Evaluating the feasibility of measures of motor threshold and cortical silent period as predictors of outcome after temporal lobe epilepsy surgery

Evaluating

the

feasibility

of

measures

of

motor

threshold

and

cortical

silent

period

as

predictors

of

outcome

after

temporal

lobe

epilepsy

surgery

O

¨ mer

Karadas¸

a

,

H.

I˙lker

Ipekdal

b,

*

,

Ersin

Erdog˘an

c

,

Zeki

Go¨kc¸il

a

,

Zeki

Odabas¸

i

a

a_{Gu¨lhaneMilitaryMedicalAcademy,DepertmentofNeurology,Ankara,Turkey} b

NearEastUniversityHospital,DepartmentofNeurology,NearEastStreet,Nycosia,Cyprus

c

UfukUniversityFacultyofMedicine,DepartmentofNeurosurgery,Ankara,Turkey

1. Introduction

Epileptic disorders are the clinical result of excitatory and inhibitorysystemimbalancewithinthecentralnervoussystem.1 Surgicalremovaloftheepilepticfocusiswidelyacceptedasan effectivetherapyforselectedpatientswithmedicallyrefractory epilepsy; however, there is no consensus regarding accurate predictorsofsurgicaloutcomedue totheuseofheterogeneous studygroups,differencesinsurgicalproceduresanddurationof follow-up,andvaryingdefinitionsofsurgicalsuccessandfailure. Theprimarymeasureoftheoutcomeofepilepsysurgery(ES)is the end of seizures, and secondary outcome measures are the frequencyandseverityofseizures,qualityoflife,levelofdisability, and mortality.2–5 Transcranial magnetic stimulation (TMS) has

beenusedtonon-invasivelyandalmostpainlesslyinvestigatethe human cerebral cortex. The motor threshold (MT) and cortical silentperiod(CSP),and intracorticalinhibitionand intracortical facilitationhavebeenusedtoevaluatemotorcortexexcitability.6 Corticalexcitabilityislikelytochangeaftersurgicalremovalof theepilepticfocus;7,8_{therefore,TMSparametersmaybeusefulfor}

predictingtheoutcomeofES.Thepresentstudyaimedtoassess the value of the MT and CSP as predictors of the outcome of temporallobeepilepsysurgery(TLES).

2. Materialsandmethods

Thestudyincluded10patients(8femaleand2male)aged25–39 years (mean age:30.7 years) withdrug-resistant temporal lobe epilepsy(Table1).Thepatientsunderwentpre-surgicalmonitoring at Gu¨lhaneMilitary MedicalHospital,Department ofNeurology, EpilepsyMonitoringUnit,Ankara,TurkeybetweenJanuary2005and May2009. Epilepticfociwereidentified andsurgicaltechniques werechosenbasedontheresultsofvideo-electroencephalography

Seizure20(2011)775–778

A R T I C L E I N F O Articlehistory:

Received25August2010

Receivedinrevisedform17July2011 Accepted18July2011

Keywords:

Temporallobeepilepsysurgery Corticalsilentperiod Motorthreshold Corticalexcitability

A B S T R A C T

Introduction: AlthoughitiswellknownthatESalterscorticalexcitability,littleisknownaboutthe

relationshipbetweenESoutcomeandcorticalexcitability.Transcranialmagneticstimulationhasbeen

successfullyusedtoevaluatecorticalexcitabilityinepilepsypatients.Thepresentstudyaimedtoassess

thevalueofthemotorthreshold(MT)andcorticalsilentperiod(CSP)aspredictorsoftheoutcomeof

temporallobeepilepsysurgery(TLES).

Materialsandmethods:Epilepticfociintheepilepsypatientswereidentifiedvia

video-electroencepha-lography (v-EEG) monitoring, brain magnetic resonance imaging (MRI), single-photon emission

computed tomography (SPECT), and positron emission tomography (PET), and neurophysiological

testing.MT,CSP-150,andCSP-maxweremeasuredin10epilepsypatientsonboththeipsilateraland

contralateralsideoftheepilepticfocus1weekbeforeand3monthsafterTLES.Pre-andpost-operative

MTandCSPmeasurementswerecompared,andtheresultswereinterpreted basedontheclinical

outcomeofTLES.

Results:Meanfollow-upperiodwas28.8months.Inall,8patientswereseizure-freepostTLES,whereas

in2patientsseizurespersisted.Nosignificantdifferenceswereobservedinipsilateralorcontralateral

hemisphereMTmeasurementsbeforeandaftersurgery.BothCSP-150andCSP-maxvaluesinthe

non-focalhemispheresdecreasedinthe8patientsthatwereseizure-freepostTLES,whereasnodifferences

wereobservedinthe2patientswithseizuresthatpersistedpostTLES.

