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Sleep disorders in tuberous sclerosis: a polysomnographic study
ELSEVIER
Brain & Development 1995; 17:52-6
Original article
Sleep disorders in tuberous sclerosis: a polysomnographic study Oliviero Bruni *, Flavia Cortesi, Flavia Giannotti, Paolo Curatolo Department of Child Neurology and Psychiatry, Universityof Rome 'La Sapienza', Via dei SabeUi 108, 00185 Rome, Italy Received 6 June 1994; accepted 27 October 1994
Overnight polysomnography was performed in 10 subjects with tuberous sclerosis (TS) and partial epilepsy in order to investigate the relationships between sleep organization, sleep disorders and epilepsy. Sleep architecture abnormalities were observed in 9 cases. Compared with ten healthy age-matched controls, the TS group showed a shorter total sleep time, a reduced sleep efficiency, a higher number, of awakenings and stage transitions, an increased wake after sleep onset and stage 1 and a decreased ItEM sleep. Children with seizures showed a more disrupted sleep architecture compared with seizure-free children. Sleep disorders in TS were mainly due to sleep-related epileptic events and were more evident in children who showed large bifrontal or temporal tubers on MRI. Keywords: T u b e r o u s sclerosis; Sleep disorder; Polysomnography; Epilepsy
1. I N T R O D U C T I O N Sleep disorders, such as night wakings, waking early, seizure-related sleep problems, and excessive daytime sleepiness, are considered one of the most common behavioral manifestations in children with tuberous sclerosis (TS) [1,2]. In a study on 300 children investigated by postal questionnaire, Hunt [3] reported the presence of sleep problems in 58% of children and seizure-related sleep problems in 41%. In a polysomnographic (PSG) study performed on two cases with TS, both having subependymal nodules of caudate nucleus, Nezu et al. [4] demonstrated a synaptic supersensitivity of the dopamine receptor that seems to play a role in the pathophysiology of epilepsy. However, in this study sleep organization was not investigated. Since no detailed studies were available in the literature, we performed PSG in children with TS to better investigate the relationships between sleep organization, sleep disorders and epilepsy.
2. M A T E R I A L S AND M E T H O D S T e n children (9 females and 1 male, aged 2-17.1 years, mean age 11 years), referred to the Department of Child
* Corresponding author. Fax: (39) (6) 495 7857. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00118-9
Neurology and Psychiatry of the University of Rome 'La Sapienza', with a diagnosis of TS confirmed by clinical and MRI findings, were studied. All the patients had partial epilepsy and were on anti-epileptic therapy. Intellectual or developmental quotients (IQ, DQ) were evaluated by means of standardized psychometric examinations (Wechsler Scale: WPPSI or WlSC-R, Stanford-Binet and Brunet-L6zine) according to their age and mental level. Patients were classified as follows: normal intelligence (DQ or IQ > 85), borderline (DQ or IQ 70-85), mild and moderate mental retardation ((DQ or IQ 40-70), severe mental retardation (DQ or IQ < 40). Clinical, EEG and neuroimaging data are shown on Table 1. Two consecutive overnight PSG using Nicolet Ultrasom, a sleep/wake analyzer, were recorded in the Sleep Laboratory of our Department. Two montages (Fp2-C4, C4-T4, T4-O2, Fpl-C3, C3-T3, T3-O1 or Fp2-F8, F8-C4, C4-P4, P4-O2, Fpl-F7, F7-C3, C3-P3, P3-O1, C3-A2, O2-A1, left and right electro-oculography, chin EMG, EKG, abdominal respiratory effort) were used according to the main EEG focus to document epileptiform activity and nocturnal seizures. Gold-plated surface electrodes were applied to the scalp using the collodium technique according to the International 10-20 System. Sleep recordings were started at the patients' habitual bedtime and continued until spontaneous awakening. To avoid the so-called first night effect we considered only the second night recordings. Records were visually scored in 30-s epochs according to the standard criteria of Rechtschaffen and Kales
[5].
