癫痫样放电是否需要治疗？《癫痫杂志》特邀综述与评论

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文献网址：https://pmc.ncbi.nlm.nih.gov/articles/PMC6294573/



癫痫样放电是否需要治疗？

述评与特邀评论

*†伊万·桑切斯·费尔南德斯，†托比亚斯·洛登肯珀，‡阿里斯泰娅·S·加兰诺普洛，‡§所罗门·L·摩西
《癫痫杂志》，56(10):1492–1504，2015年
doi: 10.1111/epi.13108

摘要

本研究旨在评估发作模式外出现的癫痫样放电（如棘波、尖波、棘慢波）对认知功能的影响，并探讨考虑对癫痫样放电进行治疗的适用情况，研究方法为文献综述。癫痫样放电可损害人类的短期认知功能，长期频繁的癫痫样放电则可能对人类长期认知功能造成不可逆损伤。但目前关于癫痫样放电对长期认知结局的影响，相关研究证据存在矛盾，这一关联易受潜在病因、癫痫发作、药物作用等多种因素干扰。现有研究的局限性包括缺乏标准化的癫痫样放电定量方法，以及尚未形成被广泛认可的自动化棘波定量手段。尽管目前尚无确凿证据支持或反对对癫痫样放电进行治疗，本文仍提出一种非循证的实用处理原则：无其他症状的癫痫样放电患者无需治疗，因治疗的风险可能大于其不确定的获益；当患者出现认知功能障碍、认知倒退或神经系统症状，且这些表现无法用潜在病因、合并症或癫痫发作严重程度解释时，可考虑开展癫痫样放电的治疗试验；对于合并癫痫或癫痫样放电且存在认知、神经系统功能障碍的患者，需采取治疗以控制潜在的癫痫综合征。

核心要点

• 有证据表明，癫痫样放电会破坏人类的短期认知过程

• 短期认知功能的受损具有部位特异性，与癫痫样放电累及的大脑皮层区域相关

• 癫痫样放电对长期学习和认知功能的影响尚不明确

• 目前尚无证据支持或反对对无症状性癫痫样放电进行治疗

人群中约1%~5%的人脑电图存在癫痫样放电，癫痫患者的癫痫样放电检出率显著高于健康对照人群。癫痫样放电表现为棘波、多棘波、尖波或棘慢波综合波，可孤立出现或短阵发放，无明显临床相关症状。其可急性损害人类的认知或神经系统功能，且放电的持续时间、分布部位会影响功能障碍的类型；但慢性癫痫样放电对神经元环路及长期认知结局的具体影响尚未明确，抑制癫痫样放电的治疗手段，其获益与风险也尚无定论。

本文聚焦于可识别的癫痫发作模式或发作状态外出现的癫痫样放电，探讨其对认知功能的影响，并为临床是否考虑治疗癫痫样放电提供建议，研究场景限定于门诊或非急性病程，排除意识障碍状态。因近期已有相关综述探讨动物实验研究，故本研究仅纳入临床数据进行分析。

癫痫样放电的定量与认知功能

癫痫样放电的客观定量尝试

目前多数癫痫样放电定量方法为睡眠中癫痫性电持续状态（ESES）专门设计，该脑电图表现为睡眠期几乎持续的癫痫样电活动。

1. 棘慢波指数（SWI）与棘慢波百分比（SWP）
棘慢波指数和棘慢波百分比用于评估脑电图中癫痫样放电所占的比例。在早期ESES相关研究中，棘慢波指数被定义为慢波睡眠期出现癫痫样放电的占比；但因该指标的计算方法缺乏详细的方法论说明，且解读存在差异，其可重复性受限。有研究提出将棘慢波指数定义为至少出现1次癫痫样放电的1秒时间窗占总监测时间的百分比，该方法后被采纳并重新命名为棘慢波百分比。棘慢波百分比的优势为可重复性强、对资源消耗较低，但当癫痫样放电频率超过每秒1次时，该指标无法区分脑电图的异常严重程度。

2. 棘波频率（SF）
棘波频率指单位时间内癫痫样放电的总数，通常以100秒为统计单位。该方法若未实现自动化，操作耗时会远超棘慢波百分比，且易产生抽样误差，但在棘波发放极频繁时，能更精准地区分癫痫样放电的严重程度。

3. 计算机化定量方法
自动化定量方法可实现癫痫样放电的可重复、快速定量，但该方法仅能识别符合预设参数的癫痫样放电（或其组成成分），需根据不同患者调整参数，还需进行伪影筛查排除，且无法识别所有形态的癫痫样放电，因此尚未在临床实践中广泛应用。

癫痫样放电影响定量的难点

癫痫样放电评估中的诸多细节问题，导致其对临床结局的影响难以直接定量分析：

• 分布与偏侧性：临床功能障碍的表现与癫痫样放电的定位相关，累及功能区、多灶性或全面性的癫痫样放电，其危害性远高于累及非特异性认知功能区域的癫痫样放电。

• 波幅差异：目前尚未明确高波幅与低波幅癫痫样放电，对认知功能的潜在损害作用是否一致。

• 形态学特征：癫痫样放电包括棘波、多棘波、尖波的不同组合形式，可伴或不伴后续慢波，而后续慢波也被认为会破坏大脑皮层的正常功能。

• 睡眠-觉醒阶段：癫痫样放电的严重程度并非始终与睡眠-觉醒阶段无关，不同阶段的放电对癫痫性脑病严重程度的影响尚不明确。由于多数认知测试依赖患者的主动反应（即需在清醒状态下完成），因此清醒期的认知功能检测更具可行性；反之，若未在睡眠期开展主动测试，睡眠相关的认知缺陷更易被解读为与信息储存、神经可塑性相关。

癫痫样放电与认知/功能结局的相关性

癫痫样放电的短期（急性）影响评估，仅局限于可通过快速反应时间检测的认知功能；且认知评估本身可能改变癫痫样放电的表现，进一步增加结果解读的复杂性。其长期认知影响的评估则受场景、时间因素干扰，认知损害的程度可能随环境和时间变化。由于脑电图检查和特异性认知测试通常在症状出现后进行，症状（认知、癫痫发作）与癫痫样放电的时间演变关系往往不明确，因此对患者病前的认知功能和脑电图表现也难以进行准确评估。