Conclusions: Thepresentfindingsindicatethatmonitoringpre-andpost-TLESCSPchangesmaybe

predictiveoftheearlyclinicaloutcomeofTLES.

ß 2011BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.

*Correspondingauthor.Tel.:+905068433122/3123044493; fax:+903123045900.

E-mailaddress:iipekdal@yahoo.com(H.&.Ipekdal).

ContentslistsavailableatScienceDirect

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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

1059-1311/$–seefrontmatterß2011BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved. doi:10.1016/j.seizure.2011.07.009

(v-EEG) monitoring, brain magnetic resonance imaging (MRI), single-photonemissioncomputedtomography(SPECT),and posi-tronemissiontomography(PET),andneurophysiologicaltesting.All ofthepatientsprovidedwritteninformedconsenttoundergoTLES, andTMStestingbeforeandafterTLES.TheGu¨lhaneMilitaryMedical HospitalEthicsCommitteeapprovedthestudyprotocol.

Patients1and5underwentanteromedialtemporallobectomy (AMTL), and the others underwent AMTL and amygdalohippo-campectomy(AHCT).DuringAMTL,3.5cmofthetemporalpole (fromthetemporaltip)wasremoved,includinghalfofthesuperior temporalgyrus,andthemiddleandinferiortemporalgyri.During AHCT,theamygdala,anteriorpartofthetailofthehippocampus, and the entire head and body of the hippocampus and parahippocampal gyrus were surgically removed. Following surgery,thepatients’antiepilepticdrug(AED)regimensremained unchanged.Additionally,pre-surgicalandpost-surgicalAEDblood levels were identical and within therapeutic ranges. Patient characteristicsareshowninTable1.

TMS testing was performed 7 days prior to surgery by a neurologistblindedtothelocationofeachpatient’sepilepticfocus. TMS testing was repeated 3 months post surgery by another neurologistblindedtothepre-surgerymeasurements.TMStesting inpatients 4and7–whoseseizurespersistedpostTLES–was performed at least 3 days after they had seizures. TMS was performedwhilethepatientswereinaseatedposition,usinga 9-cmdiametercircularcoil(DantecMC125)capableofgeneratinga peak magneticfield of1.0T.Responses oftheabductor pollicis brevis (APB) muscles were recorded bilaterally with a Dantec EvolutionEMGapparatus,usingAg–Clsurfaceelectrodes.Thecoil wasplacedoverthescalpprojectingthemotorcortexareaabout 7cm lateralof thevertex.Thepositionofthecoilwaschanged slightly and the stimulus was administered until the optimal positionforAPBmuscleresponsewasdetermined.8–10

2.1. MTmeasurement

MTwasdefinedasthelowestintensitystimulusrequiredto elicitanMEP5010-

m

VinamplitudefromtherestingAPBmuscle, with5successfultrialsoutof10.Initialstimulusintensitywas30% ofthemaximumstimulusintensityandwasincreasedby1–5%until we obtained the MT. MT was measured for both APB muscles independently.

2.2. CSPmeasurement

CSP-150andCSP-maxmeasurementswereobtainedforeach patient.Duringtheprocedurepatientswererequestedtocontract theirAPBmusclesusing50%oftheirmaximumcontractionforce. ForCSP-150measurementthestimulusintensitywasadjustedto 1.5-foldthatoftheMTmeasurementforthesameAPBmuscleand wasadministeredfromthecontralateralsideofthescalpduring contractionoftheABPmuscle.CSP-150wasdefinedasthemean valueof5measurementsandCSP-maxwasdefinedasthemean value of 5 CSP measurements obtained with the maximum stimulusintensity.9–12

Seizure-free wasdefinedas no seizureduringthefollow-up period.Pre-and post-surgical MTand CSPmeasurementswere compared, in terms of the side of epileptic focus and the contralateral side. Statistical evaluation of the data acquired beforeandaftersurgerywasperformedusingthepairedttest. 3. Results

None of thepatients experiencedcomplications during TMS testing. Mean pre-surgical MT (as a percentage of maximum stimulus intensity) was 52.72.6% on the ipsilateral side and

Table 1 Patient characteris tics. Patient Age (years) Gender Fam ily histo ry Handedness Duration of disease (years) Seizure type(s ) before surgery

Seizures during sleep

Etiology

Seizure frequency before

surgery Surgical procedure AEDs before and after surgery Seizure frequency after surgery

