Introduction

Status epilepticus (SE) occurs much more frequently in infants and children than in adults. In the Richmond study by DeLorenzo and collaborators (16, 17), the incidence of SE in infants during the first year of life was 156 per 100,000, compared with 38 per 100,000 in children and 27 per 100,000 in adults. This heightened propensity of the developing brain to undergo SE has been demonstrated in the laboratory by in vitro (12, 28, 72) and in vivo (1, 49, 51) experiments.

The consequences of repeated seizures and/or SE on the developing brain continues to be a subject of debate (8, 83), owing to conflicting clinical reports. Although some studies have associated seizures in childhood with neuronal damage comparable to that seen in the adult (13, 42, 44, 58), extended febrile seizures occur relatively frequently in children, and many seemingly with no apparent association with brain injury, as evidenced by the lack of subsequent neurologic deficits (19, 81). Studies in the latter population have attempted to resolve the controversy surrounding the effects of prolonged seizures on the developing brain.

As noted, several studies have reported a benign course in children after febrile convulsions (19, 56, 80) or SE (45). Other reports have found measurable consequences. For example, Schiottz-Christensen and Bruhn (65) found mild deficits in intellectual performance in monozygotic twins who had sustained febrile seizures compared with their twin siblings who had not, and van Esch et al. (78) reported sequelae after a first episode of febrile SE in 24% of a cohort with no previous seizures or neurologic abnormalities. Mahar and McLachlan (41) described a strong association between febrile convulsions and temporal lobe epilepsy (TLE) with mesial temporal sclerosis in families with febrile seizures. These families had been selected in order to reduce genetic and phenotypic heterogeneity in studying the connection between febrile convulsions and TLE. A prolonged febrile convulsion was the most important determinant of this association.

Radiologic studies in children with complex partial seizures found that 57% of these children had magnetic resonance imaging evidence of hippocampal sclerosis (30). This finding was associated with a history of neurologic insults, including idiopathic febrile seizures, prior to the onset of complex partial seizures. More recent imaging studies found a strong association between prolonged febrile convulsions, acute edema, and the subsequent development of medial temporal lobe sclerosis (39, 79). These findings are supported by a number of related studies (48, 66, 67).

Because of the different causes, duration, and severity of the epileptic condition and the physiologic impacts of medical treatment (which are particularly important in the developing nervous system [7, 33]), human studies are not likely to provide unambiguous answers as to whether seizure-induced brain damage can occur in the immature brain, and when such vulnerability begins in the course of maturation. For this reason we turn to animal models to study the relevant phenomena in reduced, and well-controlled, conditions.

Several animal models of SE have been developed in many animal species. In mature animals, these models replicate many of the pathophysiologic and neuropathologic changes seen in the brains of humans with intractable temporal lobe epilepsy, or of people experiencing fatal episodes of SE (24). The use of chemical convulsants such as kainate and pilocarpine, in vivo electrical stimulation of excitatory pathways, and the induction of ischemia- and trauma-induced seizures has increased our basic understanding of how the mature brain responds to seizure events and prolonged seizure-like discharges. Interestingly, when some well-established models of SE were tried in immature animals, none of them reliably produced damage in the immature rat brain (1, 6, 49–51, 77). These basic data supported the idea that very young children were resistant, or immune, to brain damage produced by febrile seizures or even SE, and that the pathologies observed were produced by factors unrelated to seizure activity per se (e.g., birth trauma, idiopathic lesions, or systemic changes produced by severe seizures).

Despite the pioneering work of Meldrum and colleagues (47), which showed that seizure-induced damage could occur in the adolescent brain in the absence of hypoxia, only within the past decade, following the development of several new models of SE in the young, has a new, broader perspective emerged. These new models (generally involving an adaptation of an existing model to make it appropriate for the immature nervous system) have been combined with sensitive indicators of cell death and markers of synaptic rearrangement (26, 27, 36, 62, 73, 74). Analysis of these studies leads to the major conclusion that the immature brain can sustain significant damage as a result of severe seizures (85). Another major conclusion from these studies is that the severity and the phenotype of seizure-induced brain damage are model-specific. Deeply embedded in the issue of model specificity are the complicating factors of comparisons between species that may be more or less altricial or precocial at birth, as well as the significant influence of genetic (strain) differences within species (21, 23, 57). We explore these points by reviewing a number of studies that demonstrate model-specific vulnerabilities of the immature brain to seizure-induced damage, with an emphasis on the developing hippocampal region.