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Sleep phenotypes of intellectual disability: A polysomnographic evaluation in subjects with Down syndrome and Fragile-X syndrome
Clinical Neurophysiology 119 (2008) 1242–1247 www.elsevier.com/locate/clinph
Sleep phenotypes of intellectual disability: A polysomnographic evaluation in subjects with Down syndrome and Fragile-X syndrome Silvia Mianoa, Oliviero Brunib, Maurizio Eliac, Lidia Scifoc, Arianna Smerierid, Alessia Trovatoc, Elisabetta Verrilloe, Mario G. Terzanod, Raffaele Ferric,* a Department of Pediatrics, Sleep Centre, ‘‘La Sapienza’’ University, S. Andrea Hospital, Rome, Italy Department of Developmental Neurology and Psychiatry, Center for Pediatric Sleep Disorders, ‘‘La Sapienza’’ University, Rome, Italy c Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggero 73, 94018 Troina, Italy d Sleep Disorders Center, Department of Neurology, University of Parma, Parma, Italy e Department of Broncopneumology, IRCCS Ospedale Bambino Gesu`, Rome, Italy b
Accepted 5 March 2008
Abstract Objective: To analyze sleep architecture and NREM sleep alterations by means of the Cyclic Alternating Pattern (CAP) in children with Down syndrome (DS) and Fragile-X syndrome (fraX), the two most common causes of inherited mental retardation, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. Methods: Fourteen patients affected by fraX (mean age 13.1 years) and 9 affected by Down syndrome (mean age 13.8 years) and 26 agematched normal controls were included. All subjects underwent overnight polysomnography in the sleep laboratory, after one adaptation night and their sleep architecture and CAP were visually scored. Results: FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects showed the most disrupted sleep microstructure with low total CAP rate and CAP rate in S2 NREM. Both patient groups showed a lower percentage of A1 and higher percentage of A2 and A3 compared to normal controls. Conclusions: The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. Significance: The NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, seem to be distinctive features of intellectual disability. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Cyclic alternating pattern; NREM sleep microstructure; Down syndrome; Fragile-X syndrome; Sleep phenotype
1. Introduction The clinical and neurophysiological features of the syndromes with mental retardation have been well characterized during the wake state but few data are available on the sleep architecture and how sleep states are altered by the underlying neurological condition. This might repre*
Corresponding author. Tel.: +39 935 936111; fax: +39 935 936694. E-mail address: [email protected] (R. Ferri).
sent a limitation of the knowledge of this type of conditions because, for some of them, sleep can give important clues for their diagnosis. Sleep disturbances are common in children with intellectual disabilities, and several neurophysiological studies have been performed in the past in order to find specific polysomnographic phenotypes. Although it is possible to find sleep macrostructural alterations that are in most cases aspecific (such as REM and/or slow-wave sleep reduction) only few attempts have been made to modify the criteria
1388-2457/$34.00 Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2008.03.004
S. Miano et al. / Clinical Neurophysiology 119 (2008) 1242–1247
for scoring sleep in order to adapt them to the specific patterns of each syndrome (Quine, 1991; Espie and Tweedie, 1991; Stores, 1992; Lindblom et al., 2001). It is still debated if sleep disturbances are related to the associated neurological impairments or directly linked to mental retardation (Lindblom et al., 2001; Harvey and Kennedy, 2002). The two most studied syndromes with mental retardation from a sleep point of view are Down syndrome (DS) and Fragile-X syndrome (fraX) (Lindblom et al., 2001). They represent the most common causes of inherited mental retardation occurring approximately in 0.9/1000 live births for DS (Roizen, 1997) and in 0.6-1/4000 live births for fraX (Crawford et al., 2001). Some studies on DS and fraX syndrome showed a correlation between the level of mental retardation and the amount of REM sleep; sleep architecture abnormalities in fraX syndrome appear related to the level of mental retardation, rather than to the phenotype itself. Autism and DS showed less REM sleep than fraX syndrome, when matched for the level of mental retardation (Diomedi et al., 1999; Elia et al., 2000). Previous studies have shown only few abnormalities in sleep architecture of children with DS, such as sleep fragmentation, manifested by frequent awakenings and arousals, compared to normal controls, which are only partially related to obstructive sleep apnea syndrome (Levanon et al., 1999). On the contrary, polysomnographic studies in DS reported a high frequency of obstructive sleep apnea which has been suspected to have a role in the cognitive deficit of DS (Marcus et al., 1991; Andreou et al., 2002). Also an increase in central sleep apnea, related to a specific dysfunction of the central respiratory control at brainstem level (Ferri et al., 1997; Ferri et al., 1998) has been reported. In contrast, sleep studies in fraX syndrome demonstrated a normal sleep respiratory control (Musumeci et al., 1996), without particular signs of autonomic dysfunction (Ferri et al., 1999). The