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NREM sleep instability in children with sleep terrors: The role of slow wave activity interruptions
Clinical Neurophysiology 119 (2008) 985–992 www.elsevier.com/locate/clinph
NREM sleep instability in children with sleep terrors: The role of slow wave activity interruptions Oliviero Bruni
a,*
, Raffaele Ferri b, Luana Novelli a, Elena Finotti c, Silvia Miano d, Christian Guilleminault e
a
Center for Pediatric Sleep Disorders, Department of Developmental Neurology and Psychiatry, University of Rome ‘‘La Sapienza”, Via dei Sabelli 108, 00185 Rome, Italy b Sleep Research Centre, Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy c Department of Paediatrics, University of Padua, Padua, Italy d Department of Pediatrics, Sleep Centre, ‘‘La Sapienza” University, S. Andrea Hospital, Rome, Italy e Stanford University Sleep Medicine Program, Stanford, CA, USA Accepted 12 January 2008 Available online 29 February 2008
Abstract Objective: To evaluate NREM sleep instability, as measured by the cyclic alternating pattern (CAP), in children with sleep terrors (ST) vs. normal controls. Methods: Ten boys (mean age: 8.5 years, range 5–13) meeting the following inclusion criteria: (a) complaint of ST several times a month, (b) a history of ST confirmed by a third person, and (c) a diagnosis of ST according to the ICSD-2 criteria. Eleven age-matched control children with parental report of at least 8.5 h of nightly sleep, absence of known daytime consequences of sleep disorders were recruited by advertisement from the community. Sleep was visually scored for sleep macrostructure and CAP using standard criteria. Results: Sleep macrostructure showed only a significantly increased number of awakenings per hour and reduced sleep efficiency in ST subjects. CAP parameters analysis revealed several significant differences in ST vs. controls: an increase of total CAP rate in SWS, of A1 index in SWS and of the mean duration of A phases while B phases had a decreased duration, exclusively in SWS. The normalized CAP interval-distribution graphs showed significant differences in SWS with interval classes 10 6 i < 35 s higher in children with ST and intervals classes above 50 s higher in normal controls. Conclusions: Children with ST showed faster alternations of the amplitude of slow EEG bursts during SWS. This abnormally fast alternation of the EEG amplitude in SWS is linked to the frequent intrusion of CAP B phases interrupting the continuity of slow delta activity and could be considered as a neurophysiological marker of ST. Significance: This abnormal alternation of the EEG amplitude in SWS is associated with the occurrence of parasomnias and might be considered as a neurophysiological marker of disorders of arousal. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Sleep terrors; Parasomnias; Cyclic alternating pattern; NREM sleep instability
1. Introduction The International Classification of Sleep Disorders (ICSD-2) defines parasomnias as ‘‘undesirable physical
*
Corresponding author. Tel.: +39 0644712257; fax: +39 064957857. E-mail address: [email protected] (O. Bruni).
events or experiences that occur during entry into, within, or during arousals from sleep” (AASM, 2005). The disorders of arousal (DOA) are a subset of parasomnias and include confusional arousals (CA), sleepwalking (SW), and sleep terrors (ST). These disturbances occur most often during slow-wave sleep (SWS) but can also occur during sleep stage 2 or late in the night (Broughton, 2000; Kavey et al., 1990; Mason and Pack, 2007). In particular, DOA
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tend to occur in the first third of the night, when SWS is most prominent, and are characterized by an incomplete transition from slow-wave sleep, automatic behavior, altered perception of the environment, and a varying amount of amnesia (Mason and Pack, 2007). Although the sleep architecture in DOA does not show significant differences from controls (Espa et al., 2000; Pressman, 2004; Zucconi et al., 1995), several studies have shown subtle alterations of NREM sleep in adults, represented mostly by a high degree of arousal from SWS and by a peculiar EEG pattern defined as hypersynchronous delta activity (HSD) (Espa et al., 2000; Gadreau et al., 2000; Guilleminault et al., 2005a; Pilon et al., 2006; Pressman, 2004; Zucconi et al., 1995), described as continuous high-voltage (>150 lV) delta waves occurring during SWS or immediately prior to an episode (Pilon et al., 2006). This activity was first noted to precede sleepwalking events by Jacobson et al. (1965) although subsequent studies have yielded unclear results, with sleepwalking or sleep terror episodes being occasionally (Espa et al., 2000; Guilleminault et al., 2005b), often (Guilleminault et al., 1998), or always (Espa et al., 2000; Guilleminault et al., 2001) associated with HSD. A more recent investigation found that the frequency of HSD in the EEG of adult sleepwalkers was dependent on the EEG derivation used (presence of a frontocentral gradient) (Pilon et al., 2003). Pilon et al. (2006) also confirmed this frontocentral gradient of HSD and showed that this phenomenon is more evident following sleep deprivation. HSD and arousals from SWS may be present in patients without clinical history of sleepwalking or other parasomnias and, on the contrary, patients with a clear history of violent parasomnias may not have HSD or arousals from SWS. Because of these discrepancies, HSD and arousals from SWS are thought to have a low specificity and sensitivity for the diagnosis of NREM parasomnias (Pilon et al., 2006) and their eventual usefulness as diagnostic markers for DOA remains to be determined (Pressman, 2007). It is important to take into account that HSD has been defined as high-voltage (>150 lV) delta waves occurring during SWS or immediately prior to a parasomnia episode, solely in adults (Jacobson et al., 1965; Guilleminault et al., 1998, 2001; Espa et al., 2000; Schenck et al., 1998; Pilon et al., 2006). On the contrary, SWA recorded from C3– A2 or C4–A1 in an infant or child is often 100–400 lV (Grigg-Damberger et al., 2007). Thus, the current definition of HSD applied to a pediatric group of subjects would indicate that even normal controls have, almost all, this EEG pattern. For this reason, HSD does not seem to be appropriate for the description of children’s SWA with or without parasomnia. Since high-amplitude waves are also part of the cyclic alternating pattern (CAP), and hypersynchronous slow delta is part of the phase A1 and possibly A2 of the CAP (Guilleminault et al., 2006), other studies have tried to eval-
uate CAP in SW and ST subjects, with conflicting results. Zucconi et al. (1995) found an increase of A1% and of CAP rate, and a decrease in phase B duration. Guilleminault et al. (2005a, 2006), also found an increase in CAP rate but also in A2 and A3 index, while A1 index was decreased. For these reasons the aim of our study was to accurately evaluate sleep architecture, CAP, and the time structure of EEG slow oscillations in subjects with DOA: sleep terror (ST). 2. Methods 2.1. Subjects Ten boys (mean age: 8.5 years, range 5–13) were included in this study because they met the following inclusion criteria: (1) Complaint of ST several times a month. (2) A history of ST confirmed by a third person. (3) Diagnosis of ST according to the ICSD-2 (AASM, 2005) criteria, i.e., (A) a sudden episode of terror occurring during sleep, usually initiated by a cry or loud scream, that is accompanied by autonomic nervous system and behavioral manifestations of intense fear; (B) at least one of the following associated features was present: difficulty in arousing the person, mental confusion when awakened from an episode, amnesia (complete or partial) for the episode, dangerous or potentially dangerous behaviors; (C) the disturbance was not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use or substance use disorder. Eleven age-matched children with parental report of at least 8.5 h of nightly sleep, absence of known daytime consequences of sleep disorders (e.g., daytime sleepiness, cataplexy, hyperactivity, morning headache, mouth breathing), and normal health were recruited by advertisement from the community, to serve as control subjects. These children also had complete charts and underwent similar 8.5-h polysomnographic recordings. Exclusion criteria for all participants consisted of the following: (1) the presence of a major psychiatric disorder; (2) the use of drugs that could influence the sleep EEG; (3) the presence or history of a neurologic disorder including epilepsy. In particular, there were no anamnestic information or electroencephalographic signs of an underlying epileptic disorder and all patients included showed, after the participation to this study, a prompt and excellent response to the administration of L-5-hydroxytryptophan, a drug which we have already shown to be effective in this disorder and represent the first choice treatment for ST in our lab (Bruni et al., 2004). All parents were asked to sign a consent form approved by the institution in which sleep recordings were carried out.
