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抗癫痫药物临床治疗指南新看点制订临床指南的目的应用指南是一种系统性阐述，用以帮助职业医师以及患者对于特定临床情况作出适当的医疗决定临床指南的存在问题1.评估标准不统一2.缺乏证据≠不存在的证据3.时间局限性→过时、更新4.受到药厂的影响，有一定的

利益因素5.由少部分专家制定6.个体差异7.临床医生执行时困难ShorvonS.Epilepsia2019,4).1091~3制订指南原则•透明：无利益驱动•公平：所有数据采用同样的评估标准•严格：评价方法严格可行•动态：不断更新抗癫痫治疗指南大事记发布机构发布年限苏格兰临床指导协

作组(SIGN)2019英国临床优化研究所（NICE）2019美国神经学会（AAN）美国癫痫学会（AES）2019ILAE2019Payakachatetal.JManagCarePharma2019WelcometotheNationalInstituteforHealthandClin

icalExcellencewebsiteNICEistheindependentorganizationresponsibleforprovidingnationalguidanceonthepromotionofgoodhealthandthepreventionandtreatmentof

illhealth.On1April2019NICEjoinedwiththeHealthDevelopmentAgencytobecomethenewNationalInstituteforHealthandClinicalExcellence(alsotobeknownasNICE).Cl

inicalExcellencePublicHealthExcellenceNICEwassetupasaSpecialHealthAuthorityforEnglandandWaleson1April2019.Itsroleistoprovidepatients

,healthprofessionalsandthepublicwithauthoritative,robustandreliableguidanceoncurrent‘bestpractice’.(nice.org.uk/)NICE指南•对于抗癫痫药物使用的指证，药物选

择，换药，停药等原则性问题均作出了相应推荐Ref:NationalInstituteforHealthandClinicalExcellence.Technologyappraisalguidance7

6:newerdrugsforepilepsyinadults.Availableat:nice.org.uk/TA076guidance.AccessedJuly5,2019.•NICE在治疗中①尽可能选择单药治疗②不推荐常规监测看癫痫药物的血药浓

度③停药原则NICE指南Ref:NationalInstituteforHealthandClinicalExcellence.Technologyappraisalguidance76:newerdrugsforepilepsyinadults.Availableat:

nice.org.uk/TA076guidance.AccessedJuly5,2019.NICE指南•目前仍缺乏高质量的临床试验支持新药单药治疗比传统药物更有效•研究中的药物副作用和耐受性并未提供足够多且一致的结果支持新药优于传统药物•仅9项比较

新药和老药单药治疗新诊断癫痫患者生活质量的研究，未提供强有力的证据支持新药提高患者生活质量•传统抗癫痫药物单药治疗费用更便宜Ref:NationalInstituteforHealthandClinica

lExcellence.Technologyappraisalguidance76:newerdrugsforepilepsyinadults.Availableat:nice.org.uk/TA076guidance.Acc

essedJuly5,2019.•首选单药治疗药物应为传统抗癫痫药物如丙戊酸钠或卡马西平，除如下原因:–禁忌症–与患者目前服用的药物有潜在的相互作用–患者在既往治疗中对该药耐受性差–患者处于准备生育期•新型抗癫痫药物作为初始治疗的二线选择Ref:NationalInstituteforHeal

thandClinicalExcellence.Technologyappraisalguidance76:newerdrugsforepilepsyinadults.Availableat:nice.org.uk

/TA076guidance.AccessedJuly5,2019.NICE指南•NICE缺点1.评定的证据标准和证据分类没有明确的描述2.传统抗癫痫药没有进行同样的评估NICE指南Neurology.2019,62(8):1252-1260Ne

urology.2019,62(8):1261-1273AAN指南1.AAN指南有明确证据分类和证据评级2.以有效性作为主要评估指标3.缺点：未评估传统药物生活质量和成本效益未作为参考指标抗癫痫临床治疗指南比较总结

