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Retrospective studies of patients who underwent surgery for refractory temporal lobe epilepsy found a relation between history of early febrile seizures, hippocampal sclerosis, and the development of temporal lobe epilepsy.1 Previous MRI studies have reported smaller volumes of the amygdala and the hippocampus in patients with prolonged febrile seizures in childhood than in those without such a history2 suggesting that early febrile seizures are a precipitating event that leads to hippocampal sclerosis. In prospective studies, early febrile seizures or other brain injuries rarely lead to hippocampal sclerosis and temporal lobe epilepsy.3Although epidemiological studies have not yet corroborated the “surgical” correlations, there is convincing evidence that children with complicated febrile seizures have a higher risk for development of temporal lobe epilepsy. The precise pathophysiological relation, however, between febrile seizures, hippocampal sclerosis, and temporal lobe epilepsy remains controversial. Controversy exists as to whether febrile convulsions cause hippocampal sclerosis, and that this in turn is responsible for temporal lobe epilepsy, or hippocampal sclerosis develops independently, or whether there is a pre-existing pathology which predisposes children to have febrile seizures and, later on hippocampal sclerosis. Bower et al 4 in this issue (pp 733–744) report their quantitative MRI findings in 77 patients with histologically proved hippocampal sclerosis. By contrast with previous reports, they found that hippocampal atrophy determined by MRI is no more severe in patients with temporal lobe epilepsy with a history of febrile seizures compared with those without such a history. The high proportion (40%) of patients with febrile seizures in this study suggests an association between febrile seizures and hippocampal sclerosis, but the severity of hippocampal atrophy determined by MRI is independent of a history of febrile seizures. This is to be expected if early febrile seizures are a marker of an underlying cerebral injury that is associated with hippocampal sclerosis and not the precipitating injury itself. Their conclusion, however, that hippocampal sclerosis is a pre-existing abnormality providing a substrate for febrile seizures, is not supported by their data or cited publications.
Retrospective surgical series have various limitations: the selection bias in surgical series could obscure a correlation between MRI based hippocampal volume measurements and history of febrile seizures and other clinical variables; although MRI volume measurements are related to the severity of hippocampal sclerosis, these MRI parameters are not entirely explained by variations in neuronal and glial densities in the hippocampal subregions5; correlation analyses do not provide direct evidence for the existence or non-existence of a causal relation between febrile seizures and severity of hippocampal atrophy; the difficulty in recording a history of febrile seizures without a maternal history and in distinguishing complex from simple febrile seizures is well recognised.
The number of complex febrile seizures in this and previous studies2 is too small to draw meaningful conclusions. Based on the predominance of simple febrile seizures in their study and recent MRI findings in a study of familial febrile seizures,6 the authors question the assumption that brains of infants with simple febrile seizures are normal. These findings suggest that some pre-existing brain injury predisposes patients to develop febrile seizures and contribute to the development of subsequent hippocampal sclerosis. Hippocampal sclerosis is not selective to patients with a history of early febrile seizures and multiple injuries may in fact be necessary for the development of hippocampal sclerosis, such as the occurrence of febrile seizures, head trauma, meningits, or encephalitis in the presence of some pre-existing, possibly developmental abnormality. Volumetric MRI may miss those subtle developmental abnormalities.
Bower et al 4 and others2 did not find a relation between hippocampal atrophy and duration of temporal lobe epilepsy, seizure frequency, and other clinical variables. These findings did not suggest continuing hippocampal or amygdala atrophy during chronic temporal lobe epilepsy that could be detected by volumetric MRI, but did not exclude the possibility of progression of hippocampal damage in the early years of the habitual epilepsy. Further prospective, longitudinal clinical studies are needed to better understand the relation between early febrile seizures, hippocampal sclerosis, and temporal lobe epilepsy leading to more specific and effective intervention and treatment options.
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