Sleeping With the Enemy: Drug-Resistant Epilepsy and Sleep

Abstract

Factors Associated With Poor Sleep-In Children With Drug-Resistant Epilepsy

Proost R, Cleeren E, Jansen B, Lagae L, Van Paesschen W, Jansen K. Epilepsia. 2024;65(11):3335-3349. doi:10.1111/epi.18112.

Objective: We aimed to investigate sleep in children with drug-resistant epilepsy (DRE), including developmental and epileptic encephalopathies (DEEs). Next, we examined differences in sleep macrostructure and microstructure and questionnaire outcomes between children with well-controlled epilepsy (WCE) and children with DRE. Furthermore, we wanted to identify factors associated with poor sleep outcome in these children, as some factors might be targets to improve epilepsy and neurodevelopmental outcomes. Methods: A cross-sectional study was conducted in children 4 to 18-years-old. Children without epilepsy, with WCE, and with DRE were included. Overnight electroencephalography (EEG), including chin electromyography and electrooculography, to allow sleep staging, was performed. Parents were asked to fill out a sleep questionnaire. Classical five-stage sleep scoring was performed manually, spindles were automatically counted, and slow wave activity (SWA) in the first and last hour of slow wave sleep was calculated. Results: One hundred eighty-two patients were included: 48 without epilepsy, 75 with WCE, and 59 with DRE. We found that children with DRE have significantly lower sleep efficiency (SE%), less time spent in rapid eye movement (REM) sleep, fewer sleep spindles, and a lower SWA decline over the night compared to children with WCE. Subjectively more severe sleep problems were reported by the caregivers and more daytime sleepiness was present in children with DRE. Least absolute shrinkage and selection operator (LASSO) regression showed that multifocal interictal epileptiform discharges (IEDs), benzodiazepine treatment, and longer duration of epilepsy were associated with lower SE% and lower REM sleep time. The presence of multifocal discharges and cerebral palsy was associated with fewer spindles. Benzodiazepine treatment, drug resistance, seizures during sleep, intellectual disability, and older age were associated with lower SWA decline. Significance: Both sleep macrostructure and microstructure are severely impacted in children with DRE, including those with DEEs. Epilepsy parameters play a distinct role in the disruption REM sleep, spindle count, and SWA decline.

Commentary

Good sleep hygiene and sleep quality are intimately linked to various aspects of health and wellbeing throughout our lives. It is popular knowledge that brain growth occurs during sleep and babies spend several hours sleeping during their peak developmental years. Lack of sleep is commonly cited as a possible trigger for seizures. Conversely, disordered sleep is a common complaint in clinical practice and one of the most crucial factors affecting quality of life in patients with epilepsy.

Background information for those of us that don’t practice sleep medicine: Sleep is divided into macrostructures (time resolution less than 30 s therefore studied in 30 s epochs) and microstructures (time resolution more than 30 s). ¹ Macrostructures include the classical sleep stages of awake, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep stages 1, 2, and 3. Microstructures include sleep spindles, sleep arousals, K complexes, cyclic alternating pattern. These stages can be manually marked in an overnight EEG with additional chin electromyogram (EMG) and eye/electrooculogram (EOG) leads. Manual scoring is labor intensive. Macrostructures are prone to non-uniform scoring, have a limited interrater reliability especially in patients with developmental and epileptic encephalopathy (DEE) due to the high amplitude slowing in both awake and asleep states on EEG. Microstructures lend themselves to better standardization and possibly automation ¹ but could be a challenge to identify in patients with diffuse excess beta activity on EEG. REM sleep epochs are characterized by low voltage activity and show a paucity of spikes, interictal discharges (IEDs) and seizures while NREM epochs have a higher spike frequency, wider spike field and more seizures.

