癫痫是最常见和较致残的慢性神经系统疾病之一[1]，不同程度影响全球7 000多万人，包括婴儿、幼儿和老年人。癫痫的发作症状多样，可能会出现局部肢体不自主抽动、感觉异常（包括麻木、刺痛感等），还可能出现视觉、听觉等特殊感觉发作，并且发作频率不定[2]。癫痫可因癫痫发作、精神障碍、认知缺陷等严重损害患者的生活质量[1]。局灶性癫痫是最常见的癫痫类型，占所有病例的一半以上，其为大脑皮质局部病灶引起在某部位的局限发作，导致病灶与神经元发育异常，因病灶部位的不同主要分为运行性发作和感觉性发作，且在抗癫痫发作药物（anti-seizure medication，ASM）治疗中，可能产生严重的不良反应，其中约30%的患者仍会出现无法控制的难治性局灶性癫痫发作[3]。随着既往失败治疗次数的增加，可能会降低新尝试药物控制癫痫发作的效果[4]，并且难治性局灶性癫痫在没有得到控制的情况下持续发作，特别是强直阵挛发作，是癫痫不明原因猝死的最大危险因素[5]。
据报道，超过70%的癫痫患者通过ASM控制癫痫发作，且大约一半的患者可以通过单一疗法控制癫痫发作[6]，但对一些难治性局灶性癫痫患者难以实现癫痫控制，研究估计，60%~70%的癫痫患者对ASM有反应，而30%~40%的患者对ASM产生耐药性，治疗效果有限[7]，因此需要更多针对性药物对难治性局灶性癫痫进行治疗。2017年一项包含17种ASMs的网状Meta分析研究显示，托吡酯、左乙拉西坦、普瑞巴林和奥卡西平在治疗效果和不良结局风险方面优于其他药物，但该研究未精确定义纳入的人群[8]。并且不同的ASMs在治疗难治性局灶性癫痫中的疗效和安全性存在较大的差异 [9]，如有研究显示，吡仑帕奈在降低癫痫发作频率方面具有显著的疗效，且每日8 mg或12 mg剂量时效果最为显著[10]；而另一项研究则发现，吡仑帕奈疗效一般，且与更高的不良事件发生率相关 [11]。此外，目前缺乏ASMs间的比较研究，临床决策证据不足。
近几十年来，随着ASM药物的不断增加，临床应用的ASMs超过24种，并且最近开展的大量随机对照试验（randomized controlled trials，RCTs）提供了新的临床证据[8, 12-13]，但缺乏针对试验结果的系统性比较分析，且传统的Meta分析无法全面比较多种药物之间的有效性与安全性，并给出疗效排序。因此，本研究通过网状Meta分析将直接和间接证据相结合，全面评估当前ASMs对难治性局灶性癫痫的有效性与安全性，以为临床决策提供更高级别的循证医学证据支持。
1 资料与方法
1.1 纳入与排除标准
1.1.1 纳入标准
①研究对象：诊断为患有难治性局灶性癫痫的患者[14]；②干预措施：干预药物仅限于ASMs，如噻加宾、托吡酯、左乙拉西坦、唑尼沙胺、卢非酰胺、奥卡西平、氨己烯酸、加巴喷丁、普瑞巴林、苯巴那酯、拉莫三嗪、拉考沙胺、布瓦西坦、醋酸艾司利卡西平、吡仑帕奈，对于所有患者，均未限制药物传递系统、持续时间或剂量；③对照措施：对照组患者均采用安慰剂干预；④结局指标：结局包括50%应答率及头晕，纳入研究应至少包含其中一个结局；⑤研究类型：RCT。
1.1.2 排除标准
重复发表文献、联合ASM方案、缺失数据的研究、会议记录和仅以摘要形式可访问的文献。
1.2 文献检索策略
计算机检索PubMed、Embase和The Cochrane Library，搜集抗癫痫药物治疗难治性局灶性癫痫的RCT，检索时限均从建库至2024年11月1日。此外，通过追溯纳入文献的参考文献，以提供更多证据。检索采取主题词和自由词相结合的方式，英文检索词包括refractory partial-onset seizures、treatment-resistant partial-onset seizure、uncontrolled partial-onset seizures、complex partial seizures、drug-resistant focal epilepsy、drug-resistant epilepsy、drug refractory epilepsy、randomized controlled trial等。以PubMed为例，检索策略见框1。
-
框图1 PubMed检索策略
Box1.PubMed search strategy
1.3 文献筛选与资料提取
由2名研究者独立筛选文献、提取资料并交叉核对结果。如有分歧通过讨论或与第三方协商解决。资料提取内容包括年份、参与者性别比例、平均年龄、癫痫病程中位数（年）、主要纳入标准、干预措施、样本量等。
1.4 纳入研究的偏倚风险评价
由2名研究者独立评估纳入研究的偏倚风险，并交叉核对结果。采用Cochrane偏倚风险评价工具2.0（Version 2 of the Cochrane Tool for Assessing Risk of Bias in Randomised Trial，ROB 2.0）评价RCT的偏倚风险[15]。
1.5 统计学分析
