药学学报

AEDs	ABCB1		ABCC		ABCG2
Carbamazepine	×	×		×	√		×	-
Lamotrigine	√	×	×	×	？	-
Levetiracetam	？	-	×	-	-	√
Phenobarbital	√	×	×	-	×	√
Phenytoin	√	√	×	√	×	×
Topiramate	√	√	×	-	-	-
Sodium valproate	×	×	×	×	×	×

AEDs	ABCB1		ABCC		ABCG2
Carbamazepine	×	×		×	√		×	-
Lamotrigine	√	×	×	×	？	-
Levetiracetam	？	-	×	-	-	√
Phenobarbital	√	×	×	-	×	√
Phenytoin	√	√	×	√	×	×
Topiramate	√	√	×	-	-	-
Sodium valproate	×	×	×	×	×	×

Hypothesis	Advantage	Limitation
Transporter hypothesis	It can explain the resistance to multiple AEDs in patients with drug-resistant epilepsy	It is difficult to explain the resistance to some AEDs, which are not the substrate of the ABC transporter protein family
Its related studies mainly focus on the ABC transporter family, and there is a lack of research on other transporter families
Neural network hypothesis	It can explain the mechanism of drug resistance in MTLE and MCD patients	Alteration in neural networks is also present in other types of epilepsy that are well controlled by AEDs, not just in patients with drug-resistant epilepsy. There is a lack of research on specific neural networks for the drug-resistant epilepsy
It may explain the resistance to multiple AEDs in patients with drug-resistant epilepsy
It can provide a theoretical basis for surgical resection
Target hypothesis	It can explain the molecular mechanisms in patients with specific types of drug-resistance epilepsy	It cannot explain the resistance to multiple AEDs in patients with drug-resistant epilepsy
Changes in the VGSC and GABA receptors have been well-described in animal models of drug-resistance epilepsy

Hypothesis	Advantage	Limitation
Transporter hypothesis	It can explain the resistance to multiple AEDs in patients with drug-resistant epilepsy	It is difficult to explain the resistance to some AEDs, which are not the substrate of the ABC transporter protein family
Its related studies mainly focus on the ABC transporter family, and there is a lack of research on other transporter families
Neural network hypothesis	It can explain the mechanism of drug resistance in MTLE and MCD patients	Alteration in neural networks is also present in other types of epilepsy that are well controlled by AEDs, not just in patients with drug-resistant epilepsy. There is a lack of research on specific neural networks for the drug-resistant epilepsy
It may explain the resistance to multiple AEDs in patients with drug-resistant epilepsy
It can provide a theoretical basis for surgical resection
Target hypothesis	It can explain the molecular mechanisms in patients with specific types of drug-resistance epilepsy	It cannot explain the resistance to multiple AEDs in patients with drug-resistant epilepsy
Changes in the VGSC and GABA receptors have been well-described in animal models of drug-resistance epilepsy

Brain target	Reduction of seizure frequency	Adverse reaction
Centromedian thalamic nucleus	-73.4% lower (-80.2% to -43.8% lower)	#
Anterior thalamic nucleus	-60.8% lower* (-80.3% to -22.6% lower)	Depression, memory impairment, and #
Cerebellar cortex	-12.4% lower (-35.3% lower to +10.6% higher)	#
Hippocampus	-67.8% lower (-77.5% to -58.1% lower)	#
Nucleus accumbens	-33.8% lower (-100% lower to +49.8% higher)	#
RNS in EZ	-24.9% lower (-40.1 to -6.0% lower)	#
In total	The median reduction was 56%, 65%, and 75% at 2, 5, and 7 years	Implant site pain, headache, and dysesthesia

Brain target	Reduction of seizure frequency	Adverse reaction
Centromedian thalamic nucleus	-73.4% lower (-80.2% to -43.8% lower)	#
Anterior thalamic nucleus	-60.8% lower* (-80.3% to -22.6% lower)	Depression, memory impairment, and #
Cerebellar cortex	-12.4% lower (-35.3% lower to +10.6% higher)	#
Hippocampus	-67.8% lower (-77.5% to -58.1% lower)	#
Nucleus accumbens	-33.8% lower (-100% lower to +49.8% higher)	#
RNS in EZ	-24.9% lower (-40.1 to -6.0% lower)	#
In total	The median reduction was 56%, 65%, and 75% at 2, 5, and 7 years	Implant site pain, headache, and dysesthesia

Treatment	Advantage	Disadvantage or limitation
Surgical resection	Mainly for drug-resistant epilepsy patients with focal drug-resistant epilepsy (or clear epileptogenic foci)	Its therapeutic effect of generalized epilepsy is not ideal. And it can be easily affected by non-pathological factors
DBS	It has a good therapeutic effect on epilepsy of frontal lobe and temporal lobe origin It may be an alternative intervention for generalized epilepsy The adverse reactions were less	The therapeutic effect of current DBS methods on drug-resistant epilepsy is not good enough The optimal brain targets and other parameters are still under study The specific mechanism of action has not been fully proved
Ketogenic diet	It is an effective and safe method for the treatment of drug-resistant epilepsy It is an alternative therapy for patients with recurrent epilepsy after surgery and drug treatment	There are many contraindications as well as numerous short-term and long-term adverse reactions The specific mechanism is still under study
Precise treatment	Gene therapy provides a potential opportunity to cure the epilepsy from the source. It may prevent and intervene the epilepsy in the potential population The clear target can promote the development and application of the target hypothesis	The clinical evidence remains limited, which is mainly concentrated on a few typical cases (such as type 1 glucose transporter deficiency syndrome) Many therapeutic targets are still under study
TCM treatment	The clinical results show that the combination of TCM and Western medicine has a better effect than monotherapy TCM may have less side effects, can reduce patients' medical expenses, and can be an inspiration for the development of new drugs	The effective components and multiple-target mechanisms of TCM are still unclear

Treatment	Advantage	Disadvantage or limitation
Surgical resection	Mainly for drug-resistant epilepsy patients with focal drug-resistant epilepsy (or clear epileptogenic foci)	Its therapeutic effect of generalized epilepsy is not ideal. And it can be easily affected by non-pathological factors
DBS	It has a good therapeutic effect on epilepsy of frontal lobe and temporal lobe origin It may be an alternative intervention for generalized epilepsy The adverse reactions were less	The therapeutic effect of current DBS methods on drug-resistant epilepsy is not good enough The optimal brain targets and other parameters are still under study The specific mechanism of action has not been fully proved
Ketogenic diet	It is an effective and safe method for the treatment of drug-resistant epilepsy It is an alternative therapy for patients with recurrent epilepsy after surgery and drug treatment	There are many contraindications as well as numerous short-term and long-term adverse reactions The specific mechanism is still under study
Precise treatment	Gene therapy provides a potential opportunity to cure the epilepsy from the source. It may prevent and intervene the epilepsy in the potential population The clear target can promote the development and application of the target hypothesis	The clinical evidence remains limited, which is mainly concentrated on a few typical cases (such as type 1 glucose transporter deficiency syndrome) Many therapeutic targets are still under study
TCM treatment	The clinical results show that the combination of TCM and Western medicine has a better effect than monotherapy TCM may have less side effects, can reduce patients' medical expenses, and can be an inspiration for the development of new drugs	The effective components and multiple-target mechanisms of TCM are still unclear

