高血压对大鼠局灶性脑缺血再灌注损伤组织病理结构的影响

目的研究高血压对脑缺血性损伤的病理及其超微结构的影响。方法用线栓法将肾性高血压大鼠和正常大鼠制成局灶性脑缺血再灌注模型；TTC染色及图像分析系统测定局部脑缺血后不同时间的梗死灶体积．同时HE染色及透射电镜观察大鼠局灶脑缺血再灌注后及假手术组的组织病理及超微结构的变化。结果高血压大鼠与正常血压大鼠相比局部缺血再灌注在同等时间内梗死灶的面积较大，超微结构改变也较明显。结论高血压引起脑内微小动脉的改变．侧支循环减少．加重脑缺血损伤。     

两种局灶性脑缺血再灌注模型的比较

目的比较两种大鼠大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)局灶性脑缺血再灌注模型,寻找一种更加理想、稳定和可靠的模型。方法将22只SD大鼠随机分为颈外动脉插线组和颈总动脉插线组,采用线栓法建立大鼠脑缺血再灌注模型,MCAO2h再灌注24h,采用TTC染色和NF-κB免疫组化染色,并分别测定脑梗死体积和NF-κB表达量。结果两种插线方法都能造成大鼠局灶性脑梗死,颈外动脉插线组再灌注状态优于颈总动脉插线组,且脑梗死体积和NF-κB表达量均高于颈总动脉插线组。结论颈外动脉插线闭塞大脑中动脉是一种较为理想和可靠的大鼠MCAO局灶性脑缺血再灌注模型制作方法。     

丁苯酞预处理对大鼠脑缺血再灌注损伤的神经保护作用

目的研究丁苯酞预处理对大鼠局灶性脑缺血再灌注损伤的神经保护作用。方法健康成年SD雄性大鼠48只,随机分为假手术组、缺血再灌注组、丁苯酞预处理组,每组各16只。各组均灌胃5d后,采用线栓法制作大鼠局灶性脑缺血再灌注(MCAO)模型,缺血2h、再灌注24h,进行神经功能缺损评分,TTC染色及图像分析观察脑梗死体积,免疫组化法检测脑组织caspase-3、bcl-2表达的变化。结果与缺血再灌注组相比,丁苯酞预处理组神经缺损程度改善,梗死灶体积减少,caspase-3阳性细胞数量减少,bcl-2表达上调。结论丁苯酞可减轻缺血性脑血管病的发作,具有一定的神经保护作用。     

大鼠局灶性脑缺血再灌注后iNOS的表达时程及行为学变化

目的 观察大鼠局灶性脑缺血再灌注后不同时间点iNOS表达及行为学变化。方法 线栓法制备大鼠大脑中动脉闭塞再灌注模型，术后不同时间点进行神经功能缺损评分，并动态检测iNOS活性变化。结果 缺血后6h大鼠神经功能缺损程度最严重，iNOS表达在缺血后6h开始出现，缺血后48h达峰，7d时基本降至基线水平。结论 由iNOS产生的NO参与了脑缺血再灌注后的迟发性病理损伤过程。     

促红细胞生成素对大鼠局灶性脑缺血CAPSASE-3蛋白的影响

目的　研究促红细胞生成素 (erythropoietin ,rhEPO)在大鼠局灶性脑缺血再灌注损伤中对Caspase - 3蛋白的影响 ,探讨rhEPO的脑保护机制。 方法　线栓法建立大鼠局灶性脑缺血再灌注损伤模型 ,NISS染色观察缺血半暗区的病理形态变化 ,免疫组织化学方法检测活化的Caspase - 3的表达 ,TTC染色观察缺血损伤面积。结果　Caspase - 3阳性细胞在对照组脑组织内散在分布 ,缺血组和治疗组在大脑皮层较为密集。缺血组阳性细胞数显著高于对照组 (P<0 .0 1) ,治疗组阳性细胞数显著低于缺血组 (P <0 .0 1)。结论　Caspase- 3在大鼠局灶性脑缺血再灌注中活性显著增高 ,rhEPO能有效抑制Caspase - 3激活 ,从而抑制大鼠局灶性脑缺血再灌注损伤中缺血损伤及细胞凋亡 ,在大鼠局灶性脑缺血再灌注中脑损伤中起到保护作用     

