海马电刺激临床试验文章17篇不盲14 1 s2 main

Seizure(2007)16,664669

cate/yseiz

Highandlowfrequencyelectricalstimulationinnon-lesionaltemporallobeepilepsy

ColetteBoe¨xa,*,SergeVullie´moza,LaurentSpinellia,

ClaudioPollob,MargittaSeecka

aPresurgicalEpilepsyEvaluationUnit,DepartmentofNeurology,

UniversityHospitalofGeneva,Switzerland

bDepartmentofNeurosurgeryBH-13,UniversityHospitalofLausanne,Switzerland

Received19December2006;receivedinrevisedform19April2007;accepted11May2007

Deepbrainstimulation;Epilepsy

SummaryInpatientswithpharmacologicallyintractableepilepsywhoarenoi-gibleforsurgery,deepbrainstimulationiscurrentlyunderevaluationasternativetreatment.Optimalstimulationparameters,includinghigh(HFS)versuslowfrequency(LFS)stimulation,arenotwelldefined.Here,wereporttheeffectsofHFS(130pulsespersecond,pps)andLFS(5pps)oftheprincipalepileptogenicfocus,inthreepatientswithnon-lesionaltemporallobeepilepsy.HFS,butnotLFS,wasassociatedwithareductionoftheinterictaldischargesandabsenceofseizures.HFSmaybebeneficialinpatientswithnon-lesionaltemporallobeepilepsywhoarenotsurgicalcandidates.

#2007BritishEpilepsyAssociation.PublishedbyElsevier.s.

Introduction

About20%ofepilepticpatientssufferfromaphar-macologicallyintractableepilepsy.1Asurgicalinter-ventionisnotpossibleinmanycasesbecauseseizuresarisefromseveralbrainregionsand/oraresectivesurgerywouldproduceunacceptableneu-rologicalorcognitiveimpairments.2Hence,alter-nativetreatmentpossibilitiesarerequired.

Encouragedbythesuccessofdeepbrainstimula-tion(DBS)formovementdisorders,thistechnique

*Correspondingauthorat:DepartmentofNeurology,UniversityHospitalsofGeneva,CH-1211Gene`ve14,Switzerland.

.:+41223728339;fax:+41223728475.

address:

Colette.Boex@hcuge.ch

(C.Boe¨x).

hasbeenrecentlyinvestigatedfordifferentintract-ableepilepticsyndromes.Differentsitesofstimula-tion3 have been investigated targeting theamygdalo-hippocampalcomplex(AH),thecerebel-lum,thethalamicanteriornucleus,thethalamiccentro-mediannucleus,thesubthalamicnucleusandthecaudatenucleus.Sofar,AHstimulationhasbeenappliedinapproximay40patientsworldwide.412Long-termobservationsinvariousstudiesconductedonpatientsimntedforreceiv-ingchronichighfrequencystimulation(HFS,130190pulsespersecond,pps;5,8,11,12showedacom-pleteseizurecontrolin2of22patients,areductionofseizureratesofmorethan45%in13patients,amoderatereductionofbelow30%in5patients,nochangesin1patientand1patientexperiencedan

1059-1311/$ seefrontmatter#2007BritishEpilepsyAssociation.PublishedbyElsevier.s.:10.1016/j.seizure.2007.05.009

Electricalstimulationinnon-lesionaltemporallobeepilepsy

PAGE

665

PAGE

666

C.Boe¨xetal.

Ictaldeeponset

LRmesialtemporal

Rmesial>lorfronto-orbitalcortex

Rtemporalordiffuse

increaseofseizurefrequencyof114%.Thus,theeffectofHFSisveryvariable,anddespitegoodresponseinsomepatients,itmaynotbetheoptimalstimulationfrequencyforallpatients.

Ontheotherhand,asinglehumanstudyreportedabeneficialeffectofLtemporallobemesio-basalepilepticfoci.6

InterictaldeepEEG

LRmesialtemporal

Rmesialandl

L,Rmesialandltemporalcortex

SincethereareveryfewdataonLFSinhuman,andgiventhattheeffectofHFSdoesnothaveaconsistentlybeneficialeffect,weundertookthepresentstudytocomparetheeffectsofhigh(130pps)versuslowfrequency(5pps)stimulationoftheepilepticfocusontheinterictaleactivity.

Ictalscalponset

LRtemporal

Rtemporal

Rtemporalordiffuse

Methods

Patients

Seizuretype

MRI

InterictalscalpEEG

LRtemporal

Complexpartial

Normal

Partial,complexpartialsecondarygeneralized

Complexpartial,generalizedtonic

Normal

Rtemporal

Sequelaefrombliplallidotomy

andthalamo-sub-thalamotomy

L,RtemporalRfrontal

Clinical,radiological,scalpandintracranialEEGcharacteristicsforeachpatient.R:right;L:left.

