Epilepsia最新文献_第8页

Association of new onset seizure and COVID-19 vaccines and long-term follow-up: A systematic review and meta-analysis 新发癫痫与 COVID-19 疫苗和长期随访的关系：系统回顾和荟萃分析。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-27 DOI: 10.1111/epi.18102

Ali Rafati, Melika Jameie, Mobina Amanollahi, Yeganeh Pasebani, Nastaran Salimi, Mohammad Hosein Feyz Kazemi, Mana Jameie, Mohammad Yazdan Pasebani, Delaram Sakhaei, Fateme Feizollahi, Churl-Su Kwon

Objective

Seizures have been reported as an adverse event of the COVID-19 vaccine. However, there is no solid evidence of increased seizure occurrence compared to the general population. This study was undertaken to investigate seizure occurrence among COVID-19 vaccine recipients compared to unvaccinated controls.

Methods

A systematic search was made of PubMed, Web of Science, Scopus, and Cochrane Library up to April 9, 2024. Studies reporting seizure occurrence following COVID-19 vaccination were included. This study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework and was conducted using random- and common-effect models. The risk of bias in the studies was evaluated by the Newcastle–Ottawa Scale. The outcome of interest was new onset seizure incidence proportion compared among (1) COVID-19 vaccine recipients, (2) unvaccinated cohorts, and (3) various types of COVID-19 vaccines.

Results

Forty studies were included, of which seven entered the meta-analysis. Results of the pooled analysis of the new onset seizure incidence (21- or 28-day period after vaccination) in 13 016 024 vaccine recipients and 13 013 262 unvaccinated individuals by pooling the cohort studies did not show any statistically significant difference between the two groups (odds ratio [OR] = .48, 95% confidence interval [CI] = .19–1.20, p = .12, I² = 95%, τ² = .7145). Pooling four studies accounting for 19 769 004 mRNA versus 47 494 631 viral vector vaccine doses demonstrated no significant difference in terms of new onset seizure incidence between the groups (OR = 1.18, 95% CI = .78–1.78, p = .44, I² = 0%, τ² = .004).

Significance

This systematic review and meta-analysis shows no statistically significant difference in the risk of new onset seizure incidence between COVID-19 vaccinated individuals and unvaccinated individuals.

目的：据报道，癫痫发作是 COVID-19 疫苗的不良反应之一。然而，与普通人群相比，没有确凿证据表明癫痫发作的发生率会增加。本研究旨在调查 COVID-19 疫苗接种者与未接种对照者的癫痫发作情况：方法：对截至 2024 年 4 月 9 日的 PubMed、Web of Science、Scopus 和 Cochrane Library 进行了系统检索。纳入了报告接种 COVID-19 疫苗后癫痫发作情况的研究。本研究根据《系统综述和元分析首选报告项目》框架进行报告，并采用随机效应和共同效应模型。研究的偏倚风险采用纽卡斯尔-渥太华量表进行评估。研究结果是比较了(1) COVID-19 疫苗接种者、(2) 未接种者和(3) 不同类型 COVID-19 疫苗的新发癫痫发作比例：结果：共纳入 40 项研究，其中 7 项进入荟萃分析。通过汇集队列研究，对13 016 024名接种疫苗者和13 013 262名未接种疫苗者的新发癫痫发作率（接种疫苗后21天或28天）进行了汇总分析，结果显示两组之间没有任何统计学上的显著差异（几率比[OR] = .48，95%置信区间[CI] = .19-1.20，P = .12，I2 = 95%，τ2 = .7145）。将四项研究的 19 769 004 个 mRNA 剂量与 47 494 631 个病毒载体疫苗剂量进行汇总，结果表明两组在新发癫痫发作率方面无显著差异（OR = 1.18，95% CI = .78-1.78，p = .44，I2 = 0%，τ2 = .004）：本系统综述和荟萃分析表明，接种 COVID-19 疫苗的个体与未接种疫苗的个体在新发癫痫发作风险方面没有统计学意义上的显著差异。

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引用次数: 0

Optimizing ketogenic diet therapy for childhood epilepsy: Identifying key factors for seizure control and psychomotor enhancement 优化儿童癫痫的生酮饮食疗法：确定控制癫痫发作和提高精神运动能力的关键因素。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-27 DOI: 10.1111/epi.18098

Xin Tong, Qian Wang, Jie Yang, Jielan Zhou, Xiaolu Chen, Jing Gan, Qianyun Cai, Tao Yu, Rong Luo

Objective

To identify key factors influencing the therapeutic efficacy of the ketogenic diet (KD) for children with drug-resistant epilepsy and elucidate their interconnected relationships to optimize clinical practice.

