王新新，陸欽池

上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院神經(jīng)內(nèi)科，上海 200127

腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制及治療

王新新，陸欽池

上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院神經(jīng)內(nèi)科，上海 200127

腦膠質(zhì)瘤是腦部腫瘤最常見(jiàn)的類型，30%～50%的腦膠質(zhì)瘤患者可繼發(fā)癲癇發(fā)作。部分腦膠質(zhì)瘤患者在接受腫瘤切除術(shù)后依然有癲癇發(fā)作。因此，探討腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制及治療具有重要的臨床意義。本文對(duì)腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制進(jìn)行探討，包括谷氨酸及其轉(zhuǎn)運(yùn)體的變化、腦膠質(zhì)瘤細(xì)胞內(nèi)Cl－濃度調(diào)節(jié)異常、γ-氨基丁酸（gamma-amino butyric acid，GABA）信號(hào)通路介導(dǎo)的抑制性作用的變化以及哺乳動(dòng)物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信號(hào)通路異常等，并介紹了基于腦膠質(zhì)瘤繼發(fā)癲癇發(fā)病機(jī)制的治療藥物，包括胱氨酸-谷氨酸轉(zhuǎn)運(yùn)體（cystineglutamate transporter，xCT）阻斷劑柳氮磺吡啶、Cl－濃度調(diào)節(jié)劑布美他尼以及mTOR抑制劑雷帕霉素等，以期為腦膠質(zhì)瘤繼發(fā)癲癇提供新的有效治療藥物。本文還對(duì)控制腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的傳統(tǒng)抗癲癇藥物（anti-epileptic drugs，AEDs）的使用方法進(jìn)行了小結(jié)。

神經(jīng)膠質(zhì)瘤；癲癇；發(fā)病機(jī)制；治療

To cite: WANG X X, LU Q C. Pathogenesis of glioma-associated epilepsy and its therapy.J Neurol and Neurorehabil, 2016, 12(4):208-214.

腦膠質(zhì)瘤是腦部最常見(jiàn)的腫瘤類型，通常繼發(fā)癲癇發(fā)作[1-4]。腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作與腫瘤細(xì)胞分化程度存在一定的關(guān)聯(lián)，已有研究發(fā)現(xiàn)90%的繼發(fā)癲癇發(fā)作的腦膠質(zhì)瘤為低分化膠質(zhì)瘤，50%～60%為高分化膠質(zhì)瘤[3,5]。癲癇發(fā)作可能是腦膠質(zhì)瘤最初的臨床癥狀，也可以在腦膠質(zhì)瘤的治療過(guò)程中出現(xiàn)。反復(fù)的癲癇發(fā)作不僅給患者帶來(lái)嚴(yán)重的生理和心理負(fù)擔(dān)，還增加了腦膠質(zhì)瘤患者的死亡率[6]。因此，對(duì)腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作進(jìn)行及時(shí)而有效的干預(yù)治療，顯得尤為重要。然而，部分接受手術(shù)切除治療的腦膠質(zhì)瘤患者在術(shù)后仍有癲癇發(fā)作[7]；部分腦膠質(zhì)瘤繼發(fā)的癲癇屬于藥物難治性癲癇，因此傳統(tǒng)的抗癲癇藥物（anti-epileptic drugs，AEDs）對(duì)這部分癲癇發(fā)作的療效較差[2]。導(dǎo)致這一現(xiàn)象的原因是腫瘤內(nèi)部及其周圍組織發(fā)生復(fù)雜的結(jié)構(gòu)和分子變化，包括多種耐藥蛋白的表達(dá)、興奮性與抑制性通路的失衡以及早期手術(shù)對(duì)腦組織的損傷等。因此，了解腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制，并針對(duì)這些發(fā)病機(jī)制進(jìn)行干預(yù)，對(duì)有效抑制膠質(zhì)瘤繼發(fā)癲癇發(fā)作具有重要的臨床意義。