sleep architecture in fraX subjects seems to show few and unspecific differences vs. normal controls: reduced total sleep time and increased wakefulness after sleep onset (Musumeci et al., 1994; Ferri et al., 1999). Previous studies evaluated mainly the alteration of REM sleep and of spindles in sleep of mentally retarded subjects and little attention was devoted to NREM sleep for which recent studies have highlighted the key role in cognitive functioning, mainly mediated by the slow oscillations in slow-wave sleep (SWS) (Diomedi et al., 1999; Tononi and Cirelli, 2003; Huber et al., 2004). We recently analyzed the microstructure of sleep in autistic children with mental retardation by means of the Cyclic Alternating Pattern (CAP) methodology (Terzano et al., 2001) and found subtle alterations of NREM sleep represented by a reduction of the slow components of CAP (A1 subtypes) during SWS, suggesting that they might play a role in the impairment of cognitive functioning in autism (Miano et al., 2007). More recently, a direct role of CAP in sleep-related cognitive processes has been shown in normal controls (Ferri et al., 2008) and confirmed in
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children with Asperger syndrome (Bruni et al., 2007). Therefore the analysis of CAP might disclose new important findings in the sleep structure of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. The aim of our study was to analyze CAP in the two most common causes of inherited mental retardation: DS and fraX syndrome, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. 2. Subjects and methods 2.1. Subjects A total of 14 males affected by fraX syndrome (mean age 13.1 years, SD 6.02 years, range 7–25) and 9 affected by DS (8 males and 1 female, mean age 13.8 years, SD 3.96 years, range 8–20) attending the Oasi Institute of Troina were recruited for this study. The molecular genetics confirmed the presence of the FMR1 gene mutations for fraX subjects and karyotyping confirmed trisomy 21 for all DS patients. All subjects were evaluated from the neuroimaging (including brain computed tomography scans or magnetic resonance imaging) and the neurophysiological points of view (EEG) and showed no neurological focal signs, seizures or paroxysmal EEG abnormalities. The intelligence level was measured by means of the Wechsler Intelligence Scale for Children – Revised (1973) or the Wechsler Adult Intelligence Scale – Revised (1997), as appropriate. Informed consent was obtained by the parents of all participants to the study. Eight fraX subjects had severe mental retardation (corresponding to IQ in the range 25–40), 6 had moderate mental retardation (IQ in the range 40–55); 4 DS children had severe mental retardation and 5 had moderate mental retardation. All subjects with fraX or DS who were obese or had signs and symptoms of sleep disordered breathing were excluded. 2.2. Polysomnographic study DS and fraX subjects whose parents accepted to participate, underwent a PSG overnight recording in the Sleep Laboratory of the Oasi Institute of Troina, after one adaptation night, in order to avoid the first-night effect. The PSG data were compared with those of a control group formed by 26 children matched for age and gender (16 males and 10 females, mean age 15.0 years, SD 5.72 years, range 8–26). The subjects were recruited from the same urban area, were of Caucasian origin, and had middle socioeconomic status. The PSG montage included at least 3 EEG channels referenced to the contralateral mastoid, left and right electrooculogram (EOG) referred to one mastoid, chin electromyogram (EMG), and electrocardiogram (ECG).
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All recordings started at the patients’ usual bedtime and continued until spontaneous awakening. 2.3. Sleep macrostructure In all subjects, 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/h (SS/h); - Number of awakenings/h (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. Sleep microstructure 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 long. 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 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 nonCAP. 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 cardiorespiratory 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 cardiorespiratory 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). All the recordings were visually scored by one of the investigators (SM) and the sleep parameters derived were tabulated for statistical analysis. 2.5. Statistical analysis The comparisons between sleep parameters obtained in DS, fraX syndrome and normal controls were carried out by means of the nonparametric Kruskall–Wallis ANOVA followed by the Mann–Whitney U test between the different groups used as a post-hoc comparison, when ANOVA resulted to be significant. Differences were considered statistically significant at p < 0.05. The commercially available software STATISTICA (data analysis software system), version 6, StatSoft, Inc. (2001) was used for all statistical tests. 3. Results Table 1 shows the comparison of sleep macrostructure parameters between fraX and DS patients and normal controls. We did not find statistical differences for total sleep time, sleep period time and sleep onset latency. FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects also showed a lower number of REM periods compared to normal controls.
