难治性癫癎患者外周血中多药耐药相关蛋白1的表达

难治性癫癎，指经过2年以上的正规抗癫癎治疗，试用所有主要的抗癫癎药物（AED）单独或联合应用，且已达到患者所能耐受的最大剂量，血药浓度在正常范围之内，每月仍有4次以上发作，我们对癫癎患者外周血中多药耐药相关蛋白（MRP1）的表达进行检测，探讨与其与癫癎耐药的关系。     

多药耐药相关蛋白与难治性癫痫

难治性癫痫的发病机制尚不完全清楚,近年来发现在难治性癫痫患者病灶脑组织可检测出多药耐药相关蛋白(MRP)的过度表达,表明MRP与难治性癫痫耐药关系密切。MRP的过度表达受多种因素影响,其可能通过降低抗癫痫药物在血脑屏障的通透性,减少药物的有效浓度,从而引起抗癫痫药物耐药发生。鉴于MRP在难治性癫痫多药耐药中可能的重要作用,筛选非MRP底物的抗癫痫药物和选用适合长期服用的特异性强﹑安全性高﹑毒副作用性小的MRP抑制剂,可能会为今后临床治疗难治性癫痫翻开新的一页。     

难治性癫癎多药耐药机制研究进展

难治性癫(refractoryepilepsy ,RE)的发病机制一直是近年来研究的难点与热点。以往的研究发现,某些临床特征可能预示RE的发生,包括发病年龄早(1岁以前)、治疗前发作频繁、有高热惊厥史、第一种抗癫药物治疗失败、联合使用两种抗癫药而不能控制发作、有结构性脑损伤以及癫发作类型(如部分性发作)等[1] 。引起RE的原因可能由多因素造成,比如遗传因素、治疗期间抗癫药物耐受问题以及目前所使用的抗癫药作用机制的局限性等[2 ] 。近年来对RE的研究重点集中在多药耐药机制上,与肿瘤患者对多种化疗药物耐药的机制相似,RE的发生可…     

多药耐药蛋白及其在难治性癫痈中作用的研究进展

难治性癫痫的耐药性研究已取得了许多突破性进展。近年发现,难治性癫痫与多药物耐药蛋白存在着密切联系。文中介绍3种主要多药耐药蛋白（P-糖蛋白、多药耐药相关蛋白1、主穹窿蛋白）的结构和功能,并对其近年在难治性癫痫耐药中作用的研究进展作一综述。     

药物难治性癫痫患者脑内多药耐药相关蛋白1表达的研究

目的 研究药物难治性癫痫患者脑内皮层多药耐药相关蛋白1（multidrug resistant-associated protein 1，MRP1）表达的情况。方法 选择12例药物难治性癫痫患者癫痫切除灶与12例正常对照脑组织标本．用逆转录聚合酶链反应（RT-PCR）、免疫组化及免疫蛋白印记（Western blot）方法，分析比较MRP1基因在各组的表达。结果 药物难治性癫痫患者组脑内MRP1的表达显著高于正常对照组（P〈0．01）。在癫痫病灶内广泛分布的MRP1免疫阳性细胞主要为毛细血管内皮细胞和星形胶质细胞。结论 脑内高表达的MRP1参与了难治性癫痫的耐药机制。     

难治性癫痫耐药机制的研究

癫痫是一种常见的神经系统疾病。大多数的癫痫患者经过一段时间的正规药物治疗后,病情可以得到控制。但是仍有大约三分之一的患者,药物治疗并不能够减轻发作的频率和强度,被称为难治性癫痫。目前对难治性癫痫还缺少一个确切的定义,国内学者[1]将难治性癫痫概括为:应用适当的抗癫痫药物正规治疗,且药物的血浓度在有效范围内,至少观察2年,发作次数仍在每月4次以上,排除进行性中枢神经系统疾病或颅内占位性病变者。据我国流行病学调查,癫痫终生患病率为7.0‰,活动性癫痫患病率(5年内有发作)为4.9‰,我国估计难治性癫痫患者不少于100万。难治性…     

难治性癫(癎)患者血清层粘连蛋白的表达

目的 探讨难治性癫(癎)患者的层粘连蛋白(1aminin)在血清的表达,并研究其发病机制.方法 2009-10~2010-12期间,我院诊治20例难治性癫(癎)患者,采用ELISA测定血清中层粘连蛋白的含量,同时正常对照者20例,也同样方法测定血清中层粘连蛋白含量.结果 ELISA结果显示层粘连蛋白含量难治性癫(癎)组...     

