RNA therapeutics for epilepsy: An emerging modality for drug discovery

治疗癫痫的RNA疗法：一种新兴的药物发现方式

Drug discovery in epilepsy began with the finding of potassium bromide by Sir Charles Locock in 1857. The following century witnessed the introduction of phenotypic screening tests for discovering antiseizure medications (ASMs). Despite the high success rate of developing ASMs, they have so far failed in eliminating drug resistance and in delivering disease-modifying treatments. This emphasizes the need for new drug discovery strategies in epilepsy. RNA-based drugs have recently shown promise as a new modality with the potential of providing disease modification and counteracting drug resistance in epilepsy. RNA therapeutics can be directed either toward noncoding RNAs, such as microRNAs, long noncoding RNAs (ncRNAs), and circular RNAs, or toward messenger RNAs. The former show promise in sporadic, nongenetic epilepsies, as interference with ncRNAs allows for modulation of entire disease pathways, whereas the latter seem more promising in monogenic childhood epilepsies. Here, we describe therapeutic strategies for modulating disease-associated RNA molecules and highlight the potential of RNA therapeutics for the treatment of different patient populations such as sporadic, drug-resistant epilepsy, and childhood monogenic epilepsies.

治疗癫痫的药物发现始于1857年查尔斯·罗科克爵士发现的溴化钾。接下来的一个世纪见证了表型筛选试验的引入，以发现抗癫痫药物(ASM)。尽管开发ASM的成功率很高，但到目前为止，它们在消除耐药性和提供改善疾病的治疗方面都失败了。这强调了治疗癫痫的新药发现策略的必要性。基于RNA的药物最近显示出作为一种新的治疗方式的前景，具有提供疾病修饰和对抗癫痫耐药的潜力。RNA疗法既可以针对非编码RNA，如microRNAs、长非编码RNA(NcRNAs)和环状RNA，也可以针对信使RNA。前者在散发性、非遗传性癫痫中显示出希望，因为对ncRNAs的干扰允许调节整个疾病途径，而后者在单基因儿童癫痫中似乎更有希望。在这里，我们描述了调节疾病相关RNA分子的治疗策略，并强调了RNA疗法用于治疗不同患者群体的潜力，如散发性、耐药癫痫和儿童期单基因癫痫。

REF: Hansen SN, Holm A, Kauppinen S, Klitgaard H. RNA therapeutics for epilepsy: An emerging modality for drug discovery. Epilepsia. 2023;64(12):3113-3129. doi:10.1111/epi.17772 PMID: 37703096

A scoping review of the functional magnetic resonance imaging-based functional connectivity of focal cortical dysplasia-related epilepsy

局灶性皮质发育不良相关性癫痫基于功能磁共振成像的功能连接的范围回顾

Focal cortical dysplasia (FCD) is the most frequent etiology of operable pharmacoresistant epilepsy in children. There is burgeoning evidence that FCD-related epilepsy is a disorder that involves distributed brain networks. Functional magnetic resonance imaging (fMRI) is a tool that allows one to infer neuronal activity and to noninvasively map whole-brain functional networks. Despite its relatively widespread availability at most epilepsy centers, the clinical application of fMRI remains mostly task-based in epilepsy. Another approach is to map and characterize cortical functional networks of individuals using resting state fMRI (rsfMRI). The focus of this scoping review is to summarize the evidence to date of investigations of the network basis of FCD-related epilepsy, and to highlight numerous potential future applications of rsfMRI in the exploration of diagnostic and therapeutic strategies for FCD-related epilepsy. There are numerous studies demonstrating a global disruption of cortical functional networks in FCD-related epilepsy. The underlying pathological subtypes of FCD influence overall functional network patterns. There is evidence that cortical functional network mapping may help to predict postsurgical seizure outcomes, highlighting the translational potential of these findings. Additionally, several studies emphasize the important effect of FCD interaction with cortical networks and the expression of epilepsy and its comorbidities.

