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Roberts, Matthew, Northmore, Tessa, Shires, Joanne, Taylor, Peter and Hayhurst, Caroline 2018.

Diffuse low grade glioma after the 2016 WHO update, seizure characteristics, imaging correlates

and outcomes. Clinical Neurology and Neurosurgery 175 , pp. 9-15. 10.1016/j.clineuro.2018.10.001

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Diffuse low grade glioma after the 2016

WHO update, seizure characteristics,

imaging correlates and outcomes

MatthewRoberts(BSc),TessaNorthmore(RNLLM),JoanneShires(BScRN)andCarolineHayhurst

(FRCS).

DepartmentofNeurosurgery,UniversityHospitalofWales,HeathPark,Cardiff,UK,CF144XW.

Correspondingauthor:MatthewRoberts(mdgr@hotmail.co.uk).

Correspondingauthoraddress:

DepartmentofNeurosurgery

UniversityHospitalofWales

HeathPark

Cardiff

UK

CF144XW.

ABSTRACT

Objective

ThemajorityofpatientswithsupratentorialdiffusegradeIIgliomapresentwithseizures,which

adverselyaffectqualityoflife.Theexactmechanismofepileptogenesisisunknownandthe

influenceoftumourcharacteristics,radiologicalandhistological,arenotwellstudied,particularly

followingtheintroductionofmoleculargeneticsinthe2016WHOreclassificationofgliomas.We

soughttodefinepredictorsofseizuredevelopmentandoutcomeinlowgradeglioma.

PatientsandMethods

AretrospectivereviewofpatientswhounderwentresectionofasupratentorialgradeIIgliomaina

singleinstitution.Allpatientsunderwentsurgeryatinitialpresentationwiththeaimofmaximalsafe

resection.Presentingsymptomsandradiologicalvariableswererecorded,includingeloquent

location,corticalinvolvement,tumourmarginsandtumourvolume.Extentofresection(EOR),

surgerytype(awakevsasleep)andseizureoutcomewereanalysed.Usingmoleculargeneticsdata

theoriginalhistologywasreclassifiedaccordingtothe2016WHOupdate.

Results

63patientswereincluded,45(71%)presentedwithseizures.36(57%)hadoligodendrogliomaand

27astrocytoma.IDH-1mutationwaspresentin53(84%).18(29%)hadtumourinaneloquent

location.33(73%)wereEngelclassIfollowingsurgeryatmedianfollowupof43months.6patients

wereEngelII,6classIII.CompleteandneartotalresectionwereassociatedwithimprovedEngel

classcomparedtosubtotalresection.Nofactorssuchasage,tumourlocation,tumourmarginsor

tumourmoleculargenetics(includingIDH-1mutation)predictedbetterseizureoutcome.Updated

histologicalsubtypedidnotpredictthepresenceofseizuresatinitialdiagnosis,onlytumour

heterogeneousityoninitialMRI(p=0.043).Morepatientswhounderwentawakecraniotomywith

intraoperativemappingwereEngelclass1post-operativelythanthoseoperatedundergeneral

anaesthetic(84%vs65%).Tumourvolumeatpresentationdidnotcorrelatewithseizureoutcome

butimpactsontheEOR.

Conclusion

SeizureoutcomeisdirectlyrelatedtoEORinlowgradeglioma,whichcanbepredictedbytheinitial

tumourvolume.Tumourhistologicalsubtype,includingupdatedmoleculargeneticclassificationdid

notpredictseizuredevelopmentoroutcomeinthisseries.Theuseofawakecraniotomyresultsin

greaterEORandimprovedEngelClassfollowingsurgery.

Keywords

Low-gradeglioma;seizureoutcome;extentofresection;updatedmoleculargenetics;riskfactors

1. Objective

WorldHealthOrganisation(WHO)gradeIIgliomas(low-gradegliomas;LGGs)areaheterogeneous

groupofprimarycentralnervoussystem(CNS)tumoursarisingfromglialcells(1).LGGsareshown

toexhibitanaveragegrowthrateofaround4mm/yearandwilleventuallyundergomalignant

transformation(2,3).TherecentWHOclassificationsystemofLGGsclassifiesthemaseither

astrocytomaoroligodendroglioma,emphasisingtheuseofmoleculargeneticstodistinguishtumour

type.Previously,anadditionalclassificationofoligoastrocytomaexisted,however,thishasbeen

removedintherecentupdatedclassificationsystem(4).

