Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis

Abstract

Experimental prolonged febrile seizures (FS) lead to structural and molecular changes that promote hippocampal hyperexcitability and reduce seizure threshold to further convulsants. However, whether these seizures provoke later-onset epilepsy, as has been suspected in humans, has remained unclear. Previously, intermittent EEGs with behavioural observations for motor seizures failed to demonstrate spontaneous seizures in adult rats subjected to experimental prolonged FS during infancy. Because limbic seizures may be behaviourally subtle, here we determined the presence of spontaneous limbic seizures using chronic video monitoring with concurrent hippocampal and cortical EEGs, in adult rats (starting around 3 months of age) that had sustained experimental FS on postnatal day 10. These subjects were compared with groups that had undergone hyperthermia but in whom seizures had been prevented (hyperthermic controls), as well as with normothermic controls. Only events that fulfilled both EEG and behavioural criteria, i.e. electro-clinical events, were considered spontaneous seizures. EEGs (over 400 recorded hours) were normal in all normothermic and hyperthermic control rats, and none of these animals developed spontaneous seizures. In contrast, prolonged early-life FS evoked spontaneous electro-clinical seizures in 6 out of 17 experimental rats (35.2%). These seizures consisted of sudden freezing (altered consciousness) and typical limbic automatisms that were coupled with polyspike/sharp-wave trains with increasing amplitude and slowing frequency on EEG. In addition, interictal epileptiform discharges were recorded in 15 (88.2%) of the experimental FS group and in none of the controls. The large majority of hippocampally-recorded seizures were heralded by diminished amplitude of cortical EEG, that commenced half a minute prior to the hippocampal ictus and persisted after seizure termination. This suggests a substantial perturbation of normal cortical neuronal activity by these limbic spontaneous seizures. In summary, prolonged experimental FS lead to later-onset limbic (temporal lobe) epilepsy in a significant proportion of rats, and to interictal epileptifom EEG abnormalities in most others, and thus represent a model that may be useful to study the relationship between FS and human temporal lobe epilepsy.

Gender difference in acquired seizure susceptibility in adult rats after early complex febrile seizures

“…This process was repeated 10 times and the total behavioral seizure time was ~26 min, which is considered to be prolonged [17] . The latency and temperature threshold to the first onset of hyperthermiainduced seizures were recorded in male and female pups.…”

Novel Animal Models of Pediatric Epilepsy

“…No evidence of hippocampal neuronal loss (using Nissl stain counting methods) have been found [24], but hyperexcitability in brain slices and an increase in seizure susceptibility have been reported [25]. More recently, spontaneous recurrent seizures have been recorded using concurrent hippocampal and cortical EEG video EEG monitoring [26,27].…”

Neuropeptide Y: Potential role in recurrent developmental seizures

“…In order to study the consequences of complex FS, and thus to gain a better understanding of their potential contribution to human epilepsy, an animal model of FS was established in our laboratory [10,18,19,32,33,73]. In this model, experimental FS are induced in rat pups on postnatal days 10 or 11, an age that corresponds to the hippocampal developmental stage at which human infants are most susceptible to febrile seizures (see comparison of developmental milestones in humans and rodent hippocampus in [4]).…”

“…Rats were then returned to their mothers and further investigated weeks or months later. The major findings of these studies are that prolonged FS do not lead to cell death nor to other neuroanatomical abnormalities, although transient neuronal injury occurs [10,11,33,35,73]. Nevertheless, rats that had experienced prolonged FS early in life have a reduced seizure threshold later in life and ~35% develop spontaneous seizures, i.e.…”

“…Nevertheless, rats that had experienced prolonged FS early in life have a reduced seizure threshold later in life and ~35% develop spontaneous seizures, i.e. limbic (temporal lobe) epilepsy, as adults [32,33]. This may be due in part to profound and long-lasting changes in the expression of the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel genes after FS [12,18,19,66].…”