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Volume 13 No. 10
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Scientific Investigations

Non-REM Sleep Instability in Children With Primary Monosymptomatic Sleep Enuresis

Leticia Azevedo Soster, MD, PhD1; Rosana Cardoso Alves, MD, PhD1; Simone Nascimento Fagundes, MD, PhD2; Adrienne Lebl, MD, MsC2; Eliana Garzon, MD, PhD1; Vera H. Koch, MD, PhD2; Raffaele Ferri, MD, PhD3; Oliviero Bruni, MD, PhD4
1Neurology Division, Hospital das Clínicas, São Paulo University (HC/FMUSP), São Paulo, Brazil; 2Pediatric Division, Hospital das Clínicas, São Paulo University (HC/FMUSP), São Paulo, Brazil; 3Sleep Research Centre, Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy; 4Center for Pediatric Sleep Disorders, Department of Developmental and Social Psychology, Sapienza University, Rome, Italy

ABSTRACT

Study Objectives:

Sleep enuresis is one of the most common sleep disturbances in childhood. Parental perception of deeper sleep in children with sleep enuresis is not confirmed by objective studies. However, evidence of disturbed sleep has been demonstrated by questionnaire, actigraphy, and polysomnographic studies, but no neurophysiological correlation with low arousability has been found. The goal of this study was to analyze the sleep microstructure of children with sleep enuresis using cyclic alternating pattern (CAP) analysis.

Methods:

Forty-nine children were recruited, 27 with enuresis (19 males and 8 females, mean age 9.78 years, 2.52 standard deviation) and 22 normal control patients (11 males and 11 females, mean age 10.7 years, 3.43 standard deviation); all subjects underwent clinical evaluation followed by a full-night polysomnographic recording. Psychiatric, neurological, respiratory, and renal diseases were excluded.

Results:

No differences in sex, age, and apnea-hypopnea index were noted in the patients with enuresis and the control patients. Sleep stage architecture in children with sleep enuresis showed a decrease in percentage of stage N3 sleep. CAP analysis showed an increase in CAP rate in stage N3 sleep and in phase A1 index during stage N3 sleep in the sleep enuresis group, but also a significant reduction of A2% and A3% and of phases A2 and A3 indexes, supporting the concept of decreased arousability in patients with sleep enuresis. The decrease of phase A2 and A3 indexes in our patients might reflect the impaired arousal threshold of children with sleep enuresis. Sleep fragmentation might result in a compensatory increase of slow wave activity (indicated by the increase of CAP rate in stage N3 sleep) and may explain the higher arousal threshold (indicated by a decrease of phase A2 and A3 indexes) linked to an increased sleep pressure.

Conclusions:

The findings of this study indicate the presence of a significant disruption of sleep microstructure (CAP) in children with sleep enuresis, supporting the hypothesis of a higher arousal threshold.

Citation:

Soster LA, Alves RC, Fagundes SN, Lebl A, Garzon E, Koch VH, Ferri R, Bruni O. Non-REM sleep instability in children with primary monosymptomatic sleep enuresis. J Clin Sleep Med. 2017;13(10):1163–1170.


INTRODUCTION

Sleep enuresis is one of the most common problems in the pediatric population, with a general prevalence of 3% to 15%.18 The prevalence of sleep enuresis in 5-year-old children decreases from approximately 15% to 20% to 10% at age 6 years and to 1% to 3% in adolescence and adulthood.9 The International Classification of Sleep Disorders, Third Edition10 describes 2 types of enuresis: primary sleep enuresis, which is defined as recurrent involuntary voiding during sleep, occurring at least twice a week in a patient older than 5 years that has been present for at least 3 months and the patient has never been consistently dry during sleep; and secondary sleep enuresis, which is similar to the primary form but the patient has previously been consistently dry during sleep for at least 6 months. Sleep enuresis also can be classified as monosymptomatic (without other symptoms) and nonmonosymptomatic, which also includes diurnal voiding.11

Sleep enuresis is potentially harmful to a child's psychological development. A recent study has indicated most children with sleep enuresis are unhappy, have impaired quality of life and sleep, and a very low self-esteem12 as a consequence of their voiding difficulties. However, we should also take into account that, in most cases, sleep enuresis does not present with significant behavioral comorbidity or psychiatric disturbances.13

BRIEF SUMMARY

Current Knowledge/Study Rationale: Almost all data converge toward a higher arousal threshold in children with sleep enuresis linked to sleep fragmentation. No neurophysiological correlate of low arousability has been found.

