Management of refractory status epilepticus in adults: still more questions than answers

Summary

Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite treatment with benzodiazepines and one antiepileptic drug. RSE should be treated promptly to prevent morbidity and mortality; however, scarce evidence is available to support the choice of specific treatments. Major independent outcome predictors are age (not modifiable) and cause (which should be actively targeted). Recent recommendations for adults suggest that the aggressiveness of treatment for RSE should be tailored to the clinical situation. To minimise intensive care unit-related complications, focal RSE without impairment of consciousness might initially be approached conservatively; conversely, early induction of pharmacological coma is advisable in generalised convulsive forms of the disorder. At this stage, midazolam, propofol, or barbiturates are the most commonly used drugs. Several other treatments, such as additional anaesthetics, other antiepileptic or immunomodulatory compounds, or non-pharmacological approaches (eg, electroconvulsive treatment or hypothermia), have been used in protracted RSE. Treatment lasting weeks or months can sometimes result in a good outcome, as in selected patients after encephalitis or autoimmune disorders. Well designed prospective studies of RSE are urgently needed.

Introduction

With an annual incidence of 10–40 per 100 000 population,1, 2, 3 status epilepticus (SE) is the second most frequent neurological emergency (acute stroke being the first) with a risk of major morbidity or mortality.⁴ Irrespective of the timeframe, SE that persists despite adequate administration of benzodiazepines and at least one antiepileptic drug is labelled refractory SE (RSE).5, 6 This resistance to treatment occurs in 23–43% of patients with SE; the only prospective study of RSE frequency⁶ estimates lower proportions than retrospective assessments that are based in the intensive care unit (ICU).7, 8, 9 RSE is mostly associated with acute, severe, and potentially fatal underlying causes, such as encephalitis, massive stroke, or rapidly progressive primary brain tumours, and is typically accompanied by severe impairment of consciousness.6, 7, 10

Over the past few decades, important advances in the understanding of the basic mechanisms underlying SE and RSE have been achieved, mostly from seminal animal studies. However, animal data cannot be automatically translated to patients, and up to now, well designed studies of epidemiological, clinical, and therapeutic aspects remain scarce. Treatment for RSE is not evidence-based, despite the disorder being recognised as an important entity in emergency and intensive care settings.

Our principal aim in this Review is to summarise present knowledge of RSE in adults, with particular attention to the balance between risks and benefits of different treatment strategies, including rarely used options. In view of the substantial differences in pathophysiologcal mechanisms and treatment approaches in neonates and infants, our focus is on older children and adults. We also identify areas in need of further research, and draw attention to some practical difficulties that need to be overcome for well designed, prospective clinical studies to take place.