MRI-NegativeEpilepsy

EvaluationandSurgicalManagement

MRI-NegativeEpilepsy

EvaluationandSurgicalManagement

Editedby

ElsonL.So,MD

ProfessorofNeurology,EpilepsyandEEG,MayoClinicCollegeofMedicine,Rochester,MN,USA

and

PhilippeRyvlin,MD,PhD

ProfessorofNeurology,andHeadoftheDepartmentofClinicalNeurosciences,CHUV,Lausanne,Switzerland

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MRI-negativeepilepsy:evaluationandsurgicalmanagement/editedby

ElsonL.So,PhilippeRyvlin.

p.;cm.

Magneticresonanceimaging-negativeepilepsy

Includesbibliographicalreferencesandindex.

ISBN978-1-107-03423-5(Hardback)

I.So,Elson,editor.II.Ryvlin,Philippe,editor.III.Title:Magnetic

resonanceimaging-negativeepilepsy.

[DNLM:1.Epilepsypathology.2.Epilepsysurgery.3.Magnetic

ResonanceImagingmethods.4.Neuroimagingmethods.

5.TreatmentOutcome.WL385]

RC373

616.85307548dc232014017472

ISBN978-1-107-03423-5Hardback

CambridgeUniversityPresshasnoresponsibilityforthepersistenceoraccuracyofURLsforexternalorthird-partyinternetwebsitesreferredtointhispublication,anddoesnotguaranteethatanycontentonsuchwebsitesis,orwillremain,accurateorappropriate.

Everyefforthasbeenmadeinpreparingthisbooktoprovideaccurateandup-to-date

informationwhichisinaccordwithacceptedstandardsandpracticeatthetimeofpublication.Althoughcasehistoriesaredrawnfromactualcases,everyefforthasbeenmadetodisguisetheidentitiesoftheindividualsinvolved.Nevertheless,theauthors,editorsandpublisherscanmakenowarrantiesthattheinformationcontainedhereinistotallyfreefromerror,notleastbecauseclinicalstandardsareconstantlychangingthroughresearchandregulation.Theauthors,editorsandpublishersthereforedisclaimallliabilityfordirectorconsequentialdamagesresultingfromtheuseofmaterialcontainedinthisbook.Readersarestronglyadvisedtopaycarefulattentiontoinformationprovidedbythemanufacturerofanydrugsorequipmentthattheyplantouse.

Tomyparents

Elson.

Tomybelovedwifeandchildren

Philippe.

Contents

Listofcontributors

Preface

1. ScopeandimplicationsofMRI-negativerefractoryfocalepilepsy

ElsonL.SoandPhilippeRyvlin

2. SeizuresemiologyandscalpEEGinMRI-negativerefractoryfocalepilepsy

SoheylNoachtarandElisabethHartl

3. ClinicalandadvancedtechniquesforoptimizingMRIinrefractoryfocalepilepsy

NedaBernasconiandAndreaBernasconi

4. PETinMRI-negativerefractoryfocalepilepsy

AlexanderHammers

5. AdvancedSPECTimageprocessinginMRI-negativerefractoryfocalepilepsy

ElsonL.So,TerenceJ.OBrien,andBenjaminH.Brinkmann

6. MEGandmagneticsourceimaginginMRI-negativerefractoryfocalepilepsy

KojiIida,AkiraHashizume,andHiroshiOtsubo

7. ElectricsourceimaginginMRI-negativerefractoryfocalepilepsy

ChristophM.MichelandMargittaSeeck

8. FunctionalMRIinMRI-negativerefractoryfocalepilepsy

FriederikeMllerandStephanUlmer

9. MultimodalityimagecoregistrationforMRI-negativeepilepsysurgery

BenjaminH.BrinkmannandVlastimilSulc

10. SubduralelectrodeimplantationandrecordinginMRI-negativeepilepsysurgery

MichaelR.SperlingandChristopherT.Skidmore

11. DepthelectrodeandstereoelectroencephalographyinMRI-negativeepilepsy

PhilippeRyvlin,AlexandraMontavont,KarineOstrowsky-Coste,andMarcGunot

12. Ultraslowandhigh-frequencyrecordingsinMRI-negativerefractoryfocalepilepsy

VlastimilSulcandGregoryA.Worrell

13. CorticalmappinginMRI-negativeepilepsysurgery

GonzaloAlarcnandAntonioValentn

14. LocalizationandsurgeryforMRI-negativetemporallobeandtemporal-plusepilepsies

SangKunLeeandHye-JinMoon

15. LocalizationandsurgeryinMRI-negativefrontallobeepilepsies

ChaturbhujRathoreandKurupathRadhakrishnan

16. LocalizationandsurgeryinMRI-negativeposteriorcortexepilepsies

ChristophBaumgartnerandSusannePirker

17. MRI-negativerefractoryfocalepilepsyinchildhood

PrasannaJayakarandMichaelDuchowny

18. SurgicalapproachesandtechniquesinMRI-negativefocalepilepsy

SumeetVaderaandWilliamBingaman

19. HistopathologyfindingsinMRI-negativefocalepilepsy

IngmarBlmckeandRolandCoras

20. NeuropsychologicalissuesinMRI-negativefocalepilepsysurgery:evaluationandoutcomes

RosanaEsteller,DanielL.Drane,KimfordJ.Meador,andDavidW.Loring

21. Conclusion

PhilippeRyvlinandElsonL.So

Index

Contributors

GonzaloAlarcnMD,PhD

DepartmentofClinicalNeuroscience,KingsCollegeLondon;DepartmentofClinicalNeurophysiology,KingsCollegeHospital,London,UK

ChristophBaumgartnerMD

KarlLandsteinerInstituteforClinicalEpilepsyResearch&CognitiveNeurology,2ndNeurologicalDepartment,GeneralHospitalHietzingwithNeurologicalCenterRosenhgel,Vienna,Austria

AndreaBernasconiMD

NeuroimagingofEpilepsyLaboratory,DepartmentofNeurologyandMcConnellBrainImagingCenter,MontrealNeurologicalInstitute,McGillUniversity,Montreal,Quebec,Canada

NedaBernasconiMD,PhD

NeuroimagingofEpilepsyLaboratory,DepartmentofNeurologyandMcConnellBrainImagingCenter,MontrealNeurologicalInstitute,McGillUniversity,Montreal,Quebec,Canada

WilliamBingamanMD

SectionofEpilepsySurgery,NeurologicInstitute,ClevelandClinic,Cleveland,OH,USA

IngmarBlmckeMD

DepartmentofNeuropathology,UniversityHospitalErlangen,Erlangen,Germany

BenjaminH.BrinkmannPhD

MayoSystemsElectrophysiologyLaboratory,MayoClinic,Rochester,MN,USA

RolandCorasMD

DepartmentofNeuropathology,UniversityHospitalErlangen,Erlangen,Germany

DanielL.DranePhD

DepartmentsofNeurologyandPediatrics,EmoryUniversitySchoolofMedicine,Atlanta,GA,USA

MichaelDuchownyMD

DepartmentofNeurologyandtheBrainInstitute,MiamiChildrensHospitalandtheDepartmentofNeurology,FloridaInternationalUniversityCollegeofMedicine,Miami,FL,USA

RosanaEstellerPhD,EE

NeuroPaceInc.,MountainView,CA,USA

MarcGunot

DepartmentofFunctionalNeurosurgery,NeurologicalHospital,Lyon,France

AlexanderHammersMD,PhD

NeurodisFoundation,c/oCERMEPImagerieduVivant,Lyon,France;PETImagingCentre,DivisionofImagingSciences&BiomedicalEngineering,KingsCollegeLondon,London,UK

ElisabethHartl,MD

EpilepsyCenter,DepartmentofNeurology,UniversityofMunich,Munich,Germany

AkiraHashizumeMD,PhD

EpilepsyCenter,DepartmentofNeurosurgery,HiroshimaUniversityHospital,Hiroshima,Japan

KojiIidaMD,PhD

EpilepsyCenter,DepartmentofNeurosurgery,HiroshimaUniversityHospital,Hiroshima,Japan

PrasannaJayakarMD,PhD

DepartmentofNeurologyandtheBrainInstitute,MiamiChildrensHospitalandtheDepartmentofNeurology,FloridaInternationalUniversityCollegeofMedicine,Miami,FL,USA

SangKunLeeMD

DepartmentofNeurology,SeoulNationalUniversityHospital,Seoul,Korea

DavidW.LoringPhD

DepartmentsofNeurologyandPediatrics,EmoryUniversitySchoolofMedicine,Atlanta,GA,USA

KimfordJ.Meador,MD

StanfordComprehensiveEpilepsyCenter,DepartmentofNeurology&NeurologicalSciences,StanfordUniversitySchoolofMedicine,Stanford,CA,USA

ChristophM.MichelPhD

DepartmentofFundamentalNeurosciences,UniversityofGeneva,Geneva,Switzerland

FriederikeMllerMD

UniversityHospitalofPediatricNeurology,ChristianAlbrechtsUniversityofKiel,Kiel,Germany

AlexandraMontavont

DepartmentofFunctionalNeurology&Epilepsy,NeurologicalHospital,Lyon,France

Hye-JinMoon

DepartmentofNeurology,KeimyungUniversityHospital,Daegu,Korea

SoheylNoachtarMD

EpilepsyCenter,DepartmentofNeurology,UniversityofMunich,Munich,Germany

TerenceJ.OBrienMD,FRACP

DepartmentofMedicine,RoyalMelbourneHospital,UniversityofMelbourne,Parkville,Victoria,Australia

KarineOstrowsky-CosteMD

DepartmentofEpilepsy,Sleep,andPediatricNeurophysiology,Femme-Mre-EnfantHospital,Lyon,France

HiroshiOtsuboMD

NeurophysiologyLaboratory,DivisionofNeurology,HospitalforSickChildren,Toronto,Ontario,Canada

SusannePirkerMD

KarlLandsteinerInstituteforClinicalEpilepsyResearch&CognitiveNeurology,2ndNeurologicalDepartment,GeneralHospitalHietzingwithNeurologicalCenterRosenhgel,Vienna,Austria

KurupathRadhakrishnanMD,DM

R.MadhavanNayarCenterforComprehensiveEpilepsyCare,SreeChitraTirunalInstituteforMedicalSciencesandTechnology,Trivandrum,Kerala,India

ChaturbhujRathoreMD,DM

R.MadhavanNayarCenterforComprehensiveEpilepsyCare,SreeChitraTirunalInstituteforMedicalSciencesandTechnology,Trivandrum,Kerala,India

PhilippeRyvlinMD,PhD

DepartmentofClinicalNeurosciences,CHUV,Lausanne,Switzerland

MargittaSeeckMD

EEG&EpilepsyUnit,DepartmentofClinicalNeurosciences,UniversityHospitalGeneva,Geneva,Switzerland

ChristopherT.SkidmoreMD

JeffersonComprehensiveEpilepsyCenter,DepartmentofNeurology,ThomasJeffersonUniversity,Philadelphia,PA,USA

ElsonL.SoMD

SectionofElectroencephalography,DepartmentofNeurology,MayoClinicCollegeofMedicine,Rochester,MN,USA

MichaelR.SperlingMD

JeffersonComprehensiveEpilepsyCenter,DepartmentofNeurology,ThomasJeffersonUniversity,Philadelphia,PA,USA

VlastimilSulcMD

MayoSystemsElectrophysiologyLaboratory,MayoClinic,Rochester,MN,USA;InternationalClinicalResearchCenter,St.AnnesUniversityHospital,Brno,CzechRepublic

StephanUlmerMD

MedicalRadiologicalInstitute,Zrich,Switzerland;InstituteofNeuroradiology,UniversityHospitalSchleswig-HolsteinCampusKiel,Kiel,Germany

SumeetVaderaMD

DepartmentofNeurosurgery,UniversityofCaliforniaIrvine,CA,USA

AntonioValentnMD,PhD

DepartmentofClinicalNeuroscience,KingsCollegeLondon;DepartmentofClinicalNeurophysiology,KingsCollegeHospital,London,UK

GregoryA.WorrellMD,PhD

MayoSystemsElectrophysiologyLaboratory,DivisionsofEpilepsy&ClinicalNeurophysiology,DepartmentofNeurology,MayoClinic,Rochester,MN,USA

Preface

MRI-negative refractory focal epilepsy is well known to present major challenges inseizure localization and surgical treatment.Many epilepsy centers around theworld areencounteringincreasingnumbersofpatientswithMRI-negativerefractoryepilepsy.Asaresult, there has been a growing number of publications on the topic of presurgicalevaluationandpostsurgicaloutcomeofMRI-negativesurgery.Agreatproportionofthesepublications emanate from advances in imaging techniques. The MRI is one of thehistoricallymostversatilediagnostic tools,withnewtechniquesstilldevelopingdecadesafteritsadvent.However,otherimagingmodalitiesarekeepingpaceintheirdevelopmentfor detecting functional alterations that can serve as surrogates or markers of theepileptogenicfocus.Atthesametime,datahavebeenaccruingfromelectrophysiologicaland histopathological investigations in MRI-negative patients who have undergonepresurgicalevaluationandsurgicalmanagement.