Methods

Participants were selected from children receiving KD treatment at West Second University Hospital of Sichuan University from September 2015 to October 2023. Clinical factors pre-KD and post-KD (at the third month) were analyzed systematically using an analytical framework. Descriptive analyses, univariate analyses, and multivariate regression analyses were performed for the entire cohort and subgroups of genetic and non-genetic (i.e., structural and unknown) etiologies. Thereby, the most significant predictors were identified for each relevant dependent variable. Path analysis diagrams were used for visual representation.

Results

Of 156 patients, genetic etiology was prevalent (38.5%). In the genetic subgroup, channelopathies predicted lower baseline seizure frequency and increased chance of seizure freedom with KD. Frequent seizures and complex history of anti-seizure medications (ASMs) predicted severe baseline psychomotor abnormalities. Younger age at KD initiation benefited psychomotor improvement. In the non-genetic subgroup, lower baseline seizure frequency increased the likelihood of seizure freedom post-KD. Concurrent use of multiple ASMs helped achieve ≥50% seizure reduction. Boys were more likely to experience psychomotor improvement. A significant correlation was found between ≥50% seizure reduction and psychomotor improvement in both subgroups. Delayed KD initiation (longer epilepsy duration at KD start) was related to a greater number of ASMs used, infrequent seizures, and older age at epilepsy onset. In addition, patients with channelopathies had delayed initiation of KD.

Significance

Children with genetic epilepsy display more pronounced characteristics of epileptic encephalopathy. Early KD intervention is crucial for channelopathies, notably SCN1A variants. For other drug-resistant epilepsy cases, KD alongside diverse ASMs may improve seizure control and developmental outcomes. However, the patient population benefiting most from early KD tends to start the treatment later, urging a re-evaluation of KD decision-making paradigms.

目的找出影响耐药癫痫患儿生酮饮食（KD）疗效的关键因素，并阐明其相互关系，以优化临床实践：研究对象选自2015年9月至2023年10月在四川大学华西第二医院接受生酮饮食治疗的儿童。采用分析框架对KD前和KD后（第三个月）的临床因素进行系统分析。对整个队列以及遗传和非遗传（即结构性和未知）病因亚组进行了描述性分析、单变量分析和多变量回归分析。由此，确定了每个相关因变量最重要的预测因素。结果：结果：在 156 名患者中，遗传病因占多数（38.5%）。在遗传亚组中，通道病预示着较低的基线癫痫发作频率，并增加了KD患者摆脱癫痫发作的几率。频繁的癫痫发作和复杂的抗癫痫药物（ASMs）史预示着严重的基线精神运动异常。开始使用 KD 时年龄较小，有利于精神运动的改善。在非遗传亚组中，较低的基线癫痫发作频率增加了KD后癫痫发作自由的可能性。同时使用多种 ASMs 有助于使癫痫发作减少≥50%。男孩更有可能获得精神运动方面的改善。在两个亚组中，癫痫发作减少≥50%与精神运动改善之间存在明显的相关性。延迟开始 KD（开始 KD 时癫痫持续时间较长）与使用的 ASM 数量较多、癫痫发作不频繁以及癫痫发病年龄较大有关。此外，患有通道病的患者启动 KD 的时间也较晚：意义：遗传性癫痫患儿的癫痫性脑病特征更为明显。对于通道病，尤其是 SCN1A 变异型，早期 KD 干预至关重要。对于其他耐药癫痫病例，KD与多种ASMs一起使用可改善癫痫发作控制和发育结果。然而，从早期 KD 中获益最多的患者群体开始治疗的时间往往较晚，这就要求对 KD 决策范式进行重新评估。

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引用次数: 0

Interictal stereo-electroencephalography features below 45 Hz are sufficient for correct localization of the epileptogenic zone and postsurgical outcome prediction 发作间期低于 45 Hz 的立体脑电图特征足以正确定位致痫区并预测手术后的结果。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-24 DOI: 10.1111/epi.18081

Petr Klimes, Petr Nejedly, Valentina Hrtonova, Jan Cimbalnik, Vojtech Travnicek, Martin Pail, Laure Peter-Derex, Jeffery Hall, Raluca Pana, Josef Halamek, Pavel Jurak, Milan Brazdil, Birgit Frauscher

Objective

Evidence suggests that the most promising results in interictal localization of the epileptogenic zone (EZ) are achieved by a combination of multiple stereo-electroencephalography (SEEG) biomarkers in machine learning models. These biomarkers usually include SEEG features calculated in standard frequency bands, but also high-frequency (HF) bands. Unfortunately, HF features require extra effort to record, store, and process. Here we investigate the added value of these HF features for EZ localization and postsurgical outcome prediction.

