The effects of seizures in the developing brain differ compared with those in the mature brain. In adult animals, frequent seizures and/or status epilepticus result in neuronal loss, aberrant axon sprouting, and long-term deficits in learning, memory, and behavior (1,2). Similar experiments in immature rats demonstrate minimal or no pathology unless the brain insults are severe, and even then, the amount of damage is generally less than with the same insult in adult rats (3–5). Some authors have concluded, therefore, that the immature brain is resistant to seizure-induced neuronal damage. However, these experiments do not address whether seizures adversely affect other developmental processes, such as postnatal neurogenesis, axogenesis, and synaptogenesis, which are equally important components of early brain development.
Previous animal studies demonstrated that neonatal seizures may adversely affect some aspects of brain development, and in adult rats, reported increased postseizure neurogenesis of fascia dentata granule cells (6–10). Another study, however, showed that granule cell neurogenesis was reduced in postnatal (PN) day 1–4 rats with repeated flurothyl-induced seizures (11). Hence, it is unclear if seizures during early hippocampal development might alter postnatal granule cell neurogenesis, and whether this is associated with aberrant mossy fiber sprouting. Previous human studies from our laboratory found decreased granule cell densities in young patients with extratemporal seizures (12,13). Whether decreased granule cell densities began early in life or were the consequence of repeated seizures over time was unclear because of the small sample size. Likewise, it was unknown if decreased granule cell numbers were from reduced neurogenesis or seizure-induced cell death of already formed granule cells. The current human study addresses these questions by performing immunocytochemistry (ICC) for polysialic acid (PSA) neural cell adhesion molecule (NCAM), which identifies newly formed and migrating granule cells, and TUNEL to detect cell death (14,15). We hypothesized that human hippocampi would show decreased neurogenesis and aberrant axon connections in association with repeated early-onset seizures.