MRI-negative epilepsy is not a single disease entity or epilepsy type, and the globalexperiencewithitsevaluationandsurgeryhasbeenvaried.Nooneepilepsycenterhasallthemostadvancedpresurgicaldiagnosticorsurgicaltechniquesatitsdisposal.Experienceorskillsinthetechniquesareexpectedtovarybetweencenters.Perhapsforthesereasons,outcomesofMRI-negativeepilepsysurgeryarenotuniformbetweencenters.Therefore,indevelopingdiagnostic and therapeutic approaches forMRI-negative epilepsy surgery,thereisaneedforcriticallyassessingsurgicaloutcomesintermsoffactorsthatcontributetopostsurgicalseizurecontrolandneuropsychologicalimpact.

Theeditorsandauthorshavedevelopedthisbooksothatcliniciansandresearchersinepilepsywouldfindittobeusefulbecauseofthefollowingfeatures:

Thebookcollatesandintegratesinonemediumthefast-evolvingstateoftheartandthe science in the evaluation and surgical management of MRI-negative focalepilepsy.Content of the book is clearly organized by diagnostic and treatment options andapproaches,andbythetypeofrefractoryepilepsy.Contributors to this book are experts in their respective areas, with recognizedresearchinvestigationsandclinicalexperienceintheareas.Eachdiagnostictechniqueandsurgicalapproachdiscussediscriticallyappraisedforitsvalueandlimitations.Clinical relevance of thematerials in this book is enhanced by patient cases,withmanyimagesprovidedtoillustratesalientpointsineachchapter.

ElsonL.So

PhilippeRyvlin

Chapter1 ScopeandimplicationsofMRI-negativerefractoryfocalepilepsy

ElsonL.SoandPhilippeRyvlinMRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press. CambridgeUniversityPress2015.

DefinitionofMRI-negativeepilepsyIn the absence of a demonstrable epileptogenic lesion, epilepsy is often referred to asnonlesional epilepsy. In this book, we preferentially use the term MRI-negativeepilepsyinsteadofnonlesionalepilepsy.OurreasonforthispreferenceisthatMRIofpatientswith refractory epilepsy not infrequently shows structural lesions or alterationswhicharenottheimmediatecauseoftheepilepsy.Someoftheselesionsorabnormalitiesthat are noncausative for epilepsy are cerebral atrophy, nonspecificwhitematter signalchanges,andslightasymmetryinsizeorshapeofregionsinthebrain.Inthesesituations,theMRIcannotbesaidtobenormal.Therefore,weavoidedtheuseofthetermepilepsywithnormalMRI.

Another reason for our preferential use of the term MRI-negative epilepsy is thathistopathologicalexaminationofresectedtissueshasrevealedlesionsinasmanyas50%of nonlesional MRI patients, especially neuronal migrational abnormalities such asmicrodysgenesisandfocalcorticaldysplasias[1].Conversely,histopathologicallyprovencorticaldysplasia lesionsareundetectablebyMRI in30%of thepatients [2].For thesereasons,thetermnonlesionalepilepsywouldbeliterallyandtechnicallyincorrect.ThetermMRI-negativeepilepsybetterconveys thecontext inwhich it isused, in that thepresurgical MRI is devoid of a structural abnormality as the probable cause of theepilepsy,andforwhichepilepsysurgeryevaluationcouldbeconsidered.

The term cryptogenic epilepsy has also been used in reference to MRI-negativeepilepsy [3]. Whereas there is some overlap between the population of patients withcryptogenicepilepsyand thepopulationwithMRI-negativeepilepsy, the twoconditionsdonotalwayscoexistinpatients.Thetermcryptogenicepilepsyarosefromtheconceptof classifying different types of epilepsy according to etiology [4]. An example of thecomplex interface between epilepsy etiology and MRI findings is in familial focalepilepsies. Unless clinical and laboratory investigations are conducted to establish theheredo-familialbasisof theepilepsy, familial temporalor frontal lobeepilepsycouldbeclassifiedascryptogenicepilepsy.SomemembersinaffectedfamilieshavenegativeMRI,whereas others have epileptogenic lesions such as mesial temporal atrophy [5]. Yet,epilepsysurgeryhasbeeneffectiveinsomeMRI-positiveandsomeMRI-negativefamilialfocal epilepsies. Nonetheless, MRI findings have overall been consistently a moreimportantfactorthanepilepsyetiologyinidentifyingpatientsforepilepsysurgery,andinprognosticatingtheoutcomeofthesurgery.

ImplicationsofMRI-negativeepilepsy

Despite the use of optimal conventional MR-imaging techniques, the proportion ofepilepsy surgery candidates withMRI-negative epilepsy still ranges from 20% to 40%among epilepsy centers. Moreover, data from the USA show a trend of declininghospitalizations in large epilepsy centers over about 20 years [6]. Some large epilepsycenters have verbally reported increasing proportions of MRI-negative patients, anddecliningvolumesofresectivesurgeries.Astudyisunderwaytoverifytheseobservations.

EpilepsysurgeryislesslikelytobeconsideredinMRI-negativeepilepsypatientsthaninMRI-positive patients.Up to 30%of patients prospectively evaluated in experiencedepilepsysurgerycenterswerenotdeemedtobesurgicalcandidates,andamajorfactorfornotundergoingsurgeryistheabsenceofanMRIlesionandotherlocalizingevidence[7].In a single-center study of both temporal and extratemporal epilepsy patients who hadmodernMRIimaging,only15%ofMRI-negativepatientswereofferedsurgeryvs.73%ofMRI-positivepatients[8].

OnereasonwhyonlyaminorityofMRI-negativerefractoryepilepsypatientsproceedtosurgeryisthatseizurelocalizationevidenceinMRI-negativepatientsisoftenlacking.Localization to the epileptogenic zone by seizure semiologywas correct in only about34%ofthepatients,14%byinterictalscalpEEG,28%byictalscalpEEG,29%byPET,and15%bySISCOM.Therateofdiscordancebetween the resultsof these tests isalsohigh inMRI-negative patients. This overall deficiency in concordant seizure-localizingfindings often necessitates intracranial electrode implantation to identify the ictal onsetzone.Aretrospectivestudyofpatientswhounderwentepilepsysurgeryevaluationshowsthat all MRI-negative patients, compared with 50% of MRI-positive patients, hadundergone intracranial electrode implantation [9]. The extent and complexity ofintracranialelectrodeimplantationareoftengreaterinMRI-negativethaninMRI-positivepatients, in whom the cerebral lesion would have guided the extent of intracranialelectrodecoverage.The riskofcomplicationswith intracranialelectrode implantation isassociatedwiththeextentof theimplantation.Theriskhasbeenreportedtoincreaseby40%foreveryadditional20subduralelectrodesimplanted[10].Yet,extensiveintracranialelectrodeimplantationmaynotassurehigherprobabilityofpostsurgicalseizurecontrol.IthasbeenreportedthatneithertheextentnorthetypeofintracranialictalEEGdischargepredictspostsurgicalseizurefreedominMRI-negativeepilepsysurgery[11].

Thepresenceofanepileptogenic lesion inasurgicallysafeandaccessible location isthe singlemost favorable factor indeterminingoutcomeof epilepsy surgery.Numerousstudies have consistently contrasted the prognosis between MRI-positive and MRI-negativeepilepsy surgery.Meta-analysisof studieson the subject shows that, comparedwithMRI-negativepatients,MRI-positiveorhistopathology-positivepatientshavea2.5times higher chance for seizure freedom following epilepsy surgery. Selected groups oflesional temporal lobe epilepsy surgeries are associatedwith a90%chanceof excellentpostsurgicalseizurecontrol,whereastherateisonly65%inMRI-negativetemporallobesurgeries[12].Similarly,lesionalfrontallobeepilepsysurgerieshavea72%probabilityofexcellent postsurgical seizure control, whereas the rate is only 41% in MRI-negativefrontal lobe surgery [13]. In one study of both temporal and extratemporal refractoryepilepsy,surgeryresultedinseizurefreedominonly38%oftheMRI-negativepatientsvs.76% of the MRI-positive patients [8]. However, many studies have shown that theoutcomeofMRI-negative epilepsy can be improvedwith the use ofmodern diagnostic

measures,withinstancesofexcellentsurgicaloutcomeratesapproximatingthoseinMRI-positiveepilepsy[14].Therefore,amajorobjectiveofthisbookistocriticallyassessandidentify measures that can improve the surgical outcome of MRI-negative epilepsysurgery.

MRI-negative epilepsy surgeries also carry a higher risk for postoperative functionaldeficitsthansurgeriesinvolvinganMRIlesion.MRI-demonstratedlesionssuchastumorsorencephalomalacias are generally expected to be devoid of intrinsic cortical function;thus, theirbordersprovidegood, thoughimperfect,demarcationbetweennonfunctioningand functioning tissues. Such anatomical guidance is lacking inMRI-negative epilepsy.Additionally,agreaterdegreeofintrinsiccorticalfunctionresidesinepileptogenictissuesthat are MRI-negative than in MRI-demonstrated lesions. Helmstaedter and colleagueshaveobservedthatMRI-negativepatientsexperiencemoreprominentmemorylossaftertemporallobectomythanMRI-positivepatients[15].

MRI-negative refractory epilepsy patients could still benefit from surgery [16, 17],especially ifamoremodestpostsurgicalprognosis thanseizurefreedomisacceptable tothe patient. Alarcon and colleagues found that postsurgical seizure frequency of threeseizuresorlessperyearisaslikelytobeachievedinMRI-negativesurgeriesasinMRI-positive surgeries (74% vs. 73%) [9]. Nonetheless, in their subgroup of extratemporalepilepsy,MRI-negativepatientshadamuchlowerrateofachievingseizurefreedomthanMRI-positive patients (16.7% vs. 39.1%). The putative goal of surgery for medicallyrefractoryepilepsyshouldbeseizure freedom,given that improvement inqualityof lifeaftersurgeryisbestassociatedwiththeachievementofcompleteseizurecontrol[18].

ThelessfavorableoutcomeofMRI-negativeepilepsysurgerymaybeduetoanumberoffactors.Withoutavisiblepotentiallyepileptogeniclesion,theepileptogeniczonemaybemissedorunderestimated.InsomeMRI-negativepatientswithextratemporalepilepsyas proven by intracranial EEG and favorable postsurgical outcome, presurgical video-scalpEEGrecordingshadwronglylocalizedseizureonsettothetemporallobe[19].Thepathology underlying MRI-negative epilepsy is also poorly understood and possiblywidespreadormultifocal.Althoughcorticaldysgenesis is increasingly found in resectedtissuesfrompatientswithMRI-negativeepilepsy, thehistopathologyinasmanyas50%shows only nonspecific changes such as gliosis. In fact, the absence of a clear-cutepileptogeniclesioninthehistopathologyandthepersistenceofseizuresaftersurgeryinmanyMRI-negativepatientsmaybeconsequencesofmisguidedresectionwhichfailedtoinclude the epileptogenic histopathological lesion, or the absence of a well-delineatedepileptogenic lesion for resection. In the latter situation, the pathophysiology ofepileptogenesismightinvolvemolecularorcellularabnormalitiesaffectinglargeportionsof the brain, which constitutes a more widespread epileptogenic network than that ofepilepsywithadefiniteMRI-detectableorhistopathology-provenlesion.Examplesofthisconceptincludefocalepilepsiesassociatedwithmutationsofthenicotinicacetyl-cholinereceptorsubunit (autosomaldominantnocturnal frontal lobeepilepsy)orof the leucine-richglioma-inactivated1gene(autosomaldominantfocalepilepsywithauditoryfeatures),ormultifocaltype1corticaldysplasia.