O. Bruni et aL / Brain & Development 1995; 17:52-6
53
Table 1 Clinica~ EEG and neuroimaging data of TS children No./sex
Age
1/F 2/F 3/F 4/F 5/F 6/M 7,)F 8/F 9/F 10/F
10.7 16.6 13.7 14 14.5 2 15.3 3.1 17.1 3.7
Seizures Type
Frequency a
Timing
PM PM+PC PC PM PM PM P M + P C + Ton PC PM + PC PM
+ + + + + +
N D N D,N D D,N
+ +
+ + + + +
EEG focus
Tubers topography
IQ/DQ
Drug therapy
rT ITrT rO IO IO rP rO IT BiF IF rF IT IT ITO rF
rP IO rT rTO IP IPO rP rPO rO ITP rF ITO rF IT ITP IO
70 64 < 40 104 119 93 < 40 68 71 62
CBZ CBZ+GVG CBZ CBZ CBZ CBZ CBZ+ GVG CBZ CBZ CBZ+ GVG
PM, partial motor; PC, partial complex; Ton, tonic; - , absent; +, sporadic/monthly; + +, weekly; + + +, daily; N, nocturnal; D, diurnal; T, temporal; F, frontal; O, occipital; P, parietal; 1, left; r, right; Bi, bilateral; CBZ, earbamazepine; GVG, vigabatrin. a Seizure frequency during the previous 3 months preceding the PSG. Sleep histograms and s l e e p / w a k e statistics, including total sleep time, sleep efficiency, sleep latency, R E M latency, number of awakenings and the percentage of time spent in each stage of sleep, were carried out by the c o m p u t e r based on visual scoring. For each patient we also determined the presence of the interictal epileptiform activity and the occurrence of epileptic seizures during the recording. In order to quantify epileptiform activity we determined (for each patient) the paroxysmal activity (PA) density, defined as the number of seconds with P A over the total recording time in seconds. Spike, spike and waves, and sharp waves were considered as PA. PSG data of TS children were c o m p a r e d with those of an age-matched control group of 10 healthy children (6 F, 4 M; mean age 9.6 yrs, range 2.10-17) who had no history of disease or neurological or psychiatric problems. Physical and neurological examinations of each child were normal, I Q / D Q were all within normal ranges. Awake and sleep E E G were normal. A brief structured interview including several items on the subjects sleeping habits (sleep latency, nighttime sleep, numTable 2
ber and duration of night wakings, presence of nocturnal seizures, daytime sleepiness) was c a r d e d out with the parents. Parents were also asked to observe their childrens' s l e e p / w a k e cycle and to fill in a daily sleep log for a period of at least 2 months, recording any event, Statistical analysis was carried out by means of M a n n Whitney U-test.
3. R E S U L T S
3.1. PSG findings Sleep architecture Sleep parameters of ITS group are shown in Table 2. Sleep efficiency higher than 90% was found only in one case (no. 4), who also showed a regular cyclic organization. The remaining nine cases showed a sleep efficiency ranging from 60.1 to 88.4%. Several night wakings (5-26) were observed in six cases and a percentage of wake after sleep onset ( W A S O ) higher than 10% was found in seven cases.
Polysomnographic variables of TS children No. (age)
TIB (min) TST (min) SPT (min) SEI (%) SL (rain) # Awak # St trans MT (%) WASO (%) TS1 (%) TS2 (%) TSWS (%) TREM (%) REM Lat No. of REM PA density (%)
1 (10.7)
2 (16.6)
3 (13.7)
4 (14)
5 (14.5)
6 (2)
7 (15.3)
8 (3.1)
9 (17.1)
10 (3.7)
491 433 449.5 88.2 18.5 2 33 1.7 1.9 5.4 44.5 30 16.5 156.5 5 0
553 342.5 546.5 61.9 8 26 64 12.5 24.8 7.4 30.2 22.1 3 386.5 2 30
378.5 334.5 363.5 88.4 15 4 37 2.6 5.4 10.5 44.2 17.1 20.2 70 5 31
379.5 356 360.5 93.8 14.5 0 58 1.2 0 12.5 31.9 41.6 12.8 72.5 4 0
462 378 438 81.8 12.5 7 96 2.7 11 23.2 28.2 27.4 7.5 129.5 2 0
531 319.0 525.5 60.1 5.5 25 57 7.5 31.8 16.4 24.1 11.2 9 134 3 8
688 537 679.5 79.2 5.5 21 127 3.7 17.3 18.3 39.2 21.5 0 176 0 78
569.5 405.5 556.5 71.2 3.5 7 36 1.7 25.4 10.3 34.1 16.1 12.4 47 4 2
483.5 306.5 436.0 63.4 22 5 109 0 29.7 15.4 30 12.8 12.1 77 4 0
519 395.5 514 76.2 5.0 13 63 8.9 14.2 22.6 28.4 19 7.0 179 3 10
TIB, time in bed; TST, total sleep time; SPT, sleep period total; SEI, sleep efficiency index; SL, sleep latency; # Awak, number of awakenings; # St trans, number of stage transitions; MT, movement time; WASO, wake after sleep onset; TS1, time spent in stage 1; TS2, time spent in stage 2; TSWS, time spent in slow wave sleep; TREM, time spent in REM sleep; REM lat, Rein latency; PA, paroxysmal activity.
