Guillain-Barré Syndrome-Like Polyneuropathy Associated ...
Transcript of Guillain-Barré Syndrome-Like Polyneuropathy Associated ...
Review ArticleGuillain-Barré Syndrome-Like Polyneuropathy Associated withImmune Checkpoint Inhibitors: A Systematic Review of 33 Cases
Yan Li, Xiuchun Zhang, and Chuansheng Zhao
Department of Neurology, The First Hospital of China Medical University, Shenyang 110001, China
Correspondence should be addressed to Chuansheng Zhao; [email protected]
Received 10 April 2021; Revised 8 June 2021; Accepted 5 August 2021; Published 19 August 2021
Academic Editor: Steven De Vleeschouwer
Copyright © 2021 Yan Li et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Immune checkpoint inhibitors (ICIs) have been increasingly used in the treatment of various types of tumors with favorableresults. But these treatments also led to a variety of immune-related adverse events (irAEs). Neurological irAEs such asGuillain-Barré Syndrome are rare and may have serious consequences once they occur. A systematic literature search wasperformed in PubMed and Embase for all case reports of GBS associated with ICIs published in English reporting onhuman beings from 1990 up to date. A total of 30 case reports (total patients = 33) were used for final analysis. Theincluded cases were from 11 countries, covering 10 tumor types, with melanoma accounting for the largest number. Themean age was 62:2 ± 11:1 years old, and males were dominant (male: 26 and female: 7). The median time of initialsymptoms was 8.2 weeks after the 1st dose of ICIs. The most common manifestations of GBS associated with ICIs wereweakness, hyporeflexia or areflexia, and paresthesia in order. The GBS subtypes suggested by electrophysiological resultswere acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and MillerFisher syndrome (MFS). The protein level of CSF in patients with GBS related to ICIs was 180:68 ± 152:51mg/dl.Immediate termination of ICIs followed by intravenous immunoglobulin was the preferred treatment option. 72.7% ofpatients recovered or had residual mild dysfunction after treatment. Elderly male patients with melanoma were most likelyto develop ICI-related GBS. The specific neurological symptoms, CSF analysis, and electrophysiological examination wereimportant means of diagnosis.
1. Introduction
In the last decade, with a better understanding of the factorsthat promote or inhibit T cell response, great progress hasbeen made on tumor immunotherapy. Immune checkpointinhibitors (ICIs) have become a powerful clinical strategyfor treating cancer, including an antibody targeting cytotoxicT lymphocyte-associated antigen-4 (CTLA-4, e.g., ipilimu-mab), antibodies directed against programmed cell deathprotein-1 (PD-1, e.g., nivolumab, pembrolizumab, and cemi-plimab), and anti-PD-1 ligand (PD-L1, e.g., atezolizumab,durvalumab, and avelumab) [1]. These drugs can be usedalone or in combination with other immunotherapy [2] orchemotherapy [3] to improve the survival of cancer patients.Currently, it has been used for the treatment of tumors oflung, kidney, liver, bladder and breast cancer, melanoma,and lymphomas [4–6]. ICIs improve the prognosis and qual-
ity of life of patients, whereas the increase of use also bringsvarious immune-related adverse events (irAEs). The derma-tologic, gastrointestinal, pulmonary, hepatic, and endocrinesystems were most frequently involved.
Cases of neurological irAEs are rare, accounting for lessthan 3% [7]. So far, the best-characterized central nervoussystem irAEs are encephalitis and meningitis. And neuro-logic irAEs known to be most relevant to the peripheral ner-vous system are peripheral neuropathies, GBS, myastheniagravis, and myositis [8]. Once they occur, such as encephali-tis, Guillain-Barré syndrome, or myasthenia gravis, they candevelop into serious consequences or even death.
Epidemiology shows that nearly two-thirds of patientswith GBS have a recent history of infection before the illness[9]. GBS with potentially life-threatening consequencesoccurs in approximately 0.1-0.2% of patients treated withICIs [10]. To date, information on the incidence,
HindawiBioMed Research InternationalVolume 2021, Article ID 9800488, 17 pageshttps://doi.org/10.1155/2021/9800488
characteristics, and outcomes of GBS associated to ICIs treat-ment is very limited. And the available information varieswidely in diagnosis and treatment. Multidisciplinary treat-ment of tumors urgently requires neurologists and oncolo-gists to accurately understand the clinical manifestationsand treatment of ICI-related GBS.
This review summarized the published data on GBS orGBS-like disease occurring in patients after treatment withICIs from 1990 up to date and analyzed their time patternsof occurrence, clinical presentation, diagnosis, treatment,and prognosis.
2. Methods
A systematic literature search was performed in PubMed andEmbase for all case reports of GBS associated with ICIs pub-lished in English reporting on human beings from 1990 up todate. For the case reports search, the keywords used were asfollows: [“Guillain-Barré Syndrome” OR “acute inflamma-tory demyelinating polyradiculoneuropathy” OR “MillerFisher Syndrome” OR “acute motor axonal neuropathy”OR “acute motor-sensory axonal neuropathy”] AND[“Immune Checkpoint Inhibitors”OR “Immune CheckpointBlockers” OR “PD-L1 Inhibitors” OR “Programmed Death-Ligand 1 Inhibitors”OR “CTLA-4 Inhibitors”OR “CytotoxicT-Lymphocyte-Associated Protein 4 Inhibitors” OR “PD-1Inhibitors” OR “Programmed Cell Death Protein 1 Inhibi-tor”]. Abstracts of medical conference were excluded. Foreach case, we extracted data on demographics and clinicalmanifestations and adjuvant examinations (imaging, cere-brospinal fluid, and electrophysiology). If gender, age, GBSclinical variation [11], electrophysiological subtype [12], orresults of the relevant examination were not explicitlyreported in the article, this case could not be considered foranalysis. The search was conducted by Yan Li and XiuchunZhang. The selection of the articles should be agreed uponby the above two persons.
GraphPad Prism 8 was used for statistical analysis, andcontinuous data were expressed in the form of mean ±standard deviation or median. P < 0:05 was considered statis-tically significant. Since the proportion of males and femalesin the included cases was significantly different, unpaired t-test was used to analyze the ages of males and females.
Because the patient’s personal information was providedin the original case report, authorization from the EthicsCommittee was not required for this study.
3. Results
Using the search terminology, 38 case reports were identifiedfrom our database search, covering the period from January2008 to February 2021. Three patients were excluded due tolack of age and CSF protein concentration, respectively.One case report was excluded because it was written in Japa-nese. Two case reports were not included because the diagno-sis of GBS was ambiguous due to a disease progressionsimilar to acute-onset CIDP. In addition, two patients witha history of GBS had no serious toxicities or deteriorationof the previous autoimmune disorders after ICI therapy.
The two patients were also excluded. A total of 30 casereports (total patients = 33) were used for final analysis [13–42]. According to the diagnostic criteria of GBS in NINDS,all the above 33 cases were consistent with the features ofGBS. The clinical data and diagnostic details of all includedpatients were summarized in Tables 1–3.
3.1. Demographic Characteristics. GBS cases (n = 33) werefrom the United State (n = 13), United Kingdom (n = 3),Japan (n = 2), Italy (n = 2), Belgium (n = 2), Australia (n = 2), China (n = 1), Greece (n = 1), Netherlands (n = 4), France(n = 2), and German (n = 1) (Table 1). Of the 33 cases,twenty-six of these cases were male and seven were female,with an average of 62:2 ± 11:1 years (median: 65 years andrange: 37-81 years). There was a male preponderance in 33ICI-associated GBS patients we collected, with 3.7 times asmany cases as female (26 vs. 7 cases: 78.8% vs. 21.2%). Therewas a significant difference between male and female ages atonset (mean: 64:4 ± 10:3 vs. 54:1 ± 11:1 years, P = 0:0278).The reports of comorbidities were variable, and no epidemicsof specific diseases had been observed, so we did not analyzethe comorbidities.
3.2. Immune Checkpoint Inhibitors and Tumor Type. Of ICI-associated GBS patients, sixteen patients exposed to nivolu-mab, eleven patients were investigated with ipilimumab,and seven patients were treated with pembrolizumab. Ofthese, four patients received nivolumab in combination withipilimumab, and one patient received nivolumab in combi-nation with pembrolizumab. In the above cases, the types oftumor the patients suffered from were melanoma (n = 20)[13, 14, 16, 17, 23, 24, 28, 29, 31–37, 39–42], lung tumor(n = 7) [18, 21, 25, 26, 28, 30, 38], urinary tumor (n = 5)[13, 15, 19, 20, 22], and nasal cancer (n = 1) [27]. The detailswere summarized in Tables 4 and 5.
3.3. Clinical Features of GBS Spectrum. The onset time ofsymptoms in 32 patients was analyzed, and the results sug-gested that the median time was 8.2 weeks after the initiationof ICI treatments. The minimum was 0.7 weeks (5 days) [37],and themaximumwas 59 weeks [19]. As shown in Table 1, thetime to neurological plateau was mentioned in 23 cases, withan average of 16:0 ± 8:4 days (range 7-44 days). The mostcommon manifestations of GBS associated with ICIs wereweakness (93.9%, 31/33), hyporeflexia or areflexia (90.9%,30/33), and paresthesia (81.8%, 27/33). Among them, sensorysymptoms and paraparesis or tetraparesis cooccurred in 45.5%(15/33) of cases. Other less common symptoms included cra-nial nerve involvement (20.7%, 7/33), dysphagia or dysarthria(18.2%, 6/33), respiratory symptoms (21.2%, 6/33), and ataxia(9.1%, 3/33). There were also 2 rare cases of GBS patients withdysautonomia as the onset symptoms [17, 36]. The HughesFunctional Grading Scale (HFGS) [43] was used to evaluatethe clinical severity, and higher numbers indicated moresevere disability. The average was 3:85 ± 1:42, with a highscore of 6 and a low score of 1 (Table 2).
