Granule
cell
dispersion
is
associated
with
memory
impairment
in
right
mesial
temporal
lobe
epilepsy
Rafael
Scarpa
da
Costa
Neves
a,*
,
Ivanda
de
Souza
Silva
Tudesco
a,b,
Anaclara
Prada
Jardim
a,
Luı´s
Ota´vio
Sales
Ferreira
Caboclo
a,
Carmen
Lancellotti
c,d,
Taı´ssa
Ferrari-Marinho
a,
Ana
Paula
Hamad
a,
Murilo
Marinho
a,
Ricardo
Silva
Centeno
a,
Esper
Abra˜o
Cavalheiro
e,
Carla
Alessandra
Scorza
e,
Elza
Ma´rcia
Targas
Yacubian
aaDepartmentofNeurologyandNeurosurgery,UniversidadeFederaldeSa˜oPaulo,EscolaPaulistadeMedicina,Sa˜oPauloSP,Brazil bDepartmentofPsychobiologyUniversidadeFederaldeSa˜oPaulo,EscolaPaulistadeMedicina,Sa˜oPauloSP,Brazil
cDepartmentofPathology,SantaCasadeSa˜oPaulo,Sa˜oPauloSP,Brazil
dDepartmentofPathology,Associac¸a˜oFundodeIncentivoa` Pesquisa(AFIP),MedicalDiagnosis,Sa˜oPauloSP,Brazil
eDepartmentofNeurologyandNeuroscience,ExperimentalNeurology,UniversidadeFederaldeSa˜oPaulo,EscolaPaulistadeMedicina,Sa˜oPauloSP,Brazil
1. Introduction
Mesialtemporalsclerosis(MTS)isthemostcommontypeof lesion abnormality observed in mesial temporal lobe epilepsy (MTLE).1Otherthan segmentalneuronallosswithin the
hippo-campal subfields, different patterns of pathology are often described in the dentate gyrus (DG), including granule cell dispersion (GCD), bilaminar DG, granule cell loss, and ectopic granulecellsinthemolecularlayeroftheDG.2
GCDisacommonphenomenonthatoccursinapproximately 50%ofallMTSspecimens.3Thecriteriafordeterminingdispersion
varyfromsubjectivequalitativeimpressionsofthewidthofthe molecular layer toobjective quantitative measuresof width.4,5
Little is known about the pathogenic mechanisms and clinical significance of GCD. Seizures that occur earlyin the maturing hippocampus6,7 and developmental abnormalities have been
hypothesized to cause GCD.8 Previous studies have failed to correlate GCD with seizure outcome following surgery for MTLE.2,9,10 The associationbetween GCD and clinicaldata also
remainscontroversial.6,7,11
Thehippocampusplaysacrucialroleinlearningandmemory. Explicit episodic memory is strongly associated with mesial temporalstructures12,13andisthemoststrikingcognitivedeficit
inMTLEpatients.14,15Verbalmemorydeficitsaremorecommonly
associated with the left mesial epileptogenic zone, whereas nonverbalmemoryimpairmentsaremorefrequentlyassociated with non-dominant MTLE.16,17 Seizure frequency, duration of
epilepsy, the use of antiepileptic drugs (AEDs), and interictal epileptiform discharges have been implicated in memory dysfunction observed in MTLE patients.18–20 Histopathological investigation of surgical specimens may help to understand memoryimpairmentinthesepatients.2,21
ARTICLE INFO
Articlehistory: Received15May2012
Receivedinrevisedform13July2012 Accepted14July2012
Keywords:
Mesialtemporallobeepilepsy Mesialtemporalsclerosis Dentategyrus
Granulecelldispersion Memory
ABSTRACT
Purpose:We analyzedthe associationof granulecell dispersion(GCD)withmemoryperformance,
clinicaldataandsurgicaloutcomeinaseriesofpatientswithmesialtemporallobeepilepsy(MTLE)and mesialtemporalsclerosis(MTS).
