Original Article
Sleep Structure in Children With Attention-Deficit/Hyperactivity Disorder
Journal of Child Neurology 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815573318 jcn.sagepub.com
Gulcin Akinci, MD1, Ibrahim Oztura, MD2, Semra Hiz, MD3, Ozlem Akdogan, MD2, Dilay Karaarslan, MD4, Handan Ozek, MD4, and Aynur Akay, MD4
Abstract The authors evaluated basic sleep architecture and non–rapid eye movement (NREM) sleep alterations in drug-naı¨ve attentiondeficit/hyperactivity disorder (ADHD) children without psychiatric or other comorbidities. This cross-sectional case-control study included 28 drug-naı¨ve children with ADHD and 15 healthy controls. This subjective studies revealed that children with ADHD had a worse sleep quality and increased daytime sleepiness. Polysomnography data showed that the sleep macrostructure was not significantly different in children with ADHD. Sleep microstructure was altered in ADHD children by means of reduced total cyclic alternating pattern rate and duration of cyclic alternating pattern sequences. This reduction was associated with a selective decrease of A1 index during stage 2 NREM. SpO2 in total sleep was slightly decreased; however, the incidence of sleep disordered breathing showed no significant difference. The authors suggest that cyclic alternating pattern scoring would provide a further insight to obtain a better understanding of the sleep structure in children with ADHD. Keywords attention-deficit/hyperactivity disorder, children, sleep, nocturnal polysomnography, cyclic alternating pattern scoring. Received November 2, 2014. Received revised January 21, 2015. Accepted for publication January 24, 2015.
Attention deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric condition, which has an onset at childhood. The worldwide prevalence of ADHD has been estimated to be 5% in school age children.1 ADHD is characterized by the symptoms of inattention, hyperactivity, and/or impulsivity that have an onset before the age of 7, and impaired functioning in 2 or more settings such as at home, at school, and so on. ADHD has 4 subtypes, predominantly inattentive, predominantly hyperactive/impulsive, a combination of both and not otherwise specified.2,3 Although questionnaire studies suggest that sleep problems are very common in children with ADHD, the results of objective studies are heterogeneous.4-6 Furthermore, the relationship between sleep disorders and ADHD is still poorly understood. Besides, very limited data is available on the microstructure of sleep in children with ADHD. Arousals are a very important part of the sleep microstructure and its fluctuations without awakenings have been demonstrated in cyclic alternating pattern, an endogenous rhythm characterized by a periodic electroencephalography (EEG) activity with sequences of transient arousal complexes (phase A) that are distinct from the background EEG activity (phase B) of non–rapid eye movement (NREM). Cyclic alternating pattern analyses encompass the process of sleep maintenance and provide information on the time structure of these events and allow a better
understanding of sleep disturbances and neurophysiological mechanisms.7,8 Two studies so far have evaluated sleep microstructure with cyclic alternating pattern in children with ADHD.9,10 However, these 2 studies reported conflicting results. While Miano et al9 found a lower cyclic alternating pattern rate and a lower number of cyclic alternating pattern sequences in children with ADHD, Prihodova et al10 reported no significant alteration in sleep microstructure. In this study, the authors have aimed to evaluate sleep macrostructure and microstructure in children with ADHD. The authors have hypothesized that a comprehensive analysis of sleep structure including the cyclic alternating pattern
1
Department of Pediatric Neurology, Dr Behcet Uz Children’s Hospital, Izmir, Turkey 2 Sleep Disease Center, Department of Neurology, Dokuz Eylul University, Izmir, Turkey 3 Division of Pediatric Neurology, Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey 4 Department of Child and Adolescent Psychiatry, Dokuz Eylul University, Izmir, Turkey Corresponding Author: Gulcin Akinci, MD, Department of Pediatric Neurology, Dr Behcet Uz Children’s Hospital, Izmir 35210, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
2
Journal of Child Neurology
analysis can provide new information on the association of ADHD and sleep disturbances.
