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Effect of valproate on the sleep microstructure of juvenile myoclonic epilepsy patients – a cross-sectional CAP based study
Sleep Medicine 17 (2016) 129–133
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Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Original Article
Effect of valproate on the sleep microstructure of juvenile myoclonic epilepsy patients – a cross-sectional CAP based study Chetan S. Nayak a,b, Sanjib Sinha a,*, Madhu Nagappa a, Thennarasu Kandavel c, Arun B. Taly a a
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Department of Clinical Neurosciences, NIMHANS, Bangalore, India c Department of Biostatistics, NIMHANS, Bangalore, India b
A R T I C L E
I N F O
Article history: Received 29 August 2015 Received in revised form 14 October 2015 Accepted 5 November 2015 Available online Keywords: Arousals CAP Juvenile myoclonic epilepsy Sleep microstructure
A B S T R A C T
Objective: Studies looking at the effect of anti-epileptic medications on sleep microstructure of patients with epilepsy are almost non-existent. The aim of this study was to compare sleep microstructural characteristics of drug-naïve juvenile myoclonic epilepsy (JME) patients with those on valproate (VPA) monotherapy. Methods: Three age- (p = 0.287) and gender- (p = 0.766) matched groups (N = 20 in each group): (1) drugnaïve JME (mean age: 21.2 ± 4.06 years; M : F = 9:11); (2) JME on VPA (mean age: 21.85 ± 4.28 years; M : F = 11:9); (3) healthy controls (mean age: 23.2 ± 3.82 years; M : F = 9:11) underwent overnight polysomnography. Scoring and analysis of arousals American Sleep Disorders Association (ASDA, 2002), cyclic alternating pattern (CAP) (Terzano et al., 2002) parameters were performed. Comparison of arousal and CAP parameters was performed using one-way ANOVA, followed by pairwise comparisons using Fisher’s LSD test (p ≤ 0.05). Results: Rapid eye movement (REM) arousal indices were higher in JME patients (Group 1 [p = 0.002] and Group 2 [p < 0.001]), whereas the overall and NREM arousal indices were comparable between the three groups. CAP rate was higher in JME patients as compared to controls (p < 0.001). Duration of phase A and its subtypes (p < 0.001) was reduced in drug-naïve patients as compared to VPA group and controls. Finally, percentage of phase A1 (p = 0.003) was decreased and A3 (p = 0.045) was increased in drugnaïve patients as compared to VPA group and controls. Conclusions: We found significant alterations in REM arousal indices and several CAP parameters in JME patients. However, many of these alterations were not seen in the valproate group. This might indicate that anti-epileptic medications such as valproate may beneficially modulate arousal instability in JME patients, and hence promote sleep quality and continuity. © 2015 Elsevier B.V. All rights reserved.
1. Introduction The sleep quality in patients with epilepsy is frequently compromised by various factors interfering with the continuity of the sleep state. These factors lead to disruption of normal sleep architecture causing frequent arousals, awakenings, and stage shifts, and eventually manifesting as sleep disorders [1]. Most antiepileptic medications (AEDs), especially the conventional ones, might exacerbate sleep disorganization and further impair sleep quality in these patients on AEDs [2,3]. However, sodium valproic acid (VPA), a frequently used AED for most of the generalized epilepsy syndromes, is shown to have little or even no effect on sleep amount and mac-
* Corresponding author. NIMHANS, Hosur Road, Bengaluru 560029, India. Tel.: +91 080 26995123; mobile: +91 9972872570; fax: +918026564830. E-mail address: [email protected] (S. Sinha). http://dx.doi.org/10.1016/j.sleep.2015.11.006 1389-9457/© 2015 Elsevier B.V. All rights reserved.
rostructure under therapeutic doses [4] and has sometimes been reported to improve sleep efficiency [5]. Although traditional visual sleep scoring provides a valuable description of the overall sleep macrostructure [6,7], it fails to provide information regarding electroencephalogram (EEG) frequency characteristics or rhythmicity that underlies sleep disturbances and needs to be addressed using sleep microstructural analysis [8]. Analysis of sleep microstructure using cyclic alternating pattern (CAP) can provide additional insights regarding the subtle beneficial or deleterious effects of VPA on sleep architecture in patients with epilepsy. In this study, we hypothesized that there is probably an alteration in the pathophysiologic mechanisms regulating arousal patterns in patients with JME. Our aim was to compare the microstructural polysomnographic (PSG) characteristics in drug-naïve juvenile myoclonic epilepsy (JME) patients and those on valproate monotherapy, using Arousal and CAP analysis, which may highlight the role of VPA in causing alteration of arousal patterns in patients with epilepsy.
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2. Materials and methods 2.1. Patients This is a cross-sectional, hospital-based, case-control study that was conducted at a tertiary neurology centre in south India from March 2010 to February 2013. The International League Against Epilepsy (ILAE) commission on Classification and Terminology (1989) defined JME (impulsive petit mal) as follows: “Impulsive petit mal appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. Often, there are generalized tonic-clonic seizures (GTCS) and, less often infrequent absences. The seizures usually occur shortly after awakening and are often precipitated by sleep deprivation [9].” Forty patients diagnosed with JME, 20 drug naïve (mean age: 21.2 ± 4.06 years; M : F = 9:11) and 20 on VPA monotherapy (mean age: 21.85 ± 4.28 years; M : F = 11:9), attending the neurological services and fulfilling the criteria for JME laid down by the ILAE commission [9] were recruited. Patients were excluded if: (1) they used any medications (other than VPA) known to affect sleep at study-entry; (2) they had history of drug or substance abuse of any degree; (3) they had abnormal brain imaging; (4) they had a primary sleep disorder; or (5) they reported any co-existing medical, psychiatric or surgical disorder known to affect sleep. Patients on VPA monotherapy were excluded if they were non-compliant or stopped medications during the period of the study. Twenty healthy controls (mean age: 23.2 ± 3.82 years; M : F = 9:11) consisting of friends/unrelated volunteers (N = 14) of the patients from similar educational and socioeconomic status and medical personnel (doctors = 3; medical technologists = 3) from the hospital on routine day duties (9.00 a.m.– 4.30 p.m.) were also recruited, which were age (p = 0.287) and gender (p = 0.766) matched with patients. Controls were not related to patients and also did not have a family history of seizures, or any other medical or neurological illness. All subjects were screened for underlying sleep disorders such as sleep-disordered breathing, periodic limb movement disorders, narcolepsy, insomnia, restless legs syndrome, and parasomnias using the NIMHANS Comprehensive Sleep Disorders Questionnaire (NCSDQ) [10]. All subjects were ≥12 years of age in view of their participation in the evaluation and completing the sleep questionnaires. Ethical approval for the study was obtained from the Institute Ethics Committee (IEC). A written informed consent was obtained from the study subjects and/or parents. 