Therefore, the critical issue in the presurgical evaluation of refractoryMRI-negativeepilepsy is the development and validation of diagnostic strategies for localizing the

epileptogenic zone and surgical approaches for resecting the zone. Accordingly,biomarkers could be developed to identify subgroups of MRI-negative patients withfavorable surgical prognosis, such as those with MRI-occult focal cortical dysplasia(FCD). When used alone or in combination, clinical information, scalp EEG, MEG,SPECT,orPETmay in the future presurgically distinguishbetweenMRI-occult type IIFCD where surgical prognosis is favorable, and type I multifocal/extensive corticaldysplasiawheretheprognosisispoorer.Itisalsoconceivablethatadvancesincurrentandfuture diagnostic techniques may prove that a comprehensive understanding of thepathophysiology underlying each case ofMRI-negative epilepsy is more important forpostsurgicaloutcomethanthecurrentstrategyofidentifyingtheseizureonsetzone.

ScopeoftheissuesOurterminologyofMRI-negativeepilepsyincludesinstanceswhenMRIshowsasubtlefocalfindingthat issuspectedordisputedtobethecauseof therefractoryepilepsy[20,21](Figure1.1)ThereasonisthatevaluationforepilepsysurgeryisjustascomplexandrigorouswhetherornotasubtleordisputablefindingispresentontheMRI.Thetestsandstrategiesavailableforlocalizingandresectingtheictalonsetzoneareapplicableineithercase.

Figure1.1 ExamplesofsubtleabnormalitiesappreciatedonMRIre-review.UpperpanelshowsFLAIR(left)andT1-SPGR(right)imagesofsubtlelefthippocampalsignalabnormalitywithoutatrophy.LowerpanelshowsFLAIR(left)andT1-SPGR(right)imagesofsubtlelefthippocampalatrophywithoutsignalabnormality.(Fromreference[20];reproducedwithpermissionofpublisherJohnWileyandSons.)

There are also instances when the histopathological examination of resected tissuesdisclosed lesional pathology,which thenprompted reassessment of thepresurgicalMRIthatwasperviouslypronouncedtobenegative[20].WithreassessmentofthepresurgicalMRI, a subtle lesion or alteration at the location of the surgery was then recognized.

Visual reassessment of the MRI combined with morphometric analysis haveretrospectivelyidentifiedasubtlelesionineightofninepatientswhosepresurgicalMRIwasdeemednegative,butpostsurgicaltissueexaminationshowedlesionalpathology[8].These situations should still be considered as MRI-negative epilepsy, because thepresurgicalknowledgeoftheMRIresulthadbeenthebasisfordevelopingthestrategiesin identifyingandresecting the ictalonsetzone,andalso inprognosticating thesurgicaloutcome.

BothpresurgicallyandpostsurgicallydetectedsubtleMRIalterationsshouldbefurtherscientifically investigated,becausestudieshavesuggested thatsubtle focalalterations inotherwiseMRI-negativeepilepsycouldbeassociatedwithexcellentpostsurgical seizurecontrol [8, 20].With continuing advancements inMRI imaging,MRI findings that arecurrentlynegative,subtle,ordisputableforepilepsysurgeryconsiderationmayeventuallybedetectedandrecognizedasdefiniteanatomicallesionswithpotentialepileptogenicity.Even before then, advancements in functional imaging and electrophysiology mayestablishsubtlealterationstobehighlyprobableictalonsetzones,whichmaybetargetedforfurtherseizurelocalizationstudiesandsubsequentsurgicalresection.Accumulationofexperience in surgery of patients with subtle MRI alterations will lead to betterunderstandingoftheirhistopathologicalnature[3].

There are many types of MRI-negative epilepsies that are of generalized orindeterminateonset,butthisbookconcentratesonthesurgicalevaluationandtreatmentsof refractory focal epilepsy. Nonetheless, much of the methods and approaches insearching for the seizure onset zone for focal resective surgery are also applicable inevaluatingpatientswith suspectedgeneralizedor indeterminate seizureonset.When theevaluation process has more confidently excluded focal refractory epilepsy, and thegeneralized-onset nature of the epilepsy is affirmed, the appropriate pharmacologic orsurgicaltreatmentsforthenonfocalepilepsymaythenbeconsidered.

Inconcentratingthetreatiseofthisbookonrefractoryfocalepilepsy,theauthorsmakenopresumptiverestrictionregardingthesizeorextentoftheseizurefocusforinclusioninthisbook.Theextentoftheseizurefocusorfoci,andtheirrelationshiptoeloquentcortex,is at the crux of the complexities and nuances of MRI-negative epilepsy surgeryevaluation.Wehavealsospecificallyincludedinthisbookthediscussionoftemporal-plusepilepsy and posterior cortical epilepsy, in which the clinical and scalp EEG findingsappeartoinvolvetheparietal,occipital,ortemporallobe,oracombinationoftheselobes,and the intracranial recording subsequently confirming either a unilobar or multilobarregionofseizureonset.

References1. Siegel,A.,etal.,Medicallyintractablelocalization-relatedepilepsywithnormalMRI:Presurgical evaluationandsurgicaloutcome in43patients.Epilepsia,2001.42:883888.

2. Hauptman,J.andG.Mathern,Surgicaltreatmentofepilepsyassociatedwithcorticaldysplasia:2012update.Epilepsia,2012.53(Suppl4):98104.

3. Bernasconi,A.,etal.,AdvancesinMRIforcryptogenicepilepsies.NatureReviews,

2011.7:99108.

4. Commission onClassification andTerminology of the International LeagueAgainstEpilepsy.ProposalforClassificationofEpilepsiesandEpilepticSyndromes.Epilepsia,1985.26:268278.

5. Kobayashi,E.,etal.,Outcomeofsurgical treatment infamilialmesial temporal lobeepilepsy.Epilepsia,2003.44(8):10801084.

6. Englot, D.J., et al., Epilepsy surgery trends in the United States, 19902008.Neurology,2012.78(16):12001206.

7. Berg,A.,etal.,Themulticenterstudyofepilepsysurgery:Recuitmentandselectionofpatientsforsurgery.Epilepsia,2003.44(1):14251433.

8. Bien, C., et al., Characteristics and surgical outcome of patients with refractorymagneticresonanceimaging-negativeepilepsies.ArchivesofNeurology,2009.66(12):14911499.

9. Alarcon,G., et al., Is itworthpursuing surgery for epilepsy inpatientswithnormalneuroimaging? Journal of Neurology, Neurosurgery&Psychiatry, 2006. 77(4): 474480.

10. Hamer, H., et al., Complications of invasive video-EEGmonitoringwith subduralgrids.Neurology,2002.58:98103.

11. Lee,S.K.,etal.,Surgicaloutcomeandprognosticfactorsofcryptogenicneocorticalepilepsy.[seecomment].AnnalsofNeurology,2005.58(4):525532.

12. Radahkrishnan,K.,etal.,Predictorsofoutcomeofanterior temporal lobectomyforintractableepilepsy.Amultivariatestudy.Neurology,1998.51:465471.

13. Mosewich, R., et al., Factors predictive of the outcome of frontal lobe epilepsysurgery.Epilepsia,2000.41:843849.

14. Carne, R.P., et al., MRI-negative PET-positive temporal lobe epilepsy: a distinctsurgicallyremediablesyndrome.Brain,2004.127(Pt10):22762285.

15. Helmstaedter, C., I. Petzold, andC. Bien, The cognitive consequence of resectingnonlesionaltissuesinepilepsysurgery:ResultsfromMRI-negativeandhistopathology-negativepatientswithtemporallobeepilepsy.Epilepsia,2011.52(8):14021408.

16. Wetjen, N., et al., Intracranial electroencephalography seizure onset patterns andsurgical outcomes in nonlesional extratemporal epilepsy. Journal of Neurosurgery,2009.110(6):11471152.

17. Fong, J., et al., Seizure outcome and its predictors after temporal lobe epilepsysurgeryinpatientswithnormalMRI.Epilepsia,2011.52(8):13931401.

18. Seiam,A.,H.Dhaliwal,andS.Wiebe,Determinantsofqualityoflifeafterepilepsysurgery:Systematicreviewandevidencesummary.EpilepsyandBehaviour,2011.21:441445.

19. Lee, S., et al., Intracranial ictal onset zone in nonlesional lateral temporal lobeepilepsyonscalpictalEEG.Neruology,2003.61:757764.

20. Bell,M.,etal.,Epilepsysurgeryoutcomesin temporal lobeepilepsywithanormalMRI.Epilepsia,2009.50(9):20532060.

21. Pillay,N.,etal.,Parahippocampalepilepsywithsubtledysplasia:Acauseofimagenegativepartialepilepsy.Epilepsia,2009.50(12):26112618.

Chapter2 SeizuresemiologyandscalpEEGinMRI-negativerefractoryfocalepilepsy

SoheylNoachtarandElisabethHartlMRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press. CambridgeUniversityPress2015.

The rationale of epilepsy surgical intervention depends on the localization of theepileptogenic zone and its complete removal [1]. The followingmethods were used todelineatetheepileptogeniczone[2]:

seizuredescriptionandpatienthistoryMRIinterictalEEGictalEEGvideomonitoringictal(andinterictal)SPECTinterictalPETneuropsychologicalevaluation

Several studieshave shown that it ismoredifficult to identify theepileptogeniczone ifMRI does not reveal any abnormality [2, 3]. In general, the chance of a postoperativeseizure freedom outcome from epilepsy surgery is less favorable in nonlesional MRI-negative patients as compared to patients withMRI-documented lesions [3].However,thanks to advances inMRI technology, the sensitivity indetectingepileptogenic lesionsimproveddramaticallyoverthelasttwodecades[4].Itis,therefore,mandatorytoperformstate of the art epilepsy-oriented MRIs before stating that a given patient has MRI-negativeepilepsy.

Concordanceofnoninvasiveresultsimplicatingaresectablefocusisusuallyconsideredtheprerequisitetoproceedtoepilepsysurgerybasedonnoninvasivestudiesonly.Thisismostly true in temporal lobe epilepsy,which is themost common focal epilepsy that isreferredtoepilepsysurgerycenters.However,inalargeseriesofunselectedpatientswithextratemporallesions,discrepancyofEEGandMRIlocalizationwasmorecommonthancongruence[5].Discrepancydidnotnecessarilyimplythatresectiveepilepsysurgerywasassociatedwithpoorpostsurgicaloutcome[5].

Invasive evaluation may be used in patients in whom noninvasive studies areinconclusive or reveal discrepant results, but still support a testable hypothesis of aresectable focus. Under these circumstances, properly placed invasive electrodesfrequentlyprovideusefuladditional informationabout the localizationandextentof theepileptogeniczone.IfMRIisnegative,thedefintionoftheepileptogeniczonehastorelyon localization information derived frommethods such as seizure semiology andEEG,whichthenbecomemoreimportant.Frequently,inMRI-negativepatients,invasivestudiesarerequiredtodefinethelocalizationoftheepileptogeniczone.

InterictalEEG

Electroencephalography is themost specificmethod to define the epileptogenic cortex.Interictalepileptiformdischarges,particularly ifconsistentover time,canprovideusefulinformation[6].Intemporallobeepilepsy,consistentlyunitemporalinterictalepileptiformdischarges (IED)haveabetterprognosis forseizure freedomthanbilateral IEDs.Focal,particularlyextratemporal,epilepsiesinwhichtheEEGshowsactiveregionalpolyspikesaremorelikelyassociatedwithcorticaldysplasiaasetiologyoftheepilepsythanpatientswithother IEDs [7].Rhythmicmidline theta activity,which is distinct frompatterns ofdrowsinessofmentalactivation, ishighlysignficant for frontal lobeepilepsyand rarelyseenintemporallobeepilepsy[8].Thisisparticularlyinterestingsinceoneoutoffourofthesefrontallobeepilepsypatientsdidnotshowanyinterictalepileptiformdischargesonnoninvasive long-term EEG-monitoring and the rhythmic midline theta was the onlyinterictalEEGabnormality[8].