Post-surgical follow-up period

(months) 1 3 4 Fem ale No Ambidextrous 33 CPS Yes Left MTS 2–3/month Left AMTL VPA, OXC, LEV No seizure 15 2 2 5 Fem ale No Right 19 CPS, SGTCS No Right MTS 1–2/month Right AMTL + AHCT CBZ, LEV No seizure 51 3 3 8 Fem ale No Right 14 CPS No Right MTS 1–2/week Right AMTL + AHCT CBZ, TP, LEV No seizure 11 4 3 9 Fem ale No Right 38 CPS, SGTCS Yes Right MTS 1–2/week Right AMTL + AHCT VPA, CBZ, LEV 1–2/w eek 24 5 2 8 Fem ale Aun t Left 11 CPS, SGTCS No Right MTS 1–2/month Right AMTL VPA, CBZ No seizure 53 6 2 8 Fem ale Sister Right 26 CPS, SGTCS Yes Left MTS 1–2/month Left AMTL + AHCT VPA, CBZ, LEV No seizure 57 7 2 9 Fem ale Fathe r and brother Right 17 CPS, SGTCS No Right MTS 2–3/month Right AMTL + AHCT CBZ, LEV, TP 2–3/month 23 8 2 9 M ale No Right 27 CPS, SGTCS No Left MTS 1–2/month Left AMTL + AHCT CBZ, TP No seizure 12 9 2 6 M ale No Right 13 CPS, SGTCS Yes Right MTS 5–6/month Right AMTL + AHCT CBZ, LEV No seizure 27 10 31 Fem ale Fathe r Right 25 CPS No Left MTS 1–2/week Left AMTL + AHCT VPA, CBZ No seizure 15 CPS: complex partial seizure; SGTCS: secondary generalized tonic–clonic seizure; MTS: mesial temporal sclerosis; AMTL: anteromedial temporal lo bectomy; AHCT: amygdalohippocampectomy; VPA: valproic acid; CBZ: carbamazepine; OXC: oxcarbazepine; LEV: levetiracetam; TP: topiramate.

O¨.Karadas¸etal./Seizure20(2011)775–778 776

53.31.7% on the contralateral side. Post-surgical MT was 53.42.9%ontheipsilateralsideand51.71.6%onthe

contralat-eralside(Table2).Pre-andpost-surgicalMTvaluesfortheipsilateral

andcontralateralsidesdiddiffersignificantly(P=0.42andP=0.04, respectively).

Pre-surgicalmeanCSP-150was145.711.3msonthe ipsilat-eralsideand146.310.1msonthecontralateralside.Post-surgical mean CSP-150 was 142.312.2ms on the ipsilateral side and 137.212.2msonthecontralateralside.Differenceswerenotnoted betweenpre-andpost-surgicalCSP-150valuesontheipsilateralside, but post-surgical mean CSP-150 on the contralateral side was significantly shorter than the pre-surgical value (P=0.19 and P=0.008,respectively).

Pre-surgical mean CSP-max was 153.711.2ms on the ipsilateralsideand157.212.1msonthecontralateralside. Post-surgicalmeanCSP-maxwas147.611.8msontheipsilateralside and142.212.2ms onthe contralateral side.Post-surgical mean CSP-maxontheipsilateralandcontralateralsideswassignificantly shorter than the pre-surgical values (P=0.011 and P=0.007, respectively).Additionally,meanCSP-maxwassignificantlylonger than mean CSP-150 on the contralateral side post-surgically (P=0.005).CSPresultsaresummarizedinTable3.

Postsurgery,thepatientscontinuedtoreceivethesameAED treatmenttheyreceivedpre-surgery.Meandurationoffollow-up was28.8months(range:11–57months);8patientswere seizure-free post TLES,whereas patients 4 and 7 had no reduction in seizurefrequencyorseverity(Table1).

4. Discussion

Thepresentstudy’sresultsindicatethatthepost-TLESCSP–not MT–wasshorterinthe8patientsthatwereseizure-freepostTLES. Patients 4 and 7 had no improvement in seizure frequency or seizureseveritypostsurgeryandtheirMTandCSPvaluesbefore andafterESweresimilar.

Epilepticdisordersarecharacterizedbyheterogeneous patho-physiological processes that lead to alteration in the balance betweenexcitatoryandinhibitoryinfluencesatthecorticallevel.It hasbeenproventhatAEDscanaltertheMTandCSPinepilepsy patients by reorganizing cortical excitability. The MThas been reportedtobelow,normal,andhighinepilepsypatients.Many studies have suggested that the discrepancy between MT measurementsmightbeduetothefactthattheMTisadynamic phenomenonthatvariesaccordingtoseizuretype.Althoughthe resultsofstudiesontheeffectsofAEDsontheMTareinconsistent, CSP duration has been reported to decrease following AED treatment,13,14 _{which maybe a result of theclose relationship}

between theCSP and theGABAergicsystem.GABA-Areceptors mediateshort-durationinhibitorypostsynapticpotentials(IPSPs), whereas GABA-B receptors mediate long-duration IPSPs. Some researchersproposethatCSPdurationisanindicatorofGABA-B receptor-mediatedmotorcorticalinhibition.14–16

The epileptic focus can affect excitatory and inhibitory mechanismsonboththeipsilateralandcontralateralsides.Several studiesonfocalepilepsysupportthenotionthattheepilepticfocus hasbilateraleffectsthatmaybestrongeronthecontralateralside. Themechanismsunderlyingthesechangesremaintobe elucidat-ed; a low local inhibitory level caused by the presence of an excitatory epileptic focus is 1 hypothesis.9,17,18 _{As with AED}

treatment,surgicalexcisionoftheepilepticfocuscanreorganize corticalexcitability.

