帕金森诊治新进展20090514课件

帕金森病诊断新进展张振馨北京协和医院神经内科帕金森病的诊断标准帕金森病的诊断运动减少：随意运动在始动时缓慢，疾病进展后，重复性动作的运动速度及幅度均降低。至少符合下述一项： ⑴肌肉僵直；⑵静止性震颤4-6Hz；⑶姿势不稳（非原发性视觉，前庭功能，脑功能及本体感受功能障碍造成）还需要至少符合下列各项条件中3个或3个以上 ⑴单侧起病，⑵静止性震颤，⑶逐渐进展，⑷发病后多为持续性的不对称性受累，⑸对左旋多巴的治疗反应非常好（70-100%），⑹左旋多巴导致的严重的异动症，⑺左旋多巴的治疗效果持续5年或5年以上，⑻临床病程10年或10年以上排除非帕金森病的诊断帕金森叠加综合征继发帕金森征帕金森病病理分级:Braak2003帕金森病病理并非始于黑质致密部运动前期1：(延髓:IX,X神经背核dm,前嗅核,嗅球)嗅觉；运动前期2：(延髓和桥脑被盖：尾状核、中缝核、巨细胞核，蓝斑下区合成物co)睡眠，头痛，运动减少，情感；运动前期3：(+中脑：杏仁核,黑质致密部sn)色觉，体温调节，认知，抑郁，背疼；期4：四主症(丘脑,mesocortex

mc)；期5：(新皮层hc)运动波动，频发疲劳；期6：(新皮层fc)错乱，视幻觉，痴呆，精神症状帕金森病的临床特征运动症状静止性震颤肌强直运动迟缓姿势平衡障碍非运动症状:精神症状：抑郁、焦虑、认知障碍、幻觉、淡漠、睡眠障碍自主神经症状：便秘、体位性低血压、多汗、性功能障碍、排尿障碍、流涎。感觉障碍：麻木、疼痛、痉挛、不安腿综合征、嗅觉障碍症状的新评估法、非运动症状新诊断标准FirstPDcasereportinChina:(1151-1231)PDwithNon-motorsymptoms:Depressivesymptom久欲自尽手不能绳

Sleepbehaviordisorder夜卧发热衣被尽去

ZhangZi-He(Jindynasty,1151-1231AD)

«RuMenShiQin»:

acasereport:windshakingduetofright.

ZhangZX,etal.ArchNeurol,2006,63:39-41

FeaturesofdementiaassociatedwithParkinson'sdisease

I.Corefeatures

1.DiagnosisofParkinson'sdiseaseaccordingtoQueenSquareBrainBankcriteria2.Adementiasyndromewithinsidiousonsetandslowprogression,developingwithinthecontextofestablishedParkinson'sdiseaseanddiagnosedbyhistory,clinical,andmentalexamination,definedas:ImpairmentinmorethanonecognitivedomainRepresentingadeclinefrompremorbidlevelDeficitssevereenoughtoimpairdailylife(social,occupational,orpersonalcare),independentoftheimpairmentascribabletomotororautonomicsymptomsMuratEmreetal.MovDisorders22,No12,2007,pp1689-1707GoetzCG,EmreM,DuboisB.AnnNeurol2008;64:S81-S92FeaturesofdementiaassociatedwithPDⅡ AssociatedClinicalFeaturesCognitiveFeatures

Attention:inspontaneousandfocusedattention,poorperformanceinattentionaltasks;performancemayfluctuateduringthedayandfromdaytodayExecutivefunctions:intasksrequiringinitiation,planning,conceptformation,rulefinding,setshifting,orsetmaintenance;mentalspeedVisuospatialfunctions:intasksrequiringvisuospatialorientation,perception,orconstructionMemory:infreerecallofrecenteventsorintasksrequiringlearningnewmaterial;memoryusuallyimprovedwithcueing;recognitionisusuallybetterthanfreerecallLanguage:CorefunctionslargelypreservedBehavioralFeaturesApathy:decreasedspoteneity;lossofmotivation,interest,andeffortfulbehaviorChangesinpersonalityandmood:includingdepressivefeaturesandanxietyHallucinations:mostlyvisual,usuallycomplex,formedvisionsofpeople,animals,orobjectsDelusions:usuallyparanoid,suchasinfidelity,orphantomboarderdelusionsExcessivedaytimesleepiness疾病严重度评估

