1陈生弟帕金森病各阶段治疗策略-2013-8-30-安徽合肥

早晚期帕金森病的治疗策略上海交通大学医学院附属瑞金医院神经科上海交通大学医学院神经病学研究所帕金森病及运动障碍研究中心陈生弟黑质多巴胺(DA)神经元变性危害人类健康的神经变性病：高患病率、高致残率、高治疗费帕金森病（震颤麻痹）1.运动迟缓2.肌强直3.静止性震颤4.姿势步态障碍1.嗅觉减退2.抑郁、焦虑3.睡眠障碍、RBD4.便秘运动症状非运动症状帕金森病的诊断流程图及诊断标准干预治疗常规磁共振、肛门括约肌肌电图检查传统诊断模式瑞金诊断模式病史和体格检查嗅觉检测和头颅超声检查体液PARK7蛋白检测磁共振SWI序列及功能磁共振网络模式DATSPECT检查病史和体格检查常规磁共振、肛门括约肌肌电图检查干预治疗V.S制定诊断标准医学会多种生物学标志物联合检测明显提高临床早期诊断水平临床诊断率JNeurolSci2008;271(1-2):153-157ParkinsonismRelatDisord2012；1780%++++嗅觉检测88%92%头颅超声体液生物标志物94%磁共振SWI及网络模式98%DATSPECT99%+帕金森病治疗药物治疗：西药、中药手术治疗：毁损术、刺激术神经重塑：基因治疗、干细胞移植康复、心理治疗JosephJankovicetal.NeuropsychiatricDiseaseandTreatment.2008,4(4).PharmacologictreatmentoptionsforPD一、帕金森病的早期治疗策略GoalsofTherapyinParkinson’sdiseaseNeuroprotection:DelayorpreventdiseaseworseningSymptomatictherapy:Stop/decreasesymptomsofdiseasePrevention:Current:AvoidofminimizesideeffectsoftreatmentsFuture?:Preventdisease1stGoaloftreatment:NeuroprotectionBUTnoknownneuroprotectiveagent2ndGoaloftreatment:MotorbenefitBUTnotneededifqualityoflifenotimpaired3rdGoaloftreatment:PreventionofsideeffectsBUTallsymptomatictreatmentshaveriskofsideeffectsWhenShouldTreatmentBeStartedinPD?Reasonsforstartingsymptomatictherapy:-Impairmentinactivitiesofdailyliving-ImpairmentinoccupationalstatusWhenShouldTreatmentBeStartedinPD?Oldidea!startedimmediatelyondiagnosis(ideally)butwaitingforsignificantfunctionaldisabilitytodevelop(actually)employment,hobbies,self-care!NaturalRateofProgressioninEarlyPD•EarlyS(H&Y1-2.5)：annual5.1%•LaterS(H&Y3-5)：annual0.4%Clinicalstudies---UPDRSevaluationSchragA,etal.MovDisord2007;22:938-945Neuropathologicalstudytherewasfasterlossofstriataldopaminergicneuronesinearlydisease.FearnleyJM,LeesAJ.AgingandParkinson’sdisease:substantianigraregionalselectivity.Brain1991;114:2283–2301.PD早期多巴胺能神经元丢失与神经退行性变过程呈负指数关系，即随病程的延长多巴胺能神经元丢失减缓。6年PET连续研究的结论：BruckA,etal.MovDisord2009,24:1009-1015HilberR,etal.ArchNeurol2005,62:378-382临床、病理和影像研究的结果均表明：疾病的早期对控制疾病的进展速度相当重要，因为这个阶段才有进行改变疾病病程的干预机会。结论—提倡PD应早期治疗TreatmentinearlyPDshouldbestartedimmediatelyondiagnosisratherthanwaitingforsignificantfunctionaldisabilitytodevelop新理念！（一）神经保护性治疗•Existingdrugsassociatedwith:–mainlysymptomaticreliefformotordisability–graduallossofefficacy–longtermsideeffects•Ifpartialneuroprotectionisachieved,slowingdiseasedeteriorationmayreduceorpreventsignificantdisability&sustainqualityoflifeNoeffectivewaytostoporreversecelldeathRationaleforneuroprotectivetherapyinPD司来吉兰（Selegiline）ZydisSelegilineRasagiline单胺氧化酶B型（MAO-B）抑制剂作用机制•Propargylamine-derivative•Potentanti-apoptoticeffects