易卒中型肾血管性高血压大鼠模型

用内径为0.30mm的银夹钳夹双侧肾动脉,复制出一种易卒中型肾血管性高血压大鼠模型,其血压峰值高且稳定在26.7kPa以上,并发生与人类高血压病类似的脑动脉损害:细小动脉纤维素样坏死、透明变性和微动脉瘤形成等,在此基础上,0.56的大鼠自发产生各种类型的脑卒中:脑梗塞、脑出血、蛛网膜下腔出血和混合性脑卒中。本文还着重将这种易卒中型肾血管性高血压大鼠与易卒中型自发性高血压大鼠作了比较。     

实验性高血压所致的颈动脉损害

为了探讨高血压性颈动脉损害与血压水平的关系及其在脑卒中发病中的意义，将易卒中型肾血管性高血压大鼠的颈总动脉进行了形态学测量，并观察了硝苯吡啶、卡托普利和美托洛尔抗高血压治疗后这些测量参数的改变。结果发现，易卒中型肾血管性高血压大鼠的颈动脉损害主要表现为中层肥厚，由平滑肌细胞增生、肥大、弹力纤维增多和管壁重构引起。抗高血压治疗后，平滑肌细胞的增生、肥大受到抑制，但弹力纤维增多和管壁重构无改善。提示脑动脉管壁结构未能恢复正常是抗高血压治疗不能完全防止脑卒中的原因之一。     

脑小血管病脑白质损伤动物模型

脑小血管病是导致认知功能减退、步态情感障碍和痴呆的重要脑血管疾病,脑白质弥漫 性损伤是该病的重要影像学特征。结合国内外近年来相关研究内容,本文对不同的脑小血管病白质 损伤动物模型制作进行了系统性回顾,包括单一型动物模型如双侧颈总动脉狭窄模型、脑淀粉样血 管病模型、Notch3 转基因小鼠模型、自发性高血压大鼠模型、易卒中型肾血管性高血压大鼠模型,以 及由两个或两个以上单一型动物模型组合而成的复合型动物模型等。     

易卒中肾血管性高血压大鼠血液流变学分析

目的 探讨易卒中肾血管性高血压大鼠血液流变学的变化。方法 运用双肾双夹法建立易卒中肾血管性高血压大鼠模型，常规饲养4个月后检测其血液流变学的变化。结果 术后4个月，易卒中肾血管性高血压大鼠的低切、中切、高切全血粘度、红细胞比积、低切全血还原粘度均显著高于正常血压大鼠。结论 易卒中肾血管性高血压大鼠具备了高血压病的血液流变学改变，是研究高血压性脑卒中的理想模型。     

美托洛尔抗高血压预防脑卒中的实验病理学研究

目的探讨抗高血压治疗预防脑卒中的形态学机制。方法采用易卒中型肾血管性高血压大鼠口服美托洛尔治疗，观察抗高血压治疗各级脑动脉和心室壁厚度的形态学改变。结果治疗组大鼠血压仅短期轻度低于未治疗的高血压对照组，但治疗组各级脑动脉损害和左心室肥厚明显改善，脑卒、中发生率也显著低于高血压对照组。结论美托洛尔抗高血压治疗预防脑卒中的效果，不单纯由血压下降决定，还与其具有保护脑血管和逆转心室肥厚等作用有关。     

实验性肾性高血压大鼠脑动脉瘤模型的建立及发生机制探讨

目的 探讨高血压大鼠脑血管早期病理改变与脑微动脉瘤形成的关系。方法 建立肾性高血压大鼠模型,应用光镜及电镜观察脑血管组织学改变。结果 实验组发现2个肉眼可见的动脉瘤及10个镜下早期动脉瘤。动脉分叉部内膜垫的变化与动脉瘤的病理改变程度有密切关系,动脉瘤形成早期即有内皮细胞损伤。结论 持续高血压引起的内弹力膜与平滑肌的破坏导致了动脉瘤的发生。     

