Spindles‐Inducing Mechanism Modulates Sleep Activation of Interictal Epileptiform Discharges in the Landau—Kleffner Syndrome

Abstract

Summary:Purpose: Landau-Kleffner syndrome (LKS) is characterized by a marked increase of interictal epileptiform discharges (IEDs) during sleep. During nonrapid eye movement (NREM) sleep, neuronal membrane potential oscillations lead to the appearance of spindles and delta waves in the surface EEG and might develop into paroxysmal synchronization. Spectral analysis allows the quantitative description of the dynamics of delta (slow-wave activity, SWA, 0.5-4.5 Hz) and sigma activity (SA, 12.0-16.0 Hz) and can be used to assess the relation between SA, SWA, and IEDs during sleep.Methods: We performed six overnight continuous EEGpolysomnographic studies in three patients with LKS. The temporal series of SWA and SA were obtained from a spike-free derivation lead. The IEDs count was performed on the most active lead. Relations between sigma and SWA and time series of IEDs were tested by means of correlation techniques after data normalization. Results:Our results revealed a significantly higher correlation between IEDs and SA with respect to SWA in all the subjects, in total sleep time. The same analysis limited to NREM sleep highlights the better correlation between SA and IEDs.Conclusions: Our data suggest that neural mechanisms involved in the generation of sleep spindles facilitate IEDs production in LKS. Key Words: Landau-Kleffner syndromeSleep-Spindles-Slow-wave activity-Interictal epileptic discharges.The activating properties of nonrapid eye movement (NREM) sleep on interictal epileptiform discharges (IEDs) have been attributed to the synchronizing functions of thalamocortical oscillations active during this sleep state (1). During NREM sleep, there are three main EEG rhythms: spindles, delta waves, and slow oscillations. Due to the reduction of input coming from the brainstem reticular formation in light NREM sleep, membrane potential oscillations appear in the frequency range of spindles. Approaching deep sleep, paralleling the degree of hyperpolarization of thalamocortical cells, spindles oscillations are progressively replaced by slowfrequency oscillations in the delta range (2). The slow oscillations (< 1 Hz) are generated intracortically and synchronize, trigger, and group the spindle and delta oscillations (1,2).The application of spectral analysis to sleep EEG alAccepted July 2, 1999. Address correspondence and reprint requests to Dr. L. Nobili at Cattedra di Neurofisiopatologia, Ospedale S. Martino, Largo R. Benzi 10, 16132 Genova, Italy. E-mail: nblino@dism.unige.it lowed the description of the time course of sigma activity (SA,(12)(13)(14)(15)(16) Hz) and slow-wave activity (SWA, 0.5-4.5 Hz) whose dynamics reflects, respectively, the behavior of spindles and delta waves. Within NREM sleep and especially in the first part of the night, SA and SWA oscillate inversely while they show a parallel decline during REM sleep, in both adults and children (3)(4)(5).The activating properties of spindles, delta waves, and slow oscillations on spike and waves generation was identified by experimental observations...

Impaired vocal communication, sleep‐related discharges, and transient alteration of slow‐wave sleep in developing mice lacking the GluN2A subunit of N‐methyl‐d‐aspartate receptors

“…Although debated, this hypothesis could apply to Grin2a KO mice and to patients with GRIN2A pathogenic defects. A link between the generation of sleep spindles and the facilitation of interictal epileptiform discharges has been proposed in patients with LKS . However, power spectral analysis of discharges revealed peaks that, although still in the spindle frequency range, were at significantly higher frequencies in Grin2a KO than in WT mice, further emphasizing the pathological nature of the discharges seen in Grin2a KO mice.…”

“…A link between the generation of sleep spindles and the facilitation of interictal epileptiform discharges has been proposed in patients with LKS. 48 However, power spectral analysis of discharges revealed peaks that, although still in the spindle frequency range, were at significantly higher F I G U R E 5 Longitudinal electroencephalographic (EEG) analysis in Grin2a knockout (KO) mice reveals transiently altered duration of slow-wave sleep (SWS) and spike-and-wave discharges during SWS. Wild-type (WT) and Grin2a KO mice (n = 8 for each cohort) were evaluated by simultaneous chronic in vivo EEG, electromyographic (EMG), and video recordings at 1 month (postnatal day [P] 30) and then 2 months (P60) of age.…”

Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language‐related NMDA receptor subunit gene Grin2a

“…Of interest, both delta and spindling activities are elements of non-REM (rapid eye movement) sleep. In children with EAS, the activation of interictal epileptiform discharges in sleep has been associated with the occurrence of spindles, 42 and it was proposed that the thalamocortical circuitry that generates spindles might be hijacked to generate spike and wave discharges. 43 Consistently, power spectrum and current source density analyses indicated the possible involvement of the granular neocortical layer that receives afferent connections from the thalamus.…”

Interictal Epileptic Spiking during Sleep and Wakefulness in Mesial Temporal Lobe Epilepsy: A Comparative Study of Scalp and Foramen Ovale Electrodes

“…There is accumulating evidence that this may depend on the type of epilepsy syndrome being studied. According to recent spectral analysis results, a range of idiopathic childhood epileptic syndromes (3)(4)(5)(6)(7)(8) can be characterized by increased spiking in the sigma range related to spindle synchronization present mainly during NREM2. Adult partial epilepsies, conversely, are accompanied by increased spiking related to the delta frequency range (9,10).…”