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Interrelationship of sleep and juvenile myoclonic epilepsy (JME): A sleep questionnaire‐, EEG‐, and polysomnography (PSG)‐based prospective case–control study
Epilepsy & Behavior 25 (2012) 391–396
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Interrelationship of sleep and juvenile myoclonic epilepsy (JME): A sleep questionnaire‐, EEG‐, and polysomnography (PSG)‐based prospective case–control study C.T. Ramachandraiah a, S. Sinha a,⁎, A.B. Taly a, S. Rao b, P. Satishchandra a a b
Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560029, Karnataka, India Department of Biostatistics, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India
a r t i c l e
i n f o
Article history: Received 1 June 2012 Revised 6 August 2012 Accepted 8 August 2012 Available online 24 October 2012 Keywords: Electroencephalogram Juvenile myoclonic epilepsy Polysomnogram Sleep questionnaire Valproic acid
a b s t r a c t We studied the effects of ‘epilepsy on sleep and its architecture’ and ‘sleep on the occurrence and distribution of interictal epileptiform discharges (ED)’ using ‘sleep questionnaires’, ‘EEG’, and ‘PSG’ in patients with JME. Forty patients with JME [20 on valproate (Group I — 20.8±4.0 years; M: F=9:11) and 20 drug-naïve (Group II — 24.4± 6.7 years; M: F=9:11)] and 20 controls (M: F=9:11; age: 23.5±4.7 years) underwent assessment with Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), overnight PSG, and scalp-EEG. Epileptiform discharges (EDs) were quantified in different sleep stages. The ‘ED Index’ was derived as number of EDs/min per stage. Statistical Package for the Social Sciences (SPSS) vs. 11 was used for statistical analysis. A ‘p’ b0.05 was considered as statistically significant. There was poor sleep quality in patients compared to controls (p=0.02), while there was no significant difference in ESS scores between the groups. The PSG parameters were comparable in both groups. Routine EEG revealed EDs in 22/40 (Group I: 7 and Group II: 15) patients. Thirty-five patients had EDs in various sleep stages during PSG (Group I: 17 and Group II: 18): N1 — Group I: 9 and Group II: 14, N2 — Group I: 14 and Group II: 14, N3 — Group I: 14 and Group II: 10, and REM — Group I: 9 and Group II: 11. The ED Index was higher during N2/N3 in Group I and N1/REM in Group II. The epileptiform discharges were frequently associated with arousals in N1/REM and K-complexes in N2. There was no other significant difference between Groups I and II. In conclusion, there was poor sleep quality in patients with JME compared to controls, especially those on valproate who had altered sleep architecture. Epileptiform activity was observed more often in sleep than wakefulness. Sleep stages had variable effect on epileptiform discharges with light sleep having a facilitatory effect in the drug‐naïve group and slow wave sleep having a facilitatory effect in the valproate group. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Juvenile myoclonic epilepsy (JME) is a common primary epilepsy syndrome characterized by adolescent-onset myoclonic jerks (MJ) with or without generalized tonic-clonic (GTCS) or absence seizures. Myoclonic jerks or GTCS classically occur on awakening and following a night of sleep deprivation, either partial or total. Routine electroencephalograph (EEG) shows generalized 4‐ to 6‐Hz spike–polyspike– slow wave discharges. Seizures have specific precipitating factors such as physical and mental stress, photic stimulation, menstrual cycles, alcohol consumption, and very particularly, sleep deprivation [1]. Seizures in about 70–85% of the patients respond to valproate monotherapy [2]. Epilepsy has a complex relationship with sleep, the latter affecting the former and vice versa. Sleep has been known to play a protective role in JME [3], whereas certain seizure types are known to occur more commonly in sleep than the waking state [4,5]. In another study from the same center, patients with JME had significant sleep disturbances ⁎ Corresponding author. Fax: +91 8026564830. E-mail address: [email protected] (S. Sinha). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.08.009
characterized by excessive daytime sleepiness and disturbed night sleep, despite adequate medications and good seizure control [6]. Although sleep has been known to have a protective effect in JME, interictal epileptiform discharges (ED) are known to occur in sleep [7–9]. What about the IEDs occurring during sleep in JME? Are they any different with AED therapy? In this study, we sought to understand this complex relationship using overnight polysomnography (PSG) studies in patients with JME on valproate monotherapy and others who were drug‐naïve. To do so, we studied the effects of ‘epilepsy on sleep and its architecture’ and ‘sleep on the occurrence and distribution of interictal epileptiform discharges (ED) across various stages of sleep’ and compared between drug-naïve patients with JME, JME on valproic acid (VPA) monotherapy, and healthy volunteers using structured sleep questionnaires, EEG, and overnight PSG studies. 2. Patients and methods Forty patients with JME (M: F= 18:22, age at evaluation: 22.6 ± 5.7 years) meeting the ILAE diagnostic criteria [10,11] and 20 age‐ and gender‐matched controls (M: F= 9:11; age: 23.5 ±4.7 years) were
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recruited from Aug 2010 to July 2011 for the study from the out-patient neurological services of a university teaching hospital and major referral center for neuro-psychiatric illness in south India. The sleep studies were carried out in the sleep laboratory, Department of Neurology at our center. Ethical approval from the institutional ethics committee and written informed consent from all the subjects were obtained. Patients with co-morbid illness (medical or psychiatric) or on medication affecting sleep (other than VPA) were excluded from the study to minimize the effect of confounding factors. Twenty age‐ and gender‐matched healthy controls were also recruited for the study (Male: Female = 9:11; age: 23.5 ±4.7 years) who were friends of the patients and hospital medical personnel on routine day duties. They were not related to any of the patients and did not have a family history of epilepsy. Forty patients with JME could be subdivided into two groups of twenty patients each: (a) Group I — on valproate monotherapy (age: 20.8 ± 4.0 years; Male: Female = 9:11) and (b) Group II — drug‐naïve (age: 24.4± 6.7 years; Male: Female = 9:11). Patients in Group II were either never on VPA or who had stopped VPA or other AEDs on their own for more than 4 weeks prior to evaluation. Drug‐naïve patients were evaluated on the same day of recruitment into the study including PSG on the same night, and the appropriate AED was initiated the very next day. Patients also could be divided into two subgroups: Gr A (n= 18): controlled seizures (those on valproate — 18/20) and Gr B (n= 22): had seizures during initial evaluation (Day 1), i.e., drug‐naïve −20 plus 2/20 of the valproate group. All patients and controls underwent a structured evaluation, including a detailed clinical, family, and treatment history, neurological examination, 16-channel electroencephalogram (EEG), and other investigations when indicated. Imaging of the brain was normal in all patients and controls. They were administered validated sleep questionnaires such as the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Following this evaluation, overnight PSG was recorded for only one night. During the PSG study, precautions were taken to keep the patient comfortable as per their routine as far as possible. All subjects underwent PSG conducted at the sleep laboratory in the Department of Neurology according to the American Association of Sleep Medicine (AASM) 2007 guidelines. Valproic acid was continued unaltered during the study in Group I, but non-essential drugs (if any) were discontinued. The PSG recording was carried out using an eight-channel EEG, electrocardiograph, chin electromyography (EMG), right anterior tibialis EMG, electro-oculogram, nasal thermistor, snore monitor, chest and abdominal movements, pulse rate, and oximetry. Routine scalp‐EEG was carried out before the overnight PSG using standard procedures. It was recorded on 16-channel “Galileo NT (EBN)” machine, employing the international 10‐20 system of electrode placement using standard parameters and procedures, e.g., High Filter — 70 Hz; Low Filter — 0.1 Hz; Recording time: 30 min; Sensitivity: 7 uV/mm; Sweep speed: 10 s/page; and Sampling rate: 256 Hz. The paroxysmal abnormalities in the form of spike–polyspike and waves were noted during the awake segment of the routine EEG. The EEG and PSG records were reported according to the AASM 2007 guidelines [12] by 2 investigators (CTR, SS), and in case of disagreement, the conclusions were sorted out by discussion. The epileptiform discharges (EDs), namely spike/polyspike–slow wave complexes and occasionally spikes, were identified and quantified throughout each PSG. The number of each ED event and duration was noted across all stages of sleep. The EDI (Epileptiform Discharge Index) per stage of sleep was calculated using the number of EDs in each sleep stage (in min) and ED rate by total EDs in min/sleep stage in min × 100 (modified from [13]). The presence of arousal in various stages of sleep and its relation with EDs and K‐complexes were noted.
