The human photosensitive epilepsy model for clinical proof-of-principle trials of novel antiseizure medications. 1. Use of the EEG in drug development and characteristics of the model

用于新型抗癫痫药物临床原理验证试验的人类光敏性癫痫模型。1. 脑电图在药物研发中的应用及模型特点

Clinical development of novel antiseizure medications (ASMs) would benefit from an early proof-of-principle (POP) model. The photosensitivity model, which uses the photoparoxysmal electroencephalography (EEG) response (PPR) as a surrogate for seizures, is currently the only human model that allows POP trials of investigational compounds after a single drug administration. Typically, trials in this model are performed as single-blinded, placebo-controlled Phase IIa POP studies, evaluating a range of doses in small groups of patients with epilepsy. Although most patients in such trials exhibit generalized epilepsies, photosensitivity also occurs in focal-onset epilepsies. In the first part of this review, we describe the use of epileptiform discharges in drug testing, historical development of the photosensitivity model, the genetics and pathophysiology underlying the photosensitive response in patients with epilepsy, clinical characteristics of the patients, and details on drug testing. In the second part of this review, the outcome of numerous drug trials will be described in detail, including a critical discussion of the limitations of the model. In the past 50 years, the original and later standardized photosensitivity model has shown to be an unbiased, accurate, inexpensive method determining the potential efficacy of a novel ASM before entering large add-on trials with chronic drug administration, irrespective of the type of epilepsy.

新型抗癫痫药物（ASM）的临床开发将受益于早期原理验证（POP）模型。光敏性模型以光阵发脑电图（EEG）反应（PPR）作为癫痫发作的替代指标，是目前唯一允许在单次给药后对研究性化合物进行原理验证试验的人体模型。通常，该模型的试验以单盲、安慰剂对照的 IIa 期原理验证研究形式进行，在小样本癫痫患者群体中评估一系列剂量。尽管此类试验中的大多数患者患有全身性癫痫，但光敏性也可见于局灶性癫痫。在本综述的第一部分，我们将介绍癫痫样放电在药物测试中的应用、光敏性模型的历史发展、癫痫患者光敏反应的遗传学和病理生理学基础、患者的临床特征以及药物测试的细节。在本综述的第二部分，将详细描述众多药物试验的结果，包括对该模型局限性的批判性讨论。在过去 50 年中，最初的以及后来标准化的光敏性模型已被证明是一种公正、准确、经济的方法，可在开展长期药物给药的大型附加试验之前确定新型抗癫痫药物的潜在疗效，且与癫痫类型无关。

REF: Kasteleijn-Nolst Trenité D, Löscher W. The human photosensitive epilepsy model for clinical proof-of-principle trials of novel antiseizure medications. 1. Use of the EEG in drug development and characteristics of the model. Epilepsia. 2025;66(8):2605-2618. doi:10.1111/epi.18468 PMID: 40411480

The human photosensitive epilepsy model for clinical proof-of-principle trials of novel antiseizure medications: 2. Analysis of drug trials and predictive value of the model

用于新型抗癫痫药物临床原理验证试验的人类光敏性癫痫模型：2. 药物试验分析及模型的预测价值

Clinical development of novel antiseizure medications (ASMs) would benefit from an early proof of principle (POP) model. The photosensitivity model, which uses the photoparoxysmal electroencephalographic response (PPR) as a surrogate of seizures, is currently the only human model that allows POP trials of investigational compounds after a single drug administration. Typically, trials in this model are performed as single-blinded, placebo-controlled phase IIa POP studies, evaluating a range of doses in small groups of epilepsy patients. In the second part of this review, based on the background information provided in Part 1, we analyze the outcome of all published trials performed over roughly 50 years. Many of the 35 drugs tested in the model were also examined in traditional add-on trials in patients with epilepsy, thus allowing analysis of the predictivity of the model. Drugs were categorized into three groups: drugs that suppressed PPR; drugs that exerted no effect on PPR; and drugs that increased PPR, indicating a proconvulsant effect. For the vast majority of drugs, the model correctly predicted the drugs' activity during long-term studies in patients with different types of epilepsy, including focal onset epilepsies. For some investigational compounds, the model detected proconvulsant activity that had not been observed in preclinical animal experiments and phase I studies in healthy volunteers, demonstrating the value of the model for adverse event assessment in patients with epilepsy. Limitations of the model are that it does not predict the extent of drug resistance of patients' seizures during chronic administration or efficacy differentiation of the novel drug from existing ASMs. Photosensitive POP trials are a useful tool to quantitatively predict drug efficacy and in aiding dose selection for subsequent larger phase IIb trials with chronic drug administration.

