Neuroendocrine aspects of improving sleep in epilepsy

Abstract

Sleep plays an intricate role in epilepsy and can affect the frequency and occurrence of seizures. With nearly 35% of U.S. adults failing to obtain the recommended 7 h of sleep every night, understanding the complex relationship between sleep and epilepsy is of utmost relevance. Sleep deprivation is a common trigger of seizures in many persons with epilepsy and sleep patterns play a role in the occurrence of seizures. Some patients have their first seizure or repeated seizures after an "all-nighter" at college or after a long period of chronic sleep deprivation. The strength of the relationship between sleep and seizures varies between patients, but improving sleep and optimizing seizure control can have significant positive effects on the quality of life for all these patients. Research has shown that the changes in the brain's electrical and hormonal activity occurring during normal sleep-wake cycles can be linked to both sleep and seizure patterns. Many questions remain to be answered about sleep and epilepsy. How can sleep deprivation trigger an epileptic seizure? How do circadian and hormonal changes influence sleep pattern and seizure occurrence? Can hormones or sleeping pills help with sleep in epilepsy? In this article we discuss these and many other questions on sleep in epilepsy, with an emphasis on sleep architecture, hormone changes, mechanistic factors, and possible prevention strategies.

Keywords: Antiepileptic; Epilepsy; Insomnia; Melatonin; Sleep; Tonic inhibition.

Fig. 1.

Representation of sleep stages with corresponding EEG activity traces (Arrigoni and Fuller, 2012).

Fig. 2.. GABA-A Receptor Structure and GABAergic synapse.

(A) A top view of pentameric GABA-A receptor. There are 19 known subunits: α1–6, β1–3, γ1–3, δ ,ε, θ , π , ρ1–3. The most common combination contains 2 αs, 2 βs and 1 γ; the γ subunit can be replaced by δ, ε, θ, or π. (B) GABA-A receptors belong to the cys-loop family of ligand-gated ion channels. Each GABA-A receptor subunit contains four transmembrane domains (TM1–4) and one extracellular N terminal and one intracellular C terminal. (C) In GABAergic synapse, GABA is released from the presynaptic neuronal terminal and acts at synaptic and extrasynaptic receptors in the postsynaptic neuron, exerting inhibitory phasic and tonic currents, respectively. BZ, benzodiazepine.

Fig. 3.. Novel molecular mechanisms of sleep disturbances in epilepsy.

(A) Disrupted activity rhythm in Kv1.1 KO animals under diurnal or constant conditions, measures across several days. (B) Progressive decline in “rest” epochs in KO mice compared to WT controls and KO mice treated with ketogenic diet (KD-KO). (C) Time sent in sleep and wake under diurnal or constant conditions total (above) and each individual day across 10 days of recording (Iyer et al, 2017; Wallace et al, 2018).

Fig. 4.. Expression of clock genes in experimental model.

Transcript levels of four clock genes (bmal1, clock, per1 and per2) were measured at four time points (ZT 0, 6, 12 and 18) in diurnal (A, C, E, G) and constant conditions (B, D, F, H) in Kv1.1 KO and wild-type mice ( n=3–4 each/genotype/time point/lighting condition and 2 replicates) (Wallace et al, 2018).

Fig. 5.. Sirt1 transcription in experimental model.

Sirt 1 expression patterns of Kv1.1−/− (KO) and wild-type (WT) (n=3–4 per genotype/time point/lighting condition and 2 replicates) (Wallace et al, 2018).

Fig. 6.. Alterations in GABA-A receptor subunit expression following sleep disturbance.

Note reduced α5 and δ subunit mRNA. Data represents mean+ SEM (n=5–6 per group).

Fig. 7.. Relationship between sleep deprivation and tonic currents.

Acute sleep deprivation (4 hours, A-D) significantly diminishes frequency of mIPSCs and the magnitude of tonic GABAergic currents in normal mice. E) Kv1.1−/− also show reduced tonic inhibition.

Fig. 8.. Effect of tonic inhibition promoting drug ganaxolone on sleep.

(A) Differences in seizure frequency with and without ganaxolone. (B) Sleep data at baseline and with ganaxolone. (C) Survival data with and without ganaxolone for 60 day observation period.