Method: Hippocampalspecimensfrom54patientswithMTLE(27patientswithrightMTLEand27with
leftMTLE)andunilateralMTS,whowereseparatedintoGCDandno-GCDgroupsandthirteencontrols werestudied.Quantitativeneuropathologicalevaluationwasperformedusinghippocampalsections stainedwithNeuN.Patients’ neuropsychological measures,clinicaldata,type ofMTSandsurgical outcomewerereviewed.
Results:GCDoccurredin28(51.9%)patients.NocorrelationbetweenGCDandMTSpattern,clinicaldata
orsurgicaloutcomewasfound.ThepresenceofGCDwascorrelatedwithworsevisuospatialmemory performanceinrightMTLE,butnotwithmemoryperformanceinleftMTLE.
Conclusion:GCDmayberelatedtomemoryimpairmentinrightMTLE-MTSpatients.However,therole
ofGCDinmemoryfunctionisnotpreciselydefined.
ß2012BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.
*Correspondingauthorat:UnidadedePesquisaeTratamentodasEpilepsias,Rua Napolea˜odeBarros737,138andar,04024-002Sa˜oPauloSP,Brazil.
Tel.:+551155764136.
E-mailaddress:rafaelscarpa@uol.com.br(R.S.d.C.Neves).
ContentslistsavailableatSciVerseScienceDirect
Seizure
j o urn a lhom e pa g e :ww w . e l se v i e r. c om / l oca t e / y se i z
Humanstudiesandanimalmodelshavecorrelatedthedegree ofcelllossinthehippocampusandDGwithmemorydecline.22,23
Neurogenesis of DG cells may play a role in behavior and the acquisitionofnewmemoriesinrodents.24,25Similarmechanisms
arelikelytooccurinhumans.21
The influence of GCD in the formation of memory remains unclear.Toaddressthisissue,westudiedtheoccurrenceofGCDin thehippocampiofrefractoryMTLE-MTSpatientsandinvestigated the relationship between this abnormality and memory perfor-mance,clinicalcharacteristics,MTSpatterns,andsurgicaloutcome.
2. Materialsandmethods
2.1. Subjects
Fifty-four patients (27 men), who were identified as right-handed using the Handedness Inventory26, with medically
refractoryMTLE and unilateral MTS (27 rightMTS and 27 left MTS)visualizedviaMRIwereincludedinthepresentstudy.These patientsarepartofapreviouslypublishedseriesofstudies.27The
meanagewas38.510.48yearsfortherightMTLEpatientgroup and36.710.84yearsfortheleftMTLEgroup.RightandleftMTLE patientswere dividedinto GCDandno-GCD groups.Diagnosisof MTLEwasestablishedaccordingtopreviouslyreportedclinicaland electrographiccharacteristics.28Patientsweredefinedasmedically
refractoryifseizurewasnotcontrolledusingatleasttwofirst-line AEDs,inmonoorpolytherapyuptotoxiclevels.
This retrospective study is based on review of previously collected tissue samples. This study was approved by the institutionalEthicsCommittee,andallparticipantsgaveinformed consent.
Clinical features were reviewed using a specific protocol developedforthisstudythatfocused onsixvariables. Presence and age of the initialprecipitant insult (IPI) were assessed as definedbyMathernetal.29Thepatientageatonsetofhabitual
seizures, which was defined as the age at which habitual and recurrentseizuresdeveloped,wasrecorded.Similarly,theduration ofepilepsy,whichwasdefinedastheintervalbetweentheageat onsetofhabitualseizuresandthetimeofsurgery,wasnoted.We also examined the average frequency of preoperative complex partial seizures (CPS) per month, as well as the approximate numberof generalized tonic–clonicseizures (GTCS)throughout life,whichwascategorizedas>or<20.