耐药性癫痫发病机制及其治疗研究进展

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徐骋昊 ¹ , 邬鹏程 ¹ , 黄通敏 ¹ , 陆海美 ² , 许正浩 ²^,³^,^*

药学学报 | 综述 2023,58(3): 581-592

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药学学报 | 综述 2023, 58(3): 581-592

耐药性癫痫发病机制及其治疗研究进展

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徐骋昊¹, 邬鹏程¹, 黄通敏¹, 陆海美², 许正浩²^,³^,^*

作者信息

1.浙江中医药大学第二临床医学院, 浙江杭州 310053

2.浙江中医药大学基础医学院, 浙江杭州 310053

3.浙江省神经药理学与转化研究重点实验室, 浙江杭州 310053

通讯作者:

*许正浩, Tel: 86-571-86613587, E-mail: xuzhenghao@zcmu.edu.cn

Research progress on pathogenesis and treatment of drug-resistant epilepsy

Cheng-hao XU¹, Peng-cheng WU¹, Tong-min HUANG¹, Hai-mei LU², Zheng-hao XU²^,³^,^*

Affiliations

1. The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China

2. School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China

3. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Hangzhou 310053, China

出版时间: 2023-03-12 doi: 10.16438/j.0513-4870.2022-1096

文章导航

摘要

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癫痫是一种慢性神经系统疾病, 影响着全球7 000多万人。尽管已有30多种抗癫痫药物(antiepileptic drugs, AEDs) 上市, 但仍有约1/3癫痫患者的癫痫发作无法被药物有效控制, 而成为耐药性癫痫患者。明确耐药性癫痫机制和开发有效的耐药性癫痫治疗方法已经成为癫痫研究领域的热点内容。本篇综述从中枢转运体、神经网络和药物靶点3个假说对耐药性癫痫发病机制研究进展进行探讨, 并对现有的切除手术、深部脑刺激、生酮饮食、精确治疗及中医药治疗等耐药性癫痫潜在治疗方法及其研究进展进行整理, 以期为耐药性癫痫的机制研究及临床治疗提供参考。

关键词

耐药性癫痫 / 发病机制 / 精确治疗 / 生酮饮食 / 中医药治疗

Abstract

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Epilepsy is a chronic nervous system disease, which affects more than 70 million people all over the world. Although more than 30 kinds of antiepileptic drugs (AEDs) have been on the market, about one third of the patients with epilepsy fail to respond to medical treatment, who become drug-resistant epilepsy patients. Identifying the mechanism and developing effective treatment methods for drug-resistant epilepsy have become a hot area in the field of epilepsy research. This review discussed resent advance on the pathogenesis of drug-resistant epilepsy from the transporter hypothesis, neural network hypothesis and target hypothesis, and we also summarized the existing potential treatment methods and research progress of drug-resistant epilepsy, such as surgical resection, deep brain stimulation, ketogenic diet, precise treatment, and traditional Chinese medicine treatment. Our review may provide useful clues for the mechanisms research and clinical treatments of drug-resistant epilepsy.

Key words

drug-resistant epilepsy / pathogenesis / precise treatment / ketogenic diet / traditional Chinese medicine treatment

引用本文

徐骋昊, 邬鹏程, 黄通敏, 陆海美, 许正浩. 耐药性癫痫发病机制及其治疗研究进展. 药学学报, 2023 , 58 (3) : 581 -592 . DOI: 10.16438/j.0513-4870.2022-1096

Cheng-hao XU, Peng-cheng WU, Tong-min HUANG, Hai-mei LU, Zheng-hao XU. Research progress on pathogenesis and treatment of drug-resistant epilepsy[J]. Acta Pharmaceutica Sinica, 2023 , 58 (3) : 581 -592 . DOI: 10.16438/j.0513-4870.2022-1096

正文

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癫痫是最常见慢性神经系统疾病之一, 以反复的自发发作为特征。尽管已有30多种上市的抗癫痫药物(antiepileptic drugs, AEDs), 但仍然有大约1/3癫痫患者的癫痫发作不能被药物完全控制^[1]。2010年国际抗癫痫联盟(International League Against Epilepsy, ILAE) 将耐药性癫痫定义为经过两种合理选择且可耐受的AEDs治疗方案(无论是作为单一疗法还是联合使用) 治疗后仍无法被持续有效控制的癫痫发作^[2]。由于癫痫发作无法被有效控制, 耐药性癫痫患者不但社会功能与心理健康受到较大影响, 而且还存在极大的脑功能损伤和猝死风险^[3]。因此, 明确耐药性癫痫的机制和开发有效的耐药性癫痫治疗方法至关重要。本篇综述梳理了近年来有关耐药性癫痫发病机制及治疗方法方面的研究进展, 希望能为临床有效治疗耐药性癫痫提供参考。

1 耐药性癫痫的发病机制

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目前有关耐药性癫痫的发病机制尚不完全清楚, 以往研究主要包括中枢转运体假说、神经网络假说和药物靶点假说等。