La¨ppchen et al. were the first to study changes in cortical excitabilityfollowingsuccessfulES.9_{TheyobservedthattheMTon}

the ipsilateral side was significantly higher than that on the contralateralsidefollowingsuccessfulES.Inthepresentstudyno differencesinMTonboththeipsilateralandcontralateralsides wereobservedbefore andafterTLES.Suchcontradictoryresults may be related to the surgical procedures employed or the dynamic nature ofthe MT.On theotherhand,La¨ppchen et al. reportedthattheCSPwasprolongedontheipsilateralsidebefore ES,whichindicatesthattheepilepticfocushasasignificantaffect on the contralateral hemisphere, and that the changes on the ipsilateral sidewerecomparatively minor.TheCSP was signifi-cantly shorter on the contralateral side after successful ES, indicating that there wasa reductionin intracorticalinhibition onthecontralateralsidefollowingES.9

InthepresentstudyCSP-150andCSP-maxonthecontralateral sidewereshorterinthe8patientsthatwereseizure-freeduring post-surgical follow-up; however, although v-EEG monitoring, brain MRI, SPECT, and PET, and neurophysiological testing facilitated identification of the epileptic foci, TLES failed in 2 patients (patients4and7)thathadno improvementinseizure frequencyorseverityduringfollow-up.Surprisingly,althoughthe epilepticfocus in patient4 was locatedon theleft side before surgery, v-EEG monitoring performed 14 months post surgery showedthattheepilepticfocuswasontheleftside.Furthermore, MT,CSP-150,andCSP-maxmeasurementsontheipsilateraland contralateralsidespre-andpostsurgerydidnotdifferinpatients4 and7.Additionally,asbothCSP-150andCSP-maxmeasurements onthecontralateralsidewerethesame,werecommendusing CSP-150insteadofCSP-maxinordertoavoidthepotentialside-effects ofTMStesting.

ResearcheshaveshownthatTLEScanresultincompleteseizure remission rates of up to80% in patients withmesial temporal sclerosisandunilateralseizures.Theseizure-freerateafterTLESin patients withextratemporal non-lesional epilepsy is 30–40%.19

Thedurationofpost-surgicalfollow-upisimportantin determin-ingseizure-freeandqualityoflifeoutcomesfollowingTLES.Ithas beensuggestedthatoutcomeat1yearpostTLESisagoodpredictor oflong-termoutcome.20–24

Themainlimitationsofthepresentstudyarethesmallnumber of patients and the lack of final diagnoses supported by histopathology.Additionally,thepresentresultsmayhavebeen affectedbythedifferentsurgicalproceduresemployed;however, thesurgicalprocedureswerechosenbasedonthetestsusedto evaluatethepatientsandidentifytheepilepticfoci,andtheclinical experienceoftheneurosurgeons.Largerwell-designedstudiesare needed in order to obtain more definitive results. There is a possibilitythatTMStestinginthe2patientsthatstillhadseizures post surgery may have contributed to the persistence of the seizures; however, we think it unlikely as we performed TMS testing5daysafterseizureinpatient4and9daysafterseizurein patient7.

Table2

Pre-andpost-surgicalMTvalues. MeanMT(%)

Ipsilateralside Contralateralside

Pre-surgical 52.72.6 53.31.7

Post-surgical 53.42.9 51.71.6

Table3

Pre-andpost-surgicalCSPvalues.

CSP-150(ms) CSP-max(ms) Ipsilateral side Contralateral side Ipsilateral side Contralateral side Pre-surgical 145.711.3 146.310.1 153.711.2 157.212.1 Post-surgical 142.312.2 137.212.2 147.611.8 142.212.2

Althoughthedurationofpost-surgicalfollow-upisessentialfor theassessmentofseizure-freeoutcomeofTLES,thepresentresults indicatethatevaluationofthedifferencebetweenpre-and post-TLES CSP may be predictive of clinical outcome. Although the presentstudygroupwassmall,thefindingsinpatients 4and7 indicatethatunalteredCSPvaluesfollowingTLESmayberelatedto apooroutcome;however,theresultsofthissmall-scalefeasibility studyindicatethatCSPmaybeausefulpredictoroflonger-term post surgical outcome and that larger prospective studies are warranted.

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