In the United States Court of Federal Claims 

OFFICE OF SPECIAL MASTERS

Filed: August 31, 2020

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

SAURABH AGARWAL and MUKTA *

AGARWAL, Parents of R.A., a minor, * PUBLISHED

*

Petitioners, * No. 16-191V

*

v. * Special Master Gowen

*

SECRETARY OF HEALTH * Tetanus-Diphtheria-Acellular Pertussis

AND HUMAN SERVICES, * (Tdap); Meningococcal (Menactra);

* Autoimmune Limbic Encephalitis (ALE);

Respondent. * FIRES.

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

Ronald C. Homer and Meredith Daniels, Conway, Homer, P.C., Boston, MA, for petitioners.

Camille C. Collett, United States Department of Justice, Washington, DC, for respondent. 

RULING ON ENTITLEMENT1

On February 8, 2016, Saurabh and Mukta Agarwal, on behalf of their minor daughter 

R.A., filed a petition in the National Vaccine Injury Compensation Program.2 Petition (ECF No. 

1). Petitioners alleged that as a result of receiving tetanus-diphtheria-acellular pertussis (Tdap) 

and meningococcal (Menactra) vaccines on August 5, 2013, R.A. developed autoimmune limbic 

encephalitis (ALE) with the associated biomarker of GAD antibodies, and the residual effects of 

cognitive deficits and intractable epilepsy. I conclude that petitioners have established these 

injuries and causation-in-fact. Accordingly, petitioners on behalf of R.A. are entitled to 

compensation.3

1 Pursuant to the E-Government Act of 2002, see 44 U.S.C. § 3501 note (2012), because this opinion contains a

reasoned explanation for the action in this case, I intend to post it on the website of the United States Court of

Federal Claims. The court’s website is at http://www.uscfc.uscourts.gov/aggregator/sources/7. Before the opinion is 

posted on the court’s website, each party has 14 days to file a motion requesting 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). An objecting party must provide the court with a proposed 

redacted version of the opinion. Id. If neither party files a motion for redaction within 14 days, the opinion will be 

posted on the court’s website without any changes. Id.

2 The National Vaccine Injury Compensation Program is set forth in Part 2 of the National Childhood Vaccine 

Injury Act of 1986, Pub. L. No. 99-660, 100 Stat. 3755, codified as amended, 42 U.S.C. §§ 300aa-10 to 34 (2012) 

(hereinafter “Vaccine Act” or “the Act”). Hereinafter, individual section references will be to 42 U.S.C. § 300aa of 

the Act.

3 Pursuant to section 300aa-13(a)(1) of the Vaccine Act, I have considered the entire record in arriving at this 
2

I. Procedural History

Petitioners timely filed the petition on February 8, 2016, followed by records of R.A.’s 

extensive medical care and a statement of completion on April 7, 2016. During an initial status 

conference on April 26, 2016, respondent indicated that he would defend the case. I ordered 

petitioners to file an expert report, followed by respondent’s responsive report and report 

pursuant to Rule 4(c). Scheduling Order (ECF No. 18). 

On August 26, 2016, petitioners filed the first expert report of A.H.M. Mahbubul Huq, 

MBBS, Ph.D.

4

, who opined that R.A.’s course was consistent with a subtype of ALE with the 

associated biomarker of GAD antibodies, which was caused-in-fact by the Tdap and Menactra 

vaccines. Petitioner’s Exhibit (Pet. Ex.) 29. On February 27, 2017, respondent filed the Rule 

4(c) report and the first expert report of Michael Kruer, M.D.5 Respondent’s (Resp.) Ex. A. Dr. 

Kruer disagreed with the assessment of ALE and opined that R.A.’s “lack of response despite 

early, intensive immunotherapy indicates that another inflammatory process is far more likely to 

account for her symptoms.” Id. at 5. During a Rule 5 status conference on March 30, 2017, I 

conclusion. This opinion will discuss the aspects of the record that were most relevant to the resolving the issue of

entitlement.

4 Dr. Huq is licensed to practice medicine in the state of Michigan. Pet. Ex. 44 at 2. He is board-certified in 

neurology (with a subspecialty in child neurology) and genetics. Id. He obtained a Bachelor of Medicine and a 

Bachelor of Surgery (MBBS) at Dhaka University/ Dhaka Medical School in Bangladesh in 1984, where he 

completed an internship in 1985. He obtained a Ph.D. in medical science at Tokushima University in Japan in 1991. 

He completed simultaneous residencies in pediatrics at the Children’s Hospital of Michigan and neurology at Wayne 

State University from 1991 – 1992. He was a fellow in medical genetics at Baylor College of Medicine from 1993 –

1996. In 1998, he returned to Children’s Hospital of Medicine where he is still a pediatric neurologist. Pet. 29 at 1; 

Pet. Ex. 44 at 1-3. Dr. Huq used to spend half of his time on research, which has been published in per-reviewed 

journals. He is now a full-time clinician seeing approximately 50 – 60 patients each week, in both inpatient and 

outpatient settings. Tr. 47-48. Dr. Huq has diagnosed and treated patients with ALE as well as FIRES. Dr. Huq is 

also a Professor-Clinician Educator in the departments of Pediatrics and Neurology at Wayne State University. Pet. 

29 at 1; Pet. Ex. 44 at 1-3. Dr. Huq was offered and admitted without objection as an expert in pediatric neurology 

and clinical genetics. Tr. 51.

5 Dr. Kruer is board-certified in neurology (with a subspecialty in child neurology), pediatrics, and 

neurodevelopmental disabilities. He obtained a Bachelor of Science from Arizona State University Barrett Honors 

College in 2001 and a medical degree with distinction in research from the University of Arizona College of 

Medicine in 2004. He had a residency in pediatrics at Phoenix Children’s Hospital/ Maricopa Medical Center from 

2005 – 2007. Afterwards, he had an overlapping clinical fellowship in neurodevelopmental disabilities and a postdoctoral fellowship in molecular neurogenetics at Oregon Health & Science University from 2007 – 2011. Dr. 

Kruer previously practiced and taught in South Dakota. Resp. Ex. E at 1-2. He is currently the Director of the 

Cerebral Palsy and Pediatric Movement Disorders Program at Barrow Neurological Institute in Arizona. Resp. Ex. 

E at 1. Dr. Kruer also sees a significant number of patients in both inpatient and outpatient settings. Tr. 159-61. He 

has treated “a great many... over a hundred” patients with encephalitis (not specifying which type(s)) and “more 

than a dozen” patients with FIRES. Tr. 162. Dr. Kruer is also an Associate Professor in the Child Health, Cellular 

and Molecular Medicine, and Neurology departments, as well as the Graduate Interdisciplinary Program in Genetics, 

at the University of Arizona College of Medicine College of Phoenix. Resp. Ex. E at 1; Tr. 159. He has also 

researched and published on topics including various forms of encephalitis. He is on the editorial board of the 

Journal of Child Neurology and conducts peer review for other journals in that filed. Resp. Ex. E at 2; Tr. 164. Dr. 

Kruer was offered and admitted without objection as an expert in child neurology, neurogenetics, and 

neuroimmunology. Tr. 165.
3

noted that Dr. Huq had set forth a reasonable opinion supporting causation-in-fact, but the parties 

disagreed on the timing and the underlying diagnosis. The parties requested to file additional 

expert reports and for a hearing to be scheduled. Scheduling Order (ECF No. 37). 

On July 31, 2017, respondent filed Dr. Kruer’s second report in which he opined that a 

more likely explanation for R.A.’s condition was febrile illness-related refractory epilepsy 

syndrome (FIRES). Resp. Ex. C at 3. Respondent filed the literature therein on November 16, 

2017, Resp. Ex. C Tabs 1-14. On January 25, 2018, petitioners filed Dr. Huq’s second report 

and cited literature. Pet. Ex. 31 and Tabs A-ZZ. During a pre-hearing status conference on April 

5, 2018, I stated that I found persuasive the treating physicians and Dr. Huq’s assessment that 

R.A. developed ALE, which Dr. Huq opined was caused-in-fact by the vaccines she received. I 

noted that I had previously adjudicated a case involving both autoimmune limbic encephalitis 

and FIRES, and that the latter typically depends on the absence of any other diagnosis. 

McCulloch v. Sec’y of Health & Human Servs., No. 9-293v, 2015 WL 3640610 (Fed. Cl. Spec. 

Mstr. May 22, 2015). The parties indicated that informal resolution was unlikely. Pre-Hearing 

Order (ECF No. 65). On September 5, 2018, respondent filed a third report from Dr. Kruer. 

Resp. Ex. D. The parties filed simultaneous pre-hearing submissions (ECF Nos. 82-83), which I 

reviewed during another pre-hearing status conference on October 24, 2018. Pre-Hearing Order 

(ECF No. 84).

The entitlement hearing was held in Chicago, Illinois on November 14-15, 2018. See

Hearing Transcript (ECF Nos. 89-90). On December 13, 2018, respondent filed several articles 

introduced during Dr. Kruer’s testimony and Dr. Kruer’s updated curriculum vitae. Resp. Ex. D 

Tabs 1-3; Resp. Ex. E. On March 6, 2019, respondent filed MRI images annotated by Dr. Kruer 

during his testimony. Resp. Trial Ex. 1. On April 5, 2019, petitioners filed Dr. Huq’s third 

report addressing issues raised by Dr. Kruer at the hearing and additional medical literature. Pet. 

Ex. 45 and Tabs A-J. On April 10, 2019, petitioners filed a motion for interim attorneys’ fees 

and costs which were awarded. Int. Fees Decision (ECF No. 106), at 2019 WL 2281744 (Fed. 

Cl. Spec. Mstr. April 23, 2019). Petitioners filed a post-hearing brief on June 4, 2019 (ECF No. 

110), followed by respondent’s response on October 31, 2019 (ECF No. 115) and petitioners’ 

reply on November 21, 2019 (ECF No. 116). This matter is now ripe for adjudication.

II. Legal Standard

The Vaccine Act was established to compensate vaccine-related injuries and deaths. § 

300aa-10(a). “Congress designed the Vaccine Program to supplement the state law civil tort 

system as a simple, fair and expeditious means for compensating vaccine-related injured persons. 

The Program was established to award ‘vaccine-injured persons quickly, easily, and with

certainty and generosity.’” Rooks v. Sec’y of Health & Human Servs., 35 Fed. Cl. 1, 7 (1996) 

(quoting H.R. No. 908 at 3, reprinted in 1986 U.S.C.C.A.N. at 6287, 6344).

A petitioner bears the burden of establishing entitlement to compensation from the 

Vaccine Program. There are two avenues to compensation. The first avenue requires the 

petitioner to demonstrate a Table injury (not alleged here). The second avenue requires the 

petitioner to prove that a vaccine listed on the Vaccine Table was the cause-in-fact of the injury. 
4

To prove causation-in-fact, the petitioner must “show by preponderant evidence that the 

vaccination brought about the injury by providing 1) a medical theory connecting the vaccination 

and injury; 2) a logical sequence of cause and effect showing that the vaccination was the reason 

for the injury; and 3) a showing of proximate temporal relationship between vaccination and 

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

There must be preponderant evidence for each Althen prong. Caves v. Sec’y of Health & Human 

Servs., 100 Fed. Cl. 119, 132 (2011), aff. per curiam, 463 Fed. Appx. 932 (Fed. Cir. 2012).

The preponderance of the evidence standard requires demonstrating that it is “more likely

than not” that the vaccine caused the injury. Moberly v. Sec’y of Health & Human Servs., 592 

F.3d 1315, 1322 n.2 (Fed. Cir. 2010). Proof of medical certainty is not required. Bunting v. 

Sec’y of Health & Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991). A petitioner must 

demonstrate that the vaccine was “not only [a] but for cause of the injury but also a substantial 

factor in bringing about the injury.” Moberly, 592 F.3d at 1321 (quoting Shyface v. Sec’y of 

Health & Human Servs., 135 F.3d 1344, 1352-53 (Fed. Cir. 1999); Pafford v. Sec’y of Health 

and Human Servs., 451 F.3d 1352, 1355 (Fed. Cir. 2006). Causation is determined on a case-bycase basis, with “no hard and fast per se scientific or medical rules.” Knudsen v. Sec’y of Health 

& Human Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). A fact-finder may rely upon “circumstantial 

evidence” which is consistent with the “system created by Congress, in which close calls 

regarding causation are resolved in favor of injured claimants.” Althen, 418 F. 3d at 1280. 

A petitioner often presents expert testimony in support of his or her claim. Lampe v. 

Sec’y of Health & Human Servs., 219 F.3d 1357, 1361 (Fed. Cir. 2000). Expert testimony in the 

Vaccine Program is usually evaluated according to the factors set forth in Daubert v. Merrell 

Dow Pharm., Inc., 509 U.S. 579, 594-96 (1993); see also Cedillo, 617 F.3d at 1339 (citing 

Terran v. Sec’y of Health & Human Servs., 195 F.3d 1302, 1316 (Fed. Cir. 1999). A special 

master may use the Daubert framework to evaluate the reliability of expert testimony, but expert 

testimony need not meet each Daubert factor to be reliable. Boatmon v. Sec’y of Health & 

Human Servs., 941 F.3d 1351 (Fed. Cir. 2019). The Daubert factors are “meant to be helpful, 

not definitive,” and all factors “‘do not...necessarily apply even in every instance in which the 

reliability of scientific testimony is challenged.’” Boatmon, 941 F. 3d at 1359 (citing Kumho 

Tire Co. v. Carmichael, 526 U.S. 137, 151, 119 S. Ct. 1167, 143 L.Ed.2d 238 (1999). Thus, for 

Vaccine Act claims, a “special master is entitled to require some indicia of reliability to support 

the assertion of the expert witness.” Moberly at 1324. Where both sides offer expert testimony, 

a special master’s decision may be “based on the credibility of the experts and the relative 

persuasiveness of their competing theories.” Broekelschen v. Sec’y of Health & Human Servs., 

219 F.3d 1339, 1347 (Fed. Cir. 2010) (citing Lampe, 219 F.3d 1357 at 1362). 

Once a petitioner has proven causation by preponderant evidence, the burden shifts to 

respondent to show by a preponderance of the evidence that the injury is instead due to factors 

unrelated to the administration of the vaccine. Deribeaux v. Sec’y of Health & Human Servs., 

717 F.3d 1363, 1367 (Fed. Cir. 2013) (citing § 13(a)(1)(B)). Respondent has the burden of 

demonstrating that “a factor unrelated to the vaccination is the more likely or principal cause of 

injury alleged. Such a showing establishes that the factor unrelated, not the vaccination, was 

‘principally responsible’ for the injury. If the evidence or alternative cause is seen in equipoise, 
5

then the government has failed in its burden of persuasion and compensation must be awarded.” 

Knudsen, 35 F.3d at 551. 

III. Summary of Relevant Facts

1. Before August 5, 2013 Tdap and Menactra Vaccines

R.A. was born in 2002. She had normal growth and development. She received regular 

vaccinations including DTaP in October 2002; December 2002; January 2003; November 2003; 

and August 2007. Ex. 1 at 1; Ex. 2 at 4, 5, 14, 44-46. Her family history included hypothyroidism and an autoimmune hematologic disorder. Pet. Ex. 11 at 63; Pet. Ex. 13 at 134, 151. 

She lives with her family in the Chicago, Illinois metropolitan area.

2. August 5, 2013 Tdap and Menactra Vaccines and Subsequent Primary Care and 

EMS Responses

On August 5, 2013, when R.A. was eleven years old, she had an annual well child 

appointment. R.A. had not received any medical care in the past year. The examination was 

normal. R.A. was administered a tuberculosis test as well as her sixth Tdap vaccination and first 

Menactra vaccination. She was advised to follow up in one year. Pet. Ex. 2 at 44-46.

On August 8, 2013 in the morning, R.A. developed a fever reaching 103 degrees 

Fahrenheit, for which she started acetaminophen and amoxicillin. See Pet. Ex. 4 at 49-51; Pet. 

Ex. 2 at 47-49; Pet. Ex. 20 at 1. 

On August 9, 2013 at 11:10 p.m., R.A. presented to urgent care solely for a chief 

complaint of fever. Pet. Ex. 4 at 49-50. She had no associated symptoms (denying, e.g., pain, 

sore throat, cough, earache, chest pain, cough, shortness of breath, and diarrhea). Id. at 50. The 

review of symptoms and physical exam were unremarkable. Id. at 50-51. The assessment was 

“Viral syndrome post-vaccine”. R.A. was discharged home with acetaminophen. Id. at 51. 

On August 12, 2013, the primary care provider recorded R.A.’s chief complaint as: “C/o 

fever x 4 days. Was in the office for 11y check and given vaccines – Tdap, Menactra 7 PPD. 

Per dad, has been very lethargic over the past few days.” Pet. Ex. 2 at 47. The history of present 

illness was: “Fever: 4 day temp 102-103 first 2 daus [sic, days] & then below 101. Meds: 

Motrin, last night & has not had fever since then. Chills: no. Temp. comes down with fever 

medication. No other associated symptoms. Child has been less active, appetite decreased. 

Received vaccines 1 week ago, fever started 3 days later...” Id. The review of systems and 

physical exam were unremarkable. The diagnostic code was “fever, unspecified.” Id. at 49. The

assessment was “? Viral illness”. Id. R.A. should continue alternating acetaminophen and 

amoxicillin, go to the emergency room if she got worse, and follow up with the primary care 

provider if her symptoms worsened or fever persisted for more than 3-4 days. Id.

