Effective treatment for lithium pilocarpine-induced status epilepticus: clonazepam and lacosamide combination

This study aimed to investigate the potential of clonazepam (CLZ), one of the benzodiazepines used in the first-line treatment of status epilepticus, in combination with anti-seizure medications such as levetiracetam (LEV), lacosamide (LCM), valproic acid (VPA), and fosphenytoin (fPHT), which are used in second-line treatment, in polytherapy. Fifty-six male Sprague-Dawley rats were randomly assigned to seven groups. A status epilepticus model was induced by injection of lithium Cl (5 mEq/kg, s.c.) and pilocarpine HCl (320 mg/kg, i.p.). After induction of status epilepticus, CLZ (1 mg/kg) was administered either alone or in combination with LEV (200 mg/kg), LCM (50 mg/kg), VPA (300 mg/kg), and fPHT (100 mg/kg). Video-EEG recordings were taken from the animals, and behavioral tests were performed. Mortality rates were significantly lower in the CLZ + LCM, CLZ + VPA, and CLZ + fPHT groups compared to the status epilepticus group (p < 0.01, p < 0.05, p < 0.01, respectively), and in the CLZ + LCM and CLZ + fPHT groups compared to CLZ monotherapy (p < 0.05). Spike frequency decreased in all combination groups (p < 0.01). Spike amplitude decreased in the CLZ + LCM and CLZ + VPA combinations (p < 0.01, p < 0.05, respectively). Anxiety levels increased in the CLZ + LCM and CLZ + VPA groups (p < 0.05). Performance impairment related to spatial memory was observed in the CLZ + fPHT group (p < 0.05). A decrease in forced motor functions was observed in the CLZ + VPA and CLZ + fPHT groups compared to the control group (p < 0.01). In conclusion, CLZ alone and the CLZ-LEV combination were insufficient to prevent epileptiform activity associated with status epilepticus, whereas CLZ-based polytherapies -most notably CLZ-LCM, followed by CLZ-VPA and CLZ-fPHT- were more effective in reducing epileptiform spike frequency and amplitude.