Seizures: About the right time to explore their mechanisms

Abstract

Ancient treaties report that behavioral seizures tend to occur at specific times during the night and day cycle in some individuals with epilepsy. Recently, continuous long-term recordings (months to years) in patients living at home provided a wealth of data, directly showing that seizures are regulated in a circadian manner in 80% of the cases. In addition, these recordings demonstrated the presence of a much slower rhythm (days to weeks) of seizures. This is developed in the first two papers of this supplement (Baud; Karoly and Cook). Previous studies have taught us that predicting seizures is a very difficult task. Combining the circadian and multidien rhythms might help predict better periods of low and high risk of seizure occurrence. Clinical data demonstrate that the time of occurrence of seizures is widespread during the night and day cycle. The circadian and multidien rhythms only indicate a period of increased (or decreased) probability. This means that seizures do not occur for each cycle and might occur outside the increased probability period. These results are also important for basic science. Decades of research did not allow outlining of the mechanisms of seizure genesis. We now have strong indirect evidence that “something” drives neuronal networks close to seizure threshold rhythmically (and/or that the threshold moves up and down in a circadian/multidien way). Perhaps our quest for mechanisms could start here: trying to understand why seizure probability oscillates that way. One entry point is the genes that control circadian rhythms. The circadian machinery in the suprachiasmatic nucleus is controlled by translational/transcription loops, with the oscillation of numerous proteins including CLOCK, PER, BMAL and CRY. The paper by Chan and Liu focuses on the role of core clock genes in epilepsy. The relationship seems bidirectional, with alterations in some genes leading to epilepsy and epilepsy dysregulating these genes. The final paper by Bernard attempts to synthesize these findings in a unified functional framework. The fact that hundreds of genes and proteins oscillate during the night and day cycle in epileptogenic networks, hence their molecular architecture, may provide the conditions sufficient to bring networks close to seizure threshold (and/or decrease the threshold itself). Even though circadian rhythmicity of seizures has been known for decades, surprisingly few studies have focused on the underlying mechanisms. Strong clinical data and recent advances in basic research offer now a fantastic opportunity to explore seizure rhythmicity. This may be appealing to young researchers, as nearly everything remains to be discovered. In particular, the multidien rhythm remains a complete mystery. Its existence in the “control” population remains to be established. As for the possible mechanisms of multidien rhythms, even an educated guess is difficult to provide—we do not even know where/what to look. Although the circadian/multidien field of research offers great promise, one must remain humble against the complexity of the task. We also need to keep in mind that we deal with probabilities of occurrence and not clockwork processes. This should not prevent us from getting to work; the clock is ticking.