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2.2. Polygraphic sleep recordings For this study, subjects underwent an overnight PSG recording in the Sleep Laboratory of the Department of Developmental Neurology and Psychiatry, after one adaptation night, in order to avoid the first-night effect. The EEG recordings and electrode placement were performed according to the 10–20 system (Jasper, 1958) and the PSG montage included at least four EEG channels (C3, C4, O1, O2) referenced to the contralateral mastoid, left and right electrooculogram (EOG), chin electromyogram (EMG), left and right tibialis EMG, electrocardiogram (ECG), thorax and abdominal effort, nasal cannula, peripheral oxygen saturation, pulse and position sensors. All recordings started at the subjects’ usual bedtime and continued until spontaneous awakening. 2.3. Sleep stage scoring Sleep was subdivided into 30-s epochs and sleep stages were scored according to the standard criteria by Rechtschaffen and Kales (1968). The following conventional sleep parameters were evaluated: – Time in bed (TIB). – Sleep period time (SPT): time from sleep onset to sleep end. – Total sleep time (TST): the time from sleep onset to the end of the final sleep epoch minus time awake. – Sleep latency (SL): time from lights out to sleep onset, defined as the first of two consecutive epochs of sleep stage 1 or one epoch of any other stage, in minutes. – REM latency (RL): time from sleep onset to the first REM sleep epoch. – Number of stage shifts/hour (SS/h). – Number of awakenings/hour (AWN/h). – Sleep efficiency (SE%): the percentage ratio between total sleep time and time in bed (TST/TIB * 100). – Percentage of SPT spent in wakefulness after sleep onset (WASO%), i.e., the time spent awake between sleep onset and end of sleep. – Percentage of SPT spent in sleep stages 1 (S1%), 2 (S2%), slow-wave sleep (SWS%), and REM sleep (REM%).
2.4. Cyclic alternating pattern (CAP) scoring CAP was scored following the criteria by Terzano et al. (2001) CAP is a periodic EEG activity of NREM sleep characterized by repeated spontaneous sequences of transient events (phase A), recurring at intervals up to 2 min in duration. The return to background activity identifies the interval that separates the repetitive elements (phase B). In particular, phase-A candidates are scored within a CAP sequence only if they precede and/or are followed by another phase A in the temporal range of 2–60 s. If
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there were three consecutive A-phases followed by a NCAP condition, the CAP sequence is stopped at the end of the second B-phase and the third A-phase A is quantified as non-CAP. This is because the CAP procedure is based on the succession of complete CAP cycles (phase A + phase B). CAP A phases have been subdivided into a 3-stage hierarchy of arousal strength: – A1: A phases with synchronized EEG patterns (intermittent alpha rhythm in S1; sequences of K complexes or delta bursts in the other NREM stages), associated with mild or trivial polygraphic variations. – A2: A phases with desynchronized EEG patterns preceded by or mixed with slow high-voltage waves (K complexes with alpha and beta activities, K-alpha, arousals with slow-wave synchronization), linked with a moderate increase of muscle tone and/or cardio-respiratory rate. – A3: A phases with desynchronized EEG patterns alone (transient activation phases or arousals) or exceeding 2/3 of the phase A length, and coupled with a remarkable enhancement of muscle tone and/or cardio-respiratory rate. The following CAP parameters were measured: – CAP rate (percentage of total NREM sleep time occupied by CAP sequences). – Percentage and duration of each A phase subtype. – A1 index (number of phases A1 per hour of NREM sleep, and of S1, S2, and SWS sleep stage). – A2 index (number of phases A2 per hour of NREM sleep, and of S1, S2, and SWS sleep stage). – A3 index (number of phases A3 per hour of NREM sleep, and of S1, S2, and SWS sleep stage). – Duration of B phases. – Number and duration of CAP sequences. All these variables were analyzed by means of the Hypnolab 1.2 sleep software analysis (SWS Soft, Italy). 2.5. Statistical analysis The comparisons between sleep architecture and CAP parameters, obtained in children with ST vs. normal controls, were conducted using the nonparametric Mann– Whitney test for independent data sets. All intervals between subsequent CAP A phases were subdivided into 25 duration classes (<5 s, P5 < 10 s, P10 < 15 s,. . .., P 115 < 120 s, P120 < 125 s) and counted in each subject; this count was used to draw individual normalized intervaldistribution graphs. The normalization was obtained by calculating the percentage of each class with respect to the total individual count. In this way, data from different individuals could be pooled together. The intervals between subsequent CAP A phases occurring during light NREM
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sleep (stages 1 and 2) were counted separately from those occurring during SWS (sleep stages 3 and 4). In addition, two different normalized distribution graphs were obtained, one for light sleep and another for SWS, in each subject group. The differences between the two groups and their light sleep or SWS for each interval class were evaluated by means of a Bonferroni-corrected nonparametric Mann–Whitney test for independent data sets. The commercially available software STATISTICA (StatSoft, Inc. 2004, version 6. www.statsoft.com) was used for all statistical tests. 3. Results 3.1. Sleep architecture Table 1 shows the statistical comparison between the sleep architecture parameters obtained from children with ST and controls. Only a few statistically significant differences were found between the two groups. The numbers of awakenings per hour and WASO% were significantly higher while the sleep efficiency was reduced in ST subjects. No symptoms or recordings of restless legs syndrome and/or periodic leg movements were found in ST and control children. Presence of flow limitation with ‘‘flattening” at the nasal cannula curve, and of isolated obstructed and/or central apneas were noted in three children, but only the latter type of events were tabulated and the average AHI index was 0.8 ± 0.3 events/h with a mean oxygen saturation above 96%. 3.2. Cyclic alternating pattern The evaluation of CAP parameters (Table 2) revealed that subjects with ST had several significant differences from normal controls. They showed a higher total CAP rate% in sleep stage 1 and in SWS. Moreover, they showed an increased A1 index, while the A2 and A3 indexes were
similar between the two groups. In particular, the A1 index was increased during SWS but decreased in S1 and S2. Also, the number of CAP sequences was significantly lower in patients with ST compared to controls. Table 3 synthesizes other data relative to the duration of CAP parameters. Overall, the mean duration of A phases was longer, with significant differences for A1 and A2 subtypes. On the contrary, B phases had a decreased duration, exclusively in SWS. Also the entire CAP cycle duration was shorter in ST subjects while the CAP sequence mean duration was longer. Fig. 1 shows an example of a CAP sequence during slow-wave sleep in a child with ST in which the short duration of the phase B (interval between two A1 phases) is evident. The top panel of Fig. 2 shows the comparison between the normalized CAP interval-distribution graphs obtained from children with ST and normal controls during light sleep. These distributions appear to be very similar, with no statistically significant differences. The bottom panel shows the same comparison during SWS. Even though the distribution is similar, in this case, we found statistically significant differences, with interval classes 10 6 i < 35 s higher in children with ST and intervals classes above 50 s higher in normal controls. This distribution pattern is related to the shorter duration of phase B in SWS (Table 3) and therefore the increase of the shorter intervals between A phases in this sleep stage. 4. Discussion This study represents the first attempt to evaluate the NREM sleep structure by CAP analysis in children with ST considering not only CAP total NREM sleep but CAP NREM sleep stage distribution and phase A and B durations. Other attempts have been made to evaluate the EEG patterns of this parasomnia, including adults and children, showing conflicting results (Guilleminault
Table 1 Sleep architecture in ST patients and control subjects ST (n = 10)
TIB (min) SPT (min) TST (min) SOL (min) REM latency (min) SS/h AWN/h SE (%) WASO (%) S1 (%) S2 (%) SWS (%) REM (%)
Controls (n = 11)
Mann–Whitney test, p
Mean
S.D.
