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?

Whereas most febrile seizures (FSs) carry a benign outcome, a subpopulation of individuals with prolonged FSs are at risk for later temporal lobe epilepsy. Signal changes on magnetic resonance imaging (MRI) may provide early markers for changes in neuronal integrity that may promote epileptogenesis in such individuals. Here, we used serial MRIs, obtained before and at several time points after experimental prolonged FSs, to determine the prevalence and distribution of signal changes on T2-weighted images and to investigate the pathological substrates leading to these changes. Seventy-five percent of immature rats with experimental prolonged FSs had abnormal T2 signal enhancement at 24 hours, and 87.5% at 8 days after the seizures. The altered T2 values involved the dorsal hippocampus (75%), the piriform cortex (87.5%), and the amygdala (25%). However, these changes were not accompanied by evidence of neuronal injury or death in these regions, as assessed using the Fluoro-Jade method. Thus, experimental prolonged FSs lead to relatively frequent abnormal MRI signal in "temporal lobe" structures. Although these changes do not signify cell death, they may denote pathological cellular processes that promote epileptogenesis. .

The neuropeptide corticotropin releasing hormone (CRH) is the central nervous system (CNS) transducer of stressful stimuli. Endogenous CRH is released from neuronal terminals in several central nervous system regions-for example, amygdala and hypothalamus-during stress, and exogenous CRH administration mimics stress-related behaviors and hormonal patterns. However, whereas the role of endogenous CRH as a stress neuromodulator has been established, recent findings suggest that the peptide also functions to influence cognitive, emotional, and neuroimmune functions by modulating neuronal communication in a number of circuits. Although anatomic and pharmacologic approaches have provided evidence for this wider spectrum of CRH actions, the discrete regions and specific circuits activated by CRH have not been fully elucidated. In this article, the authors report on the use of two complementary methods to discern specific regions and cell groups activated by the administration of CRH. Glucose metabolism analysis provided quantitative measures of CRH-induced activation, but at a regional resolution; expression of the immediate early gene c-fos permitted a single cell resolution, but underestimated the neuroanatomic extent of CRH-induced activation. Overlapping regions activated using both methods delineated discrete cortical, limbic. and motor pathways. Importantly, cell groups activated by CRH included those possessing either or both members of the CRH receptor family, suggesting that both receptors may mediate the effects of the endogenous ligand. In summary, CRH activates a broad but selective array of neuronal structures belonging to cortical, limbic, and motor circuits. These findings indicate that stress-related release of this peptide may contribute to a spectrum of important modulations of CNS function.

Studies of febrile seizures have been driven by two major enigmas: first, how these most common of human seizures are generated by fever has not been known. Second, epidemiological studies have linked prolonged febrile seizures with the development of temporal lobe epilepsy, yet whether long or recurrent febrile seizures cause temporal lobe epilepsy has remained unresolved. To investigate these questions, a model of prolonged (complex) febrile seizures was developed in immature rats and mice, permitting mechanistic examination of the potential causal relationships of fever and seizures, and of febrile seizures and limbic epilepsy. Although the model relied on hyperthermia, it was discovered that the hyperthermia-induced secretion of endogenous fever mediators including interleukin-1beta, which contributed to the generation of these 'febrile' seizures. In addition, prolonged experimental febrile seizures provoked epilepsy in a third of the animals. Investigations of the mechanisms of this epileptogenesis demonstrated that expression of specific ion (HCN) channels and of endocannabinoid signaling, may be involved. These may provide novel drug targets for intervention in the epileptogenic process.

Epidemiological and recent prospective analyses of long febrile seizures (FS) and febrile status epilepticus (FSE) support the idea that in some children, such seizures can provoke temporal lobe epilepsy (TLE). Because of the high prevalence of these seizures, if epilepsy was to arise as their direct consequence, this would constitute a significant clinical problem. Here we discuss these issues, and describe the use of animal models of prolonged FS and of FSE to address the following questions: Are long FS epileptogenic? What governs this epileptogenesis? What are the mechanisms? Are there any predictive biomarkers of the epileptogenic process, and can these be utilized, together with information about the mechanisms of epileptogenesis, for eventual prevention of the TLE that results from long FS and FSE.

Chronic stress causes dendritic regression and loss of dendritic spines in hippocampal neurons that is accompanied by deficits in synaptic plasticity and memory. However, the responsible mechanisms remain unresolved. Here, we found that within hours of the onset of stress, the density of dendritic spines declined in vulnerable dendritic domains. This rapid, stress-induced spine loss was abolished by blocking the receptor (CRFR(1)) of corticotropin-releasing hormone (CRH), a hippocampal neuropeptide released during stress. Exposure to CRH provoked spine loss and dendritic regression in hippocampal organotypic cultures, and selective blockade of the CRFR(1) receptor had the opposite effect. Live, time-lapse imaging revealed that CRH reduced spine density by altering dendritic spine dynamics: the peptide selectively and reversibly accelerated spine retraction, and this mechanism involved destabilization of spine F-actin. In addition, mice lacking the CRFR(1) receptor had augmented spine density. These findings support a mechanistic role for CRH-CRFR(1) signaling in stress-evoked spine loss and dendritic remodeling.

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.

Fever can provoke "febrile" seizures (FS). Because complex FS may promote development of temporal lobe epilepsy, understanding their mechanisms is clinically important. Using an immature rodent model and transgenic technology, we examined the role of interleukin-1beta, (IL-1beta), a pyrogenic, proinflammatory cytokine, in FS. IL-1beta receptor-deficient mice were resistant to experimental FS. This resistance appeared independent of genetic background and was attributed to lack of IL-1beta signaling, because exogenous cytokine reduced seizure threshold in wild-type but not receptor-deficient mice independent of strain. In addition, high IL-1beta doses induced seizures only in IL-1beta receptor-expressing mice. These data indicate that IL-1beta signaling contributes critically to fever-induced hyperexcitability underlying FS, constituting a potential target for their prevention.

Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. Most individuals with TLE do not have a family history, suggesting that this limbic epilepsy is a consequence of acquired rather than genetic causes. Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20-->60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. However, the statistical correlation between febrile seizures and TLE does not necessarily indicate a causal relationship. For example, preexisting (genetic or acquired) 'causes' that result independently in febrile seizures and in TLE would also result in tight statistical correlation. For obvious reasons, complex febrile seizures cannot be induced in the human, and studies of their mechanisms and of their consequences on brain molecules and circuits are severely limited. Therefore, an animal model was designed to study these seizures. The model reproduces the fundamental key elements of the human condition: the age specificity, the physiological temperatures seen in fevers of children, the length of the seizures and their lack of immediate morbidity. Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. Experimental prolonged febrile seizures did not lead to death of any of the seizure-vulnerable populations in hippocampus, and the rate of neurogenesis was also unchanged. Neuronal function was altered sufficiently to promote synaptic reorganization of granule cells, and transient and long-term alterations in the expression of specific genes were observed. The contribution of these consequences of febrile seizures to the epileptogenic process is discussed.