2.2. Clinical evaluation All patients underwent a structured evaluation, including a detailed clinical, family and treatment history, neurological examination, 21-channel digital EEG recording using the international 10–20 system of electrode placement, brain imaging (magnetic resonance imaging, MRI), and other investigations when indicated. The mean age at onset of illness was 16.2 ± 4.04 years in Group 1 and 14.05 ± 4.29 years in Group 2. The average duration of illness was 5.0 ± 4.1 years in Group 1 and 6.9 ± 4.73 years in Group 2. All patients had myoclonic jerks, five of them (three in Group 1 and two in Group 2) not developing any other type of seizures till the time of the study. The mean duration (p = 0.186) and frequency (p = 0.684) of myoclonus in Group 1 (5.0 ± 4.1 years; 7.05 ± 1.96/ day) and Group 2 (6.9 ± 4.73 years; 6.75 ± 2.61/day) was comparable. Except for five patients (three [15%] Group 1 and two [10%] Group 2), the rest had GTCS during the course of their illness. It was preceded by a series of myoclonic jerks (heralding myoclonus) in 8/17 (47.1%) in Group 1 and 3/18 (16.66%) in Group 2. The mean duration (p = 0.181) and frequency (p = 0.688) of GTCS in Group 1 (4.01 ± 4.65 years; 2.29 ± 1.89/month) and Group 2 (6.19 ± 5.05 years;
2.06 ± 1.55/month) were comparable. Only one patient had status epilepticus (Group 1: 0/20 [0%]; Group 2: 1/20 [5%]; p = 0.311) at any time during their disease course and three patients (Group 1: 1/20 [5%]; Group 2: 2/20 [10%]; p = 0.548) had features suggestive of absence attacks. Five patients (Group 1: 3/20 [15%]; Group 2: 2/20 [10%; p = 0.633) had a history of typical febrile seizures. 2.3. Sleep questionnaire assessment Validated sleep questionnaires including Epworth Sleepiness Scale (ESS) to assess daytime somnolence [11] and Pittsburgh Sleep Quality Index (PSQI) to assess night-time sleep quality [12] were administered to all the study subjects. NCSDQ was administered to rule out various sleep disorders [13]. 2.4. Polysomnography Overnight PSG recording was done (Sleepscan Vision Collection Software, version 7.11.01, Biologic Systems Corp, IL, USA) after obtaining a written informed consent from all participants using standard protocols. The parameters recorded included (1) an eight-channel EEG using bi-hemispheric referential montage (F7-A2, C3-A2, T3-A2, O1A2 and F8-A1, C4-A1, T4-A1, O2-A1): sensitivity 7 μV/mm, low-pass filter 0.3 Hz, high-pass filter 35 Hz; (2) two-channel electro-oculogram (EOG): for eye movements, sensitivity 10 μV/mm, low-pass filter 0.3 Hz, highpass filter 35 Hz; (3) electromyogram (EMG) from the sub-mentalis and right tibialis anterior muscle: sensitivity 3 μV/mm and 20 μV/mm, respectively, low-pass filter 0.3 Hz, high-pass filter 100 Hz; (4) electrocardiogram (ECG): sensitivity 20 μV/mm, low-pass filter 0.5 Hz, highpass filter 35 Hz; (5) body position monitor; and (6) respiratory events: oro-nasal airflow using thermistor (sensitivity 7 μV/mm, low-pass filter 0.5 Hz, high-pass filter 15 Hz), chest and abdominal wall movements using strain gauge (sensitivity 10 μV/mm, low-pass filter 0.5 Hz, highpass filter 15 Hz), snore (sensitivity 2 μV/mm, low-pass filter 10 Hz, highpass filter 100 Hz), and arterial oxygen saturation (sensitivity 7 μV/ mm, high-pass filter 70 Hz). All channels were sampled at 256 Hz; electrode impedance was kept less than 5000 Ω and a notch filter of 50 Hz was applied to remove noise artifact caused by electrical power lines. The subjects were allowed to fall asleep spontaneously and the recording was continued until their spontaneous awakening in the morning. All subjects reported a comfortable, undisturbed, and refreshing sleep. None of the subjects had generalized seizures within the last 2 weeks of the PSG recording. 2.4.1. Analysis of sleep macrostructure Sleep was scored visually in 30-s epochs using standard criteria [14]. The conventional PSG parameters studied included: total time in bed (TIB, min), total sleep time (TST, min), sleep latency (min), rapid eye movement (REM) latency (min), sleep efficiency (%), wake after sleep onset (WASO) (min), as well as percentage of NonREM (N1, N2, N3) and REM stages. Visual analysis of the chin EMG tone during REM was performed in both patients and controls. Periodic limb movement (PLM) as well as apnea–hypopnea indices (AHI) were also assessed. 2.4.2. Analysis of sleep microstructure Sleep microstructure evaluation included detection of the arousals and CAP analysis. 2.4.2.1. Detection and analysis of arousals. The number of arousals occurring during the entire period of sleep, as well as that during each of the various sleep stages, was computed according to the standard ASDA criteria [15]. The following arousal parameters were measured: arousal index (number of arousals per hour of sleep), NREM arousal index (number of arousals per hour of NREM sleep), and REM arousal index (number of arousals per hour of REM sleep).
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2.4.2.2. Cyclic alternating pattern analysis. CAP analysis was performed manually as per the criteria provided by Terzano et al. [16]. The following CAP variables were measured: total CAP time (total CAP time in NREM sleep) and total non-CAP time (total non-CAP time in NREM sleep); CAP time in N1, N2 and N3; CAP rate (the percentage ratio of CAP time to NREM sleep time) of total NREM sleep, N1, N2 and N3; number and duration of CAP cycles; number and duration of CAP sequences; total and average duration of phase A and phase B; number, indices and percentages of each phase A subtypes (A1, A2, A3); and total and average duration of each phase A subtype (A1, A2, A3). 2.5. Statistical analysis The data obtained were analysed using Statistical Product and Service Solutions (SPSS), version 22. Macrostructural and microstructural sleep characteristics were compared between the drugnaïve patients, patients on VPA and controls using one-way analysis of variance (one-way ANOVA) followed by pairwise comparisons between the three groups using Fisher’s LSD post hoc test. The significance level was placed at ≤0.05. 3. Results The study subjects were divided into three groups, each having 20 subjects: Group (1) – drug-naïve JME (mean age: 21.2 ± 4.06 years; M : F = 9:11); Group (2) – JME on valproate monotherapy (mean age: 21.85 ± 4.28 years; M : F = 11:9); Group (3) – controls (mean age: 23.2 ± 3.82 years; M : F = 9:11). The subjects in all three groups were age (p = 0.28) and gender (p = 0.76) matched. The mean body mass index (BMI) was also comparable in the three groups (p = 0.49). 3.1. Sleep questionnaires The mean ESS scores in Groups 1, 2, and 3 were 5.65 ± 4.03, 6.85 ± 3.3, and 3.80 ± 2.37, respectively, and they differed statistically (p = 0.018). Similarly, the mean PSQI scores in Groups 1, 2, and 3 were 4.85 ± 2.72, 4.9 ± 2.31, and 2.35 ± 1.18, respectively, and they also differed statistically (p < 0.001). Based on the NCSDQ, none of the patients and controls had symptoms suggestive of sleepdisordered breathing, periodic limb movement disorders, narcolepsy, insomnia, restless legs syndrome, or parasomnias.
