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Original Articles

Relationship Between Sleep Characteristics and Sudden Unexplained Death Risk in Epilepsy

Dede, Hava Ö. MD*; Bebek, Nerses MD, PhD*; Oğuz Akarsu, Emel MD*; Samanci, Bedia MD*; Karbay, Merih MD*; Gürses, Candan MD*; Baykan-Baykal, Betül MD*; Karadeniz, Derya MD; Gökyiğit, Ayşen MD*

Author Information
doi: 10.1097/NRL.0000000000000254

Abstract

Erratum

In an article appearing in the November 2019 issue of , an author’s name was spelled incorrectly. Instead of Betül Baykan-Baykal, it should have been simply Betül Baykan. This error has been noted in the online version of this article, which is available at .

The Neurologist. 25(1):17, January 2020.

There are many similarities between sleep and epilepsy regarding the functional and neurochemical organizations. Cholinergic and monoaminergic stimuli in the brainstem decrease as sleep progresses and cause relative hyperpolarization or synchronization in the thalamocortical neurons.1 Similar thalamic and cortical mechanisms come into play under sleep spindles among the electrophysiological patterns of sleep and epileptic spike-wave discharges.2 In a healthy brain, the thalamocortical network produces sleep spindles, whereas the same pathway mechanism leads to absence of seizures in an epileptic brain.3

Sleep disorders are grouped into 6 major categories: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, and sleep-related movement disorders [International Classification of Sleep Disorders-3 (ICSD-3)].4 The most commonly observed complaints in patients with epilepsy are difficulties in falling asleep, having frequent awakening after sleep onset, and excessive daytime sleepiness.5 Tiredness, lack of attention and concentration, and short-term memory loss are also commonly observed. Seizures per se in patients with epilepsy, ictal and interictal findings in electroencephalography (EEG), medications, and psychiatric presentations, such as reactive depression and anxiety because of chronic illness, have all negative effects on sleep and cause excessive daytime sleepiness.6

Epilepsy and sleep disorders are enhanced risk of hypoxia during seizures in sleep and autonomic nervous system dysfunction leading to increased risk of sudden unexplained death in epilepsy (SUDEP). There is a strong association of SUDEP with sleep, suggesting that sleep is a significant risk factor for SUDEP. However, the risks of SUDEP associated with sleep are unknown and likely multifactorial. Furthermore, obstructive sleep apnea syndrome (OSAS) is more common in patients with epilepsy than in the general population.7 The risk of SUDEP may be increased because of OSAS 7 and any other sleep disorders when the mechanism and risk factors are related to SUDEP are examined.8,9

Parasomnias can cause comorbidity in patients with epilepsy. Neuronal excitability is presumably affected by different neurochemical effects during nonrapid eye movement (REM) and REM periods. The “synchronized state” that emerges during the non-REM (NREM) period plays an important role in triggering the pending epileptic neurons. In addition, there are sudden, synchronous stimulating inputs during awakenings. These inputs may contribute to the induction of seizures.10

According to some studies, the frequency of restless legs syndrome-Willis Ekbom Disease (RLS/WED) is higher in patients with epilepsy. Findings of RLS/WED may have a negative effect on falling asleep and continuing in patients with epilepsy. The severity of the associated sleep deprivation can also increase the frequency of seizure.11

In the present study, we aim to investigate the importance of issues related to sleep that is likely to be ignored most of the time when the patients are being subjected to many complex examinations, and the importance of analyzing sleep disorders and determining their incidence, particularly in patients with drug-resistant epilepsy. The effects of common sleep disorders in the epilepsy clinic and their relationship with the risk of SUDEP were also examined in this study.

METHODS

A total of 139 patients with epilepsy who admitted to the epilepsy center were included in this study. The local ethics committee approved the study (2015/1741) and written informed consent was obtained from all patients. The patients were evaluated in terms of age, sex, seizure frequency, age at seizure onset, circadian characteristics of the seizure, presence of nocturnal seizures over the last 6 months, and use of antiepileptic drugs (AEDs), findings of the most recent EEG examination performed within the previous 6 months, and body mass indexes (BMI). The AEDs were categorized as new-generation drugs (eg, zonisamide, oxcarbazepine, lamotrigine, levetiracetam, topiramate, and lacosamide) or old generation drugs (eg, valproic acid, carbamazepine, and phenytoin).12,13 The patients were classified according to their epilepsy syndrome on the basis of EEG, magnetic resonance imaging, and clinical findings (ILAE, 2010).14