局灶性皮质发育不良(FCD)是儿童可手术耐药癫痫最常见的病因。越来越多的证据表明，与FCD相关的癫痫是一种涉及分布式大脑网络的疾病。功能磁共振成像(FMRI)是一种允许人们推断神经元活动并非侵入性地绘制全脑功能网络的工具。尽管功能磁共振成像在大多数癫痫中心得到了相对广泛的应用，但它的临床应用仍然主要是基于任务的癫痫。另一种方法是使用静息状态功能磁共振成像(RsfMRI)来绘制和表征个体的皮质功能网络。这篇范围综述的重点是总结到目前为止关于FCD相关癫痫网络基础的研究证据，并强调rsfMRI在探索FCD相关癫痫的诊断和治疗策略方面的许多潜在的未来应用。大量研究表明，在FCD相关的癫痫中，皮质功能网络发生了全球性的破坏。FCD的潜在病理亚型影响整体功能网络模式。有证据表明，皮质功能网络图可能有助于预测手术后癫痫发作的结果，突出了这些发现的翻译潜力。此外，一些研究强调了FCD与皮质网络的相互作用以及癫痫及其共病的表达。

REF: Cohen NT, Xie H, Gholipour T, Gaillard WD. A scoping review of the functional magnetic resonance imaging-based functional connectivity of focal cortical dysplasia-related epilepsy. Epilepsia. 2023;64(12):3130-3142. doi:10.1111/epi.17775 PMID: 37731142

Solving the unsolved genetic epilepsies: Current and future perspectives

解决未解决的遗传性癫痫：现状和未来

Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for patients with epilepsy: (1) the underlying cause is not genetic; (2) there is a complex polygenic explanation; (3) the illness is monogenic but the causative gene remains to be linked to a human disorder; (4) family segregation with reduced penetrance; (5) somatic mosaicism or the complexity of, for example, a structural rearrangement; or (6) limited knowledge or diagnostic tools that hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance. The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: (1) re-analysis of older exome/genome data as knowledge increases or symptoms change; (2) looking for somatic mosaicism or long-read sequencing to detect low-complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing; (3) exploration of the non-coding genome including disruption of topologically associated domains, long range non-coding RNA, or other regulatory elements; and finally (4) transcriptomics, DNA methylation signatures, and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic workup. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients who are currently undiagnosed.

许多癫痫患者接受外显子组或基因组测序，作为诊断工作的一部分；然而，许多人仍然没有从基因上解决。有多种因素导致癫痫患者外显子组/基因组测序结果为阴性：(1)潜在原因不是遗传；(2)复杂的多基因解释；(3)该病是单基因疾病，但致病基因仍与人类疾病有关；(4)外显性降低的家族分离；(5)体细胞嵌合体或结构重排等的复杂性；或(6)知识或诊断工具有限，阻碍了对变体的正确分类，导致其被指定为未知意义的变体。这篇综述的目的是概述一些超出外显子组/基因组的诊断选项，这些选项可能在可预见的未来变得与临床相关。这些选择包括：(1)随着知识的增加或症状的改变，重新分析旧的外显子组/基因组数据；(2)寻找体细胞嵌合体或长读测序，以检测传统外显子组/基因组测序遗漏的低复杂性重复变异体或特定结构变异体；(3)探索非编码基因组，包括破坏拓扑相关结构域、长距离非编码RNA或其他调控元件；以及(4)转录组学、DNA甲基化特征和代谢组学，作为可用于评估未知意义的变异体的补充诊断方法。其中一些工具目前没有集成到标准诊断检查中。然而，有理由预计，它们将变得越来越可用，并改善现有的诊断能力，从而使目前未确诊的患者能够进行精确诊断。

REF: Johannesen KM, Tümer Z, Weckhuysen S, Barakat TS, Bayat A. Solving the unsolved genetic epilepsies: Current and future perspectives. Epilepsia. 2023;64(12):3143-3154. doi:10.1111/epi.17780 PMID: 37750451

Scoping review and expert-based consensus recommendations for assessment and management of psychogenic non-epileptic (functional) seizures (PNES) in children: A report from the Pediatric Psychiatric Issues Task Force of the International League Against Epilepsy

儿童心理性非癫痫 (功能性) 癫痫发作 (PNES) 评估和管理的范围审查和基于专家的共识建议: 国际抗癫痫联盟儿童精神病学问题工作组的报告

Limited guidance exists regarding the assessment and management of psychogenic non-epileptic seizures (PNES) in children. Our aim was to develop consensus-based recommendations to fill this gap. The members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment-There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a "probable" diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management-There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities-There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.