癫痫样放电对认知功能的影响

无癫痫病史的无症状癫痫样放电人群

在无癫痫病史的无症状人群中，儿童癫痫样放电的检出率为0%~6%，成人为0%~7%。这类在健康人群中偶然发现的癫痫样放电，其临床意义尚不明确：一方面，此类人群后续发生癫痫的概率较低（儿童约6%，成人约2%）；另一方面，相关研究提示其可能存在少量认知和行为异常，但该结论仍需前瞻性、严格对照的大样本研究进一步验证。

合并癫痫发作外神经系统疾病的癫痫样放电患者

无癫痫发作史的住院和门诊患者，癫痫样放电的检出率（2%~14%）高于社区人群研究结果，这类放电的认知学意义尚不明确，或可作为大脑功能异常的生物标志物。

注意缺陷多动障碍（ADHD）

在48名平均年龄9.4岁（6.7~14.9岁）的儿童研究中，16名合并中央颞区棘波的ADHD儿童、16名无中央颞区棘波的ADHD儿童与16名健康对照儿童相比，合并棘波的ADHD儿童更易出现冲动性增加、持续反应抑制能力下降、干扰控制能力受损。此外，夜间睡眠监测显示ADHD患者的癫痫样放电检出率更高：42名接受多导睡眠图检查的ADHD儿童中，53.1%存在癫痫样放电，其中3名在监测期间出现癫痫发作，其余患儿合并语言障碍、运动障碍等其他神经系统疾病。23名4~17岁的史密斯-莱姆利-奥皮茨综合征患者的系列脑电图检查显示，51%的患儿存在脑电图异常（多为癫痫样放电）；且同一患者中，某次脑电图出现癫痫样放电，其ADHD症状严重程度平均会升高27%。但目前尚无证据证实，癫痫样放电可独立于其他潜在病因，直接导致ADHD症状的发生。

语言障碍

多导睡眠图或标准脑电图研究证实，语言障碍儿童的癫痫样放电检出率显著升高：52名4~11岁的言语障碍儿童中，50%检出癫痫样放电（84%位于左侧大脑），而年龄匹配的健康对照组检出率仅为10%。少数研究显示，言语障碍的类型与癫痫样放电的检出率、严重程度相关：表达性发育性言语障碍儿童的癫痫样放电检出率（37.5%）显著高于健康对照组（5.1%），放电形式以非快速眼动睡眠期的全面性放电为主，9名患儿中有2名在清醒期或快速眼动睡眠期也检出放电；56%的表达性发育性言语障碍儿童存在频繁的癫痫样放电，其睡眠期棘慢波指数为2.5%~66%。目前无证据表明，这类癫痫样放电除反映潜在病因外，还与语言障碍存在直接的因果关系。

自闭症谱系障碍（ASD）与智力障碍（ID）

自闭症谱系障碍和智力障碍人群的癫痫及癫痫样放电检出率，均显著高于健康对照人群，但目前尚未明确，这类患者的癫痫样放电是直接导致认知损害，还是仅为大脑潜在功能异常的表现。总体而言，20%~60%的自闭症谱系障碍儿童存在癫痫样电活动异常；排除癫痫患儿后，仍有8%~20%的自闭症谱系障碍患者检出癫痫样放电。与其他自闭症谱系障碍亚型相比，阿斯伯格综合征患者的癫痫样放电和临床癫痫发作率更低；且攻击行为史与癫痫样放电的存在相关，与临床癫痫发作无明显关联。

即使无癫痫病史，自闭症倒退儿童的癫痫样放电也更为常见，但二者的时间关联难以明确。与单纯语言倒退（兰道-克莱夫纳综合征，LKS）相比，自闭症倒退与癫痫发作（8% vs 33%）、癫痫样放电（28% vs 56%）的关联度更低，发病年龄更小，且更易合并发育迟缓。因此，与单纯语言倒退相比，癫痫样放电在自闭症倒退的发病机制中作用更弱，或仅为其较弱的替代标志物。现有实验证据还支持另一种可能性：这类年龄特异性综合征的潜在病因对发育的影响，可能会进一步受年龄、性别、地域特异性因素的调节。

癫痫患者

多项研究探讨了癫痫样放电对部分局灶性或全面性放电相关癫痫综合征的短期和长期影响，发现癫痫样放电可影响中枢信息处理、刺激反应时间及认知应答。在对比癫痫样放电与癫痫发作对学习和认知功能影响的研究中，无癫痫发作时的癫痫样放电，对注意力和信息处理速度要么无影响，要么仅产生轻微的独立影响，高频放电时该效应更明显。

短期影响

1. 对神经心理学测试的影响：癫痫样放电引发的短期认知损害，并非均由全面性注意力障碍导致，更多反映为受累脑区特异性功能的破坏；且认知缺陷的表现与癫痫样放电的出现时间相关，特定认知功能障碍的发生，需癫痫样放电在特定时间出现在特定脑区。

2. 对日常活动的影响：对20名儿童的学业表现评估显示，癫痫样放电频率越高，测试成绩越差，尤以算术学科为著。对6名癫痫样放电患者的驾驶能力监测显示，患者以90km/h的速度在高速公路行驶420km时，放电期间3人出现车辆行驶轨迹维持能力受损，1人出现受损趋势，且该损害在多年无癫痫发作的患者中也可出现。而这些患者在放电期间完成的科尔西积木测试、短期言语记忆测试等标准实验室检查结果，无法预测其驾驶测试的表现。提示癫痫样放电可损害部分注意力敏感的任务执行能力（即使在无癫痫发作的人群中），且该损害无法通过标准神经心理学测试预测。

3. 与短暂性认知障碍、短暂非惊厥性癫痫发作的区别：若癫痫样放电导致可检测的认知功能改变，则其并非亚临床表现，而是具有临床意义的短暂性认知障碍或发作期的轻微癫痫发作。多项视觉、听觉反应测试显示，癫痫样放电出现的时段与反应延迟存在时间关联，有研究提出癫痫样放电的影响始于棘波出现前，止于后续慢波结束。另一项研究对188名6~18岁儿童进行2小时认知测试并同步脑电图监测，将研究对象分为三组：测试期间出现短暂非惊厥性癫痫发作的癫痫患儿（表现为持续数秒的凝视或细微动作的电-临床事件）、测试期间无短暂非惊厥性癫痫发作的癫痫患儿、健康对照儿童。结果显示，短暂非惊厥性癫痫发作对认知功能的损害显著，这类发作持续时间多短于19秒，以局灶性发作为主，失神发作或肌阵挛发作少见；无癫痫发作的癫痫样放电也会损害认知功能，但影响更轻微。目前尚未明确：癫痫样放电是非惊厥性癫痫发作谱系中程度较轻的类型，还是易引发认知功能障碍和/或癫痫发作的潜在病因/状态的早期标志物，明确这一问题有助于制定癫痫样放电患者的最佳管理方案。

