Epilepsy & Behavior 35 (2014) 50–53
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Sleep alterations in children with refractory epileptic encephalopathies: A polysomnographic study Marco Carotenuto a, Pasquale Parisi b,⁎, Maria Esposito a, Samuele Cortese c, Maurizio Elia d a
Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, Second University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy Child Neurology, Pediatric Headache & Sleep Disorders Centre, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, “Sapienza University”, Via Di Grottarossa 1035-1039, 00189 Rome, Italy c Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK d Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggiero 73, 94018 Troina (EN), Italy b
a r t i c l e
i n f o
Article history: Received 8 February 2014 Revised 8 March 2014 Accepted 10 March 2014 Available online xxxx Keywords: Epileptic encephalopathy Pediatric polysomnography Sleep-related breathing disorders Sleep obstructive apnea syndrome Periodic limb movements
a b s t r a c t Data on the relationship between sleep disturbances and refractory epileptic encephalopathies (EEs) are scarce. Our aim was to assess, by means of nocturnal polysomnography, if children with EEs present with objective alterations in sleep organization. Twenty-three children with EEs (12 males; mean age: 8.7 ± 1.4 years) and 40 healthy controls (22 males; mean age: 8.8 ± 1.1 years) underwent an overnight full polysomnography (PSG). Relative to controls, children with EEs showed a significant reduction in all PSG parameters related to sleep duration time in bed (TIB-min p b 0.001), total sleep time (TST-min p b 0.001), and sleep percentage (SPT-min p b 0.001), as well as significantly higher REM latency (FRL-min p b 0.001), rate in stage shifting (p = 0.005), and number of awakenings/hour (p = 0.002). Relative to controls, children with EEs also showed significant differences in respiratory parameters (AHI/h p b 0.001, ODI/h p b 0.001, SpO2% p b 0.001, SpO2 nadir% p b 0.001) and a higher rate of periodic limb movements (PLMs% p b 0.001). Our findings suggest that sleep evaluation could be considered mandatory in children with refractory epileptic encephalopathy in order to improve the clinical management and the therapeutic strategies. © 2014 Elsevier Inc. All rights reserved.
1. Introduction In clinical literature, there has been a growing interest in the mutual relations between sleep and epilepsy, kindled by the realization of several potentially relevant two-way interactions [1]. Seizures are frequent during sleep, and the epileptogenic discharges can alter and/or disrupt the sleep architecture, leading to an increase in seizure frequency [1–5]. The nonrapid eye movement (NREM) sleep phases can activate interictal epileptiform discharges (IEDs), but the facilitating influences on IED production may be exerted separately by either spindle activity or delta synchronization mechanisms, and the activating properties of sleep are not due to the stage per se but depend largely on the level of activity of synchronizing mechanisms [6]. Indeed, the REM sleep stage tends to suppress IEDs and may restrict their field of distribution to
⁎ Corresponding author. Tel./fax: +39 6 33775941. E-mail addresses: [email protected] (M. Carotenuto), [email protected], [email protected] (P. Parisi), [email protected] (M. Esposito), [email protected] (S. Cortese), [email protected] (M. Elia).
http://dx.doi.org/10.1016/j.yebeh.2014.03.009 1525-5050/© 2014 Elsevier Inc. All rights reserved.
the epileptogenic region [7,8]. On the other hand, with regard to the causes of sleep fragmentation, sleep-related breathing disorders (SRBDs) could be considered a potential trigger for paroxysmal activity and IEDs. This suggests that children with obstructive sleep apnea syndrome (OSAS) may have a dysfunction of the arousal system control, which is probably due to the putative effect of a primary brain insult as a predisposing factor for both OSAS and paroxysmal EEG activity [9]. The effect of the epilepsy etiology on sleep architecture during childhood has not been studied in detail, and, to our knowledge, there are no specific sleep studies related to epileptic encephalopathies (EEs). Epileptic encephalopathies are described as epilepsy with ictal and interictal epileptiform anomalies (clinical and EEG) and progressive cerebral dysfunction [10]. According to the classification and terminology criteria of International League against Epilepsy (ILAE), the following syndromes meet the EE criteria: Dravet syndrome, Doose syndrome, CSWSS (continuous spike–wave during slow-wave sleep), Landau– Kleffner syndrome, Lennox–Gastaut syndrome, Ohtahara syndrome, and West syndrome. Severe epilepsy with multiple independent spike foci is recently included in this group [11]. The importance of the relationship between EEs and sleep is also supported by the role of the ketogenic diet in improving sleep quality with increased REM sleep [12].