Table 1 Phenotypic features of 40 patients with juvenile myoclonic epilepsy (JME) and 20 healthy controls. Parameters
Gr I (n = 20) [on VPA]
Gr II (n = 20) [drug‐naïve]
Controls (n = 20)
p
Mean age (years) M:F MJs GTCS Absence > 1 MJs/day >1 GTCS/year VPA dose (mg) Abnormal routine EEG Abnormal EEG–PSG ESS PSQI ESS ≥10 PSQI ≥5
20.8 ± 4.0 9:11 20 18 1 15 10 795 ± 196 7 17 6.9 ± 3.6 4.3 ± 2.3 5 9
24.4 ± 6.7 9:11 20 20 1 9 7 – 15 18 5.1 ± 3.6 6.1 ± 4.9 2 10
23.5 ± 4.7 9:11 – – – – – – – – 4.6 ± 2.4 2.8 ± 1.7 0 3
NS 1.0 1.0 0.5 1.0 0.1 0.5 – 0.02 1.0 0.09 0.06 0.4 0.9
GTCS: generalized tonic‐clonic seizures; MJs: myoclonic jerks; PSG: polysomnograph. ESS: Epworth Sleepiness Scale; PSQI: Pittsburgh Sleep Quality Index; VPA: sodium valproate.
modified t test was used to compare means of two groups. Analysis of variance was used for comparing means of three groups. Fisher's Exact Probability test was used to compare the counts (frequencies). 3. Results 3.1. Phenotypic features Forty patients with JME aged between 15 and 45 years (Male: Female = 18:22, age at evaluation: 22.6 ± 5.7 years) were studied. The mean body mass index (BMI) in both the subgroups and controls were Group I — 20.9 ± 2.7, Group II — 24.1 ± 6.6, and controls — 21.6 ± 2.8 (p = 0.068). The mean duration of seizures (in years) in Group I was 7.7 ± 4.9 and Group II — 7.5 ± 5.8. All the patients in Group I (age — 20.8 ± 4.0 years; Male: Female = 9:11) and Group II (age — 24.4 ± 6.7 years; Male: Female = 9:11) had myoclonic jerks (MJs — 100%). Along with MJs, eighteen (90%) patients in Group I and all twenty patients in Group II (100%) had GTCS, and only one (5%) patient in each group had absence seizures. Seizures were controlled in 18/20 patients in Group I with VPA. There was no GTCS at least for a week in either of the groups prior to the evaluation. Imaging was normal in all the 40 patients and 20 controls. (Table 1). 3.2. EEG observations Routine 16-channel awake EEG revealed normal background in all the patients. The epileptiform discharges (EDs) were noted during the awake part of the routine EEG with significant abnormalities
2.1. Statistics Statistical Package for the Social Sciences (SPSS) (version 11) software was used to carry out the statistical analysis. Student's t test or
Fig. 1. Distribution of epileptiform discharges (EDs) in sleep stages in patients on VPA (Group I) vs. those who were drug‐naïve (Group II).
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b) Polysomnographic (PSG) parameters such as total sleep time (TST), sleep efficiency, N1%, N2%, N3%, REM%, total NREM%, arousal index (AI) of NREM and REM, isolated leg movement index (IMI), periodic leg movement index (PLMI), and apnea–hypopnea index (AHI) were calculated and compared between the two groups. All the parameters were statistically insignificant between the groups. 3.4. Effect of sleep on epileptiform discharges (EDs)
Fig. 2. Distribution of epileptiform discharges (EDs) in sleep stages in patients with good seizure control (Group A) vs. those with persistent seizures (Group B).
seen in Group II (p = 0.025). Epileptiform discharges were present in twenty-two out of forty patients (Group I: 7; Group II: 15; p = 0.02), six during photic stimulation (Group I: 2; Group II: 4, p = 0.7), and seven during hyperventilation (Group I: 3; Group II: 4, p = 1.0). As expected, drug‐naïve patients (Gr II) had EEG abnormalities more often. All twenty controls had a normal awake EEG (Fig. 1).
3.3. Effect of epilepsy on sleep a) Assessment using structured sleep questionnaires: the details are shown in Table 1. There was no statistically significant difference between the groups in terms of mean PSQI score or PSQI score ≥ 5 and mean ESS score or ESS score ≥ 10. There results were significant in terms of PSQI scores when both Group I and Group II patients were combined together and compared with the controls (p = 0.019), indicating altered sleep quality in JME patients.
During overnight PSG, thirty‐five patients showed abnormal EDs in all the sleep stages (Group I: 17 and Group II: 18). The EDs were then quantified in every patient in all stages of sleep. Group I had a total of 656 EDs (32.8 ± 40.0) in 7481.0 min (0.09 EDs/min) of sleep (including NREM + REM), and Group II had 493 EDs (24.6 ± 31.0) in 7477.5 min (0.07 EDs/min). The number and distribution of EDs in different sleep stages are given in Fig. 1 and Table 2. Epileptiform Discharge Index (EDI) was calculated for each patient by counting the number of EDs per minute of sleep in the various stages of sleep (Table 2). The duration of each ED was measured in all the patients, and the total ED duration per minute per stage was calculated (ED rate = total EDs in min/sleep stage in min × 100). The results are given in Table 2. Group I patients were found to spend a total of 4.936 min in EDs out of 7481.0 min of sleep (0.07%), and Group II patients spent 4.208 min in EDs out of 7477.5 min of sleep (0.06%). Epileptiform discharges were frequently associated with arousals in N1/REM and K-complexes in N2. All the patients in Group I had well‐controlled seizures except for two (patients 6 and 12). The number of patients with well-controlled seizures (Gr A) vs. those with persistent seizures (Gr B) showing EDs in different stages of sleep is given in the chart (Fig. 2). Patients in Group B had decreased EDs in N2 (p = 0.04) and N3 (p = 0.03) compared to Group A. A trend toward association of EDs with arousals was more often observed in Group A compared to Group B (p = 0.06). The ED indices and ED rate were also calculated in Group A and Group B patients. There were no differences in any of the parameters in those with (n = 6) and without (n = 34) a photoparoxysmal response.
Fig. 3. Epileptiform discharges (EDs) during awake and sleep in patients with JME: (A) is from an eighteen‐year‐old drug-naïve woman with polyspike–wave complexes during photic stimulation in a 16-channel EEG; Panel (B) is from a nineteen‐year‐old man on VPA with epileptiform discharges (ED) with a K-complex and spindle in a polysomnograph (PSG); (C) is from a twenty-one‐year‐old woman on VPA with ED in N3 in a PSG and (D) is from a nineteen‐year‐old woman on VPA with ED in REM sleep in PSG.