采用STATA 15.0和R 4.2.2软件进行统计学分析。50%应答率及头晕结局均采用相对危险度（relative risk，RR）及其95%置信区间（confidence interval，CI）为效应指标。I2用于判断异质性的大小，其中I2值 ≥40%表示存在显著异质性 [16]。在网状Meta分析中，采用网状关系图展示各药物间相互比较内在关联，并采用“环不一致性”方法进行不一致性检验[17]。为了更好地展示多种药物的有效性与安全性排序，采用累积排序曲线下面积（surface under the cumulative ranking curve，SUCRA）对药物的有效性与安全性进行排序，SUCRA分值越高意味着干预措施的疗效越好或安全性更高[18]。此外，网状漏斗图被用于检测潜在的发表偏倚。P＜0.05为差异有统计学意义。
2 结果
2.1 文献筛选流程及结果
初检共获得相关文献5 009篇，经逐步筛选，最终共纳入56篇文献，涉及57项RCT，包括15 667例患者和15种ASMs，文献筛选流程见图1。
-
图1 文献筛选流程图
Figure1.Flow chart of literature screening
注：*检索的数据库及检出文献数具体为PubMed（n=2 058）、Embase（n=544）、The Cochrane Library（n=2 407）。
2.2 纳入研究的基本特征与偏倚风险评价
本研究共纳入56项研究，纳入研究的基本特征见表1。本研究采用ROB 2.0进行质量评价，共有3项研究为高风险，16项研究为低风险，其余均为有一定风险，纳入研究的偏倚风险评价结果见表2。
-
表格1 纳入研究的基本信息
Table1.Basic information of included studies
注：ASMs. 抗癫痫药物；POS. 局部性发作性癫痫；NA. 没有报道。
-
表格2 纳入研究质量评价
Table2.Quality evaluation of included studies
2.3 50%应答率
56项研究[12-13, 19-72]报告了50%应答率，涉及16种治疗措施，50%应答率的网状关系图见图2。
直接比较结果显示，与安慰剂相比，噻加宾[RR=3.57，95%CI（2.11，6.04）]、托吡酯[RR= 2.61，95%CI（2.21，3.09）]、唑尼沙胺[RR=2.36，95%CI（1.87，2.97）]、左乙拉西坦[RR=2.33，95%CI（1.97，2.75）]、卢非酰胺[RR=2.27，95%CI（1.49，3.48）]、奥卡西平[RR=2.20，95%CI（1.84，2.63）]、普瑞巴林[RR=2.08，95%CI（1.78，2.43）]、氨己烯酸[RR=2.08，95%CI（1.46，2.98）]、加巴喷丁[RR=2.00，95%CI（1.56，2.55）]、苯巴那酯[RR=1.98，95%CI（1.58，2.48）]、拉莫三嗪[RR=1.85，95%CI（1.38，2.47）]、拉考沙胺[RR=1.78，95%CI（1.60，1.98）]、醋酸艾司利卡西平[RR= 1.75，95%CI（1.52，2.00）]、布瓦西坦[RR=1.70，95%CI（1.41，2.05）]和吡仑帕奈[RR=1.39，95%CI（1.07，1.81）]能够提高50%应答率，差异具有统计学意义（P＜0.05），见表3。
-
图2 50%应答率的网状关系图
Figure2.Network relationship diagram of 50% response rate
注：节点代表干预措施，两点间连线代表两种干预措施间存在直接比较；节点大小代表研究数目，节点越大，代表研究数目越多，线条粗细代表配对间研究数目，线条越粗，代表研究数目越多。
-
表格3 50%应答率的网状与传统Meta分析结果[RR（95%CI）]
Table3.Results of network and traditional Meta-analysis of 50% response rate [RR (95%CI)]
注：抗癫痫药物之间的比较结果应从右至左阅读，结果均为右下角定义的治疗方案与左上角定义的治疗方案的比较；表格以抗癫痫药物为分界线分为左下和右上两部分，右上部分为网状比较结果，左下部分为直接比较结果；结果显示，当RR＜1时，倾向于在左侧定义治疗方案，当RR>1时，倾向于在右侧定义治疗方案；“/”表示结果不可用。