95% C.I.
Mean
S.D.
95% C.I.
569.9 525.6 491.7 32.7 135.2 6.8 1.0 86.2 6.5 4.6 48.3 21.4 19.3
41.59 39.84 55.95 20.68 35.18 1.94 0.62 6.11 7.00 1.53 6.34 4.45 4.90
540.1–599.7 497.0–554.1 451.6–531.7 17.9–47.5 110.0–160.4 5.4–8.2 0.6–1.4 81.8–90.5 1.5–11.5 3.5–5.7 43.8–52.8 18.2–24.5 15.8–22.8
544.3 510.9 505.0 25.3 116.0 5.3 0.2 92.8 1.2 3.4 48.0 24.3 23.1
39.79 43.45 44.79 15.50 34.21 1.58 0.25 5.50 1.57 2.18 5.35 3.06 4.17
517.5–571.0 481.7–540.1 474.9–535.1 14.9–35.7 93.0–139.0 4.2–6.3 0.0–0.4 89.1–96.5 0.1–2.2 1.9–4.8 44.4–51.6 22.2–26.3 20.3–25.9
NS NS NS NS NS NS 60.002 60.009 60.015 NS NS NS NS
TIB, Time in bed; SPT, Sleep period time; TST, Total sleep time; SOL, Sleep onset latency; SS/h, Stage shifts per hour; AWN/h, Awakenings per hour; SE, Sleep efficiency; WASO, Wakefulness after sleep onset; S1 and S2, Sleep stages 1 and 2; SWS, Slow-wave sleep; REM, Rapid eye movement sleep.
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Table 2 CAP parameters in ST patients and control subjects ST (n = 10) Mean
Controls (n = 11) Mean
S.D.
95% C.I.
Total CAP rate (%) S1 (%) S2 (%) SWS (%)
40.6 94.9 20.2 92.5
3.10 3.14 6.82 5.14
38.4–42.8 92.6–97.1 15.3–25.1 88.8–96.2
35.5 44.8 27.9 52.5
9.30 19.37 9.06 13.65
29.2–41.7 31.8–57.8 21.8–34.0 43.3–61.6
60.029 60.0001 NS 60.0001
A1 (%) A2 (%) A3 (%)
84.8 5.5 9.7
6.42 2.73 4.79
80.2–89.4 3.5–7.4 6.3–13.1
84.0 7.7 8.3
5.87 3.54 4.43
80.0–87.9 5.4–10.1 5.4–11.3
NS NS NS
52.9 1.6 25.3 138.4 2.7 1.4 4.1 3.1 9.7 14.7 6.9 3.6 22.2
6.08 2.51 10.50 17.44 1.90 1.96 2.24 3.10 4.79 7.82 4.67 1.76 6.29
48.5–57.2 0.2–3.4 17.7–32.5 125.0–150.8 1.3–4.0 0.0–2.8 2.5–5.7 0.8–5.2 2.0–6.0 9.1–20.3 3.5–10.2 2.3–4.7 17.7–26.7
40.8 20.43 40.74 67.99 3.3 7.22 4.58 3.48 8.3 9.52 5.63 2.44 35.5
8.88 21.23 7.59 14.07 2.07 15.15 2.69 1.88 4.43 11.91 3.26 1.89 6.74
34.9–46.8 4.8–25.2 30.7–43.9 61.3–83.0 1.9–4.7 1.0–14.8 2.7–7.6 2.3–4.6 1.7–5.3 3.2–23.6 3.5–7.5 1.4–3.7 30.9–40.0
60.004 60.033 60.005 60.0002 NS NS NS NS NS NS NS NS 60.0014
A1 index In S1 In S2 In SWS A2 index In S1 In S2 In SWS A3 index In S1 In S2 In SWS CAP sequences (n)
S.D.
95% C.I.
Mann–Whitney test, p
et al., 2001, 2005a, 2006; Pilon et al., 2003; Pressman, 2007; Zucconi et al., 1995). We found a characteristic feature of NREM sleep in these patients consisting of a faster alternation of the amplitude of the slow EEG components in SWS that has been named HSD, SWS arousals or CAP A1 in different studies (Espa et al., 2000, 2002; Gadreau et al., 2000; Guilleminault et al., 2005a; Pilon et al., 2006; Pressman, 2004, 2007; Schenck et al., 1998; Zucconi et al., 1995).
Different attempts have been made in order to find a ‘‘neurophysiological marker” of DOA (mainly for forensic implications). An increased number of HSD and of SWS arousals has been reported (Pressman, 2004), but, HSD was absent in many sleepwalkers prior to SWS arousal or before episodes of complex behaviors. Additionally, HSD is present in patients without history of sleepwalking but with sleep apnea or periodic leg movements (Espa et al., 2002; Guilleminault et al., 2003, 2005a, 2006; Pressman,
Table 3 Duration of CAP components in ST patients and control subjects ST (n = 10) Mean
Controls (n = 11) S.D.
95% C.I.
Mean
A1 mean duration (s) In S1 In S2 In SWS
7.7 1.8 5.6 8.4
1.47 2.38 0.81 1.90
6.7–8.8 0.1–3.5 5.1–6.4 7.2–9.9
5.6 4.77 4.82 6.44
0.94 3.36 0.51 1.29
5.0–6.2 2.2–6.6 4.4–5.2 5.6–7.3
60.001 60.033 NS 60.012
A2 mean duration (s) In S1 In S2 In SWS
12.0 4.4 11.4 10.1
2.97 6.78 3.13 6.06
9.9–14.2 0.5–9.2 9.2–13.6 6.2–15.2
9.7 5.11 9.04 11.92
1.32 7.13 1.32 2.08
8.8–10.6 2.3–10.9 7.9–9.5 10.8–13.8
60.032 NS NS NS
A3 mean duration (s) In S1 In S2 In SWS
23.3 17.5 22.8 30.3
4.06 8.21 4.31 9.44
20.4–26.2 11.6–23.4 19.7–26.0 24.0–37.5
19.8 8.49 19.20 22.78
4.24 9.40 4.22 10.38
17.0–22.7 3.5–15.3 16.6–22.4 15.7–28.4
NS 60.033 NS NS
B mean duration (s) In S1 In S2 In SWS
17.7 18.8 24.5 14.9
1.78 12.72 2.82 2.58
16.4–19.0 9.7–27.9 22.5–26.5 13.1–16.8
23.8 19.9 24.9 22.7
1.91 11.97 1.60 2.71
22.5–25.1 11.8–27.9 23.8–26.0 20.9–24.5
60.0001 NS NS 60.0001
CAP cycle duration (s)
26.5
1.85
25.2–27.8
30.4
1.39
29.5–31.4
60.0003
Sequence mean duration (s)
464.5
358.1–570.9
233.6
47.92
201.4–265.8
60.0001
148.76
S.D.
Mann–Whitney test, p 95% C.I.
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Fig. 1. Example of a CAP sequence during slow-wave sleep in a child with ST. Note the short duration of the B phases of CAP.
Fig. 2. Comparison between the normalized (as a percentage of the individual total number) cyclic alternating pattern interval-distribution graphs obtained in our groups of children with ST and normal controls during light sleep (LS; sleep stages 1 and 2) and slow-wave sleep (SWS; sleep stages 3 and 4). Data shown as means ± SE; gray bars indicate interval classes significantly different in each graph.
