Lehner v. Secretary of Health and Human Services

In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
No. 08-554V
Filed: July 22, 2015
For Publication
****************************
RICK LEHNER and *
SHELLEY LEHNER, as parents and *
natural guardians, on behalf of their * Influenza [“Flu”] Vaccination; Autism
minor daughter, C.L., * Spectrum Disorder [“ASD”];
* Autoimmune Encephalopathy; Voltage
Petitioners, * Gated Potassium Channel [“VGKC”]
v. * Antibodies; Treating Physicians;
* Expert Qualifications; Causation;
SECRETARY OF HEALTH * Motion to Exclude Expert as
AND HUMAN SERVICES, * Duplicative.
*
Respondent. *
****************************
Sheila A. Bjorklund, Esq., Lommen Abdo Law Firm, Minneapolis, MN, for petitioners.
Traci R. Patton, Esq., U.S. Department of Justice, Washington, DC, for respondent.
DECISION AND RULING1
Vowell, Chief Special Master:
On August 1, 2008, Rick and Shelley Lehner [“petitioners”] filed a petition for
compensation under the National Vaccine Injury Compensation Program, 42 U.S.C.
§300aa-10, et seq.2 [the “Vaccine Act” or “Program”], on behalf of their minor daughter,
C.L.
1
Because this decision contains a reasoned explanation for my action in this case, it will be posted on the
United States Court of Federal Claims’ website, in accordance with the E-Government Act of 2002, Pub.
L. No. 107-347, 116 Stat. 2899, 2913 (Dec. 17, 2002). Each party has 14 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
entire decision will be available to the public.
2
National Childhood Vaccine Injury Act of 1986, Pub. L. No. 99-660, 100 Stat. 3755. Hereinafter, for
ease of citation, all “§” references to the Vaccine Act will be to the pertinent subparagraph of 42 U.S.C. §
300aa (2012).
Petitioners initially claimed that thimerosal in C.L.’s childhood vaccines caused
their daughter’s autism spectrum disorder [“ASD”].3 Petition, filed Aug. 1, 2008, at 2. In
2011, they amended their claim to allege that their daughter sustained an autoimmune
encephalopathy as the result of an influenza vaccine received in November 2005.
Petitioners’ Amended Petition, filed Feb. 22, 2011, at 3.
In order to prevail under the Program, petitioners must prove either that C.L.
sustained a “Table” injury4 or that a vaccine listed on the Table was the actual cause of
an injury (an “off-Table” injury). Because C.L.’s alleged injury is not a Table injury for
the influenza vaccine, petitioners must produce preponderant evidence that the
influenza vaccine was substantially responsible for C.L.’s injury. After considering the
record as a whole,5 I hold that petitioners have failed to establish their entitlement to
compensation.
I. Procedural History.
A. Omnibus Autism Proceeding.
When petitioners filed their original petition, they requested to be included in the
Omnibus Autism Proceeding [“OAP”].6 Petition at 2. The OAP was created to resolve
3
“Autism Spectrum Disorder” or “ASD” is an umbrella term for certain developmental disorders, including
autism (also referred to as autistic disorder), pervasive developmental disorder-not otherwise specified
[“PDD-NOS”], and Asperger’s Disorder. See R. Luyster, et al., Language Assessment and Development
in Toddlers with Autism Spectrum Disorders, J. AUTISM DEV. DISORD., 38: 1426-38 (2008), filed as Res.
Ex. DD [hereinafter “Luyster, Res. Ex. DD”], at 1426.
4
A “Table” injury is an injury listed on the Vaccine Injury Table [“Table”], 42 C.F.R. § 100.3 (2011),
corresponding to the vaccine received within the time frame specified.
5
See § 13(a): “Compensation shall be awarded . . . if the special master or court finds on the record as a
whole–(A) that the petitioner has demonstrated by a preponderance of the evidence the matters required
in the petition by section 300aa-11(c)(1);” see also § 13(b)(1) (indicating that the court or special master
shall consider the entire record in determining if petitioner is entitled to compensation).
6
By opting into the OAP, petitioners alleged that:
[a]s a direct result of one or more vaccinations covered under the National Vaccine Injury
Compensation Program, the vaccinee in question has developed a neurodevelopmental
disorder, consisting of an Autism Spectrum Disorder [“ASD”] or a similar disorder. This
disorder was caused by a measles-mumps-rubella (MMR) vaccination; by the
“thimerosal” ingredient in certain Diphtheria-Tetanus-Pertussis (DTP), Diphtheria-
Tetanus-acellular Pertussis (DTaP), Hepatitis B, and H[a]emophilus Influenza[e] Type B
(HIB) vaccinations; or by some combination of the two.
In re: Claims for Vaccine Injuries Resulting in Autism Spectrum Disorder or a Similar Neurodevelopmental
Disorder, Various Petitioners v. Sec’y, HHS, Autism General Order #1, 2002 WL 31696785, at *2 (Fed.
Cl. Spec. Mstr. July 3, 2002).
2
what ultimately totaled about 5,700 petitions alleging that vaccines or the thimerosal
preservative contained in some vaccines caused autism spectrum disorders. In an
omnibus proceeding, cases presenting similar theories of injury are grouped together in
a manner similar to class action litigation. Test cases are selected in which to present
the common question of vaccine causation, but unlike class action litigation, the parties,
other than those in the test cases themselves, are not bound by the results. Instead,
omnibus proceedings develop evidence on the issue of vaccine causation, and that
evidence is available to resolve the remaining omnibus cases. In the OAP, the
selection of test cases was made by the Petitioners’ Steering Committee, a group of
lawyers representing OAP petitioners. Three OAP test cases were selected for each of
the two theories of vaccine causation advanced by the petitioners’ bar. Hearings were
conducted in 2007 and 2008 and decisions denying compensation issued in 2009 and
2010.7 The decisions in the Theory 1 test cases (which advanced the theory that the
MMR vaccine, either alone or in concert with thimerosal-containing vaccines, caused
autism) were appealed; the decisions in the Theory 2 test cases (which advanced the
theory that thimerosal-containing vaccines caused autism) were not appealed.8
C.L.’s case was filed after the hearings in the test cases began, but before the
decisions were issued. Thus, unlike the early OAP petitioners, petitioners were required
to produce medical records in order to position C.L.’s case for resolution after the
special masters’ decisions were issued in the test cases and appellate review
concluded. Petitioners’ Exhibits [“Pet. Exs.”] 1 through 8 were filed on October 21,
2008.
When the final appellate decision in the OAP test cases was issued in August
9
2010, the court began the process of notifying petitioners in the approximately 4,800
remaining OAP cases of the results and asking them how they intended to proceed.10
7
The Theory 1 test cases are Cedillo v. Sec’y, HHS, No. 98-916V, 2009 WL 331968 (Fed. Cl. Spec. Mstr.
Feb. 12, 2009), aff’d, 89 Fed. Cl. 158 (2009), aff’d, 617 F.3d 1328 (Fed. Cir. 2010); Hazlehurst v. Sec’y,
HHS, No. 03-654V, 2009 WL 332306 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), aff’d, 88 Fed. Cl. 473 (2009),
aff’d, 604 F.3d 1343 (Fed. Cir. 2010); Snyder v. Sec’y, HHS, No. 01-162V, 2009 WL 332044 (Fed. Cl.
Spec. Mstr. Feb. 12, 2009), aff’d, 88 Fed. Cl. 706 (2009). Petitioners in Snyder did not appeal the
decision of the U.S. Court of Federal Claims. The Theory 2 test cases are Dwyer v. Sec’y, HHS, No. 03-
1202V, 2010 WL 892250 (Fed. Cl. Spec. Mstr. Mar. 12, 2010); King v. Sec’y, HHS, No. 03-584V, 2010
WL 892296 (Fed. Cl. Spec. Mstr. Mar. 12, 2010); Mead v. Sec’y, HHS, No. 03-215V, 2010 WL 892248
(Fed. Cl. Spec. Mstr. Mar. 12, 2010). The petitioners in each of the three Theory 2 test cases chose not to
appeal.
8
A more detailed explanation of the creation of the OAP and the effects of opting into it can be found in
Dwyer, No. 03-1202V, 2010 WL 892250, at *3.
9
Cedillo, 617 F.3d 1328.
10
The vast majority of these petitioners either voluntarily dismissed their cases or failed to respond,
eventually resulting in dismissals for failure to prosecute. Petitioners’ case is one of approximately 70
ASD cases currently proceeding to a decision on one of several alternative theories of causation.
3
B. Procedural History Post-Test Cases.
On February 22, 2011, petitioners asked that their petition be removed from the
OAP,11 and filed an amended petition alleging that the influenza vaccine that C.L.
received on November 25, 2005, “substantially contributed to her development of
clinically significant levels of VGKC-ABs [voltage-gated potassium channel antibodies12],
leading to an autoimmune encephalopathy with resultant injury to brain cells and
developmental regression.” Amended Petition [“Am. Petition”] at 3. The amended
petition was accompanied by an expert report from Dr. Richard Frye (Pet. Ex. 10)
setting forth this new theory.
Between February 22, 2011, when petitioners filed their amended petition, and
October 8, 2013, when I issued the pre-hearing order, petitioners filed both new and
updated medical records. During the same time period, the parties filed multiple expert
reports, as well as extensive medical literature.
Respondent initially filed an expert report from Dr. Mark Gorman in response to
Dr. Frye’s report. Respondent’s Exhibit [“Res. Ex.”] A, filed Apr. 26, 2011. Thereafter,
on October 19, 2011, petitioners filed a status report informing the court that Dr. Frye
would not be able to testify on petitioners’ behalf.13 On April 2, 2012, after being
afforded additional time to locate a new expert, petitioners filed the report of Dr. Yuval
Shafrir. Pet. Ex. 11. A supplemental report from Dr. Shafrir was filed on August 15,
11
The special master initially assigned to this case granted petitioners’ motion on February 25, 2011.
12
Neurons in the central and peripheral nervous systems use proteins to communicate (signal) within and
between cells. Voltage-gated potassium channels [“VGKC”] are cell membrane proteins that allow
potassium ions to cross the cell membrane, generating electrical signals. The “gates” open and close
based on changes in the cell membrane. In the central nervous system, these neuronal voltage-gated
potassium channel proteins play an important role in axonal conduction and synaptic transmission.
Autoantibodies, which were once thought to be targeted against the VGKC, have been reported to play a
role in some types of neurological illnesses in children and adults. R. Dhamija, et al., Neuronal Voltage-
Gated Potassium Channel Complex Autoimmunity in Children, PEDIATR. NEUROL., 44(4): 275-81 (2011),
filed as Pet. Ex. 11c and as Res. Ex. N [hereinafter “Dhamija, Pet. Ex. 11c”]. “Autoantibodies against the
voltage-gated potassium channel (VGKC) complex measured by radioimmunoprecipitation have been
reported in a broad spectrum of immunotherapy-responsive neurological illnesses in children and adults.”
R. Patterson, et al., Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex
antibodies: experience from a tertiary referral centre, J. NEUROL. NEUROSURG. PSYCHIATRY, published
online June 11, 2013, filed as Res. Ex. CC [hereinafter “Patterson, Res. Ex. CC”], at 1. Recently, “it has
become clear that VGKC antibodies are not directed against the VGKC itself, but against other cell
surface antigens that form part of the VGKC complex.” Id. As one of C.L.’s treating physicians, Dr.
Deborah Renaud, explained to C.L.’s family, “[i]t is presumed that the antibodies against the potassium
channels caused them to malfunction and, therefore, the electrical current in the neurons which are the
electrical cells of the brain [are] impaired.” Pet. Ex. 9, p. 7
13
Doctor Frye’s inability to testify in Program cases was due to changed employment. See Order, issued
Sept. 19, 2011.
4
2012. Pet. Ex. 16. Petitioners also filed a letter from Angela Vincent, Ph.D., to
petitioners’ counsel. Pet. Ex. 21.
Following the filing of Dr. Gorman’s initial report, respondent filed two
supplemental expert reports from Dr. Gorman (Res. Ex. I, filed July 16, 2012; Res. Ex.
W, filed Jan. 2, 2013) and two expert reports from Dr. Joseph Dalmau (Res. Ex. J, filed
Nov. 14, 2012; Res. Ex. AA, filed Aug. 23, 2013).
Prior to the two-day entitlement hearing on January 27-28, 2014, the parties filed
pre-hearing briefs and a joint statement of facts not in dispute. Petitioners also filed a
supplemental expert report from Dr. Shafrir (Pet. Ex. 23, filed Dec. 11, 2013), and
shortly before the hearing, an affidavit from Mr. Lehner, and photographs and videos of
C.L. Petitioners appeared at the hearing via video teleconference. The three expert
witnesses appeared in person.
Post-hearing, petitioners filed supplemental medical records as well as additional
video and photographs of C.L., pursuant to my order. Petitioners also filed a written
motion to exclude Dr. Gorman’s testimony, which supplemented and explained the oral
motion to exclude that petitioners’ counsel made during the hearing. Respondent filed a
response to the motion to exclude on April 7, 2014, to which petitioners filed a reply on
April 10, 2014.
This case presents diagnostic and causation issues, complicated by a change in
the scientific and medical understanding of the role of voltage-gated potassium channel
autoantibodies in autoimmune encephalitis that occurred around the time Dr. Frye
authored his initial expert report in this case. The issues to be resolved include whether
C.L. experienced encephalitis after her influenza vaccination, whether the vaccination
played any role in her development of the antibodies found years later, and whether
these antibodies played any role in her developmental regression. Ultimately, the issue
is whether petitioners have demonstrated by preponderant evidence that the influenza
vaccine caused the developmental regression which was diagnosed as an autism
symptom by several treating specialists, and which was later characterized as
autoimmune encephalitis or autoimmune encephalopathy by Dr. Frye and some of
C.L.’s treating physicians.
II. Legal Standards Applying to Off-Table Causation Claims.
When petitioners allege an off-Table injury, eligibility for compensation is
established when, by a preponderance of the evidence, petitioners demonstrate that the
vaccinee received, in the United States, a vaccine appearing on the Table and
sustained an illness, disability, injury, or condition caused by the vaccine or experienced
a significant aggravation of a preexisting condition. They must also demonstrate that
5
the condition has persisted for more than six months.14 Vaccine Act litigation rarely
concerns whether the vaccine appears on the Table, the geographical location of
administration, or whether the symptoms have persisted for the requisite time. Rather,
in the very small minority of Vaccine Act cases that proceed to a hearing, the most
common issue to be resolved by the special master is whether the injury alleged was
caused by the vaccine.
To establish legal causation in an off-Table case, Vaccine Act petitioners must
establish by preponderant evidence: (1) a reliable medical theory causally connecting
the vaccination and the injury; (2) a logical sequence of cause and effect showing that
the vaccination was the reason for the injury; and (3) a proximate temporal relationship
between vaccination and injury. Althen v. Sec’y, HHS, 418 F.3d 1274, 1278 (Fed. Cir.
2005); see de Bazan v. Sec’y, HHS, 539 F.3d 1347, 1351-52 (Fed. Cir. 2008); Caves v.
Sec’y, HHS, 100 Fed. Cl. 119, 132 (2011), aff’d per curiam, 463 Fed. Appx. 932 (Fed.
Cir. 2012) (specifying that each Althen factor must be established by preponderant
evidence). The applicable level of proof is the “traditional tort standard of ‘preponderant
evidence.’” Moberly v. Sec’y, HHS, 592 F.3d 1315, 1322 (Fed. Cir. 2010) (citing de
Bazan, 539 F.3d at 1351; Pafford v. Sec’y, HHS, 451 F.3d 1352, 1355 (Fed. Cir. 2006);
Capizzano v. Sec’y, HHS, 440 F.3d 1317, 1320 (Fed. Cir. 2006); Althen, 418 F.3d at
1278). Although special masters are not bound by the formal rules of evidence
generally applicable in federal courts, they are required to find evidence reliable before
they may consider it. Knudsen v. Sec’y, HHS, 35 F.3d 543, 548-49 (Fed. Cir. 1994)
(Petitioner has the burden to present a reliable and reputable medical theory, which
must be “legally probable, not medically or scientifically certain.”); Daubert v. Merrell
Dow Pharmaceuticals, 509 U.S. 579, 590 (1993) (holding that scientific evidence and
expert opinions must be reliable to be admissible). The preponderance standard
“requires the trier of fact to believe that the existence of a fact is more probable than its
nonexistence.” In re Winship, 397 U.S. 358, 371 (1970) (Harlan, J., concurring)
(internal quotation and citation omitted).
Another formulation of the causation requirement in off-Table cases is the “Can it
cause?” and “Did it cause?” inquiries used in toxic tort litigation. These queries are also
referred to as issues of general and specific causation. Prong 1 of Althen has been
characterized as an alternative formulation of the “Can it cause?” or general causation
query. Prong 2 of Althen, the requirement for a logical sequence of cause and effect
between the vaccine and the injury, has been characterized as addressing the “Did it
cause?” or specific causation query. See Pafford v. Sec’y, HHS, No. 01-165V, 2004 WL
1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004), aff’d, 64 Fed. Cl. 19 (2005), aff’d,
451 F.3d 1352 (2006). Prong 3 of Althen, the requirement that the injury sustained
occur within a medically appropriate interval after vaccination, is subsumed into the
14
Section 13(a)(1)(A). This section provides that petitioner must demonstrate “by a preponderance of the
evidence the matters required in the petition by section 300aa–11(c)(1) . . . .” Section 11(c)(1) contains
the factors listed above, along with others not relevant to this case.
6
other inquiries. Even if a particular vaccine has been causally associated with an injury,
petitioner must still establish facts and circumstances that make it more likely than not
that this vaccine caused the particular injury. Timing may be one of those
circumstances.
Whether a case is analyzed under Althen or the “Can it cause?” formulation,
petitioners are not required to establish identification and proof of specific biological
mechanisms, as “the purpose of the Vaccine Act’s preponderance standard is to allow
the finding of causation in a field bereft of complete and direct proof of how vaccines
affect the human body.” Althen, 418 F.3d at 1280. Petitioners need not show that the
vaccination was the sole cause, or even the predominant cause, of the injury or
condition; showing that the vaccination was a “substantial factor”15 in causing the
condition, and was a “but for” cause, are sufficient for recovery. Shyface v. Sec’y, HHS,
165 F.3d 1344, 1352 (Fed. Cir. 1999); see also Pafford, 451 F.3d at 1355 (petitioners
must establish that a vaccination was a substantial factor and that harm would not have
occurred in the absence of vaccination). Petitioners cannot be required to show
“epidemiologic studies, rechallenge, the presence of pathological markers or genetic
disposition, or general acceptance in the scientific or medical communities to establish a
logical sequence of cause and effect” (Capizzano, 440 F.3d at 1325), but the special
master may certainly consider such evidence when filed. Andreu v. Sec’y, HHS, 569
F.3d 1367, 1379 (Fed. Cir. 2009) (Special masters may consider medical literature and
epidemiological evidence, when it is submitted, in “reaching an informed judgment as to
whether a particular vaccine likely caused a particular injury.”). Causation is determined
on a case by case basis, with “no hard and fast per se scientific or medical rules.”
Knudsen, 35 F.3d at 548 (Fed. Cir. 1994). Close calls regarding causation must be
resolved in favor of petitioners. Althen, 418 F.3d at 1280; but see Knudsen, 35 F.3d at
550 (when evidence is in equipoise, the party with the burden of proof fails to meet that
burden).
In Vaccine Act cases, special masters are frequently confronted by expert
witnesses with diametrically opposing positions on causation. When experts disagree,
many factors influence a fact-finder to accept some testimony and reject other contrary
testimony. As the Federal Circuit noted, “[a]ssessments as to the reliability of expert
testimony often turn on credibility determinations, particularly in cases . . . where there
is little supporting evidence for the expert’s opinion.” Moberly, 592 F.3d at 1325-26.
Objective factors, including the qualifications, training, and experience of the expert
witnesses; the extent to which their proffered opinions are supported by reliable medical
research and other testimony; and the factual basis for their opinions are all significant
15
The Restatement (Third) of Torts has eliminated “substantial factor” in the factual cause analysis. § 26
cmt. j (2010). Because the Federal Circuit has held that the causation analysis in the Restatement
(Second) of Torts applies to off-Table Vaccine Act cases (see Walther v. Sec’y, HHS, 485 F.3d 1146,
1151 (Fed. Cir. 2007); Shyface, 165 F.3d at 1352), this change does not affect the determination of legal
cause in Vaccine Act cases: whether the vaccination is a “substantial factor” is still a consideration in
determining whether it is the legal cause of an injury.
7
factors in determining what testimony to credit and what to reject. Lalonde v. Sec’y,
HHS, 746 F.3d 1334, 1340 (Fed. Cir. 2014) (noting that “as the finder of fact, the special
master was responsible for assessing the reliability of [the expert’s] testimony by looking
for reliable medical or scientific support” (citing Moberly, 592 F.3d at 1324-25)).
Congress contemplated that special masters would weigh and evaluate opposing
expert opinions in determining whether petitioners have met their burden of proof.
Congress clearly specified petitioners’ burden of proof in off-Table cases as the
preponderance of the evidence standard. It directed special masters to consider the
evidence as a whole, but stated that special masters are not bound by any particular
piece of evidence contained in the record.16 In weighing and evaluating expert opinions
in Vaccine Act cases, the same factors the Supreme Court has considered important in
determining their admissibility provide the weights and counterweights. See Kumho
Tire Co. v. Carmichael, 526 U.S. 137, 149-50 (1999); Terran v. Sec’y, HHS, 195 F.3d
1302, 1316 (Fed. Cir. 1999). As the Supreme Court has noted, a trial court is not
required to accept the ipse dixit of any expert’s medical or scientific opinion because the
“court may conclude that there is simply too great an analytical gap between the data
and the opinion proffered.” Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997).
Although special masters are not bound by the formal rules of evidence generally
applicable in federal courts, the Federal Rules of Evidence and cases interpreting them
can guide special masters in their decisions. Daubert, which interpreted Rule 702 of the
Federal Rules of Evidence, provides a useful framework for evaluating scientific
evidence in Program cases. Terran, 195 F.3d at 1316 (concluding that it was
reasonable for the special master to use Daubert to evaluate the reliability of an expert’s
testimony); Cedillo v. Sec’y, HHS, 617 F.3d 1328, 1339 (Fed. Cir. 2010) (noting that
special masters are to consider all relevant and reliable evidence filed in a case and
may use Daubert factors in their evaluation of expert testimony); Davis v. Sec’y, HHS,
94 Fed. Cl. 53, 67 (2010) (describing the Daubert factors as an “acceptable evidentiary-
gauging tool with respect to persuasiveness of expert testimony already admitted . . . by
special masters in vaccine cases”); see also Snyder, 88 Fed. Cl. at 718 (quoting Ryman
v. Sec’y, HHS, 65 Fed. Cl. 35, 40-41 (2005) (special masters perform gatekeeping
function when determining “whether a particular petitioner’s expert medical testimony
supporting biological probability may be admitted or credited or otherwise relied upon”
and as a “trier-of-fact [a special master] may properly consider the credibility and
applicability of medical theories”)). The special master’s use of the Daubert factors to
evaluate the reliability of expert opinions in Vaccine Act cases has been cited with
approval by the Federal Circuit more recently in Andreu, 569 F.3d at 1379 and Moberly,
16
See § 13(a)(1)(A) (preponderance standard); § 13(a)(1) (“Compensation shall be awarded . . . if the
special master or court finds on the record as a whole . . . .” ); § 13(b)(1) (indicating that the court or
special master shall consider the entire record in determining if petitioner is entitled to compensation and
special master is not bound by any “diagnosis, conclusion, judgment, test result, report, or summary”
contained in the record).
8
592 F.3d at 1324. See also Vaughan v. Sec’y, HHS, 107 Fed. Cl. 212, 222 (2012)
(“The Federal Circuit has repeatedly stated that the Special Master may refer to Daubert
to assess reliability of expert testimony in vaccine cases.”). Special masters decide
questions of credibility, plausibility, probability, and reliability, and ultimately determine
to which side the balance of the evidence is tipped. See Pafford, 451 F.3d at 1359.
Bearing all these legal standards in mind, I now turn to the evidence presented in
this case.
III. Medical History.
Most of C.L.’s medical history is not in dispute.17 Although C.L. experienced a
loss of skills at some point between an early intervention evaluation in September 2005
and an evaluation by a neurologist in February 2006, more precise dating is difficult.
Given the wide disparity in reports concerning when she began losing skills, it is unlikely
that the loss of skills was sudden or abrupt. C.L.’s autism diagnosis is not seriously
disputed; she met the diagnostic criteria on two different tests performed by different
specialists in the spring and summer of 2006. Petitioners acknowledge the diagnosis,
but claim that it is the result of an autoimmune encephalopathy as evidenced by the
presence of voltage-gated potassium channel autoantibodies. Whether C.L. showed
improvement in behavior and skills as the result of treatment for an autoimmune
encephalopathy is a matter upon which the parties disagree. Petitioners contend that
any improvement is evidence that the antibodies were responsible (or a marker) for
autoimmune encephalitis and thus evidence that she had encephalitis, not autism per
se. The ultimate basis for their claim for compensation is that the influenza vaccination
triggered an autoimmune condition, a claim that respondent vigorously contests.
I set forth most of C.L.’s history prior to the vaccination in a summarized fashion
while examining therapy records, contemporaneous medical records, and histories
provided to specialists surrounding the regression/loss of skills in more detail. The
records pertaining to her diagnosis and treatment for the VGKC antibodies are also set
forth at greater length.