UPDRS：创建于1980s新修订的UPDRS 日常生活的非运动症状 日常生活的运动症状 运动检查 运动并发症新修订的UPDRS的附件 ‘建议的’进一步评估量表，例如：认知/SCOPA-cog，白天思睡/SCOPA-sleepNewUPDRSWorkingDocumentPartII:MotorAspectsofExperiencesofDailyLiving(M-EDL)2.1-2Speech,Saliva&drooling2.3-4Chewingandswallowing，Eatingtasks2.5-6Dressing，Hygiene2.7-8Handwriting，Doinghobbiesandotheractivities2.9Turninginbed2.10Tremor2.11Gettingoutofbed,acar,oradeepchair2.12Walkingandbalance2.13FreezingNewUPDRSWorkingDocumentPartIV:MotorcomplicationsA.Dyskinesias[exclusiveofoff-statedystonia]4.1Timespentwithdyskinesias4.2FunctionalimpactofdyskinesiB.Motorfluctuations4.3Timespentintheoffstate4.4Functionalimpactoffluctuations4.5ComplexityofmotorfluctuationsC.“Off”dystonia4.6Panfuloff-statedystonia黑质致密部受损后(蛋白聚积),增加了多巴胺能神经元的特异性氧化应激过程:增加多巴胺转换,Fe＋＋兴奋性毒性作用,改变细胞的内环境加速黑质细胞的死亡,使黑质变性达到症状阈（黑质细胞减少50％，多巴胺减少70%-80%），这种过程比疾病其他方面（非黑质变性）的临床表现进展更快在疾病的进展期，多巴胺缺乏的临床症状占主导地位；发展到疾病的后期，此时其他的脑区受累的程度到达症状阈值时，他们所引起的非多巴胺能的症状变得明显而导致残疾（掩盖了多巴胺缺乏产生的症状）。重新认识帕金森病临床症状阈的假设诊断TestAcuteL-dopa&apomorphinechallengetestsShouldnotbeusedinthedifferentialdiagnosisofPDGradeBTheuseofacuteapomorphinechallengetoassesswhereapersonwithlaterPDwillstillrespondtodopaminergicmedicationStandardpracticeoftreatingpeoplewithL-dopaasanout-patientTestPDNon-PDSe%Sp%AcuteAPO0.7-10mg2361268685AcuteLD275mg135397587ChroLD<1000mg155479177PD：对L-dopa反应好PSPorMSA：无震颤、对称、迅速恶化Olfactorydysfunction(hyposmia)inneurodegenerativediseaseOlfactorydysfunctionina-synucleinopathiesPD:in80-100%ofnon-dementedpatientsimpaired(olfactorythreshold>discrimination/identification)50%anosmic,35%severehyposmia,15%moderatehyposmiaindependentoftheseverityanddurationofPD,earlyinthecourseoftheclinicaldisease哪些诊断Testing有助于鉴别诊断Olfaction:UPSIT(3ClassIIstudies)PSPsimilartonormal/sig.differenttoPD“Sniffin’sticks”PD/Hyposmiaoranosmia(modtosevere)MSA,PSP,ET/normal,miltomodUPSITPSP,CBD/normalMSA/worsethancontrol,betterthanPDCutoff25,鉴别PD和PDS,se77%,sp85%TestPDvs.PDSCutoffSe%Sp%SniffinSticksPD7

MSA819.5/24.878/100100/63UPSITtestPD118MSA29PSP15CBD7257785UPSITtestPD18

VP14>2285.788.9哪些PD临床特征有助于鉴别诊断鉴别PD/PDS：

跌倒诊断第1年内反复跌倒：PSP较晚跌倒：CBD>DLB>MSA>PD鉴别PD/PDSPDS高HY分级，高UPDRS得分的运动慢少、姿势不稳、步态困难低UPDRS震颤分辅助诊断实验室检查主要针对排除其他疾病和鉴别诊断：常规、生化、电生理、影像。应用帕金森病的生物学标志进行诊断：其意义目前尚无定论。嗅觉功能测试,系统生化指标,基因标志。功能影像：有助于原发性PD早期诊断，及其与PSP、MSA等的鉴别诊断，意义有限。有助于鉴定无症状高危人群,研究PD之予后,评估突触内多巴胺和评估PD的非多巴胺区域PET、SPECT功能显像：DA能神经元突触前功能显像：分为多巴类显像、DA转运蛋白（DAT）显像、2型囊泡单胺转运体显像（VMAT2）DA能神经元突触后功能显像：主要为D1、D2受体显像。 早期PD患者壳核DAD2受体密度升高，而尾状核无变化。 早期PD患者D2受体上调或正常，而PSP、MSA患者的D2受体下降。重新认识帕金森病

