Demirtas Cumaali, Akca Metehan, Aykin Ugur, Surmeneli Yunus Emre, Yildirim Hava, Yildirim Mehmet
Department of Physiology, Hamidiye Faculty of Medicine, University of Health Sciences, İstanbul, Türkiye.
Department of Physiology, Faculty of Medicine, Tokat Gaziosmanpaşa University, Tokat, Türkiye.
Brain Behav. 2025 May;15(5):e70546. doi: 10.1002/brb3.70546.
Status epilepticus causes the most severe condition related to epilepsy in terms of high mortality rate. Although status epilepticus treatment guidelines specify a treatment process based on three-stage monotherapy, effective control cannot yet be achieved in all cases. In the presented study, with electrophysiological and behavioral tests, it was aimed to investigate the effectiveness of the combination of midazolam (MDZ), one of the most commonly used benzodiazepines in the first-line treatment of status epilepticus, with the second-line antiepileptics levetiracetam (LEV), lacosamide (LCM), valproic acid (VPA), and fosphenytoin (fPHT).
A status epilepticus model was created with lithium-pilocarpine (5 mEq/kg-320 mg/kg) in adult male Sprague-Dawley rats with implanted electroencephalography (EEG) electrodes. MDZ (9 mg/kg) alone or in dual combinations with antiepileptic drugs (200 mg/kg LEV, 50 mg/kg LCM, 300 mg/kg VPA, 100 mg/kg fPHT) was injected i.p. to the experiment groups with status epilepticus. After video-EEG recordings were taken from the rats during and after status, the effects of drug interactions on cognitive and motor behaviors were examined by applying behavioral tests (open field, Rotarod, radial arm maze, and passive avoidance).
Compared with the untreated status epilepticus group, it was determined that MDZ alone and the combination of four antiepileptic drugs administered with MDZ significantly reduced the mortality rate, spike frequency, and spike amplitude of epileptic seizures and suppressed epileptic seizures at certain levels (p < 0.01). Compared to MDZ monotherapy, it was determined that the mortality rate and spike frequency and amplitude decreased significantly in the MDZ + LCM group (p < 0.01), whereas on the other hand, mortality and spike frequency increased in the MDZ + LEV group (p < 0.01). No negative effects were observed in learning and memory in all treatment groups, but it was determined that the motor functions of the animals treated with MDZ + fPHT were impaired compared to both the control group without any treatment and the MDZ group (p < 0.01).
In the status epilepticus model induced by lithium-pilocarpine, the combination of MDZ + LCM was found to be the most effective polytherapy option in reducing seizures and mortality. Additionally, it was observed that LEV, LCM, and VPA administered together with MDZ did not negatively affect both cognitive and motor functions.
癫痫持续状态在高死亡率方面导致了与癫痫相关的最严重情况。尽管癫痫持续状态治疗指南规定了基于三阶段单一疗法的治疗过程，但并非所有病例都能实现有效控制。在本研究中，通过电生理和行为测试，旨在研究咪达唑仑（MDZ）（癫痫持续状态一线治疗中最常用的苯二氮䓬类药物之一）与二线抗癫痫药物左乙拉西坦（LEV）、拉科酰胺（LCM）、丙戊酸（VPA）和磷苯妥英（fPHT）联合使用的有效性。
在植入脑电图（EEG）电极的成年雄性Sprague-Dawley大鼠中，用锂-匹罗卡品（5 mEq/kg - 320 mg/kg）建立癫痫持续状态模型。将MDZ（9 mg/kg）单独或与抗癫痫药物（200 mg/kg LEV、50 mg/kg LCM、300 mg/kg VPA、100 mg/kg fPHT）联合腹腔注射到患有癫痫持续状态的实验组。在癫痫持续状态期间和之后对大鼠进行视频脑电图记录后，通过应用行为测试（旷场试验、转棒试验、放射状臂迷宫试验和被动回避试验）检查药物相互作用对认知和运动行为的影响。
与未治疗的癫痫持续状态组相比，确定单独使用MDZ以及与MDZ联合使用的四种抗癫痫药物组合均显著降低了癫痫发作的死亡率、棘波频率和棘波幅度，并在一定程度上抑制了癫痫发作（p < 0.01）。与MDZ单一疗法相比，确定MDZ + LCM组的死亡率、棘波频率和幅度显著降低（p < 0.01），而另一方面，MDZ + LEV组的死亡率和棘波频率增加（p < 0.01）。在所有治疗组中均未观察到对学习和记忆的负面影响，但确定与未接受任何治疗的对照组和MDZ组相比，接受MDZ + fPHT治疗的动物的运动功能受损（p < 0.01）。
在锂-匹罗卡品诱导的癫痫持续状态模型中，发现MDZ + LCM组合是减少癫痫发作和死亡率方面最有效的联合治疗方案。此外，观察到与MDZ一起使用的LEV、LCM和VPA对认知和运动功能均无负面影响。
