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OPINIONOpenAccessDrug-induceddyskinesiainParkinson'sdisease.
ShouldsuccessinclinicalmanagementbeafunctionofimprovementofmotorrepertoireratherthanamplitudeofdyskinesiaJean-FranoisDaneault1,2,BenoitCarignan2,3,AbbasFSadikot1,MichelPanisset4andChristianDuval2,5*AbstractBackground:Dyskinesia,amajorcomplicationinthetreatmentofParkinson'sdisease(PD),canrequireprolongedmonitoringandcomplexmedicalmanagement.
Discussion:Thecurrentpaperproposesanewwaytoviewthemanagementofdyskinesiainanintegratedfashion.
Wesuggestthatdyskinesiabeconsideredasafactorinasignal-to-noiseratio(SNR)equationwherethesignalisthevoluntarymovementandthenoiseisPDsymptomatology,includingdyskinesia.
ThegoalofcliniciansshouldbetoensureahighSNRinordertomaintainorenhancethemotorrepertoireofpatients.
Tounderstandwhysuchanapproachwouldbebeneficial,wefirstreviewmechanismsofdyskinesia,aswellastheirimpactonthequalityoflifeofpatientsandonthehealth-caresystem.
TheoreticalandpracticalbasesfortheSNRapproacharethendiscussed.
Summary:Cliniciansshouldnotonlyconsiderthelevelofmotorsymptomatologywhenassessingtheefficacyoftheirtreatmentstrategy,butalsobreadthofthemotorrepertoireavailabletopatients.
Keywords:LID,DID,Levodopa,Deepbrainstimulation,DBS,Treatment,Qualityoflife,Motorcomplication,Motorfluctuations,AlgorithmBackgroundParkinson'sdisease(PD)isaprogressiveneurodegenera-tivediseasecharacterizedbyapredominantlossofdopa-minergicneuronsinthesubstantianigraparscompacta[1]leadingtothedevelopmentofmotorsymptoms.
FourcardinalmotorsymptomsareassociatedwithPD:tremor,musclerigidity,posturalinstabilityandakinesia/bradyki-nesia[2].
PDisalsoassociatedwiththedevelopmentofnon-motorsymptomsstemmingfromthepathologicalinvolvementofparticularbrainstructuresandcomplexneurochemicalimbalances[3].
Thesesymptomsincludepsychiatricmanifestations[4],rapideyemovementandothersleepdisturbances[5,6],mooddisturbance[7,8],bradyphreniaandcognitivedeficits[9-12],anosmia[13],fatigue,autonomicsystemdysfunctionandpain[14].
Althoughbothmotorandnon-motorsymptomscanbedisablingforpatients,currenttreatmentstargetpredomi-nantlythemotordysfunctionusingmainlydopaminergictherapies.
Prolongeduseofdopaminergicagentscanleadtodrug-induceddyskinesia.
Dyskinesiamayhavedeleteriouseffectsonthequalityoflifeofbothpatientsandtheircaregivers,andcreateanadditionalstrainonthehealth-caresystem.
Whileseveralapproachesaretakenbymovementdisorderspecialiststodelayormanagedyskinesia,neurologistsnotspecializedinthetreatmentofmovementdisordersandgeneralpracti-tionersmayfinditdifficulttocontroldyskinesiawhilemaintainingclinicallysignificantreductionsintypicalPDsymptoms.
Inthispaper,weproposeanovelwaytoviewtheclinicalmanagementofdyskinesia,whichcouldbenefitpatientcare.
Inordertocomprehendfullythecomplexityoftheproblemofdyskinesia,wefirstprovideanoverview*Correspondence:duval.
christian@uqam.
ca2CentredeRecherchedel'InstitutUniversitairedeGériatriedeMontréal,4545CheminQueen-Mary,Montréal,Québec,H3W1W4,CanadaFulllistofauthorinformationisavailableattheendofthearticleDaneaultetal.
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biomedcentral.
com/1741-7015/11/762013Daneaultetal;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
ofthetreatmentsforPDandhowtheycaninducedyski-nesia.
Wethenprovideareviewoftheimpactofdyskine-siaonqualityoflifeandhealth-carecosts.
DiscussionHowprominentistheproblemofPDTheprevalencerateofPDwasestimatedafewyearsagotobebetween100to200/100,000population[15-19],withanincidencerateof10to20/100,000population[20,21].
However,thenumberofPDcasesisincreasingandwillhavegrownfrom10millionworldwideinthelate1980s[22]to40millionin2020[23]duemainlytotheagingpopulation.
WhilemostpatientswithPDarediagnosedaftertheageof55(see[24,25]),about10%ofpatientsarediagnosedbeforetheageofforty[26,27]andcharacterizedas'young-onsetPD'[22].
Whilemostyoung-onsetpatientsexhibittypicalparkinsoniansymp-toms[28],theyappeartodisplayslowerdiseaseprogres-sion[25]andshowatendencyforincreasedprevalenceandseverityofmotorfluctuationsanddyskinesiawithprolongedL-3,4-dihydroxyphenylalanine(L-DOPA)ther-apy[22,29-32].
Earlyonsetofmotorcomplicationsmaybeespeciallyrelevantinthesepatientsastheywilllivewiththediseaseforlongerperiods[33]withadiminishedqualityoflife[34]andimpairedsocialandeconomicpro-ductivity[34,35].
WhatarethecurrenttreatmentsofPDBasedontheclassicalmodelofbasalgangliamovementdisorders[36-38],thelossofdopaminergicneuronsassociatedwithPDresultsindepletionofdopaminecontentintotheneostriatum.
Thistranslatesintoalteredbasalganglianeuralactivity,producingachangeintheoutputofthebasalganglia-thalamo-corticalpathways.
ThecardinalhypokineticsymptomsofPDresultfromachangeintheactivityofthalamo-corticalinputstomotorcorticalareaswhichimpairsvoluntarymovement[36,39,40].
Consequently,theprimarygoalofPDtreat-mentistocounteractthedepletionofdopamine.
Sincedopaminecausesseverenausea,andcannoteasilycrossthebloodbrainbarrier,othermeansofcounteractingthisdopaminergicdeficiencyhavebeendeveloped(see[41]and[42]forcomprehensivereviewsofcurrenttreatmentoptions).
Inbrief,thecurrentgoldstandardforthetreatmentofPDmotorsymptomsisL-DOPA[24,25,41,43-46]associatedwithadecarboxylaseinhibitorsuchascarbidopa[47-49].
Overtheyears,severalcom-poundsweredevelopedtobeusedasadjunctstoL-DOPAorasreplacementtherapy.
Catechol-O-methyltransferase(COMT)inhibitorssuchasentacaponeandtolcaponeareusedasadjunctstoL-DOPAinordertoenhanceitsbioa-vailability[26,50,51].
Monoamineoxidase-B(MAO-B)inhibitors,ontheotherhand,areusedtoextendthedura-tionofactionofL-DOPAbydecreasingthemetabolicdegradationofdopamineinthesynapticcleft[1,22,29,46,52-55].
AnotherclassofdrugsthatcanbeusedasanadjunctorreplacementtoL-DOPAisdopamineagonistsastheybindtodopaminergicreceptors,mimickingtheactionofdopamine.