A. C.L.’s Early Medical History.
C.L. and her fraternal twin sister were born prematurely in late July 2003. There
were initial concerns about C.L.’s oxygen levels after birth and her newborn metabolic
screening test results, resulting in a week in a special care nursery on oxygen, tube
17
The parties identified the following issues as disputed (1) “the extent of C.L.’s pre-existing
developmental delay;” (2) “[t]he onset of C.L.’s neurological condition;” and (3) “[t]he cause of C.L.’s
neurological condition.” Joint Pre-hearing Submission Identifying Issues, filed Jan. 7, 2014, at 1.
9
feedings, and antibiotics before being discharged to home.18 C.L. developed on the
slower side of normal in her first 14 months of life. Pet. Exs. 7, p. 8; 4, p. 50; 13, p. 2; 3,
p. 8; 9, p. 2. She experienced colic, gastroesophageal reflux [“GER”], formula
intolerance, and bronchitis in her first three months of life. Pet. Ex. 3, pp. 10-13.
However, petitioners testified that there were no concerns regarding C.L.’s development
during her first year.19 Transcript [“Tr.”] at 10, 105.
Between October 2003 and October 2004, C.L. was seen for routine illnesses
and received the standard childhood vaccinations, including an influenza vaccination in
October 2004, without any apparent ill effects. Pet. Ex. 3, p. 2; see generally Pet. Ex. 3,
pp. 14-31.
B. Concerns about Developmental Delay.
On October 27, 2004, C.L. was seen for her 15 month well child checkup. She
was described as a “picky eater” and was still taking formula. Pet. Ex. 3, p. 32. The
medical record reflected that problems or concerns about C.L.’s behavior were
discussed, specifically noting a “? [question of] mild GM [Gross Motor] delay – just
starting to walk beyond a few steps.” Id. The examining physician noted a “[p]lan” to
“watch [C.L.’s] GM closely.” Id. Mrs. Lehner testified that “there was really no concern”
at this time and the physician “just wanted to keep an eye on [C.L.] to make sure she
kept progressing in her gross motor skills” and after that C.L. “started walking . . . and
there were no issues at all.” Tr. at 12. In an August 2008 letter to petitioners, C.L.’s
pediatrician, Dr. Judith Snook, noted that C.L. was not using “mama” or “dada”
specifically at this checkup. Pet. Ex. 8, p. 1.20
Behavior concerns were also raised at C.L.’s 18 month well child checkup on
January 27, 2005. Pet. Exs. 3, p. 36; 8, p. 1. This time the pediatrician noted a few
specific problems, including difficulty in getting C.L. to go to sleep and that she was a
dramatic child prone to temper tantrums. Id. However, developmental issues were not
specifically identified as a concern. Id. Her vocabulary contained at least three words,
and the pediatrician and Mrs. Lehner estimated that C.L. had more than 10 words. Id.
She scribbled and used a spoon. Id. Mrs. Lehner testified that C.L. was, and still is, a
“very energetic, very strong-willed child” and that “there were no concerns as far as
18
These facts are derived from histories in C.L.’s treatment records. Neither Mrs. Lehner’s labor and
delivery records nor C.L.’s medical records from her stay in the Special Care Unit following birth were filed
by petitioner. See Res. Pre-hearing Br. at 2, n.1.
19
As C.L.’s primary caretaker, Mrs. Lehner provided testimony that was much more detailed than Mr.
Lehner’s. Accordingly, as petitioners testified consistently with one another, I have focused on Mrs.
Lehner’s testimony.
20
This letter was dated August 4, 2008, three days after the original petition was filed in this case. The
first line of the letter indicated that the letter was intended as a summary of how concerns with C.L.’s
development became apparent, and was prepared at petitioners’ request. Pet. Ex. 8, p. 1.
10
behavior issues” at C.L.’s 18 month well child checkup. Tr. at 13. She was seen again
in February 2005 for an upper respiratory infection [“URI”]. Pet. Ex. 3, p. 37.
C.L. was evaluated again about a month later, this time specifically for
“behavioral concerns,” including temper tantrums that lasted more than one hour,
excessive crying, extreme clinginess, insensitivity “to temperature, sound, touch,” and
restricted food choices. Pet. Ex. 3, p. 38. She was described as an “emotional child.”
Id. Although she slept “ok” and usually took a one hour nap, she was not well-rested.
Id. Appropriate responses to these behaviors were discussed, including recommended
reading about the “strong willed child.” Id. This visit is not mentioned in Dr. Snook’s
August 2008 letter. Pet. Ex. 8, p. 1. Mrs. Lehner testified that the causes of these
behavioral concerns were the URIs that C.L. suffered between October 2004 and
February 2005.21 Tr. at 14. However, no illnesses (other than a pustule on C.L.’s heel)
were listed as concerns on this visit. Pet. Ex. 3, p. 38. Mrs. Lehner testified to her
belief that the physician simply thought C.L. was “a very strong-willed child”, and that
“there were no concerns about her behavior.” Tr. at 14.
At her two year well child checkup on August 9, 2005, C.L. was diagnosed with a
mild language delay. Pet. Ex. 3, p. 41. Doctor Snook, the same physician who saw
C.L. at her 18 month well child visit and who had evaluated the behavioral concerns in
February 2005, again noted behavioral concerns, including occasional temper tantrums.
Id.; Pet. Ex. 8, p.1. She noted that C.L. had less than 20 words, spoke no sentences,
and babble[d]“a lot.” Id. C.L. could not name pictures. Pet. Ex. 8, p. 1. Doctor Snook
also recorded that C.L. had mild constipation and was a picky eater. Pet. Exs. 3, p. 41;
8, p. 1. She referred C.L. for a speech and language evaluation. Id.
Mrs. Lehner testified that when C.L. was two years old, she spoke about 20
words, was walking and running, had no eating concerns, and was a very social child
who used eye contact, words, and gestures to communicate. Tr. at 15-17. Mrs. Lehner
recalled that Dr. Snook had some concerns at this visit because C.L. “was not yet
making full sentences” and suggested that she be evaluated through the school system
where C.L.’s twin sister was receiving speech and physical therapy.22 Tr. at 17-18. Mr.
Lehner testified that he had no concerns about C.L.’s language development at this
time, noting she was clearly “outpacing” her twin sister. Tr. at 107.
21
C.L.’s pediatric records document three visits during this time period for URI symptoms. Pet. Ex. 3, pp.
31, 33, 37.
22
Mrs. Lehner reported that C.L.’s twin had developmental delay as well, and received early intervention
services due to motor and speech delays. Pet. Ex. 9, p. 233. C.L.’s twin sister had a history of significant
delays earlier than C.L. and had features of pervasive developmental disorder [“PDD.”]. Pet. Ex. 7, p. 8.
11
C. Initial Developmental Evaluation.
C.L.’s speech and language evaluation was conducted by the Shakopee Public
Schools in September 2005, with a written report issued on October 12, 2005. Pet. Ex.
5, p. 2. During the evaluation, Mrs. Lehner stated that the reason for the referral was
concern by C.L.’s pediatrician that she was not putting two words together. Id.
C.L. was evaluated using several diagnostic tests, including the Bayley Scales of
Infant Development [“BSID”] and three types of language tests. Pet. Ex. 5, pp. 2-4.
She was classified as “mildly delayed” in cognitive development (id., p. 2), but was
significantly delayed in language (id., p. 4).23 During the in-home evaluation, C.L.
laughed and vocalized, but did not spontaneously use words during play. Id., p. 3. The
only recognizable words uttered during the visit were “mommy” and “bye.” Id. These
observations contrasted somewhat with C.L.’s scores on the Preschool Language
Scale, which showed her expressive and receptive language to be in the low average
range. Id. The most concerning language delay was observed in the evaluation of her
spontaneous language sample. C.L. made 20 “utterances,” only 10 of which were
understood as words; the other 10 were scored as babbling. A child of C.L.’s age
should have been able to make 50 utterances. The only items C.L. could name during
one test were “dog,” “boat,” “apple,” and “eye.” The evaluator commented that C.L.’s
expressive vocabulary was “significantly delayed.” Id., p. 4.
Mrs. Lehner’s impression of C.L.’s performance during this evaluation was that
she was found to be “right on track” in her mental abilities, to have “normal” gross motor
skills (“running, jumping, climbing”) (something not formally evaluated during this
testing), and a “mild language delay.” Tr. at 19-20. She testified that at the time of this
evaluation, C.L. was “using words constantly,” “cleaning up [her] articulation,” and
pairing words “with eye contact, gesturing, [and] pointing.” Id. at 20. This testimony
contrasts with what Mrs. Lehner reported at the time of the evaluation, which was that
C.L. had “about 20 words, and [was] not saying two or more words together in a
phrase.” Pet. Ex. 5, p. 2. Additionally, on a form completed by Ms. Lehner prior to the
evaluation that asked her to list any concerns she had about C.L., Mrs. Lehner wrote
that C.L. “tries to communicate but babbles instead of using words.” Id., p. 9.
C.L. was found eligible for special education services as a child with a language
disorder. Pet. Ex. 5, p. 5. She received a weekly home visit and was eligible to attend
a weekly toddler group and a parent and child group. Id., p. 12. Records of individual
23
During testimony, Dr. Shafrir asserted that C.L.’s language delay was “mild.” Tr. at 143, 145, 208-13.
Although C .L. scored in the low average range on the Preschool Language Scale-4 test, she qualified for
speech and language services because her expressive vocabulary was 2.6 standard deviations below the
norm, and her spontaneous language was 3.0 deviations below the norm. Pet. Ex. 5, p. 5. On the
expressive vocabulary test, she scored below the first percentile. Id., p. 4. Taken together, the language
tests establish that C.L.’s expressive language was significantly delayed.
12
therapy sessions were not filed, but C.L.’s six-month review by the school district was
filed and is discussed in more detail in Part D. 2, below.
D. Allegedly Causal Vaccination and Subsequent Development.
1. Vaccination.
C.L. received an influenza vaccination on November 25, 2005. Pet. Ex. 3, p. 2.
Since no office visit notes were prepared for this visit, it is likely that C.L. was not
otherwise examined or treated that day. Mrs. Lehner testified that C.L. had an
immediate reaction to this vaccination,24 developing a low grade fever and becoming
cranky and irritable. Tr. at 23. Mrs. Lehner indicated that she had been warned that
this type of reaction was a normal side effect of vaccination and she treated C.L. with
Advil for several days, as instructed at her vaccination appointment. Tr. at 23-24. No
subsequent contemporaneous medical record reported any reaction.
2. Post Vaccination Development.
Petitioners claim that C.L. experienced a dramatic developmental regression
after her influenza vaccination. Tr. at 24. However, the formal assessments of her
development during that period do not reflect a sudden regression, but rather a gradual
loss of skills and abilities. Indeed, it was not until February 13-14, 2006, that her
parents became concerned enough about the loss of vocabulary and other symptoms to
request an urgent neurology consultation. Although it is clear that C.L. experienced a
plateau (if not a regression) in her language skills and a significant loss of social and
cognitive abilities between September 2005 and December 2006 (compare Pet. Ex. 5,
pp. 2-5 (initial evaluation) with pp. 22-35 (reevaluation)), the contemporaneous medical
and therapy records do not show a sudden regression on the heels of—or even within a
month of—her influenza vaccination.
Mrs. Lehner testified that over the course of the month following her influenza
vaccination, C.L.’s behavior became much worse, she became withdrawn, and she
began “the rocking, the humming, . . .finger-flicking . . . she kind of went into her own
world.” Tr. at 24.
However, on December 19, 2005, during a speech and language pathology
evaluation at St. Francis Capable Kids [“St. Francis”], C.L.’s parents recounted that they
had become concerned about her speech and language development six months earlier
when she was not gaining new words, was unable to combine words, and most of her
24
In responding to a question from her attorney that contained an incorrect date for this vaccination,
Mrs. Lehner implied that the vaccination occurred on November 21, 2005. Tr. at 23. C..L. received her
vaccination on November 25, 2005.
13
sounds came out as “da-da.” Pet. Ex. 14, p. 2.25 At this evaluation, Mrs. Lehner
reported that C.L. was currently in good physical health, but “has difficulty with her sleep
and has feeding issues.” Id. The background information reflected that C.L.’s
“developmental pattern consists of an overall delay.” Id. Mrs. Lehner also reported that
C.L. communicated largely through gestures and that she and her husband were able to
understand her speech only about 10% of the time. Id. C.L. was frustrated when she
was not understood. Id. None of these concerns were noted as sudden or recent.
The evaluation included the Rosetti Infant-Toddler Language Scale, which
included an assessment of preverbal and verbal areas of communication and
interaction, based on direct observation or elicitation of a behavior or caregiver report.
Pet. Ex. 14, p. 3. C.L.’s pragmatic language skills evaluation reflected that she did not
vocalize to call others, respond to other children’s vocalizations, or attend to her name.
Id. Overall, C.L. showed mastery of language skills primarily at the level of a six to nine
month infant (except for gestures, in which she scored at the 12-15 month level), with
scattered skill mastery from the 15-27 month level. Id. The evaluator concluded that
C.L. had significant delays in expressive and receptive language, and delays in
pragmatic and play skills. Id. Cognitive development was not evaluated. Id., p. 5.
There were no references in the several pages of observations to C.L. rocking,
humming, finger-flicking, or being disengaged from others. The evaluation apparently
included some assessments of her interaction with other children, but it is unclear
whether these were observations by the speech and language pathologist or based on
parental report. Pet. Ex. 14, pp. 3-5. The therapist noted that her play was appropriate
and that C.L. initiated eye contact. Id., p. 6.
C.L. saw Dr. Snook again on December 22, 2005, for concerns about “sleep
problems” and “feeding issues,” some of the same concerns raised at the St. Francis
evaluation three days earlier. Pet. Ex. 3, p. 42. No reactions to or concerns about the
influenza vaccination were reported. This pediatric record reflected that C.L. was
receiving Pediasure to supplement her diet and that she refused many solids. Id. It
noted that she put her hands in her mouth “a lot.” Id. A referral to St. Francis for
feeding issues was discussed at this visit. Id.; Pet. Ex. 8, p. 2. She slept about 10-11
hours per night but would not nap. Id.26 When placed in her crib to nap, she cried and
jumped but refused to sleep. Id. In the evening, she would cry for a minute and then
fall asleep. Id. In her August 2008 letter, Dr. Snook interpreted the next part of the note
as stating that C.L. was awakening “3-4 times at night.” Pet. Ex. 8, p. 2. She would
then cry for 30-90 minutes before returning to sleep. Pet. Ex. 3, p. 42. Neither the
25
Mrs. Lehner testified that the statement that their concerns arose “six months ago [June 2005]” is
inaccurate and that the evaluator must have “rounded up” because the first time she became concerned
about C.L.’s speech was at her two year well child check with Dr. Snook in August of 2005. Tr. at 26-27.
26
In the August 2008 letter, Dr. Snook phrased this as C.L. “stay[ed] in bed for 10 to 11 hours at night,
but was not sleeping very well.” Pet. Ex. 8, p. 2.
14
sleep nor the eating issues were precisely new; both had been reported at various times
during sick and well child visits. See, e.g., Pet. Ex. 3, pp. 32, 36, 38. However, Dr.
Snook thought the sleep problems were a significant departure from C.L.’s previous
sleep patterns (Pet. Ex. 8, p. 2), a point echoed by Mrs. Lehner in her testimony. Tr. at
25.
C.L. had her first speech therapy session at St. Francis on January 4, 2006.
Pet. Ex. 14, p. 7. She put her fingers in her mouth upon entering the session, a
mannerism C.L. reportedly employed when unsure of her environment. Id. She
warmed to the therapist quickly and imitated the words “up,” “baba” for bubbles, and
called her mother by name to get her attention. Id. Eye contact was sporadic but
purposeful. Id. No concerns regarding recent regression or loss of words were noted.
At the next therapy session on January 18, C.L. vocalized two syllables for
“cracker” and “bubbles” and made eye contact with the therapist about 20% of the time.
Pet. Ex. 14, p. 1. She was frequently frustrated, however, with attempts to relate
pictures to the actual item. Id.
On January 20, 2006, Dr. Snook saw C.L. for a URI and her ongoing feeding
problems and referred her to a gastroenterologist. Pet. Exs. 3, p. 43; 8, p. 2. Again, no
concerns regarding regression were noted in the record.
On January 24, 2006, C.L. returned to St. Francis for an occupational therapy
(“OT”) evaluation regarding her feeding issues. Pet. Ex. 14, pp. 9-15. She reportedly
responded “fairly well to all activities presented, but . . . did become agitated at times”
and kept her blanket close throughout most of the session as a self-soothing
mechanism. Id., p. 11. Mrs. Lehner reported that C.L. had a sinus infection and was on
antibiotics, but indicated that C.L.’s behavior during the evaluation was typical of what
she saw at home. Id. Mrs. Lehner shared that she was concerned about the
“significant limitations” in what food C.L. was willing to eat and the poor volume of food
she consumed. Id. The evaluator, occupational therapist Margaret Taylor, found that
C.L. displayed “emerging imitation skills, comprehension of simple one-step directions,
and positive response to routine.” Id., p. 12. However, she also found that C.L. had
“substantial delays in sensory processing skills, oral[-]motor strength and coordination
and decreased muscle tone,” which impacted “her nutritional well-being and overall
health.” Id.
Ms. Taylor concluded that “these delays can, in part, be attributed to [C.L.’s] birth
history and her developmental delays following a period of reportedly normal
development until 2 years of age.” Pet. Ex. 14, p. 12. Doctor Snook’s concern about
C.L.’s gross motor development at 15 months of age was not mentioned. Mrs. Lehner
reported that C.L. “met most of her developmental milestones late” and exhibited “signs
of regression in terms of her communication development at the same time she started
having feeding difficulties around two years of age.” Id., p. 13. Individual feeding
15
therapy was recommended on a weekly basis, as were changes to home feeding
routines. Id., pp. 14-15.
At C.L.’s February 1, 2006 speech session at St. Francis, she did not make eye
contact with her mom, but did hand her bubbles upon request. Pet. Ex. 14, p. 16. She
used the word “no” twice, but did not say “hi” or “bye,” words she had previously used.
Id. She was still having trouble using the picture exchange system (abbreviated as
“PECS” in the therapy records). Id.; see also Pet. Ex. 4, p. 69 (explaining PECS).
At the February 8, 2006 speech session, Mrs. Lehner reported that C.L. was
“doing more lining up of items at home.” Pet. Ex. 14, p. 17. C.L. smiled at and made
eye contact with the therapist during a game, and used the words “bubble” and “quack.”
Id. During her feeding therapy session, which she tolerated for only about 15 minutes,
she made poor eye contact. Id., p. 18. Her response to bath time had reportedly
improved, but she had decreased tolerance for changes in her routine. Id.
Mrs. Lehner’s testimony about the period between the Christmas holiday of 2005
and February 2006 was that C.L. became “a completely different child.” Tr. at 30. The
changes included a loss of previously acquired words, episodes of staring into space,
and repetitive behaviors, such as rocking, humming, and finger flicking. Tr. at 30. Mrs.
Lehner testified that she was troubled by these changes and contacted Dr. Snook in
February 2006 for a consultation. Tr. at 31-32. There is no record reflecting an office
visit, but the telephone records for the pediatric practice reflect that Mrs. Lehner
communicated with the pediatric practice on February 13 and 14, 2006, to voice
concern about C.L.’s “loss of milestones, loss of words.” Pet. Ex. 3, p. 109; see also
Pet. Ex. 8, p. 2 (noting that “therapists had similar concerns” about loss of words, not
talking much, waving or pointing). C.L. was referred to a specific neurologist, Dr. Steve
Janousek, at petitioners’ request for a “sooner appointment.” Id.; Pet. Ex. 7, p. 2.
Apparently, petitioners were already familiar with Dr. Janousek, possibly because C.L.’s
twin had seen him. See Pet. Ex. 7, p. 2.
C.L. demonstrated the use of two signs in lieu of words at the speech therapy
session on February 15, 2006. Pet. Ex. 17, p. 20. She paid attention to the therapist
during the feeding session, and imitated gestures. Id. She vocalized during feeding,
but without any apparent meaning. Id. She used “mommy” once. She would not
imitate new words. Id. She made eye contact during a game, and said “hi” three times.
Id. The therapist noted that C.L.’s attention was better at this session, but reported that
she had staring episodes that were unaffected by calling her name or moving into her
space. Pet. Ex. 17, p. 20. The therapy note indicated that C.L. was going to have a
neurological checkup, as recommended by her physician. Id.
On February 22, 2006, C.L. saw Dr. Janousek for developmental delay and “a
new regression of skills.” Pet. Ex. 7, pp. 2, 8. Petitioners completed a checklist at the
time of the appointment, which included a developmental history. Pet. Ex. 7, pp. 3-6.
16
They reported that C.L. said her first word with meaning and without prompting between
12-16 months of age, but was still not putting two words together. Pet. Ex. 7, p. 4. She
“sometimes” had problems making or maintaining eye contact, difficulty with change or
transitions, and “school problems.” Pet. Ex. 7, p. 4. Presumably the latter reference
was to the speech or occupational therapy C.L. was receiving. They also noted that
C.L. had “always” had problems with outbursts in response to frustration and tended to
be isolated in play. Id. Additionally, they indicated that there had been a worsening of
motor or intellectual skill. Id.
The chart notes from this visit reflected that C.L.” has had a concerning degree of
developmental regression.” Id., p. 8. By history, she had “mild delays” in her
development, but otherwise was doing well. Id. The primary focus had been on C.L.’s
twin sister, who reportedly had significant delays and “some PDD [pervasive
developmental disorder] features.” Id. Doctor Janousek recorded that “[o]ver the last
several months, [C.L.] stopped talking,” developed poor eye contact, exhibited
outbursts, and became more isolated in her play, whereas she was previously reported
to be very social.” Id. No significant decline in motor function was noted. Id.
In comparing Dr. Janousek’s notes to those of the speech therapist at St.
Francis, the reference to C.L. having stopped talking was not completely accurate, as
the therapy records did reflect the use of words. The few words recorded in the
January-February 2006 therapy sessions did not add up to the 20 words C.L. had (as
reported by Mrs. Lehner) during the September 2005 school system evaluation,
indicating a possible loss of language. C.L.’s eye contact was diminished as compared
to the September evaluation as well. The temper tantrums, reported as “outbursts” in
Dr. Janousek’s records, were not new; they had been a subject of concern since C.L.’s
15 month checkup. And, C.L.’s parents had reported the day of Dr. Janousek’s
evaluation that C.L. had “always” engaged in isolated play. The only new symptom
reported to Dr. Janousek was the staring spells, and those were first noted by the
therapist two days after the requested referral to a neurologist.
On neurological examination, C.L. was described as alert, avoidant of eye
contact, exhibiting “significant tactile defensiveness,” and nonverbal. Pet. Ex. 7, p. 8.
Her motor examination and reflexes were normal and she was not ataxic. Id. Doctor
Janousek diagnosed regression, and ordered an MRI,27 EEG,28 genetic testing, blood
tests for lactate, pyruvate, and ammonia, and urine amino and organic acid testing,
tests typically performed to assess the possibility of a mitochondrial disorder. Id., pp. 9-
12. The EEG was performed the same day as the initial visit to Dr. Janousek and,
27
Magnetic resonance imaging (MRI) is “a method of visualizing soft tissues of the body.” DORLAND’S
ILLUSTRATED MEDICAL DICTIONARY (31st ed. 2007) [“DORLAND’S”] at 928.
28
An electroencephalogram (EEG) records the electrical activity of brain cells and is typically performed
“to identify and evaluate patients with seizures.” K. Pagona & T. Pagona, MOSBY’S MANUAL OF
DIAGNOSTIC AND LABORATORY TESTS (4th ed. 2009) [“MOSBY’S LABS”] at 573.
17
although the testing was terminated early, the results were read as normal. Id., p. 10.
Serum lactate and pyruvate levels were normal and the ammonia level was very slightly
below the reference range. Id., pp. 13-14. Urine amino acids were assessed as
essentially normal, as were the urine organic acids. Genetic testing ruled out Fragile X
and Rett syndromes.29 Id., p. 24. The MRI was normal as well. Id., p. 27. Doctor
Janousek diagnosed C.L. with “encephalopathy, other.” Id., p. 23.
According to Mrs. Lehner’s testimony, Dr. Janousek “agreed that [C.L.] exhibited
autistic features,” but he “could not officially diagnose her.”30 Tr. at 33. Mrs. Lehner
further testified that Dr. Janousek felt C.L.’s regression was more pronounced than was
typical and that she exhibited developmental delay.31 Id.
On April 11, 2006, C.L. was reevaluated by the Shakopee Public Schools to
determine her progress in achieving the goals set in October 2005 after the September
evaluation. Since C.L. failed to meet any of the goals set to improve her speech and
language, these goals were adjusted downward. Pet. Ex. 5, p. 20. In view of her
problems with social interaction, goals regarding joint activities were set, to include
increasing eye contact, verbalizing and gesturing greetings, and engaging in joint
activity with another person for short periods of time. Id., p. 18. C.L.’s vocabulary
continued to be limited to about 20 words—the same level reflected in the October 2005
report.32 Id., p. 20.
C.L. was seen by her pediatrician, Dr. Snook, on April 25, 2006, to clear her for
anesthesia for the MRI. Doctor Snook noted that C.L. was experiencing a regression of
skills to include social skills, language, and eye contact. Pet. Ex. 3, p. 45. She also
29
The test interpretation contained a note that reflected an “understanding that this individual has clinical
features that are consistent with a diagnosis of Rett syndrome” and that the “negative results neither
confirm nor rule out the diagnosis of Rett syndrome.” Pet. Ex. 4, p. 15. Rett syndrome is an autism
spectrum disorder that has a known genetic cause. Snyder, 2009 WL 332044, *31, 36, 48. Symptoms
include loss of language and motor skills, as well as some characteristic stereotypic movements
(handwringing). Id. at *36, 42. Other than the complete or near complete lack of language, C.L. did not
present with symptoms indicative of Rett syndrome. Thus, this disclaimer on the laboratory report may
have been standard language and not specific to C.L.’s case.