网状Meta分析结果显示，与安慰剂相比，噻加宾[RR=3.43，95%CI（1.91，6.14）]，托吡酯[RR= 2.61，95%CI（2.11，3.23）]、左乙拉西坦[RR=2.28，95%CI（1.84，2.83）]、唑尼沙胺[RR=2.28，95%CI（1.70，3.08）]、卢非酰胺[RR=2.28，95%CI（1.24，4.19）]、奥卡西平[RR=2.10，95%CI（1.61，2.74）]、氨己烯酸[RR=2.06，95%CI（1.28，3.30）]、加巴喷丁[RR=2.02，95%CI（1.51，2.70）]、普瑞巴林[RR=2.00，95%CI（1.60，2.50）]、苯巴那酯[RR=1.97，95%CI（1.40，2.76）]、拉莫三嗪[RR=1.85，95%CI（1.09，3.12）]、拉考沙胺[RR=1.78，95%CI（1.51，2.10）]、醋酸艾司利卡西平[RR= 1.75，95%CI（1.43，2.14）]和布瓦西坦[RR=1.74，95%CI（1.37，2.21）]能够提高50%应答率，差异具有统计学意义（P＜0.05）。此外，除了以上与安慰剂比较的药物外，其余药物与安慰剂的比较结果无统计学意义（表3）。
SUCRA结果显示，噻加宾（93.3%）治疗癫痫的效果最佳，其次是托吡酯（85.3%）、左乙拉西坦（70.4%）、唑尼沙胺（69.6%）和卢非酰胺（63.9%）；效果较差的三种药物分别是安慰剂（0.5%）、吡仑帕奈（14.2%）和醋酸艾司利卡西平（31.1%）（图3）。
-
图3 结局指标的SUCRA排序结果
Figure3.SUCRA ranking results of outcome indicators
注：外圆圈为50%应答率指标，内圆圈为头晕指标。
2.4 头晕
共46项研究[12-13, 19-22, 24-25, 27-31, 33-40, 42-47, 49-55, 57-60, 62, 64, 66-70, 72]报道了头晕的结局，涉及12 866名患者，图4展示了16种癫痫治疗措施在头晕结局上的网状关系图。
-
图4 头晕的网状关系图
Figure4.Network relationship diagram of dizziness
注：节点代表干预措施，两点间连线代表两种干预措施间存在直接比较；节点大小代表研究数目，节点越大，代表研究数目越多，线条粗细代表配对间研究数目，线条越粗，代表研究数目越多。
直接比较结果显示，与安慰剂相比，醋酸艾司利卡西平[RR=4.49，95%CI（3.64，5.54）]、吡仑帕奈[RR=3.83，95%CI（2.54，5.77）]、拉莫三嗪[RR=3.59，95%CI（1.50，8.58）]、唑尼沙胺[RR=3.46，95%CI（1.90，6.29）]、卢非酰胺[RR=3.43，95%CI（2.00，5.88）]、普瑞巴林[RR=3.13，95%CI（2.44，4.00）]、拉考沙胺[RR=3.09，95%CI（2.51，3.79）]、加巴喷丁[RR= 2.52，95%CI（1.86，3.42）]、奥卡西平[RR=2.46，95%CI（2.00，3.02）]、噻加宾[RR=2.04，95%CI（1.50，2.78）]、托吡酯[RR=1.63，95%CI（1.42，1.88）]和左乙拉西坦[RR=1.57，95%CI（1.13，2.19）]增加了头晕发生风险，差异具有统计学意义（P ＜0.05）。然而，其他活性药物与安慰剂相比时结果均无统计学意义（表4）。
-
表格4 头晕的网状与传统Meta分析结果[RR（95%CI）]
Table4.Results of a network and traditional Meta-analysis of dizziness [RR (95%CI)]
注：抗癫痫药物之间的比较结果应从右至左阅读，结果均为右下角定义的治疗方案与左上角定义的治疗方案的比较；表格以抗癫痫药物为分界线分为左下和右上两部分，右上部分为网状比较结果，左下部分为直接比较结果；结果显示，当RR<1时,倾向于在左侧定义治疗干预，当RR>1时,倾向于在右侧定义治疗干预；“/”表示结果不可用。
网状Meta分析结果显示，与安慰剂相比，醋酸艾司利卡西平[RR=4.13，95%CI（3.08，5.54）]、吡仑帕奈[RR=3.83，95%CI（2.17，6.74）]、拉莫三嗪[RR=3.59，95%CI（1.28，10.07）]、卢非酰胺[RR=3.43，95%CI（1.58，7.42）]、唑尼沙胺[RR=3.36，95%CI（1.73，6.52）]、普瑞巴林[RR=3.00，95%CI（2.19，4.10）]、拉考沙胺[RR=2.98，95%CI（2.22，3.98）]、加巴喷丁[RR= 2.49，95%CI（1.73，3.60）]、奥卡西平[RR=2.38，95%CI（1.72，3.29）]、噻加宾[RR=2.03，95%CI（1.34，3.08）]、托吡酯[RR=1.65，95%CI（1.28，2.13）]和左乙拉西坦[RR=1.55，95%CI（1.04，2.31）]增加了头晕发生风险，差异具有统计学意义（P ＜0.05）。此外，除了以上与安慰剂比较的药物外，其余药物与安慰剂的比较结果均无统计学意义（表4）。
SUCRA结果显示，安慰剂（96.9%）头晕的发生率最低，其次是苯巴那酯（86.8%）、布瓦西坦（82.6%）、左乙拉西坦（75.3%）和托吡酯（72.4%）。头晕发生率最高的三种药物分别是醋酸艾司利卡西平（11.3%）、吡仑帕奈（17.0%）和拉莫三嗪（23.3%）（图3）。