•IndependentofMAO-BinhibitionKaplan-MeierEstimateofCumulativeProbabilityofReachingEndPointEarlyPDpatients(n=800)randomizedtoselegiline,-tocopherol,selegiline/-tocopherol,placebo,takenforupto24monthsSelegiline(DATATOPstudy)TheParkinsonStudyGroup;NEJM1993;328:176-183.PalhagenetalNeurology2006;66:1200-1206DATATOPtrial:延缓运动功能丧失DATATOPtrialSelegilinemonotherapydelayedtheneedforlevodopaalmost9monthsWhencombinatedwithlevodopa,selegilinewasabletoslowtheprogressionofPD.reducedrequiringlevodopatherapyby50%.ShoulsonI,AnnNeurol2002;51:604–612.HolfordNH,JPharmacokinetPharmacodyn2006;33:281–311.雷沙吉兰（Rasagiline）雷沙吉兰（Rasagiline）雷沙吉兰（Rasagiline）p=0.02Earlytreatment(1mg):effectEarlytreatment(2mg):noeffectProtectedagainsttoxicityinneuronalandanimalexperimentalmodelsofPDCALM-PDstudy:Prospective,parallelgroup,double-blind,randomizedPramipexoleorL-dopamonotherapyinearlyPDREAL-PETstudy:Prospective,parallelgroup,double-blind,randomizedRopiniroleorL-dopamonotherapyinearlyPDJAMA2002;287:1653-61AnnNeurol2003;54:93-101NeuroprotectionwithDopamineagonistsTheParkinson’sStudyGroup.NEJM2004;351:2498-508Levodopa(ELLDOPAstudy)•316drug-naïvePDpatientsrandomizedtoplacebo,or3differentdosesoflevodopafor40weekswith2weeksofwashout•?worsensprogression•Dose-relatedbenefitwithlessdeteriorationinUPDRSscoresvsplacebo•?diseasemodification•Inconsistentwithstriatal[123I]-CITuptakeonSPECT（二）早期症状性治疗•Symptomatictreatmentisrequiredwhenthepatientexperiencesmotordisability•Whatclassofdrugstostart?•MaybehavingdiseasemodifyingeffectsonPDwithexistingsymptomaticdrugs,andpossiblywithanumberofputativeneuroprotectiveagentsUseofexistingsymptomatictherapies?earlytreatmentwhenmotorsymptomsemergeDiagnosisDecisiontotreatYesEvaluatepatientcharacteristics,degreeofdisabilityModerate/severeAged65/70+Significantco-morbidityCognitiveimpairmentMild/moderatedisabilityNocognitiveimpairmentLevodopaDopamineAgonistNoReviewSchapiraandOlanow,AnnNeurol2008;64:S47-55MildmotordisabilityNocognitiveimpairmentMAO-Binhibitor++TreatmentAlgorithmforEarlyPD早期PD治疗患者(≤65岁)且无认知功能障碍患者（65岁）或有认知障碍患者非麦角类DR激动剂MAO-B抑制剂Stalevo复方左旋多巴•金刚烷胺•苯海索复方左旋多巴或＋COMT抑制剂中华神经科杂志2009早期帕金森病的治疗策略首选药物原则1、老年前（65岁）患者，且不伴智能减退，可有如下选择：（1）非麦角类DR激动剂；（2）MAO-B抑制剂司来吉兰，或加用维生素E；（3）金刚烷胺或/和抗胆碱能药：多用金刚烷胺；震颤明显而其他抗PD药物效果不佳时，可选用抗胆碱能药；（4）复方左旋多巴+COMT抑制剂，即Stalevo；（5）复方左旋多巴：一般在①、②、③方案治疗效果不佳时加用。若有认知功能减退，或因特殊工作之需，需要显著改善运动症状，复方左旋多巴也可作为首选。首选药物并非完全按照以上顺序，需根据不同患者的情况，而选择不同方案。若顺应美国、欧洲治疗指南应首选①方案，也可首选②方案，或可首选④方案；若不能承受高价格药物，则可首选③方案；若因特殊工作之需，力求显著改善运动症状，或出现认知功能减退，则可首选⑤或④方案，或可小剂量应用①、②或③方案时，同时小剂量合用⑤方案。首选药物原则2、老年（≥65岁）患