation
issues presented herein.
4
Acute nasolacrimal stenosis is the short term narrowing of the tear duct. Dorland’s Illustrated Medical Dictionary
(32d ed. 2012) at 24, 1233, 1769 [hereinafter Dorland’s]. See also Nasolacrimal Duct Obstruction, AMERICAN
ASSOCIATION FOR PEDIATRIC OPHTHALMOLOGY AND STRABISMUS (July 2014),
http://www.aapos.org/terms/conditions/72.
5
Gastro-esophageal reflux is defined as the “reflux of the stomach and duodenal contents into the esophagus, which
sometimes occurs normally, particularly in the distended stomach” after meals, or “as a chronic pathological condition
that leads to the conditions known as gastroesophageal reflux disease and reflux esophagitis.” Dorland’s at 1616
(emphasis in original).
6
Onychia refers to the “inflammation of the matrix of the nail resulting in shedding of the nail.” Dorland’s at 1321.

2
L.V. again received the DTaP, Hib, IPV, and PCV vaccines. Id. at 113, 114. On August 15, 2005,
L.V. developed cold symptoms including a cough, as well as a possible toe infection. Id. at 54, 56,
59. L.V. was prescribed augmentin7 for his toe infection and his parents subsequently reported that
he experienced vomiting and an upset stomach. Id. at 61, 63.

On September 16, 2005, L.V. had his fourth well-child visit, and once again Dr. Corcoran
evaluated L.V. as developing appropriately for his age. Pet’rs’ Ex. 3 at 66. At this time L.V.
received the DTaP, IPV, and PCV vaccines, after which he developed a localized rash. Id. at 69,
113, 114. Months later, on December 16, 2005, L.V. was again evaluated by Dr. Corcoran as
developing appropriately for his age. Id. at 77.

As L.V. approached his first birthday, there remained no obvious signs of developmental
problems. In February of 2006, L.V. was taken to the pediatrician because he was experiencing
diarrhea, and was diagnosed with gastroenteritis.8 Pet’rs’ Ex. 3 at 93. On March 16, 2006, Dr.
Corcoran determined that L.V. was still developing appropriately for his age, and at that time he
received the hepatitis B; measles, mumps, and rubella (“MMR”); and varicella vaccines. Id. at 96,
98, 114. In March of 2006, L.V. was diagnosed with both peanut butter and blueberry allergies.
Id. at 100, 102, 110. On July 10, 2006, L.V. was again evaluated as overall developing
appropriately for his age and received the DTaP and PCV vaccines. Id. at 112, 194. L.V. was taken
back to Dr. Corcoran’s office on August 7, 2006, where he was diagnosed with “other acute
sinusitis” and prescribed amoxicillin.9 Pet’rs’ Ex. 3 at 115, 117. In September of 2006, the Vs
called Dr. Corcoran to report that L.V. was experiencing diarrhea, and Dr. Corcoran prescribed
home management. Id. at 119.

On September 8, 2006, L.V. visited the pediatrician for a 17-18 month well-child
appointment. At this visit, L.V. was assessed as having normal growth and development (including
motor skills such as use of a cup and spoon), and received the hepatitis A vaccine. Pet’rs’ Ex. 3 at
123-24, 194. Later that same month, the Vs also brought L.V. to Allergy and Asthma Specialists,
P.C. in Flourtown, Pennsylvania, because L.V. had developed a large hive after eating blueberry
yogurt and pancakes. Pet’rs’ Ex. 7 at 39-40.

7
Augmentin is “the trademark for combination preparations of amoxicillin and clavulanate potassium.” Dorland’s at
179.
8
Gastroenteritis refers to the “inflammation of the lining of the stomach and intestines.” Dorland’s at 764.
9
Amoxicillin is a “semisynthetic derivative of ampicillin effective against a broad spectrum of gram-positive and
gram-negative bacteria.” Dorland’s at 65.

3
B. Flu Vaccine Administration and Subsequent Developmental Regression.

L.V. received the first dose of flu vaccine on November 8, 2006 (at approximately 20
months of age), and the second on December 8, 2006 (at approximately 21 months of age).10 Pet’rs’
Ex. 3 at 125, 128-29. Records from these two pediatric visits say nothing about developmental
problems, and there are no records from the intervening period between visits.

Three days after L.V. received the second flu vaccine dose, on December 11, 2006, Mrs.
V phoned the pediatrician’s office to report that L.V. was experiencing serious constipation “for a
while,” and had not had a bowel movement since December 9th. Pet’rs’ Ex. 3 at 132. She reported
no other problems, however. An office appointment was set for December 13, 2006. Id.

At the December 13th visit, Mrs. V again identified only constipation as the reason for the
appointment. Pet’rs’ Ex. 3 at 134-35. Thus, the medical records explicitly state that L.V. had not
been “going regularly for 1-2 months” despite alteration of his diet. Id. In addition to the
constipation, L.V. also now presented with left otitis media,11 although the records do not state
that he had a fever, and in fact state he displayed no acute distress. Id. at 135. Significantly, for the
first time the pediatric records reflect a concern with “speech delay,” although no details are given
as to the source of this concern. Id. L.V. was prescribed miralax for constipation and amoxicillin
for the ear infection, with the recommendation that any pain/fever that later resulted be treated
with an over-the-counter medication such as Tylenol or Motrin. Id. Mrs. V was instructed to return
to the pediatrician if symptoms did not improve in three days. Id. The speech delay was to be
evaluated through a hearing screen once the ear infection resolved, but the record also notes that
Mrs. V was supplied with a phone number for early intervention services in Montgomery County,
Pennsylvania. Id. at 135, 137.

Over a week passed without any further contact with L.V.’s pediatrician. Then, on
December 22, 2006, Mrs. V called Dr. Corcoran’s office to report that L.V. (who had been on
antibiotics to treat the ear infection for nine days) had now developed a fever of 102 degrees (which
later that same day rose to 104 degrees). Pet’rs’ Ex. 3 at 138-40. L.V.’s treaters prescribed

10
The flu vaccine is an “inactivated trivalent virus vaccine, containing two influenza A virus strains and one influenza
B virus strain, usually prepared from virus subunits.” Dorland’s at 2016. “The composition of the vaccine is changed
each year in response to antigenic shifts and changes in prevalence of influenza virus strains.” Id. L.V. received the
trivalent influenza vaccination, including one type B and two type A strains. Am. Pet. at 1 (ECF No. 27); see also
2006-2007 Influenza (Flu) Season, CENTERS FOR DISEASE CONTROL AND PREVENTION (July 8, 2009),
http://www.cdc.gov/flu/pastseasons/0607season.htm.
11
Acute suppurative otitis media refers to a short course inflammation of the ear with a discharge of pus. Dorland’s
at 24, 1351.

4
augmentin and recommended an in-office visit if L.V.’s symptoms did not improve in the next few
days. Id. at 138.

L.V.’s follow-up pediatric visit occurred on December 26, 2006. Pet’rs’ Ex. 3 at 142-47.
At this point, the Vs reported to L.V.’s treaters that he was suffering from rashes on his face,
shoulders, back, and diaper area that had first become evident on December 23rd, along with a
cough and runny nose. Id. at 144. The records make no mention, however, of an ongoing fever
(beyond reference to the fever that the Vs reported on December 22nd), and indicate that L.V.
displayed no particular distress. Dr. Corcoran diagnosed L.V. as suffering from an augmentin
allergy (based upon the circumstantial link between the time that medication was started and the
rash development), and he was prescribed omnicef as a substitute for augmentin. Id. at 142, 144.

Before their first visit to the pediatrician in 2007, the Vs obtained an initial early
intervention assessment from Montgomery County’s provider on January 17, 2007, after
requesting it on January 10th. See generally Pet’rs’ Ex. 13 at 1-11 and Ex. 30 at 475. The written
report generated from this initial assessment (based on observation of L.V. along with parental
reports) placed L.V. at eleven months for cognitive development, ten months for communication
development, six months for social development, and sixteen months for fine motor/physical
development. Pet’rs’ Ex. 13 at 5-6. The report contains references to L.V. having lost language or
expressive abilities, but notes that “he lost these abilities around 18 months.” Id. at 8. In addition,
other developmental problems (such as not responding to his name, or making eye contact) are
noted as uncommon occurrences, rather than behaviors that abruptly ceased or regressed. See, e.g.,
Id. at 5 (L.V. “did not respond to his name today. Parents report that he will respond to his name
20% of the time (at best)”).

L.V.’s next pediatric visit was on January 18, 2007. Pet’rs’ Ex. 3 at 148-49. Although L.V.
returned to Dr. Corcoran in part for a follow-up visit regarding his ear infection, the Vs also made
it clear that they wished to discuss “developmental issues.” Id. at 149. Specifically, the medical
records from that visit note the Vs’ statements that L.V. had “lost some of his language and does
not make a lot of eye contact.” Id. at 149. The January 18th records do not indicate when the lost
language began or was first observed – nor do they make any reference to the flu vaccine or L.V.’s
subsequent ear infection, brief fever, or rash as having any role in such developmental matters.
However, these records substantiate that the Vs had already initiated the process for obtaining an
early intervention assessment, as noted above. Id. at 149.

Dr. James Coplan, M.D., of Neurodevelopmental Pediatrics of the Main Line, P.C. in
Rosemont, Pennsylvania thereafter (upon referral by Dr. Corcoran) performed another early
evaluation assessment, completing his write-up of the assessment on January 23, 2007. See
generally Pet’rs’ Ex. 5 at 3-7. The assessment was based on both a physical examination and a
medical and personal history provided by the Vs (including the January 17th early assessment
5
report). Dr. Coplan’s conclusions were discouraging: he diagnosed L.V. with autism or autism
spectrum disorder (“ASD”).12 Id. at 4, 6. Consistent with the prior assessment performed by
Montgomery County, Dr. Coplan noted regressive developmental issues, as well as developmental
plateaus or behaviors that had not properly manifested. L.V.’s use and acquisition of words is said
to have “faded and disappeared” around 18-20 months (id. at 4), but L.V. never “reliably” said
“mama” or “dada” at all (a ten-month developmental milestone), while other behaviors (such as
fine motor skills in self-feeding) that should have begun earlier were only recently manifesting
(such as scoop-feeding with a spoon, which the Vs identified to Dr. Coplan as having begun only
“within the past week or two”). Id. at 1, 3-4.13 L.V. was scored at 40 on the Childhood Autism
Rating Scale14 (with 30 being the cutoff for autism). Id. at 6.

Dr. Coplan’s assessment included some discussion of the course of L.V.’s developmental
problems. He thus noted that the developmental and skills “deterioration” in a child’s second year,
as evidenced by L.V.’s history, occurs in 20 percent of autistic children. Pet’rs’ Ex. 5 at 6.
However, Dr. Coplan also proposed that despite the “striking history of developmental
deterioration” at 18 months provided by the Vs’ personal recollections, it was not entirely clear
that L.V. was truly regressing developmentally, given other information provided by the Vs about
L.V.’s earlier developmental abnormalities (such as his failure to “acquire appropriate use of
‘mama’ and ‘dada’). Id. at 6. Dr. Coplan also indicated that it was unlikely the immunizations that
L.V. had received played any role in his development of autism (and this record does not contain
any statement from the Vs linking L.V.’s alleged regression and his receipt of the flu vaccine in
November and December of 2006). Id. at 6.

The Vs later obtained a child development evaluation from Dr. Hillary Kruger, M.D., at
Children’s Hospital of Philadelphia (“CHOP”). See generally Pet’rs’ Ex. 6. In her initial pediatric
evaluation, dated May 21, 2007, Dr. Kruger concurred with the autism diagnosis proposed earlier
that year by Dr. Coplan. Id. at 5. Her written report also references previous records from 2007 in
which the Vs had stated to treaters that they noticed L.V.’s regression when he was 18 to 19 months
old. Id. at 1.

12
Section IV(A) of this decision contains a discussion of ASDs generally.
13
As discussed below, however, Petitioners contest the accuracy of Dr. Coplan’s assessment that L.V.’s spoon usage
was delayed, pointing to a contrary, earlier pediatric record suggesting normal development. See Pet’rs’ Ex. 3 at 122.
14
The Childhood Autism Rating Scale “helps to identify children with autism and determines symptom severity
through quantifiable ratings based on direct observation.” Childhood Autism Rate Scale, Second Edition (CARS-2),
WPS, http://www.wpspublish.com/store/p/2696/childhood-autism-rating-scale-second-edition-cars-2 (last visited
Feb. 3, 2016).
6
C. Dating the Onset of L.V.’s Regression.

In this action, Petitioners have alleged that L.V. experienced a dramatic developmental
regression after he received the second flu vaccine. However, as the medical records
contemporaneous with L.V.’s alleged regression consistently reveal, the Vs repeatedly reported to
doctors that L.V.’s regression began no later than when he was 18 to 19 months old.

As noted above, the contemporaneous records from January of 2007 (when Dr. Coplan
evaluated L.V. at 22 months of age) reveal that the Vs informed treaters such as Drs. Coplan and
Kruger that L.V.’s developmental problems and/or regression had been evident to them since L.V.
was 18 months old, or around September of 2006. Pet’rs’ Ex. 5 at 3. This reported onset is repeated
numerous other times in the subsequent medical record. Thus, Mrs. V informed Dr. James A.
Neubrander in September of 2007 (when L.V. was almost two and a half years old) that at 19
months she noticed L.V. had lost the few words he had, lost social interest, and appeared
withdrawn and irritable, and at around 20 months, L.V. lost eye contact, began constantly jumping,
became increasingly irritable, and began making only a few sounds with vibrations. Pet’rs’ Ex. 8
at 4. Dr. Bryan Jepson’s 2008 notes corroborate the same timeframe, reporting that according to
the Vs “[t]here was a regression from normal development around age 12 months in hindsight:
more noticeable around 18 months” including “arm flapping, loss of contact, less socially
interactive, [and] loss of his few words.” Pet’rs’ Ex. 10 at 5.