3.4. Electrophysiological, CSF, and Imaging Results. Twenty-seven patients underwent electrophysiological examination,and 18 cases had detailed electrophysiological reports. In
2 BioMed Research International
Table1:Maincharacteristicsanddiagno
sticdetails
ofinclud
edcases.
Case
Article
Cou
ntry
Age
Sex
Tum
ortype
ICIs
Tim
eof
GBSon
set
after
theinitiation
treatm
ent(w
eek)
Tim
eto
neurological
plateau(days)
GBSdiagno
sis
1Muralikrishnan,Setal.[14]
USA
65Female
Melanom
aPem
brolizum
ab4weeks
44Clin
ical+CSF
+electrop
hysiology
2Han,C
etal.[15]
China
55Male
RCC
Pem
brolizum
ab16
weeks
Nomention
Clin
ical+CSF
+electrop
hysiology
3Arora,A
etal.[16]
USA
70Male
Melanom
aand
prostatecancer
Pem
brolizum
ab12
weeks
16Clin
ical+CSF
+electrop
hysiology
4Yuen,
Cetal.[17]
USA
66Male
Melanom
aNivolum
ab12
days
(1.7weeks)
34Clin
ical+CSF
+electrop
hysiology
5Pom
erantz,M
etal.[18]
Italy
58Male
SCLC
Acombination
ofnivolumab
and
pembrolizum
ab
59days
(8.4weeks)
Nomention
Clin
ical+CSF
+electrop
hysiology
6Pierrard,
Jetal.[19]
Belgium
70Male
Urothelial
carcinom
aNivolum
ab59
weeks
14Clin
ical+CSF
+electrop
hysiology
7McN
eill,C.J
etal.[20]
UK
68Male
RCC
Nivolum
ab8weeks
13Clin
ical+CSF
+electrop
hysiology
8Kyriazoglou
,Aetal.[22]
Greece
74Male
Bladd
ercancer
Nivolum
ab8weeks
15Clin
ical+CSF
+electrop
hysiology
9Mazzaschi,G
etal.[21]
Italy
80Male
Lung
adenocarcino
ma
Nivolum
ab12
days
(1.7weeks)
22Clin
ical+CSF
+electrop
hysiology
10Gravbrot,N
etal.[23]
USA
71Male
Melanom
aIpilimum
ab10
weeks
Severald
ays
Clin
ical+CSF
+electrop
hysiology
11Wilson
,Retal.[24]
UK
52Male
Melanom
aNivolum
abIpilimum
ab4weeks
7Clin
ical+CSF
+electrop
hysiology
12Thapa,B
etal.[25]
USA
60Male
Lung
adenocarcino
ma
Nivolum
ab14
weeks
Nomention
Clin
ical+CSF
+electrop
hysiology
13Ong,S
etal.[26]
UK
66Male
Lung
adenocarcino
ma
Pem
brolizum
ab6.5weeks
16Clin
ical+electrop
hysiology
14Nuk
ui,T
etal.[27]
Japan
45Male
Nasalcancer
Nivolum
ab10
weeks
14Clin
ical+CSF
+electrop
hysiology
15Manam
,Retal.[28]
USA
73Male
Lung
adenocarcino
ma
Pem
brolizum
ab3weeks
Nomention
Clin
ical+CSF
16Manam
,Retal.[28]
USA
81Male
Melanom
aPem
brolizum
ab10
weeks
Nomention
Clin
ical+CSF
+electrop
hysiology
17Garcia,C.A
etal.[29]
USA
55Male
Melanom
aIpilimum
ab6weeks
Nomention
Clin
ical+CSF
+electrop
hysiology
18Fu
kumoto,Yetal.[30]
Japan
66Male
NSC
LCNivolum
ab3weeks
16Clin
ical+CSF
+electrop
hysiology
19Cafuir,Letal.[31]
USA
42Male
Melanom
aIpilimum
ab10
weeks
13Clin
ical+CSF
+electrop
hysiology
20Baird-G
unning,
J.J.D
etal.[31]
Australia
58Female
Melanom
aNivolum
abIpilimum
ab10
days
(1.4weeks)
12Clin
ical+CSF
+electrop
hysiology
3BioMed Research International
Table1:Con
tinu
ed.
Case
Article
Cou
ntry
Age
Sex
Tum
ortype
ICIs
Tim
eof
GBSon
set
after
theinitiation
treatm
ent(w
eek)
Tim
eto
neurological
plateau(days)
GBSdiagno
sis
21Supakornnu
mpo
rn,
Setal.[33]
USA
77Male
Melanom
aNivolum
abIpilimum
ab10
weeks
14Clin
ical+CSF
+electrop
hysiology
22Schn
eiderbauer,R
etal.[34]
German
51Male
Melanom
aNivolum
ab20
weeks
Nomention
Clin
ical+CSF
+electrop
hysiology
23Patel,R
.Jetal.[35]
USA
71Male
Melanom
aIpilimum
ab10
weeks
10Clin
ical+electrop
hysiology
24KellyWu,
Wetal.[36]
USA
37Female
Melanom
aand
papillary
thyroidcancer
Ipilimum
abNomention
9Clin
ical+CSF
+electrop
hysiology
25Gu,
Yetal.[37]
Australia
49Female
Melanom
aIpilimum
abNivolum
ab5days
(0.7weeks)
11Clin
ical+CSF
+electrop
hysiology
26Jacob,Aetal.[38]
USA
68Female
Lung
squamou
sandcellcarcinom
aNivolum
ab12
weeks
14Clin
ical+CSF
+electrop
hysiology
27Gaudy-M
arqu
este,C
etal.
[40]
France
65Male
Melanom
aIpilimum
ab6weeks
11Clin
ical+CSF
28Bot,I
etal.[41]
Netherlands
63Male
Melanom
aIpilimum
ab12
weeks
Afewdays
Clin
ical+CSF
+electrop
hysiology
29Wilgenho
f,Setal.[42]
Belgium
57Female
Melanom
aIpilimum
ab8weeks
Nomention
Clin
ical+CSF
+electrop
hysiology
30de
Maleissye,M
.F.etal.[39]
France
45Female
Melanom
aPem
brolizum
ab9weeks
21Clin
ical+CSF
+electrop
hysiology
31Janssen,
J.B.E.etal.[42]
Netherlands
74Male
Prostatecancer
Pem
brolizum
ab6weeks
21Clin
ical+CSF
+electrop
hysiology
32Janssen,
J.B.E.etal.[13]
Netherlands
67Male
Melanom
aNivolum
ab3weeks
7Clin
ical+CSF
33Janssen,
J.B.E.etal.[13]
Netherlands
55Male
Melanom
aPem
brolizum
ab16
weeks
15Clin
ical+CSF
LEs:lowerextrem
ities;UEs:up
perextrem
ities;NSC
LC:non
-small-celllung
cancer;SCLC
:small-celllung
cancer;R
CC:renalcellcarcinom
a.Tim
etoNadir:daysbetweentheon
setofn
eurologicalsym
ptom
sandthe
developm
entof
theworstclinicalsymptom
s(noprogression).
4 BioMed Research International
Table2:The
clinicaldata
anddiagno
sticdetails
ofallincludedpatients.
Case
GBSclinicalpicture
Hughes
scale
Onset
Motor
Sensory
Reflex
Auton
omic
disturbances
Respiratory
involvem
ent
1LE
sascend
ingnu
mbn
ess
bilaterally
Muscleweakn
essin
lower
limbs
andlefthand
Lefttongue
numbn
essanddiminished
facialsensation.
Generalized
areflexia
Non
eNo
2
2Weakn
essandnu
mbn
essof
the
extrem
ities
Amild
decreasein
musclestrength
ofthelim
bsParesthesiaof
thefour
extrem
ities
Absence
oftend
onreflex
ofthelim
bs.N
opathologicalreflex.
