According to the EEG, EOG and EMG, sleep can be divided into two alternating phases: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.
NREM sleep is characterized by no obvious eye movement, reduced muscle tone, and flat EMG; according to the change of EEG frequency from fast to slow and voltage from low to high, NREM sleep is further divided into four stages: I, II, III, IV, in which stage III and IV sleep are also called slow wave sleep, when consciousness is completely lost and cortical cells are fully rested. REM sleep, also known as fast wave sleep, is a heterogeneous sleep in which the EEG changes are separated from the behavioral changes, thus becoming a heterogeneous sleep. During this period, the EOG appears as a rapid coordinated eye movement, the EMG is completely flat or significantly suppressed, and the EEG is a desynchronized low voltage fast wave.
Sleep in children is characterized by rapid and prolonged entry into NREM sleep stages III and IV, followed by periodic periods of slow-wave sleep throughout the night, with fewer awakenings during sleep. The duration of sleep decreases with age. The daily sleep duration is about 15-20h for newborns, 13-14h for 1 year old, 10-12h for 2-12 years old, 9-10h for 12-18 years old, and 7-8h for adults.
1. The effect of sleep on epilepsy
1.1 Sleep and seizures in children
Sleep is an important activating factor for abnormal brain neuron firing or causing seizures. This is due to the weakened activation of the brainstem upward reticular activation system on the cerebral cortex and limbic system during sleep, and the tendency of brain waves to slow down and synchronize, which tends to release the electrical activity of epileptic foci and cause intercellular ignition, thus facilitating the issuance and conduction of epileptic waves. Sleep can induce seizures and/or interictal epileptiform discharges.
NREM sleep has a tendency to activate seizures in an already highly excited cortex, whereas REM sleep inhibits synchronization in the thalamocortex and weakens the propagation of interhemispheric impulses through the corpus callosum, resulting in attenuation of bilateral synchronized epileptiform discharges and therefore an inhibitory effect on epileptiform activity. Many studies have also found an increase in seizures during NREM sleep and a decrease in seizures during REM sleep, but there are conflicting reports about which phase of seizures is most prevalent during NREM sleep.
After studying 600 patients with epilepsy, Herman et al. found that 43% of patients had seizures during sleep, of which about 23% occurred in NREM sleep I, 68% in NREM sleep II, 11% in NREM sleep III and IV, and none in REM sleep. nobili et al. did not find any seizures in the first sleep cycle in NREM Nobili et al. did not find a statistical difference in spike index (number of spikes per minute) between the time phases of sleep in the first sleep cycle, but overall epileptiform activity was stronger in NREM sleep than in REM sleep.
1.2 Sleep deprivation and seizures
Sleep deprivation is a suitable condition for seizures due to hypofunction of the central reticular upward agonist system, where the cerebral cortex and limbic system are out of control of the excitatory system. Due to prolonged sleep deprivation, there is a higher activation rate than natural sleep versus pharmacological sleep, and the activation mechanism may be related to causing increased cortical excitability. The relationship between epileptiform discharges and sleep deprivation is particularly evident in Lennox-Gastaut and West syndromes. shahar analyzed the EEG of 55 children (5-17 years old) with more than one clinical convulsion after 6 hours of sleep deprivation and showed that 44% of the children had focal discharges and 20% widespread discharges.
2. Effects of epilepsy on children’s sleep
2.1 Effect of epilepsy on sleep structure
There are multiple associations between sleep-wake rhythms and epilepsy. The most common sleep structure abnormalities include prolonged sleep latency, prolonged NREM sleep stages I and II and shortened stages III and IV, reduced REM sleep, broken sleep structure, increased number of sleep stage transitions, increased number of awakenings and awakening time, and reduced sleep efficiency. Abnormalities in sleep architecture vary among children with different types of epilepsy.
Klobucníková et al. used EEG, EOG, and EMG to observe nocturnal sleep in patients with epilepsy and found that epileptic seizures altered sleep structure, decreasing the proportion of NREM sleep stages III and IV and REM sleep, and increasing NREM sleep stage II, and these changes were not associated with the use of antiepileptic drugs. In a study of generalized epilepsy, Bazil et al. found that nocturnal generalized seizures were able to alter sleep structure, accompanied by a decrease in sleep efficiency and a decrease in the proportion of REM sleep, in agreement with the findings of Klobucníková et al. A prolongation of the REM latency period can also occur if the seizure occurs before the REM sleep period.
