Sleep disturbances in people with epilepsy; prevalence, impact and treatment

Sleep Medicine Reviews 15 (2011) 357e368

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Sleep Medicine Reviews journal homepage: www.elsevier.com/locate/smrv

CLINICAL REVIEW

Sleep disturbances in people with epilepsy; prevalence, impact and treatment Esther G.A. van Golde a, Therese Gutter b, Al W. de Weerd* Department of Clinical Neurophysiology and Sleep Centre SEIN Zwolle, Dokter Denekampweg 20, 8025 BV Zwolle, The Netherlands

a r t i c l e i n f o

s u m m a r y

Article history: Received 22 November 2010 Received in revised form 14 January 2011 Accepted 15 January 2011 Available online 24 March 2011

The interaction between epilepsy and sleep is thoroughly studied and is very complex. This review focuses on prevalence, impact on quality of life and effects of treatment of sleep disorders on the course of epilepsy. Self-reported sleep disturbances in people with epilepsy are about twice as prevalent as in healthy controls. People with epilepsy with sleep disturbances have a significant impairment of quality of life compared to those with no sleep disturbances. In children with epilepsy, sleep problems may lead to detrimental effects on daytime behavior and cognition. Most is known about obstructive sleep apnea syndrome (OSAS). Co-morbidity of epilepsy and OSAS is shown to be far higher than expected by chance. Treatment of OSAS significantly improves seizure control in people with epilepsy. More studies on the prevalence of other sleep disorders in people with epilepsy and the effect of treatment are required. Reports on the effect of treatment for other sleep disorders are scarce and not unequivocal. Ó 2011 Published by Elsevier Ltd.

Keywords: Epilepsy Sleep disorders Quality of life Obstructive sleep apnea syndrome

Introduction Since sleep disorders and epilepsy are both common conditions in the general population, co-morbidity and mutual influence are likely to exist.1 For example, sleep disturbances can lead to excessive daytime sleepiness (EDS), which is also one of the most frequently reported complaints of people with epilepsy. Both conditions are known to have negative effects on quality of life (QoL).2e4 It is likely that the co-morbidity of these disorders may cause further deterioration of QoL and may even interfere with seizure control. The interaction between epilepsy and sleep is complex and clinically pertinent. Over a century ago, Gowers (1885) classified timings of seizure occurrence as diurnal, nocturnal and diffuse (cited in 5). His observations were the first suggestion of an interaction between the sleepewake status and the occurrence of seizures. Later, after the introduction of electroencephalography (EEG) and polysomnography (PSG), the epilepsyesleep interaction was studied more thoroughly and proved to have numerous aspects. Sleep can activate the occurrence of seizures and epileptiform EEG abnormalities. In general, seizures and interictal epileptic discharges (IEDs) are facilitated during non-rapid-eye-movement (NREM) sleep and suppressed during rapid-eye-movement (REM) sleep. It is thought that focal epileptiform EEG discharges in NREM sleep are * Corresponding author. Tel.: þ31 (0) 38 8457185; fax: þ31 (0) 38 8457170. E-mail addresses: [email protected] (E.G.A. van Golde), tgutter@ sein.nl (T. Gutter), [email protected] (A.W. de Weerd). a Tel.: þ31 (0) 649321565; fax: þ31 (0) 38 8457170. b Tel.: þ31 (0) 38 8457171; fax: þ31 (0) 38 8457190. 1087-0792/$ e see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.smrv.2011.01.002

facilitated by the synchronized EEG pattern. In contrast, during REM sleep the EEG pattern is desynchronized and thus less likely to propagate these discharges. The occurrence of seizures during the sleepewake cycle depends mainly on the seizure type and etiology. For example, absence seizures occur only in the waking state and seizures in autosomal dominant nocturnal frontal lobe epilepsy (NFLE) occur only during sleep.6 One of the most striking examples of the activation of epileptiform discharges by sleep is the syndrome of continuous spike-wave activity during slow-wave sleep (CSWS), defined by an EEG pattern consisting of diffuse multifocal slow-spikewave discharges present for >85% of slow-wave sleep.7 Sleep deprivation is also well-recognized as activating epileptiform activity, although it remains controversial whether the activating effects of sleep deprivation are due to increased neuronal excitability or simply to induction of sleep.6,8 Furthermore, sleep deprivation seems to provoke seizures in some well-delineated epileptic syndromes and even in people with no prior history or only a remote history of seizures,5 but is not seen in all epilepsy syndromes.8 On the other hand seizures, both diurnal and nocturnal, are thought to disrupt sleep structure. Reduction and instability of REM sleep is most often reported, but shorter total sleep time and lower sleep efficiency, more sleep fragmentation, longer sleep latency and increased stage shifts and awakenings are also found. People with temporal lobe epilepsy have more severe sleep disorganization than those with extratemporal foci and sleep architecture is more disrupted during nights with seizures than in seizure-free nights.6,8,9 For a more detailed overview of the interaction between epilepsy and sleep architecture see overviews by Bazil et al.5 and Matos et al.8

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Abbreviations AEDs AHI AS BMI BQS

anti-epileptic drugs apneaehypopnea index angelman syndrome body mass index bologna questionnaire on sleepiness-related symptoms CPAP continuous positive airway pressure CSWS continuous spike-wave activity during slow-wave sleep DIMS disorders of initiating and maintaining sleep EDS excessive daytime sleepiness EEG electroencephalography ESS Epworth sleepiness scale FLEP frontal lobe epilepsy and parasomnias IEDs interictal epileptic discharges IQ intelligence quotient MOS-SS medical outcome study e sleep scale

It appears that the occurrence of seizures depends not only on the sleep and wake state, but also on a circadian, 24-h rhythmicity. Seizures have been shown to have an uneven distribution over the day, depending on the lobe of origin.10 This is in line with animal studies that showed a true endogenously mediated circadian pattern in the occurrence of seizures in rats placed in constant darkness.11 The treatment of epilepsy with anti-epileptic drugs (AEDs) influences sleep structure. There is strong evidence suggesting that barbiturates, benzodiazepines and e to a lesser degree e phenytoin have detrimental effects on sleep.9 These drugs induce sleep more easily and increase total sleep time but, in contrast, reduce REM sleep. Sleep may therefore be impaired overall and may lead, at least in part, to EDS which is often seen in people taking these AEDs. On the other hand, gabapentin, levetiracetam and lamotrigine probably have a positive effect on sleep structure resulting in more REM and slow-wave sleep (stage 3 NREM).9 Thus the newer generation AEDs may have fewer detrimental effects on sleep structure than the older ones. It is, however, very difficult to measure the direct effects of AEDs on sleep because of the many confounding factors (seizures, concurrent sleep disturbances and polypharmacy). In short, the clinically important interaction between epilepsy and sleep is complex and reciprocal. The disease per se and its therapy may disrupt sleep. This may result in chronic sleep deprivation and fragmentation, both of which have possible detrimental effects on seizure control, causing a vicious circle. The aim of this paper is to review the epidemiology of sleep complaints and the co-morbidity of sleep disorders in people with epilepsy. The effect of sleep on daily functioning and QoL will also be discussed. Finally, the literature on the effect of treating sleep disorders on seizure control and QoL will be discussed.