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3.2. Polysomnography 3.2.1. Sleep macrostructural analysis The REM sleep duration percentage was significantly higher in Group 2 as compared to Group 1 (p < 0.001) and Group 3 (p < 0.001). Sleep latency (p = 0.137) was comparable between the three groups. Visually, loss of chin EMG atonia during REM was not observed in the PSG of either patients or controls. AHI (p = 0.125) and PLM indices (p = 0. 270) were comparable between the three groups. None of the patients had clinical or electrographic seizures during the study. The conventional sleep parameters are summarized in Table 1. 3.2.2. Sleep microstructural analysis 3.2.2.1. Analysis of arousals during sleep. The total number of arousals during the night was 1147, 1280, and 875 in Group 1, Group 2, and in Group 3, respectively. The arousal indices during REM sleep were significantly higher in patients with JME (Group 1 [p = 0.002] and Group 2 [p < 0.001]) as compared to healthy controls (Group 3). The arousal parameters are summarized in Table 1. 3.2.2.2. Cyclic alternating pattern analysis. The overall CAP rate was significantly higher in patients with JME (Group 1 and Group 2) as compared to healthy controls (p < 0.001) and conversely, the nonCAP (NCAP) Rate was significantly lower in patients with JME (Group 1 and Group 2) as compared to healthy controls (p < 0.001). Moreover, the CAP rate was significantly increased in patients with JME during N1 (Group 1 [p = 0.006] and Group 2 [p = 0.020]) and N2 (Group 1 [p = 0.010] and Group 2 [p = 0.036]) sleep periods as compared to healthy controls. However, the CAP rate was comparable during N3 (p = 0.072) sleep period. The average duration of CAP cycles and CAP sequences were lower in Group 1 as compared to Group 2 (p < 0.001) and Group 3 (p < 0.001). However, the CAP cycle and CAP sequence indices were comparable between the three groups (p = 0.455). The average duration of phase A was higher in Group 2 as compared to Group 1 (p < 0.001) and Group 3 (p < 0.001), and conversely, the average duration of phase B was lower in Group 1 (p < 0.001) as well as in Group 2 (p = 0.011) in comparison with Group 3. There was a decrease in phase A1, A2, and A3 durations in Group 1 as compared to Group 2 (p < 0.001). On the other hand, there was an increase in the phase A2 and A3 duration in Group 2 as compared to Group 3 (p < 0.001). Finally, there was a decrease in phase A1 percentage (p < 0.001) and conversely an increase in phase A3
Table 1 Comparison of conventional polysomnographic parameters and arousal parameters in normal controls and patients with JME (drug naïve and on VPA). Parameter
TIB (h) TST (h) TST/TIB (%) Wake (%) N1 (%) N2 (%) N3 (%) REM (%) NREM (%) Sleep latency (min) Arousal index R arousal index NREM arousal index Isolated limb movement index PLM index AHI
Value (mean ± SD)
p-value
Drug naïve (Group 1) (N = 20)
On VPA (Group 2) (N = 20)
Controls (Group 3) (N = 20)
7.66 ± 0.61 6.10 ± 1.52 79.69 ± 19.21 22.61 ± 26.10 7.10 ± 3.40 39.02 ± 12.62 22.91 ± 9.78 13.83 ± 5.91 69.07 ± 14.68 12.60 ± 9.08 10.01 ± 6.72 7.83 ± 6.59 10.54 ± 8.54 5.48 ± 3.36 3.54 ± 5.13 1.17 ± 2.40
8.20 ± 0.65 6.26 ± 1.08 76.62 ± 13.96 23.42 ± 14.23 11.36 ± 11.15 35.51 ± 8.91 21.57 ± 7.98 28.76 ± 12.23 66.20 ± 10.00 32.42 ± 47.07 11.42 ± 6.58 9.37 ± 8.60 8.15 ± 5.33 7.87 ± 510.04 7.14 ± 19.72 0.27 ± 0.46
7.58 ± 0.64 6.40 ± 0.81 84.85 ± 10.03 16.13 ± 11.07 8.08 ± 4.12 41.28 ± 9.38 19.45 ± 6.94 16.26 ± 4.01 68.83 ± 8.47 18.60 ± 17.75 9.01 ± 5.67 1.37 ± 0.88 7.75 ± 5.18 6.14 ± 2.93 1.05 ± 1.96 0.40 ± 0.72
* Statistical significance (p < 0.05). TIB, time in bed; TST, total sleep time; TST/TIB, sleep efficiency; PLM, periodic limb movement; AHI, apnea–hypopnea index.
0.006* 0.725 0.219 0.392 0.152 0.221 0.420 <0.0001* 0.677 0.137 0.487 <0.001* 0.351 0.475 0.270 0.125
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Table 2 Comparison of cyclic alternating pattern parameters in normal healthy controls and patients with JME (drug naïve and on VPA). Parameters
CAP rate (%) NCAP rate (%) CAP rate N1 (%) CAP rate N2 (%) CAP rate N3 (%) Phase A1 index Phase A2 index Phase A3 index CAP cycle index Average CAP cycle duration (s) CAP sequence index Average CAP sequence duration (s) Average phase A duration (s) Average phase B duration (s) Average phase A1 duration (s) Phase A1 (%) Average phase A2 duration (s) Phase A2 (%) Average phase A3 duration (s) Phase A3 (%)
Value (mean ± SD)
ANOVA p-value
Drug naïve (Group 1) (N = 20)
On VPA (Group 2) (N = 20)
Controls (Group 3) (N = 20)
58.86 ± 9.70 41.84 ± 10.16 53.36 ± 14.22 63.99 ± 15.64 56.83 ± 15.42 16.91 ± 22.07 10.90 ± 16.95 21.05 ± 26.18 48.87 ± 61.00 17.24 ± 3.75 24.43 ± 30.25 34.48 ± 7.5 8.47 ± 2.04 8.76 ± 3.02 7.12 ± 2.39 36.31 ± 7.05 11.90 ± 5.51 22.05 ± 6.70 8.94 ± 3.28 41.62 ± 10.78
55.03 ± 9.95 44.83 ± 2.66 50.98 ± 20.43 58.37 ± 16.46 50.26 ± 17.08 25.24 ± 7.17 15.62 ± 5.48 19.65 ± 7.30 60.51 ± 12.94 33.98 ± 6.14 30.25 ± 6.47 67.97 ± 12.29 23.44 ± 4.27 12.01 ± 5.30 15.36 ± 5.42 41.31 ± 6.92 30.87 ± 13.56 25.99 ± 8.12 29.48 ± 8.38 32.68 ± 10.86
44.96 ± 7.89 55.03 ± 7.89 38.55 ± 13.83 48.66 ± 9.78 45.00 ± 15.34 20.39 ± 4.29 14.00 ± 5.77 12.81 ± 4.81 47.19 ± 8.31 34.50 ± 3.46 23.59 ± 4.15 69.01 ± 6.93 15.71 ± 1.96 18.78 ± 2.96 17.27 ± 5.45 45.84 ± 8.11 13.28 ± 4.44 24.16 ± 9.29 18.84 ± 8.43 29.99 ± 12.51
Fisher’s LSD post hoc Group comparisons
<0.001* <0.001* 0.013* 0.005* 0.072 0.161 0.381 0.225 0.455 <0.001* 0.455 <0.001* <0.001* <0.001* <0.001* 0.001* <0.001* 0.314 <0.001* 0.006*
1=2>3 1=2<3 1=2>3 1=2>3 — — — — — 1<2=3 — 1<2=3 2 > 3; 1 < 3 1<2<3 1<2=3 1<3 2 > 3; 1 < 3 — 2 > 3; 1 < 3 1>2>3
CAP, cyclic alternating pattern; NCAP, non-cyclic alternating pattern. * Statistical significance (p < 0.05).
