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Imaging Spectrum of Cortical Dysplasia in Children James L. Leach M.D., Hansel Greiner M.D., Lili Miles M.D., Francesco Mangano D.O.

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S0037-198X(13)00072-2 http://dx.doi.org/10.1053/j.ro.2013.10.007 YSROE50450

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Seminar in Roentgenology

Cite this article as: James L. Leach M.D., Hansel Greiner M.D., Lili Miles M.D., Francesco Mangano D.O., Imaging Spectrum of Cortical Dysplasia in Children, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2013.10.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ImagingSpectrumofCorticalDysplasiainChildren  JamesL.Leach,M.D.1,HanselGreiner,M.D.2,LiliMiles,M.D.3,FrancescoMangano,D.O.4  Departmentsof1Radiology,2Neurology,3Pathology,and4Neurosurgery CincinnatiChildren’sHospitalMedicalCenter 3333BurnetAvenue Cincinnati,Ohio,45229  Correspondingauthor: JamesL.Leach,M.D. CincinnatiChildren’sHospitalMedicalCenter 3333BurnetAvenue ML5031 Cincinnati,OH45229 Phone:(513)6364251 Page:(513)3032012 Fax:(513)6361388  

Introduction 

Surgicaltherapyforpediatricepilepsyisanincreasinglyrecognizedoptionfortreatment

ofchildrenwithintractableseizures.(1,2)Itisestimatedthatupto30%ofpatientsbecome resistanttooptimizedmedicaltherapyandarepotentialsurgicalcandidates.(2)Criteriafor thisdistinctionhavevaried,butmostagreethatfailureof2appropriateantiepilepticdrugsto adequatelycontrolseizures,withmorethanoneseizure/monthoveran18month–2year periodconstituteintractability.(2)Additionalimportantclinicalfeaturesindicatingthatthe patientmaybeasurgicalcandidateinclude:stereotyped,lateralizingseizureswithfocalityof semiology,alocalized“epileptogeniczone”byscalpelectroencephalography(EEG), Magnetoencephalography(MEG),orsurfaceEEG,andalocalizedanatomictargetonMRI(2). Infact,thepresenceofanimagingabnormalityisoneofthekeyfindingsthatpredictresistance tomedicaltherapyandmaybeacriticalfindingindeterminingsuitabilityforsurgicaltherapy. (3)Interestinglyitisthoughtbymanypediatricepileptologiststhatyoungerchildrenmayin factbebettercandidatesforepilepsysurgerythanadultsbecauseoftheirincreased neuroplasticityandthedetrimentaleffectofrepeatedseizuresonnormalneurologic development.(4) 

Corticaldysplasiaisthemostcommonneuropathologynotedaftersurgicalresectionfor

intractableepilepsyinchildren,andrecentclinical/pathologicclassificationsystemshavehad asignificantimpactonthetreatmentandunderstandingofthisdisorder.(5,6)Someformsof focalcorticaldysplasia(FCD)(suchasTypeIIb)havetypicalimagingmanifestations,whileother typessuchasisolatedtypeIcorticaldysplasiahavevariable,andoftennonlocalizingimaging

features.Asimagingfindingsindicatingcorticaldysplasiamaysignificantlyimpactselectionfor potentialsurgery,radiologistsinvolvedwiththeworkupofthesepatientsmustbefamiliarwith theimagingspectrumofFCD,especiallyinchildren.Inthisarticlewewillreviewthecurrent pathologicclassificationandimagingfindingsincorticaldysplasiawithanemphasisonthe pediatricpopulation. PathologicClassification 

Focalcorticaldysplasia(FCD)wasfirstdescribedandpopularizedasadistinct

clincopathologicentitybyTayloretalin1971.(7)Theydescribedabnormalcellmorphology andalteredcorticallaminationinbrainspecimensfromsurgeryforintractableepilepsy.This “Taylortype”dysplasiawasfoundsubsequentlytohavetypicalimagingfeaturesonMRI, greatlyfacilitatingpreoperativeimagingdiagnosis.(8)Otherlessseveredysplasiasand‘mild’ malformationsofcorticaldevelopmentwerealsoidentifiedhistopathologicallyinthese patientswithlessclearimagingcorrelates.FCDisthoughtbepresentinupto10%ofall patientswithepilepsy,andinupto50%ofallchildrenundergoingsurgeryforintractable epilepsy(upto80%undertheageofthree).(9)Itisimportanttounderstandthattheterm “Focalcorticaldysplasia”wasinitiallydescribedandistypicallyusedinthecontextofbrain resectionforintractableepilepsy.Extensive,oftenbilateral,abnormalitiesofcorticalformation suchaslissencephaly,extensivepachygyria,bandheterotopia,symmetricpolymicrogyria,and tuberoussclerosisaretypicallynotincludedinthisspectrumalthoughtheymaybesimilarata histologiclevel.



Histologically,FCDisdefinedascorticaldisorganizationandabnormallaminar

architecture,withvariableotherfindingsincluding:heterotopicneuronsinwhitematterand molecularlayer,immaturelarge‘cytomegalic’neurons,dysmorphic‘bizarre’neurons,and ballooncells.Findingsofpolymicrogyria,associatednodularheterotopia,andgliosis(cortical andwhitematter)canalsobeidentified.(10)Palminietal(11)describedaschemein2004 thatbecamewidelyusedinthepathologicclassificationofFCD,allowingimproved understandingofthedifferentclinicalandimagingappearancesofthesepatients.Common amongstallsubtypeswasabnormalcorticalorganizationandabnormallaminararchitecture. Subclassificationincluded:Abnormalcorticalorganizationandlaminationinisolation(TypeIa); presenceoflargeorimmatureneurons(TypeIb);dysmorphicneurons(TypeIIa);and dysmorphicneuronsandballooncells(TypeIIb).Socalledmildmalformationsofcortical development(mMCD)withonlyectopicneuronsinlayerIorwhitematterhavelessspecific pathologicandimagingfindings.PreviousclassificationshavetypicallytermedTypeIas‘mild’ or‘architectural’or‘cytoarchitectural’dysplasiaandTypeII“moderate”or“severe,Taylor type”dysplasia.Thisclassificationschemewasrecentlyupdatedbyataskforceformedbythe InternationalLeagueAgainstEpilepsy(ILAE)in2011(5),drivenbyimprovementsin understandinghistologiclaminationpatterns,andtherealizationthatFCDmayaccompany encephaloclastic,vascular,andneoplasticentities. 

