Delirium and High Fever Are Associated with Subacute Motor ...

Taken together, systemic inflammation with delirium may precipitate subacute deterioration of motor symptoms in PD patients. The purpose of this ... BrowseSubjectAreas ? ClickthroughthePLOStaxonomytofindarticlesinyourfield. FormoreinformationaboutPLOSSubjectAreas,click here. Article Authors Metrics Comments MediaCoverage ReaderComments(0) Figures Figures Abstract Background InParkinsondisease(PD),systemicinflammationcausedbyrespiratoryinfectionssuchaspneumoniafrequentlyoccurs,oftenresultingindeliriumintheadvancedstagesofthisdisease.Deliriumcanleadtocognitiveandfunctionaldecline,institutionalization,andmortality,especiallyintheelderly.InflammationcausesrapidworseningofPDmotorsymptomsandsigns,sometimesirreversiblyinsome,butnotall,patients. Purpose ToidentifyfactorsassociatedwithsubacutemotordeteriorationinPDpatientswithsystemicinflammation. Methods Theassociationofclinicalfactorswithsubacutemotordeteriorationwasanalyzedbyacase-controlstudy.SubacutemotordeteriorationwasdefinedassustainedworseningbyoneormoremodifiedHoehnandYahr(H–Y)stages.Usingmultivariablelogisticregressionincorporatingbaselinecharacteristics(age,sex,PDduration,modifiedH–Ystage,dementia,andpsychosishistory)andstatisticallyselectedpossiblepredictors(peakbodytemperature,durationofleukocytosis,andpresenceofdelirium),theoddsratiosforthesefactorswereestimatedasrelativerisks. Results Of80PDpatientswithsystemicinflammation,26withassociatedsubacutemotordeteriorationweredesignatedascasesandtheremainderascontrols.Inthe26cases,6monthsafteritsonsetthemotordeteriorationhadpersistedin19patientsandresolvedinfour(threewerelostforfollow-up).Multivariablelogisticregressionanalysisshowedthatdeliriumandbodytemperaturearesignificantlyassociatedwithmotordeteriorationaftersystemicinflammation(P = 0.001fordeliriumandP = 0.026forbodytemperature),theadjustedoddsratiosbeing15.89(95%confidenceinterval[CI]:3.23–78.14)and2.78(95%CI:1.13–6.83),respectively. Conclusions InpatientswithPDandsystemicinflammation,deliriumandhighbodytemperaturearestrongriskfactorsforsubsequentsubacutemotordeteriorationandsuchdeteriorationcanpersistforover6months. Citation:UmemuraA,OedaT,TomitaS,HayashiR,KohsakaM,ParkK,etal.(2014)DeliriumandHighFeverAreAssociatedwithSubacuteMotorDeteriorationinParkinsonDisease:ANestedCase-ControlStudy.PLoSONE9(6): e94944. https://doi.org/10.1371/journal.pone.0094944Editor:MathiasToft,OsloUniversityHospital,NorwayReceived:November19,2013;Accepted:March21,2014;Published:June2,2014Copyright:©2014Umemuraetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.Funding:ThestudywassupportedbytheNationalHospitalOrganization.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofmanuscript.Competinginterests:Theauthorshavedeclaredthatnocompetinginterestsexist. IntroductionParkinsondisease(PD),acommonneurodegenerativedisorder,occursmainlyintheelderly.Itischaracterizedbybradykinesia,muscularrigidity,andtremor,thesemotorsymptomsandsignsbeingcausedbyprogressivedopaminergicneuronaldegenerationinthebrain.Dopaminergicneuronaldegenerationprogressesinsidiouslyandconstantly;accordingly,motordisturbancedeterioratesgraduallyinmostpatients[1]–[3].However,somepatientsexperiencesubacuteworseningofmotorsymptomsincertainsituations,themostcommonofwhichareinfections,anxiety,andmedicationproblems[4],[5].Mostsuchsubacutemotordeteriorationsaretransientandreversible.However,evenafteradjustmentofanti-Parkinsonianmedications,theyareirreversibleinsomepatients,suggestingthatsystemicinflammationcanbeassociatedwithpersistentmotorexacerbation.Althoughthemechanismbywhichsystemicinflammationcausessubacuteworseningofmotorsymptomsandsignsisunknown,evidenceobtainedinPDanimalmodelsinwhichinflammationisexperimentallyinducedinthecentralnervoussystemwithattendantsystemicinflammatorystimulihassuggestedthatonepossiblemechanismisaccelerationofdopaminergicneurodegenerationinthesubstantianigra[6]–[8]. Delirium,anacuteandprofounddisturbanceofconsciousness,isaccompaniedbycognitiveandperceptivedisturbancesandfluctuatesdaily[9],[10].Evenafterrecoveryfromdelirium,furtherdeclinesincognition[11]–[14]andfunctionalstatuscanoccurintheelderly[11],[12],sometimeswithconsequentinstitutionalization[11],[14]andmortality[11],[14].Serioussystemicinflammationisamajorcauseofdelirium[15],[16].Takentogether,systemicinflammationwithdeliriummayprecipitatesubacutedeteriorationofmotorsymptomsinPDpatients. ThepurposeofthisstudywastoidentifyfactorsprecipitatingmotordeteriorationaftersystemicinflammationinpatientswithPD,withthefocusontheseverityofsystemicinflammationanddelirium.Usingmultivariablelogisticregression,theoddsratiosforthepredictorswereestimatedasrelativerisks. MaterialsandMethods StudyDesign Anestedcase-controlstudytoinvestigatefactorsprecipitatingmotordeteriorationaftersystemicinflammationinpatientswithPDwasperformed.Theoddsratiosofmotordeteriorationaccordingtovariousprecipitatingfactorswerecalculatedbymultivariablelogisticregressionanalysis. StudySubjects Themedicalrecordsof888consecutivehospitalpatientswithPDwhofulfilledtheUnitedKingdomParkinson’sDiseaseSocietyBrainBankclinicaldiagnosticcriteria(steps1and2)[17]andhadbeenadmittedtotheDepartmentofNeurologyoftheNationalHospitalofUtanofromNovember2006toApril2013werereviewed.Inaccordancewiththepurposeofthestudy,eligibilitycriteriaforthisstudywereasfollows. Inclusioncriteria.(i)Hospitalpatientswithsystemicinflammationand(ii)inmodifiedHoehnandYahr(H–Y)stage4orlessatbaseline. Exclusioncriteria.(i)Deliriumwithinthe6monthspriortotheepisodeofsystemicinflammation.(ii)Comorbidconditionssuchasanoxicencephalopathy,stroke,persistenthypoglycemia,brainsurgery,fractureofthelegsorvertebrae,myelopathy,andsurgery(excludedbecausetheseconditionscouldhaveinterferedwithevaluationofmodifiedH–Ystage).(iii)Medicationerrorsduringperiodofevaluationofsubacutemotordeterioration.(iv)Increaseddosagesofanti-psychoticdrugsordecreaseddosagesofanti-Parkinsonianmedications(L-DOPAequivalentdose[LED]>100mg/day)inpatientswithsubacutemotordeterioration(becauseworseningcouldhavebeeninducedbysuchmedicationchanges).(v)Reductionindosageofanti-psychoticdrugsorincreaseindosageofanti-Parkinsonianagents(LED>100mg/day)inpatientswithoutsubacutemotordeterioration(forthesamereason).