高血压大鼠脑白质病变中髓鞘和轴索改变

目的探究高血压大鼠脑白质病变中轴索微结构的变化。方法 18只雄性Sprague-Dawley大鼠,随机分为假手术组(n=9)与手术组(n=9),手术组先行双肾双夹术制作易卒中型肾血管性高血压大鼠模型,12周后间隔1 d先后夹闭双侧颈总动脉。颈总动脉夹闭术后12周对大鼠进行水迷宫试验评价大鼠是否存在认知功能受损,组织病理学评价小血管病理学改变、脑白质病变、胶质细胞改变及轴索微结构的变化。结果水迷宫实验:手术组的逃避潜伏期较假手术组明显升高,穿越平台次数较假手术组明显降低,差异具有统计学意义(P0.05)。手术组大鼠存在小动脉内膜增厚、管腔狭窄;手术组较假手术组有明显的脑白质病变,且伴有少突胶质细胞减少;手术组病变部位Caspr表达明显减少,病变周围髓鞘正常区域出现郎飞结长度增加、结侧区长度增加及直径增粗。结论脑白质病变过程同时存在轴索和髓鞘的损伤。     

高胆固醇、高血压对大鼠脑动脉内皮糖萼的作用

目的分别给易卒中型肾血管性高血压大鼠、正常血压大鼠饲以高脂饲料6周和16周,在电镜下观察其脑动脉内皮糖萼的变化。结果高胆固醇可引起大鼠颈内动脉、大脑中动脉内皮糖萼变薄、分布不均匀,常伴缺失、结块现象,且高胆固醇时间越久、损害越严重。高血压也可引起大鼠大脑中动脉内皮糖萼同样的改变。这在增加脑血管的通透性,促进脂质的沉积和动脉粥样硬化的形成中可能起重要作用。     

高血压动脉硬化性混合性中风的实验病理学研究

用双肾双夹法复制易卒中型肾血管性高血压大鼠55只,肾动脉狭窄术后40周内自发脑卒中31只,其中单纯出血或缺血性中风20只(64.5％),混合性中风11只(35.5％)。混合性中风的大鼠脑内细小动脉的透明变性、纤维素样坏死、微动脉瘤形成及增生性反应等病变比单纯出血或缺血性中风者更为广泛、严重。表明高血压是混合性中风的重要病因,高血压性血管损害是其发病基础。本文还根据中风灶的大小将混合性中风进一步分型,并探讨了各型的发生机制。     

新型脑白质病变动物模型及其脑小血管的病理学研究

目的建立一个新型的具有高血压及脑小血管病理改变的脑白质病变(white matter lesions,WMLs)动物模型。方法 13只雄性Sprague-Dawley大鼠,随机分为假手术组(n=6)与易卒中型肾血管性高血压-改良的2VO组(stroke-prone renovascular hypertensive rat-modified 2 vessel occlusion RHRSP/Modified 2VO)(n=7),RHRSP/Modified 2VO组先行双肾双夹术制作RHRSP模型,12周后间隔1周先后夹闭双侧颈总动脉。双肾双夹术后20周对大鼠进行水迷宫试验观察大鼠是否存在空间记忆功能的受损,组织病理学检测观察是否存在脑白质病变及相应的脑小血管病理学改变。结果双肾双夹术后12周,RHRSP/Modified 2VO组7只大鼠收缩压均大于180 mm Hg;水迷宫实验:RHRSP/Modified 2VO组的逃避潜伏期较假手术组明显升高(P0.05),穿越平台次数及原平台象限停留时间比较假手术组明显降低[(2.5±1.05 vs.5±1.67);(28.04%±14.13%vs.49.69%±13.12%)],差异具有统计学意义(P0.05);RHRSP/Modified 2VO组脑白质病变的分级明显高于假手术组(2.17±0.75 vs.0.33±0.52),差异具有统计学意义(P0.05),且RHRSP/Modified 2VO大鼠存在脑小血管的病理改变(小动脉管壁增厚、血脑屏障破坏及静脉胶原沉积)。结论 RHRSP/Modified 2VO是适用的WMLs动物模型,可用于探究WMLs的发病机制及治疗靶点。     

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 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.     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

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.     

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.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

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.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.