Methods

In 50 patients we analyzed 30 min of SEEG recorded during non–rapid eye movement sleep and tested a logistic regression model with three different sets of features. The first model used broadband features (1–500 Hz); the second model used low-frequency features up to 45 Hz; and the third model used HF features above 65 Hz. The EZ localization by each model was evaluated by various metrics including the area under the precision-recall curve (AUPRC) and the positive predictive value (PPV). The differences between the models were tested by the Wilcoxon signed-rank tests and Cliff's Delta effect size. The differences in outcome predictions based on PPV values were further tested by the McNemar test.

Results

The AUPRC score of the random chance classifier was .098. The models (broad-band, low-frequency, high-frequency) achieved median AUPRCs of .608, .582, and .522, respectively, and correctly predicted outcomes in 38, 38, and 33 patients. There were no statistically significant differences in AUPRC or any other metric between the three models. Adding HF features to the model did not have any additional contribution.

Significance

Low-frequency features are sufficient for correct localization of the EZ and outcome prediction with no additional value when considering HF features. This finding allows significant simplification of the feature calculation process and opens the possibility of using these models in SEEG recordings with lower sampling rates, as commonly performed in clinical routines.

目的：有证据表明，在机器学习模型中结合多种立体脑电图（SEEG）生物标志物，可取得最有希望的致痫区（EZ）发作间期定位结果。这些生物标志物通常包括以标准频段计算的 SEEG 特征，也包括高频（HF）频段。遗憾的是，高频特征需要额外的记录、存储和处理工作。在此，我们研究了这些高频特征对 EZ 定位和手术后结果预测的附加价值：我们分析了 50 名患者在非快速眼动睡眠期间记录的 30 分钟 SEEG，并用三组不同的特征对逻辑回归模型进行了测试。第一个模型使用宽带特征（1-500 Hz）；第二个模型使用 45 Hz 以下的低频特征；第三个模型使用 65 Hz 以上的高频特征。每个模型的 EZ 定位效果都通过各种指标进行了评估，包括精确度-召回曲线下面积 (AUPRC) 和阳性预测值 (PPV)。模型之间的差异通过 Wilcoxon 符号秩检验和 Cliff's Delta效应大小进行检验。McNemar检验进一步检验了基于PPV值的结果预测差异：结果：随机机会分类器的 AUPRC 得分为 0.098。模型（宽带、低频、高频）的中位数AUPRC分别为.608、.582和.522，分别正确预测了38、38和33名患者的结果。三种模型的 AUPRC 或其他指标在统计学上没有明显差异。在模型中加入高频特征没有任何额外的贡献：意义：低频特征足以正确定位 EZ 和预测结果，在考虑高频特征时没有额外价值。这一发现大大简化了特征计算过程，并为在采样率较低的 SEEG 记录中使用这些模型提供了可能性，而这在临床常规中是很常见的。

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引用次数: 0

Oscillatory and nonoscillatory sleep electroencephalographic biomarkers of the epileptic network 癫痫网络的振荡性和非振荡性睡眠脑电图生物标志物。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-24 DOI: 10.1111/epi.18088

Véronique Latreille, Justin Corbin-Lapointe, Laure Peter-Derex, John Thomas, Jean-Marc Lina, Birgit Frauscher

Objective

In addition to the oscillatory brain activity, the nonoscillatory (scale-free) components of the background electroencephalogram (EEG) may provide further information about the complexity of the underlying neuronal network. As epilepsy is considered a network disease, such scale-free metrics might help to delineate the epileptic network. Here, we performed an analysis of the sleep oscillatory (spindle, slow wave, and rhythmic spectral power) and nonoscillatory (H exponent) intracranial EEG using multiple interictal features to estimate whether and how they deviate from normalcy in 38 adults with drug-resistant epilepsy.

Methods

To quantify intracranial EEG abnormalities within and outside the seizure onset areas, patients' values were adjusted based on normative maps derived from the open-access Montreal Neurological Institute open iEEG Atlas. In a subset of 29 patients who underwent resective surgery, we estimated the predictive value of these features to identify the epileptogenic zone in those with a good postsurgical outcome.

Results

We found that distinct sleep oscillatory and nonoscillatory metrics behave differently across the epileptic network, with the strongest differences observed for (1) a reduction in spindle activity (spindle rates and rhythmic sigma power in the 10–16 Hz band), (2) a higher rhythmic gamma power (30–80 Hz), and (3) a higher H exponent (steeper 1/f slope). As expected, epileptic spikes were also highest in the seizure onset areas. Furthermore, in surgical patients, the H exponent achieved the highest performance (balanced accuracy of .76) for classifying resected versus nonresected channels in good outcome patients.

Significance

This work suggests that nonoscillatory components of the intracranial EEG signal could serve as promising interictal sleep candidates of epileptogenicity in patients with drug-resistant epilepsy. Our findings further advance the understanding of epilepsy as a disease, whereby absence or loss of sleep physiology may provide information complementary to pathological epileptic processes.