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Table 2 Polysomnographic (PSG) parameters among patients with juvenile myoclonic epilepsy (JME = 40) and healthy controls (n = 20). TST
N1%
N2%
N3 %
Total NREM%
REM%
AI-NREM
AI-REM
IMI
PLMI
AHI
5.3 2.9 10.8 6.5 9.1 14.0 18.5 17.3 6.4 13.3 11.1 10.8 6.0 7.7 5.1 3.9 2.2 5.7 6.0 7.6 8.5 4.5
42.7 44.8 33.2 39.9 45.9 35.4 39.1 38.0 26.2 26.2 43.8 30.1 32.1 44.3 37.1 37.4 31.2 22.2 33.4 26.0 35.4 7.1
36.4 24.7 30.5 37.1 0 19.9 10.4 20.1 30.3 29.8 7.9 20.1 18.4 15.8 24.5 33.3 32.5 19.9 20.3 19.5 22.6 9.7
84.4 72.4 74.5 83.6 55.0 69.3 68.0 75.5 62.8 69.3 62.8 61.0 56.5 67.7 66.6 74.6 65.9 47.8 59.7 53.1 66.5 9.6
12.6 13.7 13.0 9.0 6.4 17.0 9.1 14.4 5.7 14.0 15.6 12.7 9.0 25.8 13.6 24.7 12.9 10.3 14.0 9.7 13.2 5.1
3.9 9.8 9.3 12.8 9.6 20.1 10.9 8.4 6.7 13.6 7.7 17.4 13.3 8.2 3.8 5.0 4.5 13.3 7.6 11.1 9.8 4.3
2.0 5.3 6.3 16.8 8.9 7.5 20.5 2.7 10.4 9.0 6.1 11.8 4.7 6.3 4.9 1.9 1.8 13.3 6.3 2.5 7.5 5.1
4.2 4.2 6.6 9.2 22.8 4.7 24.2 3.2 5.0 4.7 14.5 6.5 0.6 4.8 7.4 3.0 0.1 8.1 4.0 1.7 7.0 6.5
2.1 0 0 4.8 0 3.4 87.6 0.9 6.3 0 8.2 3.6 0 0.5 3.3 0 0 1.3 0 0 6.1 19.3
0.5 0.1 0.1 1.3 0.2 0 0.8 0 0 0 0 0 0 0 0.6 0.2 0 0.4 0 0 0.2 0.3
GROUP II — drug‐naïve (n = 20) 1 5.5 75.4 2 7.4 91.8 3 7.2 86.6 4 6.5 87.4 5 5.8 95.5 6 7.7 95.0 7 4.5 62.5 8 6.2 84.1 9 7.3 93.7 10 7.1 90.9 11 7.1 92.6 12 6.4 77.1 13 5.5 70.0 14 7.2 88.5 15 7.2 88.6 16 7.9 92.8 17 3.9 53.6 18 1.2 17.2 19 6.9 89.7 20 6.1 81.7 Mean 6.2 80.7 SD 1.6 18.7
4.3 1.0 3.7 2.9 2.2 6.8 6.6 6.4 2.4 7.6 12.0 14.1 9.5 6.8 15.9 6.8 19.5 7.3 5.1 8.5 7.5 4.8
47.3 27.1 34.6 35.4 27.1 40.9 16.5 16.5 24.7 41.1 51.3 32.3 34.8 52.4 52.7 42.3 40.1 6.6 34.8 51.5 35.5 12.9
20.0 49.1 34.1 37.5 53.4 30.2 43.5 47.4 51.4 21.4 6.6 20.6 18.4 17.6 8.3 15.5 0.9 10.7 38.7 16.2 27.1 16.3
71.6 77.2 72.3 75.8 82.7 77.9 66.6 70.3 78.5 70.0 69.9 67.0 62.8 76.8 77.0 64.7 60.4 24.5 78.5 76.2 70.0 12.3
8.8 16.8 17.8 8.7 14.5 18.7 1.3 17.3 18.4 22.6 23.8 12.4 11.9 13.3 12.5 32.3 0 0 16.0 13.8 14.0 7.9
14.3 3.1 5.4 4.4 2.8 7.2 9.9 10.7 9.4 12.1 9.8 8.8 11.2 11.5 14.6 14.6 38.9 11.6 9.0 18.1 11.4 7.6
26.7 1.5 0.7 4.9 1.2 4.7 0 4.9 5.7 6.3 2.2 5.0 5.7 20.8 21.0 14.8 0 0 11.9 8.6 7.3 7.8
6.0 2.4 3.2 4.6 9.7 8.6 9.7 11.6 13.4 14.0 6.8 2.8 9.3 5.0 4.9 5.2 15.4 8.3 1.3 10.7 7.6 4.1
0.5 0 0 0 3.1 47.5 7.1 8.2 18.1 3.8 11.7 0 12.5 10.6 1.5 4.0 4.6 3.3 0 12.5 7.4 10.8
0.1 0.4 0 0 3.4 0.1 0 0.2 1.5 0 0.1 0.3 1.1 0.3 7.1 0.3 0.3 0 0.3 3.0 0.9 1.7
Healthy control (n = 20) 1 6.4 2 6.1 3 7.2 4 6.8 5 6.2 6 6.8 7 6.3 8 6.8 9 6.7 10 6.0 11 6.6 12 4.9 13 7.1 14 7.6 15 6.5 16 7.3 17 6.2 18 4.4 19 6.2 20 6.2 Mean 6.4 SD 0.7 p value 0.9
16.1 13.0 5.7 16.3 6.8 2.8 7.5 12.2 8.6 6.3 6.8 15.3 12.1 8.2 7.7 7.6 8.9 11.4 4.7 9.5 9.3 3.7 0.4
42.5 36.9 47.0 39.9 33.1 51.2 46.3 32.1 41.3 41.4 38.7 32.6 54.6 47.8 54.3 37.2 36.3 25.2 46.3 52.8 41.9 8.1 0.06
24.9 15.2 21.4 18.6 38.2 22.2 22.0 28.7 26.3 23.9 26.1 8.0 13.0 20.0 13.4 26.2 21.0 13.0 26.3 12.6 21.0 7.1 0.2
83.5 65.1 74.2 74.7 78.1 76.2 75.8 73.0 76.1 71.6 71.6 55.9 79.7 76.0 75.4 71.0 66.2 49.6 77.4 74.8 72.3 7.9 0.2
7.3 20.2 20.9 12.2 18.4 21.0 20.6 19.6 16.0 20.7 18.2 9.0 14.8 17.2 16.2 25.4 20.4 14.6 10.5 12.1 16.8 4.7 0.2
15.5 18.4 5.9 18.0 7.0 10.1 6.8 10.4 10.6 7.1 12.5 31.8 10.1 8.9 18.8 8.2 13.8 8.3 15.2 22.0 13.0 6.4 0.3
9.7 11.0 3.2 14.6 7.7 2.7 3.7 10.3 6.0 6.7 2.2 4.4 12.6 4.3 20.0 17.7 1.4 3.0 5.4 12.7 8.0 5.4 0.9
9.8 8.0 2.9 5.8 9.6 6.7 3.3 6.3 5.4 1.5 2.3 7.8 8.1 5.0 7.1 11.4 5.5 3.4 7.2 5.8 6.1 2.6 0.6
11.3 0 0 0 1.0 1.6 2.4 0.9 0.7 0 0 0 1.0 5.0 0 2.3 3.7 0 1.1 0 1.5 2.7 0.3
0.2 0 0 0.4 1.3 0.8 1.8 0 0 0.2 0 0 0.9 0.8 0.3 0.7 0 0 0 0.2 0.4 0.5 0.1
Group I — on 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean SD
Sleep efficiency
VPA (n = 20) 7.7 94.0 7.2 81.2 7.5 85.8 7.9 92.4 4.3 52.1 6.8 79.4 6.2 71.5 6.8 84.1 4.6 58.4 6.7 79.8 6.6 77.7 4.9 60.7 4.7 51.5 7.4 90.4 7.3 79.2 6.4 98.0 6.7 75.7 4.7 55.5 5.0 69.0 5.2 59.9 6.2 74.8 1.2 14.4
85.8 79.4 91.2 85.0 84.6 96.9 94.7 91.0 89.9 90.8 86.2 61.9 92.2 92.8 89.5 90.2 79.9 59.2 82.3 84.8 85.4 9.7 0.08
TST: total sleep time; AI-NREM: apnea index-non rapid eye movement; AI-REM: apnea index-rapid eye movement; ILMI: isolated limb movement index; PLMI: periodic limb movement index; AHI: apnea–hypopnea index.
