多药耐药基因1C3435T多态性在癫(癎)患者中的分布

目的了解多药耐药基因1（MDR1）C3435T多态性在癫痫患者分布特点，探讨其与患者耐药的相关性。方法用常规酚-氯仿法提取72例癫痫药物治疗耐药患者和62例癫痫药物治疗有效患者的外周血DNA，应用PCR-RFLP方法检测其MDR1基因外显子26（exor26）C3435T的多态性。结果患者的MDR13435位点存在3种基因型，野生型CC、杂合突变型CT和纯合突变型TT在134例癫痫患者中分布频率分别为24．63％、53．73％和21．64％。TT基因型在耐药患者组和药物有效组中分别为18．1％和25．8％，CT基因型分别为48．6％和59．7％，差异均无统计学意义（P：0．277和P=0．200）。CC基因型在耐药患者组中的频率为33．3％，在药物有效组为14．5％，两者比较差异有统计学意义（P=0．012）。等位基因C和T在癫痫人群中分布频率为51．5％和48．5％，其中C等位基因在耐药组的频率（57．6％）明显高于药物有效组（44．4％）；相反，T等位基因在药物有效组的频率（55．6％）分布要高于耐药组（42．3％，P=0．03）。结论MDR1基因多态性分布中，CC基因型、C等位基因可能与癫痫耐药有关。癫疴治疗有效可能与TT基因型、T等位基因有相关趋势。     

回、汉族癫痫患者ABCB1基因C3435T多态性与癫痫耐药的相关性研究

目的 研究ABCB1基因C3435T的单核苷酸多态性在回、汉族癫痫人群中的分布特点;探讨回、汉族癫痫患者人群中ABCB1基因型对癫痫耐药的影响,进一步阐明癫痫耐药机制.方法 收集宁夏地区同族癫痫耐药患者33例,回族药物敏感癫痫患者29例,汉族癫痫耐药患者62例,汉族药物敏感癫痫患者61例,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法对入选患者的ABCB1基因C3435T位点进行基因分型,并随机抽取11%的基因分型样本进行直接测序证实.统计4组癫痫患者中C3435T的基因型、等位基因频率,分别用x2等检验进行统计分析.结果 回、汉族对照比较,回族癫痫患者中外显子26 C3435T位点基因型及等位基因频率与汉族癫痫患者均没有差异,(均P＞0.05).与药物敏感组比较,耐药组外显子26C3435T-CC基因型明显多于药物敏感组(P＜0.001),而TT基因型则少于药物敏感组(P＜0.001).与药物敏感组比较,耐药组C等位基因频率高于药物敏感组,而T等位基因频率低于药物敏感组(P＜0.001).结论 在中国回、汉族人群中均存在的ABCB1-C3435T位点基因多态性与癫痫耐药有关联,这一位点的基因多态性可以影响癫痫患者对抗癫痫药物(AEDs)的反应性.     

ABCB1基因C3435T多态性与癫痫耐药关系的Meta分析

目的 运用Meta分析的方法综合评价ATP结合盒B亚家族成员1转运蛋白基因(ABCB1)C3435T多态性与癫痫耐药的相关性. 方法 制定原始文献的纳入和排除标准及检索策略,检索中外文数据库,收集有关ABCB1 C3435T多态性与抗癫痫药物(AEDs)治疗反应相关性的研究报告,采用等位基因型(C vs T)以及共显性模型(CC vs TT,CT vs TT)、显性模型(CC+CT vs TT)和隐性模型(CC vs CT+TT)等基因遗传模型进行对比与定量综合分析,同时按人种所属地域(亚裔人与白种人)进行亚组分析. 结果 共23篇文献纳入Meta分析,包括3704例癫痫耐药患者和4160例治疗有效患者,入选文献无发表偏倚.统计分析显示:C3435T位点多态性与癫痫耐药无统计学关联;等位基因C与T相比,随机效应模型:OR=1.05,95％ CI:0.94～1.18,P=0.390.各基因型对比以及进行亚组分析后也未发现统计学关联. 结论 ABCB1 C3435T多态性与癫痫耐药无关联.     

