2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions without Side Effects

Abstract

Epilepsy Resources and UpdatesThe Epilepsy Benchmark goals in Area III focus on making progress in understanding and controlling seizures and related conditions as well as on developing biomarkers and new therapies that will reduce seizures and improve outcomes for individuals with epilepsy. Area III emphasizes a need to better understand the ways in which seizures start, propagate, and terminate and whether those network processes are common or unique in different forms of epilepsy. The application of that knowledge to improved seizure prediction and detection will also play a role in improving patient outcomes. Animal models of treatment-resistant epilepsy that are aligned with etiologies and clinical features of human epilepsies are especially encouraged as necessary tools to understand mechanisms and test potential therapies. Antiseizure therapies that target (either alone or in combination) novel or multiple seizure mechanisms are prioritized in this section of the Benchmarks. Area III goals also highlight validation of biomarkers of treatment response and safety risk, effective self-management, and patient-centered outcome measures as important areas of emphasis for the next five to ten years. Key Advances in Area III Developing and Refining Animal ModelsAnimal models are needed to test interventions targeted to various features of epilepsy, such as delaying the latency between initial insult and onset of spontaneous seizures, preventing the progression of epilepsy severity over time, converting pharmacoresistant to anticonvulsant-responsive seizures, and alleviating behavioral comorbidities. Progress has been made to address some of these aspects of disease modification and to identify etiologically relevant epilepsy animal models. One etiologically relevant animal model of cerebral viral infection is that produced by inoculation of mice with Theiler murine encephalomyelitis virus, which produces a strong neuroinflammatory reaction coupled with seizures and the development of long-term cognitive deficits (1). A similar model of cerebral malaria produces epilepsy that appears dependent on an intact complement pathway (2).Posttraumatic epilepsy is a leading cause of epilepsy in young adults. Much effort has been devoted to developing etiologic animal models that lend themselves to drug screening and can be used to understand mechanisms of epileptogenesis in this condition. A recent study (3) reported the parametric optimization of a rat fluid percussion model that results in focal, nonconvulsive, brief seizures. In this model young (1 month old) male Sprague Dawley rats are subjected to an abrupt percussive injury to the parietal cortex. Within

Loss of normal Alzheimer's disease-associated Presenilin 2 function alters antiseizure medicine potency and tolerability in the 6-Hz focal seizure model

“…This study highlights a potential untapped opportunity to apply precision medicine strategies in the management of seizures in AD. Furthermore, the characterization of the ASM response of PSEN2-KO mice in the acute 6-Hz model closely aligns with NINDS Research Benchmarks for epilepsy to prioritize discovery for the many forms in which epilepsy presents clinically ( 39 , 40 ). Thus, ASM screening in the acute 6-Hz model in PSEN2-KO mice addresses an urgent need to diversify preclinical research for ASM discovery so that therapeutic options for people with seizures in AD can be more rationally discovered and, ultimately, prescribed to minimize the burden of AD.…”

“…The preclinical profiling of ASM efficacy and tolerability has been historically defined in young, neurologically intact male wild-type rodents ( 35 – 37 ), which does not wholly reflect the extent of epilepsy prevalence across the lifespan ( 38 ). There has been a concerted effort to improve twenty-first-century ASM discovery efforts to address these remaining unmet medical needs of people with epilepsy ( 39 , 40 ), including increasing the integration of syndrome-specific models of pediatric epileptic encephalopathies and models of drug-resistant epilepsy into early ASM discovery ( 41 – 43 ). However, this approach does not go far enough to address the pressing global increase in seizures in older adults including individuals with seizures in AD.…”

Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy

“…Identifying biomarkers is a key benchmark for epilepsy research (Dlugos et al, 2016). This work provides two important innovations to this research.…”

The Benchmarks: Progress and Emerging Priorities in Epilepsy Research

“…The reviews in this issue provide summaries of progress in epilepsy research in each of the benchmark areas since the last such series of reviews in 2016. [6][7][8][9] Epilepsy Benchmarks Area I, Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric and Somatic Conditions, has seen major advances in the discovery of genetic epilepsies and autoimmune epilepsies, with new discoveries as well as the development of animal models of these causes. Emerging studies have begun to dissect the causes of epilepsy-related comorbidities.…”