- Email: [email protected]
Sleep Spindle Abnormalities in Children With Generalized Spike-Wave Discharges
Sleep Spindle Abnormalities in Children With Generalized Spike-Wave Discharges Ivan Myatchin, MD and Lieven Lagae, MD, PhD This study investigated sleep and sleep spindle parameters in children with primary generalized spike-and-wave discharges (untreated primary generalized group, nine patients; treated primary generalized group, six patients) and compared these with an age- and sex-matched nonepileptic control group (n ⴝ 47). In the untreated primary generalized group, stage 2 onset was significantly shorter, with less spindles in stage 2. In the last stage 2 period of the night, significantly less fast frequency spindles were observed, indicating abnormal dynamics of sleep architecture. In the treated group, sleep patterns were comparable to that of the control group. The data indicate sleep architecture dysfunctions in children with generalized spike-and-wave discharges. These dysfunctions could account for the frequently encountered sleep problems in children with primary generalized epilepsy. © 2007 by Elsevier Inc. All rights reserved. Myatchin I, Lagae L. Sleep spindle abnormalities in children with generalized spike-wave discharges. Pediatr Neurol 2007;36:106-111.
Introduction The close relationship between epilepsy and sleep has been recognized for a long time. In many epileptic syndromes, the epileptic electroencephalographic activity increases during sleep [1-6]. Also, the epileptic process itself has an influence on sleep parameters. Different changes in the sleep pattern and sleep architecture of epileptic patients have been described: increased sleep onset latency, more frequent and long awakenings, abnormalities of K-complexes and spindles, fragmentation and reduction of rapid eye movement sleep, increase of stage 1 non–rapid eye movement sleep, and increased stage
From University Hospitals KULeuven, Division Pediatric Neurology, Leuven, Belgium.
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shifts, all resulting in decreased sleep efficiency in some patients [1,7,8]. These changes are not only related to the epilepsy itself, but apparently also to the chronic use of antiepileptic drugs [1,7]. Most of the clinical research on the relationship between sleep and epilepsy has been performed in adults [7,9] and in specific childhood epilepsy syndromes such as benign Rolandic epilepsy [10], Landau-Kleffner syndrome [11], benign epilepsy with occipital spikes [12], epilepsy with continuous spike-waves during slow-wave sleep [13], and other partial epilepsy syndromes [7,14]. Few studies deal with sleep architecture dysfunctions in children with generalized seizures [2,15]. In generalized epilepsy, this relationship between sleep and epileptic electroencephalographic discharges has been studied extensively in animal models and in humans. It has been known for a long time that thalamic structures play an essential role in the generation of absence seizures, the prototype of generalized epilepsy [16,17]. In 1978, Pierre Gloor for the first time hypothesized that generalized spike-and-wave discharges that are typical for absence seizures develop in the same circuits, which normally generate sleep spindles. This thalamo-cortical circuit is now well defined [18-20]. Although the experimental data are convincing [21], the clinical correlates of the association between spindles and generalized spike-and-wave discharges is much less clear. Kellaway [22] reported an inverse relationship between the amount of spindles and spikeand-wave discharges in human generalized epilepsy, therefore confirming the experimental findings of Prince and Farrell [23]. It is therefore believed that in absence epilepsy, spindles are “transformed” into generalized spike-and-wave discharges. If these findings are correct, one should find specific sleep and sleep spindle abnormalities in children with generalized spike-and-wave discharges on their electroen-
Communications should be addressed to: Dr. Lagae; University Hospitals Gasthuisberg; Department of Paediatric Neurology, Developmental Neurophysiology Laboratory; Herestraat 49, B3000 Leuven, Belgium. E-mail: [email protected] Received August 7, 2006; accepted September 25, 2006.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.09.014 ● 0887-8994/07/$—see front matter
Table 1. Clinical data of the patients of the untreated primary generalized group
Patient
Age (yr)
Sex
Epilepsy Type
1
6
M
2 3 4 5 6 7 8 9
7 7 7 8 9 10 11 11
F F M M F M F M
Epilepsy with generalized tonic-clonic seizures No history of clinical seizures No history of clinical seizures Childhood absence epilepsy No history of clinical seizures Childhood absence epilepsy Myoclonic absence epilepsy Childhood absence epilepsy Myoclonic epilepsy
Seizure Frequency ⬍ 2/year — — ⬍10/day — ⬍10/week ⬍5/year ⬍10/day ⬍2/month
cephalogram. The present study investigated sleep parameter changes in children with generalized spike-and-wave discharges. Materials and Methods In this cross-sectional study, candidate subjects with generalized spike-and-wave discharges were carefully selected out of the videoelectroencephalography studies that were performed in our neurophysiology laboratory. The database consisted of more than 2500 video electroencephalograms that were collected in the last 10 years. Strict inclusion criteria were used to select subjects: 1) presence of typical primary generalized spike-waves on the electroencephalogram with a frequency of 2.5-4 Hz; 2) normal and age adequate background activity of the 24-hour video-electroencephalography; 3) absence of focal epileptic signs on the electroencephalogram; 4) no antiepileptic or other drugs at the time of the study; 5) normal clinical neurologic examination. This selection process yielded a group (hereafter called the untreated primary generalized group) of nine children (five males, four females) from 6 to 11 years of age (mean 8.5, S.D. ⫾ 1.9). Three of them had absence seizures, two myoclonic seizures, and one generalized tonicclonic seizures. Three had no history of clinical seizures (Table 1). Another group of children was known with primary generalized epilepsy and generalized spike-and-wave discharges on their electroencephalogram; these children were receiving adequate antiepileptic monotherapy. The same strict inclusion criteria were applied for this group, except for the fact that they were receiving antiepileptic medication, that was appropriate for the treatment of their epileptic seizures and that was prescribed at the right dose. This group, hereafter called the treated primary generalized group, consisted of six children (four males, two females) from 6 to 16 years of age (mean 9.6, S.D. ⫾ 3.7). Five of six children were on valproic acid, the other one received ethosuximide. There were four children with absences in that group, one with myoclonic-absence seizures and one with juvenile myoclonic epilepsy (Table 2). Also studied was a control group of 47 normal children who were ageand sex-matched with the children of the untreated and treated primary
Table 2.
