Verapamil attenuates the malignant treatment course in recurrent status epilepticus

Abstract

In the scenario of refractory status epilepticus, the recommended approach of intensive care treatment is limited with respect to the available pharmacodynamic variability and its impeding, severe side effects. Alternative treatment options are therefore urgently needed. In the case described, a patient with nonlesional frontal lobe epilepsy had a high-frequency series of tonic seizures, which evolved into a malignant form of status epilepticus. Co-administration of verapamil, a potent multidrug transporter inhibitor, was followed by significant reduction in seizure frequency. We discuss the putative role of verapamil and the specific risk factors for this malignant treatment course.

Introduction

Status epilepticus (SE) remains refractory to first- or second-line drug treatment in 31 to 50% of cases [1]. In such cases, urgent treatment with anticonvulsant anesthetics, such as midazolam, propofol, and barbiturates, is recommended [1], but unfortunately is associated with severe adverse effects, such as respiratory depression, arterial hypotension, and immunosuppression [2]. Thus, longer hospitalization and poor functional outcome can become consequences of this aggressive, but possibly lifesaving, treatment approach.

The therapy for refractory SE is hampered by the limited pharmacodynamic variability of the currently recommended anesthetic anticonvulsants: midazolam, propofol, and the barbiturates act predominantly via γ-aminobutyric acid (GABA)-mediated inhibition [3]. The efficacy of this GABAergic treatment modality, however, decreases the longer SE lasts [4], so that anesthetic anticonvulsants can fail to terminate refractory SE. An available alternative, the glutamatergic-N-methyl-d-aspartate (NMDA) receptor antagonist ketamine, is restricted in view of only anecdotal promising reports [5] and its limited clinical applicability [4]. Consequently, other therapeutic strategies have been used in an attempt to treat SE: either addition of non-GABAergic drugs, such as topimarate [4] and levetiracetam [1], or use of nonpharmaceutical techniques, such as brain stimulation, hypothermia, and resective surgery [1].

Experimental data increasingly suggest that multidrug transporters (MDTs) play a role in the pathogenesis of pharmacoresistance in epilepsy [6], [7] by returning exogenous substances, such as antiepileptic drugs (AEDs), to the blood vessels at the blood–brain barrier (BBB). Verapamil unselectively inhibits the P-glycoprotein (P-gp) transporter, which is a widespread MDT for several AEDs (see Table 1) [7], [8], [9]. Verapamil, therefore, is a potential candidate for adjunctive treatment in refractory SE.

In comparison to incident SE, recurrent SE is usually less likely to become refractory and is associated with a better outcome [10]. There are only a few reports of refractory SE that does not respond to anesthetic anticonvulsant drug therapy. In this subgroup, a recent study identified acute encephalitis as a sole independent risk factor, and previous diagnosis of epilepsy was rare [5].

The following case report illustrates the malignant treatment course of recurrent SE in a patient with nonlesional, pharmacoresistant epilepsy. Adjunctive treatment with verapamil was initiated and partial reduction in seizure frequency was observed within a short observation period.