研究生课程-GBS指南解读

武汉大学人民医院湖北省人民医院卢祖能lzn196480,GBS诊疗指南解读,炎症性神经病的分类,DonofrioPD.MuscleNerve,200328(3):273-92.,WinerJB.GBS:clinicalvariantsandtheirpathogenesis.JNeuroimmunol,2011,231(1-2):70-2,GBS亚型及其相互关系,双侧面瘫,pharyngealcephalobrachialvariant,Pathogenesisandrecovery发病机制以及恢复Campylobacterjejuniinfection空肠弯曲杆菌感染ImmuneresponsetoLOS对脂寡糖的免疫反应Cross-reactiveantibodiestonervegangliosides神经节苷脂类的交叉反应性抗体Nervedysfunction神经功能障碍Nerverepair神经修复Outcome转归,Antigenpresentingcell抗原呈递细胞,Complement补体,TcellT细胞,BcellB细胞,Plasmacell浆细胞,Antibodies抗体,Macrophage巨噬细胞,Conductiondysfunction/block传导功能障碍/传导阻滞,Antibodies抗体,Antibodies抗体,Antibodies抗体,Antibodies抗体,Disease-modifyingfactors疾病修饰因素Bacterialfactors细菌因素LOSbiosynthesiscluster脂寡糖生物合成簇GangliosidemimicryofLOS脂寡糖的神经节苷脂拟态Hostfactors宿主因素Geneticpolymorphisms遗传多态性Immunestatus免疫状况Extentofnervedamage神经损害的程度Gangliosidedistributioninnerves神经节苷脂在神经的分布Specificity/affinityantibodies特异性抗体/亲和抗体Complementactivation补体激活Clinicalprognosticfactors临床预后因素Age年龄Severityatonset起病时的严重程度Diarrhoea腹泻,vanDoornPA,etal.LancetNeurol,2008,GBS的免疫生物学,AIDP的免疫机制从巨噬细胞到T细胞所呈现的细菌蛋白抗原表位。T细胞被激活，渗透到内皮，识别交叉反应性抗原，并且在较低的区段释放细胞因子，细胞因子可激活神经内膜的巨噬细胞。这些过程可释放酶和毒性一氧化氮（NO）自由基，并最终侵入致密的髓鞘。在较高的区段，活化T细胞可释放细胞因子，这有助于B细胞产生抗体；所产生的抗体可穿过受损的血神经屏障，并在远离轴突的雪旺细胞表面与未识别的交叉反应性抗原表位相连接，固定补体，损害雪旺细胞，由此产生髓磷脂的水泡样分解,Bacterium细菌,A,Systemicimmunesystem全身免疫系统,Endoneurium神经内膜,血神经屏障,HughesRA,CornblathDR.Guillain-Barrsyndrome.Lancet,2005,AMAN、AMSAN和Fisher综合征的免疫机制细菌的神经节苷脂样抗原表位刺激B细胞诱导抗体，该抗体具有调理交叉反应性轴膜抗原的作用，可固定补体并使得巨噬细胞靶向性侵入轴周间隙，并且阻断传导或引起轴突变性。在Fisher综合征，运动神经末端、突触周围的雪旺细胞也可受到靶向性侵入,Systemicimmunesystem全身免疫系统,Endoneurium神经内膜,Bacterium细菌,B,血神经屏障,HughesRA,CornblathDR.Guillain-Barrsyndrome.Lancet,2005,WillisonHJ,YukiN.Brain,2002.,神经节甙脂类和半乳糖脑苷脂的结构与GBS亚型的相关性,GangliosidesagainstwhichantibodiesarefoundinAMANAMAN中发现的抗神经节甙脂类抗体,GangliosidesagainstwhichantibodiesarefoundinFisherssyndromeFisher综合征中发现的抗神经节甙脂类抗体,Gangliosideagainstwhichantibodiesarefoundinacutesensoryneuronopathy急性感觉神经元病中发现的抗神经节甙脂抗体,GangliosideGM2Galactocerebroside神经节苷脂GM2半乳糖脑苷脂,GalNeuAcGalNAcGlu神经酰胺,ClassificationofGBSandrelateddisordersandtypicalantigangliosideantibodies,bypathology根据病理对GBS及其相关病变分类以及典型抗GM抗体,HughesRA,CornblathDR.Guillain-Barrsyndrome