BRIEF COMMUNICATION
and neuromyelitis optica,5 its efficacy has not been investi-
Tocilizumab Treatment for
New Onset Refractory Status
Epilepticus
Jin-Sun Jun, MD,1*
Soon-Tae Lee, MD, PhD ,2* Ryul Kim, MD,2
Kon Chu, MD, PhD ,2 and
Sang Kun Lee, MD, PhD2
We investigated the therapeutic potential of the
interleukin-6 receptor inhibitor tocilizumab in 7 patients
with new onset refractory status epilepticus (NORSE)
who remained refractory to conventional immunother-
apy with rituximab (n = 5) or without rituximab (n = 2).
Status epilepticus (SE) was terminated after 1 or 2 doses
of tocilizumab in 6 patients with a median interval of
3 days from the initiation. They had no recurrence of SE
during the observation. However, 2 patients experi-
enced severe adverse events related to infection during
the tocilizumab therapy. Further prospective controlled
studies are warranted to validate the efficacy and safety
of tocilizumab in patients with NORSE.
ANN NEUROL 2018;84:940–945
N ew onset refractory status epilepticus (NORSE) is a
rare clinical condition usually characterized by the
occurrence of a prolonged period of refractory seizures in
otherwise healthy individuals.1 Although a previous study
showed that refractory status epilepticus (SE) occurred in
approximately 30% of patients with SE,2 no data exist
regarding the frequency of NORSE. Autoimmune or para-
neoplastic etiology account for the majority of NORSE
cases with an identifiable cause.1
The use of conventional immunotherapies and ritux-
imab has been considered for the treatment of NORSE.3
However, a multicenter retrospective study including
130 patients with NORSE showed that approximately
60% of the patients had poor functional outcomes,
although such immunotherapies were attempted.1 These
observations raise an important question of which immu-
notherapy should be given next.
Tocilizumab is an interleukin (IL)-6 receptor inhibi-
tor that blocks IL-6–mediated signal transduction. This
drug is known to improve various autoimmune diseases
because IL-6 plays an important role in autoimmune pro-
cesses.4 Although recent studies have identified a clinical
benefit of tocilizumab in refractory central nervous system
autoimmune disorders, such as autoimmune encephalitis4
940 © 2018 American Neurological Association
gated in patients with NORSE. The aim of this study was
therefore to evaluate the therapeutic potential of tocilizu-
mab in these patients.
Patients and Methods
Patients
We have generated a prospective cohort for autoimmune
encephalitis since June 1, 2012, in which all patients who
received an autoantibody test were enrolled regardless of
their results. From the dataset, we identified 35 NORSE
patients aged 18 years or older who were treated through
February 28, 2018. Patients were subjected to further
analysis if they were treated with tocilizumab. Tocilizu-
mab has been considered for intractable NORSE that was
unresponsive to conventional immunotherapies and rituxi-
mab since August 2015. NORSE was defined as new
onset SE refractory to appropriate doses of 2 or more
types of antiepileptic drugs (AEDs) without a clear struc-
tural, toxic, or metabolic cause in patients without active
epilepsy or a pre-existing relevant neurological disorder.6
Patients underwent diagnostic workups including brain
magnetic resonance imaging, metabolic investigations
(blood urea nitrogen, creatinine, urine analysis, liver func-
tion tests, electrolytes, cobalamin, methylmalonic acid,
homocysteine, folate, porphyria screening, lactate, ammo-
nia, and creatinine phosphokinase), infectious investiga-
tions (cerebrospinal fluid [CSF] bacterial and fungal stains
and cultures, CSF polymerase chain reaction for viruses
[herpes simplex virus 1 and 2, varicella zoster virus,
Epstein–Barr virus, cytomegalovirus, human herpesvirus
6 and 8, enterovirus, respiratory virus, and JC virus] and
for Mycobacterium tuberculosis, and neurosyphilis screen-
ing), systemic tumor screening (chest and abdomen com-
puted tomography), autoimmune-associated investigations
(screening for antibodies in the serum and CSF, including
From the 1Department of Neurology, School of Medicine, Kyungpook
National University, Kyungpook National University Chilgok Hospital,
Daegu, South Korea; and 2Department of Neurology, Seoul National
University Hospital, Seoul, South Korea
Address correspondence to Dr S. K. Lee, Department of Neurology, Seoul
National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080,
South Korea; E-mail: sangkun2923@gmail.com or Dr K. Chu, Department of
Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu,
Seoul, 03080, South Korea; E-mail: stemcell.snu@gmail.com
Received Jun 7, 2018, and in revised form Oct 31, 2018. Accepted for
publication Oct 31, 2018
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.25374.
*J.-S.J. and S.-T.L. share first authorship.
 15318249, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ana.25374 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [14/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Jun et al: Tocilizumab for NORSE