Non
eNo
1
3Progressive
bilateralL
Eweakn
ess
Decreased
strength
inlower
extrem
ities
Slight
impairmentof
touchandpinp
rick
sensation,
worsening
back
pain
and
painfulb
urning
infeetbilaterally
Bilaterally
absent
patellarandankle
reflexes
Non
eNo
6
4Bilateralfi
nger
andtoeparesthesia
followed
byweakn
essof
thelower
andthen
upperlim
bs
Absentpinp
rick
sensationandvibratory
sensation
Generalized
areflexia
Tachycardia
hypo
tension
Respiratory
distress
6
5BilateralL
Eparesthesias,p
ain
BilateralL
Eweakn
essand
progressivelyworsenedto
acompleteinability
toam
bulate
Dim
inishedsensoryperception
inLE
s,pinp
rick
over
alld
istalextremities,
markeddecrease
invibrationsensation
andabsent
prop
rioception
inLE
s
Generalized
areflexia
Non
eNo
4
6Rapidlyprogressingweakn
essof
LEs
Rapidlyprogressingup
perlim
bweakn
essover
2weeks
Non
eNormal
Non
eNo
3
7Progressive
weakn
essandsensory
disturbancein
face
andlim
bs
Generalweakn
ess.slurredspeech,
doub
levision
,diffi
culty
swallowing,within72
hours,
rapidlyworsening
bulbar
symptom
s
Paresthesiaof
hishand
sandfeet,an
unsteady
gait
Normaltone,pow
erand
deep
tend
onreflexes
Non
eShortnessof
breath
5
8Muscleweakn
essandfatigue
Severe
proxim
odistalw
eakn
essin
theUEsandLE
sIm
pairmentof
position
sense,vibration,
stereognosisn,
andgraphesthesia
Areflexiaof
the4lim
bsandabsent
pathologic
reflexes
Non
eNo
3
9Paresthesiaandbu
rningpain
arose
inLE
s,followed
byaprogressive
bilateralw
eakn
ess
Symmetricdistaldo
minant
weakn
essanddram
atically
worsened.
Lossof
fine
motor
controlo
ndistalUEs
Painandsevernu
mbn
ess.
Hypoareflexiaand
decreaseddeep
tend
onreflexes
Non
eNo
4
10Severe,p
rogressive,sym
metric
ascend
ingweakn
ess
The
paralysisprogressed
toinability
tostandandarm
weakn
ess
Mild
dysphagia
Witho
utsensoryloss
Uno
btainabledeep
tend
onreflexes
Non
eShortnessof
breath
4
11Headacheandgeneralized
tiredn
ess
Bilateralfacialw
eakn
ess,distal
limbweakn
ess
Progressive
hand
andfeetnu
mbn
ess
Reduced
deep
tend
onreflexes
Non
eNo
3
12Severe
weakn
essof
allextremities
Mild
tomod
eratedecrease
inmotor
strength
inall4
extrem
ities,
LEsworse
than
UEs
Sensoryloss
ofvibration/prop
rioception
inbilateralL
Es
Dim
inishedreflexes
inbilateralL
Esbu
tno
rmal
reflexes
inbilateralU
Es
Non
eNo
4
5BioMed Research International
Table2:Con
tinu
ed.
Case
GBSclinicalpicture
Hughes
scale
Onset
Motor
Sensory
Reflex
Auton
omic
disturbances
Respiratory
involvem
ent
13LE
pain,p
aresthesiaandweakn
ess
UEweakn
essandalower
motor
neuron
patternofright-sidedfacial
weakn
ess
Bilateral,predom
inantly
distalLE
weakn
ess
Reduced
sensation
Generalized
areflexia
Non
eNo
2
14Diplopia,muscleweakn
ess,and
numbn
essof
extrem
ities
Bed-bou
ndRight
externalop
hthalm
oplegia,
leftfacialnervepalsyandbu
lbar
palsy,severe
muscleweakn
ess
Bilateralfaciald
ysesthesia
Absentdeep-tendo
nreflexes
Non
eNo
4
15Generalized
weakn
ess
Progressive
weakn
essin
the
bilateralL
Esgreaterthan
theUEs
Witho
utsensoryloss
Absentdeep
tend
onreflexes
inthebilateral
UEsandLE
sNon
eNo
3
16Progressive
weakn
essin
the
bilateralL
Esandthen
spreadingto
thebilateralU
Es
Astrength
of2/5in
thebilateral
UEsand0/5in
thebilateralL
Es
andno
bulbar
muscleweakn
ess
Witho
utsensoryloss
Areflexia
Non
eRequiring
mechanical
ventilation
4
17Paresthesiasin
distalLE
sbilaterally
Ascending
weakn
ess
Ascending
paresthesias
Lossof
deep
tend
onreflexes
Non
eNo
2
18Muscleweakn
essof
theLE
sWeakn
essrapidlyprogressed
and
becamebed-boun
dParesthesiasof
thedistallim
bsAbsence
ofdeep
tend
onreflexes
ofthefour
extrem
ities
Non
eNo
4
19Bilateralthigh
weakn
essand
paresthesiaof
thesolesof
hisfeet
LEsweakn
ess,worsenedrapidly
Painandnu
mbn
ess.
Vibration
inthetoes
impaired
Tendo
nreflexes
inthe
LEswereabsent.
Non
eNo
3
20Bilateralp
tosisandexternal
ophthalm
oplegia
Proximalup
perandlower
limb
weakn
ess,neck
flexionweakn
ess
Markedtrun
caland
limbataxiawere
evidentaccompanied
byim
paired
prop
rioception
.Areflexia
Non
eNo
2
21
Rapidlyprogressivenu
mbn
essand
tinglin
gsensationin
both
hand
sandfeet,generalized
muscle
weakn
esswithmultiplefalls
Severe
distalandproxim
almuscle
weakn
essin
both
upperandlower
extrem
ities
Lossof
allsensory
mod
alitiesin
distal
upperandlower
extrem
ities
Generalized
areflexia
Non
eNo
4
22Muscularweakn
essin
both
legs
andperiph
eralparesthesias
Muscularweakn
essin
both
legs
Form
icationin
both
hand
s,bilateral
hypo
esthesiaof
thelegs
upto
theup
per
thigh
Absenttend
onreflexes
inboth
legs
Non
eNo
1
23Progressive
LEweakn
ess
Progressive
andascend
ingmuscle
weakn
ess
Witho
utsensoryloss
Absentdeep
tend
onreflexes
Non
eNo
4
24
Ton
icallydilatedpu
pil,
gastrointestinaldysm
otility,
urinaryretention,
andprofou
ndorthostatichypo
tension
Worsening
dysarthria,generalized
weakn
ess
Ascending
paresthesias,absent
prop
rioception
Absentdeep
tend
onreflexes
Non
eNo
5
6 BioMed Research International
Table2:Con
tinu
ed.
Case
GBSclinicalpicture
Hughes
scale
Onset
Motor
Sensory
Reflex
Auton
omic
disturbances
Respiratory
involvem
ent
25Painful
paresthesiain
the
extrem
ities
Proximallossof
antigravitypo
wer
andlossof
independ
entmobility
Sensoryloss
Absentreflexes
Nausea,
postural
hypo
tension
constipation
No
4
26FatigueandbilateralL
Eweakn
ess
Profoun
dweakn
essin
lower
extrem
ities,progressiveloss
ofmotor
function
Tinglingsensationin
feet,p
rogressive
loss
ofsensoryfunction
Lossof
deep
tend
onreflexesinallextremities
associated
with
completelack
ofstrength
Non
eRespiratory
muscle
paralysis
5
27Pruritus,abdo
minalmeteorism
,andnatisea
Symmetricalw
eakn
essin
the4
limbs
Mild
bilateralh
ypoesthesiain
the
extrem
ities
Disappearance
ofdeep
tend
onreflexes
Abd
ominal
meteorism
andnatisea
Worsening
ofthe
respiratory
function
6
28Paresthesiasof
thefeetand
fingertips
andun
steady
gait
Amild
tetraparesis
Sensorylossin
both
hand
sandfeet
Generalized
areflexia
Non
eNo
5
29Dysesthesia(num
bnessand
tinglin
g)at
thehand
sandfeet
Rapidlyascend
inglossof
motor
function
Rapidlyascend
inglossof
sensory
function
Lossof
thedeep
tend
onreflexes
Non
eRespiratory
insufficiency
5
30Paresthesiaandhypo
esthesiaof
all
limbs
Rapidlyfollowed
bysymmetrical
motor
weakn
essin
legs
Peripheralfacialp
aralysis
Paresthesiaandhypo
esthesia
Areflexiain
thelegs
Non
eNo
6
31Painful
fingersandloss
oftaste
Weakn
essin
allextremities
Sensorylossin
allextremities
Areflexiain
both
legs
Non
eRespiratory
function
was
affected
6
32Muscularpainsin
hisarmsand
legs
witho
utparalysis
Lossof
motor
function
sin
the
hand
sandLE
sLo
ssof
sensor
function
sin
thehand
sand
LEs
Areflexiaof
LEs
Non
e
The
respiratory
function
preserved
4
33Ascending
weakn
ess,paresthesia,
andsensorylossprogressive
Weakn
essof
thelegs
Sensorydisturbances
ofthelower
extrem
ities
Areflexia
Non
e
The
respiratory
function
preserved
3
LEs:lower
extrem
ities;UEs:up
perextrem
ities.
7BioMed Research International
Table3:Electroph
ysiology,C
SF,imaging,treatm
ent,andclinicalou
tcom
es.
Case
NCSfind
ing
CSF
Imaging
Treatment
Outcome
Protein
(15-45
mg/dl)
Cell(<5
/μl)
1
4weeks
afterICIs:n
otsuggestive
ofneurop
athy
78OL(+)
17IV
IGover
5days
forthe
firsttime
Significant
improvem
entin
muscle
weakn
ess.18
days
afterdischarge,the
diseasedevelopedan
ascend
ingparalysis
oftheextrem
ities.
44days
later:acuteandchronic
demyelin
atingpo
lyneurop
athy
175OL(-)
3
PLE
Xfor7days
and
solumedrolfor
5days
insteadof
IVIG
for
reoccurrence
Melanom
aprogressionoccurred
abou
t1
year
afterthelastdo
seof
pembrolizum
ab.