2004; Schenck et al., 1998). There are significant variations between the studies reporting HSD and SWS arousals in DOA (Blatt et al., 1991; Broughton, 1991, 2000; Espa et al., 2000, 2002; Gadreau et al., 2000; Joncas et al., 2002; Pilon et al., 2006) supporting the concept that HSD and SWS arousals have low specificity and sensitivity for the diagnosis of DOA (Pressman, 2007). In summary, data indicate that HSD is not specific for the diagnosis of NREM parasomnias (Pressman, 2007) in adults and even less in children. CAP represents a more refined tool for the analysis of NREM sleep structure, and we prospectively explored if the neurophysiological alteration of NREM sleep in subjects with DOA could be more accurately defined. Moreover, CAP seems even more appropriate if we consider that the definition of HSD is suitable only for adults and does not seem to be adequate for the description of children’s SWA, with or without parasomnia, as we have already pointed out in Section 1. In agreement with other studies (Espa et al., 2002; Guilleminault et al., 2005a) we found only a small increase in the number of awakenings per hour and of WASO%; but our study differed in that previous sleep architecture analyses have failed to show significant differences in subjects with DOA versus controls (Gadreau et al., 2000; Guilleminault et al., 2005a, 2006; Schenck et al., 1998). CAP analysis revealed several differences in NREM sleep structure between ST children and controls. The main results are the increase in CAP rate, A1 index, decrease in phase B duration (in SWS), and of CAP cycle duration. Our findings are similar to those of Zucconi et al. (1995) but these authors failed to recognize the value of this in the pathogenesis of DOA. We found some differences from the study by Guilleminault et al. (2006) that showed a
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similar increase in CAP rate but a decrease in A1 index and an increase in A2 and A3 indexes. However, these two studies were on adults and the only other study evaluating CAP in children with sleepwalking reported an increase of the global CAP rate without specifying the A subtypes (Guilleminault et al., 2005a). In our study, we found an increase of A1 differently from Guilleminault et al. (2006). This discrepancy could be linked to the different prevalence of sleep disordered breathing (SDB) in the samples studied. Recently, it has been reported that the CAP rate is reduced and the A1 subtypes are decreased in children with SDB (mainly mild OSA) (Kheirandish-Gozal et al., 2007); therefore the low level of A1 in Guilleminault’s study could be linked to the presence of SBD that we did not find in our small sample. Several authors showed that respiratory events are frequent in patients with parasomnias and SW/ST (Espa et al., 2002; Guilleminault et al., 2003, 2005a, 2006; Pressman et al., 1995) and that NREM sleep instability (CAP rate) correlated with the presence of sleep respiratory disturbances (Guilleminault et al., 2006). Guilleminault (2006), when commenting the paper of Pilon et al. (2006), highlighted the importance of the CAP phase B, reporting that what is abnormal in sleepwalking is not the HSD per se, but the reappearance of the background activity (phase B) that interrupts the persistence of the slow delta and determines the bursting pattern of delta during SWS and, finally, questions why the delta burst (CAP A1) is abruptly interrupted (Guilleminault et al., 2006). It might be possible to hypothesize that the numerous recurrent arousals from SWS create a slow wave activity (SWA) deficit within sleep, leading to a continued SWA reappearance due to an ultra short intrasleep recovery process in SWS parasomnia. The coexistence of pressure for delta sleep and a high level of arousal intrusion in SWS might contribute to triggering SWS parasomnias, confirming the hypothesis of Broughton (Broughton, 1968; Broughton et al., 1994) that arousal disorders are precipitating factors for some sleep disturbances related to delta sleep, such as somnambulism and ST and also Espa et al. (2000) concluded, in adults, that high SWS fragmentation might be responsible for the occurrence of sleepwalking or ST episodes. Nearly all studies on sleep EEG analysis of adult and children patients with DOA agree on the presence of SWS sleep fragmentation; however, the time structure or the alternation of the amplitude of the sleep EEG determining SWS fragmentation was never carefully considered. As an example, Espa et al. (2000) reported that SWS interruptions occurred approximately every 13 min in parasomnias, while they occurred approximately every 25 min in controls and the different analysis of short sleep disturbances, constantly reported frequent brief arousals or microarousals from SWS (Blatt et al., 1991; Broughton, 1991, 2000; Halasz et al., 1985) or an increased sleep instability and arousal oscillations in SWS (Zucconi et al., 1995). All of these studies support or indicate a tendency
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towards a decrease of intervals between EEG slow oscillation bursts in SWS. Our study shows a difference between CAP intervals during SWS and during light sleep: this difference is related to a high frequency of shorter intervals during SWS compared to light sleep. Our children with ST show a CAP interval distribution similar to that of controls but with a significant increase of shorter intervals (10–35 s) in their SWS histogram. This difference suggests a fast alternation of the amplitude of slow EEG bursts during SWS in patients with ST. This pattern can be linked to the frequent intrusion of CAP B phases interrupting the continuity of slow delta activity. We suggest that this abnormally fast alternation of the EEG amplitude in SWS is associated with the occurrence of parasomnias and might be considered as a neurophysiological marker of DOA. References AASM. International classification of sleep disorders. 2nd ed. Diagnostic and coding manual. American Academy of Sleep Medicine: Westchester, Illinois; 2005. Blatt I, Peled R, Gadoth N, Lavie P. The value of sleep recording in evaluating somnambulism in young adults. Electroencephalogr Clin Neurophysiol 1991;78:407–12. Broughton R. Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in ‘‘dreaming sleep”. Science 1968;159:1070–8. Broughton R. Phasic and dynamic aspects of sleep: a symposium review and synthesis. In: Terzano MG, Halasz P, Declerck AC, editors. Phasic events and dynamic organization of sleep. New York: Raven Press; 1991. p. 185–205. Broughton R, Billings R, Cartwright R, Doucette D, Edmeads J, Edwardh M, et al. Homicidal somnambulism: a case report. Sleep 1994;17:253–64. Broughton R. NREM arousal parasomnias. In: Kryger MH, Dement WC, editors. Principles and practice of sleep medicine. 3rd ed. Philadelphia: W.B. Saunders; 2000. p. 693–706. Bruni O, Ferri R, Miano S, Verrillo E. L-5-Hydroxytryptophan treatment of sleep terrors in children. Eur J Pediatrics 2004;163:402–7. Espa F, Ondze B, Deglise P, Billiard M, Besset A. Sleep architecture, slow wave activity, and sleep spindles in adult patients with sleepwalking and sleep terrors. Clin Neurophysiol 2000;111:929–39. Espa F, Dauvilliers Y, Ondze B, Billiard M, Besset A. Arousal reactions in sleep walking and night terror adults: the role of respiratory events. Sleep 2002;25:871–5. Gadreau H, Joncas S, Zadra A, Montplaisir J. Dynamics of slow wave activity during the NREM sleep of sleepwalkers and control subjects. Sleep 2000;23:755–60. Grigg-Damberger M, Gozal D, Marcus CL, Quan SF, Rosen CL, Chervin RD, et al. The visual scoring of sleep and arousal in infants and children. J Clin Sleep Med 2007;3:201–40. Guilleminault C, Leger D, Philip P, Ohayon MM. Nocturnal wandering and violence: review of a sleep clinic population. J Forensic Sci 1998;43:158–63. Guilleminault C, Poyares D, Abat F, Palombini L. Sleep and wakefulness in somnambulism: a spectral analysis study. J Psychosom Res 2001;51:411–6. Guilleminault C, Palombini L, Pelayo R, Chervin R. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 2003;111:17–25. Guilleminault C, Lee JH, Chan A, Lopes MC, Huang Y, Da Rosa A. Non-REM-sleep instability in recurrent sleepwalking in pre-pubertal children. Sleep Med 2005a;6:515–21.