Methods Subjects Twenty-eight ADHD children (20 boys and 8 girls; age range 8-12 years, median age 10), who were consecutively referred to the Departments of Child and Adolescent Psychiatry and Pediatric Neurology at Dokuz Eylul University from September 2010 to August 2011, were included. All patients were independently examined by 2 child psychiatrists, and fulfilled the ADHD inclusion criteria according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Twenty-one children presented the hyperactive or combined type (75%) and 7 the inattentive type (25%). Patients were excluded if they received any pharmacological treatment for ADHD, if they have a history of any chronic physical condition, or neurological or other psychiatric disorders or being administered with any type of medication. To avoid potential selection biases, prestudy sleep behavior was not a selection criterion. A control group was formed by 15 healthy children matched for age, sex, and intelligence quotient (IQ) (9 boys and 6 girls, age range 9-13 years, median age 10). The diagnosis of ADHD was ruled out according to Diagnostic and Statistical Manual of Mental Disorders criteria in healthy controls. All participants were in the prepubertal or early pubertal stages as assessed by the Tanner scale (Tanner stage 1-2). All 28 children diagnosed with ADHD and their parents underwent a semistructured psychiatric interview (Kiddie-SADS), Conners’ Teacher Rating Scale, Conners’ Parents Rating Scale. The IQ level was assessed by the Wechsler Intelligence Scale for Children-Revised. Subjects were excluded if they had an IQ score less than 70. The histories reported by the parents were used to record the general demographic data. To question sleep habits and disturbances, children and their parents were invited for a clinical appointment. A detailed structured interview with a questionnaire of sleep habits and parasomnias was conducted. Parents were asked to fulfill the Pittsburgh Sleep Quality Index questionnaire and modified Epworth Sleepiness Scale for their children. Several studies have suggested that children with ADHD are more likely to have restless legs syndrome than healthy children.11,12 To evaluate this possible association, a specific diagnostic interview for restless legs syndrome was applied. Subjective assessment of sleep was determined with the Pittsburgh Sleep Quality Index questionnaire. The Pittsburgh Sleep Quality Index questionnaire assesses sleep quality subjectively from good to poor sleep. A total score greater than 5 indicates poor sleep. The Pittsburgh Sleep Quality Index has been translated to Turkish and validated both for adults and children.13,14 Daytime sleepiness symptoms were evaluated by the modified Epworth Sleepiness Scale. The Epworth Sleepiness Scale is an 8-item questionnaire with scores ranging from 0 to 24. An Epworth Sleepiness Scale score of 10 indicates increased daytime sleepiness in adults. The test can be used in children with minor modifications. All subjects were questioned for chronic sleep onset insomnia, which was defined regarding to previous studies.15,16 After completing clinical evaluation and questionnaires in the Department of Child Neurology, all patients were sent to the Sleep Disease Center at Dokuz Eylul University. Patients were given an appointment for the sleep study. Children and their parents were invited for an adaptation visit before the real test. No records were taken at the
adaptation night. At the study night, patients were asked to sleep at their usual bedtime and recordings continued until spontaneous awakening. The records were done for 1 night. A video polysomnography, including 10 EEG leads (10-20 International System), electro-oculography, submental and bilateral tibialis EMGs, electrocardiography (1 derivation), oro-nasal air flow (by thermistors and nasal cannulas), thoracic and abdominal pneumograms (by strain gauges), oxygen saturation (pulse-oxymetry), and video-recording using an infra-red light camera were applied. Polysomnography recordings were performed using a commercial recording system (S4000, Embla Systems Inc., Broomfield, CO, USA) and sleep diagnostic software (RemLogic 2.0, Embla Systems Inc., Broomfield, CO, USA). This protocol was approved by the local Ethics Committee of the Medical Faculty of Dokuz Eylul University, and a written consent was given by the parents of each subject.
Sleep Macrostructure Sleep stages were visually scored in accordance with the 2007 AASM Manual for Scoring Sleep.17 Total sleep time, sleep efficiency, percentage and latencies of sleep stages, sleep-onset latency, and REM sleep latency were recorded. Apneas and hypopneas were scored. The apnea–hypopnea index was determined.18 Apnea–hypopnea index > 1 was considered as abnormal.19 Periodic limb movements were scored according to ICSD-2 criteria.2 However, the duration was defined as 0.5-10 s. as recommended by the American Academy of Sleep Medicine and the International Restless Legs Syndrome Study Group.20 The periodic limb movement index was recorded as the number of periodic limb movements per hour during the sleep. A periodic limb movement index greater than 5 was considered abnormal as previously reported.2 All recordings were read by 2 independent neurologists with specific sleep and EEG reading expertise to obtain detailed video-EEG/polygraphic reports.
Sleep Microstructure Cyclic alternating pattern is described as an endogenous rhythm in NREM sleep which consists of arousals fluctuations without awakenings.7,8 Cyclic alternating pattern is characterized by a periodic EEG activity with sequences of transient electrocortical activations which recurs at intervals up to 2 minutes. These sequences have an organized cyclic pattern and repeated several times during the sleep. It is characterized by an EEG transient pattern (phase A of the cycle) separated by intervals of background activity (phase B of the cycle). Subtype A1 is predominantly composed of slow waves (EEG synchrony), while subtype A3 shows fast EEG activities (EEG desynchrony). Subtype A2 is a combination of both.21 It has been proposed that the percentage of cyclic alternating pattern time to NREM sleep time (cyclic alternating pattern rate) can be a physiologic marker of NREM sleep instability.7,8 Noncyclic alternating pattern is characterized by a stable sleep period which is longer than 60 s. without any oscillations. Cyclic alternating pattern scores were recorded as described by Terzano et al.8 The variables were analyzed by RemLogic 2.0 sleep analysis software (Embla Systems Inc., Broomfield, CO, USA). All the recordings were visually scored by the investigators (IO and OA). The sleep parameters derived were used for statistical analyses.
Statistical Analysis Statistical analysis was performed using Statistical Package of Social Science (SPSS Inc, Chicago, IL, USA), version 15.0 for Windows.