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4. Discussion The effect of sleep on epilepsy in general and vice versa has been well documented. Nocturnal seizures usually occur during Stages 1 and 2 of NREM (non-rapid eye movement) sleep. Seizures in certain epilepsy syndromes characteristically occur in sleep, such as frontal lobe epilepsy, temporal lobe epilepsy (TLE), benign childhood epilepsy with centro-temporal spikes, Lennox–Gastaut syndrome; while others follow awakening from sleep, such as JME. Despite the well-established association with sleep in patients with JME, effects of epilepsy on sleep and vice versa have not been adequately studied. Sleep disturbances in patients with epilepsy may be secondary to AEDs, nocturnal seizures, or a concomitant sleep disorder such as sleep apnea or restless leg syndrome. The previous studies on JME and sleep have used patients on multiple AEDs or on polytherapy and EEG alone to analyze sleep [6,13]. The present study focused on patients with JME on VPA monotherapy vs. drug-naïve patients using sleep questionnaires, overnight PSG, and EEG. It is believed that VPA and other AEDs are used to reduce the occurrence of epileptic discharges and alleviate sleep disruption due to epileptic seizures. Hence, this study was planned to analyze the difference in the occurrences of interictal epileptiform discharges (EDs) across sleep stages between those on VPA monotherapy and drug-naïve individuals, and the effect of these EDs on sleep (Fig. 3). 4.1. Clinical and EEG profile The phenotypic characteristic of JME observed in this study is consistent with the published literature worldwide [14–16]. The mean age in drug‐naïve patients was more compared to that on valproate. The difference was statistically insignificant. Absences were significantly less than those reported from other studies, probably related to the older age and also to effective therapy. As in some studies, a rise in myoclonus frequency was noted during menstruation [17]. Myoclonic jerk as the only seizure type was seen in 6% of patients, which is the case in 7–17% of JME patients [17,18]. Routine awake EEG revealed abnormalities in 55% of patients, slightly lower than the 60–90% reported in the literature [1,17]. In this study, half of the patients underwent EEG while on a stable regimen of VPA. This may have impacted the prevalence of EEG abnormalities. However, prolonged recording with overnight PSGs showed abnormalities in 87.5% of cases. However, in this study, the duration of the EEG (30 min) was short compared to that of the PSG (overnight), which might have led to occurrence of increased epileptiform activity in PSG–EEG. 4.2. Sleep disturbances Assessment by sleep questionnaires in the patient groups (Group I + Group II) revealed significantly higher PSQI scores compared to the control group (p = 0.02), indicating that epilepsy might have contributed to the poor quality of sleep. Similar findings were reported in studies on other types of epilepsy [14]. However, there is lack of similar published studies on patients with JME. In a study on refractory temporal lobe epilepsy (TLE = 40) evaluated with ESS and PSQI, the Global PSQI was high (mean = 5.65 ± 3.71; p b 0.001). Pittsburgh Sleep Quality Index revealed higher and statistically significant scores in three components as well as in the global score, when analyzed by predominance of daytime or nocturnal seizures [19]. Pung and Schmitz studied 20 patients with JME and temporal lobe epilepsy (TLE) using standardized questionnaires with respect to the sleep– wake rhythm and personality profiles. They found that patients with JME had a tendency to go to bed later at night, to get up later in the morning, and to feel fit at a later time during the day compared to patients with TLE [20].
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In the current study, none of the PSG parameters were statistically significant between the groups except a trend toward a slightly higher sleep efficiency (p = 0.08), and higher N2% (p = 0.06) was seen in the control group. Gigli et al. (1992) found higher CAP rates in 10 JME patients (46.7%) when compared to age-matched controls (23%) during all-night PSG recording [8]. Dhanuka et al. studied sleep EEG findings in 15 patients to evaluate for abnormal IEDs, without an attempt to study sleep macrostructure [13]. The patients were either on various AEDs — single or multiple AEDs (n = 5) or drug‐ naïve (n = 9). Bonakis and Koutroumanidis studied video-EEG of patients with JME (n = 19) vs. controls (n = 9) on various AEDs. Sleep EEG was recorded after partial sleep deprivation for a period of 30–45 min, aiming mainly to attain light sleep (Stages 1 and 2). Slow wave sleep (SWS) and REM sleep were rare. Higher CAP rates were noted than for controls (p b 0.05) [7]. 4.3. Effect of sleep on epileptiform discharges (EDs) Sleep has a modulating effect on the distribution of EDs in different forms of epilepsy. Epileptiform discharges occur more commonly in NREM sleep, which acts as the precipitating factor for EDs [19,21–23], than REM sleep which is an inhibiting factor [21,24–26]. Lighter stages of NREM sleep are more prone for the abnormal epileptic activity [24,27]. Nocturnal frontal lobe seizures are known to occur during sleep [5], and temporal lobe seizures often secondarily generalize in slow wave sleep. Idiopathic generalized epilepsies are documented to have EDs more commonly in the lighter stages of NREM sleep [7,8,27]. The present study showed that the distribution of EDs in sleep was frequent (ED Index) in N1 (p = 0.053*) in Group II and N3 (p = 0.059*) in Group I and Group A (p = 0.035), and a relatively higher total number of EDs occurred in N2 in Group I (p = 0.078*). The average rate of EDs was higher in Group II compared to Group I (0.2 EDs/min vs. 0.06 EDs/min). The EDs in Group I were more frequent in N2/N3, whereas Group II showed a higher frequency of EDs/min in N1 and REM but without statistical significance. The presence of excess of EDs in REM in drug‐naïve patients is an interesting observation, and the role of valproate in suppressing such discharges in REM stage or alteration in sleep architecture requires further studies. Previous reports showed an increased discharge rate in NREM, either light sleep [7,13] or slow wave sleep [8]. However, comparison between the studies cannot be truly made due to difference in the patient group, methods of recording, or analysis of sleep architecture. 4.4. Effect of seizure control and VPA on sleep and EDs As there were two patients with uncontrolled seizures on valproate (patients 6 and 12 in Group I) due to poor adherence, we calculated the difference between patients with nil clinical seizures (Group A, n=18) and patients with persistent clinical seizures on day 1 of evaluation (Group B, n=22) in terms of number of EDs, ED indices, and ED rates. Group A showed significantly higher number of EDs in N2 (p=0.043), a higher ED Index in N3 as well (p=0.035) similar to that observed by Gigli et al. [8], and a slight trend with higher frequency of EDs in N1 and N2. The other parameters were statistically insignificant between Group A and Group B. Based on the findings of this study on the effect of EDs on sleep and vice versa between a group of drug-naïve and patients on VPA monotherapy, EDs seem to be frequent (ED Index) in N3 in Group I (p=0.059) and in N1 in Group II (p=0.053), but Group A with good control of clinical seizures showed an overall higher frequency in NREM sleep, especially SWS (p=0.03) and increased total number of EDs noted in N2 in (p=0.04). Spike–wave and polyspike–wave complexes are preferentially known to occur during sleep onset due to the augmented synaptic responsiveness of cortical neurons [28–30]. They commonly occur during the depolarization phase of cortical slow oscillation. The cortical
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slow oscillations are initiated in N2 and become more pronounced in N3 [9]. Due to the enhanced synaptic responsiveness of the cortical neurons during sleep onset and prolonged depolarizing membrane potentials, EDs are more common in NREM sleep [21,22,25,27]. Our study shows a similar finding in Group I and Group A. There was no difference in terms of ED indices (p = 0.5) or ED rates (p = 0.7) in light sleep (N1 + N2) between Groups I and II. The EDs are not easily facilitated by REM sleep as it is characterized by irregular tonic activation (resynchronization) of cortical neurons similar to the awake state [21,25,31]. In spite of this, REM sleep also represents a transition of vigilance state from NREM sleep, usually after SWS. Most of the EDs in REM sleep seen in both the groups, especially in Group II, were seen more so during the transition phases and less so during the established REM sleep [21]. This could explain EDs being more common in REM in Group II than Group I as there was a frequent interruption of REM sleep by other vigilance states. Although the seizures seemed to be controlled in patients on VPA (Group I), interictal EDs during sleep were noted in as many as in drug-naïve patients (Group II). Patients on VPA spend as much time in EDs in sleep as in the drug-naïve group (Total ED rate, p > 0.05). In spite of being on a conventional antiepileptic dose of VPA, it does not seem to have an effect against IEDs in sleep. Interictal EDs in sleep do not respond to valproate. On the contrary, patients on usual dosages of VPA have slightly higher frequency of abnormal epileptiform discharges in N3 (Group I — p = 0.059 and Group A — p = 0.03) and a higher total number of discharges in N2 (Group A, p = 0.04) when compared to drug-naïve (Group II) or patients who are still symptomatic (Group B). This may be explained as the patients on VPA therapy had a slightly longer duration of illness compared to the drug-naïve group (Group I — 7.7 ± 4.9 years and Group II — 7.5 ± 5.8 years). The controls showed a trend toward higher sleep efficiency and N2% than the patients with JME. Time spent in EDs in sleep in these patients is equivalent to sleep lost (for that amount of time) however insignificant and hence may lead to a vicious unbreakable cycle of sleep disruption and partially controlled or uncontrolled seizures, further affecting the daytime functioning. The first-night effect of PSG could not be excluded since the subjects underwent study only for one night due to financial limitations. Analysis regarding CAP was not carried out. Comparison of 16 channel EEG vs. 8 channel PSG–EEG might have its own limitation. This is one of the first studies on JME that highlighted alterations in sleep quality and architecture and interictal epileptiform activity observed more often in sleep than wakefulness with light sleep (N1) and REM possibly having facilitation, especially in drug‐naïve patients when compared to patients on valproate (N3). These abnormalities were noted despite all the patients being on adequate treatment and a majority reporting good seizure control. This study highlights the persistent nature of the sleep-epilepsy association, which has significant therapeutic implications in a sleep-sensitive epilepsy like JME.
