Combination drug therapy for the treatment of status epilepticus

Abstract

Status epilepticus (SE) is a common neurological emergent disease with high mortality and disability rates. Rapidly and effectively controlling seizures is key to saving the lives of patients and improving their prognoses. Traditional antiepileptic drugs for SE are ineffective in 30–40% of cases. In light of the diverse etiology and complex pathogenesis of SE, combination drug therapy for SE might be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms. This review summarizes combination drug therapies used for SE in animal experiments and clinical practice, the potential advantages of combination drug therapy and specific combination drug therapies using different antiepileptic drugs. The aim is to help researchers seek better treatments for early termination of SE.

Keywords:

• AEDs
• animal experiment
• clinical practice
• combination drug therapy
• monotherapy
• SE
• seizure

Financial & competing interests disclosure

This work was supported by the National Clinical Key Specialty Construction Foundation of China and the National Natural Science Foundation of China (grant number is 81271445). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Status epilepticus (SE) is a multifactorial and heterogeneous disease with high mortality and disability rates. Traditional antiepileptic drugs (AEDs) for SE are ineffective in 30–40% of cases. In light of the diverse etiology and complex pathogenesis of SE, combination drug therapy for SE might be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms.

• SE is a continuous disease process, and the pathogenesis might not be the same at different time points. Repeated and prolonged seizures induce the increasing incidence of RSE. The combined application of drugs that act on different neurotransmitters may have more advantages. In particular, the use of some new AEDs as additive drugs might improve the prognoses of patients.

• Sustained seizures can cause substantial damage to the brain, including neuronal loss and cerebral edema. The early use of AEDs that affect multiple mechanisms is conducive to terminating SE early to improve prognoses.

• Combination drug therapy with levetiracetam (LEV), ketamine and stiripentol for SE has been studied using animal experiments. These studies have supported the idea that characteristics of combination therapy include synergistic and rapid effects, low toxicity and nerve protection.

• Both animal experiments and clinical studies have supported the rationale for combination therapy for SE. The currently available combination drug therapies mainly involve LEV, ketamine, midazolam, phenytoin, barbiturates, stiripentol, steroids and other drugs that can terminate SE, RSE and ESES syndrome.

• The following aspects of specific combination drug therapies with different AEDs (benzodiazepines, LEV, ketamine, midazolam, phenytoin, barbiturates, stiripentol and immunomodulatory drugs) were discussed separately: combination therapy methods, indications, modes of administration, the effective time, adverse reactions and precautions.

• Future research will examine combination drug therapy, particularly involving LEV, ketamine, steroids and immunomodulatory drugs. More prospective large-scale and multicenter studies of combination drug therapies are needed to provide better treatment strategies for clinicians.

• Randomized, double-blind, controlled clinical trials of SE are not allowed in general because no effective medicines can be used for comparison. In addition, the low prevalence of RSE makes the study of a large sample impossible. We recommend the establishment of a network of case files in a registered system to collect more data on clinical treatment.