1.1 中枢转运体假说

中枢转运体假说认为AEDs发挥作用必须通过血脑屏障(blood brain barrier, BBB), 而BBB上外排转运蛋白的过度表达使抗癫痫药不能到达其作用靶点, 从而降低了耐药性癫痫患者的脑内AEDs水平^[4]。其中ATP结合盒(ATP binding cassette, ABC) 超家族是一种普遍存在的外排转运蛋白, 目前根据其氨基酸结构, 48种ABC转运蛋白可以被分为A~G (ABCA~ABCG) 7个不同的家族。目前研究最广泛的家族有3个, 包括ABCB1基因编码的P糖蛋白(P-glycoprotein, P-gp)^[5]、ABCC1/ABCC2基因编码的多药耐药相关蛋白(multidrug resistance-associated protein, MRP)^[6]和ABCG2基因编码的乳腺癌抗性蛋白(breast cancer resistance protein, BCRP)^[7]。这3个亚家族的生理作用是共同保护大脑免受外来物质侵入, 同时也可以减少代谢产物的积累。但是当它们活性增强或表达升高时, 则会抑制AEDs到达脑组织。P-gp是在耐药性癫痫方面研究最多的外排转运蛋白, 是一种在血脑屏障高表达的能量依赖性药物泵, 可以将细胞内药物泵出细胞外^{[5, 8]}。在一项对19例耐药性癫痫患者手术切除的脑标本的研究中, Tishler等^[8]发现其中11例ABCB1基因(又称为MDR1基因) 表达水平高于正常10倍, 并且毛细血管内皮的P-gp表达明显高于正常, 其中8名患者的星形胶质细胞的P-gp表达高于正常。脑毛细血管内皮和星形胶质细胞都是BBB的基本结构, 说明BBB的P-gp高表达可能与耐药性癫痫有关。高表达的P-gp可能促使部分AEDs逆浓度梯度转移出细胞, 从而减少脑内及特定细胞内的AEDs浓度^[9]。类似的, 其他转运体BCRP、MRP等也可能与耐药性癫痫的耐药性有关。如表 1^[10]所示, 大部分常见AEDs均是ABC超家族的底物。值得注意的是, 目前造成耐药性癫痫患者ABC超家族外排转运蛋白高表达的分子机制并不清楚。Shao等^[11]研究发现抑制p38MAPK信号通路可降低P-gp表达, 降低大鼠癫痫模型多药耐药性, 提示p38MAPK可能是导致P-gp高表达的重要分子通路。此外, 还有研究发现沉默miR-146基因可以降低P-gp的表达^[12], 而提高miR-542-3p的表达则可以下调P-gp的水平^[13], 提示miRNA在P-gp的表达调节中发挥着重要作用。

总之, 转运体假说虽然可以较好地解释耐药性癫痫的多药耐药特点, 但需要注意的是, 一些AEDs并非ABC家族转运体蛋白的底物但依然存在耐药, 而且外排转运蛋白过度表达的程度是否足以造成耐药性癫痫也存在争论。

1.2 神经网络假说

神经网络假说主要认为在遗传因素和环境因素的影响下, 反复发作的过度神经活动可以导致脑可塑性改变, 包括轴突萌芽、突触重组和神经胶质增生等, 这些脑可塑性改变可能导致异常神经网络的形成。这些异化或重构的神经网络可能通过破坏AEDs相关的内源性抗癫痫系统等方式从而导致耐药^[14]。如图 1所示，该假说的支持证据主要来自内侧颞叶癫痫(medial temporal lobe epilepsy, MTLE) 和皮质发育畸形(malformation of cortical development, MCD) 的相关研究。

MTLE是最常见的耐药性癫痫类型之一, 通常起源于颞叶内侧的神经网络, 包括海马体和杏仁核, 还有一些紧邻的皮质区域。海马硬化是MTLE标志性的病理表现^[15], 主要包括神经元丢失与神经胶质增生等脑实质改变^[1]。颞叶前内侧切除术(切除部分硬化的海马) 治疗的MTLE患者的康复效果明显优于只进行药物治疗的患者^[16]。并且在进行射频消融杏仁核-海马体复合体手术后, 大约70%的MTLE患者可以实现长期无癫痫发作^[17]。这些研究结果表明, 针对海马相关神经网络的手术治疗策略有可能在MTLE取得较好的疗效。苔藓纤维出芽(mossy fiber sprouting, MFS) 被广泛认为是MTLE海马硬化导致耐药性癫痫的重要机制。在MTLE患者中, 苔藓纤维侧支经常性投射到海马齿状回的分子层, 使兴奋性突触与内部分子层中的颗粒细胞的顶端树突和棘突接触, 造成局部短路, 导致癫痫的反复发作^[18]。但是, MFS与耐药性癫痫之间的确切关系仍然有待进一步研究。最近本课题组Xu等^{[19, 20]}发现IL-1β介导的海马下托环路异化可能是大鼠MTLE模型耐药的关键, 而Chen等^{[21, 22]}发现距离海马病灶更远的黑质网状部到丘脑束旁核的神经通路在小鼠MTLE模型中具有癫痫发作的放大器作用, 为海马齿状回外其他关键脑区的潜在耐药神经网络提供了新的线索。

MCD是另一种常见的耐药性癫痫的病理表现, 是儿童耐药性癫痫的主要原因。其主要是由基因编程和/或神经元细胞增殖、迁移和组织过程中损伤所导致的^[23]。MCD可以分为轻度MCD (mild MCD, mMCD)、局灶性皮质发育不良(focal cortical dysplasia, FCD) 和半侧巨脑畸形(hemimegalencephaly, HME) 等亚型, 其中FCD是MCD最重要也最常见的一种亚型^{[23, 24]}。FCD也是手术治疗中最常见的MCD, 与海马硬化耐药性癫痫患者类似, 手术切除发育不良的皮质同样可以为耐药性癫痫患者提供较好的疗效^[25]。Pohlen等^[26]发现在MCD患者中, 进行新一代AEDs治疗的疗效远不如进行手术切除治疗, 提示皮质的异常结构改变可能阻止了AEDs发挥作用。MCD的皮质异常结构主要表现为: ①皮层结构紊乱; ②巨型锥体神经元; ③轮廓不清晰的球囊细胞。这些异常结构与细胞生长相关基因的异常表达或突变有关^[27]。如在结构紊乱的皮层中, N-甲基-D-天冬氨酸受体(NMDARs) 中NR1和NR2等亚基突变造成的高表达会导致神经元兴奋性增高而引起癫痫^[28]。雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR) 是细胞生长和增殖的重要调节因子, Marsan等^[29]研究发现在巨型锥体神经元和球囊细胞中mTOR被过度激活, 使病变区域的大脑皮质发育异常, 可能造成局部短路、突触重组而导致耐药性癫痫的发生。同时, 与MCD亚型相关的DNA甲基化突变会控制生长基因的表达, 也可能造成异常神经网络的形成^{[26, 27]}。

总之, 海马硬化和皮质异常折叠可能分别是MTLE和MCD癫痫耐药的关键。需要注意的是, 不论是海马硬化还是MCD, 其病变结构内都存在异常髓鞘形成^{[30, 31]}。癫痫状态下反复的异常神经兴奋会加强少突胶质细胞生成和异常髓鞘形成, 而阻断异常髓鞘形成可以改善动物的癫痫发作, 提示异常髓鞘形成可能参与了癫痫异常网络的形成。另一方面, 切除病变部位对MTLE和MCD的癫痫发作具有非常好的治疗作用^[32]。因此, 局部异常的神经网络形成可能是MTLE和MCD癫痫耐药的主要原因。可见, 神经网络假说能较好地解释MTLE和MCD癫痫耐药的诸多临床现象。但是, MTLE和MCD关键的异常神经网络目前还不清楚, 需要进一步研究。后续研究可以尝试利用单细胞测序、空间测序等新技术对耐药和不耐药的癫痫患者的脑内差异进行比较, 从而找寻一些关键的信息。此外, 其他类型的耐药性癫痫是否存在关键性的耐药神经网络机制目前也尚不完全清楚。