S. Miano et al. / Clinical Neurophysiology 119 (2008) 1242–1247
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Table 1 Polysomnographic parameters in normal controls and fraX and DS patients
TIB-min SPT-min TST-min SOL-min FRL-min SS-h AWN-h SE% No-REMp WASO-% S1-% S2-% SWS-% REM-%
1-Normal controls (n = 26)
2-fraX patients (n = 14)
3-DS patients (n = 9)
Kruskall–Wallis ANOVA
Mann–Whitney U test
Mean
SD
Mean
SD
Mean
SD
p<
1 vs. 2 p<
1 vs. 3 p<
2 vs. 3 p<
518.9 495.0 484.1 18.5 114.7 7.8 0.7 93.5 7.2 2.2 3.5 46.5 25.1 22.6
51.98 45.72 43.71 13.76 50.47 3.62 0.69 4.43 2.29 2.18 3.87 5.81 7.20 5.01
484.9 466.8 447.2 15.6 129.1 5.9 0.9 92.1 5.2 4.2 6.7 47.1 24.4 17.7
58.80 69.93 72.81 21.76 68.93 1.71 0.68 8.79 2.12 5.85 5.56 6.12 7.22 5.73
532.8 495.1 430.0 34.7 154.6 7.7 2.5 80.8 6.2 13.5 6.1 39.9 22.7 17.9
115.99 104.48 106.62 50.12 59.58 1.39 1.05 10.84 2.49 8.40 2.73 5.76 6.40 5.61
0.05 NS NS NS NS NS 0.0005 0.005 0.05 0.005 0.01 0.05 NS 0.05
NS
NS
0.05
NS NS 0.05 NS 0.05 NS
0.0001 0.001 NS 0.0001 0.01 0.01
0.001 0.01 NS 0.005 NS 0.05
0.01
0.05
NS
TIB, time in bed; SPT, sleep period time; TST, total sleep time; SL, sleep latency; FRL, first REM latency; SS, stage shifts; AWN, awakenings number; SE, sleep efficiency; WASO, wakefulness after sleep onset; S1, stage 1; S2, stage 2; SWS, slow-wave sleep; REM, REM sleep. Significant p values are indicated in bold characters; NS, not significant.
two most common causes of inherited mental retardation: DS and fraX syndrome. FraX subjects showed a relatively preserved sleep architecture, compared to DS patients; however, the CAP analysis disclosed peculiar differences between DS and fraX syndrome and some common features, probably related to mental retardation itself. Our results show that subjects affected by DS have more sleep macro-architecture alterations than those with fraX: DS subjects spent more time in bed, had a lower sleep efficiency, a higher percentage of wakefulness after sleep onset and a lower percentage of stage 2 NREM. As expected, DS and fraX subjects showed a lower percentage of REM sleep than normal controls, confirming the previous findings by Diomedi et al. (1999) and Elia et al. (2000); moreover, fraX subjects showed a decreased number of REM periods. Interestingly, we did not find differences in slow-wave sleep percentage in fraX and DS compared to normal controls. These results confirm literature data on a relatively
Table 2 shows the comparison of CAP parameters between the three groups. FraX subjects show the most disrupted sleep microstructure: total CAP rate and CAP rate in S2 NREM were lower than those of DS patients and controls and CAP rate in SWS was lower than in controls. Regarding CAP A phase subtypes, fraX and DS patients showed a lower percentage of A1 and higher percentage of A2 and A3, compared to normal controls. FraX subjects also showed a higher percentage of A3 subtypes than DS patients. The A1 index (i.e. the number of A1 subtypes/h of NREM sleep) in S2 and SWS was significantly lower in fraX syndrome than in DS and controls; no differences were found between DS and controls. 4. Discussion To our knowledge, this study represents the first attempt to evaluate CAP, as an index of sleep microstructure, in the Table 2 CAP parameters found in normal controls and fraX and DS patients
CAP Time CAP_Rate% In S1 In S2 In SWS A1 Index In S1 In S2 In SWS A1% A2% A3%
1- Normal controls (n = 26)
2-fraX patients (n = 14)
3-DS patients (n = 9)
Kruskall–Wallis ANOVA
Mann–Whitney U test
Mean
SD
Mean
SD
Mean
SD
p<
1 vs. 2 p<
1 vs. 3 p<
2 vs. 3 p<
140.6 37.7 28.4 33.7 46.8
41.38 10.06 22.78 11.92 11.81
91.3 24.5 30.5 20.7 30.3
31.47 5.88 13.97 7.42 12.82
136.2 40.6 36.8 41.4 43.2
30.55 5.39 20.34 9.45 15.46
0.001 0.00001 NS 0.001 0.01
0.0005 0.0001
NS NS
0.005 0.0001
0.001 0.0001
NS NS
0.0001 NS (0.08)
26.4 43.4 73.9 77.1 13.5 9.4
25.03 10.97 20.98 9.79 7.04 4.47
28.7 19.4 45.6 57.2 18.7 24.2
20.09 5.85 16.58 6.94 5.84 5.85
25.8 43.6 71.3 63.0 18.7 18.3
14.30 13.10 28.96 7.13 6.80 4.25
NS 0.00001 0.0005 0.00001 0.05 0.00001
0.00001 0.0001 0.00001 0.05 0.00001
NS NS 0.001 0.05 0.0001
0.0005 0.02 NS NS 0.05
A1 index, number of A1 phases per hour of NREM; A1%, percentage of A1subtypes; A2%, percentage of A2 subtypes; A3%, percentage of A3 subtypes. Significant p values are indicated in bold characters; NS, not significant.