Allpatients completedanextensive preoperativeevaluation, whichincludedhigh-resolutionMRIand prolongednoninvasive video-EEGrecording.VisualinspectionoftheMRIimagesrevealed thatallpatientshadclearevidenceofMTS,whichincludesvarying degreesofhippocampalsclerosis(e.g.,atrophy,increasedT2-and decreasedT1-weightedsignal,anddisruptedinternalstructureof thehippocampus)aswellasatrophyandsignalalterationofthe amygdalaandtemporalpole.PatientswithunilateralMTSthatwas associatedwithstructuralabnormalitiesotherthanbrainatrophy wereexcluded.
Surgicalresectionwasperformedwhenthisevaluationyielded evidenceofMTLEwithMTS.Thissurgeryconsistedofresectionof 3.5cmofthetemporalneocortexfromthetemporalpoleofthe dominant hemisphere and 4.5cm from the non-dominant hemisphere.Thissurgicalresectionyielded3.5cmofhippocampus andapproximatelytwo-thirdsoftheamygdala.Allpatientswere followedforseizurecontrolaccordingtoEngel’sclassification30for
atleastsixmonthsfollowingthesurgery.
2.2. Neuropsychologicalmeasures
Astandardclinicalmeasureofintelligencewasused(estimated fullscaleIQfromtheWechslerAdultIntelligenceScale-Revised
[WAIS-R]).31TheLogicalMemoryIandIIsubtests32(immediate
anddelayedrecall)wereusedtoassessverbalmemory,andthe VisualReproduction IandIIsubtests32(immediateand delayed
recall)wereusedtoassessvisualmemory.Inaddition,theRey– OsterriethComplexFigureTest33(immediateanddelayedrecall)
wasusedto assessvisuospatialmemory, and theReyAuditory VerbalLearningTest(RAVLT)33wasusedtoassesverballearning.
2.3. Tissuepreparation
Thehippocampiofallpatientswerecollectedfromthearchives of neuropathology from the years 2005 to 2011. Samples containinglessthanthreehippocampalsubfieldsorlackinglayers CA1and/orCA4wereexcluded.
Thehippocampuswasdissectedintofive-mm-thickslicesalong the anterior–posterior axis, fixed overnight in a 4% formalin solutionandthenprocessedinliquidparaffin.Asingleblockof tissuecorrespondingtothemid-hippocampalbodywasselected fromeachcaseforhistopathologicalexamination.34Blockswere
cutto7
mm
(Leica,Germany),expandedinhotwater,mountedon slidescoatedwithsalineandair-driedovernightinanincubatorat 568C.Twoslidesfromeachcaseweredeparaffinizedinxylolanda descending alcohol concentration. One slide was stained with hematoxylinandeosin(HE)forpathologicaldiagnosisofMTS,and theotherslidewassubmittedtoanautomatedstainingapparatus (AutostainerLink48,Dako,USA)forNeuNimmunohistochemistry (Chemicon,Temecula,USA,dilution1:1000,pre-treatedinPTLink equipment, Dako, USA) and hematoxylin counterstaining. Two independent observers(AJand RN) completedquantitativeand qualitative analysesof alltissuesamples,whichincludedslides stainedwithNeuNandHE.Specimenscollectedatautopsyfromthehippocampiofthirteen neurologicallyhealthyindividuals,withoutahistoryofepilepsy, served as controls (mean age 57.614.34 years). Postmortem tissue samples were stained with HE and NeuN. As reported in previous studies5,9 there was no difference in accuracy between
controls’HE-andNeuN-stainedsections.
2.4. Morphologicanalysisandneuronalcellcounts
MicroscopicimageswereobtainedusinganE600microscope equippedwithaMoticam2300camera(Nikon,Japan). Measure-mentsofgranulecelllayer(GCL)widthandneuronalcellcounts were performed with ImageJ software (National Institutes of Health,NIH,USA).Immunohistochemicallystainedneuronalcell bodieswerevisualizedonacomputerscreen(MoticImagesPlus software).
