Molecular biomarkers of epileptogenesis

Abstract

Epileptogenesis, a process leading to a reduced threshold for seizures after transient brain insults, as well as the mechanisms underlying the propensity to generate spontaneous epileptic seizures, are highly dynamic processes. Biomarkers--objective measures of biological processes--would be excellent tools for monitoring epileptogenesis and the dynamics of increased seizure propensity, as well as the potential to interfere, for example pharmacologically, with these key pathological aspects of epilepsy. Molecular biomarkers have revolutionized therapies, as well as response prediction and monitoring of therapies in other biomedical fields. However, high-impact molecular biomarkers are still not available in the context of epilepsy. Several factors, such as the large heterogeneity of epileptic syndromes and their underlying pathological patterns, as well as the limited availability of tissue samples, represent a particular challenge to the development of molecular biomarkers in epileptogenesis and epilepsy. However, substantial technical progress has been made recently with respect to biomarker characterization and monitoring by large throughput analysis on the genomic, mRNA, and proteomic levels, starting from minute amounts of brain tissue or body fluids, for example cerebrospinal fluid, blood, serum, or plasma. Given the substantial cellular- and network-level functional pathophysiology involved in epilepsy, it may be beneficial in the future to combine molecular analysis with other methods, such as imaging and electrophysiological biomarkers.

Fig. 1

Schematic overview of key alterations during epileptogenesis. The key pathological elements of epileptogenesis are summarized. Epileptogenesis can emerge from different, potentially epileptogenic, insults. A plethora of mechanisms and potential biomarkers contribute to the conversion from a normal to a chronic epileptic brain structure. Notably, during epileptogenesis, occasional seizures can occur, but do not necessarily reflect the transition to the stage of chronic recurrent seizure activity (modified from [28]). BBB = blood–brain barrier