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
Akinci et al
3
Table 1. Demographic and Clinical Characteristics of ADHD Patients and Healthy Controls.
Median age Gender, boys % IQ by WISC-R Total IQ Verbal IQ Performance IQ BMI (kg/m2) ADHD subtype (%) Hyperactive and combined Inattentive Conners’ Parents Rating Scale Conners’ Teacher Rating Scale Adenotonsillectomy Abnormal EEG (%) Serum iron parameters Iron level Total iron binding capacity Ferritin Transferrin saturation
Control (n ¼15)
ADHD (n ¼28)
10 (9-13) 9 (60%)
10 (8-12) 20 (71.4%)
91.5 (83-99.75) 93 (87.25-106.75) 96.5 (84-104) 18.73 (14.98-21.48)
100 (91.25-107.75) 97.5 (89.25-106.75) 104.5 (89.25-108) 17.33 (16.03-21.95) 21 (75%) 7 (25%) 39 (33.5-46.5) 34 (26-40.5) 4 (14.3%) 5 (17.9)
3 (20%)
57.5 (36.25-101) 345.5 (318.75-414.25) 14.25 (8.78-41.84) 17.55 (9.7-29.5)
66 (43-84) 328.5 (305-349.25) 25.44 (16.66-42.76) 20.4 (14.65-28.9)
P .408 .507 .172 .716 .224 .990
.680
.740 .109 .441 .167
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index; EEG, electroencephalography; WISC-R, Wechsler Intelligence Scale for Children-Revised. Data are presented as median (25-75 percentiles), unless otherwise noted.
Mann–Whitney U tests were used to compare variables of patients. Categorical variables were compared by the chi-square test. Correlation analyses were performed using Spearman’s coefficients, according to variable distribution. Regression analysis was employed to assess correlations between studied parameters. Data were expressed as median (25-75 percentiles). A P value less than .05 was accepted as statistically significant.
Results Demographic, cognitive, clinical (ADHD subtypes and Conner scores) variables, EEG abnormalities, and serum iron parameters of the children participating in the study are shown in Table 1. None of the subjects diagnosed with ADHD and controls showed intellectual deficit; there was no significant difference between the groups by means of IQ. An abnormal EEG was observed in 17.9% of children with ADHD. There was no difference in serum iron parameters between ADHD children and controls. Table 2 includes sleep disorders as reported by clinical interview, and Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale results. Subjective data on sleep habits and disturbances provided information mainly on chronic sleep onset insomnia (P < .001) and sleep talking (P ¼ .001), which were higher in the ADHD group compared to controls. Although more children in the ADHD group subjectively reported restless legs syndrome, the difference was not statistically significant. Similarly, slightly more children with ADHD had positive family history for restless legs syndrome, although the difference between the groups was not statistically significant (Table 2). Pittsburgh Sleep Quality Index total score was significantly higher in the ADHD group compared to controls. Sleep latency
was higher and sleep efficiency was lower in children diagnosed with ADHD. Epworth Sleepiness Scale scores were higher in the ADHD group. Table 3 shows the comparison of macrostructural sleep parameters between children with ADHD and normal controls. The sleep architecture did not differ significantly between the groups, with the exception of percentage of REM sleep, which was higher in the ADHD group. There was no statistical difference in terms of apnea–hypopnea index between both groups, although more children in the ADHD group had apnea–hypopnea index > 1 by polysomnography. On the other hand, children diagnosed with ADHD had lower SpO2 and NREM SpO2. Periodic limb movement index was higher in the ADHD group (P ¼ .024). However, it was not statistically different between the groups when periodic limb movement index > 5 per hour of sleep was applied as a cutoff, a value generally considered abnormal in children. Table 4 shows the comparisons of microstructural sleep parameters between children diagnosed with ADHD and normal controls. Children diagnosed with ADHD had lower cyclic alternating pattern rate % in total NREM and also N2, reduced A1 index in N2, shorter sequences mean duration, and lower cyclic alternating pattern rate A1. Compared to children without sleep onset insomnia, ADHD children with sleep onset insomnia had reduced mean duration of sequences (3.7 [3.25] vs 5.75 [3.55-7.33], P ¼ .043). Although sleep onset insomnia positive children also had lower cyclic alternating pattern rate % in total NREM and N2, the differences were not statistically significant (cyclic alternating pattern rate % in total NREM: 46.8 [18.5-58.2] vs 60.65 [30.6-65.73], P ¼ .052; cyclic alternating pattern rate % in N2: 46.2 [22.1-61.6] vs 59.65 [35.08-70.23], P ¼ .056).
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
4
Journal of Child Neurology
Table 2. Results of Subjective Studies for Sleep. Control (n ¼15) Confusional arousal Chronic sleep onset insomnia Night terror Sleep talking Bruxism Motor restlessness Snoring Restless leg syndrome Family history for RLS PSQI Total sleep quality score Sleep latency (min) Sleep efficiency (%) ESS score
Table 3. Comparison of Sleep Macrostructural Parameters in Children With ADHD and Controls.