神經(jīng)網(wǎng)絡(luò)興奮性與抑制性的失衡通常會(huì)引發(fā)癇樣放電。任何能夠增強(qiáng)谷氨酸能通路介導(dǎo)的興奮性作用或降低γ-氨基丁酸（gamma-amino butyric acid，GABA）通路介導(dǎo)的抑制性作用的因素，均可引發(fā)癲癇發(fā)作。腦膠質(zhì)瘤患者體內(nèi)發(fā)生的一系列病理生理變化，包括遞質(zhì)及其受體的變化、血管重建以及細(xì)胞結(jié)構(gòu)和信號(hào)轉(zhuǎn)導(dǎo)通路的變化，都將不同程度地導(dǎo)致神經(jīng)網(wǎng)絡(luò)興奮性的改變。BEAUMONT等[8]認(rèn)為，腦膠質(zhì)瘤繼發(fā)癲癇涉及多種機(jī)制，包括代謝失衡、pH值異常、遞質(zhì)及其受體的改變，免疫系統(tǒng)的過(guò)度激活等均不同程度地參與了癲癇的發(fā)生。本文從谷氨酸及其轉(zhuǎn)運(yùn)體的異常、細(xì)胞內(nèi)Cl－濃度與GABA信號(hào)通路異常和哺乳動(dòng)物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信號(hào)通路異常這3個(gè)方面探討腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制；根據(jù)相關(guān)機(jī)制探討胱氨酸-谷氨酸轉(zhuǎn)運(yùn)體（cystineglutamate transporter，xCT）阻斷劑柳氮磺吡啶、Cl－濃度調(diào)節(jié)劑布美他尼和mTOR抑制劑雷帕霉素治療腦膠質(zhì)瘤繼發(fā)癲癇的最新進(jìn)展；對(duì)控制腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的常規(guī)AEDs使用方法進(jìn)行總結(jié)。

1 腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制

1.1 谷氨酸及其轉(zhuǎn)運(yùn)體的異常

在腦膠質(zhì)瘤及其周圍組織中，常出現(xiàn)谷氨酸水平的調(diào)節(jié)異常。文獻(xiàn)報(bào)道，腦膠質(zhì)瘤細(xì)胞外的谷氨酸水平超過(guò)正常組織細(xì)胞外水平的10倍[9]。導(dǎo)致腦膠質(zhì)瘤細(xì)胞外谷氨酸水平升高的因素有很多，其具體機(jī)制見(jiàn)圖1所示。腦膠質(zhì)瘤組織內(nèi)的xCT水平通常較高[1,10-12]，xCT可將腦膠質(zhì)瘤細(xì)胞內(nèi)的谷氨酸轉(zhuǎn)運(yùn)至細(xì)胞外，并將細(xì)胞外的胱氨酸轉(zhuǎn)運(yùn)至細(xì)胞內(nèi)。被轉(zhuǎn)運(yùn)至腦膠質(zhì)瘤細(xì)胞內(nèi)的胱氨酸經(jīng)代謝后轉(zhuǎn)化為半胱氨酸，進(jìn)而合成一種抗氧化劑谷胱甘肽[13]，可促進(jìn)腦膠質(zhì)瘤細(xì)胞的增殖；同時(shí)，細(xì)胞外增多的谷氨酸不能被有效地重吸收回細(xì)胞內(nèi)，這是由于腦膠質(zhì)瘤細(xì)胞膜上表達(dá)的興奮性氨基酸轉(zhuǎn)運(yùn)體1（excitatory amino acid transporter 1，EAAT1）和興奮性氨基酸轉(zhuǎn)運(yùn)體2（excitatory amino acid transporter 2，EAAT2）水平下調(diào)[1,10]，而腦膠質(zhì)瘤周圍組織中激活的小膠質(zhì)細(xì)胞表達(dá)的EAAT2水平下降，從而進(jìn)一步導(dǎo)致腦膠質(zhì)瘤細(xì)胞外谷氨酸水平的升高[14]。因此，腦膠質(zhì)瘤細(xì)胞外增多的谷氨酸就會(huì)作用于神經(jīng)元突觸后膜上的N-甲基-D-天冬氨酸（N-methyl-D-aspartate，NMDA）受體和α-氨基-3-羥基-5-甲基-4-異噁唑丙酸（α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid，AMPA）受體，使神經(jīng)元發(fā)生去極化，進(jìn)而引發(fā)同步化癇樣放電。此外，70%～80%的低級(jí)別腦膠質(zhì)瘤伴有異檸檬酸脫氫酶1（isocitrate dehydrogenase 1，IDH1）基因突變[15]。IDH1基因突變會(huì)導(dǎo)致異檸檬酸不能轉(zhuǎn)變?yōu)棣?酮戊二酸，反而轉(zhuǎn)變?yōu)镈-2-羥戊二酸（D-2-hydroxyglutarate，D-2HG）[16]。D-2HG的結(jié)構(gòu)與谷氨酸類似，細(xì)胞間隙內(nèi)大量聚集的D-2HG可激動(dòng)神經(jīng)元突觸后膜谷氨酸受體，進(jìn)而導(dǎo)致神經(jīng)元發(fā)生去極化，發(fā)生同步化癇樣放電。已有文獻(xiàn)報(bào)道，腦膠質(zhì)瘤細(xì)胞中xCT過(guò)表達(dá)[17]和IDH1基因突變與癲癇發(fā)作相關(guān)[18-19]。