2.4.1. Granulecelldispersion
GCD was considered present when three conditions wereobservedconcurrently:(a)straightportionsoftheGCLwere greaterthan120
mm
inwidth;(b)granulecellswerenotinclose opposition to each other; and (c) the boundary between themolecularlayerandtheGCLwasnolongerclearlydefined.4SectionsstainedwithNeuNwereusedtocalculatetheaverage widthoftheGCLineachsurgicalcase.Thedistancefromtheinner borderoftheGCLtotheouterborderofthemostdistalgranulecell wasdeterminedintheinternalaswellasintheexternallimbsand midportionoftheDG.EightregionsofmaximalGCDalongtheGCL weremeasured9tocalculatethemeanandstandarddeviationof
eachcase.Curvedregionswerenotconsidered.
2.4.2. Neuronalcellcounts
AlltissuesamplescollectedfromMTLEpatientsandcontrols wereanalyzedaccordingtoBlumckeetal.5Hippocampalsubfields
regions of 0.0625mm2 in areas were outlined in each sector (CA1–CA4).AllNeuN-positiveneurons,despiteanydifferencesin sizeormorphology,werecountedintheselectedfieldsunder20
magnification. For each subfield, neuronal cell density was calculatedinneurons10 4/mm2.
2.5. Statisticalanalysis
Neuronal cell counts from each hippocampal subfield were transformed into z-scores. z-Score is the number of standard deviationsfromthemeanexpectedvalue,whichinthiscaseisthe meanneuronaldensityinthecontrols’hippocampalsubfields.z -Scores for neuronal density were calculated according to the following formula: z=(observed density score mean control density score)/standard deviation of the control density score. Neuronalcellcountsgreaterthantwostandarddeviationsaway fromthemeanwereconsideredabnormal;onlynegativez-scores wererelevant.FivedifferentpatternsofHSweredefined bythe followingcriteria:noMTS(z-score<2inallhippocampalsubfields);
MTStype1a(z-score<2inCA2but>2inallothersectors);MTStype
1b(z-score>2inallsubfields);MTStype2(z-score>2inCA1and<2
inCA4);andMTStype3(z-score>2inCA4).9
StatisticalanalysiswascompletedwithSPSS10.0forWindows, Version10.01.Student’st-testwasusedtocompareclinicaldata betweendifferentgroups.Theresults(meansSD)obtainedfrom allofthememorytestsadministeredtopatientswithrightandleft MTLE with MTS, including those with and without GCD, were comparedandtransformedintoz-scores.Forthiscomparison,a one-wayanalysisofvariance(ANOVA)wasperformed.Whenappropriate, theposthocBonferroniprocedurewasperformed;Pvalues<0.05
wereconsideredstatisticallysignificant.
Toinvestigatewhethermemoryimpairmentcouldbe second-arytovariablesotherthanthepresenceofGCD,suchasdurationof epilepsy,ageatsurgery,monthlyseizurefrequency,MTStypeand postoperativeoutcome,weperformed ananalysisofcovariance (ANCOVA)inrightandleftMTLE-MTSgroups.
3. Results
GCDwasobservedin28cases(51.9%):14inrightMTLEand14 in left MTLE(Fig. 1). Clinical variables, including age at onset, presenceandtypeofIPI,durationofthelatencyperiod,durationof epilepsyandageatsurgeryweresimilarbetweentheGCDand no-GCD groups in both right MTLE and left MTLE.No statistically significantdifferencewasfoundbetweenrightMTLEandleftMTLE patientsintermsoftheiryearsofeducationandIQ(Table1).MTS patternwasnotassociatedwithGCDinMTLE-MTSpatients(Table 2).MonthlyseizurefrequencyandestimatedlifetimeGTCSwere similarinbothgroups.
