Epileptiform activity (EA) is associated with worse outcomes including increased risk of disability and death. However, the effect of EA on the neurologic outcome is confounded by the feedback between treatment with anti-seizure medications (ASM) and EA burden. A randomized clinical trial is challenging due to the sequential nature of EA-ASM feedback, as well as ethical reasons. However, some mechanistic knowledge is available, e.g., how drugs are absorbed. This knowledge together with observational data could provide a more accurate effect estimate using causal inference. We performed a retrospective cross-sectional study with 995 patients with the modified Rankin Scale (mRS) at discharge as the outcome and the EA burden defined as the mean or maximum proportion of time spent with EA in six-hour windows in the first 24 hours of electroencephalography as the exposure. We estimated the change in discharge mRS if everyone in the dataset had experienced a certain EA burden and were untreated. We combined pharmacological modeling with an interpretable matching method to account for confounding and EA-ASM feedback. Our matched groups' quality was validated by the neurologists. Having a maximum EA burden greater than 75% when untreated had a 22% increased chance of a poor outcome (severe disability or death), and mild but long-lasting EA increased the risk of a poor outcome by 14%. The effect sizes were heterogeneous depending on pre-admission profile, e.g., patients with hypoxic-ischemic encephalopathy (HIE) or acquired brain injury (ABI) were more affected. Interventions should put a higher priority on patients with an average EA burden higher than 10%, while treatment should be more conservative when the maximum EA burden is low.

翻译：癫痫样活动（EA）与不良结局（包括残疾和死亡风险增加）相关。然而，EA对神经学结局的影响受到抗癫痫药物（ASM）治疗与EA负荷之间反馈的混杂作用。由于EA-ASM反馈具有序列性及伦理原因，开展随机临床试验具有挑战性。但部分机制性知识已有积累（例如药物吸收过程），这些知识结合观察性数据可通过因果推断提供更精确的效应估计。我们开展了一项回顾性横断面研究，纳入995例患者，以出院时改良Rankin量表（mRS）评分作为结局指标，暴露因素定义为：在脑电图监测前24小时内，以六小时为时间窗内EA所占时间的平均值或最大比例表示的EA负荷。我们估算了若数据集中所有患者均经历特定EA负荷且未经治疗时出院mRS评分的变化。我们将药理学建模与可解释性匹配方法相结合，以控制混杂因素和EA-ASM反馈。匹配组质量经神经科医师验证。未经治疗时最大EA负荷超过75%的患者出现不良结局（严重残疾或死亡）的概率增加22%，而轻度但持续存在的EA使不良结局风险增加14%。效应量因入院前特征而异，例如缺氧缺血性脑病（HIE）或获得性脑损伤（ABI）患者受影响更大。干预措施应优先关注平均EA负荷高于10%的患者，而当最大EA负荷较低时应采取更保守的治疗策略。