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Guilleminault C, Kirisoglu C, Bao G, Arias V, Chan A, Li K. Adult chronic sleepwalking and its treatment based on polysomnography. Brain 2005b;128:1062–9. Guilleminault C, Kirisoglu C, da Rosa AC, Lopes C, Chan A. Sleepwalking, a disorder of NREM sleep instability. Sleep Med 2006;7:163–70. Guilleminault C. Hypersynchronous slow delta, cyclic alternating pattern and sleepwalking (Editorial). Sleep 2006;29:14–5. Halasz P, Ujszaszi J, Gadoros J. Are microarousals preceded by electroencephalographic slow wave synchronization precursors of confusional awakenings? Sleep 1985;8:231–8. Jacobson A, Kales A, Lehmann D, Zweizig J. Somnambulism: all night electroencephalographic studies. Science 1965;146:975–7. Jasper HH. The 10–20 electrode system of the international federation. Electroencephalogr Clin Neurophysiol 1958;10:370–5. Joncas S, Zadra A, Paquet J, Montplaisir J. The value of sleep deprivation as a diagnostic tool in adult sleepwalkers. Neurology 2002;58: 936–40. Kavey NB, Whyte J, Resor Jr SR, Gidro-Frank S. Somnambulism in adults. Neurology 1990;40:749–52. Kheirandish-Gozal L, Miano S, Bruni O, Ferri R, Pagani J, Villa MP, et al. Reduced NREM sleep instability in children with sleep disordered breathing. Sleep 2007;30:450–7. Mason TB, Pack AI. Pediatric parasomnias. Sleep 2007;30:141–51. Pilon M, Zadra A, Joncas S, Rompre´ S, Montplaisir J. Hypersynchronous delta activity and somnambulism: differences between frontal and central leads. Sleep 2003;26:A318.
Pilon M, Zadra A, Joncas S, Montplaisir J. Hypersynchronous delta waves and somnambulism: brain topography and effect of sleep deprivation. Sleep 2006;29:77–84. Pressman MR, Meyer TJ, Kendrick-Mohamed J, Figueroa WG, Greenspon LW, Peterson DD. Night terrors in an adult precipitated by sleep apnea. Sleep 1995;18:773–5. Pressman MR. Hypersynchronous delta sleep EEG activity and sudden arousals from slow-wave sleep in adults without a history of parasomnias: clinical and forensic implications. Sleep 2004;27:706–10. Pressman MR. Factors that predispose, prime and precipitate NREM parasomnias in adults: clinical and forensic implications. Sleep Med Rev 2007;11:5–30. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques, and scoring system for sleep stages of human subjects. Washington: Washington Public Health Service, US Government Printing Office; 1968. Schenck CH, Pareja JA, Patterson AL, Mahowald MW. Analysis of polysomnographic events surrounding 252 slow-wave sleep arousals in thirty-eight adults with injurious sleepwalking and sleep terrors. J Clin Neurophysiol 1998;15:159–66. Terzano MG, Parrino L, Smerieri A, Chervin R, Chokroverty S, Guilleminault C, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537–53. Zucconi M, Oldani A, Ferini-Strambi L, Smirne S. Arousal fluctuations in non-rapid eye movement parasomnias: the role of cyclic alternating pattern as a measure of sleep instability. J Clin Neurophysiol 1995;12:147–54.
NREM sleep instability in children with sleep terrors: The role of slow wave activity interruptions Oliviero Bruni
a,*
, Raffaele Ferri b, Luana Novelli a, Elena Finotti c, Silvia Miano d, Christian Guilleminault e
a
Center for Pediatric Sleep Disorders, Department of Developmental Neurology and Psychiatry, University of Rome ‘‘La Sapienza”, Via dei Sabelli 108, 00185 Rome, Italy b Sleep Research Centre, Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy c Department of Paediatrics, University of Padua, Padua, Italy d Department of Pediatrics, Sleep Centre, ‘‘La Sapienza” University, S. Andrea Hospital, Rome, Italy e Stanford University Sleep Medicine Program, Stanford, CA, USA Accepted 12 January 2008 Available online 29 February 2008
Abstract Objective: To evaluate NREM sleep instability, as measured by the cyclic alternating pattern (CAP), in children with sleep terrors (ST) vs. normal controls. Methods: Ten boys (mean age: 8.5 years, range 5–13) meeting the following inclusion criteria: (a) complaint of ST several times a month, (b) a history of ST confirmed by a third person, and (c) a diagnosis of ST according to the ICSD-2 criteria. Eleven age-matched control children with parental report of at least 8.5 h of nightly sleep, absence of known daytime consequences of sleep disorders were recruited by advertisement from the community. Sleep was visually scored for sleep macrostructure and CAP using standard criteria. Results: Sleep macrostructure showed only a significantly increased number of awakenings per hour and reduced sleep efficiency in ST subjects. CAP parameters analysis revealed several significant differences in ST vs. controls: an increase of total CAP rate in SWS, of A1 index in SWS and of the mean duration of A phases while B phases had a decreased duration, exclusively in SWS. The normalized CAP interval-distribution graphs showed significant differences in SWS with interval classes 10 6 i < 35 s higher in children with ST and intervals classes above 50 s higher in normal controls. Conclusions: Children with ST showed faster alternations of the amplitude of slow EEG bursts during SWS. This abnormally fast alternation of the EEG amplitude in SWS is linked to the frequent intrusion of CAP B phases interrupting the continuity of slow delta activity and could be considered as a neurophysiological marker of ST. Significance: This abnormal alternation of the EEG amplitude in SWS is associated with the occurrence of parasomnias and might be considered as a neurophysiological marker of disorders of arousal. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Sleep terrors; Parasomnias; Cyclic alternating pattern; NREM sleep instability
1. Introduction The International Classification of Sleep Disorders (ICSD-2) defines parasomnias as ‘‘undesirable physical
*
Corresponding author. Tel.: +39 0644712257; fax: +39 064957857. E-mail address: [email protected] (O. Bruni).