M. Carotenuto et al. / Epilepsy & Behavior 35 (2014) 50–53
The aim of this study was to compare, by means of polysomnography, sleep objective parameters in a group of children with EEs and in healthy controls. We hypothesized we would find a significantly higher prevalence of objective sleep alterations in children with EEs. 2. Materials and methods Twenty-three children with EEs (12 males) (mean age: 8.7 years; SD ± 1.4) and 40 healthy children (22 males) (mean age: 8.9 years; SD ± 1.1) underwent an overnight polysomnography (PSG) recording in the Sleep Laboratory of the Clinic of Child and Adolescent Neuropsychiatry of Naples and in the Unit of Clinical and Instrumental Neurology and Neurophysiopathology of the Oasi Institute of Troina after one adaptation night in order to avoid the first-night effect. Children were considered eligible for the full PSG if affected by one of EEs diagnosed according to the ILAE classification. The subjects in both groups were recruited from the same urban area; participants were all Caucasian and were of middle-class socioeconomic status (between class 2 and class 3, corresponding to 28,000–55,000 euros/year to 55,000–75,000 euros/year, respectively, according to the current Italian economic legislation parameters). Neuroimaging pathological findings were an exclusionary criterion. All subjects with EEs enrolled in this study were on polypharmacological treatment and were taking at least three or more antiepileptic drugs. All parents gave written informed consent during the first screening visit. The reported investigation was carried out in accordance with the principles of the Declaration of Helsinki [13]. The Departmental Ethics Committee of the Second University of Naples approved the study. 2.1. Polysomnographic evaluation The EEG recordings and electrode placement were performed according to the 10–20 system [14], and the PSG montage included at least 19 EEG channels (Fp1, Fp2, F7, F8, F3, F4, C3, C4, T3, T4, T5, T6, P3, P4, O1, O2, Fz, Cz, and Pz) referenced to the contralateral mastoid, left and right electrooculogram (EOG), chin electromyogram (EMG), left and right tibialis EMG, electrocardiogram (ECG) (1 derivation), nasal cannula, measures of thorax and abdominal effort, peripheral oxygen saturation, and pulse and position sensors [15]. Recordings were carried out using a Brain Quick Micromed System 98 recording machine, and signals were sampled at 256 Hz and stored on a hard disk for further analysis. Electroencephalography signals were digitally band-pass filtered at 0.1–120 Hz, 12-bit A/D precision. Moreover, the presence of high-amplitude sharp waves or spikes and slow waves together with the reduced occurrence of K complexes, sleep spindles, and rapid eye movements made it difficult to score sleep using usual criteria. Therefore, as per Miano et al. [16] and a previous report [17], we scored sleep stages based on the following criteria: 1. N1 was detected when, after wakefulness or movement, the EMG tone was clearly diminished, movement artifacts were absent, and the EEG did not show sleep-specific patterns (such as spindles or K complexes). 2. N2 was recognized because of the presence of sleep spindles and K complexes even during the pauses between the different runs of epileptiform discharges. 3. N3 was also defined when composed mostly of subcontinuous sharp wave or spike–slow-wave complexes. 4. Rapid eye movement sleep was characterized by decreased EMG tone with shorter epileptiform discharge duration and lower frequency compared with NREM sleep.
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Accordingly, the following conventional sleep parameters were evaluated: – Time in bed (TIB); – Sleep period time (SPT): the time from sleep onset to sleep end; – Total sleep time (TST): the time from sleep onset to the end of the final sleep epoch minus time awake; – Sleep latency (SL): the time from lights out to sleep onset, defined as the first of two consecutive epochs of sleep stage 1 or one epoch of any other stage, in minutes; – REM latency (RL): the time from sleep onset to the first REM sleep epoch; – Number of stage shifts/hour (SS/h); – Number of awakenings/hour (AWN/h); – Sleep efficiency (SE%): the percentage ratio between total sleep time and time in bed (TST/TIB ∗ 100); – Percentage of SPT spent in wakefulness after sleep onset (WASO%), i.e., the time spent awake between sleep onset and end of sleep; – Percentage of SPT spent in sleep stages 1 (N1%), 2 (N2%), slow-wave sleep (N3%), and REM sleep (REM%). All recordings started at the subject's usual bedtime and continued until spontaneous morning awakening. Sleep was subdivided into 30-s epochs, and sleep stages were scored according to the standard criteria [18] and analyzed by means of Hypnolab 1.2 sleep software analysis (SWS Soft, Italy). All the recordings were visually scored, and the sleep parameters derived were tabulated for statistical analysis. With regard to respiratory parameters, central, obstructive, and mixed apnea and hypopnea events were counted according to the standard criteria [19]. In particular, the apnea–hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of total sleep time; an obstructive apnea index N 1 was selected as the cutoff for normality [20,21]. The episodes of periodic limb movements (PLMs) were identified according to the standard criteria [22], and a PLMI ≥ 5 was considered abnormal. 3. Statistical analysis The study design was based upon data collected from an independent pilot study (5 subjects with EEs versus 5 control children) that showed a strong difference between the mean duration of the TST between the groups (412 ± 49.9 in the group of children with EEs versus 520 ± 32.7 in normal subjects; p = 0.004). The sample size was calculated with the online software http:// www.dssresearch.com/toolkit/sscalc/size_a2.asp. Group differences in demographic and clinical characteristics (fullscale intelligent quotient (FIQ), PSG parameters, respiratory (AHI, ODI, and mean oxygen saturation%) patterns, and PLMs%) were assessed by means of the Mann–Whitney U test or the chi-squared test where appropriate. Full scale intelligent quotient (FIQ), PSG parameters, respiratory (AHI, ODI and mean oxygen saturation%) patterns and PLMs% between EE subjects and control group children using the MannWhitney U test and the chi-squared test where appropriate. The statistical power was calculated with the online software http://www.dssresearch.com/toolkit/spcalc/power_a2.asp. The alpha error level of confidence interval was 5%. p values b 0.05 were considered statistically significant. The STATISTICA software version 6.0 (StatSoft, Inc.; 2001) was used for all statistical tests. 4. Results The study population and the control group were matched for age (p = 0.596), sex (chi-squared = 0.002; p = 0.963), and BMI
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M. Carotenuto et al. / Epilepsy & Behavior 35 (2014) 50–53
Table 1
Age Sex ratio (M/F) BMI (body mass index) Full scale IQ
Patients with EEs (N = 23)
Healthy controls (N = 40)
p
8.69 ± 1.459 12/11 18.152 ± 2.374 73.083 ± 10.287
8.87 ± 1.151 22/18 19.018 ± 1.836 109.752 ± 9.526
0.596 0.963 0.114 b0.001
(p = 0.114). The FIQ evaluation showed a clear and obvious difference between the two groups (p b 0.001) (Table 1). Fourteen subjects presented with Lennox–Gastaut syndrome (LGS), 5 with severe myoclonic epilepsy of infancy (SMEI; Dravet syndrome), and 4 with myoclonic–atonic (or astatic) epilepsy (MAE; Doose syndrome). Table 2 shows the comparisons of macrostructural sleep parameters, respiratory patterns, and PLM percentage between children affected by EEs and healthy controls. Children with EEs showed significantly decreased values of TIB (p b 0.001), SPT (p b 0.001), and TST (p b 0.001) parameters as well as a longer first REM latency (FRL) (p b 0.001) compared with controls. Moreover, the sample with EEs showed a higher rate of stage shifts per hour (SS/h) (p = 0.005) compared with controls. No differences among the sleep stage percentage distributions were found, except for N3% (SWS%) (38.279 ± 7.928 of EE group versus 28.98 ± 10.027; p = 0.006), the mean duration in minutes of N2 (138.6 ± 45.8 of EE versus 227.37 ± 55.75; p b 0.001), and REM (98.2478 ± 2.94 of EE versus 123.06 ± 35.15; p = 0.026), which were lower than those in controls. As for respiratory parameters, children with EEs had a slightly significant increase of all parameters in comparison with the control group, as shown in Table 2, and for PLMs% (13.93 ± 2.53 versus 2.81 ± 1.098; p b 0.001). The statistical power analysis showed the following values: 100% for TIB, SPT, TST, FRL, AHI, ODI, SpO2%, SpO2 nadir%, and PLMs, 97.9% for stage shifts per hour (SS/h), 97.1% for awakenings/h, 99.2% for N3%, 85.8% for WASO%, and 100% for REM%. 5. Discussion The main findings of the present study can be summarized in the significant alteration in sleep and autonomic nocturnal parameters in children affected by EEs with respect to healthy controls.