percentage (p = 0.002) in Group 1 as compared to Group 3. Similarly, A3 percentage was also higher in Group 1 as compared to Group 2 (p = 0.016). All the CAP parameters are summarized in Table 2. 4. Discussion Most studies that have been conducted to analyse the sleep profile of patients with epilepsy on VPA have concentrated either on sleep questionnaire assessment [17,18] or on macrostructural sleep analysis [3,19–22] using 30-s epochs, based on a composite of EEG, EOG, and EMG criteria [14]. These are measures of global sleep organization and tell us very little about the transient, brief alterations in arousal occurring during the sleep state. On the other hand, sleep microstructure provides a more complete description of momentary and dynamic brain electrical activity during sleep [23]. This has been elucidated in a recent study which showed that unstable NREM sleep is an important determinant of objective resistance to AEDs in patients with nocturnal frontal lobe epilepsy (NFLE) [24]. The present study conducted on 40 patients diagnosed with JME (drug naïve: on VPA = 20:20) attempted to compare the sleep microstructural changes occurring in drug naïve and those on VPA with healthy controls. We found that the arousal index during REM sleep was significantly higher in JME patients, both drug naïve and those on VPA as compared to healthy controls. However, the overall arousal index, as well as the arousal index during NREM, was comparable with that of healthy controls. These findings suggest greater arousal instability during REM sleep in patients of JME as compared to controls, irrespective of VPA therapy. However, a previous study comparing the arousal parameters between healthy controls and JME patients on VPA did not find any significant differences between the two groups [21]. The notable important finding of the present study is that the overall CAP rate was significantly higher in patients with JME, both drug naïve and those on VPA as compared to controls. Moreover, the CAP rate was also increased during N1, N2, and N3 sleep stages in JME patients. However, N3 CAP rate was comparable between controls and JME patients on VPA. This suggests that patients with JME spend most of their NREM sleep time in the CAP phase and this is
not altered even in those taking VPA, except in N3 sleep stage. Our findings are comparable with previous studies which showed that the average CAP rate was significantly higher in idiopathic generalized epilepsy (IGE) [25], JME [26], and NFLE [27] as compared to healthy controls. Other studies performed on partial epilepsies have shown that CAP rate significantly increases in the post-seizure period, and this is true both for isolated nocturnal seizures or in the case of seizure clustering at night [28]. Although the number of CAP cycles and sequences were comparable in our study, there was a reduction in the duration of phase A and its subtypes (A1, A2, and A3) in drug-naïve patients as compared to those on VPA treatment and healthy controls. Similarly, previous studies performed on IGE patients did not find any significant differences between the average percentage of CAP cycles as compared to healthy controls [25]. However, one study assessing CAP parameters in patients with NFLE found that the number of CAP cycles in patients was significantly higher as compared to controls [27], but the effect of AEDs was not controlled for. Therefore, our study suggests that patients with JME are prone to have shorter durations of CAP cycles, more so with phase A and its subtypes, and these microstructural alterations may be reversible after initiating treatment with VPA. Previous studies dealing with the microstructural sleep characteristics in patients with epileptic seizures have improved our understanding about the complex and reciprocal relationship between sleep and epilepsy [29–31]. This instability of arousal mechanisms during sleep not only contributes to sleep disorganization but is also believed to act as a potential trigger for the activation of epileptiform activity [28,32]. Consequently, the occurrence of epileptiform activity during sleep can further hamper sleep continuity and worsen arousal instability [28], causing a vicious cycle of poor sleep quality and intractable seizures. However, studies looking at the effect of anti-epileptic drugs on the sleep microstructure are few and far between. 5. Conclusions The findings in this study, the first of its kind, may indicate that there is probably an alteration in the pathophysiologic mechanisms regulating arousal pattern in patients with JME, which is
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further modulated by the use of VPA. This finding is in parallel to a previous longitudinal sleep questionnaire-based study by Nayak et al. [33] that reported improvement in nocturnal sleep quality after initiation of treatment with VPA. Further studies looking at the influence of VPA on microstructural sleep parameters can provide better understanding of the patho-mechanisms responsible for the beneficial effects of VPA on sleep quality. Conflict of interest None. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.11.006. References [1] Touchon J, Baldy-Moulinier M, Billiard M, et al. Sleep organization and epilepsy. Epilepsy Res Suppl 1991;2:73–81. [2] Bazil C. Sleep and epilepsy: something else we did not know. Epilepsy Curr 2003;3:48–9. [3] Manni R, Ratti MT, Perucca E, et al. A multiparametric investigation of daytime sleepiness and psychomotor functions in epileptic patients treated with phenobarbital and sodium valproate: a comparative controlled study. Electroencephalogr Clin Neurophysiol 1993;86:322–8. [4] Dunn K. Sleep and Epilepsy: The Clinical Spectrum. Edited by C.W. Bazil, B.A. Malow, and M.R. Sammaritano, with 54 contributing authors, Elsevier Science, Amsterdam, 2002. 404 pp. $180. ISBN 0-444-50479-6. Epilepsy Behav 2002;3:402–3. [5] Ehrenberg BL, Eisensehr I, Corbett KE, et al. Valproate for sleep consolidation in periodic limb movement disorder. J Clin Psychopharmacol 2000;20:574–8. [6] Rush AJ, Erman MK, Giles DE, et al. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Arch Gen Psychiatry 1986;43:878–84. [7] Reynolds CF 3rd, Kupfer DJ, Hoch CC, et al. Sleep deprivation as a probe in the elderly. Arch Gen Psychiatry 1987;44:982–90. [8] Terzano MG, Monge-Strauss MF, Mikol F, et al. Cyclic alternating pattern as a provocative factor in nocturnal paroxysmal dystonia. Epilepsia 1997;38:1015– 25. [9] ILAE. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–99. [10] Panda S, Basavaraju S, Taly A. Insight into prevalence of sleep related disorders among healthy Indians. Ann Indian Acad Neurol 2007;10:24. [11] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5.
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[12] Buysse DJ, Reynolds CF 3rd, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. [13] Panda S, Taly A, Sinha S, et al. Sleep-related disorders among a healthy population in South India. Neurol India 2012;60:68–74. [14] Iber C. AASM manual for the scoring of sleep and associated events. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007. [15] ASDA. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15:173–84. [16] Terzano M, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537–53. [17] Schmitt B, Martin F, Critelli H, et al. Effects of valproic acid on sleep in children with epilepsy. Epilepsia 2009;50:1860–7. [18] Krishnan P, Sinha S, Taly A, et al. Sleep disturbances in juvenile myoclonic epilepsy: a sleep questionnaire-based study. Epilepsy Behav 2012;23:305–9. [19] Legros B, Bazil CW. Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med 2003;4:51–5. [20] Harding GF, Alford CA, Powell TE. The effect of sodium valproate on sleep, reaction times, and visual evoked potential in normal subjects. Epilepsia 1985;26:597–601. [21] Krishnan P, Sinha S, Taly AB, et al. Altered polysomnographic profile in juvenile myoclonic epilepsy. Epilepsy Res 2014;108:459–67. [22] Nunes ML, Ferri R, Arzimanoglou A, et al. Sleep organization in children with partial refractory epilepsy. J Child Neurol 2003;18:763–6. [23] Terzano M, Parrino L, Rosa A, et al. CAP and arousals in the structural development of sleep: an integrative perspective. Sleep Med 2002;3(3):221–9. [24] De Paolis F, Colizzi E, Milioli G, et al. Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy. Sleep Med 2013;14:597–604. [25] Terzano MG, Parrino L, Anelli S, et al. Effects of generalized interictal EEG discharges on sleep stability: assessment by means of cyclic alternating pattern. Epilepsia 1992;33:317–26. [26] Gigli GL, Calia E, Marciani MG, et al. Sleep microstructure and EEG epileptiform activity in patients with juvenile myoclonic epilepsy. Epilepsia 1992;33:799– 804. [27] Parrino L, De Paolis F, Milioli G, et al. Distinctive polysomnographic traits in nocturnal frontal lobe epilepsy. Epilepsia 2012;53:1178–84. [28] Manni R, Zambrelli E, Bellazzi R, et al. The relationship between focal seizures and sleep: an analysis of the cyclic alternating pattern. Epilepsy Res 2005;67:73–80. [29] Niedermeyer E. Sleep and EEG. In: Niedermeyer E, da Silva FL, editors. Ernst Niedermeyer. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. [30] Wieser HG. Temporal lobe epilepsy, sleep and arousal: stereo-EEG findings. Epilepsy Res Suppl 1991;2:97–119. [31] Malow BA, Varma NK. Seizures and arousals from sleep – which comes first? Sleep 1995;18:783–6. [32] Bonakis A, Koutroumanidis M. Epileptic discharges and phasic sleep phenomena in patients with juvenile myoclonic epilepsy. Epilepsia 2009;50:2434–45. [33] Nayak C, Sinha S, Ramachandraiah CT, et al. Differential improvement of the sleep quality among patients with juvenile myoclonic epilepsy with valproic acid: a longitudinal sleep questionnaire-based study. Ann Indian Acad Neurol 2015;18.