ADHD (n ¼28)
0 0
7 (25%) 15 (53.6%)
0 1 2 4 2 1 1
2 17 12 15 9 9 7
(6.7%) (13.3%) (26.7%) (13.3%) (6.7%) (6.7%)
2 (1-3)
Control (n ¼15)
P .077 1)
ADHD (n ¼28)
P
473.3 (455.3-494.3) 460.85 (429.28-487.9)
.296
424.2 (358.1-457.5) 432.25 (376.25-457.45)
.558
12.95 (7.08-26.7)
.565
10.95 (5.25-31.28)
14.2 (7.2-29.4) 8.15 (3.58-27.43) 25.1 (8.2-30.8) 12.45 (4.88-32.73) 39.4 (20.2-67.9) 25.55 (13.5-41.75) 163 (96-237) 253 (165.38-307.75) 3.5 (2.5-7.5) 4.75 (2.63-7.25) 0.9 (0.6-2) 1.05 (0.58-1.88) 218.5 (164-254) 208.75 (147.13-266.38) 53.6 (44-60.3) 51.6 (37.53-65.88) 120 (104.5-168.5) 154.45 (104-203.85) 33.5 (24.9-39.4) 35.15 (26.6-47.25) 44 (33-69) 31.25 (21.33-56.5) 12.8 (9.6-14.5) 8.35 (4.53-12.73) 87 (71.2-92) 88.8 (82.6-96.55)
.126 .226 .114 .05 .838 .929 .899 .999 .194 .221 .053 .015 .181
0.1 (0-0.3) 97.9 (97.4-98) 98 (97.85-98.1) 97.9 (97.4-98)
0.25 (0-0.6) 97.1 (96.35-97.88) 98.05 (97-98.15) 97.05 (96.53-98.88)
.499 .006 .927 .007
98.2 (98-98.6) 1.6 (0-4.6) 4 (26.7%) 1 (6.7%)
97.75 (96.90-97.18) 3.95 (1.73-8.23) 10 (35.7%) 5 (17.9%)
.038 .024 .735 .403
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AHI, apnea– hypopnea index; PLMI, periodic limb movement index; REM, rapid eye movement; TST, total sleep time. Data are presented as median (25-75 percentiles), unless otherwise noted.
with ADHD. Gruber et al22 have suggested that the major differences between children with or without ADHD might be related to a difficulty the regulating and organizing the sleep-wake rhythms, which in turn would determine the irregularity of their arousal levels. The results revealed a higher modified Epworth Sleepiness Scale scores in children diagnosed with ADHD, suggesting that they were sleepier during the day than control children. Partly inconsistent results between the subjective and objective tests observed in this study by means of sleep efficiency, sleep latency and the sleep disorders might be possibly attributable to night-to night variability. In fact, it has been repeatedly observed that subjective data on sleep disturbance and objectively established facts and figures in children diagnosed with ADHD can vary.4,23,24 Two studies reported different results on the analysis of sleep microstructure in children with ADHD. Miano et al9 reported a lower cyclic alternating pattern rate and a lower
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
Akinci et al
5
Table 4. Comparison of Sleep Microstructural Parameters in Children With ADHD and Controls
CAP rate, % In total NREM In N1 In N2 In N3 CAP rate A1 CAP rate A2 CAP rate A3 A1 index, n/h In N1 In N2 In N3 A2 index, n/h In N1 In N2 In N3 A3 index, n/h In N1 In N2 In N3 A mean duration, s B mean duration, s Sequences (n) Sequences mean duration, s
Control (n ¼15)
ADHD (n ¼28)
P
61.1 (37.8-66.35) 6.1 (1.15-22.4) 67.3 (44.4-70.8) 49.2 (33.5-67.55) 48 (29.35-55.15) 6.2 (2.6-10.35) 2.7 (1.35-4.6) 66.2 (40.45-81.85) 0 (0-12.85) 65.9 (39.8-83.6) 70.7 (45.3-86.75) 7.6 (3.8-13.2) 0 (0-0) 12.4 (7.1-16.5) 1.7 (0.2-3.85) 2.8 (1.75-6.2) 8.6 (0-21) 4.8 (2.1-9) 0 (0-1) 6.4 (5.85-8.55) 19 (17.85-20.95) 30 (24-41.5) 6 (4.05-7.7)
48.95 (19.25-59.65) 0 (0-22.6) 48.8 (22.38-62.05) 47.3 (18.43-56.63) 39.55 (17.83-47.08) 4.85 (1.38-6.93) 1.45 (0.5-3.45) 53 (21.48-69.5) 0 (0-2.4) 46.75 (23.83-60.18) 60.1 (25.08-78.05) 6.25 (1.73-10.3) 0 (0-2.1) 8.9 (2.35-16.18) 1.25 (0.33-4.58) 2 (0.8-5.08) 0 (0-0) 3.6 (1.13-9) 0 (0-0.95) 6.75 (5.93-8.03) 19.85 (17.95-23.95) 32 (15.75-39.75) 3.95 (3.2-6.75)
.031 .217 .019 .353 .025 .186 .090 .058 .407 .033 .249 .249 .648 .226 .989 .249 .187 .338 .772 .688 .260 .750 .044
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CAP, cyclic alternating pattern; NREM, non–rapid eye movement. Data were presented as median (25-75 percentiles), unless otherwise noted.