總之，xCT過(guò)表達(dá)與IDH1基因突變都將使谷氨酸水平升高，繼而激活大量的谷氨酸受體，使神經(jīng)元興奮性增加，促進(jìn)同步化癇樣放電的產(chǎn)生。

圖1 谷氨酸信號(hào)通路在腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作中的作用機(jī)制。腦膠質(zhì)瘤細(xì)胞膜上xCT過(guò)表達(dá)及星形膠質(zhì)細(xì)胞內(nèi)EAAT1/2表達(dá)不足是導(dǎo)致腦膠質(zhì)瘤細(xì)胞外谷氨酸水平升高的主要因素。谷氨酸水平升高會(huì)過(guò)度激活NMDA受體和AMPA受體，進(jìn)而引起突觸神經(jīng)元介導(dǎo)的興奮性電流增加，繼而引發(fā)同步化癇樣放電

1.2 腦膠質(zhì)瘤細(xì)胞內(nèi)Cl－濃度與GABA信號(hào)通路異常

HAGLUND等[20]和MARCO等[21]發(fā)現(xiàn)，腦膠質(zhì)瘤患者腦組織錐體神經(jīng)元鄰近的GABA能突觸密度降低，GABA介導(dǎo)的抑制性作用減弱。錐體細(xì)胞內(nèi)Cl－濃度的變化會(huì)影響神經(jīng)元對(duì)GABA的反應(yīng)以及膠質(zhì)細(xì)胞的特性。正常的成熟神經(jīng)元細(xì)胞內(nèi)的K＋濃度高于細(xì)胞外，K＋-Cl－共轉(zhuǎn)運(yùn)體2（K＋-Cl－CO－transporter 2，KCC2）依賴于這種濃度梯度將Cl－運(yùn)至細(xì)胞外，從而使細(xì)胞內(nèi)的Cl－濃度維持于較低濃度。然而，腦膠質(zhì)瘤細(xì)胞常伴有Cl－轉(zhuǎn)運(yùn)體的改變，即KCC2表達(dá)下調(diào)，而Na＋-K＋-Cl－共轉(zhuǎn)運(yùn)體1（Na＋-K＋-Cl－CO－transporter 1，NKCC1）表達(dá)上調(diào)。NKCC1的作用主要是將細(xì)胞外的Cl－轉(zhuǎn)運(yùn)至細(xì)胞內(nèi)，其表達(dá)上調(diào)可導(dǎo)致細(xì)胞內(nèi)Cl－濃度高于細(xì)胞外。文獻(xiàn)報(bào)道，腦膠質(zhì)瘤細(xì)胞內(nèi)的Cl－濃度約為正常細(xì)胞的10倍[22]，GABA作用于GABA A型受體（GABA type A receptor，GABAAR）后可使Cl－出現(xiàn)外流，繼而發(fā)生去極化作用，促進(jìn)癲癇樣活動(dòng)的發(fā)生。已有文獻(xiàn)報(bào)道，海馬硬化癲癇樣活動(dòng)的產(chǎn)生與Cl－調(diào)節(jié)異常導(dǎo)致的GABA能信號(hào)通路異常有關(guān)[23-24]。