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Department of Systems Medicine, University of Rome ‘Tor Vergata”, Rome, ItalyEpilepsy Centre, Neurology Unit, University Hospital “Tor Vergata”, Rome, Italy
Department of Systems Medicine, University of Rome ‘Tor Vergata”, Rome, ItalyEpilepsy Centre, Neurology Unit, University Hospital “Tor Vergata”, Rome, Italy
Sleep alterations and lower daytime activity were evident in patients with epilepsy.
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Patients with epilepsy showed poor sleep efficiency and longer sleep latency.
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An evening chronotype preference was documented in patients with epilepsy.
Abstract
Objective
This study aimed to assess the sleep-wake pattern in patients with epilepsy compared to controls.
Methods
Patients with epilepsy and controls underwent a 14-day actigraphic recording to evaluate the rest-activity cycle. A sleep medicine interview was performed to exclude conditions interfering with the sleep-wake cycle in both patients and controls. Patients presenting seizures during the actigraphic recording were excluded. Daytime activity, nocturnal sleep, and non-parametric circadian rhythm activity (NPCRA) were analysed.
Results
Twenty-two patients (mean age 49.5 ± 19.84 years; 50% female) and 17 controls were included. Patients showed lower sleep efficiency and longer sleep latency than controls. NPCRA analysis showed lower inter-daily stability and higher intra-daily variability in patients, who also presented lower daytime activity and a longer central phase measure (CPM) than controls.
Conclusions
Patients showed a significant alteration of the sleep-wake pattern, featured by lower synchronization and higher fragmentation of the rest-activity rhythm. Moreover, patients showed a delayed CPM compared with controls, corresponding to an evening chronotype tendency. Nocturnal sleep alteration and lower daytime activity were also evident. Therefore, patients with epilepsy present an alteration of the sleep-wake pattern and clinicians should increase their awareness about circadian rhythmicity dysregulation in epilepsy.
The relation between sleep and epilepsy has been widely investigated since epilepsy may alter sleep, and sleep deprivation may induce epileptic seizures [
]. Sleep disturbances are frequently reported by patients with epilepsy, as well as daytime sleepiness, which is particularly prevalent in those who are treated with more than one antiseizure medication (ASM) [
]. Several lines of evidence suggested an association between sleep and epilepsy, and the numerous questionnaire-based and polysomnographic studies investigating nocturnal sleep in patients with epilepsy hypothesized a global circadian rhythm dysregulation in these patients [
]. Epileptiform activity (or ictal/interictal activity) can be modulated by endogenous circadian rhythms or by sleep cycles, and core circadian genes may influence neuronal excitability and seizure threshold [
]. Although the supposition of a strong association between circadian rhythm and epilepsy, no study objectively investigated the sleep-wake cycle in patients with epilepsy by using actigraphy, which represents the best instrument to investigate the rest-activity rhythm [
]. Consistently, actigraphic monitoring has been validated to study nocturnal sleep in patients with epilepsy, however, no study used this instrument to monitor the 24-hour rest-activity rhythm [
Therefore, the present study aimed at measuring the rest-activity pattern in patients with epilepsy by using a prolonged actigraphic recording and comparing it with healthy controls; moreover, this study aimed at preliminary testing the hypothesis of sleep-wake pattern dysregulation in patients with epilepsy.
2. Methods
2.1 Participants and study design
Patients affected by epilepsy admitted to the Epilepsy Centre of the University Hospital of Rome “Tor Vergata” were included in the present study. Epilepsy was diagnosed and seizures were classified according to the guidelines of the International League Against Epilepsy (ILAE) [
]. Moreover, as clinical common practice at our centre, all patients with epilepsy are provided with a log sheet to fill out when they present a seizure or a clinical event of interest.
Inclusion criteria for patients with epilepsy were seizure freedom during the actigraphic monitoring, no diagnosis of neurological or psychiatric or medical disorders other than epilepsy. Conversely, exclusion criteria included: shift work; any known sleep disorder based on the International Classification for Sleep Disorders (ICSD-3) that can influence the sleep-wake cycle.
Healthy subjects were enroled from the community and served as the control group. All the controls underwent a neurological screening and a sleep-medicine interview excluding sleep and wake disturbances. The control group was similar to the patients group for age and gender.
The study design included a sleep medicine interview for screening and excluding sleep and wake disturbances diagnosed based on the ICSD-3 [
], clinical and neurological visits, 14-days actigraphic monitoring coupled with a sleep diary and a seizure diary. At the neurological visit before enrolment, none of the patients reported seizures in the last month.