30
In August 2006, Mrs. Lehner also reported to a developmental pediatrician that Dr. Janousek told her
that C.L. exhibited “autistic features.” Pet. Ex. 9, p. 232.
31
Doctor Janousek’s records did indicate that C.L.’s regression was more pronounced than would be
expected in a typical autism case, but this was at a follow-up visit in May 2006, not at the initial visit. See
Pet. Ex. 7, p. 29.
32
The record indicates “October 2006.” Clearly this was an error, given that Pet. Ex. 5, p. 2 reflects that
the initial evaluation took place in September 2005 and the report was dated in October 2005. Based on
the many concerns about loss of language reflected in other reports and the few words reported by C.L.’s
teachers at St. Francis and in the school system evaluation, it is unlikely that C.L. still had the 20 word
vocabulary reported here.
18
indicated that C.L. had no intelligible words and repetitively placed her hand in front of
her face. Id.
Doctor Janousek evaluated C.L. again on May 30, 2006, and noted that despite
“[e]xtensive evaluation . . . no definable reason for [C.L.’s] developmental regression”
had been found. Id., p. 29. Doctor Janousek described C.L. as having “typical features
of autism” but “a more pronounced developmental regression than one would expect,
given an autism spectrum diagnosis.”33 Id., p. 29. Doctor Janousek also indicated that
C.L. had experienced no further regression in her developmental skills, was alert during
her examination, exhibited some tactile defensiveness, and made some eye contact,
although no language was heard. Id.
3. Formal Autism Diagnosis.
In June of 2006, a psychological evaluation was conducted at Children’s
Hospitals and Clinics of Minnesota. The evaluation was at the request of Drs. Snook
and Janousek “due to concerns regarding the possibility of an autism spectrum
disorder.” Pet. Ex. 4, p. 50. C.L.’s parents reported that their concerns regarding her
language began when she turned two and was not yet putting two words together. Id.
They reported that C.L. began to lose skills (particularly social skills) at two and one-half
years of age (which would have been in late January 2006), and developed feeding
problems in January 2006. Id. Her social functioning had “greatly decreased” as well.
Id. She had difficulty getting to sleep and would often scream for over an hour when put
to bed. Id. Newer symptoms included a loss of interest in others, often seeming to be
in her own world, not acknowledging the presence of others, and the emergence of
repetitive, self-stimulatory behaviors. Pet. Ex. 4, p. 50. C.L. no longer allowed others to
read to her and appeared to resent others imposing themselves on her. Id. She was
described as seldom happy and typically irritable. She reportedly laughed for no
reason. Id.
During testing, C.L. wandered around the room, calmed herself by lying on the
floor with a blanket over her head, made minimal eye contact, banged toys just to hear
a repetitive noise, displayed minimal pointing, and used some single words mixed with
33
Three articles filed by respondent suggest that C.L.’s “pronounced developmental regression” was not
unusual for a child with an autism diagnosis. See S. Rogers, Developmental Regression in Autism
Spectrum Disorders, MENTAL RETARDATION & DEVELOP. DISAB. RESEARCH REV, 10: 139-43 (2004), filed as
Res. Ex. S [hereinafter “Rogers, Res. Ex. S”], at 140 (reporting that a clear developmental loss of
previously acquired skills is well-documented as one of the patterns of regression in ASD); C. Lord, et al.,
Regression and word loss in autistic spectrum disorders, J. CHILD PSYCH. & PSYCHIAT., 45(5): 936-55
(2004), filed as Res. Ex. R [hereinafter “Lord, Res. Ex. R”], at 946 (reviewing literature on loss of words
and noting that almost all children who experienced a loss of words also experienced a loss of social
skills); R. Landa, Diagnosis of autism spectrum disorders in the first 3 years of life, NATURE CLINICAL
PRACTICE NEUROL., 4(3): 138-47 (2008), filed as Res. Ex. EE [“Landa, Res. Ex. EE”], at 141 (observing
that retrospective reviews found regression in 10-50% of those with an ASD diagnosis).
19
gibberish. Pet. Ex. 4, p. 51. She also engaged in visual stimulation by waving her hand
in front of her eyes. Id. Mrs. Lehner testified that C.L.’s abilities at the time of this
testing “were pretty much the same as they were right after she regressed.” Tr. at 36.
C.L. spoke a few words but most vocalizations were just sounds. Id.
Her cognitive skills had improved since the initial administration of the BSID; she
was now functioning at the developmental age of 23 months, but the improvement had
not kept pace with her age. Pet. Ex. 4, p. 51. Because she was older (35 months of
age), her cognitive score dropped from 80 to 52.34 Id. Her score of 41 on the Childhood
Autism Rating Scale [“CARS”] fell within the autistic range. Id., p. 52.
After a thorough evaluation,35 Dr. (Ph.D.) Mary Zielinksi diagnosed C.L. with
significantly delayed cognitive skills, scattered skill development, and significantly
delayed adaptive skills, particularly in language, social functioning, and interaction.
These difficulties resulted in a diagnosis of “pervasive developmental disorder (a.k.a.
autism spectrum disorder).” Pet. Ex. 4, pp. 52, 63.
4. Subsequent Evaluations.
Robert Voight, M.D., performed a developmental pediatric assessment of C.L. at
the Mayo Clinic on August 10, 2006. Pet. Ex. 9, p. 231. By report, C.L. began waving
“bye-bye” at just over one year of age, but then stopped and currently used the gesture
only with prompting.36 Id. She began using “mama” and “dada” at 12-18 months of age
specifically to refer to her parents and had never lost this skill.37 Id. By two years of
age, she used between 20-25 words, but at the time of the assessment, she used only
two or three words spontaneously. Id. Her pediatrician first became concerned about
34
Doctor Shafrir described this decline in the cognitive score on the BSID when compared to C.L.’s score
on the first administration of the BSID as a “profound regression” adding that “you can’t have a better
example of regression.” Tr. at 150. Rather than showing a loss of skills—the usual definition of
regression in the context of ASD—the test components showed that C.L. had acquired skills as she aged,
but not at the rate expected for a typically developing child. Doctor Shafrir did not comment on the third
administration of the BSID in which C.L.’s cognitive abilities were scored as 90, within the normal range.
Pet. Exs. 9, p. 232; 5, p. 24. In a re-evaluation by Shakopee Public Schools on December 5, 2006, the
evaluator commented on these discrepant scores by noting that C.L.’s symptoms could be highly
variable. Pet. Ex. 5, p. 24. Doctor Renaud, who first treated C.L. for the VGKC antibodies discovered in
2008 commented that C.L. had good days and bad days as well. Pet. Ex. 9, p. 3.
35
The evaluation included interviews with petitioners, C.L.’s speech pathologist, the evaluations for
speech and occupational therapy performed by St. Francis staff and the school district (all discussed
supra), and the test results from these evaluations as well as administration of additional tests, including
the CARS. Pet. Ex. 4, p. 51.
36
Mrs. Lehner did not indicate when C.L. lost this skill.
37
Doctor Snook’s letter suggests that C.L. began using these words with specificity between 15-18
months of age. Pet. Ex. 8, p. 1.
20
her development when she was two years old but not yet combining words. Id., p. 232.
C.L. learned to indicate body parts before the age of two and never lost this skill. Id., p.
231. She was able to follow single-step commands without gestures, but had never
mastered two-step commands. Id. Her language acquisition stopped between the ages
of 24 and 30 months of age. Mrs. Lehner indicated that she first became concerned
about C.L.’s social and behavioral interactions when C.L. was around the age of two
and one-half.38 Id., pp. 231-32. Sometime thereafter, C.L began engaging in
stereotypic behavior and repetitive running in circles. Id., p. 232.
Prior to Dr. Voigt’s assessment, C.L. was tested on August 4, 2006, by a child
psychologist at the Mayo Clinic. Pet. Ex. 9, p. 232. One of the tests performed was the
BSID, the same test performed by the school system in September 2005, and by Dr.
Zielinksi at Children’s Hospitals and Clinics of Minnesota in June 2006. C.L.’s cognitive
function score on the September 2005 test was 80 (with 100 being average and a
standard deviation of 15). See Pet. Ex. 5, p. 2. Her score in June 2006 was 52. See
Pet. Ex. 4, p. 51. In the August testing, her cognitive functioning score had risen to 90,
placing her within the average range, but she scored well below the norm in social-
emotional and adaptive functioning. Pet. Ex. 9, p. 232. Testing specific for ASD was
performed using the Autism Diagnostic Observation Schedule [“ADOS”]. C.L.’s
communication score was 5, exceeding the autism cutoff of 4, and her ADOS social
interaction score was 14, exceeding the cutoff of 7. Id. Her overall score of 19
significantly exceeded the autism cutoff of 12. Id.
At this visit, Dr. Voigt diagnosed C.L. with autism. Pet. Ex. 9, pp. 234-36. He
noted concerns about regression in speech and language development at two years of
age, with “persistent discrepant and disproportionate delays in her speech and
language development relative to her nonverbal, visual problem solving and gross
motor development over time.” Id., p. 234. He also diagnosed her with developmental
dysphasia/communication disorder. Id., pp. 236-37.
She was seen again at the developmental pediatric clinic at Children’s Hospitals
and Clinics of Minnesota on August 15, 2006 “to discuss medical and development[al]
issues related to autism.” Pet. Ex. 4, p. 60. By history, C.L. was colicky and irritable as
an infant, in contrast with her twin sister, who was described as “laid back.” Id. C.L.
had early problems with reflux, and was reported to be a “high need” infant who had
tantrums with little provocation. Id. Mrs. Lehner reported that C.L. walked at 15 months
of age, began combining words at two years of age,39 and had adequate social skills.
Id. Mrs. Lehner indicated that she and her husband began to be concerned in
December (referring to December 2005). Id. C.L.’s language was described as “mainly
38
C.L. would have been two and one-half years old in late December 2005.
39
Once again, Mrs. Lehner’s recall was imprecise, as, at two years of age, C.L. was referred to early
intervention services precisely because she was not combining words.
21
gibberish and squeals.” Id. She had a couple of words and would say “no.” Id. She
was reported to understand what was said to her. Id. Mrs. Lehner also described
repetitive behaviors, including running in clockwise circles and putting her hand over her
right eye. Id. Additionally, C.L. occasionally walked on tiptoes, enjoyed tactile
simulation,40 and had difficulty with sitting and having a book read to her. Id.
On examination, C.L.’s height and weight were both reported as greater than the
50th percentile, and she was observed to have coarse facial features and mildly
flattened affect. Pet. Ex. 4, p. 61. She did not seek assistance, but engaged in self-
directed activities. Id. She spun a puzzle, ran back and forth, put her right hand to her
face at times, and had some high pitched vocalizations. Id. Although she had a stable
walk, she could not jump on command or throw or catch a ball. Id. She was able to
point at pictures in a book and stack six blocks, but could not identify colors or count.
Id. Mrs. Lehner asked for and received information about supplements and other
supports.41 Id.; see also id., p. 83.
Prior to this appointment, C.L.’s early childhood special education teacher
completed a questionnaire about C.L.’s abilities and performance to be used during the
August 15 evaluation. Pet. Ex. 4, p. 68. She identified C.L.’s ability to pick up on ideas
presented and to follow a schedule as strengths, but found her cognitive,
communication, and social skills, along with her sleep and feeding problems, to be
areas of concern. Id., p. 69. She described C.L. as withdrawing from other children and
adults. Id., p. 70. Goals for C.L.’s new IEP were to include increasing her
communication (through pictures, words, or signs), social interaction, and problem
solving (cognitive) skills, as well as working on sensory integration. Id. In response to a
question about progress, she noted that C.L. had begun using PECS. Id. Also, C.L.
was sharing eye contact and laughter when she enjoyed an activity. Id. The teacher
wrote that beginning in April, she had begun thinking that C.L. needed much more time
in therapy as well as more peer involvement time. Id. She noted that she had
suspected for some time that C.L. might have ASD, as C.L. exhibited many ASD
characteristics. Id., p. 71.
The parent questionnaire completed for this evaluation reflected that C.L.’s
parents first became concerned about her lack of verbal and social skills, lack of eye
contact, and poor eating and sleeping when C.L. was about 27 months of age. Pet. Ex.
4, p. 72. C.L. was 27 months of age in October 2006, around the same time the school
system completed C.L.’s initial evaluation. On the form, C.L.’s parents noted a loss of
40
Based on reports of tactile defensiveness, this likely referred to C.L.’s desire to touch different textured
items, such as books with a tactile focus, rather than a desire to be touched, tickled, or otherwise
stimulated by the touch of others. Pet. Ex. 5, p 26 (Shakopee Public Schools’ Evaluation of December 5,
2006, showed C.L. to be seeking books with tactile themes).
41
Doctor Voigt had cautioned against the use of alternative treatments for autism, including dietary
supplements. See Pet. Ex. 9, p. 236.
22
verbal and social skills, and described her as withdrawn, easily frustrated, and prone to
temper tantrums. Id., pp. 76-77. They reported that the regression had occurred about
six to seven months prior to this visit. Id., p. 77. This would place the onset of
regression in the January-February 2006 time frame (assuming the form, which is
undated, was completed in late July or early August in preparation for the August 15
appointment).
Doctor Snook saw C.L. for her three year well child visit on August 18, 2006, and
reported that she had been diagnosed with autism, but was “sleeping better, [had] fewer
tantrums, [and] less extreme behavior.” Pet. Ex. 3, p. 47.
C.L.’s occupational therapist at St. Francis reported on October 18, 2006, that
C.L. demonstrated “increased participation, cooperati[on], tolerance, and independence
with activities,” as well as “increased eye contact.” Pet. Ex. 14, p. 115.
A reevaluation of C.L. by the Shakopee school system took place on December
5, 2006. Her special education teacher reported that she had limited vocabulary, with
three words used spontaneously, but not consistently or frequently. Pet. Ex. 5, p. 22.
She was beginning to use the picture exchange system, but was not imitating words.
Id. Any eye contact was fleeting. Id., p. 23. She played by herself in the classroom
and did not show any awareness of her twin sister there. Id. She did not use toys
functionally and did not demonstrate any pretend play. Id. Mrs. Lehner shared that C.L.
“appeared to regress in her skills approximately around December of 2005.” Id., p. 23.
She and Mr. Lehner noted the loss of social and verbal skills. Id.
Prior to this evaluation, C.L. was retested with many of the same testing
instruments used in September 2005. Although the school system did not re-administer
the BSID, the evaluators compared C.L.’s initial September 2005 score with the June
2006 test performed by Minneapolis Children’s Hospital (scored as 52) and the August
2006 test performed at the Mayo Clinic (scored as 90). Pet. Ex. 5, p. 24. The
evaluation team noted the “great variability or inconsistency” in these test scores. Id.
Her teacher commented that it was difficult to assess C.L.’s cognitive skills because of
her communication delays. Id. She was unable to perform most tasks on the Hawaii
Early Learning Profile at the 36 month level. Id. Her receptive vocabulary was scored
at 80, with 100 being the mean score and a standard deviation of 15, placing her in the
9th percentile. Id., p. 25. Her expressive vocabulary was not scored, as she did not
identify any pictures. Id. In summarizing C.L.’s speech and language, the evaluators
noted that she had decreased eye contact, no verbal communication in the classroom
setting, was avoidant of physical proximity to other children and adults, and had
difficulty initiating or responding to joint attention and reciprocal social communication.
Id., p. 26.
C.L. was observed by an ASD consultant for the school district as part of the
evaluation. Pet. Ex. 5, pp. 31-33. The observations were scored against a school
23
system checklist for ASD eligibility, and C.L. was found eligible for special education
services as a student with ASD and also required occupational and speech therapy.
Id., p. 33.
Doctor Janousek evaluated C.L. again on January 23, 2007 and found that she
had “made slow gains in development” since her last appointment in May 2006,
including “some gains in eye contact and language development.” Pet. Ex. 7, p. 36.
Mrs. Lehner testified that C.L. began to receive ABA therapy in January 2007, after an
extended time on the Minnesota Autism Center’s waiting list. Tr. at 37-38. The therapy
was recommended by Dr. Janousek. Tr. at 35.
C.L. continued to be seen by Metropolitan Pediatric Specialists throughout 2007
and 2008 for various routine illnesses, including URIs, chronic cough, rhinitis,
constipation, and thrush. See generally Pet. Ex. 3, pp. 53-70. She was also seen at the
University of Minnesota Children’s Hospital-Fairview in 2007-08 for a variety of testing
and treatment, mostly related to potential allergies. See generally, Pet. Ex. 6, pp. 1-87.
Doctor Janousek examined C.L. on September 26, 2008 and found that, while
she “has received ABA therapy and is making some progress, . . . she continues to
have profound neurodevelopmental deficiency.” Pet. Ex. 7, p 51. Doctor Janousek
found that C.L. “continued to exhibit autistic features,” had experienced a “pronounced
neurodevelopmental regression at one point,” and “has a twin who also has autistic
features, but is higher functioning.” Id. He referred C.L. for an evaluation with Dr.
Renaud at the Mayo Clinic, as Mrs. Lehner sought further evaluation into the cause of
C.L.’s developmental regression. Id. Precisely why he selected Dr. Renaud was not
clearly stated in the record of his referral but, as discussed below in Part E, Dr. Renaud
was engaged in research into voltage-gated potassium channels and autoimmune
encephalopathy, and Dr. Janousek may have been aware of this research.
E. Voltage-Gated Potassium Channel Antibodies: Testing and Treatment.
1. Background Information.
According to respondent’s expert, Dr. Dalmau, autoimmune encephalitis—C.L.’s
appropriate diagnosis, according to petitioners—was discovered in 2005-07. Tr. at 297;
see also J. Dalmau, et al., Clinical experience and laboratory investigations in patients
with anti-NMDAR encephalitis, LANCET NEUROL. 10: 63-74 (2011), filed as Pet. Ex. 16b
[hereinafter “Dalmau, Pet. Ex. 16b”] (explaining how various forms of autoimmune
encephalitis came to be recognized as diagnostic entities); M. Gable, et al., The
Frequency of Autoimmune N-Methyl-D-Aspartate Receptor Encephalitis Surpasses That
of Individual Viral Etiologies in Young Individuals Enrolled in the California Encephalitis
Project, CLINICAL INFECTIOUS DISEASES, 54(7): 899-904 (2012), filed as Pet. Ex. 16a
[hereinafter “Gable, Pet. Ex. 16a”], at 899 (discussing a novel form of autoimmune
24
encephalitis first reported in 2007 (anti-NDMAR encephalitis)).42 In another article, Dr.
Dalmau was credited with being the first to describe limbic encephalitis associated with
anti-NMDAR antibodies. See T. Hung, et al., Anti-N-Methyl-D-Aspartate Receptor
Encephalitis, PEDIATR. AND NEONATOL., 52: 361-64 (2011), filed as Pet. Ex. 16c
[hereinafter “Hung, Pet. Ex. 16c”], at 361.
The discovery that some previously idiopathic forms of encephalitis were
attributable to autoantibodies produced as the result of tumors (paraneoplastic
syndromes) or from unknown causes generated considerable research.43 Doctor
Angela Vincent’s laboratory in England, the Mayo Clinic in Minnesota, and Dr. Dalmau
were major contributors to the growing body of information filed as exhibits in this
case.44 The idea that autoantibodies could be responsible for otherwise idiopathic forms
of encephalitis began to encompass other newly identified antibodies in the absence of
tumors. According to Dr. Dalmau, voltage-gated potassium channel antibodies were so
named in a study performed about 16 years prior to the hearing. Tr. at 301. They
eventually became suspects as causal of some forms of encephalitis, based in part on
work done at the Mayo Clinic.45
In 2001-07, the Mayo Clinic’s Neuroimmunology Laboratory began widespread
autoantibody screening of patients suspected of having an autoimmune neurological
disorder, as a part of a prospective clinical study. See Tan, et al., Clinical spectrum of
voltage-gated potassium channel autoimmunity, NEUROL., 70(20): 1883-90 (2008), filed
as Pet. Ex. 10i [hereinafter “Tan, Pet. Ex. 10i], at 2.46 Out of more than 130,000 serum
42
Doctor Dalmau was a co-author of this study, which reported findings of the California Encephalitis
Project, an entity established to study encephalitis and its causes. Anti-NDMAR encephalitis was first
reported in 2007 and later discovered to be “a significant cause of encephalitis in certain age groups.”
Gable, Pet. Ex. 16a at 899-900.
43
Doctor Gorman’s testimony reflected that body of research has continued to grow. He testified that
since July 16, 2012, around the time he authored his second report in this case, about 50 new journal
articles on voltage-gated potassium channel antibody encephalitis had been published. Tr. at 469.
44
Of the medical journal articles filed as exhibits, Dr. Vincent was a contributor or senior researcher on at
least nine articles; Drs. Renaud and McKeon (both of whom treated C.L.) on at least three articles, and
Dr. Dalmau a contributor to or senior researcher on at least eight articles. Doctor Vincent is not a
practicing physician. However, she is a well-known researcher in the field of autoimmune
neuroimmunology who has published with Dr. Dalmau. Tr. at 382, 448.
45
As discussed in more detail later in this decision, Dr. Dalmau testified at some length that only certain
subtypes of the so-called VGKC antibodies, with antibodies against specific proteins, are pathogenic or
disease-causing, and that limbic encephalitis, which had been attributed to VGKC antibodies was actually
caused by other autoantigens. See generally, Tr. 300-20; Pet. Ex. J at 7-9 (Dr. Dalmau’s expert report);
Dalmau, Pet. Ex. 16b, at 63 (noting that leucine-rich, glioma-inactivated 1 (LGI1) is a synaptic antibody
“which is the main autoantigen of limbic encephalitis previously attributed to voltage-gated potassium
channels”).
46
Ordinarily, I cite to the page numbers of the article itself, rather than the page numbers assigned by the
party filing the medical journal article, in order to allow those reading the decision who do not have access
25
samples, 80 patients (with a median age of 65) were found to have VGKC
autoantibodies. Additional information for 72 of the 80 patients was obtained. Sixty of
the patients had diagnoses which included inflammatory or neurodegenerative
disorders, Creutzfeldt-Jakob disease [“CJD”],47 recurrent transient amnesia, and several
other psychiatric disorders. Id., p. 5. Cognitive impairment was the most common
neurological complaint. Id., p. 6.
Doctors Renaud and McKeon, two of C.L.’s treaters, were co-authors of an
article discussing documentation of VGKC antibodies in children. C.L. was one of the
12 children discussed in the article as positive for the VGKC antibodies. C.L. was
Patient No. 11 in the report. Tr. at 398-99; Dhamija, Pet. Ex. 11c. This article is
discussed in more detail in Section V.B.1.b.(2)(b), below.
2. Referral to Mayo Clinic Child and Adolescent Neurology.
Mrs. Lehner testified that Dr. Janousek referred C.L. to Dr. Renaud at the Mayo
Clinic because her regression was “more pronounced than a typical autistic regression.”
Tr. at 40. Doctor Renaud, a pediatric neurologist, examined C.L. on October 20, 2008.
She found C.L. to be “a 5-year-old girl with a history of normal early development and
subsequent regression with a diagnosis of autism.” Pet. Ex. 9, p. 4. Doctor Renaud
noted that Mrs. Lehner “feels that the regression followed an influenza vaccine.” Id.
Doctor Renaud ordered a number of laboratory tests as part of her evaluation. Id., pp.
4-5. She diagnosed C.L. with “[d]evelopmental regression with autistic features” and
“[p]ossible coarsening of the features, rule out storage disorder.” Id., p. 1.
The history of onset of C.L.’s regression reported at this visit was somewhat
different from the histories appearing in more contemporaneous records and histories
provided by Mrs. Lehner at around the time of the autism diagnosis. Mrs. Lehner
reported that after the influenza vaccination in November 2005, C.L. developed self-
stimulatory behaviors in December, including rocking her body and humming—reported
behaviors that do not appear in any of the therapy or medical records from December
2005 or January 2006. Pet. Ex. 9, p. 2. Decreased eye contact and flicking her fingers
in front of her eyes were also reported as occurring prior to the loss of words. Id. At the
December 2005 St. Francis evaluation, the therapist noted that C.L. initiated eye
contact, but one can infer some loss of eye contact from contemporaneous therapy
records from January and February 2006. Pet. Ex. 14, pp. 1, 6-7, 16. The finger
flicking was not reported during this time. Some stereotypic behaviors were reported,
including placing her hand in front of her face (April 2006) (Pet. Ex. 3, p. 45) and putting
to the exhibits to follow the citations. The copy of the article filed does not contain page numbers integral
to the article. Therefore, for this exhibit, citations are made to the exhibit page numbers assigned by
petitioners, which are found at the bottom of each page.
47
A variant of CJD is caused by the same agent that causes bovine spongiform encephalopathy or “mad
cow disease.” DORLAND’S at 538, 622.
26
her hands in her mouth (December 2005) (Pet. Ex. 3, p. 42). Mrs. Lehner indicated at
the St. Francis evaluation that C.L. put her hands in her mouth when she was unsure of
her environment, suggesting that this mannerism was not of recent origin. Pet. Ex. 14,
p. 7. Waving her hand or fingers in front of her eyes was not reported until June 2006.
Pet. Ex. 4, p. 51. Although Mrs. Lehner did not provide Dr. Renaud a specific time
period for when the loss of social skills and affectionate behavior were first observed,
the contemporaneous records indicate that a regression of C.L.’s social skills was first
reported in February 2006. Pet. Ex. 7, p. 8.
Mrs. Lehner also reported at Dr. Renaud’s evaluation that C.L. then had
approximately 50 words or approximations of words, but rarely combined two words.
