BrainStimulationforTorsionDystoniaMichaelDFoxMDPhDRonLAltermanMDystoniaisdefinedasaneurologicdisordercharacterizedbysustainedorintermittentmusclecontractionscausingabnormalmovementsandorposture ID: 951809
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BrainStimulationforTorsionDystoniaMichaelD.Fox,MD,PhD;RonL.Alterman,MDystoniaisdefinedasaneurologicdisordercharacterizedbysustainedorintermittentmusclecontractionscausingabnormalmovementsand/orpostures.Dystoniaisaheterogeneousgroupofdisorderswithmanyunderlyingcausesbothknownandunknown.Themostrecentconsensusguidelinesclas-sifydystoniabasedonclinicalpresentationandetiology.Keyclini-calfactorsincludepatientageatonset,extentofthebodyaf-fected,temporalpattern,andwhetherdystoniaistheonlymajormotorfinding(isolateddystonia)oronefeatureofabroaderdisor-der(combineddystonia).Etiologicclassificationrelatestowhetherdystoniaisinherited,acquired,orduetoidentifiablenervoussys-temabnormalities.Differenttypesofdystoniaspanthespectrumofthisclassificationschemefromgeneralizedchildhood-onsetdys-toniaduetogeneticmutation(eg,DYT1genemutation)tomorefo-caladult-onsetdystoniaaffectingthehand(writerscramp),neck(cervicaldystonia/torticollis),orface(cranialdystonia/Meigesyn-drome).Dystoniacanarisesecondarytobraininsult,includingstroke,trauma,oradversemedicationeffect(tardivedystonia)orasasymp-tomofotherdiseases,suchasParkinsonorWilsondisease.Pharmacologictherapiesfordystonia,includinganticholiner-gicagents,dopaminergicagents,benzodiazepines,tetrabenazine,andbaclofen,generallyprovidemodestsymptomaticimprove-mentandcancausesignificantadverseeffects.Arareexceptionisdopa-responsivedystonia,whichrespondsprofoundlytotreat-mentwithlevodopa.Botulinumtoxininjectionscanprovidesymp-tomaticrelieffortargetedmuscles;however,theinjectionsmustberepeatedeveryfewmonths,patientscanbecomeresistantorim-munetothetherapyovertime,adverseeffects(eg,weakness)arecommon,andtheinjectionsbecomebothcostlyandimpracticalifmanymusclesareaffected.Surgicalinterventionshaveincludedrhi-zotomyforseverecervicaldystoniaandablationofthethalamus(thalamotomy)and/orbasalganglia(pallidotomy)formoregener-alizeddystonias.Theseablativeprocedurescanprovidesignifi-cantbenefit,andpallidotomyisstillusedinselectcases.However,IMPORTANCEDystoniaisaheterogeneousneurologicdisordercharacterizedbyabnormalmusclecontractionsforwhichstandardmedicaltherapyisofteninadequate.Forsuchpatients,therapeuticbrainstimulationisbecomingincreasinglyused. OBJECTIVESToreviewtheevidenceandeffectsizesfortreatingdifferenttypesofdystoniawithdifferenttypesofbrainstimulationandtodiscussrecentadvancesrelevanttopatientselection,surgicalapproach,programming,andmechanismofaction. EVIDENCEREVIEWPubMedwassearchedforpublicationsontheclinicaleffectofbrainstimulationindystoniaupthroughDecember31,2014.Recentmeta-analyses,consensusstatements,andevidence-basedguidelineswereincorporated.Emphasiswasplacedondeepbrainstimulation(DBS)andrandomizedclinicaltrials;however,otherstimulationmodalitiesandtrialdesignswereincluded.Foreachinterventionthemeanchangeindystoniaseverity,numberofpatientsstudied,andevidenceofefficacybasedonAmericanAcademyofNeurologycriteriaweredetermined. FINDINGSStrong(levelB)evidencesupportstheuseofDBSforthetreatmentofprimarygeneralizedorsegmentaldystonia,especiallywhenduetomutationintheDYT1gene,aswellasforpatientswithcervicaldystonia.LargeeffectsizeshavealsobeenreportedforDBStreatmentoftardivedystonia,writerscramp,cranialdystonia,myoclonusdystonia,andoff-statedystoniaassociatedwithParkinsondisease.Lesserbenefitisgenerallyseenindystoniasecondarytostructuralbraindamage.Otherbrainstimulationtechniques,includingepiduralcorticalstimulationandnoninvasivebrainstimulation,havebeeninvestigated,butgenerallyreportsmallereffectsizesinfewerpatients. CONCLUSIONSANDRELEVANCEPatientswithdystoniathatisnotadequatelycontrolledwithstandardmedicaltherapyshouldbereferredforconsiderationofDBS,especiallypatientswithgeneralized,segmental,orcervicaldystonia.Otherless-invasivestimulationmodalitiesrequirefurtherresearchbeforebeingconsideredatherapeuticalternative.JAMANeurol.2015;72(6):713-719.doi:10.1001/jamaneurol.2015.51PublishedonlineApril20,2015. Supplementalcontentjamaneurology.comAuthorAffiliations:Berenson-AllenCenterforNoninvasiveBrainStimulation,DepartmentofNeurology,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,Massachusetts(Fox);DepartmentofNeurology,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,Massachusetts(Fox);AthinoulaA.MartinosCenterforBiomedicalImaging,HarvardMedicalSchool,Boston,Massachusetts(Fox);DivisionofNeurosurgery,DepartmentofSurgery,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,Massachusetts(Alterman).CorrespondingAuthor:MichaelD.Fox,MD,PhD,Berenson-AllenCenterforNoninvasiveBrainStimulation,DepartmentofNeurology,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,330BrooklineAve,KirsteinSte448,Boston,MA02215(foxmdphd@gmail.com).SectionEditor:DavidE.Pleasure,MD.ClinicalReview&EducationReviewjamaneurology.com(Reprinted)JAMANeurologyJune2015Volume72,Number6713 