During the face-to-face interviews, the patients provided answers to 4 different sleep disorders questionnaires that were asked by neurologists (H.Ö.D., M.K., and B.S.) in the outpatient clinic. The subjective sleep quality was evaluated according to the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness was evaluated using the Epworth Sleepiness Scales (ESS), and the Berlin questionnaire (BQ) was used to evaluate the obstructive sleep apnea risk. Restless legs syndrome (RLS) was determined from the clinical characteristics of the patients according to the ICSD 3 criteria.4 These criteria are: RLS is an urge to move the legs because of uncomfortable sensations. These symptoms must begin or be worse during periods of rest, relieved by movements, and occur exclusively predominantly in the evening or night rather than day. The severity of RLS was assessed by the International Restless Legs Syndrome Study Group (IRLSSG) in patients having RLS diagnosis. The NREM and REM parasomnia histories of the patients were obtained from the patients themselves and their first-degree relatives, along with their clinical characteristics.

In addition, SUDEP risk was determined through the SUDEP-7 Inventory scores.

PSQI

In PSQI, general sleep patterns are evaluated according to 7 subheadings: subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction over the last month, for which 18 questions are asked. A total score of “5” or greater, indicates poor sleep quality.15

ESS

ESS is an 8-question questionnaire that evaluates the daytime sleepiness. A total score of “10” and greater indicates the excessive daytime sleepiness.16,17

BQ

BQ screens for OSAS in the community, and comprises 10 questions in 3 categories. Each category is evaluated within itself, and if ≥2 categories have positive results, the OSAS risk is considered high.18

IRLSSG Severity Scale

The IRLSSG’s severity rating scale is considered to be the gold standard among scales used to evaluate the severity of RLS.19 This rating scale comprises 10 questions, with each question scored at a range of 0 to 4. The obtained score is classified as 1 to 10: mild; 11 to 20: moderate; 21 to 30: severe; 31 to 40: very severe.

Parasomnias

The presence of parasomnia was asked to the patients and their relatives who share the same house. The ICSD-3 criteria were used in the diagnosis of NREM and REM parasomnias. Somnambulism and night terrors were included in NREM parasomnias. REM behavioral disorders (RBD) and sleep paralyzes were included in REM parasomnias. RBD was defined as repeated episodes of sleep-related vocalization and/or complex motor behaviors that can result in injury to the patient or bed partner. The overall symptoms related to RBD were defined as “probable RBD” because polysomnography (PSG) is necessary to determine the diagnosis REM sleep without atonia and RBD.20

SUDEP-7 Inventory

SUDEP-7 Inventory is a 7-category test to determine the SUDEP risk in patients with epilepsy.21 The test evaluates seizure frequency, duration of epilepsy, number of used AEDs, and intellectual disability.22

Statistical Analysis

Epilepsy types, both focal and generalized, were compared by analyzing the factors associated with sleep features. Depending on the categorical or continuous variables and the distribution of the data, a χ2 test/Fisher exact test, an unpaired Student t test, or a Kruskal-Wallis test were performed, and a Pearson’s product Spearman’s rank correlation was performed when appropriate. The level of significance was 0.05 in all tests.

The duration of epilepsy was treated as a continuous variable. To investigate the effects of epilepsy and other factors, risk of apnea, daytime sleepiness, poor quality of sleep according to PSQI and SUDEP risk, the logistic or linear regression models included the following variables: age, sex, BMI, number of AEDs, type of AEDs (new or old generation), presence of nocturnal seizures, type of seizures (generalized or focal), duration of epilepsy, and presence of EEG abnormalities. In addition, factors determining SUDEP were analyzed. All tests were calculated using SPSS (Statistical Package for the Social Sciences).

RESULTS

A total of 139 epileptic patients were included in this study (Table 1). In the focal epilepsy group, 44 patients had temporal lobe epilepsy (TLE), 27 patients had extratemporal lobe epilepsy (extra-TLE), and 21 patients had focal epilepsy that could not be localized. In the focal epilepsy group, 62 patients had structural/metabolic causes of focal epilepsy, whereas 30 patients had focal epilepsy of unknown cause. All patients in the generalized epilepsy group had idiopathic/genetic epilepsy syndromes.

TABLE 1
TABLE 1:
Clinical and Demographic Characteristics of the Patients

According to the PSQI questionnaire, 34 (24.5%) patients experienced poor sleep quality with scores of >5. According to the ESS, 7 (5%) patients suffered from excessive daytime sleepiness. According to the BQ, 25 patients (18%) fell in the high-risk group regarding apnea during sleep. The duration of epilepsy (P=0.006; odds ratio, 1.17; 95% confidence interval, 1.0-1.1) and age (P=0.03; odds ratio, 1.18; 95% confidence interval, 1.0-1.3) were independent risk factors for high risk of sleep apnea (Table 2). During the face-to-face interviews, 24 patients diagnosed as RLS (17.2%) according to ICSD criteria. Sleep evaluation results and their relationship with clinical features are shown in Table 3.