Threesubjects,allsufferingfrommesialtemporalepilepsy,wereenrolledinthepresentstudy.DuetothepresenceofconflictingscalpEEGdataandthefactthattheMRIwasnegative,invasiveevaluationwithdepthelectrodeswasproposed(forpatientdetailsseeTable1).All3patientswereimntedwithdepthelectrodes(SD-8PX1,Ad-TechInstru-ments,Racine,Wisc.,USA)containingeightcontactseachunderstereotacticconditions.Theamygdala,anteriorhippocampusandposteriorhippocampusweretargetedbilallythroughanorthogonalapproach.Thedorsalfrontalcortexwasalsoimntedbilally,targetingthesupplementarymotorcortexandtheanteriorcingulatedgyrusinpatientS3throughthesameapproach.Inaddition,electrodesintotheorbito-frontallobewereimntedontheleftinpatientS1andbilallyinpatientsS2andS3throughanobliqueapproachinthecoronalne.Reconstructionofpost-imnta-tionhigh-resolutionCTscanswithpre-operativeMRIallowedassessmentofthepositionoftheelectrodes(Fig.1).Drugtreatmentwastaperedinallpatients

Table1Clinicalpatientcharacteristics

Handedness

25daysbeudyenrollmentandkeptconstantduringthestudyperiod(Table2).

onset

15

R

L

R

TheresearchprotocoldescribingthisstudywasapprovedbytheEthicsCommitteeoftheUniversityHospitalofGeneva.Allsubjectsgavetheirinformedconsent.

22

15

Electricalstimulation

Age

3A0geatM

S1

S2 35

M

S3 41

F

Aheadcomputedtomography(CT)wasperformedwith1mmslicesaftertheimntation.Co-regis-trationwiththepatient’sMRIusingasixparametersrigidbodyalgorithmenabledinter-modalityregis-trationinordertopreciselyassessthelocationofthedepthelectrodecontacts.13

Figure1 PatientS1,electrode-positionreconstructionusingpost-imntationhigh-resolutionCTwithpre-operativeMRI.Contact1isalwaysthemostmesialcontactandcontact8themostla l.(LA:leftamygdala).

Table2Stimulationcharacteristics

AEDadmission/aftertapering

Sideofstimulation

Stimulatedcontacts

Day1/Day2(pps)

Durationofstimulationperiod

S1

Levetiracetam3g/day)withdrawal

Left

LA2—LAH2

5/130

6h

S2

Clonazepam2mg/day)withdrawal

Right

RA2—RAH2

130/5

6h

S3

Oxcarbazepine900mg/day)withdrawalPregabaline300mg/day)nochangePhenytoine350mg)nochange

Right

RAH1—RPH1

130/5

3h

Antiepilepticdrug(AED)taperingandstimulationcharacteristicsforeachpatient.Day1/Day2:orderoftheLFSandHFS.LA:leftamygdala;LAH:leftanteriorhippocampus;RA:rightamygdala;RAH:rightanteriorhippocampus;RPH:rightposteriorhippocampus.

Bipolarelectricalstimulationwasappliedtothetwocontactsthatshowedtheearliestictalinvolve-ment(Table2).WeusedanexternalMedtronicM3625stimulator(MedtronicInc.,Minnesota,USA).High(130pps)andlowfrequency(5pps)sti-mulationswereapplied(450ms/phase,1V).Stimu-lationwascarriedoutduringwakefulness,i.e.

Table3Temporo-spatial

epatternsusedfor

interictal ecounting,onspecifiedcontactsineach

patient(horizontally:100msduration,vertically:100mVperinterline)

Ipsi Ipsi ContraPattern1 Pattern2 Pattern1

S1

Contra

Pattern2

—

LA3—LA4 LA3—LA4 RA2—RA3

S2

—

—

—

RA1—RA3

S3

RA2—RA3 RAH2

LA1—LA2 LAH1

LA:leftamygdala;RA:rightamygdala;RAH:rightanterior

hippocampus;LAH:leftanteriorhippocampus.

startingbetween10and11a.m.andlastingfor

36h.Additionaltechnicaldetailsofthestimula-tionusedforeachpatientaregiveninTable2.

ysis

Inordertoevaluatetheefficacyoftheelectricalstimulationontheinterictalactivity,wecomputedtherateofesperminute,2hbefore,during,and2hafterthestimulationperiodsonthecontactsadjacenttothestimulationsitesaswellasinthecontrala lhomologousstructures(Table2).Inordertoavoidabiasduetovigilancechangesrelatedtoincreaseordecreaseofinterictaldis-charges,ysiswasrestrictedtoawakeperiods.StereotacticEEG(SEEG,CEEgraphXLsystem,BiologicInc.,Illinois,USA)wasrecordedcontinu-ouslywithasamplingfrequencyof512Hz.InordertoremoveDBSartifactsSEEGwerelo ss(15or30Hz)andhigh-pass(1.6Hz)filteredbeforees

werecounted(Table3).