Rechallengingwithipilimum
ab.O
nly
ongoingbilateralleg
tinglin
ganddiarrhea
2Acutemotor
andsensoryaxon
alneurop
athy
58.33
8MRIof
thebrainandspinalcord
was
norm
al.
Oraltreatmentwith
dexamethasone
andthen
switched
toIV
IGalon
gwithprednisone
Symptom
sim
proved
during
1weekof
treatm
ent.After
1mon
th,w
alking
and
standing
was
norm
al.
Norecurrence
oftumor
3AID
P405
4SpinalMRI:abno
rmalthickening
and
enhanced
posteriornerveroots(L4-L5
,L5
-S1),n
ofeatures
ofmetastaticdisease
Dexam
ethasone
for6
days
andIV
IGfor5days
Hydroceph
alus,ventricular
enlargem
ent
andbed-boun
dDiedafterwithd
rawfrom
lifesupp
ort
4Dysautono
miasecond
aryto
AID
P91
0IV
IG+prednisone+PLE
XLife-sustainingtherapies
Respiratory
distress,tachycardia,and
hypo
tension
Diedafterwithd
rewlife-sustain
5AID
P124
41Brain
aswellasthelumbarandthoracic
spineMRI:no
clearcord
orcaud
aequina
involvem
entdespitespinemetastases
IVIG
for5days
Rehabilitation
Nootherpo
tentialagentsweregivenand
alive6mon
thsaftertheuseof
last
immun
otherapies.
6AID
P105
8SpineMRI:severe
stenosisof
lumbar
spinalcanal
IVIG
for5days
and
methylpredn
isolon
edu
ring
7days
Arapidclinicalim
provem
entwas
observed
withinthefirst3days.
Methylpredn
ison
ewas
tapered
progressivelyover
10weeks.C
ompletely
recovered.6mon
thslater,cancer
remains
stable.
7MFS
175
5Brain
andcervicalspineMRI:no
rmal
IVIG
andintravenou
smethylpredn
ison
efollowed
byoral
prednisolone
Severe
globallim
bweakn
essand
respiratorydecompensationdeveloped
after3days
ofIV
IG.
Respiratory
function
andmotor
weakn
ess
improved
after9days
ofcorticosteroid
treatm
ent.
Rehabilitation
after3mon
thsoftreatm
ent
8AID
P140
2Brain
andcord
MRI:no
nspecificcerebral
white-m
atterlesion
s
IVIG
for5days
alon
gwithprednisone
for1
mon
th
Improvem
ent.
Disease
progressed
withincreased
numberandsize
oflung
metastases.Died
from
sepsis
8 BioMed Research International
Table3:Con
tinu
ed.
Case
NCSfind
ing
CSF
Imaging
Treatment
Outcome
Protein
(15-45
mg/dl)
Cell(<5
/μl)
9AID
P88
2Brain
andspinalMRI:no
evidence
ofmetastasesor
ischaemicand/or
hemorrhagiclesion
s
Methylpredn
isolon
eIV
IGfor5days
Predn
ison
e
Witho
utclinicalbenefit
Legweakn
ess,nu
mbn
essin
patient’s
fingers,andparesthesiadram
atically
improved.
Afurtherim
provem
entw
asobtained
after
2weeks
ofprednisolone.
10Acutesensorim
otor
polyradiculoneurop
athy
with
mixed
axon
al/dem
yelin
ating
<45
<5SpinalCT:n
ormal
IVIG
for5days
and
prednisone
30mgdaily
atthesametime
3weeks
later,im
proved
rapidlyand
transition
topembrolizum
abwithno
evidence
ofGBS
11AID
P230
0SpinalMRI:no
rmal
IVIG
Goodrecovery
12AMAN
37mg/dl
but
elevated
IgG
levels
2Predn
ison
eIV
IG
Symptom
scontinuedto
worsen.
Minim
allyim
proved
butprevented
furtherprogression
13AID
PNolumbarpu
ncture
was
performed.
SpinalMRI:degenerative
changeswith
noevidence
ofcord
compression
Methylpredn
ison
eand
IVIG
Predn
ison
e
19days
afteradmission
,weakn
essand
numbn
essmostly
resolved.
1mon
thlater,neurologicalrecovery
except
formild
residu
alparesthesias
ofthefeet
14Multiplecranialn
europathyand
AID
P350
7Lu
mbarspineMRI:aredu
ctionof
gado
linium
enhancem
entof
nerveroots
andcaud
aequina
IVIG
Steroidpu
lsetherapy
Multiplecranialn
europathieswere
mod
eratelyim
proved
after4weeks
oftreatm
ent.
Muscleweakn
essremarkablyim
proved
afterthe3coursesof
therapy.
15AID
P680
<5Methylpredn
isolon
ealon
gwithIV
IGPLE
X
Strength
diminishedto
2/5in
thebilateral
UEsandLE
s.Respiratory
status
worsened.
Respiratory
status
improved,and
motor
function
gradually
recovered.
16AID
P560
<5Brain
CT:a
hemorrhagewithinon
eof
his
metastaticlesion
sandassociated
vasogenicedem
a
Methylpredn
isolon
ealon
gwithIV
IGfor5
days
PLE
X
Acutehypo
xicrespiratoryfailu
re,
requ
iringmechanicalventilation
.After
five
days
oftreatm
entw
itho
utanyclinical
improvem
ent.
Ahemorrhagewithinon
eof
metastatic
lesion
sandassociated
vasogenicedem
a.Diedafterthewithd
rawnof
care
9BioMed Research International
Table3:Con
tinu
ed.
Case
NCSfind
ing
CSF
Imaging
Treatment
Outcome
Protein
(15-45
mg/dl)
Cell(<5
/μl)
17AID
P175
Lymph
ocytic
pleocytosis
Brain
andspinalMRI:abno
rmal
enhancem
entinvolvingthebilateral5
th,
7thand8thcranialn
erves,caud
aequina
nerverootsas
wellastheconu
ssurface
andperiph
eralnerves
atthe
thoracolum
barjunction
Methylpredn
isolon
e
Motor
symptom
sin
hand
sandlower
extrem
itiesim
proved
rapidlyafter2days
andgradually
recoveredover
a12-w
eek
period
.Weakn
essresolved
completely,residu
alminim
alparesthesias
18AID
P339
4Predn
ison
e(60mg/day)
IVIG
(0.4g/kg)for5days
Symptom
sworsened
Gradu
allyim
proved
3mon
thslater,he
was
ableto
walkwitha
cane.
19
Asymmetric,subacuteto
early
chronicandon
goinglumbar
polyradiculoneurop
athy
with
axon
alinvolvem
entand
demyelin
ating
>300
1SpinalMRI:diffuseenhancem
ent
surrou
ndingtheentire
conu
sandallo
fthenerveroots
Dexam
ethasone
Partialrespon
sesystem
icallyand
neurologicim
provem
ent
6.5mon
thslater,melanom
aprogressed.
20MFS
anddemyelin
ating
sensorim
otor
polyneurop
athy
125
0
IVIG
2g/kg
for5days
andmethylpredn
isolon
efollowed
byaweaning
dose
oforalprednisolone
PLE
X
Mod
estclinicalim
provem
ent
Significant
function
alim
provem
entand
completerecoveredatlast.B
utmelanom
ahadprogressed.
21AID
P86
0IV
IGover
5days
Predn
ison
e90
mg/day
Dysph
agiarequ
iringnasogastrictube
for
feeding
After
6mon
ths,neurologicalcond
ition
improved
significantlyandthedysphagia
completelywas
resolved.N
umbn
esswas
still
presentbu
tim
proved.
22AID
P73
<5IV
IGfor5days
Methylpredn
isolon
e
Did
notlead
toanyclinicalim
provem
ent
Clin
icalrecovery
started48
hlaterand
was
nearlycompleteafter6weeks.
23Acutesensorim
otor
polyradiculopathywithmixed
axon
al/dem
yelin
atingfeatures
39<5
Tho
racicspineandlumbarspineCT:
degenerative
changes
IVIG
Markedim
provem
enton
treatm
entday5
24
GBSpresenting
asdysauton
omia,
alength-dependent,sensorimotor
polyneurop
athy
withaxon
aland
demyelin
atingprop
erties
Nolumbarpu
ncture
was
performed.
IVIG
Dysautono
miaandweakn
esspersisted,
andcardiovascular
andrespiratorystatus
improved
by2mon
ths.
Persistenturinaryretention,
orop
haryngealdysph
agia,and
generalized
weakn
ess
10 BioMed Research International
Table3:Con
tinu
ed.
Case
NCSfind
ing
CSF
Imaging
Treatment
Outcome
Protein
(15-45
mg/dl)
Cell(<5
/μl)
25AMSA
Nwithautono
mic
symptom
s115
15SpinalMRI:no
rmal
IVIG
(0.4g/kg/d)for5
days
Methylpredn
isolon
e(1g/dfor5days,then
500mg/dfor3days)
followed
bytapering
oral
prednisone
(1mg/kg/d)
PLE
X(5
changesover
2weeks,followed
byweeklyexchanges)
Symptom
sstabilizedwithmild
improvem
ent,yeton
emon
thlater,it
developedworsening
weakn
essand
ongoingpainfulp
aresthesia.P
ersistent
nausea
coup
ledwithpo
sturalhypo
tensin
andconstipation
6weeks
later(12weeks
afterinitial
treatm
ent),the
patienthadon
lymild
weakn
ess.