IctalEEGvideomonitoringIctal EEGvideo recording is critical in localizing the epileptogenic zone. A carefulanalysisof thefirstclinicalsignsandsymptomsofaseizureandof theevolutionof theseizure symptomatology can provide important clues on the epileptogenic zone [911].Onemust keep inmind, however, that often an epileptic seizure arises from a silentregionof cortex andwould remain asymptomaticunless it spreads to eloquent cortexsuchasprimarymotor,primarysensory,orsupplementarysensorimotorareas(Figure2.1).Unfortunately, ictal EEG frequently documents discrepant results in extratemporalepilepsies [5].Good concordance toMRI lesions and interictal EEG is only typical fortemporallobeepilepsy[5].

Figure2.1 Illustrationoftherelationoftheseizureonsetandsymptomatogeniczones.Seizureonsetintheprefrontalregionislikelytostayunnoticedunlesstheepilepticactivityspreadsintosymptomatogeniccortex:

1. Spreadintothesupplementarysensorimotorarealeadstobilateralasymmetrictonicseizure

2. Spreadintothesomatosensoryhandarealeadstorightfaceclonicseizure

3. Spreadintothefrontaleyefieldleadstorightversiveseizure

4. Spreadintofrontalspeecharealeadstoaphasicseizure

Seizureonsetintheleftoccipitallobeleadstothefollowingseizureevolution:

5. RightvisualaurarightversiveseizureSeizureonsetinthetemporallobeleadstothefollowingseizureevolution:

6. Acousticaura/abdominalauraautomotorseiurerightfaceclonicseizure.

SeizuresemiologyCareful clinicalobservationsanddetailed reportsof seizure semiologyby thepatientorobservershavebeenusedsincethe18thcenturytoclassifyepilepticseizuresandepilepticsyndromes. A detailed analysis of seizure semiology is still essential for the propermanagementof epilepticpatients.Acleardefinitionof the seizure type is important forclassifyingtheepilepsysyndromeofthepatient.Thesyndrome,togetherwiththeetiologyof the epilepsy, are the essential factors determining the prognosis aswell as themosteffective pharmacological treatment. Seizure semiology plays an important role in thepresurgicalwork-up,particularlywhenanalyzed independentlyofotherpresurgical tests

(EEG monitoring, neuroradiology, etc.). In addition, seizure semiology can be usedeffectivelytodifferentiatebetweenepilepticandnonepilepticseizures.

It is very important to emphasize that as a rule epileptic discharges limited to theseizure onset zone do not cause clinical symptoms unless located in an eloquent area(Figure2.1).Thisisbecausetheepileptogeniczonedoesnotnecessarilyoverlapwiththesymptomatogenic zone [1]. The term symptomatogenic zone refers to the area of thecortex that produces certain clinical symptoms as a result of epileptic activation. Forexample,seizuresthatoriginateinthefrontalconvexityremainasymptomaticaslongastheydonotspreadintothesymptomatogeniczones.Iftheepilepticactivationreachestheprimary motor area, versive or focal clonic seizures result (Figure 2.1). If thesupplementary sensorimotor area is activated, focal tonic or hypermotor seizures occur;and if the activation spreads into the limbic system (cingulate gyrus), features of theseizure possibly become those of automotor seizures [12] (Figure 2.1). There is someassociationofspecificseizuretypeswithbrainregions:seizurescharacterizedbyoralandmanual automatisms (automotor seizures) [13, 14] are more common in temporal lobeepilepsy than in extratemporal epilepsy [15].However, the specificity to temporal lobeepilepsy is much higher if automotor seizures are preceded by epigastric (abdominal)auras[15].Similarly,unilateralclonicseizuresofthefacearefrequentlyseeninpatientswith paracentral epilepsies.However, the same seizure typemay occur in patientswithtemporal lobe epilepsy but then is usually preceded by manual and oral automatisms(automotor seizure. In fact, this evolution ismore likely to occur in lateral thanmesialtemporallobeepilepsy[16].Unilateralclonicseizuresmaybeassociatedwithbothfrontaland temporal lobe epilepsies. However, the sequence of the seizure evolutionmakes amajordifference.Intemporallobeepilepsy,unilateralfacialclonicseizuresaretypicallypreceded by manual and oral automatisms, which are rarely the case in frontal lobeepilepsy. Thus, the association of single-seizure types to particular localizations of theepileptogeniczonesisnotasstrongastheassociationoftheevolutionofseizuretypestospecific brain regions. This may explain why several studies which neglected this factfound poor localizing value of seizure semiology [17].Another limitation is thatmanystudies relied on the description of seizures rather than investigating adequate video-recordedseizures[17].Patientsorwitnessessdescriptionsofseizurearesubject tobiasandnotsufficientlyreliable.

Table2.1summarizesstudiesonnonlesionalepilepsypatients.AcomputerizedonlinesearchviaMEDLINE(onlinePubMedfromfirstavailableyeartoApril2013)usingthesearchtermnonlesionalepilepsyidentified121studies,ofwhich78wereexcludedforbeing reviewarticles (n=16),meta-analysis (n=1),or acommentary (n=1).Animalstudies(n=2),geneticstudies(n=4),aswellas tenstudies investigatingsymptomaticepilepsy and 19 not clearly differentiating between nonlesional and lesional epilepsypatients (n = 19) were excluded. Seven publications including patients with status orgeneralizedepilepsysyndromeswereexcluded,astheydonotlocalizeinearlyinfancy.Inaddition,studieswereexcludediftheydidnotuseMRimaging(n=6)orwerewritteninlanguagesotherthanEnglishorGerman(n=9).Twopublicationswereexcluded,becausethefulltextwasnotavailableonline.Intotal,43studiesmetourinclusioncriteria.

Table2.1 Characteristicsofselectedstudiesaboutnonlesionalepilepsy

Author(year) Trial

Patientnumber(m/f)

Semiology

EEG

PET/SPECTinterictal ictal invasive(n)

Helmstaedteretal.(1993)[23]

CCT 8(5/3) 5CPS,3GTC

n.a. - - N

Blum(1994)[24]

pUCT 57(-/-) - n.a. n.a. n.a.(-) N

Stanleyetal.(1998)[25]

pCCT 20(10/10)

20PS n.a. n.a. n.a.(10) N

Sweareretal.(1999)[26]

pUCT 23(12/11)

23PS n.a. - n.a.(13) N

Velascoetal.(2000)[19]

pUCT 22(11/11)

22CPS,1GTC,12SGC

a. a. a.(22) N

Mathejaetal.(2001)[18]

pCCT 62(26/36)

- a. - - Y

Mendonaetal.(2001)[27]

pCCT 19(10/9) 19PS n.a. - - N

Hongetal.(2002)[22]

rUCT 41(27/14)

- n.a. a. n.a.(-) Y

Horietal.(2001)[28]

pUCT 20(-/-) - - - - N

Wieshmannetal.(2003)[29]

pCCT 16(7/9) - a. a. a.(16) N

Leutmezeretal.(2003)[30]

pCCT 18(-/-) - n. n.a. - Y

Merletetal.(2004)[31]

pCCT 5(5/0) - n.a. n.a. a.(5) Y

Carneetal.(2004)[32]

rCCT 30(16/14)

30CPS,30SGC

a. a. - Y

Ohetal.(2004)[33]

pUCT 8(6/2) 6CPS,3SGC

n.a. n.a. - N

Brzdiletal.(2006)[34]

CR 1(1/0) 1SPS a. a. a.(1) Y

Najmetal.(2006)[35]

CR 1(1/0) 1CPS,1SGC

a. a. a.(1) Y

Itoetal.(2007)[36]

pCCT 13(8/5) 4SPS,13CPS,5SGC

a. n.a. a.(3) Y

Boxetal.(2007)[37]

pUCT 3(2/1) 3CPS,1GTC,1SGC

a. a. a.(3) N

Shieldsetal.(2007)[38]

CR 1(1/0) 1PS a. a. a.(1) Y

Kaczmareketal.(2007)[39]

pCCT 89(-/-) 89PS - - - N

Adamsetal.(2008)[40]

pUCT 91(41/50)

91PS n.a. n.a. - N

Conchaetal.(2009)[41]

pCCT 13(5/8) 13CPS n.a. n.a. n.a.(4) N

Nakayamaetal.(2009)[42]

CR 1(1/0) 1CPS,1GTC

a. - - Y

Tanriverdietal.(2009)[43]

rUCT 393(191/202)

- - - - N

Velascoetal.(2009)[44]

CR 2(1/1) 2SPS,2SGC

a. a. a.(2) N

Aubertetal.(2009)[45]

rUCT 8(3/5) - n.a. n.a. a.(8) N

Poonetal.(2010)[46]

CR 1(0/1) 1CPS a. a. a.(1) Y

Loweetal.(2010)[47]

rUCT 76(-/-) - n.a. - n.a.(24) N

Olivaetal.(2010)[48]

pUCT 12(4/8) - a. - - N

Mankinenetal.(2011)[49]

pCCT 21(10/11)

- a. - - N

Boxetal.(2011)[50]

rUCT 6(3/3) 6CPS a. a. a.(5) Y

Kimetal.(2011)[51]

rUCT 55(31/24)

4SPS,7CPS,16GTC,28SGC

n.a. n.a. n.a.(55) Y

Hindi-Lingetal.(2011)[52]

rUCT 33(-/-) - n.a. n.a. n.a.(-) Y

Auetal.(2011)[20]

pUCT 4(2/2) 2SPS,3CPS,2GTC

n.a. a. a.(4) Y

Tyrandetal.(2012)[53]

pUCT 4(3/1) 4CPS,1SGC

n.a. n.a. a.(4) N

Wangetal.(2012)[54]

CR 1(1/0) 1SPS a. - a.(1) Y

Mankinenetal.(2012)[55]

pCCT 21(10/11)

- a. - - N

Schneideretal.(2012)[56]

rUCT 14(10/4) - n.a. n.a. a.(14) Y

Kovacetal.(2012)[57]

CR 1(0/1) 1PS,1GTC

a. a. a.(1) Y

Sunetal.(2012)[58]

CR 1(1/0) 1PS,1GTC,reflexep.

a. a. a.(1) N

Chaudharyetal.(2012)[59]

pUCT 8(6/2) 8PS,3reflexep.

a. a. - N

Bienetal.(2013)[60]

rUCT 567(297/270)

- n.a. n.a. n.a.(-) N

Muelleretal.(2013)[61]

pCCT 36(13/23)

- n.a. n.a. n.a.(6) N

n = number of subjects, m =male, f = female, bihem. = bihemispheric, histop. =histopathology,r=retrospective,p=prospective,UCT=uncontrolledclinical trial,CCT=controlledclinicaltrial,CR=casereport,SPS=simplepartialseizure,CPS=complexpartial seizure,GTC=generalized tonicclonic seizure,SGC= secondarygeneralizedseizure,n.a.=nodataavailable,a.=dataavailable,TL=temporallobe,FL=frontallobe,PL=parietallobe,OL=occipitallobe,CR=centralregion,Y=yes,N=no.

Differentterminologieswereusedtoclassifyorlabelseizuresemiology.Itwasmostlylabeledafterthelobe,suchastemporallobeseizureorfrontallobeseizure,providingnoreliableclinical informationontheseizurecharacteristics.Otherstudiesusedtheseizureclassification system of the International League against Epilepsy with terms such ascomplexpartialseizures(CPS)orsimplepartialseizures(SPS).Thesetermsonlyprovidetheinformationwhetherconsciousnessisdisturbedornotinpatientswithfocalepilepsiesregardlessof the actual seizure semiology.Only fewpublicationsof case seriesprovidedetailedinformationonseizuresemiologyandEEGfindings[1820].We,therefore,usethesemiologicalseizureclassificationtoprovideclinicallylocalizinginformation[13,14].With the help of EEGvideo-recorded seizures, several very reliable lateralizing signshavebeenidentifiedwhichhaveanaccuracyof80100%(Table2.2)[12,21].