That same day, August 12, 2013 at about 10:30 p.m., emergency medical services (EMS) 

were dispatched in response to an episode in which R.A. vomited in the bathroom and passed 

out. EMS recorded that R.A. had been having a fever of up to 103 degrees Fahrenheit, which 
6

had gone down to 99 degrees Fahrenheit that day. EMS did not record R.A.’s temperature. R.A. 

appeared alert and oriented; she did not want to go to the hospital. EMS said to call again if R.A. 

began acting abnormal. Pet. Ex. 5 at 1-2.

Three hours later, on August 13, 2013 at 1:39 a.m., EMS were called back to the house. 

The parents reported that R.A. was “sleeping in bed when she began shaking and acting 

inappropriately.” EMS observed R.A. to be “flushed, hot and dry... lying in bed... responsive 

to painful stimuli and mumbling incoherently... unable to respond to questioning... postictal.” 

Pet. Ex. 5 at 3-8.

3. August 13, 2013: Advocate Sherman Hospital

R.A. was brought via ambulance to the emergency department (ER) at Advocate 

Sherman Hospital (ASH) in Elgin, Illinois for “altered mental status and possible seizure”. Pet. 

Ex. 3 at 434. R.A. was agitated and unable to follow commands. Id. She was sedated for a 

lumbar puncture, from which cerebrospinal fluid (CSF) analysis yielded unremarkable glucose, 

protein, and white blood cell counts, with no oligoclonal bands. Id. at 459. R.A. was 

administered vancomycin, ceftriaxone, acyclovir, versed, and ketamine. It was then decided to 

transfer R.A. to another hospital with greater resources. Id. at 434-35.

4. August 13 - 29, 2013: Advocate Lutheran General Hospital

That same day, R.A. was transferred to Advocate Lutheran General Hospital (LGH) in 

Park Ridge, Illinois, where she was admitted to the Pediatric Intensive Care Unit (PICU). R.A. 

was agitated, did not know where she was, and was unable to recognize people. Pet. Ex. 11 at 7. 

R.A. was given another 2 mg of versed. One hour after admission, R.A. had a 4-minute tonicclonic seizure, which resolved with oxygen and 5 mg of pentobarbital. Shortly after the seizure, 

R.A. underwent an EEG which was: “abnormal... due to the presence of disorganization and 

slowing of the background activity... suggestive of diffuse cerebral dysfunction, pointing 

towards an encephalopathic pattern. Right hemispheric sharp activity does point to some 

potential epileptogenic activity.” Id. at 168-69. A pediatrician assessed “seizures and altered 

mental status, concern for encephalitis”; prescribed additional antibiotics, additional antivirals, 

and levetiracetam; and referred to neurology. Id. at 11.

That same day, pediatric neurologist Natalie Sgarlata, M.D. conducted an initial 

evaluation, recorded that the EEG “showed encephalopathy and small right frontal sparks”, and

ordered further work-up. Pet. Ex. 11 at 41-43. R.A. also underwent an MRI of the brain, which 

was unremarkable. Id. at 48. An infectious disease specialist, Elaine Rosenfeld, M.D., recorded: 

“concern for encephalitis”. Id. at 45-49. On a follow up visit, Dr. Rosenfeld recorded that 

R.A.’s initial presentation was not typical for NMDAR encephalitis, which usually involves 

“psychotic symptoms and/or abnormal movements.” Dr. Rosenfeld ordered a work up for both 

bacterial and viral etiologies. Id. at 86-88. This included CSF analysis for NMDAR antibodies, 

which were eventually found to be negative. Pet. Ex. 23 at 644-45. 
7

On August 13, 2013, at approximately 9:00 p.m., R.A. had another tonic-clonic seizure 

lasting approximately four minutes which prompted the start of lorazepam. Pet. Ex. 11 at 39. 

Approximately three hours later, R.A. went into continuous tonic-clonic seizures constituting

status epilepticus.

6

 She was given lorazepam, propofol, and phenobarbital to no avail. After

R.A. had been in status epilepticus for approximately ninety (90) minutes, she was started on 

intravenous pentobarbital to induce burst suppression.

7

 R.A. was started on continuous EEG 

monitoring. R.A. maintained a fever throughout this time and was placed on a cooling blanket. 

In the evening, the pentobarbital drip was briefly discontinued, but was restarted8following the 

reappearance of epileptic bursts and seizures. Pet. Ex. 11 at 13-19; Pet. Ex. 23 at 299-301.

A second EEG was “markedly abnormal... due to the presence of significant 

disorganization of the background activity with periods of lower amplitude activity interrupted 

by higher amplitude bursts of activity, reminiscent of a burst suppression pattern, albeit brief 

periods of suppression compared to the bursts. Some right hemispheric sharp activity and spike 

activity is noted pointing to some epileptiform potential. Ongoing electrographic seizures were 

not noted.” Pet. Ex. 11 at 166-67.

At this point, R.A.’s parents and the LGH treaters agreed to contact Lurie Children’s 

Hospital (Lurie) in Chicago, Illinois for at least a second opinion. Pet. Ex. 11 at 20-21. 

An August 14, 2013 blood serum sample showed anti-microsomal antibodies of 6,240 

unit/mL and anti-thyroglobulin antibodies of 3,423 unit/mL (significantly elevated above the 

reference range for both, of less than 60 unit/mL). Pet. Ex. 11 at 249. An August 16, 2013 blood 

serum sample showed glutamic acid decarboxylase (GAD) antibodies at 250.0 IU/mL 

(significantly elevated above the reference range of less than 5.0 IU/mL). Id. at 253. 

Also on August 16, 2013, a repeat lumbar puncture and CSF analysis showed elevated 

protein of 93 mg/dL and 15 cells. Pet. Ex. 23 at 358. A cohort of treating providers agreed that 

the CSF results were “suggestive of inflammatory process.” Pet. Ex. 11 at 28. They continued 

to consider autoimmune encephalitis, more specifically the Hashimoto’s and limbic forms. Id. 

The treaters recognized “reports of some [forms of autoimmune encephalitis?] responding to 

steroids and some needing more aggressive immunosuppression.” Id. “In view of the fact that 

[R.A.] is already in pentobarb[ital] coma, considering urgency of situation, will start 

plasmapheresis to remove existing antibodies while continuing steroid at the same time” despite: 

“Lack of very clear evidence for either form of therapy from literature is lacking due to small 

number of cases.” Id. At that time, CSF testing for NMDAR antibodies remained pending; CSF 

6 Status epilepticus is “any prolonged series of similar seizures without return to full consciousness between them; 

the two major types are convulsive s. epilepticus, which is life-threatening, and non-convulsive s. epilepticus, which 

is serious but not usually life-threatening.” Dorland’s at 1767.

7 Respondent provides: “In patients with persistent seizures, pentobarbital at sufficient doses produces an EEG that 

demonstrates varying periods of high voltage followed by inactivity. This ‘burst-suppression’ pattern is felt to be 

characteristic of an inactivated brain and thus is felt to be neuroprotective in ‘shutting down’ the brain by coma in a 

patient whose seizures cannot be stopped by conventional medications.” Resp. Rep’t (ECF No. 82) at n. 5.

8 As discussed below, R.A. remained on a pentobarbital drip for approximately two months until October 2014.
8

testing for “other neuronal antibodies” including GAD was ordered. Id.

On August 22, 2013, R.A. had completed five courses of plasmapheresis and was started 

on IVIG. Pet. Ex. 11 at 108-10. The working diagnosis continued to be “thyroid [antibody] 

associated encephalopathy or other autoimmune encephalopathy”. Id. at 123-32. Repeat EEGs 

remained abnormal. Id. at 150, 663.

On August 23, 2013, a repeat brain MRI showed: “1. Interval abnormal signal elicited 

from the hippocampal formations bilaterally as well as the amygdala... Findings are most 

suspicious for limbic encephalitis. Consider an autoimmune etiology as most likely cause.” Pet. 

Ex. 11 at 203-04. On August 26, 2013, R.A. was started on rituximab. Pet. Ex. 23 at 537. On 

August 27, 2013, the primary care provider’s office submitted a VAERS report concerning 

R.A.’s vaccinations and subsequent course. Pet. Ex. 2 at 3.

On August 29, 2013, R.A. was transferred with a working diagnosis of “anti-GAD related 

autoimmune encephalitis” from LGH to Lurie. Pet. Ex. 23 at 541-46.9 The LGH medical team 

concurred with the family’s request to seek a second evaluation at Lurie “in view of the rarity of 

the current diagnosis and lack of a definitive treatment for autoimmune encephalitis.” Id. at 524. 

When LGH received the results of “a few outstanding labs” (including the CSF analysis for 

GAD antibodies), those would be forwarded to Lurie. Id.

5. August 29, 2013 – March 17, 2014: Lurie Children’s Hospital and Rehabilitation 

Institute of Chicago

Upon R.A.’s admission to the Lurie PICU, Jena Krueger, M.D., a neurologist, conducted 

an initial consult and recorded:

Work up thus far has been remarkable for (+) anti-microsomal, anti-thyroglobulin 

and anti-GAD [antibody], in the setting of an evolving MRI. Exam is confounded 

by sedation, but remarkable for absent brainstem findings. Etiology of seizures 

unclear. The leading possibility is an inflammatory or autoimmune process. 

Possibly FIRES syndrome. An infectious or post-infectious process also possible, 

although initial CSF WBC unremarkable. A metabolic/genetic or structural 

etiology is also possible, although it would not account for the positive antibodies. 

Pet. Ex. 13 at 152-56. Another neurologist, Mark Wainwright, M.D., Ph.D., added:

Imp[ression]/ Rec[ommendation]: 1. Acute onset of RSE [refractory status 

epilepticus] in the setting of a febrile illness in a previously healthy child with 

exam now confounded by [pentobarbital]-induced coma. 2. Leading differential 

is an antibody-mediated epilepsy based on anti-thyroid and GAD antibodies. 

9 During the LGH hospitalization, R.A. was also evaluated and ruled out for a host of infectious diseases including 

Erlichiosis, Rocky Mountain Spotted fever, Lyme disease, influenza A/B, RSV, adenovirus, metapneumovirus, 

parainfluenza virus, mycoplasma, arboviruses, brucella, bartonella, fungal, measles, toxoplasmosis, CMV, malaria) 

were negative. Pet. Ex. 11 at 78, 79, 115, 236-241, 249-252, 262-280.
9

Alternatively, the antibodies may be a secondary response to a primary CNS

injury caused by either (a) CNS vasculitis or (b) underlying metabolic illness 

unmasked by febrile illness. FIRES is also in the differential but this is 

descriptive not mechanistic.

Pet. Ex. 13 at 157. R.A.’s case was also discussed with a third neurologist, John Millichap, 

M.D., who would later manage her outpatient care. Id. at 157. 

An infectious disease specialist, Leena Bhattacharya, M.D., recorded that R.A. had 

undergone “an extensive and comprehensive infectious disease workup at OSH including rare 

cases of encephalopathy.” She did not recommend “any further infectious disease work-up at 

this time.” Pet. Ex. 13 at 123-26. 

At Lurie, R.A. remained in a pentobarbital-induced coma and on a cooling blanket for 

fever control. She was given additional antivirals, antibiotics, seizure suppressants, steroids, 

IVIg10, and rituximab.11 She was started on a ketogenic diet on August 30, 2013, but did not 

achieve ketosis due to the continued steroids. On September 11, 2013, R.A. received what 

would be the first of six monthly treatments of cyclophosphamide.12 However, none of these 

treatments were associated with meaningful improvement; she continued to have seizure activity. 

See generally Pet. Ex. 13 at 10-18. 

On October 2, 2013, the Food and Drug Administration (FDA) granted Dr. Wainwright’s 

investigational new drug (IND) application for allopregnanolone, a neuro-steroid which, as 

stated in R.A.’s medical records, was “being studied in adult TBI [traumatic brain injury] related 

seizures, had anecdotal evidence of good response in RSA [refractory status epilepticus], and 

works on the non-synaptic GABA receptor.” Pet. Ex. 13 at 855. Dr. Wainwright was granted 

permission to use allopregnanolone for treatment of R.A.’s “super-refractory status epilepticus 

due to autoimmune limbic encephalitis” with the “primary objective” of “weaning off 

pentobarbital”. Id. at 836-38.

From October 4- 9, 2013, R.A. received the course of allopregnanolone. She was taken 

out of the pentobarbital-induced coma. She exhibited psychiatric features including memory 

loss, hallucinations, delusions, intermittent events of staring up, reaching hands to grab 

imaginary objects, and unprovoked laughter. These symptoms were recorded consistently until 

at least mid-November 2013. The symptoms prompted treatment with risperdal, consultation 

with psychiatry, and an EEG which did not find an ictal correlate. Pet. Ex. 13 at 21, 31-32, 33-

35, 58-59, 56-57, 347-49, 472, 681-82. R.A. continued to have intermittent seizures which were 

treated with Ativan as needed. On October 31, 2013, she was fitted with a laparoscopic 

gastrojejunostomy [GJ] tube. Id. at 15.

10 As discussed below, IVIg is an immune suppressant which targets B cells and antibodies.

11 As discussed below, rituximab is an immune suppressant which targets B cells and antibodies.

12 As discussed below, cyclophosphamide is an immune suppressant which targets T cells.
10

While R.A. was hospitalized at Lurie, a Mayo Clinic laboratory determined that her CSF 

sample was negative for GAD65 antibodies. The lab report provides: “The patient’s serum was 

previously evaluated in this laboratory and reported positive. Serum is often more sensitive for 

detecting GAD65 antibody as a marker for autoimmune neurological disorders.” Pet. Ex. 23 at 

644-45. This was subsequently noted by Lurie treaters. For example, on September 25, 2013,

Craig M. Smith, M.D. noted that the Mayo Clinic’s findings and maintained the assessment of 

“refractory status epilepticus and limbic encephalitis likely secondary to an autoimmune process 

given her anti-microsomal, anti-thyroglobulin, and anti-GAD antibodies.” Id. at 932-33.

Repeat serum testing confirmed elevated but stable anti-GAD65 antibodies in October 

2013, November 2013, and February 2014. Pet. Ex. 13 at 1287, 1253; Pet. Ex. 19 at 131. Dr. 

Wainwright recorded that he “[w]ould not expect these antibodies to become negative in the near 

future and it is possible that these antibodies will always remain positive.” Pet. Ex. 19 at 310. 

From November 2013 to March 2014, R.A. moved between Lurie and the Rehabilitation 

Institute of Chicago. Her diagnoses remained “autoimmune limbic encephalitis (due to antimicrosomal, anti-thyroglobulin and anti-GAD antibodies)” and “refractory seizures”. Pet. Ex. 13 

at 1699-1700, 1915. On March 17, 2014, R.A. was discharged home. Pet. Ex. 9 at 42-44. The 

plan was to continue on anti-seizure medications, ketogenic diet, and steroids. She would 

proceed with IVIg treatments already scheduled for the next few months, then switch to 

mycophenolate daily and rituximab infusions every six months. Id. at 44, 79.

6. March 17, 2014 – On: Subsequent History

Upon discharge, R.A. was able to ambulate short distances with mobility aids, although 

that was “less safe due to decreased safety awareness, limited awareness of surroundings and 

impulsivity, as well as unpredictable nature of [her] seizures.” She required assistance with 

many activities of daily living. She also had limitations with eating, attention to tasks, and 

thought organization. Pet. Ex. 9 at 42-55. In 2014 and 2015, R.A. had several additional inpatient stays at Lurie for repeated seizures and their consequences, including falls from her 

wheelchair. See Pet. Ex. 2 at 150-56; Pet. Ex. 13 at 2163-66; Pet. Ex. 2 at 192-96; Pet. Ex. 3 at 

590; Pet. Ex. 5 at 5; Pet. Ex. 4 at 24-27; Pet. Ex. 5 at 7; Pet. Ex. 3 at 624-26. She received 

regular PT, OT, and speech therapy. Pet. Ex. 2 at 65-68; see generally Pet. Ex. 14.

Dr. Millichap and the pediatric epilepsy team at Lurie continued to follow R.A. as an 

outpatient. They maintained an assessment of autoimmune limbic encephalopathy with 

secondary intractable epilepsy and focal seizures. See, e.g., Pet. Ex. 2 at 108, 132-39. R.A.

remained on multiple antiseizure medications and a ketogenic diet. Id. at 75-76. Mycophenolate 

was weaned in December 2014. Pet. Ex. 19 at 1337, 1682. The last dose of rituximab was in 

September 2015 (according to subsequent records), after which she continued to receive steroid 

and IVIg infusions approximately once per month.

7. March 31 – April 1, 2016: Mayo Clinic

The parents brought R.A. to the Mayo Clinic in Rochester, Minnesota for another 

opinion. See generally Pet. Ex. 40. 
11

A pediatric neurologist, Adam D. Wallace, M.D., reviewed the thousands of pages of 

outside records and conducted the initial consult. Id. at 19-28. Dr. Wallace’s impression was 

that R.A.’s “initial course was likely a manifestation of severe bilateral hippocampal 

inflammation which likely led to her super refractory status epilepticus requiring about two 

months of intermittent pentobarbital infusion”, which then resulted in a “subsequent epilepsy”. 