variationinlesionlocationorsizecanyieldheterogeneousresultsandposeariskofirreversibleadverseeffects,particularlywithbi-lateralinterventions.Becauseoftheselimitations,deepbrainstimu-lation(DBS)hasemergedasthep
referredsurgicalinterventionformedicallyrefractorytorsiondystonia.ThemainadvantagesofDBSrelativetoablationare(1)theeffectsofstimulationarereversible,yieldingasignificantmarginofsafety;(2)thestimuluscanbeti-tratedtoclinicaleffectandmodifiedasneededovertime;and(3)bilateralinterventionscanbeperformedsafely.In2003,theUSFoodandDrugAdministrationgrantedahu-manitariandeviceexemptionfortheuseofDBSinprimarygener-alizedorsegmentalandcervicaldystoniabasedontherelativelysmallnumberofpatientsthoughttobesurgicalcandidatesandthero-bustclinicalresponsesreportedatthattime,albeitinopen-labelas-sessments.ThehumanitariandeviceexemptionrequiresthatDBSfordystoniabeperformedwiththeoversightofalocalinstitutionalreviewboard.Since2003,thebodyofevidencesupportingtheuseofDBSindystoniahasgrown,includingtheresultsof2largeran-domizedclinicaltrials,bothperformedinEurope.3,4Toidentifyrel-evantpublications,weperformedaPubMedsearchthroughDe-cember31,2014,includingthetermsdystoniaandbrainstimulationdytsoniaandDBS,anddystoniaandTMSortDCS.Literaturecitedbyidentifiedarticleswasalsoincorporated.Herein,wereviewthecurrentstatusofDBSforthetreatmentofdystonia,incorporatingrecentevidence-basedguidelines,meta-analyses,9,10reviews.2,11Thepotentialimpactofinvestigationalnoninvasivebrainstimulationtechniquesfordystoniaisalsodiscussed. SelectingPatientsforDBSTherapyDecidingwhichpatientswithdystoniaarecandidatesforDBStherapycanbecomplexgiventheheterogeneousnatureofthedisorder,thevariedresponsestostimulationofdifferentdystoniasubtypes,andthepotentialrisksofsurgery.Giventhiscomplexity,DBSfordysto-niaisprobablybestperformedthroughadedicatedmultidisci-plinarymovementdisordercenter.Regardingpatientselection,onemaybeginwiththeUSFoodandDrugAdministration approvedin-dications,whicharesupportedmoststronglybytheavailableevi-dence.Underthecurrenthumanitariandeviceexemption,DBSisap-provedonlyforthetreatmentofprimarygeneralized,segmental,orcervicaldystonia.TheuseofDBStotreatotherdystoniasub-typesisconsideredoff-label;however,evidenceisemergingthatitmaybeeffective.Theevaluationofpatientswithdystoniapresentingforconsid-erationofDBSshouldfocuson(1)excludingconditionsthatwouldrespondfavorablytoless-invasivetreatmentsand(2)identifyingfac-torspredictiveofapositive(eg,DYT1mutation)ornegative(eg,sec-ondarydystonia)responsetostimulation.Alevodopatrialshouldbeperformedinallpatientswithsymptomonsetbeforeage21yearsandconsideredinpatientswithsymptomonsetbeforeage50yearstoruleoutlevodopa-responsivedystonia.TestingforWilsondis-easeshouldbeconductedinpatientswithsuggestivefeatures.Pa-tientswithfocalorcervicaldystoniareferredforDBSowingtore-sistancetobotulinumtoxintherapyshouldbeevaluatedtoensuretheywouldnotbenefitfrommoreappropriatelytargetedordosedinjections.Onecantestforresistancebyinjectingasmallamountofbotulinumtoxinintoaforeheadwrinkleandassessingforeffect.PatientswithpsychogenicdystoniamaybereferredforDBSsincetheyareoftenrefractorytotreatment.Differentiatingpsycho-genicfromorganicdystoniaisdifficultandconsidereddefinitiveonlyifsymptomsresolvewithpsychotherapy.13,14Clinicalfeaturessug-gestiveofapsychogeniccauseincludeinconsistencyovertime,in-congruencewithorganicdystoniasyndromes,suddenonset,peakseverityatonset,fixedortonicfeatures,andcomorbidpsychiatricdiseaseorotherpsychogenicsymptoms.Itisimportanttoevalu-atepatientsforfixedskeletaldeformities,spasticity,andmyelopa-thy,allofwhichmaymitigatethepatientsresponsetoDBS.Simi-larly,thepreoperativeworkupshouldincludebrainmagneticresonanceimaging(MRI)toexcludestructuralabnormalitiesthatcouldindicateasecondarydystoniaoraffectsurgicaltargeting.Fi-nally,screeningforpremorbidpsychiatricsymptomsorcognitivedys-functionisreasonablekeepinginmindthatglobuspallidusparsin-terna(GPi)DBShasbeenusedsuccessfullyinpsychiatricpatientswithtardivedystoniaandinsomepatientswithcognitiveimpairment.ThereisnoevidencethatDBSexacerbatesthesesymp-tomsinpatientswithdystonia.ThepropertimingofDBSsurgeryremainsacontroversialis-sue.Ingeneral,interventionshouldbeconsideredonceitisdeter-minedthatmedicaltherapyhasfailedtoadequatelycontrolsymp-tomsandbeforethedevelopmentoffixedskeletaldeformitiesorcervicalmyelopathy.Asrecentlyas2011,theMovementDisor-dersSocietyconcludedthattherewasinsufficientevidencetorec-ommendearlysurgery;however,accumulatingdatasuggestthattheearlieroneinterveneswithDBS,thebettertheoutcome,especiallyingeneralizeddystoniaduetomutationintheDYT1gene.ciselyhowearlyDBSshouldbeperformedisunclear,however,be-causetherearescantdataregardingsurgicaloutcomesinchildrenyoungerthan7yearsorforsymptomdurationoflessthan2years. SurgicalProcedureTheDBSdeviceincludes3keycomponents:astimulatingelectrode(alsocalleda),anextensioncable,andaprogrammablepulsegenerator(PG),whichissimilartoacardiacpacemaker(Figure1).Thedeviceisimplantedin2stages.Duringthefirststage,unilateralorbi-lateralleadsareimplantedstereotacticallyintoaspecifictherapeutictarget.ByfarthemostcommontargetfordystoniaistheGPi(Figure2butothertargets,includingthesubthalamicnucleus,havebeenstudied.Duringthesecondstage,whichmaybeperformedonthesamedayorlater,thePGisimplan
tedundertheskinoftheanteriorchestwallortheabdomenandconnectedtotheleadwireviasubcu-taneouslytunneledextensioncables.Inmostinstances,bilateralim-plantsarerequired;however,patientswithhemidystoniamaybenefitfromunilateralstimulation.Leadinsertionsmaybeaccomplishedwithavarietyofimage-andphysiologicallyguidedtechniques,althoughuseofacranial-mountedstereotacticheadframeremainsthecriterionstandardagainstwhichallothertechniquesaremeasured.Alternativestotheframeincludeframelessstereotactictargetinganddirect,image-guidedplacementwithintheMRIscanner.Regardlessofthetargetingtechnique,targetvisualizationisaccomplishedwithMRIutilizingtechniquesthatpro-videexcellentdelineationofthebasalganglia.Intraoperatively,propersitingofthetherapeutictargetmaybeaccomplishedwithsingle-unitmicroelectrodeand/orlocalfieldpotentialrecordings.Traditionally,ClinicalReview&EducationReviewBrainStimulationforTorsionDystonia714JAMANeurologyJune2015Volume72,Number6(Reprinted)jamaneurology.com theserecordingsareobtainedwiththepatientfullyawake;however,acceptablerecordingscanbeobtainedinpatientsunderanesthesia,andsomeanestheticagentsmaybebetterthanothersatnotdisrupt-ingthetypicalpatternsseeninanawakepatient.Oncepropertarget-ingisconfirmed,theleadisinsertedandtheacuteeffectsofstimula-tionaretested.DystoniadiffersfromParkinsondiseaseandessentialtremorinthatdaysorweeksofstimulation,ratherthansecondsormin-utes,areusuallyrequiredtoachieveclinicalresponse.Therefore,animprovementindystoniasymptomsinresponsetointraoperativeteststimulationisnotexpected.Instead,teststimulationisusedtoassessforadverseeffectsthat,ifpresent,willappearimmediatelyandshouldpromptrepositioningofthelead.Oncesatisfactorilypositioned,theleadisanchoredattheskullusingthesurgeonspreferredtechnique.Followingimplantation,properleadlocationcanbeconfirmedandintracerebralhemorrhageexcludedwitheithercomputedto-mographicscanningorMRI.BrainMRIcanbeperformedsafelyde-spitethepresenceoftheimplantedleadsandallowsonetobetterassesstheiranatomicalposition.Low-energyMRIsequencesmustbeusedtoadheretoUSFoodandDrugAdministration mandatedsafetyregulations,althoughstandard(higher-energy)MRIse-quenceshavebeenusedinmanypatientswithoutadverseeffects.ThesecondstageoftheDBSsurgery,duringwhichthePGsandextensioncablesareimplantedandconnectedtotheleads,canbeper-formedonthesamedayastheleadimplantationbutisoftensched-uledfor1to2weeksaftertheoperation.Thisstageisperformedun-dergeneralanesthesia.Inpatientsrequiringbilateralstimulation,animportantquestioniswhethertoimplantasinglePGtopowerbothleadsor2single-channelPGs,1foreachside.Althoughimplantationof2PGsrequiresanextraincisionandaslightlylongeroperation,single-channelPGshavealowerprofilethandual-channelPGsandlastlon-ger.Further,thepresenceof2PGsprovidessomeprotectionagainstsuddencessationofallstimulationtherapyifonebatteryissuddenlyexhaustedorneedstobeexplantedowingtoinfection.Althoughnotapprovedforuseindystonia,thedual-channelrechargeabledevice,whichhasthelowestprofileofallPGs,mayminimizetheriskofinfec-tionandreducethefrequencyofPGreplacementsthatmayprovepar-ticularlyvaluableintreatmentforchildrenwithgeneralizedsymptoms. DBSProgrammingImmediatelyafterleadimplant,somepatientsexperienceatran-sientimprovementintheirdystonia;aphenomenontermedthecrolesioneffect.Althoughlesscommonlyobservedindystoniathaninotherdisorders,whenitoccurs,thiseffectoftenheraldsagoodresponsetostimulation.Becausetheeffectcanlastupto3weeksandcomplicatetheassessmentofstimulationresponse,somecen-terswaituntilafterthisperiodtobeginprogramming.Othercen-tersbeginprogrammingimmediatelyorwait7to10daysafterPGimplantation,allowingtimeforthesurgicalincisionstoheal.Ofpar-ticularsignificanceispatientswhoundergoimplantationduringadystoniccrisis,apotentiallylife-threateningsituationinwhichapa-tientsdystoniaacutelyworsensandismanifestassevere,active,painfulcontractionsthatcanleadtorhabdomyolysis,respiratorycompromise,andothermetabolicderangements.SmallcaseseriessuggestthatDBSmayhelpbreakdystoniccrisesmorereadilythanmedicationsalone.Underthesecircumstances,immediateactiva-tionofstimulationiswarranted.Duringprogramming,thecliniciancontrols4stimulusfactors:amplitude,pulsewidth,frequency,andtheactivecontact.Thegoalistofindthecombinationofsettingsthatimprovesmotorfunctionand/orreducespainwithoutcausingadverseeffects.DeterminingthesesettingsismoredifficultindystoniathaninessentialtremororParkinsondiseasebecausethetherapeuticbenefitisoftennotapparentforweekstomonths.Moreover,thereisnoconsensusre-gardingthemostefficientapproachtoachievingtheoptimalset-tings,althoughpracticalguidelinesareavailable.Ingeneral,onestartsbyactivatingeachcontactinisolation(monopolarstimula-tion),slowlyraisingthestimulusamplitudewhileexaminingforthethresholdatwhichadverseeffects(eg,musclecontractions,dys-arthria,orworseningdystonia)occur.Somepatientsmayalsoshowacutebeneficialeffects,suchasareductionindystonictremor,iden-tifyingapreferredcontact.Ifnobeneficialeffectsareseen,onecanconducttrialstimulationateachcontactforlongerperiods(daystoweeks)orselectcontactslocatedintheposteroventralGPisincepriorst
udiessuggestthatposteroventralGPicontactsaremostlikelytoyieldmaximalbenefit(Figure2).Somecentersselectthecon-tactatorimmediatelysuperiortothatwhichproducesphos- Figure1.IllustrationofBilaterallyImplantedDeepBrainStimulation(DBS)Devices © Medtronic, Inc. 2008 EachDBSdeviceiscomposedofastimulatingleadinthebrain,extensioncable,andprogrammablepulsegenerator,usuallyimplantedinthechest(usedwithpermissionfromMedtronic,Inc). BrainStimulationforTorsionDystoniaReviewClinicalReview&Educationjamaneurology.com(Reprinted)JAMANeurologyJune2015Volume72,Number6715 phenes,indicatingproximitytotheoptictract,andothersselectthemostventralcontactsthatdonotproduceadverseeffectsatthera-peuticvoltage.UnlikewithParkinsondisease,inwhichonemostoftenusesthelowesteffectivestimulusamplitude,increasingitasneeded,manyneurologistsstartwitharelativelyhighvoltagefordystonia,onejustbelowtheadverseeffectthreshold,andthendecreaseittoconservebatterypoweroncebenefithasbeenachieved.Themostcommonlyusedstimulationsettings(frequency,130-180Hz;pulsewidth,60-210microseconds;amplitude,2-5V)arebasedonpublishedtrials,althoughsomeevidencesuggeststhatlowerstimulationfrequencies(60-80Hz)maybeequallyeffectiveinchildhooddystoniawhileprolongingbatterylife.Patientsreturnforevaluationandprogrammingadjustmentseveryfewweeksforthefirstfewmonthsandthenevery3to6monthsforthefirst1to2years.Patientresponsesareoftenquantifiedusingstandardizedscales,suchastheBurke-Fahn-MarsdenDystoniaRatingScaleortheTorontoWesternSpasmodicTorticollisRatingScale.AlthoughusefulformeasuringimprovementfollowingDBS,thesescalescanbeinsensitivetosmallchanges;therefore,assessmentoftenmustbeindividualizedtoaddressthepatientsmostdisablingorbother-somesymptom.Thetrial-and-errorapproachroutinelyusedforDBSprogram-mingwasdevelopedlargelyontheexperienceofprovidingtreatmentforpatientswithParkinsondiseaseandessentialtremorforwhomthetherapeuticbenefitatdifferentelectrodecontactscanberapidlyassessed.Giventhedelayedtherapeuticeffectscharacteristicofdystonia,thisprocessisclearlynotideal.Algorithmsthatallowonetoidentifytheidealcontactandstimu-lationsettingsbasedonneuroimaging,brainconnectivity,andmodelingofthestimulationfieldcouldrepresentamajoradvanceforprogrammingDBSindystoniainthenearfuture(eg,Figure2). ClinicalResultsTheresultsoftheclinicalstudiesofDBSfordystoniaaresumma-rizedintheeTableintheSupplementandinFigure3.Factorsrel-evantforevaluatingtheseclinicaltrialresultsincludethemagnitudeofclinicalbenefit,numberofpatientsstudied,andleveloftheevidencethattheinterventionworksbetterthanplacebo.Tocompilethissummary,weborrowedheavilyfrommeta-analyses9,10thatincorporatetheresultsofnumerousindi-vidualtrials.Thesedatawerethenupdatedtoincludemorerecentstudiesoradditionalindicationsnotcoveredbytheoriginalmeta-analyses.Althoughmuchoftheefficacydatawerederivedfromopen-labelstudies,prospectiverandomizedclinicaltrialswithdouble-blindassessmentshavebeencompletedinpatientswithgeneralizedorsegmentalprimarydystoniaandcervicaldys-tonia,bothdemonstratingthatGPiDBSissuperiortoshamstimulation.3,4Pallidalstimulationforgeneralizedorsegmentaldystoniastandsoutasthebest-studiedtherapy,withthemostpatientsandlargesteffectsizes.4,18GreaterclinicalimprovementshavebeenreportedinpatientswiththeDYT1mutationthaninpatientswiththeDYT6mutationorwithanunknowncauseoftheirprimarygeneralizeddystonia,althoughthelatteralsodowell.ImprovementinseverityscoresfollowingDBSforcervicaldystoniaislessimpressivethaningeneralizeddystonia;however,otherclinicalfeatures(eg,painanddisability)mayimprovetoagreaterextent,yieldingsignificantfunctionalbenefit.Similarly,inpatientswithmyoclonusdystonia,theimprovementinmyoclonuscanbemoredramaticthantheimprovementindystoniaseverity(73%vs53%).DeepbrainstimulationappearsveryeffectiveforalleviatingdystoniaassociatedwithParkinsondisease,tardivedystonia,andwriterscramp,althoughthelatterissupportedbylimitedevidenceinfewpatients.Patientswithsecondarydysto- Figure2.DeepBrainStimulationTargetintheGlobusPallidusBasedonRetrospectiveAnalysisoftheSiteofEffectiveElectrodeContactsandModelingofStimulationFields Magneticresonanceimagingwasusedtoidentifythelocationofthedeepbrainstimulationelectrode(shownasmulticoloredrod)inpatientswithgeneralizeddystoniaduetomutationintheDYT1gene(A)andcoregisteredintoacommonatlasspace(B).Thestimulationfieldfortheeffectiveelectrodecontactineachpatientwasmodeled(C).Aprobabilisticvolumeintheposteroventralaspectoftheglobuspallidusparsinternawasidentifiedthatcouldbeusedtoguidefutureelectrodeplacementorprogramming.Colorsindicatetheproportionofelectrodesactivatingagivenvoxellocation,withhottercolorscorrespondingwithahigherprobabilityofactivation(DthroughF).ModifiedwithpermissionfromCheungetal.ClinicalReview&EducationReviewBrainStimulationforTorsionDystonia716JAMANeurologyJune2015Volume72,Number6(Reprinted)jamaneurology.com nia,particularlythosewithstaticencephalopathy,exhibitmodestresponsestoDBSandmorecomplicationratescomparedwithpatientswithprimarydystonia.Nevertheless,a24%reportedmeanclinicalimprovementindystoniaseveritycanstillresultinclinicallymeaningfulbenefit.Inac
omparisonofsurgicaltargets,GPiDBSissupportedbyhigher-qualityevidenceinmorepatientsandthusremainsthetargetofchoice.However,smallstudiesofsubthalamicnucleusDBSfordys-toniahavereportedlargeeffectsizesandpotentiallydifferentadverseeffectprofiles,withalowerincidenceofbradykinesiaandahigherin-cidenceofdyskinesiarelativetoGPi.Furtherworkdirectlycomparingthe2targetsisrequiredbeforedefinitiveconclusionscanbemade.Regardingthetimecourseofimprovement,monthsofDBSmayberequiredbeforeanyclinicalbenefitisobservedandfullbenefitmaynotberealizedfor1yearorlonger.Phasicoractivedystonicmovementsgenerallyimprovemorerapidlythandofixeddystonicpostures.Incer-vicaldystonia,paininducedbymuscularcontractionsmayimprovebe-foreandindependentofanychangeinheadposition.Becauseoftherelativelystaticnatureofmostdystoniasubtypes,theresponsetoDBSappearstobedurable.Longer-termfollow-uphasdocumentedcon-tinuedbenefitoutto5yearsandeven10years. Deepbrainstimulationposes3typesofrisk:surgical,stimulationre-lated,andhardwarerelated.ForallpatientswhoundergoDBS(includ-ingthosewithParkinsondiseaseandtremor)theriskofintracranialhemorrhageisreportedtobeapproximately3%,theriskofpermanentneurologicmorbidityisapproximately1%,anddeathwithin30daysofsurgeryis0.4%;however,theseratesarelikelytobelowerinwithdystoniawhoaresignificantlyyoungeronaveragethanpatientswithParkinsondiseaseoressentialtremor.Theratesofhardwaremal-functionorinfectionrequiringrehospitalizationvarybutcanbeashighas10%overtime.InarecenttrialofDBSforcervicaldystonia,theriskofseriousadverseeventswas26%;ofthese,8%failedtoresolve.Ad-verseeventsrelatedtostimulationincludeslurredspeechandparkin-sonism,althoughtheseeffectsgenerallyresolvewithcessationoftherapyoradjustmentsinstimulationsettings.Althoughnotcom-mon,suicidehasbeenreported3,17inpatientswithDBSfordystonia,generallyinpatientswithpresurgicalsuicidalideation.Somediseases,includingcerebralpalsyanddystoniasecondarytostructurallesions,mayhaveahighercomplicationrateowingtoagreaternumberofmedi-calcomorbidities.OfallthepotentialcomplicationsassociatedwithDBS,infec-tionisthemostcommonandcanbedishearteninginpatientswhohaveachievedarobusttreatmentresponse.Inmostinstances,in-fectedcomponentsmustbeexplanted,temporarilyinterruptingtherapy.Becausemostinfectionsoccuratthechestpocket,rapidremovalofthePGandtheextension,followedbyaggressiveanti-biotictherapy,cansalvagethebrainlead,therebyminimizingtheriskanddifficultyofreimplantation.Childrenyoungerthan15yearsareparticularlypronetoinfection;therefore,lowerprofileimplant-ablePGsmaybeadvantageousinthisgroup. Figure3.EvidenceofEfficacyforBrainStimulationinDystonia 100 90 80 70 60 50 40 30 20 10 Change in Dystonia Severity, % DBS-STN Level B evidence Level C evidence Level U evidence ECSGeneralizedCervicalHandCranialAxialSecondaryCombinedDYT-6DYT-1DYT-1ECSOtherMyo-DystLesch-NyanCerebral PalsyCranialWriterÕs Cramp Eachbubblerepresentstheevidencethataparticulartypeofbrainstimulationiseffectiveforaparticulartypeofdystonia.Thepositionofthebubblealongthey-axisindicatesthemeanimprovementindystoniaseverity;thesizeofthebubble,thenumberofpatientsstudied;andthebubbleoutline,thequalityoftheevidenceassessedbyAmericanAcademyofNeurologycriteria(levelB,thickblackoutline;levelC,thickgrayoutline;levelU,nooutline).Treatmentswiththebestevidenceofefficacyhavelargerbubbleshigheronthegraphandareoutlinedbydarkerlines.DBSindicatesdeepbrainstimulation;Dyst,dystonia;DYT-1,generalizeddystoniaduetomutationintheDYT1gene;DYT-6,generalizeddystoniaduetomutationintheDYT6gene;ECS,epiduralcorticalstimulation;GM1,GM1gangliosidosis;Gpi,globuspallidusparsinterna;Myo,myoclonus;PD,Parkinsondisease;PKAN,panthothenatekinase associatedneurodegeneration;RODP,rapid-onsetdystoniaparkinsonism;STN,subthalamicnucleus;TD,tardivedyskinesia;tDCS,transcranialdirectcurrentstimulation;andTMS,transcranialmagneticstimulation. BrainStimulationforTorsionDystoniaReviewClinicalReview&Educationjamaneurology.com(Reprinted)JAMANeurologyJune2015Volume72,Number6717 Copyright 2015 American Medical Association. All rights reserved. AlternativestoDBSAlthoughhighlyeffectiveinproperlyselectedpatients,DBStherapyinvolvesrisks,discomfortsofsurgery,andlong-termlimitations.Dif-ficultiesposedbythechronicallyimplanteddeviceincludeongoingriskofinfection,skinbreakdown,wirebreakage,devicemalfunction,andperiodicbatteryreplacementsurgeryand/ordevicerecharging.Fur-thermore,DBScurrentlyprecludestheuseofbodyMRIunderanyconditionsandbrainMRIcanbeperformedonlyunderrestrictivecon-ditions.Theserisksandlimitationsaremotivatingresearchintoless-invasivebrainstimulationalternatives,suchasepiduralcorticalstimu-lation,inwhichelectrodesareimplantedonthesurfaceofthebrain,andcompletelynoninvasivetechniques,suchastranscranialmagneticstimulationandtranscranialdirectcurrentstimulation.Althoughuseoftheselattertechniquesindystoniaremainsinvestigational,wein-cludetheminthisreviewtoprovideacomparisonbetweenmodalitiesandbecausedystoniapatientswhoarecandidatesforDBSincreasinglyexpressinterestaboutthesealternativetechnologies(eTableintheSupplementandFigure3).ComparedwithDBS,noninva
sivebrainstimulationandepidu-ralcorticalstimulationhavebeenstudiedinafarsmallernumberofpatientsandwithlowereffectsizes.Thereexistssignificanthetero-geneityintrialsofnoninvasivestimulationfordystonia.Targetshaveincludedthepremotorcortex,primarymotorcortex,andthesupple-mentarymotorarea.Stimulationhasbeenappliedatrestanddur-ingspecifictasks,whichmayproveimportantasevidencedinatleastonestudyofpatientswithmusiciansdystonia.Theonlyrandom-izedclinicaltrialwithoutanaccompanyingconflictingreportevalu-atedtranscranialmagneticstimulationtotheanteriorcingulate/supplementarymotorareaforblepharospasm.HowtargetsusedfornoninvasivebrainstimulationrelatetothoseusedforDBSisatopicofactiveinvestigationFigure4 