Thecurrent2011ILAEclassification(Table1)usesathreetieredsystemtodescribeFCD.

TypeIFCDrepresentsisolatedalterationsincorticalorganizationandlaminationeitherradially (Type1a),tangentially(Type1b),orboth(Type1c).TypeIIFCDrepresentsisolatedalterations incorticalorganizationandlaminationwith(asinthepriorsystem)dysmorphicneurons(Type

IIa);ordysmorphicneuronsandballooncells(TypeIIb).TypeIIIFCDaredefinedintheILAE classificationschemeasFCDassociatedwithaprinciple(nonFCD)lesion:Inthetemporallobe withhippocampalsclerosis(TypeIIIa),adjacenttoaglialorglioneuronaltumor(FCDIIIb), adjacenttoavascularmalformation(TypeIIIc),oradjacenttoanearlyacquired encephaloclasticlesion(e.g.traumatic,ischemic,encephalitisrelated).IncreatingatypeIII classification,theILAEtaskforcetakesintoaccountinsightsfromstudiesofneurodevelopment whichdescribesustainedneuroplasticityandneurogenesisinthepostnatalbrainwhichmaybe compromisedbyvariousacquiredpathologicconditionsincludingrepeatedseizures.(1214) AlthoughcomponentsoftheILAEclassificationremaincontroversialandtheclinicalimportance ofsomesubclassifications(i.e.TypeI)areuncertain,atthistimeitformsthestandard pathologicnomenclaturedescribingthisentity,andshouldbeunderstoodbyradiologists evaluatingthesepatients. 

ThepathogenesisofFCDisincompletelyunderstood,butisthoughttoarisefrom

abnormalmaturation,migration,andapoptosisduringontogenesis.(15)Accordingtoevolving classificationsystemsofmalformationsofcorticaldevelopment(16,17),TypeIIFCDseemsto evolvefromadisturbanceofcellularproliferation,likelydevelopingduringthefirsttrimesterof pregnancy.FCDtypeImayresultfromlaterdisturbancesincorticalorganizationduringthe thirdtrimesterofpregnancy(orevenpostnatally).(13,14) ImagingEvaluation 

Magneticresonanceimaging(MRI)ofthebrainprovidesthecriticalinitialanatomic

evaluationinchildrenwithepilepsy.Inmultiplestudiesofbothchildrenandadultswith

intractableepilepsyandFCD,theidentificationandresectionofadefinedimagingabnormality (lesion)isoneofthebestpredictorsofseizurefreedomaftersurgery.(15,17)Applicationofa sensitivededicatedseizureprotocolMRIexaminationisthereforecriticalinevaluatingpatients withintractableseizures(1820)(Table2.).Imagingathigherfieldstrength(3T)with multichannelheadcoilsincreasessensitivityforsubtleabnormalitiesandshouldbeperformed ifavailable.(18)Theutilizationof3Disotropicsequences(T1weightedandT2weighted FLAIR),allowroutineapplicationofmultiplanarreformationswhichmaybeimportantfor identifyingsubtlecorticalabnormalities,andsubtleabnormalitiesinvolvingthehippocampus. (21,22)PositronEmissionTomography(PET)isacriticaladjunctinevaluatingthesesubjects, oftendemonstratinglateralizingandlocalizinghypometabolism,eveninsubjectswithnormal MRImaging.(23)EvaluationofavailablePETimagingwhileinterpretingMRIimagingstudiesas wellasMRIPETfusiontechniquescanincreasesensitivityforsubtleabnormalities.(24) StatisticalparametricmappingofPETdata(comparedwithanormalpopulation)hasbeen describedtoaidinvisualevaluationandmorepreciselylocalizeareasofhypometabolism.(25) 

Communicationwithclinicalepileptologists,andunderstandingthepresumptive

lateralization(andlocalizationifknown)ofthepatient’sintractableseizuresbasedonseizure semiologyandscalpelectroencephalography(EEG)resultsmayalsoincreasesensitivity. Multimodalityevaluationisimportant,especiallyforpatientswithnonspecificornormalMRIs. (26)Atourinstitution,routineapplicationofSubtractionIctalSPECTCOregisterdtoMRI (SISCOM)(27),Magnetoencephalography(MEG)(28),andSPManalysisofPETdata(25)isused inmostpatients.Discussionofpotentialsurgicalcasesinamultidisciplinaryformatallowsfor

reevaluationofMRimagingstudieswithallclinical,EEG,MEG,andnoninvasivefunctional dataandisperformedinmostcenterswithexperienceinepilepsysurgery. MRImagingfindings 

