JCN Open Access LETTER TO THE EDITOR

pISSN 1738-6586 / eISSN 2005-5013 / J Clin Neurol 2019;15(2):259-261 / https://doi.org/10.3988/jcn.2019.15.2.259

Immune-Checkpoint-Inhibitor-Induced Severe
Autoimmune Encephalitis Treated by Steroid and
Intravenous Immunoglobulin
Ahwon Kima Dear Editor,
Bhumsuk Keamb Immune checkpoint inhibitors have been spotlighted as a recent crucial therapy in many
Hyeon Cheunc kinds of solid cancers. Atezolizumab is an immune checkpoint inhibitor that increases anti-
Soon-Tae Leea tumor T-cell activity through binding to programmed death-ligand 1 that suppresses effec-
Hyung Seok Gooka tor T cells.1 The potentiation of T-cell activity by atezolizumab may induce an uncontrolled
Moon-Ku Hand immune response that can lead to a wide range of adverse events.2 One of the rare adverse
a
Departments of Neurology and reactions of atezolizumab is meningitis or encephalitis. Here we report a severe case of auto-
b
Internal Medicine, immune encephalitis that developed after administering atezolizumab to a patient with blad-
Seoul National University Hospital,
Seoul, Korea
der cancer.
c
Seoul National University, A 49-year-old male was admitted to our hospital for status epilepticus and encephalitis of
College of Medicine, Seoul, Korea unknown origin. He was diagnosed with urothelial carcinoma of the bladder, and received
d
Department of Neurology,
Seoul National University, the first cycle of 1,200-mg atezolizumab (Fig. 1). After administering atezolizumab he suf-
College of Medicine, Seoul, Korea fered general weakness and eventually showed stuporous mentality and three generalized
tonic-clonic seizures upon admission. Brain MRI showed diffuse leptomeningeal enhance-
ment. A cerebrospinal fluid (CSF) examination showed an opening pressure of 23 cm H2O
and that a sample of 50 white blood cells comprised 8 polymorphonuclear cells, 1 lympho-
cyte, and 41 cells of other types. Leptomeningeal seeding was first suspected considering his
past medical history and the dominant CSF profile of the other cells. However, no malignant
cells were found in CSF cytology. Antibiotics were administered since we could not fully
exclude bacterial meningitis. However, the CSF profile had worsened at follow-up. We were
concerned about the possibility that atezolizumab might have caused autoimmune enceph-
alitis, and so steroid pulse therapy (1 g of methylprednisolone daily) was administered. This
did not produce any improvement, and so intravenous immunoglobulin (IVIG) therapy
was started. The patient initially improved clinically and follow-up MRI showed the resolu-
tion of leptomeningeal enhancement. All findings in the CSF study were negative: paraneo-
plastic antibodies (anti-Hu, anti-Ri, and anti-Yo antibodies), bacterial culture, fungus cul-
ture, tuberculous PCR, and viral PCR including herpes simplex virus 1 and 2, Epstein-Barr
virus, varicella zoster virus, cytomegalovirus, and John Cunningham virus.
The patient experienced drowsiness about 1 month after the first IVIG therapy, so a sec-
Received September 11, 2018 ond round of IVIG therapy was applied. However, this did not produce any further clinical
Revised November 12, 2018
Accepted November 13, 2018 improvement. There was no epileptiform discharge in electroencephalography, and the find-
ings of a follow-up CSF study were completely normal with no malignant cells in cytology
Correspondence
Moon-Ku Han, MD, PhD (Fig. 1). The patient had suffered persistent fever and his CRP level had seldom dropped
Department of Neurology, below 20 mg/dL despite receiving antibiotics. The median onset delay for immune-related
Seoul National University,
colitis in patients with urothelial carcinoma who receive atezolizumab was 1.7 months.3 The
College of Medicine,
82 Gumi-ro 173beon-gil, Bundang-gu, present patient was suspected as having immune-related colitis because of continuous dis-
Seongnam 13620, Korea
Tel +82-31-787-7464 cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Com-

Fax +82-31-787-4059 mercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial

E-mail mkhan@snu.ac.kr
‌ use, distribution, and reproduction in any medium, provided the original work is properly cited.

Copyright © 2019 Korean Neurological Association 259

 JCN Autoimmune Encephalitis Induced by Atezolizumab
CSF profile 1st CSF study (Day 0) 2nd CSF study (Day 2) 3rd CSF study (Day 7) 4th CSF study (Day 42) 5th CSF study (Day 74)

Opening pressure (cmH2O) 23 32 23 9 8

WBC (/㎕)
CSF profile 50 (P18
st L 1 Ostudy
CSF 41) (Day
350
0) (P 2
298 L 10study
nd CSF O 42)(Day 2) 3rd8CSF study (Day 7) 4th 4CSF study (Day 42) 5th 0CSF study (Day 74)

ProteinOpening
(mg/dL) pressure (cmH2O) 218.1 23 352.1 32 139.5 23 58 9 34 8

Glucose (mg/dL)
WBC (/㎕) 124
50 (P 8 L 1 O 41) 156
350 (P 298 L 10 O 42) 156 8 158 4 124 0