1.3 药物靶点假说

药物靶点假说是指AEDs分子靶点在遗传性或获得性因素的影响下发生了结构和功能上的改变, 使靶点对AEDs的敏感性降低而产生耐药。如图 2所示, 这些靶点包括电压门控离子通道和神经递质受体等。

该学说主要源自于卡马西平(carbamazepine, CBZ) 对海马齿状回神经元电压门控Na⁺通道(voltage-gated sodium channel, VGSC) 的相关研究^[33]。VGSC是CBZ、苯妥英钠(phenytoin sodium, PHT)、拉莫三嗪(lamotrigine, LTG) 等多种抗癫痫药物在海马神经元的作用靶点^[34], 这些AEDs可以阻断癫痫发作时频繁的VGSC活动而发挥抗癫痫作用^[35]。研究发现, 在耐药性癫痫患者以及具有一定耐药性的毛果芸香碱颞叶癫痫(temporal lobe epilepsy, TLE) 大鼠模型中, 海马齿状回的VGSC对AEDs的敏感性降低^{[33, 36]}。同时, 在对苯巴比妥无反应的TLE大鼠大脑海马中CA1、CA3c、CA4区及齿状回门区的神经元明显丢失^[33]。因此, 齿状回门区等特定脑区的VGSC的敏感性及其相关的细胞类型的变化可能导致CBZ等AEDs耐药。VGSC由α和β亚基组成^[37], 编码β1亚基的SCN1B突变与耐药性癫痫有关。Kruger等^[38]首次发现SCN1B-C121W是与耐药性癫痫相关的VGSC突变, 可导致遗传性耐药癫痫, 使VGSC对苯妥英钠等AEDs的敏感性降低^[39]。也有研究发现, SCN4B在伴有海马硬化的颞叶癫痫(temporal lobe epilepsy with hippocampal sclerosis, TLE-HS) 中表达下调, 提示β4亚基同样有可能参与癫痫耐药^[35]。因此, VGSC特定亚基的表达异常或突变可能是其对CBZ等特定AEDs敏感性下降的潜在机制。同时, 癫痫的高频神经活动导致Na⁺通道转录和翻译相关的细胞外信号调节激酶表达增加, 也会使VGSC敏感性降低^[40]。

γ-氨基丁酸(GABA) 是大脑皮层中主要的抑制性神经递质, GABA在GABA能轴突终末内形成并释放到突触, 在突触中它作用于GABA_A和GABA_B两种受体^[41]。在对耐药TLE患者研究中, 除了抑制性神经元丢失外, 还发现有GABA_A受体的改变^[36]。研究发现, 癫痫状态下突触GABA_A受体功能丧失以及GABA_A受体亚基显著内化, 会使可用的GABA_A受体数量减少。此外, GABA_A信号传导取决于胞内氯离子的浓度, 而在TLE患者海马部分椎体细胞的胞内氯离子浓度升高导致GABA_A受体抑制功能降低甚至兴奋化^[42]。这些GABA_A受体的相关改变可以使氯离子流入胞内的数量减少, 抑制了突触后电位, 使苯二氮卓类和巴比妥类等AEDs通过GABA_A受体降低神经元放电的作用大幅下降^[43]。本课题组^[44]前期发现在海马下托存在明显氯离子稳态失衡, 导致GABA_A受体兴奋化, 而局部海马下托注射GABA_A受体抑制剂可以改善部分耐药的电点燃癫痫大发作。GABA_B的作用是通过增加钾电导使神经元产生长时间的超极化以达到抑制作用, 癫痫状态下大脑皮层的同步放电也可能使GABA_B的受体数量减少^[45]。但GABA_B受体激活会同时引起兴奋性和抑制性神经元的超极化, 因此在癫痫中的作用非常复杂, 可能需要从特定神经类型或神经通路的角度去研究。本实验室^[46]发现阻断腹侧海马GABA_B受体可以削弱内嗅皮层低频率电刺激在小鼠TLE癫痫模型中的抗癫痫作用, 提示在特定神经通路中GABA_B受体的改变有可能参与耐药性癫痫发病过程。

综上所述, 该机制目前的研究证据集中在与VGSC及GABA有关的AEDs上, 尚不清楚其他类型AEDs耐药机制与靶点特性改变的相关性。但是, 靶点假说较难解释大多数难治性患者对作用于不同治疗靶点的几种AEDs具有抗药性这一常见临床现象, 因此该假说可能只作为一种补充机制。上述3种耐药性癫痫发病机制假说的优点及局限性如表 2所示。

2 耐药性癫痫的治疗进展

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2.1 手术治疗

美国癫痫学会(American Epilepsy Society, AES) 建议, 对于病灶明确的局灶性耐药癫痫患者, 两种或两种以上种类的AEDs治疗均无效时建议考虑癫痫手术^{[47, 48]}。手术治疗包括切除性手术、姑息性手术和其他手术^[47]。手术的基本理念是移除“癫痫病灶”, 即移除大脑皮质中致痫的最小区域——“致痫区” (epileptogenic zone, EZ)^[49], 因此定位明确的耐药性癫痫为手术治疗的主要适应症。EZ的定位方法主要包括无创性定位和有创性定位两种。无创性定位包括: ①基于症状学的定位; ②发作期的脑电; ③高分辨脑部核磁共振成像检查(nuclear magnetic resonance, MRI) 及其他影像学检查方法。而对于仍然无法定位的耐药性癫痫, 则需要采取有创性定位, 包括: ①侵袭性脑电的长期评估; ②观察术中脑电图^[50]。切除性手术的代表是MTLE的病灶切除手术, MTLE主要支持神经网络假说, 由于其病灶精确定位在海马^[15], 因此对海马进行切除符合移除EZ的手术理念。然而, 30%~50%TLE患者无法通过传统MRI找到明确的海马病灶。Caldairou等^[51]对传统MRI的学习预测框架进行改良后使其定位准确率达到了93%, 为TLE患者的无创性定位提供了新的可能。在术后的发作结果来看, 在MRI指导下进行切除手术的效果明显优于AEDs治疗^[16]。但是对于泛发性病灶和定位于有功能皮质而导致无法安全切除的患者来说, 则需要进行姑息性手术^[52]。姑息性手术包括大脑半球切开术与胼胝体(corpus callosum, CC) 切开术, 其中最常用的是CC切开术, 其目的是阻断癫痫发作的大脑半球间通过CC的快速传播^[53]。CC是最大的前脑联合, 具有传递大脑半球兴奋性的功能^[54]。研究发现全身性癫痫发作患者在进行CC切开术后, 即使出现复发, 也仅局限于局灶性癫痫发作, 表明CC可能是局灶性癫痫泛化的主要途径^[55]。在治疗效果上, 高分辨脑部MRI可以准确定位CC的7个功能区域, 同时结合术中脑电图, CC切开术可以获得良好的疗效和预后^[56]。随着癫痫理论与治疗设备的进步, 许多其他手术方式也在逐渐取得更好的疗效。磁共振引导的激光间质热疗(laser interstitial thermotherapy, LITT) 的发展, 最大限度地减少了到达深层靶点时对正常组织的破坏, 非常适合海马硬化与MCD的治疗^[57], 同时使用γ射线、X射线的立体定向放射外科治疗也在进一步研究中^[58]。手术治疗主要针对的是反复发作的耐药性癫痫患者, 有一定概率完全治愈疾病, 但是开颅手术具有较大的风险, 容易引发危险的并发症, 也有可能破坏功能正常的脑组织。

