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,

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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).


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


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


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.


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


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


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


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.


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.


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.


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


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.

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