Abstracts

RATIONALE: There is ample evidence from both clinical and animal studies that the efficacy of benzodiazepine intervention in the adult is inversely related to seizure duration. This relationship has not been well studied in children. The objective of this study is to investigate the relationship between age and success of benzodiazepine treatment in the lithium-pilocarpine (Li-Pilo) model of secondarily generalized seizures in the rat using three age groups, roughly corresponding to the human ages of infancy, adolescence, and adult. At the end of this activity, the participants should be able to discuss the relationship between seizure duration, age, and treatment of prolonged seizures.
METHODS: Male Sprague-Dawley rats had left frontal and parietal epidural electrodes implanted on P8, P12, P18, and P58. Status epilepticus (SE) was induced through pretreatment with intraperitoneal lithium (3 meq/kg) followed approximately 20 hours later by subcutaneous pilocarpine on P10 (100mg/kg), P15 (60mg/kg), P20 (30mg/kg), and P60 or later (30mg/kg). Electrographic onset of SE was defined as the onset of continuous, rhythmic epileptiform discharges lasting at least 30 seconds. Prior to pilocarpine injection, animals were randomized to time of diazepam (DZP) injection: 5, 15, 30, 60, and 120 minutes after seizure onset. DZP was administered intraperitoneally. The dosage of DZP in each age group (n=3) was determined in pilot studies as the minimum dose required to consistently terminate seizures of 5 minutes in duration. Seizure termination was defined as the absence of continuous or periodic seizure activity as well as the absence of spikes 15 minutes after the administration of DZP.
RESULTS: Behavioral changes were observed within 3 minutes of pilocarpine injection in all age groups. The electrographic onset of SE typically occurred 15-30 minutes following the injection of pilocarpine and, in the majority of animals, corresponded to or was observed just prior to the onset of forelimb clonus. Of interest, while behavioral changes such as shivering were observed in the P10 rat, forelimb clonus was never observed and continuous surface EEG recording for up to 2 hours after pilocarpine injection failed to reveal continuous, rhythmic epileptiform discharges. Therefore, the P10 age group was not used in the assessment of DZP efficacy. Based on the design of this experiment, DZP was effective in terminating all seizures of 5 minutes in duration in all age groups. However, the DZP dose was less effective in terminating seizures of longer duration in the two younger age groups (P15 and P20) as well as in the adults. This decline in efficacy was present as early as 15 minutes after seizure onset in all age groups.
CONCLUSIONS: These findings demonstrate that DZP efficacy in the Li-Pilo model of secondarily generalized status epilepticus is inversely related to seizure duration in these age groups and provide further evidence that intervention for SE should commence early.
[Supported by: The National Epifellows, NIH grant 32NS07473, and NINDS NS27984.]