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Original Article
Effect of valproate on the sleep microstructure of juvenile myoclonic epilepsy patients – a cross-sectional CAP based study Chetan S. Nayak a,b, Sanjib Sinha a,*, Madhu Nagappa a, Thennarasu Kandavel c, Arun B. Taly a a
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Department of Clinical Neurosciences, NIMHANS, Bangalore, India c Department of Biostatistics, NIMHANS, Bangalore, India b
A R T I C L E
I N F O
Article history: Received 29 August 2015 Received in revised form 14 October 2015 Accepted 5 November 2015 Available online Keywords: Arousals CAP Juvenile myoclonic epilepsy Sleep microstructure
A B S T R A C T
Objective: Studies looking at the effect of anti-epileptic medications on sleep microstructure of patients with epilepsy are almost non-existent. The aim of this study was to compare sleep microstructural characteristics of drug-naïve juvenile myoclonic epilepsy (JME) patients with those on valproate (VPA) monotherapy. Methods: Three age- (p = 0.287) and gender- (p = 0.766) matched groups (N = 20 in each group): (1) drugnaïve JME (mean age: 21.2 ± 4.06 years; M : F = 9:11); (2) JME on VPA (mean age: 21.85 ± 4.28 years; M : F = 11:9); (3) healthy controls (mean age: 23.2 ± 3.82 years; M : F = 9:11) underwent overnight polysomnography. Scoring and analysis of arousals American Sleep Disorders Association (ASDA, 2002), cyclic alternating pattern (CAP) (Terzano et al., 2002) parameters were performed. Comparison of arousal and CAP parameters was performed using one-way ANOVA, followed by pairwise comparisons using Fisher’s LSD test (p ≤ 0.05). Results: Rapid eye movement (REM) arousal indices were higher in JME patients (Group 1 [p = 0.002] and Group 2 [p < 0.001]), whereas the overall and NREM arousal indices were comparable between the three groups. CAP rate was higher in JME patients as compared to controls (p < 0.001). Duration of phase A and its subtypes (p < 0.001) was reduced in drug-naïve patients as compared to VPA group and controls. Finally, percentage of phase A1 (p = 0.003) was decreased and A3 (p = 0.045) was increased in drugnaïve patients as compared to VPA group and controls. Conclusions: We found significant alterations in REM arousal indices and several CAP parameters in JME patients. However, many of these alterations were not seen in the valproate group. This might indicate that anti-epileptic medications such as valproate may beneficially modulate arousal instability in JME patients, and hence promote sleep quality and continuity. © 2015 Elsevier B.V. All rights reserved.
1. Introduction The sleep quality in patients with epilepsy is frequently compromised by various factors interfering with the continuity of the sleep state. These factors lead to disruption of normal sleep architecture causing frequent arousals, awakenings, and stage shifts, and eventually manifesting as sleep disorders [1]. Most antiepileptic medications (AEDs), especially the conventional ones, might exacerbate sleep disorganization and further impair sleep quality in these patients on AEDs [2,3]. However, sodium valproic acid (VPA), a frequently used AED for most of the generalized epilepsy syndromes, is shown to have little or even no effect on sleep amount and mac-
* Corresponding author. NIMHANS, Hosur Road, Bengaluru 560029, India. Tel.: +91 080 26995123; mobile: +91 9972872570; fax: +918026564830. E-mail address: [email protected] (S. Sinha). http://dx.doi.org/10.1016/j.sleep.2015.11.006 1389-9457/© 2015 Elsevier B.V. All rights reserved.
rostructure under therapeutic doses [4] and has sometimes been reported to improve sleep efficiency [5]. Although traditional visual sleep scoring provides a valuable description of the overall sleep macrostructure [6,7], it fails to provide information regarding electroencephalogram (EEG) frequency characteristics or rhythmicity that underlies sleep disturbances and needs to be addressed using sleep microstructural analysis [8]. Analysis of sleep microstructure using cyclic alternating pattern (CAP) can provide additional insights regarding the subtle beneficial or deleterious effects of VPA on sleep architecture in patients with epilepsy. In this study, we hypothesized that there is probably an alteration in the pathophysiologic mechanisms regulating arousal patterns in patients with JME. Our aim was to compare the microstructural polysomnographic (PSG) characteristics in drug-naïve juvenile myoclonic epilepsy (JME) patients and those on valproate monotherapy, using Arousal and CAP analysis, which may highlight the role of VPA in causing alteration of arousal patterns in patients with epilepsy.
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2. Materials and methods 2.1. Patients This is a cross-sectional, hospital-based, case-control study that was conducted at a tertiary neurology centre in south India from March 2010 to February 2013. The International League Against Epilepsy (ILAE) commission on Classification and Terminology (1989) defined JME (impulsive petit mal) as follows: “Impulsive petit mal appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. Often, there are generalized tonic-clonic seizures (GTCS) and, less often infrequent absences. The seizures usually occur shortly after awakening and are often precipitated by sleep deprivation [9].” Forty patients diagnosed with JME, 20 drug naïve (mean age: 21.2 ± 4.06 years; M : F = 9:11) and 20 on VPA monotherapy (mean age: 21.85 ± 4.28 years; M : F = 11:9), attending the neurological services and fulfilling the criteria for JME laid down by the ILAE commission [9] were recruited. Patients were excluded if: (1) they used any medications (other than VPA) known to affect sleep at study-entry; (2) they had history of drug or substance abuse of any degree; (3) they had abnormal brain imaging; (4) they had a primary sleep disorder; or (5) they reported any co-existing medical, psychiatric or surgical disorder known to affect sleep. Patients on VPA monotherapy were excluded if they were non-compliant or stopped medications during the period of the study. Twenty healthy controls (mean age: 23.2 ± 3.82 years; M : F = 9:11) consisting of friends/unrelated volunteers (N = 14) of the patients from similar educational and socioeconomic status and medical personnel (doctors = 3; medical technologists = 3) from the hospital on routine day duties (9.00 a.m.– 4.30 p.m.) were also recruited, which were age (p = 0.287) and gender (p = 0.766) matched with patients. Controls were not related to patients and also did not have a family history of seizures, or any other medical or neurological illness. All subjects were screened for underlying sleep disorders such as sleep-disordered breathing, periodic limb movement disorders, narcolepsy, insomnia, restless legs syndrome, and parasomnias using the NIMHANS Comprehensive Sleep Disorders Questionnaire (NCSDQ) [10]. All subjects were ≥12 years of age in view of their participation in the evaluation and completing the sleep questionnaires. Ethical approval for the study was obtained from the Institute Ethics Committee (IEC). A written informed consent was obtained from the study subjects and/or parents. 