.Lancet,2005,GBSisknowntooccuratallagesGBS在任何年龄均可发生Mostsurveysshowaslightpeakinlateadolescenceandyoungadulthood,andasecondpeakintheelderly轻微高峰：青春期晚期、成人早期另一个高峰：老年期,HahnAF.Guillain-Barrsyndrome.Lancet,1998,352(9128):635-41.,GBSincidenceincreasedby20%forevery10-yearincreaseinageGBS发病率随年龄增长，每增加10岁升高20%TheriskofGBSwashigherformalesthanfemales男性患GBS的风险高于女性,MF,SejvarJJ,BaughmanAL,WiseM,MorganOW.Neuroepidemiology,2011;36(2):123-33.PopulationincidenceofGuillain-Barrsyndrome:asystematicreviewandmeta-analysis.,罗瑛,卢祖能,等.2012,待发表资料,HoTW,MishuB,LiCY,etal.Guillain-BarrsyndromeinnorthernChina.Brain,1995,118(Pt3):597-605.,SeasonaldistributionofGBSpatientsGBS患者发病季节的分布,n=25,n=13,n=24,0%,5%,10%,15%,20%,25%,30%,35%,40%,45%,JantoMar1-3月份,AprtoJun4-6月份,JultoSep7-9月份,OcttoDec10-12月份,夏-秋之交+冬-春之交：64.5%,n=14,64.5%,罗瑛,卢祖能,等.2012,待发表资料,PrecedinginfectionsdetectedserologicallyintwolargeseriesofpatientswithGuillain-Barrsyndrome两大系列GBS患者中通过血清学检测到的前驱感染,HughesRA,CornblathDR.Guillain-Barrsyndrome.Lancet,2005,HoTW,MishuB,LiCY,etal.Guillain-BarrsyndromeinnorthernChina.Brain,1995,118(Pt3):597-605.,中国北方GBS，尤其是AMAN空肠弯曲菌感染可能起重要作用,YeY,ZhuD,WangK,etal.Clinicalandelectrophysiologicalfeaturesofthe2007Guillain-BarrsyndromeepidemicinnortheastChina.MuscleNerve,2010,42(3):311-4.,东北：因饮生水而患GBS73%：腹泻前驱表现仅1例为CJ感染但54%显示为AMAN特征,JNeurolNeurosurgPsychiatry.2011Mar;82(3):300-5.,空肠弯曲菌感染与轴索型GBS密切相关，但并非完全如此某些患者符合目前脱髓鞘的标准,Distributionofprodromiceventsin3mainGBSsubtypes三种主要亚型的前驱事件分布,PlutaRM,LynmC,GolubRM.JAMApatientpage.Guillain-Barresyndrome.JAMA,2011,305(3):319.,DiagnosisoftypicalGBS典型GBS的诊断,AsburyAK,CornblathDRAssessmentofcurrentdiagnosticcriteriaforGuillain-BarrsyndromeAnnNeurol,1990,27(suppl):S21-S24,Deeptendonreflexes(DTRs)couldbenormalorhyperexcitableduringtheentireclinicalcourseinapproximately10%ofGBSpatientsThispossibilityshouldbeaddedinthediagnosticcriteriaforGBStoavoiddelaysindiagnosisandeffectivetreatmenttothesepatients.,YukiN,KokubunN,KuwabaraS,etal.Guillain-Barresyndromeassociatedwithnormalorexaggeratedtendonreflexes.JNeurol,2011,Dec6.Epubaheadofprint,DiagnosisoftypicalGBS典型GBS的诊断,AsburyAK,CornblathDR.AssessmentofcurrentdiagnosticcriteriaforGuillain-Barrsyndrome.AnnNeurol,1990,27(suppl):S21-S24.,DiagnosisoftypicalGBS典型GBS的诊断,AsburyAK,CornblathDR.AssessmentofcurrentdiagnosticcriteriaforGuillain-Barrsyndrome.AnnNeurol,1990,27(suppl):S21-S24.,急性炎症性脱髓鞘性多发性神经根神经病Acuteinflammatorydemyelinatingpolyradiculoneuropathy(AIDP),常有前驱感染史，呈急性起病，进行性加重，多在2周左右达高峰对称性肢体和延髓支配肌肉、面部肌肉无力，重症者可有呼吸肌无力；四肢腱反射减低或消失可伴轻度感觉异常和自主神经功能障碍脑脊液出现蛋白-细胞分离现象电生理检查提示远端潜伏期延长、传导速度减慢、F波异常、传导阻滞、异常波形离散等脱髓鞘表现病程有自限性,中华神经科杂志,2010,43(8):583-585.,学组指南,急性运动轴突性神经病Acutemotoraxonalneuropathy(AMAN),参考AIDP诊断标准，突出特点是神经电生理检查提示近乎纯运动神经受累，并以运动神经轴突损害明显电生理标准运动神经传导：远端刺激时CMAP波幅较正常值下限下降20%以上，严重时引不出CMAP波形，24周后重复测定CMAP波幅无改善；除嵌压性周围神经病常见受累部位的异常外，所有测定神经均不符合AIDP标准中脱髓鞘的电生理改变（至少测定3条神经）感觉神经传导：通常正常针电极肌电图：早期即可见运动单位募集减少，发病12周后，可见大量异常自发电位，此后随神经再生则出现运动单位电位的时限增宽、波幅增高、多相波增多,中华神经科杂志,2010,43(8):583-585.,学组指南,急性运动感觉轴突性神经病Acutemotorandsensoryaxonalneuropathy(AMSAN),参照AIDP诊断标准，突出特点是神经电生理检查提示感觉和运动神经轴突损害明显除感觉神经传导测定可见SNAP波幅下降或无法引出波形外，其他同AMAN,中华神经科杂志,2010,43(8):583-585.,学组指南,Miller-Fisher综合征,急性起病，病情在数天至数周内达到高峰临床上以眼外肌麻痹、共济失调和腱反射减低为主要症状，肢体肌力正常或轻度减退脑脊液出现蛋白-细胞分离病程呈自限性鉴别诊断首先需要与Bickerstaff脑干脑炎（BBE）相鉴别,中华神经科杂志,2010,43(8):583-585.,学组指南,急性泛植物神经病Acutepandysautonomia,急性发病，快速进展，多在2周左右达高峰广泛的交感神经和副交感神经功能障碍，伴或不伴有轻微肢体无力和感觉异常视物模糊、畏光、瞳孔散大、光反应减弱或消失；头晕、体位性低血压；恶心、呕吐、腹泻、腹胀，重症者可出现肠麻痹、便秘、尿潴留、阳萎、热不耐受、出汗少、眼干和口干等可出现脑脊液蛋白-细胞分离现象病程呈自限性排除其他病因,中华神经科杂志,2010,43(8):583-585.,学组指南,AIDPAMANAMSAN,WalgaardC,JacobsBC,vanDoornPA.EmergingdrugsforGuillain-Barresyndrome.ExpertOpinEmergDrugs,2011,16(1):105-20,_,HoTW,MishuB,LiCY,etal.Brain,1995HaddenR,CornblathDR,HughesRA,etal.AnnNeurol,1998HughesRA,CornblathDR.Lancet,2005,AIDP、AMSAN和AMAN的神经生理标准,HoTW,MishuB,LiCY,etal.Brain,1995HaddenR,CornblathDR,HughesRA,etal.AnnNeurol,1998HughesRA,CornblathDR.Lancet,2005,HoTW,MishuB,LiCY,etal.Brain,1995HaddenR,CornblathDR,HughesRA,etal.AnnNeurol,1998HughesRA,CornblathDR.Lancet,2005,HoTW,MishuB,LiCY,etal.Brain,1995HaddenR,CornblathDR,HughesRA,etal.AnnNeurol,1998HughesRA,CornblathDR.Lancet,2005,通常远端明显-因为神经越长倾向于首先受累症状和体征呈远-近梯度-临床上呈袜套-手套样分布-肢体远端较近端更明显,轴突损害为主,脱髓鞘为主,沿神经行程多灶脱髓鞘-起病时或病程早期：远、近端均受累临床上-远端+近端：无力、感觉障碍,脱髓鞘性多神经根神经病-远端+近端-肌肉+皮肤脱髓鞘性神经病-通常会有不同程度的轴突损害脱髓鞘为主v.s.