In recent years, studies of sleep structure in children with idiopathic generalized epilepsy and idiopathic focal epilepsy have shown increased wakefulness, decreased sleep efficiency and reduced sleep in NREM sleep IV in children with idiopathic generalized epilepsy, but no significant differences in REM sleep between the two groups. One study showed a shortened sleep REM period, an increased proportion of stage I sleep, and a decreased proportion of stage III / IV sleep in children with benign epilepsy with central-temporal spikes (BECTS), while the sleep latency was normal and the proportion of stage II sleep did not change significantly.
Patients with temporal lobe epilepsy had significantly longer sleep latency, increased NREM sleep stages I and II and decreased stages III and IV, as well as decreased REM sleep duration and increased awakenings; whereas patients with frontal lobe epilepsy mainly had decreased NREM sleep stages III and IV. In children with epilepsy, the sleep structure is altered and the quality of sleep is affected, which is mainly related to the ease of activation of epileptiform discharges during sleep and frequent inter-phase transitions during sleep.
The presence of sleep spindle waves is an important factor in maintaining sleep stability and suppressing epileptiform discharges. The presence of spindle waves is a sign of entering stage II sleep. In normal infants, sleep fusiform waves appear at 2-3 months of age, some as early as 6-8 weeks after birth, and appear early in stage II sleep – stage III sleep, with waves in the midline and left and right frontal, central and parietal regions, which can be asymmetrical or asynchronous with non-constant left and right. The sleep fusiform wave can inhibit the spike-full complex wave burst activity, and the thalamic reticular nucleus plays a “pacing point” role for its occurrence and periodic activity. Inhibition of the thalamus by the cerebral cortex can affect the sleep spindle wave and is associated with the formation of spike waves. Extensive hyperexcitability of cortical neurons leads to a strong response from the thalamus, which may be manifested on the EEG as spike waves instead of sleep spindle waves.
2.2 Epilepsy and sleep disorders in children
Almeida et al. used the Epworth Sleepiness Scale and the complex sleep latency test to investigate 39 patients with temporal lobe epilepsy and found that 85% of patients had daytime sleepiness, 26% had insomnia, 13% had sleep apnea syndrome, 15% had restless legs syndrome, and 5% had periodic sleep disorders. syndrome, and 5% had periodic leg movements.
A study of 515 patients with epilepsy showed that the incidence of combined obstructive sleep apnea syndrome was 18.06%, and the incidence of combined obstructive sleep apnea in refractory epilepsy was as high as 33.3%, and the frequency of seizures was reduced by 50% to 100% after continuous positive airway pressure treatment. showed that 14.2% of children had epileptiform discharges.
Obstructive sleep apnea causes sleep fragmentation, frequent awakenings, and microarousals, which may contribute to seizures. Effective treatment of obstructive sleep apnea may lead to better seizure control. In patients with obstructive sleep apnea syndrome, the recurrence of hypoxemia and hypercapnia increases sympathetic excitability and affects the excitability of the brain, thus triggering and aggravating seizures.
Sleep-related epilepsy refers to epilepsy in which seizures occur only during sleep or are more likely to occur during sleep, and involves various types of seizures such as benign childhood epilepsy with central-temporal spikes, epilepsy with slow-wave sleep-period sustained spikes, frontal lobe epilepsy, and temporal lobe epilepsy. One of the clinical features of benign childhood epilepsy with central-temporal spike-wave is nocturnal seizures, most often occurring shortly after going to sleep.
Both acquired epileptic aphasia (Landau-Kleffner syndrome (LKS) and epilepsy with slow-wave sleep-phase sustained spike-like complex waves (ESES) are evident in epileptiform discharges during sleep. The former EEG is characterized by continuous spike-wave discharges during sleep either bilaterally or unilaterally. The latter is characterized by the persistence of diffuse, high-amplitude 1 to 3 Hz spike-slow complex waves during NREM sleep stages III and IV, accounting for more than 85% of the entire slow-wave sleep period. Frontal lobe epilepsy is more prone to seizures during sleep than temporal lobe epilepsy. Myoclonic seizures tend to occur during the transition from sleep to wakefulness. Infantile spasms tend to occur just after sleep or during the transition from sleep to wakefulness.
