Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

Abstract

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy—one-third of patients—emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.

On the Digital Psychopharmacology of Valproic Acid in Mice

“…These patients remain at risk for PBSE cross-sensitivity ( Chen et al, 2018 ), drastically limiting treatments for a population already vulnerable to suicide and sudden death. The development of AEDs with improved side effect profiles remains a consensus research benchmark ( Traynelis et al, 2020 ). Nevertheless, preclinical assessments of AED “tolerability” in rodents remain largely limited to measures of acute motor “toxicity” ( Wilcox et al, 2020 ) (e.g., rotarod or open field testing) and/or subjectively scored ordinal scales of well-being (e.g., Irwin screen), which may not capture changes in anxiety, mood, motivation or sociability.…”

Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine‐pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug‐resistant epilepsy

“…According to epilepsy benchmarks Area-III (NINDS), the development of new approaches can be advanced by better animal model. 6 To date, three variants of lamotrigine kindling model have shown resistance to antiseizure drugs: (a) lamotrigine-amygdale kindling in rats (electric stimulation) 7 ; (b) lamotrigine-corneal kindling in mice (electric stimulation) 8 ; and (c) lamotrigine-pentylenetetrazole kindling in mice (chemoconvulsant administration). 9 The lamotrigine amygdale kindling model was first described by Postma et al in 2000 and soon after it was adopted by the ETSP.…”

Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler’s murine encephalomyelitis virus

“…Approximately 30-40% of epilepsy patients remain refractory to therapy, indicating a substantial need to identify new targets for anti-seizure or antiepileptogenic treatments [11][12][13]. While aberrant hyperexcitability and hypersynchronization of neurons are hallmarks of seizure activity, the presence of reactive glial cells or glial scar formation is nearly universal within epileptic lesions or foci.…”