Study Impact: Our findings indicate the presence of a disruption of sleep microstructure in children with sleep enuresis. The decrease of A2 and A3 indexes (ie, low and high power arousals) might reflect the impaired arousal threshold of enuretics.

Although various hypotheses have been formulated for the pathogenesis of sleep enuresis, the most accepted hypothesis involves 3 systems: excessive nocturnal urinary production, nocturnal bladder overactivity, and failure to awaken in response to bladder sensations.14 Other pathophysiological mechanisms are mostly related to sleep fragmentation determined by sleep-related breathing disorders (SRBD)15 or periodic limb movements during sleep (PLMS).16 SRBD have been frequently reported in children with sleep enuresis, with a prevalence ranging from 8% to 47%. A direct correlation exists between apnea-hypopnea index (AHI) and occurrence of sleep enuresis.17 Also, PLMS have been reported in a group of children with treatment-resistant sleep enuresis.18

According to 1 study, parents universally agree that sleep of children with sleep enuresis is deeper than that of children without sleep enuresis and that they are very difficult to arouse.19 This parental perception, however, has not always been confirmed by objective studies: although some investigations using spectral analysis of sleep electroencephalography (EEG) suggested an increase in delta power as a sign of deeper sleep,20,21 others have found sleep to be lighter in children with sleep enuresis,22 with an increase of stage N1 sleep and elevated arousal index and reduced stage N3 and R sleep, compared to normal control patients. Other studies found no differences between sleep parameters of children with sleep enuresis and normative data.2327 Fewer studies have been performed using a control group, and again, no difference in sleep parameters was found.28,29

Enuretic events happen mainly during the first part of the night, and can occur in all sleep stages; moreover, sleep structure is similar during nights when enuresis occurs and when it does not occur.2327 The recent finding that patients with enuresis are subjectively sleepier than normal control patients and more difficult to awaken has been attributed to sleep fragmentation that might be responsible for the higher arousal threshold and is consistent with a large body of sleep research.5,17,19 A recent study using actigraphy and sleep logs5 evaluated sleep of children with sleep enuresis over 3 to 5 nights and found that natural sleep in these children is significantly more fragmented and that they experience higher levels of daytime sleepiness. Sleep fragmentation in children with sleep enuresis could cause an increased sleep pressure with a consequent higher arousal threshold.

The analysis of the cyclic alternating pattern (CAP) represents a marker of sleep instability30 and is an established approach for the detailed evaluation of sleep fragmentation. Periods of the night when the arousal level is unstable can be detected with CAP analysis. The concept of instability is a basic tenet of all complex systems and supports the dynamics of biological variability. Within certain ranges, instability warrants flexible and adaptive features to the complex system. In normal sleep CAP accompanies the stage transitions, maintaining in-phase both the EEG and autonomic functions through regular fluctuations.

CAP, therefore, is a periodic EEG activity of non-REM (NREM) sleep that reflects the processes of sleep maintenance and arousability. The hierarchical activation from the slower EEG patterns (moderate autonomic activation without sleep disruption, named CAP A1 phases) to the faster EEG patterns (robust vegetative activation associated with visible sleep fragmentation, named A2 and A3 phases)3133 can have different meanings. A1 subtypes are involved in the buildup and maintenance of deep NREM sleep and can play a protective role in sleep continuity, ensuring the maintenance or even deepening of sleep; instead of having an arousing effect, CAP A1 subtypes can be interpreted as “antiarousals.” However, phases A2 and A3 can be involved in the REM-on activity and function to maintain subject arousability.33

Therefore, according to the parental impression of a “deeper sleep” in children with sleep enuresis, we should expect a decrease of arousals and of phase A2 and A3 CAP subtypes but also an increase of phase A1 subtypes during slow wave sleep that should represent the protective role of sleep continuity. Conversely, if the studies reporting an increased sleep fragmentation in children with sleep enuresis are taken into account, an increase in arousal index should be expected. In order to clarify this controversy, we decided to analyze the sleep microstructure of children with sleep enuresis by means of CAP.