Methods PubMed was searched up to June 2010. The following search terms were used; “epilepsy” combined with “sleep disturbances”, “sleepiness”, “insomnia”, “parasomnia”, and “obstructive sleep apnea syndrome”. The selection was limited to randomized clinical trials, clinical trials and comparative studies, and published in English or Dutch. We screened the abstracts of the papers found to retrieve those articles that specifically dealt with the topic of sleep disturbances

NFLE NREM OSAS PLMI PLMS PSG PSQ QoL RBD REM RLS SA-SDQ SBQ SDL SDSC SWTD TS VNS

nocturnal frontal lobe epilepsy nonerapideeyeemovement obstructive sleep apnea syndrome periodic leg movement index periodic leg movements during sleep polysomnography pediatric sleep questionnaire quality of life REM sleep behavior disorder rapideeyeemovement restless leg syndrome sleep apnea scale of the sleep disorders questionnaire sleep behavior questionnaire sleep disturbance list sleep disturbance scale for children sleepewake transition disorder tuberous sclerosis vagus nerve stimulation

and disorders in people with epilepsy. All identified papers were searched for relevant references or citations. No formal categorization of level of evidence of (case-control) epidemiological studies exists; we therefore constructed our own level of evidence scale (see Table 1.).

Sleep disturbances in adults with epilepsy Questionnaire-based studies Most studies used self-reported answers to questionnaires to assess the occurrence of sleep problems in people with epilepsy (see Table 2). Comparing 486 people with focal-onset epilepsy with 492 healthy controls, the prevalence of sleep disturbances in the past six months in people with epilepsy was twice that of controls (38.6% vs. 18.0%), as measured with the sleep disturbance list (SDL).3 In a more heterogeneous population of 100 people with either focal or generalized epilepsy compared with controls (hospital staff and their relatives) there was a three-fold higher prevalence of sleep complaints: 30% vs. 10% respectively.12 In a group of 201 people with refractory focal epilepsy 34% reported having a diagnosis of sleep disturbances during the past 12 months.13 Table 1 Level of evidence categorization for questionnaire studies and PSG studies. Evidence level

Criteria

Questionnaire studies 1a Comparison with healthy controls; N > 100 1b Comparison with healthy controls; N 50e100 or Comparison with non-healthy controls; N > 100 1c Comparison with healthy controls; N < 50 2a No Comparison; N > 100 2b No Comparison; N 50e100 2c No Comparison; N < 50 PSG studies 1a 1b 2a 2b 3

Prospective; N Prospective; N available Prospective; N Prospective; N available Retrospective

> 50; clear definitions and raw data available > 50; no clear definitions and/or raw data < 50; clear definitions and raw data available < 50; no clear definitions and/or raw data

Table 2 Sleep problems in adults with epilepsy, questionnaire-based studies. Authors Malow et al., 199714

#

Subjects

Controls

Questionnaires

Results

1b

N ¼ 158 Focal and generalized epilepsy, 40% SF, 44% nocturnal seizures N ¼ 244 Focal and generalized epilepsy, 41% SF, 2 AEDs N ¼ 486 Focal epilepsy, 2 AEDs

N ¼ 68 Neurology patients

ESS, SA-SDQ, RLS question

N ¼ 205

ESS

N ¼ 492

ESS, GSQ, MOS-SS, SDL, SF-36 Health Survey MOS-SS, QOLIE-10, EQ-5D

Patients more often EDS; 28% vs. 18% SA/SDQ and symptoms of RLS significant predictors of elevated ESS in people with epilepsy and controls Correlation higher ESS score with snoring and/or apneas and recurrent seizures past year People with epilepsy had a higher prevalence of sleep disturbance during previous 6 months (36.8% vs. 18.0%) QoL impairment highest in people with epilepsy with sleep disturbances

Manni et al., 200015

1a

De Weerd et al., 20043

1a

Xu et al., 200613

2a

N ¼ 201 Refractory, focal epilepsy, 2 AEDs

No controls

Khatami et al., 200612

1b

N ¼ 95e100 Focal and generalized epilepsy, 39% of seizures predominately/only occurring during sleep

N ¼ 90 Hospital staff and their relatives

ESS, SA-SDQ, UNS

Vignatelli et al., 200617

1c

N ¼ 33 NFLE, 36% seizures every night

N ¼ 27

ESS, BQS

Piperidou et al., 200816

2a

N ¼ 124 Focal and generalized, 41.7% nocturnal seizures

No controls

ESS, SA-SDQ, AIS, QOLIE-31

Haut et al., 200918

1c

N ¼ 31 65 year, focal epilepsy

N ¼ 31

MOS-SS, BIMC, PHQ Depression and Anxiety modules

Carrion et al., 201019

2c

N ¼ 48 Refractory TLE, surgery candidates, 89.6% nocturnal seizures

N ¼ 43 Refractory TLE, waiting completion of surgery evaluation

ESS, PSQI 2 days before; 3 þ 12 months after surgery

Worse scores on MOS-SS compared to de Weerd et al.3 Sleep problems associated with female gender, last seizure  1wk ago, anxiety and depression, use of sleep medication More sleep problems correlated with impaired QoL People with epilepsy more sleep complaints in general (30% vs. 10%), sleep maintenance insomnia (52 vs. 38%) and problems at work related to EDS (9% vs. 2%) ESS score correlated with age, loud snoring and apneas Loud snoring only independent predictor of EDS People with epilepsy more frequently tiredness after awakening at least almost all mornings (36% vs. 11%) and spontaneous midsleep awakenings at least almost all nights (50% vs. 22%) People with epilepsy with complaints of midsleep awakenings have higher mean scores on ESS and BSQ and more frequently tiredness after awakening (54% vs. 19%) EDS 16.9% Pathological SA-SDQ 28.2% Pathological AIS 24.6% Pathological SA-SDQ more often in men and older patients Correlation insomnia and seizure frequency EDS, OSAS and insomnia impair QoL People with epilepsy poorer scores on categories of somnolence and shortness of breath/awaking with headache. People with epilepsy higher mean scores on BIMC and more often depressed (18% vs. 0%) Poor seizure control associated with sleep disturbances in general and shortness of breath/awakening with headache No difference at baseline between groups ESS and PSQI scores decreased after surgery PSQI scores higher in patients with predominantly nocturnal seizures

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E

# also PSG performed; AEDs: anti-epileptic drugs; AIS: Athens insomnia scale; BIMC: Blessed information memory and concentration test; BQS: Bologna questionnaire on sleepiness-related symptoms; E: level of evidence; ESS: Epworth sleepiness scale; EQ-5D: five-item EuroQol survey; GSQ: Groningen sleep questionnaire; MOS-SS: medical outcome study sleep scale; PHQ: patient health questionnaire; PSQI: Pittsburgh sleep quality Index; QOLIE: Quality of life in epilepsy inventory; RLS: restless legs syndrome; SA/SDQ: sleep apnea scale of the sleep disorders questionnaire; SDL: sleep disturbance list; SF: seizure free; SF-36 Health Survey: short form (36) of health survey; TLE: temporal lobe epilepsy; UNS: Ullanlinna narcolepsy scale.