Pet. Ex. 9, p. 3. She could follow simple one-step commands. Id. C.L. had bad and
good days, but had no new regressions. Id. She learned slowly and made gains, but
the gap between C.L. and her peers was widening. Id. Intelligence testing in January
2008 had placed her IQ at 70. Pet. Ex. 9, p. 3.
Other reported symptoms included flicking her hands,48 humming, galloping, and
teeth grinding. Pet. Ex. 9, p. 3. She reportedly had “hypotonia since the regression,”
fell asleep well, was rested in the morning, and did not nap. Id. The number of
nighttime awakenings had improved in the past six months. Id.
On examination, C.L. was noted to be “mildly coarse-appearing,” with acne,
bilateral ear pits, slightly coarse facial features, bushy eyebrows, coarse thin hair, mild
hypotonia with good strength and symmetric deep tendon reflexes. Pet. Ex. 9, p. 4.
Doctor Renaud noted that Mrs. Lehner “felt that the regression occurred following a flu
vaccination” and had brought with her to the appointment “a number of items from the
internet” regarding autism and developmental regression, which Dr. Renaud reviewed
with the family. Id.
Doctor Renaud proposed a battery of tests. Because C.L.’s regression was
described as “sudden,” a “paraneoplastic antibody panel” was ordered “to ensure that
there are no antibodies against the brain which could represent a treatable autoimmune
disorder.” Pet. Ex. 9, p. 5. This panel encompassed the testing for VGKC antibodies to
determine if C.L. had experienced autoimmune encephalitis.49
48
This appears to be the first report of C.L. “flicking” her hands, but this does not seem to be materially
different from the “finger flicking” previously reported. Such stereotypic mannerisms are common in
children diagnosed with ASD. See Landa, Res. Ex. EE at 138, 141 (discussing stereotypical behavior in
ASD).
49
The test results appear at Pet. Ex. 9, pp. 9-16. As Dr. Renaud did not comment on any of the results
other than the VGKC antibodies, presumably none of the testing raised any diagnostic concerns.
27
3. Diagnosis of VGKC Antibodies and Possible Autoimmune Encephalitis.
On November 17, 2008, Dr. Renaud saw C.L. for a follow-up visit after C.L.’s
laboratory tests indicated in October 2008 that C.L. had an abnormal level of “antibodies
to neuronal voltage-gaited potassium channels.” Pet. Ex. 9, p. 7. Prior to this visit, C.L.
had been placed on prednisolone to suppress any ongoing immune response. Pet. Ex.
9, p. 7. Increased appetite and thirst along with flushed cheeks were reported. Id.
There had been no dramatic changes in C.L.’s behavior while on this steroid, but C.L.
may have had an increase in eye contact, both as reported by C.L.’s parents and as
observed by Dr. Renaud. Id.
During the visit, Dr. Renaud “discussed the function of potassium channels” in
detail with petitioners. Pet. Ex. 9, p 7. She noted that “it is unclear at this time whether
this is the cause of her developmental regression and autism,” but as the antibodies are
“a potentially treatable cause of deterioration, we will treat this as an autoimmune
disorder.” Id. Although no significant change in C.L. was seen with the 18 days of
prednisolone treatment, Dr. Renaud indicated that, in view of the three years since
C.L.’s deterioration, a response to treatment might not be seen for “several months.” Id.
Her plan was to continue with prednisolone50 to suppress “the ongoing immune
response” and intravenous immunoglobulin [“IVIG”] to “hopefully remove the
antibodies.” Id., pp. 7-8. She revised her diagnosis of C.L. to include neuronal voltage-
gated potassium channel antibodies with possible autoimmune encephalopathy, in
addition to the global developmental delay and autistic features in her earlier
diagnosis.51 Id., p. 8
4. Treatment for VGKC Antibodies and Response.
a. Petitioners’ Assertions.
From October 2008 through the time of the hearing, C.L. was treated, more or
less continuously, for presumed autoimmune encephalopathy or encephalitis, based on
the presence of high levels of VGKC antibodies.52 Mrs. Lehner testified that C.L.
50
The text of Dr. Renaud’s notes in the Impression/Report/Plan section indicated in one sentence that
C.L. was taking prednisolone, and in a later sentence that she was taking prednisone. The “Current
Medications” section indicated that she was taking prednisolone. Pet. Ex. 9, p.7. A telephone message
from Mrs. Lehner to Dr. Renaud on November 25, 2008, reflected that C.L. had been on prednisone for a
month or so, and was reporting side effects. However, her medication listing referred to prednisolone.
51
In February 2009, Dr. Renaud changed C.L.’s diagnosis from possible to probable autoimmune
encephalopathy, with the global developmental delay and “autistic features” diagnoses unchanged. Pet.
Ex. 9, p. 26
52
It does not appear that C.L. received any treatment for her VGKC antibodies between April 2010 and
November 2011. Pet. Exs. 6, p.128 (noting last rituximab treatment in April 2010); 9, pp. 118-19
(resuming treatment in late November 2011).
28
exhibited “gains” while on treatment, but suffered some side effects. Tr. at 43-44. By
2010, C.L. was making “slow and steady gains,” but was still globally developmentally
delayed. Tr. at 46. Mrs. Lehner testified that in the fall of 2011 she began to see
improvement in C.L.’s “attending” (i.e., ability to pay attention and observe her
environment and imitate others) after C.L. resumed treatment with Dr. Renaud (which
occurred in September 2011, Pet. Ex. 9, p. 81) and started a higher dose of the steroid
prednisolone. Tr. at 48. C.L. made further improvements in her behavior after the
dosage was increased in March 2012. Tr. at 48-49. Mrs. Lehner testified that at the
time of the hearing [January 28, 2014], C.L. was able to make requests with eye
contact, label things, seek out affection without prompting, read words, write letters, and
respond to two step commands. Tr. at 53-55. She conceded that C.L. was still not able
to read sentences and that her articulation needed to be “clean[ed] up.” Tr. at 54. Mrs.
Lehner testified that C.L. received special services in an autism classroom and ABA
therapy at home on a part-time basis during the school year and full-time during the
summer. Tr. at 54-56. A more objective assessment of C.L.’s level of performance is
found in C.L.’s school records during 2009-11 and December 2012-March 2013, see
generally Pet. Ex. 5, pp. 45-266, portions of which are discussed in subsections b and f,
below.
b. Initial Treatment at Mayo Clinic and Response.
C.L.’s initial treatment, from October 2008 through June 2009, was provided by
Dr. Renaud. C.L. was treated with a steroid (prednisolone) and an immune suppressant
drug (CellCept)53 to suppress production of the VGKC antibodies, and with intravenous
immunoglobulin [“IVIG”] therapy to remove the antibodies from her system. Steroid
therapy began in late October 2008, but due to side effects reported by her parents,54
she was weaned off prednisolone beginning in January 2009. See Pet. Ex. 9, pp. 7
(beginning treatment), 22 (discussion about discontinuation of prednisolone due to side
effects and lack of any significant improvement). In February 2009, CellCept was
substituted, initially at a low dose (id., p. 26), but when the dose was substantially
increased in April 2009 (id., p. 36), severe side effects ensued55 and she was abruptly
53
“Mycophenolate (CellCept) is used with other medications to help prevent transplant organ rejection
(attack of the transplanted organ by the immune system of the person receiving the organ) in people who
have received kidney, heart, and liver transplants. . . . It works by weakening the body's immune system
so it will not attack and reject the transplanted organ.” U.S. National Library of Medicine, MedlinePlus,
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601081.html (last visited July 9, 2015).
54
Mrs. Lehner reported that C.L. experienced sleep disturbances, became very clingy, and made a new
noise when crying or shouting. Pet. Ex. 9, p. 19. She was advised that prednisolone is known to often
cause behavioral disturbances and restless sleep, but IVIG was unlikely to cause such side effects. A
reduction in the dose of prednisolone was suggested. Id. The family temporarily reduced the dose, but
observed no changes in her behaviors. Id., p. 20.
55
See Pet. Ex. 9, pp. 39, 41-43 (telephone calls and office visits reporting significant side effects,
including incontinence and a facial rash from CellCept). Doctor Renaud consulted a rheumatologist who
recommended stopping the treatment, as incontinence was a recognized side effect of CellCept. Id., p.
29
taken off the drug (id., pp. 39, 41-43). IVIG therapy began in November 2009, initially
on a monthly basis, but when therapy with CellCept ended, the IVIG schedule was
increased to every two weeks beginning in April 2009. Id., pp. 35-36.
In mid-April 2009, C.L.’s parents indicated that they were not sure if they wanted
to continue with the treatment for the VGKC antibodies, including IVIG and medications.
Pet. Ex. 9, p. 42. However, at a visit near the end of April 2009, they agreed to try three
more IVIG infusions at two week intervals. Id., p. 46. On July 2, 2009, C.L.’s parents
notified Dr. Renaud that they were stopping IVIG therapy. Id., p. 61.56
During her treatment, C.L.’s blood was drawn regularly to measure the levels of
VGKC antibodies in her system. Antibody levels fluctuated over the course of
treatment, but remained persistently abnormal. Pet. Ex. 9, p. 106.
Doctor Renaud’s treatment records, including parental reports and her own
observations, reflect overall improvement in C.L.’s behavior and symptoms; however,
the improvements did not appear to correspond to the varying antibody levels measured
throughout her treatment.57 Although parental reports at most of the appointments
42. The incontinence improved when CellCept was stopped, but some problems persisted as of April 29,
2009. Id., p. 45.
56
C.L.’s parents thought the IVIG treatment might be causing some side effects as well. In February
2009, Mrs. Lehner called Dr. Renaud’s office to report that C.L. was being very clingy and more irritable.
Pet. Ex. 9, p. 27. This behavior persisted through March 5, 2009. Id., pp. 29, 32 (telephone calls
concerning behaviors they thought might be related to IVIG treatment). However, it appears that the lack
of any real improvement may have contributed to this decision. See id., pp. 58-59 (Mr. Lehner’s
assessment of C.L.’s progress after being out of the country for a period of time).
57
A normal potassium channel antibody level is less than 0.02 according to the Mayo Clinic’s laboratory
reports. See, e.g., Pet. Ex. 9, p. 106. C.L.’s antibody levels fluctuated over time, as did her behavior and
skills; however, there was no consistent correlation between low antibody levels and improved behavior
or, conversely, between high antibody levels and poor behavior or loss of skills. On January 8, 2009
C.L.’s antibodies had dropped to 0.78 (down from 1.69 on November 18, 2008), but there was no
significant change in her behavior reported at her January 7, 2009 doctor visit. Pet. Ex. 9, pp. 22-23,106.
Improvement was reported at the February 18 visit, although C.L.’s antibodies had risen to 0.94 as
measured on February 19, 2009. Pet. Ex. 9, pp. 26, 106. On April 15, 2009, C.L.’s antibodies were 1.74
and Mrs. Lehner reported that she thought C.L. was regressing (although this regression was attributed to
C.L.’s use of CellCept). Pet. Ex. 9, pp. 39-42, 106. On May 14, 2009, C.L.’s antibodies measured 1.18
and she was reported to be doing well and talking more. Pet. Ex. 9, pp. 50, 106. On August 26, 2009,
C.L.’s VGKC antibody level was up to 1.82 after not having IVIG for two months and she was reported to
have greater understanding and to be more focused. Pet. Ex. 9, pp. 63,106. On February 18, 2012,
C.L.’s VGKC antibodies measured 0.92, up from 0.31 on January 21, 2012, and C.L. was reported to
have experienced some gains at her March 7, 2012 doctor’s visit. Pet. Ex. 9, pp. 127-28. On July 26,
2012, C.L.’s antibodies were measured at 0.56, slightly up from 0.44 on May 17, 2012, and she was
reported to be “having some tantrums and aggressive behavior” although her “skills, language, and
cognitive abilities” remained stable. Pet. Ex. 9, pp. 183, 141.
30
included some area in which C.L. had improved,58 other evidence suggests that the
improvements may not have been as substantial as reported. At the end of June 2009,
just prior to the July 2, 2009 decision to stop IVIG treatment, Mr. Lehner was out of the
country for a period of time, which was variously reported as three weeks and three
months. Upon his return, he commented that he thought C.L. was vocalizing more, but
had not noticed any other specific changes. Pet. Ex. 9, p. 58. Her eye contact with
family members was described as “reasonable.” Id.
In March 2009, C.L. received an assessment of her progress by a psychologist.
See Pet. Ex. 5, p. 78. Her scores on the Vineland Adaptive Behavior Scale were largely
in the 1st percentile or below, and her score on the ADOS was again in the autistic
range. Id.
Additionally, C.L.’s school records from the period of March through November
2009 (including a classroom observation and two IEP reviews) do not reflect the
increased vocabulary and significantly improved eye contact reported at the monthly
visits to Dr. Renaud. See Pet. Ex. 5, pp. 45-49 (classroom observations in March 2009
noting C.L.’s use of two-word phrases only when motivated and prompted; C.L.’s need
for prompting to produce 20 different two-word requests within three hours; her making
eye contact only with a familiar person; her non-responsiveness to questions; and her
need for an assistive device to make “I want” requests); pp. 55, 57 (observations on her
April 2009 IEP which noted that she was not spontaneously putting words together in a
sentence); pp. 57-59 (observations for IEP progress in June and November 2009); p. 61
(noting at April 2009 meeting to develop IEP for the following school year that C.L.’s
58
C.L. was reported in February 2009 as improving in vocabulary, using two-word phrases, and having
slightly improved eye contact; however, when frustrated she ground her teeth, gagged herself, and
banged her head. Pet. Ex. 9, p. 25. Shortly after the February IVIG treatment, Mrs. Lehner reported her
as very clingy and more irritable. Id., p. 27. In March 2009, she was reported as acquiring a few new
words and having reasonable eye contact, but continued to have behavioral problems. Id., pp. 30-31. In
early April 2009, Mrs. Lehner reported that C.L. was combining words, making requests, and interacting
more, but continued to have stereotypical behavior and had begun gagging herself. At a visit on April 15,
2009, though, Mrs. Lehner reported that C.L.’s behaviors had “not improved at all” and she felt that “in
general she was regressing.” Id., p. 39. She was concerned that the school would not permit C.L. to
return the following school year, due to her behavior problems. She reported that C.L.’s vocabulary had
remained stable while off the prednisolone. Doctor Renaud commented that C.L. did not use any words
during this visit. Id., p. 41. At a visit on April 29, 2009 (when C.L. was off prednisolone and CellCept, and
had not received IVIG since April 1, 2009 (see Pet. Ex. 9, pp. 94,101)), she was reported to be using two-
to three-word phrases, seeking out more social interaction, and was more content at school. Id., p. 45. In
mid-May 2009, C.L.‘s family thought her communication and interaction had improved since the last IVIG
dose. Doctor Renaud noted that C.L. greeted her and answered a few questions with single words. Id.,
p. 53. She assessed C.L. with incremental improvements after each IVIG infusion on the two-week
interval schedule. At the end of June 2009, C.L. was reported to be calmer, with improved
understanding, but still galloping and humming. Id., p. 58. At the end of August 2009, two months after
the last IVIG treatment, C.L. was described as more focused, with better understanding. A recent EEG
was described as normal, and C.L. had not had any regressions since stopping treatment. Id., pp. 63-64,
67 (phone call reflecting that C.L. had an EEG, not an MRI as reported at the August 26 visit).
31
progress had been “limited” and that she had struggled with irritability and behavioral
problems in the past few months); p. 63 (evaluation from summer session reflecting that
she could say familiar words in a song, would say her own name when asked, followed
one-step directions, and played alongside peers without interaction); p. 65 (October
2009 IEP report reflecting that she could use one-word phrases, needed frequent
prompting, and was using PECS at home to make “I want” requests).
C.L. was retested to confirm her continued need for special education services in
December 2009 (a state-mandated requirement). While she had gained skills since the
initial testing in September 2005 (performed by the school system) and June 2006
(testing outside the school system), she again scored as severely impaired—frequently
in the 1st percentile ranking or below. Pet. Ex. 5, pp. 70-72. Her parents reported their
primary concerns were her autism diagnosis and her lack of communication and peer
interactions. Id., p. 70. C.L. was also retested for an autism spectrum disorder. The
cut-off score for an autism diagnosis was 85 or higher; C.L. was scored over 100 in
separate evaluations by her parents, kindergarten teacher, and special education
teacher. Id., p. 74.
During the same time frame when C.L. received VGKC antibody treatments from
Dr. Renaud, she was also receiving ABA therapy at the Lovaas Institute and speech
and occupational therapy through the school system. Pet. Ex. 17, pp. 22-23 (Lovaas
history of services received by C.L. from 2005-10). Consequently, it is difficult to
attribute C.L.’s improvement, if any, to the specific therapies prescribed by Dr. Renaud.
What is clear is that there was not a dramatic or significant improvement in C.L.’s
functioning. This is especially evident when considering that her April 2009 IEP goals
were continued at the June and November 2009 progress reviews, rather than marked
as achieved. See Pet. Ex 5, pp. 56-60.
c. Switch in Therapies and Providers.
On August 26, 2009, C.L. saw Dr. Renaud again. She had received her last IVIG
treatment on June 24, 2009. Pet. Ex. 9, pp. 63-64. She was reported to be more vocal
and having better understanding since the June visit. Off therapy, her antibody level as
measured on this visit had risen to 1.82. Id., p. 66. In a sample taken in October 2009,
C.L.’s antibody level again rose, this time to 2.17. Id., pp. 67-68.
C.L. saw Dr. Renaud and Dr. Ann Reed, a rheumatologist, on November 3, 2009.
C.L. had been ill about a month earlier and had eye surgery about two weeks prior to
the visit. Pet. Ex. 9, p. 72. Her parents reported regression in C.L.’s communication
and behavior over the prior four to six weeks. Id. Doctor Reed recorded that since July,
C.L. had more aggressive behavior, screaming, and bedwetting. Id., p. 69. I note that
this appears to contradict the reports of her behavior at the August visit to Dr. Renaud.
On examination by Dr. Reed, C.L. was interactive but distractible. Id., p. 70. The side
32
effects and potential benefits of rituximab59 were discussed. Id. In discussions with Dr.
Renaud, the family expressed concern about her deterioration, and Dr. Renaud
attributed it to withdrawal of treatment. Id., p. 73.
In December 2009, Mrs. Lehner requested that C.L.’s treatment records from
Mayo be sent to the University of Minnesota, Fairview. Pet. Ex. 9, p. 75. In February
2010, C.L. had her first appointment at the pediatric rheumatology clinic there. The
reason for the appointment was described as to obtain a second opinion regarding
C.L.’s VGKC autoantibodies. Pet. Ex. 6, p. 89. Doctor Binstadt reviewed C.L.’s records
with petitioners, noting that her “primary symptoms are developmental delay on the
autism spectrum.” Id. C.L.’s parents reported to Dr. Binstadt that C.L. had been “doing
well” until she was found to have speech delay in October of 2005. Id. They described
a loss of words and the onset of self-stimulatory behaviors as beginning two weeks after
her November 2005 influenza vaccination. Id.
Doctor Binstadt referenced the Tan article, Pet. Ex. 10i, for the work done by the
Mayo group on VGKC antibodies, the link of such antibodies to neurological disorders in
adults, and the success in treating patients by immunosuppressive therapy. Pet. Ex. 6,
p. 89. He summarized C.L.’s treatment by Dr. Renaud. Id.
After discussion of the risks and potential benefits, Dr. Binstadt and petitioners
elected to treat C.L. with rituximab. Pet. Ex. 6, pp. 90-91, 96-97, 119. No evidence of
improvement in C.L.’s condition was observed after she received two rituximab
treatments and treatment was discontinued in April 2010, notwithstanding Dr. Binstadt’s
view that it was likely too early to see a benefit. Id., p.128. Her VGKC antibodies,
which were measured at 1.68 prior to receiving the first treatment (id., p. 98), rose
between the first and second treatments to 1.89 (id., p. 119); and were 2.69 after the
second treatment (id., p. 130). Doctor Binstadt did not know what clinical significance
the increase in VGKC antibodies might have. Id. (“Whether there is any clinically
significant difference between these two values is not known, to my understanding.”).
d. Involvement with Dr. Vincent.
Petitioners’ Ex. 20 contains a series of email messages from Dr. Vincent to Mrs.
Lehner, C.L.’s maternal grandfather, or to Dr. Binstadt. Although the exhibit does not
contain their messages to Dr. Vincent, the one-sided messages give a fairly clear
59
Rituximab (trade name Rituxan) was described by Dr. Bryce Binstadt, a physician who later prescribed
it as a treatment, as a monoclonal antibody that acted as a B-cell depletion therapy. Pet. Ex. 6, p. 90. He
explained that it “works by depleting the CD20-expressing B cells, the precursor cells to antibody-
producing plasma cells” and is “well tolerated and leads to improvement in patients with autoantibody
mediated disorders.” Id.
33
picture of what transpired in their correspondence between March 2011 and December
2012.60
C.L.’s grandfather, who attended many of C.L.’s appointments with Dr. Renaud,
somehow learned of Dr. Vincent’s work on VGKC antibodies. He wrote Dr. Vincent
about C.L.’s history and treatment. On March 22, 2011, Dr. Vincent responded,
commenting on several aspects of C.L.’s recent treatment and testing. Pet. Ex. 20, pp.
2-3. She stated that it was not unusual for antibody levels to vary and speculated that
the variations could be due to the possible presence of two specific proteins, LGI1 and
CASPR2.61 Id., p. 3. She offered to test a sample of C.L.’s serum for these specific
antibodies and the “proteins they are against – eg. caspr2 or lgi1 [sic].” Id. She
indicated that what had been reported to her about C.L.’s clinical course was “difficult to
understand well,” but that “rituximab may take some time to work.” Id.
Throughout the correspondence, Dr. Vincent expressed excitement at finding a
possible connection between VGKC antibodies and autism. She mentioned an
unpublished study she had conducted looking for CASPR 2 antibodies in children with
autism but the wording suggested that she had been unable to find the antibodies. Pet.
Ex. 20, p. 3. She also mentioned her research into maternal antibodies and autism. Id.
Doctor Vincent’s email messages to Dr. Binstadt concerned the testing of C.L.’s
serum for antibodies. Pet. Ex. 20, pp. 4-5. When C.L.’s serum sample was finally
obtained, shipped and tested in May 2011, she tested negative for CASPR2 and LGI1
antibodies, but positive (at a level of 0.91) for VGKC antibodies. Pet. Ex. 20, pp. 14-17.
Doctor Vincent then suggested she continue to study C.L.’s “serum to try to determine
the exact target of her antibodies.” Id., p. 19. She suggested testing C.L.’s serum on
cultured brain cells to see where there might be binding of the antibodies present. Id.,
pp. 19-21, 23. The email messages do not indicate whether this testing was ever
performed.
Doctor Vincent’s opinions on the significance of the antibodies present in C.L. are
discussed in Section V.B.1.b.(1)(c), below.
e. Return to Treatment at Mayo.
C.L. resumed treatment with Dr. Renaud in September 2011. Pet. Ex. 9, p. 81.
Doctor Renaud noted that C.L.’s VGKC antibody level increased during her treatment
by Dr. Binstadt, but that the level had declined to 1.30 in November 2010, some four
60
One additional message, which is undated, appears at Pet. Ex. 20, p. 24, after the last dated message
from December 31, 2012. Id., p. 23.
61
These are the two antibodies found in the VGKC complex that have specific pathogenic associations.
See, e.g., Tr. at 416-17; Pet. Ex. 21, p. 1.
34
months after rituximab treatment ended.62 Pet. Ex. 9, p. 81. She also noted that there
had been no obvious regression of skills. Id. Although C.L. was not communicating
much verbally, she was using single words to label things, was beginning to use an iPad
as an assistive communication device, seemed to understand more than she could say,
followed two step commands, and had occasional two word combinations. Id. Her
words, however, were “often approximations.” Id. Additionally, she noted that C.L.’s
eye contact had improved “over time despite not receiving ABA therapy since
September 2010.” Id. The foregoing suggests that the reports provided of C.L.’s
functioning during Dr. Renaud’s earlier treatment were either somewhat inflated or C.L.
had indeed lost some skills. Given that this description of C.L.’s level of functioning was
more consistent with what was recorded in her school records, the “improvements”
noted earlier may not have been accurate. Compare id. with descriptions in n.58,
supra. Although Dr. Renaud assessed C.L. as not having regressed since her last
evaluation in November 2009, C.L.’s family felt that she had “not made two years of
progress” in that time. Pet. Ex. 9, p. 82.
Doctor Renaud recommended intermittent pulse IV methylprednisolone, rather
than the oral prednisolone C.L. had received in 2008. Pet. Ex. 9, p. 82. She also
suggested pairing this therapy with another drug, Imuran.63 Interestingly, Dr. Renaud
recorded C.L.’s diagnoses as global developmental delay with autistic features and
neuronal voltage-gated potassium channel antibodies, but, in contrast to her earlier
diagnoses, did not record either a possible or probable autoimmune encephalopathy as
a diagnosis. Id.
The family apparently agreed with the recommendation to treat C.L. with IV
steroids monthly, as she received her first infusion in late November 2011. Pet. Ex. 9,
pp. 118-19. Her antibody level was measured at 1.0 prior to beginning the infusion,
which was slightly higher than the level in September 2011, when she returned to Dr.
Renaud’s practice. Id., p. 119. No side effects were reported. Doctor Renaud also
noted that ABA therapy had resumed full-time in September. Id. Her antibody levels
declined to 0.69 on December 5, 2011. Id., p. 121. The antibody levels were even
lower at the time of the second infusion on December 23, 2011, down to 0.42, and lower
still, to 0.31, after a subsequent infusion. Id., pp. 124-25.