Table2.2 Lateralizingseizurephenomena

Lateralizingseizurephenomena Hemisphereofseizureonset Authors

Headandeyedeviation Contralateral [6264]

Dystonichandposturing Contralateral [63,65]

Figure4sign Contralateraltoextendedarm

[66]

Automatismswithpreservedresponsiveness

Nondominant [67,68]

Ictalspeech Nondominant [69]

Postictalaphasia Dominant [69]

Ictalvomiting Nondominant [70]

Ictalspitting Nondominant [71]

Peri-ictalurinaryurge Nondominant [72]

Postictalnoserubbing Ipsilateral [73]

Postictalcoughing Nondominant [74]

Unilateralclonicseizure Contralateral [75]

Unilateraltonicseizure Contralateral [76]

Unilateraleyeblinking Ipsilateral [7779]

Asymmetricending Ipsilateraltoclonia [80]

TheEEGdataweremostly reportedasbeingconcordantordiscordantwith theotherdiagnostic findings (Table 2.1). Highest diagnostic sensitivity in the localization ofepileptogenic foci and seizure lateralization was demonstrated for ictal scalp EEG.Concordanceratewashigherinthegoodthaninthepoorsurgicaloutcomegroup[22].

The lateralizing and localization value of seizure semiology, and their role inMRI-negative surgery, are further discussed elsewhere in this book according to the brainregionsaffectedbyepilepsy(Chapters14,15,16,and18), inchildren(Chapter17),andwithrelevancetocorticalmapping(Chapter13).

IllustrativepatientsHowseizuresemiologyandEEGhelptodevelopahypothesisontheepileptogeniczoneinpatientswithnegativeMRIisillustratedbythefollowingtwopatients:

Patient1:This27-year-old,right-handedfemalebankclerkhashadepilepticseizures

sincetheageof8years.Shehadfrequentpredominantlynocturnalhypermotorandasymmetric bilateral tonic seizureswhichwere sometimes preceded by an aura offear.HerMRIwasnormal.InterictalEEGrevealedevenlydistributedrightandleftmesial temporal interictal epileptiform discharges and slowing. Ictal EEG showedfrontal, nonlateralized seizurepatterns.Postictally, thepatientwas at times aphasicand her generalized tonicclonic seizureswere preceded by right versive seizures.Her medical history was unremarkable. Antiepileptic medications in monotherapyandseveralcombinationsdidnotcontroltheseizures.

In summary, MRI was negative, ictal EEG showed nonlateralized frontalabnormalities, and interictal EEG demonstrated bitemporal discharges. However,semiology was pointing to a left hemisphere and a likely frontal onset (sleeppredominance,hypermotorseizure,bilateralasymmetrictonicseizures,rightversiveseizure, postictal aphasia). Based on these noninvasive findings, an invasiveevaluation was performed with subdural grid electrodes covering the left frontalconvexity, and strip electrodes over the leftmesial frontal and right lateral frontalregion.Seizureonsetcouldbeidentifiedoverwideareasofthemesialandlateralleftfrontallobesparingthespeechareasandthemotorstrip.Afterspeechareaandmotorstripwereidentifiedbyelectricalstimulationof thecortex,anextensiveleftfrontalloberesectionsparingonlytheprecentralgyrus,theinferiorfrontalgyrus,andpartsof the orbitofrontal region,was performed.Histology revealedwidespread corticaldysplasiatypeI.Thepatientisseizure-freefor5yearswithantiepilepticmedication.Neuropsychologicalperformanceimprovedpostoperatively.

Patient2:This34-year-old,right-handedaccountanthashadepilepticseizuressincethe age of 24 years. He had acoustic auras which would evolve into automotorseizuresconsistingoforalandmanualautomatisms.Rarely,healsohadabdominalauras. Before seizures further evolved into generalized tonicclonic seizures,sometimesrightfaceclonicseizuresoccurred.TheMRIwasnormal.InterictalEEGshowed left temporal (85%) and rare right mesial temporal (15%) epileptiformdischarges, mostly in sleep. Ictal EEG showed consistently left temporal seizurepatterns. Interictal FDG-PET showed left lateral temporal and less severe mesialtemporal hypometabolism. Ictal SPECT revealed left lateral and mesial temporalhyperperfusion. Subtraction of interictal PET and ictal SPECT showed lateralpredominanceoftheleftictalhyperperfusion.Hisverbalmemorywasaboveaveragebutsubjectivelydecliningoverthelastfewyears.Severalantiepilepticdrugsfailedtocontrol the seizures. Hismedical historywas remarkable for a febrile illness withconfusionandheadacheatage22whichwasnotfurtherdiagnosedatthattime.Nofamilyhistoryofepilepsy.

In summary,MRIwas normal butEEG,PET, andSPECTpoint to a left temporalseizure onset. However, seizure semiology with acoustic auras is suggestive of alateralneocorticaltemporalseizureonset.ThisissupportedbythefactthatMRIdidnotrevealaleftmesialtemporalsclerosis,PETandSPECTshowedalateraltemporalpredominance, and his verbal memory was still above average (though markedlydecliningsubjectively).Aninvasiveevaluationwithstereotacticallyimplanteddepthelectrodescoveringtheleftmesialandlateraltemporalregionrevealedseizureonsetinthesuperiorandmiddletemporalgyrus,whichwereresected.Themesialtemporal

structureswere spared.Histology revealedmild gliosis. The patient is seizure-freepostoperatively for 8 years with medication. Postoperatively, he developed someminorverbalmemorydeficit,whichimprovedoverseveralmonthsbutdidnotreachbaselinelevel.

References1. RosenowF,LudersH.Presurgicalevaluationofepilepsy.Brain2001;124:1683700.

2. Noachtar S, Borggraefe I, Rmi J. When to consider epilepsy surgery, and whatsurgicalprocedure?.InSchachterSC,editor.Evidence-basedManagementofEpilepsy.Shrewsbury,UK:TFMPublishingLtd.2011.pp.3353.

3. Tellez-ZentenoJF,HernandezRonquilloL,Moien-AfshariF,etal.Surgicaloutcomesin lesionalandnon-lesionalepilepsy:asystematicreviewandmeta-analysis.EpilepsyRes2010;89:31018.

4. Duncan JS.Neuroimaging for epilepsy: quality andnot just quantity is important.JNeurolNeurosurgPsychiatry2002;73:61213.

5. RemiJ,VollmarC,deMarinisA,etal.CongruenceanddiscrepancyofinterictalandictalEEGwithMRIlesionsinfocalepilepsies.Neurology2011;77:138390.

6. NoachtarS,BorggraefeI.Epilepsysurgery:acriticalreview.EpilepsyBehav2009;15:6672.

7. NoachtarS,BilginO,RemiJ,etal.InterictalregionalpolyspikesinnoninvasiveEEGsuggestcorticaldysplasiaasetiologyoffocalepilepsies.Epilepsia2008;49:101117.

8. BelezaP,BilginO,NoachtarS.Interictalrhythmicalmidlinethetadifferentiatesfrontalfromtemporallobeepilepsies.Epilepsia2008;50:5505.

9. NoachtarS.Seizuresemiology.InLdersHO,editor.Epilepsy:ComprehensiveReviewandCaseDiscussions.London:MartinDunitzPublishers.2000.pp.12740.

10. Lders HO, Noachtar S. Atlas of Epileptic Seizures and Syndromes. Philadelphia:Saunders.2001.

11. Lders H, Noachtar S, editors. Epileptic Seizures: Pathophysiology and ClinicalSemiology.NewYork:ChurchillLivingstone.2000.

12. NoachtarS.Videoanalysisinthedefinitionofthesymptomatogeniczone.InDaubeJ,MauguiereF,editors.HandbookofClinicalNeurophysiology.Amsterdam:Elsevier.2004.pp.187200.

13. Lders H, Acharya J, Baumgartner C, et al. Semiological seizure classification.Epilepsia1998;39:100613.

14. NoachtarS,LdersHO.Classificationofepilepticseizuresandepilepticsyndromes.InTextbookofStereotacticaandFunctionalNeurosurgery.1997.pp.176374.

15. HenkelA,NoachtarS,PfanderM,etal.Thelocalizingvalueoftheabdominalauraanditsevolution:astudyinfocalepilepsies.Neurology2002;58:2716.

16. Pfander M, Arnold S, Henkel A, et al. Clinical features and EEG findings

differentiatingmesial fromneocortical temporal lobeepilepsy.EpilepticDisord2002;4:18995.

17. ManfordM,FishDR,ShorvonSD.Ananalysisofclinicalseizurepatternsandtheirlocalizingvalueinfrontalandtemporallobeepilepsies.Brain1996;119:1740.

18. MathejaP,KuwertT,LudemannP,etal.Temporalhypometabolismat theonsetofcryptogenictemporallobeepilepsy.EurJNuclMed2001;28:62532.

19. VelascoAL,BoleagaB,BritoF,etal.Absoluteandrelativepredictorvaluesofsomenon-invasiveandinvasivestudiesfortheoutcomeofanteriortemporallobectomy.ArchMedRes2000;31:6274.

20. Au L, Leung H, Kwan P, et al. Intracranial electroencephalogram to evaluaterefractorytemporalandfrontallobeepilepsy.HongKongMedJ2011;17:4539.

21. Leutmezer F, Baumgartner C. Postictal signs of lateralizing and localizingsignificance.EpilepticDisord2002;4:438.

22. HongKS,LeeSK,KimJY,etal.Pre-surgicalevaluationandsurgicaloutcomeof41patientswithnon-lesionalneocorticalepilepsy.Seizure2002;11:18492.

23. HelmstaedterC,WagnerG,ElgerCE.Differentialeffectsof firstantiepilepticdrugapplication on cognition in lesional and non-lesional patients with epilepsy. Seizure1993;2:12530.

24. Blum D. Prevalence of bilateral partial seizure foci and implications forelectroencephalographictelemetrymonitoringandepilepsysurgery.ElectroencephalogrClinNeurophysiol1994;91:32936.

25. Stanley JA, Cendes F, Dubeau F, et al. Proton magnetic resonance spectroscopicimaginginpatientswithextratemporalepilepsy.Epilepsia1998;39:26773.

26. Swearer JM, Kane KJ, Phillips CA, et al. Predictive value of the intracarotidamobarbitaltestinbihemisphericseizureonset.Neurology1999;52:40911.

27. Mendona PB, Piccinin LC, Capucho CM, et al. Effect of lateralized epilepticdischargesonthethoughtflow.ArqNeuropsiquiatr2001;59:31823.

28. Hori T, Yamane F, Takenobu A. Microanatomy of medial temporal area andsubtemporal amygdalohippocampectomy.Stereotact Funct Neurosurg 2001; 77: 20812.

29. Wieshmann UC, Denby CE, Eldridge PR, et al. Foramen ovale recordings: apresurgicalinvestigationinepilepsy.EurNeurol2003;49:37.

30. Leutmzer F, Schernthaner C, Lurger S, et al. Electrocardiographic changes at theonsetofepilepticseizures.Epilepsia2003;44:34854.

31. Merlet I,OstrowskyK,CostesN, et al. 5-HT1A receptorbindingand intracerebralactivity in temporal lobeepilepsy:an[18F]MPPF-PETstudy.Brain2004;127:90013.

32. CarneRP,OBrienTJ,KilpatrickCJ,etal.MRI-negativePET-positivetemporallobeepilepsy:adistinctsurgicallyremediablesyndrome.Brain2004;127:227685.

33. OhJB,LeeSK,KimKK,etal.Roleofimmediatepostictaldiffusion-weightedMRIin localizing epileptogenic foci of mesial temporal lobe epilepsy and non-lesionalneocorticalepilepsy.Seizure2004;13:50916.

34. BrzdilM,MiklM,ChlebusP,etal.Combiningadvancedneuroimagingtechniquesin presurgical workup of non-lesional intractable epilepsy.EpilepticDisord 2006; 8:1904.

35. Najm IM, Naugle R, Busch RM, et al. Definition of the epileptogenic zone in apatientwithnon-lesionaltemporallobeepilepsyarisingfromthedominanthemisphere.EpilepticDisord2006;8Suppl2:S2735.

36. ItoS,SuharaT,ItoH,etal.Changesincentral5-HT(1A)receptorbindinginmesialtemporal epilepsy measured by positron emission tomography with [(11)C]WAY100635.EpilepsyRes2007;73:11118.

37. BoxC,VulliemozS,SpinelliL,etal.High-andlow-frequencyelectricalstimulationinnon-lesionaltemporallobeepilepsy.Seizure2007;16:6649.

38. ShieldsDC,CostelloDJ,GaleJT,etal.Stereotacticcorticalresectioninnon-lesionalextra-temporalpartialepilepsy.EurJNeurol2007;14:11868.