AvarietyofMRIabnormalitieshavebeendescribedinpatientswithintractableseizures

andcorticaldysplasiaidentifiedatsubsequenthistopathology.TheprevalenceofMRI abnormalities,however,isveryvariableintheliteratureandisheavilydependentuponsurgical selection,MRItechnique,expertiseofimagingevaluation,rangeofhistopathology,andcohort demographics.MRImaybecompletelynormalin20–46%ofcases(asanoverallgroup).(29) KeyimagingfindingsthatmayindicatethepresenceofFCDonMRIinclude:abnormalgyral pattern,increasedcorticalthickness,blurringofgraymatter/whitematterjunction,increased corticalsignal,increasedwhitemattersignal,focal/lobarvolumeloss,‘transmantle’signal changes,andlocalizedsignalalongthegraymatterwhitematterjunctionatthedepthofa sulcuslinearlyextendingintotheadjacentwhitematter(bottomofsulcusphenotype).(16, 19,29,30,31,32)SomeofthesefindingsaredemonstratedinFigure1andwillbediscussedin moredetailinthefollowingsections.Althoughsomeimagingfindings(forexample transmantlesignalchangesandbottomofsulcusphenotypeintypeIIbFCD)appeartobe highlypredictiveofpathology,manyofthesefindings,particularlyifinisolation,maynot correlatewellwithpathologicsubtypes(20).Atourinstitutionwehavedefineda“lesional MRI”asoneinwhichthecombinationofMRIfindingssuggestsFCDorotherfocallesionand candirectsurgicaltherapy.(26,33)Inourcurrentinstitutionalcohort(53consecutivesurgically treatedpediatricpatientswithFCDathistologyandhighqualitypreoperativeMRimaging),we

foundlesionalMRIabnormalitiesin58%ofpatients.(34)Inarecentreviewofpreoperative MRIinpediatricFCDatourinstitution,overlookedimagingfindingswerenotedin15/53cases (28%)aftersecondreviewinthecontextofapreoperativemultidisciplinaryconference.18 findingswereoverlookedinthesecases,predominantlycorticalandsubcorticalincreasedsignal intheanteriortemporallobe(usuallyinpatientswithtypeIIIaFCD).(34) 

TheremaybesignificantdifferencesinappearanceofFCDintheimmatureand

incompletelymyelinatedbrainthatmayimpactidentification.Someimagingfindingsmaybe actuallymorevisibleduringearlylife(neonateandinfancy),becomelessapparentduringmajor myelination(uptotwoyears),andbecomemoremanifestasthechildagesandmyelination completes.(9) 

AssessmentofetiologyofthemajorMRIfindings(corticalthickening,signalchanges,

GM/WMblurring)inchildrenwithcorticaldysplasiabycomparingMRIresultswithdetailed histopathologyislimited.Potentialcausesfortheseabnormalitiescouldinclude:Neruonal heterotopiaandcytoplasmicchanges(increasedneurofilaments,neuronalloss),dysmyelination ordemyelination,andgliosis.(10,33,35,36,37,38)Furthercorrelativeimagingand histopathologicstudiesinthiscohortareneeded. SpecificPathologicSubtypes TypeIFCD(isolated) 

TypeIFCD,asdescribedabove,indicatesisolatedalterationsinradialandortangential

laminationandorganizationofthecortex,withoutanotherassociatedlesion.The

histopathologicdistinctionbetweenlaminationtypesisaidedbyadherencetocarefulspecimen orientationandapplicationofimmunohistochemicaltechniques(e.g.NeuNstaining)(5)but stillneedsevaluationtodetermineitswidespreadclinicalfeasibility.(39).Inmanyprior imagingbasedstudiesnonisolatedFCDtypeIassociatedwithotherlesions(nowknownasFCD typeIII)wereincludedwithisolatedtypeIFCD,limitingconclusionsregardingoutcomesand imagingfindings. 

Clinically,adultpatientswithtypeIFCDmaybeolderatseizureonsetwithlonger

durationofseizurespriortosurgeryalthoughthishasnotbeenconsistentlyshowninchildren (29,33,40,41).Theyhavebeentypicallyfoundtohavemorecommonmultilobarinvolvement, greaternumberofseizuretypes(33)andhaveworsesurgicaloutcomescomparedwithTypeII CDpatients.(33,42,40,41). 

OnMRimaging,onlybetween22and64%ofpatientswithisolatedTypeIFCDmayhave

identifiableimagingabnormalities.(29,33,34,40,41)Whenimagingfindingshavebeen identified,thesearetypicallysubtle,anddifficulttodistinguishfromothernonspecific pathology.Findingsincludelocalizedvolumeloss,subtlegraymatterwhitematterblurring, subtleilldefinedincreasedwhitemattersignal,orsubtlesulcalasymmetries.(33,40,41,43) (Figures2and3).ApplicationofPETMRIfusiontechniquesandmultiplanarreformationsmay help,butoftennolocalizingMRIabnormalitiescanbedetected.Inourcohortof43pediatric subjectswithisolatedFCD,only12%ofTypeIFCDhadlesionalMRIexams(38).Additional techniquessuchasMEG,SISCOMandelectrocorticographyfromsubduralgridEEGelectrodes becomemuchmoreimportantinthissubgrouptoidentifytheepileptogeniczone.(26,44)More

imagingstudiesinvestigatingisolatedTypeIFCDarenecessarytobetterdefinethispatient group.ClinicalandimagingdifferencesbetweensubtypesoftypeIFCDareunknownatthis time. TypeIIFCD 

Asdescribedabove,TypeIIFCDisdefinedpathologicallyasdisorderedcortical

laminationwithadditionalspecificcytologicabnormalities.Corticaldyslaminationisusually morepronouncedthanwithTypeIFCDwithnodiscerniblecorticallayeringexceptforlayerI, commonheterotopicneurons,andblurredwhitematter–graymatterdifferentiation.Both typesIIaandIIbhaveassociated‘bizzare’dysmorphicneurons(enlargedcellbodyandnucleus, abnormalneuronalorientations,accumulationofneurofilaments).Thehistologichallmarkof TypeIIbFCDisthepresenceof“ballooncells”whicharedistinctfromdysmorphicneurons, haveanenlargedcellbodywitheosinophiliccytoplasm,lackingNisslsubstance.Coexpression ofneurofilamentandglialfibrillaryacidicprotein(GFAP)withinballooncellshavebeen describedsuggestingbothglialandneuronalcelllineage(45).Gliosisisoftenseen,occurring morecommonlythanwithtypeIFCD.(33)Oftenhypomyelinationisseenintheadjacentwhite matter.(10)Similarhistomorpohologyhasbeendescribedinthecorticaltubersintuberous sclerosiscomplex(TSC),whichhaveclearimagingsimilaritiestoisolatedTypeIIbFCD.(46) 

