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Since the early 1990s, many new antiepileptic drugs (AEDs) that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug-drug interactions have entered the market. However, despite the therapeutic arsenal of old and new AEDs, approximately 30% of patients with epilepsy still suffer from seizures. Thus, there remains a substantial need for the development of more efficacious AEDs for patients with refractory seizures. Here, we briefly review the emerging knowledge on the pathological basis of epilepsy and how it might best be used in the design of new therapeutics. We also discuss the current approach to AED discovery and highlight some of the unique features of newer models of pharmacoresistance and epileptogenesis that have emerged in recent years.

Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in populationbased cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (noninfectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered.

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Summary Purpose:  To examine the role of innate immunity in a novel viral infection–induced seizure model. Methods:  C57BL/6 mice, mouse strains deficient in interleukin (IL)‐1RI, IL‐6, tumor necrosis factor (TNF)‐RI, or myeloid differentiation primary response gene 88 (MyD88), or transgenic mice (OT‐I) were infected with Theiler’s murine encephalomyelitis virus (TMEV) or were mock infected. Mice were followed for acute seizures. Tissues were examined for neuron loss, the presence of virus (viral RNA and antigen), perivascular cuffs, macrophages/microglia, and gliosis, and mRNA expression of IL‐1, TNF‐α, and IL‐6. Results:  IL‐1 does not play a major role in seizures, as IL‐1RI‐ and MyD88‐deficient mice displayed a comparable seizure frequency relative to controls. In contrast, TNF‐α and IL‐6 appear to be important in the development of seizures, as only 10% and 15% of TNF‐RI‐ and IL‐6‐deficient mice, respectively, showed signs of seizure activity. TNF‐α and IL‐6 mRNA levels also increased in mice with seizures. Inflammation (perivascular cuffs, macrophages/microglia, and gliosis) was greater in mice with seizures. OT‐I mice (virus persists) had a seizure rate that was comparable to controls (no viral persistence), thereby discounting a role for TMEV‐specific T cells in seizures. Discussion:  We have implicated the innate immune response to viral infection, specifically TNF‐α and IL‐6, and concomitant inflammatory changes in the brain as contributing to the development of acute seizures. This model is a potential infection‐driven model of mesial temporal lobe epilepsy with hippocampal sclerosis.

Epilepsy is broadly characterized by aberrant neuronal excitability. Glutamate is the predominant excitatory neurotransmitter in the adult mammalian brain; thus, much of past epilepsy research has attempted to understand the role of glutamate in seizures and epilepsy. Seizures induce elevations in extracellular glutamate, which then contribute to excitotoxic damage. Chronic seizures can alter neuronal and glial expression of glutamate receptors and uptake transporters, further contributing to epileptogenesis. Evidence points to a shared glutamate pathology for epilepsy and other central nervous system (CNS) disorders, including depression, which is often a comorbidity of epilepsy. Therapies that target glutamatergic neurotransmission are available, but many have met with difficulty because of untoward adverse effects. Better understanding of this system has generated novel therapeutic targets that directly and indirectly modulate glutamatergic signaling. Thus, future efforts to manage the epileptic patient with glutamatergic-centric treatments now hold greater potential.

The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included "Indications overlapping with epilepsy" and "Securing the successful development of an investigational antiepileptic drug in the current environment". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Nav1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a N641Y/N641Y knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Nav1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Nav1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.