4. 结果解读的难点：短期认知测试的研究对象存在固有偏倚，因研究通常优先选择清醒、警觉状态下癫痫样放电频繁的受试者，因此研究结果不一定适用于放电频率较低或仅睡眠期出现放电的人群。此外，外界刺激和受试者对特定任务的注意力水平，也可能改变癫痫样放电的频率和特征。

长期影响

1. 儿童局灶性癫痫综合征：儿童中央颞区棘波癫痫（CECTS）、帕纳约托普洛斯综合征、晚发性儿童枕叶癫痫（加斯托型）具有共同特征：癫痫发作相对轻微、发作频率低，癫痫样放电频繁且在睡眠期增强，且放电在癫痫发作停止后仍可持续数年。中央颞区棘波癫痫儿童中，睡眠期放电越频繁，越易出现神经心理发育异常，尤以语言领域为著；另一项研究显示，29%的该类患儿存在学业和家庭功能受损，且预后不良的预测因素为癫痫样放电，与癫痫发作无关。但也有研究未发现中央颞区棘波癫痫患儿的棘波频率与认知功能存在关联。26名合并局灶性癫痫样放电的学习困难儿童（19名中央颞区棘波癫痫、2名帕纳约托普洛斯综合征、1名局灶性癫痫、4名无癫痫发作史）的研究显示，基线时的中枢信息处理速度与癫痫样放电频率呈负相关（未排除无癫痫发作的患儿）；随访发现，中枢信息处理速度下降与癫痫样放电增多、癫痫持续发作均相关，目前尚未明确二者对中枢信息处理是否存在独立影响。局灶性癫痫综合征患儿中，左侧中央颞区放电者在复杂语言任务中表现更差，枕叶棘波者在同步信息处理中表现受损，尤以视觉转换任务为著。综上，基于小样本儿童局灶性癫痫合并癫痫样放电的研究证据提示，这类患者的长期认知结局较差，且认知损害的表现与癫痫样放电的定位相关。

2. 全面性癫痫：儿童失神癫痫患者的棘慢波放电，可在短期内扰乱注意力、意识和信息处理功能，且有证据提示其存在长期认知缺陷。一项对比16名儿童失神癫痫、14名1型糖尿病和15名健康儿童的研究显示，失神癫痫患儿在智力、记忆力、学业成绩、精细运动速度、信息处理速度方面与对照组无差异，但在问题解决、字母流畅性、复杂运动控制、注意力/行为抑制及社会心理功能方面表现更差；且与幼年类风湿关节炎等非癫痫性慢性疾病患者相比，儿童失神癫痫患儿的长期社会心理结局更差。青少年肌阵挛癫痫也可出现长期、轻微的额叶加工功能障碍。推测癫痫样放电可能逐渐破坏丘脑-额叶神经元网络，导致该网络介导的功能受损；但也可能功能缺陷和癫痫样放电均为遗传决定的丘脑-额叶神经元网络异常的生物标志物。

3. 合并语言或认知倒退的癫痫性脑病：睡眠中癫痫性电持续状态的特征为非快速眼动睡眠期几乎持续的棘波发放，且常伴不同程度的认知倒退，传统观点认为该电活动持续时间过长是认知结局不良的标志。一项纳入209例病例的文献综述显示，睡眠中癫痫性电持续状态持续超过2年的患者，认知结局较差；30例对治疗有反应的该类患者研究显示，电活动持续时间与随访时认知功能恢复至基线水平的程度相关，其中持续时间短于13个月的患儿中50%恢复至基线，而持续超过18个月的患儿无一恢复。癫痫手术前后的认知功能客观评估显示，终止睡眠中癫痫性电持续状态可改善认知功能；但因相关研究样本量较小，且存在潜在病因、癫痫发作负荷、抗癫痫药物治疗等混杂因素，将认知改善仅归因于癫痫样放电减少时需谨慎。此外，一项7例患者的研究未发现睡眠中癫痫性电持续状态的持续时间与认知结局存在关联。

共同的病理生理机制

部分基因突变可使同一患者同时出现不同程度的自闭症谱系障碍、癫痫样放电、癫痫和智力障碍，提示这类疾病存在共同的发病机制，可能由突触可塑性异常和兴奋/抑制平衡失调介导。这一发现为这类疾病的治疗提供了新方向，但也提示癫痫样放电可能仅为潜在病理过程的表现，而非认知倒退的直接病因。不同的潜在机制均可导致睡眠中癫痫性电持续状态这一以显著癫痫样电活动为特征的脑电图表现，其中谷氨酸离子型N-甲基-D-天冬氨酸2A受体（GRIN2A）基因突变和早期丘脑病变，均与后期显著癫痫样放电及睡眠中癫痫性电持续状态的发生相关，进一步证实了不同病因可通过共同通路导致相似临床表型的观点。

癫痫样放电认知影响的评估方法

长期暴露于癫痫样放电是否会损害认知功能、治疗癫痫样放电是否能逆转该潜在损害，目前仍无定论。癫痫样放电的短期认知影响，通常通过同一受试者在放电和无放电两种状态下进行检测，实验在清醒后数小时内完成，以受试者自身为对照。睡眠中癫痫性电持续状态或中央颞区棘波癫痫患者适用于该评估方法：基线时对患者进行正式神经心理学检查，通过抗癫痫药物减少其癫痫样放电，干预后再次复查神经心理学检查。但治疗前后的对比分析，仅能校正癫痫发作负荷等少数混杂因素，无法校正性别、遗传背景等个体固有因素。这类研究对评估短期结局有一定价值，但长期结局的解读存在难点——难以区分治疗相关的认知改善，与自然发育、教育体系或生活环境变化带来的认知能力提升。若初步研究结果理想，可开展更大规模的同质人群研究（如相同综合征或遗传背景），在考虑多种已知混杂因素的前提下，对比接受治疗与未接受治疗的癫痫样放电患者的发育轨迹；而对癫痫样放电的负荷、类型、定位进行细致评估，对两类研究均至关重要。

