Topiramate as an Adjunctive Treatment in Patients with Refractory Status Epilepticus An Observational Cohort Study

Background: Refractory status epilepticus (RSE) is the most severe manifestation of status epilepticus (SE), often requiring intensive care and therapeutic coma. It is associated with prolonged intensive care unit (ICU) and hospital stays, as well as increased morbidity and mortality. Treatment involves both intravenous anaesthetics and antiepileptic drugs (AEDs) that can be administrated intravenously, by nasogastric tube or by percutaneous endoscopic gastrostomy. Experience with some of the newer AEDs for the treatment of RSE is restricted and higher-class evidence regarding tolerability and efficacy is lacking. Topiramate is a potent broad-spectrum AED with several modes of action, including blockade of the ionotropic glutamatergic AMPA receptor, which is likely to be an important mechanism for the treatment of SE. While there is no commercially available intravenous formulation, topiramate can be administered enterally, which may make it suitable for the treatment of RSE. Objective: The objective of this study was to evaluate the tolerability, safety profile and efficacy of adjunctive and enterally administered topiramate in patients with RSE. Methods: A medical chart review was performed of all consecutive patients treated for RSE between August 2004 and December 2011 at the ICU of the University Hospital Basel (Basel, Switzerland). Results: 113(43%) of all consecutive 268 patients with SE developed RSE. Of those, 35 (31%) were treated with topiramate. Median age was 60.5 years. Topiramate was used as an add-on treatment after 1-6 (median 4) prior administered AEDs had failed. It was introduced after a median of 2 (range 2-23) days for a duration of 1-24 (median 3) days. The response rate after topiramate administration as the third AED was 86% (6/7 patients), and remained stable at 67% after administration as the fourth, fifth, sixth or seventh AED when the groups of successfully and probably successfully treated patients were pooled. Overall, RSE was terminated in 71% of patients within 72 hours after first administration of topiramate, in 9% of patients, within 24 hours (none in the 800 mg/day group; 9% in the 400-799 mg/day group; and 11% in the <400 mg/day group). Mortality was 31% and was not strictly dependent on failure to terminate RSE, but also on the underlying aetiology of RSE. There were no serious or fatal adverse events directly attributable to topiramate. Adverse effects included slight hyperchloremic acidosis and hyperammonemia (all associated with co-medication with valproic acid). Conclusion: Treatment with enterally administered topiramate was feasible, well tolerated and had a good safety profile in patients with RSE in this observational, single-centre, cohort study. Refractory SE was terminated in the majority of patients within 3 days after initiation of topiramate. Prospective studies are warranted to further evaluate topiramate for the treatment of RSE.