大鼠局灶性脑缺血再灌注后iNOS的表达时程及行为学变化

目的观察大鼠局灶性脑缺血再灌注后不同时间点iNOS表达及行为学变化。方法线栓法制备大鼠大脑中动脉闭塞再灌注模型,术后不同时间点进行神经功能缺损评分,并动态检测iNOS活性变化。结果缺血后6h大鼠神经功能缺损程度最严重,iNOS表达在缺血后6h开始出现,缺血后48h达峰,7d时基本降至基线水平。结论由iNOS产生的NO参与了脑缺血再灌注后的迟发性病理损伤过程。     

雌二醇对大鼠脑缺血再灌注损伤的保护作用

目的探讨雌二醇对大鼠局灶性脑缺血再灌注损伤的改善作用及其脑保护机制。方法线栓法建立大鼠局灶性脑缺血再灌注损伤模型，通过HE染色在光镜下观察神经细胞损伤变化，TTC染色测脑梗死体积．免疫组化法检测bel-2阳性表达。结果与脑缺血再灌注组相比，雌二醇用药组大鼠脑标本光镜下细胞损伤变性程度轻．脑梗死体积显著缩小（P〈0．01），bel-2阳性细胞数明显上升（P〈0．01）。结论雌二醇对大鼠局灶性脑缺血再灌注损伤有保护作用，雌二醇可通过促进bcl-2的上调发挥脑保护作用。     

大鼠线栓法局灶性脑缺血模型的改良

目的对大鼠线栓法局灶性脑缺血再灌注模型的制备方法进行优化。方法采用线栓法建立SD大鼠局灶性脑缺血模型,从局部脑血流、神经功能缺损和梗死体积方面评价尼龙线包被材料、麻醉、翼腭动脉(PPA)结扎等因素对该模型的影响。结果在牙用树脂、聚赖氨酸和硅酮3种包被材料中,以硅酮效果最佳;与水合氯醛麻醉相比,异氟烷麻醉能明显提高模型的成功率;结扎PPA可提高模型的稳定性。结论采用气体吸入麻醉和硅酮包被的尼龙线,同时结扎PPA,可提高大鼠线栓法局灶性脑缺血模型的成功率。     

脑缺血再灌注损伤模型大鼠大脑皮质BDNF mRNA表达减少

目的制备局灶性脑缺血再灌注损伤大鼠模型,并观察大脑皮质脑源性神经营养因子(BDNF)mR-NA表达的变化。方法雄性SD大鼠,采用线栓法闭塞大脑中动脉2h后进行再灌注3d,制备局灶性脑缺血再灌注损伤模型。采用神经缺失评分观察大鼠的行为学表现;TTC染色检查脑组织梗死情况;HE染色观察大鼠脑组织形态结构;RT-PCR技术检测大鼠大脑皮质BDNF mRNA的表达。结果假手术组大鼠无神经功能障碍表现;脑组织未见梗死灶;脑组织神经细胞形态规则;大脑皮质BDNF mRNA的相对表达量,与正常组相比,未见明显变化。与假手术组相比,局灶性脑缺血再灌注损伤模型大鼠出现神经功能障碍;左侧半球可见梗死灶;梗死侧脑组织形态学观察显示神经细胞大量坏死脱落、胞质呈空泡变性、疏松、胞核浓缩深染;大脑皮质BDNF mRNA表达量明显减少。结论大脑中动脉闭塞2h后进行再灌注3d可造成脑缺血再灌注损伤,可能与大脑皮质BDNF mRNA的表达减少有关。     

NE1反义抑制剂对局灶性脑缺血作用的初步研究

目的 探讨NR1反义寡核苷酸对局灶性脑缺血的治疗作用。方法 于大鼠大脑中动脉闭塞后2小时、24小时分别经侧脑室注射磷酸缓冲液（PBS）、错义寡核苷酸（MSODN）及反义寡核苷酸（ASODN），然后在不同时间点进行神经功能缺损评分，术后第5天进行Nissl染色、TTC染色及梗死体积比测定。结果 各组局灶性脑缺血的神经功能缺损评分无显著性差异；反义寡核苷酸治疗组的梗死体积比显著低于单纯缺血组；反义寡核苷酸治疗海马各区神经元损伤轻，神经元丢失相对较少。结论 局灶性脑缺血后侧脑室注入NR1反义寡核苷酸，可以减轻缺血脑组织病理学损害，具有脑保护作用。     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.