2.5 不一致性检验
本研究中，所有结局的抗癫痫药物均未形成闭环，因此，未检验任何结果的循环不一致性。
2.6 发表偏倚
50%应答率（图5）和头晕（图6）的网状漏斗图均提示不存在发表偏倚。
-
图5 50%应答率的网状漏斗图
Figure5.Network funnel plot of 50% response rate
-
图6 头晕的网状漏斗图
Figure6.Network funnel plot of dizziness
3 讨论
本研究结果显示，噻加宾、托吡酯、左乙拉西坦和唑尼沙胺对难治性局灶性癫痫发作频率的控制更有效，而吡仑帕奈的效果低于其他所有ASMs。噻加宾的抗癫痫作用是通过抑制突触前和神经胶质对神经递质γ-氨基丁酸（γ-aminobutyric acid，GABA）的摄取而实现[73]。GABA作为一种抑制性神经递质，在控制难治性局灶性癫痫发作、改善发作严重程度、稳定发作频率、防止发作恶化等方面均有疗效 [74]。但也有研究表明，噻加宾的疗效和不良反应均随着剂量的增加而增加，32 mg/d和56 mg/ d相对16 mg/d的疗效较好，但不良反应也有一定程度增加[75-76]。唑尼沙胺可通过阻断钠离子和T型Ca2+通道，抑制神经元过度同步放电[77]，从而减少难治性局灶性癫痫的发作频率。此外，唑尼沙胺的疗效与剂量呈正相关，唑尼沙胺500 mg/ d剂量在控制难治性局灶性癫痫发作方面效果显著，但同时带来了更多的不良事件和停药风险；300 mg/d剂量在疗效和不良事件之间呈现一种相对平衡的状态，在取得一定疗效的同时，不良事件发生率和停药率虽高于低剂量组但仍处于可接受范围；100 mg/d剂量疗效相对较弱，但不良事件发生率和停药率较低，安全性较好[46]，因此在治疗难治性局灶性癫痫时应根据患者癫痫的严重程度等个体性差异制定不同的药物使用方案。
托吡酯用于难治性局灶性癫痫治疗时，可以减轻癫痫发作的强度和频率，促进整体稳定，使其成为控制病情恶化的有效选择[78]，但托吡酯用于治疗难治性局灶性癫痫方面的疗效也与剂量有关，剂量越高，其疗效越好。然而，不良事件发生率随剂量增加也有一定变化趋势，在最常见的中枢神经系统相关不良事件中，200 mg/d剂量组头晕发生率为36%，400 mg/d剂量组为33%，600 mg/d剂量组为35%[66]，三种剂量用法对头晕的发生率并未产生较大差异。同时，左乙拉西坦也是常用的一线ASM，其可作为男性全身性癫痫患者的初始治疗选择，在育龄女性患者中，左乙拉西坦具有更好的安全性，可作为丙戊酸盐的替代品[79]。并且高剂量静脉注射左乙拉西坦在治疗儿童难治性癫痫急性发作加重时，疗效显著，多数患儿发作频率明显降低甚至达到无发作状态 [80]。同时，在短期内药物耐受性良好，高剂量未明显增加不良事件发生率。然而，长期使用高剂量药物的安全性尚未明确，需要进一步研究来全面评估其风险与获益，为临床治疗提供更可靠的依据 [81]。本研究中，托吡酯和左乙拉西坦在50%应答率的结局中获得较高排名，同时，这两种药物在头晕等方面的发生率较低，这表明其可能是用于治疗难治性局灶性癫痫的首选药物。
加巴喷丁和普瑞巴林在结构上与GABA相似。加巴喷丁能够穿透血脑屏障，但其作用机制不依赖于GABA。加巴喷丁分布量大，缺乏刺激或抑制肝酶的能力，蛋白质结合和代谢活性通常可忽略不计[82]。加巴喷丁作为难治性局灶性癫痫患者辅助治疗的有效性已得到证实，且普遍耐受性良好。同时，普瑞巴林是第二代ASM，由于其抗焦虑和镇痛特性，2004年被批准作为局灶性癫痫的辅助治疗药物[83]，有研究表明其在降低成人难治性局灶性癫痫患者癫痫发作频率方面有显著效果 [84]。本研究中普瑞巴林在50%应答率上表现出中等效果，然而，由于加巴喷丁和普瑞巴林在头晕等不良事件方面的发生率较高，是导致患者退出研究的常见原因[47, 82]。
与以往的ASM研究相比，本研究观察到新开发的抗癫痫药，包括布瓦西坦、左乙拉西坦、奥卡西平、氨己烯酸和托吡酯，在治疗难治性局灶性癫痫方面与丙戊酸盐具有相同疗效 [85]，但在使用时，应该兼顾疗效和安全性来调整治疗方案。
本研究存在一定局限性。首先，本研究缺乏足够的数据，未对参与者的种族和合并症进行亚组分析，这可能对总体结论产生影响。其次，给药途径可能会影响与每种药物和治疗时间相关的潜在副作用，导致纳入的研究之间存在较大差异。最后，由于缺乏其他安全性数据，一些不良事件结局并未纳入研究进行比较。
综上所述，本研究结果显示噻加宾、托吡酯、左乙拉西坦和唑尼沙胺疗四种药物治疗难治性局灶性癫痫的疗效较好，且不良事件发生风险较低，因此，推荐以上四种药物用于难治性局灶性癫痫的治疗。
1.Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy[J]. Nat Rev Dis Primers, 2018, 4: 18024. DOI: 10.1038/nrdp.2018.24.