TheywereinitiallyusedtoreducethedoseofL-DOPAtocontrolmotorcomplications[24,41]andmaybeconsideredforinitialmonotherapy[56,57],especiallyinyoungerpatientstodelaytheonsetofdyskinesia.
WhilemedicationsarethemaintherapeuticavenueforthealleviationofPDsymptoms,surgicalprocedurescanalsoprovidesymptomaticreliefinsomepatients.
AblativesurgerieshavebeenusedinthetreatmentofmotordysfunctioninPDforseveraldecadesandcanbeveryeffective[58].
Severalnucleiofthebasalganglia-thalamo-corticalpathwaysaretargetedusingthistechni-que,suchasthethalamus[58-69],theglobuspallidusinternus(GPi)[70-80]andthesubthalamicnucleus(STN)[76,81-90].
Morerecently,deepbrainstimulation(DBS)hasbecomeaninvaluableclinicalmanagementtoolformedicallyintractablemotorsymptoms.
Interest-ingly,DBStargetsthesamestructuresthataretargetedinablativesurgeries[91].
DBStherapyhastheadvantagethatitisreversibleandcanbetitratedbutitsuffersfromcomplicationsandinconveniencesrelatedtopros-theticimplants[92-98].
Inrecentyears,STNandGPiDBS[95,99-109]havebecomethetargetsofchoiceforeffectivereliefofmanymotorsymptomsassociatedwithPD,includingmarkedreductionofdyskinesia[110,111].
Otherstructureswererecentlyinvestigatedforthealle-viationofspecificsymptoms[112].
Forexample,thepedonculopontinenucleus(PPN)[113-116]wastargetedforDBSinpatientswithgaitandposturalimbalanceissues.
Thecentro-median-parafascicular(CM/Pf)com-plex[117]andthezonaincerta[118-121],ontheotherhand,weretargetedinpatientswithtremor,asanalter-nativetothewell-establishedthalamicventrolateral(VL)nucleus.
However,whetherDBSwithinthesealternativestructureshasanimpactondyskinesiahasyettobeassessed.
NovelandexperimentaltreatmentsofmotorsymptomsofPD,someofwhicharepotentiallydisease-modifying,havealsobeenintroduced.
OnepromisingavenueisthedevelopmentofnoveldrugsforthetreatmentofPDsymp-toms.
Forinstance,AdenosineA2A-receptorantagonistsofferthepotentialtoprovidebenefitsthatarenotdeliv-eredbytraditionaldopaminergicmedicationsandmightavoiddopaminergicsideeffectsthroughareductionoftheover-activityinthestriatopallidalpathway[122].
Manyofthesedrugsarecurrentlyindevelopmentandareatdiffer-entphasesofclinicaltrials.
Prodrugsareanotherclassofmedicationcurrentlyunderdevelopment.
Theyareinac-tiveorpoorlyactivecompoundsthatundergoinvivoche-micalorenzymaticactivationthattransformsthemintoDaneaultetal.
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com/1741-7015/11/76Page2of18anactivedrug[123].
Theyhavebetterpharmacokineticandpharmacodynamicpropertiesthanactivedrugs,thushavingthepotentialofimprovedoralabsorption,stabilityandpassageofthebloodbrainbarrier.
Forinstance,differ-entprodrugsareunderdevelopmentfordopamine,dopa-minereceptoragonists,betteruseoftheendogenoustransportsystemsofthebloodbrainbarrieraswellasdifferentpeptideandglutamatergictransportsystems[124].
CelltransplantapproachesforPDhavebeencon-sideredforseveraldecadeswithequivocalinitialresults,especiallywhencomparedtocurrentlyavailabletreat-ments.
However,recentworkhashighlightedthepotentialofthistreatmentfordopaminergicneuronreplacement[125-127].
Finally,therearemanypotentialusesforgenetherapyinPD.
Forexample,itcanbeusedtopromotetheexpressionofagentswhichcannotcrosstheblood-brainbarrier,suchasneurotrophins[128-131].
Preclinicalmod-elsusingneurotrophicfactorsprovidedpromisingneuro-protectiveorneuroregenerativeoutcomes,butinitialtrialsinhumanshavebeenmainlydisappointing.
Genetherapycanalsobeusedtomodifytheinherentpropertiesofneu-ronswithinspecificanatomicalstructures.
Forexample,genetherapywasusedtomodifythephenotypeofSTNneuronsfrompredominantlyexcitatorytopredominantlyinhibitoryinordertorestorebalancewithinthebasalganglia-thalamo-corticalnetwork[132-134].
WhiletheseareallpromisingtreatmentsforPD,muchworkisrequiredwithregardtotherapyandsideeffectspriortoclinicalapplicationtolargerpatientgroups.
Relevanttothepresentpaper,itismainlyunknownwhethertheseemergingtherapiesmaydelay,treatorworsendyskinesia.
WhatarethemainissueswithcurrenttreatmentsLong-termuseofdopamimeticagents,incombinationwithcontinueddopaminergicdenervation,cangeneratedyskinesia.
Indeed,whiledyskinesiaaremainlyasso-ciatedwithfunctionalalterationswithinthebasalgang-liapathwaysrelatedtoprolongedexposuretoL-DOPA,dopamineagonistsandDBScanalsocausetheappear-anceofdyskinesia[135-138].
Theexactmechanismunderlyingdopamineagonist-orDBS-induceddyskinesiaisstillunderinvestigation,butitisbelievedtostemfrommaladaptivemechanismsrelatedtodopaminergicandglutamatergicsystems(see[135]forreview).
Patientsreceivingintra-striataldopaminergicneuralgraftscanalsoexperiencedyskinesia,alsowithoutthepresenceofexogenousdopaminergicagents(off-dyskinesia),possiblyduetoinappropriateresponsestodopaminereleasebygraftedneurons[126,139-141].
Thereareseveraldifferentclassificationsortypesofdys-kinesia,suchasdystonic,ballistic,choreicandmyoclonic,whichcanbemonophasicorbi-phasic[142-145],occur-ringatdifferenttimesinrelationtoadministrationofdopaminergicmedication.
Themostcommondyskinesiaremainthemonophasicchoreictype,whichareinvolun-tarymovementsthatoccuratpeak-doseandareconsid-eredtobepurposeless,non-rhythmic,abrupt,rapid,irregularandun-sustained[143].
Wehaverecentlypro-videdthefirstcharacterizationofthemovementpatternsofmonophasicchoreicdyskinesiabasedonquantitativemeasuresofwhole-bodymovementswhichhighlighttheircomplexity,andvariabilityinamplitudeandlocationovershortperiodsoftime[146-150].
Thismightexplaintherelativedifficultyofpatientstocontrolorcompensatefortheirdyskinesiawhileattemptingtoeitherplanorexecuteeverydaymotoractivities.
SeveralriskfactorsareassociatedwiththeoccurrenceofdyskinesiaincludingageofonsetofPD[151-154],bodyweight[155,156],diseaseduration[157,158],andthelevelofexposuretoL-DOPA[153,159,160].
