Epileptogenesis Provoked by Prolonged Experimental Febrile Seizures: Mechanisms and Biomarkers

Abstract

Whether long febrile seizures (FSs) can cause epilepsy in the absence of genetic or acquired predisposing factors is unclear. Having established causality between long FSs and limbic epilepsy in an animal model, we studied here if the duration of the inciting FSs influenced the probability of developing subsequent epilepsy and the severity of the spontaneous seizures. We evaluated if interictal epileptifom activity and/or elevation of hippocampal T2 signal on magnetic resonance image (MRI) provided predictive biomarkers for epileptogenesis, and if the inflammatory mediator interleukin-1␤ (IL-1␤), an intrinsic element of FS generation, contributed also to subsequent epileptogenesis. We found that febrile status epilepticus, lasting an average of 64 min, increased the severity and duration of subsequent spontaneous seizures compared with FSs averaging 24 min. Interictal activity in rats sustaining febrile status epilepticus was also significantly longer and more robust, and correlated with the presence of hippocampal T2 changes in individual rats. Neither T2 changes nor interictal activity predicted epileptogenesis. Hippocampal levels of IL-1␤ were significantly higher for Ͼ24 h after prolonged FSs. Chronically, IL-1␤ levels were elevated only in rats developing spontaneous limbic seizures after febrile status epilepticus, consistent with a role for this inflammatory mediator in epileptogenesis. Establishing seizure duration as an important determinant in epileptogenesis and defining the predictive roles of interictal activity, MRI, and inflammatory processes are of paramount importance to the clinical understanding of the outcome of FSs, the most common neurological insult in infants and children.

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

“…Complex FSs were induced in rat pups on P9-P10 according to previous studies [11,15] with modifi cations. After weighing, the body temperature of the pups was raised in a chamber at 42-46°C.…”

“…Most FSs are simple, having a brief duration and a low risk of developing epilepsy [9,10] . In contrast, one-third of FSs are 'complex', prolonged (>10-20 min) or repeated, and may be associated with a risk of subsequent mesial temporal sclerosis and intractable epilepsy [11][12][13] . Although some risk factors for developing epilepsy after FSs have been summarized in previous work [14] , these retrospective studies could not separate the effect of a FS itself (e.g., severity, seizure duration, and type) from that of pre-existing brain pathology (e.g., brain injury and non-FSs) and the infl uence of treatment.…”

Loss of dendritic inhibition in the hippocampus after repeated early-life hyperthermic seizures in rats

“…In particular, a loss of distal dendritic inhibition in seizure rats may affect spatial coding by a direct entorhinal to CA1 distal-dendritic excitation (Brun et al, 2008;Leung, 2011). Abnormal place cell activity was found in animals with early-life seizures (Dube et al, 2009(Dube et al, , 2010. Attenuation in GABA B R function may be a critical component of epilepsy, and it may participate in a role of ''seizures beget seizures'' (Tsai et al, 2008).…”

“…As a model of febrile seizures, hyperthermia-induced seizures in immature rats (Baram et al, 1997) were found to increase longterm seizure susceptibility and induce spontaneous seizures (Dube et al, 2010), without significant cell loss or sustained brain damage (Dube et al, 2000). Additionally, long-term behavioral changes have been reported after hyperthermic seizures (Chang et al, 2003;Dube et al, 2000Dube et al, , 2009Dube et al, , 2010. Long-term physiological changes after febrile seizure models include alteration of intrinsic membrane currents and an increased in GABA A receptor-mediated transmission in hippocampal slices in vitro (Chen et al, 1999).…”

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].…”