下期内容预告

本刊2011年第4期报道专题为抗癫癎药物的疗效与安全性,重点内容包括:新型抗癫癎药物在国内的应用;抗癫癎药性脑病;抗癫癎药物对心血管系统的影响;抗癫癎药物对内分泌及妇女妊娠的影响;抗癫癎药物对血液系统的影响;常用抗癫癎药物在临床应用中出现的皮肤不良反应;抗癫癎药物对患儿生长发育及认知功能的影响;唑尼沙胺添加治疗部分性癫癎有效性与安全性的多中心随机双盲安慰剂对照临床研究;不同底物对难治性癫癎细胞模型中整合素α₂表达的影响;低频重复经颅磁刺激治疗难治性癫癎大鼠模型的作用及对BDNF和NPY表达的影响;中药治疗癫癎的实验前研究     

拉莫三嗪作为首次用药对癫癎患儿的临床疗效及不良反应的评价

癫癎是一种常见的神经系统慢性反复发作性疾病。拉莫三嗪作为一种新型抗癫癎药物,于1994年开始在我国用于抗癫癎治疗,对多种类型的癫癎发作均有效[1],通过作用于钠通道、抑制兴奋性神经递质的病理性释放而发挥抗癫癎作用[2-3],其不良反应相对于其他抗癫癎药物较小,且对认知功能的影响较小或有保护作用。     

抗癫癎药物的心血管系统不良反应

几乎所有抗癫癎药物（AEDs）都是针对细胞膜或突触膜上钠、钾、钙离子通道，以及参与信号转导的神经递质或调质如叫一氨基丁酸（GABA）等而发挥抗癫癎作用。细胞膜是人体基本功能单位，抗癫癎药物在通过细胞膜离子通道发挥抗癫癎作用的同时，也可能影响细胞膜的生理功能，从而出现药物不良反应，而对心血管系统的影响，则是抗癫癎药物最为重要的不良反应之一。     

成人幕上脑胶质母细胞瘤术后癫癎发作的预防

目的探讨成人幕上脑胶质母细胞瘤（GBM）术后预防性应用抗癫癎药物对癫癎发作的影响。方法回顾性分析86例术前无癫癎发作的幕上GBM病例资料,根据病人术后预防性应用抗癫癎药物情况分为对照组（不使用抗癫癎药物）、研究1组（使用抗癫癎药物4周）和研究2组（使用抗癫癎药物24周）,统计术后癫癎发作情况和术后24周各组Karnofsky评分。结果术后4周内出现癫癎发作对照组5例（16．7％）,研究组1例（1．8％）,两组癫癎发作有显著性差异（P〈0．05）。术后5～24周新发癫癎发作对照组7例（23．3％）．研究1组7例（25．0％）,研究2组1例（3．6％）,研究2组新发癫癎发作屁著低于对照组和研究1组（P〈0．05）。研究2组术后24周Karnofsky评分为66．96±10．30,明显高于对照组和研究1组（P〈0．05）。结论预防性应用抗癫癎药物可减少GBM术后癫癎发作发病率,术后癫癎发作治疗困难且影响生活质量,术后预防性应用抗癫癎药物应当不少于24周。     

急性脑血管病并发癫癎33例临床分析

目的分析急性脑血管病与癫癎的关系。方法回顾性分析近2年来,经CT或MRI证实的急性脑血管病并发癫癎患者33例的临床资料。结果本组急性脑血管病465例,继发癫癎的发生率为7.1%（33/465）。脑血管病急性期继发癫癎的多不需长期抗癫癎治疗,而在恢复期和后遗症期继发癫癎的多需长期抗癫癎治疗。结论急性脑血管病是老年人继发癫癎的重要原因之一,早期发作较易控制,晚期发作由于大多数有致灶存在需长期服用抗癫癎药。急性脑血管病的发病部位、病灶大小、病变性质与癫癎发作有一定的相关性。     

急性脑血管病并发癫(癎)33例临床分析

目的分析急性脑血管病与癫癎的关系。方法回顾性分析近2年来,经CT或MRI证实的急性脑血管病并发癫癎患者33例的临床资料。结果本组急性脑血管病465例,继发癫癎的发生率为7.1%（33/465）。脑血管病急性期继发癫癎的多不需长期抗癫癎治疗,而在恢复期和后遗症期继发癫癎的多需长期抗癫癎治疗。结论急性脑血管病是老年人继发癫癎的重要原因之一,早期发作较易控制,晚期发作由于大多数有致灶存在需长期服用抗癫癎药。急性脑血管病的发病部位、病灶大小、病变性质与癫癎发作有一定的相关性。     