events or experiences that occur during entry into, within, or during arousals from sleep” (AASM, 2005). The disorders of arousal (DOA) are a subset of parasomnias and include confusional arousals (CA), sleepwalking (SW), and sleep terrors (ST). These disturbances occur most often during slow-wave sleep (SWS) but can also occur during sleep stage 2 or late in the night (Broughton, 2000; Kavey et al., 1990; Mason and Pack, 2007). In particular, DOA
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tend to occur in the first third of the night, when SWS is most prominent, and are characterized by an incomplete transition from slow-wave sleep, automatic behavior, altered perception of the environment, and a varying amount of amnesia (Mason and Pack, 2007). Although the sleep architecture in DOA does not show significant differences from controls (Espa et al., 2000; Pressman, 2004; Zucconi et al., 1995), several studies have shown subtle alterations of NREM sleep in adults, represented mostly by a high degree of arousal from SWS and by a peculiar EEG pattern defined as hypersynchronous delta activity (HSD) (Espa et al., 2000; Gadreau et al., 2000; Guilleminault et al., 2005a; Pilon et al., 2006; Pressman, 2004; Zucconi et al., 1995), described as continuous high-voltage (>150 lV) delta waves occurring during SWS or immediately prior to an episode (Pilon et al., 2006). This activity was first noted to precede sleepwalking events by Jacobson et al. (1965) although subsequent studies have yielded unclear results, with sleepwalking or sleep terror episodes being occasionally (Espa et al., 2000; Guilleminault et al., 2005b), often (Guilleminault et al., 1998), or always (Espa et al., 2000; Guilleminault et al., 2001) associated with HSD. A more recent investigation found that the frequency of HSD in the EEG of adult sleepwalkers was dependent on the EEG derivation used (presence of a frontocentral gradient) (Pilon et al., 2003). Pilon et al. (2006) also confirmed this frontocentral gradient of HSD and showed that this phenomenon is more evident following sleep deprivation. HSD and arousals from SWS may be present in patients without clinical history of sleepwalking or other parasomnias and, on the contrary, patients with a clear history of violent parasomnias may not have HSD or arousals from SWS. Because of these discrepancies, HSD and arousals from SWS are thought to have a low specificity and sensitivity for the diagnosis of NREM parasomnias (Pilon et al., 2006) and their eventual usefulness as diagnostic markers for DOA remains to be determined (Pressman, 2007). It is important to take into account that HSD has been defined as high-voltage (>150 lV) delta waves occurring during SWS or immediately prior to a parasomnia episode, solely in adults (Jacobson et al., 1965; Guilleminault et al., 1998, 2001; Espa et al., 2000; Schenck et al., 1998; Pilon et al., 2006). On the contrary, SWA recorded from C3– A2 or C4–A1 in an infant or child is often 100–400 lV (Grigg-Damberger et al., 2007). Thus, the current definition of HSD applied to a pediatric group of subjects would indicate that even normal controls have, almost all, this EEG pattern. For this reason, HSD does not seem to be appropriate for the description of children’s SWA with or without parasomnia. Since high-amplitude waves are also part of the cyclic alternating pattern (CAP), and hypersynchronous slow delta is part of the phase A1 and possibly A2 of the CAP (Guilleminault et al., 2006), other studies have tried to eval-
uate CAP in SW and ST subjects, with conflicting results. Zucconi et al. (1995) found an increase of A1% and of CAP rate, and a decrease in phase B duration. Guilleminault et al. (2005a, 2006), also found an increase in CAP rate but also in A2 and A3 index, while A1 index was decreased. For these reasons the aim of our study was to accurately evaluate sleep architecture, CAP, and the time structure of EEG slow oscillations in subjects with DOA: sleep terror (ST). 2. Methods 2.1. Subjects Ten boys (mean age: 8.5 years, range 5–13) were included in this study because they met the following inclusion criteria: (1) Complaint of ST several times a month. (2) A history of ST confirmed by a third person. (3) Diagnosis of ST according to the ICSD-2 (AASM, 2005) criteria, i.e., (A) a sudden episode of terror occurring during sleep, usually initiated by a cry or loud scream, that is accompanied by autonomic nervous system and behavioral manifestations of intense fear; (B) at least one of the following associated features was present: difficulty in arousing the person, mental confusion when awakened from an episode, amnesia (complete or partial) for the episode, dangerous or potentially dangerous behaviors; (C) the disturbance was not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use or substance use disorder. Eleven age-matched children with parental report of at least 8.5 h of nightly sleep, absence of known daytime consequences of sleep disorders (e.g., daytime sleepiness, cataplexy, hyperactivity, morning headache, mouth breathing), and normal health were recruited by advertisement from the community, to serve as control subjects. These children also had complete charts and underwent similar 8.5-h polysomnographic recordings. Exclusion criteria for all participants consisted of the following: (1) the presence of a major psychiatric disorder; (2) the use of drugs that could influence the sleep EEG; (3) the presence or history of a neurologic disorder including epilepsy. In particular, there were no anamnestic information or electroencephalographic signs of an underlying epileptic disorder and all patients included showed, after the participation to this study, a prompt and excellent response to the administration of L-5-hydroxytryptophan, a drug which we have already shown to be effective in this disorder and represent the first choice treatment for ST in our lab (Bruni et al., 2004). All parents were asked to sign a consent form approved by the institution in which sleep recordings were carried out.
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2.2. Polygraphic sleep recordings For this study, subjects underwent an overnight PSG recording in the Sleep Laboratory of the Department of Developmental Neurology and Psychiatry, after one adaptation night, in order to avoid the first-night effect. The EEG recordings and electrode placement were performed according to the 10–20 system (Jasper, 1958) and the PSG montage included at least four EEG channels (C3, C4, O1, O2) referenced to the contralateral mastoid, left and right electrooculogram (EOG), chin electromyogram (EMG), left and right tibialis EMG, electrocardiogram (ECG), thorax and abdominal effort, nasal cannula, peripheral oxygen saturation, pulse and position sensors. All recordings started at the subjects’ usual bedtime and continued until spontaneous awakening. 2.3. Sleep stage scoring Sleep was subdivided into 30-s epochs and sleep stages were scored according to the standard criteria by Rechtschaffen and Kales (1968). The following conventional sleep parameters were evaluated: – Time in bed (TIB). – Sleep period time (SPT): time from sleep onset to sleep end. – Total sleep time (TST): the time from sleep onset to the end of the final sleep epoch minus time awake. – Sleep latency (SL): time from lights out to sleep onset, defined as the first of two consecutive epochs of sleep stage 1 or one epoch of any other stage, in minutes. – REM latency (RL): time from sleep onset to the first REM sleep epoch. – Number of stage shifts/hour (SS/h). – Number of awakenings/hour (AWN/h). – Sleep efficiency (SE%): the percentage ratio between total sleep time and time in bed (TST/TIB * 100). – Percentage of SPT spent in wakefulness after sleep onset (WASO%), i.e., the time spent awake between sleep onset and end of sleep. – Percentage of SPT spent in sleep stages 1 (S1%), 2 (S2%), slow-wave sleep (SWS%), and REM sleep (REM%).