TABLE 2
TABLE 2:
Risk of Sleep Apnea and Related Conditions
TABLE 3
TABLE 3:
The Relationship with Sleep Features/Disorders and Patients’ Clinic/Demographic Features

Epilepsy Syndromes

The incidences of sleep-related disorders in the focal and generalized epilepsy groups are shown in Table 3. In ESS (P=0.03) and PSQI tests, daytime dysfunction (P=0.043) was found to be significantly higher in the TLE group within the focal epilepsy group (Table 4A and B).

TABLE 4
TABLE 4:
The Sleep Characteristics in the Temporal or Extra-temporal Lobe Epilepsy Groups

When the seizure frequency and sleep scales were compared, a statistically significant relationship was identified between PSQI scores and seizure frequency (P=0.01; r, 0.185), whereas no relationship was found between seizure frequency and ESS scale (P=0.47) and BQ scores (P=0.16) (Table 3).

No significant relationship was observed between the presence of epileptic discharges on the EEG and the investigated scale scores evaluating sleep patterns and sleep-related diseases. No significant association was found between the use of multiple AEDs and sleep questionnaire’s scores and sleep disorders in the AED subgroups (Table 3).

All of our patients who had nocturnal seizures had generalized seizures during sleep. No relationship was found between nocturnal seizures and sleep scales, whereas a significant relationship was disclosed between nocturnal seizures and SUDEP-7 scores (P=0.006; B, 0.93). The presence of nocturnal seizure was an independent risk factor for SUDEP. The mean SUDEP-7 score was 2.6±1.3 in patients who experience seizures during sleep, whereas it was 1.9±1.4 in patients, not experiencing seizures while sleeping (Table 5). SUDEP risk was found to be higher in patients who experience seizures during sleep. In this section, there was no difference between the focal and generalized epilepsy groups in terms of SUDEP-7 score.

TABLE 5
TABLE 5:
Relationship Between SUDEP-7 Scores and Sleep Quality, Sleep-related Disorders

No statistically significant relationship was identified between SUDEP-7 scores and sleep quality or sleep-related disorders (Table 5).

For parasomnia, 11 of the patients (7.9%) had a history of NREM parasomnia, and 9 (6.4%) had REM parasomnia history. Among the patients with NREM parasomnia, the rate of sleepwalking was found to be 7.2%, and confusional awakening was found in 0.7% of the subjects. Among those with REM parasomnia, vocalization and/or complex motor behaviors rate was 5% (probable RBD) and sleep paralysis was 1.4%. No significant relationship was identified between NREM and REM parasomnias, and sleep scale scores, and SUDEP-7 Inventory scores.

DISCUSSION

In our study, we have demonstrated that subjective sleep quality is impaired in patients with epilepsy (especially TLE), the risk of OSAS is higher, RLS/WED findings are more frequent, and REM and NREM parasomnias are more common in epilepsy than expected in the general population. Although we could not correlate between SUDEP risk and sleep-related characteristics, we have indicated that having nocturnal seizures had a high SUDEP risk.

General Sleep Patterns in Patients With Epilepsy

The incidence of impaired PSQI scoring that evaluates the subjective sleep quality was 24.5% in our patients with epilepsy, whereas this was 16% in the general population according to the results of previous population-based studies.13 Similar to previous studies, we found that the frequency of sleep-related disorders differs in patients with epilepsy compared with the general population.23,24 We noted that the overall sleep quality scale of PSQI was significantly associated with monthly seizure frequency. Patients with poor seizure control were found to have a lower quality of sleep, similar to previous studies.25 This statistical correlation with the frequency of seizures was more significant in the subheading, especially demonstrating the loss of daytime function, remarkably. We think that this relationship can be explained bi-directionally. First, patients with poor sleep quality at night with frequent arousal episodes may have lowered seizure thresholds, consequently and that discharges during sleep can further disrupt sleep quality in these patients who have more frequent seizures associated with frequent EEG discharges.1,2,26 Both pathophysiological hypotheses reveal a direct, multidirectional relationship between epilepsy and sleep.