MostpatientswithLGGspresentwithinthethirdorfourthdecadesoflifewithanoverallincidence

of0.63-1.8/100,000adultsperyear(5,6).Theyarehighlyepileptogenictumourswith60-88%of

patientspresentingwithseizureactivity(7–10).Theexactmechanismsoftumourepileptogenesis

arenotfullyunderstoodbutmultiplefactorsappeartoplayroles.Potentialfactorspredominantly

involveperitumouralchangesinmetabolism,perfusion,electrolytesandenzymeactivity.(11).For

example,IDHmutationsoccurinupto80%ofLGGsandarebelievedtocontributeto

epileptogenesisbycausingproductionofastructurallysimilarcompoundtoglutamateandthus

activatingNMDAreceptors(11).

Previously,managementofLGGsinvolveda‘watch-and-wait’approach.However,therehasbeena

recentshifttowardsearlierandmoreaggressivemanagementduetotheinevitablemalignant

transformation(2,12).Arangeofstudieshaveshownmorefavourableoutcomeswithearlysurgical

resection,particularlywithagreaterextentofresection(EOR)(13,14).Intermsofseizureoutcome,

studieshaveshownseizurefreedominupto65-81%ofpatientspost-resection,buttheexact

prognosticfactorsthatinfluenceseizureoutcomearenotyetfullyunderstood(6,8,9,15).

ThisstudyaimedtoassessseizureoutcomeinaseriesofoperatedLGGpatientsandidentifyany

pre-orpost-operativepredictorswhichmayinfluenceeventualseizureoutcome,includingtumour

typebasedontheup-to-datemoleculargeneticanalysisofthe2016WHOclassificationupdate.

2. Patients and Methods

2.1PatientPopulation

Atotalof63patientswithoperatedsupratentorialgradeIIgliomaswereincludedinthisstudy,

consistingof36oligodendrogliomasand27astrocytomas(accordingtoWHO2016classification).All

patientsunderwentsurgicalresectionoftheirtumouratinitialpresentation,betweenMay2011to

December2016inasingleinstitution.Thosepatientsthatonlyunderwentbiopsywereexcluded

fromthestudy.Additionally,allcaseswithtumoursclassifiedgradeII/IIIwereexcluded.

Clinicalrecordswereretrospectivelyanalysedforsymptomsatpresentation,seizuretype,typeof

resection(awakevsasleep),adjuvanttreatments,seizureoutcome(Engelclass;table1)andthe

presenceandgradeoftumourrecurrence.Seizureoutcomewasassessedat3,6and12months

post-operativelyandatmostrecentclinicfollowup(medianfollowuptimeof40months).Tissue

sampleswereanalysedforallbut2patientsintermsoftheirimmunohistochemistry(IHC)and

moleculargeneticsandtumourswerereclassifiedaccordingtothe2016systemretrospectively.

ReclassificationwasperformedonthebasisthatatumourwithanIDHmutationplus1p19q

mutationisanoligodendrogliomaandanIDHmutationplusATRXmutationisanastrocytoma.All

tissuesamplesinourinstitutionhavehadIDH1mutationIHCandmoleculargeneticsperformed

since2011enablingretrospectivereclassificationinthemajorityofcases.

Engelclass

I Seizurefreewithoutaura;seizuresonlyonwithdrawalofanti-epilepticdrug(AED)

II Raredisablingseizures

III Worthwhileimprovement

IV Noworthwhileimprovement/worseningseizures

2.2MRIAnalysis

TherecordedMRIinformationincludedlaterality(leftorrighthemisphere),location(frontal,

temporal,parietal,insularoracombination),presenceofcorticalinvolvement,masseffectand

locationinaneloquentregion.Tumourswerealsodescribedwithrelationtotheirborders(distinct

vsindistinct)andtumoursignalonMRI(homogenousvsheterogenous).Tumoursizewasanalysed

usingthewidestdiameterinthreedirectionsandtumourvolumecalculated(ellipsoidmethod

volume=D1xD2xD3/2).EORwasdescribedascomplete,near-total(>90%)andsubtotal(<90%),

basedonimmediatepost-

A B

Table1–OverviewofEngelclassificationsystem;fromTanriverdietal.16.

C

Figure1–AxialMRIimagesfromtwopatients.A)Showsanexampleofaheterogenousgliomawith

indistinctbordersonT2.B)showsanexampleofahomogenousLGGwithdistinctborders.C)Post-

operativesurgicalcavityonFLAIRafterresectionoftumourB.

operativeMRI.