新型抗癫痫药物（ASM）的临床开发将受益于早期原理验证（POP）模型。光敏性模型以光阵发性脑电图反应（PPR）作为癫痫发作的替代指标，是目前唯一允许在单次给药后对研究性化合物进行POP试验的人体模型。通常，该模型的试验是以单盲、安慰剂对照的IIa期POP研究形式开展，在小规模癫痫患者群体中评估一系列剂量。在本综述的第二部分，基于第一部分提供的背景信息，我们分析了大约50年来所有已发表试验的结果。在该模型中测试的35种药物中，许多也在传统的癫痫患者附加治疗试验中进行了研究，从而能够分析该模型的预测性。药物被分为三组：抑制PPR的药物；对PPR无影响的药物；以及增加PPR、显示出促惊厥作用的药物。对于绝大多数药物，该模型正确预测了药物在不同类型癫痫（包括局灶性癫痫发作）患者长期研究中的活性。对于一些研究性化合物，该模型检测到了在临床前动物实验和健康志愿者I期研究中未观察到的促惊厥活性，证明了该模型在癫痫患者不良事件评估中的价值。该模型的局限性在于，它无法预测患者在长期用药期间癫痫发作的耐药程度，也无法区分新型药物与现有ASM的疗效差异。光敏性POP试验是一种有用的工具，可定量预测药物疗效，并有助于为后续更大规模的慢性给药IIb期试验选择剂量。

REF: Löscher W, Trenité DK. The human photosensitive epilepsy model for clinical proof-of-principle trials of novel antiseizure medications: 2. Analysis of drug trials and predictive value of the model. Epilepsia. 2025;66(8):2619-2638. doi:10.1111/epi.18444 PMID: 40347110

Effects of antiseizure medications on sexual hormones and functions in males with epilepsy: A systematic review and meta-analysis

抗癫痫药物对男性癫痫患者性激素及性功能的影响：一项系统评价和荟萃分析

The fertility effects of antiseizure medications (ASMs) have been highlighted in females of reproductive age; however, the effects in males have not been extensively analyzed. This review aims to summarize the existing evidence of how ASMs affect sexual hormones and functions in males with epilepsy. We searched the Embase, PubMed, and MEDLINE databases in January 2024 to identify studies measuring sexual hormones, sexual function, or sperm parameters of males with epilepsy taking any ASM except valproic acid who were compared to a control group. A systematic review summarizing the effects of valproic acid on sexual function was published in 2018; therefore, we excluded valproic acid to avoid duplicating existing evidence. Risk of bias assessments were specific to the study type and included the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, NIH Quality Assessment Tool for Before-After (Pre-Post) Studies, and Cochrane Risk of Bias-2 tool for randomized trials. The systematic review included 32 studies, and the meta-analysis included 22 studies. Using random effect models, we calculated mean differences or rate ratios for studies assessing the association between ASMs and male sexual hormones or functions. Analyses were run for each combination of individual ASM or ASM characteristic, outcome, and comparison group. Males taking oxcarbazepine had significantly higher levels of testosterone, luteinizing hormone, and follicle-stimulating hormone compared to healthy controls. Conversely, there was no evidence of differences in any outcomes between levetiracetam or lamotrigine and comparison groups. Analyses that included untreated males with epilepsy rarely differed from males taking ASMs, highlighting the potential importance of epilepsy on altered sex hormones and functions. However, results should be interpreted cautiously, as many analyses included only a few studies and had high heterogeneity.

