Research

JAMA Neurology | Original Investigation

Association of Autoimmune Encephalitis With Combined

Immune Checkpoint Inhibitor Treatment for Metastatic Cancer
Tanya J. Williams, MD, PhD; David R. Benavides, MD, PhD; Kelly-Ann Patrice, MBBS; Josep O. Dalmau, MD, PhD;
Alexandre Leon Ribeiro de Ávila, MD, PhD; Dung T. Le, MD; Evan J. Lipson, MD; John C. Probasco, MD; Ellen M. Mowry, MD, MCR

Editorial page 907

IMPORTANCE Paraneoplastic encephalitides usually precede a diagnosis of cancer and are Supplemental content at
often refractory to immunosuppressive therapy. Conversely, autoimmune encephalitides are jamaneurology.com
reversible conditions that can occur in the presence or absence of cancer.
CME Quiz at
jamanetworkcme.com and
OBJECTIVE To report the induction of autoimmune encephalitis in 2 patients after treatment CME Questions page 1040
of metastatic cancer with a combination of the immune checkpoint inhibitors nivolumab and
ipilimumab.

DESIGN, SETTING, AND PARTICIPANTS A retrospective case study was conducted of the clinical
and management course of 2 patients with progressive, treatment-refractory metastatic
cancer who were treated with a single dose each (concomitantly) of the immune checkpoint
inhibitors nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg.

EXPOSURES Nivolumab and ipilimumab.

MAIN OUTCOMES AND MEASURES The clinical response to immunosuppressive therapy in

suspected autoimmune encephalitis in the setting of immune checkpoint inhibitor use.

RESULTS Autoantibody testing confirmed identification of anti–N-methyl-D-aspartate

receptor antibodies in the cerebrospinal fluid of 1 patient. Withdrawal of immune checkpoint
inhibitors and initiation of immunosuppressive therapy, consisting of intravenous
methylprednisolone sodium succinate equivalent to 1000 mg of methylprednisolone for
5 days, 0.4 mg/kg/d of intravenous immunoglobulin for 5 days, and 2 doses of rituximab,
1000 mg, in 1 patient and oral prednisone, 60 mg/d, in the other patient, resulted in
improved neurologic symptoms.

CONCLUSIONS AND RELEVANCE Immune checkpoint inhibition may favor the development of
immune responses against neuronal antigens, leading to autoimmune encephalitis. Early Author Affiliations: Department of
recognition and treatment of autoimmune encephalitis in patients receiving immune Neurology, Johns Hopkins University
checkpoint blockade therapy will likely be essential for maximizing clinical recovery and School of Medicine, Baltimore,
Maryland (Williams, Benavides,
minimizing the effect of drug-related toxic effects. The mechanisms by which immune
Patrice, Probasco, Mowry);
checkpoint inhibition may contribute to autoimmune encephalitis require further study. Department of Neurology, Hospital
Clínic/Institut d'Investigació
Biomèdica August Pi i Sunyer,
University of Barcelona, Barcelona,
Spain (Dalmau); Institució Catalana
de Recerca i Estudis Avançats,
University of Barcelona, Barcelona,
Spain (Dalmau); Bristol-Myers
Squibb, Plainsboro, New Jersey
(de Ávila); Department of Oncology,
Johns Hopkins University School of
Medicine, Baltimore, Maryland
(Le, Lipson).
Corresponding Author: Ellen M.
Mowry, MD, MCR, Department of
Neurology, Johns Hopkins University
School of Medicine, 600 N Wolfe St,
Pathology Bldg, Ste 627,
JAMA Neurol. 2016;73(8):928-933. doi:10.1001/jamaneurol.2016.1399 Baltimore, MD 21287
Published online June 6, 2016. (emowry1@jhmi.edu).