generalized groups (mean age 8.6 years, S.D. ⫾ 2.7); for each child in both these groups, at least three control children with the same age and sex were selected. The control group was also selected out of our video-electroencephalography studies database. Control children were referred to the neurophysiology laboratory for suspected epilepsy. None of them had a diagnosis of attention-deficit hyperactivity disorder, or had clinical sleep problems. In all 47 control children, the 24-hour videoelectroencephalography study was completely normal.
Video-Electroencephalography Study In all 62 subjects, electrode placement was performed according to the international 10-20 system with use of 24 electrodes. All electroencephalograms were sampled at a frequency of 250 Hz with 12-bit A/D converter. Low-frequency filter was set at 0.53 Hz, and high-frequency filter was set at 70 Hz. During the 24-hour video-electroencephalography study, all children went to sleep at a time that was usual for them. None of the children had clinical seizures during the night they were studied with video-electroencephalography. Because this was primarily a videoelectroencephalography study, and not a standardized sleep study, standard polysomnographic parameters such as electro-oculogram and electromyogram were not used [24]. The software program automatically calculates frequency content of the brain signals in ␣, ␦, and -bands, so that sleep staging becomes possible at a first level. Sleep spindles were searched manually on the basis of the following rules: typical rhythmical sinusoidal waves over the fronto-central regions with a frequency range from 10 to 16 Hz, minimum amplitude 10 V [25], and minimum length of 0.5 second. The spindle’s frequency was then calculated using the electroencephalographic software. The choice of the frequency range (10-16 Hz) was based on different values available in the literature [12,26-28]. Sleep staging was performed manually using 30-second epochs and was based on the following rules: stage 2 was scored when sleep spindles or K-complexes were present in the absence of high-amplitude slow activity that defines the presence of stages 3 and 4: less than 20% of the epoch consists of waves of 2 Hz or slower with an amplitude greater than 75 V from peak to peak. If more than 20% or 50% of epoch consists of waves of 2 Hz or slower with amplitude greater than 75 V from peak to peak, such an epoch was considered as stage 3 or 4 respectively. We were specifically interested in stage 2 of sleep and in sleep spindles within stage 2, so no detailed study of deeper sleep was made. The following parameters during nocturnal sleep were analyzed: 1) Sleep architecture. Time of the beginning and ending of the nocturnal sleep was determined, yielding total sleep time. The total time of all stage 2 periods was expressed as a percentage of total sleep time. Also, the stage 2 latency was calculated: time from the beginning of sleep to the beginning of the first stage 2 (i.e., to the first spindle or K-complex in the recording which meets the criteria for stage 2). 2) Spindle densities. First, the number of spindles in all stages 2 was calculated, and this was expressed as a percentage of the total number of spindles during the full night. Further, spindle density refers to the amount of spindles per minute a) in the entire sleep (more precisely in stages 2, 3, and 4), b) in all stages 2, and c) in the first and in the last stages 2 of the sleep.
Clinical data of the patients of the treated primary generalized group
Patient
Age (yr)
Sex
Epilepsy Type
Seizure Frequency
Medication
10 11 12 13 14 15
6 7 7 10 11 16
F F M M M M
Childhood absence epilepsy Childhood absence epilepsy Myoclonic absence epilepsy Childhood absence epilepsy Childhood absence epilepsy Juvenile myoclonic epilepsy
⬍5/day ⬍10/day ⬍2/month ⬍5/week ⬍10/day Seizure-free
Valproic acid Ethosuximide Valproic acid Valproic acid Valproic acid Valproic acid
Myatchin and Lagae: Spindle Abnormalities in Epilepsy 107
3) Frequency content of spindles. The mean frequency of all spindles within stage 2 was calculated in the three groups. To study possible dynamic changes during the night, the mean spindle frequency was also calculated for the first and last stage 2 periods in the sleep. Next, the 10-16 Hz spindle interval was divided into two bands: 10-12 Hz (slow) and 12-16 Hz (fast). Again, the number of spindles in each band was calculated for the entire night, as well as for the first and last stage 2 periods separately. This value was expressed as a percentage of total number of spindles in all stage 2 periods or total number of spindles in first or last stage 2 respectively.