TABLE 1. Clinical Features and Treatment History of Patients and Their Response to Tocilizumab
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7

Sex/age, yr M/58 F/61 F/24 M/22 M/47 F/19 F/25

Prodrome Behavior change, Fever Fever Fever, Behavior change, None Behavior change,
headache headache fever fever

Etiology Anti-NMDAR Cryptogenic Cryptogenic Cryptogenic Cryptogenic Cryptogenic Cryptogenic

encephalitis

Seizures Nonconvulsive Simple partial Tonic–clonic Tonic–clonic Tonic–clonic Tonic–clonic Nonconvulsive

Epileptiform Generalized onset Bilateral, Generalized Lateralized Lateralized onset, Generalized onset Lateralized onset,
discharges independent onset onset, unilateral unilateral
unilateral

Brain MRI Normal T2 HSI at T2 HSI at T2 HSI at Normal T2 HSI at Normal

findings left frontal bilateral medial bilateral
lobe cerebral temporal basal ganglia
and bilateral hemisphere lobe and
hippocampi bilateral
claustrum

CSF findings WBC 98, WBC 4, WBC 1, WBC 8, WBC 13, WBC 10, WBC 191,
protein 105 protein 58 protein 52 protein 59 protein 63 protein 32 protein 38

AEDs LMT, OXC, PHB, fPHT, LCM, fPHT, LCM, fPHT, LEV, fPHT, LCM, CLB, LCM, CLB, LEV,
PGB, VPA, ZNS LEV, PHB, LEV, PHB, PHB, LEV, OXC, LEV, OXC, OXC, PGB,
PGB, TPM VPA, TPM PGB, TPM PHB, TPM, TPM, VPA
OXC, VPA
VPA

Anesthesia MDZ KE, MDZ, KE, MDZ, MDZ MDZ KE, MDZ, TPT MDZ
TPT TPT

Immunotherapy IVIg plus steroid, IVIg plus IVIg plus IVIg plus IVIg plus steroid IVIg plus steroid IVIg plus steroid,
history rituximab steroid, steroid, steroid, rituximab
rituximab rituximab rituximab

Duration of 73/2 35/6 48/2 11/4 6/10 25/5 24/2

SE before/after
TOC, days

Duration of 30 18 72 23 12 26 13
ICU stay, days

Duration of hospital 222 143 442 60 78 26 79

stay, days

Response to TOC Cessation of SE Cessation of Cessation of Cessation of Cessation of SE Unclear Cessation of SE

SE SE SE

mRS at discharge 5 5 5 3 3 6 2

mRS at last f/u 5 5 6 3 3 — 1

Adverse events None Leukopenia None Pneumonia Leukopenia (grade 2), Sepsis (grade 5) Leukopenia
(grade 2) (grade 3) diarrhea (grade 2) (grade 2)

AED = antiepileptic drug; CLB = clobazam; CSF = cerebrospinal fluid; F = female; f/u = follow-up; fPHT = fosphenytoin; HSI = high signal intensity; ICU = intensive care
unit; IVIg = intravenous immunoglobulin; KE = ketamine; LCM = lacosamide; LEV = levetiracetam; LMT = lamotrigine; M = male; MDZ = midazolam; MRI = magnetic res-
onance imaging; mRS = modified Rankin Scale; NMDAR = N-methyl-D-aspartate receptor; OXC = oxcarbazepine; PGB = pregabalin; PHB = phenobarbital; SE = status epi-
lepticus; TOC = tocilizumab; TPM = topiramate; TPT = thiopental; VPA = valproic acid; WBC = white blood cell count; ZNS = zonisamide.