此外，腦膠質(zhì)瘤細(xì)胞及激活的小膠質(zhì)細(xì)胞釋放的腦源性神經(jīng)生長(zhǎng)因子（brain-derived neurotrophic factor，BDNF）可上調(diào)錐體神經(jīng)元細(xì)胞膜上NKCC1的表達(dá)，降低KCC2的表達(dá)[25]，從而導(dǎo)致錐體神經(jīng)元內(nèi)Cl－濃度調(diào)節(jié)異常。也有證據(jù)表明，NMDA介導(dǎo)的活動(dòng)會(huì)抑制KCC2的表達(dá)[26]，因此腦膠質(zhì)瘤組織中異常的谷氨酸能信號(hào)通路也會(huì)導(dǎo)致Cl－濃度調(diào)節(jié)障礙。

總之，腦膠質(zhì)瘤細(xì)胞膜上Cl－轉(zhuǎn)運(yùn)體表達(dá)異?？墒辜?xì)胞內(nèi)Cl－濃度高于細(xì)胞外，使GABA介導(dǎo)的抑制性作用轉(zhuǎn)變?yōu)榕d奮性作用，繼而促使神經(jīng)元興奮性升高，產(chǎn)生同步化癲樣放電活動(dòng)。

1.3 mTOR信號(hào)通路異常

腦膠質(zhì)瘤發(fā)生的病理生理過(guò)程中，常伴有mTOR信號(hào)通路調(diào)節(jié)異常，而mTOR信號(hào)通路的功能障礙是癲癇發(fā)生的原因之一。mTOR信號(hào)通路在結(jié)節(jié)硬化癥（tuberous sclerosis complex，TSC）的病理生理過(guò)程中發(fā)揮著一定的作用。常染色體顯性基因TSC1和TSC2突變與TSC有關(guān)，TSC1和TSC2基因突變會(huì)導(dǎo)致mTOR復(fù)合體1和2活性增加，進(jìn)一步增加神經(jīng)元興奮性[27]。在TSC動(dòng)物模型中，海馬CA1區(qū)錐體神經(jīng)元中的谷氨酸能和GABA能信號(hào)通路均發(fā)生了改變；mTOR信號(hào)通路減弱了GABA介導(dǎo)的抑制作用，卻能增強(qiáng)谷氨酸介導(dǎo)的興奮性作用，從而使海馬神經(jīng)網(wǎng)絡(luò)的興奮性發(fā)生改變[28]。已有文獻(xiàn)報(bào)道，mTOR參與了癲癇性腦病的形成[29]。此外，腦膠質(zhì)瘤細(xì)胞中過(guò)度激活的mTOR信號(hào)通路及某些突變的基因與藥物難治性癲癇相關(guān)[30]。由此可見(jiàn)，mTOR信號(hào)通路異常與腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)生密切相關(guān)。

2 基于腦膠質(zhì)瘤繼發(fā)癲癇發(fā)病機(jī)制的干預(yù)治療

對(duì)腦膠質(zhì)瘤繼發(fā)癲癇發(fā)病機(jī)制的認(rèn)識(shí)有助于針對(duì)相應(yīng)的發(fā)病機(jī)制進(jìn)行干預(yù)治療，這對(duì)于指導(dǎo)手術(shù)療效差及常規(guī)AEDs治療無(wú)效的腦膠質(zhì)瘤繼發(fā)癲癇的治療具有重要的臨床意義。

