Abstracts

Rationale: The epileptogenic effects of seizures and their response to treatment have been examined extensively in adult animal models, but there is a paucity of information on these phenomena the developing brain. We examined the long-term effects of several anticonvulsant drugs on epileptogenesis in the lithium-pilocarpine model of status epilepticus (SE) in juvenile rats at postnatal day 28 (P28), an age when the rat brain shows a high metabolic rate and an abundance of synaptic connections.  Diazepam (Dz) , levetiracetam (Lev), fosphenytoin (FPh), dizocilpine (MK-801) and the diazepam-levetiracetam (Dz+LEV) combination (previously shown to be synergistic in adult rats) were used to treat acute SE, and the incidence, severity and frequency of recurrent spontaneous seizures (SRSs) was followed by video/EEG telemetry 3-4 months later. Methods: We induced SE in male P28 rats with lithium and pilocarpine. Drugs or vehicle were injected intraperitoneally (ip), 20, 40 or 70 min after pilocarpine. We injected MK-801 (0.5 mg/kg), fosphenytoin (50 mg/kg PE, phenytoin equivalents), Lev (200 or 1000 mg/kg), Dz (5 mg/kg) or Dz (5 mg/kg) + Lev (200 mg/kg) (Lev/Dz). All groups received atropine (10 mg/kg, i.p.) at the same time as drug or vehicle, in order to block the effect of pilocarpine. For acute studies, animals were monitored by video/EEG telemetry for 24 hours. For chronic studies, another group of animals was continuously monitored for at least one week, 3-4 months after SE. Results: Acute effects: Early treatment (20 min) with Lev 200 reduced cumulative seizure time in comparison to atropine controls, but late treatment was ineffective. Lev 1000, Dz and the Lev/Dz combination reduced cumulative seizure time at all time points tested. Fosphenytoin had no significant acute or chronic benefits, except for reducing mortality. MK-801 had a mild but significant anticonvulsant effect on acute SE when given early (20 min.), no effect at later time points.Chronic effects: Lev 200 reduced behavioral severity but not frequency or incidence of spontaneous recurrent seizures (SRS) at all time points treated. Lev 1000 reduced behavioral severity and frequency of SRSs (2.1 1.1, 3.2 1.5, 2.1 0.7 seizures/day, atropine controls 17.7 7.3). The effect of the Lev/Dz combination depended on time of treatment. Early treatment (20 or 40 min) completely protected against epileptogenesis. Late treatment (70 min) only reduced frequency of SRS (2.6 1.5 vs. 17.7 7.3 seizures/day) but not their incidence. Fosphenytoin had no effect at any time point, but MK801 eliminated (at 20 or 40 min.) or reduced (at 70 min.) SRS even when it had failed to alter acute SE. Conclusions: This study confirmed that, in immature rats as in adults, the most critical factor for the chronic outcome of SE is time of treatment. However, some agents were antiepileptogenic (e.g. at MK801 at 40 min.) or disease-modifying (e.g. Lev 200 at 20-40 min.) without having a significant anticonvulsant effect. Other treatments (High-dose Lev, Dz + Lev combination) were effective acutely and chronically.  These results suggest that, in this model, long-term outcome of experimental SE depends in part on factors other than the duration of the acute seizures, and that combination therapy can reduce the long-term consequences of SE. They also suggest that, in juvenile rats, some currently available drugs have a modest antiepileptogenic or disease-modifying action. Funding: Supported by the Research Service, Veterans Health Administration, by Research Grants R01 NS 13515, R21 NS59704 and UO1 NS074926 from NINDS and by the James and Debbie Cho Foundation.