Table 2
TIB-min SPT-min TST-min SOL-min FRL-min SS-h AWN-h SE% WASO% N1% N2% N3% REM% AHI/h ODI/h SpO2% SpO2 nadir% PLMs%
Children with EEs (N = 23)
Healthy controls (N = 40)
461.478 432.313 413.457 29.165 200.130 12.091 4.404 89.605 4.431 2.522 31.718 38.279 23.050 11.539 3.148 93.583 87.196 13.930
585.775 558.075 531.063 19.763 120.363 8.220 1.870 90.730 4.690 3.118 45.433 28.980 22.165 0.994 0.413 98.383 95.833 2.810
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
57.543 53.482 53.995 15.124 51.662 4.299 3.167 3.124 1.154 1.234 8.223 7.928 2.804 2.729 1.308 1.399 3.624 2.534
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
83.612 85.450 79.971 14.297 45.760 3.512 1.760 5.145 4.425 3.828 27.708 10.027 5.555 0.205 0.307 0.810 1.163 1.098
Mann–Whitney U test U
p*
84.0000 78.0000 80.0000 287.0000 126.0000 224.0000 236.5000 373.0000 430.0000 406.0000 196.0000 189.0000 437.0000 0.0000 0.0000 1.5000 0.0000 0.0000
0.000 0.000 0.000 NS 0.000 0.005 0.002 NS NS NS NS 0.006 NS 0.000 0.000 0.000 0.000 0.000
In general, the evaluation of the impact of epilepsy on sleep represents an important area for research with potential useful consequences on clinical management of seizures and long-term follow-up of these relative rare conditions [5]. Moreover, a number of AEDs could contribute to sleep disruption [23] such as in the presence of cerebral lesions [2]. In fact, it has been estimated that about 40% of patients with epilepsy tend to exhibit sleep related breathing disorder (SRBD), in particular as primary snoring (about 42%). In this perspective, our sample showed a high rate of SRBD. Moreover, the rate of periodic limb movements in one study was found to be 10% [24]. In 1994, Kotagal et al. [25] performed a PSG study in 9 patients with epilepsy and spastic quadriparesis, showing that the cerebral palsy group with epilepsy exhibited significantly more respiratory disturbances per hour of sleep, and about 55% were diagnosed as affected by OSAS. Moreover, in 2003, Becker et al. performed a study using a validated pediatric sleep questionnaire to evaluate the sleep-disordered symptoms in 14 children with epilepsy and in 14 age-matched subjects with known obstructive sleep apnea, with no evidence of differences among the SRBD gravity, sleep fragmentation, disrupted sleep [5], and decreased sleep-onset latency between the two groups [26]. On the other hand, our findings tend to confirm the higher prevalence of altered respiratory patterns (AHI, ODI, SpO2%, and nadir) in EE subjects compared with the control group. In general, a recent report among Brazilian children with drugresistant epilepsy showed a greater incidence of sleep problems regarding the qualitative aspects, the macrostructural organization, and the NREM sleep instability [27]. In light of this, our findings confirm the presence of abnormalities in quality and macrostructural organization of children with EEs. The etiology of sleep disruption in children with epilepsy could be considered as multifactorial and not only linked to the epilepsy per se or to the AED administration [5]. In fact, a variety of treatable sleep disorders, such as SRBD and PLMd, are frequent in patients with epilepsy, leading to an important sleep fragmentation with resultant excessive daytime sleepiness, which, in turn, could lead to poor seizure control [24,28]. The epileptic encephalopathy per se and its therapy may contribute to the sleep disruption, and this may result in chronic sleep deprivation and fragmentation, both of which have possible detrimental effects on seizure control, causing a vicious circle [29]. In addition, the PLMs, which have also been associated with Rett syndrome [17], could be a cause of sleep fragmentation in our sample (p b 0.001). Further, in 2003, Nunes et al. [30], in a PSG evaluation of 17 patients affected by partial refractory epilepsy, reported a significant reduction of TIB and TST in children with epilepsy, as clearly shown in our results. A recent report about the role of therapy on sleep in children with epilepsy showed decreased REM sleep efficiency percentage as well as a significant reduction in sleep duration and the absence of relevant differences in light sleep and slow-wave sleep in subjects with polytherapy compared with those on monotherapy [31]. Moreover, according to our findings, we hypothesize that the sleep abnormalities reported in children with EEs could be due to altered neuronal networks subserving sleep/wake regulation, as previously suggested by Quigg et al. who proposed that disruptions of hypothetically mediated circadian regulation could generate seizures [32]. According to this point of view, we should also take into account the increased SS/h found in our children with EEs (12.091 ± 4.299 versus 8.22 ± 3.512; p = 0.005), as reported by Kaleyias et al. in 2008 [24]. This finding confirms the importance of seizure control in order to avoid altered sleep, with a lower sleep efficiency (SE%) and a higher arousal index. In our children with EEs, we also found a higher arousal index (4.404 ± 3.167 versus 1.87 ± 1.76; p = 0.002) and a lower REM duration in minutes (98.2478 ± 2.94 versus 123.06 ± 35.15; p = 0.001) in