There are many other similar examples from the medical record. See, e.g., Pet’rs’ Ex. 7 at
29-30 (January 31, 2007 visit to CHOP for genetic testing); Pet’rs’ Ex. 10 at 78 (April 15, 2007
visit at Thoughtful House with Dr. Jepson); Pet’rs’ Ex. 6 at 1 (May 21, 2007 visit with Dr. Kruger);
Pet’rs’ Ex. 9 at 6 (June 14, 2007 visit with Dr. Krigsman); Pet’rs’ Ex. 8 at 3 (September 27, 2007
visit with Dr. Neubrander); Pet’rs’ Ex. 8 at 32 (September 29, 2007 visit with Dr. Neubrander).

D. The Vs’ Attempts to Explain L.V.’s ASD.

After L.V.’s initial ASD diagnosis in January of 2007, the Vs (whom the record
underscores were extremely dutiful in caring for their son) explored possible explanations for
L.V.’s autism, as well as treatments that would be effective under the circumstances. Eventually
they became very interested in determining whether L.V.’s purported post-vaccine regression had
something to do with an underlying disorder involving dysfunction (if not disease) in his
mitochondria and their efficiency in producing energy.

To that end, the Vs consulted with a variety of autism specialists, some of whom were
themselves exploring the links between autism and mitochondrial diseases. In May of 2007, L.V.
saw Dr. Corcoran and Dr. Hilary Kruger, a developmental pediatrician, both at CHOP, who
determined after genetic testing and evaluation that L.V. had no clinically significant genetic

7
abnormalities15 and had normal weight gain and growth. Pet’rs’ Ex. 6 at 1-5; Pet’rs’ Ex. 7 at 36-
37.16 L.V.’s ASD diagnosis was at that time confirmed as well. Id.

The Petitioners next brought L.V. to Texas specifically in search of a Defeat Autism Now
(“DAN”)17 doctor, and found Dr. Arthur Krigsman at Thoughtful House, in Austin, Texas. Tr. at
92. The Thoughtful House is associated with the DAN movement. Pet’rs’ Ex. 9 at 1. Dr. Krigsman
referred L.V. for an endoscopy and colonoscopy, which were performed by Mount Sinai on June
14, 2007. Id. His results showed mild lymphonodular hyperplasia. Id. L.V. was also diagnosed
with duodenal ulcers, gastritis, and suspected esophagitis. Id. at 2. L.V. also saw Dr. Jepson (a
member of Thoughtful House) for the first time on June 19, 2007. Pet’rs’ Ex. 10 at 7. Dr. Jepson
continued treating L.V. through the end of 2008, prescribing various medications and supplements
and at-home behavioral intervention therapy to treat L.V.’s autism. Id. at 1.

At the recommendation of Dr. Krigsman and other Thoughtful House practitioners, the Vs
traveled to New Jersey to bring L.V. to see Dr. Neubrander, another noted DAN doctor, who L.V.
first saw on September 29, 2007. Pet’rs’ Ex. 8 at 1-3. Following a physical exam performed that
same day, Dr. Neubrander confirmed L.V.’s autism diagnosis, and also diagnosed him with
“gastroenteritis associated with autistic spectrum disorders” and nutritional deficits. Id. at 36-37.18

The Vs eventually obtained treatment from Dr. Richard Frye, beginning in August of 2008,
who at the time was a physician at the Child and Adolescent Neurology Clinic at the University of
Texas Health Science Center in Houston, Texas. Pet’rs’ Ex. 8 at 2. Petitioners learned of Dr. Frye
from Dr. Krigsman, and it was Dr. Frye who first proposed to them that L.V. might have some

15
L.V. was found to have a duplication of 1q44, which he appears to have inherited from his father, but the lab
interpretation noted that this may represent a normal population variant. Pet’rs’ Ex. 7 at 1.
16
During this time, the Vs continued seeking assessments of L.V. to better his daily life. In April of 2007, the Vs took
L.V. for an occupational therapy assessment after which he received ongoing occupational therapy through at least
July of 2007, when the records stop. See generally, Pet’rs’ Ex. 15. They also brought L.V. for an applied behavior
analysis/verbal behavior evaluation in May of 2007. See generally Pet’rs’ Ex. 16. In July of 2007, L.V. had a
communication evaluation. See generally Pet’rs’ Ex. 17. Finally, in November of 2007, L.V. underwent a Behavior
Language Assessment. See generally Pet’rs’ Ex. 18, 19.
17
DAN is composed of doctors and medical professionals who believe, among other things, that autism can be caused
by vaccines. See Dwyer v. Sec’y of Health & Human Servs., No. 03-1202V, 2010 WL 892250, at *165 (Fed. Cl. Spec.
Mstr. Mar. 12, 2010).
18
The Vs later brought L.V. back to Pennsylvania and saw Dr. Coplan again in the winter of 2008. Dr. Coplan
maintained his diagnosis of autism with unclear underlying cause; he also recommended some additional metabolic
testing, but noted that testing performed for methylene tetrahydrofolate reductase did not indicate any abnormality.
Pet’rs’ Ex. 5 at 11-13.

8
kind of mitochondrial disease that had played a role in his ASD. Tr. at 93-94. The Vs traveled back
to Texas in order to obtain Dr. Frye’s services.

Dr. Frye performed testing to evaluate whether in fact L.V. displayed any of the clinical
indicia necessary for a mitochondrial disease diagnosis. At L.V.’s first visit with Dr. Frye on
August 1, 2008, extensive blood work was performed. Pet’rs’ Ex. 11 at 3. Then, on December 3,
2008, Dr. Frye had Quest Diagnostics, Inc. perform an amino acid analysis and a comprehensive
metabolic panel, intended to clarify what type of mitochondrial disorder L.V. had, if any. Id. at 17-
22.

Initial test results did not suggest the existence of a specific or inherited metabolic defect,
and returned an essentially normal acylcarnitine profile.19 Pet’rs’ Ex. 11 at 2, 6, 18, 20. But the
same lab results also showed elevated lactate (with values of 18 and 23 on a normal range of 4-16)
(Pet’rs’ Ex. 21 at 29), urinary tricarboxylic acid20 excretion (indicated by high levels of ammonia,
of which L.V. had a value of 83 when normal is equal to or below 47) (id. at 12), and the presence
of ethylmalonic aciduria. Id. at 13. 21

In 2009, L.V. underwent additional testing at Dr. Frye’s direction, through the
Mitochondrial Diagnostic Laboratory of the Medical Genetics Laboratories of the Baylor College
of Medicine (“BCM”) in Houston, Texas. See generally Pet’rs’ Ex. 34. There, specialists
performed a MitoMet oligo aCGH analysis22 that came back negative, showing no abnormalities.
Pet’rs’ Ex. 34 at 4. A year later, on September 9, 2010, the Urinary Creatine and Guanidinoacetate
results from BCM, Biochemical Genetics Lab suggested the possibility of a creatine transporter
deficiency,23 but further clinical correlation was needed. Pet’rs’ Ex. 26 at 37. Shortly thereafter,

19
Acylcarnitine profile analysis “is performed for the biochemical screening of disorders of fatty acid oxidation and
organic acid metabolism.” P. Rinaldo, et al., Acylcarnitine profile analysis, 10 GENETICS IN MEDICINE 151 (2008),
http://www nature.com/gim/journal/v10/n2/full/gim200822a.html (last visited Feb. 11, 2016).
20
The Krebs Cycle, or the tricarboxylic acid cycle, is “the final common pathway for the oxidation to CO2 of fuel
molecules, most of which enter the cycle as acetyl coenzyme A.” The cycle occurs “in the mitochondria and generates
ATP by providing electrons to the electron transport chain.” Dorland’s at 454.
21
Ethylmalonic aciduria is a genetically heterogeneous disorder due to deficiencies in the electron transport system,
characterized by the accumulation and excretion of acids normally oxidized by mitochondria. Dorland’s at 652, 791.
The presence of high ethylmalonic acid is a biomarker for mitochondrial disease and/or dysfunction. Tr. at 449-50;
560-62.
22
The MitoMet oligo aCGH analysis is used to detect some genetic deletions or duplications involved in mitochondrial
and metabolic related diseases. Medical Genetics Test: MitoMet®Plus aCGH Analysis, BAYLOR MIRACA GENETICS
LABORATORIES, https://www.bcm.edu/research/medical-genetics-labs/test_detail.cfm?testcode=2000 (last visited
Feb. 11, 2016).
23
Creatine transport deficiency is a genetic syndrome caused by mutations in the SLC6A8 gene on the X chromosome.
Pet’rs’ Ex. 26 at 6.

9
on September 16, 2010, a Magnetic Resonance Spectroscopy (“MRS”)24 test produced results
indicating that L.V.’s major metabolites were normal for his age, and there was evidence of a
normal creatine peak25 as well. Id. at 40. Not long thereafter, on October 14, 2010, the
Mitochondrial Diagnostic Lab at BCM preformed a creatine transporter 1 sequencing test that
detected no known deleterious mutations in the CRTR.26 Pet’rs’ Ex. 34 at 8.

During the time of this testing under Dr. Frye’s direction, the Vs brought L.V. back to
CHOP. Pet’rs’ Ex. 36 at 18. Metabolic studies of L.V. performed on August 12, 2010, “were
essentially normal and were not suggestive of metabolic or mitochondrial dysfunction.” Id.; Pet’rs’
Ex. 26, Part 2 at 1-9. During their September 2, 2010, visit, the doctors confirmed that
interpretation. Pet’rs’ Ex. 36 at 18.

By the fall of 2010, the Vs sought the opinion of another specialist with views similar to
Dr. Frye’s regarding the possible metabolic causes of autism, Dr. Richard Kelley at the Kennedy
Krieger Institute in Baltimore, Maryland. Dr. Frye had recommended in August of 2010 that
Petitioners speak with Dr. Kelley (Pet’rs’ Ex. 33 at 30), and (in written communication introducing
the Vs to him) set forth the opinion that L.V. had a “mitochondrial complex deficiency.” Pet’rs’
Ex. 26 at 4. Dr. Kelley and his assistants subsequently reviewed L.V.’s lab work. Id. at 32-33.
After review of the relevant results and L.V.’s history, however, Dr. Kelley expressed the belief
that there were “no metabolic abnormalities,” and thus nothing consistent with mitochondrial
dysfunction (although he acknowledged that L.V.’s condition could be consistent with an
encephalitis). Id.

Despite such inconclusive results, the Vs nevertheless pursued further attempts to identify
the source of L.V.’s ASD. To that end, on January 21, 2011, L.V. underwent a muscle biopsy,
performed to measure lactic acid27 levels (with the tested sample taken from L.V.’s right lateral

24
MRS is “a noninvasive diagnostic test for measuring biochemical changes in the brain, especially the presence of
tumor.” Magnetic Resonance (MR) Spectroscopy, Mar. 2010, MAYFIELD BRAIN & SPINE,
http://www mayfieldclinic.com/PE-MRspectroscopy.htm (last visited Feb. 11, 2016). “Spectroscopy is a series of tests
that are added to the MRI scan of your brain or spine to measure the chemical metabolism of a suspected tumor.” Id.
25
Creatine is “an amino acid formed by methylation of guanidinoacetic acid, found in vertebrate tissues, particularly
in muscle.” Dorland’s at 429.
26
The CRTR “is in a sodium chloride dependent transporter 1 that belongs to the solute carrier family 6 member 8
(SLC6A8).” Pet’rs’ Ex. 34 at 8. “In patients with CRTR deficiency, the urinary creatine excretion relative to the
creatinine excretion is elevated, and the creatine/creatinine ratio can be used as a first biochemical diagnostic marker
for CRTR deficiency.” Id.
27
Lactic acid is “a metabolic intermediate involved in many biochemical processes; it is the end product of glycolysis,
which provides energy aerobically in the heart for energy production or can be converted back to glucose.” Dorland’s
at 997. While elevated lactic acid in the blood is not specific for a diagnosis of mitochondrial disease (Tr. at 133-34),
it has previously been used as a measurement of autism in children. Dorland’s at 571.

10
thigh muscle), at BCM. Pet’rs’ Ex. 23 at 3. The results showed: “[f]iber type 1 predominance,
moderate” and “[m]ildly increased oxidative enzyme reaction (COX), and increased mitochondria
by electron microscopy.” Id. Nevertheless, L.V.’s muscle biopsy was interpreted by the performing
neuropathologist to show “no specific pathologic findings,” and he recommended further enzyme
tests aimed at analyzing the functioning of the electron transport chain [“ETC”]28 in L.V.’s
mitochondria, or additional attempts to measure mitochondrial DNA. Pet’rs’ Ex. 33 at 121.

Such additional testing was performed at Dr. Frye’s direction in late January of 2011, but
detected no deficiencies in L.V.’s mitochondrial ETC enzymes. Pet’rs’ Ex. 23 at 1-3. However,
the mitochondrial DNA content analysis performed at BCM on February 7, 2011, showed that
L.V.’s muscle contains approximately 189% of the mean value of the age and tissue-matched
controls, suggesting a compensatory amplification of mitochondrial DNA due to some other kind
of mitochondrial dysfunction. Pet’rs’ Ex. 34 at 16. A follow-up ETC test performed at BCM on
February 22, 2011, once again did not detect any deficiencies. Id. at 9.