Acknowledgment This study was supported by partial funding from the Department of Science and Technology, Govt. of India, New Delhi (SR/SO/HS/108/ 2007). The contribution of Mr. Perumal, Electrophysiology Technologist, in recording polysomnography is acknowledged.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Interrelationship of sleep and juvenile myoclonic epilepsy (JME): A sleep questionnaire‐, EEG‐, and polysomnography (PSG)‐based prospective case–control study C.T. Ramachandraiah a, S. Sinha a,⁎, A.B. Taly a, S. Rao b, P. Satishchandra a a b
Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560029, Karnataka, India Department of Biostatistics, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India
a r t i c l e
i n f o
Article history: Received 1 June 2012 Revised 6 August 2012 Accepted 8 August 2012 Available online 24 October 2012 Keywords: Electroencephalogram Juvenile myoclonic epilepsy Polysomnogram Sleep questionnaire Valproic acid
a b s t r a c t We studied the effects of ‘epilepsy on sleep and its architecture’ and ‘sleep on the occurrence and distribution of interictal epileptiform discharges (ED)’ using ‘sleep questionnaires’, ‘EEG’, and ‘PSG’ in patients with JME. Forty patients with JME [20 on valproate (Group I — 20.8±4.0 years; M: F=9:11) and 20 drug-naïve (Group II — 24.4± 6.7 years; M: F=9:11)] and 20 controls (M: F=9:11; age: 23.5±4.7 years) underwent assessment with Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), overnight PSG, and scalp-EEG. Epileptiform discharges (EDs) were quantified in different sleep stages. The ‘ED Index’ was derived as number of EDs/min per stage. Statistical Package for the Social Sciences (SPSS) vs. 11 was used for statistical analysis. A ‘p’ b0.05 was considered as statistically significant. There was poor sleep quality in patients compared to controls (p=0.02), while there was no significant difference in ESS scores between the groups. The PSG parameters were comparable in both groups. Routine EEG revealed EDs in 22/40 (Group I: 7 and Group II: 15) patients. Thirty-five patients had EDs in various sleep stages during PSG (Group I: 17 and Group II: 18): N1 — Group I: 9 and Group II: 14, N2 — Group I: 14 and Group II: 14, N3 — Group I: 14 and Group II: 10, and REM — Group I: 9 and Group II: 11. The ED Index was higher during N2/N3 in Group I and N1/REM in Group II. The epileptiform discharges were frequently associated with arousals in N1/REM and K-complexes in N2. There was no other significant difference between Groups I and II. In conclusion, there was poor sleep quality in patients with JME compared to controls, especially those on valproate who had altered sleep architecture. Epileptiform activity was observed more often in sleep than wakefulness. Sleep stages had variable effect on epileptiform discharges with light sleep having a facilitatory effect in the drug‐naïve group and slow wave sleep having a facilitatory effect in the valproate group. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Juvenile myoclonic epilepsy (JME) is a common primary epilepsy syndrome characterized by adolescent-onset myoclonic jerks (MJ) with or without generalized tonic-clonic (GTCS) or absence seizures. Myoclonic jerks or GTCS classically occur on awakening and following a night of sleep deprivation, either partial or total. Routine electroencephalograph (EEG) shows generalized 4‐ to 6‐Hz spike–polyspike– slow wave discharges. Seizures have specific precipitating factors such as physical and mental stress, photic stimulation, menstrual cycles, alcohol consumption, and very particularly, sleep deprivation [1]. Seizures in about 70–85% of the patients respond to valproate monotherapy [2]. Epilepsy has a complex relationship with sleep, the latter affecting the former and vice versa. Sleep has been known to play a protective role in JME [3], whereas certain seizure types are known to occur more commonly in sleep than the waking state [4,5]. In another study from the same center, patients with JME had significant sleep disturbances ⁎ Corresponding author. Fax: +91 8026564830. E-mail address: [email protected] (S. Sinha). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.08.009
characterized by excessive daytime sleepiness and disturbed night sleep, despite adequate medications and good seizure control [6]. Although sleep has been known to have a protective effect in JME, interictal epileptiform discharges (ED) are known to occur in sleep [7–9]. What about the IEDs occurring during sleep in JME? Are they any different with AED therapy? In this study, we sought to understand this complex relationship using overnight polysomnography (PSG) studies in patients with JME on valproate monotherapy and others who were drug‐naïve. To do so, we studied the effects of ‘epilepsy on sleep and its architecture’ and ‘sleep on the occurrence and distribution of interictal epileptiform discharges (ED) across various stages of sleep’ and compared between drug-naïve patients with JME, JME on valproic acid (VPA) monotherapy, and healthy volunteers using structured sleep questionnaires, EEG, and overnight PSG studies. 2. Patients and methods Forty patients with JME (M: F= 18:22, age at evaluation: 22.6 ± 5.7 years) meeting the ILAE diagnostic criteria [10,11] and 20 age‐ and gender‐matched controls (M: F= 9:11; age: 23.5 ±4.7 years) were
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recruited from Aug 2010 to July 2011 for the study from the out-patient neurological services of a university teaching hospital and major referral center for neuro-psychiatric illness in south India. The sleep studies were carried out in the sleep laboratory, Department of Neurology at our center. Ethical approval from the institutional ethics committee and written informed consent from all the subjects were obtained. Patients with co-morbid illness (medical or psychiatric) or on medication affecting sleep (other than VPA) were excluded from the study to minimize the effect of confounding factors. Twenty age‐ and gender‐matched healthy controls were also recruited for the study (Male: Female = 9:11; age: 23.5 ±4.7 years) who were friends of the patients and hospital medical personnel on routine day duties. They were not related to any of the patients and did not have a family history of epilepsy. Forty patients with JME could be subdivided into two groups of twenty patients each: (a) Group I — on valproate monotherapy (age: 20.8 ± 4.0 years; Male: Female = 9:11) and (b) Group II — drug‐naïve (age: 24.4± 6.7 years; Male: Female = 9:11). Patients in Group II were either never on VPA or who had stopped VPA or other AEDs on their own for more than 4 weeks prior to evaluation. Drug‐naïve patients were evaluated on the same day of recruitment into the study including PSG on the same night, and the appropriate AED was initiated the very next day. Patients also could be divided into two subgroups: Gr A (n= 18): controlled seizures (those on valproate — 18/20) and Gr B (n= 22): had seizures during initial evaluation (Day 1), i.e., drug‐naïve −20 plus 2/20 of the valproate group. All patients and controls underwent a structured evaluation, including a detailed clinical, family, and treatment history, neurological examination, 16-channel electroencephalogram (EEG), and other investigations when indicated. Imaging of the brain was normal in all patients and controls. They were administered validated sleep questionnaires such as the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Following this evaluation, overnight PSG was recorded for only one night. During the PSG study, precautions were taken to keep the patient comfortable as per their routine as far as possible. All subjects underwent PSG conducted at the sleep laboratory in the Department of Neurology according to the American Association of Sleep Medicine (AASM) 2007 guidelines. Valproic acid was continued unaltered during the study in Group I, but non-essential drugs (if any) were discontinued. The PSG recording was carried out using an eight-channel EEG, electrocardiograph, chin electromyography (EMG), right anterior tibialis EMG, electro-oculogram, nasal thermistor, snore monitor, chest and abdominal movements, pulse rate, and oximetry. Routine scalp‐EEG was carried out before the overnight PSG using standard procedures. It was recorded on 16-channel “Galileo NT (EBN)” machine, employing the international 10‐20 system of electrode placement using standard parameters and procedures, e.g., High Filter — 70 Hz; Low Filter — 0.1 Hz; Recording time: 30 min; Sensitivity: 7 uV/mm; Sweep speed: 10 s/page; and Sampling rate: 256 Hz. The paroxysmal abnormalities in the form of spike–polyspike and waves were noted during the awake segment of the routine EEG. The EEG and PSG records were reported according to the AASM 2007 guidelines [12] by 2 investigators (CTR, SS), and in case of disagreement, the conclusions were sorted out by discussion. The epileptiform discharges (EDs), namely spike/polyspike–slow wave complexes and occasionally spikes, were identified and quantified throughout each PSG. The number of each ED event and duration was noted across all stages of sleep. The EDI (Epileptiform Discharge Index) per stage of sleep was calculated using the number of EDs in each sleep stage (in min) and ED rate by total EDs in min/sleep stage in min × 100 (modified from [13]). The presence of arousal in various stages of sleep and its relation with EDs and K‐complexes were noted.
