2014 Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

Abstract

The prevention of epilepsy and its progression after initial diagnosis represents one of the most challenging goals of epilepsy research (1). Although epilepsy diagnoses lack a formal component of disease stage, anecdotal clinical observation suggests that individual patients usually fall into one of at least three types of presentation: an easily treated type that is responsive to the first or second antiseizure medications tried, a relapsing/ remitting type in which seizure control is intermittent, and a drug-resistant type in which the patient never achieves seizure control with medication (2). As drug-resistant epilepsy is extremely difficult to treat, the successful prevention of epilepsy in at-risk patients may provide the best strategy to alleviate the negative impact of epilepsy. Benchmark II aims to establish therapeutic approaches for preventing the development and progression of epilepsy by 1) understanding epileptogenic processes related to genetic or neurodevelopmental causes, 2) understanding epileptogenic processes related to acquired brain injuries, 3) identifying biomarkers for monitoring epileptogenesis, 4) developing models closely aligned with etiologies of human epilepsies, and 5) identifying molecular targets that drive epileptogenesis or are opposed to it. Key Advances in Area II Understanding Epileptogenesis Epileptogenesis is not a single process. It can be triggered by numerous genetic or nongenetic factors, and its course,

Antiepileptogenesis and disease modification: Progress, challenges, and the path forward—Report of the Preclinical Working Group of the 2018 NINDS‐sponsored antiepileptogenesis and disease modification workshop

“…• Registries of preclinical studies (eg, https://www.precl inica ltria ls.eu) The need for individualized or precision medicine approaches has been discussed for both genetic and nongenetic etiology epilepsies, considering the vast interactions and complexity of molecular, cellular, signaling, and network interactions and the age-, sex-, and timing-dependent effects of various treatments. [137][138][139][140][141] The preclinical WG emphasized the need to improve the infrastructure to allow precision medicine approaches for epilepsies, of both genetic and nongenetic etiologies, but also help optimize their translation into the clinics. Such infrastructure may include repositories of data and specimens to enable validation and translation of preclinical discoveries to the clinics, tools, and biomarkers to help identify target populations, deliver prognosis, and optimize treatment delivery decisions, but also research toward novel treatment delivery approaches targeting specific genes, cells, and circuits, at discreet time windows to minimize adverse effects.…”

“…The need for individualized or precision medicine approaches has been discussed for both genetic and nongenetic etiology epilepsies, considering the vast interactions and complexity of molecular, cellular, signaling, and network interactions and the age‐, sex‐, and timing‐dependent effects of various treatments 137‐141 . The preclinical WG emphasized the need to improve the infrastructure to allow precision medicine approaches for epilepsies, of both genetic and nongenetic etiologies, but also help optimize their translation into the clinics.…”

Pro-inflammatory cytokines, but not brain- and extracellular matrix-derived proteins, are increased in the plasma following electrically induced kindling of seizures

“…Furthermore, in some other clinical studies, the role of proinflammatory cytokines as potential biomarkers of epilepsy severity has been suggested [ 42 – 45 ]. Therefore, the American Epilepsy Society (AES) and the National Institute of Neurological Disorders and Stroke (NINDS) identified IL-1β as a potential biomarker of epilepsy [ 46 ].…”

Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

“…In addition to epilepsy being the direct consequence of pathogenic variants in genes encoding proteins in epilepsy disorders, such as in glucose transporter type 1 deficiency syndromes, 2 it has been shown that maladaptive changes in metabolism contribute to epilepsy development. 3 Conversely, metabolic therapeutic approaches, such as the ketogenic diet (KD), have been shown (1) to influence the epigenome and (2) to prevent epileptogenesis. [4][5][6][7][8] The KD suppresses seizures in some patients, reflecting the antiepileptic effects of specific metabolic changes.…”