number of cyclic alternating pattern sequences in the ADHD group, suggesting that the microstructure of sleep was altered in children with ADHD. Their findings supported the hypothesis of the existence of a hypoarousal state in these patients. After all, they speculated that intrinsic sleep problems specific to ADHD might play a role in the etiology of ADHD. On the other hand, in the following study, Prihodova et al10 reported no significant alteration in sleep microstructure in children with ADHD. As for the microstructure of sleep, they were not able to confirm the hypothesis of a disorder of arousal mechanisms, conflicting with the former study. In this study, the authors showed that total cyclic alternating pattern rate and cyclic alternating pattern sequences mean duration were reduced in children diagnosed with ADHD, mostly because of the low cyclic alternating pattern rate during sleep stage 2. This reduction was associated with a selective decrease of A1 index during stage 2 NREM, in consistent with the study of Miano et al.9 Considering that A1 subtype, which is involved in the build-up and maintenance of deep NREM sleep, has a protective role for sleep continuity, the significant decrease in A1 cyclic alternating pattern subtypes might present a characteristic feature for ADHD. The cyclic alternating pattern changes observed in the ADHD group in this study seem to be similar to changes, which Ferri et al25 reported recently in narcoleptic patients, who displayed reduced cyclic alternating pattern rate and a low percentage/number of A1 subtypes. These similarities also can
support the hypothesis of that insufficient vigilance is the underlying pathology in ADHD and excessive motor activity is seen as a strategy to stay awake and alert. Lower cyclic alternating pattern rate during stage 2 NREM was also reported in Fragile X patients previously.26 Cyclic alternating pattern alterations observed in children with ADHD might link to a deficit of executive functions as it is the case for patients with Fragile X syndrome. Although the incidence of sleep disordered breathing, which was defined as apnea–hypopnea index > 1, showed no significant difference between the groups, SpO2 in total sleep was decreased mostly because of NREM SpO2 in children with ADHD. Pittsburgh Sleep Quality Index total score was significantly correlated with SpO2 and NREM SpO2, and modified Epworth Sleepiness Scale scores was correlated with apnea– hypopnea index. Several studies have reported that children with ADHD can have a mild form of sleep disordered breathing.5,27-29 Evidence suggests that intermittent hypoxia during sleep is the main causes of the diurnal neurocognitive consequences which are observed in subjects with obstructive sleep apnea syndrome (OSAS).30,31 However, since the authors chose apnea–hypopnea index > 1 as the cut-off value for abnormality and yet found no difference between children diagnosed with ADHD and controls, the authors cannot support this hypothesis. Furthermore, we should note that, although statistically significant, the difference in NREM SpO2 was very slight between the 2 groups making it doubtful if the difference in NREM SpO2 observed in this study had a clinical translation.
Conclusion By using both subjective and objective tests, the authors were able to show that children diagnosed with ADHD had impaired sleep quality even in the absence of any medication. Cyclic alternating pattern scoring would provide a further insight to obtain a better understanding of the sleep structure in children diagnosed with ADHD. Author Contributions The manuscript was prepared by GA. Objective sleep studies were conducted and interpreted by GA, IO, and OA. Subjective studies and neurological assessments were done by GA and SH. Psychiatric evaluation was done by DK, HO, and AA. Mentors were SH, IO, and AA.
Acknowledgments The authors would like to acknowledge the children and parents who participated in this study.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Dokuz Eylul University Scientific Research Projects (2010KBSAG047).
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
6
Journal of Child Neurology
Ethical Approval The protocol was approved by the local Ethics Committee of the Medical Faculty of Dokuz Eylul University (2010-12/18).
16.
References 1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942-948. 2. International Classification of Sleep Disorders. Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association; 2000. 4. O’Brien LM, Ivanenko A, Crabtree VM, et al. Sleep disturbances in children with attention deficit hyperactivity disorder. Pediatr Res. 2003;54(2):237-243. 5. O’Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity disorder. Pediatrics. 2003;111(3):554-563. 6. Cortese S, Faraone SV, Konofal E, Lecendreux M. Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies. J Am Acad Child Adolesc Psychiatry. 2009;48(9):894-908. 7. Terzano MG, Gatti PL, Manzoni GC, Formentini E, Mancia D. Is the EEG cyclic alternating pattern a true autonomous entity? Analytic study in a case of post-traumatic coma with good prognosis. Eur Neurol. 1982;21(5):324-334. 8. Terzano MG, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med. 2001;2(6):537-553. 9. Miano S, Donfrancesco R, Bruni O, et al. NREM sleep instability is reduced in children with attention-deficit/hyperactivity disorder. Sleep. 2006;29(6):797-803. 10. Prihodova I, Paclt I, Kemlink D, Nevsimalova S. Sleep microstructure is not altered in children with attention-deficit/hyperactivity disorder (ADHD). Physiol Res. 2012;61(1):125-133. 11. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. J Child Neurol. 1998;13(12):588-594. 12. Picchietti DL, Underwood DJ, Farris WA, et al. Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord. 1999;14(6):1000-1007. 13. Agargun MY, Kara H, Anlar O. The validity and reliability of the Pittsburgh Sleep Quality Index. Turk Psikiyatri Derg. 1996;7: 107-115. 14. Erdem E, Ersu R, Karadag B, et al. Effect of night symptoms and disease severity on subjective sleep quality in children with noncystic-fibrosis bronchiectasis. Pediatr Pulmonol. 2011;46(9):919-926. 15. Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in
17.