54
O. Bruni et al. / Brain & Development 1995; 17:52-6
Table 3 Comparison of PSG parameters of TS children and control group Tuberous sclerosis a TIB (min) TST (min) SPT (min) SEI (%) Sleep latency (min) # Stage transitions # Awakenings Movement time (%) WASO (%) TS1 (%) TS2 (%) TSWS (%) TREM (%) REM latency (min) # REM periods
Controls b
p
Mean
S.D.
Mean
S.D.
505.5 380.7 486.9 76.4 11.4 68.1 13.5 4.7 16.1 14.2 33.5 21.7 10.1 142.8 3.2
91.3 67.9 97.3 11.9 6.4 32.3 15.4 3.9 11.5 6.01 7.02 9.12 5.9 77.7 1.3
556.0 505.3 542.8 91.1 14.5 20.8 1.5 2.6 2.1 6.9 45.0 22.6 20.8 72.5 4.85
37.1 32.3 30.9 5.5 10.7 8.8 1.5 2.3 2.3 3.5 3.07 4.6 5.3 23.3 1.2
NS < 0.05 NS < 0.005 NS < 0.005 < 0.05 NS < 0.05 < 0.05 NS NS < 0.05 NS < 0.05
TIB, time in bed; TST, total sleep time; SPT, sleep period total; SEI, sleep efficiency index; WASO, wake after sleep onset; TS1, time spent in stage 1; TS2, time spent in stage 2; TSWS, time spent in slow wave sleep; TREM, time spent in REM sleep, a n = 10, 1 M:9 F. Mean age 11, range 2-17.1. b n = 10, 4 M:6 F. Mean age 9.6, range 2.10-17. We also observed mild abnormalities in the first half of the night, such as frequent awakenings (Cases 3, 9 and 10), absence of REM in the first cycle (Cases 5, 10), and severe alterations with poorly organized cycles and frequent awakenings (Cases 2, 6 and 7). The latter patient, who presented twelve brief tonic seizures, showed a profoundly altered sleep cyclicity, several night wakings, stage shifts and absence of REM sleep. Compared with controls, the TS group showed a shorter total sleep time, a reduced sleep efficiency, a higher number of awakenings and stage transitions, an increased wake after sleep onset and stage 1, and a decreased REM sleep (Table 3).
Relationship between sleep and seizures Nocturnal seizures, all occurring during NREM sleep, were recorded in three patients: Case 2 presented one partial complex seizure, Case 7 twelve tonic seizures, and Case 8 two partial complex seizures. Interictal epileptiform activity were found in all cases with a PA density ranging from 4 to 78%. Correlation between sleep alterations and the degree of PA density did not show significant differences. However, children with seizures showed a more disrupted sleep architecture with a reduced sleep efficiency (mean 68.66% vs. 88.05%), an increased WASO (mean 23.86% vs. 4.57%) and a higher number of awakenings (mean 16.16 vs. 3.2) compared with seizure-free
During seizures
Seizure-free 0
ply
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Fig. 1. Sleep hypnograms of Cases 6 (top) and 8 (bottom) during seizures and seizure-free periods show reduced number of awakenings, increased duration of REM and slow wave sleep, reduced REM latency and number of stage transitions in seizure free period.
55
O. Bruni et al. / Brain & Development 1995; 17:52-6
children (P < 0.05). Furthermore comparative sleep profiles of Cases 6 and 8 showed a marked improvement of sleep organization after a seizure-free period (Fig. 1).
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Relationship between sleep and tubers topography Sleep alterations were more evident in subjects who showed several large bilateral tubers mainly localized in frontal and temporal areas on MRI (Cases 2, 7, 8, 9) than in those who had isolated cortical parietal and posterior tubers (Cases 1, 3, 4, 5, 6, 10). Although our results showed a reduced sleep efficiency (mean 68.9% vs. 81.4%), an increased WASO (mean 24.3% vs. 10.7%), a higher number of awakenings (mean 14.7 vs. 8.5) and a higher number of stage transitions (mean 84 vs. 51.3), no statistical significance were found for all these parameters.
4 | i
I i
~ i
II
3.2. Sleep interview and log Parents reported a night-time sleep ranging from 8 to 10.5 h, time to fall asleep higher than 20 min (2 cases), and more than 3 nocturnal awakenings (8 cases), lasting more than 30 min in 4 cases. Nocturnal seizures were reported in 4 cases and day-time sleepiness in 6 cases. Sleep log showed a distinct circadian rhythm in nine cases. Case 7 showed a marked irregular sleep/wake pattern consisting of inability to initiate and maintain sleep at night with day to day variability in the timing of sleep and wakefulness (Fig. 2). This patient also presented a high frequency of nocturnal seizures with an elevated PA density (78%) and a more severe disruption of sleep architecture.