2.1 谷氨酸能信號(hào)通路的調(diào)控

由于腦膠質(zhì)瘤細(xì)胞外谷氨酸水平升高是腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制之一，因此對(duì)谷氨酸轉(zhuǎn)運(yùn)體及其受體進(jìn)行調(diào)控可以作為治療腦膠質(zhì)瘤繼發(fā)癲癇的途徑之一。前期臨床模型及癲癇患者的遺傳藥理學(xué)數(shù)據(jù)證實(shí)了這一治療途徑的有效性。xCT阻斷劑柳氮磺吡啶最初被美國(guó)食品藥物管理局（Food and Drug Administration，F(xiàn)DA） 和歐洲藥品管理局（European Medicines Agency，EMA）批準(zhǔn)用于克羅恩病的治療。最近的動(dòng)物實(shí)驗(yàn)結(jié)果顯示，柳氮磺吡啶可抑制腦膠質(zhì)瘤細(xì)胞過(guò)表達(dá)xCT，從而抑制谷氨酸水平的升高，減弱癲癇樣活動(dòng)[31]。研究顯示，通過(guò)小干擾RNA抑制人腦膠質(zhì)瘤細(xì)胞xCT系統(tǒng)的活性后，腦膠質(zhì)瘤細(xì)胞釋放谷氨酸減少，NMDA介導(dǎo)的興奮性作用降低[11]。此外，2012年，非競(jìng)爭(zhēng)性AMPA受體拮抗劑吡侖帕奈在歐洲和美國(guó)獲得批準(zhǔn)用于治療部分性癲癇發(fā)作，同時(shí)也被用于腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的治療。另一項(xiàng)腦膠質(zhì)瘤動(dòng)物模型的研究結(jié)果表明，NMDA受體拮抗劑地佐環(huán)平、1-氨基-3,5-二甲基金剛烷胺鹽酸鹽和利魯唑可以抑制腦膠質(zhì)瘤細(xì)胞增殖以及繼發(fā)癲癇的發(fā)作[32-33]，其中1-氨基-3,5-二甲基金剛烷胺鹽酸鹽已被應(yīng)用于Ⅱ期臨床試驗(yàn)。

此外，還可通過(guò)核受體過(guò)氧化物酶增殖體激活受體γ（peroxisome proliferator-activatedreceptor-γ，PPAR-γ）來(lái)調(diào)控腦膠質(zhì)瘤細(xì)胞外谷氨酸的水平。PPAR-γ是一種轉(zhuǎn)錄調(diào)節(jié)子，可以調(diào)節(jié)一系列基因的表達(dá)，包括編碼EAAT2基因。PPAR-γ激動(dòng)劑吡格列酮可以上調(diào)腦膠質(zhì)瘤細(xì)胞表達(dá)EAAT2，從而促進(jìn)細(xì)胞外谷氨酸的轉(zhuǎn)運(yùn)，繼而降低細(xì)胞外谷氨酸的水平[34]。PPAR-γ激動(dòng)劑還可通過(guò)阻斷煙堿型乙酰膽堿受體介導(dǎo)的突觸后電流而抑制癲癇樣活動(dòng)[35]。此外，IDH1基因突變抑制劑可以抑制IDH1基因突變的腦膠質(zhì)瘤細(xì)胞合成D-2HG，進(jìn)而抑制癲癇樣活動(dòng)的發(fā)生[36]。