2.2 神经调节疗法

当无法进行手术或者手术失败时, 神经调节疗法是一种可以实施的姑息性替代疗法。目前, 已得到批准的神经调节疗法包括迷走神经刺激(vagal nerve stimulation, VNS)、深部脑刺激(deep brain stimulation, DBS) 和1个或多个致痫区域的响应式神经刺激(responsive nerve stimulation, RNS)^[59]。其作用机制是将电脉冲施加到周围神经或特定的大脑区域, 以响应增强的节律性, 并抵消潜在癫痫波的产生或传播^[60]。就治疗效果而言, 虽然只有极少数人在治疗后1年无癫痫发作, 但是有超过一半的患者长期癫痫发作频率减少超过50%^[59]。VNS是将脉冲发生器植入锁骨下方, 包裹在颈动脉鞘中的左侧迷走神经周围, 通过刺激迷走神经经孤束核投射到其他脑干核团, 扩散到皮质, 从而影响皮质活动^[61]。在2~4年的VNS治疗后, 大约8%的患者无癫痫发作, 50%~60%的患者癫痫发作频率至少降低50%^[62]。新的研究表明, 经皮耳廓迷走神经刺激(transcutaneous vagal nerve stimulation, t-VNS) 是一种不需要手术干预的迷走神经刺激替代方法。在一项对46名患者进行的为期8周的t-VNS治疗结果表明, 有41%的患者癫痫发作频率降低50%, 说明t-VNS极有可能是有效的无创VNS方法, 但是仍然需要更多临床数据支持^[63]。DBS是近年来使用越来越多的耐药性癫痫治疗方法, DBS的具体机制目前还不清楚, 研究表明DBS对丘脑前核(anterior thalamic nucleus, ATN)、丘脑中央中核(centromedian thalamic nucleus, CMT)、海马(hippocampus, HIP)、基底神经节[basal ganglia, BG, 包括尾状核(caudate nucleus, CN) 和丘脑底核(subthalamic nucleus, STN)]、下丘脑后部(posterior hypothalamus, PH) 和小脑(cerebellum, CE) 等刺激靶点有良好的治疗作用^[64]。目前, 大多数现有文献建议以ATN作为刺激靶点^[65], 常见脑靶点的疗效和主要不良反应如表 3^[66-69]所示。

研究认为, 对ATN的慢性刺激可促进海马体中抑制性神经递质GABA的释放以及抑制兴奋性神经递质谷氨酸(glutamate, Glu) 和天冬氨酸(aspartate, Asp) 的释放, 恢复兴奋与抑制平衡, 从而减少癫痫发作^{[70, 71]}。DBS的特点是不同频率的刺激对神经元活动有不同的影响, 如低频刺激已被证明可以在癫痫发作后帮助恢复正常的神经元电活动, 而高频刺激通常能有效地破坏发作时同步神经元活动的传播^[72]。DBS的优点是可以通过调整植入后的治疗参数来产生最大的疗效, 避免了切除手术的不良反应^[73]。治疗效果上, 临床研究中的一半患者使用ATN-DBS可减少46%~90%的癫痫发作^[64], 在一项对110名接受DBS患者的术后随访中, 所有患者术后7年的癫痫总发作频率减少了75%, 最严重的癫痫发作类型(局灶性至双侧强直-阵挛) 减少了71%^[74]。RNS旨在连续监测疑似癫痫发作区域的颅内脑电图, 并在检测到发作性颅内脑电图时提供短时间的高频电刺激, 以中止任何可能即将发生的癫痫发作^[59]。一项对230名使用RNS的耐药性癫痫患者的术后随访中, 所有患者术后9年癫痫发作频率降低的中位数百分比为75%, 其中35%的患者癫痫发作频率降低≥ 90%^[75]。与其他神经调节疗法相比, RNS系统最突出的优点是其可以不断收集和存储大脑活动数据, 从而实现数据驱动的个性化治疗^[76]。神经调节疗法的优点是组织伤害小, 对额叶及颞叶起源的癫痫有良好效果, 但是依然存在植入部位的感染与疼痛以及植入过程导致的颅内出血等常见的不良反应。

2.3 生酮饮食

生酮饮食(ketogenic diet, KD) 是指一种为诱导酮症或酮体的产生而采用的低碳水化合物、适中蛋白质含量、高脂肪含量的配方饮食, 可用于所有年龄和癫痫发作类型的耐药性癫痫患者^[77], 是一种公认的、有效的非药物治疗耐药性癫痫方案。KD的近代概念在1921年由Wilder RM博士首次提出, 并被用于治疗儿童耐药性癫痫^[78]。我国于2004年首次应用此疗法治疗耐药性癫痫^[79]。KD用于治疗耐药性癫痫, 对儿童失神癫痫、皮质畸形、青少年肌阵挛癫痫、Rett综合征、Landau-Kleffner综合征和Lennox-Gastaut综合征中度有益^[80]。KD治疗耐药性癫痫的作用机制可能与影响神经元能量代谢、神经递质功能、神经元膜转运体功能有关^[81]。还有证据表明, 生酮饮食可能会影响肠道微生物而发挥对耐药性癫痫的治疗作用^[82]。具体作用机制尚需更多证据支持。KD主要用于治疗儿童耐药性癫痫及患有顽固性癫痫且不适合手术等方案的成年人^[83]。在治疗方法上, KD主要包括4种治疗方案: ①经典KD (classic ketogenic diet, CKD)。这是一种个性化和结构化的饮食治疗方案, 要求食物中脂肪质量比蛋白质加碳水化合物质量为3:1或4:1。CKD主要用于儿童耐药性癫痫, 患者常因为难以耐受限制性的饮食而停止该方案。此外, CKD对成人顽固性癫痫的综合有效率为42%, 所以也可以作为成人耐药性癫痫的辅助治疗^[84]; ②中链甘油三酯生酮饮食(medium chain triglyceride ketogenic diet, MCT KD)。这也是一种个性化和结构化的饮食, 方案中额外增加了高度生酮的中链甘油三酯。MCT KD相较于经典的生酮饮食增加了碳水化合物和蛋白质的摄入比例, 使得该方案具有更好的耐受性, 但其因在治疗上的复杂性而需要特别接受过MCT KD疗法培训的治疗师参与; ③改良阿特金斯饮食法(modified Atkins diet, MAD)。1972年, 心脏病专家Robert C. Atkins博士推广了阿特金斯饮食法饮食。2002年, 约翰霍普金斯医院的Eric Kossoff医生首先提出改良。与CKD相比, MAD在保持较高比例的脂肪外, 增加了更多比例的蛋白质和部分碳水化合物。在MAD中, 需要在第一阶段将患者每日净碳水化合物的摄入量严格地限制在10~20 g的较低水平, 以快速到达酮症。MAD具有更好的耐受性, 越来越多应用于成人; ④低血糖指数治疗(low glycemic index treatment, LGIT)。此方案允许食用低血糖指数食物, 同时鼓励脂肪摄入, 对于无法耐受传统KD治疗的儿童耐药性癫痫患者疗效良好。