StatisticalanalysiswasperformedusingSPSS,Version24IBMCorp,ArmonkNY.Univariateanalysis

wasperformedusingχ2andFishersexacttestwhereappropriateandpairedttestsforcontinuous

variables.APvalueof<0.05wasconsideredsignificant.

3. Results

Ourcohortincludedatotalof63patients,43maleand20female,withamedianageof34years.36

patientshadoligodendogliomasand27hadastrocytomaswith30beinglocatedintheright

hemisphereand33inthelefthemisphere.Thekeyclinicalanddemographiccharacteristicsare

displayedintable2.

Parameter Totalnumberofcases

Totalpatients 63

Males 43(68%)

Females 20(32%)

Medianage 34

Medianfollowuptime 40months

Deceasedpatients 4

Mediantimetodeath 29months(range11-44)

Tumour

Oligodendroglioma 36(57%)

Astrocytoma 27(43%)

IDH-1mutation 53(84%)

Righthemisphere 30(48%)

Lefthemisphere 33(52%)

Eloquentregion(+SMA) 18(29%)

Non-eloquent 45(71%)

Seizures

Totalseizures 45(71%)

GTC 17(38%)

Partial 15(33%)

CombinedGTCandpartial 13(29%)

Surgery

Awake 25

Generalanaesthetic(GA) 38

Themainpresentingcomplaintwasseizurein45(71%)patients,ofwhich17(38%)were

generalisedtonic-clonicseizures(GTC),15(33%)werefocalseizuresand13(29%)hadacombination

offocalandgeneralised.Otherpresentingsymptomsincludedheadache(3%),focalneurological

deficit(5%),acombinationofthetwo(11%)orwereincidentalfindings(5%).Therewere53patients

withIDH-1mutationspresent(84%)ofwhich41presentedwithseizures(77%).Four

oligodendrogliomasandfourastrocytomasdidnothaveIDH-1mutationspresentandthusclassifyas

Table2–Summaryofoverallpatientparameters.Tumourssituatedwithinthesupplementary

motorarea(SMA)havebeenincludedintheeloquentgroup.

oligodendroglioma,NOS,andastrocytoma,NOS,respectively.Twopatientswithmorphological

astrocytomasdidnothavemoleculargeneticsavailable.

3.1PatientsPresentingwithSeizures

SeizureoutcomewasassessedusingtheEngelclassificationsystem(table1).33outof45patients

(73%)presentingwithseizureswereEngelclassIpost-operativelyatamedianfollowupof43

months.Allremainingpatientsgainedsomebenefitfromresection(6patientswereEngelclassII,6

wereclassIII).Seizureoutcomewasassessedat3,6and12monthspost-operativelyaswellasupto

mostrecentstatus.41patientswereEngelclassIat3months(91%),39at6months(87%)and36at

12months(80%).NopatientswereEngelclassIV.Medianandmeantimestoseizurerecurrence

were10.5monthsand17.8monthsrespectively(range3-48months).Ofthe12patientswith

seizurerecurrence,6(50%)hadevidenceoftumourrecurrenceatthetime.Seizurerecurrencewas

notsignificantlyassociatedwithtumourrecurrenceorprogression,withseizurerecurrenceornew

seizuresoccurringinonly8outofthe25patients(32%)withtumourrecurrenceintheseries.

WeanalyseddataforothervariablesthatmightpredicteventualEngelclassaftersurgery.Greater

EORtendedtogivebetterseizureoutcome,withcompleteandnear-totalresectionresultingin

EngelclassIin76%and87.5%respectivelycomparedto62.5%ofsubtotalresections.Complete

resectionisthestrongestpredictorofseizurefreedomcomparedtoeithernearorsubtotalresection

(p=0.066).Demographicsincludingpatientage,IDHstatusandtypeofsurgerydidnotsignificantly

predictseizureoutcome,butthismayberelatedtothesmallsamplesizewithinsubgroups.Tumour

typedidnotsignificantlypredictseizureoutcome,whetherusingthe2016WHOclassification

systemortheprevioussystem.Basedonthe2016classificationsystem,patientswith

oligodendrogliomashadaslightlygreaterseizurefreedomratethanthosewithastrocytomas,but

thisisnotsignificant(79%vs67%;p=0.299).Thisissimilartoresultsbasedontheprevious

classificationsystem,where88%ofoligodendrogliomas,61%ofastrocytomasand60%of

oligoastrocytomaswereseizurefree.Morepatientswhounderwentanawakecraniotomywith

intra-operativefunctionalmappingwereEngelclassIpost-operativelycomparedtothoseunderGA

butthiswasnon-significant(84%vs65%;p=0.80).Therewerenoradiologicalvariablesthat

significantlypredictedseizureoutcome,includingeloquentlocation,corticalinvolvement,border

distinction,masseffectortumoursignal.