928 (Reprinted) jamaneurology.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Larissa Germana Silva Oliveira on 03/09/2021

 Autoimmune Encephalitis Following Immune Checkpoint Inhibitor Treatment
I
mmune checkpoint blockade for cancer therapy aims to en-
hance antitumor immunity. Nivolumab is a fully human
IgG4 antibody that blocks programmed cell death protein
1 and potentiates activation of T cells.1 Similarly, ipilimumab
is a fully human monoclonal antibody that binds and inhibits
cytotoxic T-lymphocyte–associated antigen 4, an inhibitory re-
ceptor on T cells.2 Both therapies have demonstrated im-
proved tumor-related outcomes in multiple types of cancer.3
Although these therapies hold great promise in treating
various malignant neoplasms, checkpoint inhibitors uncom-
monly trigger varied immune-related adverse events of the cen-
tral and peripheral nervous systems.4-9 We describe 2 pa-
tients who developed autoimmune encephalitis, including
anti–N-methyl-D-aspartate receptor (anti-NMDAR) encepha-
litis, shortly after treatment with the combination of nivol-
umab and ipilimumab for metastatic cancer. Administration
of immunosuppressive therapy and cessation of combina-
tion checkpoint inhibition led to marked neurologic improve-
ment. Although causality cannot be proven, these cases illus-
trate important factors for consideration in the use of immune
checkpoint inhibitors.
Report of Cases
Case 1
Written consent was provided by the first patient and the wife
of the second patient, as he was deceased at time of manu-
script preparation. The Johns Hopkins University Institu-
tional Review Board waived approval.
A woman in her mid-50s with a history of metastatic mela-
noma had previously received adoptive T-cell transfer therapy
(NCT01993719) (Figure 1A) with partial response initially (per
the Response Evaluation Criteria in Solid Tumors, guideline
version 1.110), followed subsequently by disease progression,
including new metastases to the brain treated with stereotactic
radiosurgery. She received 1 dose each (concomitantly) of
nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg (NCT02186249).
During the next week, the patient reported fever, generalized
body aches, nausea, and vomiting. Within 2 weeks, she
developed syncopal episodes, memory loss, gait disturbance,
and abnormal behaviors, including unresponsiveness and
inappropriate laughing. The patient was hospitalized. Vital signs
showed evidence of dysautonomia with hypotension and
bradycardia. By 18 days after receiving the infusion of nivolumab
and ipilimumab, results of her neurologic examination revealed
disorientation, inattention, bradykinesia, and hyperreflexia.
Results of extensive serologic evaluations for metabolic
derangements were unremarkable. Computed tomographic scan
of the head showed no acute pathologic conditions.
During the next few days, the patient became stuporous,
with episodic agitation. Magnetic resonance imaging (MRI) of
the brain showed stable encephalomalacia at sites of prior ra-
diosurgery with no additional metastases (eFigure in the Supple-
ment). No changes were noted at previously irradiated tumor
sites on brain MRI. Cerebrospinal fluid (CSF) demonstrated a
monocytic pleocytosis (white blood cells, 8/μL; 100% lympho-
cytes, 0% monocytes, and 0% neutrophils; institutional nor-
jamaneurology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by Larissa Germana Silva Oliveira on 03/09/2021
Original Investigation Research
Key Points
Question What is the management of autoimmune encephalitis in
patients receiving immune checkpoint inhibitor treatment?
Findings In this case report review of 2 patients with autoimmune
encephalitis following treatment for metastatic cancer, withdrawal
of the immune checkpoint inhibitors nivolumab and ipilimumab
and initiation of immunosuppressive therapy resulted in improved
neurologic symptoms.
Meaning The mechanisms by which immune checkpoint
inhibition favors the development of immune responses against
neuronal antigens requires further study.
mal range, 0-5/μL [to convert white blood cells to ×109/L, mul-
tiply by 0.001; and lymphocytes to proportion of 1.0, multiply
by 0.01]). Results of cytologic tests showed no evidence of ma-
lignant neoplasm. Cerebrospinal fluid protein and glucose lev-
els, results of cytologic tests, and IgG index were normal. Oli-
goclonal bands were present and matched in the CSF and serum.
Results of polymerase chain reaction were negative for herpes
simplex virus in CSF. Results of an extensive evaluation of blood
and CSF revealed no evidence of infection. Serial electroen-
cephalography showed intermittent bilateral slowing, then a
subclinical seizure of left temporo-occipital origin. Continu-
ous electroencephalographic monitoring showed intermittent
periods of rhythmic epileptiform activity in the left temporal
lobe without clinical correlate. The patient remained stupor-
ous. Subsequent analysis of CSF demonstrated a persistent
monocytic pleocytosis (white blood cells, 6/μL; 100% lympho-
cytes, 0% monocytes, 0% neutrophils), resolution of the oli-
goclonal bands, and no other abnormality.
Given the high suspicion for autoimmune encephalitis,
paraneoplastic antibody testing was performed using CSF and
serum, and the patient was treated empirically with high-
dose intravenous methylprednisolone sodium succinate
equivalent to 1000 mg/d of methylprednisolone for 5 days, fol-
lowed by 0.4 mg/kg/d of intravenous immunoglobulin for 5
days, without significant improvement. Analysis demon-
strated IgG NMDAR antibodies in the CSF only (first per-
formed by Athena Laboratories, Marlborough, Massachu-
setts; confirmed in the laboratory by one of us [J.O.D.]). The
patient was treated with 2 doses of intravenous rituximab, 1000
mg, resulting in gradual improvement in mental status for 4
weeks. The patient’s score on the Montreal Cognitive Assess-
ment 6 months after discharge was 28 of 30 (normal, ≥26), sug-
gesting no cognitive impairment, and she had otherwise nor-
mal neurologic examination results. She experienced an initial
partial response (per the Response Evaluation Criteria in Solid
Tumors, guideline version 1.110) 4 months after receiving the
checkpoint inhibitors.
The patient received 2 doses of rituximab. One month af-
ter the second dose, she developed evidence of disease pro-
gression in a single external iliac lymph node, which was
treated with stereotactic body radiation therapy. The patient
has not received further anticancer or immunosuppressive
agents and remains in stable condition 12 months after nivol-
umab and ipilimumab treatment.
(Reprinted) JAMA Neurology August 2016 Volume 73, Number 8 929
 Research Original Investigation Autoimmune Encephalitis Following Immune Checkpoint Inhibitor Treatment