评价指标NICE指南AAN指南有效性安全性生活质量×成本效益×Payakachatetal.JManagCarePharma2019Payakachatetal.JManagCarePharma2019AEDsasMonotherapyo

fPartial/MixGeneralizedTonic-ClonicSeizureANN*NICE†SIGN‡Phenobarital1st¶--Carbamazepine(genericTegretol)TegretolXR1st1st1stPhenytoin(genericDilant

in)1st1st-Valproicacid(genericDepakene)Divalproex(Depakote)Divalproex(DepakoteER)1st1st1stPrimidone(genericMysoline)---Gabapentin(gene

ricNeurontin)1st--Zonisamide)Zonegran)---Tiagabine(Gabitril)---Oxcarbazepine(Trileptal)1st2nd1stTopiramate(Topa

max)1st2nd-Levetiracetam(Keppra)---Lamotrigine(Lamictal)1st2nd1stNICE指南和AAN指南对于新药的使用推荐LancetNeurol2019;3:618–21

DrugNewlydiagnosedepilepsyRefractoryepilepsyPartialAbsencePartialPartialIdiopathicSymptomatiemixedmonotherapygeneralisedgeneralisedUSUKUSUKU

SUKUSUKUSUKUSUKFelbamate*NoNANoNAYes†NAYesNANoNAYes†NAGabapentinYes§NoNoNoYesYes¶NoNoNoNoNoNoLamotrigineYes§Yes||

Yes§Yes||YesYes**YesYesNoYes**YesYes**LevetiracetamNoNoNoNoYesYes††NoNoNoNoNoNoOxcarbazepineYesYes¶NoNoYesYes¶YesYes¶NoNoNoNoTiagabine

NoNoNoNoYesYes||NoNoNoNoNoNoTopiramateYes§Yes¶NoNoYesYes**Yes§Yes¶Yes††Yes††**YesYes**Vigabatrin§§NANoNANoNAYesNANoNA

NoNAYes¶¶ZonisamideNoNANoNAYes||||NANoNANoNANoNANoneofthedrugsisrecommendedasfirstchoiceinnewlydiagnosedepilepsybytheUKguidelines(seetext)

.NA=notavailable.*PatientsUnresponsivetostandarddrugsinWhomtherisk/benefitratiosupportsuse;†onlypatie

nts>18years;‡onlypatients>4yearswithLennox-Gastautayndrome;§indicationnotapprovedFDA;¶onlypatients≥6years;||onlypatients≥12years;**onlypa

tients>2years;††onlypatients≥16years;††onlygeneralizedtonic-clonicseizures;§§intheUKtheindicationsarelimitedtoadjunctiveuseafterfailure

ofallotherappropriatedrugcombinations;¶¶onlyWestayndrome;||||onlyadulte.新药的严重/非严重不良事件LancetNeurol2019;3:618–21AEDSeriousad

versevevntsNonseriousadverseFelbamateAplasticanaemia,hepatotoxicityGastrointestinaldisturbancse,anorexi

a,insomniaGabapentinAggresion*Weightgain,peripheralcedema,behaviouralchanges†LamotrigineRash,includingSte

vensJohnsonandtoxicepidermalnecrolysisTics†andinsomnia(highriskforchildren,alsomorecommonwithconcomitantvaiproic-acidu

seandlowwithslowtitration);hypereensitivityreactions,includinghepaticandrenalfailure,DIC,andarthritisLevetiracetamNoneIrritabil

ity/behaviourchangeOxcarbazepineHyponatraemia(morecommoninelderlypeople),rashNoneTiagabineNonconvulsivestatusepilepticusDiz

ziness,astheniaTopiramateNephrolithiasis,openangleglaucoma,hypohidrosis,†Metabolicacidosis,weightloss,depression,psy

chosislanguagedysfunxtion,paraesthesiaVigabatrinVisualfielddefects,psychosis,depressionWeightgainZonisamideR

ash,renalcalculi,hypohidrosis†Irritability,photosensitivity,weightlossAED=antiepticdrug;DIC=disseminatedintravascularcoagulation.*Mosth

yincognitivelyimpairedpatients;†predominantlychildren.上述各抗癫痫药治疗指南的差异在于单药治疗的推荐上（新药与传统药）原因：1.证据的评估标准2.制定指南的目的差异临床医生在应用指南时特别注意临床医生在应用