Anecessaryfactorinthedevelopmentofdyskinesiaappearstobethecombina-tionofdopaminergicdenervationandlong-termexposuretodopaminereplacementtherapythatpromoteschangesinthereceptorenvironmentandresultsinanalteredclinicalresponsetodopamine[161-164].
Underphysiologicalcondi-tions,striatalandsynapticdopaminelevelsaremaintainedatarelativelyconstantlevel[165].
Thedopaminergicdenerva-tionobservedinPD,inassociationwiththeadministrationofL-DOPAatintervalsduringtheday,inducesoscillationsintheconcentrationofstriatalandsynapticdopaminelevels[166,167].
Thispulsatilestimulationofdopaminergicrecep-torisassociatedwithfunctionalchangeswithinthebasalganglia[168,169],whichresultsinalteredneuralactivityinthebasalganglia,thalamusandcerebralcortex[115]withassociatedinvoluntarymovements.
Severalfundamentalfunctionalalterationsinthesynapticenvironmentofthestriatumareassociatedwithdevelopmentofdyskinesia.
Dopaminergicdenervation-inducedpre-synapticmodificationsoccuratthecellularlevelwhichhindersdopaminehomeostasis[153,170-172].
Inaddition,morphologicalandfunctionalalterationsoccurinserotoninergicneurons,whichmaybeahomeostaticattempttocounteractthedysregulationindopaminelevels[173].
Changesalsooccuratthepost-synapticlevelwheredopaminereceptortrafficking[158,174],signalling[157]andsensitivity[161,175]areallalteredindyskineticPDpatients.
Furthermore,N-methyl-D-aspartate(NMDA),a-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA)[151,152,176,177]aswellasmetabotropicglutamatereceptors[178-181]havebeenimplicatedinthemaladaptiveplasti-cityassociatedwithdyskinesia(see[135]forreview).
Whilethedefinitemechanismsbehindtheirrelativeinvolvementremaintobedetermined,thesereceptorsarecurrentlybeinginvestigatedaspotentialtargetsforthemanagementofdyskinesia.
Asidefromthesepre-andpost-synapticchanges,otherfunctionalandstructuralchangesalsoplayaroleDaneaultetal.
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com/1741-7015/11/76Page3of18inthepathogenesisofdyskinesia.
Astrocytesmodulatetheexpressionofvascularendothelialgrowthfactor[182],resultinginmicrovascularremodellingwhichmaybeanintegralpartofthechangesintheneuralenviron-mentthatleadtodyskinesia.
Over-activityofadenosineA2Areceptorsmayalsoplayaroleinthegenerationofdyskinesia[183-188]throughfacilitationofthestriatopalli-dalpathway[189].
Additionally,modifiedextracellularconcentrationsofglutamate[190-193]aswellasanalteredexpressionofglutamatetransportergenes[191,194,195]havebeenobservedindifferentbasalgangliastructureswhendyskinesiaarepresent.
Finally,recentstudiessug-gestedthatdegenerationofinter-hemisphericstriatalmechanismsmayplayasignificantroleinthegenesisofdyskinesiathroughyetundefinedmechanisms[196,197].
Takentogether,thesefunctionalalterationspointtowardsacomplexmulti-factorialmechanismbehindthegenera-tionandexpressionofdyskinesiawhichcouldexplainwhythemanagementofthosemotorcomplicationsissoproblematic.
WhyismanagingdyskinesiaasmuchartasscienceDuetothecomplexpathophysiologyofdyskinesia,therehasbeenconsiderabledebateaboutwhichtreatmentismoreefficaciousforbestsymptommanagementwhilestillavoidingmotorcomplications[28,32-34,40,44,47,48,51,52,198-201].
Severalstudiesexaminedtheincidenceofdyskinesiawithdifferentmedication(see[41]foranexten-sivereview).
Here,wefocusonpossibletreatmentoptionswhendyskinesiahavealreadyoccurred.
Theprimaryoptionforcliniciansistoreducemedicationdosage;how-ever,thiscanleadtotheresurgenceoftypicalparkinso-niansymptoms.
Thesecondoptionistofragmentdosage,reducingeachdoseandincreasingitsfrequencyformoreconstantdeliveryasthepulsatiledeliveryofL-DOPAis,inpart,responsiblefortheobservedfunctionalalterationswithinthebasalganglia.
Theuseofcontrolled-releaseoralmedicationmaylimitthispulsatileeffect[202].
However,theefficacyofsuchcontrolledreleasedrugsintreatingdyskinesiaisinvestigationalatbestandthereislittleevi-dencetosuggestthattheymaydelaytheonsetofdyskine-sia[41].
Nonetheless,theconceptbehindcontrolled-releaseformulations,thatis,amorecontinuousdeliveryofmedicationratherthanapulsatileincreaseinmedicationnormallyobservedwithPDmedication,hasspurredthedevelopmentofcontinuousdrugdelivery(CDD)sys-temssuchasmini-pumpguidedcontinuousapomorphineinfusion[203],duodenalL-DOPAinfusion(Duodopa)[30,201],andtransdermaldeliveryofrotigotine(dopamineagonist)throughapatch[204].
Severalcontinuousdrugdeliverytreatmentsareproposedasusefulinreducingtheincidenceortreatmentofdyskinesia[203,205-207],butthereisinsufficientevidencetocharacterizethemasunequivocallyeffective[41].
Forexample,astudyonananimalmodelofPDdemonstratedthatcontinuousdeliv-eryofrotigotinedidnotinducedyskinesiaandfunctionalsensitization,whereasusinganoralformulationatdiffer-entintervalsdid[208].
Ontheotherhand,apilotstudyonduodenalinfusionofL-DOPAwasshowntoinducesimi-larlevelsofdyskinesiaaspulsatiledeliverysystems;how-ever,oncedyskinesiaarepresent,switchingtoduodenalL-DOPAreducesthedurationofdyskinesia[209].
Thishighlightsthevariabilityintheeffectivenessofthesetreat-ments.
Furthermore,theseapproachestodyskinesiatreat-mentarelimitedduetothecomplexityoftheprocedureandthedifficultlong-termmanagementofpatients.
Indeed,theinvasivenatureofsomeofthesetreatmentslimitsthenumberofpotentialcandidates;andthepoten-tialforseverecomplicationsrequiresadequatemonitoring.
AnotheroptionistocontroldyskinesiabyreducingtheL-DOPAdoseandintroducingdopamineagonists.
Again,thisoptionisnotwithoutproblems,includingthelowerefficacyofdopamineagonistsintreatingmotorsymptoms[210-213],aswellasincreasingtheincidenceofotherdis-ablingsideeffectssuchassomnolence,sleepattacks,dizzi-ness,nausea,delusions,impulsecontroldisorders,hallucinationsandconfusion[214,215].
Inaddition,onemustkeepinmindthatsomestudieshaveobservedtheappearanceofdyskinesiawiththeuseofdopamineago-nistswithouttheconcomitantpresenceofL-DOPA[213].
Therearecurrentlyverylimiteddirectdrugtreatmentsfordyskinesiaasonlytwomedicationswereshowntobeefficacious:amantadineandclozapine[41].
AmantadineisaNMDAreceptorantagonist[216]thatwasshowntoreducesignificantlythedurationandseverityofdyskinesiainseveralstudies[216-218].