Figure 1. Timelines of Clinical Courses and Treatments for Patients With Autoimmune Encephalitis Associated With Nivolumab and Ipilimumab

A Case 1: Anti-NMDAR encephalitis

Diagnosis of melanoma MRI shows brain Neurologic

(BRAF mutant) metastases symptoms

PD: metastatic Progression of PR

melanoma lymph node
metastasis

Time since cancer diagnosis, mo

0 6 12 18 24 30 36

Wide excision and Surgical Rituximaba

lymphadenectomy resection
for primary melanoma IV steroids, IVIGa

Clinical trial: adjuvant Stereotactic Nivolumab 1 mg/kg and

dabrafenib + trametinib radiosurgery for ipilimumab 3 mg/kg
vs placebo for resected brain metastases (NCT02186249)
BRAF-mutant melanoma
(NCT01682083; placebo
group)

Clinical trial: adoptive

T-cell transfer therapy
including CPM, fludarabine,
and IL-2 (NCT01993719)

B Case 2: Autoimmune limbic encephalitis

MRI shows brain
Diagnosis of limited-stage Neurologic
SCLC metastases symptoms

PD PD PD PD PR Death
PD: extensive-stage
SCLC

Time since cancer diagnosis, mo

0 6 12 18 24 30 36 40

Completed 4 cycles Completed 4 cycles Completed Completed Completed Oral corticosteroidsa

chemoradiation cisplatin-etoposide temozolomide paclitaxel irinotecan
(cisplatin-etoposide)
plus prophylactic
cranial irradiation
Clinical trial: temozolomide Stereotactic Nivolumab 1 mg/kg and
with or without veliparibin radiosurgery for ipilimumab 3 mg/kg
(NCT01638546; brain metastases (NCT01928394)
temozolomide-only group)

A, Case 1. Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in a
patient with melanoma. B, Case 2. Autoimmune limbic encephalitis in a patient
with small cell lung cancer (SCLC). CPM indicates cyclophosphamide;
IL-2, interleukin 2; IV, intravenous; IVIG, intravenous immunoglobulin;
MRI, magnetic resonance imaging; PD, progressive disease; PR, partial response
per the Response Evaluation Criteria in Solid Tumors, guideline version 1.1.10
BRAF gene (OMIM 164757).
a
Indicates immunosuppressive therapy for paraneoplastic encephalitis.