MechanismandFutureDirectionsAtpresentitisunclearhowelectricalbrainstimulationyieldsthera-peuticbenefitindystoniaoranydisorder,whichisanimportantlim-itingfactorinthefurtherdevelopmentofthetherapy.Researchdi-rectedatthisquestionishamperedbyrestrictionsimposedbytheUSFoodandDrugAdministrationregardingtheperformanceofbrainMRIinpatientswithimplantedDBSdevicesandtheethicalcompli-cationssurroundingtheuseofradioligandsforperformingserialposi-tronemissiontomography,particularlyinchildren.Toaddressthisgapinourknowledge,effortsareunderwayatmultiplecenters,in-cludingours,todeveloplow-energyfunctionalMRItechniquestostudytheacuteandlong-termeffectsofDBS.ThefactthattheclinicalresponsetoDBSisdelayedfordaysorweeksandthatsomepatientswhohavereceivedDBStreatmentformanyyearsmaynotexperienceareturnofsymptomsforpro-longedperiodsoftimeafterstimulationceases,suggestthatindys-tonia,DBSmayinduceneuroplasticchangesthatareasyetun-known.Increasingly,dystoniaisconceptualizedasaneuralnetwork25,26andbrainstimulationasanetwork-basedtherapy.Assuch,brainconnectivityandnetworkconsiderationsmayhelpustobetterunderstandstimulationeffectsandguidethediscoveryofnewtherapeutictargetsandtheselectionofoptimalcontactsandsettingsforstimulationwithinatarget.Recentevidencesug-geststhatdisruptingpathologicoscillationswithinthesenetworksplaysaroleinalleviatingphasicdystonicmovements.Thedisrup-tionofpathologicrhythmsoccursrapidlywiththeonsetofstimu-lationand,consistentwiththisnotion,phasicmovementsindysto-niacanrespondquicklytoDBS.However,fixeddystonicposturesthattakelongertorespondmayrequirebrainnetworkreorganiza-tion,whichisamoreslowlydevelopingprocess.Therecentapprovalofthefirstresponsiveneuralstimulatingdeviceforthetreatmentofrefractoryepilepsyhasheightenedex-pectationsforthedevelopmentofclosed-loopedDBSsystemsforthetreatmentofotherconditionsincludingdystonia.Analogoustoon-demandcardiacpacemakers,thesedevicesgeneratetherapeu-ticimpulsesonlywhenanabnormalrhythmisdetected.Thebattery-conservingpropertiesofsuchanapproachcouldproveparticularlyvaluableindystonia,whichoftenrespondsonlytostimulationpara-metersthatdepletebatteriesquickly.Finally,despiteincreasinginterestinnoninvasivestimulationfordystonia,itisclearthatsignificantadditionalresearchisneededbeforethesetherapiesreplicateorevenapproximatetheresponsescurrentlyachievedwithDBS.Criticalfactorsthatmaylimittheabilityofthesenoninvasivetechniquestoachievesignifi- Figure4.LocationandFunctionalRelationshipBetweenInvasiveandNoninvasiveBrainStimulationSitesinDystonia PMdSMA A Negative Positive A,Theglobuspallidusparsinterna,theprimarytargetofdeepbrainstimulationfordystonia,isshowninred.B,Resting-statefunctionalconnectivitywiththisdeepbrainstimulationsiteidentifiespositiveandnegativecorrelationsonthesurfaceofthebrainpotentiallyamenabletononinvasivebrainstimulation.Priortargetsofnoninvasivebrainstimulationareidentifiedincludingprimarymotorcortex(M1),dorsalpremotorcortex(PMd),andsupplementarymotorarea(SMA).ModifiedwithpermissionfromFoxetal. ClinicalReview&EducationReviewBrainStimulationforTorsionDystonia718JAMANeurologyJune2015Volume72,Number6(Reprinted)jamaneurology.com cantresultsindystoniaincludethefactthat(1)atpresent,onlythecortexmaybetargetedunlikeDBS,whichtargetssubcorticalstruc-tures;and(2)thesenoninvasivetechniquesprovideintermittentstimulation,whichmaybeinsufficienttoachievethedesiredclini-calresponse.Studiesofbrainconnectivitymayallowforidentifi-cationofnoninvasivetargetsconnectedtodeepbrainstructures(Figure4).Moreover,noninvasivestimulationmightbecombinedwithaparticularphysicalactivitytoinducenetworkplasticityinashorteramountoftime.Finally,noninvasivetechniquescom-binedwithfunctionalimagingstudiesmayrevealcorticalregionsofinterestthatmaybeamenabletostimulationviachronicallyimplantedstimulatingdevices. Patientswithdystonianotadequatelycontrolledwithstandardmedi-caltherapyshouldbereferredforconsiderationofDBS,especiallypa-tientswithgeneralized,segmental,orcervicaldystonia.Deepbrainstimulationmayalsoprovidebenefitinpatientswithotherdystoniasyndromesincludingtardivedystonia,writerscramp,cranialdystonia,myoclonusdystonia,andoff-statedystoniaassociatedwithParkinsondisease.Less-invasivebrainstimulationmodalitiesmaycircumventsomeoftherisksandlimitationsofDBSbutrequirefurtherresearchbeforebeingconsideredatherapeuticalternativefordystonia. ARTICLEINFORMATIONAcceptedforPublication:Jan