Statistical Analysis Analysis of variance and Kruskal-Wallis nonparametric testing were used, as well as the Post test [29]. Results with P ⬍ 0.05 were considered significant. Graphpad and Statistica software packages were used to run the statistical tests.
Results Sleep Architecture (Fig 1) In all children from the three groups, the hypnogram, as constructed with our software and manual calculation (see Methods), did not disclose any abnormality. Total sleep time was not different in the three groups. The percentages spent in stage 2 during sleep (stage 2 proportion) did not differ significantly between the three groups. However, a major difference was observed in “stage 2 latency”: in the untreated primary generalized group, sleep latency was 14 minutes on average, whereas it was significantly longer in the control group (mean 47 minutes; analysis of variance P ⬍ 0.01; Kruskal-Wallis P ⬍ 0.03). The treated primary generalized group was not significantly different for this
parameter, but was more comparable with the control group than with the untreated primary generalized group. Amount of Spindles (Fig 2) As could be expected, the majority of spindles was found in stage 2 in the control group (mean 68.7%). In the untreated children with primary generalized electroencephalographic abnormalities, the percentage of spindles in stage 2 was significantly lower (analysis of variance P ⬍ 0.02; Kruskal-Wallis P ⬍ 0.03). Medication seems to restore this disequilibrium: the treated primary generalized group did not differ significantly from the control group, but did so compared with the untreated primary generalized group (analysis of variance P ⬍ 0.02; Kruskal-Wallis P ⫽ 0.007). Looking more in depth to spindle density, no significant differences were evident: the number of spindles per minute during the entire sleep, during stage 2 sleep, or during the first or last stage 2 sleep did not differ significantly between or within the three groups. Frequency of Spindles (Fig 3) The mean spindle frequency in all stages 2 was between 12 and 13 Hz in all three groups, without any significant differences. In the control group, there was an increase of mean spindle frequency when the first stage 2 was compared with the last stage 2 period (12.60 Hz vs 12.21 Hz). This significant increase was not found back in the primary generalized groups. Another difference was observed in the first stage 2 period, comparing the control
Figure 1. Sleep architecture. C ⫽ control group; UPG ⫽ untreated primary generalized group; TPG ⫽ treated primary generalized group; ns ⫽ not significant. *P ⬍ 0.05.
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Figure 2. Amount of spindles. C ⫽ control group; UPG ⫽ untreated primary generalized group; TPG ⫽ treated primary generalized group; Sp ⫽ sleep spindles; SpD ⫽ spindles density (an amount of spindles per minute); ns ⫽ not significant. *P ⬍ 0.05.
group with the untreated primary generalized group: in the untreated primary generalized group, mean spindle frequency was higher (12.87 compared with 12.21 Hz). These parameters were separately analyzed for the slow (⬍12 Hz) and the fast (12-16 Hz) frequency groups. In all three groups, the majority of spindles was found in the fast frequency group. The aforementioned increase of spindle frequency in the control group in the last stage 2 period is reflected by a significantly higher number of spindles in the fast frequency group (88.7 vs 79.6%), with concurrent decrease of slow frequency spindles (22.7 vs 12.5%). These significant changes were not observed back in the untreated primary generalized and the treated primary generalized group, although a similar tendency is clear in the medicated group. Discussion This study examined, in a highly selected group of 15 children with generalized spike-and-wave discharges on their video-electroencephalography recordings, whether there were associated sleep spindle dysfunctions based on the known relationship between spindles and generalized spike-and-waves. In view of the abundant experimental data on this topic, special attention was paid to spindle organization throughout sleep. The main finding of this study is that in untreated children with spike-and-wave discharges, stage 2 sleep occurred earlier than in a control group and there were less spindles in stage 2. In view of
the same total sleep time in these children and the equal total amount of spindles in the three groups, this decrease of spindles in stage 2 indicates that spindles are now more scattered throughout the night. With our methodology it was not possible to demonstrate that spindles were actually “replaced” by spike-wave discharges in stage 2 [15]. Another finding was that the normal frequency increase of fast spindles during the night (comparing last stage 2 with first stage 2) was not observed in the untreated primary generalized group. These differences were not present or were less clear in a group of treated children with spike-and-wave discharges. The findings demonstrate that in primary generalized epilepsy, the thalamo-cortical circuits can still make normal spindles: the mean frequency and length of the spindles are normal. This result at least indicates that the generating circuit is intact, which is not surprising, knowing that in typical generalized epilepsy no thalamic or cortical structural abnormalities are present [30,31]. On the other hand, the macro-organization of sleep seems to be dynamically disturbed: onset of stage 2 is earlier, there are fewer spindles in stage 2 and the normal frequency increase in the last stage 2 sleep is not observed. Perhaps the most striking finding was the earlier onset of the first stage 2 in children with generalized spike-andwave discharges. Williams et al. [32] reported an agedependent maturational course of stage 2 latency, with shorter latencies in older children. It is therefore difficult to interpret our findings of a decreased latency in
Myatchin and Lagae: Spindle Abnormalities in Epilepsy 109
Figure 3. Frequency of spindles. UPG ⫽ untreated primary generalized group; TPG ⫽ treated primary generalized group; SpFr ⫽ mean spindles frequency (Hz); SpFr ⬍12 Hz ⫽ spindles within the frequency band 10-12 Hz; SpFr 12-16 Hz ⫽ spindles within the frequency band 12-16 Hz.