Figure3-SeizureoutcomesusingEngelclassificationsystembasedonoperativefactors-EOR

(complete,near-totalorsub-total)andtypeofsurgery(awakevsGA).BluebarsindicateEngel

classI,orangebarsindicateEngelclassIIorabove.Dataonlyusedfrompatientspresentingwith

seizures(totaln=45).Individualbartotalsarethetotalnumberofpatientspresentingwith

seizureswithineachcategory.

16

710

16 17

5

1

6

3

9

0

5

10

15

20

25

30

Complete Near-total Subtotal Awake GA

OperativeFactorsvsSeizureOutcome

EngelII+

EngelI

Figure2–SeizureoutcomesusingEngelclassificationsystembasedonpre-operativefactors

(tumourtype,seizuretypeandtumourlocationaseithereloquent(includingSMA)ornon-

eloquent.BluebarsindicateEngelclassI,orangebarsindicateEngelclassIIorabove.Dataonly

usedfrompatientspresentingwithseizures(n=45).Individualbartotalsarethetotalnumberof

patientspresentingwithseizureswithineachcategory.

33

1914 12 12 10 10

23

12

5

75 3

3 3

9

0

5

10

15

20

25

30

35

40

45

50

Pre-OperativeFactorsvsSeizureOutcome

EngelII+

EngelI

Wealsoanalyseddatatoidentifyifanyfactorspredictedwhetherseizureswerethepresenting

symptom.Theonlyvariabletosignificantlypredictseizuresasapresentingsymptomwastumour

signalonMRI,where81%oftumourswithaheterogeneousappearanceproducedseizures

comparedto58%ofhomogenoustumours(p=0.043).Otherdemographicsincludingage,IDHstatus

andtumourvolumeandradiologicalvariablesofeloquentlocation,corticalinvolvement,masseffect

andborderdistinctiondidnotsignificantlypredictwhetherseizureswerethepresentingsymptom.

Wetriedtoidentifywhetheranyvariablescorrelatedwithtumourtypebasedonthe2016WHO

classificationsystem.Moreoligodendrogliomashadindistinctborders(59%)comparedto

astrocytomas(35%),p=0.05.Nootherfactors,includingseizuresasapresentingsymptoms,IDH

status,tumourrecurrenceandtumoursignalonMRI,significantlycorrelatedwithreclassified

tumourtype.

Tumourvolumeatpresentationdidnotcorrelatewitheventualseizureoutcome(p=0.70).However,

EORwassignificantlygreaterintumourswithsmallervolumes.Themeantumourvolumeinpatients

whounderwentcompleteornear-totalresectionwas23.8cm3comparedto54.9cm

3inthosewho

underwentsubtotalresection(p=<0.01).Tumoursineloquentlocationshadsignificantlysmaller

volumesthanthoseinnon-eloquentlocations,withmeanvolumesof22.0cm3and37.7cm

3

respectively(p=0.035).

3.2Patientswithnoseizuresatpresentation

Parameter Numberofcases

18patientsdidnotpresentwithseizuresandtheirkeyparametersareoutlinedintable3.As

previouslystated,theonlyvariablethatsignificantlypredictedseizuresasapresentingsymptom

washeterogeneousMRIappearance,withthosewithheterogenoustumoursignalbeingmorelikely

topresentwithseizures,althoughthisdidnotcorrelatewithaspecifictumourtype.Mediantumour

sizeinpatientswhodidnotpresentwithseizureswas14.55cm3comparedto36.85cm

3inthosewho

did.

7patientsdideventuallydevelopseizures(6GTC;1partial)atamediantimeof29months.Ofthese

newcasesofseizures,6wereoligodendrogliomasand1wasastrocytoma.Onlyonenewseizure

casewasassociatedwithradiologicaltumourprogressionrecurrenceofanoligodendrogliomawhich

hadundergonesubtotalresection.Therewerenofactorsthatpredictwhichpatientswouldgoonto

developseizures.EORwascompleteorneartotalin5patientswithnewseizures(71%)comparedto

10outof11patientswhoneverhadseizures(91%).

3.3TumourOutcome

Tumourrecurrenceorprogressionoccurredin25(40%)patientsintheseries,withmediantimeto

recurrenceof22months.Ofthese,fourteenrecurredasgradeII,eightasgradeIIIandthreeas

gradeIV.