METHODS

Subjects

After Institutional Review Board approval, families were invited via press release to participate in the project; responders completed quality-of-life evaluation through clinically validated questionnaires, followed by a 1-day multidisciplinary clinical evaluation. Sleep, urinary, and intestinal diaries were evaluated. Urinary somnography along with urinary and blood analysis were performed to exclude secondary enuresis.

Inclusion criteria were age 6 to 17 years; at least 2 episodes of sleep enuresis in 1 month; complete control of urinary voiding during the daytime; and absence of specific treatment (pharmacological or behavioral) for the enuretic episodes.

Exclusion criteria were clinical diagnosis of any disease or condition that could affect sleep; presence of renal, urologic, neurologic, or psychiatric disorder; and presence of diurnal lower urinary tract symptoms (such as incontinence or urgency).

All patients and families signed an informed consent form approved by the ethical committee of the institution where the clinical examination and the polysomnography (PSG) studies were carried out. The patients submitted to a standardized interview on pediatric (including urinary and bowel symptoms) and neurological symptoms. Also, sleep was assessed using the Sleep Disturbance Scale for Children,34 as well as a complete neurological and pediatric physical examination. Age-matched control patients were normal, healthy children with no history of organic or mental illness and without neurological or psychiatric disabilities. All attended regular primary, middle, or secondary/high schools, with normal performances.

Polysomnographic Recordings

The polysomnographic examination was carried out in the pediatric sleep laboratory of the Children's Institute, University of Sao Paulo Medical School in a quiet room with video monitoring. All recordings started at the patients' usual bedtime and continued until spontaneous awakening.

The EEG recordings and electrode placement were performed according to the 10–20 system and the PSG montage included 6 EEG channels Fp1-A2, Fp2-A1, C3-A2, C4-A1, O1-A2 and O2-A1, left and right electrooculogram, chin electromyogram, electrocardiogram, electromyogram of left and right tibialis anterior muscles, nasal cannula, thoracic and abdominal respiratory effort, and oxygen saturation. All recordings were visually scored by one of the investigators (LS), and the sleep parameters derived were tabulated for statistical analysis.

Sleep data were recorded and stored on an external hard drive by means of a digital PSG system (Embla N7000, Medcare, Iceland) and its related software (Remlogic, Medcare).

Sleep Stage Architecture

Sleep was subdivided into 30-second epochs and sleep stages were scored according to the standard American Academy of Sleep Medicine (AASM) criteria.35 Awakenings were identified as 2 or more consecutive epochs scored as wakefulness, surrounded by epochs of sleep.

The following conventional sleep parameters were evaluated: time in bed; sleep period time (SPT), time from sleep onset to sleep end; total sleep time, the time from sleep onset to the end of the final sleep epoch excluding awake time; sleep latency, time from lights out to sleep onset; REM sleep latency, time from sleep onset to the first stage R sleep epoch; number of awakenings/hour; sleep efficiency, the percentage ratio between total sleep time and time in bed; percentage of SPT spent in wakefulness after sleep onset; and percentage of SPT spent in stages N1 (N1%), N2 (N2%), N3 (N3%), and R (REM%) sleep. Arousals were scored according to AASM criteria: an abrupt shift of EEG frequency including alpha, theta, and/or frequencies greater than 16 Hz (but not spindles) that last at least 3 seconds, with at least 10 seconds of stable sleep preceding the change. Scoring of arousal during REM requires a concurrent increase in submental electromyogram lasting at least 1 second. The arousal index was defined as the number of arousals per hour of sleep.

Cyclic Alternating Pattern

According to Terzano et al.,31 CAP was defined as a periodic EEG activity of NREM sleep characterized by repeated spontaneous sequences of transient events (phase A), recurring at intervals up to 2 minutes 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 preceded and/or followed by another phase A in the temporal range of 2 to 60 seconds. If there were 3 consecutive A phases followed by a non-CAP condition, the CAP sequence is stopped at the end of the second B phase and the third A phase is quantified as non-CAP.

