Invited reviewDefining “epileptogenesis” and identifying “antiepileptogenic targets” in animal models of acquired temporal lobe epilepsy is not as simple as it might seem
Highlights
► “Epileptogenesis” and “epileptic maturation” defined. ► Animal models of acquired temporal lobe epilepsy with hippocampal sclerosis. ► Spontaneous granule cell layer events in epileptic rats. ► Hippocampal c-Fos expression after spontaneous epileptic seizures. ► “Keeping focal seizures focal” as a primary therapeutic strategy.
Section snippets
What is “epileptogenesis” exactly, and how can it be prevented?
Experimental and clinical studies have used antiepileptic drugs to abort post-injury epileptogenesis, but with minimal success (Dichter, 2009; Temkin, 2009; Löscher and Brandt, 2010; Pitkänen, 2010; Eastman et al., 2011; Langer et al., 2011). Although the right drugs may have been tested at the wrong doses, for the wrong duration, or at the wrong time after brain injury, it is also possible that antiepileptic drugs do not influence the injury-induced “epileptogenic” process. Because acquired
Animal models of acquired temporal lobe epilepsy with hippocampal sclerosis
If chemoconvulsant-induced status epilepticus causes widespread brain damage and seizures of unknown origin, why has “hippocampal epileptogenesis” been so widely assumed?
Although epilepsy can arise from a variety of brain regions, most experimental studies have focused on modeling acquired temporal lobe epilepsy (TLE) with hippocampal sclerosis. Acquired TLE is of particular interest experimentally for several reasons. First and foremost, the pattern of selective hippocampal formation pathology
The “latent period” and the implication that epileptogenesis involves an obligatory secondary mechanism
In our studies of epileptogenesis in kainate and pilocarpine-treated rats, we noted unexpectedly that spontaneous behavioral seizures nearly always began within the first week following status epilepticus (Sloviter et al., 2003; Harvey and Sloviter, 2005), before any secondary mechanism could have had time to develop, and this has now been confirmed by other laboratories (Goffin et al., 2007; Raol et al., 2006; Jung et al., 2007). Although the lack of any detectable seizure-free “latent period”
“Keeping focal seizures focal” as a primary therapeutic strategy
The concept of a virtually immediate “epileptogenic” change in network behavior, followed by a longer-lasting secondary process of “epileptic maturation,” suggests that “disease prevention” and “disease modification” are distinct therapeutic targets. Thus, antiepileptogenesis therapy might focus productively on neuroprotection, i.e., targeting potentially reversible neuronal injury during the immediate post-injury period (Langer et al., 2011; Jimenez-Mateos et al., 2011; Serrano et al., 2011).
Caveats and clarifications
Several caveats and clarifications relate to our analyses and assertions. First, in terms of clarifications, we emphasize that acquired epilepsies involve a variety of insults that presumably produce clinically distinct epilepsies that originate in different locations and exhibit different latencies to clinical seizures. We do not suggest that there must be one common epileptogenic mechanism, and we recognize that future studies using chronic depth recording will need to determine whether other
Acknowledgements
We thank Drs. Wolfgang Löscher (University of Veterinary Medicine Hannover), Daniel H. Lowenstein (University of California, San Francisco), Robert Schwarcz (University of Maryland), H. Steve White (University of Utah), and Hitten Zaveri (Yale University) for useful discussions and constructive criticism of the manuscript. Grant sponsor: National Institute of Neurological Disorders and Stroke, NIH; Grant NS18201.
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