In spite of such generally inconclusive data, on August 4, 2011, Dr. Frye diagnosed L.V.
(who was at that time six years old) with a mitochondrial disorder. Pet’rs’ Ex. 72, Part 2 at 25-26.
He did so by applying criteria set forth in an article written by Morava, entitled Mitochondrial
Disease Criteria, Diagnostic Applications in Children (the “Morava criteria”). Pet’rs’ Ex. 41, Ref.
25 at 31 (E. Morava, et al., Mitochondrial disease criteria: Diagnostic applications in children,
67 NEUROLOGY 1823 (Nov. 2006) [hereinafter Morava]). As discussed in greater detail below,
Morava set forth diagnostic guidelines for evaluating whether a child suffers from some kind of
mitochondrial disease, through application of a point system for various symptoms or test results
observed in the diagnosed patient. Pet’rs’ Ex. 24 at 1; Tr. at 120-21, 442-44.

In a “to whom it may concern” letter dated February 29, 2012, Dr. Frye identified the
specific grounds for his conclusion that L.V. suffered from a “definite” mitochondrial disease
(based on application of the Morava criteria). See generally Pet’rs’ Ex. 24 at 1-3. In his opinion,
L.V. exhibited three clinical signs consistent with a mitochondrial disorder, including: (i) exercise
intolerance, (ii) history of regression in skills, and (iii) gastrointestinal abnormalities. Id. at 1. Dr.
Frye then listed three metabolic indicators (based on previous bloodwork) he found significant,
including: (i) elevated lactate,29 (ii) urinary tricarboxylic acid excretion, and (iii) ethylmalonic
aciduria. Id. Dr. Frye also noted that L.V. had abnormal mitochondrial morphology30 as viewed

28
An electron transport chain is embedded within the inner mitochondrial membrane, and makes the same chemical
reduction of oxygen to water. Tr. at 428. “The oxidation of the carbon to carbon dioxide regenerate ATP as opposed
to an explosive force” and then the ATP is used by the cell to function, including muscle contraction, allowing the
eyes to see, the heart to beat, the ears to hear, etc. Id. at 428-29.
29
Lactate is the anionic form of lactic acid. Dorland’s at 997.
30
Mitochondrial morphology refers to the form and structure of the mitochondria. Dorland’s at 1169, 1181.
11
via electron microscopy (“EM”).31 Id. These factors were enough to score a “9” in Dr. Frye’s
application of the Morava criteria, resulting in the conclusion that L.V. definitely had a
mitochondrial disease. Dr. Frye also suggested, without elaboration, that the ETC test results and
muscle biopsy results supported his conclusion, while admitting at the same time that the genetic
evidence supporting his diagnosis was lacking. Id.

II. PROCEDURAL HISTORY

As stated above, the Vs filed this petition in 2008. On May 6, 2009, Respondent filed a
statement expressing no objection to the jurisdiction and appropriateness of Petitioners proceeding
within the Omnibus Autism Proceeding (“OAP”).32 However, after the relevant test cases in the
OAP were litigated, and their causation theories rejected, the Vs elected to remain in the Vaccine
Program, filing an amended petition on April 9, 2012, that explained how their revised theory of
vaccine causation differed from the decided test cases. ECF No. 27.

31
Electron microscopy involves the use of a microscope “in which an electron beam, instead of light, forms an image
for viewing, allowing much greater magnification and resolution.” Dorland’s at 1162.
32
This case was initially among the more than 5,400 cases initially filed under short form petition in the OAP, where
thousands of petitioners’ claims that certain vaccines caused autism were joined for purposes of efficient resolution.
A “Petitioners’ Steering Committee” was formed by many attorneys who represent Vaccine Program petitioners, with
about 180 attorneys participating. This group chose “test” cases to represent the entire docket, with the understanding
that the outcomes in these cases would be applied to cases with similar facts alleging similar theories.

The Petitioners’ Steering Committee chose six test cases to present two different theories regarding autism causation.
The first theory alleged that the measles portion of the measles, mumps, rubella (“MMR”) vaccine precipitated autism,
or, in the alternative, that MMR plus thimerosal-containing vaccines caused autism, while the second theory alleged
that the mercury contained in thimerosal-containing vaccines could affect an infant’s brain, leading to autism.

The first theory was rejected in three test case decisions, all of which were subsequently affirmed. See generally
Cedillo v. Sec’y of Health & Human Servs., No. 98-916V, 2009 WL 331968 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot.
for review den’d, 89 Fed. Cl. 158 (2009), aff’d, 617 F.3d 1328 (Fed. Cir. 2010); Hazlehurst v. Sec’y of Health &
Human Servs., No. 03-654V, 2009 WL 332306 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for review den’d, 88 Fed.
Cl. 473 (2009), aff’d, 605 F.3d 1343 (Fed. Cir. 2010); Snyder v. Sec’y of Health & Human Servs., No. 01-162V, 2009
WL 332044 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), aff’d, 88 Fed. Cl. 706 (2009).

The second theory was similarly rejected. Dwyer v. Sec’y of Health & Human Servs., No. 03-1202V, 2010 WL
892250 (Fed. Cl. Spec. Mstr. Mar. 12, 2010); King v. Sec’y of Health & Human Servs., No. 03-584V, 2010 WL 892296
(Fed. Cl. Spec. Mstr. Mar. 12, 2010); Mead v. Sec’y of Health & Human Servs., No. 03-215V, 2010 WL 892248 (Fed.
Cl. Spec. Mstr. Mar. 12, 2010).

Ultimately a total of eleven lengthy decisions by special masters, the judges of the U.S. Court of Federal Claims, and
the panels of the U.S. Court of Appeals for the Federal Circuit, unanimously rejected petitioners’ claims. These
decisions found no persuasive evidence that the MMR vaccine or thimerosal-containing vaccines caused autism. The
OAP proceedings concluded in 2010.

12
After filing a statement of completion on September 25, 2012, Petitioners offered the expert
report of Dr. Frances Kendall on August 20, 2013. ECF No. 64. On February 19, 2014, Respondent
filed a Rule 4(c) Report, contending that the record failed to establish by preponderant evidence
the causal connection between the flu vaccine and L.V.’s subsequent conditions, and disputing the
reliability of Petitioners’ medical theory. ECF No. 71. In response, Respondent filed an expert
report from Dr. Bruce Cohen. ECF No. 72. The Vs then elected to file a supplemental expert report
from Dr. Yuval Shafrir on December 30, 2014. ECF No. 95. With records gathering and the filing
of relevant evidence and expert reports complete, a two-day entitlement hearing was set for April
of 2015. (Petitioners later moved to file out of time a second supplemental expert report from Dr.
Shafrir on March 17, 2015 (ECF No. 129), and I permitted them to do so.)

On January 4, 2015, Petitioners filed a second amended petition that presented facts and
allegations relevant to Petitioners’ claim for compensation.33 ECF No. 105. The next day,
Petitioners filed: (i) their Prehearing Submissions (ECF No. 111); and (ii) a motion to compel
Respondent’s admission of Petitioners’ medical theory, alleging that Respondent had conceded
Petitioners’ theory in the case Poling v. Sec’y of Health & Human Servs., No. 02-1466v, 2008 WL
1883059 (Fed. Cl. Spec. Mstr. Apr. 10, 2008) through Respondent’s Rule 4(c) Report in that case.
ECF No. 112. After considering each side’s arguments, I denied Petitioners’ Motion for Judicial
Estoppel in my March 6, 2015, Order. ECF No. 124.34 In the meantime, Respondent filed her
prehearing submissions on February 24, 2015. ECF No. 119. Petitioners then filed their prehearing
submissions reply on March 9, 2015. ECF No. 127.

On April 13-14, 2015, a two-day entitlement hearing was held. During the hearing, I heard
testimony from Mrs. V; Petitioners’ experts Drs. Kendall and Shafrir; and Respondent’s expert
Dr. Cohen. After requesting two extensions of time (ECF Nos. 147 and 152) both of which I
granted, Petitioners filed their post-hearing brief on July 13, 2015. ECF No. 155. In response,
Respondent then filed her post-hearing brief on September 14, 2015. ECF No. 157. Petitioners
replied to Respondent’s argument on October 14, 2015.

III. TESTIMONY PRESENTED AT HEARING

A. Mrs. V

E.V., L.V.’s mother, was the only non-expert witness who testified at the entitlement
hearing. See generally Tr. at 7-103. Her testimony provided some context about L.V.’s overall
development – and also sought to rebut the notion, reflected in the medical records, that the Vs

33
On July 6, 2015, the Parties filed a stipulation for interim fees and costs (ECF No. 148), and I entered a decision
awarding the stipulated amount on July 7, 2015. ECF No. 150.
34
Petitioners filed a Motion for Reconsideration of that Order on April 4, 2015 (ECF No. 137) which I subsequently
denied by Order dated April 10, 2015. ECF No. 148.
13
were aware of signs of L.V.’s regression before he received the flu vaccines in November and
December 2006. In order to do so, she frequently attempted to diminish the weight to be given
statements in the medical record reporting earlier onset.

Thus, Mrs. V repeatedly stressed that the first time she or her husband had observed
developmental issues with L.V. was in mid-December of 2006, after he received the second dose
of flu vaccine. Compare Tr. at 29, 36, 40 with Tr. at 56, 58. Some photographs of L.V. were offered
to bulwark her assertions that L.V.’s pre-vaccination development was completely normal. Id. at
54-74.35 Yet she also admitted that she had witnessed some “subtle issues” pertaining to L.V.’s
development a month to two months before the second flu vaccine was administered. Id. at 54, 88.

More significantly, Mrs. V was unable to deny the many instances from the
contemporaneous medical records in 2007 in which she and/or her husband reported to treaters
evaluating L.V.’s autism that L.V. first displayed such symptoms by the time he was 18 months
old. For example, on cross-examination, Respondent pointed out that the excel sheet prepared by
Mrs. V documenting L.V.’s issues and presented to Dr. Neubrander at L.V.’s September 29, 2007,
visit reported that at 19 months L.V. “lost a few words he had, lost social interest, seemed
withdrawn, irritable.” Tr. at 87-88; Pet’rs’ Ex. 8 at 4. This is in apparent contradiction to Mrs. V’s
testimony (nearly nine years after the events in question) and her affidavit (prepared nearly three
years after the vaccination), both of which maintain that L.V.’s regression manifested no sooner
than 21 months, or after his receipt of the flu vaccine in December 2006. Compare Tr. at 29, 36,
40 with Tr. at 56, 58. Mrs. V had also prepared a narrative for Dr. Krigsman for L.V.’s June 2007,
visit, which is similarly inconsistent with her testimony and affidavit. Id. at 90; Pet’rs’ Ex 9 at 6
(reporting that L.V. “did always seem to be more difficult than other children” and that he “began
flapping his arms as early as 12 to 18 months”).

To the extent Mrs. V admitted that she had made such statements about the actual onset of
L.V.’s ASD-related symptoms, she attempted to downplay their significance, suggesting that she
and her husband had not considered L.V.’s earlier symptoms to be alarming enough to merit a
medical response. Tr. at 63. This line of reasoning – that L.V.’s “real” regression began only after
the second flu vaccine administration, and that any earlier signs of developmental problems were
too inconclusive to meaningfully relate to the later, agreed-upon developmental difficulties L.V.
experienced – was a general theme that Petitioners and their experts came back to during the

35
The Vs provided an array of photographs, and three videos, in an attempt to demonstrate visually that L.V. had
experienced a significant change in behavior and affect following his receipt of the second dose of flu vaccine in
December of 2006. See generally Pet’rs’ Ex. 43-65, 74-79. Neither of Petitioners’ experts commented on this evidence
at length. While these photographs do show L.V. demonstrating a variety of emotions and engaging in multiple social
interactions, and generally support the conclusion that L.V. has been well-loved and cared for, I do not find this
evidence probative in establishing the onset of L.V.’s purported regression. I could not draw useful conclusions or
inferences about L.V.’s capacity or developmental state at the time each photograph was taken simply by looking at
them, and testimony Mrs. V offered to explain them did not increase their evidentiary value.
14
hearing multiple times. See, e.g., id. at 86, 93, 152, 179-80.

B. Petitioners’ Experts36

1. Dr. Frances Kendall

Dr. Kendall offered an expert report and testimony at the entitlement hearing in support of
Petitioners’ theory that L.V. likely had an underlying, preexisting mitochondrial disease that was
exacerbated by receipt of the flu vaccine, thereby precipitating L.V.’s autism.

Dr. Kendall graduated from UMDNJ-New Jersey Medical School in 1987 after which she
completed her residency in pediatrics at Thomas Jefferson University Hospital in Philadelphia,
Pennsylvania. Pet’rs’ Ex. 42 at 1; Tr. at 106. From 1990 to 1993 she completed two fellowships in
genetics and metabolism at Children’s Hospital and Harvard Medical School and Tufts University
and is licensed by the American Board of Medical Genetics. Pet’rs’ Ex. 42 at 1; Tr. at 106. She
has worked and taught across the country in genetics and metabolism, including as Director of the
Mitochondrial Disorders Program at the Children’s Hospital of Boston, and written extensively,
including her own reports and reviews of others, on issues of mitochondrial energy production and
the errors of metabolism. Pet’rs’ Ex. 42 at 6-8; Tr. at 106, 108-09. She is presently board-certified
in biochemical genetics, and was previously board-certified in pediatrics. Tr. at 111. Dr. Kendall
currently treats patients from all over the world “for evaluation of and management of
mitochondrial disease” and estimates that since 2009 she has seen about a thousand patients, most
of whom she continues to treat. Id. at 105.