抗癫痫药物（ASMs）对育龄女性生育能力的影响已受到广泛关注；然而，其对男性的影响尚未得到充分分析。本综述旨在总结现有关于抗癫痫药物如何影响男性癫痫患者性激素和性功能的证据。2024年1月，我们检索了Embase、PubMed和MEDLINE数据库，以确定那些测量服用除丙戊酸以外任何抗癫痫药物的男性癫痫患者性激素、性功能或精子参数，并与对照组进行比较的研究。2018年已发表了一篇系统综述总结丙戊酸对性功能的影响；因此，我们排除丙戊酸以避免重复现有证据。偏倚风险评估针对研究类型进行，包括美国国立卫生研究院（NIH）观察性队列和横断面研究质量评估工具、NIH前后（干预前后）研究质量评估工具，以及Cochrane随机试验偏倚风险-2工具。系统综述纳入了32项研究，荟萃分析纳入了22项研究。我们使用随机效应模型，计算评估抗癫痫药物与男性性激素或性功能之间关联的研究的均值差或率比。针对每种抗癫痫药物或抗癫痫药物特征、结局和比较组的组合进行分析。与健康对照组相比，服用奥卡西平的男性睾酮、促黄体生成素和促卵泡生成素水平显著更高。相反，左乙拉西坦或拉莫三嗪与对照组在任何结局上均无差异。纳入未接受治疗的男性癫痫患者的分析结果与服用抗癫痫药物的男性很少有差异，这凸显了癫痫对性激素和性功能改变的潜在重要性。然而，应谨慎解读这些结果，因为许多分析仅纳入了少数研究，且异质性较高。

REF: Couper RG, Espino PH, Vicuna MP, Burneo JG. Effects of antiseizure medications on sexual hormones and functions in males with epilepsy: A systematic review and meta-analysis. Epilepsia. 2025;66(8):2639-2656. doi:10.1111/epi.18436 PMID: 40325998

Electroconvulsive therapy for super refractory status epilepticus: A scoping review

电休克疗法治疗超级难治性癫痫持续状态：一项范围综述

Status epilepticus (SE) is a neurologic emergency. Although evidence-based treatments exist for SE, treatment of refractory status epilepticus (RSE) and super refractory status epilepticus (SRSE) lacks evidence. Electroconvulsive therapy (ECT) is safe and efficacious when used to treat psychiatric disorders. Seizure control attributed to ECT in the setting of SRSE has been reported in case reports and case series. The objective of this scoping review was to understand the current knowledge regarding the safety and efficacy of ECT in aborting SRSE in the adult and pediatric populations. Differences between adult and pediatric patients who are treated with electroconvulsive therapy (ECT) for SRSE could reflect a combination of factors, including logistical and regulatory barriers that limit use of ECT in intensive care units (ICUs). Prospective, randomized controlled trials are needed to fully understand the risks vs benefits of ECT for SRSE compared to other treatments.

癫痫持续状态（SE）是一种神经系统急症。尽管针对SE有循证治疗方法，但难治性癫痫持续状态（RSE）和超难治性癫痫持续状态（SRSE）的治疗缺乏相关证据。电休克治疗（ECT）在治疗精神疾病方面安全有效。已有病例报告和病例系列报道了在SRSE情况下ECT对癫痫发作的控制作用。本范围综述的目的是了解当前关于ECT在成人和儿童人群中终止SRSE的安全性和有效性的知识。接受电休克治疗（ECT）治疗SRSE的成人和儿童患者之间的差异可能反映了多种因素的综合作用，包括限制在重症监护病房（ICU）使用ECT的后勤和监管障碍。需要进行前瞻性随机对照试验，以全面了解与其他治疗方法相比，ECT治疗SRSE的风险与获益情况。

REF: Dowd DK, Nunes D, Shah PD, Pardo AC. Electroconvulsive therapy for super refractory status epilepticus: A scoping review. Epilepsia. 2025;66(8):2657-2668. doi:10.1111/epi.18432 PMID: 40317487