此外, 耐药性癫痫患者经过KD治疗的不良反应包括低血糖、酸中毒、呕吐、腹泻、腹胀、腹痛和胃食管反流。长期不良反应包括高脂血症、便秘、肾结石、生长障碍、骨骼发育以及维生素、矿物质和微量元素缺乏^[85], 但不良反应与KD的相关性尚需要更多证据的支撑^[86]。

2.4 精确治疗

精确治疗是指在了解疾病的潜在机制后, 针对特定的病因进行治疗, 最终达到防止疾病再次发作的治疗方法^[87]。精确治疗为耐药性癫痫提供了潜在的治疗选择, 其治疗方式包括基因治疗与靶点药物治疗^[88]。超过一半的癫痫被发现是遗传病因, 包括一些局灶性耐药性癫痫及特定的癫痫性发育性脑病^[89]。近年来, 随着高通量测序技术或下一代测序技术(next-generation sequencing technology, NGS) 的发展, 大量与遗传性癫痫有关的基因突变被发现, 使针对分子基础的基因治疗有了更高的应用价值^{[87, 90]}。目前广泛认为基因是通过影响血脑屏障的通透性, 改变AEDs的药代动力学和药效学特征, 从而导致耐药性癫痫。比如CYP2C9和CYP2C19基因的多态性可能导致等位基因的变异而使AEDs血清浓度出现显著差异^[91]。由于原发性耐药性癫痫通常是多基因共同引起的, 机制复杂而较难进行精确治疗, 因此, 目前精确治疗的实践主要集中在单基因引起的耐药性癫痫上^[92]。成功精确治疗, 关键在于有效地将转基因输送到靶神经元, 但是由于血脑屏障的存在, 将基因输送到大脑是一项技术挑战。传统的输入途径包括鼻腔给药和立体定向手术等侵入性方法。随着技术的发展, 近年来细胞移植和开发用于基因传递的重组病毒载体方面取得了长足进展。细胞移植目前集中于使用干细胞, 通常是胚胎干细胞或成体干细胞。它们的主要优点是所移植细胞与宿主的高度兼容性。此外, 病毒载体是目前最有希望将基因直接引入大脑的工具, 特别是单纯疱疹病毒(herpes simplex virus, HSV)、慢病毒和腺相关病毒(adeno-associated virus, AAV)^[93]。精确治疗的药物靶点中目前研究最多的包括SCN1A、SLC2A1、KCNQ2、聚合酶γ (polymerase gamma, POLG)^[94], 相关研究进展如下: ①与SCN1A突变相关的耐药性癫痫通常存在Na⁺通道的功能缺失(loss of function), 而卡马西平(Na⁺通道抑制剂) 的使用可能会加重癫痫发作, 因而部分耐药性癫痫通过测序明确突变类型后可以通过停用卡马西平减轻症状甚至不再发作^[95]; ② SLC2A1是编码葡萄糖转运子1蛋白的基因, 它的显性突变会导致1型葡萄糖转运蛋白缺乏综合征, 大脑对葡萄糖的吸收受损, 葡萄糖不能有效地通过血脑屏障, 导致脑组织缺乏能量供应, 产生耐药性癫痫。这些患者对生酮饮食有反应, 生酮饮食为大脑提供了一种替代能量底物^[96]; ③ KCNQ2是编码Kv7.2钾通道的基因, KCNQ2突变导致的相关脑病中包括耐药性癫痫, 使用KCNQ2-5离子通道的正变构调节剂瑞替加滨(ezogabine) 能够打开Kv7.2, 从而恢复与功能丧失突变相关的KCNQ2脑病的正常通道功能, 对难治性癫痫发作具有良好的疗效^{[87, 97]}; ④在POLG突变引起的耐药性癫痫中, 由于肝功能衰竭的风险增加, 应当避免使用损害肝功能的丙戊酸盐^[98], 这也是精准治疗减少AEDs不良反应方面的应用。总之, 精确治疗作用靶点明确, 为从源头上根治癫痫提供了可能, 缺陷是临床证据较为有限, 并且目前临床应用局限于单基因导致的耐药性癫痫。

