In a prospective study, we have followed 347 children identified at the time of a first unprovoked seizure for a mean of 46 months. To date, 135 (39%) have experienced a seizure recurrence. In this study, we analyzed recurrence risk as a function of whether the child was asleep or awake at the time of the first seizure. The cumulative recurrence risks for children whose first seizure occurred in sleep was 28% at 0.5 years, 39% at 1 year, 53% at 2 years, and 55% at 4 years, compared with recurrence risks of 18%, 23%, 30%, and 35% at the same intervals in children whose first seizure occurred while awake (p < 0.001). The association of a first seizure during sleep with an increased recurrence risk was present primarily in children with idiopathic seizures. It occurred in both those with a normal and an abnormal EEG. On multivariable analysis, sleep state, etiology, and the EEG were statistically significant predictors of recurrence risk. In children who experienced a seizure recurrence, the recurrences occurred in the same sleep state in 73% of the cases (p < 0.0001). This was also true of subsequent recurrences. We conclude that the occurrence of a first seizure in sleep is associated with an increased risk of recurrence. Subsequent seizures, if they do occur, usually occur in the same sleep state as the initial seizure.

Behavioral characteristics of seizures have age-dependent features, which suggests that effective treatment of seizures may be age-specific as well. In experiments that used the flurothyl seizure model, we examined the effects of several drugs that affect GABAergic neurotransmission in rats of various ages. Systemic administration of phenobarbital (PB, a drug that enhances GABAA receptor-mediated inhibition) was anticonvulsant in most age groups. In contrast, gamma-vinyl GABA (VGB, a drug that increases endogenous GABA levels and enhances both GABAA and GABAB receptor transmission) did not have anticonvulsant effects. Baclofen (a GABAB receptor agonist) was proconvulsant in 9-day-old rat pups, and anticonvulsant in 15-30-day-old rats and lost its anticonvulsant activity in 60-day-old rats. CGP 35348 (a GABAB receptor antagonist) was proconvulsant in developing rats but not in 60-day-old rats. A novel GABAB receptor antagonist, CGP 36742, was proconvulsant in 9- and 15-day-old rats but had no effects in 30- and 60-day-old rats. These results indicate that the effects of presumed GABAergic agents are not uniform across the age span. The differences may reflect age-dependent maturational changes of GABA receptor subtypes, differential action of the drugs on pre- and postsynaptic sites and possible non-GABAergic effects.

We determined the effects of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (0.05, 0.1, and 0.5 mg/kg intraperitoneally, i.p.) and phenytoin (PHT, 5, 10, and 20 mg/kg i.p.) on flurothyl-induced clonic and tonic-clonic seizures in 9-, 15-, 30-, and 60-day-old male rats. Both agents had seizure-, age-, and dose-specific effects. The highest dose of MK-801 was anticonvulsant against clonic flurothyl-induced seizures only in 9- and 60-day-old rats, but suppressed tonic-clonic seizures in all ages. The lowest dose of MK-801 (0.05 mg/kg) produced significant anticonvulsant effects only in 15 day old rats. PHT did not have any effect on clonic seizures throughout development. Both doses of PHT (10 and 20 mg/kg) were anticonvulsant against tonic-clonic seizures in adult rats but not in any other age group. The results indicate that NMDA receptors play an important role in tonic-clonic flurothyl-induced seizures throughout development (especially in 15-day-old rats) and that the anticonvulsant effects of PHT may vary at different stages of brain development.

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