anti-N-methyl-D-aspartate receptor [NMDAR], anti–
leucine-rich glioma-inactivated-1, anti–contactin-associated
protein-like 2, anti–α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor [AMPAR]-1, anti-
AMPAR-2, anti–γ-aminobutyric-acid type B receptor,
anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-Ma2, antiam-
phiphysin, antirecoverin, anti-SOX1, antititin, and
anti–glutamic acid decarboxylase, and serological tests for
rheumatoid factor, antinuclear antibodies, antidouble
stranded DNA, antineutrophil cytoplasmic antibodies, anti–
cyclic citrullinated peptide antibodies, antiganglioside anti-
bodies, anti-Ro/SSA and anti-La/SSB antibodies, antithyro-
peroxidase antibodies, microsomal antibodies, and
angiotensin converting enzyme), and genetic testing for mito-
chondrial encephalopathy, lactic acidosis, and strokelike epi-
sodes. The study protocol was approved by the Seoul
National University Hospital Institutional Review Board and
conformed to the principles of the Declaration of Helsinki.

December 2018 941


ANNALS of Neurology
Immunotherapy Regimens
The use of immunotherapy in NORSE patients was initi-
ated if the diagnosis was compatible with the working cri-
teria for possible autoimmune encephalitis7 and laboratory
tests for the infectious etiologies were negative. Patients with
NORSE initially received intravenous (IV) immunoglobulin
(400mg/kg/day) combined with IV methylprednisolone
(1,000mg/day) for 5 consecutive days. Rituximab (375mg/
m2/day) was given next in the case of unresponsiveness to
those immunotherapies. Tocilizumab was administered in
patients whose SE persisted despite the use of the above
immunotherapies combined with appropriate doses of
AEDs and anesthetic agents. Tocilizumab was initiated at a
dosage of 4mg/kg administered for 2 cycles in 1-week inter-
vals. A monthly dose (8mg/kg) of tocilizumab was added if
needed.
Outcomes
Response to tocilizumab was defined as control of SE,
leading to the cessation of clinical and electrographic sei-
zures. Other clinical outcomes included good or fair func-
tional outcomes (score ≤ 3 on the modified Rankin Scale)
at discharge and at the last follow-up, presence of seizures
or use of AEDs at the last follow-up, and adverse events
assessed using the Common Terminology Criteria for
Adverse Events v4.03.
FIGURE 1: Treatment history and clinical course of 7 patients with new onset refractory status epilepticus (NORSE) treated
with tocilizumab. All of the immunologic agents applied during the treatment course are presented schematically.
AED = antiepileptic drug; CyBorD = cyclophosphamide, bortezomib, and dexamethasone; F = female; IVIg = intravenous
immunoglobulin; M = male.
942
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Cytokine Analysis
We measured the following cytokines in CSF and serum
before tocilizumab treatment in all patients: IL-1β, IL-2,
IL-4, IL-5, IL-6, IL-10, IL-12, granulocyte-macrophage
colony–stimulating factor, and tumor necrosis factor-α.
After the treatment, cytokine levels were analyzed in
1 patient. For comparisons with control subjects, data
were compared to those of 10 previously reported patients
with other noninflammatory neurological disorders.8
Standard operating procedures for cytokine analysis were
previously described in detail.8 All statistical analyses were
performed using Mann–Whitney U tests, which were con-
ducted with SPSS 21.0 (SPSS, Chicago, IL). To correct
for multiple comparisons, a p < 0.001 was considered
statistically significant.
Results
A total of 7 patients were included in this study. Their
clinical characteristics and pretreatment regimens are
shown in Table 1. The etiology was identified in only
1 patient who had an autoimmune etiology due to anti-
NMDAR encephalitis. When beginning the treatment
with tocilizumab, 5 patients had received 3 immunother-
apies according to the protocol (see Table 1 and Fig. 1).
Patient 5 received tocilizumab combined with rituximab
Volume 84, No. 6
 15318249, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ana.25374 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [14/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Jun et al: Tocilizumab for NORSE