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S. Miano et al. / Clinical Neurophysiology 119 (2008) 1242–1247
preserved sleep architecture in fraX (Elia et al., 2000) and on the presence of sleep macrostructure disruption in DS (Levanon et al., 1999) that might also be related to the presence of mild sleep obstructive apnea, not disclosed by history and clinical examination (Marcus et al., 1991). On the contrary, CAP analysis revealed a more disrupted sleep microstructure: considering both groups of mentally retarded subjects, fraX syndrome and DS patients showed a significant reduction in A1% subtypes and an increase in A2% and A3% subtypes, compared to normal controls. Moreover, only fraX subjects showed other important CAP differences vs. normal controls, represented by a lower total CAP rate during stage 2 NREM and SWS and by a lower A1 index in S2 and SWS. The differences between fraX syndrome and DS were limited to a decrease in total CAP rate and during stage 2 NREM, associated with a decrease of A1 index during stage 2 NREM and SWS, in fraX subjects. In our opinion, the most important findings of this study are represented by the decrease in total CAP rate and of A1 index in stage 2 and SWS and of A1% in fraX patients. These specific modifications of CAP represent a decrease of transient slow EEG oscillations during NREM that have been related to cognitive functioning (Ferini-Strambi et al., 2004). We recently analyzed the microstructure of sleep in autistic children with mental retardation and found a reduction of the slow components of CAP (A1 subtypes) during SWS (Miano et al., 2007). Other recent studies also support a direct role of CAP in sleep-related cognitive processes in normal controls (Ferri et al., 2008) and in children with Asperger syndrome (Bruni et al., 2007). DS subjects showed only a decrease of A1% and an increase in A2% and A3% as a typical sleep microstructural feature. The lack of differences vs. controls in the other CAP parameters could be linked to the minor cognitive impairment of our DS vs. fraX syndrome patients. Further, the alteration of sleep macrostructure of DS might be linked to other underlying sleep disorders (i.e. sleep apnea, as an example) interfering with sleep microstructure and explaining the increase in A2% and A3%. The lower CAP rate during stage 2 NREM in fraX vs. normal controls and DS is also similar to the results of a previous study on CAP in ADHD children (Miano et al., 2006). CAP similarities between these two conditions might be correlated with the deficit of the executive functions found in fraX subjects, similar to those of ADHD children (Mazzocco, 2000). The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. To our knowledge, this is the first study that considers the alteration of NREM in mentally retarded subjects. Previous studies mostly focused on REM sleep and did not consider NREM abnormalities since sleep architecture analysis failed to find differences in NREM stages vs. normal controls.
From our results, we cannot state that the microstructural alterations found are directly related primarily to the level of mental retardation or to a specific sleep phenotype of the two different syndromes (Harvey and Kennedy, 2002). However, we are convinced that the examination of NREM sleep microstructure (CAP) in developmental disabilities and subsequently in different syndromes (i.e. autism, Down syndrome, and Fragile-X syndrome), may prove able to provide key evidence for deciphering the mechanisms and timing of learning and the consolidation of learned tasks. We are also convinced that REM abnormalities are important contributors to mental retardation but we should take into account that REM represents only about 20% of entire sleep while NREM represents about 70–75%. It has been suggested that slow-wave activity of NREM sleep may be involved in producing progressive downscaling of synaptic strength which, in turn, would lead to several benefits in terms of both cellular function and network performance and is probably important for neurocognitive performance (Tononi and Cirelli, 2003). The most important component of CAP is the A1 subtype composed mostly of slow waves and mapping over the frontal and prefrontal regions of the scalp (Ferri et al., 2005). The significant decrease in A1 CAP subtypes might be the result of a possible dysfunction of these brain structures and could play a role in the impairment of cognitive functioning in these subjects. Therefore in our opinion this disturbed sleep pattern is more likely a consequence (and not the cause) of the cognitive disorder accompanying the genetic abnormality; however, this point surely deserves further research. It is also possible that other concomitant sleep disorders (i.e. sleep disordered breathing linked to craniofacial abnormalities or to hypotonia) disrupt sleep microstructure and aggravate the cognitive functioning. In this perspective, the treatment of concomitant sleep disorders might be beneficial and should be always evaluated and eventually carried out in patients with mental retardation. Based on the results of this study and those of our previous investigations on CAP in different developmental disorders (Miano et al., 2006, 2007; Bruni et al., 2007), we might hypothesize that the NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, are distinctive features of intellectual disability. The replication of these results seems now to be mandatory in future investigations, in larger cohorts of children affected by DS and fraX syndrome and in other groups of children with etiologically different intellectual disability, and correlation with neuropsychological data is needed. References Andreou G, Galanopoulou C, Gourgoulianis K, Karapetsas A, Molyvdas P. Cognitive status in Down syndrome individuals with sleep disordered breathing deficits (SDB). Brain Cogn 2002;50:145–9. Bruni O, Ferri R, Vittori E, Novelli L, Vignati M, Arico` D, et al. Sleep architecture and NREM alterations in Asperger children and adolescents. Sleep 2007;30:1577–85.