Id. at 27. Dr. Wallace noted the findings of elevated thyroid and GAD antibodies, which “both 

are increasingly thought of as non-specific markers of inflammation.” Id. Dr. Wallace’s 

impression was that R.A.’s initial course represented autoimmune limbic encephalitis, with less 

likely considerations including “an acute presentation of a genetic epilepsy leading to bilateral 

hippocampal damage” and a metabolic mitochondrial disease. Id. Dr. Wallace “quer[ied] 

whether at this point her autoimmune process might be ‘burnt out’ given the length of time since 

her initial inflammatory insult. This would be supported by the fact that her development/ 

neurocognitive status has steadily continued to improve over the years and her epilepsy, albeit 

difficult to manage, seems to be getting slightly better.” Id. If the autoimmune process was 

indeed “burnt out”, it might be appropriate to withdraw the continued, “relatively moderate 

treatment regimen for immunosuppression”. Id. Dr. Wallace also suggested “wean[ing] off the 

ketogenic diet eventually given the unknown efficacy of the treatment and [R.A.’s] recent 

increasing interest in ‘non-keto’ foods.” Id. at 28.

The Director of Pediatric Epilepsy at the Mayo Clinic, Elaine C. Wirrell, M.D.13, 

supervised Dr. Wallace and agreed with his notes. Pet. Ex. 40 at 30. Dr. Wirrell added that 

R.A.’s initial presentation “certainly [involved] some features suggestive of an autoimmune 

process” including a preceding febrile-type illness, confusion, elevated protein and cells in the 

CSF, negative cultures, and elevated autoantibodies. Id. However, R.A. had not shown “a 

marked response to multiple immunotherapy trials.” Id. at 31. Dr. Wirrell considered other 

etiologies including “febrile infection-related epilepsy syndrome [FIRES], potentially some 

genetic or metabolic etiologies; however, those I think would be less likely.” Id. 

A repeat MRI of the brain showed findings that were non-specific, but consistent with 

“limbic encephalitis related to autoimmune epilepsy and the resultant sequelae with mesial 

temporal sclerosis.” Pet. Ex. 40 at 84. Dr. Wallace recorded that the MRI showed “atrophy 

affecting mostly the bilateral hippocampi and the lack of any acute signs of inflammation.” Id. at 

53. Drs. Wallace and Wirrell then referred to a third neurologist, Jan-Mendelt Tillema, M.D., 

primarily to recommend an ongoing treatment regimen. Id. at 27-28, 30-31.

Dr. Tillema concurred with the impression of autoimmune encephalitis involving “a very 

aggressive and difficult to control prolonged status epilepticus” which was “aggressively and 

rather early on treated with IV steroids and subsequent immunosuppressive [sic?] in a very 

appropriate stepwise fashion”. Pet. Ex. 40 at 43. Dr. Tillema had an “extensive discussion” with 

R.A.’s parents about how the initial course resulted in structural injury to the hippocampi, 

causing cognitive impairment. Id. at 43-44. He did not predict a “significant return of function.” 

Id. at 44. Dr. Tillema did not have “high concern for ongoing autoimmunity at this time.” Id. at 

13 Dr. Wirrell has served as an expert for respondent in the Vaccine Program. See, e.g., Ellis v. Sec’y of Health & 

Human Servs., No. 13-336V, 2018 WL 4846547, *26 (Fed. Cl. Spec. Mstr. Sept. 6, 2018); Frette v. Sec’y of Health 

& Human Servs., No. 14-1105V, 2017 WL 7421013, *10 (Fed. Cl. Spec. Mstr. Dec. 29, 2017).
12

43. He noted that the Mayo Clinic brain MRI showed “significant volume loss” and the initial 

CSF results “showed no inflammation” and “protein and cell counts absolutely within the normal 

range.” Id. The CSF antibody testing was pending. Id. Dr. Tillema wrote: “The interesting part 

is that [R.A.] has had persistent GAD-65 antibodies at levels that are significant, without any 

clear worsening of the clinical status. I agree that evaluating the CSF GAD-65 levels seem 

reasonable and if negative there, I agree with the route that has been started of trying to continue 

to peal [sic] some of the immunosuppressive therapy off.” Id. That plan was specifically to

continue weaning off steroids and consider weaning IVIg over the next year. Id. at 44.

The Mayo Clinic CSF analysis was negative for GAD65 antibodies. Pet. Ex. 40 at 58. 

The “epilepsy, autoimmune interpretation” provides: “No informative autoantibodies were 

detected in this evaluation. However, a negative result does not exclude autoimmune epilepsy,

idiopathic or paraneoplastic. Sensitivity is enhanced by testing both serum and spinal fluid.” Id.

at 59. The Mayo Clinic also found serum GAD antibodies at 0.37 nmo/L (elevated above the 

reference range of less than or equal to 0.02 nmol/L). Id. at 58. Dr. Tillema reviewed those 

results and maintained the diagnoses of: “#1 Intractable epilepsy. #2 Auto-immune encephalitis, 

GAD-65 positive.” Id. at 47.

8. April 1, 2016 – On: Subsequent History

Following the Mayo Clinic consultation, Dr. Millichap at Lurie continued to manage 

R.A.’s care.

14

 Although the Mayo Clinic neurologists had suggested a genetics evaluation to 

assess for an underlying genetic condition, that was not ordered by Dr. Millichap. Pet. Ex. 40 at 

27, 30. Dr. Millichap did not expressly address genetic testing in his records. He did agree with

the Mayo Clinic’s recommendation of surgical insertion of a vagal nerve stimulator15, which was 

performed in June 2016. Pet. Ex. 43 at 147-53.

R.A. continued to have intermittent seizures. She continued on anti-seizure medications, 

ketogenic diet, and steroid and IVIg infusions. She still had tracheostomy and gastrostomy 

tubes. She received physical, occupational, speech, and vocational therapy. She had an 

individualized education plan (IEP) and attended school approximately three hours per day, three 

days per week accompanied by a home health nurse. See generally Pet. Exs. 35, 43.

At the entitlement hearing, Mr. Saurabh Agarwal testified that his daughter R.A. was a 

typically functioning and progressing eleven-year-old girl prior to receiving the Tdap and 

meningococcal vaccinations on August 5, 2013. R.A. has cognitive impairments particularly 

14 The Lurie Children’s records, at Pet. Ex. 43, do not address the Mayo Clinic’s suggestion of further genetics 

testing for assessment of an underlying/ comorbid genetic condition. Mr. Agarwal testified that Dr. Millichap 

reviewed the Mayo Clinic records, but Dr. Millichap “said it’s not really going to help and even the guys at Mayo, 

they are mentioning it, is really, I cannot really justify in [R.A.’s] case to have it so the insurance will pay.” Tr. 33-

34. Dr. Millichap said that if R.A.’s parents really wanted the genetic testing, they would have to pay out-of-pocket. 

Id. at 34. The parents did not see a need and did not pursue the genetic testing. Id.; see also id. at 44-45.

15 A vagal/ vagus nerve stimulator “deliver[s]... electrical current to the left vagus nerve in the neck by means of an 

electronic pulse generator implanted in the chest, just under the clavicle; used in the treatment of epilepsy”. 

Dorland’s at 1774.
13

with short-term memory. R.A. does not remember what she has for breakfast, what she does at 

school each day, or what happened in the previous chapters in a book. Tr. 34-35. Mr. Agarwal 

and R.A. used to spend significant time together studying mathematics; since the onset of her 

injury, over the course of four years, the only thing R.A. has been able to learn and retain is how 

to calculate the area of a triangle. Tr. 35. R.A. attends school, where she is enrolled in a special 

needs class. Tr. 39-40. R.A. has difficulty recognizing people and things. Tr. 35-36. She 

cannot navigate on her own: “Even if we tell [R.A.] there’s an exit sign up there, she wouldn’t be 

able to find the door. She won’t be able to find the handle.” Tr. 36. R.A. has a daily average of 

2.5 seizures, of “all different kinds” and originating from various parts of her brain. Tr. 37. The 

parents, particularly Mrs. Agarwal, spend significant time preparing a ketogenic diet and 

administering R.A.’s medications throughout the day. Tr. 37-38. They have also made 

modifications to improve the home’s accessibility for R.A. Tr. 38-39. Separate from the 

determination of entitlement in this case, the medical records and the testimony establish that the 

Agarwal family has been exceptionally devoted to R.A., who will very likely need continuing 

care for the rest of her life.

IV. Analysis

1. Nature of R.A.’s Injury

The parties first request that I resolve the nature of R.A.’s injury. Petitioners, via their 

expert Dr. Huq, contended that R.A. developed autoimmune limbic encephalitis (ALE)

associated with GAD antibodies. Respondent, via his expert Dr. Kruer, disputed the injury from

the outset. Beginning in his second report Dr. Kruer contended that a more likely explanation

was febrile illness-related refractory epilepsy syndrome (FIRES), which he contended was a 

fundamentally different condition.

In light of the experts’ disagreement, respondent contended that petitioners have the 

initial burden of establishing that R.A. developed the injury alleged before the inquiry can turn to 

causation. Resp. Pre-Hearing Brief at 14. Petitioners disagreed, contending that it is not clear 

that ALE associated with GAD antibodies and FIRES “differ significantly in their pathology.” 

Pet. Pre-Hearing Brief at 34. However, petitioners maintained that they have established that 

R.A. suffered from ALE associated with GAD antibodies.

A. Legal Standard

The Federal Circuit established the test for actual causation of an off-Table injury in 

Althen, 418 F.3d at 1278. In that case: “There was no dispute as to whether the petitioner, 

Margaret Althen, actually suffered from a central nervous system demyelinating disorder. 

Therefore, the Federal Circuit was not presented with a case in which the diagnosis itself was 

questioned, but one in which causation of the injury by the vaccine was the issue in dispute.” 

Doe v. Sec’y of Health & Human Servs., 94 Fed. Cl. 597, 611 (2010) (citing Althen, 418 F.3d at 

1282), aff’d, Lombardi v. Sec’y of Health & Human Servs., 656 F.3d 1343 (Fed. Cir. 2011). 
14

Special masters are generally not tasked with diagnosing injuries. In Lombardi, the 

Federal Circuit explained: “The function of a special master is not to ‘diagnose’ vaccine-related 

injuries, but instead to determine ‘based on the record evidence as a whole and the totality of the 

case, whether it has been shown by a preponderance of the evidence that a vaccine caused the 

petitioner’s injury.’” Lombardi, 656 F.3d at 1343, citing Andreu v. Sec’y of Health & Human 

Servs., 569 F.3d 1367, 1382 (Fed. Cir. 2009). 

However, the Federal Circuit has determined that in certain instances, “if there is a 

dispute as to the nature of a petitioner’s injury, the special master may opine on the nature of the 

petitioner’s injury.” Contreras v. Sec’y of Health & Human Servs., 844 F.3d 1363, 1368 (Fed. 

Cir. 2017), citing Hibbard v. Sec’y of Health & Human Servs., 698 F.3d 1355 (Fed. Cir. 2012); 

see also Locane v. Sec’y of Health & Human Servs., 686 F.3d 1375 (Fed. Cir. 2012); 

Broekelschen v. Sec’y of Health & Human Servs., 618 F.3d 1339 (Fed. Cir. 2010)).

In Hibbard, the Federal Circuit reasoned: “If a special master can determine that a 

petitioner did not suffer the injury that she claims was caused by the vaccine, there is no reason 

why the special master should be required to undertake and answer the separate (and frequently 

more difficult) question whether there is a medical theory, supported by ‘reputable medical or 

scientific explanation,’ by which a vaccine can cause the kind of injury that the petitioner claims 

to have suffered.” 698 F.3d at 1365. 

The case law also suggests that while the special master is not required to reach a specific 

diagnosis, the special master may appropriately evaluate at least the nature of petitioner’s injury 

and whether that aligns with petitioner’s theory. For example, in Broekelschen, the petitioner’s 

expert adopted certain treating physicians’ diagnosis of transverse myelitis, a condition that is 

inflammatory in nature. The petitioner’s expert then offered a causation opinion for that injury. 

He did not offer a theory that would support other treating physicians’ diagnosis of anterior 

spinal cord artery syndrome, which is vascular in nature. The Federal Circuit affirmed the 

special master’s approach of first determining the petitioner’s injury before evaluating the theory 

of causation. 618 F.3d 1339, 1346.

In contrast, in Contreras, the Court of Federal Claims held that the special master erred 

by first evaluating whether the petitioner had transverse myelitis, Guillain-Barré syndrome, or 

both. The parties had agreed that because both of those injuries are inflammatory/ demyelinating 

in nature and had similar causes, the special master did not have to reach an exact diagnosis in 

order to assess causation. 107 Fed. Cl. 280, 288 (2012), aff’d, 844 F.3d 1363.

Relevant to this inquiry, the Vaccine Act provides that a special master must consider the 

record as a whole including any medical diagnosis contained therein. § 300aa-13(b)(1). 

However, no diagnosis in the medical records is “binding on the special master.” Id. Rather, 

“[i]n evaluating the weight to be afforded to any such diagnosis... the special master... shall 

consider the entire record and the course of the injury, disability, illness, or condition until the 

date of the judgment of the special master.” Id. The special master shall also consider any 

expert opinions and additional medical scientific evidence in the record. Id. 
15

B. ALE associated with GAD Antibodies

Encephalitis refers to inflammation of the brain parenchyma with associated neurologic 

dysfunction and is usually defined on the basis of selected clinical, laboratory, and neuroimaging 

features. Pet. Ex. 29-KKK16 at 1. Limbic encephalitis (LE) involves injury to the medial 

temporal lobes, also termed the limbic areas, of the brain. Pet. Ex. 29 at 7; Tr. 58.

i. Prodrome

Dr. Huq opined that the limbic encephalitis prodrome, e.g., the first clinical sign(s) and 

symptom(s), can include “the subacute development in days to weeks of seizures from temporal 

lobe, short-term memory loss, and psychiatric symptoms... However, in some cases, a single 

clinical feature (e.g., seizures, amnesia, delirium, psychosis) can be prominent or isolated.” Pet. 

Ex. 29 at 7. 

Dr. Huq observed that on August 8, 2013, R.A. developed a fever reaching 104 degrees 

Fahrenheit. This fever persisted and was accompanied by fatigue, lethargy, and decreased 

appetite for the next few days. On August 12, 2013 in the late evening, R.A. continued to have a 

fever and she vomited and passed out, then began to experience seizures. Dr. Huq opined that 

R.A.’s prodrome included altered mental status, opining: “she was agitated, did not know where 

she was, and unable to recognize people.” Pet. Ex. 29 at 2; see also Tr. 53-54. This is consistent 

with the medical records of R.A.’s presentation to ASH on August 13, 2013, transfer to the LGH 

PICU that same day, and continued course up to her development of status epilepticus and 

pentobarbital-induced coma on August 14, 2013.17 Dr. Huq also noted that when R.A. was 

brought out of the pentobarbital-induced coma in October 2013, she displayed prominent 

psychiatric manifestations including memory loss, hallucinations, delusions, and unprovoked 

laughter. Pet. Ex. 29 at 4; see also Tr. 53-54, 106. Dr. Huq opined that this course is consistent 

with limbic encephalitis. Pet. Ex. 29 at 4, 7-8; Tr. 64-66.

Dr. Kruer did not raise the issue in his reports, but newly argued at the hearing that R.A. 

did not have the limbic encephalitis “typical prodrome” of “neuropsychiatric symptoms” such as 

“memory impairment, personality change, behavior abnormalities,” and “hallucinations”; as a 

treating physician, it gets [his] attention if none of that is seen”. Tr. 191, 243. Dr. Kruer did not 

16 Venkatesan et al., Autoimmune Encephalitis and its Relation to Infection, 15 Curr. Neurol. Neurosci. 3 (2015) 

[Pet. Ex. 29-KKK]. 

17 On cross-examination, respondent’s counsel asked wasn’t it true that Dr. Rosenfeld, an infectious disease 

specialist, noted that R.A.’s “presentation was not typical because this presentation was generally seen with 

psychotic symptoms and abnormal movements at the time of presentation’?” Tr. 106. Dr. Huq seemed to agree that 

R.A. did not have “psychiatric” or “psychotic” symptoms at the initial presentation. Tr. 106. On review, 

respondent’s counsel was referring to the following notation by Dr. Rosenfeld: “During summer infectious etiology 

of encephalitis include mosquito and tick born infections, viral infections. Also must consider year-round infectious 

such as HSV, non-infectious etiologies such as autoimmune disorders, such as NMDAR encephalitis, although 

patient’s presentation not typical; usually seen psychotic symptoms and/or abnormal movements at time of 

presentation.” Pet. Ex. 11 at 86 (emphasis added). Dr. Rosenfeld then ordered CSF analysis for NMDAR antibodies 

(which was negative). Id. at 87. This record does not shed much light on whether R.A.’s prodrome was consistent 

with limbic encephalitis.
16

cite any particular literature for this proposition, but he did submit some that are relevant. One 

article18 provides that patients with limbic encephalitis “have memory and cognitive disturbance, 

temporal lobe seizures, behavioral and personality changes, as well as sleep disturbance.” Resp. 

Ex. A-12 at 2. Another article19 provides that limbic encephalitis is “characterized by confusion, 

agitation, memory loss, and seizures”. Resp. Ex. C-9 at 3. A third article20 provides that limbic 

encephalitis “has a subacute onset characterized by deterioration of episodic memory and 

seizures usually occur later.” Resp. Ex. C-10 at 7. In contrast to Dr. Kruer’s characterization of 

the prodrome, this literature tends to describe a “subacute” onset of a wider spectrum of 

neuropsychiatric symptoms as well as seizures. And significantly, Dr. Huq presented and Dr. 