Dr. Kendall’s expertise thus lies in the specific field of mitochondrial disorders. Tr. at 104.
She did not, however, claim expertise in autism or in immunology. Id. at 233-34. In preparing her
expert opinion, Dr. Kendall reviewed the contemporaneous pediatric records, including L.V.’s
various evaluations discussed above, although she admitted that certain records relevant to Dr.
Frye’s analysis of L.V. were not provided to her at the time of her report’s preparation in July of

36
Petitioners’ two experts offered in total 71 individual articles or pieces of medical literature (in addition to the 101
articles also filed by Petitioners but not directly relied upon by their experts). Although I have reviewed all such
submitted evidence, I do not herein discuss, or include a summarization of, each individual article offered in this case.
La Londe v. Sec'y of Health & Human Servs., 110 Fed. Cl. 184, 209 (2013), aff’d, 746 F.3d 1334 (Fed. Cir. 2014) (on
appeal, it is presumed that special master reviewed all literature submitted in support of vaccine claim); Hennessey v.
Sec’y of Health & Human Servs., 91 Fed. Cl. 126, 137 (2010) (special master not obligated to discuss individually
each of over 200 medical or scientific journal articles filed in an action, and the failure to do so did not lead to the
conclusion that they were ignored). In most cases, discussion of a series of related articles (such as the literature
submitted by Dr. Shafrir to support Petitioners’ contention that components of the flu vaccine could have homology
with epitopes in the brain, or epitopes associated with autoimmune reaction) are not extensively reviewed herein since
my decision does not turn on an understanding or parsing of these articles. Indeed – my decision largely turns on my
factual findings about L.V.’s condition and the onset of his developmental problems.

15
2013. Id. at 130, 214. Nor did Dr. Kendall ever specifically examine or evaluate L.V.; her opinion
relied solely on test results performed by other treaters. Id. at 231.

Dr. Kendall characterized the diagnosis of mitochondrial disease as an “imperfect science”
(tr. at 198), stating that it is “not an easy process, and it’s not clean” (id. at 114), given limitations
in the available tools to evaluate it, along with a general lack of a medical/scientific consensus as
to the proper diagnostic criteria. Id. at 117, 119. Ultimately she embraced the Morava criteria
applied by Dr. Frye in his diagnosis of L.V. Pet’rs’ Ex. 10. She admitted, however, that there is
actually no accepted set of criteria (based on scientific consensus) that can be used in diagnosing
mitochondrial disease. Tr. at 119. In most cases, a definitive diagnosis of mitochondrial disease
requires a muscle biopsy or confirmation by molecular testing aimed at looking for a possible
genetic cause. Id. at 116-18, 146; Pet’rs’ Ex. 41 at 9.

Dr. Kendall also acknowledged the evolving nature of the criteria (and specific tests)
applied when attempting to diagnose a mitochondrial disease. Thus, Dr. Kendall noted that when
the science for detecting mitochondrial diseases was less advanced, muscle biopsy tests were the
“gold standard” diagnostic tool (Tr. at 241), but that more recently such tests were applied only to
confirm a mitochondrial disease diagnosis (id. at 118), and that she herself rarely performs them.
Id. at 119. She maintained that now there are many diagnostic tools available to test for
mitochondrial disease more useful than the muscle biopsy. Id. at 118-19.

Based upon her review of the results of the many tests performed on L.V., along with his
medical history, Dr. Kendall provided her opinion that the mitochondrial disease/dysfunction
diagnosis for L.V., as first proposed by Dr. Frye and based upon his application of the Morava
criteria, had evidentiary support. Tr. at 131-32. She acknowledged, however, that she did not
accept the Morava number assigned to L.V. by Dr. Frye (nine points); rather, she would reclassify
the total as six or seven,37 meaning that (under Morava) the proper diagnosis for L.V. was only
“probable” mitochondrial disorder38 rather than definitive (a diagnostic classification that she
indicated she would rarely accept, given the impossibility of confirming the diagnosis precisely).
Id. at 144, 149-50; Pet’rs’ Ex 10. To be more definitive in her diagnosis, Dr. Kendall stated that
she would require either some kind of advanced genetic testing, to look for mutations that would
directly impact mitochondrial function, or evidence that the patient’s particular symptoms matched
one of the more well-understood, and severe, forms of mitochondrial disease (such as Leigh
disease). Id. at 200, 243 (discussing that genetic testing performed on L.V. was negative for
mitochondrial disease).

37
Dr. Kendall vacillated between denoting six or seven points on the Morava scale to L.V., although either score is
sufficient to fall under its “probable” classification. Tr. at 143, 149-50.
38
See Section IV(B) below for a discussion of Morava’s points system.

16
Dr. Kendall agreed with Dr. Frye’s analysis that L.V. was properly assigned three Morava
“points” for clinical signs and symptoms. Thus, she found worthy of a Morava point the exercise
intolerance that L.V. was reported to have displayed, pointing to his limited eye movement as
evidence thereof. Tr. at 148. Yet, as Dr. Kendall acknowledged, there was little record evidence
supporting this conclusion – going so far as to admit that her embrace of Dr. Frye’s scoring for
this Morava factor was wholly dependent on what the Vs had reported to treaters about L.V. rather
than objective evidence, and that she herself did not believe based on her own review of those
records that L.V. in fact had ever displayed any such weakness. Id. at 193-94, 245. She admitted
the same with respect to L.V.’s purported low muscle tone (hypotonia), another factor relevant to
the application of the Morava criteria (and indeed acknowledged that there were contrary reports
in the medical records undermining the conclusion that L.V. displayed low muscle tone). Id. at
148, 194.

Dr. Kendall otherwise accepted the two additional points assigned by Dr. Frye in this
category, based on L.V.’s alleged autistic regression (evidence of a CNS-related symptom)39 and
purported ongoing gastrointestinal tract illness (proof that L.V.’s disease was multi-systemic). 40
Tr. at 148. She also agreed with Dr. Frye’s view of the significance of L.V.’s abnormal
mitochondria morphology as seen via electron microscopy (a diagnostic factor worth two points
on the Morava scale). Pet’rs’ Ex. 41 at 7; Tr. at 197. Certain histological tests measuring
mitochondrial proliferation also revealed a higher than normal mtDNA count. Tr. at 141-42. Dr.
Kendall acknowledged that this particular diagnostic factor was not as closely correlated with
mitochondrial dysfunction in children as a high nuclear DNA count (id. at 243), but insisted that
it was a reasonable factor to be considered, and that the results in question were (taken together
with the morphology observations) worthy of consideration. Id. at 198-99. Ultimately, she
admitted that L.V.’s overall muscle biopsy results (pertinent to the “morphology” category) did
not display any enzymatic abnormalities of his muscle tissue (tr. at 143), although she still
maintained that the results suggested some form of mitochondrial dysfunction. Id. at 197-98.

Dr. Kendall did not, however, accept every aspect of Dr. Frye’s application of the testing
results under Morava. In particular, she substantively disagreed with Dr. Frye’s point calculation
with respect to the results of the enzymatic and metabolic tests. Thus, Dr. Frye gave L.V. the four

39
Dr. Kendall acknowledged that the Morava criteria’s inclusion of autism-like symptoms as evidence of an
underlying mitochondrial disorder highlighted a circularity in the logic of Petitioners’ causation theory offered in this
case. Tr. 236-37. As Dr. Kendall admitted, individuals could be properly diagnosed with an ASD and not also have
mitochondrial disease. Id. at 237. Yet here, the very same ASD symptoms being pointed to as evidence of the impact
of the relevant vaccine were also being cited as evidence of the underlying condition that caused those symptoms. In
effect, L.V.’s illness was proof of its cause.
40
Dr. Kendall displayed some ambivalence, however, as to whether L.V.’s reported constipation was a factor
suggesting the presence of a mitochondrial disorder, or merely reflective of the autistic regression that purportedly
occurred in reaction to the vaccination. Tr. at 173-74.

17
point maximum under the Morava diagnostic framework for test results showing elevated lactate
(two points), urinary tricarbon acid excretion (one point), and ethylmalonic aciduria (two points).
Pet’rs’ Ex. 24 at 1. Dr. Kendall, however, questioned the weight given by Dr. Frye to the elevated
lactate finding because “it’s not a true elevation from a biochemical mitochondrial perspective”
and “we don’t have any concurrent data to show whether it was a collection artifact.” Tr. at 140.
She therefore indicated that she disagreed with awarding a Morava point for the lactate results
because concurrent tests of other enzyme levels (alanine to lysine ratios) did not corroborate them.
Id. at 149. But she agreed with Dr. Frye that L.V. had high tricarboxylic acid excretion (tr. at 149),
as well as high ethylmalonic acid levels, which (as corroborated by the fatty oxidation studies done
on skin fibroblasts) were in her opinion suggestive of mitochondrial disease. Id. at 138-39. Thus
she would have granted only two or three points for the test results relevant to this biomarker
category.

More broadly, Dr. Kendall admitted (consistent with the manner in which she applied the
Morava criteria) that any mitochondrial disease L.V. suffered from was on the mild end of the
spectrum, and did not approach the severity of something like Leigh disease41 (given, for example,
the normal MRI readings obtained for L.V. (tr. at 202)) or other more easily diagnosed phenotypes.
Thus, although she argued that mitochondrial diseases were “extremely variable” in their manner
of development, the most obvious forms were progressive – but that she was not aware of any
record evidence suggesting that L.V. had experienced a truly dramatic, downward progression in
his symptoms post-vaccination. Id. at 188-90.

Dr. Kendall also acknowledged that her opinions about Dr. Frye’s diagnosis arose from her
own expertise and familiarity with the Morava criteria, and that she therefore did not particularly
rely on much of the independent literature filed by the Petitioners in support of their claim, noting
that some of it was not pertinent to L.V.’s circumstances.42 Tr. at 207. However, she did in her

41
Leigh disease is a subacute necrotizing encephalomyelopathy which is a type of “encephalopathy of unclear clinical
and pathological criteria, causing neuropathologic damage like that of the Wernicke-Korsakoff syndrome. It occurs in
two forms: the infantile form is caused by mitochondrial energy metabolism protein mutations and pyruvate
carboxylase complex mutations and is characterized by degeneration of gray matter with necrosis and capillary
proliferation in the brainstem; hypotonia, seizures, and dementia; anorexia and vomiting; slow or arrested
development; and ocular and respiratory disorders, with death usually before age 3. The adult form usually first
manifests as bilateral optic atrophy with central scotoma and colorblindness, followed by quiescent period of up to 30
years and then late symptoms such as ataxia, spastic paresis, clonic jerks, grand mal seizures, psychic lability, and
mild dementia.” Dorland’s at 614.
42
Thus, Dr. Kendall discussed one piece of literature that Petitioners highlighted as significant (Pet’rs’ Ex. 41, Ref.
27 (J. Shoffner, et al., Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression, 25(4) J. OF
CHILD NEUROLOGY 429 (Jun. 2009) [hereinafter “Shoffner”]), because it suggested a relationship between fever and
subsequent regression. Dr. Kendall, however, agreed that Shoffner involved a study of individuals who plainly had
measurably high fevers lasting over a period of three to seven days – circumstances wholly distinguishable from the
facts of this case. Tr. at 210-11.

18
testimony reference literature discussing the Poling case as supportive of the theory that young
children with dysfunctional cellular metabolism may be prone to autistic regression if they
simultaneously experience infections and immunizations (both “stressors” that could exacerbate
an underlying mitochondrial disorder). Pet’rs’ Ex. 41, Ref. 26 (J. Poling, et al., Developmental
Regression and Mitochondrial Dysfunction in a Child with Autism, 21(2) J CHILD NEUROL 170-72
(2006); Tr. at 106, 136, 153, 155-56. While admitting that Poling was a single case rather than a
verifiable, reproducible scientific study, she nevertheless placed great trust in what it revealed. Id.
at 208-09, 212.

Based upon all of the above, Dr. Kendall proposed that Petitioners could meet all three of
the prongs necessary to establish causation in a non-Table case under Althen v. Sec’y of Health &
Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). First, Dr. Kendall offered the theory that the
flu vaccine could sufficiently exacerbate an underlying mitochondrial disorder, synergistically
reacting with an intercurrent infection,43 to produce an autistic regression. Specifically, she opined
that “the constellation of stressors” experienced by L.V. after receiving two flu vaccines plus his
ear infection (tr. at 211) “had a synergistic effect on him that led to worsening of his – or
aggravation of his underlying [mitochondrial] disorder or problem.” Id. at 164-65.

To support this proposition, Dr. Kendall relied on literature discussing that vaccines can
act as stressors for sufferers of mitochondrial diseases (tr. at 153-60), although she admitted that
only isolated cases, or incidents involving well-understood and particularly severe forms of
mitochondrial diseases such as Leigh disease, supported this element of her theory. Id. at 174. She
also pointed to a paper filed by Petitioners but not relied upon in her report, indicating that “the
influenza virus can, via a specific mitochondrial component . . . cause a cascade of events leading
to apoptosis, which is a kind of programmed cell death.” Id. at 162 (citing Pet’rs’ Ex. 101 (A. Tran,
et al., Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation, 87(2)
J. OF VIROLOGY 1049 (Jan. 2013)) [hereinafter “Tran”]). She then said that such a study made it
more likely or plausible that the flu vaccine could cause an injury in a person with mitochondrial
disease. Tr. at 163. Given the understanding that an infection can itself precipitate a regression or
decompensation (id. at 155-56), she testified, the introduction of flu vaccine could similarly place
stress on a patient with a preexisting mitochondrial disease. Id. at 165-66.

Second, Dr. Kendall testified that in fact the medical record confirmed that L.V. had been
affected by the flu vaccine as she proposed. But she was generally unable to reference evidence
from that record in support of this assertion. Tr. at 178-79, 184-86. At best, Dr. Kendall vaguely
cited to reports of L.V.’s loss of words or irritability, but could not recall much else. Id. at 170-72.

43
Notably, on this aspect of her testimony Dr. Kendall diverted somewhat from her original expert report, which
suggested that the flu vaccine alone had produced L.V.’s regression, rather than in concert with his ear infection.
Compare Tr. 231-32 with Pet’rs’ Ex. 42 at 11.

