Febrile seizures (FS) are the most common type of seizures in infants and preschool children. Inflammatory mediators, which are known triggers of fever, have also been implicated as contributors to the onset of these seizures. Evidence that inflammation is present following FS and during established epilepsy suggests that it could also influence epileptogenesis. However, the potential involvement of inflammatory mediators to the epileptogenic process that may follow prolonged FS has yet to be fully determined. This article reviews the current state of our knowledge and major gaps that remain by focusing on four questions: Does inflammation contribute to the generation of FS? Does prolonged FS or febrile status epilepticus (SE) cause temporal lobe epilepsy in the absence of predisposing factors? Does inflammation contribute to the process by which febrile SE causes limbic epilepsy? And finally, can inflammation be a foundation for biomarkers and therapy for FS-induced epileptogenesis?

Objective

A subset of children with febrile status epilepticus (FSE) are at risk for development of temporal lobe epilepsy later in life. We sought a noninvasive predictive marker of those at risk that can be identified soon after FSE, within a clinically realistic timeframe.

Methods

Longitudinal T₂ -weighted magnetic resonance imaging (T₂ WI MRI) of rat pups at several time points after experimental FSE (eFSE) was performed on a high-field scanner followed by long-term continuous electroencephalography. In parallel, T₂ WI MRI scans were performed on a 3.0-T clinical scanner. Finally, chronic T₂ WI MRI signal changes were examined in rats that experienced eFSE and were imaged months later in adulthood.

Results

Epilepsy-predicting T₂ changes, previously observed at 2 hours after eFSE, persisted for at least 6 hours, enabling translation to the clinic. Repeated scans, creating MRI trajectories of T₂ relaxation times following eFSE, provided improved prediction of epileptogenesis compared with a single MRI scan. Predictive signal changes centered on limbic structures, such as the basolateral and medial amygdala. T₂ WI MRI changes, originally described on high-field scanners, can also be measured on clinical MRI scanners. Chronically elevated T₂ relaxation times in hippocampus were observed months after eFSE in rats, as noted for post-FSE changes in children.

Significance

Early T₂ WI MRI changes after eFSE provide a strong predictive measure of epileptogenesis following eFSE, on both high-field and clinical MRI scanners. Importantly, the extension of the acute signal changes to at least 6 hours after the FSE enables its inclusion in clinical studies. Chronic elevations of T₂ relaxation times within the hippocampal formation and related structures are common to human and rodent FSE, suggesting that similar processes are involved across species.

A significant proportion of temporal lobe epilepsy (TLE), a common, intractable brain disorder, arises in children with febrile status epilepticus (FSE). Preventative therapy development is hampered by our inability to identify early the FSE individuals who will develop TLE. In a naturalistic rat model of FSE, we used high-magnetic-field MRI and long-term video EEG to seek clinically relevant noninvasive markers of epileptogenesis and found that reduced amygdala T2 relaxation times in high-magnetic-field MRI hours after FSE predicted experimental TLE. Reduced T2 values likely represented paramagnetic susceptibility effects derived from increased unsaturated venous hemoglobin, suggesting augmented oxygen utilization after FSE termination. Indeed, T2 correlated with energy-demanding intracellular translocation of the injury-sensor high-mobility group box 1 (HMGB1), a trigger of inflammatory cascades implicated in epileptogenesis. Use of deoxyhemoglobin-sensitive MRI sequences enabled visualization of the predictive changes on lower-field, clinically relevant scanners. This novel MRI signature delineates the onset and suggests mechanisms of epileptogenesis that follow experimental FSE.

Febrile seizures (FS) are common and are associated with increased probability of temporal lobe epilepsy (TLE). However, whether FS can provoke TLE in the nonpredisposed brain is unknown. Using an immature rat model, we established that long FS cause TLE, and that duration of FS governed the severity of epilepsy. Epileptogenesis was accompanied, perhaps causally, by ion channel dysfunction and inflammatory changes. Because FS are a prevalent antecedent of TLE, studying the epileptogenesis that follows them provides powerful insight and potential therapies for epilepsy. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AC, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at). © 2010 International League Against Epilepsy.

A significant proportion of temporal lobe epilepsy (TLE), a common, intractable brain disorder, arises in children with febrile status epilepticus (FSE). Preventative therapy development is hampered by our inability to identify early the FSE individuals who will develop TLE. In a naturalistic rat model of FSE, we used high-magnetic-field MRI and long-term video EEG to seek clinically relevant noninvasive markers of epileptogenesis and found that reduced amygdala T2 relaxation times in high-magnetic-field MRI hours after FSE predicted experimental TLE. Reduced T2 values likely represented paramagnetic susceptibility effects derived from increased unsaturated venous hemoglobin, suggesting augmented oxygen utilization after FSE termination. Indeed, T2 correlated with energy-demanding intracellular translocation of the injury-sensor high-mobility group box 1 (HMGB1), a trigger of inflammatory cascades implicated in epileptogenesis. Use of deoxyhemoglobin-sensitive MRI sequences enabled visualization of the predictive changes on lower-field, clinically relevant scanners. This novel MRI signature delineates the onset and suggests mechanisms of epileptogenesis that follow experimental FSE.

Evidence from animal models and patient data indicates that febrile status epilepticus (FSE) in early development can result in permanently diminished cognitive abilities. To understand the variability in cognitive outcome following FSE, we used MRI to measure dynamic brain metabolic responses to the induction of FSE in juvenile rats. We then compared these measurements to the ability to learn an active avoidance spatial task weeks later. T2 relaxation times were significantly lower in FSE rats that were task learners in comparison to FSE non-learners. While T2 time in whole brain held the greatest predictive power, T2 in hippocampus and basolateral amygdala were also excellent predictors. These signal differences in response to FSE indicate that rats that fail to meet metabolic and oxygen demand are more likely to develop spatial cognition deficits. Place cells from FSE non-learners had significantly larger firing fields and higher in-field firing rate than FSE learners and control animals and imply increased excitability in the pyramidal cells of FSE non-learners. These findings suggest a mechanistic cause for the spatial memory deficits in active avoidance and are relevant to other acute neurological insults in early development where cognitive outcome is a concern.