目的：除大脑振荡活动外，背景脑电图（EEG）中的非振荡（无标度）成分也可提供有关潜在神经元网络复杂性的进一步信息。由于癫痫被认为是一种网络疾病，这种无标度指标可能有助于划分癫痫网络。在此，我们利用多种发作间期特征对睡眠振荡（纺锤波、慢波和节律频谱功率）和非振荡（H 指数）颅内脑电图进行了分析，以估计 38 名成人耐药性癫痫患者的睡眠振荡和非振荡脑电图是否偏离正常以及如何偏离正常：为了量化发作起始区内外的颅内脑电图异常，根据开放访问的蒙特利尔神经研究所开放 iEEG 图谱得出的常模图调整了患者的数值。在接受切除手术的 29 例患者中，我们估算了这些特征的预测价值，以确定手术后疗效良好的患者的致痫区：我们发现，不同的睡眠振荡和非振荡指标在整个癫痫网络中的表现各不相同，其中差异最大的是：(1) 纺锤体活动的减少（10-16 Hz 频段的纺锤体率和节律性 sigma 功率）；(2) 更高的节律性 gamma 功率（30-80 Hz）；(3) 更高的 H 指数（更陡的 1/f 斜坡）。不出所料，癫痫发作区的癫痫尖峰也是最高的。此外，在手术患者中，H 指数在对结果良好患者的切除与未切除通道进行分类时达到了最高的性能（平衡准确率为 0.76）：这项研究表明，颅内脑电信号的非振荡成分可作为耐药性癫痫患者发作间期睡眠致痫性的候选成分。我们的研究结果进一步加深了人们对癫痫这种疾病的认识，睡眠生理缺失或丧失可提供病理癫痫过程的补充信息。

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引用次数: 0

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development 癫痫发作和癫痫新药进展报告：第 17 届埃拉特抗癫痫新药与新设备会议（EILAT XVII）摘要。II.处于临床开发后期的药物。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-22 DOI: 10.1111/epi.18075

Meir Bialer, Svein I. Johannessen, Matthias J. Koepp, Emilio Perucca, Piero Perucca, Torbjörn Tomson, H. Steve White

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5–8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy-related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, K_V7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic–clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT_2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, −2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Na_v1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo-controlled adjunctive-therapy trial. For the other compounds, adequately powered placebo-controlled efficacy trials have not been completed to date.

第 17 届埃拉特抗癫痫新药与新设备会议于 2024 年 5 月 5-8 日在西班牙马德里举行。与往常一样，本次会议的核心内容是介绍处于不同开发阶段的癫痫相关适应症的研究药物。有关处于临床前或早期临床开发阶段的化合物的信息摘要载于随附出版物（第一部分）。在这篇文章中，我们提供了五种处于临床开发后期的化合物的摘要，即已获得一些有关癫痫患者抗癫痫活性信息的化合物。这些研究治疗药物包括 azetukalner (XEN1101)，这是一种强效、KV7.2/7.3特异性钾通道开启剂，正在开发用于治疗局灶性癫痫发作、全身强直阵挛发作和重度抑郁症；bexicaserin (LP352)，一种选择性 5-HT2C 受体超拮抗剂，正在开发用于治疗与发育性和癫痫性脑病相关的癫痫发作；radiprodil，一种含 NR2B 亚基的 N-甲基-D-天冬氨酸谷氨酸受体的选择性负异位调节剂，正在开发中，用于治疗与 GRIN1、-2A、-2B 或 -2D 基因功能增益突变所致疾病相关的癫痫发作和行为表现；soticlestat (TAK-935)，一种胆固醇 24- 羟化酶选择性抑制剂，正在开发中，用于治疗与德雷维综合征和伦诺克斯-加斯托综合征相关的癫痫发作；以及 STK-001，一种反义寡核苷酸，旨在上调 Nav1.1蛋白的表达并改善德雷维综合征患者的预后。这些药物的作用机制各不相同，说明了在发现癫痫发作和癫痫的新疗法时所采用的不同方法。本报告中讨论的两种化合物（azetukalner 和 soticlestat）已经在随机安慰剂对照辅助治疗试验中获得了临床疗效证据。至于其他化合物，迄今尚未完成充分有效的安慰剂对照疗效试验。

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引用次数: 0

Characteristics of motor vehicle crashes and fatality risk among drivers with epilepsy 机动车碰撞事故的特点和癫痫司机的死亡风险。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-21 DOI: 10.1111/epi.18097

Yu Sun, Meng-Yun Ku, Chih-Ching Liu, Li-Nien Chien

Objective

Among motor vehicle crashes (MVCs), little is known about whether the characteristics and collision features involving drivers with epilepsy differ from those involving drivers without any history of epilepsy. We assessed MVC features and the effect of epilepsy diagnosis on the risk of severe crash-related injuries among drivers.