Case 2 on admission were unremarkable. Serologic studies showed

A man in his mid-60s with metastatic small cell lung cancer that
had progressed despite multiple prior therapies was treated with
nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg (NCT 01928394)
(Figure 1B). Within 4 days, the patient developed short-term
memory loss and progressive difficulty ambulating. Magnetic
resonance imaging of the brain demonstrated new nonspecific
T2 hyperintensities in the right mesial temporal lobe (Figure 2A).
The patient was hospitalized. Results of neurologic examination
hyponatremia (sodium, 124 mEq/L [to convert to millimoles per
liter, multiply by 1.0]; institutional normal range, 135-148 mEq
/L), consistent with a history of syndrome of inappropriate
antidiuretic hormone (serum sodium, 124-139 mEq/L in the
preceding 6 months). Results of serologic evaluations of other
metabolic derangements were otherwise normal. Gradual
correction of the hyponatremia led to subjective clinical
improvement, and the patient was discharged home.

930 JAMA Neurology August 2016 Volume 73, Number 8 (Reprinted) jamaneurology.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Larissa Germana Silva Oliveira on 03/09/2021

 Autoimmune Encephalitis Following Immune Checkpoint Inhibitor Treatment
Within 2 weeks, he was rehospitalized with lightheaded-
ness, disorientation, memory loss, and right arm paresthe-
sias. Results of a neurologic examination revealed lethargy,
poor recall, mild intention tremor, hyperreflexia, and ataxic
gait. Results of metabolic and nutritional assessment were no-
table only for hyponatremia (sodium, 126 mEq/L). Results of
subsequent serologic studies for other metabolic abnormali-
ties were unremarkable. Results of repeated brain MRI were
unchanged. No changes were noted at previously irradiated tu-
mor sites on brain MRI. Analysis of CSF demonstrated mono-
cytic pleocytosis (white blood cells, 18/μL; 89% lympho-
cytes, 11% monocytes, 0% neutrophils), an elevated protein
level (98 mg/dL [to convert to grams per liter, multiply by 10.0];
institutional normal range, 15-45 mg/dL), a normal glucose level
and IgG index, matched oligoclonal bands in the CSF and se-
rum, and no evidence of bacterial or viral infection. Cytologic
testing of CSF was not performed. Given the concern for au-
toimmune limbic encephalitis, the patient was treated with oral
prednisone, 60 mg/d, and demonstrated dramatic improve-
ment in his level of arousal and gait. The hyponatremia also
resolved. No other metabolic derangements were detected on
serologic analyses. Serum was positive for antiglial nuclear an-
tibody, with a markedly elevated titer (>1:15,000). No other
paraneoplastic autoantibody was detected in serum; CSF para-
neoplastic autoantibody testing was not performed. The pa-
tient was discharged home with a slow tapering regimen of oral
prednisone, starting at a dosage of 60 mg/d. Nivolumab and
ipilimumab treatments were withheld. One month later, the
patient’s neurologic functioning was nearly back to baseline.
He experienced a partial response (per the Response Evalua-
tion Criteria in Solid Tumors, guideline version 1.110) 8 weeks
after treatment with nivolumab and ipilimumab.
Nineteen weeks later, MRI of the brain showed resolu-
tion of the previously noted right mesial temporal lobe abnor-
mality (Figure 2B), but also showed 2 new brain metastases
(body of the corpus callosum extending along the right sep-
tum pellucidum and along the ependyma of the third ven-
tricle). Stereotactic radiosurgery was performed, but the pa-
tient experienced marked functional decline and entered
hospice care and died.
Discussion
We describe 2 patients with metastatic cancer who developed
autoimmune encephalitis after receiving combination therapy
with immune checkpoint inhibitors. Although causality can-
not be proven in these cases, several features suggest that these
syndromes were triggered by immune checkpoint blockade. The
timing of the onset of neurologic symptoms after administra-
tion of nivolumab and ipilimumab suggests immune-related
adverse events rather than classic paraneoplastic neurologic dis-
orders (PNDs). Most tumor-induced PNDs are subacute and pro-
gressive, commonly preceding the detection of tumor by
months to years.11 Here, both patients were treated for meta-
static cancer for extended periods without evidence of a PND.
Both patients received only 1 dose of combination immune
checkpoint inhibitors. Furthermore, anti-NMDAR encephali-
jamaneurology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by Larissa Germana Silva Oliveira on 03/09/2021
Original Investigation Research
Figure 2. Representative Brain Magnetic Resonance Images
From a Patient With Autoimmune Limbic Encephalitis
A Hyperintensity of the B Resolution after treatment
right hippocampus
A, Axial T2-weighted images demonstrate subtle hyperintensity of the right
hippocampus (arrowhead) at the onset of neurologic symptoms in case 2.
B, This abnormality resolved after treatment with oral corticosteroids, with
corresponding symptomatic improvement.
tis, as seen in the first patient, is believed to be caused by di-
rect effects of pathogenic antibodies12-15 rather than T-cell–
mediated responses, which are implicated in classic PNDs.
Finally, both patients had marked clinical improvement after
immunosuppressive treatment. These features suggest that im-
mune checkpoint inhibition favored the development of im-
mune responses against neuronal antigens. That encephalitis
has been reported following use of ipilimumab in metastatic
pancreatic adenocarcinoma may also lend credence to this as-
sociation, although autoantibody testing was not performed in
this report.16 Further studies are required to confirm if there
is a causal association between immune checkpoint blockade
and autoimmune encephalitis.
The induction of antibodies to NMDARs in a patient with
metastatic melanoma, as in case 1, is of particular interest. Mela-
noma is not commonly associated with PNDs, although there
are reports of melanoma-associated retinopathy17 and cer-
ebellar degeneration.18,19 The identification of anti-NMDAR an-
tibodies in a patient with melanoma has not been described,
to our knowledge. N-methyl-D-aspartate receptors are ex-
pressed on melanocytes20 and anti-NMDAR encephalitis af-
ter excision of melanocytic nevis has been recently described.21
Furthermore, the GRIN2A gene (OMIM 138253), which en-
codes the NMDAR subunit GluN2A, is highly mutated in pa-
tients with malignant melanoma,20 leading to aberrant NM-
DAR complex formation. 22 These findings may imply a
convergence of mechanisms, including aberrant tumor ex-
pression of NMDARs along with a propensity for autoimmu-
nity caused by immune checkpoint inhibitors.
More important, both patients had brain metastases be-
fore the onset of autoimmune encephalitis. It is difficult to es-
timate the contribution of this factor to the development of neu-
rologic immune-related adverse events following immune
checkpoint inhibition. Disruption of the blood-brain barrier or
the damage resulting from stereotactic radiosurgery may have
facilitated T-cell and B-cell interactions with neuronal epi-
topes. This hypothesis will require further investigation. There
(Reprinted) JAMA Neurology August 2016 Volume 73, Number 8 931
 Research Original Investigation Autoimmune Encephalitis Following Immune Checkpoint Inhibitor Treatment