妊娠合并癫癎的研究

癫癎是神经系统常见的疾病之一。妊娠与癫癎互为影响,妊娠可影响癫癎发作,癫癎发作和抗痫药也可对妊娠妇女及胎儿产生许多不利影响。在妊娠时诊断癫癎要重视症状与既往发作史相结合。尽量选用恰当的单一抗癫癎药物,应用最低有效剂量控制癫癎发作,定期检测血药浓度,最大限度降低孕产妇及胎儿的危险。     

难治性癫癎患者外周血中MDR1基因的表达及临床意义

目的 研究难治性癫癎患者外周血中多药耐药1(MDR1)基因的表达以及抗癫癎药物和癎性发作在难治性癫癎多药耐药发生中的作用.方法 采用逆转录聚合酶链反应(RT-PCR)半定量检测120例研究对象外周血中MDR1基因mRNA的表达.根据析因设计分癎性发作和抗癫癎药物两个因素,共分为A组(难治性癫癎组)、B组(癫癎治疗有效组)、C组(癎性发作未用药组)和D组(健康正常对照组),各30例.结果 4组的外周血中MDR1基因的表达水平明显不同(F=4.456,P=0.005),其中癎性发作引起MDR1mRNA的表达明显增高(F=10.005,P=0.002),抗癫癎药物的作用则不明显(F=0.919,P=0.340),抗癫癎药物与癎性发作两者之间没有交互作用(F=2.445,P=0.121).结论 难治性癫癎患者外周血中MDR1基因mRNA的表达上调是癎性发作而非使用抗癫癎药物的结果,外周血中MDR1基因mRNA表达水平的监测可以作为评价癫癎耐药的一项指标.     

高癎龄癫癎患者智力及生活质量的研究

目的　探讨高癎龄癫癎患者的智力及生活质量。方法　对 12 5例高癎龄癫癎患者进行研究。结果　高癎龄癫癎患者智力不受影响 ,生活质量低于正常人。结论　高癎龄癫癎在给予抗癫癎药物治疗的同时 ,应配合心理治疗 ,以提高其生活质量     

儿童与少年癫癎药物治疗的并发症

癫癎的有效治疗,是与多年不间断的使用抗癫癎药密切联系的。但是,抗癫癎药物易引起机体过敏和严重的变态反应。在文献中各种抗癫癎药物引起的并发症也有不少详细记载,但大多是成年患者的。本文的主要目的是研究儿童患者联合应用各种抗癫癎药物的并发症,以及弄清造成并发症的各种原因。作者观察了254例7—16岁的癫癎儿童,症状表现有大发作、失动性发作、精神运动性发作、小发作、肌阵挛性发作和皮质性发作(杰克逊氏癫癎)。采用了苯巴比妥、苯妥     

Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a new therapeutic tool in epilepsy, where it can be used to suppress seizures or treat comorbid conditions such as mood disorder. However, as rTMS carries a risk of inducing seizures among other adverse events, its safety and tolerability in the population with epilepsy warrant distinct consideration, as this group is especially seizure-prone. Accordingly, we performed a review of the literature to estimate the risk of seizures and other adverse events associated with rTMS in patients with epilepsy. We performed an English-language literature search, and reviewed all studies published from January 1990 to February 2007 in which patients with epilepsy were treated with rTMS, and complemented the literature search with personal correspondence with authors when necessary. We identified 30 publications that described patients with epilepsy who underwent rTMS, and noted total number of relevant subjects, medication usage, incidence of adverse events, and rTMS parameters including stimulus frequency, number of stimuli, train duration, intertrain interval, coil type, and stimulation sites. The data were analyzed for adverse events related to rTMS. Crude per-subject risk, as well as per-subject mean risk weighted by sample size and risk per 1000 stimuli weighted by number of stimuli in each study, were computed for seizures and for other adverse events. Adverse events or lack thereof was reported in 26 studies (n=280 subjects). Adverse events attributed to rTMS were generally mild and occurred in 17.1% of subjects. Headache was most common, occurring in 9.6%. The most serious adverse event was seizure during treatment, which occurred in four patients (1.4% crude per-subject risk). All but one case were the patients' typical seizures with respect to duration and semiology, and were associated with low-frequency rTMS. A single case of an atypical seizure appearing to arise from the region of stimulation during high-frequency rTMS is reported. No rTMS-related episodes of status epilepticus were reported. We cautiously conclude that the risk of seizure in patients with epilepsy undergoing rTMS is small, and the risk of other mild adverse events is comparable to that seen when rTMS is used to treat other diseases. Status epilepticus or life-threatening seizures have not been reported in patients undergoing rTMS treatment. rTMS thus appears to be nearly as safe in patients with epilepsy as in nonepileptic individuals, and warrants further investigation as a therapy in this population.     

Homeostatic effects of plasma valproate levels on corticospinal excitability changes induced by 1Hz rTMS in patients with juvenile myoclonic epilepsy.