治疗与否的决策原则

在获得更充分的研究证据前，临床需结合实际情况制定治疗决策。对癫痫样放电的治疗犹豫，源于目前尚无确凿证据证实或否定其对长期认知损害的因果作用，本文针对不同临床场景提出非循证的实用管理原则：

1. 无症状人群：癫痫样放电对无癫痫病史的无症状人群的认知影响尚不明确，且其后续发生癫痫的风险较低，该风险或与遗传特征相关。因此，无癫痫病史的无症状人群中偶然检出的癫痫样放电无需治疗，因治疗的获益尚不明确。

2. 无癫痫发作但合并癫痫样放电及认知功能障碍/倒退的患者：有报道称抗癫痫药物可改善这类患者的部分认知功能，但大样本研究结果存在矛盾。一项双盲交叉试验显示，8名6~12岁合并学习和行为问题的癫痫样放电儿童，随机接受丙戊酸盐或安慰剂治疗后，服用丙戊酸盐的患儿出现注意力分散增加、反应时间延长、记忆评分降低，且无临床改善。一项前瞻性开放标签研究显示，6名7~15岁合并局灶性癫痫样放电的学习困难儿童，接受左乙拉西坦治疗10周后，4名患儿的记忆与学习广泛评估量表得分改善，但韦氏个人成就测试无明显变化。综上，尽管部分患者服用抗癫痫药物后认知功能有一定改善，但这可能仅为疾病自然病程的波动，目前尚无足够证据推荐对无癫痫发作的认知功能障碍/倒退合并癫痫样放电患者使用抗癫痫药物，且部分抗癫痫药物可能加重认知功能损害。

3. 癫痫性脑病合并癫痫样放电及认知功能障碍/倒退的患者：有报道称，对合并认知倒退的癫痫性脑病患者使用促肾上腺皮质激素（ACTH）、大剂量类固醇或免疫治疗，可有效改善脑电图表现并缓解认知倒退；大剂量苯二氮䓬类药物减少睡眠中癫痫性电持续状态患者的癫痫样放电后，部分患者的认知功能得到改善；32例睡眠中癫痫性电持续状态患儿的研究显示，丙戊酸盐或乙琥胺减少癫痫样放电后，患者认知功能改善；针对睡眠中癫痫性电持续状态患者的致痫灶行癫痫手术，可阻止至少半数患者的认知功能恶化，甚至改善认知。上述研究结果需结合非受控的研究设计、疾病的自然波动状态及其他潜在影响结局的因素综合解读。综上，对于与癫痫样放电相关的癫痫性脑病合并认知功能障碍/倒退的患者，可考虑开展治疗试验。

4. 癫痫发作控制良好但合并癫痫样放电及认知功能障碍/倒退的患者：一项双盲安慰剂对照交叉试验显示，61名7~17岁癫痫发作控制良好（无或偶发局灶性/全面性发作）且合并行为/认知问题的儿童，随机接受拉莫三嗪或安慰剂治疗后，服用拉莫三嗪且癫痫样放电减少的患儿，其康纳斯父母及教师评定量表的行为评分改善，且药物对癫痫发作频率无明显影响。因此，对这类患者（尤其是认知功能障碍呈进行性加重者），可考虑试用抗癫痫药物。

5. 合并认知功能障碍/倒退且癫痫发作未控制的患者：对此类患者需及时治疗以控制癫痫发作，目前尚无足够证据支持将癫痫样放电的消失，作为现有治疗方案的更佳疗效终点。

癫痫样放电的治疗选择

目前评估抗癫痫药物治疗癫痫样放电的研究较少，且研究结果需结合癫痫样放电的自然波动进行解读。一项纳入213对脑电图的大型儿科研究，对比了使用抗癫痫药物前后的癫痫样放电情况，发现苯巴比妥的癫痫样放电抑制率（治疗后脑电图中所有类型放电完全消失）为22%，卡马西平为33%，丙戊酸盐为46%，且该抑制率在局灶性/全面性放电、不同脑电图检查间隔时间、新生儿/非新生儿人群中均保持稳定。一项双盲交叉试验显示，12名4~21岁的难治性全面性癫痫患者，加用拉莫三嗪较安慰剂可显著减少癫痫样放电的持续时间和密度。一项双盲安慰剂对照随机交叉试验显示，低剂量肌内注射氯硝西泮可显著减少儿童的癫痫样放电。大剂量苯二氮䓬类药物可减少部分睡眠中癫痫性电持续状态患者的癫痫样电活动；18名5~10岁的该类患儿研究显示，左乙拉西坦可中度减少其夜间癫痫样放电；44例接受长期氢化可的松治疗的睡眠中癫痫性电持续状态患者中，21例（48%）脑电图恢复正常，但其中14例出现复发。

综上，丙戊酸盐、拉莫三嗪、左乙拉西坦、苯二氮䓬类药物及类固醇等，均可能对癫痫样放电产生抑制作用，但目前尚未明确该作用是否独立于其抗癫痫发作效应（即是否为癫痫发作控制后的继发结果）。此外，部分抗癫痫药物可能加重癫痫样放电，或诱发多动等不良行为。

结论

癫痫样放电可通过部位特异性的方式损害短期认知功能；但关于其对长期认知结局的影响，研究证据存在矛盾。目前尚无足够证据支持单独针对癫痫样放电进行治疗，但若怀疑癫痫样放电是导致认知障碍和行为问题的原因，可考虑开展治疗试验。

致谢

伊万·桑切斯·费尔南德斯的研究得到阿方索·马丁·埃斯库德罗基金会和人类疱疹病毒6型基金会的癫痫性脑病研究基金资助。托比亚斯·洛登肯珀任职于长期（癫痫和重症监护室）监测实验室认证委员会（ABRET）、美国临床神经生理学学会（ACNS）、美国临床神经生理学委员会，担任《癫痫发作》杂志副主编，在波士顿儿童医院开展视频脑电图长时程监测、脑电图及其他电生理学检查并收取相关费用；其研究得到患者中心结局研究协会、支付方-提供者质量倡议的支持，以及美国癫痫学会、美国癫痫基金会、癫痫治疗项目、儿科癫痫研究基金会、癫痫研究公民联盟、丹尼迪德基金会的资助，同时接受卫材株式会社、灵北制药、厄普舍史密斯制药的研究者发起的研究支持。阿里斯泰娅·S·加兰诺普洛的研究得到美国国防部、癫痫研究公民联盟、美国国家神经疾病和中风研究所（NS-78333）、优时比制药、赫弗家族基金会、巴里·西格尔家族基金会、阿贝·戈德斯坦/约书亚·卢里家族及劳里·马什/丹·莱维茨家族的资助；其从摩根&克莱普尔出版社、爱思唯尔出版社、约翰·利比欧洲文本出版社获得书籍出版版税，从美国国防部获得评审酬金。所罗门·L·摩西担任神经外科和神经病学查尔斯·弗罗斯特讲席教授，研究得到美国国立卫生研究院（NS43209、NS20253、NS45911、NS-78333）、癫痫研究公民联盟、美国国防部、优时比制药、赫弗家族基金会、巴里·西格尔家族基金会、阿贝·戈德斯坦/约书亚·卢里家族及劳里·马什/丹·莱维茨家族的资助；



Should epileptiform discharges be treated?

