肠道微生态在儿童难治性癫痫发病及治疗中的研究进展CSCD

儿童难治性癫痫是一种常见的儿科神经系统疾病。许多临床前及临床证据表明儿童难治性癫痫患者体内优势菌群与健康人相比存在显著差异;抗癫痫干预后难治性癫痫儿童体内肠道菌群分布发生改变;动物粪菌移植实验进一步证实肠道菌群的改变与癫痫发病及抗癫痫疗效存在因果关系。临床上益生菌的添加可能增强抗癫痫疗效,抗生素的使用往往也影响临床的抗癫痫疗效。肠道微生态可能通过内源性机制(如改变神经递质含量等)及外源性机制(如感染和损伤等)改变儿童难治性癫痫患者的代谢、遗传、免疫和感染等。本综述通过总结近年来国内外肠道微生态与儿童癫痫发病和抗癫痫效果的相关研究,阐述肠道微生态在儿童癫痫发病及治疗中的作用并对其可能的作用机制进行探讨。     

6 Hz角膜点燃癫痫动物模型的研究进展

耐药性癫痫是临床上癫痫防治的重大难题。癫痫动物模型是研究癫痫发病机制及筛选抗癫痫药物和探究药物作用机制的有力工具,6Hz角膜点燃癫痫模型是一种优良的耐药性癫痫动物模型,被美国NIH推荐用于评价新药对抗耐药性癫痫的筛选工具。然而,迄今国内外未见6Hz点燃癫痫动物模型的系统报道,现从该模型的发展历史、制作方法、症状表现、致病机制和应用现状等方面进行综述,以期提供一种探究耐药性癫痫发病机制和筛选耐药性癫痫治疗药物的有力工具和标准模型。     

膜超极化激活离子通道及其靶向抗癫痫药物研究进展

癫痫是一种较为常见的神经系统疾病,主要以大量神经元同步异常放电为特征。目前普遍认为,神经元或神经网络兴奋性和抑制性 电信号传输的失衡,是癫痫发病的最根本原因。现有的抗癫痫药物主要以钠离子通道、钙离子通道、钾离子通道、谷氨酸受体和γ-氨基丁 酸离子通道为靶点,但接受这些药物治疗后,仍有近1/3的病人无法控制癫痫发作。因此,抗癫痫药物的研发亟需新靶点和新思路。许多 研究证据表明,膜超极化激活离子通道的基因突变可以导致遗传型癫痫的发作,且在脑部损伤后,膜超极化激活离子通道会发生表达水平、 通道生物物理学性质及通道亚基构成的改变,从而增加神经元和神经网络兴奋性,促使癫痫发病。故近年来,膜超极化激活离子通道及其 靶向抗癫痫药物研究引起人们广泛关注。综述膜超极化激活离子通道与癫痫发病之间的关系,并探讨以膜超极化激活离子通道为靶点进行 抗癫痫药物开发和治疗的可行性。     

癫痫与认知功能

癫痫是神经系统最常见的疾病之一,以反复的自发发作为特征,还伴随着对认知,心理以及社交的影响。相比一般人群,癫痫患者更容易罹患认知和行为的障碍,认知障碍在新诊断的部分或者全面性癫痫发作的成人癫痫患者中均有报道。癫痫发作类型、病因、神经病理、发作类型、发作年龄、社会心理问题等一系列因素都和认知功能障碍相关,而且目前癫痫主要的治疗方法（如抗癫痫药物治疗和外科手术）也和认知及行为障碍相关。对于这些与治疗相关的副作用,临床治疗应该警惕并且尽量避免或者缩小负面的影响。本文从生物学因素、心理社会学因素及治疗相关的因素三个方面综述了癫痫与认知障碍之间的关系,为临床治疗和预防癫痫提供指导。     

血脑屏障上P-糖蛋白与耐药性癫痫关系的研究进展

耐药性癫痫是癫痫治疗的瓶颈。P-糖蛋白通过跨膜外排泵作用阻止抗癫痫药物由血脑屏障入脑发挥期望效应是耐药性癫痫产生的重要原因。本文介绍了耐药性癫痫与血脑屏障上P-糖蛋白的相互关系,对目前提出的调节P-糖蛋白功能,改善耐药性癫痫预后应注意的问题进行说明。安全地调节P-糖蛋白功能到适度可能为耐药性癫痫的治疗带来希望。     