Kruer acknowledged an article by Malter et al.21 which describes a type of autoimmune limbic 

encephalitis associated with GAD antibodies, seen in younger female patients “whose condition 

was initially dominated by seizures, rather than cognitive features.” Tr. 148-49, 281-82, citing 

Pet. Ex. 29-OO at 472.

I have previously accepted that an initial presentation of limbic encephalitis dominated by 

seizures can make it particularly difficult to assess the patient for psychiatric symptoms. 

McCulloch, 2015 WL 3640610 at *13. But in this case, Dr. Huq observed that R.A.’s medical 

records reflect psychiatric symptoms described as “altered mental status.”

Upon review, I find that R.A.’s prodrome including both seizures and altered mental 

status is consistent with limbic encephalitis especially the subtype associated with GAD 

antibodies, which has been reported in a cohort of younger female patients whose condition is 

initially dominated by seizures rather than cognitive features (discussed further below).

ii. Further Classification of LE

Limbic encephalitis is most commonly caused by infections such as herpes simplex, 

which were ruled out in R.A.’s case. Pet. Ex. 29 at 3, 7; Tr. 58-59. Limbic encephalitis can also 

be autoimmune in nature (termed ALE). ALE is sometimes, but not always, associated with an 

underlying cancer (termed paraneoplastic), which was not discovered in the case of R.A. Pet. 

Ex. 29 at 6, 7. ALE is associated with CSF inflammation such as increased protein and cells, 

which were found in R.A.’s case. Id.

18 Suleiman & Dale, The Recognition and Treatment of Autoimmune Epilepsy in Children, 57 Dev. Med. Child 

Neurol. 431, 432 (2015) [Resp. Ex. A-12].

19 Nosadini et al., Immune Therapy in Autoimmune Encephalitis: A Systematic Review, 15 Expert Rev. Neurother. 

1391 (2015) [Resp. Ex. C-9].

20 Rivas-Coppola et al., Chronological Evolution of Magnetic Resonance Imaging Findings in Children with Febrile 

Infection-Related Epilepsy Syndrome, 55 Ped. Neurology 22 (2016) [Resp. Ex. C-10].

21 Malter et al., Antibodies to Glutamic Acid Decarboxylase Define a Form of Limbic Encephalitis, 67 Ann. Neurol. 

470 (2010) [Pet. Ex. 29OO]; cited in Zuliani, Central Nervous System Neuronal Surface Antibody Associated 

Syndromes: Review and Guidelines for Recognition, 83 J. Neurol. Neurosurg. Psychiatry 638 (2015) [Pet. Ex. 29-

PP].
17

Dr. Huq opined that even with a clinical diagnosis of ALE, it is important to further 

understand the etiology, to understand what treatment will be effective. He identified different 

subtypes. Pet. Ex. 29 at 7. First, ALE “may be associated with antibodies against cell surface 

proteins (e.g., N-methyl-d-aspartate [NMDA] receptor autoantibodies, anti-CASPR2, anti-LGI, 

GABABR, AMPAR, GlyR, mGluR1, mGluR4 antibodies)”. Id. Dr. Huq opined that the 

autoantibodies against cell surface proteins are likely to be pathogenic. Id. “Accordingly,

treatment designed to remove or deplete antibodies from the body such as plasmapheresis or 

Rituximab are often successful.” Id. In this case, R.A. underwent an extensive workup which 

was negative for antibodies against cell surface proteins.

Dr. Huq opined that R.A. developed a different subtype of ALE with the associated 

finding of antibodies against glutamic acid decarboxylase (GAD) 65, an enzyme that catalyzes 

the production of the major neurotransmitter GABA. Pet. Ex. 29 at 6.22. Dr. Huq opined in his 

first report (and throughout his subsequent reports and testimony) that GAD antibodies are not 

pathogenic. Id. at 5, 6, 9.

Dr. Huq acknowledged that GAD antibodies are found in individuals who are healthy, 

have type I diabetes, or have various autoimmune neurological conditions including stiff-person 

syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. Pet. Ex. 29 at 8-9. Dr. Huq 

opined that these antibodies might indicate a susceptibility for autoimmune disease or the 

presence of autoimmune disease at a “subclinical” level. Id. at 9-10; Tr. 96-99. The next step is 

to identify the specific autoimmune disease. Tr. 146. Dr. Huq acknowledged that he could not 

determine whether R.A. had some level of GAD antibodies prior to the onset of symptoms. Pet. 

Ex. 29 at 6; Tr. 112. However, she had no family history or indicators of diabetes. Pet. Ex. 29 at 

8; Tr. 113. Dr. Huq opined, based on R.A.’s lack of “any kind of pancreatic problem” and her 

abnormal brain MRIs, that her GAD antibodies were originating in the central nervous system. 

Tr. 61-62.

iii. Significance of Antibodies in CSF versus Serum

Dr. Kruer newly argued at the hearing that R.A. did not truly have ALE associated with 

GAD antibodies because those were only detected in serum, not in CSF. Tr. 214-15, 219-22, 

241-42. Dr. Kruer opined: “I think the current thinking indicates that where the [antibodies] are 

produced is actually exceedingly important. And so, the principle is that if an individual 

develops neurological autoimmunity and one is hypothesizing that the antibody or T-cell that’s 

involved is causing the symptoms,23 it stands to reason that the antibody or those cells should be 

found in the central nervous system.” Tr. 213-14. Dr. Kruer opined that “a lot of the earlier 

literature.... didn’t distinguish” where antibodies were found; “It’s only more recently that that 

concept has really started to gain more momentum.” Tr. 271. Dr. Kruer did not refer to any 

medical literature or any of R.A.’s medical records in support of this proposition. 

22 The medical records, medical literature, and experts refer variously to “GAD” and “GAD65”. This opinion will 

refer to “GAD”.

23 As discussed further below, not Dr. Huq, but only Dr. Kruer, argued that GAD antibodies play a pathogenic role 

in this type of ALE.
18

Dr. Huq did not directly respond to this argument raised late in the proceedings, but he 

did submit a recent review of autoimmune encephalopathies authored by several neurologists at 

the Mayo Clinic24 which provides: “some neural-specific autoantibodies are better detected in the 

CSF... while others are more easily detected in the serum”. Pet. Ex. 29-X at 255. This article 

does not address where GAD antibodies are better detected. However, that is addressed in 

R.A.’s medical records. In August 2013, a Mayo Clinic laboratory did not detect GAD 

antibodies in the CSF, only in the serum. The lab report provided: “Serum is more sensitive for 

GAD65 antibody as a marker for autoimmune neurologic disorders”. Pet. Ex. 23 at 644-45. 

This lab report was conveyed to R.A.’s treating providers at Lurie, who maintained the 

assessment of ALE associated with GAD antibodies. In spring 2016, R.A. was actually brought 

to the Mayo Clinic for a second opinion. Again, repeat testing did not detect GAD antibodies in 

the CSF, only in the serum. The lab report provided: “No informative autoantibodies were 

detected in this evaluation. However, a negative result does not exclude autoimmune epilepsy, 

idiopathic or paraneoplastic. Sensitivity is enhanced by testing both serum and spinal fluid.” 

Pet. Ex. 40 at 58. The Mayo Clinic neurologists maintained the impression of ALE associated 

with GAD antibodies, even after receiving this result. Id. at 30. Dr. Kruer did not address these 

lab reports and he did not submit any literature to rebut them. Accordingly, the available 

evidence on this issue does not preponderate in Dr. Kruer’s favor. The detection of GAD 

antibodies, even if only in the serum, is supportive of the diagnosis of ALE.

iv. Role of GAD Antibodies in ALE

Dr. Huq opined in his first report (and throughout his subsequent reports and testimony)

that antibodies directed against GAD are not the inciting pathogenic event for ALE. Pet. Ex. 29 

at 6, 9. He explained that GAD is located inside the membrane, within the cytoplasm of cells. 

Only tissue damage will release GAD, rendering it accessible to antibodies. Therefore, the 

antibodies against GAD are simply a biomarker. Id. at 6; Tr. 108. 

Dr. Kruer initially seemed to misunderstand or disregard Dr. Huq’s opinion, arguing in 

his first responsive report that GAD antibodies “have not been shown to produce disease if 

transferred to animals nor to directly affect neuronal or glial physiology.” Resp. Ex. A at 4. 

At the entitlement hearing, Dr. Kruer newly opined that GAD antibodies actually are 

pathogenic because they can “exert an effect on enzyme activity”, Tr. 222, introducing a 2005 

article by Raju et al.25 He also introduced a 2013 article by McEwan et al. 26 for the proposition 

that “antibodies can actually enter cells. And that, in fact, there’s an intracellular receptor, a 

protein whose specific job it is to recognize antibodies within cells.” Tr. 223. Dr. Kruer further 

opined that the focus of the article, TRIM21 “is the specific protein within antibodies that get 

24 Flanagan et al., Autoimmune Dementia and Encephalopathy, 133 Handb. Clin. Neurol. 247 (2016) [Pet. Ex. 29-

X].

25 Raju et al., Analysis of GAD65 Autoantibodies in Stiff-Person Syndrome Patients, 175 J. Immunol. 7755 (2005) 

[Resp. Ex. D-2].

26 McEwan et al., Intracellular Antibody-Bound Pathogens Stimulate Immune Signaling via Fc-Receptor TRIM21, 

14 Nat. Immunol. 327 (2013) [Resp. Ex. D-3].
19

into cells. So, the presence of a protein whose job it is to recognize antibodies within a cell is 

very strong support for that concept.” Tr. 224-25. Dr. Kruer testified that this represented a shift 

from the earlier thinking in immunology that antibodies are “active in the humoral but not in the 

intracellular environment.” Tr. 225. I have since reviewed the article, which describes: 

“Antibodies can be carried into cells when attached to infecting virus particles. Once inside the 

cell, antibody-coated viruses are bound by the cytosolic antibody receptor TRIM21...” Resp. Ex. 

D-3 at 1 (emphasis added). The article goes on to describe how once the antibody is inside the 

cell, TRIM21 activates immune signaling. This article does not establish that antibodies which

are not attached to infecting virus particles can enter cells. Additionally, this article is not about 

antibodies specific to GAD. 

Dr. Huq was permitted to submit a supplemental report responding to this and other 

points newly raised by Dr. Kruer at the hearing. Dr. Huq cited to his earlier filing of a 2015 

article by Gresa-Arribas et al.27 who write that “the pathogenic significance of GAD-65 

antibodies is controversial... but several lines of evidence suggest otherwise. First, GAD65-abpositive neurological syndromes do not respond well to immunotherapy compared to those 

associated with antibodies against neuronal surface antigens; second, there is no correlation 

between antibody titres and disease severity; and third, there are no convincing animal models of 

the neurological disorders.” Pet. Ex. 29-AA at 2. “An important step towards proof of 

pathogenicity would be the demonstration that GAD-ab bind to live neurons, and after 

internalization reach the intracellular GAD isoforms.” Id. In other words: “If we postulate that 

GAD65 antibodies are pathogenic, they should reach the antigen, which is intracellular, and for 

this the antibodies need to be internalized.” Id. at 9. Gresa-Arribas et al. tested this theory in 

controlled lab experiments. Id. They observed that GAD antibodies were able to react with GAD 

in neuronal cells if the membrane was first “permeabilized”. Id. However, GAD antibodies 

were not able to reach GAD in intact neuronal cells. Id. at 12.28 

Upon review, the available evidence does not establish that GAD antibodies are 

pathogenic in causing this subtype of ALE.

v. Pathogenesis of ALE associated with GAD Antibodies

Dr. Huq opined that for ALE associated with GAD antibodies, the more likely pathogenic 

mechanism is T-cell cytotoxicity, based on postmortem observations of abundant T cell 

infiltrates in the brain parenchyma in close apposition to neurons. The working understanding is 

that cytotoxic T cells (also termed CD8+ T cells) attack the limbic area of the brain, which 

releases GAD. That generates antibodies specific to GAD, which are a biomarker of the T-cell 

27 Gresa-Arribas et al., Antibodies to Inhibitory Synaptic Proteins in Neurological Syndromes Associated with 

Glutamic Acid Decarboxylase Immunity, 10 PLoS One, e01212364 (2015) [Pet. Ex. 29-AA].

28 See also Hackert et al., Anti-GAD65 Containing Cerebrospinal Fluid Does Not Alter GABA-ergic Transmission, 

10 Front. Cell Neurosci. 130 (2016) [Pet. Ex. 45-E]; Stemmler et al., Serum from a Patient with GAD65 AntibodyAssociated Limbic Encephalitis Did Not Alter GABA-ergic Neurotransmission in Cultured Hippocampal Networks, 

6 Front. Neurol. 189 (2015) [Pet. Ex. 45-I].
20

mediated autoimmune process. Pet. Ex. 29 at 6, 9-1029; see also Pet. Ex. 31 at 3-4; Pet. Ex. 45 at 

3-4; Tr. 59-62, 68-69, 107-08. 

Dr. Kruer did not rebut this explanation. He actually provided a reference30 which 

supports Dr. Huq’s theory, stating: “Cumulatively, there is no evidence for the pathogenicity of 

GAD65-specific antibodies. Instead, although also not formally proven yet, T cells might also 

play an important role in the pathogenesis of the disease. It is striking that transgenic mice with 

monoclonal T GAD65-specific CD4+ T cells develop a lethal encephalomyelitis-like disease and 

that T-cell infiltrates dominated by CD8+ T lymphocytes were also seen in the temporal lobes of 

3 patients with GAD antibody-positive limbic encephalitis, in the absence of immunoglobulin 

and complement deposition.” Resp. Ex. A-2 at 1. Accordingly, the medical community’s 

current understanding seems to be that a T-cell mediated process causes this type of ALE with 

the subsequent biomarker of GAD antibodies.

vi. Treatment of ALE associated with GAD Antibodies

Dr. Kruer opined that R.A.’s course of status epilepticus (beginning on August 14, 2013) 

which was resistant to anti-seizure medications, steroids, and immunosuppressant treatments 

(including the start of rituximab on August 26, 2013 and cyclophosphamide on September 11, 

2013), necessitating maintenance of a pentobarbital induced coma, was not consistent with ALE. 

Resp. Ex. A at 2, 5; Resp. Ex. C at 3. Dr. Kruer opined that early aggressive immunesuppressant therapy is associated with better outcomes. Resp. Ex. A at 5.31 On crossexamination, Dr. Kruer acknowledged that his cited literature did not address this type of ALE 

associated with GAD antibodies. Tr. 265-70. Dr. Kruer also acknowledged several articles 

submitted by Dr. Huq which provide that ALE with GAD antibodies is resistant to steroids and 

many immunosuppressants. Tr. 271-73.32 Dr. Kruer emphasized that one such article, by 

Zuliani et al., provided that patients with ALE associated with GAD antibodies “do not usually 

respond well to immunotherapies but were not treated aggressively at onset.” Tr. 273, discussing 

Pet. Ex. 29-PPP (Dr. Kruer’s emphasis added). Dr. Kruer opined that aggressive immunotherapy 

administered “early enough, before irreversible injury has occurred” would be beneficial even 

for ALE with GAD antibodies. Tr. 195.

29 Citing Zuliani [Pet. Ex. 29-PP]; Costa et al., T-Cell Reactivity to Glutamic Acid Decarboxylase in Stiff-Man 

Syndrome and Cerebellar Ataxia Associated with Polyendocrine Autoimmunity, 129 Clin. Exp. Immunol. 471 

(2002) [Pet. Ex. 29-LL]; Knight et al., A Distinct Immunogenic Region of Glutamic Acid Decarboxylase 65 is 

Naturally Processed and Presented by Human Islet Cells to Cytotoxic CD8 T Cells, 179 Clin. Exp. Immunol. 100 

(2015) [Pet. Ex. 29-II].

30 Bradl and Lassman, Excerpt Re: GAD65 Antibody-Associated Neurologic Syndromes, in Autoimmune Neurology, 

Handbooks of Clinical Neurology Vol. 133 (Pittock and Vincent, eds. 2013) [Resp. Ex. A-2].

31 Citing Suleiman & Dale (2015) [Resp. Ex. A-12] and Nosadini et al. (2015) [Resp. Ex. C-9].

32 Citing Malter et al. (2010) [Pet. Ex. 29-OO]; Bien & Schaffer, Autoantibodies and Epilepsy, 52 Epilepsia 18 

(2011) [Pet. Ex. 29-B]; Zuliani et al. (2012) [Pet. Ex. 29-PPP].
21

In contrast, Dr. Huq explained that because this type of ALE is T-cell mediated, immunesuppressants designed to remove B cells and antibodies are unlikely to be helpful. Pet. Ex. 29 at 

7; Pet. Ex. 31 at 4. The recent review of autoimmune encephalopathies filed by Dr. Huq 

provides:

The prognosis is variable and dependent on the underlying antibody, the presence 

of a diagnosis, and treatment delay (which worsens prognosis). In general, 

patients with autoantibodies to cell surface antigens (paraneoplastic or otherwise) 

tend to have a better prognosis while patients with autoantibodies to intracellular 

antigens have a worse prognosis...

Corticosteroids are often tried as the initial treatment in paraneoplastic and other 

ADE [autoimmune dementias and encephalopathies], but the type of autoantibody 

helps guide other treatments. In patients with autoantibodies to cell surface 

receptors (NMDAR, LGI, or CASPRA2 antibodies), we tend to focus on 

antibody-depleting or modifying therapy and targeting of B cells (plasma 

exchange/ intravenous immunoglobulin (IVIg), rituximab) while in those with 

antibodies to intracellular antigens (e.g., ANNA-1) we focus on treatments 

targeting predominantly T cells (e.g., cyclophosphamide)...