The study protocol was considered observational according to the STROBE statement by the internal review board of the Ethical Committee of the University Hospital of Rome Tor Vergata (33/18). Written informed consent was obtained from all participants in the study.
2.2 Actigraphic recording
Actigraphy was performed as previously described following the local guidelines of the sleep medicine centre owing to the same Neurology Unit [
]. Actigraphs (Actiwatch2, Philips Respironics) were worn on participants’ non-dominant wrist to gather activity and light exposure data for 14 days. Patients and controls were instructed to push the button on the side of the watch at bedtime and wake time. Participants were also instructed to follow theirdaily living routines and not to be confined to specific schedules. Patients and controls were also asked to fill out a sleep diary just before they went to bed each night and as soon as they woke in the morning, and were recommended to indicate exact times for every time they wake up during the night. Moreover, patients were instructed to continue to fill out the epilepsy log if a seizure occurred.
Sleep and wake characteristics were separately monitored and non-parametric circadian rhythm activity (NPCRA) was analysed with CamNTech MotionWare 1.2.26 by sleep medicine experts (CL, FI, FP) [
The actigraphic parameters analysed were: Time in bed (TIB), total elapsed time between the ‘Lights Out’ and ‘Got Up’ times; Actual sleep time (AST), total time spent in sleep according to the epoch-by-epoch wake/sleep categorization excluding sleep latency and wake periods between fell asleep and got up times; Sleep efficiency (SE), defined as the ratio between AST and TIB; Sleep latency (SL), the time between ‘Lights Out’ and ‘Fell Asleep’; Central Phase Measure (CPM), the midpoint between “Fell asleep” and “Wake up”, expressed as the number of minutes past midnight; Actual Wake Time (AWT), defined as the duration expressed in minutes of “wake periods” between fell asleep got up times; Total Activity Score (TAS), defined as the total of all the activity counts during the assumed sleep period; Fragmentation Index (FI) defined as the sum of the ‘Mobile time (%)’ and the ‘Immobile bouts <=1 min (%)’ and is an indicator of the degree of fragmentation of the sleep period.
Regarding NPCRA, the following parameters were analysed: inter-daily stability (IS), quantifying the degree of regularity in the activity-rest pattern, with higher values corresponding to higher synchronisation; intra-daily variability (IV), quantifying the degree of fragmentation of activity-rest periods, with higher values representing a very fragmented rest-activity rhythm; least 5 (L5) average activity, providing the average activity level for the sequence of the least five active hours; most 10 (M10) average activity, providing the average activity level for the sequence of the highest ten active hours; relative amplitude (RA), calculated by dividing the L5 to M10 and representing the synchronisation with the average 24-hour cycle, where higher values represent a better synchronised rest-activity rhythm [
]. These parameters were obtained through the traditional analysis of circadian rhythms that fits physiological indicators to a Cosine waveform shape (Cosinor analysis) [
]. Descriptive data were expressed as mean and standard deviation for quantitative analyses. The Kolmogorov-Smirnov test was used to check for the normal distribution of data. Since data were not normally distributed, Mann-Whitney U Test was used to compare demographic, clinical, and actigraphic data between patients and controls. Correlations amongst data were performed by using the Spearman correlation test. Analyses were adjusted for multiple comparisons when appropriate. P-value was set at p<0.05 for statistical significance.
3. Results
3.1 Demographical and clinical data
This study included 22 patients affected by epilepsy and 17 healthy subjects, which were recruited as controls and were similar in age and gender with the patients group. Participants’ demographic and clinical data are shown in Table 1.
Table 1Demographic and clinical data of patients and controls.
Patients with Epilepsy (n = 22)
Controls (n = 17)
p value
Gender, n. (%) Male Female
11 (50%) 11 (50%)
10 (58,82%) 7 (41,18%)
ns
Mean Age (years) (Min-Max)
49,5 ± 19,84 (18–74)
51,52±12,2 (25–67)
ns
Disease Duration (years) (Min-Max)
18,43±16,63 (1–55)
–
–
Aetiology, n. (%) Unknown Structural
14 (63,64%) 8 (36,36%)
Seizure Type, n. (%) Focal Generalized Focal and Generalized
4 (18,18%) 8 (36,36%) 10 (45,46%)
N. of ASMs (Min-Max)
1,4 ± 0,66 (1–3)
–
–
ASM therapy, n. (%) Monotheraphy Politherapy
15 (68,18%) 7 (31,82%)
ASMs, n. VPA LEV CBZ PB LCM OXC TPM
9 7 6 5 5 1 1
–
–
Continuous data are reported as Mean ± Standard Deviation.