children with epileptic abnormalities. One can argue that a normal inhibitory mechanism could be deficient in children with epileptic abnormalities, leading to an earlier onset of stage 2. The proportion of total time in stage 2 (29.5%) is lower than in other studies [32-36]. Percentages of stage 2 sleep vary between 41% and 52%. However, comparison with other data is difficult, because standard sleep analysis techniques were not used, as was explained in the methodology section. As reported, no differences in this parameter between the three groups were evident. We realize the potential weaknesses of this study. Ideally, a longitudinal and blinded study instead of a cross-sectional study is required to strengthen these findings. Also, a larger number of patients is needed. However, the number of potential subjects was deliberately limited with stringent inclusion criteria. For instance, all patients who manifested any focal abnormality on their electroencephalogram were excluded, to ensure that we were dealing with truly primary generalized epileptic abnormalities. In this respect, it is known that more than 50% of children with primary generalized epilepsies do exhibit focal abnormalities [37,38]. We did not examine whether these sleep changes were correlated with clinical sleep problems in these children. It
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is known in the literature that many children with epilepsy do have sleep problems, which are not merely related to the occurrence of overt seizures during the night [39,40]. Because spindles are believed to be a hallmark of normal sleep [26], the data presented herein suggest that the abnormalities of spindle organization during the night could indeed underlie clinical sleep problems. Spindles are “sleep-enhancing” and make a smooth transition from light to deep sleep [41]. Less spindles in stage 2 therefore indicates possible difficulties to get into the deeper stages of sleep.
References [1] Donat JE, Wright FS. Sleep, epilepsy and EEG in infancy and childhood. J Child Neurol 1989;4:84-94. [2] Autret A, Lucas B, Hommet C, Corcia P, de Toffol B. Sleep and the epilepsies. J Neurol 1997;224(Suppl. 1):S10-7. [3] Bazil CW. Sleep and epilepsy. Semin Neurol 2002;22:321-7. [4] Degen R, Degen HE. Contribution to the genetics of rolandic epilepsy: Waking and sleep EEGs in siblings. Epilepsy Res Suppl 1992;6:49-52. [5] Froscher W. Sleep and prolonged epileptic activity (status epilepticus). Epilepsy Res Suppl 1991;2:165-76. [6] Capovilla G, Beccaria F. Benign partial epilepsy in infancy and early childhood with vertex spikes and waves during sleep: A new epileptic form. Brain Dev 2000;22:93-8.
[7] Nunes ML, Ferri R, Arzimanoglou A, Curzi L, Appel C, da Costa JC. Sleep organisation in children with partial refractory epilepsy. J Child Neurol 2003;18:763-6. [8] Barreto JRS, Fernandes RMF, Sakamoto AC. Correlation of sleep macrostructure parameters and idiopathic epilepsies. Arq Neuropsiquatr 2002;60:353-7. [9] Ferrillo F, Beelke M, De Carli F, et al. Sleep-EEG modulation of interictal epileptiform discharges in adult partial epilepsy: A spectral analysis study. Clin Neurophys 2000;111:916-23. [10] Nobili L, Ferrillo F, Baglietto MG, et al. Relationship of sleep interictal epileptiform discharges to sigma activity (12-16 Hz) in benign epilepsy of childhood with rolandic spikes. Clin Neurophys 1999;110:39-46. [11] Nobili L, Baglietto MG, Beelke M, et al. Spindles-inducing mechanisms modulates sleep activation of interictal epileptiform discharges in the Landau-Kleffner syndrome. Epilepsia 2000;41:201-6. [12] Beelke M, Nobili L, Baglietto MG, et al. Relationship of sigma activity to sleep interictal epileptic discharges: A study in children affected by benign epilepsy with occipital paroxysms. Epil Res 2000;40:179-86. [13] Nobili L, Baglietto MG, Beelke M, et al. Distribution of epileptiform discharges during NREM sleep in the CSWSS syndrome: Relationship with sigma and delta activities. Epil Res 2001;44:119-28. [14] Nobili L, Baglietto MG, Beelke M, et al. Modulation of sleep interictal epileptiform discharges in partial epilepsy of childhood. Clin Neurophys 1999;110:839-45. [15] Nobili L, Baglietto MG, Beelke M, De Carli F, Veneselli E, Ferrillo F. Temporal relationship of generalized epileptiform discharges to spindle frequency activity in childhood absence epilepsy. Clin Neurophys 2001;112:1912-6. [16] Jasper HH, Dreegleever-Fortuyn J. Experimental studies on the functional anatomy of petit mal epilepsy. Res Publ Assoc Nerv Ment Dis 1947;26:272-98. [17] Jung R. Zur Klinik und Elektrophysiologie des ‘petit mal’ 4ème Cong Internat. dEEG et Neuropsychologie clinique. Acta Med Belg 1957:296. [18] Gloor P. Generalized epilepsy with bilateral synchronous spike and wave discharge: New findings concerning its physiological mechanisms. Electroencephalogr Clin Neurophysiol Suppl 1978;245-9. [19] Steriade M, McCormick DA, Sejnowski TJ. Thalamocortical oscillations in the sleeping and aroused brain. Science 1993;262:679-85. [20] Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci 2005;28:317-24. [21] Kostopoulos GK. Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: The continuing development of a hypothesis. Clin Neurophys 2000;111(Suppl. 2):S27-38. [22] Kellaway P. Sleep and epilepsy. Epilepsia 1985;26(Suppl. 1): S15-30. [23] Prince D, Farrell D. “Centrencephalic” spike-wave discharges following parenteral penicillin injections in the cat. Neurology (Minneap) 1969;19:309-10. [24] Rechtschaffen A, Kales A, editors. A manual of standardized
terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: Public Health Service, U.S. Government Printing Office, 1968. [25] Dijk DJ, Hayes B, Czeisler CA. Dynamics of electroencephalographic sleep spindles and slow wave activity in men: Effect of sleep deprivation. Brain Res 1993;626:190-9. [26] Huupponen E, Himanan S-L, Hasan J, Värri A. Automatic analysis of electro-encephalogram sleep spindle frequency throughout the night. Med Biol Eng Comput 2003;41:727-32. [27] Zeilthofer J, Gruber G, Anderer P, Asenbaum S, Schimicek P, Saletu B. Topographic distribution of sleep spindles in young healthy subjects J. Sleep Res 1997;6:149-55. [28] Zygierewicz J, Blinowska KJ, Durka PJ, Szelenberger W, Niemcewicz S, Androsiuk W. High resolution study of sleep spindles Clin Neurophys 1999;110:2136-47. [29] Dawson B, Trapp RG. Basic and clinical biostatistics, 3rd ed. Chapter 7: Research questions about means in three or more groups. Boston: McGraw-Hill, 1994:161-82. [30] Crunelli V, Leresche N. Childhood absence epilepsy: Genes, channels, neurons and network. Nat Rev Neurosci 2002;3:371-82. [31] Bernasconi A, Bernasconi N, Natsume J, Antel SB, Andermann F, Arnold DL. Magnetic resonance spectroscopy and imaging of the thalamus in idiopathic generalized epilepsy. Brain 2003;126:2447-54. [32] Williams RL, Karacan I, Hursch KJ, Davis CE. Sleep patterns of pubertal males. Pediatr Res 1972;6:643-8. [33] Acebo C, Millman RD, Rosenberg C, Cavallo A, Carscadon MA. Sleep, breathing and cephalometrics in older children and young adults. Chest 1996;109:664-72. [34] Gaudreau H, Carrier J, Montplaisir J. Age-related modifications of NREM sleep EEG: From childhood to middle age. J Sleep Res 2001;10:165-72. [35] Quan SF, Goodwin JL, Babar SI, et al. Sleep architecture in normal Caucasian and Hispanic children aged 6-11 years recorded during unattended home polysomnography: Experience from Tucson Children’s Assessment of Sleep Apnea Study (TuCASA). Sleep Med 2003;4:13-9. [36] Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic characteristics in normal preschool and early schoolaged children. Pediatrics 2006;117;741-53. [37] Lagae L, Pauwels J, Monté CP, Verhelle B, Vervisch J. Frontal absences in children. Eur J Paed Neurol 2001;5:243-51. [38] Lombroso CT. Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades. Epilepsia 1997;38:797-812. [39] Zaiwalla Z, Stores G. Sleep and arousal disorders in childhood epilepsy. Electroenceph Clin Neurophys 1989;72:107. [40] Vieth J. Vigilance, sleep and epilepsy. Eur Neurol 1986; 25(Suppl. 2):128-33. [41] De Gennaro L, Ferrara M, Bertini M. Topographical distribution of spindles: Variations between and within NREM sleep cycles. Sleep Res Online 2000;3:155-60.
Myatchin and Lagae: Spindle Abnormalities in Epilepsy 111
Introduction The close relationship between epilepsy and sleep has been recognized for a long time. In many epileptic syndromes, the epileptic electroencephalographic activity increases during sleep [1-6]. Also, the epileptic process itself has an influence on sleep parameters. Different changes in the sleep pattern and sleep architecture of epileptic patients have been described: increased sleep onset latency, more frequent and long awakenings, abnormalities of K-complexes and spindles, fragmentation and reduction of rapid eye movement sleep, increase of stage 1 non–rapid eye movement sleep, and increased stage
From University Hospitals KULeuven, Division Pediatric Neurology, Leuven, Belgium.