2.5 中医药治疗

中医上癫痫是以突然扑倒, 口吐涎沫, 肢体抽搐, 惊掣啼叫, 片刻即醒, 醒后如常人为特征, 具有反复发作性特点的一种疾病。在西医上主要对应强直-阵挛性癫痫发作^[99]。在病因上, 综合从肝论治派及多种学派的观点, 可将癫痫的病因分为以下3点: ①正气亏虚为内在基础, 即先天禀赋不足; ②痰、火、淤瘀互结贯穿始终, 并为肝风引动; ③痫毒内伏, 痰浊蒙蔽清窍而致气血逆乱, 损及脑络。其中, 正气亏虚与遗传因素有关, 而痫毒损及脑络则与神经网络假说相似。在分子机制上, 有研究表明中药的作用机制可能与降低MDR1/P-gp表达有关, 这也为中西医结合治疗提供了理论依据^[100]。结合上述观点, 中医治疗可以归纳为以下4个方面: ①益气培元, 补肾健脾固其本; ②祛痰化瘀; ③解毒定痫; ④醒脑开窍^[101]。关于癫痫是否会进一步发展为耐药性癫痫, 中医的观点是与患者体质有关, 平和质癫痫患者药物治疗效果良好, 而气郁质、阳虚质难治性倾向高^[102]。目前, 治疗耐药性癫痫使用较多的包括柴贝止痫汤(疏肝理气、化痰熄风)、血府逐淤汤(活血化瘀、行气止痛) 和柴胡疏肝汤(疏肝理气活血)。在一项60名癫痫患者的临床研究^[103]中, 使用血府逐淤汤治疗的32人中总有效率为72.00%, 使用AEDs的28人总有效率为75.00%, 说明传统中药方剂有不亚于AEDs的疗效, 并且还有价格低、不良反应小的优点。在一项56名患者的研究中, 28人进行传统AEDs治疗, 另外28人在此基础上添加柴贝止痫汤治疗, 在8周的疗程后, AEDs联合柴贝止痫汤组的有效患者为18人, 有效率为64.29%, AEDs组的有效患者为16人, 有效率为57.14%, 略低于联合用药组^[104]。在一项120名患者的研究中, 60人给予传统AEDs治疗, 其余60人在此基础上给予柴胡疏肝汤治疗, 结果表明中西医联合治疗组患者治疗期、评估期及随访期各时间点癫痫平均发生次数均明显低于传统AEDs组^[105], 提示中西医联合治疗的有效性。后续实验发现, 在上述联合用药组的中药方剂上加入龙骨、牡蛎进行配伍后, 治疗有效率从对照组的69.23%进一步提升到84.62%^[106], 表明中药配伍联合西药治疗的重要性。事实上, 其他的中西医配伍结合治疗也通常比AEDs单药治疗疗效更好, Zhou等^[107]对13种中西医结合治疗耐药性癫痫方案进行的meta分析表明, 所有组别的联合用药疗效均远大于单独使用西药。以目前临床常用的柴胡疏肝汤加AEDs新药左乙拉西坦为例, 在左乙拉西坦治疗基础上给予柴胡疏肝汤加味(原方的基础上额外添加其他中药) 治疗, 联合用药组总有效率91.11%, 高于左乙拉西坦组的73.33%^[108], 说明即使是新一代AEDs也可以联合中药发挥更好的疗效。最近本实验室Lu等^[109]通过6 Hz角膜电刺激建立的角膜电点燃小鼠癫痫模型发现其对苯妥英钠、丙戊酸钠和拉莫三嗪这些常用的AEDs以及柴胡加龙骨牡蛎汤、天麻钩藤饮均不敏感, 仅左乙拉西坦和风引汤能够明显降低动物的发作等级和大发作几率。左乙拉西坦的价格高昂, 而风引汤在该研究中具有不亚于左乙拉西坦的治疗效果, 因此这可能为多药耐药的癫痫患者提供了相对廉价的潜在中医药治疗方案。对于风引汤的有效成分, Lan等^[110]通过网络药理学归纳出大黄酚、桂皮醛、甘草酸可能是风引汤的活性成分, 其中大黄酚可能通过上调脑源性神经营养因子, 降低星形胶质细胞活性, 对海马具有明显的保护作用; 桂皮醛可能通过线粒体途径保护谷氨酸诱导PC12细胞的氧化应激损伤, 降低急性癫痫的发作; 而甘草酸可能通过阻断线粒体途径以及下调HMGB1的表达对癫痫的海马神经元和皮质神经元起保护作用。该研究揭示了风引汤作用的相关分子机制, 也为其他抗耐药性癫痫中药方剂的机制研究提供了理论指导。Chen等^[111]通过网络药理学方法总结胆南星可能的主要有效成分和潜在靶点, 并且采用电生理实验证实了其中β-谷甾醇和鹅去氧胆酸可有效降低小鼠海马CA1锥体神经元动作电位, 而两者联合应用时抑制作用更加显著, 为天南星等潜在抗耐药性癫痫中药的炮制开发提供了研究基础。综上所述, 中医治疗对于耐药性癫痫可能具有疗效好和价格相对低廉等优点, 并且中西医联合用药可能具有更好的疗效。虽然部分研究表明, 中药的作用机制可能与降低MDR1/P-gp表达、抑制神经动作电位等有关, 但是其具体作用靶点与有效成分仍然需要进一步研究。上述耐药性癫痫5种治疗方式的优势与局限性如表 4所示。

3 结语

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目前临床上针对耐药性癫痫的致病机制有多种假说, 仅仅单一的假说不足以完全阐明, 临床工作者应融会贯通各种学说, 互为补充, 根据患者的发作类型, 制定个性化的中西医诊治方案。耐药性癫痫的手术治疗技术已经较为成熟, 在其他治疗技术方面如DBS等仍需进一步研究。在AEDs开发上, 靶向药物有靶点单一的缺陷, 辅以中药多活性成分、多靶点的特点, 中西医结合可以获得更好的治疗效果。在手术治疗与药物治疗外, 对患者进行KD的指导, 也有助于耐药性癫痫的后期恢复与治疗。随着各项医疗技术水平的不断完善, 新一代AEDs的开发与中西医结合治疗的进一步推进, 人们对耐药性癫痫的机制与治疗也会上升到一个新的阶段。

作者贡献: 徐骋昊是本文的主要完成者; 邬鹏程、黄通敏协助相关文献的收集与整理; 许正浩、陆海美负责文章的指导与审阅。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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浙江省自然科学基金资助项目(LY22H280007)
国家自然科学基金资助项目(82174005)

参考文献

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2023年第58卷第3期

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doi: 10.16438/j.0513-4870.2022-1096

接收时间：2022-10-07
首发时间：2025-11-21
出版时间：2023-03-12

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收稿日期：2022-10-07
修回日期：2022-11-04

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浙江省自然科学基金资助项目(LY22H280007)

国家自然科学基金资助项目(82174005)

作者信息

1.浙江中医药大学第二临床医学院, 浙江杭州 310053

2.浙江中医药大学基础医学院, 浙江杭州 310053

3.浙江省神经药理学与转化研究重点实验室, 浙江杭州 310053

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*许正浩, Tel: 86-571-86613587, E-mail: xuzhenghao@zcmu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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AEDs	ABCB1		ABCC		ABCG2
Carbamazepine	×	×		×	√		×	-
Lamotrigine	√	×	×	×	？	-
Levetiracetam	？	-	×	-	-	√
Phenobarbital	√	×	×	-	×	√
Phenytoin	√	√	×	√	×	×
Topiramate	√	√	×	-	-	-
Sodium valproate	×	×	×	×	×	×