PatientswithtypeIIFCDaretypicallyyoungerattimeofsurgerywithshorterduration

ofseizurescomparedwithTypeIFCD.Theytypicallyhavefewerseizuretypes,havegreater seizureburden,aremorecommonlyunilobar,andaremorecommonlyextratemporal comparedwithtypeIFCD(29,33),althoughthereissomeinconsistencyintheliterature(41),

particularlywiththereclassificationofisolatedTypeIFCD.Inmostpublications,inboth childrenandadults,patientswithTypeIIFCDhavebetterpostoperativeseizurefreedom(52 91%)comparedwithTypeIFCD.(29,41,17)InourcohortofchildrenwithFCD,100%ofpatients withtypeIIb,43%ofpatientswithtypeIIa,and13%ofpatientswithtypeIFCDwereseizure freeatoveroneyearfollowupaftersurgery.(33) 

GiventheexcellentresultsforsurgeryintypeIIFCD(especiallytypeIIb),knowledgeof

imagingmanifestationsisparamount.IncontrasttoTypeIFCD,imagingisabnormalinthe majority(60100%)ofpatientswithTypeIIFCD.(29,17,47)(Figures4,5,and6).MostMR imagingfindingsofcorticaldysplasiaaremorecommoninTypeIIFCDcomparedwithtypeI FCD.(29,33,34,41,48)Theseinclude:Blurring/illdefinitionofnormalgraymatter–white matterdifferentiationoneitherT1weightedorT2–weightedFLAIRimages,focalsignal abnormalitiesinthesubcorticalwhitematter,abnormalgyral/sulcalpattern,increasedcortical thickness,andincreasedgraymattersignal.(47)Arecentstudyhassuggestedthat applicationofmagnetizationtransferimagingmayalsoincreasesensitivityforTypeIICD.(49) 

Whitemattersignalchangesoftentaperfromthesubcorticalregiontotheventricular

margin,extendingacrossthewhitematterinapatternthathasbeentermedthe“transmantle sign”(8)(Figure5).ThisfindingisfoundmostcommonlyintypeIIbFCD,andisbestdelineated usingthinsectionT2FLAIRimagingandmultiplanarreformations.Mellerioetalinamixedage, butprimarilyadultstudy,foundtransmantlesignalchangesin52%ofcasesoftypeIIFCD(82% ofthosewithabnormalimaging)butdidnotspecificallyanalyzedifferencesbetweenTypesIIa andIIb.(47)Columboetal(48)alsoinamixedage,butprimarilyadultstudy,found

transmantlesignalchangesin83%oftypeIIbversus26%oftypeIIaCD(statistically significant).Inourcohort,transmantlechangeswerefoundin20%oftypeIIbFCD,and7%of TypeIIaFCD,asmallerprevalencethanmanypriorstudies,howevermostoftheseevaluated olderpatients(primarilyadults).InterestinglyKresketal(40)inapediatricpopulation, identifiedthetransmantlesigninonly16%oftypeIICDcases(9%IIa;21%IIb),similartothe findingsinourcohort.ItispossiblethatthefindingsoftypeIIbFCDevolveandbecomemore apparentonimagingwithage(includingtransmantlesignalchanges)potentiallybasedupon myelinationchangesandprogressivegliosis,howeverthisneedsfurtherstudy.TypeIIaandIIb FCDmaybedifficulttodifferentiatebaseduponimagingalone.Inourinstitutionalcohortof43 pediatricpatientswithawiderangeofisolatedFCDsubtypes,wefoundthatincreasednumber ofspecificMRfeatures(>/=3)ofFCDpredictedhigherFCDgrade(particularlytypeIIbFCD). ThepresenceofcorticalgraymattersignalwastheonlyfeaturethatdifferentiatedtypeIIaand typeIIbFCD.(38) 

SignalchangesintypeIIFCDoftentendtoinvolvethecortexandadjacentwhitematter

atthedepthofasulcusmostprominently.Thissocalled“bottomofthesulcus”morphologyis animportantfindingaidingindetection,oftenrelatedtoanabnormallydeeporunusually formedsulcus,andshouldbespecificallysearchedforinallpatientsimagedforseizures.(31)A bottomofthesulcusabnormalityalsohasclinicalimplicationsforselectionofinvasiveEEG electrodes,includingdepthv.subduralelectrodeplacement.Thesubcorticalwhitematter changesaretypicallymorelinearandnarrowthanthefindingstypicallydescribedas “transmantle”(8,31),providingchallengesindetection(Figures4and5.)



