| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 92 === A prospective population-based case-control study was performed to ascertain whether febrile seizure in early childhood is associated with specific neurocognitive characteristics in school age. From a population survey of 4340 live-birth newborns in Tainan City, Taiwan, 103 children with confirmed febrile seizure by age 3 years were followed up until they were at least 6 years old. To 87 of these school-aged children and to 87 randomly selected age-matched controls, an achievement test, behavioral ratings and computerized neurocognitive battery assessing various sub-components of attention and memory was given. Compared with controls, febrile seizure group did not have scholastic performance or behavioral outcome disadvantage. Overall febrile seizure group performance was distinguished by significantly higher scores in Achievement Test and fewer missing errors (p < 0.005) and commission errors (p < 0.05), less variability in reaction time (p < 0.005), and a non-significant trend of impulsivity in attention test. Regarding the memory test, three analogous searching tasks dissociating the mnemonic and executive aspects of performances to assess the learning, spatial, and sequential working memory revealed that the febrile seizure group performed significantly and consistently better than controls on all but one working memory measure, jumping errors. Multivariate analysis using linear regression revealed that the onset of febrile seizure at less than age one yaer was the only significant risk factor for deficits in mnemonic function. Prior neurodevelopmental delay was the only significant risk factor for deficits in executive function. To delineate the underling mechanism for the memory deficits in children with a history of febrile seizure onset less than age 1 year, we use a heated-air febrile seizure paradigm, by which male rat pups were subjected to one, three, or nine episodes (each lasting < 5 minutes) of febrile seizure on days 10-12 postpartum (brain-development age equivalent to that of the young infants). The acute and long-term effects of febrile seizure on hippocampal development and plasticity were assessed. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS in these groups, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any febrile seizure group at adulthood. The adult rats subjected to nine episodes of early-life febrile seizure, however, showed memory deficits as assessed by the Morris water maze and inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response-element binding protein (CREB) and extracellular signal-regulated kinase (pErk)1/2 in the hippocampus was significantly lower in nine-febrile seizure-group rats than in controls. Rolipram administration, which activated the cAMP-CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long-term memory deficits in nine-febrile seizure-group rats by enhancing hippocampal CREB phosphorylation. In addition, the early-life nine-FS also led to long-term bidirectional modulation in synaptic plasticity, i.e., impaired LTP and facilitated LTD; resulted in selective deficits in N-methyl-D-aspartate (NMDA) receptor-dependent Erk1/2 phosphorylation; and caused selective suppression in NR2A subunits tyrosine phosphorylation, despite the expression levels of NMDA receptor subunits and interaction of NMDA receptors and PSD95 did not alter quantitatively. These results indicate the benign outcome after brief single febrile seizure in rat pups. In contrast, early-life frequently repetitive febrile seizure can have long-lasting effects on the function of NMDA receptors in hippocampal CA1 area, thereby compromising hippocampal plasticity and cognitive performance in later life. These findings reveal the general optimistic outcome in childhood febrile seizure, but they also raise concerns about the long-term cognitive consequences of frequently repetitive febrile seizure during early brain development.
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