9mon
thslater,melanom
aprogressed.
26GBS
850
SpineMRI:no
rmal
IVIG
+PLE
X
Within2ho
urs,respiratorymuscle
paralyzed,
andventilatorsupp
ortwas
applied.
Shewas
extubatedafter11
days
and
expiredwithinafewho
urs.
27
Acute,generalized,sym
metrical,
andsensorim
otor
neurop
athy,
impo
ssibletodistinguishaxon
alor
demyelin
atingdisorder
becauseof
severe
limbedem
a
160
0Methylpredn
isolon
ePLE
X
Clin
icalstatus
didno
tim
prove.
Diedof
multivisceralfailu
rewithinafew
days
28AMSA
N89
0Cervicalspine
MRI:no
rmal
IVIG
The
musclestrength
ofalllim
bsslightly
increased.
But
3days
later,died
from
respiratoryinsufficiency
29AID
P167
<2Brain
andspinalMRI:no
rmal
Methylpredn
isolon
eRecovery
30AID
P56
Normal
Predn
isolon
eIV
IG
The
neurologicsymptom
sreachedthe
peak
within3weeks
anddecreasedover
thenext
2mon
ths.
31MFS
81OL(+)
Normal
Centralnervou
ssystem
imagingshow
edno
cerebralor
vertebralp
atho
logy.
Predn
isolon
eIV
IGPLE
X
Aslight
improvem
entwiththese
treatm
ents
2mon
thslater,died
from
pneumon
ia
32GBS
107.5
61Predn
isolon
eIV
IG
The
pain
was
greatlydiminished.
8mon
thslater,themotor
andsensor
function
ofextrem
itieswerestill
slow
lyrecovering.
33GBS
204.6OL(+)
Normal
Predn
isolon
eIV
IGMethylpredn
isolon
e
The
mild
persistent
weakn
essof
hisfeet
extensorsandmild
sensorylossandataxia
AID
P:acuteinflam
matorydemyelin
atingpo
lyradiculoneurop
athy;M
FS:M
iller
Fisher
synd
rome;IV
IG:intraveno
usim
mun
oglobu
lin;P
LEX:plasm
aexchange;A
MAN:acutemotor
axon
alneurop
athy;A
MSA
N:
acutemotor
andsensoryaxon
alneurop
athy;O
L:oligoclonalb
ands.
11BioMed Research International
Table4:Tum
ortype
andim
mun
echeckp
oint
inhibitors.
Tum
ortype
Mon
otherapy
Com
bination
therapy
Pem
brolizum
abNivolum
abIpilimum
abNivolum
abandipilimum
abPem
brolizum
abandnivolumab
Melanom
a(20)
(M:F=
14:6)
63
74
Lung
cancer
(7)
(M:F=
6:1)
NSC
LS(1)
1
SCLS
(1)
1
Adeno
carcinom
a(4)
22
Squamou
scellcarcinom
a(1)
1
Urinary
tumor
(5)
M:5
RCC(2)
11
Urothelialcarcino
ma(1)
1
Bladd
ercancer
(1)
Prostatecancer
(1)
11
Nasalcancer
(1)
M:1
1
NSC
LS:n
on-small-celllung
cancer;SCLS:small-celllung
cancer;R
CC:renalcellcarcinom
a.
12 BioMed Research International
the remaining cases, only the GBS subtype was mentioned.54.5% (18/33) of cases were consistent with AIDP [16–19,21, 22, 24, 26–30, 33, 34, 39, 42] and axonal damageaccounted for 12.1% (4/33, AMSAN: 3 and AMAN: 1) [15,23, 25, 27]. The subtypes in four cases were equivocal becausethey showed mixed features of axonal injury and demyelin-ation [23, 31, 35, 36]. There were also three cases, two withMFS [13, 20] and the other with MFS-GBS overlap [32].Regrettably, there were two cases of GBS diagnosis with nomention of subtypes [13, 38, 40].
CSF analysis was performed in 31 out of the 33 cases. Theaverage protein level of CSF in patients with GBS related toICIs was 180:68 ± 152:51mg/dl (range: 37-680mg/dl).63.6% of the cases (21/33) presented with typical albumino-cytological dissociation (cells ≤ 5/μl and CSF protein > 45mg/dl) [14, 16, 20–22, 24, 28, 30–34, 38, 40–42]. The medianvalue of CSF protein was 124.5mg/dl (range: 73-680mg/dl).Slight pleocytosis (i.e., cell count > 5/μl) was detected in4/33 cases (12.1%) with a maximum cell count of 15/μl anda median CSF protein of 115mg/dl [15, 19, 27, 37]. CSF pro-tein values and cell counts were normal in three cases [23, 25,35], and there was elevated CSF immunoglobulin G levels inone case [25].
MRI was performed in 54.5% (18/33) of cases, of whichboth brain and spinal cord were examined in 8 cases and onlyspinal cord was 10 cases. MRI results showed nerve rootinvolvement in 4 cases [16, 27, 29, 31], severe spinal stenosisin 1 case [19], cranial nerve involvement in 1 case, and nor-mal or no metastatic signs in the rest [29].
3.5. Treatment and Prognosis of GBS. Twenty-seven cases(81.8%) were treated with intravenous immunoglobulin(IVIG), sixteen of the 27 patients with a combination of ste-roid therapy and one with PLEX. Seven of the 27 patientswere treated with all three treatments. Five cases were treatedwith steroid therapy alone, and one case was treated with ste-roid combined with PLEX. No patients were treated withPLEX alone.
After treatment, 24 cases (72.7%) recovered or had onlymild residual dysfunction, with two of them rechallenged ipi-limumab [14] or pembrolizumab [21], and 5 cases had resid-ual mild paresthesia [13, 14, 26, 29, 33]. Among the 33 ICIS-related GBS patients, 5 patients developed tumor progression
after discontinuation of ICIS treatment, including 4 patientswith melanoma [14, 31, 32, 37] and 1 patient with bladdercancer [22]. Of the eight deaths, three died of the respiratorymuscle paralysis caused by GBS [17, 38, 41], 2 died of infec-tion [13, 39], and three were due to progression of the tumorcaused by ICI discontinuation [16, 28, 40].
4. Discussion
The effects of checkpoint inhibition affect a wide range of sys-tem and trigger a wide range of autoimmune toxicity. Theexact mechanism of neurological irAEs in ICI-treatedpatients is unknown [44]. The existence of shared antigensbetween the tumor and itself may be one possible mecha-nism, such as gangliosides found in both melanoma andSchwann cells [45]. ICI-related GBS is rare as a type of neu-rological irAEs, but it can develop into life-threatening con-sequence once occurred. Diagnosis of ICI-related GBSshould be made in the shortest possible time so as not todelay the administration of immune-regulation therapy.
There was a male preponderance in 33 ICI-related GBSpatients we collected, with 3.71 times as many cases as female(male 26 and female 7). However, among GBS triggered byinfection, males were affected only 1.5 times more frequentlythan females [11]. An epidemiological study on the risk fac-tors of melanoma showed that the incidence of melanomaof men was almost three times that of by women by the ageof 75 [12]. The incidence of lung tumor in men has histori-cally been higher than in women, although the incidence oflung tumor in women has risen since the 1960s, especiallyin younger women [46–48]. Perhaps the higher incidenceof cancer in men, resulting in more opportunities for mento use ICIs, was one of the reasons for the higher incidenceof ICI-related GBS. Besides, ICIs were more effective for malecancer patients than female patients [49]. And the develop-ment of irAEs was related to the beneficial effects of immuno-therapy in malignant tumors, especially in advanced-stagemelanoma, advanced and metastatic NSCLC, and advancedrenal cell carcinoma (RCC) [50]. The high effectiveness ofICI treatment in male patients may be also responsible forthe male preponderance in ICI-related GBS.
In this study, melanoma had the largest number of tumortype that caused GBS after ICI treatment. Neurological irAEswere rare, with an incidence of less than 3% [8], whereas theoverall incidence of severe nerve injury in melanoma patientstreated with nivolumab with or without ipilimumab reached0.93% [7], nearly one-third of the total neurological irAEs.Well know, GBS is a multifactorial autoimmune disorder,cell-mediated immunity plays an important role in immuno-pathology of all types of GBS. The activation of T cell causedby bacterial and virus leads to the production of cytokinesand the release of free radicals, thus resulting in segmentaldemyelination [51]. And the cross-reaction between B-cellautoantibodies and axon gangliosides leads to axonal degra-dation [51]. Melanocytes and Schwann cells originate fromthe neural crest and have many common epitopes in humoraland cellular immune responses [52]. T cells regulate thedegree of initial response of T cells by upregulating CTLA-4, while PD-1 inhibits the response of T cells in peripheral
Table 5: Treatment and prognosis of ICIs-GBS.
Treatment (n = 33)Progression
RecoveryResidual
dysfunctionDeath
IVIG (n = 3) 2 1
IVIG+steroid (n = 16) 8 6 2
IVIG+PLEX (n = 1) 1
IVIG+steroid+PLEX(n = 7) 2 2 3
Steroid (n = 5) 1 3 1
Steroid+PLEX (n = 1) 1
Total 13 11 9
IVIG: intravenous immunoglobulin; PLEX: plasma exchange.