As we learn more about the pathogenesis and immune mechanisms involved in 

ADE [autoimmune dementias and encephalopathies], we suspect more targeted 

therapies will become available... As each neural autoantibody-mediated disorder 

may have a different pathogenesis, we suspect we will see more focused therapies 

targeted at the specific autoantibody resulting in benefits for patients.

Pet. Ex. 29-X at 250, 262, 265. 

Dr. Huq also submitted a 2010 study by Malter et al. arising from the Department of 

Epileptology at the University of Bonn, Germany, which involved fifty-three (53) subjects with 

limbic signs and symptoms (median latency of 12 months, range 0 – 12 months), brain MRI 

revealing medio-temporal encephalitis, and unclear etiology. Pet. Ex. 29-OO at 470-71, 73. 

Nine subjects were found to have antibodies against GAD, while ten other subjects were found to 

have antibodies against voltage-gated potassium channel (VGKC) proteins. Id. at 473. Malter et 

al. compared clinical outcomes in these two “largest defined LE subgroups”. Id. The patients 

received standard immunotherapies (e.g., steroids, IVIG, plasmapheresis, cyclophosphamide) as 

well as anti-seizure drugs. Id. On follow-up, compared to the patients with VGKC antibodies, 

the patients with GAD antibodies never became seizure-free, were taking more anti-seizure 

drugs, and had worse memory outcomes. Id. Malter et al. recognized that their patients were 

later in the disease course and recommended undertaking “trials of more aggressive 

immunotherapy in patients diagnosed promptly” with this type of ALE. Id. at 475.33 Dr. Huq 

33 See also Bien & Scheffer [Pet. Ex. 29-B] at 21 (citing Malter et al. for the proposition that in ALE associated with 

anti-GAD antibodies, “seizures are generally resistant to anticonvulsants in [sic? and?] immunotherapy treatment 

resulting in a chronic disorder dominated by temporal lobe epilepsy”); Zuliani et al. [Pet. Ex. 29-PPP] at 3 (citing 

Malter et al. for the sentence: “GAD-Abs have been identified in younger females with a form of LE presenting 

mainly with temporal lobe epilepsy and MRI evidence of temporal lobe inflammation; these patients did not usually 
22

testified that R.A. was clinically similar to these patients. Tr. 65-66.

Dr. Huq opined that new approaches to treatment continue to be developed. Pet. Ex. 31 

at 4; Tr. 125-26. He submitted a 2015 case report by Widman et al.,34 also based at the 

University of Bonn Department of Epileptology, of a male patient with epilepsy since the age of 

18 and displaying clinical signs of ALE and high titers of GAD antibodies in serum and CSF. 

Pet. Ex. 31-YY at 1. The patient did not respond to IV steroids. Id. Widman et al. noted that in 

previous patients with limbic encephalitis associated with GAD antibodies, immunosuppressive 

therapy was not effective and when surgical intervention occurred, the temperomesial structures 

were found to contain cytotoxic T-lymphocytes. Id. at 3, 8. Accordingly, Widman et al. 

experimented involving “therapeutic Abs against the activated interleukin-2 receptor”, “aimed at 

reducing the amount of activated T-lymphocytes”. Id. The only such treatment available was 

Basilimixab, an intravenous drug approved in 1998 to prevent rejection in organ transplantation. 

Widman et al. obtained authorization for experimental use of Basilimixab to treat ALE with 

GAD antibodies. Id. In their patient, Basilimixab was associated with reduction to normal limits 

of both CD4+ and CD8+ T cells; the reduction below detectable levels of GAD antibodies; and a 

reduction in seizure frequency. Id. at 5-9. The patient then had a clinical relapse, which may 

have been caused by the formation of human anti-drug antibodies (HADAs). Id. at 9. 

Widman et al. proposed a pathogenic role for cytotoxic CD8+ T cells in causing this 

subtype of ALE associated with GAD antibodies, via two possible pathways:

Experimental studies have shown that an attack of cytotoxic T-lymphocytes 

against neurons could result in a perforin-dependent electrical silencing, which is 

not necessarily linked to neuronal cell death. Thus, a chronic epilepsy by nonlethal cytotoxic attacks against GAD65 expressing GABAergic interneurons is 

possible. An alternative explanation... could be that primarily there is an attack 

by cytotoxic T-lymphocytes against e.g., GAD65 expressing GABAergic interneurons... and second, partly denaturized GAD65 comes into contact with the 

humoral part of the immune system, resulting in the GAD65-Abs, also against 

linear epitopes of the enzyme, due to prior lysosomal denaturation. Therefore, a 

direct therapy against GAD65-ABs should fail, whereas an attenuated activation 

[sic? attack on?] cytotoxic T-lymphocytes should be helpful.

Id. at 8. Upon publishing their article in 2015, Widman et al. “anticipat[ed] the approval of a 

new homologous therapeutic AB... daclizumab hyp” which might be more effective and 

appropriate for long-term therapy. Id. at 10. They suggested a controlled study of daclizumab 

hyp for treatment of ALE with GAD antibodies. Id.

respond well to immunotherapies but were not treated aggressively at onset”).

34 Widman et al., Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basilimixab: A Case Study, 6 

Frontiers in Neurology 1, doi:10.3389/fneur.2015.00167 (2015) [Pet. Ex. 31-YY].
23

The above literature reflects that autoimmune encephalopathies are generally treated first 

with corticosteroids and that the specific understanding of the condition guides more specific 

treatment. In patients with pathogenic antibodies to cell surface receptors such as NMDAR (for 

which R.A. was tested, early in her course), the focus is on immune suppressants which target B 

cells and antibodies, including IVIg (which R.A. started on August 16, 2013) and rituximab 

(August 26, 2013). When a patient is detected to have antibodies against intracellular 

components such as GAD, the focus is on treatments targeting T cells such as cyclophosphamide 

(which R.A. started on September 11, 2013, nearly one month into status epilepticus). The 

literature reflects that ALE associated with GAD antibodies involves persistent seizure activity, 

resistance to treatment, and worse memory. The literature suggests that earlier detection and 

initiation of treatment focused on the T cell pathogenesis, possibly including new treatments, can 

be associated with better outcomes. 

Dr. Huq opined: “It is logical to assume that [R.A.’s] initial super-refractory status 

epilepsy [sic? epilepticus?] led to significant brain damage which contributed to the pathogenesis 

of her subsequent intractable epilepsy via non-immune mechanisms... Once there is significant 

brain injury and neuronal loss, one can have continued seizures and intractability even without 

an active inflammatory process in [the] brain.” Pet. Ex. 31 at 5. Dr. Kruer agreed that it was 

“possible that R.A.’s disease course was biphasic; that is, there was an initial insult that caused 

irreparable brain damage, and that the brain injury R.A. sustained contributed to her persistent, 

refractory seizures.” Resp. Ex. C at 2. This is consistent with statements from physicians who 

subsequently examined R.A. For example, during the second opinion in 2016 at the Mayo 

Clinic, the neurologist Dr. Wallace, who agreed with the assessment of ALE, summarized that 

R.A. initially suffered “severe bilateral hippocampal inflammation which likely led to her super 

refractory status epilepticus requiring about two months of intermittent pentobarbital infusion”, 

resulting in a “subsequent epilepsy”. Dr. Wallace also suggested withdrawal of 

immunosuppressants because “at this point her autoimmune process might be ‘burned out’ given 

the length of time since her initial inflammatory insult.” Pet. Ex. 40 at 27-28. This is a logical 

explanation of how an inflammatory T-cell mediated process constituting status epilepticus, 

which persisted for nearly a month before the first dose of a drug targeting T cells 

(cyclophosphamide), could result in a subsequent epilepsy.

vii. MRIs

Dr. Kruer argued that the progression of R.A.’s MRIs (on August 30, September 11, 

October 24, and December 17, 2013) were not consistent with ALE, even the subtype associated 

with GAD antibodies. Resp. Ex. A at 2 (citing MRI images filed as Resp. Tr. Ex. 1). Dr. Kruer 

opined that the findings of mesial temporal and hippocampal sclerosis were consistent with ALE, 

but the “significant cortical and cerebellar atrophy” was not. Tr. 240-41. In support for this 

proposition, he cited Malter et al.’s finding that: “On follow-up brain MRI, there was a general 

tendency to regression of encephalitic mediotemporal signal and volume increases” in LE with 

GAD antibodies. Pet. Ex. 29-OO at 474-75. In other words, “there is an improvement”, unlike 

what is seen in R.A.’s MRIs. Tr. 227-28. Dr. Huq opined that these findings are in fact nonspecific and can be seen after status epilepticus, prolonged febrile seizures, and ALE, and cites 

literature which bears this out. Pet. Ex. 45 at 4.35

35 Citing Fujisao et al., Hippocampal Damage and Atrophy Secondary to Status Epilepticus in a Patient with 
24

viii. Treating Physicians

Dr. Kruer acknowledged that the treaters at LGH, Lurie, and the Mayo Clinic consistently 

diagnosed R.A. with ALE associated with GAD antibodies. He opined that this was a valid 

“working diagnosis” that “had its value” at the beginning of her course. Tr. 211. “It gave rise to 

a specific treatment plan that was aggressive and gave [R.A.] the best chance, with what was 

known at the time, for the best possible long-term outcome.” Tr. 211. But Dr. Kruer said that 

ALE became “chart lore... basically it’s true because... someone wrote it somewhere... it’s 

difficult to get things out of the medical chart... it will still be carried forward.” Tr. 210. He 

also testified: “As a treating physician, many of us are most keen on overturning diagnoses that 

would change a treatment course and tend to be more complacent with ones that don’t.” Tr. 211-

12. Dr. Kruer testified that the ALE diagnosis “seemed to come over with [R.A.] from [LGH]” 

and was not overturned at Lurie. But then he agreed that the Lurie treaters “conduct[ed] an 

independent analysis of the clinical and radiological findings in [R.A.’s] case.” Tr. 260. 

C. FIRES

Dr. Kruer opined that in retrospect and with the benefit of reviewing all of R.A.’s medical 

records and relevant literature, he arrived at a more likely explanation: febrile illness-related 

epilepsy syndrome (FIRES). Resp. Ex. C at 3-6; Resp. Ex. D at 1-2; see generally Tr. 166-305.

Dr. Kruer opined that FIRES is a clinical entity that was first described in approximately 

2010, although some earlier reports referred to similar conditions. Tr. 169. A consensus of 

international experts across multiple fields including epilepsy, neuroimmunology, and neurocritical care have participated in “careful vetting” leading to its current definition. Dr. Kruer’s 

reports were accompanied by articles published from 2011 – 2017.36 At the entitlement hearing, 

Schizophrenia, 8 Front Neurol. Doi: 10.3389/fneur.2017.00024 (2017) [Pet. Ex. 45-B] at 4 (providing that “several 

neuroimaging studies have demonstrated acute swelling of the hippocampus after prolonged febrile seizures”); Ikeda 

et al., Isoflurane Use in the Treatment of Super-Refractory Status Epilepticus is Associated with Hippocampal 

Changes on MRI, 26 Neurocrit. Care 420 (2017) [Pet. 45-F] at 426 (concluding that signal change in the 

hippocampus may be either a marker of neurotoxicity or seizure-related damage, and that signal change outside the 

hippocampus is the result of refractory status epilepticus); Tanabe et al., Hippocampal Damage after Prolonged

Febrile Seizure: One Case in a Consecutive Prospective Series, 52 Epilepsia 837 (2011) [Pet. Ex. 45-J] (presenting 

similar findings); Haberlandt et al., Limbic Encephalitis in Children and Adolescents, 96 Arch. Dis. Child 186

(2011) [Pet. Ex. 45-D] (a study of 10 patients, including images of “a characteristic MRI course” from a female 

pediatric patient with limbic encephalitis and GAD antibodies); Kotsenas et al., MRI Findings in Autoimmune 

Voltage-Gated Potassium Channel Complex Encephalitis with Seizures: One Potential Etiology for Mesial 

Temporal Sclerosis, 35 AJNR Am. J. Neurorad. 84 (2014) [Pet. Ex. 45-H] (indicating that “radiologic progression is 

common” due to “persistent CNS inflammation, damage done secondarily by recurrent seizures, or both”).

36 Citing Kramer et al., Febrile Infection-Related Epilepsy Syndrome (FIRES): Pathogenesis, Treatment, and 

Outcome: A Multicenter Study on 77 Children, 52 Epilepsia 1956 (2011) [Resp. Ex. C-5]; Van Baalen et al., Febrile 

Infection-Related Epilepsy Syndrome Without Detectable Autoantibodies and Response to Immunotherapy: A Case 

Series and Discussion of Epileptogenesis in FIRES, 43 Neuropediatrics 209 (2012) [Resp. Ex. C-13]; Van Baalen et 

al. (2012) [Resp. Ex. C-14]; Howell et al., Long-Term Follow-Up of Febrile Infection-Related Epilepsy Syndrome, 

53 Epilepsia 101 (2012) [Resp. Ex. C-3]; Nabbout, FIRES and IHHE: Delineation of the Syndromes, 53 Epilepsia 

54 (2013) [Resp. Ex. C-8]; Caraballo et al., Febrile Infection-Related Epilepsy Syndrome: A Study of 12 Patients, 22 

Seizure 553 (2013) [Resp. Ex. C-2]; Singh et al., Cognitive Outcomes in Febrile Infection-Related Epilepsy 

Syndrome with the Ketogenic Diet, 134 Pediatrics e1431 (2014) [Resp. Ex. C-11]; Nosadini et al. (2015) [Resp. Ex. 
25

he introduced a 2018 article by Gaspard et al.37, who offer a “consensus definition of New-Onset 

Refractory Status Epilepticus (NORSE): a clinical presentation, not a specific diagnosis, in a 

patient without active epilepsy or other preexisting relevant neurological disorder, with new 

onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic 

cause. This includes patients with viral or autoimmune causes.” Resp. Ex. D-1 at 3 (emphasis 

added). Gaspard et al. then define FIRES as “a subcategory of NORSE that requires a prior 

febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory 

SE, with or without fever at onset of SE.” Id.

Dr. Kruer opined that ALE and FIRES have some superficial similarities, but key 

differences. First, FIRES has a typical prodrome of high fever, “leading physicians to initial[ly] 

suspect a viral illness, although often no source is found.” Resp. Ex. C at 3; see also Tr. 169. 

Dr. Kruer opined that second, FIRES has a consistent clinical course. Tr. 169. The 

patient quickly develops focal onset seizures constituting status epilepticus which persists for 

weeks to months, which eventually burns itself out, but putatively causes brain damage, because 

it is followed by a second phase of persistent seizures, as well as cognitive and behavioral 

sequelae. Resp. Ex. C at 3, 5; Tr. 176-77, 187-88. Dr. Kruer opined that is “precisely what was 

observed in R.A.’s case.” Resp. Ex. C at 5.

Dr. Kruer opined that FIRES is also characterized by a lack of response to 

immunotherapy. Resp. Ex. C at 4; Tr. 169. Gaspard et al. notes that there have been 

uncontrolled reports of approximately 50% of patients with FIRES showing a dramatic response 

to the ketogenic diet. Resp. Ex. D-1 at 4. The diet is associated with reduction of plasma levels 

of pro-inflammatory cytokines. Id. However, ketogenic diet is used as a treatment not only for 

FIRES, but for drug-resistant epilepsy more generally. Id. 38 In this case, R.A. was started on a 

ketogenic diet during her hospitalization at Lurie but this was not associated with a clear 

improvement. The second opinion at the Mayo Clinic included “consideration to wean off the 

ketogenic diet eventually given the unknown efficacy of the treatment”. Pet. Ex. 40 at 28. 

Dr. Kruer opined that “FIRES is thought to represent an inflammatory epilepsy 

fundamentally different from autoimmune encephalitis.” Resp. Ex. C. at 4; see also Tr. 174. As 

support for this proposition, he submitted a 2016 case report by Dr. Elaine Wirrell and 

C-9]; Suleiman & Dale (2015) [Resp. Ex. C-12];Appavu et al., Ketogenic Diet Treatment for Pediatric SuperRefractory Status Epilepticus, 41 Seizure 62 (2016) [Resp. Ex. C-1]; Kenney-Jung et al., Febrile Infection-Related 

Epilepsy Syndrome Treated with Anakinra, 80 Ann. Neurol. 939 (2016) [Resp. Ex. C-4]; Moynagh, The Interleukin1 Signalling Pathway in Astrocytes: A Key Contributor to Inflammation in the Brain, 3 J. Anat. 265 (2005) [Resp. 

Ex. C-7]; Rivas-Coppola et al. [Resp. Ex. C-10]; Mirás Veiga et al., Effectiveness of Electroconvulsive Therapy for 

Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome, 48 Neuropediatrics 45 (2017) [Resp. 

Ex. C-6].

37Gaspard et al., Critical Review and Invited Commentary - New-Onset Refractory Status Epilepticus (NORSE) and

Febrile Infection-Related Epilepsy Syndrome (FIRES): State of the Art and Perspectives, 59 Epilepsia 745 (2018) 

Resp. Ex. D-1]. 