Achieving epilepsy care for all: Ecosystem-based transformation

实现全民癫痫护理：基于生态系统的变革

Epilepsy exemplifies many of the systemic challenges of modern health care-fragmented care delivery, inequitable access, financial strain, and so on. The current "system of systems" (SoS) structure of U.S. health care fosters siloed operations among its member systems (e.g., insurers, health care institutions, providers, researchers, pharmaceutical companies, and technology vendors), failing to address interconnected issues like care continuity, clinician burnout, and appropriate resource allocation. This article proposes embracing a health care ecosystem approach as a solution, emphasizing interdependence, collaboration, and equity. Section 1 examines the shortcomings of the current care model, with a focus on its financial challenges and the systemic inefficiencies it perpetuates. Section 2 explains the concept of a health care ecosystem and its potential to drive equity through organic coordination and collective accountability. It highlights the role of key member systems-patients, advocacy groups, professional organizations, health care providers, payers, purchasers, policymakers, researchers, and industry leaders-in achieving equity in brain health care. Finally, Section 3 presents a roadmap for transitioning from SoS to ecosystem, outlining multiple actionable strategies, such as enhancing advocacy and data sharing by professional organizations, adopting integrated and multidisciplinary care models by health care providers, and prioritizing affordability and collaboration by industry leaders. Policymakers and federal research organizations can support the transition by incentivizing collaboration, expanding funding for health services research, and supporting data-driven decision-making. Advocacy groups can amplify collective voices and help prioritize improvement opportunities. Using epilepsy care as an example condition, this article argues that coordinated, multi-sector, and multi-level efforts can successfully and efficiently address systemic challenges, improve outcomes, and reduce inequities. It offers a replicable framework for achieving sustainable, scalable, and equitable care for chronic neurological conditions.

癫痫体现了现代医疗保健的诸多系统性挑战，如医疗服务分散、就医机会不均、经济压力等。美国医疗保健目前的“系统之系统”（SoS）结构导致其成员系统（如保险公司、医疗机构、医疗服务提供者、研究人员、制药公司和技术供应商）各自为政，无法解决诸如医疗连续性、临床医生职业倦怠和资源合理分配等相互关联的问题。本文提出采用医疗生态系统方法作为解决方案，强调相互依存、协作和公平。第一部分探讨了当前医疗模式的缺陷，重点关注其面临的经济挑战以及该模式所造成的系统性低效。第二部分解释了医疗生态系统的概念及其通过自然协调和集体问责来推动公平的潜力。它强调了关键成员系统（患者、倡导团体、专业组织、医疗服务提供者、支付方、购买方、政策制定者、研究人员和行业领袖）在实现脑健康护理公平方面的作用。最后，第三部分提出了从“系统之系统”向生态系统转型的路线图，列出了多项可实施的策略，例如专业组织加强宣传和数据共享，医疗服务提供者采用综合多学科医疗模式，以及行业领袖优先考虑可负担性和协作。政策制定者和联邦研究机构可以通过激励协作、增加对卫生服务研究的资金投入以及支持基于数据的决策来支持这一转型。倡导团体可以凝聚各方声音，帮助确定改进重点。本文以癫痫护理为例，认为通过协调的、多部门和多层次的努力，可以成功且高效地应对系统性挑战、改善治疗效果并减少不公平现象。它提供了一个可复制的框架，以实现对慢性神经系统疾病的可持续、可扩展和公平的护理。

REF: Gallani S, Martin Lee B, Moura LMVR. Achieving epilepsy care for all: Ecosystem-based transformation. Epilepsia. 2025;66(8):2669-2678. doi:10.1111/epi.18400 PMID: 40184165

Frequency-specific alterations in brain connectivity induced by pulvinar stimulation