M. Carotenuto et al. / Epilepsy & Behavior 35 (2014) 50–53
comparison with the control group. Various studies have concluded that sleep fragmentation disorders and excessive daytime somnolence may provoke an increase in the frequency of seizures and hamper their control, so the same could also happen in children with EEs [33]. Our findings should be considered in light of study limitations. Our data were derived from a limited pediatric sample of subjects exclusively at an advanced clinical stage, (even if EEs could be considered as rare diseases), we did not consider in a specific way the effects of drug polytherapy, and no follow-up evaluation was performed. Notwithstanding these limitations, to the best of our knowledge, this is the first PSG study on Italian subjects with EEs in childhood. 6. Conclusion Our findings tend to show that in children with different types of EE sleep macrostructure, respiratory parameters and periodic limb movement regulation during the night are significantly affected, suggesting the key role of sleep evaluation in children with EEs in order to better understand the basic mechanisms of epileptogenesis and to improve therapeutic management strategies. Conflict of interest None declared. References [1] Bourgeois B. The relationship between sleep and epilepsy in children. Semin Pediatr Neurol 1996;3:29–35. [2] Pereira AM, Bruni O, Ferri R, Palmini A, Nunes ML. The impact of epilepsy on sleep architecture during childhood. Epilepsia 2012;53(9):1519–25. [3] Dinner DS. Effect of sleep on epilepsy. J Clin Neurophysiol 2002;19:504–13. [4] Foldvary-Schaefer N, Grigg-Damberger M. Sleep and epilepsy. Semin Neurol 2009;29: 419–28. [5] Parisi P, Bruni O, Pia Villa M, Verrotti A, Miano S, Luchetti A, et al. The relationship between sleep and epilepsy: the effect on cognitive functioning in children. Dev Med Child Neurol 2010;52(9):805–10. [6] Ferrillo F, Beelke M, De Carli F, Cossu M, Munari C, Rosadini G, et al. Sleep-EEG modulation of interictal epileptiform discharges in adult partial epilepsy: a spectral analysis study. Clin Neurophysiol 2000;111:916–23. [7] Malow BA, Lin X, Kushwaha R, Aldrich MS. Interictal spiking increases with sleep depth in temporal lobe epilepsy. Epilepsia 1998;39:1309–16. [8] Sammaritano M, Gigli GL, Gotman J. Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 1991;41:290–7. [9] Miano S, Paolino MC, Peraita-Adrados R, Montesano M, Barberi S, Villa MP. Prevalence of EEG paroxysmal activity in a population of children with obstructive sleep apnea syndrome. Sleep 2009;32(4):522–9. [10] Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001;42(6):796–803.
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[11] Parisi P, Spalice A, Nicita F, Papetti L, Ursitti F, Verrotti A, et al. “Epileptic encephalopathy” of infancy and childhood: electro-clinical pictures and recent understandings. Curr Neuropharmacol 2010;8(4):409–21. [12] Hallböök T, Lundgren J, Rosén I. Ketogenic diet improves sleep quality in children with therapy-resistant epilepsy. Epilepsia 2007;48(1):59–65. [13] World Medical Association Declaration of Helsinki — ethical principles for medical research involving human subjects. Ferney-Voltaire, France: World Medical Association, Inc.; 2008 [Available from: http://www.wma.net/en/30publications/10policies/b3/. Accessed April 25, 2013]. [14] Jasper HH. The 10–20 electrode system of the international federation. Electroencephalogr Clin Neurophysiol 1958;10:370–5. [15] Grigg-Damberger M, Gozal D, Marcus CL, Quan SF, Rosen CL, Chervin RD, et al. The visual scoring of sleep and arousal in infants and children: development of polygraphic features, reliability, validity, and alternative methods. J Clin Sleep Med 2007;3(2):201–40. [16] Miano S, Bruni O, Aricò D, Elia M, Ferri R. Polysomnographic assessment of sleep disturbances in children with developmental disabilities and seizures. Neurol Sci 2010;31(5):575–83. [17] Carotenuto M, Esposito M, D'Aniello A, Rippa CD, Precenzano F, Pascotto A, et al. Polysomnographic findings in Rett syndrome: a case–control study. Sleep Breath 2013;17(1):93–8 [Erratum in: Sleep Breath. 2013;17(2):877–8]. [18] Iber C, Ancoli-Israel S, Chesson A, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, IL: American Academy of Sleep Medicine; 2007. [19] American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 1996;153:866–78. [20] Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, et al. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 1992;146:1235–9. [21] Traeger N, Schultz B, Pollock AN, Mason T, Marcus CL, Arens R. Polysomnographic values in children 2–9 years old: additional data and review of the literature. Pediatr Pulmonol 2005;40:22–30. [22] Zucconi M, Ferri R, Allen R, Baier PC, Bruni O, Chokroverty S, et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 2006;7:175–83. [23] Foldvary-Schaefer N. Sleep complaints and epilepsy: the role of seizures, antiepileptic drugs and sleep disorders. J Clin Neurophysiol 2002;19:514–21. [24] Kaleyias J, Cruz M, Goraya JS, Valencia I, Khurana DS, Legido A, et al. Spectrum of polysomnographic abnormalities in children with epilepsy. Pediatr Neurol 2008;39:170–6. [25] Kotagal S, Gibbons VP, Stith JA. Sleep abnormalities in patients with severe cerebral palsy. Dev Med Child Neurol 1994;36:304–11. [26] Becker D, Fennel E, Carney P. Sleep disturbances in children with epilepsy. Epilepsy Behav 2003;4:651–8. [27] Pereira AM, Bruni O, Ferri R, Nunes ML. Sleep instability and cognitive status in drugresistant epilepsies. Sleep Med 2012;13(5):536–41. [28] Shaheen HA, Abd El-Kader AA, El Gohary AM, El-Fayoumy NM, Afifi LM. Obstructive sleep apnea in epilepsy: a preliminary Egyptian study. Sleep Breath 2012;16(3): 765–71. [29] van Golde EG, Gutter T, de Weerd AW. Sleep disturbances in people with epilepsy; prevalence, impact and treatment. Sleep Med Rev 2011;15(6):357–68. [30] Nunes ML, Ferri R, Arzimanoglou A, Curzi L, Appel CC, Costa da Costa J. Sleep organization in children with partial refractory epilepsy. J Child Neurol 2003;19:763–6. [31] Racaru VM, Cheliout-Heraut F, Azabou E, Essid N, Brami M, Benga I, et al. Sleep architecture impairment in epileptic children and putative role of anti epileptic drugs. Neurol Sci 2013;34(1):57–62. [32] Quigg M, Straume M, Smith T, Menaker M, Bertram EH. Seizures induce phase shifts of rat circadian rhythms. Brain Res 2001;913(2):165–9. [33] Bazil CW. Epilepsy and sleep disturbance. Epilepsy Behav 2003;4(Suppl. 2):S39–45.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Sleep alterations in children with refractory epileptic encephalopathies: A polysomnographic study Marco Carotenuto a, Pasquale Parisi b,⁎, Maria Esposito a, Samuele Cortese c, Maurizio Elia d a
Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, Second University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy Child Neurology, Pediatric Headache & Sleep Disorders Centre, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, “Sapienza University”, Via Di Grottarossa 1035-1039, 00189 Rome, Italy c Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK d Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggiero 73, 94018 Troina (EN), Italy b
a r t i c l e
i n f o
Article history: Received 8 February 2014 Revised 8 March 2014 Accepted 10 March 2014 Available online xxxx Keywords: Epileptic encephalopathy Pediatric polysomnography Sleep-related breathing disorders Sleep obstructive apnea syndrome Periodic limb movements
a b s t r a c t Data on the relationship between sleep disturbances and refractory epileptic encephalopathies (EEs) are scarce. Our aim was to assess, by means of nocturnal polysomnography, if children with EEs present with objective alterations in sleep organization. Twenty-three children with EEs (12 males; mean age: 8.7 ± 1.4 years) and 40 healthy controls (22 males; mean age: 8.8 ± 1.1 years) underwent an overnight full polysomnography (PSG). Relative to controls, children with EEs showed a significant reduction in all PSG parameters related to sleep duration time in bed (TIB-min p b 0.001), total sleep time (TST-min p b 0.001), and sleep percentage (SPT-min p b 0.001), as well as significantly higher REM latency (FRL-min p b 0.001), rate in stage shifting (p = 0.005), and number of awakenings/hour (p = 0.002). Relative to controls, children with EEs also showed significant differences in respiratory parameters (AHI/h p b 0.001, ODI/h p b 0.001, SpO2% p b 0.001, SpO2 nadir% p b 0.001) and a higher rate of periodic limb movements (PLMs% p b 0.001). Our findings suggest that sleep evaluation could be considered mandatory in children with refractory epileptic encephalopathy in order to improve the clinical management and the therapeutic strategies. © 2014 Elsevier Inc. All rights reserved.
1. Introduction In clinical literature, there has been a growing interest in the mutual relations between sleep and epilepsy, kindled by the realization of several potentially relevant two-way interactions [1]. Seizures are frequent during sleep, and the epileptogenic discharges can alter and/or disrupt the sleep architecture, leading to an increase in seizure frequency [1–5]. The nonrapid eye movement (NREM) sleep phases can activate interictal epileptiform discharges (IEDs), but the facilitating influences on IED production may be exerted separately by either spindle activity or delta synchronization mechanisms, and the activating properties of sleep are not due to the stage per se but depend largely on the level of activity of synchronizing mechanisms [6]. Indeed, the REM sleep stage tends to suppress IEDs and may restrict their field of distribution to
⁎ Corresponding author. Tel./fax: +39 6 33775941. E-mail addresses: [email protected] (M. Carotenuto), [email protected], [email protected] (P. Parisi), [email protected] (M. Esposito), [email protected] (S. Cortese), [email protected] (M. Elia).
http://dx.doi.org/10.1016/j.yebeh.2014.03.009 1525-5050/© 2014 Elsevier Inc. All rights reserved.