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The largest differences in mean scores between the two groups studied by de Weerd et al.3 were in EDS and psychiatric sleep disorders. Studies using the Epworth sleepiness scale (ESS) reported scores indicative of EDS (ESS score >10) more often in people with epilepsy than in controls.3,12,14e16 This difference reaches significance in only 2 studies with 16.9e28% of patients and 11.6e18% of controls with EDS.14,16 Comparing people with nocturnal frontal lobe epilepsy with healthy controls, tiredness in the morning was significantly more often reported by people with epilepsy (36.4 vs. 11.1%), but no difference was found in EDS.17 The largest difference in the study by Khatami et al.12 regarded sleep maintenance insomnia (52% vs. 38%). In a series of 124 people with epilepsy in Greece an insomnia prevalence of 24.6% was reported.16 People with focal-onset epilepsy had significantly more sleep disturbances on average, and on the subscale of sleep adequacy, than healthy controls assessed by a questionnaire about sleep problems in the last month (medical outcome study sleep scale; MOS-SS).3 In the study of people with refractory focal epilepsy even higher scores (indicative of more sleep problems) were reported.13 In a small group (n ¼ 31) of people  65 years old with focal-onset epilepsy, the subscales of daytime somnolence and awaking short of breath/with a headache (MOS-SS) suggested more abnormalities than in age- and gender-matched controls.18 Association between characteristics of epilepsy and sleep disturbances Many studies have tried to find factors that account for the higher prevalence of sleep disturbances in people with epilepsy compared with healthy controls. These factors are discussed here. In general, gender12,15,16 and age12,14e16 are not associated with EDS. In a study among people with focal-onset, refractory epilepsy, however, women were found to report more severe sleep problems than men.13 Focal or more generalized seizure patterns were not found to be associated with EDS12,14e16 or insomnia.16 AEDs are known to influence sleep structure and it is often suggested that sleep problems in people with epilepsy are at least partly due to AEDs. In most studies, individuals use a wide range of different AEDs and most are on polytherapy. It is difficult, therefore, to draw firm conclusions with respect to the effects of individual AEDs. In many studies of sleep complaints, no association was found between the number of AEDs taken and EDS,12,14,15,19 neither did the number of AEDs correlate with pathological scores on sleep-related questionnaires in people with focal-onset epilepsy.3 In another population, individuals taking greater numbers of AEDs reported worse sleep, but this difference did not reach statistical significance.13 However, people taking second-generation AEDs only (for example levetiracetam, gabapentin and lamotrigine) reported fewer sleep problems than those taking older generation AEDs (for example phenytoin, phenobarbital, carbamazepine and valproic acid). It seems logical that the presence of nocturnal seizures may be an important factor in sleep disturbances and daytime somnolence. However, the studies of both Malow et al.14 and Khatami et al.12 did not confirm this hypothesis. Perceived higher frequency of seizures in people with NFLE did not account for more sleep problems.17 However, people in this study with persistent midsleep awakenings had significantly higher mean scores of ESS and on a questionnaire on sleepiness-related symptoms (Bologna questionnaire on sleepiness-related symptoms; BQS) than those without such awakenings. These results suggest that individuals may underestimate the frequency of nocturnal seizures, and that these seizures do account for disturbed sleep. In a study of 48 people with refractory temporal lobe epilepsy, EDS and sleep quality were similar in people with or without nocturnal seizures.19 On the other

hand, reported sleep quality was significantly worse in people with predominance of nocturnal seizures (>50% of seizures during sleep), especially on sleep latency and efficiency. In the same study EDS and sleep quality were assessed two days before and three and twelve months after epilepsy surgery.19 EDS had significantly improved and quality of sleep was significantly better after surgery. The surgical procedure appeared to be beneficial for both seizure control and sleep quality, suggesting a correlation between seizure control and sleep quality. Although higher seizure frequency was not correlated with more sleep complaints in the previous month in the study by Xu et al., people with a seizure within the previous week reported more disturbed sleep than those whose last seizure occurred more than a week previously.13 In the elderly people with epilepsy studied by Haut et al., poor seizure control (1 seizure in the past six months) was associated with reported sleep disturbances in general in the past month and with awakening short of breath or with a headache.18 There is also some evidence that seizure frequency and insomnia are correlated.16 Despite these results, in other studies seizure frequency and EDS were not correlated.12,14,15 Anxiety and depression are more prevalent among people with epilepsy than in healthy controls.20 These disorders are known to have detrimental effects on sleep.21 Thus psychiatric co-morbidity may at least partly account for the higher prevalence of sleep problems in this population. In the population with epilepsy studied by Xu et al. 21.4% of individuals received concomitant medication for anxiety and 31.8% for depression.13 These individuals had more sleep problems in the previous four weeks than those without these comorbidities. The elderly population with epilepsy of Haut et al.,18 mentioned above, also reported more anxiety and depression than healthy controls, again suggesting an accumulating influence on sleep. Furthermore, people with poorly controlled seizures had more frequent and more severe depression than those with wellcontrolled epilepsy, and there was a similar trend for anxiety. In this population, sleep disturbances were not accounted for by depressed mood. In the study of Carrion et al. mentioned previously, there was no difference in EDS and sleep quality between people with epilepsy two days before surgery and people without epilepsy surgery in the near future,19 suggesting that anxiety related to the procedure itself is probably not the reason for poor sleep in these individuals. In addition to questionnaires about sleep disturbances in general, questionnaires assessing specific sleep disorders such as OSAS and restless legs syndrome (RLS) were also considered. Malow et al. reported higher scores (more suggestive of presence of the disease) in both questionnaires to be individually significant predictors for EDS, while AEDs or type and frequency of seizures were not.14 In line with these results, there was a significant correlation between symptoms suggestive of OSAS and higher ESS scores in the study of Manni et al., while type and number of AEDs, and frequency and type of seizures were not correlated with higher ESS scores.15 These results suggest that EDS in a person with epilepsy is not due only to epilepsy and its treatment, but also depends on the underlying sleep disorder. Based on a sleep apnea scale of a generally used sleep disorders questionnaire (SA-SDQ) 9% of people with epilepsy and 3% of controls had scores suggestive of OSAS in one study.12 When using a less conservative cut-off score (possibly more sensitive for people with epilepsy22), 30% of people with epilepsy and 23% of controls may have had OSAS. These differences did not reach significance between the groups. In this study, loud snoring and RLS-symptoms were found to be the only independent predictors of EDS in people with epilepsy, while all the epilepsy variables and higher SA-SDQ scores were not. In another study using the more conservative cut-off scores on the SA-SDQ, 28.2% (24.3% in women, 33.3% in men) had scores suggestive of OSAS.16 However, in line with Khatami et al.,12 scores on this