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 two-thirds of the phase A length, and coupled with an enhancement of muscle tone and/or cardiorespiratory rate.

The following CAP parameters were derived: CAP rate (percentage of total NREM sleep time occupied by CAP sequences); number and duration of CAP cycles; number and duration of CAP sequences; number, duration, and percentage of each phase A subtype; A1, A2, and A3 index (number of phases A1, A2, or A3 per hour of NREM sleep); and number and duration of phase B subtypes.

Respiratory Parameters

The apnea-hypopnea events were counted according to the criteria established by the AASM manual35 and the American Thoracic Society36: an obstructive apnea was defined as the absence of airflow, with continued chest wall and abdominal movement, for a duration of at least 2 breaths; a mixed apnea was defined as an apnea that usually begins as central and ends in obstruction according to changes in the chest, abdominal, and flow traces; hypopnea was defined as a decrease in nasal flow of at least 50% associated with a decrease in saturation of oxygen of at least 3%, awakening or arousal; the AHI was defined as the number of apneas and hypopneas per hour of total sleep time.

All recordings were visually scored by 1 investigator and the sleep parameters derived were tabulated for statistical analysis.

Statistical Analysis

The differences between children with sleep enuresis and normal control patients in age, respiratory parameters, sleep stage architecture, and CAP parameters were evaluated using the nonparametric Mann-Whitney U test for independent datasets, followed by Bonferroni correction in order to take into account multiple comparisons. Differences were considered statistically significant at P < .05. The commercially available software STATISTICA (data analysis software system; version 6, StatSoft Inc., 2001, Tulsa, Oklahoma, United States) was used for all statistical tests.

RESULTS

Forty-seven patients were recruited but after clinical history and physical examination, 20 of them were excluded: 11 because of renal or urologic problems, and 9 had AHI above 5 events/h. The 27 remaining patients (19 male and 8 female, mean age 9.78 years, 2.52 standard deviation [SD]) who fulfilled the inclusion criteria were compared with 22 normal children (11 male and 11 female, mean age 10.7 years, 3.43 SD) recruited as a control group. All patients with sleep enuresis had blood glucose values within normal limits and the mean body mass index was 19.99 kg/m2. Family history was negative for sleep disorders and parasomnias.

Patients with sleep enuresis and controls had no differences in sex (chi square 0.371; P = .543), age (9.78 ± 2.52 versus 10.69 ± 3.43; P = .3), or body mass index (19.99 versus 20.77; P = .67). The AHI was slightly higher in patients with sleep enuresis but failed to reach statistical significance (patients with sleep enuresis 1.59 ± 0.86 versus control patients 1.21 ± 0.74; P = .08).

Sleep Stage Architecture

Sleep stage architecture was similar in both groups; the only difference was a decrease of stage N3 sleep in patients with sleep enuresis versus control patients (Table 1). Wake after sleep onset was slightly increased in patients with sleep enuresis approaching statistical significance (P = .06). The arousal index in NREM sleep was lower in patients with sleep enuresis (2.39 versus 8.23), whereas in REM sleep it was not significantly different (6.9 versus 5.8). No differences have been found in the periodic limb movement index (PLMI): patients with sleep enuresis showed a PLMI of 0.34 (SD: 0.41) versus a PLMI of 0.15 (SD: 0.12) in the control group (P = .090, not significant).

Sleep stage architecture parameters in children with sleep enuresis and control patients.

jcsm.13.10.1163.t01.jpg

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Table 1

Sleep stage architecture parameters in children with sleep enuresis and control patients.

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Cyclic Alternating Pattern

The assessment of CAP revealed several differences between subjects with sleep enuresis and normal control patients (Table 2). With respect to the control group, children with sleep enuresis showed a similar total CAP rate but a significant increase in CAP rate during N3, in A1% and in A1 index during N3, indicating an enhancement of EEG slow oscillations. In addition, there was a significant reduction in A2% and A3% and in A2 index in N2 and A3 index in N2 and N3, supporting the concept of a decreased arousability in patients with sleep enuresis (Figure 1).

Cyclic alternating pattern parameters in children with sleep enuresis and control patients.