is a growing appreciation for anti-NMDAR encephalitis follow-
ing infection with herpes simplex virus23,24; herpes simplex vi-
rus was not detected in the first patient’s CSF, nor was there a
history thereof. Most cases of anti-NMDAR encephalitis are au-
toimmune, with only 38% found in association with tumors,
most commonly ovarian teratoma.12,25 Previous studies showed
NMDAR expression in ovarian teratomas26; we were unable to
examine whether or not NMDARs were expressed by the mela-
noma in case 1. Nonetheless, the observations in case 1 suggest
a role for T-cell activation in the development of antibody-
mediated autoimmune encephalitis, such as anti-NMDAR en-
cephalitis. Furthermore, immune checkpoint inhibition may un-
mask or accelerate preexisting autoimmune reactions that target
neuronal epitopes, leading to autoimmune encephalitis. Con-
versely, serum detection of antiglial nuclear antibody, as in case
2, is considered a marker of an underlying malignant neoplasm27
and was not likely a pathogenic antibody-mediated process in-
volving this antibody. Antiglial nuclear antibody has been as-
sociated with numerous PNDs,28 making it less relevant per se
to the autoimmune limbic encephalitis observed in case 2. How-
ever, the notion that immune checkpoint inhibition may have
accelerated autoimmune reactions to this and other targets war-
rants further investigation.
Conclusions
As immune checkpoint inhibitors are used with increasing fre-
quency in patients with malignant tumors, health care pro-
fessionals should consider immune-related adverse events trig-
gered by immune checkpoint inhibition among possible
diagnoses of new-onset neurologic syndromes of unclear etio-
logic causes. Early recognition and management of these neu-
rologic immune-related adverse events will be essential for
maximizing clinical recovery and minimizing the effect of drug-
related toxic effects.