E.G.A. van Golde et al. / Sleep Medicine Reviews 15 (2011) 357e368

questionnaire above the cut-off were not correlated with an ESS score >10 (indicative of EDS). These results again confirm that EDS in people with epilepsy is multifactorial in origin. Associations between sleep disturbances and quality of life Sleep disturbances are known to be independently associated with impairment of QoL in the general population and in people with a chronic illness.2 This was confirmed in one study3 in which people with epilepsy with reported sleep problems had significantly more impairment of QoL than comparable people without sleep problems. Similar findings were seen in people with more refractory epilepsy13 and in a population including people with both focal and generalized epilepsies.16 Polysomnographic (PSG) studies As previously mentioned, there are many well-written reviews on altered sleep architecture in people with epilepsy. Therefore, this subject will not be further discussed here. Outcomes on sleep disorders measured with PSG will be reviewed later on in this article; see section “Sleep disorders in epilepsy”. Sleep disturbances in children with epilepsy Questionnaire-based studies In children with epilepsy, sleep disturbances are mostly studied through parental questionnaires (see Table 3). In 1997 Stores et al. disclosed a poorer quality of sleep and more anxieties about sleep in 79 children with epilepsy compared with age- and gender-matched healthy controls.23 Four studies used the validated sleep behavior questionnaire (SBQ) containing a total score and subscales for bedtime difficulties, parent/child interaction during the night, sleep fragmentation, parasomnias and daytime drowsiness.4,24e26 Higher scores indicate more sleep disturbances. In all studies, higher scores were reported for children with epilepsy than for their siblings and/ or healthy controls. A group of children with relatively mild, idiopathic epilepsy exhibited higher scores on all SBQ subscales than controls.24 In line with this result, Wirrell et al. found higher scores on all subscales of SBQ apart from bedtime difficulties comparing children with epilepsy with their nearest-aged sibling.4 Byars et al. studied sleep problems in children who had their first seizure in the previous three months and found higher scores on all subscales apart from sleep fragmentation and parent/child interaction when compared to both siblings and healthy controls.26 Moreover, 45% of children with epilepsy had pathological scores (>2SD above the mean) for the total SBQ-scale. These findings may suggest that sleep disturbances in children with epilepsy are not a result of the presence of a chronic illness or of the chronic use of AEDs, but rather a result of the epilepsy per se, since all children were recently diagnosed and most were not receiving AEDs. Two studies used another validated parental questionnaire, the pediatric sleep questionnaire (PSQ) with subscales for snoring, sleep-disordered breathing/sleep apnea, RLS/limb movements of sleep, parasomnias, narcolepsy, insomnia, daytime inattention and hyperactivity, and EDS.27,28 Becker et al. studied 30 children with epilepsy with sleep complaints27 and found pathological scores on the PSQ subscales for snoring in 67%, restless sleep in 63%, EDS in 63% and sleep-disordered breathing in 13%. When compared to healthy controls, parents of 26 children with epilepsy reported more complaints of EDS (76% vs. 15%), sleep-disordered breathing (65% vs. 3.9%), and parasomnias (53% vs. 4%).28 The epilepsy group also had more self-reported EDS (46.2%) than healthy controls (19.2%). Ong et al. studied a population of children with relatively severe epilepsy and compared them to

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their nearest-aged healthy sibling29 using the sleep disturbance scale for children (SDSC/Bruni-list30), which assesses sleep disturbances in the previous six months. They found pathological scores, particularly for the subscales of disorders in initiating and maintaining sleep (DIMS) (31.5% of patients vs. 4.3% of controls) and sleepewake transition disorders (SWTD) (13% of patients vs. 2.2% of controls). The children with epilepsy more frequently experienced sleep latencies of >30 min (32.6% vs. 7.6%). Association between characteristics of epilepsy and sleep disturbances Gender does not affect the occurrence of sleep problems in children with epilepsy, but age does.23,24 Stores et al. noted significantly more anxiety about sleep in children aged eight years and below than in older children.23 More sleep problems, especially on the subscales parent/child interaction and bedtime difficulties were also reported most often in the younger children with epilepsy e aged ten years and less e by Cortesi et al.24 This difference was not seen in the healthy controls. Age and total SDSC-score were not, however, correlated in the study by Ong et al.29 A possible explanation for this difference is that the older children in the Ong et al.’s study were cognitively not ‘older’ than the younger ones because of the high proportion of mental retardation. Although Ong et al.29 found no association between aberrant cognitive functioning and sleep problems, others did.4,25,26 Wirrell et al. reported more sleep fragmentation and worse total SBQ-scores in children with epilepsy and mental retardation compared with those with epilepsy and normal cognitive function.4 This is in line with the studies of Batista et al.25 and Byars et al.26 Seizure frequency/seizure control may be an important factor in the occurrence of sleep problems in children with epilepsy. Seizure frequency was associated with more anxieties about sleep in children < 8 yr in the epilepsy population of Stores et al., but not with poor quality of sleep, parasomnia, short duration of sleep or disordered breathing.23 There was also no difference in sleep disturbances in newly diagnosed children with respect to the presence or absence of recurrent seizures in the study of Byars et al.26 EDS also seemed independent of presence or absence of seizures in the previous year.28 Cortesi et al., however, reported a significantly higher total SBQ-score, longer sleep latency and shorter sleep duration in children with current seizures compared with those who were seizure free for at least one year.24 Wirrell et al. showed similar results.4 The children with refractory epilepsy in this population had longer sleep latency, more sleep fragmentation and daytime drowsiness, resulting in a higher SBQ-score than in children with non-refractory epilepsy. In the studies by Batista et al.25 and Ong et al.29 sleep disturbances occurred more in children with refractory epilepsy, more severe seizures, or both. Nocturnal seizures were associated with more reported sleep disturbances in the study by Batista et al.,25 but others did not confirm this.4,29 There is some evidence that children with symptomatic epilepsies have more sleep problems than those with idiopathic epilepsies.4,26 The influence on sleep of generalized or focal epilepsies is not clear. Some find more sleep disturbances in children with generalized epilepsies,25 some in those with partial epilepsies4,26 whilst others see no difference.23,27,28 The effect of AEDs remains uncertain because of polypharmacy and limited numbers of patients. Some authors tried e as in adults e to find an association between the number of AEDs taken and the occurrence of sleep problems. Children taking more than one AED had more sleep disturbances than those on monotherapy or no therapy.25 Byars et al. reported more parasomnias in children on monotherapy than in those taking no AEDs.26 In other studies the

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Table 3 Sleep problems in children with epilepsy; questionnaire-based studies. E

Subjects

Controls

Questionnaires

Results

Stores et al., 199723

1b

N ¼ 79 5-16 yr, focal and generalized epilepsy

N ¼ 73

Sleep questionnaire CRPRS

Cortesi et al., 199924

1b

N ¼ 89 6-14 yr, idiopathic focal and generalized epilepsy, monotherapy VPA, normal IQ, 76.5% > 12mnth SF

N ¼ 49 þ 321 Nearest-aged sibling þ healthy school children

SBQ, CBCL

2c

N ¼ 30 7-14 yr, focal and generalized epilepsy, 2 AEDs, 17% no AED, IQ >70, 60%  2mnth SF, sleep complaints

No controls

PSQ, CPRS-R:L, ECBI, CDI, RCMAS, PPVT-III

1c

N ¼ 11 9-17 yr, primary idiopathic generalized epilepsy, SF, IQ >70, 2 AEDs

N¼8

CBCL, CPT

Wirrell et al, 20054

1c

N ¼ 55 Nearest-aged sibling

SBQ, CBCL, QOLCE

Maganti et al., 200628

1c

N ¼ 15 4-16 yr, focal and generalized epilepsy, 24%  12mnth SF, 35% refractory epilepsy, 53% mental retardation N ¼ 26 8-18 yr, focal and generalized epilepsy, 2 AEDs, IQ >60, 35%  12mnth SF

Children with epilepsy more sleep disorders; especially poor quality of sleep and anxieties about sleep 5-11 yr: association worse daytime behavior and sleep problems, especially poor quality of sleep Children with epilepsy more sleep problems, behavioral problems and maladjustment vs. both control groups 6-10 yr: more sleep problems vs. 10.1-14 yr Sleep problems associated with current seizures, age and behavioral problems 63% EDS, 63% restless sleep, 67% snoring and 13% sleep-disordered breathing 73% pathological score on CPRS, 50% on ECBI, 33% on RCMAS, 10% on CDI Sleep disruption (PSG) rather than seizure severity seems to play a role in the development of behavioral problems in children with epilepsy Children with epilepsy higher CPT-scores, and scores on CBCL scales total behavior and internalizing behavior problems Trend toward association: higher CBCL score and less REM %, and higher CPT score and more stage 1% Children with epilepsy more sleep problems than non-epileptic siblings. Those with more sleep disturbances have more behavioral problems and poorer QoL

PSQ, PDSS

Batista et al., 200725

1a

N ¼ 121 (40 þ 81) 2-6 yr, both focal and generalized epilepsy, 75% monotherapy, 47% predominantly nocturnal seizures 7-14 yr, both focal and generalized epilepsy, 73% monotherapy, 42% predominantly nocturnal seizures