2.4. Cyclic alternating pattern (CAP) scoring CAP was scored following the criteria by Terzano et al. (2001) CAP is a periodic EEG activity of NREM sleep characterized by repeated spontaneous sequences of transient events (phase A), recurring at intervals up to 2 min in duration. The return to background activity identifies the interval that separates the repetitive elements (phase B). In particular, phase-A candidates are scored within a CAP sequence only if they precede and/or are followed by another phase A in the temporal range of 2–60 s. If
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there were three consecutive A-phases followed by a NCAP condition, the CAP sequence is stopped at the end of the second B-phase and the third A-phase A is quantified as non-CAP. This is because the CAP procedure is based on the succession of complete CAP cycles (phase A + phase B). CAP A phases have been subdivided into a 3-stage hierarchy of arousal strength: – A1: A phases with synchronized EEG patterns (intermittent alpha rhythm in S1; sequences of K complexes or delta bursts in the other NREM stages), associated with mild or trivial polygraphic variations. – A2: A phases with desynchronized EEG patterns preceded by or mixed with slow high-voltage waves (K complexes with alpha and beta activities, K-alpha, arousals with slow-wave synchronization), linked with a moderate increase of muscle tone and/or cardio-respiratory rate. – A3: A phases with desynchronized EEG patterns alone (transient activation phases or arousals) or exceeding 2/3 of the phase A length, and coupled with a remarkable enhancement of muscle tone and/or cardio-respiratory rate. The following CAP parameters were measured: – CAP rate (percentage of total NREM sleep time occupied by CAP sequences). – Percentage and duration of each A phase subtype. – A1 index (number of phases A1 per hour of NREM sleep, and of S1, S2, and SWS sleep stage). – A2 index (number of phases A2 per hour of NREM sleep, and of S1, S2, and SWS sleep stage). – A3 index (number of phases A3 per hour of NREM sleep, and of S1, S2, and SWS sleep stage). – Duration of B phases. – Number and duration of CAP sequences. All these variables were analyzed by means of the Hypnolab 1.2 sleep software analysis (SWS Soft, Italy). 2.5. Statistical analysis The comparisons between sleep architecture and CAP parameters, obtained in children with ST vs. normal controls, were conducted using the nonparametric Mann– Whitney test for independent data sets. All intervals between subsequent CAP A phases were subdivided into 25 duration classes (<5 s, P5 < 10 s, P10 < 15 s,. . .., P 115 < 120 s, P120 < 125 s) and counted in each subject; this count was used to draw individual normalized intervaldistribution graphs. The normalization was obtained by calculating the percentage of each class with respect to the total individual count. In this way, data from different individuals could be pooled together. The intervals between subsequent CAP A phases occurring during light NREM
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sleep (stages 1 and 2) were counted separately from those occurring during SWS (sleep stages 3 and 4). In addition, two different normalized distribution graphs were obtained, one for light sleep and another for SWS, in each subject group. The differences between the two groups and their light sleep or SWS for each interval class were evaluated by means of a Bonferroni-corrected nonparametric Mann–Whitney test for independent data sets. The commercially available software STATISTICA (StatSoft, Inc. 2004, version 6. www.statsoft.com) was used for all statistical tests. 3. Results 3.1. Sleep architecture Table 1 shows the statistical comparison between the sleep architecture parameters obtained from children with ST and controls. Only a few statistically significant differences were found between the two groups. The numbers of awakenings per hour and WASO% were significantly higher while the sleep efficiency was reduced in ST subjects. No symptoms or recordings of restless legs syndrome and/or periodic leg movements were found in ST and control children. Presence of flow limitation with ‘‘flattening” at the nasal cannula curve, and of isolated obstructed and/or central apneas were noted in three children, but only the latter type of events were tabulated and the average AHI index was 0.8 ± 0.3 events/h with a mean oxygen saturation above 96%. 3.2. Cyclic alternating pattern The evaluation of CAP parameters (Table 2) revealed that subjects with ST had several significant differences from normal controls. They showed a higher total CAP rate% in sleep stage 1 and in SWS. Moreover, they showed an increased A1 index, while the A2 and A3 indexes were
similar between the two groups. In particular, the A1 index was increased during SWS but decreased in S1 and S2. Also, the number of CAP sequences was significantly lower in patients with ST compared to controls. Table 3 synthesizes other data relative to the duration of CAP parameters. Overall, the mean duration of A phases was longer, with significant differences for A1 and A2 subtypes. On the contrary, B phases had a decreased duration, exclusively in SWS. Also the entire CAP cycle duration was shorter in ST subjects while the CAP sequence mean duration was longer. Fig. 1 shows an example of a CAP sequence during slow-wave sleep in a child with ST in which the short duration of the phase B (interval between two A1 phases) is evident. The top panel of Fig. 2 shows the comparison between the normalized CAP interval-distribution graphs obtained from children with ST and normal controls during light sleep. These distributions appear to be very similar, with no statistically significant differences. The bottom panel shows the same comparison during SWS. Even though the distribution is similar, in this case, we found statistically significant differences, with interval classes 10 6 i < 35 s higher in children with ST and intervals classes above 50 s higher in normal controls. This distribution pattern is related to the shorter duration of phase B in SWS (Table 3) and therefore the increase of the shorter intervals between A phases in this sleep stage. 4. Discussion This study represents the first attempt to evaluate the NREM sleep structure by CAP analysis in children with ST considering not only CAP total NREM sleep but CAP NREM sleep stage distribution and phase A and B durations. Other attempts have been made to evaluate the EEG patterns of this parasomnia, including adults and children, showing conflicting results (Guilleminault
Table 1 Sleep architecture in ST patients and control subjects ST (n = 10)
TIB (min) SPT (min) TST (min) SOL (min) REM latency (min) SS/h AWN/h SE (%) WASO (%) S1 (%) S2 (%) SWS (%) REM (%)
Controls (n = 11)
Mann–Whitney test, p
Mean
S.D.
95% C.I.
Mean
S.D.
95% C.I.
569.9 525.6 491.7 32.7 135.2 6.8 1.0 86.2 6.5 4.6 48.3 21.4 19.3
41.59 39.84 55.95 20.68 35.18 1.94 0.62 6.11 7.00 1.53 6.34 4.45 4.90
540.1–599.7 497.0–554.1 451.6–531.7 17.9–47.5 110.0–160.4 5.4–8.2 0.6–1.4 81.8–90.5 1.5–11.5 3.5–5.7 43.8–52.8 18.2–24.5 15.8–22.8
544.3 510.9 505.0 25.3 116.0 5.3 0.2 92.8 1.2 3.4 48.0 24.3 23.1
39.79 43.45 44.79 15.50 34.21 1.58 0.25 5.50 1.57 2.18 5.35 3.06 4.17
517.5–571.0 481.7–540.1 474.9–535.1 14.9–35.7 93.0–139.0 4.2–6.3 0.0–0.4 89.1–96.5 0.1–2.2 1.9–4.8 44.4–51.6 22.2–26.3 20.3–25.9
NS NS NS NS NS NS 60.002 60.009 60.015 NS NS NS NS
TIB, Time in bed; SPT, Sleep period time; TST, Total sleep time; SOL, Sleep onset latency; SS/h, Stage shifts per hour; AWN/h, Awakenings per hour; SE, Sleep efficiency; WASO, Wakefulness after sleep onset; S1 and S2, Sleep stages 1 and 2; SWS, Slow-wave sleep; REM, Rapid eye movement sleep.
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Table 2 CAP parameters in ST patients and control subjects ST (n = 10) Mean
Controls (n = 11) Mean
S.D.
95% C.I.
Total CAP rate (%) S1 (%) S2 (%) SWS (%)
40.6 94.9 20.2 92.5
3.10 3.14 6.82 5.14
38.4–42.8 92.6–97.1 15.3–25.1 88.8–96.2
35.5 44.8 27.9 52.5
9.30 19.37 9.06 13.65
29.2–41.7 31.8–57.8 21.8–34.0 43.3–61.6
60.029 60.0001 NS 60.0001
A1 (%) A2 (%) A3 (%)
84.8 5.5 9.7
6.42 2.73 4.79
80.2–89.4 3.5–7.4 6.3–13.1
84.0 7.7 8.3
5.87 3.54 4.43
80.0–87.9 5.4–10.1 5.4–11.3
NS NS NS
52.9 1.6 25.3 138.4 2.7 1.4 4.1 3.1 9.7 14.7 6.9 3.6 22.2
6.08 2.51 10.50 17.44 1.90 1.96 2.24 3.10 4.79 7.82 4.67 1.76 6.29
48.5–57.2 0.2–3.4 17.7–32.5 125.0–150.8 1.3–4.0 0.0–2.8 2.5–5.7 0.8–5.2 2.0–6.0 9.1–20.3 3.5–10.2 2.3–4.7 17.7–26.7
40.8 20.43 40.74 67.99 3.3 7.22 4.58 3.48 8.3 9.52 5.63 2.44 35.5
8.88 21.23 7.59 14.07 2.07 15.15 2.69 1.88 4.43 11.91 3.26 1.89 6.74
34.9–46.8 4.8–25.2 30.7–43.9 61.3–83.0 1.9–4.7 1.0–14.8 2.7–7.6 2.3–4.6 1.7–5.3 3.2–23.6 3.5–7.5 1.4–3.7 30.9–40.0
60.004 60.033 60.005 60.0002 NS NS NS NS NS NS NS NS 60.0014
A1 index In S1 In S2 In SWS A2 index In S1 In S2 In SWS A3 index In S1 In S2 In SWS CAP sequences (n)
S.D.
95% C.I.
Mann–Whitney test, p
et al., 2001, 2005a, 2006; Pilon et al., 2003; Pressman, 2007; Zucconi et al., 1995). We found a characteristic feature of NREM sleep in these patients consisting of a faster alternation of the amplitude of the slow EEG components in SWS that has been named HSD, SWS arousals or CAP A1 in different studies (Espa et al., 2000, 2002; Gadreau et al., 2000; Guilleminault et al., 2005a; Pilon et al., 2006; Pressman, 2004, 2007; Schenck et al., 1998; Zucconi et al., 1995).
