Are Absence Epilepsy and Nocturnal Frontal Lobe Epilepsy System Epilepsies of the Sleep/Wake System?

Abstract

System epilepsy is an emerging concept interpreting major nonlesional epilepsies as epileptic dysfunctions of physiological systems. I extend here the concept of reflex epilepsy to epilepsies linked to input dependent physiological systems. Experimental and clinical reseach data were collected to create a coherent explanation of underlying pathomechanism in AE and NFLE. We propose that AE should be interpreted as epilepsy linked to the corticothalamic burst-firing mode of NREM sleep, released by evoked vigilance level oscillations characterized by reactive slow wave response. In the genetic variation of NFLE the ascending cholinergic arousal system plays an essential role being in strong relationship with a gain mutation of the nicotinic acethylcholin receptors, rendering the arousal system hyperexcitable. I try to provide a more unitary interpretation for the variable seizure manifestation integrating them as different degree of pathological arosuals and alarm reactions. As a supporting hypothesis the similarity between arousal parasomnias and FNLE is shown, underpinned by overlaping pathomechanism and shared familiarity, but without epileptic features. Lastly we propose that both AE and NFLE are system epilepsies of the sleep-wake system representing epileptic disorders of the antagonistic sleep/arousal network. This interpretation may throw new light on the pathomechanism of AE and NFLE.

Figure 1

Distribution of generalized spike-wave discharges in different vigilance levels. (a) and (b) In absence epilepsy elevating the vigilance level from NREM sleep by calling the name of the patient first results in transitory activation of the discharges, and later the application of the same stimulus inhibits the discharges. As seen in (c) insert shows the optimal decrease of vigilance level which activates the discharges, while increased arousal and deepening of sleep equally inhibit them. The critical vigilance territory is situated between sleep and wakefulness and NREM and REM, as shown in the left insert. The highest activation have been experienced in shifts from wakefulness to NREM sleep and from REM to NREM sleep (arrows). (b) Shows the typical patterns of spike-wave activation during night sleep. During full wakefulness and REM the spike-wave discharges are absent. During the course of falling asleep (stage 1, superficial stage 2) spike-wave discharges show the ictal absence type activation (even if in awake state they were not present). In deeper sleep (stages 3-4) the typical 3 Hz spike-wave pattern became disrupted; later we see more polyspike-wave forms. (d) and (e) are typical spike-wave activation conditions in absence epilepsy in two patients: in falling asleep, in transitions from wake to NREM or from REM to NREM, around transitory awake state, and before and after awakening in the morning.

Figure 2

Distribution of CAP subtypes across a sleep cycle and the typical distribution of the subtypes from cycle to cycle, compared with the distribution of spike-wave discharges (after Terzano et al. [18] and Parrino et al. [19]).

Figure 3

The thalamocortical system and its brainstem connections contain two antagonistic loops: one is responsible for the suppression-burst firing (red insert), and intrathalamic circuit connecting reticular inhibitory nuclei with thalamocortical relay neurons producing spindles and slow waves (sleep network); the other system is the ascending reticular system and thalamic connections (blue) conveying cholinergic arousal influences and inhibiting the reticular nuclei providing tonic thalamocortical neuronal discharge flow (blue upper insert), maintaining wake state. The right lower insert shows the excitatory postsynaptic effect of ascending cholinergic reticular neurons on the thalamocortical relay cell. The left lower insert shows the inhibitory postsynaptic effect of the cholinergic ascending arousal neurons on the thalamic reticular neurons (composed after Steriade [45], and Itier and Bertrand [46]).