难治性精神分裂症与亚甲基四氢叶酸还原酶基因多态性的关联分析

目的:探讨难治性精神分裂症与亚甲基四氢叶酸还原酶(MTHFR)基因C677T和A1298C多态性的关系。方法:应用聚合酶链反应-限制性片断长度多态性方法(PCR-RFLP)检测102名正常对照、138例难治性精神分裂症患者及97例非难治性精神分裂症患者MTHFR基因的C677T和A1298C多态性。结果:患者组与对照组,难治组与非难治组C677T、A1298C基因型分布差异均无统计学意义(C677T,χ2=4.83,P=0.09;χ2=1.90,P=0.39;A1298C,χ2=1.50,P=0.47;χ2=3.90,P=0.14),而患者组C677T的T等位基因频率显著高于正常对照组(P=0.04),难治组A1298C的C等位基因频率显著高于非难治组(P=0.04)。677TT/1298AA、677CT/1298AC复合基因型患病相对风险度比677CC/1298AA型显著提高(OR=4.13,95%CI=1.26～13.58,P=0.02;OR=2.95,95%CI=1.23～7.07,P=0.01),而在难治组和非难治组中,复合基因型差异无统计学意义。结论:MTHFR基因677T等位基因和677TT/1298AA、677CT/1298AC复合基因型是精神分裂症发病危险因素,MTHFR基因1298C等位基因可能是难治性精神分裂症的危险因子之一。     

PPARγ基因C1431T多态性及其与脑出血的关系

目的探讨过氧化物酶体增殖物激活受体γ(PPARγ)基因C1431T多态性在人群中的分布及其与脑出血的关系。方法用聚合酶链反应-限制性片段长度多态性分析法检测PPARγ基因C1431T多态性在脑出血组和正常对照组的分布情况。结果 PPARγC1431T基因型CC、CT+TT在脑出血患者组的分布频率分别为43.8%、56.2%,C等位基因频率为70.1%,T等位基因频率为29.9%。CC、CT+TT基因型在正常对照组中的分布频率分别为62.1%、37.9%,C等位基因频率为79.8%,T等位基因频率为20.2%。脑出血组PPARγ基因1431 T/X基因型频率(P=0.000)和T等位基因频率(P=0.000)均显著高于对照组,差异有统计学意义。结论 PPARγ基因C1431T多态性可能与脑出血存在关联,T等位基因可能与脑出血发病率呈正相关。     

难治性癫痫的耐药性与多药耐药基因MDR1C3435T多态性的相关研究

目的 探讨我国难治性癫痫患者外周血中MDRl基因C3435T多态性与耐药的相关性.方法 采用PCR-RFLP的方法检测64例癫痫患者MDRI基因C3435T多态性的表达.其中,难治性癫痫组31例,治疗有效组33例.结果 难治性癫痫组CC基冈型占64.5%,治疗有效组CC基因型占18.2%,两组病例基因型频率(X2=16.13 P＜0.001)、等位基冈频率(X2=20.17 P＜0.001)比较均有统计学意义.结论 难治性癫痫患者外周静脉血中MDRl基因表达明显增高,可作为难治性癫痫患者的一项监测指标.     

G蛋白β3亚单位基因多态性与奥氮平所致体重增加的相关性

目的 探讨G蛋白β3亚单位(G-proteinβ3 subunit,GNB3)基因C825T多态性与精神分裂症患者使用奥氮平治疗过程中体重增加的关系。方法 对90例首次住院的精神分裂症患者予奥氮平治疗12周,监测治疗前后的体重、体重指数(body mass index,BMI)变化,并检测患者GNB3基因C825T多态性,分析基因多态性与体重变化的相关性。结果 治疗后患者体重、BMI增加有统计学意义(均P0.01)。TT基因型者治疗后的增重率(weight gain rate,WGR)及BMI增加较CC基因型者更明显(均P0.01),携T等位基因(TT型+CT型)者治疗后的WGR及BMI增加较非携T等位基因(CC型)者更明显(均P0.01)。治疗后WGR≥7%者GNB3基因C825T基因型分布(CC型15.69%,CT型54.90%,TT型29.41%)与WGR7%者(CC型38.46%,CT型43.59%,TT型17.95%)差异有统计学意义(P0.05),WGR≥7%者T等位基因频率(63.33%)高于WGR7%者(39.74%)(P0.05)。多因素线性回归显示TT基因型(以CC型为参照)影响奥氮平治疗后的体重变化(β=1.83,标准化β=0.29,P0.01)。结论 GNB3基因C825T多态性与奥氮平所致的体重增加有关。     

