癫癎发作后的激素变化

癫癎发作可在二个方面改变血浆的激素水平:1,癫癎急性发作后几分钟内,血浆的高血糖素,肾上腺素、生长激素,崔乳激素、可的松以及胰岛素升高,其量和时间,是依据癫癎发作类型(例如:人的特发性全身性癫癎发作,抑郁症患者的电休克治疗,实验动物的药物诱发性癫癎发作)而不同。它们是癫癎发作时的不正常的主自性动作的直接结果,或是癫癎发作动作波及到脑,影响下丘脑释放固子的分泌量;或者是由于癫癎发作,产生系统变化的间接影响(例如:高糖血症可促进胰岛素分泌)。2、癫癎重复发作,可导致中枢神经递质功能改变。单胺系统内的变化,可通过释放     

非癫癎性心因性发作27例报告

非癫癎性心因性发作在临床上常见,与癫癎性发作容易混淆.现将我院27例非癫癎性心因性发作的临床情况报道如下.     

卒中后继发癫(癎)27例临床分析

目的探讨卒中后癫癎发作的临床特点及发病机制。方法对27例卒中继发性癫癎患者的临床资料进行回顾分析。结果卒中后癫癎发生率为6.97%,其中急性期发作占62.96%,恢复期癫癎发作占29.41%;其发作类型以部分性发作最多(占62.96%)。结论卒中后急性期性发作发生率明显高于恢复期。脑缺血缺氧是急性期性发作的重要致病因素。对于后期发生癫癎患者需正规抗癫癎治疗。     

多药转运蛋白参与难治性癫(癎)耐药机制的研究

癫(癎)是神经科仅次于脑血管意外的常见疾病,患病率达到5‰.在新确诊的癫(癎)患者中,50%以上的患者通过单药治疗,癫(癎)发作得到有效控制.另外近20%的患者接受2种抗癫(癎)药物联合治疗后,病情得到改善.大约有30%的患者,经过单药治疗以及多药联合治疗,血药浓度已达到治疗剂量,癫(癎)发作仍得不到控制,我们称之为难治性癫(癎).     

多药转运蛋白参与难治性癫(癎)耐药机制的研究

癫(癎)是神经科仅次于脑血管意外的常见疾病,患病率达到5‰.在新确诊的癫(癎)患者中,50%以上的患者通过单药治疗,癫(癎)发作得到有效控制.另外近20%的患者接受2种抗癫(癎)药物联合治疗后,病情得到改善.大约有30%的患者,经过单药治疗以及多药联合治疗,血药浓度已达到治疗剂量,癫(癎)发作仍得不到控制,我们称之为难治性癫(癎).     

抗癫癎药物的研究和临床应用进展

抗癫癎药物的应用已有100多年的历史,为了获得对癫癎满意治疗的药物,人们在近20年中不断探索新的抗癫药。本文就近年来国内外抗癫癎药的研究进展作一综述。 1　癫癎的发病机制 1.1　生物膜电生理理论　癫癎是由于大脑局部病灶神经元兴奋性过高,产生阵发性放电,并向周围扩布而出现的大脑功能失调综合征。根据癫的发作症状分为大发作、小发作、精神运动性发作、局限性发作、癫癎持续状态等。癫癎病灶的爆发式放电是由缓慢去极化变化引起的高频放电,由于脑外K+和Ca2+降低,两者皆使细胞内Ca2+升高而触发神经元爆发式放电。脑内Ca2+增加,激活了外向K+通道,加速K+外流,终止爆发放电。 1.2　叶酸假说　70年代初,文献报道应用苯妥英治疗的癫癎患者血清叶酸水平降低;用叶酸治疗的患者,癫癎发作次数增多,这就引起了癫癎发作的叶酸假说。很多抗癫癎药如苯妥英、苯巴比妥、扑米酮可使癫癎患者叶酸水平降低,从而控制癫癎发作。提示抗叶酸药可能对癫癎有效。 1.3　脑内神经递质学说　神经元总体的活动是在抑制性神经递质γ-氨基丁酸(γ-GABA)与兴奋性递质谷氨酸和天门冬酸之间的平衡协调下进行的。如果兴奋性递质相对多于抑制性递质,神经元的活动失去控制而导致癫癎发作。谷氨酸根是主要的兴奋性递质,它是谷氨酸的离子形式,是γ-GABA的前体,经谷氨酸脱羧酶的作用,转化为γ-GABA,它们之间有相对平衡的关系,当谷氨酸相对多于γ-GABA时,可使癫癎发作。依据癫癎发作的相关理论,目前已开发了许多抗癫癎新药。     

18例癫癎持续状态的发作诱因分析

癫癎持续状态是内科常见急症,其中最常见的是强直-阵挛发作,需要及时发现、有效处置.为了加深对癫癎持续状态的认识,现将我们收治癫癎持续状态患者的处置措施报告如下.     

