Among the epilepsies, temporal lobe epilepsy is often intractable and is associated with significant morbidity in terms of cognitive and psychosocial dysfunction. The most common pathology identified in resected temporal lobe tissue from patients with intractable TLE is the constellation of mesial temporal lobe sclerosis.6
This entity is characterized by selective neuronal loss, gliosis and synaptic reorganization in discrete regions of the hippocampal formation and related structures.6,16,30,56
The neuroanatomical alterations of the mesial temporal lobe, and particularly the hippocampus, can be observed using sophisticated neuroimaging studies, including magnetic resonance imaging15,17,21,33
permitting their recognition in vivo, in individual patients. The convergence of temporal lobe seizures, MRI changes and the pathological findings of mesial temporal sclerosis have been increasingly recognized as a distinct entity, mesial temporal lobe epilepsy, which is quite likely the most common of all epileptic syndromes in humans.25
Whereas the neuroparhological features of mesial TLE, i.e., mesial temporal sclerosis, have been defined and extensively studied for decades, the relationship of the anatomical abnormalities to the seizures has remained controversial.27,52,55,57,81
A significant body of evidence, including the presence of early features of mesial temporal sclerosis in young children, suggests that in some patients mesial temporal sclerosis precedes the TLE, and is thus not a consequence of the seizures.18,31,55
This has been interpreted to suggest that the hippocampal injury is also the cause of the TLE. In contrast, progression of the hippocampal lesion on magnetic resonance imaging in individuals with TLE who were imaged repetitively, and a correlation of the hippocampal atrophy with the number of partial and generalized seizures have also been reported.13,49,61,78
These observations are in support of the notion of induction of mesial temporal sclerosis by the seizures themselves. These conflicting views illustrate that an understanding of the causal relationship of neuronal loss in the hippocampal formation to temporal lobe seizures remains incomplete, and is further hampered by the difficulty inherent in human studies, i.e., their correlational nature.
A second striking correlation found in patienrs with TLE is the frequent history of childhood febrile seizures, and particularly prolonged ones.72
Thus, whereas the overall frequency of febrile seizures of the general population in western countries is 2-5%,42,74
retrospective analyses of populations with intractable TLE indicate a frequency of a febrile seizure history of 20->60%.1,17,35,40,65
This remarkable statistical relationship has raised the hypothesis that febrile seizures—particularly complex ones (i.e., focal, prolonged or repetitive)—may produce hippocampal injury that evolves into mesial temporal sclerosis.41,48,76,79
However, the high concordance of childhood febrile seizures in patients with mesial TLE is also consistent with a functional or structural ‘predisposing factor’ that leads independently to both conditions. Put differently, a genetically determined malformation or molecular dysfunction, or an early ‘acquired’ lesion or insult (e.g., pre- or perinatal injury or infection) may predate and actually cause both the hippocampal injury/mesial temporal sclerosis, as well as the complex febrile seizures.8,17,18,31,52,73
Given the high frequency of both febrile seizures and TLE, understanding the true impact of the former, and specifically their causal relationship to TLE, is of enormous clinical significance. However, studying the key questions relating to the acute and chronic effects of febrile seizures on neuronal integrity and function cannot be achieved in the human, for obvious reasons: Ethical considerations prevent the induction of febrile seizures in humans, and naturally occurring febrile seizures are typically sudden and unexpected, and rarely occur in circumstances where electrographic monitoring is possible. Funhermore, the evolution of molecular and fine structural alterations cannot be studied in the live human with currently available technology. Thus, studying febrile seizures and their consequences on the immature brain requires controlled and reproducible experiments which can only be achieved in an appropriate animal model. Here we describe such an immature rat model for prolonged febrile seizures, and discuss the contribution of data obtained using this model to the understanding of the consequences of complex febrile seizures on the developing hippocampal circuit.