(vi)Missingclinicalrecords. ThestudywasapprovedbytheBioethicsCommitteeofUtanoNationalHospital.Accordingtothiscommittee,informedpatientconsentwasnotrequiredbecausethestudywasretrospectiveandthedatawereanalyzedanonymously. DefinitionsofSystemicInflammationandSubacuteMotorDeterioration ThedefinitionofsystemicinflammationwasacombinationofleukocytosisandincreasedconcentrationofplasmaC-reactiveprotein(CRP;normalrange0.0–0.5mg/dL).Leukocytosiswasdefinedasleukocyteorneutrophilcountabovethenormalrange(4,000–9,000/µLforleukocytesand1,480–6,480/µLforneutrophils).MotordeteriorationwasdefinedasworseningofmodifiedH–Ystagebyoneormorestages,thisdefinitionbeingselectedforthefollowingthreereasons:(i)weassumedthatmodifiedH–Ystagewouldbestablefor6months;(ii)thestudywasdesignedtodetectclinicallysignificantexacerbations;and(iii)itwasnotpossibletodetermineUnifiedParkinson’sDiseaseRatingScalePartIII(UPDRS-III)scoresretrospectively. AssessedVariables Thefollowingdatawerecollectedaspossibleprecipitatingfactors:variablesdenotingseverityofinflammation(peakvaluesofbodytemperature,bloodleukocytecounts,andplasmaCRPconcentrations);variabledenotingdurationofinflammation(durationofleukocytosis);andoccurrenceofdelirium.Thedurationofleukocytosiswasdefinedastheperiodfromthetimeoffirstexceedingthenormalrangeofleukocyteorneutrophilcountstothatoftheirnormalization.Thehighestvaluesforbodytemperature,leukocytecounts,andCRPconcentrationsduringleukocytosiswereidentifiedbyassessingbodytemperaturedailyandleukocytecountsandCRPconcentrations2–13times,dependingondurationofinflammation,atmedianintervalsof3days(IQR:1–3)inpatientswithoutdeteriorationand3days(2–4)inthosewithdeterioration.DeliriumwasdiagnosedretrospectivelyinaccordancewiththecriteriaoftheDiagnosticandStatisticalManualofMentalDisorders(DSM-IV)[9]onthebasisofnotesmadeinthemedicalrecordsbyphysiciansandnursingstaff.Thelattercheckedpatientsat2hintervalsthroughoutthedayandrecordeddisturbancesandfluctuationsinconsciousness,cognition,andperception. Thebaselinecharacteristicsofsex,ageofPDonset,ageattimeofsystemicinflammation,PDduration,diseaseseverity(modifiedH–YstageandUPDRS-IIIscores),dementia,Mini-MentalStateExamination(MMSE)scores,historyofpsychosis,initialsymptoms(tremorornot),presenceofsymptomaticorthostatichypotension,LED,anduseofantipsychoticdrugs,dopamineagonists,andcentralanticholinergicdrugs(trihexyphenidyl,biperiden,profenamine,piroheptine,andpromethazine)werecollected.PDduration,UPDRS-IIIscores,dementia,MMSEscores,presenceofsymptomaticorthostatichypotension,anduseofdopamineagonistsandcentralanticholinergicdrugswerecollectedfromthemostrecentmedicalrecordspriortotheonsetofsystemicinflammation.DiagnosesofdementiaweremadeaccordingtoDSM-IVcriteriaandorthostatichypotensionwasdiagnosedbasedonUPDRS-IVcriteria.Ahistoryofpsychosisrequiredeithervisualorauditoryhallucinationsordelusionsbeforetheonsetofsystemicinflammation.ModifiedH–Ystagedatawereretrospectivelycollectedbasedoninformationinthemedicalrecords.ModifiedH–Ystagejustbeforetheonsetofinflammationwasregardedaspre-inflammatorydata,and3weeksormoreafterrecoveryfrominflammationaspost-inflammatorydata.LEDwascalculatedaccordingtothefollowingformula[18];LED = L-DOPA(mg)(or1.33×L-DOPA[mg]iftakingentacapone)+100×pramipexole(mg)+20×ropinirole(mg)+33×rotigotine(mg)+10×bromocriptine(mg)+0.1×pergolide(µg)+66×cabergoline(mg)+10×selegiline(oral,mg)+amantadine(mg)+10×apomorphine(mg).Thosevariableswereassessedanddiagnosesmaderetrospectivelybyoneoftheinvestigators(AU)basedoninformationinthemedicalrecords.DataconcerningmodifiedH–Ystage,LEDandantipsychoticdrugswerecollectedatthefollowingtimepoints. Evaluationofsubacutemotordeterioration.Thesedatawereobtainedattwotimepoints:themostrecentrecordsbeforeonsetandafterrecoveryfromsystemicinflammation.Themedianintervalwas56days(range:28–135)forpatientswithoutseriousdeteriorationand66days(range:23–133)forthosewithsuchdeterioration. Evaluationofprogressionofmotorsymptomsbeforesystematicinflammation.Thesedatawerecollectedfrom3to12monthsbeforethebaselineassessment(medianinterval:188days[range:124–336]fornon-deterioratedpatients,189days[range:133–326]fordeteriorated).Therecordsof11patientswereunavailablebecausetheyhadbeenevaluatedatotherhospitals. Eachvariablewastreatedasfollows:bodytemperature,leukocytecount,CRPconcentration,ageofPDonset,ageattimeofsystemicinflammation,PDduration,UPDRS-IIIscore,MMSEscore,andLEDasscalevariables;durationofleukocytosis(1–3days,4–8days,or9–34days)andmodifiedH–Y(stage2,2.5–3,or4)asordinalvariables;delirium,sex,dementia,historyofpsychosis,initialsymptoms,presenceofsymptomaticorthostatichypotension,anduseofdopamineagonistsandcentralanticholinergicdrugsasdichotomousnominalvariables. StatisticalAnalysis Becauseofitsnon-Gaussiandistribution,scalevariableswerecomparedbetweencasesandcontrolsbynonparametricMann–WhitneyUtest.OrdinalvariablesandnominalvariableswerestatisticallyanalyzedusingtheX2testorFisher’sexacttest,respectively. Associationsbetweenpossibleprecipitatingfactorsandmotordeteriorationaftersystemicinflammationwerestatisticallyanalyzedbymultivariablelogisticregression.First,multicollinearitybetweenscalevariableswasexaminedbySpearman’srankcorrelationcoefficient,followingwhichageofPDonsetwasexcludedfrommultivariablelogisticregressionanalysisbecauseofmulticollinearitywithage(Spearman’srankcorrelationcoefficient = 0.81,P<0.001).Baselinecharacteristics,includingsex,age,PDduration,modifiedH–Ystage,dementia,andhistoryofpsychosis,wereincorporatedintothestatisticalmodel.Precipitatingfactors,includingbodytemperature,durationofleukocytosis,anddelirium,werestatisticallyselectedbyalikelihoodtest(backward).ThefitnessofthemodelwasstatisticallyanalyzedusingtheHosmer–Lemeshowtestandpredictiveaccuracy.AllstatisticalanalyseswerecarriedoutusingGraphPadPrismforWindowsver.5.0(GraphPadSoftware,SanDiego,CA,USA,http://www.graphpad.com)andthestatisticalsoftwareprogramSPSS18.0(PASWstatistics,http://www.spss.com/).Pvaluesof<0.05wereconsideredstatisticallysignificant. Results CharacteristicsofSubjects Ofthe150eligiblepatients,33hadmotordeteriorationafterinflammationand60nodeterioration;theremaining57patientswereexcluded(54becauseofconcomitantdisease,includingdeath[n = 