106
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shifts, all resulting in decreased sleep efficiency in some patients [1,7,8]. These changes are not only related to the epilepsy itself, but apparently also to the chronic use of antiepileptic drugs [1,7]. Most of the clinical research on the relationship between sleep and epilepsy has been performed in adults [7,9] and in specific childhood epilepsy syndromes such as benign Rolandic epilepsy [10], Landau-Kleffner syndrome [11], benign epilepsy with occipital spikes [12], epilepsy with continuous spike-waves during slow-wave sleep [13], and other partial epilepsy syndromes [7,14]. Few studies deal with sleep architecture dysfunctions in children with generalized seizures [2,15]. In generalized epilepsy, this relationship between sleep and epileptic electroencephalographic discharges has been studied extensively in animal models and in humans. It has been known for a long time that thalamic structures play an essential role in the generation of absence seizures, the prototype of generalized epilepsy [16,17]. In 1978, Pierre Gloor for the first time hypothesized that generalized spike-and-wave discharges that are typical for absence seizures develop in the same circuits, which normally generate sleep spindles. This thalamo-cortical circuit is now well defined [18-20]. Although the experimental data are convincing [21], the clinical correlates of the association between spindles and generalized spike-and-wave discharges is much less clear. Kellaway [22] reported an inverse relationship between the amount of spindles and spikeand-wave discharges in human generalized epilepsy, therefore confirming the experimental findings of Prince and Farrell [23]. It is therefore believed that in absence epilepsy, spindles are “transformed” into generalized spike-and-wave discharges. If these findings are correct, one should find specific sleep and sleep spindle abnormalities in children with generalized spike-and-wave discharges on their electroen-
Communications should be addressed to: Dr. Lagae; University Hospitals Gasthuisberg; Department of Paediatric Neurology, Developmental Neurophysiology Laboratory; Herestraat 49, B3000 Leuven, Belgium. E-mail: [email protected] Received August 7, 2006; accepted September 25, 2006.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.09.014 ● 0887-8994/07/$—see front matter
Table 1. Clinical data of the patients of the untreated primary generalized group
Patient
Age (yr)
Sex
Epilepsy Type
1
6
M
2 3 4 5 6 7 8 9
7 7 7 8 9 10 11 11
F F M M F M F M
Epilepsy with generalized tonic-clonic seizures No history of clinical seizures No history of clinical seizures Childhood absence epilepsy No history of clinical seizures Childhood absence epilepsy Myoclonic absence epilepsy Childhood absence epilepsy Myoclonic epilepsy
Seizure Frequency ⬍ 2/year — — ⬍10/day — ⬍10/week ⬍5/year ⬍10/day ⬍2/month
cephalogram. The present study investigated sleep parameter changes in children with generalized spike-and-wave discharges. Materials and Methods In this cross-sectional study, candidate subjects with generalized spike-and-wave discharges were carefully selected out of the videoelectroencephalography studies that were performed in our neurophysiology laboratory. The database consisted of more than 2500 video electroencephalograms that were collected in the last 10 years. Strict inclusion criteria were used to select subjects: 1) presence of typical primary generalized spike-waves on the electroencephalogram with a frequency of 2.5-4 Hz; 2) normal and age adequate background activity of the 24-hour video-electroencephalography; 3) absence of focal epileptic signs on the electroencephalogram; 4) no antiepileptic or other drugs at the time of the study; 5) normal clinical neurologic examination. This selection process yielded a group (hereafter called the untreated primary generalized group) of nine children (five males, four females) from 6 to 11 years of age (mean 8.5, S.D. ⫾ 1.9). Three of them had absence seizures, two myoclonic seizures, and one generalized tonicclonic seizures. Three had no history of clinical seizures (Table 1). Another group of children was known with primary generalized epilepsy and generalized spike-and-wave discharges on their electroencephalogram; these children were receiving adequate antiepileptic monotherapy. The same strict inclusion criteria were applied for this group, except for the fact that they were receiving antiepileptic medication, that was appropriate for the treatment of their epileptic seizures and that was prescribed at the right dose. This group, hereafter called the treated primary generalized group, consisted of six children (four males, two females) from 6 to 16 years of age (mean 9.6, S.D. ⫾ 3.7). Five of six children were on valproic acid, the other one received ethosuximide. There were four children with absences in that group, one with myoclonic-absence seizures and one with juvenile myoclonic epilepsy (Table 2). Also studied was a control group of 47 normal children who were ageand sex-matched with the children of the untreated and treated primary
Table 2.
generalized groups (mean age 8.6 years, S.D. ⫾ 2.7); for each child in both these groups, at least three control children with the same age and sex were selected. The control group was also selected out of our video-electroencephalography studies database. Control children were referred to the neurophysiology laboratory for suspected epilepsy. None of them had a diagnosis of attention-deficit hyperactivity disorder, or had clinical sleep problems. In all 47 control children, the 24-hour videoelectroencephalography study was completely normal.