N ¼ 26 Siblings or children of employees study clinic N ¼ 121

Byars et al., 200826

1a

N ¼ 332 6-14 yr, first seizure  3mnth, 50% no AED, 50% 1 AED

SBQ, CBCL (only the 7 items on sleep are used), battery of neuropsychological questionnaires

Ong et al., 201029

1b

N ¼ 92 4-18 yr, 52% severe epilepsy, 19.6% predominantly nocturnal seizures, 57% mental retardation

N ¼ 225 Healthy siblings (for CBCL) N ¼ 321 healthy controls of Cortesi et al., 1999 (for SBQ) N ¼ 92 Nearest-aged sibling

Becker et al., 200427

#

Maganti et al., 200531

#

SHIC (2-6 yr), SBQ (7-14 yr)

SDSC

PSQ: children with epilepsy > EDS (76% vs. 15%), sleep-disordered breathing (65% vs. 4%), and parasomnias (53% vs. 4%) PDSS: children with epilepsy > EDS (46% vs. 19%) Sleep-disordered breathing and parasomnias are both independent predictors of EDS in patients, while various epilepsy variables are not 2-6 yr: children with epilepsy more often needed to be put to bed by parents, did afternoon naps, awoke during the night, had sleep latency of >30 min, expressed fear of the dark, awoke in distress, kept a nightlight on, called for a parent during the night and came to their parent’s bed during the night vs. healthy controls 7-14 yr: children with epilepsy higher mean total SBQ-score vs. healthy controls In children with epilepsy nocturnal seizures, refractory epilepsy, polypharmacy, generalized seizures, epileptic syndromes with an unfavorable outcome, and developmental delay are associated with poor sleep habits 45% of children with epilepsy pathological total SBQ-score Children with epilepsy scored higher on total SBQ and subscales of bedtime difficulties, daytime drowsiness and parasomnia vs. healthy controls Children with epilepsy scored higher on all CBCL questions about sleep, except for wetting the bed vs. siblings More sleep problems associated with more neuropsychological problems Children with epilepsy higher total SDSC, DIMS, SBD, SWTD, and DES score vs. siblings Children with epilepsy more often sleep latency > 30 min (32.6% vs 7.6%), > co-sleeping (73.7% vs. 31.5%), pathological scores for total SDCS (29.3% vs 4.3%), DIMS (31.5% vs. 4.3%) and SWTD (13% vs. 2.2%) Association between seizure severity and total SDSC-score

# also PSG performed; AEDs: anti-epileptic drugs; CBCL: child behavior checklist; CDI: children’s depression inventory (7-17 yr, self-reported); CPRS-R:L: Connors’ parent rating scale - revised, long form (3 - 17 yr, attention problems/hyperactivity-impulsiveness); CPT: Connor’s continuous performance test (daytime attentional function); DES: disorders of excessive somnolence; DIMS: disorders of initiating and maintaining sleep; E: level of evidence; ECBI: Eyberg child behavior inventory (2 - 16 yr, externalizing/opposition problems); FePSY: computerized psychological battery; the visual reaction time subtest is used; PDSS: pediatric daytime sleepiness scale (self-reported); PPVT-III: Peabody picture vocabulary test- third edition (receptive vocabulary attainment); PSQ: pediatric sleep questionnaire; QOLCE: quality of life in childhood epilepsy; RCMAS: revised child manifest anxiety scale (6 - 19 yr, self-reported); RLS: restless legs syndrome; SBD: sleep breathing disorders; SBQ: sleep behavior questionnaire; SDSC: sleep disturbance scale for children; SF: seizure free; SHIC: sleep habits inventory for preschool children; SWTD: sleep - wake transition disorders; TEA-Ch: test of everyday attention for children (6e - 16 yr).

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Authors

E.G.A. van Golde et al. / Sleep Medicine Reviews 15 (2011) 357e368

number of AEDs and sleep problems were independent factors.23,28 In line with the adult epilepsy population, the presence of symptoms of sleep-disordered breathing and parasomnias are independent predictors of EDS, whereas epilepsy variables are not.28 These results suggest that EDS in the children with epilepsy may at least partly be caused by an underlying sleep disorder.

Associations between sleep disturbances and daytime behavior problems Most studies on sleep disturbances in pediatric epilepsy also include questionnaires to assess daytime behavior. The studies comparing children with epilepsy with healthy controls report more behavioral problems in those with epilepsy.4,24,28 Inattention/ hyperactivity disturbances were seen in 73% of young people with epilepsy with sleep complaints,27 and 50% of these children experienced externalizing and opposition problems, 33% anxiety and 10% met the clinical criteria for depression. Worse daytime attention and internalizing problems (i.e., problems with respect to withdrawal, somatic complaints and anxiety/depression) were reported for a small group of 11 children with primary idiopathic generalized epilepsy when compared to 8 healthy controls.31 Behavioral problems are associated with sleep disturbances in young people with epilepsy. They may be inattentive23,27 and suffer from hyperactivity/impulsivity.4,23,27 Furthermore, pathological internalizing behavior occurs more in children with epilepsy and sleep disturbances.4,24 Byars et al., who, as mentioned above, assessed neuropsychological functioning in children with epilepsy who recently had their first seizure26 found there was an association between sleep difficulties and neuropsychological dysfunctioning: children with seizures and sleep disturbances score worse on measures of cognitive functioning than children with seizures without significant sleep disturbances. These results again emphasize the importance of recognizing sleep problems in children with epilepsy. Frequent seizures do not predispose to worse behavior, suggesting that sleep disruption, rather than seizure severity may play a significant role in behavioral problems in children with epilepsy.27 Disturbed sleep is also associated with a decrease in QoL, especially in the domains of physical, cognitive and social functioning and behavior.4 Thus in all studies that assess the occurrence of behavioral problems, outcome in children with epilepsy was worse than in siblings or healthy controls and this behavior is associated with more sleep disturbances. Inattention is most frequently reported and this may be the result of abnormal sleep. However, the effects of medication, cognitive level and seizures may also play an important role in inattention in these children. PSG studies Only small, often retrospective PSG studies have been conducted in children with epilepsy.7,27,31e33 The most consistent finding is disrupted sleep architecture, associated with poorer seizure control. A recent review addresses sleep in general in children with epilepsy,7 so this aspect will not be discussed here. The outcome in well-defined sleep disorders assessed through PSG studies will be reviewed later in this article; see section “Sleep disorders in epilepsy”. Specific syndromes and sleep disturbances Children with various neurodevelopmental disabilities with nearly 100% prevalence of epilepsy are frequently reported to have sleep problems. The most prevalent syndromes are discussed.