10],affectingmodifiedH–Ystageandthreebecauseofmissingdata).Changesinmedicationdosageaccountedforexclusionofafurthersevenpatientswith,andsixwithout,motordeterioration.Oftheremaining80patients,26withmotordeteriorationaftersystemicinflammationweredesignatedascasesandtheremaining54ascontrols(Figure1).Ofthe80studyparticipants,47hadbeenadmittedbecauseofinflammationwhereastheremaining33haddevelopedinflammationduringhospitalization.Therewerenosignificantdifferencesbetweenthesegroupsintheintervalbetweenbaselinedatainmedicalrecordsandonsetofsystemicinflammationandcausesofinflammation;however,malignantsyndrometendedtobemoreoftenresponsibleintheformerandpyelonephritisandprostatitisinthelatter(TableS1).Medianlengthofhospitalstaywas36.0days(IQR:10.0–94.0)forcontrolsand168.5days(68.8–319.5)forcases.Forty-sixof54controlsand15of26caseswerefollowedforover365daysafterrecoveryfromsystemicinflammation;theremainderwerefollowedupforamedian(IQR)of263.0days(91.0–292.0)forcontrolsand238.0days(155.0–309.0)forcases;mostofthelatterpatientswerecensoredbecausetheyweretransferred(57.9%,11of19patients).ModifiedH–Ystagechangedasfollows. Download: PPTPowerPointslidePNGlargerimageTIFForiginalimageFigure1.Flowdiagramshowingselectionofeligiblepatientsandtheenrollmentprocess.H–Y,HoehnandYahr;LED,L-DOPAequivalentdose. https://doi.org/10.1371/journal.pone.0094944.g001 Subacutemotordeteriorationaftersystemicinflammation.Of26cases,22exacerbatedbyonegrade(range:1–2.5).Twocontrolpatientschangedby0.5ofagrade.Allpatientswereappropriatelymedicated;infourcasesanti-Parkinsoniandrugdosagewasincreased(LEDrange:17–300mg/day)andineightcontrolsitwasdecreased(LEDrange:67–361mg/day). Inthecurrentstudy,exacerbationsofmotorfunctionattributabletoinflammationweredetectedbyidentifyingworseningofmodifiedH–Ystagesbetweenthefollowingtwotimepoints:beforeinflammationandafterrecoveryfrominflammation.BecausemodifiedH–Ystagemayhaveworsenedforreasonsotherthaninflammationbetweenthesetwotimepoints,changesinmodifiedH–Yduringtheperiodbeforeonsetofinflammationwereassessedin69patientsforwhomsufficientdatawereavailable.Ofthese69patients,sixhadprogressedby0.5ofagrade(onecase,fivecontrols);modifiedH–Ystagewasstableintheremaining63patients.Fourpatientshadreductionsinanti-psychoticdrugdosageandthreeincreasesindosageofanti-Parkinsonianagents(LED>100mg/day,range:150–183mg/day)(TableS2). RelevantclinicalandotherpatientvariablesareshowninTable1.Ofthevariablesdenotingseverityofinflammation,therewasasignificantdifferencebetweencasesandcontrolsinbodytemperature(P<0.001).Thedifferencebetweencasesandcontrolsindurationofleukocytosiswashighlysignificant(P<0.001).Leukocytosiscontinuedfor9daysorlongerinhalfthecasesand,incontrast,inonly1.9%ofcontrolpatients.Deliriumoccurredin10controlpatients(18.5%)and21cases(80.8%);thisdifferenceishighlysignificant(P<0.001).Therewasahistoryofpsychosisin84.6%ofcasesand59.3%ofcontrols(P = 0.040).Therewerenosignificantdifferencesinotherbaselinecharacteristicsbetweencasesandcontrols.Themostcommoncauseofsystemicinflammationwaspneumoniainbothcasesandcontrols;therewasnosignificantdifferencebetweenthegroupsincauseofinflammation(Table2).Ofthe26caseswithmotordeterioration,6monthslaterthemotordeteriorationhadpersistedin19patientsandresolvedinfour;relevantrecordswereunavailablefortheremainingthreepatients.Wefoundnosignificantdifferencesinanyfactorsbetweenpatientswhodidanddidnotrecoverfromtheirmotordeterioration(TableS3). Download: PPTPowerPointslidePNGlargerimageTIFForiginalimageTable1.Relevantclinicalandothervariablesofstudyparticipants. https://doi.org/10.1371/journal.pone.0094944.t001 