OBJECTIVE: The preliminary results of noninvasive brain stimulation for epilepsy treatment have been encouraging, but mixed. Two important factors may contribute to this heterogeneity: the altered brain physiology of patients with epilepsy and the variable presence of antiepileptic drugs. Therefore, we aimed to study the effects of 1 Hz rTMS on corticospinal excitability in patients with juvenile myoclonic epilepsy (JME) in two different conditions: low- or high-plasma valproate levels. METHODS: Fifteen patients with JME and 12 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS was assessed in JME patients with low- and high-plasma valproate levels; and these results were compared with those in healthy subjects. RESULTS: In patients with chronic use of valproate and low-plasma concentrations, 1 Hz rTMS had a similar significant inhibitory effect on corticospinal excitability as in healthy subjects. However, in the same patients when the serum valproate concentration was high, 1 Hz rTMS increased the corticospinal excitability significantly. In addition, there was a significant positive correlation between plasma valproate levels and the motor threshold changes after 1 Hz rTMS. CONCLUSIONS: Our findings can be accounted for by mechanisms of homeostatic plasticity and illustrate the dependency of the modulatory effects of rTMS on the physiologic state of the targeted brain cortex. SIGNIFICANCE: The therapeutic use of rTMS in epilepsy should take into consideration the interaction between rTMS and drugs that change cortical excitability.     

重复经颅磁刺激治疗药物难治性癫痫的临床研究进展

经颅磁刺激(TMS)可导致细胞膜去极化并激活神经元,能够短暂地兴奋或抑制特定脑区.重复TMS(rTMS)指具有不同频率或强度的重复脉冲刺激,其作用效果在刺激结束后依然持续,已经广泛用于治疗多种神经精神疾病.目前认为低频rTMS能够抑制癫痫活动从而导致局灶性癫痫发作频率降低,但多项rTMS治疗药物难治性癫痫的临床研究结果...     

In-session seizures during low-frequency repetitive transcranial magnetic stimulation in patients with epilepsy

Low-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic tool for patients with intractable epilepsy. Although seizures during treatment have been reported as adverse events in some patients, the nature and severity of seizures that may be provoked by low-frequency rTMS in patients with epilepsy have not been extensively studied. Accordingly, this article documents seizures in patients (n = 5) with intractable epilepsy and average seizure frequency greater than one per day who underwent 1-Hz rTMS for seizure suppression. We report three observations in the present case series: (1) in each instance the in-session seizure was typical in semiology to the patient’s habitual seizures, (2) the duration of each documented seizure was either the same as or shorter than the patients’ baseline seizures, and (3) the overall neurological outcome on follow-up was not affected by the in-session seizures. More data will be required for valid conclusions with respect to safety and tolerability of low-frequency rTMS in patients with epilepsy, but it is noteworthy from our perspective that seizures during rTMS in this series were similar to the patients’ habitual seizures, occurred in patients with epilepsy with baseline seizure frequency exceeding one per day, and did not correlate with a poor neurological outcome or with absence of clinical response to rTMS.     

A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy

OBJECTIVE: To study the antiepileptic effects of rTMS in patients with refractory epilepsy and malformations of cortical development in a randomized, double-blind, sham-controlled trial. METHODS: Twenty-one patients with malformations of cortical development and refractory epilepsy underwent five consecutive sessions of low-frequency rTMS, either sham or active (1Hz, 1,200 pulses), focally targeting the malformations of cortical development. The number of epileptiform discharges in the electroencephalogram and the number of clinical seizures were measured before (baseline), immediately after, as well as 30 and 60 days after rTMS treatment. RESULTS: rTMS significantly decreased the number of seizures in the active compared with sham rTMS group (p < 0.0001), and this effect lasted for at least 2 months. Furthermore, there was a significant decrease in the number of epileptiform discharges immediately after (p = 0.01) and at week 4 (p = 0.03) in the active rTMS group only. There were few mild adverse effects equally distributed in both groups. The preliminary cognitive evaluation suggests improvement in some aspects of cognition in the active rTMS group only. INTERPRETATION: Noninvasive brain stimulation for epilepsy may be an alternative treatment for pharmaco-resistant patients with clearly identifiable seizure foci in the cortical convexity and who are not eligible for surgical treatment.     