38 See, e.g., Appavu et al. (2016) [Resp. Ex. C-1] (reporting on the efficacy of ketogenic diet for children with 

“super-refractory status epilepticus” attributed to various etiologies including autoimmune encephalitis).
26

colleagues at the Mayo Clinic39, describing a pediatric patient presenting with intractable 

seizures. Resp. Ex. C-4 at 939. The authors noted prior case reports “suggest[ing] that children 

with an autoimmune epileptic encephalopathy... can mimic FIRES.” Id. at 943. However, in 

their patient, both serum and CSF were negative for the antibodies associated with autoimmune 

encephalitis. Id. at 940. The patient was also resistant to immunosuppressants. Her condition 

was labelled as FIRES. It was observed that the medication Anakinra had been “approved for 

treating autoinflammatory diseases.” Id. at 940. Anakinra inhibits the biological actions of 

interleukin (IL)-1β, “a prototypical proinflammatory cytokine implicated in a variety of 

autoinflammatory disorders” demonstrated to have “ictogenic properties in various seizure 

models and contributes to the generation of febrile seizures in immature rodents.” Id. at 939. In 

the case report, Anakinra “successfully treat[ed] super RSE [refractory status epilepticus] in [the 

child with FIRES and maintain[ed] this seizure control over the subsequent 12 months.” Id. at 

939. Dr. Kruer opined that Anakinra would never be used to treat autoimmune encephalitis, Tr. 

174, but that is not stated in the article. Indeed, the significant takeaways from this article 

include that autoimmune epileptic encephalopathy and FIRES can have similar presentations,

and that it is important to work up a patient for the former before settling on the latter. Also of 

note, this case report came from the Mayo Clinic and one of the authors is Dr. Elaine Wirrell, 

Director of the Pediatric Epilepsy Clinic. The same year the case report was published, R.A. 

went to the Mayo Clinic for a second opinion and Dr. Wirrell recorded that FIRES was a “less 

likely” explanation than autoimmune encephalitis in her case. See Pet. Ex. 40 at 30.

Dr. Kruer allowed that the pathogenesis of FIRES “has not been completely elucidated”. 

Resp. Ex. D at 1; see also Tr. 291 (Dr. Kruer’s testimony that FIRES includes inflammation but 

it’s not yet clear “what’s chicken, what’s egg”). This is consistent with the literature. For 

example, an article by Van Baalen et al. provides that that “febrile infections trigger FIRES, but 

the mediator of epileptogenesis remains hypothetical” and suggested the following possible 

factors:

39 Kenney-Jung, Wirrell, et al. Febrile Infection-Related Epilepsy Syndrome Treated with Anakinra, 80 Ann. Neurol. 

939 (2016) [Resp. Ex. C-4].
27

Resp. Ex. C-14 at 215. In another article, Nabbout suggests “A common pathophysiology based 

on a vicious circle with inflammation inducing seizures evolving to status epilepticus and status 

enhancing and keeping active the inflammatory pathways”. Resp. Ex. C-8 at 56. The 2018 

review by Gaspard et al. provides: 

A unifying mechanism that could account for all the specific features of 

cryptogenic NORSE and FIRES is still lacking. It is, however, tempting to 

speculate that it might be caused by a fulminant inflammatory response in the 

CNS. An intrathecal overproduction of proinflammatory cytokines and 

chemokines has been described in children with FIRES and was not observed in 

the CSF of controls with other inflammatory and non-inflammatory neurological 

conditions. Several of these molecules have proconvulsant activity. This 

accumulation could be the product of the activation of T cells, perivascular cells, 

and glia and could take several days, perhaps explaining the latency between the 

febrile episode and the onset of SE. However, it is currently unclear whether 

intrathecal inflammation is the cause or the consequence of the prolonged episode 

of refractory SE (RSE), as controls with RSE of noninflammatory origin were not 

studied. Furthermore, whether this cytokine storm is sufficient to explain a longlasting severe episode of SE is also unclear, and additional mechanisms such as 

mitochondrial dysfunction or synaptic plasticity may occur. Individual 

predisposition may be determined by allelic variations in HLA subtypes or 

cytokine pathways, as in other postinfectious neurological disorders. Further 

studies to confirm these hypotheses are ongoing.

Resp. Ex. D-1 at 748.

Dr. Kruer opined that histopathology of FIRES brain tissue typically shows “gliosis but 

not signs of inflammation.” Tr. 171. However, this histopathology was not obtained in R.A.’s 

case. Dr. Kruer also cited an article by Rivas-Coppola et al.40 for the proposition that unlike 

ALE, FIRES has a unique pattern of “global brain atrophy” within a month and “significant brain 

atrophy and cerebellar atrophy” on follow up for up to two years. Dr. Kruer opined that R.A.’s 

MRIs showed this unique pattern for FIRES. Resp. Ex. C at 3-4; Tr. 225-41 (citing Resp. Ex. C10; Pet. Ex. 29-OO; Ct. Ex. 1). But as noted above, Dr. Huq opined, based on supporting 

literature, that these MRI findings can be non-specific and generally consistent with status 

epilepticus, prolonged febrile seizures, and ALE.

Dr. Kruer emphasized that R.A.’s treating physicians considered FIRES. Tr. 211-12. 

First at Lurie, the neurologist Dr. Krueger recorded: “The leading possibility is an inflammatory 

or autoimmune process. Possibly FIRES syndrome...” Pet. Ex. 13 at 156. However, this record 

was reviewed by the attending neurologist Dr. Wainwright, who added: “FIRES is in the 

differential but this is descriptive not mechanistic.” Id. at 157. Dr. Kruer agreed that the Lurie

treaters independently analyzed the clinical and radiologic findings and then recorded a diagnosis 

of autoimmune encephalitis. Tr. 260-61.

40 Rivas-Coppola et al., Chronological Evolution of Magnetic Resonance Imaging Findings in Children with Febrile 

Infection-Related Epilepsy Syndrome, 55 Ped. Neurology 22 (2016) [Resp. Ex. C-10].
28

Dr. Kruer said that FIRES was also mentioned when R.A. went to the Mayo Clinic for a 

second opinion. However, those records indicate that Dr. Elaine Wirrell thought FIRES was 

“less likely” than ALE associated with GAD antibodies, and the latter diagnosis was maintained. 

Pet. Ex. 40 at 30. On cross-examination, Dr. Kruer agreed that “none of [R.A.’s treating 

physicians concluded that she had FIRES” and that their final diagnosis was ALE associated 

with GAD antibodies. Tr. 260-265. 

Dr. Huq opined that saying that a patient has FIRES is equivalent to saying that the 

etiology is “unknown”, Pet. Ex. 31 at 1. In other words “the essence of FIRES is that you don’t 

have a diagnosis”. Tr. 66. Dr. Huq opined that FIRES probably encompasses a “heterogeneous” 

set of cases; as they are further worked up and studied, “at least some cases will turn out to be 

immune mediated or autoimmune in nature.” Pet. Ex. 31 at 1; see also Tr. 139-40. For example, 

Dr. Huq provided a 2017 article by Caputo et al.41 reporting on a case of suspected FIRES 

associated with antibodies against an unidentified cell surface antigen, which was identified as 

GABAAR. Pet. Ex. 31-G at 183-84. After these antibodies were identified, Caputo et al. 

changed the diagnosis to autoimmune encephalitis. Id. Following treatments to remove the 

putatively pathogenic cell surface autoantibodies, the patient achieved a significant recovery. Id.

Caputo et al. emphasized “a prompt recognition of the immune-mediated etiology and a proper 

treatment” in cases with FIRES-like onset. Id. at 185.

Dr. Huq has personally diagnosed and treated six or seven patients with FIRES or the 

older term, new-onset refractory status epilepticus (NORSE). Tr. 74, 103. Dr. Huq opined that 

his current approach is to do a “lot more testing” including a “complete antibody panel”. Tr. 73. 

“Previously, we didn’t have any option[s] and I retrospectively think that probably I 

misdiagnosed some cases as FIRES and if it now [sic?], probably I will be able to get a more 

specific diagnosis.” Tr. 73-74.

D. Conclusion

During R.A.’s extended course at several hospitals most significantly Lurie Children’s, 

where she was subsequently followed as an outpatient, and during a second opinion at the Mayo 

Clinic, she underwent a thorough workup for the nature of her condition including repeated 

EEGs, MRIs, serum and CSF analysis. She was seen by many sophisticated practitioners, 

primarily in the field of neurology. To be sure, several of the neurologists considered a genetic 

epilepsy, a metabolic disorder, or FIRES.

42

 However, the neurologists – at least seventeen (17) 

41 Caputo et al., Febrile Infection-Related Epilepsy Syndrome (FIRES) with Super-Refractory Status Epilepticus 

Revealing Autoimmune Encephalitis due to GABAAR Antibodies, 22 Eur. J. Paediatr. Neurol. 182 (2018) [Pet. Ex. 

31-G].

42 Pet. Ex. 13 at 156 (Lurie neurologist Dr. Krueger’s notation that “A metabolic/ genetic or structural 

etiology is also possible, although it would not account for the positive antibodies” and “Possible FIRES 

syndrome”); but see Pet. Ex. 13 at 157 (Lurie supervising neurologist Dr. Wainwright’s comment that 

“FIRES is also in the differential but this is descriptive not mechanistic”); Pet. Ex. 30 at 31 (Dr. Wirrell’s 

consideration of “FIRES, potentially some genetic or metabolic etiologies, however, those I think would be 

less likely”).
29

individuals, at three different medical institutions – were more certain and consistent in an 

assessment of ALE associated with GAD antibodies, as set forth in the lengthy footnote below.43

Dr. Huq concurred with the assessment of ALE associated with GAD antibodies. Dr. 

Huq also explained that a T cell-mediated process damages tissue, which releases GAD which is 

met with antibodies; those GAD antibodies are a later biomarker rather than the inciting 

pathogenic process. The T-cell pathogenesis of this condition explains the resistance to steroids 

as well as immunosuppressants designed to target B cells and antibodies. R.A. did receive a first 

dose of cyclophosphamide nearly a month into her course of status epilepticus, but it is not clear 

that treatment was administered soon enough to prevent “irreparable damage” as argued by Dr. 

Kruer, or whether that one dose was sufficient to inhibit the pathogenesis. The experts did agree 

that an initial insult could result in lasting cognitive deficits and resultant epilepsy, as endorsed 

by R.A.’s treating providers.

On the other side, Dr. Kruer argued that the repeated assessments of ALE represented 

“chart lore” which did not explain R.A.’s condition. However, Dr. Kruer did not recognize Dr. 

Huq’s opinion identifying a subtype associated with GAD antibodies; which are thought to be 

biomarkers of a T cell-mediated process. Dr. Kruer also raised several arguments for the first 

time at hearing, which did not bear out. For example, Dr. Kruer opined that R.A. did not have 

the expected prodrome of neuropsychiatric symptoms. The early medical records, identified in 

Dr. Huq’s first report, reflect that R.A. had altered mental status as well as seizures when she 

first presented to ASH, then LGH, then Lurie. R.A.’s presentation is consistent with what is 

described in the literature about ALE, especially the subtype associated with GAD antibodies. 

Furthermore, Dr. Kruer testified that serum findings are less specific than CSF findings, while 

the lab reports in this case, conducted at the Mayo Clinic, actually provide that testing of both is 

informative, and that serum is more sensitive for GAD65 antibody as a marker for autoimmune 

neurologic disorders. Additionally, Dr. Kruer testified that GAD antibodies are pathogenic 

because they can enter cells, but Dr. Huq submitted the article by Gresa-Arribas et al. who 

43 Pet. Ex. 23 at 259, 352, 378 (“working diagnosis is autoimmune encephalitis”); Pet. Ex. 13 at 1167 (“all together, 

this is most consistent with an autoimmune epilepsy”); Pet. Ex. 13 at 493, 838, 1123 (“super-refractory status 

epilepticus likely secondary to an autoimmune process given her anti-microsomal, anti-thyroglobulin, and anti-GAD 

antibodies”); Pet. Ex. 13 at 1093 (“most likely an autoimmune mediated refractory epileptic encephalopathy related 

to GAD and thyroid antibodies”); Pet. Ex. 13 at 973 (“presumed etiology autoimmune encephalitis”); Pet. Ex. 13 at 

101 (“super-refractory status epilepticus secondary to autoimmune limbic encephalitis (anti-GAD and anti-thyroid 

antibody positive)”); Pet. Ex. 13 at 1933 (“autoimmune limbic encephalitis and refractory epilepsy as a result of her 

presentation with refractory status epilepticus”); Pet. Ex. 13 at 2032 (“autoimmune limbic encephalitis”); Pet. Ex. 13 

at 2072 (“autoimmune encephalitis ([secondary to] positive GAD, microsomal and thyroglobulin antibodies) as well 

as refractory epilepsy and trach/G-tube dependence”); Pet. Ex. 19 at 310 (“refractory status epilepticus from 

autoimmune limbic encephalitis (positive GAD, microsomal, and thyroglobulin antibodies)”); Pet. Ex. 19 at 1376 

(“epilepsy due to autoimmune limbic encephalitis (+anti-microsomal, anti-thyroglobulin, and anti-GAD antibodies), 

with super-refractory status epilepticus”); Pet. Ex. 19 at 1458 (“intractable epilepsy with focal seizures secondary to 

autoimmune limbic encephalitis (anti-GAD and anti-thyroid antibody positive)”); Pet. Ex. 40 at 27 (“medically 

refractory multifocal epilepsy likely secondary to a history of autoimmune limbic encephalitis”); Pet. Ex. 40 at 30 

(“There were certainly some features suggestive of an autoimmune process... DIAGNOSES[:] #1 Intractable 

epilepsy, possible autoimmune etiology); Pet. Ex. 40 at 43-44 (R.A. “has a history that indeed its with a refractory 

status epilepticus in the setting of autoimmune encephalitis... DIAGNOSES[:] #1 Intractable epilepsy[.] #2 Autoimmune encephalitis, GAD-65 positive”).
30

demonstrated that antibodies specific to GAD cannot enter cells unless the membrane is 

permeabilized.

Dr. Kruer argued that a more likely explanation for R.A.’s condition was FIRES. As I 

have noted in a previous case, FIRES describes a clinical subgroup of patients who develop fever 

followed shortly thereafter by refractory seizures or status epilepticus, for which no cause is 

identified and is associated with very poor outcomes. See McCulloch, 2015 WL 3640610 at *15-

16. In that case, respondent’s expert opined that if a particular antibody were identified, he 

would remove the diagnosis from the category of FIRES, the hallmark of which is an unknown 

cause. Id. at 18. In the present case, the literature submitted does not support a significant 

change in the understanding of FIRES. For example, the 2018 article by Gaspard et al. provides 

that FIRES is a clinical descriptor, not a specific diagnosis. And the 2016 case report by Wirrell 

et al. recommends a thorough workup including for autoimmune encephalitis types before 

settling on FIRES and trying experimental treatments such as Anakinra. However, in this case, 

R.A. was found to have significantly elevated GAD antibodies which the literature and her 

treating physicians identified as representing a subtype of ALE. While that discovery did not 

improve R.A.’s course, it did reveal an etiology. Therefore, she no longer fit the descriptor of 

FIRES.44 Finally, considering R.A.’s extensive evaluations by numerous neurologists at the 

well-regarded Lurie Children’s Hospital as well as a second opinion by several specialists at the 

Mayo Clinic, all concurring on an assessment of autoimmune limbic encephalitis, it seems a bit 

extreme to characterize this as simply “chart lore”.

Accordingly, petitioners have established that more likely than not, the appropriate 

explanation for R.A.’s injury is ALE associated with GAD antibodies. 

2. Althen Prong One

A. Legal Standard

Under Althen prong one, the causation theory must relate to the injury alleged. Thus, a 

petitioner must provide a “reputable” medical or scientific explanation that the vaccine received 

can cause the type of injury alleged. Pafford, 451 F.3d at 1355-56. The theory must be based on 

a “sound and reliable medical or scientific explanation.” Knudsen, 35 F.3d at 548. It must only 

be “legally probable, not medically or scientifically certain.” Id. at 549. However, the theory 

still must be based on a “sound and reliable medical or scientific explanation.” Id. at 548. The 

Federal Circuit explained in Althen that “while [that petitioner’s claim] involves the possible link 

between [tetanus toxoid] vaccination and central nervous system injury, a sequence hitherto 

unproven in medicine, 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 (emphasis added). 

44 Even were FIRES is accepted as a diagnosis unto itself, the pathogenesis is not clearly understood. FIRES is 

resistant to immunosuppressants designed to remove antibodies. Dr. Kruer’s literature suggests that FIRES can be 

mediated by cytokines, fever, inflammation, and T cells. Thus, Dr. Huq’s opinion in support of vaccine causation, 

presented below, may very well apply to FIRES as well. 
31

Drs. Huq and Kruer, and counsel in briefing this case, spent the bulk of their time 

disagreeing about R.A.’s diagnosis. This was a natural focus for Drs. Huq and Kruer, two wellqualified pediatric neurologists who are devoted to the prompt diagnosis and effective treatment 

of their patients. The theory of causation depended much more on immunology. Neither Dr. 

Huq nor Dr. Kruer are board-certified in immunology, but they agreed on many key concepts 

and submitted relevant literature. 

B. Autoimmunity

Dr. Huq opined that the normally functioning immune system recognizes, but does not 

respond to, the human body’s own tissue. Tr. 77. In rare cases, this self-tolerance breaks down, 

resulting in autoimmune disease. Id. Dr. Huq opined that certain individuals are genetically 

predisposed to autoimmunity. Environmental factors also contribute both to the development of 

an autoimmune disease and its severity. Dr. Huq opined that each individual is uniquely 

susceptible, based on particular genetic makeup, to particular environmental factors and to the 

development of particular autoimmune conditions. Pet. Ex. 29 at 645; Tr. 62-63, 132-36. 