KCNJ10基因rs1890532单核苷酸多态性与儿童癫痫易感性的相关性研究

目的探讨中国北方汉族儿童中KCNJ10基因rs1890532单核苷酸多态性与癫痫的关系。方法 212例癫痫患儿作为病例组,按照癫痫发作类型分为部分性发作(partial Seizures,PS)组120例和全面性发作(generalized seizures,GS)组和92例,同时选择200例非癫痫儿童作为对照组,收集一般临床资料,采用聚合酶链反应-限制性片段多态性法检测KCNJ10基因rs1890532单核苷酸多态性,分析其与癫痫易感性的关系。结果校正年龄、性别等混杂因素后,KCNJ10基因rs1890532位点单核苷酸多态性与儿童GS在等位基因模型(C/G)和隐性基因模型[(CC+CG)/GG)]下整体效应具有统计学意义(OR=1.325,95%CI:1.014~2.461,P=0.043;OR=3.173,95%CI:1.097~10.694,P=0.021)。对照组与病例组、PS组比较,等位基因和基因型频率差异均无统计学意义(均P0.05)。结论 KCNJ10基因rs1890532单核苷酸多态性可能与儿童GS遗传易感性相关。     

粤西汉族人群血浆谷胱甘肽过氧化物酶基因启动子区-723C/T基因多态性与脑梗死的关系

目的 研究粤西汉族人群谷胱甘肽过氧化物酶(GPX-3)基因启动子区-723C/T基因多态性的分布及其与脑梗死的关系. 方法 检测佛广东医学院附属医院神经科自2007年2月至2008年2月收治的粤西地区汉族脑梗死患者102例(病例组)和同期粤西地区汉族健康体检者101例(对照组)的GPX-3基因启动子区-723C/T基因多态性,比较2组的一般资料、卒中危险因素及-723C/T基因多态性的分布特点,多元Logistic回归分析影响脑梗死发生的危险因素,并对筛选出的危险因素进行分层分析. 结果 与对照组比较,病例组高血压、糖尿病病史比例,血糖水平,-723C/T CC基因型频率及C等位基因频率均较高,差异有统计学意义(P＜0.05);多元Logistic回归分析显示-723C/T基因型、高血压病史、糖尿病史是脑梗死发生的独立危险因素;与没有任何危险因素亦不携带风险基因型者比较,有危险因素又携带CC基因型者脑梗死发病风险明显增加,差异有统计学意义(P＜0.05). 结论 中国粤西地区汉族人群GPX -3基因启动子区-723C/T位点存在多态性,C等位基因是脑梗死的危险因素,CC基因型为脑梗死的易感基因型,也是独立危险因素.     

GABRA5基因启动子-754C／T多态性与耐药性癫痫的相关性分析

目的探讨GABRA5基因启动子-754C／T突变和癫痫耐药的相关性。方法收集125例诊断明确、治疗合理的汉族癫痫患者。根据是否符合DRE（耐药性癫痫）诊断标准将其分为耐药组（63例）和非耐药组（62例）。采用聚合酶链反应限制性片段长度多态性方法检测患者外周血GABRA5基因启动子-754c／T多态性。结果耐药组CC、CT、TT基因型分别占23．8％、41．2％、35．0％,非耐药组分别占16．1％、50．0％、33．9％,总体差异无统计学意义（x^2=1．454,P=0．483）。耐药组等位基因C、T频率分别为44．4％、55．6％,非耐药组患者分别为41．1％、58．9％,差异也无统计学意义（x^2=0．281,P=0．596）。结论本研究未发现GABRA5基因启动子-754C／T多态性与汉族DRE有关。     

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.     

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.     

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.     

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.     

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.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.