the epileptogenic region [7,8]. On the other hand, with regard to the causes of sleep fragmentation, sleep-related breathing disorders (SRBDs) could be considered a potential trigger for paroxysmal activity and IEDs. This suggests that children with obstructive sleep apnea syndrome (OSAS) may have a dysfunction of the arousal system control, which is probably due to the putative effect of a primary brain insult as a predisposing factor for both OSAS and paroxysmal EEG activity [9]. The effect of the epilepsy etiology on sleep architecture during childhood has not been studied in detail, and, to our knowledge, there are no specific sleep studies related to epileptic encephalopathies (EEs). Epileptic encephalopathies are described as epilepsy with ictal and interictal epileptiform anomalies (clinical and EEG) and progressive cerebral dysfunction [10]. According to the classification and terminology criteria of International League against Epilepsy (ILAE), the following syndromes meet the EE criteria: Dravet syndrome, Doose syndrome, CSWSS (continuous spike–wave during slow-wave sleep), Landau– Kleffner syndrome, Lennox–Gastaut syndrome, Ohtahara syndrome, and West syndrome. Severe epilepsy with multiple independent spike foci is recently included in this group [11]. The importance of the relationship between EEs and sleep is also supported by the role of the ketogenic diet in improving sleep quality with increased REM sleep [12].
M. Carotenuto et al. / Epilepsy & Behavior 35 (2014) 50–53
The aim of this study was to compare, by means of polysomnography, sleep objective parameters in a group of children with EEs and in healthy controls. We hypothesized we would find a significantly higher prevalence of objective sleep alterations in children with EEs. 2. Materials and methods Twenty-three children with EEs (12 males) (mean age: 8.7 years; SD ± 1.4) and 40 healthy children (22 males) (mean age: 8.9 years; SD ± 1.1) underwent an overnight polysomnography (PSG) recording in the Sleep Laboratory of the Clinic of Child and Adolescent Neuropsychiatry of Naples and in the Unit of Clinical and Instrumental Neurology and Neurophysiopathology of the Oasi Institute of Troina after one adaptation night in order to avoid the first-night effect. Children were considered eligible for the full PSG if affected by one of EEs diagnosed according to the ILAE classification. The subjects in both groups were recruited from the same urban area; participants were all Caucasian and were of middle-class socioeconomic status (between class 2 and class 3, corresponding to 28,000–55,000 euros/year to 55,000–75,000 euros/year, respectively, according to the current Italian economic legislation parameters). Neuroimaging pathological findings were an exclusionary criterion. All subjects with EEs enrolled in this study were on polypharmacological treatment and were taking at least three or more antiepileptic drugs. All parents gave written informed consent during the first screening visit. The reported investigation was carried out in accordance with the principles of the Declaration of Helsinki [13]. The Departmental Ethics Committee of the Second University of Naples approved the study. 2.1. Polysomnographic evaluation The EEG recordings and electrode placement were performed according to the 10–20 system [14], and the PSG montage included at least 19 EEG channels (Fp1, Fp2, F7, F8, F3, F4, C3, C4, T3, T4, T5, T6, P3, P4, O1, O2, Fz, Cz, and Pz) referenced to the contralateral mastoid, left and right electrooculogram (EOG), chin electromyogram (EMG), left and right tibialis EMG, electrocardiogram (ECG) (1 derivation), nasal cannula, measures of thorax and abdominal effort, peripheral oxygen saturation, and pulse and position sensors [15]. Recordings were carried out using a Brain Quick Micromed System 98 recording machine, and signals were sampled at 256 Hz and stored on a hard disk for further analysis. Electroencephalography signals were digitally band-pass filtered at 0.1–120 Hz, 12-bit A/D precision. Moreover, the presence of high-amplitude sharp waves or spikes and slow waves together with the reduced occurrence of K complexes, sleep spindles, and rapid eye movements made it difficult to score sleep using usual criteria. Therefore, as per Miano et al. [16] and a previous report [17], we scored sleep stages based on the following criteria: 1. N1 was detected when, after wakefulness or movement, the EMG tone was clearly diminished, movement artifacts were absent, and the EEG did not show sleep-specific patterns (such as spindles or K complexes). 2. N2 was recognized because of the presence of sleep spindles and K complexes even during the pauses between the different runs of epileptiform discharges. 3. N3 was also defined when composed mostly of subcontinuous sharp wave or spike–slow-wave complexes. 4. Rapid eye movement sleep was characterized by decreased EMG tone with shorter epileptiform discharge duration and lower frequency compared with NREM sleep.