19
She also admitted that the speech delay as reported by the Vs on December 13, 2006, was not itself
strong proof of a dramatic, vaccine-induced regression caused by an underlying mitochondrial
disease (id. at 180), and that L.V.’s constipation and related problems were ongoing, having been
present prior to his receipt of the flu vaccine. Id. She further agreed that ASD features,
development delays, developmental regression, and constipation are symptoms that are often seen
independent of a mitochondrial disorder. Id. at 196-97. Indeed, Dr. Kendall admitted on cross-
examination that, given the paucity of evidence suggesting an immediate, post-vaccination
regression, her overall theory would be undermined if it were determined that L.V.’s
developmental regression began before he received the flu vaccine. Id. at 184-86.44 However,
because it was her opinion that whatever mitochondrial dysfunction L.V. had was mild in form, it
would not be likely (in her opinion) that his regression would be as evident as in cases where a
child unquestionably was experiencing one of the more severe forms of the disease, such as
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (“MELAS”).45 Id. at
196-97.

Finally, Dr. Kendall asserted that the timeframe from the December 8, 2006, administration
of the second dose of flu vaccine to L.V.’s alleged developmental regression was medically
acceptable. Under Dr. Kendall’s proposed theory, onset of regression would occur in seven to ten
days – a length of time she derived from a single piece of literature involving a retrospective study
of individuals suffering from mitochondrial disease, some of whom experienced developmental
regression as is alleged to have occurred with L.V. Tr. at 166-69; Pet’rs’ Ex. 84 at 6 (J. Edmonds,
et al., The Otolaryngological Manifestations of Mitochondrial Disease and the Risk of
Neurodegeneration with Infection, 128 ARCH. OTOLARYNGOL. HEADNECK SURG. 355 (Apr. 2002)
[hereinafter, “Edmonds”] (setting forth that in most patients the neurologic event occurred three
to seven days after onset of infection)). Approximately one week after L.V.’s second flu
vaccination, there was “some question about some neurological changes or problems or certainly
by his parents’ report of changes in his irritability.” Tr. at 169-70. Although Dr. Kendall admitted
that irritability was not particularly strong evidence of an encephalopathy, when viewed in context

44
Dr. Kendall also made some attempt to address the fact that Petitioners’ theory required L.V. to have suffered from
a mitochondrial disease prior to his receipt of the flu vaccine. Thus, she indicated that it was not surprising to her that
L.V. might have begun to display some symptoms of autism before he received the flu vaccine, since a child suffering
from some form of a preexisting mitochondrial disease would experience ASD-like symptoms regardless of the role
a vaccine played in those symptoms’ exacerbation. Tr. at 136.
45
MELAS is a condition that “affects many of the body’s systems, particularly the brain and nervous system and
muscles.” Symptoms include “muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and
seizures.” Mitochondrial Encephalomyopathy, lactic acidosis, and stroke-like episodes, GENETICS HOME REFERENCE,
(Dec. 2013), http://ghr.nlm.nih.gov/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-
episodes (last visited Feb. 11, 2016).

20
with L.V.’s purported subsequent skill loss, in her opinion it was proof of the existence of a
“regressive encephalopathy” that was “certainly temporally related.” Id. at 170-172, 176.

2. Dr. Yuval Shafrir

Dr. Shafrir is a child neurologist who graduated from the Sackler School of Medicine at
the Tel Aviv University in 1982. He thereafter did residencies in pediatrics at Kaplan University
and the Bellinson Medical Center in Israel. Tr. at 252-53; Pet’rs’ Ex. 81 at 2. Dr. Shafrir went on
to do residencies in pediatrics at North Shore University Hospital in New York, and in pediatric
neurology at the Washington University Medical Center in Missouri. Tr. at 254; Pet’rs’ Ex. 81 at
2. From 1992 to 2000, Dr. Shafrir worked at a number of different U.S. hospitals, but currently
practices pediatric neurology in private practice affiliated with Sinai Hospital in Baltimore,
Maryland. Tr. at 252. He is licensed to practice medicine in Maryland, and has board certifications
in child neurology, although he has not renewed his board certification in pediatrics. Id. at 252,
322, 334. He has worked and taught across the country in pediatrics and neurology, and presently
does so at the University of Maryland School of Medicine. Pet’rs’ Ex. 81 at 4. He has also written
extensively on issues of pediatric neurology. Id. at 4-8.

Dr. Shafrir testified as an expert in pediatric neurology. Tr. at 252. He is not an expert in
immunology or mitochondrial disease, however. Id. at 268, 321, 361-62, 380. He is also not one
of L.V.’s treating physicians, and has never examined L.V. himself. Id. at 404. Dr. Shafrir sees
approximately 300 patients per month. Tr. at 252-54, 402. Mostly, he treats headaches and
seizures, but twenty percent of his practice is developmental in nature, and approximately ten
percent of his patients have an ASD diagnosis. Id. at 252-54, 402. But he does not have clinical
experience studying ASDs, nor does he possess specific research experience or training in that
specialty. See generally Pet’rs’ Ex. 81.46

Dr. Shafrir offered brief testimonial support for Dr. Kendall’s theory that L.V.’s autism
was related to his alleged preexisting mitochondrial disease. Tr. at 267-68, 317-18; Pet’rs’ Ex. 193
at 3. The vast majority of his testimony, however, related to his own, alternative causation theory,
which was somewhat confusing and extremely wide-ranging. Dr. Shafrir’s opinion began with a
distinction he drew between autism that proceeds on a natural course and the “regressive autism”

46
Dr. Shafrir was passionate in defending his opinions at hearing – but some of that passion was lacking in scientific
grounding. Thus, Dr. Shafrir acknowledged his belief that today, autism is present in the United States and the world
more generally at epidemic levels that cannot be explained by genetic factors (“genetics cannot occur in epidemics”
Tr. at 295; see also Id. at 257, 259, 330-31, 403. He did not, however, offer reliable evidence suggesting that the
scientific community of ASD experts shares his opinion, let alone that his opinion about an “autism epidemic” is
scientifically well-founded. He similarly denied the possibility that the rise in ASD diagnoses could be explained by
the fact that medical practitioners have become better at spotting and diagnosing the relevant behaviors and/or
symptoms, claiming that “any preschool teacher” can make the diagnosis. Pet’rs’ Ex. 80 at 31.

21
he believes L.V. experienced. Tr. at 336. Indeed, he disputed the concept of a “natural course of
autism” that would typically include a developmental regression. Id. at 329. Rather, according to
Dr. Shafrir, sudden autistic regression is more likely caused by an encephalopathy. Id. at 251. He
thus maintained that regressive autism – which in his view accounts for approximately thirty
percent of all ASD patients, and is in some cases treatable (due to its causes) – was a form of
autism, although he admitted that it does not constitute a separate clinical phenotype that is
formally recognized medically. Id. at 336-37.

In Dr. Shafrir’s opinion, L.V. experienced an “acute autistic regression following his
second influenza immunization” (tr. at 264) at 20 months (id. at 338) which “can be best explained
as an autoimmune process.” Id. at 264-65, 274. He based this view on post-vaccination evidence,
which he argued revealed “all the components” of autistic regression. Id. at 280. His opinion was
also based on scientific articles and literature that he maintained drew a connection between the
administration of the flu vaccine and L.V.’s allegedly abrupt subsequent regressive incident.

First, Dr. Shafrir testified that the flu vaccination has been demonstrated to be a cause of
autoimmune encephalopathy. Tr. at 284; Pet’rs’ Ex. 80 at 28. As proof, he mentioned several
pieces of literature associating vaccines (and particularly the flu vaccine) with antibody-mediated
autoimmune encephalitis. Tr. at 284 (citing Pet’rs’ Ex. 80, Ref. 10 (J. Dalmau, Clinical experience
and laboratory investigations in patients with anti-NMDAR encephalitis, 10 LANCET NEUROL 63
(Jan. 2011) [hereinafter “Dalmau”]); Pet’rs’ Ex. 80, Ref. 11 (T. Hung, et al., Anti-N-methyl-D-
Aspartate Receptor Encephalitis, 52 PEDIATRICS & NEUROLOGY 361 (Jan. 2011)); Pet’rs’ Ex. 80,
Ref. 12 (M. Kubota and Y. Takahasi, Steroid-Responsive Chronic Cerebellitis with Positive
Glutamate Receptors δ2 Antibody, 23(2) J. OF CHILD NEUROLOGY 228 (Feb. 2008)); and Pet’rs’
Ex. 80, Ref. 13 (J. Takanashi, et al., Late Delirious Behavior with 2009 H1N1 Influenza: Mild
Autoimmune-Mediated Encephalitis? 129 PEDIATRICS 1068 (2012)). He maintained that scientific
studies have plainly observed a tendency in individuals to develop autoantibodies following receipt
of the flu vaccine. Pet’rs’ Ex. 80 at 30 (citing Pet’rs’ Ex. 80, Ref. 31 (N. Toplak, et al., Autoimmune
response following annual influenza vaccination in 92 apparently healthy adults, 8
AUTOIMMUNITY REVIEWS 134 (2008)). Such autoantibodies, in turn, attack human brain tissues,
resulting in an encephalopathic incident. Tr. at 208 (citing Pet’rs’ Ex. 41, Ref. 26 (E. Hsiao, et al.,
Modeling an autism risk factor in mice leads to permanent immune dysregulation, PROC. OF THE
NAT’L ACAD. OF SCI. www.pnas.org/cgi/doi/10.1073/pnas.1202556109)47; Tr. at 301; Pet’rs’ Ex.
80, Ref. 19 (D. Obregon, et al., Potential Autoepitope within the Extracellular Region of

47
“Developmental Regression and Mitochondrial Dysfunction in a Child with Autism” is a case abstract of one child
who experienced severe regression following a vaccination. Petitioners have attempted on numerous occasions to
equate L.V.’s situation with that of the child in Poling. See, e.g., Motion to Compel Respondent’s Admission of the
Medical Theory, Jan. 5, 2015 (ECF No. 112). However, Poling was a severe example of a Table Injury following
vaccination, unlike the non-Table claim here.

22
Contactin-Associated Protein-like 2 in Mice, 4(1) BRITISH J. OF MED. & MED. RES. 416 (2014)
[hereinafter “Obregon”]))48; Tr. at 297 (citing Pet’rs’ Ex. 80, Ref. 14 (R. Dhamija, et al., Neuronal
Voltage-Gated Potassium Channel Complex Autoimmunity in Children, 44 PEDIATR NEUROL 44
(2011) [hereinafter “Dhamija”])49). Thus, Dr. Shafrir maintained that the flu vaccine could in
theory produce an autoimmune reaction through the creation of antibodies and/or active T-cells
which cross-react with certain proteins in the brain. Tr. at 361 (citing Pet’rs’ Ex. 80 at 31). This
“more likely than not” causes “widespread disruption of the brain function, resulting in autism.”
Tr. at 294, 296, 331.

For additional support, Dr. Shafrir referenced literature highlighting instances in which
vaccines have been associated with negative neurologic conditions. Tr. at 287-89; Pet’rs’ Ex 80,
Ref. 5 (K. Lapphra, et al., Adverse Neurologic Reactions After Both Doses of Pandemic H1N1
Influenza Vaccine With Optic Neuritis and Deymyelination, 30(1) THE PED. INFECTIOUS DISEASE
J. 84 (Jan. 2011) [hereinafter, “Lapphra”]). Lapphra describes a case study showing the occurrence
of neurologic changes in a two-year-old Filipino boy shortly after receiving the H1N1 flu virus
vaccine. Id. at 18-19. The child was diagnosed with acute disseminated encephalomyelitis
(“ADEM”)50; his initial symptoms had spontaneously resolved after the first dose of vaccine, but
worsened after the second. Id. at 19. The Lapphra authors claimed the displayed progression in
symptom development strongly suggested that the flu vaccine was a causative factor for the child’s
illness, arguing that the sequence of events was consistent with the production of greater amounts
of myelin-attacking antibodies after each vaccination. Id. Here, by contrast, L.V.’s regression has
never been attributed to ADEM, nor was he ever diagnosed with that or any other similar
demyelinating disease. In addition, the H1N151 flu vaccine at issue in Lapphra is not precisely
analogous to the vaccine L.V. received herein, further limiting the relevance of this case study to
L.V.’s circumstances. Tr. at 363-66.

48
Dr. Shafrir referenced Obregon numerous times throughout his testimony. Even though the study solely evaluated
how human viral and bacterial wild pathogens can trigger the creation of antibodies that attack certain brain proteins,
resulting in an encephalopathy, Dr. Shafrir suggested that a similar homology existed between components of the flu
vaccine and those same proteins, and thus the same result was possible. Tr. at 405-06.
49
Dr. Shafrir referenced Dhamija as evidence that influenza vaccinations cause an autoimmune attack on the brain
that produced autistic regression. Tr. at 297. This article, however, mentions only a single example of such an
association (Pet’rs’ Ex. 80, Ref 14 at 2) and concludes that larger case studies are necessary. Id. at 7.
50
ADEM is an acute or subacute inflammation involving both the brain and spinal cord characterized by perivascular
lymphocyte and mononuclear cell infiltration and demyelination. “[I]t occurs most often after an acute viral
infection…but may occur without a recognizable antecedent. It is believed to be a manifestation of an autoimmune
attack on the myelin of the central nervous system. Symptoms include fever, headache, and vomiting; sometimes
tremor seizures, and paralysis; and lethargy progressing to coma that can be fatal.” Dorland’s at 613.
51
As Dr. Shafrir admitted on cross, strains of the H1N1 virus were not added to the seasonal flu vaccine until 2010 –
four years after L.V. received the flu vaccine. Tr. at 366.