PostoperativeoutcomesweresimilarinrightMTLE-MTSand leftMTLE-MTSpatientsaswellasintheGCDandno-GCDgroups. AmongtherightMTLEpatients,85.7%withGCDand76.9%without GCDwereseizure-freeafterthesurgery.OftheleftMTLEpatients, 78.6% with GCD and 69.2% without GCD were seizure-free followingthesurgery.
In rightMTLEpatients, theGCDgroupobtained significantly lowerscoresontheimmediaterecallportionoftheRey–Osterrieth Complex FigureTest.Thisfindingmaysuggestthatvisuospatial memoryismoregreatlyaffectedbyGCDinrightMTLE.However, in the left MTLE-MTS group, the presence of GCD was not associatedwithmemoryperformance.Table3illustratesthemean adjustedz-scoresforthesegroups.
Ananalysisofcovariancewasusedtocontrolrelevantvariables that might influence memory impairment. The results of the ANCOVAshowedthatthesevariableshadnoimpactonmemory performance;thus,GCDappearstobetheonlyvariableaffecting memoryperformanceinthissampleofMTLEpatients.
4. Discussion
HouserfirstdescribedGCDinpatientswithTLE.8Hippocampal
specimenscollectedfromthesepatientslackedadistinctboundary between the granule cell and molecular layers, and numerous Fig.1.HistopathologicalfindingsinthedentategyrusofcontrolsandMTLEpatients(NeuN-stainedsections).(A)Control;(B)No-GCD:granulecellsaredenselypackedand haveadistinctborderwiththeML;(C)GCD:granulecellsaredispersedandspreadintotheML;widthofGCLexceeded120mm.Scalebars,100mm.GCD:granulecell dispersion,GCL:granulecelllayer,ML:molecularlayer,MTLE:mesialtemporallobeepilepsy.
Table1
Clinicaldata(meanSD)ofMTLEpatientsinGCDandno-GCDgroups.
RightMTLEpatients LeftMTLEpatients
No-GCD(N=13) GCD(N=14) No-GCD(N=13) GCD(N=14)
Sex(M/F) 7/6 4/10 P=0.252 6/7 10/4 P=0.252
Education(years) 9.34.61 8.33.47 P=0.519 6.84.80 6.94.22 P=0.960
IQ 80.69.20 83.411.72 P=0.496 84.411.51 81.113.85 P=0.507
IPIPercentage(N) 38.5%(5) 50.0%(7) P=0.704 53.8%(7) 64.3%(9) P=0.704
FSPercentage(N) 60.0%(3) 28.6%(2) P=0.667 57.1%(4) 44.4%(4) P=1.000
Latency(years) 13.85.72 10.45.06 P=0.305 16.08.14 13.46.77 P=0.504
Epilepsyonset(years) 16.78.40 17.69.34 P=0.783 14.58.65 11.99.12 P=0.461
Epilepsyduration(years) 17.38.63 24.512.80 P=0.102 24.710.77 23.215.72 P=0.780
Ageatsurgery(years) 34.611.33 42.18.48 P=0.060 38.78.31 34.912.79 P=0.368
granule cellsomata extendedinto themolecular layer. Further studiesdemonstratedthatGCDisnotexclusivetopatientswith HS.Inapostmortemstudy,GCDwasobservedinpatientswhohad widespreadcorticalmalformationswithouthippocampalcellloss, suggestinganeurodevelopmentaldisorder.35
In ourstudyof pure unilateral MTLE-MTS, GCD occurred in 51.9% of all cases, which is consistent with data previously reportedintheliterature.5,9TheassociationofGCDwithclinical
characteristicssuchas historyof IPIand seizure frequency has beendiscussedpreviously.6,7,11Wefoundnocorrelationbetween
theseclinicalvariablesandGCD.Consideringthatthepresenceof GCDwasnotcorrelatedwithclinicalfactors,GCDmaybemore closelylinkedtothepathologicalmechanismofMTSratherthan beingamanifestationofsevereTLE.11
Ourdataareconsistentwithpreviousstudiesthatsuggestthat thereis no correlationbetween GCD and seizureoutcome.5,9,10
ClassicpatternsofMTSexpressionweremostfrequentlyobserved inoursampleofMTLEpatients,includingboththeGCDand no-GCD group. This finding is consistent with previous reports5;
however,therewasnostatisticallysignificantdifferenceinMTS patternexpressionobservedinthesegroupsofpatients.