EtiologyofthesignalchangesinthecortexandwhitematterintypeIIFCDisthoughtto

representsomecombinationofgliosis,hypoordysmyelination,neuronalheterotopia,and ballooncells,althoughanexactcorrelationhasyettobeperformed.(10)Inourcohort,diffuse corticalgliosis(involvingallcorticallayers)wasmoreprevalentinpatientswithhigherFCD grades(33),lesionalMRIexams,andmostspecificMRIfeaturescomparedwiththosewith normalMRIexams.(34,38) TypeIIIFCD 

ThemajorconceptualchangewiththepublicationoftheILAEcombinedtaskforceFCD

classificationwastherecognitionthatabnormalcorticallaminationconsistentwithFCD(typeI FCD)canbeassociated(adjacentto)otherlesions.Inpriorstudiesevaluatingthedifferences betweenFCDsubtypes,thishadnotbeenfullytakenintoaccountparticularlywiththecommon presenceoftypeIFCDintheanteriortemporallobeinsubjectswithhippocampalsclerosis. GiventhecommonMRIvisibilityofthiscombination,thislikelyfalselyelevatedtheMRI “positiverate”andpotentiallythesurgicalsuccessratefortypeIFCDinsomestudies.Prior studiesevaluatingtypeIFCDshowgreatvariabilityinMRIpositiverate,postsurgicaloutcome, andotherclinicalfactorssecondarytoinclusionofthesesubtypes.(43) 

TypeIIIaFCDdenotestypeIFCDintheanteriortemporallobeinpatientswithadjacent

hippocampalsclerosis.Importantly,typeIFCDinanoncontiguousareaofbrain(e.g.frontal lobe)andhippocampalsclerosisshouldbemoreproperlycalled“dualpathology”ratherthan typeIIIaFCD.Inourcohortof53pediatricFCDpatients,4(7.5%)hadtypeIIIaFCD,usingthis definition.MRIfeaturesoftypeIIIaFCDaretypical.(Figure6).Theidentificationofasmall

hippocampuswithilldefinedinternalmorphology,andasymmetricincreasedsignal,is diagnosticofhippocampalsclerosis.(50)Abnormalsignalintheanteriortemporallobe,with associatedilldefinitionofgraymatter/white–matterdifferentiation(bestappreciatedon coronalFLAIRsequences)isthekeyimagingfeatureoftypeIIIaFCD.Thislikelyoverlapswith previousdescriptionsofthiscombination,socalled“temporallobesclerosis”.(50,51)Although clinicalfeaturesandoutcomeshavenotyetbeenfullyoutlinedforthissubgroup,theylikely presentsimilarlytopatientswithhippocampalsclerosis,withsimilarseizurefreeratesafter surgery.(52)Importantly,theanteriortemporallobetissueinthesepatientsmaybe epileptogenic.(53)TheetiologyoftheFCDchangesrelatedtohippocampalsclerosisisdebated, anditisuncertainwhethertheHSprecedesthedevelopmentofFCDchangesorvisaversa. 

TypeIIIbFCDrepresentsalteredcorticalarchitectureand/orcytoarchitectural

composition(suchashypertrophicneurons)adjacenttobraintumors,mostcommonly gangliogliomaordysembryoplasticneuroepithelialtumors.Thisalteredcorticalarchitectureis inregionswithoutdirecttumorinfiltration.(54)Althoughetiologyisuncertain,theassociated cytoarchitecturalchangesmayinsomecasesbeacquired.Importantly,seizureactivitymay occurfromtheseregionsratherthanfromthetumoritself.Someauthorshavefoundabetter seizurefreeoutcomeinpatientswithlowgradetumorsandepilepsywhenatailoredapproach (includingevaluationofepileptogeniczoneandextensionofsurgicalextentwhennecessary)is performedratherthanlesionectomy(55),althoughthisrequiresfurtherstudy. 

TypeIIIdFCDdescribesalteredcorticalarchitectureand/orcytoarchitectural

compositionadjacenttoencephaloclasticlesionsacquiredearlyinlife.Thesecompromisea

broadspectrumincludingpriorencephalitis,traumaticbraininjury,andischemicevents.In ourcohort7/53(13%)ofpediatriccasesofFCDfellintothiscategory(Figure8.).Thesecases arelesionalbydefinition.SpecificMRIfeaturesoftheadjacentFCDhavenotbeenwell describedandmaybeindistinguishablefromtheprimarylesionsorbeMRInonvisible. Reorganizationoftheneocortexinresponsetoanadjacentdestructiveprocesslikelyrelatesto effectsofongoingneuroplasticity,andmaybeseeninchildrenandadults.(13,43)The epileptogenicpropensityofthisreorganizedtissuemaybesignificant. 

CasesinwhichtheprimarylesionandareaofFCDarenotadjacent,orintherare

occurrenceoftypeIIFCDandanotherlesion,theterm“dualpathology”shouldapply.(5) FutureDirectionsinImaging/AdjunctiveImagingTests 

GiventhedifficultyinidentifyingFCDonMRI,andtheimportanceofidentifyinga

potentiallysurgicallyamenablelesionforseizurefreedom,multipleadjunctivetechniqueshave beendescribedtoimprovesensitivityincluding:voxelbasedmorphometryofbothT1andT2 FLAIRsequencescomparedwithnormativegroups(19,56)(Figure9.),Diffusiontensorimaging (19,57),sulcalmorphometry(32)andultrahighfieldimaging(58,59).AlternativePETagents (60)andSPManalysisofPETdata(25)havealsobeenusedinthesepatients.Mostofthese areinresearchphasesofdevelopment,butastheyimproveandarevalidated,maybecome usefulclinicaltechniquesinthefuture. Conclusions



FCDistheprimarypathologyidentifiedinpediatricpatientsundergoingsurgeryfor

intractableepilepsy.MRimagingisthekeydiagnostictestforclinicaldetection,however imagingappearanceisvariable.KnowledgeofcurrentclassificationschemesofFCDandthe differingexpectedimagingappearancesofsubtypesareofsignificantimportancetothe radiologists,asidentificationofanMRIdefinedlesionmayimpactpatientselection,surgical performanceandpostoperativeoutcomeinthesepatients.  References 1.  

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Tables.  FCDtypeI(isolated) 

TypeIA:abnormalradialcorticallamination.



TypeIB:abnormaltangentialcorticallamination.



TypeIC:abnormalradialandtangentiallamination.