39. KaczmarekI,Winczewska-WiktorA,SteinbornB.Neuropsychologicalassessmentinnewlydiagnosedcryptogenicpartialepilepsy inchildrenapilotstudy.AdvMedSci2007;52Suppl1:15860.

40. AdamsSJ,OBrienTJ,LloydJ,etal.Neuropsychiatricmorbidity infocalepilepsy.BrJPsychiatry2008;192:4649.

41. Concha L, Beaulieu C, Collins DL, et al.White-matter diffusion abnormalities intemporal-lobeepilepsywithandwithoutmesialtemporalsclerosis.JNeurolNeurosurgPsychiatry2009;80:31219.

42. Nakayama T, Otsuki T, Kaneko Y, et al. Repeat magnetoencephalography andsurgeriestoeliminateatonicseizuresofnon-lesionalfrontallobeepilepsy.EpilepsyRes2009;84:2637.

43. Tanriverdi T,Al-JehaniH, Poulin N, et al. Functional results of electrical corticalstimulationofthelowersensorystrip.JClinNeurosci2009;16:118894.

44. VelascoAL,VelascoF,VelascoM,etal.Neuromodulationofepilepticfociinpatientswithnon-lesionalrefractorymotorepilepsy.IntJNeuralSyst2009;19:13947.

45. Aubert S, Wendling F, Regis J, et al. Local and remote epileptogenicity in focalcorticaldysplasiasandneurodevelopmentaltumours.Brain2009;132:307286.

46. PoonTL,CheungFC,LuiCH.Magnetoencephalographyand its role in evaluationforepilepsysurgery.HongKongMedJ2010;16:447.

47. LoweNM,EldridgeP,VarmaT, et al.Thedurationof temporal lobe epilepsy andseizureoutcomeafterepilepsysurgery.Seizure2010;19:2613.

48. Oliva M, Meckes-Ferber S, Roten A, et al. EEG dipole source localization ofinterictalspikesinnon-lesionalTLEwithandwithouthippocampalsclerosis.EpilepsyRes2010;92:18390.

49. Mankinen K, Long XY, Paakki JJ, et al. Alterations in regional homogeneity ofbaselinebrainactivityinpediatrictemporallobeepilepsy.BrainRes2011;1373:2219.

50. Box C, Seeck M, Vulliemoz S, et al. Chronic deep brain stimulation in mesialtemporallobeepilepsy.Seizure2011;20:48590.

51. KimYH,KimCH,Kim JS, et al. Resection frequencymap after awake resectivesurgeryfornon-lesionalneocorticalepilepsyinvolvingeloquentareas.ActaNeurochir(Wien)2011;153:173949.

52. Hindi-Ling H, Kipervasser S, Neufeld MY, et al. Epilepsy surgery in childrencomparedtoadults.PediatrNeurosurg2011;47:1805.

53. TyrandR,SeeckM,SpinelliL,etal.Effectsofamygdalahippocampalstimulationoninterictalepilepticdischarges.EpilepsyRes2012;99:8793.

54. WangZI,JonesSE,RisticAJ,etal.Voxel-basedmorphometricMRIpost-processinginMRI-negative focal cortical dysplasia followed by simultaneously recordedMEGandstereo-EEG.EpilepsyRes2012;100:18893.

55. MankinenK, JalovaaraP,Paakki JJ, et al.Connectivity disruptions in resting-statefunctionalbrainnetworks inchildrenwith temporal lobeepilepsy.EpilepsyRes2012;100:16878.

56. Schneider F, Alexopoulos AV, Wang Z, et al. Magnetic source imaging in non-lesional neocortical epilepsy: additional value and comparisonwith ICEEG.EpilepsyBehav2012;24:23440.

57. KovacS,NachevP,RodionovR,etal.Neckatoniawithafocalstimulation-inducedseizurearisingfromtheSMA:pathophysiologicalconsiderations.EpilepsyBehav2012;24:5036.

58. SunYP,ZhuHW,ZhangSW,etal.Seizure-freeaftersurgeryinapatientwithnon-lesionalstartleepilepsy:acasereport.EpilepsyBehav2012;25:7003.

59. Chaudhary UJ, Carmichael DW, Rodionov R, et al. Mapping preictal and ictalhaemodynamicnetworksusingvideo-electroencephalography and functional imaging.Brain2012;135:364563.

60. BienCG,RaabeAL,SchrammJ,etal.Trendsinpresurgicalevaluationandsurgicaltreatment of epilepsy at one centre from 19882009. J Neurol Neurosurg Psychiatry2013;84:5461.

61. MuellerSG,YoungK,HartigM,etal.Atwo-levelmultimodalityimagingBayesiannetworkapproach for classification of partial epilepsy: preliminary data.Neuroimage2013;71C:22432.

62. WyllieE,LdersH,MorrisHH,etal.The lateralizingsignificanceofversiveheadandeyemovementsduringepilepticseizures.Neurology1986;36:60611.

63. BleaselA,Kotagal P,Kankirawatana P, et al. Lateralizing value and semiology ofictallimbposturingandversionintemporallobeandextratemporalepilepsy.Epilepsia1997;38:16874.

64. ODwyerR,SilvaCunhaJP,VollmarC,etal.Lateralizingsignificanceofquantitativeanalysisofheadmovementsbeforesecondarygeneralizationofseizuresofpatientswithtemporallobeepilepsy.Epilepsia2007;48:52430.

65. KotagalP,LdersH,MorrisHH,etal.Dystonicposturingincomplexpartialseizuresoftemporallobeonset:anewlateralizingsign.Neurology1989;39:196201.

66. Kotagal P, BleaselA,Geller E, et al. Lateralizing value of asymmetric tonic limbposturing observed in secondarily generalized tonicclonic seizures. Epilepsia 2000;41:45762.

67. EbnerA,DinnerDS,NoachtarS,etal.Automatismswithpreservedresponsiveness(APR):anewlateralizingsigninpsychomotorseizures.Neurology1995;45:614.

68. NoachtarS,EbnerA,DinnerDS.DasAuftretenvonAutomatismenbeierhaltenemBewusstsein. Zur Frage der Bewusstseinsstrung bei komplex-fokalen Anfllen. InScheffnerD,editor.Epilepsie91.Reinbek:Einhorn-PresseVerlag.1992.pp.827.

69. Gabr M, Luders H, Dinner D, et al. Speech manifestations in lateralization oftemporallobeseizures.AnnNeurol1989;25:827.

70. KramerRE,LudersH,GoldstickLP,etal.Ictusemeticus:anelectroclinicalanalysis.Neurology1988;38:104852.

71. VossNF,DaviesKG,BoopFA,etal.Spittingautomatismincomplexpartialseizures:anondominanttemporallocalizingsign?Epilepsia1999;40:11416.

72. BaumgartnerC,GroppelG,LeutmezerF, et al. Ictal urinaryurge indicates seizureonsetinthenondominanttemporallobe.Neurology2000;55:43234.

73. LeutmzerF,SerlesW,LehrnerJ,etal.Postictalnosewiping:a lateralizingsignintemporallobecomplexpartialseizures.Neurology1998;51:11757.

74. WennbergR.Postictalcoughingandnoserubbingcoexistintemporallobeepilepsy.Neurology2001;56:1334.

75. JacksonJH.TheLumleianlecturesonconvulsiveseizures.BrMedJ1890;1:8217.

76. Werhahn KJ, Noachtar S, Arnold S, et al. Tonic seizures: their significance forlateralizationandfrequencyindifferentfocalepilepticsyndromes.Epilepsia2000;41:115361.

77. Wada JA. Unilateral blinking as a lateralizing sign of partial complex seizure oftemporal lobe origin. InWada JA, Penry JK, editors.Advances in Epileptology, XthEpilepsyInternationalSymposium.NewYork:RavenPress.1980.p.533.

78. HenkelA,Winkler PA,Noachtar S. Ipsilateral blinking: a rare lateralizing seizurephenomenonintemporallobeepilepsy.EpilepticDisord1999;1:1957.

79. BenbadisSR,KotagalP,KlemGH.Unilateralblinking:alateralizingsigninpartialseizures.Neurology1996;46:458.

80. Trinka E, Walser G, Unterberger I, et al. Asymmetric termination of secondarilygeneralizedtonicclonicseizuresintemporallobeepilepsy.Neurology2002;59:12546.

Chapter3 ClinicalandadvancedtechniquesforoptimizingMRIinrefractoryfocalepilepsy

NedaBernasconiandAndreaBernasconiMRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press. CambridgeUniversityPress2015.

IntroductionTemporal lobe epilepsy secondary to mesiotemporal sclerosis, and extratemporal lobeneocortical epilepsy secondary to dysplasias are the two most common drug-resistantepilepsiesamenabletosurgery.Inbothsyndromes,earlyidentificationoftheseanomaliesallows timely resective surgery, limits the long-term effects of recurrent seizures andmedication,andhasbeenshowntohavepositiveconsequencesoncognitiveoutcomeandbraindevelopment.

Magneticresonanceimaging(MRI)isapivotalcomponentintheinvestigationofanyform of epilepsy because of its unmatched ability in visualizing brain pathology. Inparticular,MRI has transformed the evaluation andmanagement of patientswith drug-resistantepilepsybyallowingreliabledetectionofthestructurallesionassociatedwiththeepileptogenic zone, thus leading to increased rates of successful resective surgery [1].Despitetechnical improvementsinMRIhardwareandsequences,however,best-practiceMRIisunremarkable,andthusunabletorevealthepotentialsurgicaltargetinabout50%ofpatients[2].Notably,however,inmanycenters,despitethehighefficiencyinprovidinggoodEEG interpretation,MRI is still fully outsourced to the radiology department andusually includes only basic imaging. It can be argued that epileptology must includeresponsibilityforgood-qualityandadvancedimagingoptimizedforthepatientsparticularproblem.

It is becoming increasingly clear that both hippocampal sclerosis and neocorticaldysplasiasconstituteaspectrumofhistopathology,clinical,andradiologicalpresentationsbroader than originally suspected [39]. Indeed, epilepsies initially considered MRI-negative are not necessarily nonlesional since in 30% to 50% of those patients whoundergosurgery,histologicalexaminationoftheresectedspecimensrevealsdysplasias[2,3], mild hippocampal sclerosis [1012], or subtle isolated neocortical or hippocampalgliosis[13,14].Importantly,retrospectiveassessmentofpreoperativeMRIscans,guidedbyquantitativestructuralimageanalysis,canfrequentlyidentifyalesion.Thesefindingsreinforce the importance of obtaining high-quality, if needed, multiple-image datasetsinterpretedbyMRIexperts toevaluateand treatpatientswithso-calledMRI-negativeepilepsy.

The definition of epilepsieswith negativeMRI is amoving target that changeswithadvances in diagnostic technology. While a consensus exists that the primaryhistopathological substrates are subtle hippocampal sclerosis and dysplasias, the MRIsignatureoftheseentitiesisnotyetfullydefined,mainlybecauseofthelackofaunifiedmethodologytoevaluatetheirunderlyingstructuralchanges.Thepurposeofthischapter

istogiveanoverviewofmethodsthathavesignificantlyimprovedthedetectionofsubtlebrain lesions in drug-resistant epilepsy. After presenting clinical protocols aimed atoptimizingvisualization,wewilldiscussadvancedprotocolsincludingquantitativeimageacquisitionsandprocessingmethods.

OptimizingconventionalstructuralMRIBroadly speaking, as the field strength increases, the signal-to-noise ratio (SNR) in animageincreasesapproximatelylinearly.Consequently,theadventofhigh-fieldmagnetsat3Tesla,combinedwiththeuseofphasedarraysinsteadofaconventionalquadraturecoil,hasresultedinacceleratedimageacquisition,andimprovedsignal-andcontrast-to-noiseratios for a more detailed and complete characterization of structural changes in thehippocampusor theneocortex than thoseobtainedat1.5Tesla.While thesesystemsarebecoming the new high-field standard, their clinical value strongly depends on theexpertiseof theindividualwhointerprets theimages.Importantly,evidencesuggests thehighest sensitivity for detecting subtle epileptogenic lesions is achieved when usingepilepsy protocols that are evaluated by an experienced reader with proper clinicalinformation[15,16].