癫痫与认知功能

癫痫是神经系统最常见的疾病之一,以反复的自发发作为特征,还伴随着对认知,心理以及社交的影响.相比一般人群,癫痫患者更容易罹患认知和行为的障碍,认知障碍在新诊断的部分或者全面性癫痫发作的成人癫痫患者中均有报道.癫痫发作类型、病因、神经病理、发作类型、发作年龄、社会心理问题等一系列因素都和认知功能障碍相关,而且目前癫痫主要的治疗方法(如抗癫痫药物治疗和外科手术)也和认知及行为障碍相关.对于这些与治疗相关的副作用,临床治疗应该警惕并且尽量避免或者缩小负面的影响.本文从生物学因素、心理社会学因素及治疗相关的因素三个方面综述了癫痫与认知障碍之间的关系,为临床治疗和预防癫痫提供指导.     

迷走神经刺激在癫痫治疗中的抗炎作用机制

癫痫是一种由大脑神经元过度兴奋或异常同步放电引起脑部功能障碍的慢性神经疾病,具有反复性、发作性和短暂中枢神经系统功能失常等特征。近年来,研究发现炎症反应的异常激活在癫痫发生和发展过程中起到重要作用,炎症信号分子成为抗癫痫治疗的新靶点。迷走神经刺激(vagus nerve stimulation, VNS)作为辅助疗法通过与抗癫痫药物治疗相结合,可以减少癫痫发作,大量的临床应用表明VNS治疗具有较高的安全性和有效性,然而VNS的作用机制尚不清楚。近年来,人们已经在动物疾病模型和病人中开展了VNS抗炎作用机制的研究,该文对VNS在抗癫痫治疗中外周和中枢神经系统的免疫调节作用机制进行综述。     

抗癫痫药物的进展和临床

癫痫是一种常见病,目前仍以药物治疗为主,抗癫痫药的发展较其它药物慢。本文综述了这类药物的作用和临床方面的进展。一、苯巴比妥和苯妥英钠苯巴比妥(1912年用于临床)和苯妥英钠(DPH 1938)是继溴剂之后较早用于临床的两个抗癫痫药,至今仍是治疗大发作的主要药物。近年来对于这两个药物的研究进展主要在其作用机制和药物代谢动力学方面。苯巴比妥口服血浆半寿期平均为96小时(53～140小时)。成人血浆有效血浓度为10～15μg/ml,当血浆浓度为10μg/ml 时,脑电图(EEG)上的癫痫波可消失。个别病人4μg/ml 时也能控制发作。儿童常用3～6mg/kg/日,可使血浆浓度控制在10、25/μg/ml 间,较少引起嗜睡现象。     

尼麦角林联合AED治疗青少年癫痫伴偏头痛30例疗效分析

目的研究尼麦角林治疗青少年癫痫伴偏头痛患者的临床疗效。方法将我院收治的60例青少年癫痫伴偏头痛患者按随机化原则分为治疗组和对照组,对照组仅服用常规抗癫痫药物治疗,治疗组在常规口服抗癫痫药物的基础上加用尼麦角林10mg,每天3次,两组均治疗4周为1疗程,疗程结束分别采用VAS疼痛评分量表进行评定治疗效果。结果经过为期4周1疗程治疗后,治疗组的总有效率为90.0%明显高于对照组的53.3%,组间比较差异有统计学意义(P0.05);而且治疗后,治疗组的VAS评分明显低于对照组,组间比较差异亦有统计学意义(P0.05)。结论采用尼麦角林治疗青少年癫痫伴偏头痛患者能显著改善头痛症状,减少癫痫的发作次数,提高治疗效果,值得临床推广应用。     

海马脑片抗癫痫药物研究的离体模型

目的：建立离体海马脑片癫痫样放电模型并用于抗癫痫药物研究。方法：在豚鼠海马脑片上灌流青霉素建立颠阗痫样放电的离体模型。并用此模型对抗癫痫药物苯巴比妥钠和苯妥英钠两种药物在不同浓度下对癫痫样放电的对抗作用进行了定量分析,结果：在海马脑片上灌流致痫药物可建立一个较好的离体组织癫痫样放电模型,苯的对抗作用进行了定量分析,结果：在海马脑片上灌流致痫药物可建立一个较好的离体组织癫痫样放电模型。苯巴比妥和苯妥英钠在一定浓度下均有显著对抗癫痫样放电的作用,且与整体实验的结果相一致。结论：本实验建立有离体脑片模型具有实验手段简单,方法灵活,易于建立药物量效关系等优点,可用于抗癫痫药物筛选和研究。     

