Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link

Abstract

Sleep disturbances, such as insomnia, obstructive sleep apnea, and daytime sleepiness, are common in people diagnosed with epilepsy. These disturbances can be attributed to nocturnal seizures, psychosocial factors, and/or the use of anti-epileptic drugs with sleep-modifying side effects. Epilepsy patients with poor sleep quality have intensified seizure frequency and disease progression compared to their well-rested counterparts. A better understanding of the complex relationship between sleep and epilepsy is needed, since approximately 20% of seizures and more than 90% of sudden unexpected deaths in epilepsy occur during sleep. Emerging studies suggest that neuroinflammation, (e.g., the CNS immune response characterized by the change in expression of inflammatory mediators and glial activation) may be a potential link between sleep deprivation and seizures. Here, we review the mechanisms by which sleep deprivation induces neuroinflammation and propose that neuroinflammation synergizes with seizure activity to worsen neurodegeneration in the epileptic brain. Additionally, we highlight the relevance of sleep interventions, often overlooked by physicians, to manage seizures, prevent epilepsy-related mortality, and improve quality of life.

Keywords: epilepsy; neurodegeneration; neuroinflammation; seizures; sleep.

Figure 1

Proposed mechanisms of sleep disruption that contribute to neuroinflammation and worsen neurodegeneration in the epileptic brain. After seizures, peripheral and brain-resident immune cells become active, release danger signals, and produce pro-inflammatory mediators, including cytokines, complement factors, prostaglandins, among others, triggering a sustained vicious circle of neuroinflammation characterized by monocytic infiltration to the brain, astrocytic/microglial activation, and pro-inflammatory cytokine production, which ultimately leads to neurodegeneration. We propose that sleep disruption can act as a second inflammatory hit that increases seizure frequency and aggravates neuronal loss, thus favoring the progression of epilepsy. This figure was created with BioRender.com.

Figure 2

Neuroinflammation as a potential link in the vicious cycle of sleep and epilepsy. This figure was created with BioRender.com.