抗癫癎药物与癫癎恶化

近20年来,许多资料显示抗癫癎药物(AEDs)会使癫癎恶化,即原有类型癫癎发作增多,或激发新的癫癎类型。临床上可见以下4种情况：①非特异性的药物中毒表现：即患儿仅出现癫癎发作加重,而无其他中毒表现,减少剂量或取消不必要的多药治疗后就可好转。②药物选择失误。③药物副作用。④抗癫癎药物引起的脑病和多种类型混合发作的儿童癫癎性脑病［1］。 1　药物过量 　　早已报道苯妥英钠(PHT)中毒量可致癫癎恶化。国内报道PHT致癫癎恶化发生率8.6%［2］。Dhana报道4例卡马西平(CBZ)中毒的患者中,有1例出现一系列全身性惊厥性癫癎发作［3］。尽管没有拉莫三嗪致癫癎恶化的报道,但当剂量增至20 mg*kg-1*d-1时出现新的肌阵挛性癫癎持续状态,撤除拉莫三嗪后临床症状很快好转。 2　药物选择不当 　　可引起癫癎发作、恶化和脑电图阵发性放电增加,如：CBZ可使失神发作、不典型失神发作和肌阵挛性及失张力性已发作癫癎恶化。PHT也可使失神发作和强直-阵挛性发作恶化。临床应用以来,不少作者报道乙琥胺可致全身惊厥性癫癎恶化。苯巴比妥可使失神发作恶化并可能导致失神持续状态,应慎用［4］。有报道严重肌阵挛性癫癎患者添加拉莫三嗪治疗,其中16例(80%)病情恶化,表明拉莫三嗪不适用于严重肌阵挛性患者［5］。隐原性或继发性部分性癫癎患儿加用氨己烯酸后出现新的肌阵挛性发作。     

抗癫(癎)药物对戊四氮点燃大鼠癫(癎)发作及生命影响的研究

目的:研究抗癫癎药物(AEDs)对戊四氮(PTZ)点燃大鼠发作的控制与生存的影响。方法:选用健康雄性成年SD大鼠70只,随机分为7组,每组10只。随机选取1组作为正常对照组(NS组),其余6组用PTZ点燃,制备大鼠癫癎模型;致癎后随机选取1组作为癫癎对照组(PTZ组),其余5组分别给予卡马西平(CBZ组)、苯妥英钠(PHT组)、丙戊酸钠(VPA组)、托吡酯(TPM组)及拉莫三嗪(LTG组)控制癫癎发作。2周后观察大鼠的癫癎发作控制率和病死率。结果:PHT组有4只(4/10)持续发作,TPM组有3只(3/10)持续发作,其他3组控制良好,癫癎未再发作。PTZ组和TPM组各死亡1只(1/10),LTG组死亡2只(2/10)。结论:PHT、TPM对PTZ点燃的癫癎发作控制不良;TPM、LTG可导致大鼠死亡。     

长期服用丙戊酸钠对癫癎患者记忆功能的影响

目的观察癫癎患者长期服用丙戊酸钠后记忆功能的改变及其影响因素.方法用<临床记忆量表>对研究对象进行长期随访评估.结果服用丙戊酸钠的患者2 a内记忆商数显著性下降,影响因素有受教育年限、入组后月癫癎性发作次数、入组后日平均药物剂量.结论受教育年限、入组后月癫癎性发作次数、入组后日平均药物剂量对服用丙戊酸钠的患者的记忆功能具有显著性影响,这些因素的影响对临床和基础研究具有一定意义.     