Table 1 Phenotypic features of 40 patients with juvenile myoclonic epilepsy (JME) and 20 healthy controls. Parameters
Gr I (n = 20) [on VPA]
Gr II (n = 20) [drug‐naïve]
Controls (n = 20)
p
Mean age (years) M:F MJs GTCS Absence > 1 MJs/day >1 GTCS/year VPA dose (mg) Abnormal routine EEG Abnormal EEG–PSG ESS PSQI ESS ≥10 PSQI ≥5
20.8 ± 4.0 9:11 20 18 1 15 10 795 ± 196 7 17 6.9 ± 3.6 4.3 ± 2.3 5 9
24.4 ± 6.7 9:11 20 20 1 9 7 – 15 18 5.1 ± 3.6 6.1 ± 4.9 2 10
23.5 ± 4.7 9:11 – – – – – – – – 4.6 ± 2.4 2.8 ± 1.7 0 3
NS 1.0 1.0 0.5 1.0 0.1 0.5 – 0.02 1.0 0.09 0.06 0.4 0.9
GTCS: generalized tonic‐clonic seizures; MJs: myoclonic jerks; PSG: polysomnograph. ESS: Epworth Sleepiness Scale; PSQI: Pittsburgh Sleep Quality Index; VPA: sodium valproate.
modified t test was used to compare means of two groups. Analysis of variance was used for comparing means of three groups. Fisher's Exact Probability test was used to compare the counts (frequencies). 3. Results 3.1. Phenotypic features Forty patients with JME aged between 15 and 45 years (Male: Female = 18:22, age at evaluation: 22.6 ± 5.7 years) were studied. The mean body mass index (BMI) in both the subgroups and controls were Group I — 20.9 ± 2.7, Group II — 24.1 ± 6.6, and controls — 21.6 ± 2.8 (p = 0.068). The mean duration of seizures (in years) in Group I was 7.7 ± 4.9 and Group II — 7.5 ± 5.8. All the patients in Group I (age — 20.8 ± 4.0 years; Male: Female = 9:11) and Group II (age — 24.4 ± 6.7 years; Male: Female = 9:11) had myoclonic jerks (MJs — 100%). Along with MJs, eighteen (90%) patients in Group I and all twenty patients in Group II (100%) had GTCS, and only one (5%) patient in each group had absence seizures. Seizures were controlled in 18/20 patients in Group I with VPA. There was no GTCS at least for a week in either of the groups prior to the evaluation. Imaging was normal in all the 40 patients and 20 controls. (Table 1). 3.2. EEG observations Routine 16-channel awake EEG revealed normal background in all the patients. The epileptiform discharges (EDs) were noted during the awake part of the routine EEG with significant abnormalities
2.1. Statistics Statistical Package for the Social Sciences (SPSS) (version 11) software was used to carry out the statistical analysis. Student's t test or
Fig. 1. Distribution of epileptiform discharges (EDs) in sleep stages in patients on VPA (Group I) vs. those who were drug‐naïve (Group II).
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b) Polysomnographic (PSG) parameters such as total sleep time (TST), sleep efficiency, N1%, N2%, N3%, REM%, total NREM%, arousal index (AI) of NREM and REM, isolated leg movement index (IMI), periodic leg movement index (PLMI), and apnea–hypopnea index (AHI) were calculated and compared between the two groups. All the parameters were statistically insignificant between the groups. 3.4. Effect of sleep on epileptiform discharges (EDs)
Fig. 2. Distribution of epileptiform discharges (EDs) in sleep stages in patients with good seizure control (Group A) vs. those with persistent seizures (Group B).
seen in Group II (p = 0.025). Epileptiform discharges were present in twenty-two out of forty patients (Group I: 7; Group II: 15; p = 0.02), six during photic stimulation (Group I: 2; Group II: 4, p = 0.7), and seven during hyperventilation (Group I: 3; Group II: 4, p = 1.0). As expected, drug‐naïve patients (Gr II) had EEG abnormalities more often. All twenty controls had a normal awake EEG (Fig. 1).
3.3. Effect of epilepsy on sleep a) Assessment using structured sleep questionnaires: the details are shown in Table 1. There was no statistically significant difference between the groups in terms of mean PSQI score or PSQI score ≥ 5 and mean ESS score or ESS score ≥ 10. There results were significant in terms of PSQI scores when both Group I and Group II patients were combined together and compared with the controls (p = 0.019), indicating altered sleep quality in JME patients.
During overnight PSG, thirty‐five patients showed abnormal EDs in all the sleep stages (Group I: 17 and Group II: 18). The EDs were then quantified in every patient in all stages of sleep. Group I had a total of 656 EDs (32.8 ± 40.0) in 7481.0 min (0.09 EDs/min) of sleep (including NREM + REM), and Group II had 493 EDs (24.6 ± 31.0) in 7477.5 min (0.07 EDs/min). The number and distribution of EDs in different sleep stages are given in Fig. 1 and Table 2. Epileptiform Discharge Index (EDI) was calculated for each patient by counting the number of EDs per minute of sleep in the various stages of sleep (Table 2). The duration of each ED was measured in all the patients, and the total ED duration per minute per stage was calculated (ED rate = total EDs in min/sleep stage in min × 100). The results are given in Table 2. Group I patients were found to spend a total of 4.936 min in EDs out of 7481.0 min of sleep (0.07%), and Group II patients spent 4.208 min in EDs out of 7477.5 min of sleep (0.06%). Epileptiform discharges were frequently associated with arousals in N1/REM and K-complexes in N2. All the patients in Group I had well‐controlled seizures except for two (patients 6 and 12). The number of patients with well-controlled seizures (Gr A) vs. those with persistent seizures (Gr B) showing EDs in different stages of sleep is given in the chart (Fig. 2). Patients in Group B had decreased EDs in N2 (p = 0.04) and N3 (p = 0.03) compared to Group A. A trend toward association of EDs with arousals was more often observed in Group A compared to Group B (p = 0.06). The ED indices and ED rate were also calculated in Group A and Group B patients. There were no differences in any of the parameters in those with (n = 6) and without (n = 34) a photoparoxysmal response.
Fig. 3. Epileptiform discharges (EDs) during awake and sleep in patients with JME: (A) is from an eighteen‐year‐old drug-naïve woman with polyspike–wave complexes during photic stimulation in a 16-channel EEG; Panel (B) is from a nineteen‐year‐old man on VPA with epileptiform discharges (ED) with a K-complex and spindle in a polysomnograph (PSG); (C) is from a twenty-one‐year‐old woman on VPA with ED in N3 in a PSG and (D) is from a nineteen‐year‐old woman on VPA with ED in REM sleep in PSG.