Methods

A total of 33 174 MVC events among people with epilepsy (PWE) and 663 480 MVC events of age- and sex-matched non-PWE (1:20) were selected. Crash-related features that involved drivers with and without epilepsy were compared, including driver eligibility, medical history of comorbidities and medications, road and environmental conditions, and accident causes. Cox and logistic regression analyses were used to examine the risks of fatality and severe injury among drivers with and without epilepsy.

Results

PWE involved in MVCs were more likely to have lower socioeconomic status, comorbidities, scooter drivers without a qualified driver's license, driving under the influence of alcohol, and be involved in single-vehicle accidents than non-PWE. Drivers with epilepsy also had a higher risk of fatality within 30 days of MVC, with an adjusted hazard ratio (aHR) of 1.37 (95% confidence interval [CI], 1.20–1.57) and a higher risk of hospital admission within 3 days after MVC (aHR, 1.33; 95% CI, 1.29–1.38) compared to that of non-PWE.

Significance

The characteristics of MVCs of drivers with epilepsy were distinct from those of non-affected drivers. And higher fatality and injury rates were observed among drivers with epilepsy, which should be considered in further policymaking regarding safe driving of PWE.

目的：在机动车碰撞事故（MVCs）中，人们对患有癫痫的驾驶员与没有癫痫病史的驾驶员在特征和碰撞特征上是否存在差异知之甚少。我们评估了机动车碰撞的特征以及癫痫诊断对驾驶员在碰撞中严重受伤风险的影响：方法：我们选取了33 174起癫痫患者（PWE）与663 480起年龄和性别匹配的非癫痫患者（1:20）的机动车碰撞事故。比较了有癫痫和无癫痫的驾驶员的碰撞相关特征，包括驾驶员资格、合并症和药物的病史、道路和环境条件以及事故原因。采用Cox和Logistic回归分析来研究有癫痫和无癫痫司机的死亡和重伤风险：结果：与非癫痫患者相比，卷入机动车碰撞事故的癫痫患者更有可能社会经济地位较低、患有合并症、没有合格驾驶执照、在酒精影响下驾驶滑板车以及卷入单车事故。与非 PWE 相比，患有癫痫的驾驶员在发生交通事故后 30 天内死亡的风险也更高，调整后的危险比（aHR）为 1.37（95% 置信区间 [CI]，1.20-1.57），在发生交通事故后 3 天内入院的风险也更高（aHR，1.33；95% CI，1.29-1.38）：重要意义：患有癫痫的驾驶员与未患癫痫的驾驶员在发生车祸时的特征截然不同。癫痫症驾驶者的死亡率和受伤率都较高，在制定有关残疾人安全驾驶的进一步政策时应考虑到这一点。

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引用次数: 0

High-gamma modulation language mapping and cognitive outcomes after epilepsy surgery 高伽马调制语言图谱与癫痫手术后的认知结果。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-20 DOI: 10.1111/epi.18096

Brian Ervin, Christina Kargol, Anna W. Byars, Jason Buroker, Leonid Rozhkov, Jesse Skoch, Francesco T. Mangano, Hansel M. Greiner, Paul S. Horn, Katherine Holland, Ravindra Arya

Objective

We evaluated changes in cognitive domains after neurosurgical lesioning of cortical sites with significant high-gamma power modulations (HGM) during a visual naming task, although these sites were found language-negative on standard-of-care electrical stimulation mapping (ESM).

Methods

In drug-resistant epilepsy patients who underwent resection/ablation after stereo-electroencephalography (SEEG), we computed reliable change indices (RCIs) from a battery of presurgical and 1-year postsurgical neuropsychological assessments. We modeled RCIs as a function of lesioning even one HGM language site, number of HGM language sites lesioned, and the magnitude of naming-related HGM. The analyses were adjusted for 1-year seizure freedom, operated hemispheres, and the volumes of surgical lesions.

Results

In 37 patients with 4455 SEEG electrode contacts (1839 and 2616 contacts in right and left hemispheres, respectively), no ESM language sites were lesioned. Patients with lesioning of even one HGM language site showed significantly lower RCIs for Peabody Picture Vocabulary Test (PPVT), working memory, and verbal learning immediate (VLI) scores. RCI declines with higher number of HGM language sites lesioned were seen in PPVT (slope [β] = −.10), working memory (β = −.10), VLI (β = −.14), and letter–word identification (LWI; β = −.14). No neuropsychological domains improved after lesioning of HGM language sites. Significant effects of the HGM magnitude at lesioned sites were seen on working memory (β = −.31), story memory immediate (β = −.27), verbal learning recognition (β = −.18), LWI (β = −.16), spelling (β = −.49), and passage comprehension (β = −.33). Because working memory was significantly affected in all three analyses, patients with maximal working memory decline were examined post hoc, revealing that all such patients had HGM naming sites lesioned in the posterior quadrants of either hemisphere.