难治性癫(癎)的脑部电刺激治疗

癫癎是由多种病因引起的慢性脑部疾病，以脑部神经元过度放电所致的突然、反复和短暂的中枢神经系统功能失常为特征。据统计25％-30％的癫癎患者应用已有的抗癫癎药正规治疗后临床发作仍得不到有效控制，称为难治性癫癎。约50％的难治性癫癎患者不适合进行癫癎灶切除术，所以研究者们都在探索新的治疗方法，电刺激近年来成为人们研究的热点。     

难治性癫(癎)相关耐药蛋白在局灶性皮质发育不良脑组织中的表达

目的 通过对P-糖蛋白、多药耐药相关蛋白和肺耐药相关蛋白在难治性癫痫相关局灶性皮质发育不良脑组织中表达部位的初步研究,以及对其在不同程度病变脑组织中表达量的比较,进一步阐明难治性癫疴的耐药机制,为癫(癎)患者的临床合理用药提供理论依据.方法 选取16例难治性癫(癎)患者手术切除脑组织标本作为患者组(局灶性皮质发育不良Ⅰ型和Ⅱ型患者各8例),5例无癫(癎)发作病史的胶质瘤患者手术切除脑组织标本的非病灶区域作为对照组.应用Envision二步法进行免疫组织化学标记,观察3种耐药蛋白在脑组织中的表达部位和表达强度;应用Western blot法进行SDS-聚丙烯酰胺凝胶电泳,对3种耐药蛋白在脑组织中的表达进行定量分析.结果 P-糖蛋白主要表达于毛细血管内皮细胞,多药耐药相关蛋白主要表达于脑组织内的神经元成分,肺耐药相关蛋白的表达则涌盖了毛细血管内皮细胞、气球细胞及病灶区域部分基质.3种耐药蛋白在局灶性皮质发育不良脑组织中的表达均显著高于对照组脑组织(P-糖蛋白:0.520±0.121,多药耐药蛋白:0.132±0.018,肺耐药相关蛋白:0.092 4-0.018,U=0.000,P<0.01),其中P-糖蛋白和肺耐药相关蛋白在局灶性皮质发育不良Ⅱ型患者的病灶区域(3.809±0.842、0.655±0.303)表达高于病灶周围区域(2.636 4±0.622、0.290±0.096,U=6.000、4.500,P<0.01).结论 P-糖蛋白、多药耐药相关蛋白和肺耐药相关蛋白在不同程度的局灶性皮质发育不良脑组织中具有不同的表达部位和表达量,提示其作用机制和作用强度有所差异.     

颞叶癫癎主穹窿蛋白表达及其作用研究

目的探讨主穹窿蛋白（major vault protein，MVP）在颞叶癫癎大鼠模型脑组织的表达及其与难治性癫癎耐药是否相关。方法用氯化锂-匹鲁卡品制作颞叶癫癎模型，并将它分为药物有效组和耐药组；用免疫组化和Westernblot法检测MVP表达。结果MVP主要表达在海马和皮质区的小胶质细胞，血管内皮细胞，血管周围的星形胶质细胞也有表达，神经元中少见表达；耐药组MVP表达较药物有效组和对照组明显增高，具有统计学意义（P〈0．05）。结论耐药大鼠模型中MVP过量表达，提示MVP可能与难治性癫癎的耐药性有关。     

Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy

Tuberous sclerosis is an autosomal dominant syndrome characterized by seizures that are refractory to medication in severely affected individuals. The mechanism involved in drug resistance in tuberous sclerosis is unknown. The proteins MDR-1 (multidrug resistance) and MRP-1 (multidrug resistance-associated protein-1) are linked to chemotherapy resistance in tumor cells. However, the relationship between refractoriness to antiepileptic drugs and MDR-1 or MRP-1 brain expression has been poorly studied. We have previously described a case of tuberous sclerosis with refractory epilepsy that expressed multidrug resistance gene (MDR-1) in tuber cells from epileptogenic brain lesion. In this retrospective study, we describe the expression of MDR-1 and MRP-1 in the epileptogenic cortical tubers of three pediatric patients with tuberous sclerosis and refractory epilepsy surgically treated. Monoclonal antibodies for MDR-1 and MRP-1 proteins were used for immunohistochemistry. In epileptogenic cortical tuber brain specimens, MDR-1 and MRP-1 proteins were strongly immunoreactive in abnormal balloon cells, dysplastic neurons, astrocytes, microglial cells, and some blood-brain vessels. A more extensive MDR-1 immunoreactivity was observed. These data suggest that refractory epilepsy phenotype in tuberous sclerosis can be associated with the expression of both multidrug resistance MDR-1 and MRP-1 transporters in epileptogenic cortical tubers.     