2.2 腦膠質(zhì)瘤細(xì)胞內(nèi)Cl－水平及GABA能信號(hào)通路的調(diào)控

腦膠質(zhì)瘤細(xì)胞內(nèi)Cl－濃度的變化以及與其相關(guān)的GABA能信號(hào)通路的改變是腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制之一，因此調(diào)節(jié)Cl－轉(zhuǎn)運(yùn)體及其相關(guān)受體也成為治療腦膠質(zhì)瘤繼發(fā)癲癇的又一條途徑。

布美他尼是NKCC1的相對(duì)特異性阻斷劑。既往研究表明，布美他尼可以抑制腫瘤細(xì)胞的遷移和增殖[22]。來(lái)自于離體及在體動(dòng)物癲癇模型[37-38]和臨床癲癇患者[39]的數(shù)據(jù)顯示，布美他尼具有抑制癇樣放電的作用。此外，還有關(guān)于布美他尼應(yīng)用于新生兒或成年癲癇患者的病例報(bào)告，但由于布美他尼的不良反應(yīng)而使該藥的臨床應(yīng)用受到限制，因此研發(fā)與布美他尼具有相同藥理學(xué)特征的類似藥物已成為研究的焦點(diǎn)。LYKKE等[40]已研發(fā)出與布美他尼具有相似結(jié)構(gòu)但對(duì)NKCC1特異性更高的類似物，為癲癇的治療提供了一種新的藥物。

增強(qiáng)KCC2的作用曾被認(rèn)為是治療腦膠質(zhì)瘤繼發(fā)癲癇的另一種方法。然而，有研究在恢復(fù)大鼠KCC2功能而使腦膠質(zhì)瘤細(xì)胞內(nèi)Cl－水平恢復(fù)至正常后，并未發(fā)現(xiàn)離體腦片癲癇樣活動(dòng)被抑制或削弱，對(duì)此可能的解釋是KCC2激活導(dǎo)致K＋外流增加[41]。因此，應(yīng)更加全面而深入地理解KCC2在癲癇發(fā)生中的作用。

2.3 mTOR信號(hào)通路的調(diào)控

mTOR信號(hào)通路異常參與了腦膠質(zhì)瘤繼發(fā)癲癇的病理過(guò)程。mTOR抑制劑包括雷帕霉素和依維莫司等。已有研究認(rèn)為，雷帕霉素可以抑制癲癇動(dòng)物模型的癇樣放電或降低其發(fā)作頻率[42]。依維莫司是經(jīng)美國(guó)FDA和EMA批準(zhǔn)的抗腫瘤藥物，同時(shí)也可用于治療TSC。目前已證實(shí)，依維莫司可以通過(guò)縮小腫瘤組織的體積以降低癲癇發(fā)作的頻率[43]。一項(xiàng)關(guān)于依維莫司的Ⅲ期臨床試驗(yàn)正在評(píng)估依維莫司對(duì)于腦膠質(zhì)瘤繼發(fā)復(fù)雜部分性癲癇發(fā)作的療效[44]。

3 控制腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的常用AEDs

腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作常表現(xiàn)為部分起始性癲癇發(fā)作，一般在首次癲癇發(fā)作出現(xiàn)后開始進(jìn)行治療[45]。目前尚無(wú)證據(jù)證實(shí)預(yù)防性用藥可有效抑制癲癇發(fā)作。國(guó)際抗癲癇聯(lián)盟（International League Against Epilepsy，ILAE）根據(jù)Meta分析的結(jié)果達(dá)成共識(shí)，認(rèn)為大多數(shù)AEDs對(duì)控制成年部分性癲癇發(fā)作有效，其中A級(jí)推薦包括左乙拉西坦、唑尼沙胺、卡馬西平和苯妥英鈉，B級(jí)推薦為丙戊酸，C級(jí)推薦包括加巴噴丁、拉莫三嗪、奧卡西平、苯巴比妥、托吡酯和氨基己酸。然而，最終還是要依據(jù)每一例患者的具體情況來(lái)選擇合適的藥物，諸如年齡、性別、體質(zhì)量、病史、藥物不良反應(yīng)所致風(fēng)險(xiǎn)、并發(fā)癥以及聯(lián)合用藥時(shí)藥物之間的相互作用等。