Significance

HGM language mapping should be used as an adjunct to ESM in clinical practice and may help counsel patients/families about postsurgical cognitive deficits.

目的我们评估了在视觉命名任务中对具有显著高伽马功率调制（HGM）的皮层部位进行神经外科病变后认知领域的变化，尽管这些部位在标准护理电刺激图谱（ESM）中被发现语言阴性：在立体脑电图（SEEG）后接受切除/消融术的耐药性癫痫患者中，我们通过一系列手术前和手术后一年的神经心理学评估计算出了可靠的变化指数（RCIs）。我们将 RCIs 作为甚至一个 HGM 语言部位病变、HGM 语言部位病变数量以及与命名相关的 HGM 程度的函数进行建模。分析对 1 年癫痫发作自由度、手术半球和手术病变体积进行了调整：结果：在 37 名有 4455 个 SEEG 电极接触点的患者中（右半球和左半球的接触点分别为 1839 个和 2616 个），没有任何 ESM 语言点发生病变。哪怕只有一个 HGM 语言位点发生病变的患者，其皮博迪图画词汇测试 (PPVT)、工作记忆和即时言语学习 (VLI) 分数的 RCI 都明显较低。PPVT（斜率 [β] = -.10）、工作记忆（β = -.10）、VLI（β = -.14）和字母-单词识别（LWI；β = -.14）的 RCI 随病变的 HGM 语言位点数量增加而下降。对 HGM 语言位点进行病变后，神经心理领域均无改善。病变部位的 HGM 大小对工作记忆（β = -.31）、即时故事记忆（β = -.27）、言语学习识别（β = -.18）、LWI（β = -.16）、拼写（β = -.49）和段落理解（β = -.33）有显著影响。由于工作记忆在所有三项分析中都受到明显影响，因此对工作记忆衰退程度最大的患者进行了事后研究，结果发现所有这些患者的 HGM 命名部位都在任一大脑半球的后象限：意义：在临床实践中，HGM语言图谱应作为ESM的辅助手段，并可帮助患者/家属了解手术后的认知障碍。

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引用次数: 0

Combined value of interictal markers and stimulated seizures to estimate the seizure onset zone in stereoelectroencephalography 在立体脑电图中结合发作间期标记物和刺激性癫痫发作来估计癫痫发作起始区的价值。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-20 DOI: 10.1111/epi.18083

Lauri Rekola, Maria Peltola, Jukka Vanhanen, Juha Wilenius, Eeva-Liisa Metsähonkala, Leena Kämppi, Leena Lauronen, Päivi Nevalainen

Objective

This study was undertaken to investigate the potential of interictal electroencephalographic (EEG) findings and electrically stimulated seizures during stereo-EEG (SEEG) as surrogate markers for the spontaneous seizure onset zone (spSOZ). We hypothesized that combining the localizing information of these markers would allow clinically meaningful estimation of the spSOZ.

Methods

We included all patients (n = 63) who underwent SEEG between January 2013 and March 2020 at Helsinki University Hospital and had spontaneous seizures during the recording. We scored spikes, gamma activity, and background abnormality on each channel visually during a 12-h epoch containing waking state and sleep. Based on semiology, we classified stimulated seizures as typical or atypical/unclassifiable and estimated the stimulated SOZ (stimSOZ) for typical seizures. To assess which markers increased the odds of channel inclusion in the spSOZ, we fitted mixed effects logistic regression models.

Results

A combined regression model including the stimSOZ and interictal markers scored during sleep performed better in estimating which channels were part of the spSOZ than models based on stimSOZ (p < .001) or interictal markers (p < .001) alone. Of the individual markers, the effect sizes were greatest for inclusion of a channel in the stimSOZ (odds ratio [OR] = 60, 95% confidence interval [CI] = 37–97, p < .001) and for continuous (OR = 25, 95% CI = 12–55, p < .001) and subcontinuous (OR = 36, 95% CI = 21–64, p < .001) interictal spiking. At the individual level, the model's accuracy to predict spSOZ inclusion varied markedly (median accuracy = 85.7, range = 54.4–100), which was not explained by etiology (p > .05).

Significance

Compared to either marker alone, combining visually rated interictal SEEG markers and stimulated seizures improved prediction of which SEEG channels belonged to the spSOZ. Inclusion in the stimSOZ and continuous or subcontinuous spikes increased the odds of spSOZ inclusion the most. Future studies should investigate whether suboptimal sampling of the true epileptogenic zone can explain the model's poor performance in certain patients.