Video-Electroencephalography Study In all 62 subjects, electrode placement was performed according to the international 10-20 system with use of 24 electrodes. All electroencephalograms were sampled at a frequency of 250 Hz with 12-bit A/D converter. Low-frequency filter was set at 0.53 Hz, and high-frequency filter was set at 70 Hz. During the 24-hour video-electroencephalography study, all children went to sleep at a time that was usual for them. None of the children had clinical seizures during the night they were studied with video-electroencephalography. Because this was primarily a videoelectroencephalography study, and not a standardized sleep study, standard polysomnographic parameters such as electro-oculogram and electromyogram were not used [24]. The software program automatically calculates frequency content of the brain signals in ␣, ␦, and -bands, so that sleep staging becomes possible at a first level. Sleep spindles were searched manually on the basis of the following rules: typical rhythmical sinusoidal waves over the fronto-central regions with a frequency range from 10 to 16 Hz, minimum amplitude 10 V [25], and minimum length of 0.5 second. The spindle’s frequency was then calculated using the electroencephalographic software. The choice of the frequency range (10-16 Hz) was based on different values available in the literature [12,26-28]. Sleep staging was performed manually using 30-second epochs and was based on the following rules: stage 2 was scored when sleep spindles or K-complexes were present in the absence of high-amplitude slow activity that defines the presence of stages 3 and 4: less than 20% of the epoch consists of waves of 2 Hz or slower with an amplitude greater than 75 V from peak to peak. If more than 20% or 50% of epoch consists of waves of 2 Hz or slower with amplitude greater than 75 V from peak to peak, such an epoch was considered as stage 3 or 4 respectively. We were specifically interested in stage 2 of sleep and in sleep spindles within stage 2, so no detailed study of deeper sleep was made. The following parameters during nocturnal sleep were analyzed: 1) Sleep architecture. Time of the beginning and ending of the nocturnal sleep was determined, yielding total sleep time. The total time of all stage 2 periods was expressed as a percentage of total sleep time. Also, the stage 2 latency was calculated: time from the beginning of sleep to the beginning of the first stage 2 (i.e., to the first spindle or K-complex in the recording which meets the criteria for stage 2). 2) Spindle densities. First, the number of spindles in all stages 2 was calculated, and this was expressed as a percentage of the total number of spindles during the full night. Further, spindle density refers to the amount of spindles per minute a) in the entire sleep (more precisely in stages 2, 3, and 4), b) in all stages 2, and c) in the first and in the last stages 2 of the sleep.
Clinical data of the patients of the treated primary generalized group
Patient
Age (yr)
Sex
Epilepsy Type
Seizure Frequency
Medication
10 11 12 13 14 15
6 7 7 10 11 16
F F M M M M
Childhood absence epilepsy Childhood absence epilepsy Myoclonic absence epilepsy Childhood absence epilepsy Childhood absence epilepsy Juvenile myoclonic epilepsy
⬍5/day ⬍10/day ⬍2/month ⬍5/week ⬍10/day Seizure-free
Valproic acid Ethosuximide Valproic acid Valproic acid Valproic acid Valproic acid
Myatchin and Lagae: Spindle Abnormalities in Epilepsy 107
3) Frequency content of spindles. The mean frequency of all spindles within stage 2 was calculated in the three groups. To study possible dynamic changes during the night, the mean spindle frequency was also calculated for the first and last stage 2 periods in the sleep. Next, the 10-16 Hz spindle interval was divided into two bands: 10-12 Hz (slow) and 12-16 Hz (fast). Again, the number of spindles in each band was calculated for the entire night, as well as for the first and last stage 2 periods separately. This value was expressed as a percentage of total number of spindles in all stage 2 periods or total number of spindles in first or last stage 2 respectively.
Statistical Analysis Analysis of variance and Kruskal-Wallis nonparametric testing were used, as well as the Post test [29]. Results with P ⬍ 0.05 were considered significant. Graphpad and Statistica software packages were used to run the statistical tests.
Results Sleep Architecture (Fig 1) In all children from the three groups, the hypnogram, as constructed with our software and manual calculation (see Methods), did not disclose any abnormality. Total sleep time was not different in the three groups. The percentages spent in stage 2 during sleep (stage 2 proportion) did not differ significantly between the three groups. However, a major difference was observed in “stage 2 latency”: in the untreated primary generalized group, sleep latency was 14 minutes on average, whereas it was significantly longer in the control group (mean 47 minutes; analysis of variance P ⬍ 0.01; Kruskal-Wallis P ⬍ 0.03). The treated primary generalized group was not significantly different for this
parameter, but was more comparable with the control group than with the untreated primary generalized group. Amount of Spindles (Fig 2) As could be expected, the majority of spindles was found in stage 2 in the control group (mean 68.7%). In the untreated children with primary generalized electroencephalographic abnormalities, the percentage of spindles in stage 2 was significantly lower (analysis of variance P ⬍ 0.02; Kruskal-Wallis P ⬍ 0.03). Medication seems to restore this disequilibrium: the treated primary generalized group did not differ significantly from the control group, but did so compared with the untreated primary generalized group (analysis of variance P ⬍ 0.02; Kruskal-Wallis P ⫽ 0.007). Looking more in depth to spindle density, no significant differences were evident: the number of spindles per minute during the entire sleep, during stage 2 sleep, or during the first or last stage 2 sleep did not differ significantly between or within the three groups. Frequency of Spindles (Fig 3) The mean spindle frequency in all stages 2 was between 12 and 13 Hz in all three groups, without any significant differences. In the control group, there was an increase of mean spindle frequency when the first stage 2 was compared with the last stage 2 period (12.60 Hz vs 12.21 Hz). This significant increase was not found back in the primary generalized groups. Another difference was observed in the first stage 2 period, comparing the control
Figure 1. Sleep architecture. C ⫽ control group; UPG ⫽ untreated primary generalized group; TPG ⫽ treated primary generalized group; ns ⫽ not significant. *P ⬍ 0.05.