0
6
12
18
24
Time of Day
Fig. 2. Top: hypnogram of Case 7 shows a profoundly altered sleep cyclicity with frequent awakenings, stage shifts and absence of REM sleep. Bottom: 1 month sleep log chart based on parents' observation indicating sleeping (black bars), and waking period (open bars) that shows an irregular circadian rhythm with marked day-to-day variability in the timing of sleep and wakefulness.
4. D I S C U S S I O N Sleep organization in children with epilepsy has been reported to be permanently altered by frequent awakenings and stage shifts even in the absence of nocturnal seizures [6,7]. The most common abnormalities are a slight reduction in REM sleep, an increase in wakefulness after sleep onset, and instability of sleep stages. Night-time occurrence of seizures aggravate sleep disturbance reducing REM sleep and NREM deep sleep. In addition, epileptic children who complained of "unrefreshing sleep" had more subclinical arousals than controls detected by overnight PSG [8]. It is well known that children affected by symptomatic partial epilepsy show permanent modifications in sleep architecture including an increased number of stage shifts, a reduced number of REM periods and percentage of stage 2 and REM [9,10]. An enhancement of interictal epileptiform activity during NREM sleep with a maximal activation during the deepest NREM sleep phases and similar levels of epileptic activity during wakefulness and REM sleep were described in patients with partial epilepsy [11,12], mainly in subjects with frontal EEG focus and secondary bilateral synchrony [13,14]. Regarding the effect of anticonvulsant drugs on sleep, several studies have shown that carbamazepine improves sleep stability [15]. Also, vigabatrin seems not to alter sleep organization [16,17]. Therefore, in this study, drugs can not be incriminated as the source of the awakenings and sleep instability.
Our findings show a wide range of sleep abnormalities in children with TS similar to those reported in children with symptomatic partial epilepsy. The main perturbations that characterized the sleep organization of TS patients were a reduced REM sleep, a sleep instability and fragmentation by frequent awakenings. Although sleep disturbances were seen with and without the occurrence of nocturnal seizures a n d / o r the presence of EEG abnormalities during the course of the PSG recordings, they were more evident in the children showing seizures in the period preceding the PSG. In fact, we found a consistent improvement of sleep architecture in cases who underwent a second PSG recording after a seizure-free period. In our study, sleep activated interictal epileptic activity, particularly in patients with frontal and temporal EEG loci who were in topographic agreement with the localization of cortical tubers. Sleep alterations were more evident in subjects who showed large bifrontal and temporal tubers on MRI rather than in those who had isolated cortical parietal or posterior tubers. Therefore, sleep disorders seems to be mainly due to sleep-related epileptic events, depending on the number and on the anatomical localization of the cortical tubers. Concerning the sleep-wake rhythm, we observed a marked irregularity only in one case who also presented severe mental retardation and brain impairment, as already reported by Okawa et al. [18].
56
O. Bruni et al. / Brain & Development 1995; 17:52-6
Settling and night waking problems that cause serious disruptions of parents' sleep were very common in children with TS and were linked with current epilepsy and daytime behavioural disturbance [19]. In our series, parents reported mainly awakenings lasting more than 5 min and usually related to seizure. By contrast a high number of brief awakenings, not seizure-related and detected by PSG, were missed by parents, suggesting that sleep disorders may be underestimated. Our findings confirm that sleep alterations are a consistent feature of TS and PSG can be a valid tool in detecting sleep architecture abnormalities.
REFERENCES 1. Curatolo P, Cusmai R, Cortesi F, Jambaque I, Chiron C, Dulac O. Neurological and psychiatric aspects of tuberous sclerosis. Ann NYAcad Sci 1991; 615: 8-16. 2. Stores G. Annotation: Sleep studies in children with a mental handicap. J Child Psychol Psychiatr 1992; 33: 1303-17. 3. Hunt A. Development, behavior and seizures in 300 cases of tuberous sclerosis. J Intell Dis Res 1993; 37: 41-51. 4. Nezu A, Kimiaki U, Nomura Y, Segawa M. Roles of a subependymal nodule of tuberous sclerosis on pathophysiology of epilepsy. Jpn JPsychiatr Neurol (Tokyo) 1991; 45: 372-7. 5. Rechtschaffen A, Kales A. A manual of standardized terminology: techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service-Brain Research Institute, 1968. 6. Quine L. Sleep problems in children with severe mental handicap. J Ment Defic Res 1991; 35: 269-90. 7. Touchon J, Baldy-Moulinier M, Billiard M, Besset A, Cadilhac J. Sleep organization and epilepsy. Epzlepsy Res 1991; 2: 73-82.