脱髓鞘+轴突损害-临床鉴别很困难，EDX有帮助,潜伏期延迟/NCV减慢传导阻滞-近端波幅低于远端波幅(50%)异常时间离散,脱髓鞘的电生理表现,Abnormaltemporaldispersion,Guillain-Barr综合征患者：潜伏期均延长、波形离散同一部位连续检测4次波形基本相似，说明了结果的一致性良好,腘窝踝部胫神经,1,肘部腕部尺神经,左侧右侧,传导阻滞+异常时间离散,腕部刺激肘部刺激腋窝刺激颈部刺激,颈部刺激、对冲,10mV,异常时间离散近端波幅减低面积几乎无变化负峰时限延长,正中神经刺激拇短展肌记录,郎飞结结间,瞬态钠通道,Despitethepossibilityofmixedabnormalities,theelectrophysiologicfindingsofanytrueaxonalordemyelinatingcomponentprovidesanimportantandmajorcontributioninthedifferentialdiagnosis.Certainconductionabnormalitiessupportthediagnosisofapredominantlydemyelinatingcomponentevenwhensuperimposeduponmoderateaxonaldegenerationasdemonstratedonneedleelectromyogarphy.轴突损害+脱髓鞘：同时存在-如有肯定传导异常：速度减慢、潜伏期延长、传导阻滞-即使合并存在针肌电图显示轴突变性-还是支持脱髓鞘为主的诊断,KimuraJ.ElectrodiagnosisinDiseasesofNerveandMuscle：PrinciplesandPractice.3thed,NewYork:OxfordUniversityPress,2001:68-80.,脱髓鞘为主vs轴突丧失为主难以区别的主要原因,除了脱髓鞘神经病中的髓鞘和雪旺细胞受累之外，轴突性神经病中快传导、大纤维的继发性丧失也可引起传导减慢同样，除了轴突性神经病中的轴突变性和纤维丧失之外，脱髓鞘神经病中的时间离散或继发性轴突丧失也可引起CMAP或SNAP波幅减低(JohnsenandFuglsang-Frederiksen,2000;Tankisietal.,2007)事实上，与预期的相反，在脱髓鞘性多神经病，波幅的减低常常比轴突性多神经病更明显(BuchthalandBehse,1977;HardingandThomas,1980;Tankisietal.,2007),HoTW,MishuB,LiCY,etal.Guillain-BarrsyndromeinnorthernChina.RelationshiptoCampylobacterjejuniinfectionandanti-glycolipidantibodies.Brain,1995,118(Pt3):597-605.,我国北方地区AMAN65%；AIDP24%；未分类11%,HughesRA,CornblathDR.Guillain-Barrsyndrome.Lancet,2005,366(9497):1653-66.,北美和欧洲的GBS通常为AIDP型仅5：轴索型,N=72,HistogramofelectrophysiologicalsubtypesinGBSpatients(95%confidenceintervals,CI)GBS患者电生理亚型分布的直方图（95%可信区间）,44.4%,Axonalsubtype26.4%,InexcitableEquivocalNormal,罗瑛,卢祖能,等.2012,待发表资料,HaddenRDM,CornblathDR,HughesRA,etal.AnnNeurol,1998,44(5):780-88ElectrophysiologicalclassicationofGuillain-Barrsyndrome:clinicalassociationsandoutcome.PlasmaExchange/SandoglobulinGuillain-BarrSyndromeTrialGroup,SekiguchiY,UnciniA,YukiNetal.AJapanese-ItaliancollaborativestudyJNeurolNeurosurgPsychiatry,2012,83(1):23-8,病程不同，亚型改变,GM抗体(-),GM抗体(+),SekiguchiY,UnciniA,YukiN,etal.AJapanese-Italiancollaborativestudy.JNeurolNeurosurgPsychiatry,2012,83(1):23-8.,JNeurolNeurosurgPsychiatry,2011,82(6):592.,有必要将各种轴索型GBS再进一步细分?同一疾病谱的一部分！只是疾病范围和严重程度不同而已！