AEDs

ABCB1

ABCC

ABCG2

Human ABCB1 culture model in vitro

Animal model lacking ABCB1

Human ABCC culture model in vitro

Animal model lacking ABCC

Human ABCG2 culture model in vitro

Animal model lacking ABCG2

Carbamazepine

√

Lamotrigine

√

？

Levetiracetam

？

√

Phenobarbital

√

Phenytoin

√

Topiramate

√

Sodium valproate

Hypothesis	Advantage	Limitation
Transporter hypothesis	It can explain the resistance to multiple AEDs in patients with drug-resistant epilepsy	It is difficult to explain the resistance to some AEDs, which are not the substrate of the ABC transporter protein family
Its related studies mainly focus on the ABC transporter family, and there is a lack of research on other transporter families
Neural network hypothesis	It can explain the mechanism of drug resistance in MTLE and MCD patients	Alteration in neural networks is also present in other types of epilepsy that are well controlled by AEDs, not just in patients with drug-resistant epilepsy. There is a lack of research on specific neural networks for the drug-resistant epilepsy
It may explain the resistance to multiple AEDs in patients with drug-resistant epilepsy
It can provide a theoretical basis for surgical resection
Target hypothesis	It can explain the molecular mechanisms in patients with specific types of drug-resistance epilepsy	It cannot explain the resistance to multiple AEDs in patients with drug-resistant epilepsy
Changes in the VGSC and GABA receptors have been well-described in animal models of drug-resistance epilepsy

Hypothesis

Advantage

Limitation

Transporter hypothesis

It can explain the resistance to multiple AEDs in patients with drug-resistant epilepsy

It is difficult to explain the resistance to some AEDs, which are not the substrate of the ABC transporter protein family

Its related studies mainly focus on the ABC transporter family, and there is a lack of research on other transporter families

Neural network hypothesis

It can explain the mechanism of drug resistance in MTLE and MCD patients

Alteration in neural networks is also present in other types of epilepsy that are well controlled by AEDs, not just in patients with drug-resistant epilepsy. There is a lack of research on specific neural networks for the drug-resistant epilepsy

It may explain the resistance to multiple AEDs in patients with drug-resistant epilepsy

It can provide a theoretical basis for surgical resection

Target hypothesis

It can explain the molecular mechanisms in patients with specific types of drug-resistance epilepsy

It cannot explain the resistance to multiple AEDs in patients with drug-resistant epilepsy

Changes in the VGSC and GABA receptors have been well-described in animal models of drug-resistance epilepsy

Brain target	Reduction of seizure frequency	Adverse reaction
Centromedian thalamic nucleus	-73.4% lower (-80.2% to -43.8% lower)	#
Anterior thalamic nucleus	-60.8% lower* (-80.3% to -22.6% lower)	Depression, memory impairment, and #
Cerebellar cortex	-12.4% lower (-35.3% lower to +10.6% higher)	#
Hippocampus	-67.8% lower (-77.5% to -58.1% lower)	#
Nucleus accumbens	-33.8% lower (-100% lower to +49.8% higher)	#
RNS in EZ	-24.9% lower (-40.1 to -6.0% lower)	#
In total	The median reduction was 56%, 65%, and 75% at 2, 5, and 7 years	Implant site pain, headache, and dysesthesia

Brain target

Reduction of seizure frequency

Adverse reaction

Centromedian thalamic nucleus

-73.4% lower (-80.2% to -43.8% lower)

Anterior thalamic nucleus

-60.8% lower* (-80.3% to -22.6% lower)

Depression, memory impairment, and #

Cerebellar cortex

-12.4% lower (-35.3% lower to +10.6% higher)

Hippocampus

-67.8% lower (-77.5% to -58.1% lower)

Nucleus accumbens

-33.8% lower (-100% lower to +49.8% higher)

RNS in EZ

-24.9% lower (-40.1 to -6.0% lower)

In total

The median reduction was 56%, 65%, and 75% at 2, 5, and 7 years

Implant site pain, headache, and dysesthesia

Treatment	Advantage	Disadvantage or limitation
Surgical resection	Mainly for drug-resistant epilepsy patients with focal drug-resistant epilepsy (or clear epileptogenic foci)	Its therapeutic effect of generalized epilepsy is not ideal. And it can be easily affected by non-pathological factors
DBS	It has a good therapeutic effect on epilepsy of frontal lobe and temporal lobe origin It may be an alternative intervention for generalized epilepsy The adverse reactions were less	The therapeutic effect of current DBS methods on drug-resistant epilepsy is not good enough The optimal brain targets and other parameters are still under study The specific mechanism of action has not been fully proved
Ketogenic diet	It is an effective and safe method for the treatment of drug-resistant epilepsy It is an alternative therapy for patients with recurrent epilepsy after surgery and drug treatment	There are many contraindications as well as numerous short-term and long-term adverse reactions The specific mechanism is still under study
Precise treatment	Gene therapy provides a potential opportunity to cure the epilepsy from the source. It may prevent and intervene the epilepsy in the potential population The clear target can promote the development and application of the target hypothesis	The clinical evidence remains limited, which is mainly concentrated on a few typical cases (such as type 1 glucose transporter deficiency syndrome) Many therapeutic targets are still under study
TCM treatment	The clinical results show that the combination of TCM and Western medicine has a better effect than monotherapy TCM may have less side effects, can reduce patients' medical expenses, and can be an inspiration for the development of new drugs	The effective components and multiple-target mechanisms of TCM are still unclear

Treatment

Advantage

Disadvantage or limitation

Surgical resection

Mainly for drug-resistant epilepsy patients with focal drug-resistant epilepsy (or clear epileptogenic foci)

Its therapeutic effect of generalized epilepsy is not ideal. And it can be easily affected by non-pathological factors

DBS

It has a good therapeutic effect on epilepsy of frontal lobe and temporal lobe origin
It may be an alternative intervention for generalized epilepsy
The adverse reactions were less

The therapeutic effect of current DBS methods on drug-resistant epilepsy is not good enough
The optimal brain targets and other parameters are still under study
The specific mechanism of action has not been fully proved

Ketogenic diet

It is an effective and safe method for the treatment of drug-resistant epilepsy
It is an alternative therapy for patients with recurrent epilepsy after surgery and drug treatment

There are many contraindications as well as numerous short-term and long-term adverse reactions
The specific mechanism is still under study

Precise treatment

Gene therapy provides a potential opportunity to cure the epilepsy from the source. It may prevent and intervene the epilepsy in the potential population
The clear target can promote the development and application of the target hypothesis

The clinical evidence remains limited, which is mainly concentrated on a few typical cases (such as type 1 glucose transporter deficiency syndrome)
Many therapeutic targets are still under study

TCM treatment

The clinical results show that the combination of TCM and Western medicine has a better effect than monotherapy
TCM may have less side effects, can reduce patients' medical expenses, and can be an inspiration for the development of new drugs

The effective components and multiple-target mechanisms of TCM are still unclear