关于儿童心理性非癫痫发作 (PNES) 的评估和管理的指导有限。我们的目标是制定基于共识的建议来填补这一空白。国际抗癫痫联盟 (ILAE) 儿童精神病学问题工作组的成员进行了范围审查，遵循系统审查和范围审查的荟萃分析扩展 (prisma-sr) 标准的首选报告项目。这是发送给儿科PNES专家的Delphi流程的补充。共识定义为 ≥ 80% 一致。系统检索确定了77项研究，其中大部分 (55%) 是回顾性研究 (只有一项随机临床试验)。在84% 研究中，PNES识别的主要手段是视频脑电图 (vEEG)。更好的结果与获得咨询/心理干预有关。患有PNES的儿童比对照组更常见的精神疾病。Delphi产生了22项建议: 评估-就 (1) 全面的发展历史的重要性达成了共识; (2) 获得事件的描述; (3) 询问潜在的压力源; (4) 如果可以，需要使用vEEG父母，自我，学校报告和视频记录可能有助于 “可能的” 诊断; (5) 不应采用侵入性挑衅技术或欺骗手段。管理-关于 (1) 需要具有癫痫专业知识的专业人员在PNES诊断后继续参与一段时间的共识; (2) 向儿童和护理人员提供适当的教育材料; (3) 关于儿童PNES治疗方式的决定应考虑儿童的年龄，认知能力和家庭因素。合并症-一致认为所有患有PNES的儿童都应进行精神卫生和神经发育困难筛查。制定了促进儿童PNES评估和管理的建议。提出了填补知识空白的未来方向。

REF: Reilly C, Jette N, Johnson EC, et al. Scoping review and expert-based consensus recommendations for assessment and management of psychogenic non-epileptic (functional) seizures (PNES) in children: A report from the Pediatric Psychiatric Issues Task Force of the International League Against Epilepsy. Epilepsia. 2023;64(12):3160-3195. doi:10.1111/epi.17768 PMID: 37804168

Patterns of antiseizure medication utilization in the Human Epilepsy Project

人类癫痫项目中抗癫痫药物的使用模式

This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy. Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.

进行这项研究是为了确定最初开始单药治疗的新诊断的局灶性癫痫患者的自然病史和抗癫痫药物 (ASM) 使用模式。略高于三分之一的局灶性癫痫患者仍在接受首次处方ASM的单药治疗。大约五分之三的患者过渡到另一种ASM的单药治疗，而大约五分之二的患者最终接受了多药治疗。当作为初始单一疗法时，与左乙拉西坦相比，患者在拉莫三嗪上保持更长的持续时间。

REF: Fox J, Barnard S, Agashe SH, et al. Patterns of antiseizure medication utilization in the Human Epilepsy Project. Epilepsia. 2023;64(12):3196-3204. doi:10.1111/epi.17802 PMID: 37846772

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox–Gastaut syndrome: A multicenter, multinational study

Lennox-gastaut综合征患儿迷走神经刺激后胼胝体切开术的附加值: 一项多中心、多国研究

Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Lennox-gastaut综合征 (LGS) 是一种严重的癫痫性脑病，在生命的最初几年出现，并且对治疗非常耐药。一旦医学治疗失败，就考虑姑息性手术，例如迷走神经刺激 (VNS) 或胼胝体切开术 (CC)。尽管CC作为与LGS相关的跌落发作的主要神经外科治疗比VNS更有效，但有关VNS后CC的附加值的数据有限。本研究旨在评估先于VNS的CC的有效性。CC对于VNS失败的LGS儿童的癫痫控制至关重要。手术风险很低。对于某些癫痫发作类型，完整的CC比前CC具有更好的效果。

REF: Roth J, Bergman L, Weil AG, et al. Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study. Epilepsia. 2023;64(12):3205-3212. doi:10.1111/epi.17796 PMID: 37823366

Artificial intelligence-enhanced epileptic seizure detection by wearables

人工智能-可穿戴设备增强的癫痫发作检测

Wrist- or ankle-worn devices are less intrusive than the widely used electroencephalographic (EEG) systems for monitoring epileptic seizures. Using custom-developed deep-learning seizure detection models, we demonstrate the detection of a broad range of seizure types by wearable signals. Results from this in-hospital study contribute to a paradigm shift in epilepsy care that entails noninvasive seizure detection, provides time-sensitive and accurate data on additional clinical seizure types, and proposes a novel combination of an out-of-the-box monitoring algorithm with an individualized person-oriented seizure detection approach.