2.Quintas R, Alvarez AS, Koutsogeorgou E, et al. The relationship between health-related quality-of-life and disability in patients with controlled epilepsy: a cross-sectional observational study[J]. Am J Phys Med Rehabil, 2012, 91(13 Suppl 1): S31-S38. DOI: 10.1097/PHM.0b013e31823d4db9.
3.Sumbul O, Aygun H. Chronic effects of different quercetin doses in penicillin-induced focal seizure model[J]. Neurosci Lett, 2021, 753: 135848. DOI: 10.1016/j.neulet.2021.135848.
4.Perucca E, Perucca P, White HS, et al. Drug resistance in epilepsy[J]. Lancet Neurol, 2023, 22(8): 723-734. DOI: 10.1016/s1474-4422(23)00151-5.
5.Ryvlin P, Rheims S, Lhatoo SD. Risks and predictive biomarkers of sudden unexpected death in epilepsy patient[J]. Curr Opin Neurol, 2019, 32(2): 205-212. DOI: 10.1097/wco.0000000000000668.
6.Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial[J]. Epilepsia, 2009, 50(8): 1899-1909. DOI: 10.1111/j.1528-1167.2009.02160.x.
7.Kwan P, Brodie MJ. Early identification of refractory epilepsy[J]. N Engl J Med, 2000, 342(5): 314-319. DOI: 10.1056/nejm200002033420503.
8.Zhao T, Feng X, Liu J, et al. Evaluate the efficacy and safety of anti-epileptic medications for partial seizures of epilepsy: a network Meta-analysis[J]. J Cell Biochem, 2017, 118(9): 2850-2864. DOI: 10.1002/jcb.25936.
9.Bodalia PN, Grosso AM, Sofat R, et al. Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network Meta-analysis reveals the need for long term comparator trials[J]. Br J Clin Pharmacol, 2013, 76(5): 649-667. DOI: 10.1111/bcp.12083.
10.Bresnahan R, Hill RA, Wang J. Perampanel add-on for drug-resistant focal epilepsy[J]. Cochrane Database Syst Rev, 2023, 4(4): Cd010961. DOI: 10.1002/14651858.CD010961.pub2.
11.Wang H, Wang H, Liu Y, et al. Efficacy and safety of five broad-spectrum antiseizure medications for adjunctive treatment of refractory epilepsy: a systematic review and network Meta-analysis[J]. CNS Drugs, 2023, 37(10): 883-913. DOI: 10.1007/s40263-023-01029-0.
12.Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (ykp3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial[J]. Lancet Neurol, 2020, 19(1): 38-48. DOI: 10.1016/s1474-4422(19)30399-0.
13.Srinivasa R, Sinha S, Parthasarthy S, et al. Adjunctive brivaracetam in indian patients with uncontrolled focal epilepsy: results from a pooled analysis of two double-blind, randomized, placebo-controlled trials[J]. Neurol India, 2020, 68(6): 1400-1408. DOI: 10.4103/0028-3886.304103.
14.Shorvon SD. Epidemiology, classification, natural history, and genetics of epilepsy[J]. Lancet, 1990, 336(8707): 93-96. DOI: 10.1016/0140-6736(90)91603-8.
15.Sterne JAC, Savović J, Page MJ, et al. Rob 2: a revised tool for assessing risk of bias in randomised trials[J]. BMJ, 2019, 366: l4898. DOI: 10.1136/bmj.l4898.
16.Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions, 2nd edition[M]. Chichester (UK): John Wiley & Sons, 2019.
17.Song F, Xiong T, Parekh-Bhurke S, et al. Inconsistency between direct and indirect comparisons of competing interventions: Meta-epidemiological study[J]. BMJ, 2011, 343: d4909. DOI: 10.1136/bmj.d4909.
18.Rücker G, Schwarzer G. Ranking treatments in frequentist network Meta-analysis works without resampling methods[J]. BMC Med Res Methodol, 2015, 15: 58. DOI: 10.1186/s12874-015-0060-8.
19.Hong Z, Inoue Y, Liao W, et al. Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: a randomized, double-blind, placebo-controlled study[J]. Epilepsy Res, 2016, 127: 267-275. DOI: 10.1016/j.eplepsyres.2016. 08.032.