Phenytoin’s effect on the spread of seizure activity in the amygdala kindling model

Phenytoin is a major antiepileptic drug for treatment of limbic seizures. The effect of phenytoin on the generation and spread of seizure activity was studied in a rat model of this type of seizures. Sprague-Dawley and Wistar rats were implanted with a stimulation and recording electrode in the basolateral amygdala. Naive Sprague-Dawley rats showed an increase in current intensity necessary for eliciting afterdischarges (afterdischarge threshold) of about 200% after administration of phenytoin (75 mg/kg i.p.), while seizure severity at threshold was increased compared to controls. Afterdischarge and seizure durations were significantly prolonged under phenytoin. This result suggests that phenytoin can exert a potent anticonvulsant effect on the generation of focal seizure activity, but it does not suppress or may even increase on-going afterdischarge activity once it occurs. Following amygdala kindling in Wistar rats, administration of phenytoin again resulted in an increase in the afterdischarge threshold. However, all rats still showed generalized seizures, and epileptic afterdischarges could be recorded in various limbic brain regions at threshold current. This result suggests that phenytoin can increase the threshold for generation of epileptic discharges in kindled rats, but is not able to prevent the development of generalized seizure activity and the spread of afterdischarges within the limbic system when focal activity is initiated. We conclude that phenytoin is able to suppress focal seizure activity in the amygdala kindling model of the rat. However, it does not prevent the spread of seizure activity originating in the limbic system. Therefore, a decrease in focal seizure susceptibility seems to be the primary target for phenytoin’s anticonvulsant action. Received: 7 March 1997 / Accepted: 17 June 1997     

石菖蒲挥发油对锂-匹罗卡品诱发癫痫大鼠c-fos表达的影响

目的探讨石菖蒲挥发油对锂-匹罗卡品（毛果芸香碱）致痫大鼠癫痫发作时间及其脑内c-fos表达的影响。方法选择Wistar大鼠96只,随机分为六组,正常对照组（6只）,模型组（18只）,丙戊酸钠预处理组（18只）,石菖蒲预处理低、中、高剂量组（各18只）。观察石菖蒲挥发油对锂-匹罗卡品致痫大鼠发作时间的影响。以锂-匹罗卡品诱导制作癫痫动物模型,应用免疫组化方法观察石菖蒲挥发油对其脑内c-fos表达的影响。结果石菖蒲低、中、高剂量组大鼠首次抽搐发作时间（SB）和第1次达到Ⅴ级发作时间（RFSⅤS）较模型组明显延长,差异均有统计学意义（P〈0.05）,锂-匹罗卡品致痫大鼠脑内c-fos表达水平明显增强,丙戊酸钠预处理组、石菖蒲预处理高剂量组大鼠海马部位c-fos阳性细胞较模型组及石菖蒲预处理低、中剂量组明显减少,差异均有统计学意义（P〈0.05）。结论该研究方法快速、简便、准确、重现性好,石菖蒲挥发油能缓解锂-匹罗卡品所致的癫痫发作,其作用机制可能与降低脑内c-fos基因表达水平有关。     

COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats

Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs.Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures.The highly selective cyclooxygenase-2 inhibitors SC-58236 and NS-398 both counteracted the status epilepticus-associated increase in P-glycoprotein expression in the parahippocampal cortex and the ventral hippocampus. In line with our working hypothesis, a sub-chronic 2-week treatment with SC-58236 in the chronic epileptic state kept P-glycoprotein expression at control levels. As described previously, enhanced P-glycoprotein expression in chronic epileptic rats was associated with a significant reduction in the brain penetration of the antiepileptic drug phenytoin. Importantly, the brain delivery of phenytoin was significantly enhanced by sub-chronic cyclooxygenase-2 inhibition in rats with recurrent seizures.In conclusion, the data substantiate targeting of cyclooxygenase-2 in the chronic epileptic brain as a promising strategy to control the expression levels of P-glycoprotein despite recurrent seizure activity. Cyclooxygenase-2 inhibition may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain. It needs to be further evaluated whether the approach also enhances efficacy.     

丙戊酸钠在脑肿瘤术后的临床应用

目的 :评价丙戊酸钠在脑肿瘤术后的临床疗效。方法 :对 15 0例脑肿瘤病人随机分成丙戊酸钠治疗组 (丙戊酸钠组 ,n =77)和对照组 (n =73) ,观察手术后病人的生命体征、癫痫发作、颅内压和脑水肿变化情况。结果 :脑肿瘤术后丙戊酸钠组病人癫痫发生率 (5 % )、颅内压显著升高 (8% )和重度脑水肿 (4 % )与对照组 (分别为 19% ,2 2 % ,16% )比较差异有显著和非常显著意义 (P <0 .0 5或P <0 .0 1)。 2组治疗后 3wk病人恢复情况比较差异有显著意义 (P <0 .0 5 ) ,致残率 (5 % )明显低于对照组 (15 % ) (P <0 .0 5 )。结论 :脑肿瘤术后早期应用丙戊酸钠可以降低癫痫发生率 ,减轻脑水肿 ,降低颅内压升高幅度 ,减少致残率 ,促进病人早期康复     