一項(xiàng)關(guān)于AEDs治療的臨床研究結(jié)果表明，丙戊酸單藥可使55%～78%的腦膠質(zhì)瘤（低級(jí)別和高級(jí)別）繼發(fā)癲癇發(fā)作得以緩解[46]。左乙拉西坦和丙戊酸被認(rèn)為是控制部分性癲癇發(fā)作和局灶性癲癇引起的癲癇發(fā)作的首選藥物，且耐受性良好[47]。拉莫三嗪對(duì)于控制腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作同樣有效，耐受性也較好，并且與丙戊酸鈉具有協(xié)同作用[48]。表1對(duì)用于控制腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作相關(guān)AEDs的使用方法進(jìn)行了總結(jié)。

表1 控制腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的相關(guān)抗癲癇藥物[47]

4 結(jié) 論

綜上所述，癲癇發(fā)作是腦膠質(zhì)瘤患者較常見(jiàn)的臨床表現(xiàn)之一，除了控制癥狀發(fā)作以外，還應(yīng)針對(duì)其發(fā)病機(jī)制從根本上進(jìn)行較早期的干預(yù)治療。腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的發(fā)病機(jī)制復(fù)雜，谷氨酸能、GABA能和mTOR信號(hào)通路的改變均參與其中。因此，深入了解這些信號(hào)通路在腦膠質(zhì)瘤繼發(fā)癲癇發(fā)作的病理生理過(guò)程中的作用，有助于針對(duì)相應(yīng)的靶點(diǎn)實(shí)施干預(yù)阻斷，以及研發(fā)有效且不良反應(yīng)較小的靶向藥物。此外，在使用AEDs時(shí)，應(yīng)隨時(shí)監(jiān)測(cè)血藥濃度，并根據(jù)血藥濃度及時(shí)調(diào)整藥物劑量，從而避免藥物不良反應(yīng)的發(fā)生。

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Pathogenesis of glioma-associated epilepsy and its therapy

WANG Xinxin, LU Qinchi
Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Epilepsy can be developed in 30%-50% of the patients with glioma, which is the most common form of brain tumors. The seizures induced by glioma are still remained after resection of glioma lesions, therefore it is essential and meaningful to explore the pathogenesis and the related treatment of glioma-associated epilepsy. This paper discusses the pathogenic mechanisms involved in the development of glioma-associated epilepsy, including the alteration of glutamate and its transporters, the dysregulation of intracellular chloride (Cl)—, the alteration of gamma-amino butyric acid (GABA) signal pathway-mediated inhibitory efect, and the abnormalities in mammalian target of rapamycin (mTOR) signal pathway. The related drugs based on the pathogenic mechanisms of glioma-associated epilepsy are summarized, such as sulfasalazine—the blocker of cystine-glutamate transporter (xCT), bumetanide—the regulator for Cl—, and rapamycin which is an inhibitorof mTOR, in order to provide efective treatment strategies for glioma-associated epilepsy. Finally, the guidance about the use of anti-epileptic drugs (AEDs) in controlling the gliomaassociated seizures is also summarized.

Glioma; Epilepsy; Pathogenesis; Therapy

LU Qinchi

10.12022/jnnr.2016-0058

王新新，陸欽池. 腦膠質(zhì)瘤繼發(fā)癲癇的發(fā)病機(jī)制及治療[J]. 神經(jīng)病學(xué)與神經(jīng)康復(fù)學(xué)雜志, 2016, 12(4):208-214.

陸欽池

E-MAILqinchilu@yahoo.com.cn

E-MAIL ADDRESSqinchilu@yahoo.com.cn

CONFLlCT OF lNTEREST: The authors have no conficts of interest to disclose. Received Sept. 12, 2016; accepted for publication Oct. 10, 2016

Copyright ? 2016 byJournal of Neurology and Neurorehabilitation