Past and Present Definitions of Epileptogenesis and Its Biomarkers

Abstract

Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…The lack of antiepileptogenic therapies is one of the major unmet needs on epilepsy research, despite the availability of many animal models (Pitkanen and Engel, 2014;Trinka and Brigo, 2014;White and Loscher, 2014). To this aim, animal models have been the major source of our current understanding and have led to the identification of potential targets for epilepsy development prevention and/or progression; however, none of the currently available models has been clinically validated (Kobow et al, 2012;Pitkanen and Lukasiuk, 2011;Pitkanen et al, 2013).…”

Epileptogenesis

“…Based on this data-derived conceptual evolution, the Working Group of the International League against Epilepsy (ILAE) revised the terminologies related to disease modification, including epileptogenesis. These conceptual changes have important implications to how experimental epilepsy researchers create and analyze animal models of acquired epilepsy, how hypothetical treatments are developed and tested, and how biomarkers may be identified and implemented Pitkänen and Engel 2014).…”

“…Comorbidity-modifying treatment alleviates or reverses the symptomatic development or progression of epilepsy-related comorbidities, such as anxiety, depression, somatomotor impairment, or cognitive decline Pitkänen and Engel 2014). Both antiepileptogenic and comorbidity-modifying treatments can also alleviate or reverse the associated pathology.…”

Epilepsy Related to Traumatic Brain Injury

“…Rapamycin, a mammalian target of rapamycin inhibitor, has shown disease-modifying effects in several genetic and acquired epilepsy models, even though there are also contradicting results (see [79]). Guo et al [43] induced CCI in adult CD1 mice.…”