uary2,2015.PublishedOnline:April20,2015.doi:10.1001/jamaneurol.2015.51.AuthorContributions:DrFoxhadfullaccesstoallthedatainthestudyandtakesresponsibilityfortheintegrityofthedataandtheaccuracyofthedataStudyconceptanddesign:Allauthors.Acquisition,analysis,orinterpretationofdata:Draftingofthemanuscript:Fox.Criticalrevisionofthemanuscriptforimportantintellectualcontent:Allauthors.Studysupervision:ConflictofInterestDisclosures:DrFoxislistedasaninventorinissuedpatentsorpatentapplicationsonfunctionalconnectivityandguidanceofbrainstimulation.DrAltermanisapaidconsultanttoMedtronic,Inc.Nootherdisclosureswerereported.Funding/Support:ThepresentworkwassupportedinpartbygrantK23NS083741fromtheNationalInstitutesofHealth,byAAN/AmericanBrainFoundation,andbytheSidneyR.BaerFoundation.RoleoftheFunder/Sponsor:Thefundingorganizationshadnoroleinthedesignandconductofthestudy;collection,management,analysis,andinterpretationofthedata;preparation,review,orapprovalofthemanuscript;anddecisiontosubmitthemanuscriptforpublication..BalintB,BhatiaKP.Dystonia:anupdateonphenomenology,classification,pathogenesisandtreatment.CurrOpinNeurol.2014;27(4):468-476..YianniJ,GreenAL,AzizTZ.Surgicaltreatmentofdystonia.IntRevNeurobiol.2011;98:573-589..VolkmannJ,MuellerJ,DeuschlG,etal;DBSstudygroupfordystonia.Pallidalneurostimulationinpatientswithmedication-refractorycervicaldystonia:arandomised,sham-controlledtrial.LancetNeurol.2014;13(9):875-884..KupschA,BeneckeR,MüllerJ,etal;Deep-BrainStimulationforDystoniaStudyGroup.Pallidaldeep-brainstimulationinprimarygeneralizedorsegmentaldystonia.NEnglJMed.2006;355(19):1978-1990..KupschA,TagliatiM,VidailhetM,etal.EarlypostoperativemanagementofDBSindystonia:programming,responsetostimulation,adverseevents,medicationchanges,evaluations,andtroubleshooting.MovDisord.2011;26(suppl1):S37-S53..Bronte-StewartH,TairaT,ValldeoriolaF,etal.InclusionandexclusioncriteriaforDBSindystonia.MovDisord.2011;26(suppl1):S5-S16..StarrPA,BejjaniP,LozanoAM,MetmanLV,HarizMI.StereotactictechniquesandperioperativemanagementofDBSindystonia.MovDisord.2011;26(suppl1):S23-S30..VitekJL,DelongMR,StarrPA,HarizMI,MetmanLV.IntraoperativeneurophysiologyinDBSfordystonia.MovDisord.2011;26(suppl1):S31-S36..AndrewsC,Aviles-OlmosI,HarizM,FoltynieT.Whichpatientswithdystoniabenefitfromdeepbrainstimulation?Ametaregressionofindividualpatientoutcomes.JNeurolNeurosurgPsychiatry2010;81(12):1383-1389..RughaniAI,LozanoAM.Surgicaltreatmentofmyoclonusdystoniasyndrome.MovDisord.2013;28(3):282-287..MoroE,GrossRE,KraussJK.Whatsnewinsurgicaltreatmentfordystonia?MovDisord.2013;28(7):1013-1020..QuartaroneA.Transcranialmagneticstimulationindystonia.HandbClinNeurol.2013;116:543-553..HallettM.Physiologyofpsychogenicmovementdisorders.JClinNeurosci.2010;17(8):959-965..EdwardsMJ,BhatiaKP.Functional(psychogenic)movementdisorders:mergingmindandbrain.LancetNeurol.2012;11(3):250-260..PanovF,GologorskyY,ConnorsG,TagliatiM,MiraviteJ,AltermanRL.DeepbrainstimulationinDYT1dystonia:a10-yearexperience.Neurosurgery2013;73(1):86-93..CheungT,NoeckerAM,AltermanRL,McIntyreCC,TagliatiM.Definingatherapeutictargetforpallidaldeepbrainstimulationfordystonia.AnnNeurol.2014;76(1):22-30..TagliatiM,KrackP,VolkmannJ,etal.Long-TermmanagementofDBSindystonia:responsetostimulation,adverseevents,batterychanges,andspecialconsiderations.MovDisord.2011;26(suppl1):S54-S62..VidailhetM,VercueilL,HouetoJ-L,etal;FrenchStimulationduPallidumInternedanslaDystonie(SPIDY)StudyGroup.Bilateraldeep-brainstimulationoftheglobuspallidusinprimarygeneralizeddystonia.NEnglJMed.2005;352(5):459-467..VidailhetM,YelnikJ,LagrangeC,etal;FrenchSPIDY-2StudyGroup.Bilateralpallidaldeepbrainstimulationforthetreatmentofpatientswithdystonia-choreoathetosiscerebralpalsy:aprospectivepilotstudy.LancetNeurol.2009;8(8):709-717..OstremJL,RacineCA,GlassGA,etal.Subthalamicnucleusdeepbrainstimulationinprimarycervicaldystonia..2011;76(10):870-878..VolkmannJ,WoltersA,KupschA,etal;DBSStudyGroupforDystonia.Pallidaldeepbrainstimulationinpatientswithprimarygeneralisedorsegmentaldystonia:5-yearfollow-upofarandomisedtrial.LancetNeurol.2012;11(12):1029-1038..FuruyaS,NitscheMA,PaulusW,AltenmüllerE.Surmountingretraininglimitsinmusiciansdystoniabytranscranialstimulation.AnnNeurol.2014;75(5):700-707..KranzG,ShamimEA,LinPT,KranzGS,HallettM.Transcranialmagneticbrainstimulationmodulatesblepharospasm:arandomizedcontrolledstudy..2010;75(16):1465-1471..FoxMD,BucknerRL,LiuH,ChakravartyMM,LozanoAM,Pascual-LeoneA.Resting-statenetworkslinkinvasiveandnoninvasivebrainstimulationacrossdiversepsychiatricandneurologicaldiseases.ProcNatlAcadSc2014;111(41):4367-4375..HendrixCMC,VitekJLJ.Towardanetworkmodelofdystonia.AnnNYAcadSci.2012;1265:46-55..NeychevVK,GrossRE,LehéricyS,HessEJ,JinnahHA.Thefunctionalneuroanatomyofdystonia.NeurobiolDis.2011;42(2):185-201..BarowE,NeumannW-J,BrückeC,etal.Deepbrainstimulationsuppressespallidallowfrequencyactivityinpatientswithphasicdystonicmovements.Brain.2014;137(pt11):3012-3024.BrainStimulationforTorsionDystoniaReviewClinicalReview&Educationjamaneuro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