Dr. Huq opined that various infections have been associated with, and thus considered to 

be triggers, for various autoimmune diseases including some types of encephalitis. Pet. Ex. 29 at 

11. Dr. Huq opined that similar to infections, vaccines may also act as environmental factors. 

Id. at 11. He submitted an article by Castiblanco et al. discussing the difficulty of studying this 

issue: “Autoimmunity is a concern for many vaccines, though [autoimmune disease] presentation 

among immunized individuals is rarely observed. However, because of relatively low baseline 

incidence of many autoimmune conditions, large post-marketing and adequately powered studies 

are required to evaluate any increased risk of [autoimmune diseases] after vaccination. In fact, in 

most of the clinical trials evaluating vaccines, a systematic screening for [autoimmune diseases] 

is not performed.” Pet. Ex. 29-GG at 55.

Dr. Huq opined that autoimmunity is a developing area of study and the mechanisms are 

not fully understood. In his first report, he opined: “There is no single mechanism explaining 

how a vaccine may induce autoimmunity with precision.” Pet. Ex. 29 at 11. He opined that 

vaccines can trigger autoimmunity by means of a variety of mechanisms including cytokine 

production and molecular mimicry. These mechanisms can work concurrently and in 

conjunction with one another.” Id. 

Dr. Kruer agreed that autoimmunity is multi-factorial. He also agreed that both genetic 

susceptibility and environmental factors (such as infection and in some cases, vaccinations) can 

contribute to forming autoimmunity. Tr. 283. 

45 Citing Castiblanco et al., Genetics and Vaccines in the Era of Personalized Medicine, 16 Curr. Genomics 47 

(2015) [Pet. Ex. 29-G]; Costenbader et al., Genes, Epigenetic Regulation, and Environmental Factors: Which is the 

Most Relevant in Developing Autoimmune Diseases?, 11 Autoimmune Rev. 604 (2012) [Pet. Ex. 29-M]; see also

Ceccarelli et al., Genetic Factors of Autoimmune Diseases, J. Immunol. Res. Doi: 3476023 (2016) [Pet. Ex. 29-H].
32

C. Inflammatory Response

Dr. Huq explained that vaccines, by design, cause a rather non-specific innate immune 

response involving activation of cytokines (specifically identifying IL-1β, TNF-α, and IL-6). 

Pet. Ex. 31 at 2. I asked whether this represents “the first step” in forming immunological 

memory of that antigen and a more specific adaptive response for when it is encountered again. 

Tr. 94. Dr. Huq agreed. Tr. 95. He opined that in most individuals, the innate response to 

vaccination might include no noticeable symptoms or mild symptoms such as fever, flu-like 

symptoms, and/ or a little bit of pain. Tr. 95. 

Dr. Huq opined that in rare cases, certain susceptible individuals that receive vaccinations 

can have a more significant innate response. Tr. 96. His theory seemed to include the innate 

response’s pro-inflammatory cytokines reaching the brain, as he agreed that IL-1β signals to the 

hypothalamus to generate fever, Tr. 91, and he opined that “significant fever” is observable 

evidence of innate immune response and activation of pro-inflammatory cytokines in the brain. 

Tr. 89, 95-96, 129.46 He submitted two articles by Vezzani et al.47 which provide that when IL1β, TNF-α, and IL-6 are present in the brain, they affect synaptic transmission and neuronal 

excitability, and also cause neuronal cell loss and injury to the blood-brain barrier (BBB).

Dr. Kruer agreed that the normal immune response to vaccines involves the innate 

immune system and activation of pro-inflammatory cytokines. Tr. 199-200, 288. Dr. Kruer also 

agreed that proinflammatory cytokines can affect synaptic transmission and neuronal 

excitability. Tr. 288. He also agreed that brain inflammation contributes to seizure thresholds in 

susceptible brain regions. Tr. 288. Dr. Kruer agreed that “Tdap and Menactra could certainly 

cause an immune response. I think that it’s possible that in some cases that could contribute to

seizures, yes.” Tr. 168. Dr. Kruer agreed that inflammation is part of autoimmunity. Tr. 199. 

D. Immune Cell Cross-Reactivity

Dr. Huq also opined that autoimmunity can also develop due to structural or sequence 

similarity between a foreign antigen and a self-antigen, which is termed molecular mimicry. Pet. 

46 Dr. Huq also suggested that fever itself may be pathogenic, given the “direct effect of heat on physiological 

processes” such as the function of ion channels. Pet. Ex. 31 at 5, citing Schuchmann et al., Experimental Febrile 

Seizures are Precipitated by a Hyperthermia-Induced Respiratory Alkalosis, 12 Nat. Med. 817 (2006) [Pet. Ex. 31-

KK]; Thomas et al., Heat Opens Axon Initial Segment Sodium Channels: A Febrile Seizure Mechanism?, 66 Ann. 

Neurol. 219 (2009) [Pet. Ex. 31-QQ]. Fever may also “overlap” with the cytokines creating inflammation, to cause 

seizures. Pet. Ex. 31 at 5, citing Haspolat et al., Interleukin-1beta, Tumor Necrosis Factor-Alpha, and Nitrite Levels 

in Febrile Seizures, 17 J. Child Neurol. 749 (2002) [Pet. Ex. 31-S]; Kim et al., Analysis of Plasma Multiplex 

Cytokines and Increased Level of IL10 and IL1Ra in Febrile Seizures, 14 J. Neuroinflammation 200 (2017) [Pet. Ex. 

31-X]; Matsuo et al., Increased IL-1beta Production from dsRNA-Stimulated Leukocytes in Febrile Seizures, 35 

Pediatr. Neurol. 102 (2006) [Pet. Ex. 31-Z]; Sun et al., DPP4 Regulates the Inflammatory Response in a Rat Model 

of Febrile Seizures, 28 Biomed. Mater. Eng. S139 (2017) [Pet. Ex. 31-OO]; Vezzani (2013) [Pet. Ex. 31-SS]; 

Vezzani (2015) [Pet. Ex. 31-TT].

47 Citing Vezzani et al., The Role of Inflammation in Epileptogenesis, 69 Neuropharmacology 16 (2013) [Pet. Ex. 

31-SS]; Vezzani et al., Neuromodulatory Properties of Inflammatory Cytokines and Their Impact on Neuronal 

Excitability, 96 Neuropharmacology 70 (2015) [Pet. Ex. 31-TT].
33

Ex. 29 at 11.48 Dr. Huq opined that there were several opportunities for molecular mimicry 

relevant to this case. First, he opined that tetanus toxoid (present in the Tdap vaccine) has 

structural similarity to human IL-1α protein and IL-1β protein, and short peptide sequence

homology to human beta 2-glycoprotein-I and laminin proteins. Dr. Huq opined that these 

structural similarities favored the role of tetanus toxoid in autoimmune conditions (including 

those impacting the central nervous system), with molecular mimicry as the mechanism. Id. at 

1149; see also Tr. 79, 81, 127-29, 138-39. 

Dr. Huq also identified similarities between the Menactra vaccine and glycoproteins in 

neural tissue. Pet. Ex. 29 at 12-13. Dr. Huq explained that Menactra contains conjugates of 

groups A, C, W135 and Y meningococcal capsular polysaccharide. Research indicates that 

group C is cross-reactive with group B, which is not contained in the vaccine. Id. at 12.50 

Vaccination for group C is also associated with a decrease in the incidence of meningococcal 

group B. Id. at 1251, which Dr. Huq opined further supports cross-reactivity, see Tr. 81. Group 

B meningococcal capsular polysaccharide is almost identical to the polysaccharide found on the 

surface of brain tissues. Thus, meningococcal capsular polysaccharides, including those in the 

Menactra vaccine, can potentially act as a trigger or autoimmune stimulus in humans by inciting 

cross reactivity with brain tissue thus causing immunopathology. Specifically, the antibodies 

generated in response to the meningococcal capsular polysaccharides can cross-react with 

glycoproteins in neural and extra-neural tissue. Pet. Ex. 29 at 12.52 Dr. Huq opined that this 

48 Cusick, Libbey, and Fujinami, Molecular Mimicry as a Mechanism of Autoimmune Disease, 42 Clin. Rev. Allergy 

Immunol. 102 (2012) [Pet. Ex. 29-P].

49 Citing Blank et al., Antiphospholipid Syndrome Infectious Origin, 24 J. Clin. Immunol. 12 (2004) [Pet. Ex. 29-C]; 

Stojanovic et al., The Context of Tetanus Toxoid Application Influences the Outcome of Antigen-Specific and SelfDirected Humoral Immune Response, 53 Microbiol. Immunol. 89 (2009) [Pet. Ex. 29-HHH]; Stojanovic et al., Role 

of Molecular Mimicry and Polyclonal Cell Activation in the Induction of Pathogenic Beta2-Glycoprotein I-Directed 

Immune Response in Balb/c Mice Upon Hyperimmunization with Tetanus Toxoid, 56 Immunol. Res. 20 (2013) [Pet. 

Ex. 29-GGG]; Caronti et al., Serum Anti-Beta2-Glycoprotein I Antibodies from Patients with Antiphospholipid 

Antibody Syndrome Bind Central Nervous System Cells, 11 J. Autoimmun. 425 (1998) [Pet. Ex. 29-E]; Caronti et 

al., Anti-Beta2-Glycoprotein I Antibodies Bind to Central Nervous System, 156 J. Neurol. Sci. 211 (1998) [Pet. Ex. 

29-F].

50 Citing Robbins et al., Capsular Polysaccharide Vaccine for Group B Neisseria Meningitidis, Escherichia Coli K1, 

and Pastereurella Haemolytica A2, 108 Proc. Natl. Acad. Sci. U.S.A. 17871 (2011) [Pet. Ex. 29-X].

51 Citing Cohn et al., Changes in Neisseria Meningitidis Disease Epidemiology in the United States, 1998 – 2007: 

Implications for Prevention of Meningococcal Disease, 50 Clin. Infect. Disease 184 (2010) [Pet. Ex. 29-K].

52 Citing Finne, Occurrence of Unique Polysialosyl Carbohydrate Units in Glycoproteins of Developing Brain, 257 

J. Biol. Chem. 11966 (1982) [Pet. Ex. 29-T]; Finne et al., An IgG Monoclonal Antibody to Group B Meningococci 

Cross-Reacts with Developmentally Regulated Polysialic Acid Units of Glycoproteins in Neural and Extraneural 

Tissues, 138 J. Immunol. 4402 (1987) [Pet. Ex. 29-U]; Finne et al., Occurrence of Alpha 2-8 Linked Polysialosyl 

Units in a Neural Cell Adhesion Molecule, 112 Biochem. Biophys. Res. Commun. 482 (1983) [Pet. Ex. 29-V]; 

Finne et al., Antigenic Similarities Between Brain Components and Bacteria Causing Meningitis: Implications for 

Vaccine Development and Pathogenesis, 2 Lancet 355 (1983) [Pet. Ex. 29-W]; Saukkonen et al., Antibodies to the 

Capsular Polysaccharide of Neisseria Meningitidis Group B or E. Coli K1 Bind to the Brains of Infant Rats In Vitro 

but not In Vivo, 1 Microb. Pathol. 101 (1986) [Pet. Ex. 29-BBB]; Nedelec et al., Evidence for Autoimmune 

Antibodies Directed Against Embryonic Neural Cell Adhesion Molecules (N-CAM) in Patients with Group B 
34

represented another opportunity for the development of autoimmunity in predisposed individuals 

such as R.A. Id. at 13; see also Tr. 79-84, 128-29, 138-39.

The 2012 article by Cusick, Libbey, and Fujinami, which Dr. Huq filed to introduce the 

concept of molecular mimicry, actually details various ways that T cells can contribute to the 

development of autoimmune disease. Pet. Ex. 29-P. They explain that the etiology of 

autoimmune disease is not fully elucidated, but is likely based on a combination of hereditary 

and environmental factors. Id. at 102. A foreign antigen is met by an immune response 

including proinflammatory cytokines such as type I interferon (IFN), interleukin (IL)-1β, IL-12, 

IFN-ƴ, IL-17, and TNF-α, which facilitate inflammation. Id. This is critical for clearance of a 

virus or bacteria. Id. However, prolonged pro-inflammatory responses to infections have been 

associated with the initiation and exacerbation of autoimmune diseases. Id.

Cusick, Libbey, and Fujinami explain: “The immune system has a number of 

mechanisms that are able to detect foreign pathogens by utilizing the major histocompatibility 

complex (MHC). This locus encodes HLA genes and a variety of immune response (Ir) genes, 

thereby shaping the immune system that protects against pathogens.” Pet. Ex. 29-P at 103. They 

go on to state: “The HLA locus is extremely polymorphic leading to a heterogeneous population 

ensuring propagation of a species against novel pathogens. Unfortunately, this genetic 

heterogeneity adds to the complexity of identifying HLA genes implicated in autoimmune 

diseases.” Id. at 103. There are two main types of HLA antigens. Id. Class I (which are present 

on all cells) stimulate T cell receptors (TCRs) on the surface of CD8+ T cells, which leads to the 

killing of the specific cells. Id. Class II, for which TCRs are found on various cells of the 

immune system, can stimulate the production of B cells, antibodies, CD4+ helper T cells, and 

CD8+ cytotoxic T cells. Id. 

Cusick, Libbey, and Fujinami explain that the hallmark of autoimmunity is the 

dysregulation of the immune system, especially T and B cells recognizing self-antigens as 

foreign. Id. at 105. The ability of T cells to evade central (thymic selection) and peripheral 

(Tregs) mechanisms of tolerance is evidenced by the large number of T cell-mediated human 

autoimmune diseases. Id. The difference between other non-specific mechanisms that initiate 

autoimmunity and molecular mimicry is that microbial mimics specifically direct the immune 

response towards a tissue or organ. Id. The medical community previously thought that T cell 

recognition was highly specific and that cross-reactivity was a rare phenomenon. Id. However, 

more recent studies have demonstrated that a given MHC class II peptide binding groove can 

accept different (self or foreign) antigens which share the same amino acid sequence. Id. at 105-

06. This results in molecular mimicry, which remains a leading theory in the generation of 

autoimmunity. Id. at 106.

Cusick, Libbey, and Fujinami also describe that the medical community previously 

believed that T cell signaling was mediated by a single antigen receptor. Id. More recent 

evidence demonstrates that a single T cell is capable of expressing functional dual receptors, 

creating another opportunity for recognition of a foreign antigen to lead to activation against the 

self. What is more: “Normally, high avidity self-reactive T cells are thymically depleted, but it 

Meningitis, 29 J. Neuroimmunol. 49 (1990) [Pet. Ex. 29-TT]. 
35

has been hypothesized that the expression of a self-TCR on a T cell is lower when presented in 

the context of a second TCR, thereby providing a cover for high avidity self-TCRs from both

central and peripheral tolerance.” Id. Cusick, Libbey and Fujinami mention yet a third 

mechanism, which involves a T cell expressing chimeric TCRs generated from either a single Vα

combining with two different Vβs or a single Vβ combining with two different Vαs, resulting in 

a T cell with the potential of expressing two different chimeric TCRs specific for a self-antigen 

and a foreign antigen. Id. at 108. 

This article supports Dr. Huq’s theory that in rare cases involving susceptible individuals, 

an environmental stimulus such as vaccines can activate an innate immune response involving

fever and inflammation. This innate immune response can also activate the adaptive immune 

response by both CD4+ and CD8+ T cells which can complicate the inflammatory process and 

gave rise to cross-reactivity through molecular mimicry or degenerate T-cell binding with neural

tissue. Dr. Huq explained that this damage can result in seizures.

Dr. Kruer agreed that molecular mimicry is a well-accepted mechanism for the 

development of autoimmunity; that molecular mimicry is taught in medical school; it is 

discussed in peer-reviewed journals and textbooks; and it has been demonstrated in animal 

models. Tr. 283-84. He agreed that there is hexapeptide sequence homology between tetanus 

toxoid and beta 2 glycoprotein. Tr. 286. He agreed that tetanus toxoid induces anti-beta 2 

glycoprotein antibodies in mice. Tr. 287. 

Dr. Kruer’s main objection to the theory presented in this case was that it would not 

occur quickly enough to cause R.A.’s onset of fever four days after vaccination and seizures 

seven days after vaccination. This is better addressed below under Althen prong three.

E. Lasting Brain Damage

Dr. Huq opined that seizures constituting status epilepticus can result in permanent brain 

damage and a lower threshold for further seizures, e.g., epilepsy, even after the inciting immune 

response is “burned out”. Pet. Ex. 31 at 6; see also Tr. 86, 89-91. Dr. Kruer agreed with this 

proposition, opining: “It is possible that R.A.’s disease course was biphasic; that is, there was an 

initial insult that caused irreparable brain damage, and that the brain injury RA sustained 

contributed to her persistent, refractory seizures.” Resp. Ex. C at 2.

F. Conclusion

Dr. Huq described a “perfect storm”, in which an individual who is genetically 

predisposed to autoimmunity is confronted with an environmental stimulus such as vaccine(s)

which, via inflammation and T-cell cross-reactivity, can cause a severe autoimmune response 

such as occurred in R.A. He opined that the Tdap and Menactra vaccines can cause an immune 

response including both inflammation and T cell cross-reactivity with neural tissue, which can 

both contribute to seizures. Pet. Ex. 31 at 6. Dr. Kruer agreed with many key propositions 

including that certain individuals are genetically predisposed to autoimmunity; that 

autoimmunity also depends on environmental factors, including in some cases vaccines; that the 

Tdap and Menactra vaccines can cause an immune response involving pro-inflammatory 
36

cytokines, which in some cases can lead to seizures; and that there was evidence of molecular

mimicry between tetanus toxoid and self-antigens.