However,itsmechanismofactionleadingtoreductionindyskinesiahasyettobecon-clusivelydetermined.
Clozapineisahighaffinityserotoni-nergicagonistaswellasalowaffinitydopamineagonist[219-221].
Onestudydemonstratedtheabilityofclozapinetoreducedyskinesiasignificantly[222].
However,theseveresideeffectsassociatedwithclozapine,suchasagra-nulocytosis[223],centralnervoussystemdepression,sei-zures,dementia,andmyocarditis[224],limititsuseinclinicalpracticeasitrequiresstrictmonitoring.
SurgicalinterventionscanalsoreducedyskinesiainasubsetofpatientsasbothSTNandGPiDBSwereshowntoreducedyskinesiaeffectively[103,109].
Onepossiblemechanismbehindthereductionindyskinesiaisreduc-tioninmedicationdosefollowingsurgicaltreatment[225].
However,theendresultishighlydependentonseveralfactorssuchasleadplacement,stimulationparametersandlevelofreductioninmedications.
Anothersurgicalinterventionthathasdemonstratedareductionindyskine-siaispallidotomy[73,74,226].
Infact,thisinterventionwasshowntobeaseffectiveasSTNDBSforthereductionofdyskinesia[74].
Again,theoutcomeofthisprocedureisgreatlydependentonlesionextentandlocation.
Daneaultetal.
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com/1741-7015/11/76Page4of18FutureavenuesfordrugtreatmentofdyskinesiaincludethedevelopmentofadenosineA2Areceptorantagonists[227,228]aswellastheuseofmetabotropicglutamatereceptor5(mGluR5)antagonists[229]andorthostericmetabotropicglutamatereceptor4(mGluR4)agonists[230].
Whilethesecompoundsarecurrentlyindifferenttestingphases,afewstudiesusingadenosineA2AreceptorantagonistsandmGluR5antagonistshavedemonstratedasignificantreductionindyskinesiainductioninanimalmodels[183,186,231]andsubgroupsofhumansamples[227,229,232].
Ontheotherhand,orthostericmGluR4agonistsareonlybeginningtobestudiedfortheireffectontheindirectpathwayofthebasalganglia.
Maintainingtherapeuticefficacywhileatthesametimetryingtocontroldyskinesiacanbedifficultwithalltreat-mentsforPD.
Cliniciansoftenprogressivelyintroduceanintricatecombinationofmedicationsthatcouldhelpre-establishneurotransmitterbalanceandavoidmotorfluctuations.
Unfortunately,theunavoidabledopaminergicdenervationandreceptorimbalancesrenderthistaskincreasinglydifficultasthediseaseprogresses.
HowprominentistheproblemofdyskinesiaanditsmanagementTheincidenceofdyskinesiaisestimatedat30%to50%afterfiveyearsofinitiatingL-DOPAtreatment[142,198].
Asthediseaseprogresses,theincidencecanincreaseto60%to100%after10years[65,198,211,233,234].
Thesefiguresareevenhigherinyoung-onsetPDwhereitisobservedthatalmostallpatientsexperiencedyskinesiaafteronlysixyearsoftreatment[22].
Oncethesemotorfluctuationsoccur,increasedmonitoringofpatientsisrequired.
However,thelackofmovementdisordersspecia-listsabletohandlesuchcomplexsideeffectsofmedica-tionhinderspropermonitoringofthesepatients.
IntheUnitedStates,theratioofneurologistsvariesdrasticallybetweenregionsrangingfromalowof1andahighof11/100000population[235]withanaveragecloseto5/100000population[236].
InCanada,in2008,thenum-berofneurologistsvariedbetween0and3/100000popu-lationindifferentregionsofageographicallyvastcountry[237].
WhilemostEuropeancountriesfarerelativelywellwithanaverageof5neurologistsper100000population[236],Asia,wherethemajorityoftheworld'spopulationresidesandwheretheexpectednumberofPDcasesisexpectedtogrowseveralfoldinupcomingyears[238],isindireneedofneurologistswithlessthan1/100000population[236].
Ofnoteisthatthesefiguresencompassallneurologists;thenumberofmovementdisordersspe-cialists,whopossessthenecessarytoolstoadequatelymanagethesymptomsofPDandmotorcomplicationsassociatedwiththeirtreatment,ismuchlower,andtoourknowledge,hasneverbeenevaluated.
Anotherissuefacingpatientswithmotorfluctuationsisthatmostmovementdisordersspecialistsarelocatedinlargercities;thusfor-cingpatientsfromremotecommunitiestotravelgreatdis-tancesformedicalconsultationsandfollow-ups.
Theseissuesmayexplainwhyonly45%ofpatientswithPDinOntario(Canada)haveaccesstoaspecialistatleastonceayear[239].
Thelackofaccesstotrainedclinicianshasanegativeimpactonpatientcaresinceconstantmanage-mentofmedicationisrequiredtodelayornegatetheundesiredmotorfluctuations.
WhatwouldbetheimpactofbettermanagementofdyskinesiaonqualityoflifeTheabilitytoengageandmaintainsocialinteractionsisinevitablylinkedtotheabilitytointeractwiththephysicalenvironmentand,assuch,isassociatedonthelevelofindependenceofpatients.
InpatientswithPD,reducedparticipationinsocialactivitiesappearsinpartrelatedtolossofmobilityandimpairsqualityoflife[240,241].
Thisphenomenonislaterexacerbatedduetodiseaseprogres-sionandcomplicationsrelatedtotreatments[242,243].
However,theactualimpactofdyskinesiaonqualityoflifeisstillcontroversial.
Someresearchershavesuggestedthatdyskinesiahaveonlyamoderateimpactonqualityoflifeofpatients[198,244-246].
OnestudyevenobservedanimprovementinqualityoflifeinPDpatientswithdyskine-sia[244].
Anotherrecentstudydemonstratedthat'PatientswithPDexperiencingdyskinesiaarelesslikelytobeconcernedaboutdyskinesiaandmorelikelytopreferdyskinesiaoverparkinsoniansymptomscomparedtopatientswithoutdyskinesia'[247].
Thismaybeexplainedbythepatient'sownperspectiveontheimpactofdyskine-siaonhis/hermotorrepertoire,thatis,themovementsaparticularpatientdeemsimportantforhis/herqualityoflife.
Ofcourse,ifdyskinesiahaveamoderateimpactonthemotorrepertoire,itislikelythathe/shewillnotcon-siderdyskinesiaasproblematic.
Patientswouldratherbeabletoperformtheiractivitiesthanbeconstrictedbytheirparkinsoniansymptoms.
However,suchfindingsmustbeinterpretedcarefully,inlightofrecentevidenceshowingthatdyskineticpatientsmaysufferfromanosognosia,thatisunawarenessofdeficitsassociatedwithanillness[248].
Accordingly,eveniftheydonotcomplainabouttheirinvoluntarymovements,dyskinesiamaystillhaveadele-teriouseffectontheirmotorrepertoire.
Assuch,milddys-kinesiathemselvesmaynotbeproblematic,butmoresevereformsmayreducequalityoflifebyimpactingonthepatients'motorrepertoire.