研究目的本研究旨在调查发作间期脑电图（EEG）结果和立体脑电图（SEEG）期间电刺激癫痫发作作为自发性癫痫发作起始区（spSOZ）替代标记的潜力。我们假设，将这些标记的定位信息结合起来，就能对 spSOZ 进行有临床意义的估计：我们纳入了 2013 年 1 月至 2020 年 3 月期间在赫尔辛基大学医院接受 SEEG 且在记录期间有自发癫痫发作的所有患者（n = 63）。在包含清醒状态和睡眠状态的 12 小时内，我们对每个通道上的尖峰、伽马活动和背景异常进行了视觉评分。根据符号学，我们将受刺激的癫痫发作分为典型或非典型/不可分类，并估算出典型癫痫发作的受刺激 SOZ（stimSOZ）。为了评估哪些标记物会增加通道被纳入刺激性 SOZ 的几率，我们建立了混合效应逻辑回归模型：结果：在估计哪些通道属于 spSOZ 的一部分时，包括刺激 SOZ 和睡眠时发作间期标记物的组合回归模型比基于刺激 SOZ 的模型表现更好（p .05）：与单独使用其中一种标记物相比，将视觉评分的发作间期 SEEG 标记物和刺激性癫痫发作结合在一起能更好地预测哪些 SEEG 通道属于 spSOZ。纳入刺激SOZ和连续或亚连续尖峰增加了纳入spSOZ的几率。未来的研究应探讨真正致痫区的次优取样是否可以解释该模型在某些患者中表现不佳的原因。

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引用次数: 0

Predictors of drug-resistant epilepsy in childhood epilepsy syndromes: A subgroup analysis from a prospective cohort study 儿童癫痫综合征耐药性癫痫的预测因素：一项前瞻性队列研究的分组分析。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-16 DOI: 10.1111/epi.18100

Dana Ayoub, Fatima Jaafar, Amal Al-Hajje, Pascale Salameh, Jeremy Jost, Ghassan Hmaimess, Jaafar Wazne, Zein Ismail-Fawaz, Sandra Sabbagh, Farid Boumediene, Ahmad Beydoun

Objective

Previous studies assessing factors associated with drug-resistant epilepsy (DRE) were constrained by their amalgamation of all epilepsy syndromes in their analyses and the absence of uniform criteria for defining DRE. Our objective was to identify predictors of DRE among the four primary childhood epilepsy syndrome groups within a cohort of children with new onset seizures, using the International League Against Epilepsy (ILAE) definition of DRE and the recent classification of epilepsies.

Methods

This is a prospective study of 676 children with new onset seizures initiated on antiseizure medication. Patients were monitored for the occurrence of DRE according to the ILAE criteria and were categorized into one of four epilepsy groups: self-limited focal epilepsies (SeLFEs), genetic generalized epilepsies (GGEs), developmental epileptic encephalopathies (DEEs), and focal epilepsies. Cox regression analysis was performed to identify predictors of DRE within each epilepsy group.

Results

Overall, 29.3% of children were classified as having DRE, with the highest incidence observed among children diagnosed with DEEs (77.7%), followed by focal epilepsies (31.5%). Across the entire cohort, predictors of DRE included the presence of an epileptogenic lesion, a higher pretreatment number of seizures, experiencing multiple seizure types, presence and severity of intellectual and developmental delay, myoclonus, and younger age at epilepsy onset. Within the GGEs, only a younger age at seizure onset and experiencing multiple seizure types predicted DRE. Among focal epilepsies, predictors of DRE included the presence of an epileptogenic lesion, experiencing multiple seizure types, and having a greater number of pretreatment seizures. Within the DEEs, predictors of DRE were the occurrence of tonic seizures. Predictors of DRE within SeLFEs could not be identified.

Significance

This study indicates that different epilepsy syndromes are associated with distinct predictors of drug resistance. Anticipation of drug resistance within various groups is feasible using accessible clinical variables throughout the disease course.