Inpatientspresentingwithseizures(n=20)themediantimetorecurrencewas22.5monthsvs21

monthsinthosewhodidnotpresentwithseizures(n=5)Figure1.Table4showstheEORand

tumourgradeatrecurrenceforthe25patientswhoprogressed.Inthiscohort,patientswho

underwentsubtotalresectionweremorelikelytohaveprogressionthanthosewithcompleteor

near-totalresection,withprogressionoccurringin52%ofsubtotalresectionsand27%of

complete/near-totalresections(p=0.044).Importantly,oftumoursrecurringasgradeIIIorIV,only

oneoutofninepatientshadundergonecompleteresection(11%).

Totalpatients 18

Tumourtype

Oligodendroglioma 12(67%)

Astrocytoma 6(33%)

IDHmutation

Present 16(89%)

Absent 2(11%)

DevelopmentofSeizures 7(39%)

GTC 6(86%)*

Partial 1(14%)*

EORandMRICharacteristics

Complete 9(50%)

Near-total 6(33%)

Sub-total 3(17%)

Eloquent 5(28%)

Non-eloquent 13(72%)

Corticalinvolvement 7(39%)

MassEffect 6(33%)

Distinctborders 10(56%)

Homogenousappearance 11(61%)

GradeatRecurrence Complete

resection

Near-

total

resection

Subtotal

resection

Table3–Parametersforpatientswhomdidnotpresentingwithseizures.*indicatespercentage

ofseizurecases

Table4–comparisonofEORratesindifferentgradesoftumourrecurrence

Largertumourswerealsomorelikelytorecur.Themeantumourvolumeinpatientswhohad

recurrencewas44.2cm3comparedto26.0cm

3inpatientswithnorecurrence(p=0.008).Mass

effectwasalsopredictiveoftumourrecurrence,whererecurrenceoccurredin67%ofpatientswith

evidenceofmasseffectonpre-operativeMRI,comparedto19%ofthosewithnomasseffect

evident(p=<0.01).IDHstatus,typeofsurgeryandradiologicalvariablesofborderdistinction,cortical

involvementandtumoursignaldidnotsignificantlypredictrecurrence.

Overall,greaterEORwasgenerallyachievedwithawakecraniotomywith13undergoingcomplete

resection(52%),7near-total(28%)andonly5sub-total(20%).Incomparison,inthegeneral

anaesthesia(GA)groupacompleteresectionwasachievedin17patients(45%),near-totalin7

patients(18%)andsub-totalin14patients(37%).However,thisdidnotstatisticallypredictseizure

freedom(p=0.80).

MostpatientsweretreatedbeforethepublicationoftheRTOG9802study,thereforetheuseof

adjuvanttreatmentwasmixed.17patientsreceivedadjuvanttherapyafterinitialtumourresection

duetosignificantresidualdisease.8receivedradiotherapyalone,2receivedchemotherapyalone

and7receivedcombinedchemo-radiotherapy.11(65%)hadoligodendrogliomas,theremainderhad

astrocytomas.Ofthepatientswhoinitiallypresentedwithseizures(n=45),9receivedadjuvant

therapy,comparedto8patientsoutofthosewhodidnotpresentwithseizures(n=18).11patients

whohadadjuvanttreatmentwereEngelclassI(65%).Ourdatadidnotshowastatisticallysignificant

improvementinseizureoutcomeafteradjuvanttherapycomparedtonoadjuvanttherapy(p=0.33).

3.4OutcomesBeforeandAfterthe2016WHOUpdate

Afterreclassificationtherewere36patientswitholigodendrogliomaand27withastrocytoma.Based

ontheoriginalhistologicalclassificationbeforethe2016updatetherewere28with

oligodendroglioma,24withastrocytoma,11witholigoastrocytoma.Oftheoligoastrocytomas,7

werereclassifiedtooligodendrogliomaand4toastrocytoma.

Totalcases Seizures EngelI EngelII+

BeforeUpdate

Oligodendroglioma 28 18 16(89%) 2(11%)

Astrocytoma 24 17 11(63%) 6(37%)

Oligoastrocytoma 11 10 6(60%) 4(40%)

AfterUpdate

Oligodendroglioma 36 24 19(79%) 5(21%)

Astrocytoma 27 21 14(67%) 7(33%)

II 6 3 5

II/III 2

III 1 1 4

III/IV 1

IV 1 1

Table5–Comparisonofcasesbeforeandafterreclassificationusing2016WHOupdate

Asshownintable5,tumourspreviouslyclassifiedasoligoastrocytomaweremostlikelytopresent

withseizures.OligodendrogliomaswerealsomorelikelytobeEngelclassIpost-operatively,

whereasoligoastrocytomaswereleastlikely.Moreoligoastrocytomaswerereclassifiedas

oligodendrogliomathanastrocytoma,whichmayhaveaffectedEngelclassoutcomespost-updateas

therewere10%feweroligodendrogliomapatientsEngelclassIafterreclassification.However,

seizureoutcomewasvirtuallyunchangedinastrocytomasbeforeandaftertheupdate.