Quantitativehistologicalanalysisof thetissueresectedfrom thehippocampalsubfieldsandDGhasbeenassociatedwith pre-andpost-operativememorydeficits.36,37Inahuman
electrophys-iological study,Grunwald et al.38 reported that limbic P300 (a
memoryrelatedcomponent)recordedfromelectrodesplacedata intrahippocampal depth correlated significantly with neuronal density of the DG, but not with pyramidal cell density in hippocampal subfields CA1 through CA4. Animal studies con-firmedthis finding.23,39 Blumckeet al.2 collected data from 26 patients; the authors observed significantly better memory performance in patients without dentate granule cell loss or dispersion.Thesamegroup21foundthatneuronalcelllosswithin
theinternallimbofthedentategyrus,adevelopmentallydistinct subregionofthehippocampalformationknowntogeneratenew neuronsthroughout life,wasa highlyaccuratepredictorof the abilitytolearnandrecallmemories.
Although previous studies have proposed a relationship betweengranulecellabnormalityandmemoryfunctionduring intracarotidamobarbitalprocedure(IAP),2,21IAPwasnotusedin
our study of pure unilateral MTLE-MTS we tested memory function using a number of neuropsychological assessments, which are commonly administered in other epilepsy centers. Despite its diagnostic value, IAP is an invasive procedure; complicationshavebeen reportedinupto11.6%ofpatients.40
Although IAP has often been cited as the gold standard in assessmentoflanguagelateralization,ithasnotbeenestablished asapredictorofpostoperativememorydecline.Rather, postop-erative memory decline can generally be measured using noninvasive methods. Baxendale et al.41 suggested that it is
inappropriate to conduct an invasive procedure, such as IAP, solelytogainprognosticdata regardingpostoperativememory decline.
WedidnotfindasignificantrelationshipbetweenGCDand memoryperformanceinleftMTLE-MTSpatients.However,GCD wasassociatedwith visuospatialmemory impairment inright MTLE-MTSpatientsontheimmediate,butnotthedelayedrecall portionoftheRey–OsterriethComplexFigureTest.Retentionof visuospatial learningprocesses may not beas greatlyaffected possiblybecausememoryofnovelstimuliiswidelyrepresented in the entire brain.42 Instruments used to assess nonverbal
memoryfunctionsareconsideredtobenotassensitiveasthose used to assess verbal memory.43 IAP results have been most
predictiveofverbalmemorychangesinpatientswithdominant temporallobeepilepsy.However, IAPresultshavenot faredas wellasapredictorofnonverbalmemorychangesafterresection ofareasofthenon-dominanthemisphere.44,45Previousstudies havealsofailedtoconfirmthattheextentofrighthippocampal pathology is related to performance on test of non-verbal memory.22,46Thefindingsofthisstudymayincreaseknowledge
and understanding of the clinical role of GCD in memory impairmentin MTLEpatients.
TheDGgeneratesneuronsthroughoutlife47andmayplayarole
in the acquisition of new memories.24 Animal studies have
describedthefunctionalintegrationofnewlygeneratedneurons anditsimpactonmemoryacquisition.24,48Thesedataindicatethat
new granule cells are not only affected by the formation of hippocampal–dependentmemorybutalsoparticipateinit.These granule cells mayalso increase witheffortstolearn and recall memories. Coras et al.49 studied neural stem cells from 23 surgically sampledhumanhippocampiand assessedthe neuro-genic potential of DG cells. Patients with high proliferation capacitystemcellsperformednormallyonassessmentsofmemory prior toepilepsysurgery, whereasthose withlow proliferation capacityshowedseverelearningandmemoryimpairments.The authorsconcludedthatencodingnewmemorieswasrelatedtothe regenerativecapacityofthehippocampusinthehumanbrain.In Table2
DistributionofMTSpatternsinGCDandno-GCDMTLEpatientsgroups.