指南时特别注意•要特别注意癫痫药物加重癫痫发作可能加重某些癫痫综合征的抗痫药物药物综合症可能加重的情况卡马西平失神癫痫肌阵挛、失神发作青少年肌阵挛癫痫肌阵挛性发作进行性肌阵挛癫痫肌阵挛中央回癫痫CSWS.肌阵挛苯巴英钠失神癫痫失神发

作进行性肌阵挛癫痫小脑综合症，肌阵挛苯巴比妥失神癫痫大剂量时失神发作苯二氮卓类药物LGS强直性发作氨已烯酸失神癫痫失神发作伴肌阵挛的癫痫肌阵挛加巴喷丁失神癫痫失神发作伴肌阵挛的癫痫肌阵挛拉莫三嗪严重的肌阵挛癫痫大剂量时GTCS青少年肌阵挛癫痫肌阵挛性发作Ref:E

pilepsia.39(Suppl.3):S15-S18,2019TopiramateVigabatrin0246810ClonazepamClobazamSodiumValproate(德巴金)CarbamazepineB

arbexaclonePrimidonePhenobarbitalEthosuximideSulthiameOxcarbazepinePhenytoinLamotrigineGabapentinElger等对100

6例局灶性癫痫（包括单药和添加治疗）荟萃分析抗癫痫药物恶化发作癫痫患者发作增加的百分比临床医生在应用指南时特别注意•治疗要个体化,要特别关注特殊人群:儿童、妇女、老人临床医生在应用指南时特别注意认识的更新SANAD试验发现丙戊酸和其它新抗癫痫药在癫痫治疗的综合作用中明显优于其

它药物研究A:基线的人口学资料和临床表现CBZ(n=378)GBP(n=377)LTG(n=378)OXC(n=210)TPM(n=378)Total(n=1721)性别,n(%)男女208(55)170(45)207(55)170(45)208(55)170(45)111(

53)99(47)208(55)170(45)942(55)779(45)治疗史,n(%)未治疗单药治疗(效果差)发作较少后最近发作309(81.8)60(15.9)9(2.4)306(81.2)60(15.9)11(2.9)30

8(81.5)61(16.1)9(2.4)181(86.2)25(11.9)4(1.9)308(81.5)60(15.9)10(2.7)1412(82.1)266(15.5)43(2.5)病史,n(%)高热惊厥其他急性症

状性发作1o级亲属患癫痫27(7.1)6(1.6)39(10.3)16(4.2)15(4.0)44(11.7)25(6.6)18(4.8)38(10.1)7(3.3)8(3.8)24(11.4)17(4.5)13(3.4)34(9.0)92(5.4)60(3.5)179(10.0)

癫痫综合征,n(%)特发性部分性症状性或隐源性部分性特发性全面性其他综合征未分类4(1.1)338(89.4)3(0.8)2(0.5)31(8.2)5(1.3)333(88.6)3(0.8)0(0)35(9.3)6(1.6)330(88.0)4(1.1)0(0)35(9.3)3(1.4

)180(85.7)5(2.4)1(0.5)21(10.0)6(1.6)322(85.4)7(1.9)1(0.3)41(10.9)24(1.4)1503(87.6)22(1.3)4(0.2)163(9.5)平均年龄±标准差,岁39.2±18.337.8±17.936.8±

18.340.1±18.038.4±18.638.3±18.3Ref:SANAD研究结果研究A:治疗无效的时间,意向性治疗集Log-RankChi-square=22.150,df=3,p<0.0001-O-LTG-O-CBZ-O-TPM-O-GBP时间