Weusedautomaticedetectionsoftwarealgo-rithmbasedonspatio-temporalcorrelation(BESA,MEGISSoftwareGmbHPenzberg,Germany).Tosta-tisticallycomparethenumberofesperminutecomputedbefore,duringandafterthestimulationperiods,weusedtheSignTestgiventhatthesampleddataforthesamepatientaredependentvariablesandtheirdistributionwasnotnormal.

Figure2InterictalactivityinpatientS1.erate(numberofesperminute)averagedoversuccessive10minperiodsbefore(closedcircles),during(greytriangles)andafter(opensquares)LFS-AH5pps(A)andHFS-AH130pps(B)sessionsappliedattheleftamygdalaandhippocampuscomplex.Errorbarsindicatestandarddeviationsofthenumberof

eperminute,computedover10min.

Results

TheelectrodeswerecorrectlyintedinthetargetedstructuresasshownasanexampleinFig.1inpatientS1.Fig.2describesthemeannumberofinterictaleperminute,before,duringandafterLFSperiod(A)andHFSperiod(B)inpatientS1.Fig.3describesthemeannumberofinterictaleperminute,computedoverperiodsofabout2h,before,dur-ingandafterHFSandLFSperiodsinallthreepatients.

Highfrequencystimulation(HFS)

HFSoftheamygdala-hippocampalstructuresresultedinareductionoftheinterictalerateatthestimulatedsiteshortlyafterthebeginningofthestimulationforS1(p<0.001)andS3(trend)andaffewhoursofstimulationforS2(p<0.01).ereductionextendedtothecon-tralalmesialtemporallobeinS1andS3.

WhentheHFSwasturnedoff,asignificantincreaseoftheerateinthestimulatedsitewasobservedintwooutof3patients.Thisreboundeffectextendedtothecontralalmesialtem-porallobeinpatientS3.Inall3patients,noseizureoccurredduringthestimulationandpost-stimula-tionperiods(i.e.18h).

Lowfrequencystimulation(LFS)

Importantvariations,resultinginoverallincreasesoftheinterictalerates,intheipsilalandinthecontralalamygdala,wereobservedin2subjects(S1,S3)withLFS.LFSdidnotproduceanysignificantchangesinS2.

HabitualseizuresoccurredinpatientsS1andS3duringandafterLFS,similartotheirbaselinefre-quency.

Discussion

Thisstudyreportstheshort-termeffectsofHFS(130pps)andLFS(5pps)innon-lesionaltemporalepilepsy.Stimulationwith130pps,butnotwith5pps,wasassociatedwithareductionofinterictaledischargesandabsenceofanyclinicalorsub-clinicalseizuresduringandafterthestimulationperiods.WhiletheyzedperiodsweretooshorttoallowdefiniteconclusionontheclinicalefficacyofchronicDBSinthesepatients,ourstudyprovidespreliminaryevidencethatHFSismoreusefulthanLFSforthetreatmentofthisepilepsysyndrome.Inrecentyears,studieshaveshownthatMRI-negativetemporallobeepilepsydoesnotnecessarilyrepre-sentsacontraindicationtosurgicaltreatment,especiallyifthePETprovidesevidenceofunila lonset.14However,manypatientshavebila lsei-zureonset,andintactmemoryfunctions.Inthesecases,surgeryisunlikelytoprovidecompletesei-zurecontrol,butinsteadmaycreatemajorneurop-

sychologicaldeficits.2

Evenifitcanbearguedthattherateofinterictalepilepticdischargesmightnotbeavalidmeasure-mentoftheepileptogenicactivity,15,16ourstudyaddsfurtherevidencetotheeffectofDBSappliedontheepileptogenicfocusintemporallobeepi-lepsy.OurobservationsareinagreementwithotherstudiesshowingthereductionofinterictaleratesobservedafterHFSoftheamygdala-hippo-campalcomplex7,9measuredduringshortoffstimu-lationperiodsduringinvasiveexplorations.Studies

Figure3Meaninterictaleratesmeasuredbefore,duringandafterthe130ppsandthe5ppsstimulationperiod(SignTestfordependentsamples).Eachbariscomputedoveraperiodofabout2h.TheblackbarsindicateeratesbeforeHFS(leftpartoffigures)orLFS(rightpartoffigures).Thegreybarsindicateeratesduringstimulation.Theopenbarsindicateeratesafterstimulation.Errorbarsindicatestandarddeviationsofthenumberofeperminute,computedoverabout2h.PatientS2showedonlyinterictaldis-chargesipsilaltothestimulation.

ofchronicmesialtemporalHFSstudiesconductedwithimnteddevicesshowedanincreaseofthebeneficialeffectofDBSovertimeintheresponderpatients.5,11,8,12Long-termfollow-upofpatientsimntedDBSdevicesarerequiredtodetermineifsuchaprogressiveantiepileptogeniceffectcanbe

predictedbyshort-termevaluationthroughintra-cranialelectrodes.