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Sleep phenotypes of intellectual disability: A polysomnographic evaluation in subjects with Down syndrome and Fragile-X syndrome Silvia Mianoa, Oliviero Brunib, Maurizio Eliac, Lidia Scifoc, Arianna Smerierid, Alessia Trovatoc, Elisabetta Verrilloe, Mario G. Terzanod, Raffaele Ferric,* a Department of Pediatrics, Sleep Centre, ‘‘La Sapienza’’ University, S. Andrea Hospital, Rome, Italy Department of Developmental Neurology and Psychiatry, Center for Pediatric Sleep Disorders, ‘‘La Sapienza’’ University, Rome, Italy c Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggero 73, 94018 Troina, Italy d Sleep Disorders Center, Department of Neurology, University of Parma, Parma, Italy e Department of Broncopneumology, IRCCS Ospedale Bambino Gesu`, Rome, Italy b
Accepted 5 March 2008
Abstract Objective: To analyze sleep architecture and NREM sleep alterations by means of the Cyclic Alternating Pattern (CAP) in children with Down syndrome (DS) and Fragile-X syndrome (fraX), the two most common causes of inherited mental retardation, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. Methods: Fourteen patients affected by fraX (mean age 13.1 years) and 9 affected by Down syndrome (mean age 13.8 years) and 26 agematched normal controls were included. All subjects underwent overnight polysomnography in the sleep laboratory, after one adaptation night and their sleep architecture and CAP were visually scored. Results: FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects showed the most disrupted sleep microstructure with low total CAP rate and CAP rate in S2 NREM. Both patient groups showed a lower percentage of A1 and higher percentage of A2 and A3 compared to normal controls. Conclusions: The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. Significance: The NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, seem to be distinctive features of intellectual disability. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Cyclic alternating pattern; NREM sleep microstructure; Down syndrome; Fragile-X syndrome; Sleep phenotype
1. Introduction The clinical and neurophysiological features of the syndromes with mental retardation have been well characterized during the wake state but few data are available on the sleep architecture and how sleep states are altered by the underlying neurological condition. This might repre*
Corresponding author. Tel.: +39 935 936111; fax: +39 935 936694. E-mail address: [email protected] (R. Ferri).
sent a limitation of the knowledge of this type of conditions because, for some of them, sleep can give important clues for their diagnosis. Sleep disturbances are common in children with intellectual disabilities, and several neurophysiological studies have been performed in the past in order to find specific polysomnographic phenotypes. Although it is possible to find sleep macrostructural alterations that are in most cases aspecific (such as REM and/or slow-wave sleep reduction) only few attempts have been made to modify the criteria
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for scoring sleep in order to adapt them to the specific patterns of each syndrome (Quine, 1991; Espie and Tweedie, 1991; Stores, 1992; Lindblom et al., 2001). It is still debated if sleep disturbances are related to the associated neurological impairments or directly linked to mental retardation (Lindblom et al., 2001; Harvey and Kennedy, 2002). The two most studied syndromes with mental retardation from a sleep point of view are Down syndrome (DS) and Fragile-X syndrome (fraX) (Lindblom et al., 2001). They represent the most common causes of inherited mental retardation occurring approximately in 0.9/1000 live births for DS (Roizen, 1997) and in 0.6-1/4000 live births for fraX (Crawford et al., 2001). Some studies on DS and fraX syndrome showed a correlation between the level of mental retardation and the amount of REM sleep; sleep architecture abnormalities in fraX syndrome appear related to the level of mental retardation, rather than to the phenotype itself. Autism and DS showed less REM sleep than fraX syndrome, when matched for the level of mental retardation (Diomedi et al., 1999; Elia et al., 2000). Previous studies have shown only few abnormalities in sleep architecture of children with DS, such as sleep fragmentation, manifested by frequent awakenings and arousals, compared to normal controls, which are only partially related to obstructive sleep apnea syndrome (Levanon et al., 1999). On the contrary, polysomnographic studies in DS reported a high frequency of obstructive sleep apnea which has been suspected to have a role in the cognitive deficit of DS (Marcus et al., 1991; Andreou et al., 2002). Also an increase in central sleep apnea, related to a specific dysfunction of the central respiratory control at brainstem level (Ferri et al., 1997; Ferri et al., 1998) has been reported. In contrast, sleep studies in fraX syndrome demonstrated a normal sleep respiratory control (Musumeci et al., 1996), without particular signs of autonomic dysfunction (Ferri et al., 1999). The sleep architecture in fraX subjects seems to show few and unspecific differences vs. normal controls: reduced total sleep time and increased wakefulness