Theidealsequenceshouldprovidehighspatialresolution,highcontrast,andcompletebraincoverage.Anincreaseinvoxelresolutionisanempiricalchoicebasedonacceptableimagequalityparametersandclinically reasonableacquisition time.However, there isacostintermsofSNRthatispaidforsuchincrease.Recentlycommercialized32-channelphased-arrayheadcoilsprovideanelegantsolutiontothischallengeleadingtosignificantsignal-to-noise increase and obviating the use of small single surface coils. Althoughsensitivityofthesemultiplearraysishigherattheneocortex,upto30%increasecanbeachievedinthemesialtemporallobescomparedtoan8-channelheadcoil,andupto60%with respect to a conventional quadrature coil. Consequently, a number of sequencesimplemented on 3 Tesla scanners currently offer superb anatomical images atsubmillimeterresolution(Figure3.1).

Figure3.1 High-resolutionsubmillimetricMRIat3Teslawith32-channelphased-arraycoils.Comparedtothe1mmisotropicT1-weightedimages(leftpanels),T1-andT2-weightedimagesatmicrometricresolution(middleandrightpanels)unveilanatomicaldetailsofthemesiotemporallobethatareessentialforreliablequantitativestudies,suchasvolumetry.

In our experience, high-resolution magnetization prepared rapid acquisitions withgradientecho(MPRAGE)sequencesprovideexcellentcontrastandsignificantlyreducedpartial voluming effects; they have been documented to be superior for digital imageprocessing.TheT1-weightedinversionrecovery(IR)alsooffersahighGM/WMcontrast,whichimprovesthevisualdistinctionbetweenglioticchangesandnormaltissue,andthevisualization of medullary veins and enlarged perivascular spaces. The T2-weightedimages are useful for detecting signal changes, usually hyperintensity, associated withgliosis.Ascurrent3Teslasystemsofferflexibilityinparallelimagingperformance,suchasgeneralizedautocalibratingpartiallyparallelacquisitions(GRAPPA),itisnowpossibleto acquire multispectral volumetric images (T1, IR, T2, and FLAIR) with isotropicresolution equal or below 1mm3 voxels in about 30 minutes, obviating the need fordedicated epilepsy protocols as the rater canmanipulate and reformat the image in anyplane without losing resolution. Nevertheless, when evaluating the temporal lobe,particularly mesiotemporal structures, in addition to the above-mentioned volumetricsequences,itisadvisabletoacquire2DT2-weightedimagesperpendiculartothelongaxisofthehippocampuswithanin-planeresolutionof0.4to0.5mm3andaslicethicknessof2 to 3 mm, which many systems allow to achieve in about 5 minutes. The practicalimplicationofhigh-fieldscannersbecomingincreasinglyavailableforclinicalimagingis

that patients with normal-appearing 1.5 Tesla MRI should be re-examined at 3 Tesla.Unfortunately, however, clinical radiologists may choose to evaluate lower-resolutionimages that have been reconstructed into thicker slabs instead of the original high-resolutionvolumetricacquisitionasameanstodecreasethenumberofsectionstoinspect.Forexample,T1orFLAIRimagesacquiredoriginallyat1mm3 isotropic resolutionareresampled at 3 mm, at times with the addition of interslice gaps. This procedure isobviouslydetrimental,asinpatientswithdrug-resistantepilepsythehighestresolutionisassociated with lesser partial volume effects, thus favoring the detection of subtleanomalies(Figure3.2).

Figure3.2 Imageresamplingvs.originalresolution.Axial3TeslaFLAIRimagesofapatientwithhistologicallyprovenfocalcorticaldysplasiaILAEtypeIIb.Theradiologicalevaluationwasinitiallyperformedonimagesreconstructedfromtheoriginal3Dhigh-resolution1mmacquisitionintothick3mmslabs(upperpanels),andhasbeenreportedasunremarkable.Therepeatedinspectionoftheoriginal1mmisotropicimages(lowerpanels),however,revealedasubtledysplasia,mainlycharacterizedbyblurringofthelesionalboundaries(seenonalltheslices,arrows)andaminutetransmantlesign(arrowhead).Slicenumbersforeachdatasetareshown.

While 7 Tesla systems appear quite promising for an even more detailedcharacterizationof epileptogenic lesions[17], it is currently unclear if theywill replaceoptimized 3 Tesla systems to become the new clinical standard for structural MRI.Challengingdisadvantagesofultra-highfieldimagingincludefargreaterradiofrequencysignal inhomogeneities, higher energy deposition in tissue, as quantified by specificabsorption rate (SAR), and more pronounced imaging artifacts from static fieldinhomogeneities at soft tissueair and soft tissuebone interfaces. To remainwithin the

SARlimits,thenumberofslicespermeasurementoftenhastobedecreased,especiallyinspin-echoT2-andFLAIR-weightedsequences.Thus,coverageoftheentirebrainathighin-plane resolutions cannot currently be achieved at 7 Tesla within a single spin-echosequence. With appropriate coils, pulse sequence modifications, and imaging protocoloptimizations,however, it islikelythat7Teslascannerswillbeusedwithoutlosingkeyinformationobtainedatlowerfieldstrengths.

ImageprocessingofstructuralMRIInmanypatients,routinevisualMRIinspectiondoesnotpermitdiagnosisofepileptogeniclesionswithasufficientdegreeofconfidenceor it issimplyunremarkable.Thisclinicaldifficultyhasmotivatedthedevelopmentofcomputer-aidedmethodsaimedatanalyzingbrainmorphology and signal intensities. These procedures provide distinct informationthroughquantitativeassessmentwithoutthecostofadditionalscanningtimeorexposureto ionizing radiation.Whereas the general tendency is to automate analyses generatingresultsthatarebothreplicableandraterindependent,itisadvisablethatthefundamentalimage preprocessing steps (e.g., intensity nonuniformities correction, registration, andtissuesegmentation)remainaccessibletotheuserforpurposesofqualitycontrol.

TemporallobeepilepsyHippocampal sclerosis is the histopathological term used to describe neuronal loss andastrogliosisinthehippocampusproper,particularlyCA1andCA4,andthedentategyrus[4,18].Althoughthesefeaturesarecommonlyexaminedatthelevelofthemidbodyofthehippocampus, there is significant variability in their extent and severity. In addition, astissue obtained from surgical resectionsmay be incomplete due to partial resections orfragmented as a result of subpial aspiration, a comprehensive evaluation of themesiotemporal lobe structures is limited; a neuropathological assessment of the entirehippocampus,theamygdala,andentorhinalcortexinthesamepatientsisthusrarelydone.Nevertheless, when available, surgical specimens and postmortem data have shownevidenceforextendedpathologyinvolvingalsotheentorhinalcortexandamygdala[19].Humanpathologicaldataonneocorticalabnormalitiesoutsidethetemporallobeshasalsobeen infrequent due to difficulties in obtaining postmortem specimens. In their seminalstudy,Margerison andCorsellis [20] described neuronal loss and gliosis in frontal andoccipital cortices in 22% of patients. In a single patient who underwent temporal lobesurgery, another autopsy report showed varying degrees of architectural abnormalitiesinvolvingvirtuallyalllobes[21].

QuantitativeanalysisofthemesiotemporallobeFor the last two decades, MRI volumetry has been the most commonly employedquantitativetechniquetoassessmesiotemporallobepathologyasitismoresensitivethanvisual evaluation. In TLE, hippocampal atrophy is considered a surrogate marker ofhippocampalsclerosis;thedegreeofatrophycorrelateswiththeseverityofneuronallossinthecornuammonis,particularlyCA1[22].Theutilityofhippocampalvolumetrystemsfrom its ability to lateralize the seizure focus in about 70% of cases at the individual

patient level [23]. Yet, in clinical settings, manual volumetry of mesiotemporal lobestructures,oftenrestrictedtothehippocampus,islargelyunderutilizedasitisconsideredprohibitively time consuming and requires an anatomy expert to perform the task.Automatic hippocampal segmentation studies in TLE have been sparse andmany haveprovidedupuntil now ratherunsatisfactory results [2426].Wedevelopeda robust andreliablealgorithmthatintegratesdeformableparametricsurfacesandmultipletemplatesina unified framework [27]. Our method showed excellent overlap with manual labels,achievingsubmillimetricaccuracyinpatients,regardlessofthedegreeofatrophy,thatwasvirtuallyidenticaltothatobtainedinhealthycontrols.Importantly,theproducedlabelsofthevariousstructuresmaybeusedformoreadvancedprocessing,asdetailedbelow.

Sincevolumetryprovides a global estimate of atrophy, its sensitivity to detect subtlediffuseor focalanomalies is limited.Thismayexplainwhy in3040%ofpatientswithunambiguous electroclinical features of drug-resistant TLE, hippocampal volumetry isunremarkable even though histopathology reveals subtle sclerosis. Indeed, surgicalspecimens in MRI-negative TLE have clearly demonstrated 20% cell loss in thehippocampalCA1subfield[4,12]orisolatedgliosis.Neuronal lossmaypredominate intheentorhinalcortexortheamygdala[19].Inlightoftheseobservations,entorhinalcortexvolumetry provides a valuable alternative, lateralizing the focus in 25% of cases withnormal hippocampal volume [11]. Shape analysis has the potential to further refine theMRI correlates of hippocampal pathology [28].Wehave developed andvalidated a 3Dsurface-based method relying on spherical harmonic shape descriptors that localizessubmillimetric variations of volume between a given structure and a template whileguaranteeing anatomical correspondence across subjects [29], a requisite for reliablestatistics. In our experience, this technique is effective in detecting subtle atrophy inpatientswithnormalwholehippocampalvolume(Figure3.3).

Figure3.3 Hippocampalshapeanalysis.Coronal3TeslaT1-andT2-weightedMRIandhippocampalsurfacemapsofatrophynormalizedwithrespecttohealthycontrols(z-score,shownbythecolorbar)fortwopatientswithrightTLE.Inthefirstpatient(A),therighthippocampusisclearlyatrophicandshowsT1hypo-andT2hyperintensity.Surface-basedanalysisconfirmsandlocalizesareasofatrophyalongtherostrocaudalextentoftherighthippocampus.Incase(B),theinspectionofconventionalMRIwasreportedasnormal.Conversely,thesurface-basedmapsrevealsubtleatrophy,attheleveloftherighthippocampalheadandthebody.Histologyconfirmedthepresenceofsubtlehippocampalsclerosis.DottedlinesonthesurfacemapsindicatethelevelofthecoronalMRIcuts.Rightisrightonthepanels.

ComparedtothevisualanalysisofT2-weightedMRI,T2-relaxometry,whichprovidesa quantitative estimate of T2-weighted signal, has been shown to yield an increasedsensitivityindetectingmesiotemporalgliosis[3032].WedemonstratedthathippocampalT2-relaxometry correctly lateralizes the seizure focus in 82% of patients with normalhippocampalvolume[31].WealsoshowedthatprolongationofwhitematterT2signalinthetemporalstemoccursinabout70%ofthesepatients;inhalfofthemtheincreasewasbilateral and symmetric. However, white matter T2-relaxometry provided a correctlateralization of the seizure focus in a third of patients, demonstrating that suchmeasurementmayprovidecomplementaryinformation[32].

QuantitativeanalysisoftheneocortexSince the early 2000s, the technique of voxel-based morphometry (VBM) has beenextensively used to assess structural abnormalities in TLE as it permits an automatedwhole-brain structural analysis without prior anatomical segmentation. However, fordetecting focalpathologywithin themesiotemporal lobe,voxel-basedmeasurementsareinsufficientlysensitive,especiallywhenpathomorphologicalchangesarerelativelysubtle,as is the case in hippocampal sclerosis [33]. On the other hand, VBM [34] andmeasurementofcortical thickness [35,36] offer a sensitivemeans for assessingwhole-brainstructuralintegrity.Indrug-resistantTLE,theyhaveshownwidespreadatrophyandevidencefordiseaseprogression,particularlyinthefrontocentralareas[37].Notably,wedemonstrated that patients with obvious hippocampal atrophy and those with normalhippocampalvolumehavesimilarpatternsofstaticanddynamicpathologyinneocorticalregions remote from the seizure focus [35]. Equivalent neocortical dynamics occurringdespitedifferentdegreesofmesiotemporallobepathologysupportstheconceptthatthesetwoTLE entities are part of the same spectrum and that longitudinal changes aremostlikely reflective of secondary effects of seizures. In light of functional data showingprogressive cognitive decline and extension of the epileptogenic network in relation torecurrent epileptic discharges, these results provide compelling evidence that drug-resistantTLE,regardlessofthedegreeofhippocampalatrophy,isaprogressivedisorderthatwarrantsearlysurgery.