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Table 2

Cyclic alternating pattern parameters in children with sleep enuresis and control patients.

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Comparison between A1 and A2 + A3 indexes in patients with sleep enuresis versus control patients.

* = P < .005.

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Figure 1

Comparison between A1 and A2 + A3 indexes in patients with sleep enuresis versus control patients.

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DISCUSSION

The findings of this study indicate the presence of a significant disruption of sleep microstructure (CAP) in children with sleep enuresis.

Sleep Stage Architecture (Macrostructure)

The only parameter that differed in sleep macrostructure was stage N3, which was decreased in patients with sleep enuresis. In this study we did not find differences in PLMS index and in AHI among patients with sleep enuresis and control patients, although some studies reported an increase in PLMS in children with refractory sleep enuresis37 or of SRBD and obstructive apnea in both adults and children.3840

Studies have shown that children with sleep enuresis do not present with grossly abnormal sleep recordings,23,27 and the polysomnographic differences between children with sleep enuresis and those without sleep enuresis have usually been small or nonexistent,28,29 although increased delta power or other subtle signs of “deep sleep” have been detected.21

The first published studies on sleep stage architecture in patients with sleep enuresis reported only a small increase in delta sleep in bedwetters20 associated with disturbed arousal in comparison with control patients.21 Another important study showed that sleep of children with enuresis is polysomnographically normal but showed a tendency for increased motor activity of short duration (< 5 seconds).29

Sleep Microstructure

In contrast, in our study we found a decrease of slow wave sleep (stage N3) but CAP analysis revealed a higher CAP rate and A1 index in N3, indicating an increase of EEG slow oscillations and more generally of NREM sleep instability. The increase of CAP rate and of A1 index in N3 might be in agreement with previous studies showing an increase of ”rhythmic slow wave” activity on the EEG and of delta power, or other subtle signs of “deep sleep.”20,21,28 An augmented presence of ”rhythmic slow wave” activity on the EEG immediately prior to bladder emptying has been reported by a Japanese study on 15 children with sleep enuresis in whom the study authors found no differences in the other standard polysomnographic parameters.28

One of the hypotheses to explain the subjective “deep sleep” of patients with sleep enuresis is linked to sleep fragmentation leading to sleep deprivation that, in turn, results in a rebound increase of slow wave activity (or an increase of EEG slow oscillations) and may explain the higher arousal threshold induced by increased sleep pressure.41 The increase in sleep pressure might manifest in the children in our study with sleep enuresis with the increase of slow EEG oscillations, reflected by the increase of A1 CAP subtypes but not with an increase of stage N3. However, the significant reduction of A2 and A3 percentages and indexes in these patients might reflect the impaired arousal threshold of children with sleep enuresis, reported in a 1997 study.19 This finding supports the concept of a decreased arousability and the observation made by parents that they have difficulty arousing their children with sleep enuresis.

Several studies have undermined the classic concept of decreased arousability in sleep enuresis. A 1982 study reported that children with sleep enuresis exhibited less delta sleep and lower sleep efficiency than children who awoke dry, but most children with sleep enuresis in this study had significant psychiatric or neurological comorbidity.22 An increase of light sleep and a decrease of deep sleep with an increase of cortical arousal index (6.32 versus 3.90) has been reported by Yeung et al.42 A more recent study on children with refractory sleep enuresis reported nonsignificant differences in sleep stages between children with enuresis and control patients but an increase in awakening index (9.7 versus 7.7) and in cortical arousal index (7.3 versus 5.3).16

Nevertheless, it should be considered that these studies dealt with refractory sleep enuresis and included secondary enuresis with several important comorbidities (such as attention deficit hyperactivity syndrome or restless legs syndrome). Therefore, the increase of arousals probably could be more linked to the secondary causes or comorbidities rather than to enuresis per se. In contrast to these previous reports, in our study we found a decreased arousal index in NREM sleep; this finding could be related to the fact that we selected subjects with primary enuresis, recruited from the general population and without specific comorbidities.