提 示出现帕金森病四主症已是疾病中、晚期帕金森病需要早期发现、早期诊断、早期治疗帕金森病的非运动症状可能独立于运动症状单独存在帕金森病治疗目标不仅要缓解运动症状，还要治疗非运动症状和预防运动并发症的发生DDCI-=dopa-decarboxylaseinhibitor;UPDRS=UnifiedParkinson’sDiseaseRatingScaleLevodopaconsistentlyprovidesbettersymptomcontrolcomparedwithdopamineagonistsPramipexoleLevodopa/carbidopap=0.003Levodopa/carbidopaversuspramipexole1–4–2024122442ChangeinUPDRStotalscore–16–14–12–10–8–66183648Time(months)ImprovementFigureadaptedfrom1PSG.ArchNeurol2004;61(7):1044;2Rascoletal.NEnglJMed2000;342(20):1484;3Braccoetal.CNSDrugs2004;18(11):733TreatmentregimenImprovementversuslevodopa/DDCIPramipexole15.9pointsontotalUPDRSscore(p=0.003)at4yearsRopinirole24.48pointsonUPDRSmotorscore(p=0.008)

at5yearsCabergoline32.9pointsonUPDRSmotorscore(p<0.001)at5yearsLevodopa/DDCIversusdopamineagonists–improvementinUPDRStotalafter4or5years300MostpatientseventuallyrequirethesuperiorefficacyoflevodopaforsymptomcontrolNeedforlevodopainpatients

initiatedwithadopamineagonist(pramipexole)1,2Needforlevodopainpatients

initiatedwithadopamineagonist(ropinirole)3,4YearsafterrandomizationYearsafterrandomization

Patientsrequiringsupplementallevodopa(%)53%72%02040608024Figureadaptedfrom1PSG.ArchNeurol2004;61(7):1044;Figureadaptedfrom2PSG.JAMA2000;284(15):1931;Figureadaptedfrom3Rascoletal.NEJM2000;342:1484;Figureadaptedfrom4Rascoletal.MovDisord1998;13(1):39

Patientsrequiringsupplementallevodopa(%)4%66%02040608050.5推荐的一线治疗药物选择:与下列指南一致:TheAmericanAcademyofNeurologyClinical-practiseguidelineTheMovementDisorderSocietyEvidencebasedrecommendationforPDtherapyStarttherapywithanon-ergotdopamineagonistbecauseofthelowriskofmotorcomplicationsduringthefirst5treatmentyears.*循证医学推荐N.N.:Neurology199343:1296-7;MiasakiJM.:Neurology200258:11-17GoetzCG.:MovementDisorder2002(17)Suppl4:S1-166;GoetzCG:MovementDisorder200520:523-39*nopatientpreference;<70yearsold,cognitiveabilityintact.

NuttJG.:NEJM2005

(333)10:1021-27Chronictherapywithconventionallevodopaisassociatedwiththedevelopmentofwearing-offanddyskinesiaResponsethresholdDyskinesiathresholdEarlydiseaseMid-stagediseaseAdvanceddiseaseLongdurationofclinicalbenefitLowincidenceofdyskinesiasDiminisheddurationofclinicalbenefitleadstowearing-offIncreasedincidenceofdyskinesiasClinicalresponsemirrorslevodopaplasmapharmacokineticprofileON-timeisassociatedwithdyskinesiasandwearing-offLevodopa246ClinicaleffectONOFFLevodopa246ClinicaleffectTime(hours)Levodopa246ClinicaleffectFigureadaptedfromObesoetal.Neurology2000;55(4Suppl):S13Time(hours)Time(hours)Wearing-offDyskinesiaInParkinson’sdisease,theabilitytoregulateandmaintainsteadylevelsofdopamineinthebrainisreducedduetoprogressingneuronallossInParkinson’sdisease,conventionallevodopadeliveryleadstopulsatilestimulationofthebrainDeeptroughsinplasmalevodopalevelsleadtopulsatilestimulationofthebrainTheshorthalf-life