RightMTLEpatients LeftMTLEpatients
No-GCD (N=13)
GCD (N=14)
No-GCD (N=13)
GCD (N=14)
NoMTS 7.7%(1) 0.0%(0) 15.4%(2) 0.0%(0)
MTStype1a 38.5%(5) 21.4%(3) 23.1%(3) 42.9%(6)
MTStype1b 53.8%(7) 78.6%(11) 46.2%(6) 50.0%(7)
MTStype2 0.0%(0) 0.0%(0) 15.4%(2) 7.1%(1)
P=0.298 P=0.448
GCD:granulecelldispersion;N:numberofpatients.
Table3
Visualandverbalmemorytestresults(z-scoreSD)obtainedfromrightandleftMTLEpatientsinGCDandno-GCDgroups.
RightMTLE LeftMTLE Bonferroniposthocanalysis(Pvalue)
No-GCD(N=13) GCD(N=14) No-GCD(N=13) GCD(N=14) BetweenR-MTLE
GCDandno-GCD
BetweenL-MTLE GCDandno-GCD
VisualReproductionI 0.43(0.847) 0.84(0.714) 0.58(0.881) 0.81(1.084) NS NS
VisualReproductionII 0.72(0.799) 1.37(0.916) 0.72(0.950) 0.94(1.228) NS NS
ReyComplexFigureII 1.49(1.293) 2.84(0.912) 1.31(1.290) 1.13(1.538) 0.05 NS
ReyComplexFigureIII 0.92(0.944) 1.52(0.544) 0.94(0.699) 0.68(0.991) NS NS
LogicalMemoryI 0.80(1.054) 0.76(0.772) 0.99(0.968) 1.07(0.853) NS NS
LogicalMemoryII 1.08(0.869) 0.94(0.772) 1.18(0.838) 1.29(0.816) NS NS
RAVLT–Total 0.62(0.841) 1.14(1.385) 0.57(1.302) 1.27(1.117) NS NS
RAVLT–30min 0.76(0.511) 1.09(1.219) 1.04(1.135) 1.61(1.282) NS NS
RAVLT–Recognition 0.22(0.590) 0.68(1.598) 0.05(0.813) 0.31(1.445) NS NS
our study, neurogenesis was not examined; studies involving newly generated neurons and memory function are therefore highlyencouraged.
Itshouldbenotedthatthehippocampuscontralateraltothe resected side in MTLE patients may play a role in memory functions that would otherwise be attributed to the resected hippocampus.Thisprocess,knowasmemoryplasticity,maybe presentinearlyonsetcasesinparticularandmayhaveimpacted theresultsofouranalyses,thusrepresentingalimitationofour study.
In conclusion, the occurrence of GCD was associated with visuospatialmemorydeficitinrightMTLEpatients.However,the presenceofGCDwasnotassociatedwithmemoryperformancein leftMTLE patients.Thepresentfindingsemphasizethe impor-tanceofperformingahistopathologicalevaluationaspartofthe epilepsy surgery protocol as well as the contribution of histopathology tounderstanding memory performance in TLE patients.However,theroleofGCDinmemoryisnotyetprecisely defined.
Conflictofinterest
Theauthorshavenoconflictsofinteresttodeclare.
Acknowledgement
ThisworkwasfundedinpartbytheFundac¸a˜o deAmparoa` Pesquisado Estadode Sa˜oPaulo(FAPESP), theCoordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nı´vel Superior (CAPES), the ConselhoNacional deDesenvolvimentoCientı´fico eTecnolo´gico (CNPQ)andtheInstitutoNacionaldeNeurocieˆnciaTranslacional (INNT),Brazil.
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