Comparing actigraphic sleep parameters, patients with epilepsy showed lower sleep efficiency and higher sleep latency than controls. The CPM (Central Phase Measure) was longer in patients with epilepsy than controls, specifically, patients with epilepsy showed a delayed sleep-wake pattern (going later to bed and waking up later than controls). Data are summarised in Table 2 and a mere example of an actigraphy plot of a patient with epilepsy and a control (selected according to the mean values of all groups) are presented in Fig. 1.
Table 2Actigraphic data of patients and controls.
Patients with Epilepsy (Mean ± SD)
Controls (Mean ± SD)
p value
Time in bed (min)
528,93 ± 68,42
476,32 ± 70,28
0,008
Actual sleep time (min)
435,21 ± 79,3
416,46 ± 65,63
ns
Sleep efficiency (%)
81,89 ± 9,15
86,62 ± 6,51
0,034
Sleep latency (min)
25,88 ± 20,46
12,5 ± 9,52
0,023
Actual wake time (min)
60,22 ± 29,6
49,5 ± 27,58
ns
Central Phase Measure (min)
208,5 ± 71,51
148,94 ± 94,78
0,034
Total activity score
7831,49 ± 5613,97
7372,78 ± 3631,5
ns
Fragmentation Index
41,27 ± 14,68
36,95 ± 10,41
ns
NPRCA analysis
L5 Average
1139,37 ± 1323,57
791,17 ± 229,02
ns
M10 Average
20,215,38 ± 8621,81
26,640,13 ± 5279,04
0,001
Relative Amplitude (RA)
0,89 ± 0,11
0,93 ± 0,02
ns
Inter-daily Stability (IS)
0,61 ± 0,11
0,75 ± 0,06
0,0001
Intra-daily Variability (IV)
0,81 ± 0,18
0,67 ± 0,16
0,002
Abbreviations: L5 Average: Least Active Five Hours Average; M10 Average: Most Active 10 Hours Average; NPRCA, non-parametric circadian rhythm activity; ns, not significant; SD: Standard Deviation.
Considering NPCRA data, patients with epilepsy showed a lower average activity during the most active 10 -hour period (M10) compared to controls. No differences were found considering the average activity during the least active 5‐hour period (L5) and the synchronisation of the rest-activity rhythm in the average 24-hour cycle (RA). Finally, patients with epilepsy were found to have a lower degree of regularity in the activity-rest pattern and a sleep-wake cycle more fragmented than healthy controls, namely patients showed a lower Inter-daily Stability (IS) and higher Intra-daily Variability (IV) compared to controls. All actigraphic data are reported in Table 2.
3.4 Correlation analysis
A correlation analysis was performed amongst the actigraphic parameters and the clinical data of patients with epilepsy. The results showed a significant negative correlation between age and sleep latency in patients with epilepsy (R= −0.427). All the other correlations are described in Supplemental Table 1.
4. Discussion
The present study aimed at evaluating the sleep-wake pattern in patients with epilepsy through actigraphy, which is a validated instrument for investigating the rest-activity cycle in both clinical practice and research [
]. Although it has been described a nocturnal sleep impairment in patients with epilepsy through the use of actigraphic recordings, no study has yet performed the rest-activity rhythm analysis [
]. In particular, NPCRA allows identifying circadian activity by analysing data from an easy and available instrument in outpatient clinics, such as the actigraphy [
The novelty of the present study is the documentation of a significant alteration of the sleep-wake cycle in patients with epilepsy, featured by both low synchronisation and high fragmentation of the rest-activity pattern. Although it has been widely hypothesised, no previous study investigated the sleep-wake pattern by using the NPCRA based on actigraphic recordings [
Moreover, sleep impairment and diurnal wake activity reduction were evident in patients when compared to controls. Taking the findings of this study into account, it appears evident that patients with epilepsy present both nocturnal sleep alteration and diurnal wake activity impairment, thus confirming the previous evidence of sleep and wake dysregulation in patients with epilepsy [
]. Notably, the NPCRA documented an alteration of the entire sleep-wake pattern in patients with epilepsy, since both IS and IV resulted impaired in patients when compared to the controls. Conversely, the rhythm amplitude was similar to controls, reflecting the synchronisation of the rest-activity cycle of patients with epilepsy with the 24-hour cycle. Although the documentation of this sleep-wake pattern dysregulation in epilepsy, the lack of studies investigating the events underlying it cannot allow defining a clear pathophysiological mechanism. For instance, considering that exposure to light activates the production and regulation of melatonin, a circadian rhythm regulator, the lower sun exposure hypothesizsed in patients with epilepsy can reflect this dysregulation [
]. Future studies may explore this aspect through the monitoring of light exposure to provide a more comprehensive description of the sleep-wake pattern in patients with epilepsy. A further parameter significantly altered in patients with epilepsy is the CPM, a measure that objectively identifies the patient's chronotype considering the going to bed and wake up times, and the position of sleep time during the 24-hour rhythm [
]. In particular, patients with epilepsy showed a delayed CPM reflecting the evening preference and a delayed going to bed and wake up times.