ARTICLE INFORMATION REFERENCES 12. Dalmau J, Lancaster E, Martinez-Hernandez E,

Accepted for Publication: April 1, 2016.
Published Online: June 6, 2016.
doi:10.1001/jamaneurol.2016.1399.
Author Contributions: Drs Williams and Benavides
contributed equally to the manuscript, and Drs
Probasco and Mowry contributed equally to the
manuscript. Drs Probasco and Mowry had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Williams, de Ávila,
Lipson, Probasco, Mowry.
Acquisition, analysis, or interpretation of data:
Benavides, Patrice, Dalmau, de Ávila, Le, Lipson,
Probasco, Mowry.
Drafting of the manuscript: Williams, Benavides,
Lipson, Probasco.
Critical revision of the manuscript for important
intellectual content: Benavides, Patrice, Dalmau,
de Ávila, Le, Lipson, Probasco, Mowry.
Administrative, technical, or material support: Le,
Lipson.
Study supervision: Dalmau, de Ávila, Probasco,
Mowry.
Conflict of Interest Disclosures: Dr Benavides
reported receiving a fellowship grant from
Mallinckrodt Pharmaceuticals. Dr Dalmau reported
receiving royalties from Euroimmun for a patent for
the use of N-methyl-D-aspartate receptor as an
autoantibody test. Dr de Ávila reported being
employed by and owning stock in Bristol-Myers
Squibb. Dr Le reported receiving research funding
from Merck, BMS, and Aduro Biotech to run clinical
trials. Dr Lipson reported serving as a paid
consultant for Amgen, Castle Biosciences, Merck,
and Bristol-Myers Squibb. Dr Mowry reported that
Teva Pharmaceuticals provided free glatiramer
acetate for a randomized clinical trial of vitamin D
supplementation, of which Dr Mowry is principal
investigator. Dr Mowry reported serving as site
principal investigator for a trial for Sun
Pharmaceuticals, and reported that Johns Hopkins
University School of Medicine receives funding
from Biogen Idec to conduct research, and funding
from the National Multiple Sclerosis Society. No
other disclosures were reported.
1. Brahmer JR, Drake CG, Wollner I, et al. Phase I
study of single-agent anti–programmed death-1
(MDX-1106) in refractory solid tumors: safety, clinical
activity, pharmacodynamics, and immunologic
correlates. J Clin Oncol. 2010;28(19):3167-3175.
2. Camacho LH. CTLA-4 blockade with ipilimumab:
biology, safety, efficacy, and future considerations.
Cancer Med. 2015;4(5):661-672.
3. Lipson EJ, Forde PM, Hammers HJ, Emens LA,
Taube JM, Topalian SL. Antagonists of PD-1 and
PD-L1 in cancer treatment. Semin Oncol. 2015;42
(4):587-600.
4. Bot I, Blank CU, Boogerd W, Brandsma D.
Neurological immune-related adverse events of
ipilimumab. Pract Neurol. 2013;13(4):278-280.
5. Maur M, Tomasello C, Frassoldati A, Dieci MV,
Barbieri E, Conte P. Posterior reversible
encephalopathy syndrome during ipilimumab
therapy for malignant melanoma. J Clin Oncol. 2012;
30(6):e76-e78.
6. Bompaire F, Mateus C, Taillia H, et al. Severe
meningo-radiculo-neuritis associated with
ipilimumab. Invest New Drugs. 2012;30(6):
2407-2410.
7. Boyd K, Kalladka D, Overell J, Waterston A.
Ipilimumab induced encephalitis: a case report.
Immunome Res. 2015;11:092. doi:10.4172/1745-
7580.1000092
8. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S.
Atypical neurological complications of ipilimumab
therapy in patients with metastatic melanoma.
Neuro Oncol. 2014;16(4):589-593.
9. Conry RM, Sullivan JC, Nabors LB III.
Ipilimumab-induced encephalopathy with a
reversible splenial lesion. Cancer Immunol Res. 2015;3
(6):598-601.
10. Eisenhauer EA, Therasse P, Bogaerts J, et al.
New response evaluation criteria in solid tumours:
revised RECIST guideline (version 1.1). Eur J Cancer.
2009;45(2):228-247.
11. Darnell RB, Posner JB. Paraneoplastic
syndromes involving the nervous system. N Engl J
Med. 2003;349(16):1543-1554.
Rosenfeld MR, Balice-Gordon R. Clinical experience
and laboratory investigations in patients with
anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):
63-74.
13. Dalmau J, Gleichman AJ, Hughes EG, et al.
Anti–NMDA-receptor encephalitis: case series and
analysis of the effects of antibodies. Lancet Neurol.
2008;7(12):1091-1098.
14. Hughes EG, Peng X, Gleichman AJ, et al. Cellular
and synaptic mechanisms of anti-NMDA receptor
encephalitis. J Neurosci. 2010;30(17):
5866-5875.
15. Planagumà J, Leypoldt F, Mannara F, et al.
Human N-methyl D-aspartate receptor antibodies
alter memory and behaviour in mice. Brain. 2015;
138(pt 1):94-109.
16. Royal RE, Levy C, Turner K, et al. Phase 2 trial
of single agent ipilimumab (anti-CTLA-4) for
locally advanced or metastatic pancreatic
adenocarcinoma. J Immunother. 2010;33(8):
828-833.
17. Keltner JL, Thirkill CE, Yip PT. Clinical and
immunologic characteristics of melanoma-
associated retinopathy syndrome: eleven new
cases and a review of 51 previously published cases.
J Neuroophthalmol. 2001;21(3):173-187.
18. Valpione S, Zoccarato M, Parrozzani R, et al.
Paraneoplastic cerebellar degeneration with anti-Yo
antibodies associated with metastatic uveal
melanoma. J Neurol Sci. 2013;335(1-2):
210-212.
19. Hauspy J, Nevin A, Harley I, et al.
Paraneoplastic syndrome in vaginal melanoma:
a case report and review of the literature. Int J
Gynecol Cancer. 2007;17(5):1159-1163.
20. Wei X, Walia V, Lin JC, et al; NISC Comparative
Sequencing Program. Exome sequencing identifies
GRIN2A as frequently mutated in melanoma. Nat
Genet. 2011;43(5):442-446.
21. Yang XZ, Cui LY, Ren HT, Qu T, Guan HZ.
Anti-NMDAR encephalitis after resection of
melanocytic nevi: report of two cases. BMC Neurol.
2015;15:165.