丘脑枕刺激诱发的脑连接频率特异性改变

Deep brain stimulation (DBS) is emerging as a promising therapy for patients with drug-resistant epilepsy, particularly those who are either unsuitable for or unresponsive to resective surgery. The potential benefit of DBS in these patients may stem from its ability to reduce excessive brain functional connectivity (FC). Given that patients undergoing presurgical evaluation in our institution are implanted with stereoelectroencephalographic (SEEG) electrodes in the thalamus, specifically in the pulvinar medialis (PuM), our aim was to investigate the impact of different stimulation frequencies on brain FC. We sought to determine whether specific frequencies were more effective in modulating FC. These results underscore the potential of high-frequency stimulation to decrease interictal FC in epilepsy patients, although intermediate frequencies may exacerbate it and warrant caution. Crucially, this study highlights the effects of PuM stimulation on FC patterns, supporting the role of high-frequency thalamic stimulation as a promising DBS parameter for improving epilepsy management strategies.

深部脑刺激（DBS）正逐渐成为一种有前景的治疗药物难治性癫痫患者的疗法，尤其是那些不适合接受切除性手术或对其无反应的患者。DBS对这些患者的潜在益处可能源于其降低大脑过度功能连接（FC）的能力。鉴于在我院接受术前评估的患者会在丘脑，特别是丘脑枕内侧核（PuM）植入立体脑电图（SEEG）电极，我们的目的是研究不同刺激频率对大脑FC的影响。我们试图确定特定频率是否在调节FC方面更有效。这些结果强调了高频刺激降低癫痫患者发作间期FC的潜力，尽管中频刺激可能会加重这种情况，需要谨慎使用。至关重要的是，这项研究凸显了PuM刺激对FC模式的影响，支持高频丘脑刺激作为一种有前景的DBS参数，可用于改善癫痫管理策略。

REF: Acerbo E, Jegou A, Lagarde S, et al. Frequency-specific alterations in brain connectivity induced by pulvinar stimulation. Epilepsia. 2025;66(8):2690-2702. doi:10.1111/epi.18405 PMID: 40252213

Impact of epilepsy surgery on the adaptive behavior of children with drug-resistant epilepsy

癫痫手术对耐药性癫痫患儿适应行为的影响

This study was undertaken to assess the impact of surgical treatment on the adaptive abilities of children with drug-resistant epilepsy (DRE) and moderate or severe developmental delays, and to identify factors that could potentially predict adaptive outcomes following epilepsy surgery. Before surgery, patients exhibited severe adaptive delays, with an average age equivalence (AE) of 18.2 months compared to an average chronological age of 78 months. Postoperatively, significant improvements in AE were observed, particularly among patients who achieved seizure freedom (Engel class I). At the first postoperative evaluation (median of 15 months after surgery), the average AE increased to 24.1 months (p < .01). At the second postoperative evaluation (median of 34 months after surgery), the average AE further increased to 27.5 months. Seizure-free patients demonstrated greater improvements in adaptive skills compared to those who continued to experience seizures (F = 5.845, p = .018) SIGNIFICANCE: This study reinforces that epilepsy surgery can lead to significant adaptive improvements in children with DRE, including those with severe neurological impairments. The findings highlight the positive impact of seizure freedom on developmental progress and underscore the importance of early intervention to minimize adaptive delays.

本研究旨在评估手术治疗对耐药性癫痫（DRE）且伴有中度或重度发育迟缓儿童适应能力的影响，并确定可能预测癫痫手术后适应能力转归的因素。手术前，患者存在严重的适应能力迟缓，平均年龄当量（AE）为18.2个月，而实际平均年龄为78个月。术后，观察到年龄当量有显著改善，尤其是在实现无癫痫发作（恩格尔分级I级）的患者中。在首次术后评估时（术后中位时间15个月），平均年龄当量增至24.1个月（p < 0.01）。在第二次术后评估时（术后中位时间34个月），平均年龄当量进一步增至27.5个月。与仍有癫痫发作的患者相比，无癫痫发作的患者在适应技能方面有更大改善（F = 5.845，p = 0.018）。研究意义：本研究进一步证实，癫痫手术可使耐药性癫痫儿童，包括患有严重神经功能障碍的儿童，在适应能力方面得到显著改善。研究结果凸显了无癫痫发作对发育进程的积极影响，并强调了早期干预对于减少适应能力迟缓的重要性。