18.
19.
20.
21.
22.
23.
24.
25.
26. 27.
28.
29.
30. 31.
children: a randomized placebo-controlled trial. J Child Neurol. 2001;16(2):86-92. Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003;42(11):1286-1293. AASM Manual for the Scoring of Sleep and Associated Events. Rules, Terminology and Technical Specifications. Darien, IL: American Academy of Sleep Medicine; 2007. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med. 1996;153(2):866-878. Marcus CL, Omlin KJ, Basinki DJ, et al. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis. 1992;146(5 pt 1):1235-1239. Zucconi M, Ferri R, Allen R, et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2006;7(2):175-183. Bruni O, Novelli L, Miano S, Parrino L, Terzano MG, Ferri R. Cyclic alternating pattern: a window into pediatric sleep. Sleep Med. 2010;11(7):628-636. Gruber R, Sadeh A, Raviv A. Instability of sleep patterns in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(4):495-501. Corkum P, Tannock R, Moldofsky H. Sleep disturbances in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1998;37(6):637-646. Owens JA, Maxim R, Nobile C, McGuinn M, Msall M. Parental and self-report of sleep in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2000;154(6):549-555. Ferri R, Miano S, Bruni O, et al. NREM sleep alterations in narcolepsy/cataplexy. Clin Neurophysiol. 2005;116(11): 2675-2684. Mazzocco MM. Advances in research on the fragile X syndrome. Ment Retard Dev Disabil Res Rev. 2000;6(2):96-106. Walters AS, Silvestri R, Zucconi M, Chandrashekariah R, Konofal E. Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. J Clin Sleep Med. 2008;4(6):591-600. Chervin RD, Dillon JE, Bassetti C, Ganoczy DA, Pituch KJ. Symptoms of sleep disorders, inattention, and hyperactivity in children. Sleep. 1997;20(12):1185-1192. Chervin RD. How many children with ADHD have sleep apnea or periodic leg movements on polysomnography? Sleep. 2005;28(9): 1041-1042. Kheirandish L, Gozal D. Neurocognitive dysfunction in children with sleep disorders. Dev Sci. 2006;9(4):388-399. Chervin RD, Ruzicka DL, Archbold KH, Dillon JE. Snoring predicts hyperactivity four years later. Sleep. 2005;28(7):885-890.
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
Sleep Structure in Children With Attention-Deficit/Hyperactivity Disorder
Journal of Child Neurology 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815573318 jcn.sagepub.com
Gulcin Akinci, MD1, Ibrahim Oztura, MD2, Semra Hiz, MD3, Ozlem Akdogan, MD2, Dilay Karaarslan, MD4, Handan Ozek, MD4, and Aynur Akay, MD4
Abstract The authors evaluated basic sleep architecture and non–rapid eye movement (NREM) sleep alterations in drug-naı¨ve attentiondeficit/hyperactivity disorder (ADHD) children without psychiatric or other comorbidities. This cross-sectional case-control study included 28 drug-naı¨ve children with ADHD and 15 healthy controls. This subjective studies revealed that children with ADHD had a worse sleep quality and increased daytime sleepiness. Polysomnography data showed that the sleep macrostructure was not significantly different in children with ADHD. Sleep microstructure was altered in ADHD children by means of reduced total cyclic alternating pattern rate and duration of cyclic alternating pattern sequences. This reduction was associated with a selective decrease of A1 index during stage 2 NREM. SpO2 in total sleep was slightly decreased; however, the incidence of sleep disordered breathing showed no significant difference. The authors suggest that cyclic alternating pattern scoring would provide a further insight to obtain a better understanding of the sleep structure in children with ADHD. Keywords attention-deficit/hyperactivity disorder, children, sleep, nocturnal polysomnography, cyclic alternating pattern scoring. Received November 2, 2014. Received revised January 21, 2015. Accepted for publication January 24, 2015.