Low‐frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: A controlled clinical study

Purpose: This study was designed to evaluate the therapeutic effect of low‐frequency repetitive transcranial magnetic stimulation (rTMS) on patients with refractory partial epilepsy. Methods: Sixty‐four patients with refractory focal epilepsy were screened and 60 patients were randomly divided into two groups by stimulation intensity: 90% (group 1) or 20% (group 2) of resting motor threshold (rMT). Seizure frequency and interictal EEG epileptic discharges were compared between the baseline and follow‐up periods. Key Findings: Seizures significantly decreased following 2‐weeks high intensity (90% rMT) rTMS treatment compared with baseline level (p < 0.05). rTMS also decreased interictal epilepsy discharges and improved the scales of Symptom Checklist‐90 significantly (p < 0.05). Seizures and spikes in the follow‐up period in the patients who received low intensity (20% rMT) rTMS did not show any difference compared with baseline data (p > 0.05, respectively). Significance: Low‐frequency high intensity rTMS (90% rMT) delivered into the epileptogenic zone had a significant antiepileptic effect on patients with refractory partial seizures. rTMS treatment can also reduce the interictal epileptic discharge frequency and improve the psychological condition of these patients.     

Repetitive transcranial magnetic stimulation does not replicate the Wada test

The authors compared inferior frontal speech arrest from repetitive transcranial magnetic stimulation (rTMS) with bilateral Wada tests in 17 epilepsy surgery candidates. Although rTMS lateralization correlated with the Wada test in most subjects, rTMS also favored the right hemisphere at a rate significantly greater than the Wada test. Postoperative language deficits were more consistent with Wada results. Available methods for inducing speech arrest with rTMS do not replicate the results of Wada tests.     

Experimental therapy of epilepsy with transcranial magnetic stimulation: lack of additional benefit with prolonged treatment

OBJECTIVE: To investigate the effect of three months of low-frequency repetitive transcranial magnetic stimulation (rTMS) treatment in intractable epilepsy. METHODS: Five patients (four males, one female; ages 6 to 50 years), were enrolled in the study; their epilepsy could not be controlled by medical treatment and surgery was not indicated. rTMS was performed twice a week for three months; patients kept records of seizure frequency for an equal period of time before, during, and after rTMS sessions. rTMS was delivered to the vertex with a round coil, at an intensity 5% below motor threshold. During rTMS sessions, 100 stimuli (five series of 20 stimuli, with one-minute intervals between series) were delivered at a frequency of 0.3 Hz. RESULTS: Mean daily number of seizures (MDNS) decreased in three patients and increased in two during rTMS--one of these was treated for only one month; the best result was achieved in a patient with focal cortical dysplasia (reduction of 43.09% in MDNS). In the whole patient group, there was a significant (p<0.01) decrease in MDNS of 22.8%. CONCLUSION: Although prolonged rTMS treatment is safe and moderately decreases MDNS in a group of patients with intractable epilepsy, individual patient responses were mostly subtle and clinical relevance of this method is probably low. Our data suggest, however, that patients with focal cortical lesions may indeed benefit from this novel treatment. Further studies should concentrate on that patient subgroup.     

Antiepileptic effects of low-frequency repetitive transcranial magnetic stimulation by different stimulation durations and locations.

OBJECTIVE: To evaluate the antiepileptic effect of low-frequency rTMS (repetitive transcranial magnetic stimulation) in the patients with intractable epilepsy. METHODS: We enrolled 35 patients with localization-related epilepsy who had experienced at least one complex partial seizure or a secondarily generalized seizure per week on a constant antiepileptic drug regimen over an 8-week period. rTMS was administered using a Rapid(2) magnetic stimulator with an air-cooled coil at 0.5Hz for 5 consecutive days at 100% of rMT (resting motor threshold). Patients were divided into a focal stimulation group with a localized epileptic focus, or a non-focal stimulation group with a non-localized or multifocal epileptic focus. These two groups were then randomly subdivided into four subgroups depending on the total number of stimulations administered, i.e., 3000 pulse and 1500 pulse subgroups. Weekly seizure frequencies were determined for 8 weeks before and after rTMS. To compare the number of interictal spikes before and after rTMS, EEG was recorded twice before (1st day) and after rTMS (5th day). RESULTS: Mean weekly seizure frequency was non-significantly decreased after rTMS (8.4-->6.8/week, -13.9%). Longer stimulation subgroups (3000 pulses, -23.0%) tended to have fewer seizures than shorter stimulation subgroups (1500 pulses, -3.0%), without statistical significance. TMS stimulation site and structural brain lesions did not influence seizure outcome. However, interictal spikes significantly decreased (-54.9%, P=0.012) after rTMS and they totally disappeared in 6 patients (17.1%, 6/35). CONCLUSIONS: Low-frequency rTMS reduced interictal spikes, but its effect on seizure outcome was not significant. Focal stimulation for a longer duration tended to further reduce seizure frequency. SIGNIFICANCE: These findings may help clinicians to further investigate the therapeutic potential of the rTMS for patients with intractable epilepsy.     

Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial

PURPOSE: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy. METHODS: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, double-blind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex. RESULTS: "Active" rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability). CONCLUSIONS: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to "active" rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.