23
Dr. Shafrir next opined that autoimmune encephalitis (as well as immune dysfunction more
generally) is a recognized cause of regressive autism. Tr. at 285; Pet’rs’ Ex. 80 at 30-31. As
exemplifying a portion of the “accumulating evidence” that an autoimmune process can start in
the brain and precipitate autism, he pointed to a series of case studies: one of which occurred in a
child with Voltage-Gated Potassium Channel [“VGKC”]52 antibodies (Dhamija), and two others
where the patients had measurably heightened levels of anti-NMDA-receptor53 antibodies, which
have been linked to a specific kind of encephalitis.54 See Pet’rs’ Ex. 80, Ref. 15 (O. Scott, et al.,
Anti-N-Methyl-d-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic
Regression in a Toddler, J. OF CHILD NEUROLOGY 1 (2013)), and Ref. 16 (C. Creten, et al., Late
onset autism and anti-NMDA-receptor encephalitis, 378 LANCET 98 (2011)). He also referenced
an article that speculates about the possible relationship between autoimmune synaptic encephalitis
and autism. Tr. at 376-77 (citing Pet’rs’ Ex. 80, ref. 18, M. Kayser, et al., The Emerging Link
Between Autoimmune Disorders and Neuropsychiatric Disease, 23(1) NEUROPSYCHIATRIC CLIN.
NEUROSCI. 90 (Winter 2011) [hereinafter “Kayser”]); see also Pet’rs’ Ex. 80 at 29.

However, Dr. Shafrir acknowledged limitations to the portion of his theory connecting the
flu vaccine to autoimmune-mediated encephalopathies. On cross-examination, Dr. Shafrir
admitted that the literature he cited (and in particular, Dalmau) observed no more than an
association between the flu vaccine and encephalopathy, and thus did not support the conclusion
that the flu vaccine was itself causative of any form of encephalopathy. Tr. at 366-67, 370. He also
conceded that, because there is no evidence that L.V. has anti-NMDA encephalitis, anti-NMDA
antibodies, or anti-VGKC encephalitis or antibodies, studies focusing on such narrow forms of
autoimmune illnesses were largely inapposite. Id. Indeed, as Dr. Shafrir admitted, L.V. displayed
no objective evidence of an autoimmune reaction in his brain, and no MRI findings that would be
associated with an autoimmune encephalopathy. Id. at 362-63, 369, 508. Dr. Shafrir nevertheless
stressed there were individual case studies where regression associated with an encephalopathic
event had occurred, and that such regressions could be treated. Id. at 373-75.

52
As noted in Dhamija, voltage-gated potassium channels are proteins in neurons in the central and peripheral nervous
systems that play a role in membrane repolarization, axonal conduction, and synaptic transmission. Dhamija at 275.
53
NMDA stands for “N-methyl-d-Aspartate.” NMDA is a “neurotransmitter similar to glutamate, found in the central
nervous system; a synthetic preparation is used experimentally to study the excitatory mechanisms of glutamate
transmitters.” Dorland's at 1152.
54
Anti-NMDA receptor encephalitis is a clinical disorder, mostly in adolescents, that presents with a sudden onset of
altered mental status, with and without seizures, behavior change, often fever, and ovarian or testicular tumors. Tr.
515-16.

24
To explain the biologic mechanism by which the flu vaccine could precipitate an
autoimmune encephalopathy as Petitioners alleged to have happened with L.V., Dr. Shafrir
proposed molecular mimicry through homology of epitopes.55 Tr. at 267; Pet’rs’ Ex. 80 at 29-30
(citing Obregon). In a typical immune response, he explained, cells produce antibodies in reaction
to the viral or bacterial invader. Tr. at 301, 405. However, due to similarities (the “mimicry”) in
the structure of the amino acid sequences in the healthy tissue and the virus, the antibodies
produced mistakenly attack healthy tissue (as well as the virus they were intended to attack), thus
triggering an autoimmune reaction. Id. at 405. The same process could occur with vaccination; as
evidence, Dr. Shafrir offered specific literature that demonstrated homology between components
of the flu vaccine and brain tissues. Id. at 298-99. In particular, Dr. Shafrir discussed the homology
between the amino acid sequence in the CSPR-2 protein56 found in the brain and the hemagglutinin
protein of influenza A virus, which he maintained have been found by reputable studies to be
sufficiently similar to cross-react and thereby create the necessary autoantibodies to attack self,
and which he purported is a component of the flu vaccine.57 Id.

In further support of his proposed molecular mimicry mechanism (and also as evidence of
the pathogenic potential of the flu vaccine), Dr. Shafrir cited a Finnish study involving narcolepsy
among children after receipt of the H1N1 Pandemrix flu vaccine, along with other literature
addressing the same event. See, e.g.,Tr. at 291; Pet’rs’ Ex. 80 at 31 (citing Pet’rs’ Ex. 80, Ref. 33
(A. Kӓll, The Pandemrix – narcolepsy tragedy: how it started and what we know today, 102
FOUNDATION ACTA PAEDIATRICA 2 (2013)); Pet’rs’ Ex. 80, Ref. 34 (M. Partinen, Narcolepsy as
an autoimmune disease: the role of H1N1 infection and vaccination, 13 LANCET NEUROL 600
(2014));, Pet’rs’ Ex. 80, Ref. 35 (M. Partinen, et al., Does autoreactivity have a role in
narcolepsy?, 13 LANCET NEUROL 1072 (Nov. 2014)); and Pet’rs’ Ex. 80, Ref. 36 (A. Singh, et al.,
Genetic association, seasonal infections and autoimmune basis of narcolepsy, 43 J. AUTOIMMUN.
26 (Jun. 2013)). However, Dr. Shafrir admitted that the formulation of the Pandemrix vaccine was
not equivalent to what L.V. received (and indeed is not even administered in the U.S. (tr. at 365)),

55
As Dr. Shafrir explained, “epitope” is a term in immunology to describe a short segment of an amino acid that can
produce an immune reaction to an antigen. Tr. at 267. He argued that the best example of how molecular mimicry
worked in L.V.’s case was provided by the studies that show a relationship between the H1N1 vaccination and
narcolepsy. Id. at 291.
56
Dr. Shafrir explained that CSPR-2 protein is one of the two major proteins (the other being Lg-1) that are targets
for an autoimmune attack. Tr. at 301. Antibodies against this particular protein could, according to Dr. Shafrir,
precipitate symptoms related to autism. Id. at 302.
57
Dr. Shafrir specifically testified that the influenza-a and influenza-b components were both present in the flu vaccine
L.V. received, but it was the homology between hemagluttinin protein in the influenza-a virus and the CSPR-2 protein
in the brain that caused the autoimmune reaction. Tr. at 300-02. Although L.V.’s brain had never been tested for these
proteins, Dr. Shafrir maintained that this component of his theory still had plausibility. Id. at 302-03.

25
although he nevertheless maintained that, because both versions had some of the same protein
sequence components, the study still had relevance to his theory. Id. at 366.

Dr. Shafrir also maintained that an individual like L.V. could be especially sensitive to
stimulation by the flu vaccine given other aspects of his overall health. Tr. at 318, 380-81; Pet’rs’
Ex. 190 (G. Morris, et al., The Many Roads to Mitochondrial Dysfunction in Neuroimmune and
Neuropsychiatric Disorders, 13 BIOMED CENTRAL 68 (2015)). Thus, Dr. Shafrir asserted that L.V.
was immunosensitive (tr. at 285-86), having obvious abnormalities in his immune system, as
evidenced by his multiple, severe allergies, high erythrocyte sedimentation rate, documented IgA
deficiency, and inflammatory bowel disease diagnosis. Id. at 285-86, 296; Pet’rs’ Ex. 80 at 27. He
emphasized that patients who are susceptible to immune abnormalities are more likely to suffer
autoimmune reactions. Tr. at 323 (citing Pet’rs’ Ex. 187 (Y. Takahashi, et al., Vaccination and
infection as causative factors in Japanese patients with Rasmussen syndrome: Molecular mimicry
and HLA class I 13(2-4) CLINICAL & DEVELOPMENTAL IMMUNOLOGY 381 (Jun.-Dec. 2006))).
Individuals with allergies are also more likely to be autistic. Id. However, he admitted that he could
cite no objective evidence from the record of L.V.’s purported immune-sensitivity, and that (once
again) existing MRI findings did not support this aspect of his theory. Tr. at 362-63.58

Based upon the above, Dr. Shafrir offered an interpretation of L.V.’s medical history aimed
at demonstrating that the regression L.V. experienced appeared suddenly, after L.V.’s second flu
vaccination. He maintained that the medical record showed that L.V. was developing normally
until December 8th, with a sudden and severe regression thereafter, beginning within a week (or
around the time of the December 13th pediatric visit). Tr. at 268-69, 339. Yet Dr. Shafrir admitted
that he lacked data from the medical record that substantiated this assertion, beyond some mention
of constipation and the ear infection L.V. was experiencing at the time. Id. at 342-44. He could
point to little else in the record (beyond the Vs’ recollections) that L.V. ever experienced anything
medically dramatic, in this period or thereafter.

Dr. Shafrir also attempted to grapple with contrary evidence in the record suggesting that
L.V.’s ASD symptoms were evident before he received even the first flu vaccine. Thus, he
admitted that L.V.’s medical records were “all over the place,” in identifying the onset of his
alleged regression and/or ASD symptoms. Tr. at 328, 409. However, he posited that the Vs became
“very concerned” about L.V.’s development only at 21 months, downplaying the significance of
pre-vaccination evidence of developmental problems they may have observed (and reported to
treaters as having occurred at 18 and 19 months – before receipt of the first dose of the flu vaccine).

58
At best, Dr. Shafrir proposed that L.V. likely possessed a genetic defect inherited from his parents (as evidenced by
a gene “deletion that was found in [L.V.’s] father” (tr. at 296)), offering additional literature to support the conclusion
that autistic children with demonstrated allergies more likely also suffer from immune system abnormalities. Id.

26
Id. at 277-78, 347, 387. Thus, Dr. Shafrir proposed that the Vs likely mistook normal childhood
behaviors, such as flapping (which the medical records show was observed at 12 months), as the
first signs of autism. Id. at 277-78, 347-58.

Dr. Shafrir similarly attempted to rebut the many instances in the medical record, beginning
in January 2007, where the Vs directly informed a treater (such as Dr. Coplan) that L.V.’s
developmental regression had been evident at 18 months of age rather than 21 months. Tr. at 347.
To do so, he persistently relied on a pediatric well-child visit record from September 2006, which
reported that L.V. was, at that time, a “normal child,” as well as Mrs. V’s testimony. Id. at 281.
Dr. Shafrir characterized all subsequent, contrary medical records that referenced an earlier start
to L.V.’s autism symptoms as “profoundly wrong.” Id. at 348. But Dr. Shafrir was generally
unsuccessful in his efforts to explain why such records were untrustworthy.59 He otherwise
categorically dismissed the many contemporaneous statements about L.V.’s onset of symptoms as
instances in which the Vs simply repeated a “story” about L.V.’s onset by rote. Id. at 324-25, 350-
51, 356.60

Ultimately, Dr. Shafrir opined that the flu vaccine was the “only obvious cause” of L.V.’s
regression. Tr. at 283; Pet’rs’ Ex. 80 at 31. In so determining, he rejected the possibility of some
underlying genetic or other environmental explanation. Tr. at 294, 296. Indeed, Dr. Shafrir went
so far as to reject genetic causes of autism in general, stating that “genetics cannot occur in
epidemics.” Id. at 295.61

In an attempt to support Petitioners’ overall burden of demonstrating a medically
acceptable timeframe between vaccination and onset of L.V.’s autistic regression, Dr. Shafrir

59
For example, Dr. Shafrir questioned a statement set forth in Dr. Coplan’s January 23, 2007, record regarding L.V.’s
purported delay in use of a spoon and/or cup to feed, pointing out that a contemporaneous record from a 12-month
visit suggested that L.V. had by that time already mastered spoon-feeding (thus not only calling into question the
accuracy of Dr. Coplan’s record but also suggesting the degree of L.V.’s post-vaccination regression). Tr. at 397-400.
As discussed below, however, even if this part of Dr. Coplan’s evaluation is inconsistent with an earlier record (a
conclusion I do not adopt given other records), I do not find that it is meaningfully so, such that I would find Dr.
Coplan’s January 2007 written evaluation overall untrustworthy in the manner urged by Petitioners.
60
Thus, Dr. Shafrir was cross-examined about several specific such instances in the medical record from 2007 and
into 2008, where the Vs were reported to have specified an earlier onset of L.V.’s ASD regression and/or symptoms.
In every case, Dr. Shafrir disputed the record’s accuracy. See, e.g., Tr. at 347, 350, 351, 353 (disputing references to
regression beginning at 18 months in the Early Intervention evaluation (Pet’rs’ Ex. 13 at 8); the Vs’ report to Dr.
Coplan (Pet’rs’ Ex. 5 at 3); reports to Dr. Brian Jepson at the Thoughtful House in Austin, Texas (Pet’rs’ Ex. 10 at
78); Dr. Hillary Kruger’s records in May of 2007 (Pet’rs’ Ex. 6 at 1); Dr. Arthur Krigsman’s records in June of 2007
(Pet’rs’ Ex. 9 at 6); and Dr. James Neubrander’s chart in September of 2007 (Pet’rs’ Ex. 8 at 3)).
61
Dr. Shafrir later, however, admitted that the interaction of environmental factors with a genetic predisposition is, in
his view, the most likely cause of autism in the majority of cases. Tr. at 404.