Protein (mg/dL) 218.1 352.1 139.5 58 34

Admission day
Glucose (mg/dL) 124 156 156 158 124

-14 -1 0 1 2 3 5 7 10 12 37 42 44 74 75 77 84
Admission day
Clinical He became He started to speak He became drowsy and
Mental Status
events Continuous fever and elevated CRP despite Abx.
Immune-related colitis suspected. Cancer progressed. Death
-14 drowsiness epilepticus
-1 0 1 2 3 5 alert.
7 10 12 his name and answer could
37 not follow
42 44 74 75 77 84
observed in EEG Extubated. simple questions. commands.
Clinical He became He started to speak He became drowsy and
Mental
GTCS Status
events Continuous fever and elevated CRP despite Abx.
Immune-related colitis suspected. Cancer progressed. Death
drowsiness
3 times Seizure-free alert.
epilepticus his name and answer could not follow
observed in EEG Extubated. simple questions. commands.
Immuno- GTCS
Steroid 2nd 3rd
therapy 1st atezolizumab 3 times
pulse
Seizure-free
1st IVIG Oral steroid IVIG IVIG
Infliximab
Immuno-
Steroid 2nd 3rd
AED therapy 1st atezolizumab
LCS, VPA LEV TPM
pulse
1PRP
st IVIG
Oral steroid IVIG IVIG
Infliximab
loaded loaded added added

Other AED LCS, VPAMDZ LEV TPM PRP

medication ACV
ABx loaded loaded added added
CIV
Other
Brain medication
MRI MDZ
ABx ACV
CIV
Leptomeningeal Resolved state of
Brain MRI enhancement in leptomeningeal
GD-enhanced T1 enhancement in
image.Leptomeningeal ResolvedT1state of
GD-enhanced
enhancement in
No abnormality image.leptomeningeal
in DWIGD-enhanced
and T2 T1 enhancement
No abnormality in in
FLAIR. image. GD-enhanced T1
T2 FLAIR.
No abnormality image.
DWI T2 FLAIR GD-enhanced T1 in DWI and T2 T2 FLAIR GD-enhanced T1 No abnormality in
FLAIR. T2 FLAIR.

DWI T2 FLAIR GD-enhanced T1 T2 FLAIR GD-enhanced T1

Fig. 1. Clinical course of the patient. ABx: antibiotics, ACV: acyclovir, AED: anti-epileptic drug, CRP: C-reactive protein, CSF: cerebrospinal fluid, DWI:
diffusion-weighted image, EEG: electroencephalography, FLAIR: fluid-attenuated inversion recovery, GD-enhanced T1: gadolinium-enhanced T1, GTCS:
generalized tonic-clonic seizure, IVIG: intravenous immunoglobulin, L: lymphocytes, LCS: lacosamide, LEV: levetiracetam, MDZ CIV: continuous intrave-
nous infusion of midazolam, O: other cells, P: polymorphonuclear cells, PRP: perampanel, TPM: topiramate, VPA: valproic acid, WBC: white blood cells.

tension of the colon in abdominal X-rays and Clostridium- ab. A paraneoplastic neurological syndrome is rare in bladder
difficile-negative loose stools that occurred 2 months after cancer11 and usually precedes its diagnosis.12 The rapid pro-
the administration of atezolizumab. Changing from predniso- gression of neurological symptoms after only a single dose of
lone to methylprednisolone, increasing the dose, and admin- atezolizumab and the neurological improvement after admin-
istering infliximab were not effective, and his cancer progressed istering immunosuppressive therapy suggests that the disease
with increased metastasis. His general condition declined and course was far from a paraneoplastic syndrome. In addition,
he eventually died of septic shock and multiorgan failure. the patient was suspected as having immune-related colitis,
There have been several cases of autoimmune encephalopa- which is not expected in other types of autoimmune enceph-
thy caused by immune checkpoint inhibitors,4 most common- alitis.
ly associated with ipilimumab. Three cases of autoimmune en- It would be reasonable to attempt immunosuppressive
cephalopathy caused by the administration of ipilimumab and therapy such as steroid pulse therapy and IVIG therapy: the
nivolumab have been reported, all of which received steroid former might suppress autoimmune T-cell activity and the
pulse therapy and IVIG therapy.5-7 Rituximab was also admin- latter might help neutralizing the immune checkpoint inhibi-
istered in two of these cases.5,6 Another case of autoimmune tor. Our case suggests that IVIG should be considered in
encephalitis induced by ipilimumab and nivolumab was im- atezolizumab-associated encephalopathy that does not re-
proved by a steroid and natalizumab.8 Two cases of atezolizum- spond significantly to steroid therapy. Besides, the half-life of
ab-associated autoimmune encephalopathy improved rapidly atezolizumab is 27 days,13 and it was on the 27th day after the
following the administration of steroid therapy.9,10 administration of atezolizumab when the patient started to
We could not prove the direct causality of the encephalitis show clinical improvement. We therefore suggest that immu-
in the present case. Moreover, autoimmune antibodies such as nosuppressive therapy was effective not only against the con-
anti-NMDAR, anti-AMPA, and anti-LGI1 antibodies were not dition itself, but also helped with the natural decrement of
checked for. However, several aspects strongly suggest that it atezolizumab. Additional IVIG therapy could be considered
had been triggered by atezolizumab. The patient was diagnosed in cases of aggravation of the neurological status, but this did
with bladder cancer 1 year before administering atezolizum- not bring any improvement in our case. Perhaps natalizumab

260 J Clin Neurol 2019;15(2):259-261


could have been another option, since this might be able to
reduce inflammation of the CNS through blocking the entry
of lymphocytes into the blood–brain barrier.8
This case report raises several important clinical issues. If a
patient is suspected as having autoimmune encephalitis after
receiving an immune checkpoint inhibitor, steroid pulse ther-
apy should be started as soon as possible. Antibacterial and
antiviral therapy should also be administered concurrently in
cases where the etiology of encephalitis is uncertain. If the pa-
tient does not show clinical improvement even after steroid
pulse therapy, immediate IVIG should be considered next.
Conflicts of Interest
The authors have no potential conflicts of interest to disclose.
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