8. ZaiwaUa Z, Stores G. Sleep and arousal disorders in childhood epilepsy. Electroencephalogr Clin Neurophysiol 1989; 72: 107. 9. Baldy-Moulinier M, Touchon J, Billiard M, Carriere A, Besset A. Nocturnal sleep studies in the Lennox-Gastaut syndrome. In: Nyedermeyer R, Degen Reds. The Lennox-Gastaut syndrome. New York: Liss, 1988: 243-60. 10. Deray MJ, Epstein MA. Sleep abnormalities in children with intractable epilepsy. Sleep Res 1991; 20: 98. 11. Rossi GF, Colicchio G, Pola P. Interictal epileptic activity during sleep: a stereo-EEG study in patients with partial epilepsy. Electroencephalogr Clin Neurophysiol 1984; 58: 97-106. 12. Sammaritano M, Gigli GL, Gotman J. Interictal spiking during wakefulness and sleep and localization of loci in temporal lobe epilepsy. Neurology 1991; 41: 290-7. 13. Blume WT, Pillay N. Electrographic and clinical correlates of secondary bilateral synchrony. Epilepsia 1985; 26: 636-41. 14. Kobayashi K, Ohtsuka Y, Oka E, Ohtahara S. Primary and secondary bilateral synchrony in epilepsy: differentiation by estimation of interhemispheric small time differences during spikewave activity. Electroencephalogr Clin Neurophysiol 1992; 83: 93-103. 15. Touchon J, Baldy-Moulinier M, Carlander B, et al. Organisation du sommeil dans l'epilepsie recente du lobe temporal avant etapes. Traitement par carbamazepine. Rev Neurol 1987; 143: 733-7. 16. Alken R. Tolerance and effects of gamma-vinylGABA on sleep parameters and psychometrics in healthy volunteers. Kansas City: Merrel Dow Research Institute, 1982 (unpublished data). 17. Curatolo P. Vigabatrin for refractory partial seizures in children with tuberous sclerosis. Neuropediatrics 1994; 25: 55. 18. Okawa M, Takahashi K, Sasaki H. Disturbance of circadian rhythms in severely brain-damaged patients correlated with CT findings. J Neurol 1986; 233: 274-82. 19. Hunt A, Stores G. Sleep disorders and epilepsy in children with tuberous sclerosis: a questionnaire based study. Dev Med Child Neurol 1994; 36: 108-15.
Brain & Development 1995; 17:52-6
Original article
Sleep disorders in tuberous sclerosis: a polysomnographic study Oliviero Bruni *, Flavia Cortesi, Flavia Giannotti, Paolo Curatolo Department of Child Neurology and Psychiatry, Universityof Rome 'La Sapienza', Via dei SabeUi 108, 00185 Rome, Italy Received 6 June 1994; accepted 27 October 1994
Overnight polysomnography was performed in 10 subjects with tuberous sclerosis (TS) and partial epilepsy in order to investigate the relationships between sleep organization, sleep disorders and epilepsy. Sleep architecture abnormalities were observed in 9 cases. Compared with ten healthy age-matched controls, the TS group showed a shorter total sleep time, a reduced sleep efficiency, a higher number, of awakenings and stage transitions, an increased wake after sleep onset and stage 1 and a decreased ItEM sleep. Children with seizures showed a more disrupted sleep architecture compared with seizure-free children. Sleep disorders in TS were mainly due to sleep-related epileptic events and were more evident in children who showed large bifrontal or temporal tubers on MRI. Keywords: T u b e r o u s sclerosis; Sleep disorder; Polysomnography; Epilepsy
1. I N T R O D U C T I O N Sleep disorders, such as night wakings, waking early, seizure-related sleep problems, and excessive daytime sleepiness, are considered one of the most common behavioral manifestations in children with tuberous sclerosis (TS) [1,2]. In a study on 300 children investigated by postal questionnaire, Hunt [3] reported the presence of sleep problems in 58% of children and seizure-related sleep problems in 41%. In a polysomnographic (PSG) study performed on two cases with TS, both having subependymal nodules of caudate nucleus, Nezu et al. [4] demonstrated a synaptic supersensitivity of the dopamine receptor that seems to play a role in the pathophysiology of epilepsy. However, in this study sleep organization was not investigated. Since no detailed studies were available in the literature, we performed PSG in children with TS to better investigate the relationships between sleep organization, sleep disorders and epilepsy.