FCDtypeII(isolated) 

TypeIIA:presenceofdysmorphicneurons



TypeIIB:presenceofdysmorphicneuronsandballooncells.

FCDtypeIII(associatedwithanotherprincipallesion) 

TypeIIIA:abnormalcorticallaminationassociatedwithhippocampalsclerosis.



TypeIIIB:abnormalcorticallaminationadjacenttoaglialorglioneuronaltumor.



TypeIIIC:abnormalcorticallaminationadjacenttoavascularmalformation.

 

TypeIIID:abnormalcorticallaminationadjacenttoanearlyacquiredencephaloclasticlesion (e.g.trauma,ischemia,infection).

Table1.2011ILAEclassificationforfocalcorticaldysplasias.(5)Notethatthethreetiered classificationsystemdividesthosepatientswithIsolatedFCD(notrelatedtoanotherlesion),andthose withFCDassociatedwithotherprinciplelesions.Notethathippocampalsclerosisandanotherprinciple lesion(TypeIIFCD,vascularmalformation,glialscar)orTypeIIFCDandanotherprinciplelesionshould beclassifiedas“dualpathology”.  3Disotropic1mmT1weightedsequence(e.g.MPRAGE,FSPGR) 

Routinereformats(1mm)axialandcoronal

 

Goodfor:Gyralabnormalities,baseanatomicsequenceforfMRI,Operativeintegration,MEG, MPRevaluation,advancedprocessing

3Disotropic1mmsagittalT2FLAIR 

Routinereformats(1mm)axialandcoronal

  

Goodfor:assessmentofsubtlesignalabnormalities,graymatterwhitematterdifferentiation, surfacerenderingforgrids,operativeplanning,SISCOM,PETMRfusion,MPRevaluationfor evaluationofpotentialsubtleFCD.

AxialT2(3mm,nogap) 

Goodfor:Anatomyassessment,signalchanges,sulcalanatomy

AxialGRE/SWIorvariants 

Goodfor:Detectionofhemosiderin/sequleaeofhemorrhage

CoronalobliqueT2FLAIR(4mm,nogap) 

Orientedperpendiculartothehippocampalformation

 

Goodfor:hippocampalsclerosis,sulcaldepthassessment,graymatterwhitematter differentiation.Keysequenceforhippocampusandcorticalsignalevaluation.

CoronalobliqueIR(4mm,nogap)  

Orientedperpendiculartothehippocampalformation.Oftenviewedasaninvertedimagefor graymatterwhitematterdifferentiationassessments.

 

Goodfor:Internalhippocampalsignal,morphology,andinternalstructure;evaluationofgray matterwhitematterdifferentiation.

DTI(2mmisotropic,16direction) 

Goodfor:Tractography,evaluationofdiffusionrestriction

ASLperfusion  

Allowsassessmentofpotentialasymmetriesinbloodflowrelatedtoseizures/seizurerelated pathology

 Table2.Typicalimagingprotocolusedforevaluationofpatientswithseizuresatourinstitution. Imagingat3Tispreferred.Forincompletelymyelinatedchildren(youngerthan18months),Proton density/T2weightedimagingisperformedinlieuofFLAIRimaging.Realtimereformationsofisotropic sequencesareinvaluableforassessingsubtleabnormalities.

FigureLegends: Figure1.KeyMRIimagingfeaturesoffocalcorticaldysplasia.A.AxialT2FLAIR.Abnormalcortical signal(arrowheads),illdefinedgraymatterwhitematterdifferentiation(largerarrows),andsubtleill definedincreasedsignalinthewhitematter(smallarrows).TypeIIbFCD.B.AxialT1weightedimage. Abnormalcorticalthickening(arrows).TypeIIaFCD.C.AxialT1weightedimage.Illdefinedgraymatter –whitematterjunction(arrows).TypeIIaFCD.D.CoronalT2FLAIR.Abnormalsignalinvolvingthe cortex(arrowheads)andsubjacentwhitematteratthe(largerarrow),withsubtleilldefined,tapering signalinthedeeperwhitematter(smallarrows).TypeIIaFCD.E.AxialT2weightedimage.Abnormal gyralpattern(arrows)andlocalizedvolumeloss(*).TypeIIbFCDF.CoronalT2weightedimage. Abnormalsignalandlossofnormalgraymatterwhitematterdifferentiationintheanteriortemporal lobe(arrows)comparedwithNormalfrontallobe(*)(TypeIIIaFCD). Figure2.TypeIFCD,normalMRI.14yearrighthandedoldmalewithintractablecomplexpartial seizures.IctalEEGsuggestedleftfrontalonset.A.3TMRIshowednoabnormalitiesonrepeated evaluation.B.MEGdemonstratedincreasedspikinesspredominantlyintheleftfrontallobe(arrow)