TABLE 2. CSF and Serum Cytokine Profiles

Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 NORSE, n = 7 Control, n = 10 p

CSF, pg/ml
IL-6 2,461.0 7.6 93.7 24.5 2,157.5 1,045.7 480.8 895.8  1,035.0 1.7  0.0 <0.001
IL-1β 1.1 0.4 0.3 0.4 0.5 0.9 0.9 0.6  0.3 0.6  0.7 0.475
IL-2 4.9 6.4 4.7 7.3 6.2 2.7 2.6 5.0  1.8 0.6  0.0 <0.001
IL-4 1.4 1.2 0.7 1.3 1.6 0.5 0.6 1.0  0.4 0.2  0.0 <0.001
IL-5 3.3 3.3 1.3 3.5 4.1 8.6 8.7 4.7  2.8 2.2  0.0 0.014
IL-10 9.5 8.7 5.4 10.0 9.2 12.9 10.3 9.4  2.2 2.4  0.0 <0.001
IL-12 1.1 1.7 1.5 2.4 1.4 3.6 3.3 2.1  1.0 2.7  0.0 0.161
GM-CSF 288.3 332.8 497.8 320.7 328.8 139.3 125.3 290.4  127.3 287.5  37.4 0.536
TNF-α 5.7 6.9 9.5 5.7 6.3 18.3 34.3 12.4  10.6 1.7  0.0 <0.001
Serum, pg/ml
IL-6 4.6 22.9 4,565.7 3.6 48.2 20.4 5.1 667.2  1,719.1 3.5  3.7 0.003
IL-1β 1.2 10.3 0.4 1.0 2.0 1.7 2.5 2.7  3.4 0.6  1.0 0.014
IL-2 3.0 4.6 8.0 4.2 5.6 3.4 4.3 4.7  1.7 0.6  0.0 <0.001
IL-4 0.9 0.9 0.7 0.8 0.8 0.1 0.0 0.6  0.4 0.9  1.6 1.000
IL-5 4.7 4.1 1.2 4.0 7.8 8.7 8.3 5.5  2.8 2.2  0.0 0.014
IL-10 8.7 8.7 212.3 12.1 12.2 3.7 9.1 38.1  76.9 12.5  16.3 0.315
IL-12 4.9 2.8 19.6 3.8 54.6 3.6 3.8 13.3  19.2 11.0  26.5 0.005
GM-CSF 0.3 117.3 177.8 26.0 57.5 15.5 41.7 62.3  63.5 42.3  56.3 0.536
TNF-α 3.8 3.5 21.8 5.7 82.2 9.4 5.2 18.8  28.7 4.4  8.5 0.003
Group data are represented as the mean  standard deviation.
GM-CSF = granulocyte-macrophage colony–stimulating factor; IL = interleukin; TNF = tumor necrosis factor; CSF = cerebrospinal fluid;
NORSE = new onset refractory status epilepticus; Pt = patient.

after failure of conventional immunotherapies, which was
determined by the attending physician. Patient 6 did not
receive rituximab therapy due to sepsis.
Cytokine analysis showed that IL-6 in the CSF was
the most highly upregulated factor, and a significant differ-
ence was found between the NORSE and control groups
(mean  standard deviation = 895.8  1035.0pg/ml in the
NORSE group and 1.7  0.0pg/ml in the control group;
p < 0.001). Other cytokine profiles are presented in Table 2.
In Patient 3, the cytokine levels were normalized after the
improvement of NORSE, except for a mild persisting eleva-
tion of IL-6 in the CSF (9.8pg/ml) and serum (10.5pg/ml).
Effect and Safety of Tocilizumab
The median period from seizure onset to administration
of tocilizumab was 25 (range = 6–73) days. SE was termi-
nated after 1 or 2 doses of tocilizumab in all patients
except Patient 6, which resulted in sedation withdrawal
and ventilation weaning. The median interval was
3 (range = 2–10) days from the initiation of tocilizumab
to remission of SE. No other AEDs, anesthetic agents, or
immunotherapies were added during this interval. The
patients did not exhibit recurrence of SE during the same
hospitalization. Patient 6 expired without cessation of SE
at 6 days after the initiation of tocilizumab.
During tocilizumab therapy, 2 patients experienced
adverse events of grade 3 or higher, including pneumonia
(grade 3, Patient 4) and the worsening of pre-existing
sepsis, resulting in death (grade 5, Patient 6). Other
adverse events included leukopenia (grade 2, n = 3) and
diarrhea (grade 2, n = 1; see Table 1).
The functional outcome at discharge was good or
fair in 3 patients (43%). Follow-up data were obtained
from all survivors, with a median follow-up time of