Infact,otherstudiesshowedthatthepresenceofdys-kinesiaisakeyfactorindeterminingthequalityoflifeofpatients[249-251],especiallyinyoungpatientswhoparticipateintheworkforce.
Studiesshowedthatthemaindimensionsofqualityoflifethatareaffectedbydyskinesiaarepsychological,social[252,253]andstigma[253-255].
Thismaybetheresultoflossinmobility,Daneaultetal.
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com/1741-7015/11/76Page5of18increasedfalls[256],weightloss[156]andevenmodifi-cationsofmotorbehaviorintheOFFstate[257].
OtherstudiesdemonstratedthatthereductioninqualityoflifeofPDpatientswithdyskinesia[258-260]couldalsobearesultofhigherlevelsofanxiety[261-264]anddepres-sion[260],moresothaninpatientswithoutdyskinesia.
However,inthestudyofMonteletal.
[253],theonlyfactorthathadasignificantimpactonqualityoflifewasthepresenceofdyskinesia,notneuropsychiatricmani-festations.
Thisindicatesthatdyskinesiacanaffectpatientqualityoflifedirectlyandalsobyinducing,oratleastmodulatingthelevelofdifferentneuropsychiatricdisorders.
TheimpactofdyskinesiaonthequalityoflifeofPDpatientscanalsobeevaluatedbyassessingtheeffective-nessofinterventionsaimedatcontrollingdyskinesiaonqualityoflife.
Forinstance,arecentstudydemonstratedthatPDpatientshadasignificantimprovementinqualityoflifeafter18monthsofcontinuousintra-duodenalL-DOPAinfusion[265].
Interestingly,theydidnotobserveasignificantchangein'ONmedication'motorsymptoma-tologyaftertreatmentbutdidobserveasignificantreduc-tionindyskinesia.
Assuch,thereductionindyskinesiamayhaveplayedaroleintheimprovementofqualityoflife.
SimilarresultswereobtainedinpatientsundergoingGPiDBSwherethereductionindyskinesiascoreswashighlycorrelatedwiththeimprovementinoverallqualityoflife[266].
Whilethesearemerelytwoexamplesofstu-diesusingqualityoflifeasprimaryorsecondaryendpointstoassesstheimpactofdifferentinterventions,itisbecom-ingmorecommontousequalityoflifetoevaluatethera-peuticeffectiveness.
Anotherissuetoconsideristhatdyskinesiaalsoimpactupononthequalityoflifeofpatients'primarycaregivers(forexample,spouses).
Indeed,asthediseaseprogressesandpatientswithPDbegindealingwithalossofindepen-dence,thequalityoflifeoftheircaregiveralsodegradesastheyaremorepronetosocialisolation,psychologicalpro-blems,suchasdepression,andphysicalissues[267-270].
ThisisevidentthroughtheresultsofMcCabeetal.
[271]wherePDpatientsandcaregiversonlydifferedinphysical-andpsychological-relatedqualityoflife.
Socialinteractionandenvironmentalqualityoflifescoreswerenotsignifi-cantlydifferent[271].
Theseissuesbecomemorepromi-nentwithdiseaseprogressionwhenmotorcomplications,suchasdyskinesia,areapparent[272].
Importantly,ithasbeendemonstratedthatpsychosocialfactorssuchassocialsupportarecriticallyimportanttothecaregivers'qualityoflife[273].
Ashealth-caresystemsareover-extendedandpromotetheimplementationofcommunitycareprogramsasameansofalleviatingpressureonthesystem,thecapa-cityofcaregiverstoprovidesupportbecomesessential[274].
Ifcaregiverburdenisexcessive,itmayreducethequalityofthecarepatientsrequire[273].
Assuch,itisimportanttoacknowledgeandfindwaystooptimizethecaregivers'qualityoflife.
Whatwouldbetheimpactofbettermanagementofdyskinesiaonthehealth-caresystemAsthediseaseprogresses,sodoestheburdenonpatientsandthehealthcommunity[83,275].
Studieshavedemon-stratedtheimmenseeffectofdyskinesiaonthecostsoftreatingPDpatients.
Forinstance,aEuropeanstudyshowedthattheaveragecostperannumforthetreat-mentofPDpatientswithoutdyskinesiawas11,412,butitmorethandoubledto24,990inpatientswithseveredyskinesia[260].
Thisincreaseintreatmentcostwasaccountedforbybothnon-medicalexpenditures,suchascommunityservicesandunpaidhelpprovidedbythecaregiver,andmedicalexpendituresrelatedtomedica-tionandhospitalizationduetomorecomplexandexpen-sivetreatmentregimens[260].
AFrenchstudyalsodemonstratedthatthepresenceofdyskinesiamorethandoubledtreatmentcostsandincreasedmedicalvisits[276].
Theyalsoobservedthattheseverityofdyskinesiaincreasedmedicalcostsbyincreasingtheneedforcare-givers.
ThisledthemtoestimatethetotalannualmedicalcostofdyskinesiainFrancetobebetween588and812millionfrancs[276].
Furthermore,arecentstudyfromtheUnitedStatesshowedthatdyskinesiaresultedinanincreaseintotaltreatmentcostsby29%,andPD-relatedtreatmentcostsby78%comparedtocostsincurredbyPDpatientswithoutdyskinesia[277].
Thistranslatesintoanincreaseof$5,549intheyearfollowingthefirstappearanceofdyskinesiawhencomparedtoPDpatientswithoutdyskinesia.
ThemajorityofthisamountwasrelatedtoanincreaseinPD-relatedcostsof$4,456inpatientswithdyskinesia;nottocostsassociatedwithco-mobidities[277].
Amajorproblemisthatthesedirectcostshavetobeaddedtothealreadyincreasedhealth-relatedexpendi-turesassociatedwithhavingPDcomparedtohealthyaging[278].
InCanada,theannualdirectcostsrelatedtoPDwereestimatedat$202million,whichincludeshospital(44%),drugs(49%)andphysicianconsultations(7%).
Indirectcostsassociatedwithmortality(38%)andmorbidity(62%)wereestimatedat$245million,foratotalofapproximately$447million[278].
Interestingly,agreatproportionofindirectcostsarerelatedtoearlyretirement.
Thedirecthealth-carecostofPDintheUnitedStateswasestimatedat$10,349perpatientperyear[279].
Combiningthesedirectcostswithestimatesofindirectcosts,thetotalcostsofPDintheUnitedStatesmaybeashighas$23billionannually[279].
Ifweconsiderthatthenumberofpersons65yearsofageandolderisexpectedtoincreasesignificantlyovertheupcomingyears,thecostoftreatingPDpatientsislikelytoexceed$50billionannuallyintheUnitedStatesbyDaneaultetal.
BMCMedicine2013,11:76http://www.
biomedcentral.
com/1741-7015/11/76Page6of182040[279].
InChina,theproblemisevengreaterbecauseofthelargernumberofpatients.
In2004,itwasestimatedthattheyearlyhealth-carecostwasabout$925perpatient,whichrepresentshalfofthemeanindividualannualincome[280],foratotalof$1.
57bil-lionannually.