CRITICAL REVIEW AND INVITED COMMENTARY

*†Ivan Sanchez Fernandez, †Tobias Loddenkemper, ‡Aristea S. Galanopoulou, ‡§Solomon L. Moshe
Epilepsia, 56(10):1492–1504, 2015
doi: 10.1111/epi.13108

SUMMARY

To evaluate the impact of epileptiform discharges (EDs) that do not occur within seizure patterns – such as spikes, sharp waves or spike waves – on cognitive function and to discuss the circumstances under which treatment of EDs might be considered. Methods used in this article is “Review of the literature”. EDs may disrupt short-term cognition in humans. Frequent EDs for a prolonged period can potentially impair long-term cognitive function in humans. However, there is conflicting evidence on the impact of EDs on long-term cognitive outcome because this relationship may be confounded by multiple factors such as underlying etiology, seizures, and medication effects. Limitations of existing studies include the lack of standardized ED quantification methods and of widely accepted automated spike quantification methods. Although there is no solid evidence for or against treatment of EDs, a non–evidence-based practical approach is suggested. EDs in otherwise asymptomatic individuals should not be treated because the risks of treatment probably outweigh its dubious benefits. A treatment trial for EDs may be considered when there is cognitive dysfunction or regression or neurologic symptoms that are unexplained by the underlying etiology, comorbid conditions, or seizure severity. In patients with cognitive or neurologic dysfunction with epilepsy or EDs, treatment may be warranted to control the underlying epileptic syndrome.

Key Points

• There is evidence supporting that epileptiform discharges disrupt short-term cognitive processes in humans

• Disruption of short-term cognitive processes is location specific, as it reflects the area of cortex affected by epileptiform discharges

• The impact of epileptiform discharges on long-term learning and cognition is unclear

• At present, there is no evidence for or against treatment of asymptomatic epileptiform discharges

Approximately 1–5% of the population has epileptiform discharges (EDs) on EEG. EDs are seen more commonly in people with epilepsy than in controls, and include spikes or polyspikes, sharp waves, or spike and slow-wave complexes, occurring isolated or in brief runs, without obvious clinical correlates. EDs may acutely disrupt cognitive or neurologic functions in humans, and their duration and distribution influences the type of dysfunction. However, the exact long-term impact of chronic EDs on neuronal circuitry and on cognitive outcome has not been clarified. The benefits and risks of treatments to suppress EDs are not clear.

The purpose of this article is to discuss the impact of EDs on cognition, focusing on EDs that do not occur within recognizable seizure patterns or states, and to provide recommendations on when treatment of EDs might be considered. We will specifically refer to situations in the ambulatory or nonacute settings, excluding states with impaired consciousness. We focused this review on clinical data, as recent reviews discuss the animal studies.

Quantification of EDs and Cognitive Function

Attempts to objectively quantify EDs

Most methods for quantification of EDs have been designed specifically for electrical status epilepticus in sleep (ESES), an EEG pattern with almost continuous epileptiform activity during sleep.

1. Spike–wave index (SWI) and spike–wave percentage (SWP)
Spike–wave index (SWI) and spike–wave percentage (SWP) provide measures of the percentage of EEG tracings occupied by EDs. In the original reports on ESES, SWI was defined as percent of slow wave sleep with EDs. Lack of methodologic details and variable interpretations on how to calculate SWI limit reproducibility. One study proposed quantifying SWI as percentage of 1-s bins occupied by at least one ED, and this was subsequently adopted and renamed as SWP. Advantages of SWP include reproducibility and being relatively non–resource intensive. However, SWP is not able to discriminate severity between EEG recordings when EDs occur at rates higher than one ED per second.

2. Spike frequency (SF)
Spike frequency (SF) is the total number of EDs per unit of time, typically 100 s. This method-if not automated-is more time consuming than SWP and may be liable to sampling errors, but may discriminate ED severity when spiking is very frequent.

3. Computerized methods
Automated methods may achieve reproducible and faster ED quantification. However, these methods can identify only the EDs (or their components) with predefined parameters, may require adaptations for different patients, screening for rejection of artifacts, and do not always identify the different morphologies of EDs. Therefore, automated computerized methods are still not widely used in clinical practice.

Challenges quantifying the impact of EDs

Several nuances in the evaluation of EDs do not lend themselves to a straightforward quantification of their impact on clinical findings.

• Distribution and lateralization: The clinical dysfunction may reflect the localization of EDs. EDs located in eloquent areas, multifocal EDs, or generalized EDs are expected to be more deleterious than EDs originating from regions that do not contribute to specific testable cognitive functions.

• Voltage differences: It is unknown whether high-voltage EDs have the same potentially deleterious effect on cognition than low-voltage EDs do.

• Morphology: EDs include spikes, polyspikes, and sharp waves in different combinations, with or without an aftergoing slow wave, which has also been proposed to disrupt cortical functioning.

• Sleep-wakefulness stages: ED severity is not always independent of the sleep-wakefulness stage. It is unclear how EDs at different stages affect the severity of the epileptic encephalopathy. Because most cognitive tests depend on the patient’s response (i.e., are done in wakefulness), it is more feasible to test cognitive functions in wakefulness. Conversely, it is more likely to interpret sleep-related deficits as related to information storage and plasticity when no active testing is done in sleep.

Correlation of EDs to cognitive/functional outcomes

Evaluation of the short-term (acute) impact of EDs is limited to cognitive functions that can be assessed based on quick response times. Cognitive assessment could also modify EDs, further complicating the interpretation of results. Evaluation of long-term impact of EDs on cognitive function can be complicated by the possibility that the cognitive impact may be context and timing dependent. The temporal evolution of symptoms (cognitive, seizures) and EDs is often unclear because EEG studies and specific cognitive tests are usually performed after symptom onset. Accurate evaluation of the premorbid cognitive function and EEG is therefore limited.