December 2018 943


ANNALS of Neurology
11 (range = 8–24) months. At the last follow-up, the func-
tional outcome was good or fair in 3 patients (50%) and
improved compared to the functional outcome at discharge in
1 patient (see Table 1). All patients except for Patient 7 had
seizures and were receiving AEDs at the last follow-up.
Discussion
Our results showed that the cessation of SE was achieved
after tocilizumab administration in 6 of 7 patients who
failed to respond to conventional immunotherapies with
or without rituximab, which suggests that tocilizumab
may provide potential benefits for patients with intractable
NORSE. Although the pathophysiology of NORSE
remains elusive, the overproduction of cytokines and the
effect of immunotherapies implicate a putative role of
inflammation in NORSE.1,3,9 Particularly, IL-6 plays a
key role in inflammation-mediated neuronal damage
through (1) induction of B-cell differentiation and prolif-
eration, (2) promoting the differentiation of IL-17
producing T-helper cells from naive T cells, (3) inhibition
of regulatory T-cell differentiation, (4) stimulating the
differentiation of CD8+ cytotoxic T cells, and (5) support-
ing plasma cell survival.4,10 In contrast to rituximab,
which does not influence cytokines or antibody-producing
plasma cells, tocilizumab blocks those IL-6–mediated pro-
cesses, which may explain our findings.
Despite this potential of tocilizumab to halt NORSE,
the functional outcome in our patients does not appear to
be better than that reported in a large case series of NORSE
patients.1 However, this finding might be explained by dif-
ferences in clinical settings. Because the current study
included NORSE cases refractory to conventional immuno-
therapies and rituximab, patients with more severe condi-
tions might have been enrolled. In addition, our patients
had a much longer duration of SE (median = 30 days) than
the previously reported case series (median = 5 days), which
contributes to poor functional outcomes.1 Interestingly,
patients with good or fair functional outcomes in this study
had a relatively short duration of SE before tocilizumab
treatment (median = 11 days) compared to the other
patients (median = 42 days). These observations suggest
that early treatment with tocilizumab may be more effective
for better functional outcomes of intractable NORSE.
With respect to the adverse events caused by tocili-
zumab, a slightly increased risk of infection has been
reported in patients with rheumatoid arthritis11 because
IL-6 plays a crucial role in immune activation. In our
study, 2 patients experienced severe adverse events related
to infection, 1 of whom died due to aggravation of pre-
existing sepsis. Although the increased risk of infection
can be also attributed to a prolonged intensive care unit
944
15318249, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ana.25374 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [14/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
stay or NORSE itself,12 tocilizumab should be used cau-
tiously in NORSE patients with infection. In particular,
the multiple immunosuppressive therapies used in the cur-
rent study have not been generalized in clinical practice
and could increase the risk of infection.
This study has several limitations. It was an uncon-
trolled retrospective study of a small number of patients
without historical controls. The included patients had het-
erogeneous pretreatment histories, and some variation
occurred in the tocilizumab treatment regimen, which may
limit the generalizability of the results. In addition, sponta-
neous remission or a delayed treatment response after the
application of the other immunotherapies cannot be
excluded. Although rituximab rapidly reduces CD19+ B-cell
levels within 1 week,13 a delayed effect of rituximab is still
possible in our patients. Lastly, it is unclear whether the
primary pharmacologic action of tocilizumab occurs cen-
trally in the brain or systemically in the blood/bone mar-
row. Although tocilizumab exhibits low permeability of the
blood–brain barrier (BBB),14 increased cytokine levels or
prolonged seizures could promote disruption of the BBB
and thus increase the permeability of tocilizumab. The
mechanism of action should be investigated further. Never-
theless, we demonstrated the therapeutic potential of tocili-
zumab in patients with intractable NORSE. Further
prospective controlled studies are necessary to validate the
efficacy and safety of tocilizumab for treatment of NORSE.
Acknowledgment
This work was supported by National Research Founda-
tion of Korea grants funded by the Ministry of Science,
ICT, and Future Planning, Republic of Korea (2016
R1C1B2011815 and 2016M3C7A1914002 from the
Brain Research Program). J-S.J. and S-T.L. were sup-
ported by the Lee Sueng Moon Research Fund of Seoul
National University Hospital (3020170130).
Author Contributions
Study concept and design: J.-S.J. and S.-T.L. Data acqui-
sition and analysis: all authors. Drafting the manuscript
and figure: all authors. All authors participated in revision
of the manuscript and approved the final version.
Potential Conflicts of Interest
Nothing to report.
References
1. Gaspard N, Foreman BP, Alvarez V, et al. New-onset refractory status
epilepticus: etiology, clinical features, and outcome. Neurology
2015;85:1604–1613.
Volume 84, No. 6

2. Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: fre-
quency, risk factors, and impact on outcome. Arch Neurol 2002;59:
205–210.
3. Gaspard N, Hirsch LJ, Sculier C, et al. New-onset refractory status epi-
lepticus (NORSE) and febrile infection-related epilepsy syndrome
(FIRES): state of the art and perspectives. Epilepsia 2018;59:745–752.
4. Lee WJ, Lee ST, Moon J, et al. Tocilizumab in autoimmune encepha-
litis refractory to rituximab: an institutional cohort study. Neurothera-
peutics 2016;13:824–832.
5. Ringelstein M, Ayzenberg I, Harmel J, et al. Long-term therapy with
interleukin 6 receptor blockade in highly active neuromyelitis optica
spectrum disorder. JAMA Neurol 2015;72:756–763.
6. Hirsch LJ, Gaspard N, van Baalen A, et al. Proposed consensus defi-
nitions for new-onset refractory status epilepticus (NORSE), febrile
infection-related epilepsy syndrome (FIRES), and related conditions.
Epilepsia 2018;59:739–744.
7. Graus F, Titulaer MJ, Balu R, et al., A clinical approach to diagnosis
of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.
8. Byun JI, Lee ST, Moon J, et al. Distinct intrathecal interleukin-
17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor
encephalitis. J Neuroimmunol 2016;297:141–147.
December 2018
15318249, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ana.25374 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [14/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Jun et al: Tocilizumab for NORSE
9. Kenney-Jung DL, Vezzani A, Kahoud RJ, et al. Febrile infection-
related epilepsy syndrome treated with anakinra. Ann Neurol 2016;
80:939–945.
10. Cassese G, Arce S, Hauser AE, et al. Plasma cell survival is mediated
by synergistic effects of cytokines and adhesion-dependent signals.
J Immunol 2003;171:1684–1690.
11. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6
receptor inhibition with tocilizumab in patients with rheumatoid
arthritis (OPTION study): a double-blind, placebo-controlled, rando-
mised trial. Lancet 2008;371:987–997.
12. Sutter R, Kaplan PW, Rüegg S. Outcome predictors for
status epilepticus—what really counts. Nat Rev Neurol 2013;9:
525–534.
13. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric
anti-CD20 monoclonal antibody therapy for relapsed indolent lym-
phoma: half of patients respond to a four-dose treatment program.
J Clin Oncol 1998;16:2825–2833.
14. Fiala M, Mizwicki MT, Weitzman R, et al. Tocilizumab infusion ther-
apy normalizes inflammation in sporadic ALS patients.
Am J Neurodegener Dis 2013;2:129–139.
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