REF: Oliveira AVD, Machado HR, Thomé Ú, et al. Impact of epilepsy surgery on the adaptive behavior of children with drug-resistant epilepsy. Epilepsia. 2025;66(8):2703-2714. doi:10.1111/epi.18437 PMID: 40298922

Comparison of children and adults undergoing subdural grid electrode implantation or stereoelectroencephalography in a refractory epilepsy cohort from four European centers

欧洲四家医疗中心难治性癫痫队列中接受硬膜下栅状电极植入或立体定向脑电图检查的儿童与成人的比较

Children with refractory focal epilepsy differ from adults, although many centers will offer invasive electroencephalography (iEEG) to both. Outcomes in terms of likelihood of resection and subsequent seizure outcome after either subdural grid electrode implantation (SDE) or stereoelectroencephalography (SEEG) have, however, not been directly compared between age groups. Either iEEG technique provides an equally valid but very different road to success, with no difference in seizure outcome between the two age groups, but with higher risk of complications in SDE. We found similar surgical results for dissimilar techniques and a higher threshold for children. In case of an assumed lower chance of focality of epilepsy or chance of seizure freedom after resection, adults were more often explored with iEEG, whereas children were more severely affected when considered for iEEG.

难治性局灶性癫痫患儿与成人有所不同，尽管许多医疗中心会为这两类患者都提供侵入性脑电图（iEEG）检查。然而，在年龄组之间，尚未直接比较硬膜下栅状电极植入术（SDE）或立体定向脑电图（SEEG）后的切除可能性及后续癫痫发作结局。两种iEEG技术都能有效达成目标，但路径截然不同，两个年龄组的癫痫发作结局并无差异，但SDE的并发症风险更高。我们发现不同技术带来了相似的手术结果，且对儿童的要求更高。如果认为癫痫局灶性可能性较低或切除术后无癫痫发作的可能性较低，成人更常接受iEEG检查，而考虑进行iEEG检查的儿童病情往往更为严重。

REF: Rados M, Beerepoot S, Tisdall MM, et al. Comparison of children and adults undergoing subdural grid electrode implantation or stereoelectroencephalography in a refractory epilepsy cohort from four European centers. Epilepsia. 2025;66(8):2715-2727. doi:10.1111/epi.18443 PMID: 40392123

Differences in patterns of outpatient epilepsy-specific medication initiation after acute ischemic stroke in the Medicare population

医保人群急性缺血性中风后门诊癫痫特异性药物起始使用模式的差异

Acute ischemic stroke (AIS) is a leading hospitalization cause and significantly contributes to seizures among older adults. We examined outpatient epilepsy-specific medication (ESM) initiation patterns after AIS discharge in adults 65 years and older, trends over time (by stratifying the analysis from 2013 to 2021), and racial/ethnic differences. Black/African American and Hispanic beneficiaries had a higher 90-day incidence of post-AIS ESM initiation than non-Hispanic Whites. ESM initiation decreased in older age groups.

急性缺血性卒中（AIS）是导致老年人住院的主要原因，且在老年人癫痫发作中起重要作用。我们研究了65岁及以上成年人AIS出院后门诊癫痫特异性药物（ESM）的起始模式、随时间的变化趋势（通过对2013年至2021年的数据进行分层分析）以及种族/民族差异。黑人/非裔美国人和西班牙裔受益人AIS后90天内开始使用ESM的发生率高于非西班牙裔白人。高龄组的ESM起始率有所下降。

REF: Donahue MA, Brooks JD, Hsu J, et al. Differences in patterns of outpatient epilepsy-specific medication initiation after acute ischemic stroke in the Medicare population. Epilepsia. 2025;66(8):2728-2742. doi:10.1111/epi.18396 PMID: 40184019