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Rett syndrome In a large cohort (n ¼ 202) of girls aged 0e18 years old, 80% had some sleep problem.35 The most commonly reported problems were nighttime laughing (58.9%) and teeth grinding (55%). Frequent daytime napping was present in over 77% of children. Others found increased total sleep time with less nighttime sleep and increased daytime sleep compared to healthy controls.36 Both studies found that these abnormalities increased with age. Since disorders of breathing during the day is one characteristic of Rett syndrome, some studies focused on breathing disturbances during sleep. Results are conflicting with breathing-related problems during sleep confirmed in some,37,38 but not in all studies.39 Our own experience is that (nocturnal) apneas in children with Rett syndrome are often seen by the parents as epileptic phenomena; this is usually not the case. Interestingly, children with Rett syndrome and seizures have significantly more daytime sleep and a higher percentage of total sleep time during the day than those without seizures.36 Angelman syndrome Epilepsy is present in 80e90% of people with Angelman syndrome (AS) and severe sleep disturbance is also common. In two large series of people with AS, problems with sleep initiation (48%) and decreased need for sleep (42e49%) were the most frequently reported sleep problems.40,41 As in children with Rett syndrome, Conant et al. showed that sleep disturbances in people with AS were significantly related to the presence of seizures.41 More hours spent napping during the day was related to both absences and generalized tonic-clonic seizures, and decreased nightly hours of sleep showed a strong association with both focal and absence seizures. The presence of multiple seizure types in one patient was strongly associated with sleep disturbances, as was taking >2 AEDs. Tuberous sclerosis A study of 300 children with tuberous sclerosis (TS) revealed that 58% suffered from sleep disturbance.42 Another study by the same author found significantly more sleep disturbances in a group of 40 children with TS compared to healthy controls and to a group with mixed learning disabilities.43 Within the TS group, current epilepsy and a high level of daytime behavioral disturbance were significantly associated with sleep disturbances. A PSG study in ten children with TS and partial epilepsy showed sleep architecture abnormalities in nine of ten patients with sleep efficiency ranging from 60 to 88%.44 These patients had shorter total sleep time, reduced sleep efficiency, higher number of awakenings and stage shifts, increased wake after sleep onset and decreased REM sleep compared with healthy controls. Children with seizures showed a more disrupted sleep architecture with a reduced sleep efficiency (69% vs. 88%), an increased time awake after sleep onset (24% vs. 5%) and a higher number of awakenings (16% vs. 3%) compared with children with no seizures in the past 3 months. Sleep disorders in epilepsy Obstructive sleep apnea The most thoroughly studied sleep disorder in people with epilepsy is obstructive sleep apnea syndrome (OSAS) (see Table 4). In the general US population, two percent of women and four percent of men are estimated to meet the minimal diagnostic criteria for OSAS (an apneaehypopnea index (AHI)  5 and daytime somnolence).45 In the Netherlands this prevalence is lower and estimated at 1%.46 Although an AHI  5 is used as criterion for OSAS, in the

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Table 4 Sleep disorders in people with epilepsy, measured with PSG-studies. E

Subjects

Study design/definitions

OSAS

PLMS

RBD

Adults Malow et al., 199748

3

17% PLMI >30: 8%

e

2b

41% AHI >50: 7.4%

15%

e

Malow et al., 200047

2a

33% Moderate-severe: 13%

e

e

Malow et al., 200349

2b

Retrospective OSAS: AHI >10 Mild: 11e20, moderate: 21e50, severe: >50 PLMS: PLMI  20 Prospective OSAS: AHI>5 PLMS: PLMI >10 Prospective OSAS: AHI  5 Mild: 5e20, moderate-severe: >20 Prospective OSAS: AHI >10

70% Severe: 16%

Malow et al., 199714

46%

e

e

Manni et al., 200351

2a

N ¼ 63 26-71 yr, referred to sleep laboratory for evaluation of EDS, suspected OSAS and nocturnal spells N ¼ 27 Twenty participating in a neurophysiological study þ seven referred to assess suspected sleep disorder N ¼ 39 18-65 yr, refractory epilepsy, complex partial seizures, no history of OSAS N ¼ 13 20-56 yr, refractory epilepsy, suspected scores on SA-SDQ N ¼ 283 18-70 yr (mean 33 yr), all consecutive patients of an epilepsy centre

73% (overall 10%) Moderate: 24% Severe: 10%

e

e

Weatherwax et al., 200322

1a

N ¼ 125 Some patients with suspected sleep disorder

e

e

Chihorek et al., 200752

2b

N ¼ 22 All aged  50 years

69% Mild: 61% Moderate: 25% Severe: 14% 52% Group 1: 82% Group 2: 20%

e

e

Manni et al., 200757

1a

e

e

12.5%

Malow et al., 200850

2b

N ¼ 80 All aged 60 years without brain malignancies or progressive degenerative diseases of CNS N ¼ 45 Refractory epilepsy, suspected scores on SA-SDQ

Prospective. OSAS: AHI  5

80%

e

e

Children Malow et al., 200349

2b

N¼5 14-17 yr, refractory epilepsy, suspected scores on SRBD-PSQ

60%

e

e

Becker et al., 200427

2a

N ¼ 30 7-14 yr, focal and generalized epilepsy, sleep complaints

80% (AHI range 1.5e35.8; 60% AHI >3)

0%

e

Maganti et al., 200531

2b

N ¼ 11 9-17 yr, primary idiopathic generalized epilepsy, seizure free

Prospective OSAS: AI  1 or more than 1.5 events/hour in which oxygen saturations falls by 4% or more or hypoventilation occurs. Prospective Pathological respiratory disturbance during sleep: AHI  1.5 PLMS: PLMI þ arousal >5 Prospective, comparative with 8 healthy controls No definitions given for OSAS or PLMS

3

N ¼ 40 6-14 yr, focal and generalized epilepsy, 42% SF, sleep complaints

Retrospective; comparative with 11 patients with OSAS OSAS: AHI >1 PLMS: PLMI þ arousal >5

No data on prevalence No significant difference vs. controls 10%

e

Kaleyias et al., 200833

No data on prevalence No significant difference vs. controls 20%

Prospective. Only those with a history suspected of OSAS underwent PSG (N ¼ 40) OSAS: AHI >5 Mild:6e15, moderate: 16e30, severe: >30 Prospective OSAS: AHI  5 Mild: 5e20, moderate: 21e50, severe: >50 Prospective. Subdivided in two groups; group 1 (N ¼ 11) had seizure onset or worsening of seizures (20% increase seizure frequency) at or after age 50, group 2 (N ¼ 10) had seizure onset before age 50 with stable or improved seizure frequency at or after age 50. OSAS: AHI  5 Prospective RBD: ICSD-2005 criteria

e

AHI: apnea Þ hypopnea index (nr/hour); CNS: central nervous system; E: level of evidence; ICSD-2005: international criteria for sleep disorders; OSAS: obstructive sleep apnea syndrome; PLMI: periodic leg movements index (nr/ hour); PLMS: periodic leg movements during sleep; RBD: REM sleep behavior disorder; SF: seizure free; SRBD-PSQ: sleep-related breathing disorder subscale of the pediatric sleep questionnaire.

