Importance Tolerability is a key determinant of the effectiveness of epilepsy treatment. It is important to evaluate whether the overall tolerability has improved. Objective To identify factors associated with poor tolerability of antiseizure medications (ASMs) and examine temporal changes in tolerability. Design, Setting, and Participants This was a longitudinal cohort study at a specialist clinic in Glasgow, Scotland. Patients with newly diagnosed and treated epilepsy between July 1982 and October 2012 were included from 2282 eligible individuals. They were followed up until April 2016 or death. Data analysis was completed in August 2019. Exposures Antiseizure medications. Main Outcomes and Measures Univariable and multivariable survival analyses were performed to examine associations between potential risk factors and development of intolerable adverse effects (AEs). Intolerable AE rates of the ASMs as the initial monotherapy were compared between 3 epochs (July 1982-June 1992, July 1992-June 2002, and July 2002-April 2016). Results Of 1795 patients, 969 (54.0%) were male, and the median (interquartile range) age was 33 (21-50) years. A total of 3241 ASMs were prescribed during the period, of which 504 (15.6%) were discontinued within 6 months owing to intolerable AEs. Children younger than 18 years had lower intolerable AE rates than adults (vs aged 18-64 years: adjusted hazard ratio [aHR], 1.58; 95% CI, 1.07-2.32; vs aged ≥65 years: aHR, 1.90; 95% CI, 1.19-3.02) while female individuals (aHR, 1.60; 95% CI, 1.30-1.96) and those who had more than 5 pretreatment seizures (aHR, 1.24; 95% CI, 1.03-1.49) were associated with having higher risk. For each ASM trial, the risk of intolerable AEs increased with the number of previous drug withdrawals due to AEs (aHR, 1.18; 95% CI, 1.09-1.28) and the number of concomitant ASMs (aHR, 1.31; 95% CI, 1.04-1.64). The proportion of second-generation ASMs prescribed as the initial monotherapy increased from 22.3% (33 of 148) in the first epoch to 68.7% (645 of 939) in the last (P < .001). Although differences in intolerable AE rates and types of AEs were found between the ASMs, there was no difference in the overall intolerable AEs rates to the initial monotherapy across the 3 epochs (first: 10.1% [15 of 148]; second: 13.8% [98 of 708]; third: 14.0% [131 of 939]; P = .41). Conclusions and Relevance In this cohort study, the increased use of the second-generation ASMs had not improved overall treatment tolerability. Greater effort to improve tolerability in ASM development is needed.

中文翻译：

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在新诊断的癫痫患者中抗癫痫药物的耐受性。

重要性耐受性是癫痫治疗有效性的关键决定因素。评估总体耐受性是否有所提高很重要。目的确定与抗癫痫药物（ASM）耐受性差相关的因素，并检查耐受性的时间变化。设计，环境和参与者这是一项在苏格兰格拉斯哥的专科诊所进行的纵向队列研究。1982年7月至2012年10月之间患有新诊断和治疗的癫痫患者来自2282名合格个体。对他们进行了跟踪，直到2016年4月或死亡。数据分析于2019年8月完成。暴露抗癫痫药物。主要结果和措施进行了单变量和多变量生存分析，以检查潜在风险因素与不可忍受的不良反应（AE）的发展之间的关联。在3个时期（1982年7月至1992年6月，1992年7月至2002年6月以及2002年7月至2016年4月）比较了ASM作为初始单一疗法的无法忍受的AE率。结果1795名患者中，有969名（54.0％）为男性，中位年龄（四分位间距）为33（21-50）岁。在此期间，总共开出了3241枚ASM，其中504枚（15.6％）由于无法耐受的AE而在6个月内停药。18岁以下的儿童的不良AE发生率低于成人（相对于18-64岁的年龄：调整后的危险比[aHR]为1.58； 95％CI为1.07-2.32； vs≥65岁的年龄段为：aHR 1.90； 95％CI ，1.19-3.02），而女性（aHR，1.60； 95％CI，1。30-1.96）和治疗前癫痫发作次数超过5次的患者（aHR，1.24； 95％CI，1.03-1.49）与较高的风险相关。对于每个ASM试验，不可耐受AE的风险随着先前因AE停药的次数增加（aHR，1.18； 95％CI，1.09-1.28）和伴随的ASM数量（aHR，1.31； 95％CI，1.04） -1.64）。规定为初始单一疗法的第二代ASM的比例从第一个时期的22.3％（148个中的33个）增加到最后一个时期的68.7％（939个中的645个）（P <.001）。尽管在ASM之间发现了不能耐受的AE率和类型的AE，但在3个时期中，与最初的单一疗法相比，总的不能耐受的AE率没有差异（第一：10.1％[148中的15]；第二：13.8％[ 708的98]；第三：14.0％[939的131]； P = 0.41）。结论与相关性在这项队列研究中，增加使用第二代ASM并没有改善总体治疗耐受性。需要付出更大的努力来提高ASM开发的容忍度。