MicroRNA与癫痫的研究进展

癫痫是大脑神经元高度同步化异常放电所导致的短暂的大脑功能障碍的一种慢性疾病。癫痫的发病原因十分复杂,目前主要治疗方式是药物治疗,但仍然有30%左右的难治性癫痫患者依靠药物治疗未能控制癫痫发作,因此从分子角度研究癫痫的发病机制及治疗是近年来癫痫研究的热点。微小RNA(miRNA)在癫痫患者及癫痫动物模型海马组织中存在差异性表达,通过抑制miRNA的差异表达在一定程度上可以缓解癫痫的症状,这为癫痫的治疗开辟了新的途径和方向。因此随着miRNA与癫痫相关性研究深度的不断加深,有望能够为癫痫的诊断及治疗提供一个全新的思路。     

Effects of Antiepileptic Drugs on Antioxidant and Oxidant Molecular Pathways: Focus on Trace Elements

Current reports on trace elements, oxidative stress, and the effect of antiepileptic drugs are poor and controversial. We aimed to review effects of most common used antiepileptics on antioxidant, trace element, calcium ion (Ca²⁺) influx, and oxidant systems in human and experimental animal models. Observations of lower blood or tissue antioxidant levels in epileptic patients and animals compared to controls in recent publications may commonly support the proposed crucial role of antioxidants in the pathogenesis of epilepsy. Effects of old and new antiepileptics on reactive oxygen species (ROS) production in epilepsy are controversial. The old antiepileptic drugs like valproic acid, phenytoin, and carbamazepine induced ROS overproduction, while new epileptic drugs (e.g., topiramate and zonisamide) induced scavenger effects on over production of ROS in human and animals. Antioxidant trace element levels such as selenium, copper, and zinc were generally low in the blood of epileptic patients, indicating trace element deficiencies in the pathogenesis of epilepsy. Recent papers indicate that selenium with/without topiramate administration in human and animals decreased seizure levels, although antioxidant values were increased. Recent studies also reported that sustained depolarization of mitochondrial membranes, enhanced ROS production and Ca²⁺ influx may be modulated by topiramate. In conclusion, there is a large number of recent studies about the role of antioxidants or neuroprotectants in clinical and experimental models of epilepsy. New antiepileptic drugs are more prone to restore antioxidant redox systems in brain and neurons.     

Recent advances in drug therapy for epilepsy.

Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug''s bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.     

Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis

BackgroundEncephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy.ResultsDuring the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had intractable seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects.ConclusionsChildren with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy.     

Intelligence and physical features of children of women with epilepsy

The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6-l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the "anticonvulsant face" or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy.     

Strengthening the Case for Epilepsy Drug Development: Bridging Experiences from the Alzheimer’s Disease Field—An Opinion

Given the sheer number of drugs (over 20!) available for treatment of seizures, epilepsy can be considered one of the most successful areas in pharmaceutical development and especially for neuroscience. However, despite the large number of drug treatment options available for managing patients with epilepsy, there remains considerable unmet need. For example, the overall impact on seizure control has not been substantial with approximately 30% of patients remaining refractory or their seizures not adequately controlled. Also there is need for epilepsy prevention and for certain sub-populations with severe intractable epilepsy. High unmet need often drives new industry investment into therapeutic market opportunities, however the profound success of antiepileptic drugs has contributed to the hurdles for industry investment in new therapies for epilepsy. Furthermore, the payor environment has also changed with new challenges for evidence generation and demonstration of additive value above existing standard of care treatments. Challenges in translational science, in the clinical trial environment including cost and operational technical difficulty, and in the commercial environment have resulted in the pharmaceutical industry directing investments away from epilepsy into other therapeutic areas such as oncology and immunology as opportunities for higher probabilities of success and returns of investment. The neuroscience area in general is perceived a high risk area and a notable exception has been the active industry involvement in Alzheimer’s disease (AD), especially for therapeutics that could modify the course or prevent AD. AD is a very high risk area with no successful efficacious treatments found to date despite recent failures, there remains promise that therapies are forthcoming. The promise is fueled by a number of innovative factors that reduced R&D challenges in the AD field and contributed to a high level of drug development activity and investment. This paper addresses hurdles facing epilepsy drug discovery and development and focuses on some key solutions that could be eased to facilitate industry interest. Similarities in drug development challenges provide opportunities that bridge experiences and learnings from AD to epilepsy. Overall, the epilepsy field is probably in a good position for advancing into the next generation therapeutics of antiepileptic drugs targeted for increased efficacy in refractory epilepsy and for antiepileptogenesis.