At a February 2012 visit with Dr. Renaud, Mrs. Lehner reported that C.L. had
experienced gains since resuming steroid therapy, including improvement in eye
contact, responsiveness to her name, imitation of vocalizations, and spontaneous
vocalizations. Pet. Ex. 9, p. 127. Although it was not a huge gain, she indicated that
there had been some benefit and none of the sleep problems and aggression seen
during the earlier oral steroid therapy. Id. On examination, Dr. Renaud observed good
62
The level had further declined as of the date of this appointment. The sample drawn on September 14,
2011, was reported as 0.83. Pet. Ex. 9, p. 90.
63
It does not appear that this additional medication was ever added to C.L.’s treatment regimen.
35
eye contact, the use of some single words, and that C.L. was calmer than on previous
visits. Id. C.L.’s most recent antibody level showed some rebound, going up to 0.92,
but the increase in antibodies was not accompanied by any clinical deterioration. Id., p.
128. Doctor Renaud opted to increase the dose of oral steroid and to infuse every two
weeks for five infusions. Id.
C. L.’s antibody level was down to 0.48 in the April 2012 blood draw. Pet. Ex. 9,
p. 151. C.L. was next seen by Dr. Renaud on May 24, 2012. Id., p. 154. C.L. was
reported as agitated for about a day after the infusion of the increased dose. Id. The
skills reported were similar to those at previous visits, but C.L. was saying things when
prompted, rather than initiating the use of words. Id. Mrs. Lehner described C.L. as
“less settled” over the past week and reported that she was having trouble falling
asleep. Id. C.L.’s grandfather raised questions about the effectiveness of plasma
exchange as a possible treatment; Dr. Renaud reviewed the papers he had found and
noted that this treatment had been used in limbic encephalitis, a more acute illness than
C.L. demonstrated.64 Id., p. 155.
Behavioral concerns resurfaced at the July 2012 visit to Dr. Renaud. C.L.’s
skills, language and cognitive abilities were described as stable, and she had not
received any steroid infusions since May 2012. Pet. Ex. 9, p. 183. However, she was
having tantrums and aggressive behavior, was scratching, and was described as “quite
emotional.” Pet. Ex. 9, p. 183. She was gagging herself to the point of vomiting, had
stopped eating solid food, and was taking more than two hours to fall asleep, after
which she would awaken during the night and not return to sleep. Id. After a review of
past and proposed treatments, Dr. Renaud suggested that C.L. see one of the clinic’s
neuroimmunologists. The family agreed, and Dr. Renaud arranged an appointment on
July 31. Id., pp. 183-84.
The reports of gains from the IV steroid treatment were undercut by other
evaluations of C.L.’s condition. A May 30, 2012 reassessment by the Minnesota Autism
Center indicated that C.L.’s “Full Scale IQ” score was 40, which was in the “mentally
deficient range,” and was certainly not improved over prior scores. Pet. Ex. 13, p. 31.
Additionally, C.L.’s CARS score remained in the “severely autistic” category.” Pet. Ex.
13, p. 33.
f. Evaluation at the Autoimmune Neurology Clinic.
64
Doctor Vincent had mentioned plasma exchange as a possible treatment in July 2011. Pet. Ex. 20, p.
20.
36
C.L. saw Drs. Andrew McKeon65 and Stacey Clardy in the Autoimmune
Neurology Clinic on July 31, 2012. Doctor Clardy reviewed the medical history provided
by C.L.’s mother and grandfather, which repeated the claim that C.L. lost milestones
and had a complete change in personality and behavior within a few weeks of her
influenza vaccination. Pet. Ex. 9, p. 189. They reported that her language had stayed
stable with about 50 words or word approximations, that she could follow some simple
two-step commands, and that she had no major regressions or dramatic improvements
since 2005, but was gaining skills at school. Id. Doctor Clardy characterized the oral
steroid treatment as producing “questionable minor improvement in language use, but
with intolerable behavioral side-effects.” Id., p. 190. She saw no “appreciable benefit”
from IVIG; no apparent benefit and some side effects from CellCept; and no significant
improvement but no side effects from the IV steroid treatment. Id. She described C.L.
as a “unique case.” Id., p. 191. She noted that the “phenotype of VGKC-antibodies in
the pediatric population is not fully characterized,” and that the few case reports
available described many manifestations.66 Id. Doctor Clardy indicated that, at this
point, it was impossible to know if C.L. had experienced autoimmune encephalitis when
she was two, whether some of her symptoms represented sequelae of that condition, or
whether the VGKC antibodies were related to her autism. Id. She commented that an
individual may have persistent antibodies without clinical symptoms. Id. Although
C.L.’s parents had focused on antibody levels in deciding whether treatment was
effective (see, e.g., Pet. Ex. 9, p. 150 (telephone message that parents did not feel
comfortable in scheduling an IV steroid infusion without knowing the antibody levels)),
Dr. Clardy recommended focusing on clinical improvement, as difficult as it might be to
objectively assess, as antibody levels “have been known to persist in patients with
clinical remission of symptoms.” Id., pp. 191. She noted that there had been
questionable improvements in the past on language, but no family member had ever
seen an improvement in social skills or cognitive function. Id., p. 192.
Doctor McKeon’s own consultation notes repeated the history of a regression
after an influenza vaccination, with the development one month later of self-stimulatory
behavior, rocking, humming, and decreased visual contact. Pet. Ex. 9, pp. 193-94.
C.L.’s grandfather reported that before the vaccination, C.L. was bright and interactive,
but a month afterwards, she would just sit in a corner and refuse to make eye contact.
He also reported that she stopped talking and was less affectionate. Id., p. 193. Doctor
McKeon observed C.L. to run around the room, making some eye contact, but she did
65
Doctor McKeon is a respected adult neurologist with a focus on autoimmune encephalopathy and has
collaborated in research with Dr. Dalmau. Tr. at 382.
66
Dhamija, Pet. Ex. 11c, reported on 12 pediatric cases of VGKC antibodies (including C.L.’s). Eleven of
the patients were seen at the Mayo Clinic. Dhamija, Pet. Ex. 11c at 278. Their symptoms varied widely,
ranging from motor tics and episodic flushing to cerebellar ataxia and limbic encephalitis. Id. at 276.
There were no symptoms common to a majority of the patients. The wide variety of symptoms reported in
this article in connection with the presence of VGKC antibodies mirrors Dr. Dalmau’s observations,
discussed in Section V.B.1.b.(2)(b), below.
37
not have the social or language skills of child of her age. Id. Consistent with the
observations of several other physicians, Dr. McKeon noted some coarse facial
features.67 Id., p. 194.
Based on the reports of “the rapid onset” of C.L.’s regression, Dr. McKeon opined
that “she may have had an unusual manifestation of an autoimmune encephalitis at that
time.” Pet. Ex. 9, p. 194. As an alternative, he hypothesized that “the potassium
channel autoantibodies, though present, are not related to her developmental
problems.” Id. He cautioned that even if she had experienced autoimmune
encephalitis, the “window” for successful treatment of the condition may have passed.”
Id.
Both physicians recommended a full dose trial of IV steroids with Dr. Renaud, but
indicated that treatment should be discontinued if no clinical improvement was
observed. Pet. Ex. 9, pp. 192, 194.
Thereafter, C.L. continued to receive immunotherapy treatments from Dr.
Renaud, who increased her dosage of steroids in September 2012. See generally Pet.
Ex. 9, pp. 200-06. In December of 2012, C.L.’s mother reported that C.L. was having
behavioral side effects as a result of the steroids, including “trying to injure herself and
others, [and] trying to kick the car door.” Id., p. 217.
Subsequently, some improvements in behavior and skills were noted. C.L.
continued to receive ABA therapy, and her family and the ABA therapist felt she had
made significant progress. Pet. Ex. 9, pp. 221, 247 (as reported to Dr. Renaud during
C.L.’s January and April 2013 appointments). Mrs. Lehner testified that they saw “the
biggest gains” in C.L.’s behavior with the increased steroid dose. Tr. at 53. During
C.L.’s January and April 2013 appointments with Dr. Renaud, C.L.’s family reported
improvements in both her behavior and skills. See Ex. 9, pp. 119, 127, 154, 221, 247.
C.L.’s antibody levels remained above normal, and continued to fluctuate. Id., pp. 222,
227, 238, 248. In January 2013, C.L.’s parents elected to reenroll her in public school,
rather than continue home school plus full time ABA therapy. Pet. Ex. 5, p. 201.
However, notwithstanding these noted improvements, C.L. continued to qualify for
“special education services as a student with Autism Spectrum Disorder.” Pet Ex. 5, p.
214.
As part of reenrolling in public school, C.L. was reevaluated for special education
services. While C.L.’s eye contact and joint attention were improved, her
communication skills were poor. She did not engage in age appropriate play, did not
interact with her peers, preferred repetitive and self-stimulatory behavior, exhibited a
67
In addition to the other observations of coarse features mentioned above, Dr. Deborah Freese, a
pediatric gastroenterologist, saw C.L. in June of 2012 and observed her to be “mildly dysmorphic with
frontal bossing and a large head size.” Pet. Ex. 9, p. 181.
38
low frustration tolerance, and sought sensory input by putting things in her mouth, and
smelling and touching them. Pet Ex. 5, p. 206. C.L.’s most recently filed IEP indicated
that she continued to have needs in the areas of social interaction, behavioral
regulation, communication, functional skills as well as academic skills. Pet Ex. 5, pp.
227-35.
g. Seizure Disorder Diagnosis.
At the end of April 2013, C.L. was found unconscious on the playground. School
personnel presumed she had hit her head. Pet. Exs. 22, p. 1; 3, p. 131. About a week
later, on May 3, 2013, C.L. suffered a seizure witnessed by her father. Pet. Exs. 22, p.
1; 3, p. 13168; 9, pp. 251, 254. On May 14, 2013, C.L. was seen by Dr. Chadwick, a
pediatric neurologist, for an evaluation of her seizures. She was diagnosed with
complex partial epilepsy in addition to autism.69 Pet. Ex. 22, pp. 1-3. C.L. experienced
another seizure several days later and was prescribed Trileptal, with good results in
seizure control. Id., p. 7. However, C.L. was experiencing “anger, aggression, and
agitation issues” with some recent improvement. Id. As of February 2014, C.L.
continued to receive Trileptal, and IV steroid infusions. Pet. Ex. 9, p. 266. A gain of
skills was also reported. Id.
5. Other conditions.
C.L.’s medical records also document treatment for a number of minor childhood
illnesses and other conditions, including surgery for “lazy eye,” evaluation, biopsies, and
treatment for gastroesophageal reflux, some alternative tests and treatments for ASD,
and many school and therapy records. See generally Pet. Exs. 3-6; 13-14; 17; 19.
Although I have reviewed these exhibits as a part of the “record as a whole” (see §
13(a)), and some are mentioned in passing in the medical records summary above, they
are not discussed further in this decision, as they are not relevant to the issues
presented in this case.
68
The history reflected in this record is that Dr. Donald Chadwick witnessed her May 3 seizure; however,
based on Dr. Chadwick’s records, the history of a witnessed seizure should reflect that C.L.’s father, not
Dr. Chadwick, witnessed it.
69
Doctor Shafrir testified that many individuals with autism eventually develop seizure disorders. Tr. at
131. He also testified that the majority of autistic children will develop seizures by the time they reach
their 18th birthday. Tr. at 255. See also Snyder, 2009 WL 332044, at *32 (“About 20–30% of children
with ASD have or will develop epilepsy over the course of their lives, often beginning during
adolescence.”).
39
IV. Experts, Opinions, Diagnoses, and Motion to Exclude.
A. Expert Qualifications.
1. Doctor Frye.
Doctor Frye’s curriculum vitae [“C.V.”] was not filed in this case, making it difficult
to assess his qualifications to offer an expert opinion on autoimmune encephalitis and
the role of VGKC antibodies in the condition, much less on whether such a condition
would present with symptoms warranting an autism diagnosis. However, I am familiar
with Dr. Frye in general, as he has testified as a pediatric neurologist specializing in the
treatment of children with neurodevelopmental disorders in other Vaccine Program
cases. See Paluck v. Sec'y, HHS, 786 F.3d 1373 (Fed. Cir. 2015); Bast v. Sec’y, HHS,
2012 WL 6858040, at *3 (Fed. Cl. Spec. Mstr. Dec. 20, 2012).
At the time Dr. Frye wrote his expert report in this case he was an Assistant
Professor of Pediatrics and Neurology at the University of Texas Health Science Center.
Pet. Ex. 10 at 3.
2. Doctor Shafrir.
Doctor Shafrir is board certified in neurology, with special qualifications in child
neurology and clinical neurophysiology. Pet. Ex. 11a at 2; Tr. at 128. After his
residency training, Dr. Shafrir completed a fellowship in pediatric neurophysiology and
epileptology at Miami Children’s Hospital. Pet. Ex. 11a at 1; Tr. at 128.
He is primarily a clinician, and is currently in private practice in Baltimore, MD,
where he sees patients five days a week. Tr. at 130; Pet. Ex. 11a at 3. He also
teaches residents at Sinai Hospital, and is an Assistant Professor at the University of
Maryland School of Medicine. Tr. at 128-29; Pet. Ex. 11a at 3. Doctor Shafrir has an
interest in autism spectrum disorders and currently sees approximately 200 ASD
patients, but he has no specialized training in the diagnosis, management, or treatment
of ASD. Tr. at 130-31, 203. He explained that he did not see most of his ASD patients
actively, because there was very little that he could do for them by way of treatment. Tr.
at 130-31. Most of his ASD patients had already been evaluated or tested for ASD by
the time he saw them. Tr. at 132. He did not appear to place much value on ASD
diagnostic criteria (Tr. at 134-35, 206-07), and indicated that he did not order many tests
to try to determine if there was a cause for the disorder in individual patients (Tr. at 136-
37).
40
He has treated approximately three patients in his career with autoimmune
encephalitis. Tr. at 139. He has not conducted any research in ASD,70 autoimmune
encephalopathies, or voltage-gated antibodies. Tr. at 203-04. He has no expertise in
autoimmunity in particular or immunology in general. He has never treated a patient
with VGKC antibodies, although he had “seen two patients” with NMDAR encephalitis.
Tr. at 208, 227. However, he claimed, based on his reading of published medical
literature, that he was an expert on “how different antibodies can cause autoimmune
encephalopathy.” Tr. at 217. In one of many tangential answers to relatively
straightforward questions, Dr. Shafrir testified that his “life is dedicated to autism.” Tr. at
148.
3. Doctor Angela Vincent.
Petitioners filed a June 4, 2013 email message from Dr. Vincent to their attorney,
Ms. Sheila Bjorkland, as Pet. Ex. 21, as well as the email correspondence from Dr.
Vincent, as Pet. Ex. 20. Although petitioner’s counsel characterized Dr. Vincent’s June
4, 2013 letter as an “Expert Report,” the letter is better characterized as a medical
record describing testing and a commentary on the significance of the results. A C.V.
for Dr. Vincent was not included; however, I note that she co-authored a number of the
medical journal articles that were filed as exhibits by both parties.
In the June 4, 2013 message, Dr. Vincent noted that she is a clinical
immunologist with 35 years of experience researching diseases of the nervous system
caused by autoantibodies to membrane receptors, ion channels, or related proteins.
Pet. Ex. 21, p. 1. Her group of researchers made some early discoveries in antibodies
thought to be involved with neurological symptoms, including the first description of the
potassium channel antibodies in 1995, and developed the first test for the antibodies.
Id. Her laboratory tests over 50,000 samples per year. Id. Doctor Dalmau testified that
Dr. Vincent is a leading contributor to the field of autoimmune neurology with whom he
has published but, to his knowledge, she is not a medical doctor and does not see
patients. Tr. at 379-80, 448.
Based on the information provided, she clearly possessed the qualifications to
test C.L.’s blood for the presence of VGKC autoantibodies and to opine on the
significance of the results. She did not offer an opinion on the role of the influenza
vaccination in causing the antibodies.
70
Doctor Shafrir has published an abstract on Landau-Kleffner Syndrome. Tr. at 204. Landau-Kleffner
Syndrome is an acquired epileptic aphasia presenting in childhood and is a condition that frequently
resembles autism spectrum disorders. See DORLAND’S at 1861.
41
4. Doctor Dalmau.
Doctor Dalmau is a world-class expert in the areas of autoimmune
encephalopathy and encephalitis and voltage-gated potassium channel antibodies. He
is a neurologist with specialties in neuroimmunology and neuro-oncology. Tr. at 293-97.
He also has a Ph.D. in immunology and cancer-associated immunology.71 Tr. at 293.
After his residency training in Spain, Dr. Dalmau completed a fellowship in neurology at
New York Hospital, Cornell University, and a fellowship in medical oncology at Memorial
Hospital for Cancer and Allied Diseases in New York, NY. Res. Ex. K at 1.
At the time of the hearing, Dr. Dalmau served as the director of laboratories
involving neuro-oncology and neuroimmunology at the University of Barcelona in Spain.
He also serves on the faculty of the University of Pennsylvania in Philadelphia and the
University of Barcelona in Spain. Res. Ex. LL at 2; Tr. at 293-94. He has been a
reviewer for over 25 medical journals and sat on the editorial board of four neurology
journals. Res. Ex. LL at 6.
Doctor Dalmau is an award-winning researcher in the field of neuroimmunology
and at the time of the hearing, was a consultant in neuroimmunology for the National
Institutes of Health [“NIH”]. Tr. at 294-95; Res. Ex. LL at 3. The current focus of Dr.
Dalmau’s research is on three aspects of autoimmune encephalitis: studying known
disorders; identifying new disorders, antibodies, and target antigens; and studying
mechanistically how antibodies act on the brain. Tr. at 298-99. He is the primary author
of or a primary contributor to approximately 270 published articles, of which nearly 95%
deal with autoimmune disorders. Tr. at 299. The articles published most recently have
largely dealt with autoimmune encephalopathies and encephalitis. Id.
His clinical practice involves many patients with autoimmune encephalitis,
predominantly referral patients seeking confirmation of an immune-mediated disorder
diagnosis. Tr. at 297-98. Twenty percent of these patients are children, all of whom
have autoimmune neurological conditions. Id. Based on these credentials, Dr. Dalmau
was offered as an expert in neuroimmunology with special expertise in autoimmune
encephalopathy and autoimmune encephalitis without objection. Tr. at 299-300. The
hearing in this case was the first time he has testified. Tr. at 300.
5. Doctor Gorman.
Doctor Gorman is a board-certified neurologist, with special qualifications in child
neurology. He specializes in pediatric neuroimmunology. Res. Ex. MM at 10, 16; Tr. at
454-55, 485. After his residency, Dr. Gorman completed a fellowship in child neurology
and multiple sclerosis. Res. Ex. MM at 1-2.
71
Because Dr. Dalmau completed his residency in Spain, he is not eligible for board certification in the
United States. Tr. at 292.
42
At the time of the hearing, Dr. Gorman was the director of the pediatric multiple
sclerosis program, the neuroimmunology program, and the inpatient neurology service
at Boston Children’s Hospital. Res. Ex. MM at 2-3. He was an assistant professor at
Harvard Medical School and taught at Boston Children’s Hospital. Id. at 2; Tr. at 455.
His clinical practice was limited to pediatric neuroimmunology patients, whom he saw
one full day a week, with the remainder of his time involving a research practice in
multiple sclerosis, and in other aspects of neuroimmunology distinct from multiple
sclerosis. Tr. at 456-57. He has numerous peer reviewed publications and has served
as a reviewer for several medical journals. Tr. at 457; Res. Ex. MM at 4, 12-14. Doctor
Gorman saw ASD patients in the context of providing autoimmunity consultations and
as part of his in-patient attending responsibilities; but he did not represent himself as
having any special expertise in ASD. Tr. at 495.
B. Petitioners’ Motion to Exclude Dr. Gorman’s Testimony.
Prior to discussing the expert opinions on diagnosis and causation, I first deal
with petitioners’ mid-hearing motion to exclude Dr. Gorman’s testimony as cumulative.
The issue was first raised by oral motion at the hearing on January 28, 2014. Tr. at
451-53. Given that nothing precluded petitioners from raising the issue in a pre-hearing
status conference or by written motion prior to the hearing, and the fact that Dr. Gorman
was present and prepared to testify, I elected to hear his testimony and decide later
whether to consider it in making my decision. Id.
In the post-hearing order, I directed petitioners to file a written motion
summarizing their arguments for excluding Dr. Gorman’s testimony. Order, issued Jan.
30, 2014. Petitioners filed their Motion to Exclude [“Pet. Motion”] on March 10, 2014;
respondent filed a Response to Petitioners’ Motion [“Res. Response”] on April 7, 2014;
and petitioners filed a Reply to Respondent’s Response [“Pet. Reply”] on April 10, 2014.
Petitioners argued that Dr. Gorman’s testimony should be excluded as violating
the “rules of fundamental fairness” because: (1) Dr. Gorman conceded he would defer
to Dr. Dalmau’s expertise72 regarding VGKC encephalopathy, and thus any testimony by
Dr. Gorman regarding autoimmune encephalopathy and VGKC antibodies would be
cumulative and duplicative; (2) Dr. Gorman’s testimony regarding the onset and
causation of ASD was beyond his expertise; and (3) his testimony on ASD was beyond
the scope of his expert reports and “amounted to trial by ambush.” See generally Pet.
Motion. Despite my instructions that petitioners provide specific objections, Tr. at 475,
72
It is unsurprising that Dr. Gorman would defer to Dr. Dalmau’s expertise regarding VGKC antibodies
and autoimmune encephalopathy, as few experts anywhere in the world possess Dr. Dalmau’s
knowledge. That does not automatically make Dr. Gorman’s testimony cumulative. I note that the motion
to exclude was made prior to hearing his testimony. Thus, petitioners were only assuming that the
testimony would be cumulative. Further, as discussed above in the post-hearing brief on the matter,
petitioners failed to cite any specific examples of cumulative testimony offered by Dr. Gorman.
43
petitioners failed to cite any specific examples of cumulative testimony offered by Dr.
Gorman. Rather, petitioners asserted that as Dr. Gorman deferred to Dr. Dalmau’s
expertise “it is a matter of simple logic than any testimony he offered regarding VGKC
antibodies and [C.L.’s] situation was merely cumulative.” Pet. Reply at 1. Petitioners
argued Dr. Gorman’s testimony on VGKC antibodies “was anecdotal of his own
experience and not specific to C.L.’s situation.” Id. at 1-2. I disagree with all of
petitioners’ arguments.
At the hearing Dr. Gorman testified consistent with his revised opinion73 that C.L.
did not have an autoimmune encephalopathy, let alone one related to VGKC antibodies.
Consistent with his initial opinion in this claim, he testified that the vaccination was not
responsible for the antibodies and that C.L. evidenced significant developmental delay
prior to her influenza vaccination. He also testified about C.L.’s autism spectrum
disorder diagnosis and his disagreements with some of Dr. Shafrir’s testimony about
ASD.
The Vaccine Act vests the special master with the authority to determine the
weight to be afforded evidence, while requiring the special master to consider the entire
record. §§ 13(a)(1), 13(b)(1). The statute further provides that the rules established to
73
Doctor Gorman initially agreed with Dr. Frye that C.L. suffered an autoimmune encephalopathy related
to VGKC antibodies, but he also opined at the same time that her condition was not caused or
exacerbated by her influenza vaccination. Res. Ex. A at 2-5. His opinion was that C.L. suffered
“significant developmental delay” prior to her November 25, 2005 influenza vaccine, that the extent of that
delay was underestimated, and that if the VGKC antibodies played any role in her condition, they were
likely present before the vaccination. Id. at 4. He clearly disagreed with Dr. Frye’s “sweeping general
statements about purported links between various vaccinations and lupus, Guillain Barré syndrome, and
autoimmune thrombocytopenia,” as well as “potential mechanisms of autoimmunity,” which Dr. Gorman
did not find relevant to C.L.’s case. Id. He pointed specifically to the “lack of scientific evidence” linking
influenza vaccine to VGKC antibody disorders. Id. at 5. After Dr. Dalmau submitted his opinion in this
case explaining that recent research had established that only certain types of VGKC antibodies
appeared to play a causal role in autoimmune encephalitis, Dr. Gorman changed his initial opinion that
C.L. suffered an autoimmune encephalopathy. Res. Ex. W. After considering the opinion and evidence
submitted by Dr. Dalmau, reviewing additional medical literature, and having recently evaluated a patient
with elevated VGKC antibodies himself, Dr. Gorman indicated that he was in agreement with Dr. Dalmau
that C.L. “did not have an autoimmune encephalopathy related to VGKC complex antibodies.” Res. Ex.
W at 1. I note that it appears that Dr. Gorman and Dr. Frye had previously collaborated on a publication,
which perhaps explains why he was willing to accept Dr. Frye’s opinion on the presence of an
autoimmune encephalopathy, but disagreed with his conclusions on the role of the vaccine in triggering it,
as the latter was a matter in which Dr. Gorman had expertise. See Res. Ex. B at 7 (“Clinical
Communications” category on Dr. Gorman’s C.V. reflecting a publication with “R. Frye”); see also id. at 7-
8 (“Original Articles” category, reflecting publications on the role of vaccines and infections in neurological
demyelinating disorders (references 4, 5, and 12)). At the hearing, Dr. Gorman summarized the reasons
for his changed opinion as including information from Dr. Dalmau about the technical limitations of the
radioimmunoassay testing performed on C.L.; the lack of any control establishing the normal range for
such antibodies by the Mayo Clinic; the testing by Dr. Vincent for the pathogenic antibodies, which was
negative; the rapidly expanding volume of scientific literature about VGKC antibodies; and his personal
experience with two patients and Mayo Clinic testing results. Tr. at 467-72.