Thetotalcostcorrelatedsignificantlywithdiseaseseverityandthefrequencyofoutpatientvisits[280].
Itisclearthatbetterpatientmanagementisrequiredandoneapproachistodevelopandimplementevidence-basedpractice.
Thequestionthenbecomesifthereductionofdyskinesiaincidenceandseveritycanmodulatethecosts.
Arecentstudyexaminedtheeffec-tiveness(timetolevodopaandtimetolevodopa-induceddyskinesia),cost,andquality-adjustedlife-yearsintwotrialsofdopamineagonists.
Theyshowedthatrasagilinedelayedtheonsetofdyskinesiaby10%andreducedcostsby18%perpatientoverfiveyears[281].
Further-more,aFrenchstudyestimatedthateach10%ofreduc-tioninOFFperiodswouldresultina5%reductionofdirectmedicalcosts[282].
Thesestudiesdemonstratethatfindingapproachestocontroleithertheincidenceortheseverityofdyskinesiaandothermotorfluctua-tionsshouldbedevelopedandimplementedinordertoreducetheburdenonthehealth-caresystem.
WhatisthetheorybehindourproposedapproachtothetreatmentofdyskinesiaEvidence-basedpracticeaimstoapplythebestavailableevidencefromscientificinvestigationstoclinicaldecisionmaking.
Toapplyevidence-basedpracticeforthemanage-mentofdyskinesia,informationabouttheinfluenceofdyskinesiaonvoluntarymovementsmustbeknownsoastounderstandthechallengesfacingpatientswhenplan-ningandexecutingmovementsfromtheirmotorreper-toire.
Itisimportanttodiscriminatebetweenactivitiesofdailylivingandmotorrepertoireofpatientsasactivitiesofdailylivingareessentialforminimalfunctionalindepen-dencewhilethemotorrepertoireencompassesallmove-mentsdeemedimportantforagoodqualityoflifeforaspecificpatient.
Assuch,themotorrepertoirewillbeper-sonalizedandwillvarygreatlydependingonthemove-mentspatientswishtoperformonaregularbasis.
Finally,itisimportanttoassesswhetherothersymptomsarecon-comitantlypresentwithdyskinesia;whichmayinfactberesponsibleformotordeficits.
Todate,severalalgorithmshavebeenproposedtomanagedyskinesia[283,284].
Inter-estingly,thesealgorithmsaregearedtowardsmarkedlyreducingoreliminatingdyskinesia,withoutnecessarilytakingintoaccounthowtheproposedstrategyaffectsthemotorrepertoireofpatients.
Thisisimportantsincesomepatientsmayratherhavemilddyskinesiathenundergotheprocessofmedicationchange,especiallyifdyskinesiadonothindertheirmotorrepertoire.
Indeed,thereductionindyskinesiathrougheitherareductioninmedicationdosageorachangeinmedicationcouldleadtoaresur-genceoftypicalhypo-orhyper-kineticparkinsoniansymptomsimpedingthepatient'svoluntarymotorbeha-viorsandhencereducehisqualityoflifeforthatspecificperiod.
Theclinicianwilljudgewhetherthereductionindyskinesiafollowingtreatmentregimenmodificationbasedonthesealgorithmsisclinicallysatisfactory.
Forthis,cliniciansrelymostlyontheirexperienceandpatientfeedback.
Theycanalsouseclinicalscales[285-288]toassesstheamplitudeofdyskinesiaandtheirimpactonactivitiesofdailyliving.
However,currentscalesonlypro-videageneralsenseoftheamplitudeofdyskinesiaandtheirimpact.
Mostdonotmeasuretheimpactoftheamplitudeofdyskinesiaonvoluntarymovementsandcer-tainlynotontheentiremotorrepertoireofpatients.
Infact,arecentreviewofthedifferentscalesfortheassess-mentofdyskinesiafoundthatoftheeightscalesusedinPD,onlytwowererecommendedforuse(thatis,theAbnormalInvoluntaryMovementScale(AIMS),andtheRushDyskinesiascale)[288].
TheAIMSassessestheamplitudeofdyskinesiaineachlimbwhereastheRushalsoincorporatesasectionontheimpactofdyskinesiaoncertainactivitiesofdailylivingsuchasputtingonacoat.
Arecentscale,thePDYS-26,apatient-basedquestion-naire,focusessolelyontheimpactofdyskinesiaonactiv-itiesofdailyliving[289].
OnemainissueofthesescalesisthattheycannotsegregatetheimpactofdyskinesiaandcardinalsymptomsofPDontheperformanceofmotorbehaviors.
Anotherpointthatrequiresattentionisthat,asmentionedabove,activitiesofdailylivingdonotcircum-scribethewholemotorrepertoiredeemednecessarybyeachpatient;theymerelyrepresentgeneraltasksthatpro-videsomefunctionalindependence.
Forexample,apatientwhoisanartistpainterwithlowamplitudedyskinesiamaydeemthathis/herdyskinesiaaredevastating,whilemostdailylivingactivitiesareactuallyintact(thatis,hecanputonacoat,cuthisfoodanddresshimselfbut,hecannotperformthefinevoluntarymovementsrequiredforhimtopaintacanvas).
Then,onecouldlegitimatelyaskthefol-lowingquestion:howdoestheamplitudeofdyskinesiarelatetoitsimpactonvoluntarymovementsperformedindailylifeTheoppositecouldalsobetrue.
Apatientwithhighlevelsofdyskinesiamayjudgethathis/herinvolun-tarymovementsarenotanissuesincetheyprefertobedyskineticratherthanOFF,asproposedinarecentpaper[247].
Weproposethattheevaluationoftheimpactofdyski-nesiabeviewedasafunctionofasignal-to-noiseratio(SNR).
TheconceptoftheSNRisbasedonthefactthatsuccessofvoluntarymovements(themotoroutput)isdirectlycorrelatedtothemagnitudeoftheintendedvoluntarymovement(thesignal)andinverselycorrelatedwiththemagnitudeoftheinvoluntarymovement(thenoise)inthemotorstream[290-297].
Inotherwords,theDaneaultetal.
BMCMedicine2013,11:76http://www.
biomedcentral.
com/1741-7015/11/76Page7of18likelihoodofsuccessinperformingvoluntarymovementsisnotonlydependentonthemagnitudeofthesymptomspresent,butalsodependentonthetypeofmovementper-formedbythepatients.
Suchananalysiswouldmakeitpossibletodeterminethemotorrepertoireavailabletopatientsbasedonthemagnitudeofsymptoms.
Forinstance,ifapatientpresentsonlywithtremor,theSNRcouldberepresentedbyequation1:Voluntarydriveforaspecicmovement[Tremor]=MotoroutputHere,tremorwouldbecomedeleteriousonlyiftheintendedmovementisbelowathresholdthatwillallowtremortobecloseto,orsupersede,thevoluntarymove-mentinamplitude.
Itcouldalsobedeleteriousifthefre-quencyoftheintendedmovementisclosetothefrequencyofthattremor[298-300].
Ofcourse,thisisanoversimplifi-cationasPDpatientsrarelyexhibitonlyonemotorsymp-tom.