2.2. Clinical evaluation All patients underwent a structured evaluation, including a detailed clinical, family and treatment history, neurological examination, 21-channel digital EEG recording using the international 10–20 system of electrode placement, brain imaging (magnetic resonance imaging, MRI), and other investigations when indicated. The mean age at onset of illness was 16.2 ± 4.04 years in Group 1 and 14.05 ± 4.29 years in Group 2. The average duration of illness was 5.0 ± 4.1 years in Group 1 and 6.9 ± 4.73 years in Group 2. All patients had myoclonic jerks, five of them (three in Group 1 and two in Group 2) not developing any other type of seizures till the time of the study. The mean duration (p = 0.186) and frequency (p = 0.684) of myoclonus in Group 1 (5.0 ± 4.1 years; 7.05 ± 1.96/ day) and Group 2 (6.9 ± 4.73 years; 6.75 ± 2.61/day) was comparable. Except for five patients (three [15%] Group 1 and two [10%] Group 2), the rest had GTCS during the course of their illness. It was preceded by a series of myoclonic jerks (heralding myoclonus) in 8/17 (47.1%) in Group 1 and 3/18 (16.66%) in Group 2. The mean duration (p = 0.181) and frequency (p = 0.688) of GTCS in Group 1 (4.01 ± 4.65 years; 2.29 ± 1.89/month) and Group 2 (6.19 ± 5.05 years;
2.06 ± 1.55/month) were comparable. Only one patient had status epilepticus (Group 1: 0/20 [0%]; Group 2: 1/20 [5%]; p = 0.311) at any time during their disease course and three patients (Group 1: 1/20 [5%]; Group 2: 2/20 [10%]; p = 0.548) had features suggestive of absence attacks. Five patients (Group 1: 3/20 [15%]; Group 2: 2/20 [10%; p = 0.633) had a history of typical febrile seizures. 2.3. Sleep questionnaire assessment Validated sleep questionnaires including Epworth Sleepiness Scale (ESS) to assess daytime somnolence [11] and Pittsburgh Sleep Quality Index (PSQI) to assess night-time sleep quality [12] were administered to all the study subjects. NCSDQ was administered to rule out various sleep disorders [13]. 2.4. Polysomnography Overnight PSG recording was done (Sleepscan Vision Collection Software, version 7.11.01, Biologic Systems Corp, IL, USA) after obtaining a written informed consent from all participants using standard protocols. The parameters recorded included (1) an eight-channel EEG using bi-hemispheric referential montage (F7-A2, C3-A2, T3-A2, O1A2 and F8-A1, C4-A1, T4-A1, O2-A1): sensitivity 7 μV/mm, low-pass filter 0.3 Hz, high-pass filter 35 Hz; (2) two-channel electro-oculogram (EOG): for eye movements, sensitivity 10 μV/mm, low-pass filter 0.3 Hz, highpass filter 35 Hz; (3) electromyogram (EMG) from the sub-mentalis and right tibialis anterior muscle: sensitivity 3 μV/mm and 20 μV/mm, respectively, low-pass filter 0.3 Hz, high-pass filter 100 Hz; (4) electrocardiogram (ECG): sensitivity 20 μV/mm, low-pass filter 0.5 Hz, highpass filter 35 Hz; (5) body position monitor; and (6) respiratory events: oro-nasal airflow using thermistor (sensitivity 7 μV/mm, low-pass filter 0.5 Hz, high-pass filter 15 Hz), chest and abdominal wall movements using strain gauge (sensitivity 10 μV/mm, low-pass filter 0.5 Hz, highpass filter 15 Hz), snore (sensitivity 2 μV/mm, low-pass filter 10 Hz, highpass filter 100 Hz), and arterial oxygen saturation (sensitivity 7 μV/ mm, high-pass filter 70 Hz). All channels were sampled at 256 Hz; electrode impedance was kept less than 5000 Ω and a notch filter of 50 Hz was applied to remove noise artifact caused by electrical power lines. The subjects were allowed to fall asleep spontaneously and the recording was continued until their spontaneous awakening in the morning. All subjects reported a comfortable, undisturbed, and refreshing sleep. None of the subjects had generalized seizures within the last 2 weeks of the PSG recording. 2.4.1. Analysis of sleep macrostructure Sleep was scored visually in 30-s epochs using standard criteria [14]. The conventional PSG parameters studied included: total time in bed (TIB, min), total sleep time (TST, min), sleep latency (min), rapid eye movement (REM) latency (min), sleep efficiency (%), wake after sleep onset (WASO) (min), as well as percentage of NonREM (N1, N2, N3) and REM stages. Visual analysis of the chin EMG tone during REM was performed in both patients and controls. Periodic limb movement (PLM) as well as apnea–hypopnea indices (AHI) were also assessed. 2.4.2. Analysis of sleep microstructure Sleep microstructure evaluation included detection of the arousals and CAP analysis. 2.4.2.1. Detection and analysis of arousals. The number of arousals occurring during the entire period of sleep, as well as that during each of the various sleep stages, was computed according to the standard ASDA criteria [15]. The following arousal parameters were measured: arousal index (number of arousals per hour of sleep), NREM arousal index (number of arousals per hour of NREM sleep), and REM arousal index (number of arousals per hour of REM sleep).
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2.4.2.2. Cyclic alternating pattern analysis. CAP analysis was performed manually as per the criteria provided by Terzano et al. [16]. The following CAP variables were measured: total CAP time (total CAP time in NREM sleep) and total non-CAP time (total non-CAP time in NREM sleep); CAP time in N1, N2 and N3; CAP rate (the percentage ratio of CAP time to NREM sleep time) of total NREM sleep, N1, N2 and N3; number and duration of CAP cycles; number and duration of CAP sequences; total and average duration of phase A and phase B; number, indices and percentages of each phase A subtypes (A1, A2, A3); and total and average duration of each phase A subtype (A1, A2, A3). 2.5. Statistical analysis The data obtained were analysed using Statistical Product and Service Solutions (SPSS), version 22. Macrostructural and microstructural sleep characteristics were compared between the drugnaïve patients, patients on VPA and controls using one-way analysis of variance (one-way ANOVA) followed by pairwise comparisons between the three groups using Fisher’s LSD post hoc test. The significance level was placed at ≤0.05. 3. Results The study subjects were divided into three groups, each having 20 subjects: Group (1) – drug-naïve JME (mean age: 21.2 ± 4.06 years; M : F = 9:11); Group (2) – JME on valproate monotherapy (mean age: 21.85 ± 4.28 years; M : F = 11:9); Group (3) – controls (mean age: 23.2 ± 3.82 years; M : F = 9:11). The subjects in all three groups were age (p = 0.28) and gender (p = 0.76) matched. The mean body mass index (BMI) was also comparable in the three groups (p = 0.49). 3.1. Sleep questionnaires The mean ESS scores in Groups 1, 2, and 3 were 5.65 ± 4.03, 6.85 ± 3.3, and 3.80 ± 2.37, respectively, and they differed statistically (p = 0.018). Similarly, the mean PSQI scores in Groups 1, 2, and 3 were 4.85 ± 2.72, 4.9 ± 2.31, and 2.35 ± 1.18, respectively, and they also differed statistically (p < 0.001). Based on the NCSDQ, none of the patients and controls had symptoms suggestive of sleepdisordered breathing, periodic limb movement disorders, narcolepsy, insomnia, restless legs syndrome, or parasomnias.