Innewcasesofseizures,therewasnochangebetweenpre-andpost-updatedclassification,with6

casesofnewseizuresinpatientswitholigodendrogliomasand1withastrocytoma.

Tumourrecurrencewasnotsignificantlyimpactedaftertheupdatedclassification.25patientshad

tumourrecurrence,12ofwhichwereoligodendrogliomaand13astrocytoma.Before

reclassification,these25patientsweremadeupof9oligodendrogliomas,11astrocytomasand5

oligoastrocytomas.

4. Discussion

ThemainoutcomeofthisstudywastoassessseizureoutcomeinpatientswithLGGsandidentify

anyimaging,molecularoroperativepredictorsofseizuredevelopmentandseizurefreedombased

onthe2016WHOclassificationsystem(4).

Ourresultof73%patientsbeingEngelclassIpost-operativelyisinkeepingwithotherdata,witha

rangeof67-81%reported(6,8,15,16).TheproportionofourpatientsbeingEngelclassIdecreases

withtimepost-operatively,asshownbytheseizurefreedomratesat3,6and12monthspost-

operatively(91%,87%and80%respectively).

EORappearstobeastrongpredictorofseizurefreedom(EngelclassI)afterresection(8,15,17).Our

resultsofEngelclassIforcomplete(76%),near-total(87.5%)andsubtotalresection(62.5%)show

preferableseizureoutcomewithgreaterEOR.Thisisinkeepingwithotherliterature,forexampleXu

etal.(15)foundanEOR>80%gavebetterseizureoutcome(EngelclassI)andameta-analysis

showed80%seizurefreedomfromgross-totalresectioncomparedto53%ofsubtotalresections

(17),againsimilartoourdata.Seizurefreedomin62.5%ofsubtotalresectionsstillshowsthe

surgicalbenefittoseizureoutcomeevenwhenalowerEORisachieved.Thewidespreadpush

towardsmaximalearlyresectionappearstoprovideimprovedseizureoutcomes.Infact,

“supratotal”resection,wherebythetumourisremovedalongwithamarginvisibleonFLAIR-

weightedMRI,hasbeenshowntoproducefavourableseizureoutcomesaswellasasignificant

reductionintheriskofmalignanttransformation(14).Thisisreflectedinthefactthatinthisstudy

EORwasalsoasignificantpredictoroftumourrecurrenceastumoursweresignificantlymorelikely

torecurwithanincompleteEORcomparedtonear-totalorcomplete,despiteadjuvanttherapy.

Adjuvanttherapydidnotappeartogivefavourableseizureoutcomesinthiscohort(p=0.33)which

maybeduetothefactthatadjuvanttherapytendedtobeusedinthosewithsignificantresidual

disease(incompleteEOR)whichisanegativeprognosticfactorinitself.

Ourdataalsoshowthatseizureoutcomeisimprovedwhenresectionisperformedasawake

craniotomywithintra-operativefunctionalmappingcomparedtounderGA(84%EngelclassIvs

65%).ThismaybeduetoanoverallgreaterEORinthoseoperatedawakecomparedtothose

operatedunderGA.Ofthe19patientswhounderwentawakecraniotomyandresection,74%had

completeornear-totalresectioncomparedto58%ofthoseoperatedunderGA.Theincreased

numberofsubtotalresectionsintheGAgroupmaycontributetothereducedrateofseizure

freedom.