与广泛使用的用于监测癫痫发作的脑电图 (EEG) 系统相比，腕戴或踝戴设备的侵入性较小。使用定制开发的深度学习癫痫发作检测模型，我们演示了通过可穿戴信号检测各种癫痫发作类型。这项住院研究的结果有助于癫痫治疗的范式转变，需要非侵入性癫痫发作检测，提供其他临床癫痫发作类型的时间敏感和准确的数据，并提出了一种开箱即用的新型组合监测算法与个性化的面向个人的癫痫发作检测方法。

REF: Yu S, El Atrache R, Tang J, et al. Artificial intelligence-enhanced epileptic seizure detection by wearables. Epilepsia. 2023;64(12):3213-3226. doi:10.1111/epi.17774 PMID: 37715325

Natural language processing for identification of refractory status epilepticus in children

识别儿童难治性癫痫持续状态的自然语言处理

Pediatric status epilepticus is one of the most frequent pediatric emergencies, with high mortality and morbidity. Utilizing electronic health records (EHRs) permits analysis of care approaches and disease outcomes at a lower cost than prospective research. However, reviewing EHR manually is time intensive. We aimed to compare refractory status epilepticus (rSE) cases identified by human EHR review with a natural language processing (NLP)-assisted rSE screen followed by a manual review. DrT provided a highly sensitive model compared to human review and an increase in patient identification through EHRs. The use of DrT is a suitable application of NLP for identifying patients with a history of recent rSE, which ultimately contributes to the implementation of monitoring techniques and treatments in near real time.

小儿癫痫持续状态是小儿最常见的急症之一，具有较高的死亡率和发病率。利用电子健康记录 (EHRs) 允许以比前瞻性研究更低的成本分析护理方法和疾病结果。然而，手动审查EHR是时间密集的。我们旨在将人类EHR审查确定的难治性癫痫持续状态 (rSE) 病例与自然语言处理 (NLP) 辅助的rSE屏幕进行比较，然后进行手动审查。与人类审查相比，DrT提供了高度敏感的模型，并且通过ehr增加了患者识别。DrT的使用是NLP用于识别具有近期rSE病史的患者的合适应用，这最终有助于近实时地实施监测技术和治疗。

REF: Chafjiri FMA, Reece L, Voke L, et al. Natural language processing for identification of refractory status epilepticus in children. Epilepsia. 2023;64(12):3227-3237. doi:10.1111/epi.17789 PMID: 37804085

Telemedicine as a path to bridging inequities in patients with epilepsy

远程医疗是弥合癫痫患者不平等的途径

Access to epilepsy specialist care is not uniform in the USA, with prominent gaps in rural areas. Understanding the reasons for nonattendance at epilepsy appointments may help identify access hurdles faced by patients. This study was undertaken to better understand clinic absenteeism in epilepsy and how it may be influenced by telemedicine. Telemedicine is effective at improving attendance, overcoming socioeconomic hurdles, and widening access to epilepsy care, particularly among underserved populations. Access to telecare depends on insurance coverage and emphasizes the need to include telemedicine in insurance plans to ensure uniform access to high-quality epilepsy care, irrespective of socioeconomic status.

在美国，获得癫痫专科护理的机会并不统一，农村地区存在明显差距。了解未参加癫痫预约的原因可能有助于确定患者面临的访问障碍。进行这项研究是为了更好地了解癫痫的临床缺勤以及远程医疗如何影响它。远程医疗在提高出勤率、克服社会经济障碍和扩大癫痫治疗的可及性方面是有效的，特别是在服务不足的人群中。获得远程医疗取决于保险范围，并强调需要将远程医疗纳入保险计划，以确保无论社会经济地位如何，都能获得高质量的癫痫护理。

REF: Yardi R, McLouth CJ, Mathias S, Jehi L. Telemedicine as a path to bridging inequities in patients with epilepsy. Epilepsia. 2023;64(12):3238-3245. doi:10.1111/epi.17793 PMID: 37811672