Themajorityofstudiesdedicatedtotheassessmentoftheneocortexhavebeengroupbased. Preliminary data suggest, however, that machine-learning techniques applied towhole-brain automated segmentationmayaid lateralizing thepresumed seizure focus insingle subjectswithvisuallynormalMRI [38].Nevertheless,as features selectedby theclassifier may challenge biologically plausible interpretations, the clinical use of thesetechniqueswarrantscross-validationthroughindependentstudies.

FocalcorticaldysplasiaNeocorticalepilepsyrelatedtofocalcorticaldysplasia(FCD)accountsformorethanhalfof pediatric and a quarter of adult patients [3]. Main FCD features on structural MRIincludeabnormallythickcorticalgraymatter(5092%ofcases)andblurringofthegraywhitematterinterface(6080%ofcases)[3,39].AnalysisofT2-weightedimagesrevealsgraymatterhyperintensityin4692%oflesionsandsensitivityofFLAIRimagesisevenhigher (71100%). The typical transmantle sign, a footprint of disrupted cellmigrationalongradialglialprocesses,presentsasafunnel-shapedhyperintensityextendingfromtheventricletothelesionandisseeninthemajorityofFCDtypeIIcases[7,39,40].

The invivovisibilityofdysplastic changesonMRIgenerallyparallels thedegreeofhistopathological derangement [3]. Even in patientswith FCD type II, however, as theradiological spectrum on MRI encompasses variable degrees and patterns of gray andwhite matter changes, visual identification can be challenging, particularly wheninspecting the convoluted neocortex in two-dimensional images. Indeed, recent surgicalseriesindicatethatupto33%FCDtypeIIand87%ofFCDtypeI[7,8,39]presentwithunremarkable routine MRI, underlining the limited power of conventional imaging toresolvesubtlecorticaldysplasia.

Gyral anomalies may be the only visible MRI sign of cortical dysgenesis. Usingautomated sulcogyral morphometry, we demonstrated that 85% of small FCD lesions,primarilythoseoverlookedduringconventionalradiologicalinspection,arelocatedatthebottom of an abnormally deep sulcus [41]. Importantly, such evidence can guide thesearch formigrational anomalies inpatients inwhom large-scaleMRI features areonlymildlyabnormalorabsent.

Several groups have appliedVBM to detect structural abnormalities related toMRI-visibleFCDinsinglepatients[16].Thisfullyautomatedimageprocessingmethod,whichidentifies differences in tissue density at a voxel level, detects increases in graymatterconcentration colocalizing with the lesion in 6386% of cases. Histopathologicalconfirmation of lesions that eluded visual inspection (despite their relatively large size)[42] suggests that VBM may be applied to investigate patients with MRI-negativeepilepsy. Importantly, however, a threshold of 2SDs above the mean gray matterconcentration inhealthycontrolsdoesnotguaranteespecificityof findingssince,at thisthreshold,falsepositivesmayoccurincontrolsubjects.Voxel-basedcomparisonhasalsobeen used to analyze intensities derived from quantitative MRI contrasts such as T2-relaxometry, double inversion recovery, and magnetization transfer imaging. Theseapproacheshaveshownhighsensitivity(87100%)indetectingobviousmalformationsofcortical development [4345]. Nevertheless, these techniques may identify areasconcordantwithclinicalandEEGfindingsinlessthanathirdofMRI-negativecasesandhavelowspecificity[44,46].

TherelativelyunspecificnatureofVBMwithrespecttopathologicalcharacteristicsofFCD has motivated the search for computer-based models of morphological imagingfeaturesdistinctiveofdysplasias.Usingmodelsofcorticalthickness,blurring,andtissueintensityderivedfrom3T1-weightedimages[47]andcombinedintoasinglecompositemap,thesensitivityofvisualidentificationofhistologicallyprovenFCDmaybeincreasedup to 40% relative to conventional MRI, while maintaining high specificity [48].Furthermore, blending thesemodelswith the quantification of high-order image texturefeatures that cannot be discriminated by the human eye, we were able to detectautomaticallyabout80%ofdysplasticanomalies[49,50].Onelimitationofvoxel-basedapproaches is that they do not fully take into account the complex topology and aretherefore prone to volume averaging of nonadjacent cortical regions across sulci,potentiallyincreasingthefalse-positiverates.Inourexperience,asurface-basedapproachpreservingtopographicanatomyiseffectiveindetectingsmalllesions(Figure3.4).

Figure3.4 Surface-basedcomputationalmodelsoffocalcorticaldysplasia.Inthispatientwithfrontallobeepilepsy,high-resolution3TeslaMRIwasreportedasnormal,likelybecauseofthesubtlenatureofthedysplasia,asdemonstratedbythecoronalT1-weightedMRIsection(rightlowercorner).TheupperpanelsdisplaytheT1-weightedderivedcomputationalmodelsnormalizedwithrespecttocontrols(z-score).Thecorticalthicknessmapisunremarkable.Conversely,thegraymatterintensitymapandthegradientmap(modelinggraywhitematterblurring)showsignificantanomalies.Thecompositemapidentifiesthelesionalareaastheonlyanomalycomparedtocontrols.HistopathologyofthesurgicalspecimenconfirmedthepresenceoffocalcorticaldysplasiaILAEtypeIIb.

We have adopted this framework also for fully automated lesion detection based onneural networks that successfully identified 89% of small FCD lesions overlooked byexperts[41].

Overall, themost relevant clinical impact of post-processing is that cases consideredMRI negative at first have been increasingly recognized as secondary to FCD type II,particularlyFCDtypeIIa.

DiffusiontensorimagingDiffusiontensorimaging(DTI)makesinferencesabouttheintegrityofaxonandmyelinsheathsthroughtheanalysisofpassivewaterdiffusionrelativetowhitemattertracts[51].In TLE, fractional anisotropy (an index of deviation ofwater diffusion from a randomspherical displacement) is consistently decreased in temporolimbic tracts [5254].

Nevertheless, the ability of DTI to lateralize the focus has been disappointing [55].Notably, the conventional whole-tract approach yielding a single value per diffusionparameterpertractreducessensitivityforthedetectionofsubtlefocalchanges.Relativetothewidespread pattern of anisotropy changes,mean diffusivity anomalies (amarker ofbulkdiffusion)followamorerestricteddistribution[52].Toovercomethislimitation,wemeasured thespatialdistributionofdiffusion indicesalongtractscarrying temporal lobeconnections and showed that the effect size of diffusivity alterations decreases as afunctionof anatomical distance to the temporal lobe, suggesting colocalizationwith thefocus[56].Importantly,oursegmentalanalysisallowedustocorrectlylateralize100%ofMRI-negativeTLEpatients(i.e.,withnormalhippocampalvolumes).Ontheotherhand,whole-tractanalysisidentifiedtheepileptogenichemisphereinonly85%ofcases.

InpatientswithMRI-visibleFCD,regionsofinterest[57]andwhole-brainvoxel-basedanalyses[58]haveshownabnormalitiesindiffusionindicesinthesubcorticalwhitematteradjacent to the malformation. Nevertheless, in some patients with no visible MRIanomaly,focalchangesmaycolocalizewiththeEEGfocus[5860](Figure3.5).

Figure3.5 Surface-baseddiffusiontensorimaginginfocalcorticaldysplasia.Theupperpanelsshowtheoutline(inyellow)ofthegraymatterportionofthelesionontheapparentdiffusioncoefficient(ADC)map,andontheT1-andT2-weightedMRI.LowerpanelsshowthemeanADCmapoftheimmediatesubcorticalwhitematterintenhealthycontrols.Inthepatient,boththemeanandz-scoreADCmapsshowabnormallyincreasedvaluesinthewhitematterbelowtheFCDlesion.Thesechangesindicatemicrostructuralabnormalitiesextendingbeyondthevisiblelesion.

Yet, abnormalities often extendbeyond the epileptogenic region and thevisibleFCD

[61],highlightingtheneedtobalancesensitivityandspecificity.Moreover,theunderlyingnatureofdiffusionabnormalitiesneedstobeclarified,ascorrelativestudieshavebeensofarlimitedtoasinglepatient[62].

MagneticresonancespectroscopyMagnetic resonance spectroscopy (MRS) measures in vivo the concentration ofmetabolites,includingN-acetylaspartate(NAA),choline(Ch)andcreatine(Cr).Spatiallyselective excitation and refocusing pulses allow acquiring a single volume (voxel),typically 1 to 8 cc. Alternatively, spectroscopic imaging allows collecting data frommultiple locations simultaneously. Numerous factors contribute to the advantages ofperformingspectroscopyat3Tesla.Primarily,thestrongerchemicalshiftathigherfieldsincreases the spread of individual peaks, resulting in improved spectral resolution andidentification of metabolites that were obscured at 1.5 Tesla, such as GABA andglutamate.Also,theimprovedSNRincreasesthesignalderivedfromeachmetabolite,sothattheirpeaksareeasiertodifferentiatefrombackgroundnoise.

Decreases inNAA,a compound specific toneurons,may lateralize the seizure focus[23] and predict surgical outcome [63] in drug-resistant TLE, thus yielding potentialclinical value. Seizure focus lateralization in patients with no visible hippocampalsclerosis, however, has been disappointing [64]. Moreover, patients with neocorticalepilepsy often have poorly defined epileptogenic regions, posing significant additionaldemandswithregardtotheselectionofthebrainregiontoexplore,andthetypeofdataacquisition(singlevoxelversuschemicalspectroscopicimaging).Nevertheless,infrontallobe epilepsy, MRS has provided some encouraging results [65, 66]. Using protonspectroscopy,itisalsopossibletomeasurebothinvivoGABAandglutamate,theprimaryexcitatoryneurotransmitterinhumanbrain.Increasesinglutamate,havebeenobservedinassociationwith the ipsilateralhippocampus inMRI-negativeTLE[67,68].Due to lowsignal to noise, however, attempts tomeasureGABAwithin the putative seizure focushaveproducedmixedresults[69,70].

Overall, spectroscopy in MRI-negative epilepsies should be regarded as acomplimentaryinvestigation.

ConclusionBy revealing subtle lesions that previously eluded visual inspection, quantitative imageanalysis, particularly image processing of structural MRI, has clearly demonstratedincreased sensitivity compared to conventional techniques. Importantly, as advancedimage post-processing can be performed on clinical MRI yielding 3D millimetric orsubmillimetricmulticontrast images, they offer a substantial costbenefit.Based on ourexperienceandmountingevidencefromtheliterature,weproposethetermMRI-negativebeusedinpatientsinwhomboththevisualinspectionandquantitativeimageprocessinganalyses at 3 Tesla interpreted by an epileptologist with expertise in neuroimaging areunremarkable.

Importantly,todate,theMRIsignatureofFCDtypeIremainimprecise.Nevertheless,

aslesionsinpatientswithMRIconsiderednondiagnosticmaypossiblydifferonlyslightlyfrom normal tissue and present unanticipated traits, future methods applied to thesecohorts should entail the design of statistical models of morphology and signal in amultivariate framework rather than be based on the current unimodal approaches. Suchefforts, ideally refined through correlative histopathology, will help clinicians devisingbetter criteria toperform timely interventions that achieve seizure control, turning thesechallengesintoopportunitiesforbetterpatientcare.

References1. Tellez-ZentenoJF,DharR,Hernandez-RonquilloL,WiebeS.Long-termoutcomesinepilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects.Brain.2007;130:33445.

2. McGonigalA,BartolomeiF,RegisJ,GuyeM,GavaretM,Trebuchon-DaFonsecaA,et al. Stereoelectroencephalography in presurgical assessment of MRI-negativeepilepsy.Brain.2007;130:316983.

3. LernerJT,SalamonN,HauptmanJS,VelascoTR,HembM,WuJY,etal.Assessmentand surgical outcomes formild type I and severe type II cortical dysplasia: a criticalreviewandtheUCLAexperience.Epilepsia.2009;50:131035.

4. de Lanerolle NC,