2. M A T E R I A L S AND M E T H O D S T e n children (9 females and 1 male, aged 2-17.1 years, mean age 11 years), referred to the Department of Child
* Corresponding author. Fax: (39) (6) 495 7857. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00118-9
Neurology and Psychiatry of the University of Rome 'La Sapienza', with a diagnosis of TS confirmed by clinical and MRI findings, were studied. All the patients had partial epilepsy and were on anti-epileptic therapy. Intellectual or developmental quotients (IQ, DQ) were evaluated by means of standardized psychometric examinations (Wechsler Scale: WPPSI or WlSC-R, Stanford-Binet and Brunet-L6zine) according to their age and mental level. Patients were classified as follows: normal intelligence (DQ or IQ > 85), borderline (DQ or IQ 70-85), mild and moderate mental retardation ((DQ or IQ 40-70), severe mental retardation (DQ or IQ < 40). Clinical, EEG and neuroimaging data are shown on Table 1. Two consecutive overnight PSG using Nicolet Ultrasom, a sleep/wake analyzer, were recorded in the Sleep Laboratory of our Department. Two montages (Fp2-C4, C4-T4, T4-O2, Fpl-C3, C3-T3, T3-O1 or Fp2-F8, F8-C4, C4-P4, P4-O2, Fpl-F7, F7-C3, C3-P3, P3-O1, C3-A2, O2-A1, left and right electro-oculography, chin EMG, EKG, abdominal respiratory effort) were used according to the main EEG focus to document epileptiform activity and nocturnal seizures. Gold-plated surface electrodes were applied to the scalp using the collodium technique according to the International 10-20 System. Sleep recordings were started at the patients' habitual bedtime and continued until spontaneous awakening. To avoid the so-called first night effect we considered only the second night recordings. Records were visually scored in 30-s epochs according to the standard criteria of Rechtschaffen and Kales
[5].
O. Bruni et aL / Brain & Development 1995; 17:52-6
53
Table 1 Clinica~ EEG and neuroimaging data of TS children No./sex
Age
1/F 2/F 3/F 4/F 5/F 6/M 7,)F 8/F 9/F 10/F
10.7 16.6 13.7 14 14.5 2 15.3 3.1 17.1 3.7
Seizures Type
Frequency a
Timing
PM PM+PC PC PM PM PM P M + P C + Ton PC PM + PC PM
+ + + + + +
N D N D,N D D,N
+ +
+ + + + +
EEG focus
Tubers topography
IQ/DQ
Drug therapy
rT ITrT rO IO IO rP rO IT BiF IF rF IT IT ITO rF
rP IO rT rTO IP IPO rP rPO rO ITP rF ITO rF IT ITP IO
70 64 < 40 104 119 93 < 40 68 71 62
CBZ CBZ+GVG CBZ CBZ CBZ CBZ CBZ+ GVG CBZ CBZ CBZ+ GVG
PM, partial motor; PC, partial complex; Ton, tonic; - , absent; +, sporadic/monthly; + +, weekly; + + +, daily; N, nocturnal; D, diurnal; T, temporal; F, frontal; O, occipital; P, parietal; 1, left; r, right; Bi, bilateral; CBZ, earbamazepine; GVG, vigabatrin. a Seizure frequency during the previous 3 months preceding the PSG. Sleep histograms and s l e e p / w a k e statistics, including total sleep time, sleep efficiency, sleep latency, R E M latency, number of awakenings and the percentage of time spent in each stage of sleep, were carried out by the c o m p u t e r based on visual scoring. For each patient we also determined the presence of the interictal epileptiform activity and the occurrence of epileptic seizures during the recording. In order to quantify epileptiform activity we determined (for each patient) the paroxysmal activity (PA) density, defined as the number of seconds with P A over the total recording time in seconds. Spike, spike and waves, and sharp waves were considered as PA. PSG data of TS children were c o m p a r e d with those of an age-matched control group of 10 healthy children (6 F, 4 M; mean age 9.6 yrs, range 2.10-17) who had no history of disease or neurological or psychiatric problems. Physical and neurological examinations of each child were normal, I Q / D Q were all within normal ranges. Awake and sleep E E G were normal. A brief structured interview including several items on the subjects sleeping habits (sleep latency, nighttime sleep, numTable 2
ber and duration of night wakings, presence of nocturnal seizures, daytime sleepiness) was c a r d e d out with the parents. Parents were also asked to observe their childrens' s l e e p / w a k e cycle and to fill in a daily sleep log for a period of at least 2 months, recording any event, Statistical analysis was carried out by means of M a n n Whitney U-test.
3. R E S U L T S
3.1. PSG findings Sleep architecture Sleep parameters of ITS group are shown in Table 2. Sleep efficiency higher than 90% was found only in one case (no. 4), who also showed a regular cyclic organization. The remaining nine cases showed a sleep efficiency ranging from 60.1 to 88.4%. Several night wakings (5-26) were observed in six cases and a percentage of wake after sleep onset ( W A S O ) higher than 10% was found in seven cases.