There is robust research and literature around the neurobiology of sleep and bidirectional relationship of sleep, cognition and epilepsy in adults.^2,3 REM sleep is important in consolidation of procedural and emotional memory and, particularly in children, developmental neuroplasticity ⁴ while slow wave sleep (SWS) plays a role in declarative memory. Winsor et al performed a systematic review and meta-analysis ⁵ that included nineteen studies of children with and without epilepsy in 2021 to quantify differences in sleep architecture, sleep efficiency and sleep difficulties. Salient findings included greater sleep difficulties with night awakenings, parasomnias, disordered breathing, increased percentage of N2 sleep and reduced sleep efficiency in 901 children with epilepsy compared to 1470 healthy children. Authors however excluded epileptic children with intellectual disability (ID), which also means that the meta-analysis did not account for a sizable proportion of pediatric drug-resistant epilepsy population (pDRE) that have DEE and therefore ID.

Does disrupted sleep architecture due to refractory epilepsy contribute independently to ID in patients with DEE?

In 2022, Proost et al embarked on a literature search specifically in pDRE and sleep ⁶ and noted a paucity of literature in pDRE and sleep disorders. There was an overall lack of adequately powered, high-quality studies with optimal sample sizes and comparator groups, homogeneity in variables measured and defined, robust statistical methodology (multivariable analysis) to accurately identify effects of several interacting variables—hindering authors’ ability to perform a systematic review and meta-analysis. This exercise, however, allowed identification of areas that needed systematic research in pDRE and sleep.

All included studies showed an overall lower percentage of REM sleep in pDRE compared to healthy children.

If REM sleep causes IED inhibition AND REM sleep is reduced in pDRE—what is the nature (directional) of this relationship and implication of this finding? Do other factors like etiology of pDRE, antiseizure medications (ASM), disease comorbidities contribute?

Research methodology used by the authors: After the literature search published in 2022, Proost et al ⁷ designed a single center cross sectional study comparing children with pDRE, well controlled epilepsy and healthy children that underwent an overnight video EEG with added channels of EMG and EOG to help stage sleep. Authors adapted and created criteria to stage sleep in pDRE. For example, in pDRE when no activity bereft of IEDs was noted- they used a slow, high voltage background (<2.5 Hz and >70 mV) as a surrogate for N3 sleep. Additionally, when no low voltage fast activity (indicating REM) could be identified due to the high voltage sleep patterns in these patients, they used low tone on chin EMG and eye movement signals on EOG channel to mark REM epochs. Additionally, automation was used for spindle counts and slow wave activity measurements in the last hour of N2 and N3. Sleep questionnaires validated for patients with ID were used. A composite sleep index that combined qualitative (snoring, daytime sleepiness, complaints related to sleep, anxiety related to sleep as examples) as well as quantitative sleep (how many night awakenings, how long before the child settles as examples) was devised. Lastly, in addition to standard multivariable analysis to study independent contribution of interrelated variables like etiology, ASM use, comorbidities as examples; authors used a multivariable analysis method called LASSO—Least Absolute Shrinkage and Selection Operator—to minimize overfitting their multivariable regression model.

Results that were not surprising but now proven with LASSO statistics as independent contributors to sleep outcomes in pDRE:

Each of the following—multifocal IEDs, benzodiazepine use, and longer duration of epilepsy are independently associated with lower sleep efficiency and lower REM time.

Multifocal IEDs and a diagnosis of cerebral palsy were independently associated with lower spindle count.

Benzodiazepine use, drug resistance, seizures during sleep, ID, older age were all independently associated with lower slow wave activity decline over the night (hence contributing to greater degree of encephalopathy).

Significantly more caregivers in the DRE group than well controlled group reported that sleep problem in the child affected overall family dynamics. However, both groups; whether well controlled or DRE; reported presence of sleep problems.

Take Home Message

Proost et al have made the initial attempt to disentangle the interactions between disturbed sleep, intellectual disability, interictal discharges, antiseizure medications and epilepsy characteristics in pDRE. Further work might allow us to use REM sleep as a biomarker to track progression of disease (loss of REM to indicate disease worsening or reappearance of REM as a marker for disease modification). Similarly, slow wave activity decline could be used as a marker to assess efficacy of treatment. We shall have to wait for further studies to see whether trying to correct the abnormal sleep patterns in pDRE eventually improves cognitive outcomes of these children.

However, the present data gives us the leverage to start making changes to how we use data recorded from sleep EEG in our epilepsy monitoring units or how we evaluate the use of specific ASMs in our clinical practice.