Download: PPTPowerPointslidePNGlargerimageTIFForiginalimageTable2.Causesofsystemicinflammation. https://doi.org/10.1371/journal.pone.0094944.t002 AdjustedOddsRatiosforMotorDeterioration Multivariablelogisticregressionanalysisshowedthatdeliriumandbodytemperatureweresignificantlyassociatedwithmotordeteriorationaftersystemicinflammation(P = 0.001fordeliriumandP = 0.026forbodytemperature).Theadjustedoddsratioswere15.89fordelirium(95%CI:3.23–78.14)and2.78forbodytemperature(95%CI:1.13–6.83)(Table3).TheHosmer–Lemeshowtestshowednosignificance(P = 0.712)andpredictiveaccuracywas89.7%. Download: PPTPowerPointslidePNGlargerimageTIFForiginalimageTable3.Adjustedoddsratiosformotordeterioration(adjustedforage,sex,PDduration,modifiedH–Ystage,dementia,andhistoryofpsychosis). https://doi.org/10.1371/journal.pone.0094944.t003 DiscussionInthisstudy,wefoundthatdeliriumwassignificantlyassociatedwithsubacutemotordeteriorationinPDpatientsafterinflammation(Table2).Althoughbodytemperaturewasalsoassociatedwithsubacutemotordeterioration,theassociationofdeliriumwithmotordeteriorationwassignificantevenafteradjustmentforbodytemperature.Medicationerror,oftenreversible,isanotherreasonformotordeterioration[4],[5];however,ourstudydesignexcludedtheeffectsofmedicationfactors.Of23patientswhodeterioratedbecauseofsystemicinflammation,thechangeswereirreversiblein19forwhomwehadsufficientdata,even6monthsafterrecoveryfrominflammation.Therewerenosignificantdifferencesbetweenpatientswithtransientdeteriorationandthosewithpersistentdeteriorationinanyoftheassessedfactors,includingmedications(TableS3).Multivariatelogisticregressionanalysisofasubgroupexcludingpatientswithtransientdeteriorationproducedsimilarresults(TableS4).Wediagnoseddeliriumaccordingtonotesmadeinthemedicalrecordsbyphysiciansandnursingstaff.Whendeliriumisdiagnosedbasedonrecordingbynurses,thesensitivityisreportedlyrelativelylowandthespecificityhigh[19];therefore,milddeliriummayhavebeenoverlookedinthisstudy,inwhichtheprevalenceofdeliriumwas38.8%(31of80patientscomprising10of34non-demented[29.4%]and21of46dementedpatients[45.7%]).Thisisinlinewithpreviousreports,theprevalencehavingbeenreportedas5–30%ofallelderlypeopleadmittedtoemergencydepartments[20]–[22],10–20%ofnon-dementedpatientswithPD[23],[24],and46%ofdementedPDpatients[24].Anticholinergicdrugscanalsoinducepsychosis[25]anddelirium[24],[26]inPDpatients.Only6.3%(5/80patients)receivedcentralanticholinergicdrugs:toofewtoallowassessmentofanyassociationwiththesedrugs. AsshowninTable2,deliriumduringinflammationwasthestrongestprecipitatorofsubacutemotordeterioration.InanimalPDmodels,cytokineactivationcausedbysystemicinflammatorystimuliinducesdegenerationofnigrostriataldopaminergicneurons[6]–[8].Inthebrain,microgliaandcytokinesplayanessentialroleindelirium[27]–[29].Althoughthepathophysiologyunderlyingsubacutemotordeteriorationremainsunclear,wepostulatethatinflammationinvolvingthecentralnervoussystemleadstocytokineactivationthatcouldbothelicitdeliriumandcausedopaminergicneurodegenerationresultinginmotordeterioration.Inthisstudy,wefoundthatbodytemperaturewasthesecondstrongestprecipitatorofmotordeterioration(Table2).OxidativestressadverselyaffectsdopaminergicneuronsinPDpatients[30]aswellasinanimalandcellculturePDmodels,leadingtodopaminergicneurodegenerationinthepresenceofneuroinflammatoryprocesses[31],[32].Thesedatasuggestthatdopaminergicneuronsmightbesusceptibletoserioussystemicinflammation,raisingthepossibilitythatearlytreatmentofinflammationcouldpreventmotordeterioration. ChangesinUPDRS-IIIscorecanaffectqualityoflifeevenwhenmodifiedH–Ystageisstable[33].However,inthisretrospectivestudy,itwasnotpossibletoaccuratelydetermineUPDRS-IIIscoresbasedondatainthemedicalrecords.BecauseweusedthemorerobustbutlesssensitivemeasureofmodifiedH–YstagetoassessthecourseofPDinourstudypatients,wewereunabletoassessanyassociationsbetweenmildmotordeteriorationandvariousclinicalfactors.However,wedididentifysomeprecipitatorsofmotordeterioration,includingmedicationerrorsandcomorbiditiessuchasdelirium,accordingtothestudyaim.Althoughourinabilitytoidentifyprecipitatorsofmildmotordeteriorationisalimitationofthisstudy,webelievetheprecipitatorswedidestablishareimportantforneurologiststreatingpatientswithPD. Insummary,ourstudyprovidesfurtherevidenceconcerningpredictorsofmotordeteriorationaftersystemicinflammationinpatientswithPD.Thepresentdataindicatethatdeliriumhasthestrongestassociation. SupportingInformationTableS1.Comparisonbetweenpatientswhowereadmittedbecauseofinflammationandthosewhodevelopedinflammationduringhospitalization. https://doi.org/10.1371/journal.pone.0094944.s001(PDF) TableS2.Progressionofmotorsymptomsintheperiodbeforeonsetofsystemicinflammation. https://doi.org/10.1371/journal.pone.0094944.s002(PDF) TableS3.Relevantclinicalandotherdataofpatientswithbothpersistentandtransientdeterioration. https://doi.org/10.1371/journal.pone.0094944.s003(PDF) TableS4.Adjustedoddsratiosforpersistentmotordeterioration(adjustedforage,sex,PDduration,modifiedH–Ystage,dementia,andhistoryofpsychosis). https://doi.org/10.1371/journal.pone.0094944.s004(PDF) AuthorContributionsConceivedanddesignedtheexperiments:AU,TO,H.Sawada.Performedtheexperiments:AUTOH.SawadaH.SugiyamaSTRHMKKP.Analyzedthedata:AUTOH.SawadaH.SugiyamaSTRHMKKP.Contributedreagents/materials/analysistools:AUTOH.SawadaSTRHMKKPH.Sugiyama.Wrotethepaper:AUTOH.Sawada.References1. 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FarooquiT,FarooquiAA(2011)Lipid-mediatedoxidativestressandinflammationinthepathogenesisofParkinson’sdisease.ParkinsonsDis15:247467.Available:http://www.hindawi.com/journals/pd/2011/247467.Accessed15February2011.33. ShulmanLM,Gruber-BaldiniAL,AndersonKE,FishmanPS,ReichSG,etal.(2010)TheclinicallyimportantdifferenceontheunifiedParkinson’sdiseaseratingscale.ArchNeurol67:64–70. ViewArticle GoogleScholar DownloadPDF   Citation XML Print Printarticle Reprints Share Reddit Facebook LinkedIn Mendeley Twitter Email   Advertisement SubjectAreas? FormoreinformationaboutPLOSSubjectAreas,click here. Wewantyourfeedback.DotheseSubjectAreasmakesenseforthisarticle?ClickthetargetnexttotheincorrectSubjectAreaandletusknow.Thanksforyourhelp! Inflammation   IstheSubjectArea"Inflammation"applicabletothisarticle? Yes No Thanksforyourfeedback. Parkinsondisease   IstheSubjectArea"Parkinsondisease"applicabletothisarticle? Yes No Thanksforyourfeedback. 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