Impact of EDs on Cognition

Asymptomatic individuals without epilepsy who have EDs

In asymptomatic individuals with no prior epilepsy, the prevalence of EDs ranges from 0% to 6% in children and from 0% to 7% in adults. The significance of these incidentally found EDs in otherwise healthy individuals is not clear because subsequent development of epilepsy is rare (approximately 6% in children and 2% in adults) and the few cognitive and behavioral disturbances suggested in these individuals warrant better confirmation with prospective, well-controlled and powered studies.

Patients with EDs who present with neurologic disorders other than seizures

Inpatient and outpatient populations with no history of seizures show a higher prevalence of EDs (2–14%) than in community-based studies. The cognitive significance of these EDs is unclear and may represent a biomarker of abnormal brain.

Attention deficit hyperactivity disorder (ADHD)

In a series of 48 children with a mean (range) age of 9.4 (6.7–14.9) years, 16 children with ADHD and rolandic spikes were compared to 16 children with ADHD and no rolandic spikes, and with 16 healthy controls. Rolandic spikes were more common in ADHD children with increased impulsivity, reduced inhibition of ongoing response, and interference control. In addition, overnight sleep recordings show a higher prevalence of EDs in ADHD. Among 42 children with ADHD studied with polysomnography, 53.1% showed EDs, three of whom also had seizures during polysomnography and others had other neurologic comorbidities (language disorder, dyspraxia). A series of 23 patients aged 4–17 years with Smith-Lemli-Opitz and serial EEG studies showed abnormalities (usually EDs) in 51% of children. Within the same individual the presence of EDs on a particular EEG predicted on average a 27% increase in ADHD symptom severity. There is yet lack of evidence proving that EDs cause ADHD symptoms independent of any other underlying etiology.

Language disorders

A higher incidence of EDs in children with language disorders has been demonstrated in studies using polysomnography or standard EEG recordings. EDs (left-sided in 84%) were detected in 50% of children with dysphasia (4–11 years old, n=52) compared to 10% of age-matched controls. The type of dysphasia relates to the incidence and severity of EDs in few studies. Children with expressive developmental dysphasia were more likely to have EDs (37.5%) in polysomnography studies than controls (5.1%). These included generalized EDs in non–rapid eye movement (NREM) sleep, although in two of nine children EDs were detected in wakefulness or REM sleep. Frequent EDs were detected in 56% of children with expressive dysphasia (SWI in sleep 2.5–66%). There is no evidence that these EDs have a causal role in language disorders other than reflecting the underlying etiology.

Autism spectrum disorders (ASDs) and intellectual disability (ID)

Both ASD and ID populations demonstrate a higher incidence of both epilepsy and EDs than controls. Whether EDs in these patients contribute to cognitive impairment or are just a reflection of an underlying abnormal brain is unknown. Overall, 20–60% of children with ASD have epileptiform abnormalities. When children with epilepsy are excluded, 8–20% of the remaining ASD patients have EDs. Asperger’s syndrome had a lower rate of EDs and clinical seizures compared to other ASD patients, whereas history of aggression was linked with the presence of EDs but not of clinical seizures.

EDs are often more common in children with autistic regression even in the absence of history of epilepsy, yet the temporal association of EDs and autistic regression is difficult to establish. Compared to pure language regression (Landau-Kleffner syndrome [LKS]), autistic regression was less frequently associated with seizures (8% vs 33% in LKS) or EDs (28% vs 56% in LKS), occurred at younger ages, and was more commonly associated with developmental delay. Therefore, EDs may either play a lesser role in the pathogenesis of or be a weaker surrogate marker for autistic regression than they are for pure language regression. An alternative possibility, also supported by existing experimental evidence, is that the developmental impact of the etiologies underlying these age-specific syndromes may be further modified by age, gender, or region-specific factors.

People with epilepsy

Several studies have examined the short- or long-term impact of EDs in certain syndromes with focal or generalized EDs: EDs affected central information processing, response times to stimuli, or cognitive responses. In other studies comparing the effects of EDs or seizures on learning and cognitive aspects, EDs in the absence of seizures had either no effect or a mild independent effect on attention and speed of information processing, especially when EDs occurred at high frequencies.

Short-term effects of EDs

1. Impact of EDs on neuropsychological tests: Short-term cognitive impairment induced by EDs is not necessarily a consequence of a global attention impairment but it may reflect disruption of brain functions specifically located in the affected brain regions. In addition, the cognitive deficits may depend on when the EDs occur. To cause specific cognitive dysfunctions, EDs may have to occur in the right place at the right time.

2. Impact of EDs on daily activities: Twenty children were evaluated for performance in scholastic tasks. A higher rate of EDs was associated with low test performance, especially for arithmetic. The driving performance of six individuals with EDs was monitored while driving at a constant speed of 90 km/h on a highway for a total of 420 km per patient. During periods with EDs, three individuals had impaired ability to maintain course and an additional individual showed trends toward impairment. The impairment in maintaining course during EDs occurred even in patients who had been seizure-free for years. The results of standard laboratory tests such as Corsi block-tapping or short-term verbal memory test during EDs in these same patients did not predict the results of the driving test. Although EDs may impair certain attention-sensitive tasks, including in seizure-free individuals, this impairment may not be predictable by standard neuropsychological tests.

3. EDs versus transient cognitive impairment (TCI) and short nonconvulsive seizures: If EDs lead to a measurable cognitive change, these discharges may not be subclinical, but instead clinical (transient cognitive impairment (TCI) or ictal (“subtle seizures”)). Various visual or auditory response tests have temporally correlated components of epochs with EDs to response delays. It has been proposed that the ED effect begins just before the spike and ends with the termination of the after-coming slow wave. In another series, the cognitive performance of 188 children (6–18 years old) was evaluated during a 2-h testing session with simultaneous EEG monitoring. The study population was divided into the following: (1) children with epilepsy who had short nonconvulsive seizures during the test (i.e., electroclinical events of staring or subtle movements lasting for seconds), (2) children with epilepsy without short nonconvulsive seizures during the test, and (3) controls without epilepsy. Short nonconvulsive seizures markedly impaired cognition. These were shorter than 19 s and were usually focal seizures and less frequently absence or myoclonic seizures. EDs without seizures also impaired cognition but their effects were more subtle. Are EDs a milder condition on the spectrum of nonconvulsive seizures? Or are EDs an early marker of the underlying etiology/state that predisposes to either cognitive dysfunction and/or epileptic seizures? Resolving these questions may help decide on the optimal management of individuals with EDs.