27
argued that there was evidentiary support from the medical record for the conclusion that a reaction
occurred within five days. Tr. at 278, 280, 289-90. He based this argument in part on the fact that
L.V. had already received the first dose of the flu vaccine in November, which he claimed played
“an obvious role” because “[p]rimary immune reaction cannot occur in five days.” Id. at 292-93.
He thus differentiated these circumstances from the typical conception of “symptomatic
rechallenge,”62 instead asserting that this was an instance of what he termed “immunological
rechallenge.” Id. at 305-06. Immunological memory from the first vaccination facilitated the
molecular mimicry and the production of antibodies which acted against parts of the brain, causing
autism. Id. at 285. In further support of the reasonableness of the time period from vaccine to
injury, Dr. Shafrir noted that neurological loss can occur within a couple of days and usually within
a week to ten days. Id. at 169. In this regard, he compared L.V.’s regression to the development of
narcolepsy and/or Guillain-Barré syndrome both of which can manifest within 72 hours of a trigger
event. Id. at 289-91.

Again, however, Dr. Shafrir had difficulty identifying record support for this aspect of his
opinion. He thus admitted that he could point to very little record evidence actually establishing
the profound regression he posited that L.V. had experienced in December, beyond statements
contained in Dr. Coplan’s assessment about behavioral and developmental changes that the Vs had
observed in L.V. – records he simultaneously attacks as inaccurate or inconsistent with the Vs’
view of L.V.’s history. Tr. at 343. At most, he referenced evidence of L.V.’s constipation around
the time immediately after the December 8th vaccination. Id. at 344-46.

C. Respondent’s Expert – Dr. Bruce Cohen

Respondent’s expert, Bruce Cohen, M.D., offered testimony mostly responding to
Petitioners’ theory that L.V. suffered from a mitochondrial disease or disorder of some kind that
related to his alleged post-vaccine developmental regression.
Dr. Cohen graduated from Albert Einstein College of Medicine of Yeshiva University in
1982 (after completing his undergraduate degree at Washington University in St. Louis). Resp’t’s
Ex. B at 2. Dr. Cohen went on to complete a pediatric residency at Children’s Hospital of
Philadelphia, followed by a Pediatric Neurology Residency at the Neurological Institute of New
York and Babies Hospital of Columbia Presbyterian Medical Center and a Pediatric Neuro-
Oncology Fellowship at the Children’s Hospital of Philadelphia. Id. Dr. Cohen is board-certified
in Neurology, with Special Competence in Child Neurology, and was previously board-certified
in Pediatrics. Id. at 3.

62
According to Dr. Shafrir, the typical concept of rechallenge is a symptomatic rechallenge, where an individual has
a reaction to a medicine or a vaccination, and then has a similar or worse reaction after the second exposure to the
medicine or vaccine. Tr. at 305-06.

28
Dr. Cohen is currently the Director of Neurology at the Children’s Hospital Medical Center
of Akron and a Professor of Pediatrics at Northeast Ohio Medical University, where he teaches
general pediatric neurology to medical students, residents, and fellows. Resp’t’s Ex. B at 3; Tr. at
414. He has also taught courses specifically on mitochondrial disease in symposia. Resp’t’s Ex. B
at 5-6. He is a reviewer for several journals and on the editorial board for the Mitochondrion and
the Pediatric Neurology Journal. Id. at 4. And he serves on various review committees – seven in
total – including the Neurofibromatosis Consortium. Id. Dr. Cohen has written extensively on
issues of mitochondrial diseases, authoring or co-authoring nearly 100 peer-reviewed articles. See
generally, id. Dr. Cohen has served in many different capacities for The United Mitochondrial
Disease Foundation since 1999 and served on many different committees regarding mitochondrial
disease. Id. at 4-5.

Dr. Cohen has particular expertise in studying and treating mitochondrial diseases. He has
been assisting with or treating patients with mitochondrial disorders or suspected mitochondrial
disorders since 1994. Tr. at 415. As a child neurologist, Dr. Cohen sees adults and children with
mitochondrial diseases and brain tumors. Id. at 412. Although Dr. Cohen does not diagnose ASDs,
some of his patients have autism as well as suspected mitochondrial diseases. Id. at 417. He
routinely diagnoses mitochondrial diseases or dysfunction in his patients, estimating that he has
seen several thousand patients in which the disease was suspected, or actually diagnosed, since
1994. Id. at 416. Of the nearly 100 peer-reviewed articles he has published, approximately a fourth
of them are readily discernible as dealing primarily with issues of mitochondrial dysfunction. See
generally, Resp’t’s Ex. B.

Relying on his experience treating patients with mitochondrial diseases, Dr. Cohen
formulated his opinion after reviewing L.V.’s medical records and the expert reports and journal
articles filed, along with Petitioners’ expert reports. Resp’t’s Ex. A at 4; Tr. at 423. Based on this
review, Dr. Cohen opined that there is no credible evidence that L.V. has a mitochondrial illness,
or that any vaccination L.V. received in any way contributed to his autism or other medical
conditions. Resp’t’s Ex. A at 4.

Dr. Cohen began by providing an overview of mitochondria, and the function they play in
the generation of energy necessary for the human body. Tr. at 424. He explained that mitochondria
exist in all mammalian cells, except for mature red blood cells. Id. at 425. Mitochondria are one
micron in length, or one-forty-thousandth of an inch, and have an outer membrane and an inner
mitochondrial membrane. Id. The mitochondria generate energy, or adenosine triphosphate
(“ATP”),63 which is held in covalent bonds, and some metallic molecules within the mitochondria
conduct the electricity via the ETC. Id at 428. The ETC is found within the inner mitochondrial

63
Adenosine triphosphate is a nucleotide involved in energy metabolism, which occurs in all cells and is used to store
energy. Dorland’s at 30.
29
membrane and allows for the regeneration of ATP, which can then be used by the cells throughout
the human body to cause muscle contractions, allow the ears to hear, or even cause the heart to
beat. Id. at 429. This process also creates heat and free radicals that can damage the cell or serve
“healthful purposes” within the body. Id.

Because not all mitochondrial diseases are the same, not every patient displays the same
symptoms, though there are some classic phenotypes. Tr. at 430. Mitochondrial diseases were
described as early as 1930, and since that time the diagnostic criteria used to discern if an individual
suffers from such a disease have been refined. Id. at 429-30. The development of genetic testing,
however, has increased the surety of the diagnosis, lessening the reliance on muscle biopsies or
enzymology,64 which were in the past the best ways to confirm a suspected mitochondrial disease.
Id. at 430, 432, 462.

Dr. Cohen discussed the differences between primary and secondary mitochondrial
disease. Tr. at 434. Primary mitochondrial disease refers to those diseases that have a “known,
verified genetic cause that is linked to the clinical phenotype of the patient” and “primarily affect
the mitochondrial structure.” Id. Although primary mitochondrial dysfunction can be most directly
diagnosed by genetic testing, it can still be properly diagnosed even in the absence of such testing
if the patient’s symptoms match a known phenotype, such as Leigh disease. Id. at 435-36.
Secondary mitochondrial disease usually involves a problem external to the mitochondria that
indirectly produces metabolic dysfunction, such as a genetic defect that causes iron not to be
processed properly, with the excess iron harming the mitochondria. Id. at 435-36, 595. Dr. Cohen
also discussed mitochondrial dysfunction, which he defined as a “global, generic term” referring
to when the mitochondria work imperfectly or are overloaded, but not necessarily as the result of
disease. Id. at 435-36. Such mitochondrial dysfunction can occur in otherwise benign, everyday
contexts (i.e. eating a high-fat meal). Id. at 436.

To diagnose a mitochondrial disease, Dr. Cohen proposed, a physician should begin with
a patient’s medical history, including a physical exam and family history. Tr. at 432. If the patient
fits a known mitochondrial disease phenotype, then the physician should conduct tests of the blood,
urine, and cerebral spinal fluid for indication of the mitochondrial process. Id. at 433. While some
biochemical markers on their own may suggest dysfunction, Dr. Cohen proposed that review of
biomarker test results should be considered collectively rather than in isolation. Id. at 461, 477.
The physician should also do a functional organ test, depending on which organ(s) the physician
suspects the mitochondrial disease may be affecting. Id. Other factors indicative of an ongoing

64
Enzymology is “the study of enzymes and enzymatic action.” Dorland’s at 629.

30
disease process are evidence of too few mitochondria or (in the case of adults) too few mtDNA.
Id. at 460.

A muscle biopsy with electron or light microscopy testing can also be performed to confirm
the presence of a mitochondrial disease. Tr. at 452. Through electron microscopy, a piece of
muscle is processed and then magnified 25 to 40,000 times. Id. at 456. In light microscopy, by
contrast, a pathologist takes a piece of muscle, slices it into thin sections for staining with different
stains, sometimes at different pH levels, and then looks at it under an ordinary microscope to make
a diagnosis. Id. at 452-53. As science has evolved, however, the emphasis placed on the importance
or meaning of certain tests used to diagnose mitochondrial disease has changed, Dr. Cohen
indicated. Thus, because over the past several years genetic testing capable of reliably confirming
a mitochondrial disease has become more widely available, the significance of muscle biopsies
and other tests have greatly diminished. Id. at 434.

One recent piece of literature Dr. Cohen co-authored and emphasized as particularly useful
in understanding what factors are most suggestive of the existence of a mitochondrial disease is R.
Haas, et al., Mitochondrial Disease: A Practical Approach for Primary Care Physicians, 120
PEDIATRICS 1326 (2007), filed as Ct. Ex. 1. ECF No. 133.65 Dr. Cohen noted that Haas
differentiates between “red flag” indicia of the presence of mitochondrial disease versus what the
article terms ‘nonspecific” criteria. Id. at l; Tr. at 431-32, 470-72. In effect, the nonspecific criteria
are far less persuasive evidence of the presence of mitochondrial disease than the red flag indicia
because they are not exclusively or predominantly associated with mitochondrial disease. Tr. at
446.

Dr. Cohen provided examples of the ways in which certain nonspecific criteria (that in the
past might have been given more weight in making a mitochondrial disease diagnosis) were not
particularly useful in signifying the presence of the disease. Thus, Dr. Cohen noted that the
gastrointestinal dysfunction commonly experienced by individuals with an ASD was not
commensurate with the far more severe kind of gastrointestinal symptoms those with classic
phenotypes of mitochondrial diseases experienced. Tr. at 441-44. Similarly, the level of brain
injury suffered in autism was not nearly as progressively debilitating and monophasic as that
experienced by someone diagnosed with Leigh disease (whose brain injuries and other symptoms
would in most cases result in death – not the outcome inevitably experienced by those diagnosed
with an ASD). Id. at 434, 439.

Dr. Cohen also expressed the overarching opinion that the scientific community rejects the
concept (based on present science) of a link between ASDs and mitochondrial disease (even

65
While I filed the Haas article as a Court Exhibit, Dr. Cohen also referenced the article extensively in his testimony.
See, e.g., Tr. at 431.

31
though in rare circumstances developmental regression is seen with certain mitochondrial
diseases). Tr. at 437. He recalled that when he began studying mitochondrial disease, it was widely
theorized that autism might be related, given similarities in how suddenly the symptoms could
develop, and/or how they seemed to involve similar energy deficiencies. Id. However, as
understanding of mitochondrial diseases expanded, in his view medical science was slowly
reaching the conclusion that there was no such relationship, given how few of those diagnosed
with autism also presented with known symptoms of a mitochondrial disease, and the lack of other
links. Id. at 438.

Turning to the record herein, Dr. Cohen explained why he differed with Drs. Kendall’s and
Frye’s mitochondrial disease diagnosis. Tr. 455-56. In Dr. Cohen’s view, L.V. merited a score of
zero on the Morava scale, given the minimal morphologic data, and lack of persuasive enzymology
test results. Resp’t’s Ex. A at 12. Rather, Dr. Cohen asserted that L.V.’s medical history and
clinical phenotype reflected autism without a known etiology. Tr. at 440.

In so doing, Dr. Cohen provided his own understanding of the value of the Morava criteria,
especially in light of subsequent scientific thinking on the diagnosis of mitochondrial disease. Tr.
at 462-63. He pointed out Dr. Kendall’s concurrence that Morava had limited application as the
most up-to-date criteria (in particular given the availability today of genetic testing), and that the
community of mitochondrial disease-oriented specialists were generally “walking away” from its
use. Id. at 463-64, 551, 567. He reiterated the general point that Morava gives too much weight to
nonspecific symptoms (for example, “exercise intolerance”). Id. at 445-46. He also stressed,
however, that even current clinical diagnostic criteria for evaluating whether a mitochondrial
disease was present could not be applied precisely in most cases, and could accordingly result in
certain test results being interpreted as abnormal when they did not in fact suggest the presence of
disease. Id. at 464-65.

Dr. Cohen examined Dr. Frye’s specific application of the Morava criteria in detail. Tr. at
440-41, 444. At the outset, Dr. Cohen observed that L.V.’s clinical presenting features (primarily
autistic symptoms and developmental regression) were not congruent with the severe disease
phenotypes displayed by children in the study used to develop the Morava criteria (such as MELAS
or Leigh disease). Id. at 465-66, 603. Dr. Cohen therefore suggested that (although he did not take
issue with Dr. Frye’s decision to consider the possibility that L.V. had a mitochondrial disease),
the diagnostic utility of the Morava criteria in this context should have been viewed with some
skepticism.

Turning to the specific Morava criteria tallies, Dr. Cohen opined that the point given by
both Drs. Kendall and Frye for exercise intolerance was inappropriate. Exercise intolerance seen
in relation to a mitochondrial disease is typically a product of “myopathy, muscle disease, or nerve

32
neuropathy, nerve disease, or cardiomyopathy.”66 Tr. at 445. Here, however, L.V.’s medical
history not only was far more vague in depicting L.V.’s purported intolerance, but it was also a far
cry from the kind of byproduct symptom commonly seen with true mitochondrial disease. Id. at
445-46.