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Table 2 Polysomnographic (PSG) parameters among patients with juvenile myoclonic epilepsy (JME = 40) and healthy controls (n = 20). TST
N1%
N2%
N3 %
Total NREM%
REM%
AI-NREM
AI-REM
IMI
PLMI
AHI
5.3 2.9 10.8 6.5 9.1 14.0 18.5 17.3 6.4 13.3 11.1 10.8 6.0 7.7 5.1 3.9 2.2 5.7 6.0 7.6 8.5 4.5
42.7 44.8 33.2 39.9 45.9 35.4 39.1 38.0 26.2 26.2 43.8 30.1 32.1 44.3 37.1 37.4 31.2 22.2 33.4 26.0 35.4 7.1
36.4 24.7 30.5 37.1 0 19.9 10.4 20.1 30.3 29.8 7.9 20.1 18.4 15.8 24.5 33.3 32.5 19.9 20.3 19.5 22.6 9.7
84.4 72.4 74.5 83.6 55.0 69.3 68.0 75.5 62.8 69.3 62.8 61.0 56.5 67.7 66.6 74.6 65.9 47.8 59.7 53.1 66.5 9.6
12.6 13.7 13.0 9.0 6.4 17.0 9.1 14.4 5.7 14.0 15.6 12.7 9.0 25.8 13.6 24.7 12.9 10.3 14.0 9.7 13.2 5.1
3.9 9.8 9.3 12.8 9.6 20.1 10.9 8.4 6.7 13.6 7.7 17.4 13.3 8.2 3.8 5.0 4.5 13.3 7.6 11.1 9.8 4.3
2.0 5.3 6.3 16.8 8.9 7.5 20.5 2.7 10.4 9.0 6.1 11.8 4.7 6.3 4.9 1.9 1.8 13.3 6.3 2.5 7.5 5.1
4.2 4.2 6.6 9.2 22.8 4.7 24.2 3.2 5.0 4.7 14.5 6.5 0.6 4.8 7.4 3.0 0.1 8.1 4.0 1.7 7.0 6.5
2.1 0 0 4.8 0 3.4 87.6 0.9 6.3 0 8.2 3.6 0 0.5 3.3 0 0 1.3 0 0 6.1 19.3
0.5 0.1 0.1 1.3 0.2 0 0.8 0 0 0 0 0 0 0 0.6 0.2 0 0.4 0 0 0.2 0.3
GROUP II — drug‐naïve (n = 20) 1 5.5 75.4 2 7.4 91.8 3 7.2 86.6 4 6.5 87.4 5 5.8 95.5 6 7.7 95.0 7 4.5 62.5 8 6.2 84.1 9 7.3 93.7 10 7.1 90.9 11 7.1 92.6 12 6.4 77.1 13 5.5 70.0 14 7.2 88.5 15 7.2 88.6 16 7.9 92.8 17 3.9 53.6 18 1.2 17.2 19 6.9 89.7 20 6.1 81.7 Mean 6.2 80.7 SD 1.6 18.7
4.3 1.0 3.7 2.9 2.2 6.8 6.6 6.4 2.4 7.6 12.0 14.1 9.5 6.8 15.9 6.8 19.5 7.3 5.1 8.5 7.5 4.8
47.3 27.1 34.6 35.4 27.1 40.9 16.5 16.5 24.7 41.1 51.3 32.3 34.8 52.4 52.7 42.3 40.1 6.6 34.8 51.5 35.5 12.9
20.0 49.1 34.1 37.5 53.4 30.2 43.5 47.4 51.4 21.4 6.6 20.6 18.4 17.6 8.3 15.5 0.9 10.7 38.7 16.2 27.1 16.3
71.6 77.2 72.3 75.8 82.7 77.9 66.6 70.3 78.5 70.0 69.9 67.0 62.8 76.8 77.0 64.7 60.4 24.5 78.5 76.2 70.0 12.3
8.8 16.8 17.8 8.7 14.5 18.7 1.3 17.3 18.4 22.6 23.8 12.4 11.9 13.3 12.5 32.3 0 0 16.0 13.8 14.0 7.9
14.3 3.1 5.4 4.4 2.8 7.2 9.9 10.7 9.4 12.1 9.8 8.8 11.2 11.5 14.6 14.6 38.9 11.6 9.0 18.1 11.4 7.6
26.7 1.5 0.7 4.9 1.2 4.7 0 4.9 5.7 6.3 2.2 5.0 5.7 20.8 21.0 14.8 0 0 11.9 8.6 7.3 7.8
6.0 2.4 3.2 4.6 9.7 8.6 9.7 11.6 13.4 14.0 6.8 2.8 9.3 5.0 4.9 5.2 15.4 8.3 1.3 10.7 7.6 4.1
0.5 0 0 0 3.1 47.5 7.1 8.2 18.1 3.8 11.7 0 12.5 10.6 1.5 4.0 4.6 3.3 0 12.5 7.4 10.8
0.1 0.4 0 0 3.4 0.1 0 0.2 1.5 0 0.1 0.3 1.1 0.3 7.1 0.3 0.3 0 0.3 3.0 0.9 1.7
Healthy control (n = 20) 1 6.4 2 6.1 3 7.2 4 6.8 5 6.2 6 6.8 7 6.3 8 6.8 9 6.7 10 6.0 11 6.6 12 4.9 13 7.1 14 7.6 15 6.5 16 7.3 17 6.2 18 4.4 19 6.2 20 6.2 Mean 6.4 SD 0.7 p value 0.9
16.1 13.0 5.7 16.3 6.8 2.8 7.5 12.2 8.6 6.3 6.8 15.3 12.1 8.2 7.7 7.6 8.9 11.4 4.7 9.5 9.3 3.7 0.4
42.5 36.9 47.0 39.9 33.1 51.2 46.3 32.1 41.3 41.4 38.7 32.6 54.6 47.8 54.3 37.2 36.3 25.2 46.3 52.8 41.9 8.1 0.06
24.9 15.2 21.4 18.6 38.2 22.2 22.0 28.7 26.3 23.9 26.1 8.0 13.0 20.0 13.4 26.2 21.0 13.0 26.3 12.6 21.0 7.1 0.2
83.5 65.1 74.2 74.7 78.1 76.2 75.8 73.0 76.1 71.6 71.6 55.9 79.7 76.0 75.4 71.0 66.2 49.6 77.4 74.8 72.3 7.9 0.2
7.3 20.2 20.9 12.2 18.4 21.0 20.6 19.6 16.0 20.7 18.2 9.0 14.8 17.2 16.2 25.4 20.4 14.6 10.5 12.1 16.8 4.7 0.2
15.5 18.4 5.9 18.0 7.0 10.1 6.8 10.4 10.6 7.1 12.5 31.8 10.1 8.9 18.8 8.2 13.8 8.3 15.2 22.0 13.0 6.4 0.3
9.7 11.0 3.2 14.6 7.7 2.7 3.7 10.3 6.0 6.7 2.2 4.4 12.6 4.3 20.0 17.7 1.4 3.0 5.4 12.7 8.0 5.4 0.9
9.8 8.0 2.9 5.8 9.6 6.7 3.3 6.3 5.4 1.5 2.3 7.8 8.1 5.0 7.1 11.4 5.5 3.4 7.2 5.8 6.1 2.6 0.6
11.3 0 0 0 1.0 1.6 2.4 0.9 0.7 0 0 0 1.0 5.0 0 2.3 3.7 0 1.1 0 1.5 2.7 0.3
0.2 0 0 0.4 1.3 0.8 1.8 0 0 0.2 0 0 0.9 0.8 0.3 0.7 0 0 0 0.2 0.4 0.5 0.1
Group I — on 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean SD
Sleep efficiency
VPA (n = 20) 7.7 94.0 7.2 81.2 7.5 85.8 7.9 92.4 4.3 52.1 6.8 79.4 6.2 71.5 6.8 84.1 4.6 58.4 6.7 79.8 6.6 77.7 4.9 60.7 4.7 51.5 7.4 90.4 7.3 79.2 6.4 98.0 6.7 75.7 4.7 55.5 5.0 69.0 5.2 59.9 6.2 74.8 1.2 14.4
85.8 79.4 91.2 85.0 84.6 96.9 94.7 91.0 89.9 90.8 86.2 61.9 92.2 92.8 89.5 90.2 79.9 59.2 82.3 84.8 85.4 9.7 0.08
TST: total sleep time; AI-NREM: apnea index-non rapid eye movement; AI-REM: apnea index-rapid eye movement; ILMI: isolated limb movement index; PLMI: periodic limb movement index; AHI: apnea–hypopnea index.
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4. Discussion The effect of sleep on epilepsy in general and vice versa has been well documented. Nocturnal seizures usually occur during Stages 1 and 2 of NREM (non-rapid eye movement) sleep. Seizures in certain epilepsy syndromes characteristically occur in sleep, such as frontal lobe epilepsy, temporal lobe epilepsy (TLE), benign childhood epilepsy with centro-temporal spikes, Lennox–Gastaut syndrome; while others follow awakening from sleep, such as JME. Despite the well-established association with sleep in patients with JME, effects of epilepsy on sleep and vice versa have not been adequately studied. Sleep disturbances in patients with epilepsy may be secondary to AEDs, nocturnal seizures, or a concomitant sleep disorder such as sleep apnea or restless leg syndrome. The previous studies on JME and sleep have used patients on multiple AEDs or on polytherapy and EEG alone to analyze sleep [6,13]. The present study focused on patients with JME on VPA monotherapy vs. drug-naïve patients using sleep questionnaires, overnight PSG, and EEG. It is believed that VPA and other AEDs are used to reduce the occurrence of epileptic discharges and alleviate sleep disruption due to epileptic seizures. Hence, this study was planned to analyze the difference in the occurrences of interictal epileptiform discharges (EDs) across sleep stages between those on VPA monotherapy and drug-naïve individuals, and the effect of these EDs on sleep (Fig. 3). 4.1. Clinical and EEG profile The phenotypic characteristic of JME observed in this study is consistent with the published literature worldwide [14–16]. The mean age in drug‐naïve patients was more compared to that on valproate. The difference was statistically insignificant. Absences were significantly less than those reported from other studies, probably related to the older age and also to effective therapy. As in some studies, a rise in myoclonus frequency was noted during menstruation [17]. Myoclonic jerk as the only seizure type was seen in 6% of patients, which is the case in 7–17% of JME patients [17,18]. Routine awake EEG revealed abnormalities in 55% of patients, slightly lower than the 60–90% reported in the literature [1,17]. In this study, half of the patients underwent EEG while on a stable regimen of VPA. This may have impacted the prevalence of EEG abnormalities. However, prolonged recording with overnight PSGs showed abnormalities in 87.5% of cases. However, in this study, the duration of the EEG (30 min) was short compared to that of the PSG (overnight), which might have led to occurrence of increased epileptiform activity in PSG–EEG. 4.2. Sleep disturbances Assessment by sleep questionnaires in the patient groups (Group I + Group II) revealed significantly higher PSQI scores compared to the control group (p = 0.02), indicating that epilepsy might have contributed to the poor quality of sleep. Similar findings were reported in studies on other types of epilepsy [14]. However, there is lack of similar published studies on patients with JME. In a study on refractory temporal lobe epilepsy (TLE = 40) evaluated with ESS and PSQI, the Global PSQI was high (mean = 5.65 ± 3.71; p b 0.001). Pittsburgh Sleep Quality Index revealed higher and statistically significant scores in three components as well as in the global score, when analyzed by predominance of daytime or nocturnal seizures [19]. Pung and Schmitz studied 20 patients with JME and temporal lobe epilepsy (TLE) using standardized questionnaires with respect to the sleep– wake rhythm and personality profiles. They found that patients with JME had a tendency to go to bed later at night, to get up later in the morning, and to feel fit at a later time during the day compared to patients with TLE [20].