after sleep onset (Musumeci et al., 1994; Ferri et al., 1999). Previous studies evaluated mainly the alteration of REM sleep and of spindles in sleep of mentally retarded subjects and little attention was devoted to NREM sleep for which recent studies have highlighted the key role in cognitive functioning, mainly mediated by the slow oscillations in slow-wave sleep (SWS) (Diomedi et al., 1999; Tononi and Cirelli, 2003; Huber et al., 2004). We recently analyzed the microstructure of sleep in autistic children with mental retardation by means of the Cyclic Alternating Pattern (CAP) methodology (Terzano et al., 2001) and found subtle alterations of NREM sleep represented by a reduction of the slow components of CAP (A1 subtypes) during SWS, suggesting that they might play a role in the impairment of cognitive functioning in autism (Miano et al., 2007). More recently, a direct role of CAP in sleep-related cognitive processes has been shown in normal controls (Ferri et al., 2008) and confirmed in
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children with Asperger syndrome (Bruni et al., 2007). Therefore the analysis of CAP might disclose new important findings in the sleep structure of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. The aim of our study was to analyze CAP in the two most common causes of inherited mental retardation: DS and fraX syndrome, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. 2. Subjects and methods 2.1. Subjects A total of 14 males affected by fraX syndrome (mean age 13.1 years, SD 6.02 years, range 7–25) and 9 affected by DS (8 males and 1 female, mean age 13.8 years, SD 3.96 years, range 8–20) attending the Oasi Institute of Troina were recruited for this study. The molecular genetics confirmed the presence of the FMR1 gene mutations for fraX subjects and karyotyping confirmed trisomy 21 for all DS patients. All subjects were evaluated from the neuroimaging (including brain computed tomography scans or magnetic resonance imaging) and the neurophysiological points of view (EEG) and showed no neurological focal signs, seizures or paroxysmal EEG abnormalities. The intelligence level was measured by means of the Wechsler Intelligence Scale for Children – Revised (1973) or the Wechsler Adult Intelligence Scale – Revised (1997), as appropriate. Informed consent was obtained by the parents of all participants to the study. Eight fraX subjects had severe mental retardation (corresponding to IQ in the range 25–40), 6 had moderate mental retardation (IQ in the range 40–55); 4 DS children had severe mental retardation and 5 had moderate mental retardation. All subjects with fraX or DS who were obese or had signs and symptoms of sleep disordered breathing were excluded. 2.2. Polysomnographic study DS and fraX subjects whose parents accepted to participate, underwent a PSG overnight recording in the Sleep Laboratory of the Oasi Institute of Troina, after one adaptation night, in order to avoid the first-night effect. The PSG data were compared with those of a control group formed by 26 children matched for age and gender (16 males and 10 females, mean age 15.0 years, SD 5.72 years, range 8–26). The subjects were recruited from the same urban area, were of Caucasian origin, and had middle socioeconomic status. The PSG montage included at least 3 EEG channels referenced to the contralateral mastoid, left and right electrooculogram (EOG) referred to one mastoid, chin electromyogram (EMG), and electrocardiogram (ECG).
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All recordings started at the patients’ usual bedtime and continued until spontaneous awakening. 2.3. Sleep macrostructure In all subjects, 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/h (SS/h); - Number of awakenings/h (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. Sleep microstructure 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 long. 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 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 nonCAP. 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 cardiorespiratory 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 cardiorespiratory 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). All the recordings were visually scored by one of the investigators (SM) and the sleep parameters derived were tabulated for statistical analysis. 2.5. Statistical analysis The comparisons between sleep parameters obtained in DS, fraX syndrome and normal controls were carried out by means of the nonparametric Kruskall–Wallis ANOVA followed by the Mann–Whitney U test between the different groups used as a post-hoc comparison, when ANOVA resulted to be significant. Differences were considered statistically significant at p < 0.05. The commercially available software STATISTICA (data analysis software system), version 6, StatSoft, Inc. (2001) was used for all statistical tests. 3. Results Table 1 shows the comparison of sleep macrostructure parameters between fraX and DS patients and normal controls. We did not find statistical differences for total sleep time, sleep period time and sleep onset latency. FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects also showed a lower number of REM periods compared to normal controls.
