Assessment 11 – A complex relation exists between sleep disturbances and epilepsy. Despite recognizing this reciprocity for well over a century, researchers are just now defining the adversarial effects of sleep disturbances on seizure frequency and severity of epilepsy on the one hand, and, on the other hand, the equally harmful effects of epilepsy on quality of sleep. This blog will present the current understanding on the bidirectional relation of sleep disturbances and epilepsy
Introduction
Many important biological activities exhibit a cyclic function, known as circadian rhythms. The most widely known circadian rhythm is the sleep-wake cycle. This cycle exhibits a regularity of 7-9 hours of sleep, alternatively considered a transient unconscious state, and 14+ hours of conscious wakefulness. The cyclic nature is tightly regulated by a plethora of genes, some aptly called clock genes.
Sleep is essential. It provides a restorative benefit for our organs. Furthermore, It is necessary for the consolidation of long term memories. It is critical for removal of toxic metabolic waste products that accumulate in the brain during the day.
Measurements of brain wave activity show that sleep occurs in several stages numbered 1-4. Light sleep spans stages 1 and 2; deep sleep develops in stages 3 and 4. Stage 4 is followed by a period of rapid eye movement (REM) that is associated with dreaming. Humans experience these stages (1-4, REM) over 90 minutes or so, resulting in about 7 repeats per night. The more time spent in stages 3, 4 and REM, the fewer awakenings, the better rested one feels, and the greater the health benefit.
Sleep Disturbances
Sleep disturbances may take several forms. They are 1) obstructive sleep apnea (OSA), a condition of reduced airway support and subsequent serious perturbations of oxygen and carbon dioxide levels, 2) insomnia, an inability to maintain sleep and 3) poor quality of sleep with frequent awakenings and reduced deep sleep (stages 3,4) and REM sleep.
Sleep disturbances lead to complaints of excessive daytime sleepiness, reduced cognition and accidents. Untreated OSA results in additional negative changes such as an increased risk for hypertension, diabetes, and heart disease. Sleep disturbances also may exacerbate epilepsy and vice versa, epilepsy may worsen sleep disturbances.
Research Findings
Effects of Sleep Disturbances on Epilepsy
Sleep disturbances and epilepsy are intertwined. To what extent and why is not entirely clear. The most well-known finding supporting a relation of sleep disruptions and epilepsy is one used clinically to provoke seizures. That is the state of sleep deprivation. A night without sleep increases the likelihood of recording a daytime seizure with the 20 minute clinical EEG test. In other words, sleep deprivation provokes seizures. It is used clinically to verify their presence. However, unraveling the mechanism of this empirical observation represents a challenge that is just beginning to be met.
Prospective Trial – Seizure Susceptibility Influenced By Sleep Deprivation
Sleep disturbances may initiate the onset of epilepsy. A 10 year prospective population study (Harnod et al., 2017) that tracked medical records of those (~ 277,000 individuals) half with and half without sleep disturbed breathing support this observation. Harnod et al (2017) showed “the cumulative incidence of epilepsy was higher in the sleep disturbed breathing cohort than in the comparison cohort”. The authors also concluded that “Sleep deprivation increases seizure susceptibility and often provokes epileptic seizures”. The data are impressive but regrettably they lack key information relating to patient confirmation, epilepsy type, seizure frequency and other confounding factors such as smoking.
A polysomnographic study is the medical term for a sleep study. Polysomnography measures brain waves (EEG), blood gases (oxygen and carbon dioxide) and quantifies the number of reduced/absent breathing episodes per night (see detail at https://www.mayoclinic.org). Therefore, polysomnographic studies provide quantitative data.
Result from these studies, reported individually or summarized in a meta-analysis(Lin et al., 2017) indicate that the prevalence of one of the most serious sleep disturbances, obstructive sleep apnea (OSA), is about 30% in patients with epilepsy treated with antiseizure drugs and higher in those with drug-resistant epilepsy. Importantly, treatment of OSA in patients with epilepsy with continuous positive airway pressure (CPAP) not only corrects OSA but also reduces seizure frequency.