Therefore,amoreaccuraterepresentationoftheSNRobservedinPDpatientswouldbeequation2:Voluntarydriveforaspecicmovement[Tremor]+Bradykinesia+Rigidity+PosturalInstability=MotoroutputHere,thenoisewouldbethesumofallcardinalmotorsymptoms,regardlessoftheirneuralorigin.
Indeed,bradykinesiacouldbecausedbybradyphreniaduringcomplexdecisionmaking,ratherthanalackofcorticalactivationbythalamo-corticalpathways.
Inter-estingly,asthediseaseprogressesandmotorcomplica-tionsarise,more'noise'parameterscouldbeaddedtoequation2suchthatdyskinesiacouldbetakenintoaccount(equation3):Voluntarydriveforaspecicmovement[Tremor]+Bradykinesia+Rigidity+PosturalInstability+Dyskinesia=MotoroutputSuccessforaparticulartaskwouldbepredicatedupontheratiobetweentheamplitudeoftheintendedmove-ment(thesignal;thenumerator)andthemagnitudeofsymptoms(noise;thedenominator)(seeFigure1).
Thisrelationshipbetweenvoluntaryandinvoluntarymovementswasdemonstratedbyusinpreviouswork[290-297].
Forinstance,weshowedthatduringslowalter-natingmovementsatthewrist,tremorwasdetected[295],anditsamplitudewasdirectlycorrelatedwithdeficitsofaccuracy[294].
Duringfastmovement,tremorwasunde-tected,anditsamplitudepreviouslyassessedinthepos-turalconditionwasunrelatedtoperformance[294,297].
Furthermore,weshowedthatventro-lateralthalamotomy[59,61,294]hadnoimpactonfastmovements,butincreasedtheSNRbyremovingtremor,henceimprovingtremendouslytheaccuracyduringslowmovements[294].
Wealsoshowedthatintaskswherethevoluntarymove-mentwasperformedwithvaryingamplitudeandvelocity,thefastersectionspresentedwithhigherSNR,andtherewasareductionindeviationfromtheintendedtrajectoryofthemovement[294,295].
Accordingly,theamplitudeofvelocityoftheintendedmovementseemedtobeimpor-tantindeterminingtheimpactofinvoluntarymovementsonvoluntarymotoracts.
ThisconceptrelatestoFittslaw[301],whichproposesthattwomovementshavingthesameamplitudemaypossessdifferentvelocityprofiles,dependingonthedifficulty(targetsize)ofthetask.
Forexample,bringingaglassofwatertothemouthmayhavethesameamplitudeasbringingaspoonfullofsoup,butthevelocitywillnotbethesamebecauseoftheincreaseddifficultyassociatedwithkeepingthesoupinthespoon.
Assuch,inordertoproperlyassessthecomplexityofavoluntarymovement,bothitsamplitudeandvelocitymustbeexamined.
Inpatientswherewhole-bodypeak-dosedyskinesiawererecordedsimultaneouslywithvoluntarymovements(sametasksasabove),wefoundthatduringfasthandmovements,dyskinesiawerenotvisible[296].
Interestingly,patientswithdyskinesiapresentedwithlevelsofbradykinesiasimilartothoseofPDpatientswithoutdyskinesia[296].
Wealsofoundnorelationshipbetweenthelevelofdyskinesiaandaccuracyduringslowmove-ments[293],indicatingthatdyskinesiamaynothavebeentheprimarysourceoferrorduringmovementsthatrequiredaccuracy.
Thisstronglysupportstheconceptthat'noise'isnotlimitedtovisibleinvoluntarymovements,butmayalsoincludeothersymptomssuchasrigidityorbra-dykinesia[291]asproposedinequations2and3.
Intheaforementionedstudy,patientshadlittleornoclinically-detectablerigidity,sobradykinesiawasprobablythemaincauseofreductioninmotorperformance.
Takentogether,thisillustratesthatdifferenttypesofnoiseobservedinPDcanbeindependentfromeachotherattheneurophysiolo-gicallevelbutcaneachcontributetotheperformanceofagiventask.
Inanotherstudy,wedemonstratedthatpatientswithHuntington'sdiseasepresentingwithchoreawerenotimpairedduringfasthandmovements.
However,theypresentedwithlargeerrorsduringslowmanualtrack-ing,whichcorrelatedwiththeamplitudeofchorea.
ThisillustratesagainthatinvoluntarymovementscanbeofnoconsequencewhentheSNRislargeenough.
ThisalsoindicatesthattheSNRconceptcouldbeappliedtopathol-ogiesotherthanPD.
TheaforementioneddataonPDfitswellwithissuesfacingclinicians.
Indeed,anyreductionindyskinesialevelscouldleadtoincreasedtypicalparkinsonianmotorsymptoms.
Accordingly,cliniciansmayberepla-cingonekindofnoisewithanotherone(thisconceptisillustratedinFigure2).
Tobetterillustratethistheory,wepresentbelowtwohypotheticalsituationsthatcouldbeencounteredinclinicalpractice(Figure2).
Daneaultetal.
BMCMedicine2013,11:76http://www.
biomedcentral.
com/1741-7015/11/76Page8of18Situation1:theclinicianreducesL-DOPAordopa-mineagonistdosageandthelevelofdyskinesiaisreduced.
ThisresultsinanincreasedmotorrepertoirebecauseoftheincreasedSNR.
Dyskinesiamanagementiseffectiveandshouldbepursued.
Situation2:theclinicianreducesmedicationdosageandthelevelofdyskinesiaisreduced,butleadstoareductioninmotorrepertoire.
Assuch,thedyskinesiaportionofthenoiseisreducedbutisaccompaniedbyanincreaseinnoiseassociatedwithtypicalparkinsoniansymptomspresentwhenmedicationislacking,suchasbradykinesiaorrigidity.
Here,thetreatmentregimenshouldbemodifieduntilsituation1isachieved.
Ifsitua-tion1cannotbeachieved,itmaybethathavingsomedyskinesiaisthepreferredsolutionsincethemotorrepertoireisgreaterwithdyskinesia,asdiscussedbyourgroup[293,296]andothers[302].
Surgerymaybecon-sideredasanalternativeinthiscasebecause,asmen-tionedabove,itmaycontroldyskinesiapossiblythroughareductioninmedication.
Theaforementionedapproachwouldseemlogicaltomovementdisordersspecialists,butmaybemoredifficulttoimplementbylessexperiencedclinicianstreatingpatientswithPDexperiencingmotorfluctuations.
Accordingly,weproposethatthereisaSNRrelatedtodyskinesiabelowwhichtheexecutionofavoluntarymovementisrenderedimpossible(ornotfunctionallypossible).
WhetherthisSNRissystematicacrosspatientsorspecifictoeachpatientiscurrentlyunderinvestigationinourlaboratory.
Wealsoproposethatareductionofdyskinesiaamplitudethroughapropermedicationregimenmodificationwillresultinanincreasedmotorrepertoireonlyiftypicalparkinsoniansymptomsdonotre-emergetolevelsaffectingsignifi-cantlytheSNRforspecifictasks.
HowmaythisstrategybetranslatedintoclinicalpracticeWeproposethatcliniciansmaybeabletoviewtreat-mentsuccessasanoptimizationofeachpatient'smotorrepertoire,ratherthansimplytargetingsymptomatology.