44
govern Vaccine Act proceedings should “include flexible and informal standards for
admissibility of evidence.” § 12(d)(2)(b). Vaccine Rule 8(b)(1), which controls the
admission of evidence, including expert testimony, in cases filed in the Vaccine
Program, indicates that “[i]n receiving evidence, the special master will not be bound by
common law or statutory rules of evidence but must consider all relevant and reliable
evidence governed by principles of fundamental fairness to both parties.” Petitioners in
general often benefit from this approach, as Daubert and its progeny are rarely used to
exclude witnesses; instead, the Daubert factors are used to weigh and evaluate expert
testimony.74
Doctor Gorman, unlike Dr. Dalmau, is a board certified pediatric neurologist who
specializes in pediatric neuroimmunology. As such, Dr. Gorman is clearly qualified to
testify and opine in the areas of pediatric neurology and immunology, which encompass
the topics of ASD, autoimmune encephalopathy, and VGKC antibodies.75 As to his
supposed lack of qualifications to opine on ASD, Dr. Gorman has the same general
qualifications as Dr. Shafrir, another pediatric neurologist. I note that at least two of the
physicians who treated C.L. were pediatric neurologists (Drs. Renaud and Chadwick)
and Dr. Janousek was identified as a neurologist. Although Dr. Shafrir saw children
with ASD, he did not appear to have any special qualifications, apart from his training as
a pediatric neurologist, to do so, and Dr. Gorman saw children with ASD as a part of his
pediatric neuroimmunology practice. Thus, Dr. Gorman was at least as qualified on the
topic of ASD as Dr. Shafrir, and more qualified than Dr. Shafrir on the immunological
and autoimmune aspects of the causation theory petitioners chose to present.
The fact that Dr. Gorman conceded the expertise of Dr. Dalmau, who, according
to petitioners’ own expert, is a “pioneer in this field [having] essentially discover[ed] the
74
For example, much of the evidence pertaining to the causation theories presented in the OAP test
cases and considered by the special masters was excluded, based on its lack of reliability, by the state
and federal judges in the autism cases litigated outside the Vaccine Program. See Blackwell v. Wyeth,
408 Md. 575, 971 A.2d 235 (2009); Doe v. Ortho-Clinical Diagnostics, Inc., 440 F. Supp. 2d 465
(M.D.N.C. 2006); Redfoot v. B.F. Ascher & Co., No. C 05-2045 PJH, 2007 WL 1593239 (N.D. Cal. June
1, 2007).
75
I note that some of the medical journal articles filed addressed VGKC antibodies in adults, while others
focused on the antibodies in children. For example, the following articles focus on children: Dhamija, Pet.
Ex. 11c; Y. Hacohen, et al., Paediatric autoimmune encephalopathies: clinical features, laboratory
investigations and outcomes in patients with or without antibodies to known central nervous system
autoantigens, J. NEUROL. NEUROSURG. PSYCHIATRY, 84: 748-55 (2013), filed as Pet. Ex. 23a [hereinafter
“Hacohen, Pet. Ex. 23a”]; and J. Suleiman, et al., VGKC antibodies in pediatric encephalitis presenting
with status epilepticus, NEUROLOGY, 76: 1252-55 (2011), filed as Pet. Ex. 23b [hereinafter “Suleiman, Pet.,
Ex. 23b”]. These articles focus on adults: J. Lilleker et al., VGKC complex antibodies in epilepsy:
Diagnostic yield and therapeutic implications, SEIZURE, 22:776-79 (2013), filed as Pet. Ex. 23d
[hereinafter “Lilleker, Pet. Ex. 23d”]; S. Wong, et al., An effective immunotherapy regimen for VGKC
antibody-positive limbic encephalitis, J. NEUROL., NEUROSURG. & PSYCHIATRY 81: 1167-69 (2010), filed as
Res. Ex. F [hereinafter “Wong, Res. Ex. F”]; E. Lancaster, et al., Investigations of Caspr2, an Autoantigen
of Encephalitis and Neuromyotonia, ANN. NEUROL., 69: 303-11 (2011), filed as Res. Ex. Q [hereinafter,
“Lancaster, Res. Ex. Q].
45
entity of autoimmune encephalitis” does not render Dr. Gorman unqualified to testify.
Pet. Ex. 16 at 1; see also Tr. at 139, 520 (acknowledging Dr. Dalmau’s expertise and
qualifications). Nor does the fact that Dr. Gorman’s testimony overlapped to some
degree with Dr. Dalmau’s testimony make Dr. Gorman’s testimony inadmissible. While
a special master might chose to preclude a party from offering the opinions of two
medical experts within the same field, nothing in the Vaccine Rules or the Act itself
requires one to do so. Moreover, while Dr. Dalmau has specialized in the area of
autoimmune encephalopathy and encephalitis and, in particular, the VGKC antibodies
at issue in this case, he primarily treats adults; whereas Dr. Gorman specializes in
pediatric neuroimmunology and has published on the role of vaccines and infections.
See Section IV. A.; n.72, supra. Thus, they bring some differences in background to
their understanding of the causation issues in question.
Petitioners had ample opportunity to move to exclude Dr. Gorman’s testimony
prior to the hearing, rather than blindsiding respondent, not to mention the special
master, with the issue for the first time at hearing.
Petitioners’ argument that Dr. Gorman’s changed opinion should preclude his
testimony was, essentially, unsupported by law or practice. In more than nine years as
a special master, I have seen many experts modify their opinions under a variety of
circumstances, and in particular, many petitioners’ experts change their theories in mid-
hearing.76 Doctor Gorman’s changed opinion is certainly a matter to be considered in
determining how much weight to give to his opinions,77 but to preclude him from
testifying because he had changed his opinion is simply not warranted.
I conclude that Dr. Gorman should not have been precluded from testimony
based on his changed opinion in this matter, nor on his concession of Dr. Dalmau’s
superior knowledge regarding autoimmune encephalopathy and encephalitis and VGKC
76
To some degree, Dr. Shafrir did so in this case, acknowledging at the end of the hearing that Dr.
Dalmau’s explanations had changed his opinion and conceding that C.L. did not have the pathogenic
antibodies associated with autoimmune encephalitis. See Section V.B.1. b, below.
77
A trier of fact might well question the expertise and reliability of an expert who does such an about-face
on a diagnostic issue, but Dr. Gorman’s candid acknowledgment that he was wrong speaks volumes
about his honesty and credibility. The causes of autoimmune encephalitis are a “cutting edge” area of
medical and scientific research, about which Drs. Frye, Gorman, and Shafrir were all simply wrong
because new evidence became available between the filing of this claim and the hearing. I suspect that
even Dr. Dalmau might have expressed some agreement with Dr. Frye about a connection between
VGKC antibodies and autoimmune encephalitis at a point before Dr. Dalmau became suspicious about
the wide variety of symptoms attributed to VGKC antibodies, and before he completed his more recent
research identifying only certain VGKC antibodies as causal of autoimmune encephalitis—antibodies not
present in C.L. I have excluded consideration of experts’ testimony based on matters that reflected on
their credibility, see, e.g., Raymo v. Sec'y, HHS, No. 11-0654V, 2014 WL 1092274, at *16 (Fed. Cl. Spec.
Mstr. Feb. 24, 2014), but see no basis here to exclude categorically all of Dr. Gorman’s testimony. I
found his willingness to admit an error refreshing.
46
antibodies, although they are factors to be considered in the weight accorded to his
testimony. I add that Dr. Dalmau’s testimony did not require buttressing by Dr. Gorman.
As to Dr. Gorman’s testimony regarding ASDs in general, and C.L.’s ASD
diagnosis in particular, I find his testimony permissible. As I pointed out at the hearing,
Dr. Gorman has opined consistently that C.L.’s neurological injury pre-dated her
November 25, 2005 vaccination. Tr. at 453 (citing Res. Ex. A); see also Res. Reply at 5
(“Dr. Gorman has consistently stated that [C.L.’s] well-documented early developmental
delays mark the onset of her neurologic condition and that her influenza vaccination
played no role.” (citing Res. Ex. A; Res. Ex. I at 3; Res. Ex W; Tr. at 462-66, 480, 500,
511-12)). Further, the medical records are replete with references to C.L.’s ASD
diagnosis, and Dr. Shafrir discussed ASD in his testimony. Thus, petitioners cannot
claim to be surprised regarding Dr. Gorman’s thoughts about C.L.’s ASD diagnosis and
symptoms.
It was not fundamentally unfair to hear this testimony. To the contrary, the rules
of fundamental fairness require that respondent be allowed to respond to the evidence
offered by petitioners and, as a pediatric neurologist, Dr. Gorman was qualified to offer
testimony in counterpoint to that of Dr. Shafrir on ASD.
Finally, while I am overruling petitioners’ objections, my ultimate findings in this
case would be unchanged even were I to exclude Dr. Gorman’s testimony. In
particular, the testimony he offered on ASD was encompassed in the medical journal
articles that Dr. Dalmau referenced in his expert reports.
C. Diagnoses.
C.L. has received two diagnoses relevant to the issue of causation. Her ASD
diagnosis is not in dispute, but the parties are in disagreement about whether C.L. truly
experienced autoimmune encephalopathy or encephalitis78 and, if so, whether that
condition is responsible for the symptoms resulting in the ASD diagnosis.
When the injury or diagnosis itself is disputed, and “the proposed injuries differ
significantly in their pathology,” the special master may “first find which of [the]
diagnoses was best supported by the evidence presented in the record before applying
the Althen test so that the special master could subsequently determine causation
relative to the injury.” Broekelschen v. Sec'y, HHS., 618 F.3d 1339, 1346 (Fed. Cir.
2010).
78
The medical records establish that C.L. received a diagnosis of probable autoimmune encephalitis
during the first round of treatment with Dr. Renaud. However, this diagnosis did not appear in Dr.
Renaud’s later records, although she continued to treat C.L. for the condition. The fact that C.L. has
VGKC antibodies is not in dispute.
47
1. Autism Spectrum Disorder.79
a. Diagnostic Criteria and Characteristics.
The terms “autism spectrum disorder,” “autistic disorder,” or “autism” refer to a
class of neurodevelopmental disorders marked by “qualitative impairments in the
development of social and communication skills, often accompanied by stereotyped and
restricted patterns of interests and behavior.” Landa, Res. Ex. EE, at 138. Symptoms
of the onset of the disorder must occur before the child is three years old. Id.
Parents of children diagnosed with ASD often report that they first became
concerned about some aspect of their child’s behavior at about 18 months of age.
Landa, Res. Ex. EE, at 139. However, concerns may arise at other points during the
first year of life. Id. Eighty percent of parents of children subsequently diagnosed with
ASD have observed abnormal behaviors in their child by two years of age, typically
involving speech and language development and, less frequently, involving social, play,
sensory, motor, or medical problems, or problems relating to eating, sleeping, and
behavior. Id. at 139-40.
Regression or loss of skills is reported in a substantial minority of children with
ASD. Loss of language skills or vocabulary is often observed in these children,
although social skills loss is seen as well. Lord, Res. Ex. R, at 936; Rogers, Res. Ex. S,
at 141 (loss of eye contact described in 90% of children with regression as well as loss
of social interests). More than 90% of children with regression had only single-word
speech prior to the loss of vocabulary; only 3% had developed phrase speech prior to
their regression. Rogers, Res. Ex. S, at 141. C.L. had only single words, and not many
of them, at the time of her regression.
Rogers described three different patterns of autism onset: (1) developmental
concerns present from birth, with parents reporting atypical behaviors across the first
year of life; (2) early milestone achievement followed by a developmental plateau,
where the children fail to develop the social and communicative skills that differentiate
children with ASD from those with typical development; and (3) a clear developmental
loss of previously-demonstrated skills—a regression. Rogers, Res. Ex. S at 140.
Further study of children who present with regression has demonstrated that “a very
79
This subsection discusses the diagnostic criteria in effect at the time of C.L.’s initial diagnosis, the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [“DSM-IV-TR”]. The
DSM-IV-TR has since been replaced by the DSM-5. The symptoms recognized by the medical
community at large as those of an ASD have not changed, but the criteria for diagnosis have been
refined, and the distinctions drawn in the DSM-IV among the diagnoses of autistic disorder, PDD-NOS,
and Asperger’s disorder have been eliminated. See American Psychiatric Association, Autism Spectrum
Disorder Fact Sheet,
http://www.dsm5.org/Documents/Autism%20Spectrum%20Disorder%20Fact%20Sheet.pdf (highlighting
the differences between DSM-IV and DSM-V) (last visited July 15, 2015).
48
small proportion of children with autism exhibit a period of truly typical (“normal”)
development; only approximately 15% of children who later lose skills appear to have
had a full repertoire of expected skills in their infancy.” Id. Good recovery after
regression is rare, and children with regression develop similarly to children with autism
but no regression. Id., p. 141. This pattern of children with a clear loss of skills, but
whose prior development was not entirely normal, appears to describe C.L.’s
developmental trajectory. There were early behavioral concerns significant enough that
the parents raised them in several pediatric appointments, and her language was clearly
not normal prior to the influenza vaccination and regression.
b. Testing.
C.L. has consistently scored in the autistic range on several different diagnostic
tests, and received the diagnosis from several different specialists in this field. Pet. Ex.
4, pp. 50-71; Pet. Ex. 5, pp. 31-33, 70-74, 78; Pet. Ex. 9, pp. 231-37; Pet. Ex. 17. More
recent school system testing has confirmed that the diagnosis has persisted in spite of
all the therapies employed to treat C.L. Pet. Ex. 5, pp. 201-14.
c. Opinions Regarding ASD Diagnosis.
Doctor Shafrir’s testimony was inconsistent regarding his opinion about C.L.’s
ASD diagnosis. He first testified that C.L. has autism. Tr. at 214. When asked later if
she had autism, he equivocated, saying that she has “autistic regression.” Tr. at 215.
Doctor Janousek diagnosed C.L. with an encephalopathy but, according to
petitioners, he thought she had an ASD, albeit one with a more pronounced regression
than he thought was usual. It is unclear what he considered, besides petitioners’
reports, in determining that the level of regression was unusual, as the descriptions of
C.L.’s language and social skills loss in her medical and therapy records do not reflect a
profound regression.
In contrast, Dr. Dalmau described C.L.’s regression as part of “the natural course
of the autism.” Res. Ex. J at 3. C.L.’s pattern of development included the failure to
begin to put words together in phrases before the regression,80 followed by a loss of
language and social skills and a relatively poor recovery. Moreover, C.L. has a number
of other risk factors that have been associated with the diagnosis of ASD: twin birth,
prematurity, dysmorphic features, and a twin with a diagnosis on the autism spectrum.81
See Res. Ex. J at 3 (Dr. Dalmau’s expert report); Dwyer, 2010 WL 892250, at *34-35,
80
Doctor Shafrir conceded that C.L. was developmentally delayed before she received the influenza
vaccine, but thought that the delays were mild. Tr. at 150. However, it is not the degree of impairment
that is significant; it is the fact that C.L. was displaying a delay in language prior to losing language.
81
C.L.’s twin’s trajectory differed from C.L.’s in that the twin showed delayed development earlier, but
later became higher functioning than C.L. Pet. Exs. 7, pp. 8, 51; 9, pp. 191, 233; Tr. at 107.
49
44. He thought the ASD diagnosis accounted for all of C.L.’s symptoms. Tr. at 373,
376-77; see also Tr. at 473-74 (Dr. Gorman agreed).
2. Autoimmune Encephalopathy or Encephalitis.
Petitioners’ causation theory rests on the conclusion that C.L. experienced
autoimmune encephalitis, as exemplified by a sudden regression involving loss of
language, eye contact, and social skills. No one contests the fact of the regression; the
parties differ in their assertions regarding when and how fast the regression occurred,
as well as about its cause. Petitioners claim that the symptoms leading to C.L.’s ASD
diagnosis are evidence of an autoimmune encephalopathy. Pet. Exs. 10, 11, 16, 23
(expert reports of Drs. Frye and Shafrir).
a. Definitions and Characteristics of Autoimmune Encephalitis.
Not surprisingly, given his expertise in autoimmune encephalitis, Dr. Dalmau
provided a great deal of the background information about encephalopathy, encephalitis
and, in particular, autoimmune encephalitis. The terms encephalopathy and
encephalitis were used interchangeably throughout the record in this case. Tr. at 323.
Doctor Dalmau explained that encephalopathy is the broader or umbrella term and
encephalitis is one form of encephalopathy. Id. He defined encephalopathy as a
“dysfunction of the brain” and added that “any dysfunction is an encephalopathy.” Tr. at
316; see also DORLAND’S at 622. Encephalitis is a brain dysfunction associated with
inflammation. Tr. at 316-17; see also DORLAND’S at 619. By definition, autoimmune
disorders involve inflammatory reactions that produce antibodies. Tr. at 317, 323.
Inflammation of the brain can be demonstrated by the presence of inflammatory cells in
cerebral spinal fluid or the brain or based on inflammation observed on MRI. Tr. at 319.
Clinical symptoms associated with autoimmune encephalopathies vary based on
the antibodies involved. Tr. at 316; see, e.g., Hacohen, Pet. Ex. 23a at 752 (showing
symptom data for NMDAR and VGKC encephalitis). However, there are core general
symptoms that most autoimmune encephalopathies share. Tr. at 316. In general, the
presentation is subacute, which Dr. Dalmau described as falling between an acute
encephalopathy (where symptoms evolve in hours or days) and a chronic
encephalopathy (where symptoms continue for months). Tr. at 316-17; see, e.g.,
Dalmau, Ex. 16b, at 63-64 (NMDAR encephalitis patients develop psychiatric symptoms
within a few days).
Doctor Dalmau observed that the presentation of autoimmune encephalitis is “not
subtle.” Tr. at 322; see, e.g., Dalmau, Ex. 16b at 64. Children have symptoms that
raise the suspicion of a viral disorder or viral encephalitis. Tr. at 322. They frequently
present with seizures, headache and, about 50% of the time, with fever. Tr. at 317; see,
e.g., Hacohen, Pet. Ex. 23a at 752. Most will have an abnormal EEG. Tr. at 317
(referencing Hacohen, Pet. Ex. 23a at 752 (100% of the VGKC complex encephalitis
50
patients had abnormalities on EEG)). In autoimmune limbic encephalitis,82 MRIs often
show abnormalities. Tr. at 318. Doctor Dalmau explained the medical literature
indicates that, with or without seizures, the patient’s “EEG is almost always abnormal in
[cases of these autoimmune] encephalopathies.” Id.; see, e.g., Hacohen, Pet. Ex. 23a
at 752. In most cases of autoimmune encephalitis, there will be evidence of brain
inflammation on spinal tap, MRI, or autopsy of the brain. Tr. at 319.
b. C.L.’s Symptoms.
Doctor Frye described C.L.’s symptoms after the influenza vaccination as
encompassing sleeping and feeding difficulties within a month of the vaccination. He
asserted that she lost words and stopped babbling, waving, and pointing at objects.
Pet. Ex. 10 at 1. C.L.’s parents testified about a fever after vaccination that was treated
with Advil. Tr. at 23. They did not report she was acutely ill. In December 2005, about
a month after the influenza vaccination, they took her to her pediatrician for sleeping
and feeding difficulties. Pet. Ex. 3, p. 42. There was no indication in the records that
C.L. had been ill in the intervening month, and Dr. Snook did not remark that she was ill
appearing.
C.L. did not experience her first seizure until nearly eight years after her
vaccination. Around the time of the seizure, she was being treated with steroid Solu-
Medrol every two weeks, according to the record of her treating physician, Dr.
Chadwick. Pet. Ex. 22, p. 1. The Mayo Clinic’s records indicate C.L.’s last steroid
infusion before her seizures was on March 2, 2013, and her next treatment after her
seizures was on July 17, 2013. Pet. Ex. 9, pp. 247, 262. Steroid treatment is noted to
prevent seizures in those with autoimmune encephalopathies, according to Dr. Shafrir.
Tr. at 514-17.
c. Opinions Regarding Diagnosis.
Some of C.L.’s treating physicians also attributed her ASD symptoms to an
autoimmune encephalopathy, based at least in part on her “sudden” regression,83
82
Limbic encephalitis can be defined as “an inflammatory brain disorder of paraneoplastic or non-
paraneoplastic origin . . . causing memory deficits, temporal lobe seizures or affective disturbances.” E.
Haberlandt et al., Limbic encephalitis in children and adolescents, ARCH. DIS. CHILD., 96 (2): 186-191
(2011), filed as Res. Ex. C [hereinafter “Haberlandt, Res. Ex. C”], at 186. Limbic encephalitis can be, but
does not have to be, caused by a tumor or its metastases. Id.; see also DORLAND’S at 1400 (defining
“paraneoplastic” as “pertaining to changes produced in tissue remote from a tumor or its metastases”). It
can also be caused by antibodies produced without a tumor. Haberlandt, Res. Ex. C at 189.
83
The records from Drs. Renaud, McKeon, and Clardy do not reflect that any of these physicians
examined C.L.’s medical, school, and therapy records from the period between August 2005 and the two
mid-February 2006 calls to Dr. Snook’s practice, seeking a referral to Dr. Janousek. Nor does it appear
that they reviewed any of the medical histories provided to school personnel, therapists, and physicians
closer in time to the events between the vaccination and the referral request. Thus, characterizations of
51
accompanied by the presence of VGKC antibodies. Doctor Renaud first made a
diagnosis of possible autoimmune encephalitis after C.L. tested positive for VGKC
antibodies. She later changed that diagnosis to “probable autoimmune encephalitis”
when immunotherapy was somewhat effective in reducing the level of antibodies.
However, when C.L.’s parents brought her back to Dr. Renaud in 2011, she did not
return to her earlier diagnosis of autoimmune encephalitis, noting instead only that C.L.
was positive for VGKC antibodies. Nevertheless, she continued to treat C.L. with
steroids, a treatment predicated on the notion that the antibodies were contributing to
C.L.’s symptoms.
Doctor Shafrir testified that C.L. suffered autoimmune synaptic encephalitis.84 Tr.
at 207. Later, he explained that C.L. did not have acute encephalitis, or encephalitis,
but rather something that he characterized as a “subacute encephalopathy.” Tr. at 269.
He maintained that C.L. has a “probable autoimmune encephalopathy” under the Zuliani
criteria85 based on her clinical symptoms, VGKC antibodies, and response to
immunotherapy. Tr. at 277-81, 514. He did not point to any specific symptoms she
displayed after the November 25, 2005 vaccination as evidence that she had an
encephalopathy, other than her regression. He opined that C.L. responded favorably to
treatment for an autoimmune encephalopathy as evidence that autoimmune
encephalopathy is the correct diagnosis. Tr. at 187-90.
In early 2013, after an increase in C.L.’s steroid dose, C.L.’s parents and Dr.
Renaud noted improvements in her condition. Pet. Ex. 9, pp. 119, 127, 154, 221, 247.
In February 2014, Dr. Renaud noted that C.L. continued to gain new skills. Id., p. 266.
However, C.L.’s January 2013 IEP found that, while C.L.’s eye contact and joint
attention had improved, her communication skills were poor, she did not engage in age
appropriate play, lacked the skills to interact with her peers, preferred repetitive and
self-stimulatory behavior, exhibited a low frustration tolerance, and sought sensory input
by putting things in her mouth, and smelling and touching them. Pet Ex. 5, p. 206. In
June 2013, Dr. Chadwick noted that C.L. was experiencing “anger, aggression, and
agitation issues, though this has gotten better of late.” Id. at 7.
the regression as sudden and occurring within two weeks to a month after the vaccination by these
physicians must be based on parental reports made years after the events in question.
84
Dr. Dalmau explained that VGKC complex antibody encephalitis is not synaptic. Tr. at 309-11.
85
See L. Zuliani, et al., Central nervous system neuronal surface antibody associated syndromes: review
and guidelines for recognition, J. NEUROL. NEUROSURG. PSYCHIATRY 83: 638-45 (2012), filed as Pet. Ex.
23n [hereinafter “Zuliani, Pet. Ex. 23n”]. Initially, Dr. Shafrir maintained that C.L. had “a definite
autoimmune encephalopathy” based on the Zuliani criteria. Pet. Ex. 23 at 11 (Dr. Shafrir’s second expert
report, citing Zuliani, Pet. Ex 23n). After Dr. Dalmau testified that the Zuliani criteria covered only
neuronal surface antibodies and that the VGKC antibodies present in C.L. were not neuronal surface
antibodies (Tr. at 356-62), Dr. Shafrir retreated from this position (Tr. at 513-14).
52
Doctor Dalmau testified that C.L.’s clinical condition is distinct from other patients
with autoimmune encephalopathy and encephalitis that he has seen personally or who
are described in the medical literature. Tr. at 301. According to Dr. Dalmau, children
with an autoimmune encephalopathy or encephalitis share a core group of symptoms
with a subacute presentation, including: seizures, headache, and fever. Tr. at 317. An
EEG performed on a patient with encephalopathy is almost always abnormal. Tr. at 318
(citing Hacohen, Pet. Ex. 23a). Inflammation typically accompanies autoimmune
encephalopathy, which can be found by performing a spinal tap, a biopsy, or an MRI.
Tr. at 319. Doctor Dalmau noted that C.L.’s EEGs and MRI were normal. Tr. at 322.
He also pointed out that, despite having being seen by physicians (Drs. Snook and
Janousek) within a few weeks or months after her November 25, 2005 influenza
vaccination, none of C.L.’s physicians ordered a spinal tap. He considered this
evidence that her physicians did not see any evidence that C.L. had a subacute
encephalopathy. Id.
Further, Dr. Dalmau explained that it is not clear that C.L. has responded
favorably to the immunotherapy treatments. Rather, he attributed the improvements
noted by her parents and Dr. Renaud to her ongoing ABA therapy.86 Tr. at 339, 437.