4. Challenges in interpretation of results: Study participants in short-term cognitive tests are an inherently biased population, because subjects with frequent EDs in the awake and alert state are typically preferred for these studies. Therefore, these results may or may not apply to subjects with less frequent EDs or to subjects with EDs during sleep. Furthermore, external stimuli and level of attention on a particular task may modify the frequency and characteristics of EDs.

Long-term effects of EDs

1. Pediatric focal epilepsy syndromes: Childhood epilepsy with centrotemporal spikes (CECTS), Panayiotopoulos syndrome, and late-onset childhood occipital epilepsy (Gastaut type) share common features such as relatively mild and infrequent seizures and frequent and sleep-potentiated EDs, which persist for several years after seizure freedom. In children with CECTS, abnormal neuropsychological development, especially in the verbal domain, was linked to more frequent EDs during sleep, whereas, in another study, impairments in academic and familial functioning were reported in 29%. Predictors of poor evolution were related to EDs and not to seizures. No correlation between spike rates and cognitive performance was seen in a different study of CECTS. In a series of 26 children with focal EDs (19 with CECTS, 2 with Panayiotopoulos syndrome, 1 with focal seizures, and 4 with no history of seizures) and learning difficulties, central information processing speed at baseline negatively correlated with frequency of EDs, without separating those without seizures. On follow-up, worsening central information processing speed correlated with increased EDs but also with ongoing seizures. It is unclear whether the seizures or EDs had independent impact on central processing. Among children with focal epilepsy syndromes, those with left centrotemporal EDs performed worse during complex language tasks, whereas children with occipital spikes performed worse in simultaneous information processing, especially in visual transformation tasks. In summary, the evidence, based on small case series of children with EDs and focal epilepsy, suggests worse cognitive outcome in the long term and this impairment may reflect the location of EDs.

2. Generalized epilepsies: Spike–wave discharges seen in children with childhood absence epilepsy may disrupt attention, consciousness, and information processing in the short term. There is also some evidence of long-term cognitive deficits. In a study comparing 16 children with childhood absence epilepsy, 14 children with type 1 diabetes, and 15 healthy children, the children with childhood absence epilepsy did not perform differently on measures of intellectual function, memory, academic achievement, fine motor speed, or processing speed. However, they performed worse on problem solving, letter fluency, complex motor control, attention/behavioral inhibition, and psychosocial functioning. Children with childhood absence epilepsy may have worse long-term psychosocial outcomes than patients with nonepileptic chronic diseases, such as juvenile rheumatoid arthritis. Juvenile myoclonic epilepsy may also show long-term subtle frontal processing dysfunction. It is possible that EDs progressively disrupt thalamofrontal neuronal networks, leading to deficits in functions subserved by these networks. However, both functional deficits and EDs may represent just biomarkers of genetically determined abnormal thalamofrontal neuronal networks.

3. Epileptic encephalopathies with language or cognitive regression: ESES is characterized by almost continuous spiking during non-REM sleep frequently associated with different degrees of cognitive regression. Long duration of the ESES pattern has been classically considered as a marker of poor cognitive outcome. In a literature review of 209 cases, an ESES duration >2 years was associated with poor cognitive outcomes. In a series of 30 patients with ESES who responded to treatment, there was a correlation between duration of the ESES pattern and return to cognitive baseline at follow-up. Fifty percent of children with ESES lasting <13 months return to baseline but none of those with ESES lasting >18 months. Objective measures of cognitive function before and after epilepsy surgery suggest that stopping ESES improves cognition. However, relatively small series and potential confounders such as underlying etiology, seizure burden, and AED treatment may warrant caution when attributing improvement exclusively to ED reduction. Furthermore, in a series of seven patients, no association was found between duration of ESES and cognitive outcome.

Common pathophysiologic mechanisms

Some genetic mutations present different degrees of ASD, EDs, epilepsy, and ID in the same patients, suggesting a common etiopathogenesis, probably mediated by abnormal synaptic plasticity and excitatory/inhibitory imbalance mechanisms. This opens a new approach to potentially treat these disorders, but also suggests that EDs may be just a manifestation of the underlying pathologic process, not the cause of cognitive regression. Different underlying mechanisms lead to ESES, an EEG pattern with prominent epileptiform activity. Both mutations in glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) and early thalamic lesions have been associated with the development of prominent EDs and ESES later in life, further emphasizing the idea of common pathways that lead to similar clinical phenotypes.

How to assess the impact of EDs on cognition

The question of whether long-term exposure to EDs impairs cognition and whether treatment of EDs can reverse this potential impairment remains unresolved. The short-term impact of EDs on cognition is tested with individuals in two different conditions: with and without EDs. Experiments are completed within a few hours of wakefulness and individuals act as their own controls. Patients with ESES or with CECTS lend themselves to this approach as they can be tested with a formal neuropsychological examination at baseline, their EDs can be reduced with AEDs for a period of time; and a postintervention formal neuropsychological examination can be repeated. Comparisons before and after treatment then can be corrected only for a limited number of confounders such as seizure burden, but not for factors that define the individual, such as gender or genetic substrate. Although such studies may be useful for short-term outcomes, interpretation of long-term outcomes may be challenged by the difficulty in dissociating the putative treatment-related improvement from the relative improvement in cognitive skills due to natural development or changes in educational system or life situations. Promising results may then justify larger scale studies on relative homogeneous populations (e.g., same syndrome or genetic background) designed to compare the developmental trajectories of individuals with EDs, as a function of treatment, while accounting for the multiple known confounders. Careful assessment of ED burden, types, and location would be important for both types of studies.

To Treat or Not to Treat

Until better evidence becomes available, treatment decisions have to be made. The hesitancy in treatment of EDs comes from the fact that there is no strong evidence for or against the causal role of EDs on long-term cognitive impairment. We suggest a non–evidence-based practical approach to manage EDs in different clinical scenarios.

1. Asymptomatic subjects: The cognitive impact of EDs in asymptomatic persons without epilepsy is unclear, whereas the risk for subsequent epilepsy is low and probably related to genetic traits. Therefore, incidentally detected EDs in asymptomatic subjects without epilepsy should not be treated because the treatment benefit is unclear.

