Pharmacologic treatment of status epilepticus

ABSTRACT

Introduction: Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 per 100,000 per year, evidence from high-class clinical trials is only available for the early stages of SE.

Areas covered: Following a four-stage approach of SE (early, established, refractory and super-refractory), we present pharmacological treatment options and their clinical utility.

Expert opinion: Intravenous lorazepam and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal midazolam has emerged as first-line non-intravenous drug with similar efficacy and safety to other intravenous or rectal benzodiazepines. In established SE intravenous antiepileptic drugs are in use. There are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7–84.8) and phenobarbital 73.6%, (95% CI 58.3–84.8) than with levetiracetam (68.5%, 95% CI 56.2–78.7) or phenytoin (50.2%, 95% CI 34.2–66.1). Based on the favourable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin. Treatment options in refractory SE are intravenous anaesthetics. In super-refractory SE ketamine, magnesium, steroids and other drugs have been used with variable outcomes. At this stage therapeutic decisions are based on doctors’ preferences, patient factors such as age and comorbidity, and cause of SE, if identified.

KEYWORDS:

• Status epilepticus
• antiepileptic drugs
• benzodiazepines
• anaesthetics
• outcome

Article highlights

• Early treatment of status epilepticus (SE) is effectively controlled in with intravenous lorazepam or intramuscular midazolam in 64 to 73%. Intravenous clobazam might be a useful alternative, but high-class randomized trials are missing.

• In children, buccal midazolam can be used as an alternative whenever intravenous or intramuscular application of other benzodiazepines is not possible.

• After failure of benzodiazepines in the early stage, phenytoin (or fosphenytoin), valproate, levetiracetam, phenobarbital, and lacosamide are in use. Currently, there is no high-class evidence available to prefer one to the other; valproate and levetiracetam have a favorable safety profile compared to phenobarbital and phenytoin; lacosamide is now increasingly used, but available evidence is still very little and restricted to a few retrospective series, which do not allow to give stronger recommendations for its use.

• In refractory SE propofol, continuous midazolam infusion, thiopental/pentobarbital is in use. There is no randomized trial available, but retrospective series suggest a higher morbidity with thiopental/pentobarbital, compared to midazolam or propofol.

• In super-refractory SE, ketamine, magnesium, and immunomodulatory treatments should be considered early. The identification of a cause and its appropriate treatment is of utmost importance at this stage.

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Declaration of interest

E Trinka has acted as a paid consultant to Eisai, Ever Neuropharma, Biogen Idec, Medtronics, Bial, and UCB Pharma and has received speakers’ honoraria from Bial, Eisai, GL Pharma, GlaxoSmithKline, Boehringer, Viropharma, Actavis, and UCB Pharma in the past 3 years. E Trinka has received research funding from UCB Pharma, Biogen-Idec, Red Bull, Merck, the European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung. He is also part of the investigators planning the ESET-Trial and member of the Task Force on Classification of Status Epilepticus of the ILAE. J Höfler has received speakers’ honoraria from UCB Pharma and travel support from Eisai and GL Pharma. M Leitinger has received a travel grant by Medtronics and UCB Pharma. F Brigo received speaker’s honoraria from UCB Pharma and travel support from Eisai. G Kalss has received travel support from UCB Pharma. Alexandra Rohracher received travel support from Eisai and acted as a paid consultant to Neuroconsult. 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