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Authors

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Netherlands only an AHI >15 is appreciated as clinically relevant. Therefore, whenever possible, the distribution of percentages among different AHI-levels is given in the corresponding table. Thirty-nine candidates for epilepsy surgery without a history of OSAS underwent PSG.47 One-third of subjects had an abnormal AHI and five (13%) had a severe disorder requiring treatment. When studying people with epilepsy with clinical suspicion of OSAS even higher percentages of co-morbidity are reported. In a retrospective study of 63 people with epilepsy who were referred to a sleep laboratory for evaluation of EDS, suspected OSAS and nocturnal spells, 70% had OSAS defined as AHI >10 and 16% had an AHI of >5049. In a subset from a questionnaire-based study, 27 people with epilepsy e twenty participating in a neurophysiological study and seven with a suspected sleep disorder e underwent PSG.14 OSAS (AHI >5) was diagnosed in 41%. In prospective screening of people with refractory epilepsy (2 seizures/month) and clinical suspicion of OSAS, PSG confirmed OSAS in 46e80%50,51. In a larger (n ¼ 283) study of unselected people with epilepsy a structured interview suggested OSAS in forty people51 who then underwent an overnight sleep recording. In 29 (73% of those clinically suspected: 10.2% of the total group) OSAS (AHI  5) was diagnosed. People with epilepsy with OSAS are older,47,51 more frequently male47,50,51 and have higher scores on the SA-SDQ22,47,50 than people without OSAS. Manni et al. also found that people with epilepsy with OSAS had a higher body mass index (BMI), were more frequently sleepy (ESS >10) and had a later onset of seizures than people with epilepsy without OSAS.51 These associations were not significant in other studies.49,50 Nocturnal seizures may also be a risk factor for OSAS in people with epilepsy,47 although this is not a consistent finding.50,51 In most studies no association is seen between seizure frequency and a higher risk of OSAS in people with epilepsy.47,50,51 However, in a recent study, older people with epilepsy (50 years old) with OSAS had worse seizure control and/or later onset of seizures than people with epilepsy of the same age not affected by OSAS.52 PSG studies in children with epilepsy are scarce and contain only small numbers of patients. There are also only few reports on normal PSG values in the pediatric age group. An AHI  1 is suggested as the cut-off point for pediatric OSAS,53 but this is probably indicative of only mild disorder. In our centre an AHI >3 is viewed as abnormal. PSG studies of children with epilepsy with sleep complaints suggestive of OSAS often confirm this diagnosis (AHI  1/1.5).28,34,50 Becker et al. found an AHI  1.5 was prospectively disclosed in even 24/30 patients with sleep complaints and a not very severe epilepsy.27 The reason for the high prevalence of this co-morbidity is not known, but some explanations have been postulated. Barbiturates and benzodiazepines may worsen OSAS by increasing upper airway collapsibility or depressing arousal mechanisms.9 AEDs that are associated with weight gain (for example valproic acid and carbamazepine) may also worsen OSAS.6 Furthermore, treatments other than AEDs can have detrimental effects on OSAS in people with epilepsy; vagus nerve stimulation (VNS) also affects respiration during sleep and can exacerbate OSAS in both adults54 and children55 with epilepsy. Special care is needed in people with preexisting OSAS.54 Some studies suggest as an explanation for the high prevalence of co-occurrence, the exacerbation of seizures as a result of sleep fragmentation and partial sleep deprivation in people with OSAS.47,51 Restless legs syndrome and periodic leg movements during sleep Some studies of people with epilepsy also focus on symptoms of RLS and e in PSG studies e on the occurrence of periodic leg movements during sleep (PLMS). In the study of Malow et al. 35% of

365

people with epilepsy had symptoms of RLS.14 This was not significantly different from the control group of other neurology patients (29%). In this study, 27/158 underwent PSG and 15% had a periodic leg movement index (PLMI) with arousals of >10; three quarters of these reported often or always having symptoms of RLS. In the retrospective study of Malow et al., 63 adults with epilepsy underwent PSG for sleep complaints.48 A PLMI of 20 was found in 17%, of whom 45% had a PLMI of >30. However, many of the PLMS were not associated with arousals or awakenings and none of the patients needed treatment. Furthermore, no information is given on the presence or absence of RLS-symptoms in these patients. In the more recent study of Kathami et al. symptoms of RLS were not significantly more prevalent in people with epilepsy than in controls (18% vs. 12%).12 Both Malow et al.14 and Kathami et al.12 used a single question addressing RLS that did not cover all criteria for this diagnosis. Therefore, a good estimate on the prevalence of RLS in the people with epilepsy cannot be made based on these results. In children with epilepsy the occurrence of RLS-symptoms has not been assessed. No elevated PLMI was demonstrated in 30 young children with epilepsy with sleep complaints.27 Another small prospective trial in eleven children with primary generalized epilepsy and eight age- and gender-matched controls showed no significant difference in mean PLMI.31 In a more recent and somewhat larger prospective trial, 4/40 children with epilepsy had a PLMI >5.33 REM sleep behavior disorder There is some evidence that REM sleep behavior disorder (RBD) might be linked to epilepsy in elderly people with epilepsy. It is known that RBD may mimic focal seizures (especially frontal and temporal lobe seizures), potentially leading to misdiagnosis. The report of the co-occurrence of epilepsy and RBD in two elderly patients (60 and 75 years old) with late onset, sleep-related, tonicclonic seizures in which RBD preceded the onset of seizures by several years (5 and 10 years) raises the question of whether there is an association between the disorders.56 A prospective trial with video-EEG demonstrated co-morbid RBD in 10/80 (12.5%) of elderly (60 years old), unselected people with epilepsy.57 Males with cryptogenic, sleep-related seizures are especially at risk. In 6/10 the RBD episodes pre-dated seizure onset by a mean of 4.5 years (range 2e7 years). Both disorders could co-occur by chance in the elderly, as both conditions are more frequent in older age. A common pathophysiology may, however, be hypothesized; both epileptic seizures and RBD might be due to neurodegenerative processes in the brain or vascular cerebral lesions, although this was not proven in the study mentioned above. Furthermore, it can be speculated that RBD might facilitate sleep-related seizures through the disruption and partial deprivation of REM sleep. NREM sleep parasomnias Although the personal and family histories of people with NFLE often suggest the presence of NREM parasomnias, this could be easily due to misinterpetation of the nocturnal events. As far as we know there are no systematic PSG studies reporting on the cooccurrence of both disorders. There is plenty published on the difficulty in differentiating between NREM parasomnias and nocturnal seizures.1 The comorbidity between seizures and NREM parasomnia should be mentioned.58 Data is available on a final common pathway for both disorders. However, more studies are needed to further establish these co-morbidities. In particular, NFLE is difficult to distinguish from NREM arousal parasomnias not only because the clinical

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pictures are often similar, but also because of the lack of evidence of abnormalities on surface EEG in NFLE. As an aid in diagnosing NFLE, the frontal lobe epilepsy and parasomnias (FLEP) scale has been developed.59 This scale consists of questions which address those features that are thought to be useful in discriminating between both conditions, with the strongest predictors given greater weight. Clustering of multiple events occurring in a single night, association between the events and a definite aura, and coherent speech with recall during the events are the features most favoring a diagnosis of NFLE in the FLEP scale. Those features favoring parasomnia in this scale are long duration of the events (>10 min), wandering outside the bedroom and coherent speech with incomplete or no recall. The seminal work of FLEP validation gave the scale its high values of sensitivity and specificity. However the scale proved to be less sensitive and specific in distinguishing NFLE seizures from arousal parasomnias and REM sleep behavior disorder when used in a tertiary level unit of epilepsy and sleep disorders.60

epilepsy produced a marked reduction in interictal epileptiform discharges (IEDs), supporting the hypothesis that sleep-disordered breathing plays a role in increasing epileptogenicity.64 The overall finding that treatment of OSAS can improve seizure control is suggestive of detrimental effects of OSAS on seizure control. This is most likely to occur by increasing arousals during NREM sleep, nocturnal sleep fragmentation and sleep deprivation.

Insomnia

Melatonin

Although questionnaire-based studies suggest a high prevalence of insomnia in people with epilepsy (up to 52%),12,16 no literature was found on PSG studies assessing this co-morbidity.