Figure1Shownhereisthetheoreticalrelationshipbetweentheamplitudeofinvoluntarymovements(dyskinesia)andthemotorrepertoireofpatients.
Wehypothesizethathigheramplitudesofdyskinesiawillresultinlowersignal-to-noiseratio(SNR;dashedline)and,therefore,alossofmotorrepertoire.
Daneaultetal.
BMCMedicine2013,11:76http://www.
biomedcentral.
com/1741-7015/11/76Page9of18Highly-trainedmovementdisordersspecialistsprobablyusesuchanapproachintuitively,butitisthelackoftoolstohelpclinicianslessexperiencedindealingwithPDpatientsthatshouldbeaddressed.
Forinstance,thepresenceofdyskinesiashouldbedeemeddetrimentalifitsignificantlyimpactstheSNRandthusthemotorreper-toireofeachpatient.
Basedontheaforementionedevi-dence,thereisaneedtodevelopclinicalevaluationprotocolsthatspecificallyassessthemotorrepertoireofpatients.
Suchatoolmustreflectthewiderangeofmove-mentsperformedduringeverydaylifeactivities,itmustincorporateacustomizablesectionandbeeasytoperform,aswellasgiveclinicianstheabilitytofollowtheprogres-sionwithinpatientsandcomparetheresultsbetweenpatients.
Whileacknowledgingthatcurrentclinicalscalesfortheevaluationofdyskinesiaprovideinvaluableinfor-mationregardingtheiramplitudeandimpactonsomeactivitiesofdailyliving,theylackthespecificityforevalu-atingtherangeofthemotorrepertoireaccessibletopatients.
Weunderstandtheimmensedifficultiesasso-ciatedwiththedevelopmentofaclinicalscaleofthistypebut,usingsuchanevaluation,theclinicianwouldbeinabetterpositiontodeterminewhethertheinterventionwashelpfultothepatient,regardlessofitseffectonsympto-matology.
Wearecurrentlyintheprocessofassessingthemotorrepertoireofpatientswithoutdyskinesiaandwithdifferentlevelsofdyskinesiainordertodevelopamodelofinteractionbetweensymptomatologyandmotorbeha-viors.
Oncethisrelationshipisknown,thedevelopmentofsuchatoolcouldbeenvisioned.
SummaryThetreatmentofPDrequirestheevaluationofseveralmotorsymptomsaffectingthequalityoflifeofpatients.
ThelimitednumberofmovementdisordersspecialistsandtheincreasingnumberofpatientswithPDplacesatollonhealth-caresystemsworld-wide.
Theneedtodevelopandimplementevidence-basedmedicineisFigure2Twoexamplestoillustrateoppositeresultsfollowingdrugregimenchange.
Insituation1,achangeindrugregimendecreaseddyskinesiaamplitudewhichthenledtoincreasedsignal-to-noiseratio(SNR)(darkgreylines),andconsequentlyincreasedmotorrepertoire.
Insituation2,thesamechangeindrugregimenalsoledtoareductionofdyskinesiaamplitude.
However,thereisresurgenceoftypicalmotorsymptomsassociatedwithPD,thusincreasingthenoise,whichwillinduceadecreaseofoverallSNR,henceareductioninthemotorrepertoire(lightgreylines).
Here,thepatientdidnotbenefitfromthereductionofdyskinesia,ashis/hermotorrepertoireworsened.
Theseexamplesillustratethechallengesfacedbyclinicianswhenmanagingdyskinesia.
PD,Parkinson'sdisease.
Daneaultetal.
BMCMedicine2013,11:76http://www.
biomedcentral.
com/1741-7015/11/76Page10of18urgent.
Inthisreview,weproposedanovelwaytoviewtheclinicalmanagementofmotorsymptomsinPDandmorespecificallyofdyskinesia.
Whileweacknowledgethatthisviewrequiresfurthertesting,webelievethatsystematizingtheapproachtothetreatmentofmotorsymptomsinPDwillleadtoanimprovementinpatientqualityoflifeand,hopefully,areliefonourhealth-caresystem.
AbbreviationsAIMS:AbnormalInvoluntaryMovementScale;AMPA:α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid;CDD:continuousdrugdelivery;CM/pF:centro-median-parafascicularcomplex;COMT:catechol-O-methyltttransferase;DBS:deepbrainstimulation;GPi:globuspallidusinternus;L-DOPA:L-3,4-dihydroxyphenylalanine;MAO-B:monoamineoxydaseB;mGluR4:metabotropicglutamatereceptor4;mGluR5:metabotropicglutamatereceptor5;NMDA:N-methyl-D-aspartate;PD:Parkinson'sdisease;PPN:pedonculopontinenucleus;SNR:signal-to-noiseratio;STN:subthalamicnucleus;VLthalamus:ventrolateralthalamus.
CompetinginterestsJFD,BC,AFSandCDdeclarethattheyhavenocompetinginterests.
MPhasreceivedresearchgrantsfromTevaNeuroscience,Novartis,andAllergan.
HehasbeenalecturerforAllergan,Merz,NovartisandTeva.
HehasparticipatedinadvisoryboardsforMerck,EMDSerono,Allergan,Merz,Novartis,andTeva.
Authors'contributionsJFD,BCandCDcontributedtothedesignandcontentofthemanuscript.
AFSandMPcontributedtothecontentofthemanuscript.
Allauthorscontributedtorevisionsandapprovedthefinalversionofthemanuscript.
AcknowledgementsJFDandBCareeachrecipientsofaFondsdelaRechercheduQuébec-SantéDoctoralScholarship.
CDissupportedbyaFondsdelaRechercheduQuébec-Santésalarygrant.
CDisalsoaprincipalinvestigatoronaNaturalScienceandEngineeringResearchCouncilofCanadaoperatinggrant,CanadianInstituteofHealthResearchemergingteamgrantandCanadaFoundationforInnovationgrant.
ThisworkwasalsosupportedinpartbyaParkinsonSocietyCanadagranttoCD.
AFSisaprincipalinvestigatoronaNaturalScienceandEngineeringResearchCouncilofCanadaoperatinggrant.
Noneofthefundingbodieshadadirectinfluenceonmanuscriptpreparationandsubmission.
Authors'details1DepartmentofNeurologyandNeurosurgery,MontrealNeurologicalInstitute,McGillUniversity,3801Universitystreet,Montreal,Quebec,H3A2B4,Canada.
2CentredeRecherchedel'InstitutUniversitairedeGériatriedeMontréal,4545CheminQueen-Mary,Montréal,Québec,H3W1W4,Canada.
3DépartementdesSciencesBiologiques,UniversitéduQuébecàMontréal,141AvenuePrésident-Kennedy,Montréal,Québec,H2X1Y4,Canada.
4UnitédestroublesdumouvementAndré-Barbeau,CentreHospitalierdel'UniversitédeMontréal,1560rueSherbrookeEst,Montréal,Québec,H2L4M1,Canada.
5DépartementdeKinanthropologie,UniversitéduQuébecàMontréal,141AvenuePrésident-Kennedy,Montréal,Québec,H2X1Y4,Canada.
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