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Epileptogenesis: More than Just the Latent Period

Commentary Epileptogenesis is the process through which neuronal networks are altered resulting in the generation of spontaneous, chronic seizures. Epileptogenesis is thought to involve three stages: 1) the initial insult or precipitating event, 2) the latent period, and 3) the chronic epilepsy phase. It has been suggested that during the latent phase, the process of acquired epileptogenesis is completed and culminates in seizure generation (Figure 1) (1). However, the current study suggests that epileptogenesis may be progressive with continuing changes in the neuronal network extending into the chronic epilepsy period (Figure 1). In support of the idea that epileptogenesis continues into the period of chronic epilepsy is evidence for the progression of epilepsy. Over 100 years ago, British neurologist, Sir William Gowers, coined the phrase “seizures beget seizures,” which is still widely used today to indicate the progressive nature of epilepsy. The observation that seizures beget seizures was largely based on untreated patients. Today, the progression of epilepsy is more difficult to measure given the introduction of more effective anticonvulsant medications and, thus, the inability to monitor the natural progression of epilepsy in the absence of treatment. In addition, we also now appreciate the heterogeneity of the epilepsies in which there are many different types of epilepsies with differences in the underlying etiology and types of seizure presentation. While it is apparent that in some patients epilepsy is not a self-perpetuating disorder, given that seizure frequency and severity remain stable and can even regress or remit (for review, see Blume [2]); it is also clear that some patients exhibit epilepsy progression, evident by increasing seizure frequency, progressive hippocampal damage, and the development of pharmacoresistance. Several theories have been proposed regarding the mechanisms contributing to epilepsy progression, including progressive primary etiologies, such as expanding lesions and progressive neurodegeneration, development of pharmacologic resistance, and seizure-induced plasticity/ kindling (for review, see Sutula [3]). However, we still know very little about the mechanisms underlying epilepsy progression. Understanding the mechanisms contributing to the progression of epilepsy will likely require studies into the emergent properties leading to seizure activity, including circuit-level investigation into network synchronization. The use of voltage-sensitive dyes and calcium imaging enables the activity of large populations of neurons within a network to be studied. These methods have been employed to examine changes in network dynamics associated with simultaneously recorded epileptiform activity (4, 5) (for review, see Goldberg and Coulter [1] and Coulter et al. [6]). The development of in vivo imaging techniques coupled with calcium imaging allows for the activity of neurons to be measured in an intact network during abnormal spontaneous electrographic activity associated with epilepsy (7). However, these studies are typically limited to acute seizure activity rather than the evolution of epileptogenesis. Studies investigating the evolution of epileptiform activity have largely relied on in vivo cortical and depth electrode recordings or acute and chronic in vitro field potential recordings. The limitations of these types of studies are that the Evolution of Network Synchronization During Early Epileptogenesis Parallels Synaptic Circuit Alterations.