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Accordingly, the following conventional sleep parameters were evaluated: – Time in bed (TIB); – Sleep period time (SPT): the time from sleep onset to sleep end; – Total sleep time (TST): the time from sleep onset to the end of the final sleep epoch minus time awake; – Sleep latency (SL): the time from lights out to sleep onset, defined as the first of two consecutive epochs of sleep stage 1 or one epoch of any other stage, in minutes; – REM latency (RL): the time from sleep onset to the first REM sleep epoch; – Number of stage shifts/hour (SS/h); – Number of awakenings/hour (AWN/h); – Sleep efficiency (SE%): the percentage ratio between total sleep time and time in bed (TST/TIB ∗ 100); – Percentage of SPT spent in wakefulness after sleep onset (WASO%), i.e., the time spent awake between sleep onset and end of sleep; – Percentage of SPT spent in sleep stages 1 (N1%), 2 (N2%), slow-wave sleep (N3%), and REM sleep (REM%). All recordings started at the subject's usual bedtime and continued until spontaneous morning awakening. Sleep was subdivided into 30-s epochs, and sleep stages were scored according to the standard criteria [18] and analyzed by means of Hypnolab 1.2 sleep software analysis (SWS Soft, Italy). All the recordings were visually scored, and the sleep parameters derived were tabulated for statistical analysis. With regard to respiratory parameters, central, obstructive, and mixed apnea and hypopnea events were counted according to the standard criteria [19]. In particular, the apnea–hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of total sleep time; an obstructive apnea index N 1 was selected as the cutoff for normality [20,21]. The episodes of periodic limb movements (PLMs) were identified according to the standard criteria [22], and a PLMI ≥ 5 was considered abnormal. 3. Statistical analysis The study design was based upon data collected from an independent pilot study (5 subjects with EEs versus 5 control children) that showed a strong difference between the mean duration of the TST between the groups (412 ± 49.9 in the group of children with EEs versus 520 ± 32.7 in normal subjects; p = 0.004). The sample size was calculated with the online software http:// www.dssresearch.com/toolkit/sscalc/size_a2.asp. Group differences in demographic and clinical characteristics (fullscale intelligent quotient (FIQ), PSG parameters, respiratory (AHI, ODI, and mean oxygen saturation%) patterns, and PLMs%) were assessed by means of the Mann–Whitney U test or the chi-squared test where appropriate. Full scale intelligent quotient (FIQ), PSG parameters, respiratory (AHI, ODI and mean oxygen saturation%) patterns and PLMs% between EE subjects and control group children using the MannWhitney U test and the chi-squared test where appropriate. The statistical power was calculated with the online software http://www.dssresearch.com/toolkit/spcalc/power_a2.asp. The alpha error level of confidence interval was 5%. p values b 0.05 were considered statistically significant. The STATISTICA software version 6.0 (StatSoft, Inc.; 2001) was used for all statistical tests. 4. Results The study population and the control group were matched for age (p = 0.596), sex (chi-squared = 0.002; p = 0.963), and BMI
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Table 1
Age Sex ratio (M/F) BMI (body mass index) Full scale IQ
Patients with EEs (N = 23)
Healthy controls (N = 40)
p
8.69 ± 1.459 12/11 18.152 ± 2.374 73.083 ± 10.287
8.87 ± 1.151 22/18 19.018 ± 1.836 109.752 ± 9.526
0.596 0.963 0.114 b0.001
(p = 0.114). The FIQ evaluation showed a clear and obvious difference between the two groups (p b 0.001) (Table 1). Fourteen subjects presented with Lennox–Gastaut syndrome (LGS), 5 with severe myoclonic epilepsy of infancy (SMEI; Dravet syndrome), and 4 with myoclonic–atonic (or astatic) epilepsy (MAE; Doose syndrome). Table 2 shows the comparisons of macrostructural sleep parameters, respiratory patterns, and PLM percentage between children affected by EEs and healthy controls. Children with EEs showed significantly decreased values of TIB (p b 0.001), SPT (p b 0.001), and TST (p b 0.001) parameters as well as a longer first REM latency (FRL) (p b 0.001) compared with controls. Moreover, the sample with EEs showed a higher rate of stage shifts per hour (SS/h) (p = 0.005) compared with controls. No differences among the sleep stage percentage distributions were found, except for N3% (SWS%) (38.279 ± 7.928 of EE group versus 28.98 ± 10.027; p = 0.006), the mean duration in minutes of N2 (138.6 ± 45.8 of EE versus 227.37 ± 55.75; p b 0.001), and REM (98.2478 ± 2.94 of EE versus 123.06 ± 35.15; p = 0.026), which were lower than those in controls. As for respiratory parameters, children with EEs had a slightly significant increase of all parameters in comparison with the control group, as shown in Table 2, and for PLMs% (13.93 ± 2.53 versus 2.81 ± 1.098; p b 0.001). The statistical power analysis showed the following values: 100% for TIB, SPT, TST, FRL, AHI, ODI, SpO2%, SpO2 nadir%, and PLMs, 97.9% for stage shifts per hour (SS/h), 97.1% for awakenings/h, 99.2% for N3%, 85.8% for WASO%, and 100% for REM%. 5. Discussion The main findings of the present study can be summarized in the significant alteration in sleep and autonomic nocturnal parameters in children affected by EEs with respect to healthy controls.
Table 2
TIB-min SPT-min TST-min SOL-min FRL-min SS-h AWN-h SE% WASO% N1% N2% N3% REM% AHI/h ODI/h SpO2% SpO2 nadir% PLMs%
Children with EEs (N = 23)
Healthy controls (N = 40)
461.478 432.313 413.457 29.165 200.130 12.091 4.404 89.605 4.431 2.522 31.718 38.279 23.050 11.539 3.148 93.583 87.196 13.930
585.775 558.075 531.063 19.763 120.363 8.220 1.870 90.730 4.690 3.118 45.433 28.980 22.165 0.994 0.413 98.383 95.833 2.810
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
57.543 53.482 53.995 15.124 51.662 4.299 3.167 3.124 1.154 1.234 8.223 7.928 2.804 2.729 1.308 1.399 3.624 2.534
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
83.612 85.450 79.971 14.297 45.760 3.512 1.760 5.145 4.425 3.828 27.708 10.027 5.555 0.205 0.307 0.810 1.163 1.098
Mann–Whitney U test U
p*
84.0000 78.0000 80.0000 287.0000 126.0000 224.0000 236.5000 373.0000 430.0000 406.0000 196.0000 189.0000 437.0000 0.0000 0.0000 1.5000 0.0000 0.0000
0.000 0.000 0.000 NS 0.000 0.005 0.002 NS NS NS NS 0.006 NS 0.000 0.000 0.000 0.000 0.000
