What Are the Arguments For and Against Rational Therapy for Epilepsy?

Abstract

Although more than a dozen new anti-seizure drugs (ASDs) have entered the market since 1993, a substantial proportion of patients (~30 %) remain refractory to current treatments. Thus, a concerted effort to identify and develop new therapies that will help these patients continues. Until this effort succeeds, it is reasonable to re-assess the use of currently available therapies and to consider how these therapies might be utilized in a more efficacious manner. This applies to the selection of monotherapies in newly-diagnosed epilepsy, but perhaps, more importantly, to the choice of combination treatments in otherwise drug-refractory epilepsy. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action (MoAs) that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the MoA subclasses amongst available ASDs and an appreciation of the empirical evidence that supports the use of specific combinations. The majority of ASDs can be loosely categorized into those that target neurotransmission and network hyperexcitability, modulate intrinsic neuronal properties through ion channels, or possess broad-spectrum efficacy as a result of multiple mechanisms. Within each of these categories, there are discrete pharmacological profiles that differentiate individual ASDs. This chapter will consider how knowledge of MoA can help guide therapy in a rational manner, both in the selection of monotherapies for specific seizure types and syndromes, but also in the choice of drug combinations for patients whose epilepsy is not optimally controlled with a single ASD.

Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy

“…Based on the novel mechanism of action, perampanel seems to be particularly attractive for rational polytherapeutic concepts. Rational polytherapy represents a concept taking complementary mechanisms of action into consideration when selecting drugs for combination regimens . The promises and challenges of respective concepts have been critically discussed repeatedly .…”

Anti-Epileptic Drug Combination Efficacy in an In Vitro Seizure Model – Phenytoin and Valproate, Lamotrigine and Valproate

“…Many patients with drug resistant epilepsy are treated with more than one AED, and combinations of drugs with different mechanisms of action are commonly used with enhanced efficacy for seizure suppression [4, 5]. However, the preclinical and clinical evidence for optimal combinations is still sparse and no definitive evidence-based indications can be reached to guide clinicians in this choice [6].…”

“…However, the preclinical and clinical evidence for optimal combinations is still sparse and no definitive evidence-based indications can be reached to guide clinicians in this choice [6]. The goal of “rational polytherapy” has not yet been achieved [5, 7]. …”

Evaluating an Etiologically Relevant Platform for Therapy Development for Temporal Lobe Epilepsy: Effects of Carbamazepine and Valproic Acid on Acute Seizures and Chronic Behavioral Comorbidities in the Theiler’s Murine Encephalomyelitis Virus Mouse Model

“…Thus, the ASDs, valproic acid (VPA) and carbamazepine (CBZ), were subchronically administered during the acute TMEV seizure phase to determine whether these agents could suppress acute behavioral seizures and whether pharmacological inhibition of seizures is sufficient to alter the development of associated long-term behavioral deficits (Umpierre et al, 2014). VPA can reduce seizure frequency and severity through multiple ion channel-centric mechanisms (White et al, 2007;Barker-Haliski et al, 2014b). Additionally, VPA can induce brain-derived neurotrophic factor activation (Yasuda et al, 2009), as well as potently inhibit histone deactylase and glycogen synthase kinase-3 activity (Rosenberg, 2007;Hoffmann et al, 2008;Chiu et al, 2013), which may altogether contribute to network remodeling underlying epileptogenesis (Cantley and Haynes, 2013;Liu et al, 2013;Vezzani et al, 2013).…”

“…Moreover, VPA is neuroprotective in models of Alzheimer's disease (Kilgore et al, 2010), traumatic brain injury (TBI) (Dash et al, 2010), and septic encephalopathy (Wu et al, 2013). Conversely, CBZ possess notable antiseizure efficacy most likely mediated by sodium channel inhibition (White et al, 2007;Barker-Haliski et al, 2014b); however, it has yet to be associated with any direct anti-inflammatory effects or modulatory effects on signaling pathways. Thus, VPA and CBZ represent two very diverse strategies to prevent acute TMEV-induced seizures.…”