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3.2. Polysomnography 3.2.1. Sleep macrostructural analysis The REM sleep duration percentage was significantly higher in Group 2 as compared to Group 1 (p < 0.001) and Group 3 (p < 0.001). Sleep latency (p = 0.137) was comparable between the three groups. Visually, loss of chin EMG atonia during REM was not observed in the PSG of either patients or controls. AHI (p = 0.125) and PLM indices (p = 0. 270) were comparable between the three groups. None of the patients had clinical or electrographic seizures during the study. The conventional sleep parameters are summarized in Table 1. 3.2.2. Sleep microstructural analysis 3.2.2.1. Analysis of arousals during sleep. The total number of arousals during the night was 1147, 1280, and 875 in Group 1, Group 2, and in Group 3, respectively. The arousal indices during REM sleep were significantly higher in patients with JME (Group 1 [p = 0.002] and Group 2 [p < 0.001]) as compared to healthy controls (Group 3). The arousal parameters are summarized in Table 1. 3.2.2.2. Cyclic alternating pattern analysis. The overall CAP rate was significantly higher in patients with JME (Group 1 and Group 2) as compared to healthy controls (p < 0.001) and conversely, the nonCAP (NCAP) Rate was significantly lower in patients with JME (Group 1 and Group 2) as compared to healthy controls (p < 0.001). Moreover, the CAP rate was significantly increased in patients with JME during N1 (Group 1 [p = 0.006] and Group 2 [p = 0.020]) and N2 (Group 1 [p = 0.010] and Group 2 [p = 0.036]) sleep periods as compared to healthy controls. However, the CAP rate was comparable during N3 (p = 0.072) sleep period. The average duration of CAP cycles and CAP sequences were lower in Group 1 as compared to Group 2 (p < 0.001) and Group 3 (p < 0.001). However, the CAP cycle and CAP sequence indices were comparable between the three groups (p = 0.455). The average duration of phase A was higher in Group 2 as compared to Group 1 (p < 0.001) and Group 3 (p < 0.001), and conversely, the average duration of phase B was lower in Group 1 (p < 0.001) as well as in Group 2 (p = 0.011) in comparison with Group 3. There was a decrease in phase A1, A2, and A3 durations in Group 1 as compared to Group 2 (p < 0.001). On the other hand, there was an increase in the phase A2 and A3 duration in Group 2 as compared to Group 3 (p < 0.001). Finally, there was a decrease in phase A1 percentage (p < 0.001) and conversely an increase in phase A3
Table 1 Comparison of conventional polysomnographic parameters and arousal parameters in normal controls and patients with JME (drug naïve and on VPA). Parameter
TIB (h) TST (h) TST/TIB (%) Wake (%) N1 (%) N2 (%) N3 (%) REM (%) NREM (%) Sleep latency (min) Arousal index R arousal index NREM arousal index Isolated limb movement index PLM index AHI
Value (mean ± SD)
p-value
Drug naïve (Group 1) (N = 20)
On VPA (Group 2) (N = 20)
Controls (Group 3) (N = 20)
7.66 ± 0.61 6.10 ± 1.52 79.69 ± 19.21 22.61 ± 26.10 7.10 ± 3.40 39.02 ± 12.62 22.91 ± 9.78 13.83 ± 5.91 69.07 ± 14.68 12.60 ± 9.08 10.01 ± 6.72 7.83 ± 6.59 10.54 ± 8.54 5.48 ± 3.36 3.54 ± 5.13 1.17 ± 2.40
8.20 ± 0.65 6.26 ± 1.08 76.62 ± 13.96 23.42 ± 14.23 11.36 ± 11.15 35.51 ± 8.91 21.57 ± 7.98 28.76 ± 12.23 66.20 ± 10.00 32.42 ± 47.07 11.42 ± 6.58 9.37 ± 8.60 8.15 ± 5.33 7.87 ± 510.04 7.14 ± 19.72 0.27 ± 0.46
7.58 ± 0.64 6.40 ± 0.81 84.85 ± 10.03 16.13 ± 11.07 8.08 ± 4.12 41.28 ± 9.38 19.45 ± 6.94 16.26 ± 4.01 68.83 ± 8.47 18.60 ± 17.75 9.01 ± 5.67 1.37 ± 0.88 7.75 ± 5.18 6.14 ± 2.93 1.05 ± 1.96 0.40 ± 0.72
* Statistical significance (p < 0.05). TIB, time in bed; TST, total sleep time; TST/TIB, sleep efficiency; PLM, periodic limb movement; AHI, apnea–hypopnea index.
0.006* 0.725 0.219 0.392 0.152 0.221 0.420 <0.0001* 0.677 0.137 0.487 <0.001* 0.351 0.475 0.270 0.125
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Table 2 Comparison of cyclic alternating pattern parameters in normal healthy controls and patients with JME (drug naïve and on VPA). Parameters
CAP rate (%) NCAP rate (%) CAP rate N1 (%) CAP rate N2 (%) CAP rate N3 (%) Phase A1 index Phase A2 index Phase A3 index CAP cycle index Average CAP cycle duration (s) CAP sequence index Average CAP sequence duration (s) Average phase A duration (s) Average phase B duration (s) Average phase A1 duration (s) Phase A1 (%) Average phase A2 duration (s) Phase A2 (%) Average phase A3 duration (s) Phase A3 (%)
Value (mean ± SD)
ANOVA p-value
Drug naïve (Group 1) (N = 20)
On VPA (Group 2) (N = 20)
Controls (Group 3) (N = 20)
58.86 ± 9.70 41.84 ± 10.16 53.36 ± 14.22 63.99 ± 15.64 56.83 ± 15.42 16.91 ± 22.07 10.90 ± 16.95 21.05 ± 26.18 48.87 ± 61.00 17.24 ± 3.75 24.43 ± 30.25 34.48 ± 7.5 8.47 ± 2.04 8.76 ± 3.02 7.12 ± 2.39 36.31 ± 7.05 11.90 ± 5.51 22.05 ± 6.70 8.94 ± 3.28 41.62 ± 10.78
55.03 ± 9.95 44.83 ± 2.66 50.98 ± 20.43 58.37 ± 16.46 50.26 ± 17.08 25.24 ± 7.17 15.62 ± 5.48 19.65 ± 7.30 60.51 ± 12.94 33.98 ± 6.14 30.25 ± 6.47 67.97 ± 12.29 23.44 ± 4.27 12.01 ± 5.30 15.36 ± 5.42 41.31 ± 6.92 30.87 ± 13.56 25.99 ± 8.12 29.48 ± 8.38 32.68 ± 10.86
44.96 ± 7.89 55.03 ± 7.89 38.55 ± 13.83 48.66 ± 9.78 45.00 ± 15.34 20.39 ± 4.29 14.00 ± 5.77 12.81 ± 4.81 47.19 ± 8.31 34.50 ± 3.46 23.59 ± 4.15 69.01 ± 6.93 15.71 ± 1.96 18.78 ± 2.96 17.27 ± 5.45 45.84 ± 8.11 13.28 ± 4.44 24.16 ± 9.29 18.84 ± 8.43 29.99 ± 12.51
Fisher’s LSD post hoc Group comparisons
<0.001* <0.001* 0.013* 0.005* 0.072 0.161 0.381 0.225 0.455 <0.001* 0.455 <0.001* <0.001* <0.001* <0.001* 0.001* <0.001* 0.314 <0.001* 0.006*
1=2>3 1=2<3 1=2>3 1=2>3 — — — — — 1<2=3 — 1<2=3 2 > 3; 1 < 3 1<2<3 1<2=3 1<3 2 > 3; 1 < 3 — 2 > 3; 1 < 3 1>2>3
CAP, cyclic alternating pattern; NCAP, non-cyclic alternating pattern. * Statistical significance (p < 0.05).