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Table 1 Polysomnographic parameters in normal controls and fraX and DS patients
TIB-min SPT-min TST-min SOL-min FRL-min SS-h AWN-h SE% No-REMp WASO-% S1-% S2-% SWS-% REM-%
1-Normal controls (n = 26)
2-fraX patients (n = 14)
3-DS patients (n = 9)
Kruskall–Wallis ANOVA
Mann–Whitney U test
Mean
SD
Mean
SD
Mean
SD
p<
1 vs. 2 p<
1 vs. 3 p<
2 vs. 3 p<
518.9 495.0 484.1 18.5 114.7 7.8 0.7 93.5 7.2 2.2 3.5 46.5 25.1 22.6
51.98 45.72 43.71 13.76 50.47 3.62 0.69 4.43 2.29 2.18 3.87 5.81 7.20 5.01
484.9 466.8 447.2 15.6 129.1 5.9 0.9 92.1 5.2 4.2 6.7 47.1 24.4 17.7
58.80 69.93 72.81 21.76 68.93 1.71 0.68 8.79 2.12 5.85 5.56 6.12 7.22 5.73
532.8 495.1 430.0 34.7 154.6 7.7 2.5 80.8 6.2 13.5 6.1 39.9 22.7 17.9
115.99 104.48 106.62 50.12 59.58 1.39 1.05 10.84 2.49 8.40 2.73 5.76 6.40 5.61
0.05 NS NS NS NS NS 0.0005 0.005 0.05 0.005 0.01 0.05 NS 0.05
NS
NS
0.05
NS NS 0.05 NS 0.05 NS
0.0001 0.001 NS 0.0001 0.01 0.01
0.001 0.01 NS 0.005 NS 0.05
0.01
0.05
NS
TIB, time in bed; SPT, sleep period time; TST, total sleep time; SL, sleep latency; FRL, first REM latency; SS, stage shifts; AWN, awakenings number; SE, sleep efficiency; WASO, wakefulness after sleep onset; S1, stage 1; S2, stage 2; SWS, slow-wave sleep; REM, REM sleep. Significant p values are indicated in bold characters; NS, not significant.
two most common causes of inherited mental retardation: DS and fraX syndrome. FraX subjects showed a relatively preserved sleep architecture, compared to DS patients; however, the CAP analysis disclosed peculiar differences between DS and fraX syndrome and some common features, probably related to mental retardation itself. Our results show that subjects affected by DS have more sleep macro-architecture alterations than those with fraX: DS subjects spent more time in bed, had a lower sleep efficiency, a higher percentage of wakefulness after sleep onset and a lower percentage of stage 2 NREM. As expected, DS and fraX subjects showed a lower percentage of REM sleep than normal controls, confirming the previous findings by Diomedi et al. (1999) and Elia et al. (2000); moreover, fraX subjects showed a decreased number of REM periods. Interestingly, we did not find differences in slow-wave sleep percentage in fraX and DS compared to normal controls. These results confirm literature data on a relatively
Table 2 shows the comparison of CAP parameters between the three groups. FraX subjects show the most disrupted sleep microstructure: total CAP rate and CAP rate in S2 NREM were lower than those of DS patients and controls and CAP rate in SWS was lower than in controls. Regarding CAP A phase subtypes, fraX and DS patients showed a lower percentage of A1 and higher percentage of A2 and A3, compared to normal controls. FraX subjects also showed a higher percentage of A3 subtypes than DS patients. The A1 index (i.e. the number of A1 subtypes/h of NREM sleep) in S2 and SWS was significantly lower in fraX syndrome than in DS and controls; no differences were found between DS and controls. 4. Discussion To our knowledge, this study represents the first attempt to evaluate CAP, as an index of sleep microstructure, in the Table 2 CAP parameters found in normal controls and fraX and DS patients
CAP Time CAP_Rate% In S1 In S2 In SWS A1 Index In S1 In S2 In SWS A1% A2% A3%
1- Normal controls (n = 26)
2-fraX patients (n = 14)
3-DS patients (n = 9)
Kruskall–Wallis ANOVA
Mann–Whitney U test
Mean
SD
Mean
SD
Mean
SD
p<
1 vs. 2 p<
1 vs. 3 p<
2 vs. 3 p<
140.6 37.7 28.4 33.7 46.8
41.38 10.06 22.78 11.92 11.81
91.3 24.5 30.5 20.7 30.3
31.47 5.88 13.97 7.42 12.82
136.2 40.6 36.8 41.4 43.2
30.55 5.39 20.34 9.45 15.46
0.001 0.00001 NS 0.001 0.01
0.0005 0.0001
NS NS
0.005 0.0001
0.001 0.0001
NS NS
0.0001 NS (0.08)
26.4 43.4 73.9 77.1 13.5 9.4
25.03 10.97 20.98 9.79 7.04 4.47
28.7 19.4 45.6 57.2 18.7 24.2
20.09 5.85 16.58 6.94 5.84 5.85
25.8 43.6 71.3 63.0 18.7 18.3
14.30 13.10 28.96 7.13 6.80 4.25
NS 0.00001 0.0005 0.00001 0.05 0.00001
0.00001 0.0001 0.00001 0.05 0.00001
NS NS 0.001 0.05 0.0001
0.0005 0.02 NS NS 0.05
A1 index, number of A1 phases per hour of NREM; A1%, percentage of A1subtypes; A2%, percentage of A2 subtypes; A3%, percentage of A3 subtypes. Significant p values are indicated in bold characters; NS, not significant.