Doctor Gorman also testified that ABA therapy has been the most beneficial therapy
C.L. received. Tr. at 490. He noted that there have been improvements reported
throughout the period after her initial diagnosis, and attributed her improvements to her
increased maturity and intensive ABA therapy.
Although the filed photos and videos show C.L. has learned some new skills and
has some improvements in behavior, it is very difficult to draw any causal conclusions
from the videos provided. See Pet. Exs. 29-35.87 None of the filed photographs were
from the months immediately following C.L.’s influenza vaccination. The videos are
similarly unhelpful. The video that most closely predates C.L.’s November 2005
vaccination was from April 26, 2005 (Pet. Ex. 33) and the video most proximate to the
time after the vaccination was from September 2007 (Pet. Ex. 34).
D. Factual Findings.
Based on the contemporaneous medical, school, and therapy records, the early
histories provided by petitioners, the observations and testing performed resulting in an
autism diagnosis, the opinions of treating providers and the experts, and the evidence in
the medical literature, I make the following factual findings:
86
ABA therapy “is the recommended and clinical standard (evidence based) for treatment of children and
adolescents with autism.” Pet. Ex. 13, p. 12.
87
Petitioners’ Exs. 31-35 were filed on February 22, 2014 (ECF Docket No. 79); however, the docket text
and event code did not specifically identify this filing as containing exhibits. Instead, the filing is identified
as a “Status Report.”
53
1. C.L. had symptoms of delayed development and ASD prior to the
administration of the November 25, 2005 influenza vaccination. These included
language delay, behavioral difficulties (including temper tantrums and irritability), being
a “picky eater,” and mild gross motor delay.
2. Evaluations after the vaccination showed a progression of her speech, sleep,
eating, and behavior problems, the continuation of some of these older problems, and
the onset of new problems, including loss of eye contact and social skills, as well as
some loss of vocabulary. However, the histories provided at these early evaluations did
not pinpoint the influenza vaccination as the turning point.88 Rather, they variously
referred to concerns developing when C.L. was two, two and one-half, and 26-27
months of age. The most frequently referenced time periods were when the initial
speech delay was noted at the two year well-child visit, and when she was two and one-
half, which was in late January 2006. Petitioners also used the onset of feeding
problems to date when signs of regression developed and placed it at around two years
of age. Pet. Ex. 14, p. 13.
3. Contrary to the later assertions that the onset of her regression was sudden,
occurring within two weeks to a month after the influenza vaccination, I find that the
onset was more gradual. C.L. saw several therapists and her pediatrician in December
2005-January 2006. Yet, her parents did not seek a referral to a neurologist until
February 13-14, 2006, when they made two telephone calls to Dr. Snook asking to see
Dr. Janousek. As Dr. Shafrir testified, they may have been in denial because C.L.’s twin
had already been diagnosed with an ASD. Tr. at 147-48. But, given the timing of the
telephone requests, which closely followed an OT evaluation that revealed “substantial
delays in sensory processing skills, oral[-]motor strength and coordination and
decreased muscle tone” (Pet. Ex. 14, p. 12), plus the problems mentioned at the
February 9, 2006 speech session,89 it is more likely that these two events constituted
88
For example, at the December 19, 2005 St. Francis evaluation that Dr. Shafrir relied upon to show a
significant regression after the vaccination (Tr. at 147-52), C.L.’s parents reported that they became
concerned six months previously about her speech and language development as C.L. was not gaining
new words, was unable to combine words, and most of her sounds came out as “da-da.” Pet. Ex. 14, p. 2
(emphasis added). Mrs. Lehner attributed this report to a rounding error and indicated that her first
concerns regarding C.L.’s speech were in August 2005 at her two year check-up. Tr. 26-27. Apparently
Dr. Snook’s concern about C.L.’s gross motor development at 15 months of age was not specifically
mentioned, but Mrs. Lehner reported that C.L. “met most of her developmental milestones late” and
exhibited “signs of regression in terms of her communication development at the same time that she
started having the feeding difficulties around 2 years of age.” Pet. Ex. 14, p. 13.
89
Mrs. Lehner reported that C.L. was “doing more lining up of items at home.” Pet. Ex. 14, p. 17
(emphasis added). C.L. made eye contact with and smiled at the therapist during a game, and used the
words “bubble” and “quack.” Id. During her feeding therapy session, she made poor eye contact. Id.
Her response to bath time had improved, according to Mrs. Lehner’s report, but C.L. had decreased
tolerance for changes in her routine. Id., p. 18. She tolerated only 15 minutes of the feeding therapy that
day. Id.
54
the” tipping point” after months of a gradual loss of words, eye contact, and other social
skills, as well as the emergence of new autism symptoms.
4. C.L. did not experience the symptoms commonly associated with autoimmune
encephalitis, including seizures, headache, and fever.90 Nor did she have an abnormal
EEG, commonly present in children with an autoimmune encephalopathy or
encephalitis. Her MRI did not show any evidence of inflammation.
5. The diagnosis of ASD, accompanied by a regression or loss of skills, fully
accounts for all the symptoms C.L. displayed leading up to her formal diagnosis in June
2006. The parties filed a number of medical journal articles describing regression in
autism, and C.L.’s losses, age, and subsequent clinical course of gradual improvements
with “good and bad days” fit squarely within the clinical course of ASD.
6. The seizure disorder diagnosis is fully compatible with the ASD diagnosis. It
is much less compatible with autoimmune encephalitis. Although seizures are a
frequent symptom of autoimmune encephalitis, they occur during the initial presentation,
according to Dr. Dalmau and the medical literature submitted. Doctor Shafrir noted that
immunotherapy, including steroids, were used to treat seizures that were possibly or
probably autoimmune in nature. However, C.L.’s seizures abated only with antiepileptic
drugs.
7. The evidence regarding response to immunotherapy treatment is the most
amorphous, but I conclude that the objective evidence in the form of school and test
records (the same type of evidence of clinical improvement that Drs. Clardy and
McKeon suggested relying upon before continuing with treatment (Ex. 9, pp. 191-94)),
demonstrates that any response was minimal at best. In contrast to the responders to
immunotherapy cited in the medical literature filed, C.L.’s behavioral improvements
were minimal, and best explained by her age and ABA therapy. The immunotherapy
did not change her diagnosis, cognitive functioning, or speech, and sometimes failed to
affect even her antibody levels. Her antibody levels were not a good correlate for
improvement, which, in itself is evidence that the antibodies were unrelated to her
behavioral and cognitive problems. C.L.’s antibodies never reached the purportedly
normal level used by the Mayo Clinic.
Because I conclude that C.L. did not have autoimmune encephalitis after her
allegedly causal vaccination, conducting a causation analysis under the Althen and
Pafford criteria may not be necessary. However, the fact that ASD is the correct
90
Although petitioners testified that C.L. experienced a few days of fever after her vaccination, there is no
documentation of this and it was never mentioned in subsequent medical records. Even if she did have a
transient fever after vaccination, the type of fever and other symptoms suggestive of encephalitis are, in
Dr. Dalmau’s words, “not subtle.” Such symptoms would prompt parents, particularly those who took their
child to the pediatrician for colds and ear infections, to seek medical treatment.
55
diagnosis does not entirely foreclose the theory advanced by petitioners, in that autistic
symptoms may be caused, in rare cases, by other conditions. See Snyder, 2009 WL
332044, at *45, nn. 124-26 (discussing evidence that prenatal exposures to drugs or
viruses may result in autistic-like symptoms in children and listing some case reports of
autism symptoms resulting from herpes or cytomegalovirus infections after birth and
even in adulthood). I thus continue with the Althen analysis.
V. Causation Analysis.
A. Summary of Causation Determination.
To some extent, Dr. Gorman’s changed opinion provides, in a microcosm, a
summary of what happened in the scientific exploration of autoimmune encephalitis
and, in particular, the role of voltage-gated potassium channel antibodies in
encephalitis. Had this case been tried several years earlier, my causation determination
might well have been different—and wrong. Science and medicine are not immutable,
and this case demonstrates how additional research may prove that a much desired
hypothesis, one that provides some hope of improvement by treating devastating
neurological impairments with immunotherapy, is simply wrong. And, in the weighing of
contrary opinions on diagnosis and causation, this case also illustrates the importance
of expert qualifications, research, and clinical experience in selecting an expert. This
was not a battle of the experts; it was a rout.
The clear weight of the evidence is that the VGKC antibodies present in C.L. do
not cause autoimmune encephalitis. There is no reliable evidence that such antibodies
are triggered or caused by influenza or influenza vaccinations. Finally, C.L. had
symptoms of ASD prior to the allegedly causal vaccination, making it even less likely
that the loss of some language and social skills, characterized by Dr. Shafrir as an
autistic regression, that occurred after this vaccination were caused by it.
B. Applying Althen.
1. Althen Prong One.
a. Legal Standards.
Althen requires that a petitioner in an off-Table causation case present a reliable
medical theory by explaining how the vaccine administered can cause the injury in
question. Althen, 418 F.3d at 1278. This first prong of Althen’s three part causation test
has also been characterized as the equivalent of the “Can it cause?” inquiry used in
toxic tort litigation. See Pafford, 2004 WL 1717359, at *4.
The medical theory must be a reputable one, although it need only be “legally
probable, not medically or scientifically certain.” Knudsen, 35 F.3d at 548-49. The
56
Supreme Court’s opinion in Daubert likewise requires that courts determine expert
opinions to be reliable before they may be considered as evidence. “In short, the
requirement that an expert’s testimony pertain to ‘scientific knowledge’ establishes a
standard of evidentiary reliability.” 509 U.S. at 590 (footnote omitted). The Federal
Circuit has stated that a “special master is entitled to require some indicia of reliability to
support the assertion of the expert witness.” Moberly, 592 F.3d at 1324.
b. The Theory.
Petitioners changed their theory as the hearing progressed. After first
contending that the VGKC antibodies present in C.L. were pathogenic themselves, Dr.
Shafrir waffled. At the conclusion of the hearing, he conceded that only the CASPR2,
LGl1, and Contactin-2 antibodies in the VGKC complex (antibodies not present in C.L.’s
serum sample) had been shown to be pathogenic:
[N]ext is the fact that I would definitely change my mind about the
pathogenicity. I think that Dr. Dalmau made a very nice statement of what
is pathogenic, which is only three known antibodies in neurological
disorders that have to meet like [sic] Witebsky’s criteria.[91]
Tr. at 514. Nevertheless, he continued to assert that “it is definitely very likely, I have to
say more than 50 percent likely, that there was something in [the] antibodies that [C.L.]
has, it is a marker of autoimmune process that is taking place.” Tr. at 518. Although he
conceded that he could be wrong, he did not believe that he was,
because we have proof that finding the antibodies lead [sic] to treatment,
but lead [sic] to a dramatic improvement in the patient, both in epilepsy
patients and in autistic patients. But supposed that we would find not,
there is something in it, we will find one of these other antibodies or other
target protein of those antibodies and we will find that some of them is [sic]
really involved with autism. . . . [C.L.] will be the first patient every [sic]
described to have this problem. So, we don’t have any way that we can
base our—my opinion on previous testing that is going like this. So, my
opinion is based on the fact that . . . some influenza vaccines have the
capacity to produce autoimmune disease, that [C.L.] has an antibody with
very high levels, not in the typical levels that are found in the general
population that is leading to a productive treatment, which means that it is
a very substantial support to the presence of an autoimmune process and
that the treatment helped her. So, I think that this is enough for me to say
91
Doctor Shafrir was referring to E. Witebsky, et al., Chronic Thyroiditis and Autoimmunization, J.A.M.A.
164(13): 1439-47 (1957), filed as Res. Ex. V. Doctor Dalmau discussed this article in his initial expert
report, citing the article as the basis for the “accepted criteria by which to define an antibody as
pathogenic (causing a disorder),” and which were “modified as science progressed.” Res. Ex. J at 9.
57
that we had a mechanism and we had a mechanism that can explain
cause and effect in this particular case. And this is why I think, I don’t
change my mind based on it, and I think that Dr. Dalmau’s testimony
helped me to make it much clearer, helped me to remove a lot of errors or
misconceptions that they had in the initial way that I presented it.
Tr. at 519-20. In referring to epilepsy, Dr. Shafrir referenced the “Lilleker” article (Tr. at
514-17), referring to Lilleker, Pet. Ex. 23d.92 In referring to proof that treating
autoantibodies resulted in improvement in autistic patients, he may have been referring
to C.L. herself or to a paper he cited in his December 11, 2013 expert report, O. Scott,
et al., Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of
Autistic Regression in a Toddler, J. CHILD NEUROL., (Epub) 1-4 (Oct. 3, 2013), filed as
Pet. Ex. 23e.
It remains somewhat unclear whether Dr. Shafrir now believes that the type of
VGKC antibodies C.L. has are pathogenic, or merely a marker for some autoimmune
process, but it is clear that he thinks the presence of the antibodies demonstrates that
C.L. had autoimmune encephalitis and that the influenza vaccine is responsible for the
antibodies and thus the encephalitis. It is equally clear that he thinks C.L.’s autism
diagnosis is the result of this purported encephalitis.
The theory advanced has two parts. First, petitioners contend that the VGKC
antibodies are pathogenic, or a marker of autoimmune neurologic disease, and can
cause symptoms like those C.L. displayed. Pet. Pre-hearing Memorandum, filed Jan. 7,
2014, at 11-13. Second, petitioners allege these antibodies can be caused by an
autoimmune response to an influenza vaccination. Id. I note that at the hearing, Dr.
Shafrir testified that even if C.L. had never been tested for the antibodies, he would still
opine, based on the timing of the vaccination and her declining scores on language
testing after the vaccination, that the influenza vaccination was responsible for C.L.’s
regression. Tr. at 214-16. However, he did not directly argue this theory.
(1) Are the Antibodies Pathogenic or a Biomarker?
Petitioners’ theory of causation crumbled because the first cornerstone of their
theory—that the VGKC antibodies C.L. had are either pathogenic themselves or are
markers for something else that can produce autoimmune encephalitis—was refuted by
research that reflected a new and more nuanced understanding of these antibodies.
Doctor Dalmau conclusively demonstrated that only certain types of the group of
92
The Lilleker study reviewed 144 patients who developed unexplained epilepsy as adults. Six of these
patients were found to have VGKC antibodies >400pM (one of whom had LGl1 antibodies and one of
whom had CASPR2 antibodies). The six patients were given immunotherapy and experienced improved
seizure control. Lilleker, Pet. Ex. 23d at 776.
58
antibodies erroneously termed VGKC antibodies are pathogenic. The history of how he
came to this conclusion is illustrative.
(a) NMDAR Encephalitis.
I begin by discussing NMDAR encephalitis because it was the first autoimmune
encephalopathy identified, and because Dr. Shafrir relied on several medical journal
articles discussing NMDAR encephalitis for parts of his theory.
In 2005, Dr. Dalmau and other researchers discovered the first autoimmune
encephalopathy. As he wrote in 2011:
In 2005, a syndrome of memory deficits, psychiatric symptoms, decreased
consciousness, and hypoventilation was reported in four young women
with ovarian teratomas. Specific autoantibodies to the N-methyl D-
aspartate receptor (NMDAR) were soon detected in these and eight other
patients with similar neurological symptoms, seven of whom also had
ovarian teratomas. During the following 3 years we identified 419 other
patients with this syndrome, many of them children and young adults with
or without an associated tumour. The discovery of this disorder, termed
anti-NMDAR encephalitis, has changed the diagnostic approach to clinical
problems as diverse as catatonia, subacute memory disturbance,
seizures, abnormal movements, and limbic encephalitis. It has also led to
the discovery of other autoimmune synaptic encephalitides mediated by
antibodies against the AMPA receptor (AMPAR); the ᵞ-amino-butyric acid-
B receptor (GABAB-R); and leucine-rich, gliomainactivated 1 (LGI1),
which is the main autoantigen of limbic encephalitis previously attributed
to voltage-gated potassium channels.
Dalmau, Pet. Ex. 16b at 63. The significant level of recovery from NMDAR encephalitis
with immunotherapy treatments93 encouraged further research into autoimmune
encephalopathies; voltage-gated potassium channel antibodies quickly became one of
the targets for further research, testing, and treatment.
Anti-NMDAR encephalitis is probably the best studied and described of the
autoimmune encephalitides. Moreover, there is more proof of the causal nature of the
antibodies in this type of autoimmune encephalitis than in any other: the causal
antibodies are found in the brain and “have been shown to affect the brain receptors
93
Patients with NMDAR encephalopathies are divided into two groups: those with tumors (paraneoplastic
presentations) and those without tumors. Tumor resection (if a tumor is found) and immunotherapy
(corticosteroids, IVIG, and plasma exchange) as the first line of therapy and the use of rituximab and/or
cyclophosphamide as the second line of therapy, resulted in recovery or only mild sequelae in about 75%
of patients, with those who had tumors removed making the greatest recovery. Dalmau, Pet. Ex. 16b at
63.
59
and cause a decrease in their function.” Res. Ex. J, at 4. Doctor Dalmau emphasized
that this “direct link between the antibodies and a well-described specific syndrome”
was shown to produce “the same disease in all subjects.”94 Id.
(b) VGKC Encephalitis.
Given that VGKC antibodies had already been identified and a test developed to
measure them,95 these antibodies were initially considered as another possible cause of
autoimmune encephalopathies, because problems with the potassium channels in
neuronal cells could be a reason for encephalopathic symptoms.
For many years, patients with a very wide variety of symptoms were reported in
the medical literature as having “positive” VGKC antibodies. Res. Ex. J at 8, 10.
However, the initial optimism about a causal role for VGKC antibodies was tempered
because of the wide variation in symptoms reported. Doctor Dalmau reported that it
was nonsensical to attribute so many symptoms to one cause. Id. at 8. Moreover, the
testing method for VGKC antibodies could not identify a specific target protein and
these antibodies were found only in serum, not in cerebral spinal fluid. Id. This led
researchers, including Dr. Dalmau, to conclude that the VGKC antibodies did not play a
direct role in any of these disorders. Id. (citing J. Honnorat, Is Autoimmune Limbic
Encephalitis a Channelopathy?, LANCET NEUROL., 9: 753-55 (2010), filed as Res. Ex. O
[hereinafter “Honnorat, Res. Ex. O”], at 754 (“antibodies against voltage-gated
potassium channels were also found in a broad spectrum of immunological disorders
and therefore these antibodies probably did not have a direct role in all of these
syndromes”)).
Contrary to Dr. Frye’s opinion, Pet. Ex. 10 at 2 (citing the 2008 Tan study, Pet.
Ex. 10i) regarding VGKC antibodies as markers for several neurological problems as
the result of their “antigen-specific crosslinking” (id.), the current scientific understanding
is that these antibodies do not target the potassium channel itself. Pet. Ex. J at 7-8; Tr.
at 301-03. Thus, according to Dr. Dalmau, a positive VGKC antibody test does not
reflect that antibodies against the potassium channel are present.96 Tr. at 303.
94
The article about the California encephalitis project (Dr. Dalmau was a co-author and the person who
conducted the antibody testing in the study) noted specific differences in clinical presentation in NMDAR
encephalitis from those in other types of encephalitis. Seizures were more common; intubation rates
were significantly higher; and movement disorders and language dysfunction were more likely to occur,
with language dysfunction occurring about twice as often as in cases with viral causes. Gable, Pet. Ex.
16a at 899-900. Autonomic instability occurred in nearly half the NMDAR cases and psychiatric
symptoms (including psychosis) occurred in two-thirds of the NMDAR cases. Id. at 901-02.
95
Doctor Dalmau testified that the term voltage-gated potassium channel antibodies was initially used
beginning in about 1995 to describe antibodies found using radioimmunoassay (RIA). Tr. at 301-02; Res.
Ex. J at 7. Specific proteins are not identified by this test. Tr. at 303; Res. Ex. J. at 7-8.
96
Doctor Dalmau had other problems with the Mayo Clinic testing on C.L. He noted that the Mayo
laboratory website stated that VGKC antibody testing would not be performed on children under age 18
60
However, within this large group of VGKC-positive patients, two distinct subsets
of patients were identified, patients with limbic encephalitis alone and those with
neuromyotonia and limbic encephalitis (Morvan’s syndrome). Res. Ex. J at 8. This led
researchers to believe these patients had an autoimmune disorder, but not one related
to the entire complex of VGKC antibodies. Id. In 2010, Dr. Dalmau and his colleagues
identified that the patients suffering from limbic encephalitis had antibodies directed
against the LGl1 protein within the larger VGKC complex. Id. (citing M. Lai, et al.,
Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to
potassium channels: a case series, LANCET NEUROL., 9: 776-85 (2010), filed as Res. Ex.
G [hereinafter “Lai, Res. Ex. G”]). In 2011, Dr. Dalmau and his colleagues identified a
group of patients suffering from Morvan’s syndrome. However, all of the Morvan’s
syndrome patients had antibodies directed against the specific protein CASPR2, not
VGKC. Id. (citing Lancaster, Res. Ex. Q). As Dr. Dalmau explained in his initial expert
report, “these patients did have an autoimmune disorder—it just was not related to
VGKC.” Id.
While the relevant medical community may once have thought—perhaps even as
late as January 2011, when Dr. Frye authored his opinion—that VGKC antibodies in
general were disease-causing, based on the more recent research discussed by Dr.
Dalmau only the antibodies against three specific proteins in that complex appear to
cause autoimmune encephalopathies. As Dr. Dalmau observed, C.L.’s “family and
physicians were hoping to find a treatable cause of her developmental delay” when she
was referred to Dr. Renaud at the Mayo Clinic in 2008. Res. Ex. J at 3. When testing
for VGKC antibodies was positive, they made “an automatic assumption of a
relationship” (id.), but the later developments and discoveries discussed above cast
considerable doubt on the causality assumption. The only “VGKC complex” antibodies
for which causality of autoimmune encephalitis has been demonstrated are those
against the proteins LGl1 or CASPR2. See generally Tr. at 333-36. C.L. did not have
either of these proteins in her VGKC antibodies.97 Pet. Ex. 21, p. 1. The type of VGKC
because normal values had not yet been established for the pediatric population. Res. Ex. J at 10. He
commented:
Neither Dr. Renaud nor other doctors treating [C.L.], nor the other expert witnesses,
make note of the experimental nature of the VGKC testing and that the Mayo Clinic Lab
itself does not even know what the normal range of values in children is. So, [C.L.] was
diagnosed and treated for a disease based on the results of an experimental research
test for which the normal results in children are not known.
Res. Ex. J at 10. Doctor Gorman expressed similar concerns, grounded in his own experiences with the
Mayo Clinic testing. Tr. at 468-72. He was particularly concerned that the VGKC antibody testing
performed by the clinic did not include testing for specific autoantibodies such as CASPR2 or LGl1.
97
According to Dr. Vincent, C.L. also tested negative for antibodies against the protein Contactin-2. Pet.
Ex. 21, p. 1. Antibodies against the protein Contactin-2 have been implicated in a minority of patients
with encephalitis. E. Lancaster & J. Dalmau, Neuronal autoantigens—pathogenesis, associated
61
antibodies for which C.L. was positive were those “with affinity to Kv 1.1, 1.2, and 1.6
type channels.” Pet. Ex. 9, p. 78.
(c) Conclusion Regarding Significance of Antibodies.
Notwithstanding Dr. Shafrir’s opinion, there is no reliable evidence that C.L.’s
specific antibodies are pathogenic or even markers for disease. Doctor Dalmau’s vastly
greater expertise in this area of medicine provides a firm foundation for his opinions that
VGKC antibodies are associated in the literature with too many conditions to be
meaningful as a biomarker for disease. In contrast, Dr. Shafrir’s opinions are wishful
thinking premised on unverified and unsupported assumptions. Doctor Dalmau’s
testimony that VGKC antibodies have never been found to cause any neurological
dysfunction was effectively unrebutted. Tr. at 412. There is no evidence that
heightened levels of VGKC antibodies are indicative of any disease at all, unless they
are associated with the specific proteins, LGl1 or CASPR2.98 Tr. at 416-17; see also
Pet. Ex. 21, p. 1.
Petitioners also failed to produce preponderant reliable evidence that VGKC
antibodies are biomarkers of autoimmune encephalopathy or any other disease. Dr.
Frye’s report was written in 2011, around the time Dr. Dalmau and other research
scientists demonstrated that only certain types of the group of antibodies erroneously
termed VGKC antibodies are pathogenic. Accordingly, Dr. Frye’s report is outdated
and therefore unreliable. Doctor Shafrir lacks the necessary experience to rebut Dr.
Dalmau’s testimony on VGKC antibodies. He has never treated a patient with positive
VGKC antibodies. Tr. at 208. Additionally, while he purports to be an expert on how
“antibodies can cause autoimmune encephalopathy” (Tr. at 217), he has no formal
training in immunology, nor does he publish in the field of immunology, or in the area of
antibodies and autoimmune encephalopathy.
Finally, while Dr. Vincent is clearly qualified to opine regarding C.L.’s VGKC
antibodies, she essentially conceded that only VGKC complex antibodies against the
specific proteins LGl1, CASPR2, and Contactin-2 are biomarkers or causal of disease,
and that C.L. does not possess these specific antibodies. Pet. Ex. 21, pp. 1-2. While
Dr. Vincent believed that “high levels of VGKC-antibodies generally indicate the
presence of a disease that can be treated with immunotherapies with considerable hope
of improvement” (id., p. 2), this statement of belief and hope is not tantamount to
reliable evidence that VGKC antibodies in general are pathogenic. Other evidence
demonstrates that these antibodies have been found in individuals with no neurological
disorders and antibody testing, J. NAT. REV. NEUROL., 8: 380-90 (2012), filed as Res. Ex. BB [hereinafter
“Lancaster & Dalmau, Res. Ex. BB”], at 383. “However, antibodies against contactin-2 usually occur in
association with those targeting LGl1 or Caspr2, and have been identified in other disorders, raising
doubts about the importance of these antibodies.” Id.