Polysomnographic variables of TS children No. (age)
TIB (min) TST (min) SPT (min) SEI (%) SL (rain) # Awak # St trans MT (%) WASO (%) TS1 (%) TS2 (%) TSWS (%) TREM (%) REM Lat No. of REM PA density (%)
1 (10.7)
2 (16.6)
3 (13.7)
4 (14)
5 (14.5)
6 (2)
7 (15.3)
8 (3.1)
9 (17.1)
10 (3.7)
491 433 449.5 88.2 18.5 2 33 1.7 1.9 5.4 44.5 30 16.5 156.5 5 0
553 342.5 546.5 61.9 8 26 64 12.5 24.8 7.4 30.2 22.1 3 386.5 2 30
378.5 334.5 363.5 88.4 15 4 37 2.6 5.4 10.5 44.2 17.1 20.2 70 5 31
379.5 356 360.5 93.8 14.5 0 58 1.2 0 12.5 31.9 41.6 12.8 72.5 4 0
462 378 438 81.8 12.5 7 96 2.7 11 23.2 28.2 27.4 7.5 129.5 2 0
531 319.0 525.5 60.1 5.5 25 57 7.5 31.8 16.4 24.1 11.2 9 134 3 8
688 537 679.5 79.2 5.5 21 127 3.7 17.3 18.3 39.2 21.5 0 176 0 78
569.5 405.5 556.5 71.2 3.5 7 36 1.7 25.4 10.3 34.1 16.1 12.4 47 4 2
483.5 306.5 436.0 63.4 22 5 109 0 29.7 15.4 30 12.8 12.1 77 4 0
519 395.5 514 76.2 5.0 13 63 8.9 14.2 22.6 28.4 19 7.0 179 3 10
TIB, time in bed; TST, total sleep time; SPT, sleep period total; SEI, sleep efficiency index; SL, sleep latency; # Awak, number of awakenings; # St trans, number of stage transitions; MT, movement time; WASO, wake after sleep onset; TS1, time spent in stage 1; TS2, time spent in stage 2; TSWS, time spent in slow wave sleep; TREM, time spent in REM sleep; REM lat, Rein latency; PA, paroxysmal activity.
54
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Table 3 Comparison of PSG parameters of TS children and control group Tuberous sclerosis a TIB (min) TST (min) SPT (min) SEI (%) Sleep latency (min) # Stage transitions # Awakenings Movement time (%) WASO (%) TS1 (%) TS2 (%) TSWS (%) TREM (%) REM latency (min) # REM periods
Controls b
p
Mean
S.D.
Mean
S.D.
505.5 380.7 486.9 76.4 11.4 68.1 13.5 4.7 16.1 14.2 33.5 21.7 10.1 142.8 3.2
91.3 67.9 97.3 11.9 6.4 32.3 15.4 3.9 11.5 6.01 7.02 9.12 5.9 77.7 1.3
556.0 505.3 542.8 91.1 14.5 20.8 1.5 2.6 2.1 6.9 45.0 22.6 20.8 72.5 4.85
37.1 32.3 30.9 5.5 10.7 8.8 1.5 2.3 2.3 3.5 3.07 4.6 5.3 23.3 1.2
NS < 0.05 NS < 0.005 NS < 0.005 < 0.05 NS < 0.05 < 0.05 NS NS < 0.05 NS < 0.05
TIB, time in bed; TST, total sleep time; SPT, sleep period total; SEI, sleep efficiency index; WASO, wake after sleep onset; TS1, time spent in stage 1; TS2, time spent in stage 2; TSWS, time spent in slow wave sleep; TREM, time spent in REM sleep, a n = 10, 1 M:9 F. Mean age 11, range 2-17.1. b n = 10, 4 M:6 F. Mean age 9.6, range 2.10-17. We also observed mild abnormalities in the first half of the night, such as frequent awakenings (Cases 3, 9 and 10), absence of REM in the first cycle (Cases 5, 10), and severe alterations with poorly organized cycles and frequent awakenings (Cases 2, 6 and 7). The latter patient, who presented twelve brief tonic seizures, showed a profoundly altered sleep cyclicity, several night wakings, stage shifts and absence of REM sleep. Compared with controls, the TS group showed a shorter total sleep time, a reduced sleep efficiency, a higher number of awakenings and stage transitions, an increased wake after sleep onset and stage 1, and a decreased REM sleep (Table 3).
Relationship between sleep and seizures Nocturnal seizures, all occurring during NREM sleep, were recorded in three patients: Case 2 presented one partial complex seizure, Case 7 twelve tonic seizures, and Case 8 two partial complex seizures. Interictal epileptiform activity were found in all cases with a PA density ranging from 4 to 78%. Correlation between sleep alterations and the degree of PA density did not show significant differences. However, children with seizures showed a more disrupted sleep architecture with a reduced sleep efficiency (mean 68.66% vs. 88.05%), an increased WASO (mean 23.86% vs. 4.57%) and a higher number of awakenings (mean 16.16 vs. 3.2) compared with seizure-free
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O. Bruni et al. / Brain & Development 1995; 17:52-6
children (P < 0.05). Furthermore comparative sleep profiles of Cases 6 and 8 showed a marked improvement of sleep organization after a seizure-free period (Fig. 1).