13BioMed Research International
tissues and plays an important role in immune self-tolerance[53]. Due to the cross-reaction of molecular mimicry, T cell-mediated autoimmunity against melanoma cell antigens mayalso have an effect on the myelin antigens on Schwann cellmembranes. In addition, the response rate of melanoma toICIs was higher than other tumors [54]. A FAERSdatabase-based clinical study also showed that patients withmelanoma or non-small-cell lung cancer maybe at higherrisk of fatal neurologic AEs [55]. Therefore, the author spec-ulated that melanoma patients were more likely to developGBS after ICI treatment than other types of tumors.
Existing reports suggested that the overall incidence ofneurological adverse events (nAEs) at all levels was 3.8% foranti-CTLA-4 and 6.1% for anti-PD-1/PD-L1 [56]. CTLA-4and its ligands are only expressed on immune cells, whilePD-1 and PD-L1 (ligands of PD-1) are expressed on bothimmune and nonimmune cells in peripheral tissues [57].The difference in spatial distribution between the CTLA-4and PD-1 pathways may explain the high incidence of GBSin patients treated with nivolumab.
Many literatures had reported the timing of irAEs onsetafter the initiation of ICI treatments. The skin manifestationsappeared at 2-3 weeks, and immune-mediated colitis, hepati-tis, pneumonitis, and nephritis appeared approximately 5-10weeks, 12-16 weeks, 8-14 weeks, and 14-42 weeks, respec-tively. Endocrine dysfunctions appeared from 9 weeks [58].At present, there is no literature on the time to onset of neu-rologic symptom related to GBS caused by ICIs. The initialtime of symptoms in 33 patients in this article was analyzed,and the results suggested that the median time was 8.2 weeksafter the initiation of ICI treatments. Compared with GBScaused by infectious triggers, neurologic symptom appearedmuch later. This conclusion was expected to be helpful forthe rapid diagnosis of ICIs-GBS.
Of the 33 GBS related to ICI patients we collected, theinitial symptoms were very similar to infection-triggeredGBS. Lumbar puncture was performed, and CSF analysisrevealed elevated protein levels and albuminocytologic dis-sociation. A study of 962 patients with infection-inducedGBS showed that the average protein level was 113:8 ±11:8mg/dl (range: 18–450mg/dl) [59]. In this study, theaverage protein level of CSF in patients with GBS relatedto ICIs was 180:68 ± 152:51mg/dl (range: 37-680mg/dl).From a numerical point of view, the levels of CSF proteinlevel of ICI-related GBS seemed to be higher than those ofGBS induced by infection. Although it was not possible todistinguish infection-induced GBS from ICI-induced GBSbased on CSF protein levels, lumbar puncture andprotein-cell-separation were valuable in differentiating avariety of diseases such as spinal cord compression, meta-bolic diseases, side effects of drugs, vasculitis, and chronicinflammatory demyelinating polyneuropathy. In additionto elevated protein levels, lymphocytosis may also occur[37]. A similar pattern was observed in this study, with4 patients showing a mild lymphocytosis in the CSF. How-ever, multiple cases had been reported of lymphocytosis inthe CSF of patients with infection-induced GBS [60–63].Obviously, lymphocytosis in the CSF was not a character-istic of ICI-related GBS.
The electrophysiological results detailed in this studyindicated that ICI-related GBS was a generalized, sensorimo-tor polyneuropathy characterized by mixed axonal/demyeli-nation. An electrophysiological study of ICI-relatedperipheral neuropathy showed that immune-mediated neu-ropathy mainly manifested as demyelination of motornerves, followed by length dependent axonal loss in sensorynerve [60]. The results of this study were in part consistentwith the above conclusions. No matter what kind of electro-physiological changes were closely related to the autoim-mune response of ICIs against peripheral nerve tissue, theonset of symptoms of neuropathy was closely related to ICItreatment, and corticosteroid or immune-regulatory therapyhad good results.
In the treatment of all 33 patients, the immediate discon-tinuation of ICIs was an uncontroversial decision. Mostpatients received IVIG after discontinuation, with 16 patientsreceiving both IVIG and steroid therapy. Despite steroidswere generally not recommended for treatment ininfection-induced GBS, in ICI-related GBS, both AmericanSociety of Clinical Oncology (ASCO) Clinical PracticeGuideline and National Comprehensive Cancer Network(NCCN) guidelines stated that trial of (methyl) prednisolone1-2mg/Kg was reasonable [64, 65], especially when CSFpleocytosis was higher than being anticipated for GBS [10].And if the symptoms deteriorated, plasma exchange or IVIGtreatment could be considered [66].
Among the 33 ICI-related GBS patients, 5 patients devel-oped tumor progression after discontinuation of ICI treat-ment. One of the four patients with progressed melanomarechallenged different class of immunotherapy, with signifi-cant and sustained response nearly 1 year later and no recur-rence of GBS-like neuropathy. Whether or not to retreat withICIs and whether to retreat with the same or different ICIsare challenges for oncologists. There is also limited data onthe clinical efficacy and safety of retreatment. The currentguidelines suggested that corticoid therapy and temporaryor permanent discontinuing ICIs were required for grade ≥2 irAEs and permanently discontinuing ICI treatment forgrade 4 irAEs [65, 67]. A study had shown that the recurrencerate of the same irAEs resulting in discontinuation of ICItreatment in cancer patients who rechallenged the same ICIwas 28.6% (anti-PD-1 or anti-PD-L1 monotherapy), 47.4%(anti-CTLA-4 monotherapy), and 43.5% (combination ther-apy), respectively [66]. The recurrence rate of irAEs varieddepending on the organ involved in the initial irAEs, withgastrointestinal irAEs having the highest recurrence rate[68]. And the variables associated with a higher recurrencerate of irAEs were anti-CTLA-4 regimen, age, colitis, hepati-tis, and pneumonia, in order [68]. In addition, the durationfrom ICI discontinuation to rechallenge, and the severity ofthe initial irAEs did not predict whether irAEs would reap-pear after rechallenge of ICIs [69]. However, no relevant lit-erature has been reported on whether discontinuation dueto ICI-related GBS can rechallenge the same or different ICIsagain.
In addition, paraneoplastic peripheral neuropathy shouldbe excluded in the diagnosis of ICI-related GBS. Paraneoplas-tic peripheral neuropathy is a remote effect of the malignancy
14 BioMed Research International
mediated by the immune system. It develops prior or duringa cancer and is independent of tumor infiltration or cancertherapy [70]. Paraneoplastic sensory neuropathy is the mostfrequent in this group of disorders, and motor, autonomic,or central nervous systems are also involved [71]. Date onthe treatment of paraneoplastic peripheral neuropathy is lim-ited, and the combination of malignancy therapy with immu-nomodulatory therapies such as corticosteroids, IVimmunoglobulin, or immunosuppressants may be effective[72]. However, ICI-related GBS occurred in malignanttumors after ICI treatment, and the immunomodulatorytherapeutic effect was obvious. This is the most obvious dif-ference between the two.
Here are also several limitations in this study. First, thenumber of the included cases was small which limited us toperform subgroup analysis. Second, patients with variouscancers were included, which might have bias in the inci-dence of some adverse effects.
5. Conclusion
Elderly male patients with melanoma were most likely todevelop ICI-related GBS. And the median duration was 8.2weeks after the initial ICI treatment. In order to make a finaldiagnosis, physicians need to collect specific neurologicalsymptoms and signs and combine them with CSF analysisand electrophysiological examination. In addition, imagingis required to exclude tumor metastasis. Immediate termina-tion of ICIs followed by IVIG in combination with high-dosesteroids therapy or PLEX and supportive treatment couldlead to a better prognosis.
Abbreviations
ICIs: Immune checkpoint inhibitorsCTLA-4: Cytotoxic T lymphocyte-associated antigen-4PD-1: Programmed cell death protein-1PD-L1: Programmed cell death protein-1 ligandirAEs: Immune-related adverse eventsGBS: Guillain-Barré syndromeAIDP: Acute inflammatory demyelinating
polyneuropathyAMAN: Acute motor axonal neuropathyAMSAN: Acute motor and sensory axonal neuropathyMFS: Miller fisher syndromeDML: Distal motor latencyEMG: Needle electromyographyIVIG: Intravenous immunoglobulinPLEX: Plasma exchangeCSF: Cerebrospinal fluidCNS: Central nervous systemNSCLC: Non-small-cell lung cancerRCC: Renal cell carcinoma.
Conflicts of Interest
The authors have no conflicts of interest to declare.
References
[1] D. Psimaras, R. Velasco, C. Birzu et al., “Immune checkpointinhibitors-induced neuromuscular toxicity: from pathogenesisto treatment,” Journal of the peripheral nervous system : JPNS,vol. 24, no. 2, pp. S74–S85, 2019.
[2] J. D. Wolchok, H. Kluger, M. K. Callahan et al., “Nivolumabplus ipilimumab in advanced melanoma,” The New EnglandJournal of Medicine, vol. 369, no. 2, pp. 122–133, 2013.
[3] P. Schmid, S. Adams, H. S. Rugo et al., “Atezolizumab andnab-paclitaxel in advanced triple-negative breast cancer,” TheNew England Journal of Medicine, vol. 379, no. 22, pp. 2108–2121, 2018.
[4] A. Markham and S. Duggan, “Cemiplimab: first globalapproval,” Drugs, vol. 78, no. 17, pp. 1841–1846, 2018.