A change in the endogenous biorhythm can lead to considerable sleep disturbances and thus more seizures. Administering melatonin may improve sleep. Some authors describe low baseline and peak levels of melatonin in people with epilepsy, so it has been hypothesized that administering oral melatonin might also have a positive effect on epilepsy; results are conflicting.10 In a recent trial in Egypt 3e11.5 mg melatonin was administered 30 min before bedtime to twenty-three children (2e15 years) with refractory epilepsy over a period of three months.65 At the end of the trial, the children went more willingly to bed, and had improvement in sleep duration, sleep latency, nocturnal arousals, sleep walking, EDS, nocturnal enuresis, teeth grinding and sleep apnea (using children’s sleep habits questionnaire). There was also significant reduction in seizure severity, but not in frequency of seizures; in fact seizure frequency increased in 13% children. In a double-blind, cross-over, placebo-controlled trial eighteen children and young adults (3e26 years) with epilepsy, mental retardation and a circadian rhythm sleep disorder were treated with 3e9 mg melatonin.61 The AEDs were kept on the same doses during the trial. Effects were measured with sleep- and seizure diaries. The melatonin-group had a significant reduction in time to falling asleep; the duration of nocturnal sleep and early arousal were also favorably affected, although seizure frequency did not change. In the only parallel running, double-blind trial on this subject, children with epilepsy (3e12 years) who had been seizure free for at least six months and were on monotherapy with sodium valproate, were treated with add-on melatonin (6e9 mg; N ¼ 16) or add-on placebo (N ¼ 15) therapy.66 Sleep disturbances were measured with the SBQ. There was a significant improvement of total sleep score and parasomnia score in the group taking melatonin. All patients remained seizure free and no adverse effects were reported. Thus we conclude that melatonin may improve sleep disturbances in people with epilepsy, especially in those with mental retardation.

Circadian rhythm sleep disorders Circadian rhythm and epilepsy are known to interact10 and circadian rhythm sleep disorders are seen in people with neurodevelopmental disorders who often also have epilepsy.61 However, no studies have been performed to measure the prevalence of circadian rhythm sleep disorders in people with epilepsy. Effect of treatment of sleep disturbances on epilepsy Treatment of OSAS The effect of treating OSAS on epilepsy has been studied most often. In small, mostly retrospective case-series, treatment of OSAS not only improved sleep and daytime sleepiness, but also had a positive effect on seizure control. Vaughn et al. reported that OSAS treatment in 40% (4/10; two treated with continuous positive airway pressure (CPAP), two with positional therapy) of patients led to a seizure frequency reduction of 95%, without changes in AED dose.62 In another retrospective study of 28 patients with both epilepsy and OSAS treated with CPAP,15 patients persisted in wearing the device, five (33%) had fewer seizures and 12 (80%) were more alert during daytime.48 This evidence from case-series is corroborated by a small prospective trial in both adults and children with refractory epilepsy (4 seizures/month) and sleep complaints.49 Of six adults treated with CPAP, three tolerated the device and had no change in AED dose. All 3 had at least 45% reduction in seizure frequency. Even patients with mild OSAS (AHI <20) showed improvement. Of three children, only one used the CPAP successfully, and had no change in AED dose; this child had a 60% reduction of seizures. Another study of nine children with epilepsy, a neurodevelopmental disorder and OSAS demonstrated a seizure frequency reduction in five of the children after treatment for OSAS (2 tonsillectomy, 1 adenoidectomy, 1 oxygen, and 1 tracheostomy).63 Malow et al. conducted a randomized pilot trial comparing CPAP with sham treatment in adults with refractory epilepsy (2 seizures/month) and OSAS.50 This study revealed a  50% reduction in seizures in 28% of people receiving CPAP treatment versus 15% of those receiving sham CPAP. However, due to the small sample size (CPAP N ¼ 19; sham N ¼ 13) this difference was not significant. Additionally, treatment of OSAS with CPAP in people with partial

Treatment of RBD The two persons with epilepsy with RBD-nocturnal seizures comorbidity reported by Manni et al. had not experienced any seizures at 12-months follow-up after successful treatment of RBD with clonazepam; however they were also taking phenobarbital, so no definite conclusion can be drawn about a potential benefit of RBD remission on epileptic seizure control. No more data are available on these patients.56

Treatment of other sleep disorders As far as we know, there are no studies of the effect of treatment of the other mentioned sleep disorders (RLS, PMLS and insomnia) in people with epilepsy. Conclusions It is known that there is a complex interaction between epilepsy and sleep, frequently resulting in altered sleep architecture. This review suggests that adults with epilepsy also experience sleep

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disturbances significantly more often than healthy controls. The most frequently reported complaints in this epilepsy population are EDS and insomnia. Children with epilepsy also experience more sleep problems than their healthy siblings and healthy controls. In addition to EDS, bedtime difficulties and symptoms of parasomnias are common. In both the adults and children with epilepsy, the co-occurrence of sleep disturbances further impairs QoL. In children with epilepsy, sleep disturbances seem to affect daytime behavior and cognition negatively, independent of seizure frequency. Previous work has tried to find independent predictors for the occurrence of sleep problems in people with epilepsy. Results, however, are conflicting. In adults, treatment with a first generation AED, predominance of nocturnal seizures, poor seizure control and co-morbid anxiety or depression might be associated with sleep disturbances and EDS. In children these are associated with younger age, lower IQ, poor seizure control, symptomatic epilepsy and higher number of AEDs taken. In both adults and children with epilepsy, symptoms suggestive of an underlying sleep disorder (OSAS, RLS, parasomnias) were found to be stronger predictors of EDS than epilepsy variables. Multiple PSG studies confirmed the high prevalence of comorbid OSAS in people with epilepsy, ranging from 10 to 100%, depending on population variables and criteria used. People with epilepsy with OSAS are more often male, older and more obese than those without OSAS. Treating OSAS is reported to improve significantly seizure control in about 30% of patients, suggesting that OSAS has negative effects on seizure control. The underlying mechanism of seizure activation might be through increasing arousals during NREM sleep, nocturnal sleep fragmentation and sleep deprivation; there is, however, no strong evidence for this hypothesis. There is some evidence that people with epilepsy are also suspected of other sleep disorders such as RLS, PLMS and e in the elderly e RBD. In particular, the co-morbidity between seizures and NREM parasomnia should be mentioned. However, more studies are needed to further establish these co-morbidities. The prevalence of insomnia has not been studied with PSG in people with epilepsy, although a high prevalence is suspected from questionnaire-based studies. Despite the evidence that circadian rhythm and epilepsy interact, there is also no study on the prevalence of circadian rhythm sleep disorders in people with epilepsy. Finally, the good results of treating OSAS in people with epilepsy warrant exploration of the effects on seizure control of treating other sleep disorders in people with epilepsy.

Practice points 1. Sleep disturbances are about 2e3 times more prevalent in both children and adults with epilepsy than in healthy controls. 2. Especially excessive daytime sleepiness and sleep maintenance insomnia are reported which can only be partially explained by the use of AEDs and seizure occurrence. 3. Sleep problems in people with neurodevelopmental disorders seem to be due at least partly to epilepsy and not only to the underlying encephalopathy. 4. Sleep disorders which coexist in people with epilepsy have detrimental effects on seizure control and QoL. 5. OSAS is the most frequently found co-morbid sleep disorder in both children and adults with epilepsy, but data for other disorders are scarce. 6. Treatment of a co-existing primary sleep disorder may improve seizure control, QoL and daytime behavior in people with epilepsy.

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Research agenda Further research in this area should focus on the following: 1. The occurrence of treatable sleep disorders in larger groups of people with epilepsy measured with videoPSG studies. Insomnia and circadian rhythm sleep disorders warrant particular examination. 2. The effect of treating co-existing sleep disorders on seizure control and QoL.

Conflict of interest statement None to declare.

Acknowledgements This work was financially supported by the ‘Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie’.

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