(天)继续治疗的比例Ref:SANAD研究结果结论研究A•拉莫三嗪治疗无效的比例显著低于卡马西平,加巴喷丁,托吡酯•拉莫三嗪的疗效与卡马西平相似且并不低于卡马西平•拉莫三嗪对于部分性发作的患者可考虑为第一线药物Ref:SANAD研究结果LTG(n=

239)TPM(n=239)VPS(n=238)Total(n=716)性别,n(%)男女142(59)97(41)142(59)97(41)143(60)95(40)427(60)289(40)治疗史,n(%)未治疗单药治疗(效果差)发作较少后最近发作210(87.9

)19(8.0)10(4.2)209(87.5)20(8.4)10(4.2)209(87.8)21(8.8)8(3.4)628(87.7)60(8.4)28(3.9)病史,n(%)高热惊厥其他急性症状性发作1o级亲属患癫

痫16(6.7)9(3.8)53(22.2)22(9.2)6(2.5)38(15.9)21(8.8)6(2.5)38(16.0)59(8.2)21(2.9)129(18.0)癫痫综合征,n(%)特发性部分性症状性或隐源性部分

性特发性全面性其他综合征未分类1(0.4)18(7.5)145(60.7)9(3.8)66(27.6)2(0.8)11(4.6)147(61.8)12(5.0)66(27.7)0(0)20(8.4)150(63.0)

9(3.8)59(24.8)3(0.4)49(6.9)442(61.8)30(4.2)191(26.7)平均年龄±标准差,岁22.8±14.322.3±13.322.5±14.522.5±14.0研究B:基线的人口学资料和临床表现Ref:SANAD研究结果研究B:治疗无效的时间L

og-RankChi-square=10.117,df=2,p=0.006-O-VPS-O-LTG-O-TPM继续治疗的比例时间(天)Ref:SANAD研究结果结论研究B•丙戊酸的疗效显著高于拉莫三嗪和托吡酯•丙戊酸和拉莫三嗪的耐受性高于托吡酯•丙戊酸对于全身

发作或未分类的发作的患者可考虑为第一线药物传统抗癫痫药与新型抗癫痫药在疗效上无显著差异KwanP,BrodieMJ.NEnglMed.2000;342:314-3150%10%20%30%40%50%60%70%80%Patientsse

izurefreefor≥1yearTraditionalAED(n=289)NewAED(n=134)Patientstreatedwith1AEDP=NS67%69%70%10%0%Persistentseizures

Seizurefreefor≥1yearPatientswithepilepsy(n-525)60%50%40%30%20%Patients63%37%289werereceivinganestablish

eddrug(155werereceivingcarbamazepine,125valproatesodium,8phenytoin,and1ethosuximide),134weretakingoneofthenewerantiepilepticdrugs(99were

receivinglamotrigine,15gabapentin,7oxcarbazepine,9tiagabine,3topiramate,and1vigabatrin).传统抗癫痫药与新型抗癫痫药在疗效上无显著差异NEnglJMed2000;342:314-9

.470patientshasneverreceivedAnantiepilepticdrugbefore(64%seizure-free)Epilepsywasnotcontrolledby1stantiepilepti

cdrugin248;168recevedanestablisheddrugand80receivedanewdrug69HadintolerableSideeffects(41%seizure-free)29Hadanidiosyncraticreact

ion(55%seizure-free)37HadotherreasonsForstoppingtreatment(62%seizure-free)Figure3.Outcomein470PreviouslyUntreatedPatients.Thestatusofpatientsatth

etimeofthelastclinicvisitisgiveninparentheses.Epilepsywascontrolledby1stantiepilepticdrugin222(47%seiz

ure-free);151receivedanestablisheddrug(47%seizure-free)and71receivedanewdrug(47%seizure-free)Treatme

ntwasIneffectivein113(11%seizure-free)总结•传统抗癫痫药物如丙戊酸钠、卡马西平、苯妥英钠仍旧是新诊断癫痫患者的首选单药治疗药物•除非新药在疗效、成本效益和生活质量上能显示出其优越性，否则他们仍将作为二线用药Payakachatetal.JM

anagCarePharma2019