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In the current study, none of the PSG parameters were statistically significant between the groups except a trend toward a slightly higher sleep efficiency (p = 0.08), and higher N2% (p = 0.06) was seen in the control group. Gigli et al. (1992) found higher CAP rates in 10 JME patients (46.7%) when compared to age-matched controls (23%) during all-night PSG recording [8]. Dhanuka et al. studied sleep EEG findings in 15 patients to evaluate for abnormal IEDs, without an attempt to study sleep macrostructure [13]. The patients were either on various AEDs — single or multiple AEDs (n = 5) or drug‐ naïve (n = 9). Bonakis and Koutroumanidis studied video-EEG of patients with JME (n = 19) vs. controls (n = 9) on various AEDs. Sleep EEG was recorded after partial sleep deprivation for a period of 30–45 min, aiming mainly to attain light sleep (Stages 1 and 2). Slow wave sleep (SWS) and REM sleep were rare. Higher CAP rates were noted than for controls (p b 0.05) [7]. 4.3. Effect of sleep on epileptiform discharges (EDs) Sleep has a modulating effect on the distribution of EDs in different forms of epilepsy. Epileptiform discharges occur more commonly in NREM sleep, which acts as the precipitating factor for EDs [19,21–23], than REM sleep which is an inhibiting factor [21,24–26]. Lighter stages of NREM sleep are more prone for the abnormal epileptic activity [24,27]. Nocturnal frontal lobe seizures are known to occur during sleep [5], and temporal lobe seizures often secondarily generalize in slow wave sleep. Idiopathic generalized epilepsies are documented to have EDs more commonly in the lighter stages of NREM sleep [7,8,27]. The present study showed that the distribution of EDs in sleep was frequent (ED Index) in N1 (p = 0.053*) in Group II and N3 (p = 0.059*) in Group I and Group A (p = 0.035), and a relatively higher total number of EDs occurred in N2 in Group I (p = 0.078*). The average rate of EDs was higher in Group II compared to Group I (0.2 EDs/min vs. 0.06 EDs/min). The EDs in Group I were more frequent in N2/N3, whereas Group II showed a higher frequency of EDs/min in N1 and REM but without statistical significance. The presence of excess of EDs in REM in drug‐naïve patients is an interesting observation, and the role of valproate in suppressing such discharges in REM stage or alteration in sleep architecture requires further studies. Previous reports showed an increased discharge rate in NREM, either light sleep [7,13] or slow wave sleep [8]. However, comparison between the studies cannot be truly made due to difference in the patient group, methods of recording, or analysis of sleep architecture. 4.4. Effect of seizure control and VPA on sleep and EDs As there were two patients with uncontrolled seizures on valproate (patients 6 and 12 in Group I) due to poor adherence, we calculated the difference between patients with nil clinical seizures (Group A, n=18) and patients with persistent clinical seizures on day 1 of evaluation (Group B, n=22) in terms of number of EDs, ED indices, and ED rates. Group A showed significantly higher number of EDs in N2 (p=0.043), a higher ED Index in N3 as well (p=0.035) similar to that observed by Gigli et al. [8], and a slight trend with higher frequency of EDs in N1 and N2. The other parameters were statistically insignificant between Group A and Group B. Based on the findings of this study on the effect of EDs on sleep and vice versa between a group of drug-naïve and patients on VPA monotherapy, EDs seem to be frequent (ED Index) in N3 in Group I (p=0.059) and in N1 in Group II (p=0.053), but Group A with good control of clinical seizures showed an overall higher frequency in NREM sleep, especially SWS (p=0.03) and increased total number of EDs noted in N2 in (p=0.04). Spike–wave and polyspike–wave complexes are preferentially known to occur during sleep onset due to the augmented synaptic responsiveness of cortical neurons [28–30]. They commonly occur during the depolarization phase of cortical slow oscillation. The cortical
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slow oscillations are initiated in N2 and become more pronounced in N3 [9]. Due to the enhanced synaptic responsiveness of the cortical neurons during sleep onset and prolonged depolarizing membrane potentials, EDs are more common in NREM sleep [21,22,25,27]. Our study shows a similar finding in Group I and Group A. There was no difference in terms of ED indices (p = 0.5) or ED rates (p = 0.7) in light sleep (N1 + N2) between Groups I and II. The EDs are not easily facilitated by REM sleep as it is characterized by irregular tonic activation (resynchronization) of cortical neurons similar to the awake state [21,25,31]. In spite of this, REM sleep also represents a transition of vigilance state from NREM sleep, usually after SWS. Most of the EDs in REM sleep seen in both the groups, especially in Group II, were seen more so during the transition phases and less so during the established REM sleep [21]. This could explain EDs being more common in REM in Group II than Group I as there was a frequent interruption of REM sleep by other vigilance states. Although the seizures seemed to be controlled in patients on VPA (Group I), interictal EDs during sleep were noted in as many as in drug-naïve patients (Group II). Patients on VPA spend as much time in EDs in sleep as in the drug-naïve group (Total ED rate, p > 0.05). In spite of being on a conventional antiepileptic dose of VPA, it does not seem to have an effect against IEDs in sleep. Interictal EDs in sleep do not respond to valproate. On the contrary, patients on usual dosages of VPA have slightly higher frequency of abnormal epileptiform discharges in N3 (Group I — p = 0.059 and Group A — p = 0.03) and a higher total number of discharges in N2 (Group A, p = 0.04) when compared to drug-naïve (Group II) or patients who are still symptomatic (Group B). This may be explained as the patients on VPA therapy had a slightly longer duration of illness compared to the drug-naïve group (Group I — 7.7 ± 4.9 years and Group II — 7.5 ± 5.8 years). The controls showed a trend toward higher sleep efficiency and N2% than the patients with JME. Time spent in EDs in sleep in these patients is equivalent to sleep lost (for that amount of time) however insignificant and hence may lead to a vicious unbreakable cycle of sleep disruption and partially controlled or uncontrolled seizures, further affecting the daytime functioning. The first-night effect of PSG could not be excluded since the subjects underwent study only for one night due to financial limitations. Analysis regarding CAP was not carried out. Comparison of 16 channel EEG vs. 8 channel PSG–EEG might have its own limitation. This is one of the first studies on JME that highlighted alterations in sleep quality and architecture and interictal epileptiform activity observed more often in sleep than wakefulness with light sleep (N1) and REM possibly having facilitation, especially in drug‐naïve patients when compared to patients on valproate (N3). These abnormalities were noted despite all the patients being on adequate treatment and a majority reporting good seizure control. This study highlights the persistent nature of the sleep-epilepsy association, which has significant therapeutic implications in a sleep-sensitive epilepsy like JME.
Acknowledgment This study was supported by partial funding from the Department of Science and Technology, Govt. of India, New Delhi (SR/SO/HS/108/ 2007). The contribution of Mr. Perumal, Electrophysiology Technologist, in recording polysomnography is acknowledged.
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