Repeated Generalized Seizures Induce Time-Dependent Changes in the Behavioral Seizure Response Independent of Continued Seizure Induction

Abstract

This study examined both the acute and long-lasting changes in seizure susceptibility that occur in response to the repeated induction of generalized seizure activity. Daily flurothyl-induced generalized clonic seizures resulted in a progressive decrease in both the generalized seizure threshold and the latency to the first myoclonic jerk. The threshold reduction was significant as early as the second trial and was maximal by trial 5. However, a minimum of eight seizures was necessary for the maximal reduction to be long-lasting. The present study also examined the effects of the number of seizures and the duration of the stimulation-free interval on the type of generalized seizure expressed. During the induction phase of the experiment, only generalized clonic seizures ("forebrain seizures") were expressed. If, however, the animal was retested after a 1, 2, 3, or 4 week stimulation-free interval, a progressive increase in both the proportion of animals expressing "brainstem seizure" behaviors and the median seizure score was observed. The progression of flurothyl-induced generalized seizure behaviors was significantly altered if (1) a minimum of eight generalized clonic seizures had been expressed, and (2) a minimum of a 2 week stimulation-free interval followed. Fewer generalized clonic seizures failed to reliably produce changes in seizure phenotype, even after extended stimulus-free intervals. These data indicate that specific kindling processes are initiated during the interval of repeated seizure induction and evolve in the absence of continued seizure induction. Furthermore, these mechanisms of epileptogenesis were found to be manifest predominantly as a change in the seizure phenotype expressed and to proceed independent of changes in the generalized seizure threshold.

Bidirectional Transfer Between Electrical and Flurothyl Kindling in Mice: Evidence for Common Processes in Epileptogenesis

“…Flurothyl kindling was conducted according to previously reported studies (17,20,21). In brief, generalized clonic seizures were elicited through infusion (0.15 ml/ min) of a 10% solution of flurothyl dissolved in 95% ethanol on to a gauze pad, suspended at the top of an enclosed chamber.…”

“…On each flurothyl trial, the latency to generalized seizure onset and the final type of seizure expressed were recorded. Seizure responses were evaluated based on a previously described flurothyl seizure-grading system (17,20,21). In brief, after the initial loss of posture, a grade 1-2 flurothyl seizure is used to designate a forebrain or clonic seizure.…”

“…However, mice in the FLK and ELK groups expressed significantly more flurothyl-induced forebrain-brainstem seizures after the 28-day incubation period compared with the postincubation IMP group. In the flurothyl kindling model, there is a progressive decrease in the latency to generalized seizure onset (generalized seizure threshold), during the induction phase, that reaches asymptote (17,20,21,26,27) and requires additional trials to become long-lasting (2 1 ). Moreover, this decreased latency to generalized seizure onset is maintained throughout the incubation phase of this flurothyl paradigm (17,20,21).…”

“…In the flurothyl kindling model, there is a progressive decrease in the latency to generalized seizure onset (generalized seizure threshold), during the induction phase, that reaches asymptote (17,20,21,26,27) and requires additional trials to become long-lasting (2 1 ). Moreover, this decreased latency to generalized seizure onset is maintained throughout the incubation phase of this flurothyl paradigm (17,20,21). Because the initial seizure type elicited by flurothyl is always forebrain (clonic), these results suggest that repeated flurothyl seizures promote a decrease in the threshold of the forebrain seizure system involved in the expression of generalized clonic seizures.…”

“…Like electrical kindling, the effects of this flurothyl kindling appear to be permanent (21). One of the characteristic features of this flurothyl model is that after eight flurothyl-induced generalized forebrain (or clonic) seizures (referred to as the induction phase) and a subsequent 28-day stimulation-free interval (the incubation phase), the behavioral seizure phenotype of mice changes from a purely forebrain seizure to a seizure with a more complex phenotype when rechallenged with flurothyl ( 1 7, 20,21). This complex seizure phenotype is manifested as a generalized-onset forebrain seizure that rapidly progresses to a seizure with brainstem (or tonic) manifestations.…”