Daytime Sleepiness in Epilepsy

Intriguingly, ESS showed that 5% of our patients have daytime sleepiness; this result was not more than those expected in the general population. Different results have been obtained in studies on sleepiness in patients with epilepsy. Ismayilova et al13 have shown that daytime sleepiness in patients with epilepsy is not more frequent than in the healthy population, similar to our results, but Khatami and colleagues found a 30% incidence of daytime sleepiness in their patients, which was clearly more frequent than in the general population. They concluded that the cause of this finding was nighttime snoring, but not the conditions related to epilepsy.27 It should be noted, however, that ESS is a less reliable subjective test because of high false-negative results.28

OSAS in Epilepsy and SUDEP

Regarding the BQ, the high risk for sleep apnea syndrome was 8% in the general population and 18% in our patient group.13 Parallel to this result, in studies on the basis of PSG studies, the incidence of sleep apnea syndrome in epilepsy was reported to be about 33%.29,30 A statistically significant relationship was demonstrated between the duration of epilepsy and the high apnea risk determined by this questionnaire. This result is also similar to previous studies.13,31 The increased duration of epilepsy may potentiate the risk of sleep apnea syndrome in the chronic period.7 It is well known that the sleep apnea syndrome is more common in the male population, but it does not indicate a sex predilection in our epilepsy group; this fact can be interpreted as its pathophysiology differs in the presence of epilepsy as a comorbidity. The presence of sleep apnea syndrome was reported as an independent factor that increases SUDEP risk.23,32,33 Deterioration of baroreflex function in sleep apnea syndrome may increase cardiovascular risk.34 In the chronic period, sleep apnea syndrome may cause further deterioration of cerebral blood flow and autoregulation.34 Problems of autoregulation and autonomic involvement in the circulatory-respiratory systems are possible mechanisms of SUDEP.35 On the basis of this fact, it can be predicted that sleep apnea syndrome is a risk for SUDEP.34,36 We did not observe a significant statistical correlation between the SUDEP-7 Inventory and the detection of high risk with BQ in our study. However, it is important to note that sleep apnea syndrome may still pose a risk for SUDEP in patients with epilepsy as they have higher scores in BQ.

Nocturnal Seizures and SUDEP

Nocturnal seizures are associated with more prominent autonomic dysfunction than are diurnal seizures. Heart rate variability is significantly decreased during sleep in patients with epilepsy.37 Sleep is generally associated with a reduction in the ventilatory response to hypoxia and hypercapnia.36 Seventy percent of the SUDEP cases reported during the MORTEMUS study was during sleep.38 Thus, seizures during sleep seem to pose a risk for SUDEP.39,40 In our study, we found a statistically significant relationship between the frequency of nocturnal seizures and the high risk of SUDEP (P=0.006). In our data, we determined having nocturnal seizures as an independent risk factor for SUDEP.

Other Sleep Disorders and Epilepsy

The incidence of RLS in our patients with epilepsy was 17.2%. On the contrary, a previous study performed in our country, which showed the maximal incidence of 5.8% reported that the frequency of RLS was found not to differ in the epilepsy group compared with the general population.41 Geyer and colleagues showed that the incidence of RLS was 28.6% in TLE.

The incidence of NREM and REM parasomnias were 7.9% and 6.5%, respectively. NREM and REM parasomnias were more frequently observed in the focal epilepsy group, without reaching statistical significance. Increased cholinergic input in thalamocortical neurons during REM also helps to focus discharges.42 A neurochemical relationship between parasomnia and increased focal excitability in focal epilepsies has been detected.33

Effect of Epilepsy Properties on Sleep

Regarding the effect of focal or generalized epilepsy on sleep, there was no significant difference between the focal and generalized epilepsy subgroups in terms of PSQI, ESS Scale, and BQ. Compared with extra-TLE group, ESS and PSQI daytime dysfunction subscales were found to be significantly affected in the TLE group. In a previous study,26 it was reported that sleep quality is more severely affected in focal epilepsy and especially in TLE groups.

Limitations of the Study

The lack of PSG for detection of sleep disorders as a standard tool may be considered as a limitation of our study. However, our protocol has clearly identified the patients who need a PSG in a reliable and cost-effective way in an epilepsy outpatient-based examination. We send most of these cases to PSG examination afterwards to provide necessary management. PSG results of our patients were not evaluated in this study.

We determined those patients with sleep disorders during the outpatient evaluation to ensure that these patients with epilepsy undergo PSG evaluation when necessary. Our study also investigated the relationship between the incidence of sleep disorders and the SUDEP risk in patients with epilepsy by questionnaires and face-to-face interview techniques. After this step, evaluation by a sleep doctor, PSG, and treatment of the disease could be planned more reasonably. It should be considered that low sleep quality and sleepiness can be seen more frequently in patients with TLE and also that patients with seizures during sleep may be at higher risk for SUDEP.

CONCLUSION

The results of our study show that sleep disorders are more common in patients with epilepsy than in the general population and that seizures during sleep may be associated with increased risk of SUDEP as measured by SUDEP-7 Inventory.

ACKNOWLEDGMENT

The authors thank Ayse Deniz Elmali, MD, Istanbul Faculty of Medicine Clinical Neurophysiology Department, for review and suggestions.

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Keywords:

sleep; epilepsy; SUDEP; sleep apnea; parasomnia

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