Based on the documented interconnections between sleep and epilepsy, different hypotheses can be stated to explore the significance of the sleep-wake pattern dysregulation in patients with epilepsy. Although structural impairment of the suprachiasmatic nucleus cannot be considered since the unimpaired synchronisation of the rest-activity rhythm, it has been hypothesised that the alteration of the sleep-wake pattern may be due to the dysregulation of the rhythmicity of genes regulating the sleep-wake cycle, of the melatonin secretion, and of the hypothalamic-pituitary axis [
]. Moreover, studies objectively measuring dim-light melatonin onset, as a chronotype marker, suggested a dysregulation in the pineal gland activity in patients with epilepsy [
]. In particular, an evening chronotype was evident in patients with idiopathic generalized epilepsy, while patients with focal epilepsy tend to present a chronotype similar to controls [
Circadian phase typing in idiopathic generalized epilepsy: dim light melatonin onset and patterns of melatonin secretion—Semicurve findings in adult patients.
], in which patients with idiopathic generalized epilepsy showed lower MEQ scores (indicative of an evening preference), whereas patients with focal epilepsy were more morning orientated [
]. Considering the studies so far present in literature, the dysregulation of the sleep-wake cycle has been supposed but the significance of this alteration, the pathophysiological mechanisms underpinning it, and the influence of aetiology of epilepsy and ASMs were not evaluated.
Although the novelty of the present study, some limitations need to be acknowledged. A first limitation is the sample size, thus not allowing some subgroups confrontations (e.g., patients with focal epilepsy vs. patients with generalized epilepsy; seizure-free patients vs. patients with drug-resistant epilepsy). Future studies with wider samples are needed to explore the possibly epilepsy-related factors that may influence the sleep-wake rhythm. Second, this study was based on patients attending a single health care centre in Rome, and therefore there may be a selection bias. Third, all the participants were taking at least one ASM and, therefore, the ASMs may influence the sleep-wake rhythm. Nonetheless, in this study, as in clinical practice, participants were using diverse ASMs, and not only one ASM type that could exert a clear and unique effect on the sleep-wake cycle. Fourth, despite patients had a diary to register their seizures, they may unnoticed the presence of subclinical seizures and/or the arisen of seizures during sleep, and the interference of these possible seizures with actigraphy signals could not be assessed without an EEG. Conversely, the strength of the study is the use of actigraphy, which can indirectly measure sleep and has the advantage of documenting the sleep-wake pattern continuously over a 24-hour period across both day and night. Other strengths of the present study are: i) checking for seizure freedom during actigraphy monitoring with an epilepsy diary, ii) performing the sleep medicine interview to exclude conditions interfering with the sleep-wake cycle, and iii) excluding neurological (other than epilepsy), psychiatric or medical conditions interfering with the sleep-wake cycle. Finally, the sleep-wake cycle analysis was substantiated by the combination of sleep-diary results and the visual inspection of actigraphic recordings by sleep medicine experts. This combined approach, including both subjective and objective data, reinforces the documentation of the sleep-wake pattern dysregulation in patients with epilepsy. The last speculation is related to the heterogeneity of patients included in this study, counting both focal and generalized epilepsy, the various aetiologies of epilepsy, and the different ASMs regimen, counting both mono- and poly-therapies, which can increase the evidence of the sleep-wake pattern dysregulation in patients with epilepsy independently of all these parameters.
5. Conclusions
The findings of this pilot study, which reports novel although preliminary data, suggest the dysregulation of the sleep-wake circadian rhythm in patients with epilepsy, which can be responsible for both sleep and wake impairment. This data invite further studies to include selected epilepsy types and aetiologies, also considering the possibility to check the previously demonstrated different effects of ASMs on the sleep-wake cycle [
Circadian phase typing in idiopathic generalized epilepsy: dim light melatonin onset and patterns of melatonin secretion—Semicurve findings in adult patients.
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