Neural overexpression of multidrug resistance-associated protein 1 and refractory epilepsy: a meta-analysis of nine studies

Objective: Overexpression of adenosine triphosphate-binding cassette (ATP-binding cassette (ABC)) transporters may contribute to intractable epilepsy (IE) by reducing brain accumulation of antiepileptic drugs (AEDs). We conducted a meta-analysis of studies on expression and cellular distribution of multidrug resistance-associated protein 1 (MRP1) in IE patients to evaluate the contribution of this protein to AED resistance. In addition, we summarize experiments examining MRP1 expression and substrates in animal models of IE. Methods: The literature search based on pre-established inclusion and exclusion criteria, as well as quality assessment, data extraction and statistical analyses were conducted concurrently by two independent researchers. We identified nine high-quality studies (Jadad score ≥3) published between 2000 and 2014 on the expression and cellular distribution of MRP1 in IE patients. A fixed effect model was used to calculate pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). Forest and funnel plots were constructed to assess study heterogeneity and publication bias, respectively. Results: MRP1 expression was significantly higher in both astrocytes (OR = 17.04, 95% CI: 7.69?37.76, P < 0.00001) and neurons (OR = 22.13, 95% CI: 8.52?57.46, P < 0.00001) of IE patients compared to controls, while there was no significant difference in endothelial cell MRP1 expression (OR: 1.47, 95% CI: 0.09?1.79, P = 0.48). Funnel plot symmetry indicated no substantial publication bias. Most relevant preclinical studies from 2000 to 2014 found higher MRP1 expression in IE model rodents. Furthermore, MRP1 overexpression reduced the extracellular concentration of AEDs in brain, while MRP1 inhibitors enhanced brain AED concentrations. Conclusion: Pooled results strongly suggest that MRP1 is overexpressed in both neurons and astrocytes of IE patients. Inhibition of MRP1 may enhance AED efficacy by increasing local drug availability.     

Diagnosing and predicting refractory epilepsy

Over 30% of people with epilepsy will never achieve remission with antiepileptic drug (AED) therapy. These individuals are often severely disabled by their condition, have an unsatisfactory quality of life, and are at increased risk of sudden unexpected death. Early identification of refractory epilepsy would allow prompt referral to specialist services, where the diagnosis can be confirmed, seizures and syndromes classified, AED therapy optimized, and suitability for surgery assessed. Recent studies suggest that patients with symptomatic or cryptogenic epilepsy, those who experience multiple seizures before AED treatment initiation, and those with febrile convulsions, a family history of epilepsy, or psychiatric comorbidities are least likely to respond to drug therapy. Failure to achieve good seizure control with the first one or two AED monotherapies is usually sufficient to highlight the possibility of subsequent refractory epilepsy. For most of these individuals, combination therapy using AEDs with complementary modes of action is the recommended treatment approach.     