Whencomparingseizureoutcomeinpatientswitholigodendrogliomastoastrocytomasbasedon

the2016WHOupdate,slightlymorepatientswitholigodendrogliomaswereEngelclassI(79%and

67%respectively),howeverthisisnotstatisticallysignificant.Incontrast,Changetal.(8)reportthat

patientswitholigodendrogliomasaremorepronetoseizuresduetoatendencytobelocated

cortically.Itwasgenerallythoughtthatmorecorticallylocatedtumoursaremoreproneto

developingseizures,whichincludedthenolongerusedclassificationofoligoastrocytoma.Where

astrocytomaswerethoughttobemainlyfoundinwhitemattertractstheywerethoughttohaveless

seizuresapartfromprotoplasmicastrocytomaswhichwerelinkedtochronicepilepsy.After

reclassification,tumourtypedidnothaveanimpactonseizureoutcomeinourcohort.Thereis

somewhatmixeddataassessingoutcomesbasedontumourtype.Previousstudieshaveshownboth

improvedoutcomewithcertaintumourtype(oligodendroglioma;(18)ornodifferenceinoutcome

(19).Furthermore,thereisconflictedevidencethatoligodendrogliomasaremorelikelytohave

seizuresasapresentingsymptom(9,20)butinourcohorttumourtypedidnotpredictwhich

patientswouldpresentwithseizuresinitially,withnosignificantdifferencebetween

oligodendrogliomasandastrocytomasintermsofseizuresasapresentingsymptom.Additionally,

althougholigodendrogliomashadmoreindistinctbordersthanastrocytomasbasedonthe2016

classification(59%vs35%),therewasnodifferenceinEORorseizureoutcomeinthisseries,which

mayreflectthesmallnumbersineachsubgroupandrequiresfurtherstudy.

The2016WHOupdatehasnotshownsignificantchangesinprognosisinourseries.Thegreatest

differencewasinseizurefreedomratesofoligodendrogliomas,where89%wereEngelclassIpost-

operativelybasedontheoldclassificationsystemcomparedto79%afterreclassification.Thismay

beduetofactthatthemajorityofoligoastrocytomas,whichhadthehighestproportionsofpatients

presentingwithseizures(89%)andlowestproportionEngelclassIpost-operatively(40%),were

reclassifiedasoligodendrogliomasandthusreducedtherateofseizurefreedom.Asidefromthis,

therewasverylittleimpactonratesoftumourrecurrencebetweentumourtypesandnochange

betweenratesofnewseizures.Largerlongtermcaseserieswillberequiredtodemonstrate

differencesinclinicalfeaturesandoutcomeafterthe2016update.

Delfantietal.aimedtocorrelateimagingcharacteristicswithtumourclassificationbasedonthe

2016updateinaretrospectivestudyof40patients(21).Theyidentifiedthattumourclassification

hadanimpactontumourlocation,appearanceofbordersonMRIandprogressionfreesurvival

(PFS),wherepatientswithnoIDHmutationhadsignificantlyshorterPFS(24).Itmaybethattumour

histologyunderthenewclassificationhaslessimportancetoseizureoutcomecomparedtotheold

systembuthasagreaterimpactinrelationtopatientdemographics,imagingcharacteristicsand

prognosis.Inourstudy,pre-operativeradiologicalvariablesincludingcorticalinvolvement,mass

effect,eloquentlocation,borderdistinctionandtumoursignaldidnotsignificantlyimpactonseizure

development,outcomeortheabilitytoachievemaximalEOR.Interestingly,tumoursignal

(homogenousvsheterogenous)onMRIwassignificantlyrelatedtowhetherseizureswerethe

presentingsymptom,whichmayreflectasyetunknownmoleculardifferenceswithintumours.

IDHmutationstatushaspreviouslybeenshowntobeassociatedwithseizuresasapresenting

symptomandincreasedriskoffuturemalignanttransformation(5,13,25–27).However,ourdata

showednosignificantcorrelationbetweenIDHmutationsandseizuresasapresentingsymptom,

seizureoutcome,tumourtypeorrecurrence.ThereforetheuseofIDHmutationstatusaloneasa

prognosticmarkerwaslimitedinourcohort.

Tumourvolumedidnotinfluenceseizureoutcome,withsimilarmeantumourvolumesinpatients

whowereEngelclassIcomparedtoclassIIorabovepost-operatively(33.8cm3vs30.3cm

3

respectively).However,tumourvolumedidinfluencetumouroutcome,ascaseswhereprogression

occurredhadsignificantlylargerinitialtumourvolumescomparedtothosewhichdidnot(p=0.008;

meanvolumes44.2cm3vs26.0cm

3respectively).ThisislikelylinkedtothepotentialEORachievable

withlargertumours,asmeantumourvolumewassignificantlygreaterinpatientswhounderwent

subtotalresectioncomparedtothosewhohadnear-totalorcompleteresection(54.9cm3vs23.8

cm3;p=<0.01).Thus,largerinitialtumourvolumesappeartoreducethepossibleEOR,whichhasalso

beenshownelsewhere(1).Wedidnotidentifyalinkbetweentumourvolumeandseizuresasa

presentingsymptomwhereasothershaveshownthatlargertumourstendedtopresentwith

seizures(28).

