Identification of new epilepsy treatments: Issues in preclinical methodology

Abstract

Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities.

Epigenetic Mechanisms in Stroke and Epilepsy

“…Sensory, motor, or autonomic function can also be affected (Fisher et al, 2005;Berg et al, 2010). Current therapies are largely unsatisfactory, as they suppress seizures, but do not affect the underlying cause, are effective in only a subset of affected individuals, and are often toxic (Duncan et al, 2006;Galanopoulou et al, 2012). Epilepsy refers to a constellation of disorders and can be classified according to characteristic symptoms and signs, seizure type, cause, age of onset, and electroencephalographic patterns (Berg et al, 2010).…”

“…Epilepsy can also arise as a consequence of spontaneous or inherited gene mutations. Interestingly, the latter includes a vast number of channelopathies, in which recurrent seizures arise from single-point mutations, deletions, duplications, or expansions in genes encoding a component of a voltage-or ligand-gated ion channels, but also many other genes that directly or indirectly control brain development and neuronal function and activity (Catterall et al, 2008(Catterall et al, , 2010Galanopoulou et al, 2012).…”

“…Epileptogenesis is the process whereby a neural network acquires the ability to manifest recurrent epileptic seizures de novo and in response to neuronal insults, as well as the development and progression of epilepsy (Rakhade and Jensen, 2009;Galanopoulou et al, 2012). Epileptogenesis has been conceptualized as a 'cascade' of molecular and cellular events (Rakhade and Jensen, 2009).…”

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

“…There has been a lot of introspection over the last few years regarding the validity, reproducibility, and translatability of preclinical findings into clinically relevant discoveries that address the current clinical gaps and priorities 1. Concerns that the efficacy of many candidate treatments identified in preclinical studies fails to translate into positive clinical trials or to replicate in animal studies have stirred coordinated efforts from many neurologic research areas to reevaluate the priorities, methodologies, and strategies, and to propose standards for rigorous and clinically translatable practices.…”

“…Largely these critiques have been driven by the realization and angst that more needs to be done and new strategies need to be adopted to develop treatments for patient populations who do not benefit from current treatments 1, 2, 5, 6. These unmet clinical needs include the following: (1) seizures resistant to current antiseizure drugs; (2) treatments that prevent, stop, or reverse epileptogenesis; (3) epilepsies with no or very limited available treatments, for example, certain early life epileptic encephalopathies and epilepsies; and (4) disease‐modifying treatments that prevent or treat epilepsy‐related comorbidities.…”