Effect of brain serotonin level on induced hippocampal paroxysmal activity in rats

Experiments were performed to study the involvement of brain 5-HT in an experimental model of epilepsy induced by repeated electrical stimulation of the dorsal hippocampus of rats. The experiments included: (1) systemic injections of 5-hydroxytryptophan (5-HTP) and p-chlorophenylalanine (pCPA) and (2) electrolytic lesions of the midbrain raphe nuclei. The pCPA group showed a significant increase while animals which received systemic injections of 5-HTP showed a great reduction in the electrographic seizure activity. Although several reports have shown that midbrain raphe lesions do not modify the 0pileptic susceptibility, we observed a clear enhancement in the epileptiform activity in lesioned animals. The results presented here support the view that serotonergic systems may exert a tonic inhibitory effect on hippocampal epileptic activity.     

氟桂利嗪对苯妥英钠耐药癫（癎）小鼠的逆转作用

目的：研究氟桂利嗪对苯妥英钠耐药癫（癎）（drug resistant epilepsy）小鼠癫（癎）发作的逆转作用,初步探讨其作用机制.方法：采用戊四氮制作小鼠癫（癎）模型,灌胃给予苯妥英钠40 mg/（kg·d）,共14 d,制作耐药癫（癎）小鼠模型.造模成功的耐药癫（癎）小鼠30只,按随机数字表法分为3组,分别为模型组、维拉帕米组和氟桂利嗪组.在给予苯妥英钠后30 min,分别腹腔注射生理盐水、维拉帕米20mg/（kg·d）和氟桂利嗪8 mg/（kg·d）,连续给药4d,在第4天（d 4）观察给药后30 min内小鼠癫（癎）发作的严重程度.然后处死小鼠,取脑.采用蛋白质印迹法（Western blot）检测P-糖蛋白（P-gp）表达情况;用免疫组化法测定半胱氨酸蛋白酶-3（caspase-3）的表达情况.结果：给药d4,氟桂利嗪组小鼠癫（癎）发作严重程度较模型组显著减轻（P＜0.01）.维拉帕米组和氟桂利嗪组小鼠脑内P-gp的表达量显著减少（P＜0.01）,且氟桂利嗪的效果优于维拉帕米（P＜0.05）;维拉帕米组和氟桂利嗪组小鼠皮层和海马半胱氨酸蛋白酶-3表达量也显著减少（P＜0.01）,氟桂利嗪的作用优于维拉帕米（P＜0.05）.结论：氟桂利嗪能够有效降低苯妥英钠耐药小鼠的癫（癎）发作严重程度,其主要机制可能与降低小鼠脑组织P-gp的表达有关,同时氟桂利嗪也能降低耐药小鼠脑内半胱氨酸蛋白酶-3的表达,对脑组织可能有保护作用.     

Antiepileptogenic agents: how close are we?

Epilepsy is a common neurological condition, affecting about 4% of individuals over their lifetime. Epilepsy can be idiopathic, secondary to an underlying genetic abnormality or unknown causes, or acquired. Known potential causes account for about one third of epilepsy. Control of epilepsy has primarily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. Many laboratory models simulate human epilepsy as well as provide a system for studying epileptogenesis. The kindling model involves repeated application of subconvulsive electrical stimulation to the brain, leading to spontaneous seizures. Other models include the cortical or systemic injection of various chemicals. These models suggest that many antiepileptic drugs, from phenobarbital and valproate (valproic acid) to levetiracetam and tiagabine, have antiepileptogenic potential. Some promising other possibilities include N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists as well as the neurotrophins and their receptors. Phenobarbital, phenytoin, valproate, carbamazepine and, to a very limited extent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappointing. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving the active drug. In 4 of the 12, the observed rate was actually slightly higher among treated individuals. None of the newer drugs have been evaluated in antiepileptogenesis trials. Until some drugs demonstrate a clear antiepileptogenic effect in clinical trials, the best course to reduce the incidence of epilepsy is primary prevention of the risk-increasing events--for example, wearing helmets, using seat belts, or decreasing the risk of stroke by reducing smoking.     