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Figure 2. Amount of spindles. C ⫽ control group; UPG ⫽ untreated primary generalized group; TPG ⫽ treated primary generalized group; Sp ⫽ sleep spindles; SpD ⫽ spindles density (an amount of spindles per minute); ns ⫽ not significant. *P ⬍ 0.05.
group with the untreated primary generalized group: in the untreated primary generalized group, mean spindle frequency was higher (12.87 compared with 12.21 Hz). These parameters were separately analyzed for the slow (⬍12 Hz) and the fast (12-16 Hz) frequency groups. In all three groups, the majority of spindles was found in the fast frequency group. The aforementioned increase of spindle frequency in the control group in the last stage 2 period is reflected by a significantly higher number of spindles in the fast frequency group (88.7 vs 79.6%), with concurrent decrease of slow frequency spindles (22.7 vs 12.5%). These significant changes were not observed back in the untreated primary generalized and the treated primary generalized group, although a similar tendency is clear in the medicated group. Discussion This study examined, in a highly selected group of 15 children with generalized spike-and-wave discharges on their video-electroencephalography recordings, whether there were associated sleep spindle dysfunctions based on the known relationship between spindles and generalized spike-and-waves. In view of the abundant experimental data on this topic, special attention was paid to spindle organization throughout sleep. The main finding of this study is that in untreated children with spike-and-wave discharges, stage 2 sleep occurred earlier than in a control group and there were less spindles in stage 2. In view of
the same total sleep time in these children and the equal total amount of spindles in the three groups, this decrease of spindles in stage 2 indicates that spindles are now more scattered throughout the night. With our methodology it was not possible to demonstrate that spindles were actually “replaced” by spike-wave discharges in stage 2 [15]. Another finding was that the normal frequency increase of fast spindles during the night (comparing last stage 2 with first stage 2) was not observed in the untreated primary generalized group. These differences were not present or were less clear in a group of treated children with spike-and-wave discharges. The findings demonstrate that in primary generalized epilepsy, the thalamo-cortical circuits can still make normal spindles: the mean frequency and length of the spindles are normal. This result at least indicates that the generating circuit is intact, which is not surprising, knowing that in typical generalized epilepsy no thalamic or cortical structural abnormalities are present [30,31]. On the other hand, the macro-organization of sleep seems to be dynamically disturbed: onset of stage 2 is earlier, there are fewer spindles in stage 2 and the normal frequency increase in the last stage 2 sleep is not observed. Perhaps the most striking finding was the earlier onset of the first stage 2 in children with generalized spike-andwave discharges. Williams et al. [32] reported an agedependent maturational course of stage 2 latency, with shorter latencies in older children. It is therefore difficult to interpret our findings of a decreased latency in
Myatchin and Lagae: Spindle Abnormalities in Epilepsy 109
Figure 3. Frequency of spindles. UPG ⫽ untreated primary generalized group; TPG ⫽ treated primary generalized group; SpFr ⫽ mean spindles frequency (Hz); SpFr ⬍12 Hz ⫽ spindles within the frequency band 10-12 Hz; SpFr 12-16 Hz ⫽ spindles within the frequency band 12-16 Hz.
children with epileptic abnormalities. One can argue that a normal inhibitory mechanism could be deficient in children with epileptic abnormalities, leading to an earlier onset of stage 2. The proportion of total time in stage 2 (29.5%) is lower than in other studies [32-36]. Percentages of stage 2 sleep vary between 41% and 52%. However, comparison with other data is difficult, because standard sleep analysis techniques were not used, as was explained in the methodology section. As reported, no differences in this parameter between the three groups were evident. We realize the potential weaknesses of this study. Ideally, a longitudinal and blinded study instead of a cross-sectional study is required to strengthen these findings. Also, a larger number of patients is needed. However, the number of potential subjects was deliberately limited with stringent inclusion criteria. For instance, all patients who manifested any focal abnormality on their electroencephalogram were excluded, to ensure that we were dealing with truly primary generalized epileptic abnormalities. In this respect, it is known that more than 50% of children with primary generalized epilepsies do exhibit focal abnormalities [37,38]. We did not examine whether these sleep changes were correlated with clinical sleep problems in these children. It
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is known in the literature that many children with epilepsy do have sleep problems, which are not merely related to the occurrence of overt seizures during the night [39,40]. Because spindles are believed to be a hallmark of normal sleep [26], the data presented herein suggest that the abnormalities of spindle organization during the night could indeed underlie clinical sleep problems. Spindles are “sleep-enhancing” and make a smooth transition from light to deep sleep [41]. Less spindles in stage 2 therefore indicates possible difficulties to get into the deeper stages of sleep.
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