研究目的以往评估耐药性癫痫（DRE）相关因素的研究受到了限制，因为它们在分析中合并了所有癫痫综合征，而且缺乏定义 DRE 的统一标准。我们的目标是采用国际抗癫痫联盟（ILAE）对 DRE 的定义和最新的癫痫分类，在新发癫痫儿童队列中确定四个主要儿童癫痫综合征组中 DRE 的预测因素：这是一项前瞻性研究，研究对象是 676 名开始服用抗癫痫药物的新发癫痫发作儿童。根据ILAE标准监测患者是否出现DRE，并将其分为四类癫痫：自限性局灶性癫痫（SeLFEs）、遗传性全身性癫痫（GGEs）、发育性癫痫性脑病（DEEs）和局灶性癫痫。对每个癫痫组别进行了Cox回归分析，以确定DRE的预测因素：总体而言，29.3%的儿童被归类为患有DRE，其中诊断为DEEs的儿童发病率最高（77.7%），其次是局灶性癫痫（31.5%）。在整个队列中，预测 DRE 的因素包括存在致痫病灶、治疗前癫痫发作次数较多、经历多种癫痫发作类型、存在智力和发育迟缓及其严重程度、肌阵挛以及癫痫发病年龄较小。在普通癫痫患者中，只有发病年龄较小和经历多种癫痫发作类型才能预测 DRE。在局灶性癫痫中，预测 DRE 的因素包括存在致痫病灶、经历多种发作类型以及治疗前发作次数较多。在DEEs中，强直性发作是DRE的预测因素。在 SeLFEs 中，无法确定 DRE 的预测因素：这项研究表明，不同的癫痫综合征与不同的耐药性预测因素有关。利用整个病程中可获得的临床变量来预测不同群体的耐药性是可行的。

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引用次数: 0

Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity 鉴定一种新的瑞替加滨衍生物，它具有更好的光稳定性，可选择性激活神经元 Kv7 通道并具有抗癫痫活性。

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia

Pub Date : 2024-08-14 DOI: 10.1111/epi.18092

Hongbin Wang, Zhen Qiao, Kun Luan, Wei Xiang, Xiuying Chang, Yanru Zhang, Ningning Wei, KeWei Wang

Objective

Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, N,N′-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide).

Methods

Whole-cell recordings were used to evaluate Kv7 channel openers. Site-directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ-induced kindling were utilized to test compound antiepileptic activity.

Results

The novel compound 1025c selectively activates whole-cell Kv7.2/7.3 currents in a concentration-dependent manner, with half-maximal effective concentration of .91 ± .17 μmol·L⁻¹. The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV_1/2) of −18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose-dependent antiseizure activities in assays of MES, scPTZ, and PTZ-induced kindling models. Moreover, through site-directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c-mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize.

Significance

Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.

目的：抗癫痫药物雷替加滨（Retigabine，RTG；ezogabine）对神经元 Kv7 通道的药理激活已被证实对治疗部分性癫痫有效。然而，RTG 因其吩嗪二聚体代谢物导致外周皮肤变色和视网膜异常的毒性而退出市场。为了解决RTG的不良代谢特性并防止吩嗪二聚体的形成，我们对RTG进行了化学修饰，得到了一种新的RTG衍生物1025c，即N,N'-{4-[(4-氟苄基)(丙-2-炔-1-基)氨基]-1,2-亚苯基}双(3,3-二甲基丁酰胺)：全细胞记录用于评估 Kv7 通道开放剂。采用定点突变和分子对接研究 1025c 与 Kv7.2 相互作用的分子机制。利用最大电击（MES）、皮下注射戊四唑（scPTZ）和PTZ诱发的小鼠癫痫发作模型来测试化合物的抗癫痫活性：结果：新型化合物 1025c 以浓度依赖性方式选择性激活全细胞 Kv7.2/7.3 电流，半最大有效浓度为 .91 ± .17 μmol-L-1。1025c 化合物还能使 Kv7.2/7.3 电流活化向更高超极化膜电位左移，最大活化半电压（ΔV1/2）为 -18.6 ± 3.0 mV。在MES、scPTZ和PTZ诱导的激怒模型试验中，腹腔注射1025c显示出剂量依赖性抗癫痫活性。此外，通过定点突变和分子对接，确定了 Trp236 这一关键残基对 1025c 介导的 Kv7.2 通道激活至关重要。光稳定性实验进一步揭示，1025c 比 RTG 具有更高的光稳定性，并且不能二聚：我们的研究结果表明，1025c对神经元Kv7通道具有强效的选择性激活作用，且不会被代谢为酚嗪二聚体，这表明它具有作为抗癫痫治疗药物的发展潜力。

{"title":"Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity","authors":"Hongbin Wang, Zhen Qiao, Kun Luan, Wei Xiang, Xiuying Chang, Yanru Zhang, Ningning Wei, KeWei Wang","doi":"10.1111/epi.18092","DOIUrl":"10.1111/epi.18092","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, <i>N,N′</i>-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Whole-cell recordings were used to evaluate Kv7 channel openers. Site-directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ-induced kindling were utilized to test compound antiepileptic activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The novel compound 1025c selectively activates whole-cell Kv7.2/7.3 currents in a concentration-dependent manner, with half-maximal effective concentration of .91 ± .17 μmol·L<sup>−1</sup>. The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV<sub>1/2</sub>) of −18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose-dependent antiseizure activities in assays of MES, scPTZ, and PTZ-induced kindling models. Moreover, through site-directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c-mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Significance</h3>\u0000 \u0000 <p>Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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