(60–90min)ofconventionallevodopaleadstopeaksandprofoundtroughsinplasmalevodopalevels,whicharefurtherworsenedbyintermittentdosingOlanowetal.LancetNeurol2006;5(8):677NormalmovementParkinsonianstateParkinsonianstatewith

intermittentlevodopaParkinsonianstatewith

continuouslevodopaMotorcomplicationsassociatedwithchroniclevodopatherapymaybeduetopulsatilestimulationofdopaminereceptorsDeeptroughsinplasmalevodopalevelscanleadtopulsatilestimulationofthedopaminereceptors,which,inturn,

mayresultin…Wearing-offDyskinesiaHowcanweavoiddeeptroughsinplasmalevodopa?Obesoetal.Neurology2000;55(4Suppl):S13;Olanowetal.LancetNeurol2006;5(8):677疾病进展：多巴胺能细胞减少存活的黑质神经元调节多巴胺释放的能力下降

脑贮备能力下降,血浆中左旋多巴水平下降,缓冲能力下降脉冲给药：受体后机制短的半衰期致脉冲刺激纹状体多巴胺受体，使受体暴露于交替升高和降低的多巴胺环境导致基因表达和神经元的点燃下调，导致运动波动剂末现象的发病机制IncreasingthedoseofconventionallevodopadoesnotpreventdeeptroughsPlasmalevodopatroughsAdaptedfromHänninenetal.MovDisord2007;22(Suppl16):S87Levodopa/carbidopa;

100/25mg;

four-timesdaily,3.5hourly(n=10)

Levodopa/carbidopa;

150/37.5mg;

four-timesdaily,3.5hourly(n=10)Time(hours)Meanplasmalevodopa

concentration(ng/mL)0268101214160500100015002000402468101214160500100015002000IncreasingdosefrequencyofconventionallevodopadoesnotaddresstheproblemofdeeptroughsLevodopa/carbidopa

100/25mg;

four-timesdaily,3.5hourly(n=10)

Levodopa/carbidopa

100/25mg;

five-timesdaily,3hourly(n=9)Time(hours)Meanplasmalevodopaconcentration(ng/mL)PlasmalevodopatroughsAdaptedfromHänninenetal.MovDisord2007;22(Suppl16);S870246810121416050010001500200002481012141605001000150020006Controlled-releaselevodopadoesnotavoiddeeptroughsorpreventmotorcomplicationsFigureadaptedfrom1Kolleretal.Neurology1999;53(5):1012;Stocchi.ExpertOpinPharmacother2006;7(10):1399Plasmalevodopa

concentration(ng/mL)200mgTime(hours)1917151311972000150010005000DelayedON-timeduetoerraticabsorption

TroughProbabilityofdevelopingmotorcomplicationsafter5yearsoflevodopatherapy1ProbabilityTreatment25201550ImmediatereleaseControlledrelease1021.820.6p=NSNS=non-significantOrallevodopaLevodopainfusionPlasmalevodopa

concentration(ng/mL)01000200030004000500041061282Time(hours)Enteralinfusionreversesmotorcomplicationsbyavoidingdeeptroughsinplasmalevodopalevels0OFF-time

(hours/day)Dyskinesiascore

(AIMS)123456789*p<0.001AIMS=AbnormalInvoluntaryMovementScore

**DeeptroughsinplasmalevodopaFigureadaptedfromStocchietal.ArchNeurol2005;62(6):905After6months’treatment(n=6)Levodopamethyl-esterinfusion250mg/mL;

12hoursatinitialrateof125mg/h(n=1)

AvoidingdeeptroughsiskeytoavoidingmotorcomplicationsLevodopainfusionversusconventionallevodopa:Significantlyhighertroughlevels(minimumplasmalevodopaconcentrations[Cmin]),bioavailability(areaunderthecurve)andmaximumplasmalevodopaconcentrations(Cmax)Stocchietal.Ar