Only one study has been published on CAP analysis in sleep enuresis, by Zucconi et al.,43 who included 2 patients with sleep enuresis and 6 with bruxism; although difficult to compare with our results, this group showed, similar to our study, an increase of A1% and a decrease of A2 and A3%, supporting the concept of low arousability.

Enuresis may be considered an NREM disorder, associated with a decrease of N3 that could induce, through homeostatic mechanism, a decrease of arousability that can explain a low arousal index and different arousal patterns (A1 versus A2 and A3). This finding is supported by results of another study about arousal in sleep deprivation, a condition showing that homeostatic sleep processes exert an inhibitory effect on arousal response from sleep and exert a significant effect solely on microarousal density.44

The neurophysiological correlate of the low arousability of subjects with sleep enuresis should probably be sought in the brainstem and in the activity of the autonomic nervous system.45 Some studies have acknowledged the interaction between the reticular activating system and the pontine micturition center in generating autonomic arousals rather than cortical arousals.46,47

We could hypothesize that sleep fragmentation (indicated by the increase of awakenings and/or of cortical arousals) might result in a compensatory increase of slow wave activity (indicated by the increase of CAP rate in N3 in the current study) and may explain the higher arousal threshold determined by an increased sleep pressure (that might lead to a decrease of A2 and A3 CAP phases). Therefore, NREM sleep instability in children with sleep enuresis is mainly reflected by the increase of A1 that ensures the maintenance or even deepening of sleep, and this is balanced with the interplay of A2 and A3 that are reduced, supporting the concept of low arousability. Although normal amounts of A1 represent the physiological buildup of stable slow wave sleep, increased amounts might represent some degree of inability to reach such a state and a longer effort to do it, which, accompanied by a lower arousability (less arousals and A2/A3), causes long periods of A1 subtypes, leading to unstable slow wave sleep. The upsurge of A1 linked to the homeostatic process do not necessarily correspond to an increase of stage N3. Finally, it might be said that children with sleep enuresis might simultaneously present with impaired brainstem arousal mechanisms and impaired cortical synchronization mechanisms.

Impaired brainstem arousal mechanisms could be responsible for nocturnal enuresis through different mechanisms: a deficiency of inhibitory signal processing in the brainstem that accounts for the inability to inhibit detrusor activities during sleep48; or neurological impairment of the posterior hypothalamus (responsible for secretion of antidiuretic hormone) or of the locus coeruleus could be the anatomical location of most pathophysiological described mechanisms for nocturnal enuresis.42

There were several limitations of this study. The children with sleep enuresis were recruited from the general population, and might not represent the typical sample referred to a sleep clinic; this might be the reason for the differences from the previous studies. In addition, the first-night effect on polysomnographic parameters should be taken into account, but the control group was recorded in the same condition. Finally, we only analyzed the respiratory pattern only by means of AHI and probably, also the respiratory disturbance index should have been obtained.

Future studies integrating the evaluation of both autonomic and cortical arousals may be able to shed light on the concept of arousability in children with sleep enuresis using different methodologies of EEG analysis: spectral or NREM amplitude variability.49

CONCLUSION

The results of this study support the view that CAP is a sensitive tool to analyze the NREM sleep instability in sleep enuresis. Almost all data converge toward a higher arousal threshold in children with sleep enuresis linked to sleep fragmentation. Our findings indicate the presence of a disruption of sleep microstructure in children with sleep enuresis. The decrease of phase A2 and A3 indices (ie, low- and high-power arousals) might reflect the impaired arousal threshold of individuals with enuresis. Our results reinforce the parental belief of their children as “deep sleepers.” This finding might allow physicians to help parents to have a better understanding of their children's sleep and to carry out a comprehensive approach to help children overcome voiding difficulties.

DISCLOSURE STATEMENT

This work was supported by FAPESP Grant # 2011/17589-1. The authors report no conflicts of interest.

ABBREVIATIONS

AASM

American Academy of Sleep Medicine

AHI

apnea-hypopnea index

CAP

cyclic alternating pattern

EEG

electroencephalography

NREM

non-REM

PLMS

periodic limb movements during sleep

PLMI

periodic limb movements index

PSG

polysomnography

REM

rapid eye movement

SPT

sleep period time

SRBD

sleep-related breathing disorders

SD

standard deviation

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