percentage (p = 0.002) in Group 1 as compared to Group 3. Similarly, A3 percentage was also higher in Group 1 as compared to Group 2 (p = 0.016). All the CAP parameters are summarized in Table 2. 4. Discussion Most studies that have been conducted to analyse the sleep profile of patients with epilepsy on VPA have concentrated either on sleep questionnaire assessment [17,18] or on macrostructural sleep analysis [3,19–22] using 30-s epochs, based on a composite of EEG, EOG, and EMG criteria [14]. These are measures of global sleep organization and tell us very little about the transient, brief alterations in arousal occurring during the sleep state. On the other hand, sleep microstructure provides a more complete description of momentary and dynamic brain electrical activity during sleep [23]. This has been elucidated in a recent study which showed that unstable NREM sleep is an important determinant of objective resistance to AEDs in patients with nocturnal frontal lobe epilepsy (NFLE) [24]. The present study conducted on 40 patients diagnosed with JME (drug naïve: on VPA = 20:20) attempted to compare the sleep microstructural changes occurring in drug naïve and those on VPA with healthy controls. We found that the arousal index during REM sleep was significantly higher in JME patients, both drug naïve and those on VPA as compared to healthy controls. However, the overall arousal index, as well as the arousal index during NREM, was comparable with that of healthy controls. These findings suggest greater arousal instability during REM sleep in patients of JME as compared to controls, irrespective of VPA therapy. However, a previous study comparing the arousal parameters between healthy controls and JME patients on VPA did not find any significant differences between the two groups [21]. The notable important finding of the present study is that the overall CAP rate was significantly higher in patients with JME, both drug naïve and those on VPA as compared to controls. Moreover, the CAP rate was also increased during N1, N2, and N3 sleep stages in JME patients. However, N3 CAP rate was comparable between controls and JME patients on VPA. This suggests that patients with JME spend most of their NREM sleep time in the CAP phase and this is
not altered even in those taking VPA, except in N3 sleep stage. Our findings are comparable with previous studies which showed that the average CAP rate was significantly higher in idiopathic generalized epilepsy (IGE) [25], JME [26], and NFLE [27] as compared to healthy controls. Other studies performed on partial epilepsies have shown that CAP rate significantly increases in the post-seizure period, and this is true both for isolated nocturnal seizures or in the case of seizure clustering at night [28]. Although the number of CAP cycles and sequences were comparable in our study, there was a reduction in the duration of phase A and its subtypes (A1, A2, and A3) in drug-naïve patients as compared to those on VPA treatment and healthy controls. Similarly, previous studies performed on IGE patients did not find any significant differences between the average percentage of CAP cycles as compared to healthy controls [25]. However, one study assessing CAP parameters in patients with NFLE found that the number of CAP cycles in patients was significantly higher as compared to controls [27], but the effect of AEDs was not controlled for. Therefore, our study suggests that patients with JME are prone to have shorter durations of CAP cycles, more so with phase A and its subtypes, and these microstructural alterations may be reversible after initiating treatment with VPA. Previous studies dealing with the microstructural sleep characteristics in patients with epileptic seizures have improved our understanding about the complex and reciprocal relationship between sleep and epilepsy [29–31]. This instability of arousal mechanisms during sleep not only contributes to sleep disorganization but is also believed to act as a potential trigger for the activation of epileptiform activity [28,32]. Consequently, the occurrence of epileptiform activity during sleep can further hamper sleep continuity and worsen arousal instability [28], causing a vicious cycle of poor sleep quality and intractable seizures. However, studies looking at the effect of anti-epileptic drugs on the sleep microstructure are few and far between. 5. Conclusions The findings in this study, the first of its kind, may indicate that there is probably an alteration in the pathophysiologic mechanisms regulating arousal pattern in patients with JME, which is
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further modulated by the use of VPA. This finding is in parallel to a previous longitudinal sleep questionnaire-based study by Nayak et al. [33] that reported improvement in nocturnal sleep quality after initiation of treatment with VPA. Further studies looking at the influence of VPA on microstructural sleep parameters can provide better understanding of the patho-mechanisms responsible for the beneficial effects of VPA on sleep quality. Conflict of interest None. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.11.006. References [1] Touchon J, Baldy-Moulinier M, Billiard M, et al. Sleep organization and epilepsy. Epilepsy Res Suppl 1991;2:73–81. [2] Bazil C. Sleep and epilepsy: something else we did not know. Epilepsy Curr 2003;3:48–9. [3] Manni R, Ratti MT, Perucca E, et al. A multiparametric investigation of daytime sleepiness and psychomotor functions in epileptic patients treated with phenobarbital and sodium valproate: a comparative controlled study. Electroencephalogr Clin Neurophysiol 1993;86:322–8. [4] Dunn K. Sleep and Epilepsy: The Clinical Spectrum. Edited by C.W. Bazil, B.A. Malow, and M.R. Sammaritano, with 54 contributing authors, Elsevier Science, Amsterdam, 2002. 404 pp. $180. ISBN 0-444-50479-6. Epilepsy Behav 2002;3:402–3. [5] Ehrenberg BL, Eisensehr I, Corbett KE, et al. Valproate for sleep consolidation in periodic limb movement disorder. J Clin Psychopharmacol 2000;20:574–8. [6] Rush AJ, Erman MK, Giles DE, et al. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Arch Gen Psychiatry 1986;43:878–84. [7] Reynolds CF 3rd, Kupfer DJ, Hoch CC, et al. Sleep deprivation as a probe in the elderly. Arch Gen Psychiatry 1987;44:982–90. [8] Terzano MG, Monge-Strauss MF, Mikol F, et al. Cyclic alternating pattern as a provocative factor in nocturnal paroxysmal dystonia. Epilepsia 1997;38:1015– 25. [9] ILAE. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–99. [10] Panda S, Basavaraju S, Taly A. Insight into prevalence of sleep related disorders among healthy Indians. Ann Indian Acad Neurol 2007;10:24. [11] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5.
133
[12] Buysse DJ, Reynolds CF 3rd, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. [13] Panda S, Taly A, Sinha S, et al. Sleep-related disorders among a healthy population in South India. Neurol India 2012;60:68–74. [14] Iber C. AASM manual for the scoring of sleep and associated events. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007. [15] ASDA. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15:173–84. [16] Terzano M, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537–53. [17] Schmitt B, Martin F, Critelli H, et al. Effects of valproic acid on sleep in children with epilepsy. Epilepsia 2009;50:1860–7. [18] Krishnan P, Sinha S, Taly A, et al. Sleep disturbances in juvenile myoclonic epilepsy: a sleep questionnaire-based study. Epilepsy Behav 2012;23:305–9. [19] Legros B, Bazil CW. Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med 2003;4:51–5. [20] Harding GF, Alford CA, Powell TE. The effect of sodium valproate on sleep, reaction times, and visual evoked potential in normal subjects. Epilepsia 1985;26:597–601. [21] Krishnan P, Sinha S, Taly AB, et al. Altered polysomnographic profile in juvenile myoclonic epilepsy. Epilepsy Res 2014;108:459–67. [22] Nunes ML, Ferri R, Arzimanoglou A, et al. Sleep organization in children with partial refractory epilepsy. J Child Neurol 2003;18:763–6. [23] Terzano M, Parrino L, Rosa A, et al. CAP and arousals in the structural development of sleep: an integrative perspective. Sleep Med 2002;3(3):221–9. [24] De Paolis F, Colizzi E, Milioli G, et al. Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy. Sleep Med 2013;14:597–604. [25] Terzano MG, Parrino L, Anelli S, et al. Effects of generalized interictal EEG discharges on sleep stability: assessment by means of cyclic alternating pattern. Epilepsia 1992;33:317–26. [26] Gigli GL, Calia E, Marciani MG, et al. Sleep microstructure and EEG epileptiform activity in patients with juvenile myoclonic epilepsy. Epilepsia 1992;33:799– 804. [27] Parrino L, De Paolis F, Milioli G, et al. Distinctive polysomnographic traits in nocturnal frontal lobe epilepsy. Epilepsia 2012;53:1178–84. [28] Manni R, Zambrelli E, Bellazzi R, et al. The relationship between focal seizures and sleep: an analysis of the cyclic alternating pattern. Epilepsy Res 2005;67:73–80. [29] Niedermeyer E. Sleep and EEG. In: Niedermeyer E, da Silva FL, editors. Ernst Niedermeyer. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. [30] Wieser HG. Temporal lobe epilepsy, sleep and arousal: stereo-EEG findings. Epilepsy Res Suppl 1991;2:97–119. [31] Malow BA, Varma NK. Seizures and arousals from sleep – which comes first? Sleep 1995;18:783–6. [32] Bonakis A, Koutroumanidis M. Epileptic discharges and phasic sleep phenomena in patients with juvenile myoclonic epilepsy. Epilepsia 2009;50:2434–45. [33] Nayak C, Sinha S, Ramachandraiah CT, et al. Differential improvement of the sleep quality among patients with juvenile myoclonic epilepsy with valproic acid: a longitudinal sleep questionnaire-based study. Ann Indian Acad Neurol 2015;18.