20.Sperling MR, Abou-Khalil B, Harvey J, et al. Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: results of a phase Ⅲ, double-blind, randomized, placebo-controlled trial[J]. Epilepsia, 2015, 56(2): 244-253. DOI: 10.1111/epi.12894.
21.Inoue Y, Yagi K, Ikeda A, et al. Efficacy and tolerability of levetiracetam as adjunctive therapy in Japanese patients with uncontrolled partial-onset seizures[J]. Psychiatry Clin Neurosci, 2015, 69(10): 640-648. DOI: 10.1111/pcn. 12300.
22.Ryvlin P, Werhahn KJ, Blaszczyk B, et al. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial[J]. Epilepsia, 2014, 55(1): 47-56. DOI: 10.1111/epi.12432.
23.Hogan RE, Blatt I, Lawson B, et al. Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance[J]. Epilepsy Behav, 2014, 41: 136-139. DOI: 10.1016/j.yebeh.2014. 09.061.
24.French JA, Baroldi P, Brittain ST, et al. Efficacy and safety of extended-release oxcarbazepine (oxtellar xr™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial[J]. Acta Neurol Scand, 2014, 129(3): 143-153. DOI: 10.1111/ane.12207.
25.French J, Brandt C, Friedman D, et al. Adjunctive use of controlled-release pregabalin in adults with treatment-resistant partial seizures: a double-blind, randomized, placebo-controlled trial[J]. Epilepsia, 2014, 55(8): 1220-1228. DOI: 10.1111/epi.12690.
26.Chung SS, Fakhoury TA, Hogan RE, et al. Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase Ⅲ study[J]. Epilepsia, 2014, 55(7): 1077-1087. DOI: 10.1111/epi.12660.
27.Biton V, Berkovic SF, Abou-Khalil B, et al. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase Ⅲ randomized, double-blind, placebo-controlled trial[J]. Epilepsia, 2014, 55(1): 57-66. DOI: 10.1111/epi.12433.
28.Van Paesschen W, Hirsch E, Johnson M, et al. Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: a phase Ⅱb, randomized, controlled trial[J]. Epilepsia, 2013, 54(1): 89-97. DOI: 10.1111/j.1528-1167.2012.03598.x.
29.French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase Ⅲ study 304[J]. Neurology, 2012, 79(6): 589-596. DOI: 10.1212/WNL.0b013e3182635735.
30.Biton V, Krauss G, Vasquez-Santana B, et al. A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures[J]. Epilepsia, 2011, 52(2): 234-242. DOI: 10.1111/j.1528-1167.2010.02729.x.
31.Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial[J]. Epilepsia, 2010, 51(6): 958-967. DOI: 10.1111/j.1528-1167.2009.02496.x.
32.Chung S, Ben-Menachem E, Sperling MR, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase Ⅱ/Ⅲ clinical trials[J]. CNS Drugs, 2010, 24(12): 1041-1054. DOI: 10.2165/11586830-000000000-00000.
33.Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy[J]. Epilepsy Res, 2010, 89(2-3): 278-285. DOI: 10.1016/j.eplepsyres.2010.01.014.
34.Xiao Z, Li JM, Wang XF, et al. Efficacy and safety of levetiracetam (3,000 mg/day) as an adjunctive therapy in Chinese patients with refractory partial seizures[J]. Eur Neurol, 2009, 61(4): 233-239. DOI: 10.1159/000197109.
35.Wu XY, Hong Z, Wu X, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partial-onset seizures[J]. Epilepsia, 2009, 50(3): 398-405. DOI: 10.1111/j.1528-1167.2008.01729.x.
36.Peltola J, Coetzee C, Jiménez F, et al. Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: a double-blind, randomized, placebo-controlled trial[J]. Epilepsia, 2009, 50(3): 406-414. DOI: 10.1111/j.1528-1167.2008.01817.x.
37.Lee BI, Yi S, Hong SB, et al. Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial[J]. Epilepsia, 2009, 50(3): 464-474. DOI: 10.1111/j.1528-1167.2008.01954.x.
38.Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial[J]. Epilepsia, 2009, 50(3): 443-453. DOI: 10.1111/j.1528-1167.2008.01951.x.
39.Gil-Nagel A, Lopes-Lima J, Almeida L, et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures[J]. Acta Neurol Scand, 2009, 120(5): 281-287. DOI: 10.1111/j.1600-0404.2009.01218.x.
40.Elger C, Halász P, Maia J, et al. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase Ⅲ study[J]. Epilepsia, 2009, 50(3): 454-463. DOI: 10.1111/j.1528-1167.2008.01946.x.
41.Zhou B, Zhang Q, Tian L, et al. Effects of levetiracetam as an add-on therapy on cognitive function and quality of life in patients with refractory partial seizures[J]. Epilepsy Behav, 2008, 12(2): 305-310. DOI: 10.1016/j.yebeh.2007.10.003.