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Relationship between sleep and tubers topography Sleep alterations were more evident in subjects who showed several large bilateral tubers mainly localized in frontal and temporal areas on MRI (Cases 2, 7, 8, 9) than in those who had isolated cortical parietal and posterior tubers (Cases 1, 3, 4, 5, 6, 10). Although our results showed a reduced sleep efficiency (mean 68.9% vs. 81.4%), an increased WASO (mean 24.3% vs. 10.7%), a higher number of awakenings (mean 14.7 vs. 8.5) and a higher number of stage transitions (mean 84 vs. 51.3), no statistical significance were found for all these parameters.
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3.2. Sleep interview and log Parents reported a night-time sleep ranging from 8 to 10.5 h, time to fall asleep higher than 20 min (2 cases), and more than 3 nocturnal awakenings (8 cases), lasting more than 30 min in 4 cases. Nocturnal seizures were reported in 4 cases and day-time sleepiness in 6 cases. Sleep log showed a distinct circadian rhythm in nine cases. Case 7 showed a marked irregular sleep/wake pattern consisting of inability to initiate and maintain sleep at night with day to day variability in the timing of sleep and wakefulness (Fig. 2). This patient also presented a high frequency of nocturnal seizures with an elevated PA density (78%) and a more severe disruption of sleep architecture.
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Time of Day
Fig. 2. Top: hypnogram of Case 7 shows a profoundly altered sleep cyclicity with frequent awakenings, stage shifts and absence of REM sleep. Bottom: 1 month sleep log chart based on parents' observation indicating sleeping (black bars), and waking period (open bars) that shows an irregular circadian rhythm with marked day-to-day variability in the timing of sleep and wakefulness.
4. D I S C U S S I O N Sleep organization in children with epilepsy has been reported to be permanently altered by frequent awakenings and stage shifts even in the absence of nocturnal seizures [6,7]. The most common abnormalities are a slight reduction in REM sleep, an increase in wakefulness after sleep onset, and instability of sleep stages. Night-time occurrence of seizures aggravate sleep disturbance reducing REM sleep and NREM deep sleep. In addition, epileptic children who complained of "unrefreshing sleep" had more subclinical arousals than controls detected by overnight PSG [8]. It is well known that children affected by symptomatic partial epilepsy show permanent modifications in sleep architecture including an increased number of stage shifts, a reduced number of REM periods and percentage of stage 2 and REM [9,10]. An enhancement of interictal epileptiform activity during NREM sleep with a maximal activation during the deepest NREM sleep phases and similar levels of epileptic activity during wakefulness and REM sleep were described in patients with partial epilepsy [11,12], mainly in subjects with frontal EEG focus and secondary bilateral synchrony [13,14]. Regarding the effect of anticonvulsant drugs on sleep, several studies have shown that carbamazepine improves sleep stability [15]. Also, vigabatrin seems not to alter sleep organization [16,17]. Therefore, in this study, drugs can not be incriminated as the source of the awakenings and sleep instability.
Our findings show a wide range of sleep abnormalities in children with TS similar to those reported in children with symptomatic partial epilepsy. The main perturbations that characterized the sleep organization of TS patients were a reduced REM sleep, a sleep instability and fragmentation by frequent awakenings. Although sleep disturbances were seen with and without the occurrence of nocturnal seizures a n d / o r the presence of EEG abnormalities during the course of the PSG recordings, they were more evident in the children showing seizures in the period preceding the PSG. In fact, we found a consistent improvement of sleep architecture in cases who underwent a second PSG recording after a seizure-free period. In our study, sleep activated interictal epileptic activity, particularly in patients with frontal and temporal EEG loci who were in topographic agreement with the localization of cortical tubers. Sleep alterations were more evident in subjects who showed large bifrontal and temporal tubers on MRI rather than in those who had isolated cortical parietal or posterior tubers. Therefore, sleep disorders seems to be mainly due to sleep-related epileptic events, depending on the number and on the anatomical localization of the cortical tubers. Concerning the sleep-wake rhythm, we observed a marked irregularity only in one case who also presented severe mental retardation and brain impairment, as already reported by Okawa et al. [18].
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Settling and night waking problems that cause serious disruptions of parents' sleep were very common in children with TS and were linked with current epilepsy and daytime behavioural disturbance [19]. In our series, parents reported mainly awakenings lasting more than 5 min and usually related to seizure. By contrast a high number of brief awakenings, not seizure-related and detected by PSG, were missed by parents, suggesting that sleep disorders may be underestimated. Our findings confirm that sleep alterations are a consistent feature of TS and PSG can be a valid tool in detecting sleep architecture abnormalities.
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