A study of 28 cases of Lennox-Gastaut syndrome showed that 78.6% of patients had all-conductor bursts of 1.5-2.5 Hz slow spike and slow complex waves, sharp and slow complex waves, and multiple spikes and slow complex waves during sleep. 75% of patients had bilateral 10-12 Hz high amplitude fast wave rhythms during sleep. Sleep has been shown to play an important role in the learning and memory process through the plasticity of neural networks. A variety of epilepsy syndromes can present with sustained epileptiform discharges in the slow-wave sleep phase that interfere with the formation of normal sleep cycles and cause impairment of cognitive function. This suggests whether we should link the relationship between epilepsy and sleep and cognitive impairment and study the correlation between the two.
Treatment of sleep disorders may improve the quality of life of children with epilepsy and may even control seizures in some cases. In April 2010, Elkhayat et al. studied sleep in children with intractable epilepsy and found that melatonin not only significantly improved sleep disturbances, but also reduced the severity of seizures.
3. Sleep and antiepileptic drugs in children
Studies of the effects of antiepileptic drugs (AEDs) on sleep in children with epilepsy have been based on effective blood levels, stable doses, and a regular lifestyle, and have excluded the effects of other factors. The effect of each AEDs on sleep in children with epilepsy varies. The combined data from the available studies show that all AEDs have the effect of prolonging REM sleep latency or reducing the percentage of REM sleep, and that they improve sleep stability and promote sleep normalization.
Facultad study found that traditional AEDs such as oxcarbazepine can reduce sleep discontinuity without effect on REM sleep; the effect of sodium valproate on sleep structure is highly controversial, Benjamin et al. found that sodium valproate impairs sleep structure in epileptic patients by increasing stage I sleep; some scholars believe that sodium valproate can prolong NREM sleep stages III, IV and total Benjamin’s study found that phenytoin sodium impairs sleep structure in epileptic patients by increasing NREM stage I sleep and decreasing slow wave sleep and REM sleep.
The effect of new antiepileptic drugs such as lamotrigine on the sleep of epileptic patients is not much reported, some scholars believe that it can reduce NREM sleep stage III and IV and prolong REM sleep; Foldvary et al. found that gabapentin can increase the duration of slow wave sleep, but the proportion of slow wave sleep does not increase, and there is a slight decrease on the number of awakenings and sleep transition cycle. A study of 11 patients with temporal lobe epilepsy on a single dose of topiramate showed no impairment of sleep architecture.
However, a trend towards a reduction in REM and wake time was also observed, but the difference was not statistically significant. enrica et al. reported a trend towards a reduction in nocturnal sleep latency after topiramate treatment. Based on both the difference in the physiological significance of sleep in each phase and the relationship between seizure and sleep phase, oxcarbazepine, gabapentin, and topiramate tend to be beneficial for sleep in epileptic patients. Therefore, the effect of AEDs on sleep should be taken into account when using AEDs in children with seizures, for example, AEDs that increase NREM sleep stages III and IV, decrease NREM stages I and II, and increase the length of the sleep-wake cycle can be considered.
It has been suggested that frequent dose adjustments and multiple overdoses are significantly associated with sudden unexpected death in epilepsy (SUDEP), which is defined as a sudden, unexpected, non-traumatic, non-drowning death of a patient with epilepsy, with or without a witness, with or without evidence of seizures and excluding persistent epilepsy postmortem examination did not reveal structural or toxic lethal factors. In pediatric patients with epilepsy, SUDEP occurs most often during REM sleep followed by NREM II. To prevent the occurrence of SUDEP, broad-spectrum AEDs may be more effective in patients with primary generalized epilepsy that is not effectively controlled.
4. Conclusion and outlook
In summary,there is a close relationship between epilepsy and sleep. The frequency of seizures varies in different sleep phases. For children with different seizure types of epilepsy their sleep structure abnormalities also behave differently. The interaction between epilepsy and sleep disorders forms a vicious circle. Anti-epileptic drugs are selected according to their effects on sleep structure and related sleep disorders to optimize sleep patterns, control seizures, improve treatment compliance, and improve cognitive function and quality of life in children with epilepsy. With the shift in the medical paradigm, there is a great need for clinical work to have a clear understanding of the relationship between epilepsy and sleep in order to reduce medically induced damage and take effective measures to prevent and treat it.