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preserved sleep architecture in fraX (Elia et al., 2000) and on the presence of sleep macrostructure disruption in DS (Levanon et al., 1999) that might also be related to the presence of mild sleep obstructive apnea, not disclosed by history and clinical examination (Marcus et al., 1991). On the contrary, CAP analysis revealed a more disrupted sleep microstructure: considering both groups of mentally retarded subjects, fraX syndrome and DS patients showed a significant reduction in A1% subtypes and an increase in A2% and A3% subtypes, compared to normal controls. Moreover, only fraX subjects showed other important CAP differences vs. normal controls, represented by a lower total CAP rate during stage 2 NREM and SWS and by a lower A1 index in S2 and SWS. The differences between fraX syndrome and DS were limited to a decrease in total CAP rate and during stage 2 NREM, associated with a decrease of A1 index during stage 2 NREM and SWS, in fraX subjects. In our opinion, the most important findings of this study are represented by the decrease in total CAP rate and of A1 index in stage 2 and SWS and of A1% in fraX patients. These specific modifications of CAP represent a decrease of transient slow EEG oscillations during NREM that have been related to cognitive functioning (Ferini-Strambi et al., 2004). We recently analyzed the microstructure of sleep in autistic children with mental retardation and found a reduction of the slow components of CAP (A1 subtypes) during SWS (Miano et al., 2007). Other recent studies also support a direct role of CAP in sleep-related cognitive processes in normal controls (Ferri et al., 2008) and in children with Asperger syndrome (Bruni et al., 2007). DS subjects showed only a decrease of A1% and an increase in A2% and A3% as a typical sleep microstructural feature. The lack of differences vs. controls in the other CAP parameters could be linked to the minor cognitive impairment of our DS vs. fraX syndrome patients. Further, the alteration of sleep macrostructure of DS might be linked to other underlying sleep disorders (i.e. sleep apnea, as an example) interfering with sleep microstructure and explaining the increase in A2% and A3%. The lower CAP rate during stage 2 NREM in fraX vs. normal controls and DS is also similar to the results of a previous study on CAP in ADHD children (Miano et al., 2006). CAP similarities between these two conditions might be correlated with the deficit of the executive functions found in fraX subjects, similar to those of ADHD children (Mazzocco, 2000). The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. To our knowledge, this is the first study that considers the alteration of NREM in mentally retarded subjects. Previous studies mostly focused on REM sleep and did not consider NREM abnormalities since sleep architecture analysis failed to find differences in NREM stages vs. normal controls.
From our results, we cannot state that the microstructural alterations found are directly related primarily to the level of mental retardation or to a specific sleep phenotype of the two different syndromes (Harvey and Kennedy, 2002). However, we are convinced that the examination of NREM sleep microstructure (CAP) in developmental disabilities and subsequently in different syndromes (i.e. autism, Down syndrome, and Fragile-X syndrome), may prove able to provide key evidence for deciphering the mechanisms and timing of learning and the consolidation of learned tasks. We are also convinced that REM abnormalities are important contributors to mental retardation but we should take into account that REM represents only about 20% of entire sleep while NREM represents about 70–75%. It has been suggested that slow-wave activity of NREM sleep may be involved in producing progressive downscaling of synaptic strength which, in turn, would lead to several benefits in terms of both cellular function and network performance and is probably important for neurocognitive performance (Tononi and Cirelli, 2003). The most important component of CAP is the A1 subtype composed mostly of slow waves and mapping over the frontal and prefrontal regions of the scalp (Ferri et al., 2005). The significant decrease in A1 CAP subtypes might be the result of a possible dysfunction of these brain structures and could play a role in the impairment of cognitive functioning in these subjects. Therefore in our opinion this disturbed sleep pattern is more likely a consequence (and not the cause) of the cognitive disorder accompanying the genetic abnormality; however, this point surely deserves further research. It is also possible that other concomitant sleep disorders (i.e. sleep disordered breathing linked to craniofacial abnormalities or to hypotonia) disrupt sleep microstructure and aggravate the cognitive functioning. In this perspective, the treatment of concomitant sleep disorders might be beneficial and should be always evaluated and eventually carried out in patients with mental retardation. Based on the results of this study and those of our previous investigations on CAP in different developmental disorders (Miano et al., 2006, 2007; Bruni et al., 2007), we might hypothesize that the NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, are distinctive features of intellectual disability. The replication of these results seems now to be mandatory in future investigations, in larger cohorts of children affected by DS and fraX syndrome and in other groups of children with etiologically different intellectual disability, and correlation with neuropsychological data is needed. References Andreou G, Galanopoulou C, Gourgoulianis K, Karapetsas A, Molyvdas P. Cognitive status in Down syndrome individuals with sleep disordered breathing deficits (SDB). Brain Cogn 2002;50:145–9. Bruni O, Ferri R, Vittori E, Novelli L, Vignati M, Arico` D, et al. Sleep architecture and NREM alterations in Asperger children and adolescents. Sleep 2007;30:1577–85.
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