Attention deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric condition, which has an onset at childhood. The worldwide prevalence of ADHD has been estimated to be 5% in school age children.1 ADHD is characterized by the symptoms of inattention, hyperactivity, and/or impulsivity that have an onset before the age of 7, and impaired functioning in 2 or more settings such as at home, at school, and so on. ADHD has 4 subtypes, predominantly inattentive, predominantly hyperactive/impulsive, a combination of both and not otherwise specified.2,3 Although questionnaire studies suggest that sleep problems are very common in children with ADHD, the results of objective studies are heterogeneous.4-6 Furthermore, the relationship between sleep disorders and ADHD is still poorly understood. Besides, very limited data is available on the microstructure of sleep in children with ADHD. Arousals are a very important part of the sleep microstructure and its fluctuations without awakenings have been demonstrated in cyclic alternating pattern, an endogenous rhythm characterized by a periodic electroencephalography (EEG) activity with sequences of transient arousal complexes (phase A) that are distinct from the background EEG activity (phase B) of non–rapid eye movement (NREM). Cyclic alternating pattern analyses encompass the process of sleep maintenance and provide information on the time structure of these events and allow a better
understanding of sleep disturbances and neurophysiological mechanisms.7,8 Two studies so far have evaluated sleep microstructure with cyclic alternating pattern in children with ADHD.9,10 However, these 2 studies reported conflicting results. While Miano et al9 found a lower cyclic alternating pattern rate and a lower number of cyclic alternating pattern sequences in children with ADHD, Prihodova et al10 reported no significant alteration in sleep microstructure. In this study, the authors have aimed to evaluate sleep macrostructure and microstructure in children with ADHD. The authors have hypothesized that a comprehensive analysis of sleep structure including the cyclic alternating pattern
1
Department of Pediatric Neurology, Dr Behcet Uz Children’s Hospital, Izmir, Turkey 2 Sleep Disease Center, Department of Neurology, Dokuz Eylul University, Izmir, Turkey 3 Division of Pediatric Neurology, Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey 4 Department of Child and Adolescent Psychiatry, Dokuz Eylul University, Izmir, Turkey Corresponding Author: Gulcin Akinci, MD, Department of Pediatric Neurology, Dr Behcet Uz Children’s Hospital, Izmir 35210, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
2
Journal of Child Neurology
analysis can provide new information on the association of ADHD and sleep disturbances.
Methods Subjects Twenty-eight ADHD children (20 boys and 8 girls; age range 8-12 years, median age 10), who were consecutively referred to the Departments of Child and Adolescent Psychiatry and Pediatric Neurology at Dokuz Eylul University from September 2010 to August 2011, were included. All patients were independently examined by 2 child psychiatrists, and fulfilled the ADHD inclusion criteria according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Twenty-one children presented the hyperactive or combined type (75%) and 7 the inattentive type (25%). Patients were excluded if they received any pharmacological treatment for ADHD, if they have a history of any chronic physical condition, or neurological or other psychiatric disorders or being administered with any type of medication. To avoid potential selection biases, prestudy sleep behavior was not a selection criterion. A control group was formed by 15 healthy children matched for age, sex, and intelligence quotient (IQ) (9 boys and 6 girls, age range 9-13 years, median age 10). The diagnosis of ADHD was ruled out according to Diagnostic and Statistical Manual of Mental Disorders criteria in healthy controls. All participants were in the prepubertal or early pubertal stages as assessed by the Tanner scale (Tanner stage 1-2). All 28 children diagnosed with ADHD and their parents underwent a semistructured psychiatric interview (Kiddie-SADS), Conners’ Teacher Rating Scale, Conners’ Parents Rating Scale. The IQ level was assessed by the Wechsler Intelligence Scale for Children-Revised. Subjects were excluded if they had an IQ score less than 70. The histories reported by the parents were used to record the general demographic data. To question sleep habits and disturbances, children and their parents were invited for a clinical appointment. A detailed structured interview with a questionnaire of sleep habits and parasomnias was conducted. Parents were asked to fulfill the Pittsburgh Sleep Quality Index questionnaire and modified Epworth Sleepiness Scale for their children. Several studies have suggested that children with ADHD are more likely to have restless legs syndrome than healthy children.11,12 To evaluate this possible association, a specific diagnostic interview for restless legs syndrome was applied. Subjective assessment of sleep was determined with the Pittsburgh Sleep Quality Index questionnaire. The Pittsburgh Sleep Quality Index questionnaire assesses sleep quality subjectively from good to poor sleep. A total score greater than 5 indicates poor sleep. The Pittsburgh Sleep Quality Index has been translated to Turkish and validated both for adults and children.13,14 Daytime sleepiness symptoms were evaluated by the modified Epworth Sleepiness Scale. The Epworth Sleepiness Scale is an 8-item questionnaire with scores ranging from 0 to 24. An Epworth Sleepiness Scale score of 10 indicates increased daytime sleepiness in adults. The test can be used in children with minor modifications. All subjects were questioned for chronic sleep onset insomnia, which was defined regarding to previous studies.15,16 After completing clinical evaluation and questionnaires in the Department of Child Neurology, all patients were sent to the Sleep Disease Center at Dokuz Eylul University. Patients were given an appointment for the sleep study. Children and their parents were invited for an adaptation visit before the real test. No records were taken at the
adaptation night. At the study night, patients were asked to sleep at their usual bedtime and recordings continued until spontaneous awakening. The records were done for 1 night. A video polysomnography, including 10 EEG leads (10-20 International System), electro-oculography, submental and bilateral tibialis EMGs, electrocardiography (1 derivation), oro-nasal air flow (by thermistors and nasal cannulas), thoracic and abdominal pneumograms (by strain gauges), oxygen saturation (pulse-oxymetry), and video-recording using an infra-red light camera were applied. Polysomnography recordings were performed using a commercial recording system (S4000, Embla Systems Inc., Broomfield, CO, USA) and sleep diagnostic software (RemLogic 2.0, Embla Systems Inc., Broomfield, CO, USA). This protocol was approved by the local Ethics Committee of the Medical Faculty of Dokuz Eylul University, and a written consent was given by the parents of each subject.