Effects of Epilepsy on Sleep
According to several studies using a questionnaire, patients with epilepsy report a higher number of sleep complaints compared to those without epilepsy. Complaints included insomnia, excessive daytime sleepiness and disturbed breathing such as obstructive sleep apnea. The complaints were 25-50% higher in patients with epilepsy compared to those without epilepsy
Night Time Seizures
Epilepsy impacts sleep in several ways. Firstly, night time seizures, most common in frontal lobe epilepsy but occasionally occurring in other types of epilepsy, directly disrupt sleep. It may cause insomnia or poor quality sleep.
Discharges Between Seizures
Secondly, data from patients with an implantable brain recorder/stimulator device to reduce seizure frequency and severity, shed light on the indirect effects of seizures on sleep. Recall from Assessment 8, continuous brain recordings in patients with epilepsy revealed the cyclic nature of epilepsy with seizure reoccurrence in intervals of days, weeks, months. Data show that abnormal brain waves termed interictal epileptiform discharges (IEDs) occur in between seizures in patient with epilepsy. Interestingly, IEDs peak during sleep hours, specifically appearing during stages 1-4. Their presence modifies normal sleep waves in those stages. In contrast, REM sleep suppresses IEDs. It is unknown why this is. One suggestion is that the character of normal brain waves in sleep stages 1-4 (synchronous and slow) is permissive for reception of irregular discharges such as IEDs.
Anti-Seizure Medications
Thirdly, there is early recognition that some antiseizure drugs in certain types of epilepsy may enhance sleep disturbances and hence indirectly worsen the epilepsy by disturbing sleep character. This issue is correctable with an alternative medication, shifting time of drug use and defining the sleep disturbance with a polysomnographic study.
Link between sleep and epilepsy
The results of numerous studies in animal models and in humans with epilepsy point to a common link between sleep disturbances and epilepsy. Specifically, Bonilla-Jaime H. et al., (2021) reviewed an extensive body of evidence that supports the hypothesis that the common factor between sleep disturbances and epilepsy may be neuroinflammation.
Neuroinflammation
Neuroinflammation refers to a profusion of harmful changes in the brain initiated and maintained by a wealth of pro-inflammatory mediators. Dying neurons and associated neurons called astrocytes and glial cells are the source of these mediators. In measuring pro-inflammatory mediators, scientists conclude that both sleep disturbances and epilepsy promote neuroinflammation and the two together create a vicious cycle. In other words, epilepsy worsens sleep disturbances and sleep disturbances worsen epilepsy through this pathway of neuroinflammation.
This is a milestone discovery with opportunities for new therapies for epilepsy. Several therapies already have the backing of clinical trial results. For example, use of continuous positive airway pressure (CPAP) restores normal breathing in patients with epilepsy and OSA, and importantly, decreases seizure frequency and severity. Another therapy, the ketone diet (see Assessment 9) decreases neuroinflammation and reduces seizure frequency in certain types of epilepsies. Possible future therapies are anti-inflammatory medications to prevent and/or minimize neuroinflammation and additionally, therapies for insomnia and poor sleep such as cognitive behavioral therapy.
Conclusions
Unraveling the relation between sleep disturbances and epilepsy is important. The modest amount of work to date defines an adversarial reciprocity between sleep disturbances and epilepsy with each worsening the other. However, defining a common pathway such as neuroinflammation offers hope of someday diminishing both sleep disturbances and epilepsy. Clearly, future large clinical trials could provide definitive progress.
Select References
Bonilla-Jaime H. et al., Sleep Disruption Worsens Seizures: Neuroinflammation as aPotential Mechanistic Link. Int. J. Mol. Sci. 22: 12531, 2021.
Harnod T, Wang Y-C, Lin C-L, Tseng C-H. High risk of developing subsequent epilepsyin patients with sleep-disordered breathing. PLoS ONE 12(3): e0173491, 2017.
Lin Z, Si Q, Xiaoyi Z. Obstructive sleep apnoea in patients with epilepsy: a meta-analysis. Sleep Breath 21(2): 263-270, 2017.
Marlow BA et al., Treating obstructive sleep apnea in adults with epilepsy A randomized pilot trial. Neurology 71: 572–577, 2008.
Pavlova MK et al., Proceedings of the Sleep and Epilepsy Workshop: Section 2 Comorbidities: Sleep Related Comorbidities of Epilepsy. Epilepsy Currents 21(3): 210-214, 2021.
Scharf MT et al., Obstructive sleep apnea risk in patients with focal versus generalized epilepsy. Epilepsy & Behavior 111: 107190, 2020.