42.Naritoku DK, Warnock CR, Messenheimer JA, et al. Lamotrigine extended-release as adjunctive therapy for partial seizures[J]. Neurology, 2007, 69(16): 1610-1618. DOI: 10.1212/01.wnl.0000277698.33743.8b.
43.Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures[J]. Epilepsia, 2007, 48(7): 1308-1317. DOI: 10.1111/j.1528-1167.2007.01188.x.
44.Yamauchi T, Kaneko S, Yagi K, et al. Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study[J]. Psychiatry Clin Neurosci, 2006, 60(4): 507-515. DOI: 10.1111/j.1440-1819.2006.01553.x.
45.Tsai JJ, Yen DJ, Hsih MS, et al. Efficacy and safety of levetiracetam (up to 2 000 mg/day) in Taiwanese patients with refractory partial seizures: a multicenter, randomized, double-blind, placebo-controlled study[J]. Epilepsia, 2006, 47(1): 72-81. DOI: 10.1111/j.1528-1167.2006.00372.x.
46.Brodie MJ, Duncan R, Vespignani H, et al. Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures[J]. Epilepsia, 2005, 46(1): 31-41. DOI: 10.1111/j.0013-9580.2005.14704.x.
47.Beydoun A, Uthman BM, Kugler AR, et al. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy[J]. Neurology, 2005, 64(3): 475-480. DOI: 10.1212/01.Wnl.0000150932.48688.Be.
48.Sackellares JC, Ramsay RE, Wilder BJ, et al. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures[J]. Epilepsia, 2004, 45(6): 610-617. DOI: 10.1111/j.0013-9580.2004.11403.x.
49.Brodie MJ. Zonisamide clinical trials: European experience[J]. Seizure, 2004, 13 Suppl 1: S66-S72. DOI: 10.1016/j.seizure.2004.04.010.
50.Arroyo S, Anhut H, Kugler AR, et al. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures[J]. Epilepsia, 2004, 45(1): 20-27. DOI: 10.1111/j.0013-9580.2004.31203.x.
51.French JA, Kugler AR, Robbins JL, et al. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures[J]. Neurology, 2003, 60(10): 1631-1637. DOI: 10.1212/01.wnl.0000068024.20285.65.
52.Guberman A, Neto W, Gassmann-Mayer C. Low-dose topiramate in adults with treatment-resistant partial-onset seizures[J]. Acta Neurol Scand, 2002, 106(4): 183-189. DOI: 10.1034/j.1600-0404.2002.02071.x.
53.Shorvon SD, Löwenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European levetiracetam study group[J]. Epilepsia, 2000, 41(9): 1179-1186. DOI: 10.1111/j.1528-1157.2000.tb00323.x.
54.Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial[J]. Neurology, 2000, 55(2): 236-242. DOI: 10.1212/wnl.55.2.236.
55.Bruni J, Guberman A, Vachon L, et al. Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The canadian vigabatrin study group[J]. Seizure, 2000, 9(3): 224-232. DOI: 10.1053/seiz.2000.0381.
56.Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3 000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European levetiracetam study group[J]. Epilepsia, 2000, 41(10): 1276-1283. DOI: 10.1111/j.1528-1157.2000.tb04605.x.
57.Yen DJ, Yu HY, Guo YC, et al. A double-blind, placebo-controlled study of topiramate in adult patients with refractory partial epilepsy[J]. Epilepsia, 2000, 41(9): 1162-1166. DOI: 10.1111/j.1528-1157.2000.tb00321.x.
58.Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy[J]. Epilepsia, 2000, 41(12): 1597-1607. DOI: 10.1111/j.1499-1654.2000.001597.x.
59.Uthman BM, Rowan AJ, Ahmann PA, et al. Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial[J]. Arch Neurol, 1998, 55(1): 56-62. DOI: 10.1001/archneur.55.1.56.
60.Kälviäinen R, Brodie MJ, Duncan J, et al. A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern european tiagabine study group[J]. Epilepsy Res, 1998, 30(1): 31-40. DOI: 10.1016/s0920-1211(97)00082-x.
61.Faught E. Efficacy of topiramate as adjunctive therapy in refractory partial seizures: united states trial experience[J]. Epilepsia, 1997, 38 Suppl 1: S24-S27. DOI: 10.1111/j.1528-1157.1997.tb04513.x.
62.Tassinari CA, Michelucci R, Chauvel P, et al. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy[J]. Epilepsia, 1996, 37(8): 763-768. DOI: 10.1111/j.1528-1157.1996.tb00649.x.
63.Sharief M, Viteri C, Ben-Menachem E, et al. Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy[J]. Epilepsy Res, 1996, 25(3): 217-224. DOI: 10.1016/s0920-1211(96)00029-0.
64.Privitera M, Fincham R, Penry J, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study Group[J]. Neurology, 1996, 46(6): 1678-1683. DOI: 10.1212/wnl.46.6.1678.