Respondent criticized Dr. Huq for proposing a “cafeteria of mechanisms” that was 

“purely speculative”. Resp. Post-Hearing Response at 11. While Dr. Huq’s opinion 

encompassed several aspects of the immune response, he emphasized that autoimmunity is 

multifactorial and continues to be studied. After reviewing the significant record in this case, I 

referenced a helpful and concise reference text by Lauren Sompayrac, Ph.D., which happens to 

succinctly articulate Dr. Huq’s opinion. Dr. Sompayrac introduces the concept of autoimmune 

disease. He then summarizes the two leading proposed mechanisms of molecular mimicry and 

inflammation, each of which seem unlikely to work independently as the sole cause of 

autoimmune disease:

So the scenario most immunologists favor for the initiation of autoimmune 

disease is this: A genetically susceptible individual is attacked by a microbe that 

activates T cells whose receptors just happen to cross-react with a self-antigen. 

Simultaneously, an inflammatory reaction takes place in the tissues where the 

self-antigen is expressed. This inflammation could be caused either by the 

mimicking microbe itself, or by another, unrelated infection or trauma. As a 

result of this inflammatory reaction, [antigen-presenting molecules] are activated 

that can re-stimulate self-reactive T-cells. In addition, cytokines generated by the 

inflammatory response can upregulate class I MHC expression on normal cells in 

the tissues, making these cells even better targets for destruction by self-reactive 

CTLs [killer T cells, another term for cytotoxic CD8+ T cells].

Sompayrac, How the Immune System Works (5th ed. 2016) at 123. This envisions a substantial 

causal role for environmental factors, such as the Tdap and Menactra vaccines in this case and 

fits the current understanding of the ALE subtype associated with GAD antibodies, which is 

understood to be mediated by cytotoxic CD8+ T cells. Moreover, Drs. Huq and Kruer agreed 

that an initial insult can cause irreparable brain damage leading to persistent, refractory seizures, 

even when the initial process is burned out.

Accordingly, I find that petitioners have established a reputable scientific explanation of 

how the Tdap and Menactra vaccines can cause ALE associated with GAD antibodies, with 

resultant brain damage involving cognitive deficits and intractable epilepsy.

3. Althen Prong Two

A. Legal Standard 

Under Althen prong two, petitioner must prove “a logical sequence of cause and effect 

showing that the vaccination was the reason for [her] injury.” Althen, 418 F.3d at 1278. This 

prong is sometimes referred to as the “did it cause” test; i.e. in this particular case, did the 

vaccine(s) cause the alleged injury. Broekelschen, 618 F. 3d at 1345 (“Because causation is 

relative to the injury, a petitioner must provide a reputable medical or scientific explanation that 

pertains specifically to the petitioner’s case”). Temporal association alone is not evidence of 
37

causation. See Grant v. Sec’y of Health & Human Servs., 9556 F.2d 1144, 1148 (Fed. Cir. 

1992). This sequence of cause and effect is usually supported by facts derived from petitioner’s 

medical records. Althen, 418 F.3d at 1278; Andreu, 569 F.3d at 1375-77; Capizzano, 440 F.3d at 

1326; Grant, 956 F.2d at 1148. 

B. Discussion and Conclusion

Prior to the August 5, 2013 Tdap and Menactra vaccinations, R.A. was a healthy elevenyear-old girl with normal developmental milestones who had not sought any medical attention 

for any reason over the past year and who was doing very well in school. Pet. Ex. 2 at 44-46; see 

also Tr. 5-42. Dr. Kruer agreed. Tr. 297.

Dr. Huq opined that R.A. was predisposed to autoimmunity for several reasons. First, her 

family history includes hypothyroidism and an autoimmune hematologic disorder. Pet. Ex. 29 at 

8, 10, 13; Tr. 112-13. Second, after R.A.’s vaccinations and onset of fever and seizures, R.A. 

was found to have elevated antibodies directed against GAD, thyroid protein, and thyroid 

enzyme (termed anti-microsomal antibodies). As discussed above, Dr. Huq opined that the 

inflammatory and T-cell mediated process most likely caused neuronal tissue damage resulting 

in the generation of antibodies against GAD. He opined that the antibodies directed against 

thyroid protein and thyroid enzyme may have been present beforehand and further suggested a 

predisposition to autoimmunity. Pet. Ex. 29 at 10, 13; Pet. Ex. 31 at 6; Tr. 62, 113-14, 132.

Dr. Huq noted that predisposition to autoimmunity is genetic, but: “No genetic 

polymorphisms affecting autoimmunity have been investigated in [R.A.’s] case.” Pet. Ex. 29 at 

10. Of note, when R.A. presented for a second opinion in 2016, neurologists at the Mayo Clinic 

recommended genetic testing to possibly include either an epilepsy panel, microarray, or wholeexome sequencing to “assess for underlying/ comorbid genetic condition.” Pet. Ex. 40 at 27, 30. 

However, when R.A. returned home to Illinois, her neurology team at Lurie Children’s did not 

order or even discuss genetics testing in their records. 

Dr. Huq opined that genetic testing can reveal certain mutations that are clearly 

associated with neurological disorders, such as those in the sodium channel (e.g., SCN1A) 

associated with Dravet syndrome (which has never been suspected in R.A.’s case). Tr. 136. Dr. 

Huq opined that in R.A.’s case, genetic testing at best might “give us a clue what made [R.A.] 

susceptible to the vaccination[s]... I don’t think that it will give us a monogenic epilepsy gene.” 

Tr. 142. 

On the other hand, Dr. Kruer opined that if he were treating R.A., he would order genetic 

testing because she “did not seem to fit the clinical diagnosis of autoimmune encephalitis.” Tr. 

266. But as discussed above, I have concluded that the evidence supports that R.A. does fit the 

description of ALE associated with GAD antibodies. Dr. Kruer also opined that the intention 

behind genetic testing is to potentially learn something new. Tr. 204; see also id. at 266. Dr. 

Kruer stated: “I’ll be honest, most of the time when we do a whole-exome, if we find an answer, 

it’s closure. It’s predictive value. It’s anticipating the future... There’s only a small, you know, 

proportion of the time that it introduces a completely new treatment... and I can’t necessarily say 

before I run the test, who’s going to be what. I’m routinely surprised.” Tr. 205. He predicted 
38

the likelihood of finding “something new” to be about 10 to 20 percent. Tr. 204. In R.A.’s case, 

he could not contemplate a specific genetic diagnosis that would change either the prognosis or 

the treatment plan. Tr. 205, 266. The obvious corollary to Dr. Kruer’s estimate is that there was 

an 80 – 90% likelihood that genetic testing would not shed any additional light on R.A.’s case.

Based on the available evidence, I accept Dr. Huq’s opinion that R.A. was predisposed to 

autoimmunity based on her family history and the findings of elevated anti-microsomal and antithyroid antibodies. While genetic testing was suggested at the Mayo Clinic, neither that facility 

nor Dr. Kruer identified genetic factors that are known to be associated with R.A.’s condition, let 

alone whether those only predispose an individual as opposed to acting as the sole cause of the 

injury, as is held in the SCN1A/ Dravet syndrome cases.53 I disagree with respondent’s 

argument that the lack of genetic testing, for some unspecified trigger, prevents a finding of a 

logical sequence of cause and effect in this case. See Resp. Post-Hearing Response at 13. 

Dr. Huq observes that there was no other identified environmental trigger that could have 

caused R.A.’s condition. Pet. Ex. 29 at 1-15, 13-14; see also Pet. Ex. 31 at 6; Tr. 62, 92-94, 98;

Pet. Post-Hearing Brief at 65-66. R.A. was healthy upon receiving the Tdap and Menactra 

vaccinations on August 5, 2013. Pet. Ex. 2 at 44-46. Afterwards, she reported a chief complaint 

of fever with no other symptoms to urgent care. Pet. Ex. 5 at 49-51. She followed up with her 

primary care provider, who again recorded a chief complaint of fever with no other symptoms 

suggestive of a viral illness. The diagnostic code was “fever, unspecified.” Pet. Ex. 2 at 47-49. 

After R.A. suffered the onset of seizures, during her hospitalization first at LGH then at Lurie, 

she underwent an extensive workup. No other bacteria, virus, neoplasm, trauma, or other 

environmental trigger was identified. No metabolic or structural etiology was identified. Dr. 

Kruer did not dispute this fact or suggest that some specific environmental trigger was missed. 

Multiple treating physicians noted at least a temporal association between R.A.’s 

vaccines and her subsequent development of fever and seizures. See Pet. Post-Hearing Brief at 

63-65 (quoting from medical records from eleven different treating physicians). 

Dr. Huq also opined that R.A.’s development of fever was evidence of the innate immune 

response and activation of pro-inflammatory cytokines. Tr. 89. Specifically, the cytokine IL-1β

signals to the hypothalamus to generate fever. Tr. 91. Dr. Kruer agreed that the vaccines R.A. 

received on August 5, 2013 are designed to generate pro-inflammatory cytokines. Tr. 292. He 

also opined that cytokine testing “kits” are available from scientific supply companies, but those 

are not clinically available, certainly not in 2013. Tr. 203. 

As discussed above, Dr. Huq explained that the immune response to the vaccines led to 

status epilepticus which was considerably difficult to treat. He opined: “It is logical to assume 

that [R.A.’s] initial super-refractory status epilepsy [sic? epilepticus] led to significant brain 

damage which contributed to the pathogenesis of her subsequent intractable epilepsy via nonimmune mechanisms.” Pet. Ex. 31 at 4. Dr. Kruer agreed: “It is possible that R.A.’s disease 

53 See Oliver v. Sec’y of Health & Human Servs., 2017 WL 747846 (Fed. Cl. Spec. Mstr. Feb. 1, 2017) (collecting 

cases at footnote 3), review denied, 133 Fed. Cl. 341, affirmed, 900 F.3d 1357, en banc rehearing denied, 911 F.3d 

1381. 
39

course was biphasic; that is, there was an initial insult that caused irreparable brain damage, and 

that the brain injury RA sustained contributed to her persistent, refractory seizures.” Resp. Ex. C 

at 2. Accordingly, petitioners have established Althen prong two.

4. Althen Prong Three

A. Legal Standard 

Althen prong three requires establishing a “proximate temporal relationship” between the 

vaccination and the injury alleged. Althen at 1281. That term has equated to the phrase

“medically-acceptable temporal relationship.” Id. A petitioner must offer “preponderant proof 

that the onset of symptoms occurred within a timeframe which, given the medical understanding 

of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan v. Sec’y of 

Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for what is 

medically acceptable timeframe must align with the theory of how the relevant vaccine can cause 

an injury (Althen prong one). Id. at 1352. 

B. Discussion and Conclusion

It is undisputed that R.A. received the Tdap and Menactra vaccinations on August 5, 

2013. Pet. Ex. 1 at 1. Three days after vaccination, on August 8, 2013, she developed a fever. 

Four days after vaccination, on August 9, 2013, she presented to urgent care with a fever of 104 

degrees Fahrenheit. Pet. Ex. 4 at 49-51. More than seven days after vaccination, on August 13, 

2013, at approximately 1:30 a.m., R.A. had a generalized tonic-clonic seizure, prompting EMS 

transport and hospitalization. Pet. Ex. 3 at 435. She had several more tonic-clonic seizures, 

including at approximately 9:00 p.m., when she entered status epilepticus prompting a 

pentobarbital-induced coma. Elevated GAD antibodies were found in a serum sample obtained 

on August 16, 2013. Pet. Ex. 11 at 253. Elevated protein and cells were found in a CSF sample 

obtained that same day. Pet. Ex. 23 at 358.

Dr. Huq opined: “The timing of [R.A.’s] onset of symptoms from cytokines and 

inflammatory response from the vaccine is consistent with her presentation of fever at three days 

and subsequent development of seizures at one week and around two [to] three weeks, the MRI 

changes.” Tr. 121 (emphasis added).54 Dr. Huq further opined that the vaccine-induced 

inflammatory response can both cause the initial seizures and also lead to a cytotoxic T-cell 

mediated process, Tr. 97-98, 121-22, which takes more time, Tr. 89, but probably starts within 

two weeks of the vaccinations, Tr. 122. Dr. Huq opined: “This is a well-accepted timeframe for 

an immune-mediated response.” Pet. Ex. 29 at 13.

Dr. Huq also opined: “Given the overlapping mechanisms of fever and inflammation and 

the role of inflammation in epileptogenesis, as well as [the] direct effect of heat on physiologic 

processes such as ion channel function, it is likely that fever triggered by vaccination had a role 

in causing initial seizures as well as causing an earlier onset of seizures.” Pet. Ex. 31 at 5.

54 Dr. Kruer in fact agreed that a foreign antigen is first met by an innate immune response including fever, and that 

can occur within as little as one day. Tr. 250.
40

“Priming from [prior exposure to] tetanus toxoid also likely had a role in accelerating 

inflammation and immune response and triggering initial seizures.” Id. Dr. Huq stated that 

“priming” not only represents formation of memory B and T cells, but other processes such as 

induction of inflammatory cytokines and epigenetic changes. Id. at 5-6. Dr. Huq noted that R.A. 

had received five prior vaccinations with tetanus toxoid. He opined: “That [R.A.] did not 

develop any autoimmune condition during an earlier administration of tetanus vaccination does 

not exclude the possibility that priming from tetanus toxoid contributed to the development of 

autoimmune encephalitis at a later age when a combination of other susceptibility factors pushed 

her above the threshold of clinical expression.” Id. 

Dr. Kruer initially opined that the timing in this case was not medically acceptable 

because molecular mimicry would take 10 – 14 days, citing an article by Cornaby et al.55

focusing on B cells and antibodies. Resp. Ex. A at 3-4. However, Dr. Huq consistently opined 

that this condition is mediated by inflammation and T cells. See, e.g., Pet. Ex. 29 at 6, 7, 8; Pet. 

Ex. 31 at 3-4.

Dr. Kruer testified: “...[F]rom what we know about both humoral and cell-mediated

immunity, that it takes, typically, from between seven to 14 days in order for an appropriate 

response to be mounted. If the initial reaction triggered cytokine production, and then that led to 

fever on day four, I believe, it was then only three additional days until she manifested the 

seizures. Three days is not enough time, according to current scientific understanding... to 

mount an antibody or a cytotoxic response.” Tr. 248-49.

However, Dr. Kruer agreed that the cytokine response leading to fever occurs as part of 

the early innate immune response to a vaccine and can happen as early as in the first day. Tr. 

250. He also agreed that the innate immune response, which can give rise to inflammation, is the 

first step in triggering the adaptive immune response. Id. He also agreed that it could take as 

little as seven days to mount either a humoral [e.g., T cells] or cell-mediated [e.g., B cells and 

antibodies] response. Tr. 248. On cross-examination, he confirmed that it can take as little as 

seven days for autoimmunity to develop, “as a general principle”. Tr. 292-93. This fits the 

present case, in which R.A. developed fever approximately four days after vaccination and 

seizures seven days after vaccination.

Dr. Kruer also suggested that it would take longer to develop a new, adverse autoimmune 

response: “[I]f you were to hypothesize that this actually went awry at some point, you know, the 

rails went off the track, that implies that it’s not the same response. It now requires the process 

of affinity or avidity hypermutation, and it requires coronal [sic? clonal?] expansion in order to 

get a different result.” Tr. 252. After the memory response, “there’s a whole process of coronal 

[sic? clonal?] expansion where those T-cell receptors and B-cell receptors then undergo a 

process of mutation and refinement and all kinds of variants on that memory response... Now, 

those guys could end up being bad players. But it’s going to take time to do that is what I’m 

saying.” Tr. 254. Dr. Kruer did not cite to any literature in support for his opinion. I have 

reviewed his literature and have not independently found any support for his opinion. 

55 Cornaby et al., B Cell Epitope Spreading: Mechanisms and Contribution to Autoimmune Diseases, 163 Immunol. 

Lett. 56 (2015) [Resp. Ex. A-4].
41

Accordingly, it is not evident that the timing of previous immune responses to an antigen will

dictate the timing of a subsequent adverse response to the same antigen.

Past opinions in this program have recognized that the immune response to repeat 

exposure to vaccines can be more rapid than the response to the initial exposure to that vaccine; 

this is often referred to as an anamnestic response. While the timing of the autoimmune response 

is not entirely understood, there is preponderant evidence that the timing in this case was 

medically acceptable. Petitioners have established Althen prong three.

V. Conclusion

After a careful review of the entire record before me, I find that petitioners have 

established that there is preponderant evidence that after receiving the Tdap and Menactra 

vaccinations on August 5, 2013, R.A. developed autoimmune limbic encephalitis (ALE) with the 

associated biomarker of GAD antibodies, and the residual effects of cognitive deficits and 

intractable epilepsy. Petitioners have also established causation-in-fact. Respondent has not 

raised an alternative cause. See generally Resp. Pre-Hearing Brief; Resp. Post-Hearing 

Response. Accordingly, petitioners, on behalf of R.A., are entitled to compensation. A separate 

damages order will be issued. 

IT IS SO ORDERED. 

s/Thomas L. Gowen

Thomas L. Gowen

Special Master