withmoreminorareasintherightfrontal,leftparietal,rightparietalregions.Virtualsensorspiketiming suggestedleftfrontalonset.C.SISCOManalysisdemonstratedfocalincreasedflowtotheleftfrontal lobe(arrow).D.PETimagingwasfelttobenormalandnonlateralizing,confirmedonPETSPManalysis. E.FunctionalMRI(verbgeneration)demonstratedleftlateralizedlanguagefunctionwithtypical localizationofinferiorleftfrontallobeactivationnearSISCOMandMEGlocalizingregion(arrow).Phase IIevaluationwithleftfrontalandparasagittalgrids,andasmallstripalongtherightfrontalregion, confirmedleftfrontalonset,andlanguagelocalizationbygridstimulation.Operativeplanoutlinedto resectepileptogenicregiondefinedbyfunctionaltesting,whilepreservinglanguagefunction.Left frontalloberesectionperformed.F.Pathology(left:hematoxylinandeosin,right:GFAPimmunostain) demonstrateddisorganizedlaminararchitecturewithoutidentifiablezones.Mixtureofsmallimmature neurons(arrows)andlargerneuronsnotrespectingnormallaminararchitecturewerenoted.GFAP immunostaindemonstratingsuperficial(subpial)gliosis(arrow)butnosignificantgliosisinthedeeper corticallayers.Diagnosis:TypeIFCD.Nodeficitsnotedpostsurgerywith>90%reductioninseizures postoperatively.Thiscasedemonstratesthecriticalimportanceofmultimodalfunctionalimagingand evaluation(e.g.MEG,SISCOM,surfaceEEG)inidentifyingthesurgicaltargetinMRInormalcases. Figure3.TypeIFCD,abnormalMRI.7yearoldrighthandedmale.Complexpartialseizureswith generalization13/mo.Rightheadturning.A.MRI.AxialT2FLAIR.Subtlesubcorticalincreasedsignalis notedonthestandardaxialFLAIRsequence(arrow).Overlyinggyrusismildlydysmorphicandslightly thickened(arrowhead).Findingwasverysubtleonstandardslicethickness.B.Multiplanarreformations (MPR)ofisotropic3DFLAIRT2datasetbetterdemonstratesfocalsubcorticalsignalabnormality (arrows)andmoresubtleblurringofthegraymatterwhitematterinterface(circle).Nodefinite taperingsignalextendingtowardstheventriclemarginwasidentified(transmantlesign)MPRofT2 FLAIRsequencescanbeveryhelpfulforidentifyingsubtleabnormalities.C.PETMRfusionshows moderatelefttemporalparietalhypometabolismrelatedtotheareaofFLAIRsignal(arrow).D.SISCOM analysisdemonstratesleftsidedictalhyperperfusioninthelefttemporalparietalregionneartheregion ofMRabnormality(arrow).E.3DreconstructionofMRI,subduralgrids(yellowdots),andareaofMRI andSISCOMabnormalities(green)performedinBrainLab3.0.Reddotsmarkthegridpositionofictal onsetzonebasedonelectrocorticographyofseveralhabitualseizures.F.Pathologyafterresectionof theactiveelectrode,SISCOMandMRIabnormalities(left:hematoxylinandeosin,right:GFAP immunostain),demonstratesdisorganizedlaminararchitecturewithoutidentifiablezones.GFAPIHC demonstratingextensivegliosisthroughoutallcorticallayers(diffusegliosis).Diffusegliosisismore commoninhigherdysplasiagrades(33)butcanbevisibleintypeIFCD.Ourrecentexperiencesuggests thatmoreextensivegliosiscorrespondswithMRIvisibility(34).Thiscasedemonstratesthatalthough typeIIFCDmoretypicallycanhaveMRIabnormalities,theymayalsoexistinpathologicallyclassified TypeIFCD.MRIpathologycorrelationisunfortunatelyimperfect.  Figure4.TypeIIaFCD.8yearoldfemalewithintractableseizures.Localizationrightfrontalcentralarea onictalscalpEEG.Sequentialanteriortoposterior(A.,B.,C.)CoronalT2FLAIRimagesdemonstrate localizedsignalalongtheinferiormarginofaslightlythickenedsuperiorfrontalsulcus(arrows,A.and B.).Thissignalcupsthebottomofthesulcusandextendsintoanilldefined,taperinglinearsignal

abnormalityextendingtowardstheventricularmargin(smallarrows,C.)consistentwiththe“bottomof sulcus”imagingphenotypeofTypeIIFCD..Coronal(D.)andAxial(E.)reconstructionsofvolumetricT1 weightedimagesdemonstrateilldefinitionofthegraymatterwhitematterjunction(arrows,D.)and intermediatesignalwithinthethickenedcortex(arrow,E).Axialthinsection,smallFOVT2weighted image(F.)nicelydemonstratestheilldefinedcorticalmarginsalongthethickenedsuperiorfrontal sulcus(arrow).TypeIIaFCDwasfoundatpathology.Thiscasesdemonstratesthatalthough“bottomof sulcus”andsubcorticalwhitematterchangesarethoughttobespecificfortypeIIFCD,theycanoccurin bothtypeIIaandtypeIIbFCD.Givenproximitytothehandmotorregion(*),confirmedby intraoperativedirectcorticalstimulation,resectionwasrestrictedsomewhat.Atinyregionofresidual dysplasticcortexwasleft.Despitethis,thepatienthadgreaterthan90%reductioninseizurefrequency aftersurgery.  Figure5.TypeIIbFCD6yearoldfemalewithintractableepilepsy.IctalEEGdemonstratedseizureorigin inrightcentralheadregion.InitialMRI(A.coronalFLAIR,B.CoronalInversionrecovery)wasreadas demonstratinganonspecificlinearareaofsignalabnormalityintherightfrontoparietalarea(arrow, A.).PET(C.)performedonthesamedatewassubsequentlyfusedwiththeMRIexam,and demonstratedaregionoflocalizedhypometabolismintherightfrontalparietalregion(arrow,C.).3D T2FLAIRsequence(D.)wasusedformultiplanarreformations,andaregionoftaperinglinearsignal extendingfromthecortextotheventricularmarginwasidentified(smallarrows,D.).Thegraymatter– whitematterwasilldefinedatwherethelinearsignalcontactsthecortex,withcorticalthickening, suspiciousforaregionofFCD.ThecoronalIRsequence(B.)wasreevaluatedandsimilarilldefinitionof thegraymatterwhitematterjunctionidentified(arrows).SurgerywasperformedusingMRimage guidancetoremovethecorticalabnormality.TypeIIbFCDatpathology.Seizurefreesincesurgery. ThiscasedemonstratestheimportanceofcorrectlyidentifyingTypeIIFCD,whichhasexcellentresults aftersurgicalresection.TheuseofPET/MRfusioninformedreanalysisoftheinitialMRIand performanceofMPRallowingidentificationofthefullextentofthelesion,andallowingpreoperative diagnosis.Asubcorticallinearsignalabnormalityinapatientwithintractableseizuresshouldalwaysbe interrogatedforthepossibilityofrelatedFCD Figure6.TypeIIbFCD.9yearoldrighthandedmalewithintractablecomplexpartialseizures.A.) CoronalT2FLAIRdemonstratingabnormalthickgyruswithilldefinedgraymatterwhitematter differentiation(arrowheads).Focalsignalabnormalityidentifiedatthegraymatter–whitematter interface(arrow).B).CoronalPETdemonstratesfocalhypometabolismintherightinferiorfrontallobe correspondingtotheregionofabnormalityonMRI(arrows).C.)CoronalT2FLAIRdemonstratescortical signal(smallarrows),withinthethickenedgyrus(largearrows).D.CoronalT2weightedimage(narrow windowsetting)demonstratesafaint,butdefiniteareaoftaperingsignalabnormalityextending towardstheventricleinthesubjacentwhitematter,thetransmantlesign.E.MEGdemonstrated increasedinterictalspikinessintherightinferiorfrontallobe(arrow,orangeregion)encompassingthe MRIabnormalregion.InterictalEEGdemonstratedrightfrontalslowingandbifrontalrhythmicsharp waves(witharightsidedpredominance).Subduralgridelectrodeplacementdemonstratedictalonset zoneintherightinferiorfrontalregionnearMRIabnormality.Arightfrontallobectomywasperformed,