2. Patients with EDs and cognitive dysfunction/regression without epilepsy: There are reports of some cognitive improvement with AEDs in patients in this category. However, larger series demonstrate mixed results. In a double-blind, single-crossover trial, eight children (6–12 years old) with learning and behavior problems and EDs were randomized to receive valproate or placebo. Increased distractibility, increased response time, lower memory scores, and no clinical improvement were found in children on valproate. In a prospective, open-label study, six children (7–15 years old) with focal EDs and learning difficulties were treated with levetiracetam. At 10 weeks follow-up, four participants showed improvement in the Wide Range Assessment of Memory and Learning but not on the Wechsler Individual Achievement Test. In summary, although some patients may achieve some cognitive improvements on AEDs, this may reflect natural fluctuations in the course of the disease, and there is currently insufficient evidence to recommend AEDs in patients with cognitive dysfunction/regression without epilepsy. There may also be worsening of cognitive function with AEDs.

3. Patients with EDs and cognitive dysfunction/regression in the setting of epileptic encephalopathies: In epileptic encephalopathies with regression, administration of adrenocorticotropic hormone (ACTH), high-dose steroids, or immunotherapy has been reportedly effective in improving the EEG and treating regression. Reduction of EDs in patients with ESES with high-dose benzodiazepines is associated with improved cognitive function in some cases. In a series of 32 children with ESES, reduction of EDs with valproate or ethosuximide was associated with cognitive improvement. Epilepsy surgery for identified epileptogenic lesions in patients with ESES halted cognitive deterioration or even improved cognition in at least half of the patients. Results need to be interpreted in the setting of uncontrolled data acquisition, in a naturally fluctuating condition with other factors potentially influencing outcome. In summary, in patients with epileptic encephalopathies and cognitive dysfunction/regression, which can be related to EDs, a treatment trial might be justified.

4. Patients with EDs, cognitive dysfunction/regression, and well-controlled seizures: In a double-blind, placebo-controlled, single-crossover study, 61 children (7–17 years) with well-controlled seizures and behavioral and/or cognitive problems were randomized to lamotrigine or placebo. Well-controlled seizures were defined as no or infrequent focal or generalized seizures. Behavior (assessed with the Conners ratings scales for parents and teachers) improved in patients with reduced EDs while on lamotrigine. No significant effect on seizure frequency was noted. Therefore, a trial with antiepileptic drugs (AEDs) may be considered in some patients in this category, especially when the cognitive dysfunction is progressive.

5. Patients with cognitive dysfunction/regression and ongoing seizures: In patients with cognitive dysfunction/regression or ongoing seizures, treatment may be warranted to control seizures. There is insufficient evidence to support that cessation of EDs is a better therapy endpoint for the currently available treatments.

Treatment options for EDs

Few studies evaluate AEDs for EDs, and their results should be interpreted in the context of natural fluctuations in EDs. A large pediatric series compared EDs in 213 EEG pairs before and after introduction of AEDs. The ED suppression rate (complete disappearance of EDs of all types in the EEG tracing after treatment) was 22% for phenobarbital, 33% for carbamazepine, and 46% for valproate, and these values remain stable for focal or generalized EDs, time elapsed between EEG studies, and neonatal or nonneonatal EEG studies. In a double-blind single-crossover study, 12 patients (4–21 years old) with generalized drug-resistant epilepsy were treated with addon lamotrigine and placebo, with EDs markedly reduced (duration and density of EDs) on lamotrigine. In a double-blind placebo-controlled randomized crossover study low-dose intramuscular clonazepam markedly decreased EDs in children. For patients with ESES, high-dose benzodiazepines have been shown to decrease epileptiform activity in some patients. In a placebo-controlled double-blind crossover study in 18 children (5–10 years) with ESES, levetiracetam showed moderate reduction of nocturnal EDs. In a series of 44 patients with ESES treated with long-term hydrocortisone, the EEG normalized in 21 patients (48%), although relapse occurred in 14 of them. In summary, valproate, lamotrigine, levetiracetam, benzodiazepines, and steroids potentially among others, may have an effect on EDs, although it is unclear if that effect is independent of the effect on seizures and therefore the effect of seizures on EDs. However, certain AEDs can also exacerbate EDs or certain negative behaviors (e.g., hyperactivity).

Conclusions

EDs may impair cognition in the short-term in a location-specific fashion. In contrast, there is conflicting evidence on the impact of EDs on long-term cognitive outcome. Currently, there is not sufficient evidence to support treatment of EDs alone, although treatment trials may be considered if EDs are suspected to contribute to cognitive disability and behavioral problems.

Acknowledgments

Ivan Sanchez Fernandez is funded by a grant for the study of epileptic encephalopathies from “Fundacion Alfonso Martın Escudero” and the HHV6 Foundation. Tobias Loddenkemper serves on the Laboratory Accreditation Board for Long Term (Epilepsy and ICU) Monitoring (ABRET), serves as a member of the American Clinical Neurophysiology Council (ACNS), serves on the American Board of Clinical Neurophysiology, serves as an Associate Editor of Seizure, performs video-EEG longterm monitoring, EEG studies, and other electrophysiologic studies at Children’s Hospital Boston and bills for these procedures. He receives support from Patient-Centered Outcomes Research Institute, by the Payer Provider Quality Initiative, receives funding from the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, the Pediatric Epilepsy Research Foundation, Citizens United for Research in Epilepsy (CURE), and the Danny Did Foundation, and received investigator initiated research support from Eisai Inc, Lundbeck, and Upsher Smith. Aristea Galanopoulou has received research funding from the U.S. Department of Defense, CURE, NINDS NS-78333, UCB, the Heffer Family and Barry Segal Family Foundations and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. She has received royalties for book publishing from Morgan & Claypool Publishers, Elsevier, and John Libbey Eurotext; and honoraria from the Department of Defense (grant reviews). Solomon Moshe is the Charles Frost Chair in Neurosurgery and Neurology and funded by grants from the National Institutes of Health (NIH; NS43209, NS20253, NS45911, NS-78333), CURE, the U.S. Department of Defense, UCB, the Heffer Family and Barry Segal Family Foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. He receives from Elsevier an annual compensation for his work as Associate Editor in Neurobiology of Disease and royalties from two books he co-edited. He received a consultant fee from Lundbeck and UCB. SLM owns a patent for the multiple-hit model of infantile spasms (patent US7863499). There are no conflicts of interest related to this manuscript.

Disclosure

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.