[5] K. M. Hargadon, C. E. Johnson, and C. J. Williams, “Immunecheckpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors,” InternationalImmunopharmacology, vol. 62, pp. 29–39, 2018.
[6] L. A. Emens, P. A. Ascierto, P. K. Darcy et al., “Cancer immu-notherapy: opportunities and challenges in the rapidly evolv-ing clinical landscape,” European journal of cancer, vol. 81,pp. 116–129, 2017.
[7] L. B. Kennedy and A. K. S. Salama, “A review of cancer immu-notherapy toxicity,” CA: a Cancer Journal for Clinicians,vol. 70, no. 2, pp. 86–104, 2020.
[8] M. Touat, D. Talmasov, D. Ricard, and D. Psimaras, “Neuro-logical toxicities associated with immune-checkpoint inhibi-tors,” Current Opinion in Neurology, vol. 30, no. 6, pp. 659–668, 2017.
[9] B. R. Wakerley and N. Yuki, “Infectious and noninfectioustriggers in Guillain-Barré syndrome,” Expert Review of ClinicalImmunology, vol. 9, no. 7, pp. 627–639, 2013.
[10] C. Astaras, R. de Micheli, B. Moura, T. Hundsberger, and A. F.Hottinger, “Neurological adverse events associated withimmune checkpoint inhibitors: diagnosis and management,”Current Neurology and Neuroscience Reports, vol. 18, no. 1,p. 3, 2018.
[11] H. Yoshikawa, “Epidemiology of Guillain-Barré Syndrome,”Brain and nerve, vol. 67, no. 11, pp. 1305–1311, 2015.
[12] M. Rastrelli, S. Tropea, C. R. Rossi, and M. Alaibac, “Mela-noma: epidemiology, risk factors, pathogenesis, diagnosis andclassification,” In vivo (Athens, Greece), vol. 28, no. 6,pp. 1005–1011, 2014.
[13] J. B. E. Janssen, T. Y. S. Leow, K. H. Herbschleb et al., “Immunecheckpoint inhibitor-related Guillain-Barré syndrome: a caseseries and review of the literature,” Journal of immunotherapy(Hagerstown, Md : 1997), 2021.
[14] S. Muralikrishnan, L. K. Ronan, S. Coker, P. K. Rauschkolb,and K. Shirai, “Treatment considerations for patients withunresectable metastatic melanoma who developpembrolizumab-induced Guillain-Barré toxicity: a casereport,” Case reports in oncology, vol. 13, no. 1, pp. 43–48,2020.
[15] C. Han, J. A. Ma, Y. Zhang, Y. Jiang, C. Hu, and Y. Wu, “Guil-lain-Barre syndrome induced by pembrolizumab and suniti-nib: a case report,” Molecular and Clinical Oncology, vol. 13,no. 1, pp. 38–42, 2020.
[16] A. Arora, A. Shere, K. Patel, N. Gunawardhana, andE. LiFuentes, “A rare case of autoimmune demyelinating poly-neuropathy and hydrocephalus secondary to pembrolizumab,”
15BioMed Research International
Journal of Investigative Medicine High Impact Case Reports,vol. 8, p. 2324709620916358, 2020.
[17] C. Yuen, D. Kamson, B. Soliven, C. Kramer, F. Goldenberg,and K. Rezania, “Severe relapse of vaccine-induced Guillain-Barré syndrome after treatment with nivolumab,” Journal ofClinical Neuromuscular Disease, vol. 20, no. 4, pp. 194–199,2019.
[18] M. Pomerantz, D. A. Lichtenstein, I. Niesvizky-Kogan,R. Sohal, J. Leibovitch, and A. Basnet, “Nivolumab andipilimumab-induced acute inflammatory demyelinating poly-radiculoneuropathy: a case report,” Journal of immunotherapy(Hagerstown, Md : 1997), vol. 42, no. 9, pp. 348-349, 2019.
[19] J. Pierrard, B. Petit, S. Lejeune, and E. Seront, “Isolated adreno-corticotropic hormone (ACTH) deficiency and Guillain-Barrésyndrome occurring in a patient treated with nivolumab,”BML Case Reports, vol. 12, no. 8, 2019.
[20] C. J. McNeill, J. Fehmi, and J. Gladwin, “Price C: A rare case ofMiller Fisher variant of Guillain-Barré syndrome (GBS)induced by a checkpoint inhibitor,” BML Case Reports,vol. 12, no. 8, 2019.
[21] G. Mazzaschi, P. Bordi, R. Fioretzaki et al., “Nivolumab-induced Guillain-Barre syndrome coupled with remarkabledisease response in a case of heavily pretreated lung adenocar-cinoma,” Clinical Lung Cancer, 2019.
[22] A. Kyriazoglou, M. Liontos, C. Papadopoulos et al., “Guil-lain-Barre syndrome related to nivolumab: case report of apatient with urothelial cancer and review of the literature,”Clinical Genitourinary Cancer, vol. 17, no. 2, pp. e360–e364, 2019.
[23] N. Gravbrot, K. Scherer, and S. Sundararajan, “Safe Transitionto Pembrolizumab following Ipilimumab-Induced Guillain-Barré Syndrome: A Case Report and Review of the Literature,”Case Reports in Oncological Medicine, vol. 2019, 5 pages, 2019.
[24] R. Wilson, D. A. Menassa, A. J. Davies et al., “Seronegativeantibody-mediated neurology after immune checkpoint inhib-itors,” Annals of Clinical Translational Neurology, vol. 5, no. 5,pp. 640–645, 2018.
[25] B. Thapa, S. Khalid, R. Vakili, J. Ui, and S. Misbah, “Nivolu-mab-associated Guillain-Barre syndrome in a patient withnon-small-cell lung cancer,” American Journal of Therapeu-tics, vol. 25, no. 6, pp. e761–e763, 2018.
[26] S. Ong, J. Chapman, G. Young, and T. Mansy, “Guillain-Barre-like syndrome during pembrolizumab treatment,” Muscle &Nerve, 2018.
[27] T. Nukui, Y. Nakayama, M. Yamamoto et al., “Nivolumab-induced acute demyelinating polyradiculoneuropathy mim-icking Guillain-Barré syndrome,” Journal of the NeurologicalSciences, vol. 390, pp. 115-116, 2018.
[28] R. Manam, J. L. Martin, J. A. Gross et al., “Case reports ofpembrolizumab-induced acute inflammatory demyelinatingpolyneuropathy,” Cureus, vol. 10, no. 9, article e3371, 2018.
[29] C. A. Garcia, A. El-Ali, T. J. Rath et al., “Neurologic immune-related adverse events associated with adjuvant ipilimumab:report of two cases,” Journal for Immunotherapy of Cancer,vol. 6, no. 1, p. 83, 2018.
[30] Y. Fukumoto, M. Kuwahara, S. Kawai, K. Nakahama, andS. Kusunoki, “Acute demyelinating polyneuropathy inducedby nivolumab,” Journal of Neurology, Neurosurgery, and Psy-chiatry, vol. 89, no. 4, pp. 435–437, 2018.
[31] L. Cafuir, D. Lawson, N. Desai, V. Kesner, and A. Voloschin,“Inflammatory demyelinating polyneuropathy versus lepto-
meningeal disease following Ipilimumab,” Journal for Immu-notherapy of Cancer, vol. 6, no. 1, p. 11, 2018.
[32] J. J. D. Baird-Gunning, D. Weerasinghe, M. Silsby et al.,“Miller fisher syndrome associated with immunotherapy formetastatic melanoma,” The Neurohospitalist, vol. 8, no. 4,pp. 191–193, 2018.
[33] S. Supakornnumporn and B. Katirji, “Guillain-Barré syn-drome triggered by immune checkpoint inhibitors: a casereport and literature review,” Journal of Clinical Neuromuscu-lar Disease, vol. 19, no. 2, pp. 80–83, 2017.
[34] R. Schneiderbauer, M. Schneiderbauer, W. Wick, A. H. Enk,H. A. Haenssle, and J. C. Hassel, “PD-1 antibody-inducedGuillain-Barré syndrome in a patient with metastatic mela-noma,” Acta Dermato-Venereologica, vol. 97, no. 3, pp. 395-396, 2017.
[35] R. J. Patel, M. A. Liu, A. Amaraneni, and S. K. Sindhu, “Rareside effect of adjuvant ipilimumab after surgical resection ofmelanoma: Guillain-Barré syndrome,” BMJ Case Reports,vol. 2017, 2017.
[36] W. Kelly Wu, K. K. Broman, E. R. Brownie, and R. M. Kauff-mann, “Ipilimumab-induced Guillain-Barré syndrome pre-senting as dysautonomia: an unusual presentation of a rarecomplication of immunotherapy,” Journal of immunotherapy,vol. 40, no. 5, pp. 196–199, 2017.
[37] Y. Gu, A. M. Menzies, G. V. Long, S. L. Fernando, andG. Herkes, “Immune mediated neuropathy following check-point immunotherapy,” Journal of clinical neuroscience : offi-cial journal of the Neurosurgical Society of Australasia,vol. 45, pp. 14–17, 2017.
[38] A. Jacob, D. C. Unnikrishnan, A. Mathew, B. Thyagarajan, andS. Patel, “A case of fatal Guillain-Barre syndrome from anti-PD1 monoclonal antibody use,” Journal of Cancer Researchand Clinical Oncology, vol. 142, no. 8, pp. 1869-1870, 2016.