In general, the evaluation of the impact of epilepsy on sleep represents an important area for research with potential useful consequences on clinical management of seizures and long-term follow-up of these relative rare conditions [5]. Moreover, a number of AEDs could contribute to sleep disruption [23] such as in the presence of cerebral lesions [2]. In fact, it has been estimated that about 40% of patients with epilepsy tend to exhibit sleep related breathing disorder (SRBD), in particular as primary snoring (about 42%). In this perspective, our sample showed a high rate of SRBD. Moreover, the rate of periodic limb movements in one study was found to be 10% [24]. In 1994, Kotagal et al. [25] performed a PSG study in 9 patients with epilepsy and spastic quadriparesis, showing that the cerebral palsy group with epilepsy exhibited significantly more respiratory disturbances per hour of sleep, and about 55% were diagnosed as affected by OSAS. Moreover, in 2003, Becker et al. performed a study using a validated pediatric sleep questionnaire to evaluate the sleep-disordered symptoms in 14 children with epilepsy and in 14 age-matched subjects with known obstructive sleep apnea, with no evidence of differences among the SRBD gravity, sleep fragmentation, disrupted sleep [5], and decreased sleep-onset latency between the two groups [26]. On the other hand, our findings tend to confirm the higher prevalence of altered respiratory patterns (AHI, ODI, SpO2%, and nadir) in EE subjects compared with the control group. In general, a recent report among Brazilian children with drugresistant epilepsy showed a greater incidence of sleep problems regarding the qualitative aspects, the macrostructural organization, and the NREM sleep instability [27]. In light of this, our findings confirm the presence of abnormalities in quality and macrostructural organization of children with EEs. The etiology of sleep disruption in children with epilepsy could be considered as multifactorial and not only linked to the epilepsy per se or to the AED administration [5]. In fact, a variety of treatable sleep disorders, such as SRBD and PLMd, are frequent in patients with epilepsy, leading to an important sleep fragmentation with resultant excessive daytime sleepiness, which, in turn, could lead to poor seizure control [24,28]. The epileptic encephalopathy per se and its therapy may contribute to the sleep disruption, and this may result in chronic sleep deprivation and fragmentation, both of which have possible detrimental effects on seizure control, causing a vicious circle [29]. In addition, the PLMs, which have also been associated with Rett syndrome [17], could be a cause of sleep fragmentation in our sample (p b 0.001). Further, in 2003, Nunes et al. [30], in a PSG evaluation of 17 patients affected by partial refractory epilepsy, reported a significant reduction of TIB and TST in children with epilepsy, as clearly shown in our results. A recent report about the role of therapy on sleep in children with epilepsy showed decreased REM sleep efficiency percentage as well as a significant reduction in sleep duration and the absence of relevant differences in light sleep and slow-wave sleep in subjects with polytherapy compared with those on monotherapy [31]. Moreover, according to our findings, we hypothesize that the sleep abnormalities reported in children with EEs could be due to altered neuronal networks subserving sleep/wake regulation, as previously suggested by Quigg et al. who proposed that disruptions of hypothetically mediated circadian regulation could generate seizures [32]. According to this point of view, we should also take into account the increased SS/h found in our children with EEs (12.091 ± 4.299 versus 8.22 ± 3.512; p = 0.005), as reported by Kaleyias et al. in 2008 [24]. This finding confirms the importance of seizure control in order to avoid altered sleep, with a lower sleep efficiency (SE%) and a higher arousal index. In our children with EEs, we also found a higher arousal index (4.404 ± 3.167 versus 1.87 ± 1.76; p = 0.002) and a lower REM duration in minutes (98.2478 ± 2.94 versus 123.06 ± 35.15; p = 0.001) in
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comparison with the control group. Various studies have concluded that sleep fragmentation disorders and excessive daytime somnolence may provoke an increase in the frequency of seizures and hamper their control, so the same could also happen in children with EEs [33]. Our findings should be considered in light of study limitations. Our data were derived from a limited pediatric sample of subjects exclusively at an advanced clinical stage, (even if EEs could be considered as rare diseases), we did not consider in a specific way the effects of drug polytherapy, and no follow-up evaluation was performed. Notwithstanding these limitations, to the best of our knowledge, this is the first PSG study on Italian subjects with EEs in childhood. 6. Conclusion Our findings tend to show that in children with different types of EE sleep macrostructure, respiratory parameters and periodic limb movement regulation during the night are significantly affected, suggesting the key role of sleep evaluation in children with EEs in order to better understand the basic mechanisms of epileptogenesis and to improve therapeutic management strategies. Conflict of interest None declared. References [1] Bourgeois B. The relationship between sleep and epilepsy in children. Semin Pediatr Neurol 1996;3:29–35. [2] Pereira AM, Bruni O, Ferri R, Palmini A, Nunes ML. The impact of epilepsy on sleep architecture during childhood. Epilepsia 2012;53(9):1519–25. [3] Dinner DS. Effect of sleep on epilepsy. J Clin Neurophysiol 2002;19:504–13. [4] Foldvary-Schaefer N, Grigg-Damberger M. Sleep and epilepsy. Semin Neurol 2009;29: 419–28. [5] Parisi P, Bruni O, Pia Villa M, Verrotti A, Miano S, Luchetti A, et al. The relationship between sleep and epilepsy: the effect on cognitive functioning in children. Dev Med Child Neurol 2010;52(9):805–10. [6] Ferrillo F, Beelke M, De Carli F, Cossu M, Munari C, Rosadini G, et al. Sleep-EEG modulation of interictal epileptiform discharges in adult partial epilepsy: a spectral analysis study. Clin Neurophysiol 2000;111:916–23. [7] Malow BA, Lin X, Kushwaha R, Aldrich MS. Interictal spiking increases with sleep depth in temporal lobe epilepsy. Epilepsia 1998;39:1309–16. [8] Sammaritano M, Gigli GL, Gotman J. Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 1991;41:290–7. [9] Miano S, Paolino MC, Peraita-Adrados R, Montesano M, Barberi S, Villa MP. Prevalence of EEG paroxysmal activity in a population of children with obstructive sleep apnea syndrome. Sleep 2009;32(4):522–9. [10] Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001;42(6):796–803.
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