completelyresectingtheMRIabnormalityandictalonsetzone.PathologicanalysisF.)Hematoxylinand Eosin,G.)HematoxylinandEosin,H.)NeuNimmunostain.Therearelargedysmorphicneuronswhichare irregularlyshapedandcontainlargeNisslsubstances(arrows,F.).Multipleballoonneuronsare identified(arrows).NeuNimmunostain(H.)demonstratesmarkeddisorganizationofnormalcortical laminationpattern.TypeIIbcorticaldysplasia.Patientisseizurefreeatoneyearfollowup Figure7.TypeIIIaFCD.2yearoldmalewithintractablecomplexpartialseizures.A.CoronalT2FLAIR demonstratesabnormalsignalintheleftanteriortemporallobewithnearcompletelossofnormalgray matter–whitematterdifferentiation(arrows,comparewithrightside).B.CoronalIRalso demonstratesilldefinedsignalinthewhitematter,andslightvolumelossinvolvingtheanterior temporallobe(arrows).C.CoronalFLAIRT2moreposteriortoA.andB.demonstratesasmallleft hippocampus,withabnormalorientationandincreasedsignal(arrow).D.CoronalPETimage demonstrateslefthemispherichypometabolism,mostmarkedintheleftanteriortemporallobe (arrows).Lefttemporallobectomyincludingamygdalaandhippocampusperformed.Hippocampal sclerosisandadjacenttypeIcorticaldysplasiawithintheanteriortemporallobeidentifiedatpathology (TypeIIIa).>90%reductioninseizurefrequencynotedpostoperatively. Figure8.TypeIIIccorticaldysplasia.19yearoldfemalewithremotehistoryofherpesencephalitiswith subsequentdevelopmentofintractableepilepsy.EEGandMEGsuggestedRightfrontotemporalictal onsetwithrapidrightsidedspread.Axial(A.)andCoronal(B.)T2FLAIRimagesdemonstratemultifocal encephalomalaciaandadjacentgliosisintherightfrontalandtemporallobesandalongthesylvian fissure,insulaandoperculumcompatiblewithsequelaeofencephalitis(arrows).Bothafrontallobeand temporalloberesectionwereperformed.Onpathologicanalysistherewasevidenceofchronic encephalitiswithmicroglialnodulesandassociatedtypeIcorticaldysplasiainbothregions. Figure9.VoxelbasedmorphometricanalysisofMRIdata.(ImagesareinNEUROLOGICconvention,right istherightsideoftheimage).17yearoldlefthandedmalewithintractableepilepsyandrightsided centralandparietalfastactivityonictalEEG.A.AxialT1weightedimagedemonstratingalargecortical malformationintherightfrontoparietalregion(whitearrows)withmorphologycompatiblewith polymicrogyria(arrows).Noothercorticalmalformationwasidentifiedprospectively.A.Right;Research images(LR)fromvoxelbasedmorphometricanalysisofthepatient’sT1weightedimagerelatedtosex andagematchedcontrolgroupusinganalgorithmassessingmultipleimagingfeaturesincluding differencesinGMvoxels(GM)andTissuecomposition(TC)anexpressionthatassessesdifferencesin threetissueclasses;whitematter,graymatter,andCSFbetweenthepatientandnormalcontrolgroup. Differencesinallfeatures(Combined)arealsodisplayedasanoverlayontheanatomicimages.Onthe GMandTCmaps,theheightofthepeaksrelatetonumberofsuprathresholdvoxels.(56)The automatedalgorithmclearlyidentifiesthevisibleMRIabnormalityasabnormal(blackarrows).The algorithmalsoidentifiedaregionofsignificantdifferenceintheleftinferiortemporallobe(black arrows),confirmedonsubjectiveimagereevaluationtorepresentanadditionalareaofcortical malformation(B.whitearrow).Othersmaller,lesssignificantareasoftissuedifferencesarealsonoted, withoutdefinitesubjectiveimagingcorrelate.Althoughstillaresearchtool,furtherdevelopmentof VBMapproachesmayimprovedetectionofsubtleregionsofcorticaldysplasiainthispatientgroup. ImagescourtesyMarkoWilke,M.D.,PhD,andLeonidRohzkov,M.S.

Imaging spectrum of cortical dysplasia in children.

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