Forpatientsthatdidnotpresentwithseizures,itisnotobviousastowhatspecificfactorspredict

theabsenceofseizuresorwhatledtodevelopmentofseizuresin7ofthe18(39%)asourdatashow

nostatisticallysignificantpredictors.Themajorityofpatientswhowentontodevelopseizureshad

oligodendrogliomas(86%)whichcorrelateswithsomethatoligodendrogliomastendtobemore

corticalandaremorepronetoseizureactivity,butthisresultwasnotsignificantandthereismixed

evidenceintheliterature(8,9,20).Previousstudieshavesuggestedthatlargertumoursare

indicativeofalongerperiodofsilentgrowth,withmoretimeforseizurestodevelop(28).Itis

possiblethatmorepatientswouldhavegoneontodevelopseizureshadtheynotpresentedwith

othersymptomsorasanincidentalfinding.Leadingonfromthis,ourfindingthattumourvolume

wassignificantlysmallerintumourslocatedineloquentregionscomparedtonon-eloquentregions

(22.0cm3vs37.7cm

3)ismostlikelyduetoeloquentlylocatedtumoursproducingsymptomsatan

earlierstageintheirgrowth.

Weidentifiedseveralkeyfactorsthatpredicttumourrecurrence,inlinewithrecentstudies(1,26).

Evidenceofmasseffectonpre-operativeMRI,largertumourvolumesandreducedEORall

statisticallycorrelatedwithanincreasedlikelihoodofrecurrence.Masseffectmayplayaroleby

affectingresection,wherebycompressionofnearbystructureslimitstheachievableEOR.Tumour

volumeandEORappeartointerlinkintheireffectontumourrecurrence,wherebylargertumour

volumescorrelatedirectlywithtumourrecurrenceandalsoreducedEOR,whichindirectlycorrelates

withsurvivalasreducedEORisassociatedwithtumourrecurrence.Similardatahasbeenshownin

otherstudiesinthatEORisreducedinlargertumoursaswellastumourvolumebeingan

independentprognosticfactorfortumourrecurrence(1,29).

Overall,pre-operativeradiologicalvariablesdidnotpredictseizureoutcomeinourcohort,with

tumourvolumetheonlyvariablethatinfluencesEORandhenceseizureoutcome.Eventumour

locationinaneloquentregiondoesnotinfluenceEORsoitseemsthatwithjudicioususeofawake

craniotomyitispossibletoachievesignificantresectionandleadtoafavourableoutcome.Tumour

volumeappearstobeanimportantvariablerelatingtofactorssuchasEORandtumourrecurrence

butdoesnotaffectseizureoutcome.Inthisstudy,themajorityofpatientsachievedseizure

freedomandthuswereabletoreturntodriving,whichisaconsiderablebenefittoqualityoflife,

particularlyduetotheyoungageandpreviousgoodhealthofthemajorityofLGGpatients.

Thisstudyhasseverallimitationsincludingtheretrospectiveanalysisofasingleinstitutionseries.

Withmultiplevariablesitispossiblethatthelackofstatisticalsignificanceisrelatedtosmallsample

size.However,ourfindingsregardingEORandoutcomeareinlinewiththecurrentLGGliterature

andfurtherlargermulticentrestudiesofradiologicalandmoleculargeneticvariablesarerequired.

5. Conclusion

OurdataareconsistentwithsimilarstudieswhenassessingseizureoutcomeafterresectionofLGG,

inthatagreaterEORgivesimprovedseizurefreedom.EvenwhenEORwassubtotal,mostpatients

werestillEngelclassI,indicatingthatthenewerstrategyofearlierandmoreaggressiveresection

mayresultinabetteroverallprognosisforpatientswithLGGsandimprovequalityoflifewith

regardstoseizurefreedom.Radiologicalvariablesdidnotimpactseizureoutcome,indicatingthat

cautiousresection,particularlywiththeuseofintra-operativefunctionalmapping,isstillpossiblein

themajorityoftumoursevenwheneloquentlylocated.Regardlessofpre-operativevariables,it

appearsthemostimportantpredictorofseizureoutcomeismaximalsaferesection,regardlessof

tumourtype.

Funding

Thisresearchdidnotreceiveanyspecificgrantfromfundingagenciesinthepublic,commercial,or

not-for-profitsectors.

Conflictsofinterest

Nonedeclared.

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