,DifferentialdiagnosisofGBSGBS的鉴别诊断,vanDoornPA,RutsL,JacobsBC,etal.LancetNeurol,2008,GBS,treatment-relatedfluctuation(TRF)andacute-onsetCIDP(A-CIDP)GBS、治疗相关性波动(TRF)和急性起病CIDP(A-CIDP),A-CIDP,GBS,vanDoornPA,etal.LancetNeurol,2008,7(10):939-50,GBS-TRF,Upto16%ofCIDPpatientsmaypresentacutelyA-CIDPpatientsweresignificantly-morelikelytohaveprominentsensorysigns-lesslikelytohave-autonomicnervoussysteminvolvement-facialweakness-aprecedinginfectiousillness-needformechanicalventilation,DionneA,NicolleMW,HahnAF.MuscleNerve.2010;41(2):202-7.Clinicalandelectrophysiologicalparametersdistinguishingacute-onsetCIDPfromAIDP.,CIPD可能急性起病：多达16%A-CIDP患者-更可能出现突出的感觉体征-较小可能出现以下情况-自主神经功能受累-面肌无力-前驱感染-需要机械通气,DionneA,NicolleMW,HahnAF.MuscleNerve.2010;41(2):202-7.,感觉性共济失调振动觉重度障碍针刺觉异常突出的感觉症状自主神经功能障碍机械通气呼吸肌无力面肌无力前驱感染,A-CIDP,AIDP,ThediagnosisofA-CIDPshouldbeconsidered以下情况应考虑急性起病的CIDP（A-CIDP）,WhenapatientthoughttohaveGBS-deterioratesagainafter8weeksfromonset,or-whendeteriorationoccurs3timesormoreEspeciallywhenthepatient-remainsabletowalkindependently,and-hasnocranialnervedysfunction,or-electrophysiologicfeatureslikelytobecompatiblewithCIDPMaintenancetreatmentforCIDPshouldbeconsidered,起病后8周再次恶化出现3次或以上恶化,以下情况尤其如此，且应考虑CIDP的维持治疗仍然能够独立行走无颅神经功能障碍EDX符合CIDP,RutsL,DrenthenJ,JacobsBC,etal.Neurology,2010,74(21):1680-6Distinguishingacute-onsetCIDPfromfluctuatingGuillain-Barresyndrome:aprospectivestudy,GBS的实验室检查项目,HughesRA,CornblathDR.Guillain-Barrsyndrome.Lancet,2005,GBS病程中的管理(1),vanDoornPA,RutsL,JacobsBC,etal.LancetNeurol,2008,GBS病程中的管理(2),vanDoornPA,RutsL,JacobsBC,etal.LancetNeurol,2008,Guillain-BarrsyndromedisabilityscaleHughesGBS残疾评分,HughesRA,Newsom-DavisJM,PerkinGD,etal.Lancet,1978.PlasmaExchange/SandoglobulinGuillain-BarrSyndromeTrialGroup.Lancet,1997.,HughesRA.Giveortake?IntravenousimmunoglobulinorplasmaexchangeforGuillain-Barresyndrome.CritCare,2011,15(4):174,Neurology,March27,2012;78(13):1009-15.,应予以IVIG,个体化治疗很重要,GBS病程中的管理(3),vanDoornPA,RutsL,JacobsBC,etal.LancetNeurol,2008,Noneofthetreatmentssignificantlyreducedmortality任何治疗均不降低死亡率Since20%ofpatientsdieorhavepersistentdisabilitydespiteimmunotherapy即使进行了免疫治疗仍有大约20%患者死亡或持久致残Moreresearchisneededtoidentifybettertreatmentregimensandnewtherapeuticstrategies需要更多研究确定更好的治疗方案制定新的治疗策略,HughesRA,etal,Brain2007,130(9):2245-2257ImmunotherapyforGuillain-Barrsyndrome:asystematicreview,ChioA,CocitoD,LeoneM,etal.Neurology,2003,60(7):1146-50Guillain-Barresyndrome:aprospective,population-basedincidenceandoutcomesurvey,Neurology,2003,60(7):1146-50,评分3年龄50岁轴突或混合型年龄50岁无呼吸道前驱感染,运动障碍自主神经功能障碍（高血压、心动过速）二者程度直接相关高血压多发生在运动障碍最重的2448h内,DimarioFJ,EdwardsC.JChildNeurol,2012Jan12EpubaheadofprintAutonomicDysfunctioninChildhoodGuillain-Barrsyndrome,AIDP心动过速排汗过多或减少皮肤血管舒缩功能保留,AsahinaM,KuwabaraS,SuzukiA,etal.ActaNeurolScand,2002,105(1):44-50.AutonomicfunctionindemyelinatingandaxonalsubtypesofGuillain-Barrsyndrome.,AMAN一般不出现明显植物神经功能紊乱除外：严重度神经功能缺失者可见排汗功能不良,ThepatternsofautonomicinvolvementarequalitativelydifferentbetweenAIDPandAMANAIDPischaracterizedbycardio-sympathetichyperactivity,excessiveorreducedsudomotorfunctionandpreservedskinvasomotorfunctionAMANisnotnecessarilygenerallyassociatedwithmarkedautonomicdysfunctionexceptforthesudomotorhypofunctionseeninpatientswithsevereneurologicaldeficits,Neurophysiologicaltestingishelpfulforassessingriskofrespiratoryfailure,whichishighestinpatientswithevidenceofdemyelination电生理检测有助于评估呼吸衰竭的风险有脱髓鞘证据者：风险最高,DurandMC,PorcherR,Orlikowski,Detal.ClinicalandelectrophysiologicalpredictorsofrespiratoryfailureinGuillain-Barrsyndrome:aprospectivestudy.LancetNeurol,2006,5(12):1021-8.,早期识别预后差的因素高龄、病前腹泻史、MRC总分低,WalgaardC,LingsmaHF,RutsL,etal.Neurology,2011,76(11):968-75.EarlyrecognitionofpoorprognosisinGuillain-Barrsyndrome.,Relationbetweeninfections,antigangliosideandclinicalcourseofGBS感染、抗神经节苷脂类抗体、GBS临床过程之间的相互关系,vanDoornPA,etal.LancetNeurol,2008,7(10):939-50,WalgaardC,JacobsBC,vanDoornPA.ExpertOpinEmergDrugs,2011,16(1):105-20,12345678910111213141516171819202122,MildlyaffectedGBS,SeverelyaffectedGBS,SeverelyaffectedGBS,SeverelyaffectedGBS,GBS的异质性病程,CIDP临床诊断标准(EFNS/PNS),EFNS/PNSGuidelineonmanagementofCIDP:reportofajointtaskforceoftheEFNS/PNS-FirstRevision.JointTaskForceoftheEFNSandthePNS.JPeripherNervSyst,2010,15(1):1-9.,CIDP电诊断标准（EFNS/PNS指南）,EFNS/PNSGuidelineonmanagementofCIDP:reportofajointtaskforceoftheEFNS/PNS-FirstRevision.JointTaskForceoftheEFNSandthePNS.JPeripherNervSyst,2010,15(1):1-9.,CIDP治疗的推荐,EFNS/PNSGuidelineonmanagementofCIDP:reportofajointtaskforceoftheEFN