Refractory Status Epilepticus and Therapeutic Uncertainties: a Comprehensive Review on Targeting Neuroinflammation and Rationale for Developing a Platform Trial

Refractory Status Epilepticus (RSE) is a neurological emergency associated with considerable morbidity and mortality. The molecular mechanisms contributing to neuroinflammation in RSE are increasingly being recognized. Despite its severity, high-quality and conclusive evidence is lacking for many RSE treatments, especially regarding the optimization of antiseizure medications and emerging immunotherapies. In this manuscript, the use of immunotherapy as a valuable treatment option in RSE is reviewed. The example of Toclizumab is used, its potential efficacy demonstrated by a case series from our center. Traditional clinical trial designs have proven inadequate in efficiently addressing these evidence gaps for this complex and heterogeneous condition. In examining the wider evidence for the use of anti-inflammatory agents, including early immunotherapy, the scope for adaptive platform trials is explored to be utilized to develop an evidence base in this area. Neuroinflammation plays a role in propagating seizures and associated neuronal injury in RSE; these pathways may be amenable to immunomodulation. In this review, the limitations of existing observational data and the need for efficient, quickly translatable clinical trials are highlighted to evaluate multiple interventions for RSE. Innovative trial designs, such as adaptive platform trials, help generate robust evidence for rapid uptake in RSE.