98
C.L. does not have antibodies to these specific proteins. Pet. Ex. 21, p. 1.
62
impairments. J. Suleiman, et al., Autoantibodies to neuronal antigens in children with
new-onset seizures classified according to the revised ILAE organization of seizures
and epilepsies, EPILEPSIA, 54 (12): 2091-2100 (2013), filed as Res. Ex. KK [hereinafter
“Suleiman, Res. Ex. KK”].
While it remains possible that some additional component of VGKC antibodies
may someday be identified as pathogenic or as a biomarker for disease, the wide
variety of reported symptoms, coupled with the failure to identify any other candidate
components after several years of research, makes this increasingly unlikely.
Petitioners’ experts’ opinions are contrasted, not favorably, with that of Dr. Dalmau—a
world leader in this field—who cogently explained at the hearing that, based on the state
of science today, there is no evidence that C.L.’s VGKC antibodies are either
biomarkers or pathogenic.
(2) Can the Influenza Vaccine Cause VGKC Antibodies?
Petitioners similarly failed to present preponderant evidence that the influenza
vaccination causes VGKC antibodies or VGKC-mediated autoimmune encephalopathy.
Doctor Shafrir was not only unable to explain coherently his theory of causation, he also
relied upon studies and reviews which focused either on a different vaccine or a
different type of injury. In essence he parroted certain key phrases, such as “molecular
mimicry,” and pointed to journal articles without explaining how the articles supported
his theory of causation in this case. The vague nature of his testimony about molecular
mimicry underscored his lack of formal training or specialized experience in the fields of
immunology and autoimmunity upon which the theories he put forward are based.
Doctor Frye’s report possessed the same problems.99
(a) Molecular Mimicry.
Doctor Shafrir relied on “molecular mimicry” to explain how influenza vaccine
could trigger an autoimmune reaction (the production of antibodies that targeted an
individual’s own body, rather than the pathogen against which they are intended), but
both the cases he cited and his extremely vague testimony about how this happens
failed to explain the theory as it applies to influenza vaccine and brain injury.
99
Doctor Frye also advanced a medical theory of causation with little support and outside his area of
expertise. Extrapolating from medical literature indicating that autoimmune reactions such as systemic
lupus erythematosus, Guillain Barré Syndrome [“GBS”], and autoimmune thrombocytopenia have been
reported following various vaccinations, he opined that a particular vaccine (influenza) can cause another
condition (an autoimmune encephalopathy). Pet. Ex. 10 at 2. He indicated, without providing detail
regarding a specific theory, that “[v]arious theories of pathogenesis have been suggested, including
molecular mimicry and bystander activation.” Id. at 2 (citing N. Toplak & T. Avčin, Influenza and
Autoimmunity, CONTEMP. CHALLENG. AUTOIMMUN., 1173: 619-26 (2009), filed as Pet. Ex. 10k [hereinafter
“Toplak & Avčin, Pet. Ex. 10k”]; A. Balofsky, et al., The new H1N1 and HPV vaccines and old fears,
CURR. OPIN. RHEUMATOL., 22: 431-35 (2010), filed as Pet. Ex. 10a [hereinafter “Balofsky, Pet. Ex. 10a”]).
63
Doctor Shafrir relied on two journal articles to establish that molecular mimicry
was a plausible mechanism for causation in this case, the same two articles cited by Dr.
Frye. Tr. at 164-65 (citing Balofsky, Pet. Ex. 10a; Tolpak & Avčin, Pet. Ex. 10k). These
articles do not explain either molecular mimicry or how the influenza vaccination can
cause VGKC antibodies to develop. The Tolpak & Avčin article discussed the 1976-77
swine flu vaccine and GBS and indicates that molecular mimicry is one possible
explanation for how that particular vaccine resulted in a significant increase in cases of
GBS. Tolpak & Avčin, Pet. Ex. 10k at 619, 624-25. The article does not suggest that
any specific autoantibodies were involved in the immune system attack on the body’s
own peripheral nerves in GBS, nor is it a primer on what molecular mimicry involves in
general. The authors noted that their research group demonstrated “an induction of
[unspecified] autoantibodies after influenza vaccination in apparently healthy adults,”
with molecular mimicry as a possible explanation. Id. at 621. There was no indication
that such autoantibodies were pathogenic or actually involved in causing GBS or any
other condition. Further, despite the changes in autoantibodies found in subjects after
influenza vaccination, no subject “developed clinical signs of overt autoimmune
disease.” Id. at 624. This article focused primarily on adjuvants and is thus irrelevant to
the influenza vaccine C.L. received, as Dr. Shafrir conceded that the influenza vaccine
administered to C.L. did not contain an adjuvant. Tr. at 229.
The Balofsky article focused on how vaccinations containing adjuvants might
lead to autoimmune injury. Balofsky, Pet. Ex. 10a at 432-34. The authors did not
explain molecular mimicry in general, stating only that “inactivated or recombinant
antigens were also associated with autoimmunity. The most probable mechanism by
which this occurs is molecular mimicry between the infectious antigen and self-antigens,
as well as other mechanisms like epitope spreading, bystander activation and polyclonal
activations.” Id. at 432 (citation omitted).
Doctor Shafrir’s brief foray into immunology during his testimony was limited to
noting that since C.L. had received another influenza vaccination prior to the allegedly
causal one on November 25, 2005, her “immune cells and lymphocytes that carry the
memory of the molecular receptors for influenza antibodies – antigens, and there are –
the production of antibodies will be much faster and much more intense after the
second vaccination.” Tr. at 166.
When cross-examined about how molecular mimicry would be involved in the
production of VGKC antibodies, Dr. Shafrir was hard-pressed to formulate a coherent
response:
Q: I was a little confused on direct about your medical theory. You
mentioned . . . Exhibits 10k and 10a. . . . Can you just restate for me what
your medical theory – what the mechanisms you think could potentially be
involved here are?
64
A: This is an article published by the Shoenfeld group [referring to
Balofsky, Pet. Ex. 10a] that talks about the mechanism by which the
influenza vaccination causes autoimmunity in general.
Q. And what is your – what were those theories or what was discussed in
that article that you’re adopting in this case?
A: All the discussion of the molecular mimicry and bystander activation
and the role of the adjuvant.
Q: Is there adjuvant in influenza vaccine?
A: I don’t think in this vaccine – in this particular one she had adjuvant.
And as I said, adjuvant is not important here because it’s not the first
vaccination.
Tr. at 229. It was painfully obvious that Dr. Shafrir was not familiar with these two
articles, despite his reliance upon them.
(b) Medical Literature.
As evidence the influenza vaccine could cause VGKC antibodies and
autoimmune encephalitis, Dr. Shafrir relied on reports in medical journal articles100
dealing with a different type of autoimmune encephalitis (the NMDAR encephalitis
discussed in Section V.B.1.b.(1)(a), above), which, in a few of the reported cases,
identified a bout of influenza or a different type of influenza vaccine as an antecedent
event to the encephalitis. He characterized this very weak evidence as showing the
presence of “a high association between the influenza vaccination preceding the onset”
of NMDAR autoimmune encephalitis. Tr. at 167.
The Dalmau study mentioned three NMDAR autoimmune encephalitis patients
with antecedent vaccinations (two who received the H1N1 vaccine, and one who
received a common childhood vaccine), but did not draw any conclusions regarding a
causal relationship. Dalmau, Pet. Ex. 16b at 66. These three patients were among the
hundreds of patients Dr. Dalmau’s research group has studied with anti-NMDAR101
encephalitis. Doctor Dalmau testified that researchers commonly list antecedent events
100
See Dalmau, Pet. Ex. 16b; Hung, Pet. Ex. 16c; J. Takanashi et al., Late Delirious Behavior with 2009
H1N1 Influenza: Mild Autoimmune-Mediated Encephalitis?, PEDIATRICS, 129 (4): e1068-71 (2012), filed as
Pet. Ex. 16e [hereinafter “Takanashi, Pet. Ex. 16e”].
101
NMDAR antibodies are not VGKC complex antibodies. Tr. at 415-16.
65
when the cause of a phenomenon is unknown, in the hope that with enough reports,
possible causes might be identified and studied. Tr. at 325; Res. Ex. J at 4.
The Hung article was a case report of a 14 year old girl with NMDAR encephalitis
who had an H1N1 vaccination one month prior to developing neurological symptoms.
Hung, Pet. Ex. 16c at 362. The Takanashi study, Pet. Ex. 16e, discussed five children
in Japan who developed “late-onset (>3 days after fever) and long-standing (>48 hours)
delirious behavior” after suffering H1N1 influenza and who tested positive for NMDAR
antibodies. Takanashi, Pet. Ex. 16e at e1068.
Doctor Shafrir also pointed to the Dhamija article, Pet. Ex. 11c, a case series
authored in part by two of C.L.’s physicians,102 reporting on 12 patients with VGKC
antibodies. Of the 12 patients, only C.L., Patient 11, had received an antecedent
vaccination.103 Relying upon a case report involving C.L. to establish that a vaccine
could cause C.L.’s condition is circular reasoning.
This evidence fails to demonstrate that Dr. Shafrir’s theory has sufficient indicia
of reliability to be persuasive. Only C.L.’s own case, reported in Dhamija, Pet. Ex. 11c
at 276, involved the seasonal influenza vaccine and VGKC antibodies. The Dalmau
study, Pet. Ex. 16b, and Hung case report, Pet. Ex. 16c, involved different vaccines,
different antibodies, and actual encephalitis. The Takanashi article, Pet. Ex. 16e, did
not involve vaccination at all, but instead looked at a single case report of an H1N1 viral
infection, followed by NMDAR encephalitis. A report of vaccination prior to developing
symptoms of an injury is not tantamount to establishing that the antecedent event
caused the injury. Tr. at 325.
Doctor Dalmau, the lead author of Pet. Ex. 16b, testified that, based on his own
experience in investigating and researching autoimmune encephalitis, vaccination does
not play any role in its development. Tr. at 405 (“we don’t find this association”).
Reasoning by analogy, petitioners attempted to show that because NMDAR
antibodies are pathogenic, VGKC antibodies are disease-causing, too. But VGKC
antibodies, other than LGI1 and CASPR2, “have absolutely nothing to do with NMDA[R]
antibodies.” Tr. at 415-16. NMDAR antibodies and LGI1 and CASPR2 are neuronal
102
C.L.’s treating physician, Dr. Renaud, as well as her consulting physician, Dr. McKeon, are among the
named authors of this review from the Mayo Clinic.
103
The article identified the symptoms as “[g]lobal developmental regression, autism, [and] insomnia” with
onset one to four weeks after vaccination. Dhamija, Pet. Ex. 11c at 276. The article also reported that
the patient improved on IVIG, and relapsed when IVIG was stopped. While the report of timing could
arguably be based on what petitioners reported to the Mayo Clinic physicians, I find the description of a
global regression inaccurate and the report of improvement on IVIG and relapse when therapy stopped to
be exaggerated. This causes me to question the reliability of the other matters reported in this case
series.
66
surface antibodies. Tr. at 358, 446. The significance of the type of antibody in causing
encephalitis is that neuronal surface antibodies “bind to cell surface determinants of
membrane associated proteins on neuronal cells and are likely to be pathogenic.”
Zuliani, Pet. Ex. 23n at 638; Tr. at 306, 414. Neuronal surface antibodies react with the
surface of neurons. Tr. at 358. NMDAR antibody encephalopathy is a well-defined
disease, the function of the antibodies is understood, and an animal model for the
disorder exists. Tr. at 334, 358; Zuliani, Pet. Ex. 23n at 3.
(c) Epidemiology.
Finally, Dr. Shafrir made the broad assertion that “the epidemiology links the
receipt of [a] vaccine and actual [autoimmune] disease.” Tr. at 175. Assuming,
arguendo, that he is correct, he did not point to any study linking any autoimmune
disease to vaccination. As evidence for this sweeping statement, Dr. Shafrir once again
pointed to literature discussing vaccines and injuries distinct from the seasonal influenza
vaccine and autoimmune encephalopathy at issue in this claim. He mentioned the
association between the 1976-77 H1N1 (swine) influenza vaccine and GBS, as well as
literature associating childhood narcolepsy following H1N1 vaccination in Scandinavian
countries. Tr. at 175-76.104 He offered no meaningful testimony explaining how these
studies were relevant to establishing C.L.’s seasonal influenza vaccination caused her
injury. Tr. at 175-77. C.L. did not receive the H1N1 vaccine, or suffer from either GBS
or narcolepsy.
(3) Conclusions Regarding Althen Prong 1.
I find that Doctor Shafrir failed to muster plausible, much less preponderant and
reliable evidence that the influenza vaccine cause VGKC antibodies to develop. He
failed to coherently explain his theory of how C.L.’s vaccination caused her to develop
them. Moreover, he proffered no reliable or convincing evidence that the presence of
such antibodies can produce an autoimmune encephalopathy. In effect, he conceded
there is no evidence the influenza vaccination leads to the development of VGKC
antibodies. Tr. at 167.
There is no evidence, much less reliable evidence, in this record that influenza
vaccinations can cause the production of VGKC antibodies, much less that the
antibodies are pathogenic or a marker for disease. Unsupported speculation is not a
104
Doctor Shafrir referenced the journal articles accompanying his third expert report (Pet. Exs. 23o-23q).
Tr. at 176-77. These articles include: M. Partinen, et al., Increased Incidence and Clinical Picture of
Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland, PLOS ONE,
7 (3): e33723 (2012), filed as Pet. Ex. 23o; European Centre for Disease Prevention and Control,
TECHNICAL REPORT, Narcolepsy in association with pandemic influenza vaccination, filed as Pet. Ex. 23p;
E. Miller, et al., Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic
A/H1N1 2009 influenza vaccine: retrospective analysis, BMJ, 346: f794 (2013), filed as Pet. Ex. 23q.
67
basis for finding the medical theory to be reliable or a basis for finding a causal
connection between vaccination and injury.
Assuming, arguendo, that the influenza vaccination could cause the production of
VGKC antibodies and that such antibodies could cause autoimmune encephalitis, I turn
to the second Althen prong.
2. Althen Prong 2: Lack of a Logical Connection.
Even if petitioners had provided a theory which satisfied the first prong, to satisfy
the second prong of the Althen test, petitioners must establish a “logical sequence of
cause and effect showing that the vaccination was the reason for the injury.” Althen,
418 F.3d at 1278. In other words, petitioners must show that the received vaccine did,
more likely than not, cause the injury in the case at bar. Pafford, 451 F.3d at 1356. The
sequence of cause and effect need only be “‘logical’ and legally probable, not medically
or scientifically certain.” Knudsen, 35 F.3d at 548-49; accord Capizzano, 440 F.3d at
1326. Evidence from a treating physician may assist petitioner in meeting her burden of
proof under the second Althen prong. Capizzano, 440 F.3d at 1326.
In this case, none of the treating physicians ever specifically identified the
influenza vaccine as the cause of C.L.’s purported autoimmune encephalopathy. At
best, they described a temporal relationship between the vaccination and a sudden loss
of C.L.’s language and social skills—a temporal relationship not borne out by the
testing, therapy, and medical records between the vaccination and evaluation by Dr.
Janousek.
I am not ignoring the fact that Drs. Renaud and McKeon, as well as Dr. Vincent,
thought C.L.’s antibody levels warranted immunotherapy treatment, particularly given
the remarkable improvement seen in the majority of patients with true autoimmune
encephalitis on treatment. While I have fully considered these treating opinions and
note that Drs. McKeon and Vincent are well regarded researchers in this field, they
never opined that the antibodies were responsible for C.L.’s autism diagnosis. Their
notes reflect the same frustration evident in Dr. Shafrir’s testimony. Autism is a
devastating diagnosis because there is often so little that can be done to treat it. If there
is a scintilla of hope that it could be treated, improved, or even cured by autoimmune
therapy, then the possible benefit far outweighed the risk of treatment. Unfortunately for
C.L., petitioners, and others with autism diagnoses, the objective evidence in this case
is that immunotherapy did not help at all with C.L.’s behavior and cognitive problems or,
at best, the small degree of improvement observed is more likely due to ABA therapy
and C.L.’s greater maturity. It certainly does not compare to the degree of improvement
seen in NMDAR, limbic encephalitis, and Morvan’s syndrome patients treated with
immunotherapy. See Dalmau, Pet. Ex. 16b at 66; Lancaster & Dalmau, Res. Ex. BB at
384-85.
68
To establish the logical connection, Dr. Shafrir similarly relied on the temporal
relationship between vaccination and onset of regression; the presence of the
antibodies, the efficacy of immunotherapy, and the presence of an autoimmune
encephalopathy/encephalitis. The latter issue was addressed above in Section IV.C 2.
In summary, C.L.’s clinical presentation was not consistent with any known autoimmune
encephalitis. Likewise, the efficacy of C.L.’s immunotherapy is not supported by
objective evidence. See Sections III.E.4 and IV.C.2.c, supra. I have concluded that the
regression was not abrupt or sudden. See Section IV.D.3, supra. What is left is the
presence of the antibodies.
What we know about C.L.’s VGKC antibodies is that they were first discovered in
her serum approximately three years after the regression and autism diagnosis. The
antibodies have been measured over time and the levels have fluctuated. More often
than not, they have declined during immunotherapy, which is what immunotherapy is
designed to do—either remove the antibodies by IVIG or plasma exchange or suppress
the immune system producing them, via steroid administration or the use of
immunosuppressive agents such as rituximab. However, there was no reliably
demonstrated clinical correlation between C.L.’s VGKC antibody levels and
improvement in cognitive function, language, or behavior.
Moreover, if the antibodies are responsible for C.L.’s autism symptoms, then they
were likely present before the vaccination. C.L. showed symptoms of what was later
diagnosed as ASD as early as 15 months of age, and had a clear and significant
language delay by two years of age. In addition to the language problems which are
often the first symptom that prompts parents to seek medical advice, C.L.’s parents
reported that she had always enjoyed solitary play, and were concerned enough about
her temper tantrums to bring them to the attention of her pediatrician on at least two
occasions prior to the vaccination—behaviors often seen in children with ASD. Both
parties’ experts agreed that C.L. experienced developmental delay prior to her
November 25, 2005 vaccination. Tr. at 142 (Dr. Shafrir testifying: “Yes. She did have a
developmental delay prior to receiving the influenza vaccine.”). Developmental delay,
including language delay, is a symptom of an autism spectrum disorder. Luyster, Res.
Ex. DD at 1426 (“One of the primary diagnostic criteria for the diagnosis of autism
spectrum disorder (ASD) is the presence of a language delay or impairment.”); Landa,
Res. Ex. EE at 139, Table 1 (“Social, communication, and other developmental
disruptions reported before 24 months in age in retrospective and prospective studies of
children later diagnosed with autism spectrum disorder.”).
In discussing the anomalies in C.L.’s clinical presentation, vis-à-vis the
autoimmune encephalopathies with which he was well acquainted, Dr. Dalmau
described it as “unprecedented” to have an autoimmune disorder that causes a one-
time attack (i.e., C.L.’s regression and presumed encephalitis in late 2005), with the
antibodies remaining in her system for three more years, without further neurological
69
problems manifesting. Res Ex. J at 6; Tr. at 438-39. Yet, C.L. remained stable or
improved marginally and slowly, while retaining an ASD diagnosis.
Finally, while it is not necessary to evaluate the possible factors unrelated to her
vaccination105 the evidence clearly demonstrates that C.L. suffers from an autism
spectrum disorder, that the symptoms of C.L.’s autism spectrum disorder began prior to
her November 25, 2005 vaccination, and that regression is seen in children with autism
spectrum disorders. It is Dr. Dalmau’s opinion that C.L.’s brain dysfunction is not
autoimmune in nature, but representative of her ASD. Tr. at 300; Res. Ex. J at 3. C.L.
has been consistently diagnosed or noted to have an autism diagnosis by a variety of
her treating medical care providers, autism screening testing, and scholastic placement
testing. See, e.g., Pet. Exs. 3, p. 47; 4, p. 52; 5, p. 236; 7, p. 36; 9, pp. 4-5, 234-37; 13,
p. 37; 22, p. 10.
Accordingly, while C.L.’s autism diagnosis was not made until June of 2006 (Pet.
Ex. 4, pp. 50-52), it was clear that her first symptoms of developmental delay began as
early as her October 27, 2004 15 month well child checkup (Pet. Ex. 3, p. 32 (behavior
problems, feeding issues, and some mild gross motor delay)), and were readily
apparent by her two year well child exam when Dr. Snook noted a language delay (Pet.
Ex. 3, p. 41). In fact, by C.L.’s two year well child visit, she had been noted to have
behavior problems, poor eating habits, poor sleeping habits, sensitivity to touch, sound,
temperature, as well as language delay. Pet. Ex. 3, pp. 36-41. Doctor Shafrir
acknowledged that C.L. experienced developmental delay prior to her November 25,
2005 influenza vaccination, but asserted that C.L. “developed a dramatic autistic
regression following the vaccination.” Pet. Ex. 23 at 12. However, there is no evidence
of a dramatic regression following C.L.’s November 2005 vaccination—C.L.’s behavior
did not rapidly change.106 What is evident from the medical literature filed in this case is
that regression is seen in children with autism. Relying upon the medical literature, Dr.
Dalmau explained in his expert report that “a subset of children with autism have
significant social and language gains and then, often between 15 and 30 months
experience a dramatic loss of skills.” Res. Ex. J at 3. In fact a “sizable minority (15%-
47%)” of children with ASD exhibit a developmental course “associated with an
idiopathic regression in one or more domains of behavior following a period of normal or
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The special master may consider evidence of an alternate cause when determining whether petitioner
has established a prima facie case. Doe 11 v. Sec’y, HHS, 601 F.3d 1349 (Fed. Cir. 2010).
106
In his initial report, Dr. Gorman noted that at C.L.’s neurological impairment prior to November 25,
2005, was underestimated by her medical care providers, aside from those providers administering her
formal speech and language evaluation. Res. Ex. A at 4. While Dr. Gorman believed that C.L. suffered
regression, he thought it was unclear when the regression began, noting that her Bayley Scales of
Development score on August 4, 2006 was higher than her pre-vaccination score on September 27,
2005. Id.
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near normal early development.” G. Stefanatos, Regression in Autistic Spectrum
Disorders, NEUROPYSCHOL. REV., 18: 305-19 (2008), filed Res. Ex. U, at 305.
For the above reasons, I find that petitioners have not demonstrated by a
preponderance of the evidence a logical connection between C.L.’s vaccination and her
purported injury of autoimmune encephalopathy.
3. Althen Prong 3: Proximate Temporal Relationship.
Merely showing a proximate temporal connection between a vaccination and an
injury is insufficient, standing alone, to establish causation. Grant v. Sec’y, HHS, 956
F.2d 1144, 1148 (Fed. Cir. 1992). A proximate temporal relationship, even when
coupled with the absence of any other identified cause for the injury, is not enough to
demonstrate probable cause under the Vaccine Act’s preponderance standard.
Moberly, 592 F.3d at 1323 (citing Althen, 418 F.3d at 1278). In this case, Dr. Shafrir did
not identify any specific medically appropriate time frame between the influenza
vaccination and onset of an autoimmune encephalopathy. He notes “I cannot be
accurate about that [a medically acceptable time frame between C.L.’s vaccination and
regression] because . . . [w]e can’t say . . . exactly when the regression started.” Tr. at
193. Doctor Shafrir appeared to speculate, based on injuries distinct from C.L.’s (GBS,
NMDAR encephalitis) that anywhere from one week to six weeks is an appropriate time
period. Tr. at 192-200. However, he failed to explain in his testimony or within his
reports why this is an appropriate time period for C.L.’s purported injury of VGKC
autoimmune encephalopathy. Accordingly, I find that petitioners have failed to
demonstrate a medical acceptable proximate temporal relationship between C.L.’s
vaccination and injury.
VI. Conclusion.
For the reasons discussed above, I find that petitioners have not met their burden
under Althen. They did not produce preponderant evidence that C.L.’s influenza
vaccination caused an autoimmune response. They did not show that it caused the
high VGKC antibodies. They did not establish that these antibodies were “clinically
significant” in terms of causing an autoimmune encephalopathy. They did not
demonstrate that the influenza vaccine could or did cause C.L. to develop an
autoimmune encephalopathy. As the Court of Federal Claims has noted, an expert’s
“conclusions . . . are only as good as the reasons and evidence that support them.”
Davis v. Sec'y, HHS, 20 Cl. Ct. 168, 173 (1990). See also Perreira v Sec’y, HHS, 33
F.3d 1375, 1377 n.6 (Fed. Cir. 1994) (“An expert opinion is no better than the
soundness of the reasons supporting it.”) (citations omitted); Dobrydnev v. Sec’y, HHS,
566 Fed.Appx. 976, 982-83 (Fed. Cir. 2014) (an expert’s opinion is only worth as much
as the facts upon which it is based) (citing Brooke Group Ltd. v. Brown & Williamson
Tobacco Corp., 509 U.S. 209, 242 (1993)); Fehrs v. United States, 620 F.2d 255, 265
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(Ct. Cl.1980) (an expert’s opinions “can be no better than the soundness of the reasons
that stand in support of them”). Petitioners’ experts failed this well-established test.
I conclude that petitioners failed to demonstrate any of the Althen factors by
preponderant evidence. Petitioners have not demonstrated that C.L.’s injury was either
caused in fact or significantly aggravated by the influenza vaccination she received on
November 25, 2005. The petition for compensation is therefore DENIED. The clerk is
directed to enter judgment accordingly.
IT IS SO ORDERED.
s/Denise K. Vowell
Denise K. Vowell
Chief Special Master
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