p38丝裂原活化蛋白激酶信号通路特异性阻滞药对癫痫模型大鼠神经细胞的保护作用研究

目的:研究p38丝裂原活化蛋白激酶信号通路特异性阻滞药SB203580对癫痫模型大鼠神经细胞的保护作用。方法:取大鼠随机分为正常对照组、模型组和SB203580低、中、高剂量(5、10、20mg.kg-1)组,每组10只,后4组腹腔注射戊四唑建立癫痫模型,SB203580各剂量组建模前10min腹腔注射相应药物。建模给药后按Racine分级标准对各组大鼠进行行为学评价,建模给药后2h检测各组脑组织中乳酸脱氢酶(LDH)释放率,采用免疫组化法和免疫印迹法检测海马组织中半胱氨酸天冬氨酸蛋白酶3(Caspase-3)的表达。结果:正常对照组无癫痫发作;与正常对照组比较,模型组癫痫发作程度明显增强,LDH释放率明显升高,Caspase-3阳性细胞数及其表达明显增加(P<0.01);与模型组比较,SB203580各剂量组癫痫发作程度明显减轻,LDH释放率明显降低,Caspase-3阳性细胞数及其表达明显减少(P<0.05或P<0.01),且与剂量成正相关。结论:SB203580可能通过间接抑制Cas-pase-3表达实现对癫痫模型大鼠神经细胞的保护作用。     

唑尼沙胺对癫痫大鼠血清及脑组织 NO 含量及 NOS 活性的影响

摘要： 目的 探讨新型抗癫痫药物唑尼沙胺对癫痫大鼠血清及脑组织 NO 含量及一氧化氮合酶 （NOS） 活性的影响。方法 50 只健康雄性 SD 大鼠中随机抽取 8 只为正常对照组, 剩余 42 只全部腹腔注射戊四氮制成癫痫模型, 从中随机抽取 24 只, 以完全随机分组法分为癫痫模型组、 唑尼沙胺组及苯巴比妥组, 监测各组大鼠经药物干预后血清及脑组织 NO、 丙二醛（MDA）含量及 NOS、 超氧化物歧化酶（SOD）的活性变化。结果 35 只（83%）大鼠模型制备成功; 戊四氮致痫大鼠的脑电图中均可见阵发性癫痫波; 与正常对照组比较, 癫痫模型组和唑尼沙胺组大鼠的血清和脑组织的 NO、 MDA 含量及 NOS 活性明显升高, SOD 活性下降; 苯巴比妥组脑组织 NO、 MDA 含量升高, SOD 活性下降, 血清 MDA 含量升高。与癫痫模型组比较, 唑尼沙胺组和苯巴比妥组大鼠血清和脑组织 NO、 MDA 含量及 NOS 活性明显降低, SOD 活性升高, 差异有统计学意义 （P＜0.05）。结论 唑尼沙胺通过降低脑组织 NO 含量而发挥其抗癫痫作用。     

Celecoxib treatment restores pharmacosensitivity in a rat model of pharmacoresistant epilepsy

Background and purpose:

A functional link between seizure-induced P-glycoprotein overexpression at the blood–brain barrier and therapeutic failure has been suggested by several studies using rodent epilepsy models and human epileptic tissue. Recently, we reported that interference with the mechanisms that up-regulate P-glycoprotein in response to seizure activity might provide a novel approach to control its expression in the epileptic brain. Based on these data, we hypothesized that blocking the appropriate signalling cascade by cyclooxygenase-2 inhibition should improve brain penetration of antiepileptic drugs and help to overcome drug resistance.

Experimental approach:

Effects of the selective cyclooxygenase-2 inhibitor celecoxib on the response to the P-glycoprotein substrate, phenobarbital, was evaluated in a chronic model of drug-resistant temporal lobe epilepsy in rats. Drug-resistant rats selected from this model exhibit a marked overexpression of P-glycoprotein in the hippocampus and other limbic brain regions.

Key results:

Responders and non-responders were selected from a group of rats with spontaneous recurrent seizures after prolonged treatment with phenobarbital at maximum tolerated doses. The efficacy of phenobarbital was re-evaluated following a 6 day treatment with celecoxib and the frequency of spontaneous recurrent seizures was significantly reduced in both groups of rats, phenobarbital responders or non-responders selected from the previous drug trial.

Conclusions and implications:

Pretreatment with the cyclooxygenase-2 inhibitor restored the anticonvulsant activity of phenobarbital in rats that failed to exhibit a relevant response before celecoxib treatment. Our data provide further support for a novel therapeutic approach to overcome transporter-mediated drug resistance in epilepsies.