What is the promise of new antiepileptic drugs in status epilepticus? Focus on brivaracetam, carisbamate, lacosamide, NS‐1209, and topiramate

The vast majority of potential antiepileptic drugs (AEDs) are initially evaluated for their ability to prevent recurrence of seizures, usually in patients with partial-onset seizures, and clinical studies in status epilepticus are performed only exceptionally prior to regulatory approval. However, it is increasingly common to characterize the potential activity of a candidate AED in animal models of status. Information from these studies can be useful in determining whether a specific compound bears promise for the treatment of acute seizure conditions, and in finalizing administration protocols for clinical studies. This summary reviews preclinical and, where applicable, clinical findings on the potential value of brivaracetam, carisbamate, lacosamide, NS-1209, and topiramate in the treatment of status epilepticus. Among these agents, topiramate has been in clinical use for the longest. Its mechanisms of action include blockade of sodium channels, enhancement of γ-aminobutyric acid (GABA)ergic transmission and antagonism of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors. Topiramate shows “neuroprotective” or “disease modifying” activity in a number of experimental models (Willmore, 2005), including some models of epileptogenesis and brain damage secondary to status epilepticus (Suchomelova et al., 2006; Shatskikh et al., 2009). Case reports and small case series provide suggestive evidence that topiramate can be clinically effective in terminating drug-refractory status (Selvitelli & Drislane, 2007), even though these data are difficult to interpret because positive outcomes are more likely to be reported. The lack of a parenteral formulation for topiramate is a limitation, and in reported cases suggestive of clinical efficacy the termination of status occurred with a significant latency after administration of the oral formulation (usually 12–48 h). In a recent report from Israel, topiramate was tried, usually as a third-line agent, in 14 children with electrical status epilepticus in sleep, and no evidence of efficacy was found in any of these children (Kramer et al., 2009). Lacosamide received recent approval from the European Medicines Agency (EMEA) as adjunctive treatment for refractory partial-onset seizures. Its mode of action includes enhancement of slow inactivation of voltage-gated sodium channels and, possibly, a functional interaction with collapsin–response mediator protein 2 (CRMP2) (Beyreuther et al., 2007). Lacosamide is effective in the pilocarpine, cobalt-homocysteine, and electrical stimulation models of status epilepticus (Stöhr et al., 2007; Bialer et al., 2009), and potential neuroprotective properties in status epilepticus have also been reported (Bialer et al., 2009). An intravenous formulation is commercially available as replacement therapy in patients temporarily unable to take oral medication and, in a recent report, use of this formulation was associated with seizure control in a single patient with nonconvulsive status (Kellinghaus et al., 2009). The three remaining agents discussed in this summary are in phase II–III clinical development. Carisbamate shows broad spectrum activity in animal models of seizures and epilepsy through an as-yet unidentified mechanism which, however, does not seem to replicate the modes of action of established anticonvulsants (Novak et al., 2007; Bialer et al., 2009). In the lithium–pilocarpine model of status epilepticus in rats, carisbamate, when dosed 1 and 8 h after the onset of status, then twice daily for 6 days, was effective in protecting against status-induced neuronal damage and post-status epileptogenesis (Francois et al., 2005). Brivaracetam is a synaptic vesicle protein 2A (SV2A) ligand, with much higher affinity than levetiracetam for this target (Bialer et al., 2009). It shows broad spectrum anticonvulsant activity in preclinical models and, in particular, reduces markedly cumulative seizure duration in the rat model of self-sustained status epilepticus induced by stimulation of the perforant path (Wasterlain et al., 2005). In this model, brivaracetam shows marked synergism with diazepam. Another compound of particular interest as a potential new treatment for acute seizure conditions is NS-1209, a water-soluble AMPA antagonist, which has been found to potently protect against status epilepticus induced by electrical stimulation of the amygdala or by subcutaneous administration of kainic acid in rats (Pitkänen et al., 2007). NS-1209 also displays some neuroprotective activity against status-induced hippocampal neurodegeneration. Clinical testing of NS-1209 in the treatment of refractory status epilepticus has been initiated, but no results are available as yet. In conclusion, each of the five compounds discussed shows properties that are potentially useful in the treatment of status. Because their mechanisms of action differ fully or partly from those of benzodiazepines, phenytoin, barbiturates, and valproic acid, it is possible that at least some of these agents will prove to be of value in the management of status refractory to currently used drugs. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosure: The author received speaker’s or consultancy fees and/or research grants from the manufacturers of carbamazepine and oxcarbazepine (Novartis); eslicarbazepine acetate (Bial); ethosuximide, gabapentin, phenytoin, and pregabalin (Pfizer); lamotrigine (GSK); brivaracetam, levetiracetam, and lacosamide (UCB Pharma); tiagabine, valproic acid, and vigabatrin (Sanofi-Aventis); rufinamide and zonisamide (Eisai); carisbamate and topiramate (Johnson & Johnson).