Neurostimulation for refractory epilepsy

Neurostimulation is an emerging treatment for refractory epilepsy. To date the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond to such a treatment and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. In the past ten years some progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in patients and animals undergoing vagus nerve stimulation (VNS). Interesting results have been found in VNS-treated patients that underwent evoked potential measurements, cerebrospinal fluid investigation, neuropsychological testing and PET, SPECT and fMRI testing. Desynchronisation of abnormal synchronous epileptic activity is one of the hypotheses on the mode of action that might primarily be responsible for an anti-seizure effect. There is however increasing evidence from research and clinical observation that VNS might establish a true and long-term anti-epileptic effect. It has been shown that VNS influences neurotransmission in the brain and provokes long-term changes in cerebral blood flow in areas crucial for epileptogenesis such as the thalamus and medial temporal lobe structures. Deep brain stimulation (DBS) for epilepsy has regained interest. Central nervous system structures known to play a key role in the epileptogenic network such as the thalamus and subthalamic nucleus have been targeted. Another approach is to target the ictal onset zone such as the medial temporal lobe. At Ghent University Hospital 10 patients have been treated with long-term amygdalohippocampal DBS. Several hypotheses have been raised for the mechanism of action of DBS for refractory seizures. Seizure reduction may be due to a microlesion caused by electrode insertion or by provoking a reversible functional lesion due to the effect of electrical current on hyperexcitable tissue. Neurophysiological techniques such as evoked potentials monitoring and intraoperative single unit potential recordings may guide correct electrode placement, individual DBS titration and elucidation of the mechanims of action of DBS for epilepsy.     

半球切开术治疗顽固性癫痫

目的 对于单侧大脑半球弥漫性病变引起的难治性癫痫,可以用大脑半球切除术或切开术治疗.本文总结作者最近进行的3例大脑半球切开术,同时进行了相应的文献复习.方法 3例难治性癫痫,男2例,女1例,年龄分别为7、11、和15岁.均为一侧半球病变,其中实施大脑半球完全切开术2例,后象限切开术1例.手术的目的是完全孤立致痫区域.结果 3例患者分别随访22、22、12个月,其中EngelⅠ A 2例,EngelⅡ B 1例.无长期神经功能障碍或死亡病例.结论 应用神经纤维离断技术进行大脑半球切开,可获得与切除术相同的控制癫痫的良好效果.     

Medically refractory epilepsy in autism

Purpose: Epilepsy and electroencephalographic abnormalities are frequent in idiopathic autism, but there is little information regarding treatment‐resistant epilepsy (TRE) in this group. We sought to define the clinical and electrophysiologic characteristics and treatment outcomes in these patients. Methods: We retrospectively reviewed clinical and laboratory data of patients with idiopathic autism evaluated at NYU Epilepsy Center during a 20‐year period. Key Findings: One hundred twenty‐seven patients had idiopathic autism and at least one epileptic seizure; 33.9% had TRE and 27.5% were seizure free. The remaining 38.6% of patients had infrequent seizures or insufficient data to categorize. Patients with TRE had a significantly earlier onset of seizures than seizure‐free patients, and a trend for more developmental regression and motor and language delays. Three patients had surgical resection (two had limited improvement and one had no improvement) and one had an anterior callosotomy (no improvement). Vagus nerve stimulator (VNS) implantation provided limited improvement (2 patients) and no improvement (7). Significance: This study found that TRE is common in idiopathic autism and more common with early age of seizure onset. Relatively few patients underwent surgical resection due to multifocal partial epilepsy, comorbid generalized epilepsy, or limited impact of ongoing partial seizures given other problems related to autism. Our small sample suggests that surgical and VNS outcomes in this group are less favorable than in other TRE populations.     

Coping with refractory epilepsy.

We investigated the coping behaviour and its correlation with demographic and illness-related data, depression, locus of control and psychosocial adaptation in 40 patients with intractable epilepsy with primarily or secondarily generalized tonic-clonic seizures. Three standardized self-reporting questionnaires were applied, which are the Freiburg Questionnaire of Coping with Illness (FKV), the von Zerssen Depression Scale (D-S), and the IPC-questionnaire measuring generalized locus of control beliefs; the Social Interview Schedule (SIS), a semi-structured interview, was used to measure the psychosocial adaptation. Active, problem-focused and compliance strategies were predominantly used and regarded as most helpful. Hence, the epileptic patients use similar coping patterns reported in patients with other non life-threatening chronic diseases. The level of depression was moderate and in the range of other chronic somatic diseases. The use of coping patterns, which are regarded as maladaptive, was correlated with distinct depression, a small degree of internal locus of control beliefs and poor psychosocial adaption. These results indicate the possibility to improve psychosocial adjustment by supporting effective strategies.     

难治性癫(癎)的研究进展

癫(癎)是神经系统最常见的疾病之一,估计我国约有癫(癎)患者900万,其中的75%通过抗癫(癎)药物治疗可以获得满意疗效.约25%为难治性癫(癎)(intractable epilepsy或refractory epilepsy),全国的难治性癫(癎)患者至少有250万人以上.