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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([email protected]).
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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