932 JAMA Neurology August 2016 Volume 73, Number 8 (Reprinted) jamaneurology.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Larissa Germana Silva Oliveira on 03/09/2021

 Autoimmune Encephalitis Following Immune Checkpoint Inhibitor Treatment Original Investigation Research

22. Prickett TD, Zerlanko BJ, Hill VK, et al. Somatic
mutation of GRIN2A in malignant melanoma results
in loss of tumor suppressor activity via aberrant
NMDAR complex formation. J Invest Dermatol.
2014;134(9):2390-2398.
23. Leypoldt F, Titulaer MJ, Aguilar E, et al. Herpes
simplex virus-1 encephalitis can trigger anti-NMDA
receptor encephalitis: case report. Neurology. 2013;
81(18):1637-1639.
24. Venkatesan A, Benavides DR. Autoimmune
encephalitis and its relation to infection. Curr Neurol
Neurosci Rep. 2015;15(3):3.
25. Titulaer MJ, McCracken L, Gabilondo I, et al.
Treatment and prognostic factors for long-term
outcome in patients with anti-NMDA receptor
encephalitis: an observational cohort study. Lancet
Neurol. 2013;12(2):157-165.
26. Tüzün E, Zhou L, Baehring JM, Bannykh S,
Rosenfeld MR, Dalmau J. Evidence for
antibody-mediated pathogenesis in anti-NMDAR
encephalitis associated with ovarian teratoma. Acta
Neuropathol. 2009;118(6):737-743.
27. Titulaer MJ, Klooster R, Potman M, et al. SOX
antibodies in small-cell lung cancer and
Lambert-Eaton myasthenic syndrome: frequency
and relation with survival. J Clin Oncol. 2009;27
(26):4260-4267.
28. Graus F, Vincent A, Pozo-Rosich P, et al.
Anti-glial nuclear antibody: marker of lung
cancer-related paraneoplastic neurological
syndromes. J Neuroimmunol. 2005;165(1-2):
166-171.

jamaneurology.com (Reprinted) JAMA Neurology August 2016 Volume 73, Number 8 933

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Larissa Germana Silva Oliveira on 03/09/2021