     

Childhood cancer and drugs in pregnancy.

A study was carried out on 11 169 matched case-control pairs of children aged up to 15 years included in the Oxford Survey of Childhood Cancers to see whether an association exists between cancer in children and drugs given to their mothers during pregnancy. The mothers of children who developed cancer reported about 25% more illnesses during pregnancy than mothers of healthy control children. Two specific illnesses, pulmonary tuberculosis and epilepsy, were investigated. For these there was a higher than average case-control excess of reports and there had been a suggestion that the drugs used in treatment, isoniazid and phenytoin, might be carcinogenic. The results of this investigation provide no real evidence for any association between the drugs taken by the mothers during pregnancy and subsequent cancer in the child.     

Rare Fungal Infections in Children: An Updated Review of the Literature

An increasing trend of reports of rare fungal diseases has been observed to be mainly associated with the substantial increase of high-risk immunocompromised children, as well as with the selective pressure of antifungal drugs. On the other hand, recent reports have shown that several species of these rare fungi may also cause infections in immunocompetent children without obvious underlying conditions. The clinical spectrum of these infections, and most importantly their outcome, varies greatly, implying for a rather heterogenic group of pediatric infections. Various types of superficial and subcutaneous fungal infections, as well as systemic and disseminated life-threatening infections, have been reported. Prompt diagnosis and appropriate treatment of rare fungal diseases in children remains a great challenge. Several treatment options have been used, ranging from localized to combination treatment with extensive surgical excision and long-term antifungal therapy. We review contemporary data of rare fungal infections in pediatric patients focusing on epidemiology, mycology, management and outcome, published during the last three years.     

Sex hormones in patients with epilepsy-hormonal changes in epileptic men and women taking antiepileptics.

The relationship between epilepsy and endocrine system has attracted the attention of investigators for a number of years. Epilepsy is a common neurological disorder; both seizures and antiepileptic drugs can compromise the physical and hormonal aspects of sexual development. Impairment of libido and sexual potency have been frequently reported in male epileptic patients. Women with epilepsy have a greater risk of infertility (anovulatory cycles and polycystic ovary syndrome). This review analyses the main data from the literature in order to clarify the role of epilepsy and antiepileptic drugs on sex hormones in epileptic patients. As gonad dysfunction is frequently observed in women and men with epilepsy, particularly when taking antiepileptic drugs, ovarian and testicular function must be carefully monitored.     

Prognostic index for recurrence of seizures after remission of epilepsy. Medical Research Council Antiepileptic Drug Withdrawal Study Group.

OBJECTIVES--To develop and test a prognostic index for the recurrence of seizures after a minimum remission of seizures of two years in people with a history of epilepsy. DESIGN--Information from a large prospective randomised study of withdrawal of antiepileptic drugs was used to identify clinical and treatment factors of prognostic importance in determining the recurrence of seizures. A split sample approach was used to test the internal validity of predictions made on the basis of identified prognostic factors. SETTING--Centres in six European countries. MAIN OUTCOME MEASURES--Comparison of predicted and observed rates of recurrence of seizure. SUBJECTS--1013 patients randomised to the Medical Research Council study for antiepileptic drug withdrawal. RESULTS--The Cox proportional hazards model identified several factors that increased the risk of seizures recurring. These included being 16 years or older; taking more than one antiepileptic drug; experiencing seizures after starting antiepileptic drug treatment; a history of primary or secondarily generalised tonic-clonic seizures; a history of myoclonic seizures; and having an abnormal electroencephalogram. The risks of seizures recurring decreased with increasing time without seizures. The model allowed estimation of the risk of seizures recurring in the next one and two years under the policies of continued antiepileptic drug treatment and slow withdrawal of drugs. Split sample validation suggested that the model was well calibrated. CONCLUSION--The model is currently the best available aid for counselling the many patients in the community with epilepsy currently in remission who seek advice about the risks of seizures recurring if they stop antiepileptic drug treatment. The model requires validation in a broad population of patients, and such studies are in progress.