TheeffectofDBSinthecontralalmesialtemporallobeobservedintwopatientssuggeststhatDBSmightnotonlyactatsiteofthestimulationbutalsoatdistantsitesthroughinhibitory/excita-toryconnectivity.Thiseffectillustratesthestrongconnectivitybetweenbilallimbicstructuresandisconsistentwithusualfindingsintemporallobeepilepsy:contralalpropagationoftheepi-leptogenicactivityandfrequentbilalabnorm-alitiesseenonPET,SPEwellasMRvolumetryandMRspectroscopy.Thisclosefunctionalrelation-shipbetweenbothtemporallobescouldmakeDBSavaluabletoolforpatientswithbilaltemporallobeepilepsy.

TheLFSoftheamygdala-hippocampalcomplexincreasedtheepileptogenicinterictalactivityin2outof3patients,althoughitwasnotassociatedwithanyincreaseintheusualfrequencyorthedurationoftheseizures.Chkhenkelietal.6usedLFS(120pps)inpatientswithmesiobasaltemporallobefociandobservedthatstimulationwith13pps,butnot520pps,suppressesinterictaldis-charges.LFSwasalsofoundtobebeneficialinotherbrainstructuresofepilepticpatients,notablytheanteriorthalamus,17thecaudatenucleus,6cerebel-lum18andneocortex,19,20withstimulationofsev-eralsecondsorminutes,andwasfoundtobebeneficialforthesesites.FurtherstudiesareneededinvestigatingtheeffectsofLFSwithevenlowerfrequenciesinnon-lesionaltemporallobeepilepsyorotherepilepsysyndromes,notamenabletosurgery.

Acknowledgments

ThisresearchwassupportedbytheSwissNationalScienceFoundation(FNRSgrantsno.3200BO-104146,no3100-068263,no320000-113766,PMPDB

114416).Theauthorsareespeciallygratefultothepatientswhoagreedtoparticipateinthisstudy.

References

SanderJW,CockerellOC,HartYM,ShorvonSD.Istheinci-denceofepilepsyfallingintheUK?Lancet1993;342(8875):874.

WiebeS,BlumeWT,GirvinJP,EliasziwM.Arandomized,controlledtrialofsurgeryfortemporal-lobeepilepsy.NEnglJMed1993;345(5):3118.

ThreWH,RS.Brainstimulationforepilepsy.

LancetNeurol1993;3(2):11828.

VelascoAL,VelascoM,VelascoF,BoleagaB,JimenezF,BritoF,etal.Subacuteelectricalstimulationofthehippocampus

blocksintractabletemporallobeseizuresandparoxysmalEEGactivities.Epilepsia2000;42(2):15869.

VelascoAL,VelascoM,VelascoF,MenesD,GordonF,RochaL,etal.Subacuteandchronicelectricalstimulationofthehippocampusonintractabletemporallobeseizures:preli-minaryreport.AredRes2000;31:31628.

ChkhenkeliSA,SramkaM,LortkipanidzeGS,RakviashviliTN,BregvadzeES,MagalashviliGE,etal.Electrophysiologicaleffectsandclinicalresultsofdirectbrainstimulationforintractableepilepsy.ClinNeurolNeurosurg2004;106(4):

31829.

VonckK,BoonP,AchtenE,DeReuckJ,CaemaertJ.Long-termamygdalohippocampalstimulationforrefractorytem-porallobeepilepsy.AnnNeurol2002;52:55665.

VonckK,BoonP,ClaeysP,DedeurwaerdereS,AchtenR,VanRoostD.Longtermdeepbrainstimulationforrefractorytemporallobeepilepsy.Epilepsia2005;46(S5):989.

KossofEH,RitzlEK,PolitskyJM,MurroAM,SmithJR,DuckrowRB,etal.Effectofanexternalresponsiveneurostimulatoronseizuresandelectrographicdischargesduringsubduralelec-trodemonitoring.Epilepsia2004;45(12):15607.

OsorioI,FreiMG,SunderamS,GiftakisJ,BhavarajuNC,SchaffnerSF,etal.Automatedseizureabatementinhumansusingelectricalstimulation.AnnNeurol2005;57