Different attempts have been made in order to find a ‘‘neurophysiological marker” of DOA (mainly for forensic implications). An increased number of HSD and of SWS arousals has been reported (Pressman, 2004), but, HSD was absent in many sleepwalkers prior to SWS arousal or before episodes of complex behaviors. Additionally, HSD is present in patients without history of sleepwalking but with sleep apnea or periodic leg movements (Espa et al., 2002; Guilleminault et al., 2003, 2005a, 2006; Pressman,
Table 3 Duration of CAP components in ST patients and control subjects ST (n = 10) Mean
Controls (n = 11) S.D.
95% C.I.
Mean
A1 mean duration (s) In S1 In S2 In SWS
7.7 1.8 5.6 8.4
1.47 2.38 0.81 1.90
6.7–8.8 0.1–3.5 5.1–6.4 7.2–9.9
5.6 4.77 4.82 6.44
0.94 3.36 0.51 1.29
5.0–6.2 2.2–6.6 4.4–5.2 5.6–7.3
60.001 60.033 NS 60.012
A2 mean duration (s) In S1 In S2 In SWS
12.0 4.4 11.4 10.1
2.97 6.78 3.13 6.06
9.9–14.2 0.5–9.2 9.2–13.6 6.2–15.2
9.7 5.11 9.04 11.92
1.32 7.13 1.32 2.08
8.8–10.6 2.3–10.9 7.9–9.5 10.8–13.8
60.032 NS NS NS
A3 mean duration (s) In S1 In S2 In SWS
23.3 17.5 22.8 30.3
4.06 8.21 4.31 9.44
20.4–26.2 11.6–23.4 19.7–26.0 24.0–37.5
19.8 8.49 19.20 22.78
4.24 9.40 4.22 10.38
17.0–22.7 3.5–15.3 16.6–22.4 15.7–28.4
NS 60.033 NS NS
B mean duration (s) In S1 In S2 In SWS
17.7 18.8 24.5 14.9
1.78 12.72 2.82 2.58
16.4–19.0 9.7–27.9 22.5–26.5 13.1–16.8
23.8 19.9 24.9 22.7
1.91 11.97 1.60 2.71
22.5–25.1 11.8–27.9 23.8–26.0 20.9–24.5
60.0001 NS NS 60.0001
CAP cycle duration (s)
26.5
1.85
25.2–27.8
30.4
1.39
29.5–31.4
60.0003
Sequence mean duration (s)
464.5
358.1–570.9
233.6
47.92
201.4–265.8
60.0001
148.76
S.D.
Mann–Whitney test, p 95% C.I.
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O. Bruni et al. / Clinical Neurophysiology 119 (2008) 985–992
Fig. 1. Example of a CAP sequence during slow-wave sleep in a child with ST. Note the short duration of the B phases of CAP.
Fig. 2. Comparison between the normalized (as a percentage of the individual total number) cyclic alternating pattern interval-distribution graphs obtained in our groups of children with ST and normal controls during light sleep (LS; sleep stages 1 and 2) and slow-wave sleep (SWS; sleep stages 3 and 4). Data shown as means ± SE; gray bars indicate interval classes significantly different in each graph.
2004; Schenck et al., 1998). There are significant variations between the studies reporting HSD and SWS arousals in DOA (Blatt et al., 1991; Broughton, 1991, 2000; Espa et al., 2000, 2002; Gadreau et al., 2000; Joncas et al., 2002; Pilon et al., 2006) supporting the concept that HSD and SWS arousals have low specificity and sensitivity for the diagnosis of DOA (Pressman, 2007). In summary, data indicate that HSD is not specific for the diagnosis of NREM parasomnias (Pressman, 2007) in adults and even less in children. CAP represents a more refined tool for the analysis of NREM sleep structure, and we prospectively explored if the neurophysiological alteration of NREM sleep in subjects with DOA could be more accurately defined. Moreover, CAP seems even more appropriate if we consider that the definition of HSD is suitable only for adults and does not seem to be adequate for the description of children’s SWA, with or without parasomnia, as we have already pointed out in Section 1. In agreement with other studies (Espa et al., 2002; Guilleminault et al., 2005a) we found only a small increase in the number of awakenings per hour and of WASO%; but our study differed in that previous sleep architecture analyses have failed to show significant differences in subjects with DOA versus controls (Gadreau et al., 2000; Guilleminault et al., 2005a, 2006; Schenck et al., 1998). CAP analysis revealed several differences in NREM sleep structure between ST children and controls. The main results are the increase in CAP rate, A1 index, decrease in phase B duration (in SWS), and of CAP cycle duration. Our findings are similar to those of Zucconi et al. (1995) but these authors failed to recognize the value of this in the pathogenesis of DOA. We found some differences from the study by Guilleminault et al. (2006) that showed a
O. Bruni et al. / Clinical Neurophysiology 119 (2008) 985–992
similar increase in CAP rate but a decrease in A1 index and an increase in A2 and A3 indexes. However, these two studies were on adults and the only other study evaluating CAP in children with sleepwalking reported an increase of the global CAP rate without specifying the A subtypes (Guilleminault et al., 2005a). In our study, we found an increase of A1 differently from Guilleminault et al. (2006). This discrepancy could be linked to the different prevalence of sleep disordered breathing (SDB) in the samples studied. Recently, it has been reported that the CAP rate is reduced and the A1 subtypes are decreased in children with SDB (mainly mild OSA) (Kheirandish-Gozal et al., 2007); therefore the low level of A1 in Guilleminault’s study could be linked to the presence of SBD that we did not find in our small sample. Several authors showed that respiratory events are frequent in patients with parasomnias and SW/ST (Espa et al., 2002; Guilleminault et al., 2003, 2005a, 2006; Pressman et al., 1995) and that NREM sleep instability (CAP rate) correlated with the presence of sleep respiratory disturbances (Guilleminault et al., 2006). Guilleminault (2006), when commenting the paper of Pilon et al. (2006), highlighted the importance of the CAP phase B, reporting that what is abnormal in sleepwalking is not the HSD per se, but the reappearance of the background activity (phase B) that interrupts the persistence of the slow delta and determines the bursting pattern of delta during SWS and, finally, questions why the delta burst (CAP A1) is abruptly interrupted (Guilleminault et al., 2006). It might be possible to hypothesize that the numerous recurrent arousals from SWS create a slow wave activity (SWA) deficit within sleep, leading to a continued SWA reappearance due to an ultra short intrasleep recovery process in SWS parasomnia. The coexistence of pressure for delta sleep and a high level of arousal intrusion in SWS might contribute to triggering SWS parasomnias, confirming the hypothesis of Broughton (Broughton, 1968; Broughton et al., 1994) that arousal disorders are precipitating factors for some sleep disturbances related to delta sleep, such as somnambulism and ST and also Espa et al. (2000) concluded, in adults, that high SWS fragmentation might be responsible for the occurrence of sleepwalking or ST episodes. Nearly all studies on sleep EEG analysis of adult and children patients with DOA agree on the presence of SWS sleep fragmentation; however, the time structure or the alternation of the amplitude of the sleep EEG determining SWS fragmentation was never carefully considered. As an example, Espa et al. (2000) reported that SWS interruptions occurred approximately every 13 min in parasomnias, while they occurred approximately every 25 min in controls and the different analysis of short sleep disturbances, constantly reported frequent brief arousals or microarousals from SWS (Blatt et al., 1991; Broughton, 1991, 2000; Halasz et al., 1985) or an increased sleep instability and arousal oscillations in SWS (Zucconi et al., 1995). All of these studies support or indicate a tendency
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