Dr. Cohen also challenged the point denoted by Dr. Frye for L.V.’s ASD. Tr. at 469. In Dr.
Cohen’s interpretation, L.V’s developmental regression was more reflective of idiopathic autism
than a mitochondrial disease. Id. at 471-72. In patients with mitochondrial diseases, Dr. Cohen
testified, problems in brain function are clearly demonstrated through evidence of brain atrophy,
lesions in the brain, and/or lactate peaks on their MRI scans, and can result in dementia and other
severe, progressive declines in function that are measurable. Id. at 575. That kind of drastic loss of
cognitive skills associated with mitochondrial diseases is readily distinguishable from the loss of
cognitive skills in autism, or the loss demonstrated by L.V.’s history, which Dr. Cohen argued
discounted scoring it under Morava’s point system. Id.

Dr. Cohen further testified that L.V. should receive a score of zero under the Morava
criteria for his purported gastrointestinal symptoms. L.V.’s constipation was mild enough to be
relieved by miralax, and therefore did not rise to the level of severity commonly associated with
mitochondrial diseases. Tr. at 444; Resp’t’s Ex. A at 12. Dr. Cohen elaborated that the
gastrointestinal disturbances common to ASD look markedly different from those experienced by
patients with classic mitochondrial phenotypes. Tr. at 438-39. Patients with definite mitochondrial
diseases, like MELAS, experience total, severe obstruction that may require exploratory surgery
to find the blockage. Id. at 442. In contrast, ASD patient constipation is much less severe. Id. at
443.

With respect to the results of various lab tests performed on L.V., Dr. Cohen maintained
that even though some of the results revealed abnormalities that might merit some consideration
under the Morava criteria, they were either uncorroborated by other confirmatory tests or simply
overwhelmed by the weight of far more persuasive evidence that in fact L.V. did not have a
mitochondrial disease. Tr. at 477.

Thus, Dr. Cohen expressed the view that the results of L.V.’s laboratory tests were also not
worthy of any Morava points. Tr. at 446. With respect to the lactic acid measurements, Dr. Cohen
stressed that such testing is routinely prone to false elevation because “struggling” can raise the
lactic acid (and struggling is far more likely when a biopsy is obtained from a child). Id. at 447.
Here, Dr. Cohen proposed that the results showing elevated lactate levels were questionable for
that very reason. Resp’t’s Ex. A at 13. Furthermore, Dr. Cohen noted that L.V.’s amino acid testing

66
Dr. Cohen describes these, moreover, as “objective disorders” that would be readily evident to a treater. Tr. at 445.

33
and the alanine-to-lysine ratio67 results – tests well-understood as corroborating an elevated lactate
result – were both normal, and therefore undermined the elevated lactate findings. Tr. at 448-49.

As for the abnormal ethylmalonic acid and tricarboxylic acid/Krebs cycle intermediates
test results, Dr. Cohen did not consider the results to be sufficiently high, or sufficiently confirmed
by additional testing, therefore suggesting only that further in-depth evaluation was required to
determine if there was in fact mitochondrial dysfunction. Tr. at 450, 559-60. In addition, the
acylglycine test results (used to help confirm the meaningfulness of abnormal ethylmalonic acid
and kreb cycle intermediates results) were normal, further diminishing the value of some of these
abnormal biomarker test results. Id. at 450.

The last category – mitochondrial morphology – also received a score of zero from Dr.
Cohen. Resp’t’s Ex. A at 10, 12. While Dr. Cohen agreed that abnormal morphology – specifically
the presence of increased mitochondria with some swelling (Resp’t’s Ex. A at 7) – was seen on
L.V.’s electron microscopy, there were “no light microscopy correlates.” Id. at 13. According to
Dr. Cohen, there are “well-established immunohistochemical features” that should have been seen
on “light microscopy,” such as ragged red fibers and COX-negative fibers, none of which were
found in L.V.’s muscle biopsy. Id. Otherwise, the finding that L.V.’s electron miscroscopy results
showed swollen mitochondria was more consistent with a lab error than disease, and would
therefore “be a stretch” to award a point under Morava. Id. at 11; Tr. at. 451-56. If the swelling
was in fact indicative of a mitochondrial disease, the patient would also display disruption in the
interim crystalline structure. Tr. at 457. Moreover, the amount of cytochrome oxidase enzyme68
(102 percent), citrate synthase69 (107 percent), and succinate dehydrogenase70 (116 percent)
present were within normal range, and thus not elevated enough to be of concern. Id. at 459.

Dr. Cohen took issue with two of the pieces of literature offered in support of Dr. Kendall’s
report. He dismissed her reference to the Poling article (a case report involving vaccines other than
the flu vaccine) as insufficient to draw an association between vaccinations and the development
of mitochondrial disorders in children with autism. Tr. at 476-77. He similarly dismissed the

67
Alanine is a “nonessential amino acid, 2-aminopropanoic acid, occurring in proteins; high levels also occur free in
plasma.” Dorland’s at 43. Lysine is an essential amino acid and is “necessary for optimal growth in infants and for
maintenance of nitrogen equilibrium in human adults.” Dorland’s at 1089.
68
Cytochrome oxidase is “an enzyme complex of the inner mitochondrial membrane that catalyzes the transfer of
electrons from cytochrome c to oxygen, oxidizing the former and reducing the latter in the final step of the electron
transport chain by which oxygen is used for fuel combustion.” Dorland’s at 465.
69
Citrate Synthase is “an enzyme of the transferase class that catalyzes the condensation of oxaloacetate and the acetyl
group of acetyl coenzyme A to form citrate and coenzyme A.” Dorland’s at 366.
70
Succinate dehydrogenase is “an enzyme of the oxidoreductase class that catalyzes the oxidation of succinate to
fumarate, using a variety of hydrogen acceptors.” Dorland’s at 1795.

34
Shoffner article as having little bearing herein. Even if L.V. had a mitochondrial dysfunction, there
is, in Dr. Cohen’s opinion, no known association between the flu vaccine and aggravation of a
mitochondrial disease. Id. at 479-80.

Finally, Dr. Cohen addressed some components of Dr. Shafrir’s theory that L.V.’s
regression was the result of an autoimmune encephalopathy. He disputed that L.V. had
experienced a regressive form of autism caused by an autoimmune encephalopathy induced by the
first vaccination and magnified by the second vaccination, observing that the record suggested that
L.V.’s problems actually began prior to his first flu vaccination. Tr. at 482-83. Dr. Cohen also
challenged the conclusion that L.V. had experienced any traumatic brain injury along the lines of
an encephalopathy, noting that MRI scans of children with autoimmune encephalopathy will often
show particular abnormalities absent in this case. Thus, testing of brains in cases of anti-NMDA
receptor antibody autoimmune encephalopathies will often show disease in the temporal lobes or
other parts of the brain. Id. at 508-09. But, as conceded by Dr. Shafrir, L.V.’s MRI showed no
similar abnormalities. Id. at 363. Moreover, none of L.V.’s treaters performed the kinds of tests
that Dr. Cohen would expect would be performed if anti-NMDA receptor encephalitis had been
suspected (such as a spinal tap, an imaging study like a CT scan or an MRI scan, or an EEG), nor
was immunoglobulin therapy71 effective for L.V. Id. at 363, 510-13. L.V.’s change in
developmental status was far more gradual and mild overall than indicated by the timeline of
regression supported by Petitioners, and therefore not reflective of a dramatic autoimmune
reaction. Id. at 511, 514.

IV. SUMMARY OF RELEVANT MEDICAL CONCEPTS

Prior to analyzing Petitioners’ claims, it would be beneficial to briefly consider the two
medical conditions most relevant to this case (along with relevant case law dealing with both in
the Vaccine Program): ASDs and mitochondrial disorders. The summary below is derived from
materials filed by both parties in this case, as well as discussions of the conditions set forth in the
decisions of other special masters or the Court of Federal Claims.

A. Autism Spectrum Disorder

Autism or ASD encompasses a group of complex neurodevelopmental disorders
characterized by “self-absorption, impairment in social interaction and communication, and a
restricted range of activities and interests.” Dorland’s at 180; see also Autism Spectrum Disorder
Fact Sheet, NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKES, Oct. 7, 2015,
available at http://www.ninds.nih.gov/disorders/autism/detail_autism.html (last visited Feb. 11,

71
Immunoglobulin therapy is often used to treat NMDA receptor antibody autoimmune encephalopathy. Tr. at 513.

35
2016). Children diagnosed with ASD are often reported by their parents to have displayed
developmental or behavioral problems around 18 months of age, if not by the age of two, and a
significant minority of children with ASD experience regression/loss of skills, including language
or vocabulary. Lehner v. Sec’y of Health & Human Servs., No. 08-554V, 2015 WL 5443461, at
*34-35 (Fed. Cl. Spec. Mstr. July 22, 2015) (discussing the diagnostic criteria and characteristics
of ASDs).72

Since the resolution of the OAP cases, there have been numerous petitions attempting to
establish that a variety of vaccines cause autism or an ASD, based on causations theories highly
similar to those asserted in the present action. See, e.g., Hardy v. Sec’y of Health & Human Servs.,
No. 08-108V, 2015 WL 7732603, at *4-5 (Fed. Cl. Spec. Mstr. Nov. 3, 2015) (petitioners failed
to demonstrate that DTaP vaccine caused or significantly aggravated underlying mitochondrial
disease resulting in ASD); Miller v. Sec’y of Health & Human Servs., No. 02-235V, 2015 WL
5456093 (Fed. Cl. Spec. Mstr. Aug. 18, 2015) (petitioners failed to demonstrate that several
childhood vaccines caused encephalopathy or aggravated underlying mitochondrial
disease/dysfunction); Lehner, 2015 WL 5443461 (petitioners failed to demonstrate that flu vaccine
resulted in autoimmune encephalitis). As Special Master Hastings noted in the recent Hardy
decision, however, to date every post-OAP non-Table claim73 seeking compensation for autism
injuries purportedly related to a vaccine that has been tried has failed. Hardy, 2015 WL 7732603,
at *4-5 (referencing eleven autism claims unsuccessfully tried (including Miller and Lehner), plus
six that were rejected (over the petitioners’ objections) without trial)).

B. Mitochondrial Disease and Diagnostic Criteria

Mitochondrial disease is (as put by Dr. Kendall) a “heterogeneous group of disorders that
affect the body’s ability to ultimately metabolize energy through a series of complicated reactions

72
In this case, other than some occasional disagreement about the diagnostic value of the term “regressive autism,”
the parties did not dispute L.V.’s ASD diagnosis, and therefore offered no medical literature directly defining the term.
I reference Lehner (which does cite to several exhibits offered therein) and its discussion of ASD’s characteristics
only for the broad purpose of framing this topic.
73
In a single instance, petitioners (the parents of a vaccinated child) successfully established a Table injury – an
encephalopathy – after vaccination that resulted in autistic-like developmental regression. See, e.g., Wright v. Sec’y of
Health & Human Servs., No. 12-423V, 2015 WL 6665600 (Fed. Cl. Spec. Mstr. Sept. 21, 2015). In Wright, the
petitioners met the Table criteria for an “acute encephalopathy” following vaccination by establishing by preponderant
evidence that the vaccinated child experienced a seizure followed by loss of consciousness shortly after receipt of
pertussis-containing vaccine; the severe reaction lasted for more than 24 hours, with resulting demonstrable significant
changes in behavior. But the special master responsible for that decision (former Chief Special Master Vowell)
explicitly noted in her decision that petitioners would not have been able to establish entitlement under their non-
Table claim, because their expert presented a causation opinion that she found “absurd and biologically impossible.”
Wright, 2015 WL 6665600, at *2. Petitioners in this case rely on the same expert, Dr. Shafrir.

36
inside the mitochondria.” Tr. at 112-13. Mitochondrial disease can manifest with a multitude of
symptoms, including autism or autistic features and gastrointestinal symptoms, both of which L.V.
experienced. Id. at 113, 173. Classic phenotypes of mitochondrial disease are “usually progressive
and multisystemic” (Haas at 1327) and progressively severe, especially in the case of infants and
young children. Id. at 1329-30. But (as all experts testifying in this case agreed), it can be difficult
to diagnose mitochondrial disease given the variety of possible symptoms and the lack of a reliable
and agreed-upon diagnostic biomarker. Id. at 1327; Tr. at 114, 431-32. Thus, based upon up-to-
date medical and scientific thinking on the topic, the clearest diagnostic evidence that an individual
in fact has a mitochondrial disease is provided by genetic testing. Haas at 1327; Tr. at 433-44.

There are differences between a mitochondrial “disease,” “disorder,” and “dysfunction.”
As Dr. Kendall put it, “mitochondrial disease is a situation in which either you have definitive
information that clearly states that this person has a mitochondrial disease based on laboratory and
other factors,” while mitochondrial dysfunction is the proper term when there is not a clear
diagnosis. Tr. at 115. Dr. Cohen largely echoed this distinction, albeit by reframing the distinction
as between primary and secondary mitochondrial disease (which, as Haas defines it, is the result
not of a genetic mutation directly affecting the functioning of the electron transport chain, but
instead reflects impairment of the oxidative phosphorylation process by an “unrelated genetic or
environmental cause.”) Haas at 1330; Tr. at 435-36 (characterizing the phrase “mitochondrial
dysfunction” as “a very global generic term”). Ultimately, Dr. Kendall used the terms
“mitochondrial disease” and “mitochondrial disorder” somewhat interchangeably, while stressing
that the existence of a secondary mitochondrial disease, less severe than more classic phenotypes
such as Leigh disease, was nevertheless in her opinion sufficient to make the introduction of a
vaccine problematic. Tr. at 235.

The Petitioners’ argument that L.V. suffered from some form of mitochondrial disease
relies on a specific set of diagnostic criteria applicable to children first set forth in 2006 and
referred to in this decision as the “Morava” criteria. See generally Pet’rs’ Ex. 41, Ref. 25. It is
u

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Source: Frix Law Library, https://www.frixlaw.com/law-library/cases/4015413. Public record. Not legal advice.