65.French JA, Mosier M, Walker S, et al. A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Vigabatrin protocol 024 investigative cohort[J]. Neurology, 1996, 46(1): 54-61. DOI: 10.1212/wnl.46.1.54.
66.Faught E, Wilder BJ, Ramsay RE, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group[J]. Neurology, 1996, 46(6): 1684-1690. DOI: 10.1212/wnl.46.6.1684.
67.Ben-Menachem E, Henriksen O, Dam M, et al. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures[J]. Epilepsia, 1996, 37(6): 539-543. DOI: 10.1111/j.1528-1157.1996.tb00606.x.
68.Anhut H, Ashman P, Feuerstein TJ, et al. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: a double-blind, placebo-controlled study. The international gabapentin study group[J]. Epilepsia, 1994, 35(4): 795-801. DOI: 10.1111/j.1528-1157.1994.tb02513.x.
69.The US Gabapentin Study Group No. 5. Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallel-group study[J]. Neurology, 1993, 43(11): 2292-2298. DOI: 10.1212/wnl.43.11.2292.
70.Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial[J]. Epilepsy Res, 1993, 15(1): 67-73. DOI: 10.1016/0920-1211(93)90011-u.
71.Sivenius J, Kälviäinen R, Ylinen A, et al. Double-blind study of Gabapentin in the treatment of partial seizures[J]. Epilepsia, 1991, 32(4): 539-542. DOI: 10.1111/j.1528-1157.1991.tb04689.x.
72.Gabapentin in partial epilepsy. UK Gabapentin Study Group[J]. Lancet, 1990, 335(8698): 1114-1117. https://pubmed.ncbi.nlm.nih.gov/1971862/.
73.Bresnahan R, Martin-McGill KJ, Hutton JL, et al. Tiagabine add-on therapy for drug-resistant focal epilepsy[J]. Cochrane Database Syst Rev, 2019, 10(10): CD001908. DOI: 10.1002/14651858.CD001908.pub4.
74.Bershteyn M, Bröer S, Parekh M, et al. Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy[J]. Cell Stem Cell, 2023, 30(10): 1331-1350, e11. DOI: 10.1016/j.stem.2023.08.013.
75.Loiseau P. Review of controlled trials of gabitril (tiagabine): a clinician's viewpoint[J]. Epilepsia, 1999, 40 Suppl 9: S14-S19. DOI: 10.1111/j.1528-1157.1999.tb02089.x.
76.Dodrill CB, Arnett JL, Sommerville KW, et al. Cognitive and quality of life effects of differing dosages of tiagabine in epilepsy[J]. Neurology, 1997, 48(4): 1025-1031. DOI: 10.1212/wnl.48.4.1025.
77.Romigi A, Femia EA, Fattore C, et al. Zonisamide in the management of epilepsy in the elderly[J]. Clin Interv Aging, 2015, 10: 931-937. DOI: 10.2147/cia.S50819.
78.Viteva E, Zahariev Z. Topiramate effectiveness as add-on therapy in bulgarian patients with drug-resistant epilepsy[J]. Folia Med (Plovdiv), 2020, 62(4): 712-722. DOI: 10.3897/folmed.62.e50175.
79.Marson A, Burnside G, Appleton R, et al. The SANAD Ⅱ study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial[J]. Lancet, 2021, 397(10282): 1375-1386. DOI: 10.1016/s0140-6736(21)00246-4.
80.Price L, Garrity L, Stiehl S. Evaluation of the safety and tolerability of intravenous undiluted levetiracetam at a pediatric institution[J]. Pharmacotherapy, 2024, 44(2): 141-148. DOI: 10.1002/phar.2898.
81.Depositario-Cabacar DT, Peters JM, Pong AW, et al. High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy[J]. Epilepsia, 2010, 51(7): 1319-1322. DOI: 10.1111/j.1528-1167.2010.02519.x.
82.Panebianco M, Al-Bachari S, Hutton JL, et al. Gabapentin add-on treatment for drug-resistant focal epilepsy[J]. Cochrane Database Syst Rev, 2021, 1(1): CD001415. DOI: 10.1002/14651858.CD001415.pub4.
83.Morano A, Palleria C, Citraro R, et al. Immediate and controlled-release pregabalin for the treatment of epilepsy[J]. Expert Rev Neurother, 2019, 19(12): 1167-1177. DOI: 10.1080/14737175.2019.1681265.
84.Panebianco M, Bresnahan R, Marson AG. Pregabalin add-on for drug-resistant focal epilepsy[J]. Cochrane Database Syst Rev, 2022, 3(3): CD005612. DOI: 10.1002/14651858.CD005612.pub5.
85.Hu Q, Zhang F, Teng W, et al. Efficacy and safety of antiepileptic drugs for refractory partial-onset epilepsy: a network Meta-analysis[J]. J Neurol, 2018, 265(1): 1-11. DOI: 10.1007/s00415-017-8621-x.
欢迎访问中南医学期刊社系列期刊网站！