[39] M. F. de Maleissye, G. Nicolas, and P. Saiag, “Pembrolizumab-induced demyelinating polyradiculoneuropathy,” The NewEngland Journal of Medicine, vol. 375, no. 3, pp. 296-297, 2016.
[40] C. Gaudy-Marqueste, S. Monestier, J. Franques, E. Cantais,M. A. Richard, and J. J. Grob, “A severe case of ipilimumab-induced guillain-barré syndrome revealed by an occlusiveenteric neuropathy: a differential diagnosis for ipilimumab-induced colitis,” Journal of immunotherapy, vol. 36, no. 1,pp. 77-78, 2013.
[41] I. Bot, C. U. Blank, W. Boogerd, and D. Brandsma, “Neurolog-ical immune-related adverse events of ipilimumab,” PracticalNeurology, vol. 13, no. 4, pp. 278–280, 2013.
[42] S. Wilgenhof and B. Neyns, “Anti-CTLA-4 antibody-inducedGuillain-Barré syndrome in a melanoma patient,” Annals ofoncology : official journal of the European Society for MedicalOncology, vol. 22, no. 4, pp. 991–993, 2011.
[43] M. Shi, J. Zhu, and H. Deng, “Clinical characteristics of intra-venous injection of monosialotetrahexosyl gangliosidesodium-related Guillain-Barre syndrome,” Frontiers in Neu-rology, vol. 10, p. 225, 2019.
[44] M. Eltobgy, H. Oweira, U. Petrausch et al., “Immune-relatedneurological toxicities among solid tumor patients treatedwith immune checkpoint inhibitors: a systematic review,”Expert Review of Neurotherapeutics, vol. 17, no. 7,pp. 725–736, 2017.
[45] P. C. Pan and A. Haggiagi, “Neurologic immune-relatedadverse events associated with immune checkpoint inhibi-tion,” Current Oncology Reports, vol. 21, no. 12, p. 108, 2019.
16 BioMed Research International
[46] D. Twardella, K. Geiss, M. Radespiel-Tröger, A. Benner, J. H.Ficker, and M. Meyer, “Trends in incidence of lung canceraccording to histological subtype amongmen andwomen in Ger-many : analysis of cancer registry data with the application ofmultiple imputation techniques,” Federal Health Gazette, HealthResearch, Health Protection, vol. 61, no. 1, pp. 20–31, 2018.
[47] L. A. Torre, R. L. Siegel, and A. Jemal, “Lung cancer statistics,”Advances in Experimental Medicine and Biology, vol. 893,pp. 1–19, 2016.
[48] R. Meza, C. Meernik, J. Jeon, and M. L. Cote, “Lung cancerincidence trends by gender, race and histology in the UnitedStates, 1973-2010,” PLoS One, vol. 10, no. 3, article e0121323,2015.
[49] S. Wang, L. A. Cowley, and X. S. Liu, “Sex differences in cancerimmunotherapy efficacy, biomarkers, and therapeutic strat-egy,” Molecules, vol. 24, no. 18, 2019.
[50] O. Fiala, O. Sorejs, J. Sustr, R. Kucera, O. Topolcan, andJ. Finek, “Immune-related adverse effects and outcome ofpatients with cancer treated with immune checkpoint inhibi-tors,” Anticancer Research, vol. 40, no. 3, pp. 1219–1227, 2020.
[51] Z. Ebrahim Soltani, F. Rahmani, and N. Rezaei, “Autoimmu-nity and cytokines in Guillain-Barré syndrome revisited:review of pathomechanisms with an eye on therapeuticoptions,” European Cytokine Network, vol. 30, no. 1, pp. 1–14, 2019.
[52] W. Metcalfe, J. Anderson, V. A. Trinh, and W. J. Hwu, “Anti-programmed cell death-1 (PD-1) monoclonal antibodies intreating advanced melanoma,” Discovery Medicine, vol. 19,no. 106, pp. 393–401, 2015.
[53] L. Chen and D. B. Flies, “Molecular mechanisms of T cell co-stimulation and co-inhibition,” Nature Reviews Immunology,vol. 13, no. 4, pp. 227–242, 2013.
[54] M. Sade-Feldman, K. Yizhak, S. L. Bjorgaard et al., “Defining Tcell states associated with response to checkpoint immuno-therapy in melanoma,” Cell, vol. 176, no. 1-2, p. 404, 2019.
[55] T. Mikami, B. Liaw, M. Asada et al., “Neuroimmunologicaladverse events associated with immune checkpoint inhibitor:a retrospective, pharmacovigilance study using FAERS data-base,” Journal of Neuro-Oncology, vol. 152, no. 1, pp. 135–144, 2021.
[56] C. Perrinjaquet, N. Desbaillets, and A. F. Hottinger, “Neuro-toxicity associated with cancer immunotherapy: immunecheckpoint inhibitors and chimeric antigen receptor T-celltherapy,” Current Opinion in Neurology, vol. 32, no. 3,pp. 500–510, 2019.
[57] A. Cortellini, S. Buti, V. Agostinelli, and M. Bersanelli, “A sys-tematic review on the emerging association between the occur-rence of immune-related adverse events and clinical outcomeswith checkpoint inhibitors in advanced cancer patients,” Sem-inars in Oncology, vol. 46, no. 4-5, pp. 362–371, 2019.
[58] V. Kumar, N. Chaudhary, M. Garg, C. S. Floudas, P. Soni, andA. B. Chandra, “Current diagnosis and management ofimmune related adverse events (irAEs) induced by immunecheckpoint inhibitor therapy,” Frontiers in Pharmacology,vol. 8, p. 49, 2017.
[59] S. R. Sudulagunta, M. B. Sodalagunta, M. Sepehrar et al., “Guil-lain-Barré syndrome: clinical profile and management,” Ger-man medical science, vol. 13, 2015.
[60] G. T. Doctor, S. K. Alexander, and A. Radunovic, “Guillain-Barré syndrome with exaggerated pleocytosis and anti-GM1ganglioside antibodies,” BML Case Reports, vol. 2018, 2018.
[61] M. Dy, R. L. Leshner, and J. R. Crawford, “An unusual case ofrecurrent Guillain-Barre syndrome of a different subtype fiveyears after initial diagnosis,” Case reports in neurological med-icine, vol. 2013, 4 pages, 2013.
[62] H. Rauschka, K. Jellinger, H. Lassmann, F. Braier, andM. Schmidbauer, “Guillain-Barré syndrome with markedpleocytosis or a significant proportion of polymorphonucleargranulocytes in the cerebrospinal fluid: neuropathologicalinvestigation of five cases and review of differential diagnoses,”European Journal of Neurology, vol. 10, no. 5, pp. 479–486,2003.
[63] J. Berciano, J. Figols, A. García et al., “Fulminant Guillain-Barré syndrome with universal inexcitability of peripheralnerves: a clinicopathological study,” Muscle & Nerve, vol. 20,no. 7, pp. 846–857, 1997.
[64] J. A. Thompson, B. J. Schneider, J. Brahmer et al., “Manage-ment of immunotherapy-related toxicities, version 1.2019,”Journal of the National Comprehensive Cancer Network,vol. 17, no. 3, pp. 255–289, 2019.
[65] J. R. Brahmer, C. Lacchetti, B. J. Schneider et al., “Managementof immune-related adverse events in patients treated withimmune checkpoint inhibitor therapy: American Society ofClinical Oncology clinical practice guideline,” Journal of Clin-ical Oncology : Official Journal of the American Society of Clin-ical Oncology, vol. 36, no. 17, pp. 1714–1768, 2018.
[66] J. Haanen, F. Carbonnel, C. Robert et al., “Management of tox-icities from immunotherapy: ESMO Clinical Practice Guide-lines for diagnosis, treatment and follow-up,” Annals ofoncology : official journal of the European Society for MedicalOncology, vol. 28, no. 4, pp. iv119–iv142, 2017.
[67] J. Shi, J. Niu, D. Shen et al., “Clinical diagnosis and treatmentrecommendations for immune checkpoint inhibitor-relatedadverse reactions in the nervous system,” Thorac Cancer,vol. 11, no. 2, pp. 481–487, 2020.
[68] C. Dolladille, S. Ederhy, M. Sassier et al., “Immune checkpointinhibitor rechallenge after immune-related adverse events inpatients with cancer,” JAMA Oncology, vol. 6, no. 6, pp. 865–871, 2020.
[69] M. Allouchery, T. Lombard, M. Martin et al., “Puyade M:Safety of immune checkpoint inhibitor rechallenge after dis-continuation for grade ≥2 immune-related adverse events inpatients with cancer,” Journal for Immunotherapy of Cancer,vol. 8, no. 2, 2020.
[70] J. C. Antoine and J. P. Camdessanché, “Paraneoplastic neurop-athies,” Current Opinion in Neurology, vol. 30, no. 5, pp. 513–520, 2017.
[71] S. A. Rudnicki and J. Dalmau, “Paraneoplastic syndromes ofthe peripheral nerves,” Current Opinion in Neurology,vol. 18, no. 5, pp. 598–603, 2005.
[72] S. Muppidi and S. Vernino, “Paraneoplastic neuropathies,”CONTINUUM: Lifelong Learning in Neurology, vol. 20, no. 5,pp. 1359–1372, 2014.
17BioMed Research International