Sleep Macrostructure Sleep stages were visually scored in accordance with the 2007 AASM Manual for Scoring Sleep.17 Total sleep time, sleep efficiency, percentage and latencies of sleep stages, sleep-onset latency, and REM sleep latency were recorded. Apneas and hypopneas were scored. The apnea–hypopnea index was determined.18 Apnea–hypopnea index > 1 was considered as abnormal.19 Periodic limb movements were scored according to ICSD-2 criteria.2 However, the duration was defined as 0.5-10 s. as recommended by the American Academy of Sleep Medicine and the International Restless Legs Syndrome Study Group.20 The periodic limb movement index was recorded as the number of periodic limb movements per hour during the sleep. A periodic limb movement index greater than 5 was considered abnormal as previously reported.2 All recordings were read by 2 independent neurologists with specific sleep and EEG reading expertise to obtain detailed video-EEG/polygraphic reports.
Sleep Microstructure Cyclic alternating pattern is described as an endogenous rhythm in NREM sleep which consists of arousals fluctuations without awakenings.7,8 Cyclic alternating pattern is characterized by a periodic EEG activity with sequences of transient electrocortical activations which recurs at intervals up to 2 minutes. These sequences have an organized cyclic pattern and repeated several times during the sleep. It is characterized by an EEG transient pattern (phase A of the cycle) separated by intervals of background activity (phase B of the cycle). Subtype A1 is predominantly composed of slow waves (EEG synchrony), while subtype A3 shows fast EEG activities (EEG desynchrony). Subtype A2 is a combination of both.21 It has been proposed that the percentage of cyclic alternating pattern time to NREM sleep time (cyclic alternating pattern rate) can be a physiologic marker of NREM sleep instability.7,8 Noncyclic alternating pattern is characterized by a stable sleep period which is longer than 60 s. without any oscillations. Cyclic alternating pattern scores were recorded as described by Terzano et al.8 The variables were analyzed by RemLogic 2.0 sleep analysis software (Embla Systems Inc., Broomfield, CO, USA). All the recordings were visually scored by the investigators (IO and OA). The sleep parameters derived were used for statistical analyses.
Statistical Analysis Statistical analysis was performed using Statistical Package of Social Science (SPSS Inc, Chicago, IL, USA), version 15.0 for Windows.
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
Akinci et al
3
Table 1. Demographic and Clinical Characteristics of ADHD Patients and Healthy Controls.
Median age Gender, boys % IQ by WISC-R Total IQ Verbal IQ Performance IQ BMI (kg/m2) ADHD subtype (%) Hyperactive and combined Inattentive Conners’ Parents Rating Scale Conners’ Teacher Rating Scale Adenotonsillectomy Abnormal EEG (%) Serum iron parameters Iron level Total iron binding capacity Ferritin Transferrin saturation
Control (n ¼15)
ADHD (n ¼28)
10 (9-13) 9 (60%)
10 (8-12) 20 (71.4%)
91.5 (83-99.75) 93 (87.25-106.75) 96.5 (84-104) 18.73 (14.98-21.48)
100 (91.25-107.75) 97.5 (89.25-106.75) 104.5 (89.25-108) 17.33 (16.03-21.95) 21 (75%) 7 (25%) 39 (33.5-46.5) 34 (26-40.5) 4 (14.3%) 5 (17.9)
3 (20%)
57.5 (36.25-101) 345.5 (318.75-414.25) 14.25 (8.78-41.84) 17.55 (9.7-29.5)
66 (43-84) 328.5 (305-349.25) 25.44 (16.66-42.76) 20.4 (14.65-28.9)
P .408 .507 .172 .716 .224 .990
.680
.740 .109 .441 .167
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index; EEG, electroencephalography; WISC-R, Wechsler Intelligence Scale for Children-Revised. Data are presented as median (25-75 percentiles), unless otherwise noted.
Mann–Whitney U tests were used to compare variables of patients. Categorical variables were compared by the chi-square test. Correlation analyses were performed using Spearman’s coefficients, according to variable distribution. Regression analysis was employed to assess correlations between studied parameters. Data were expressed as median (25-75 percentiles). A P value less than .05 was accepted as statistically significant.
Results Demographic, cognitive, clinical (ADHD subtypes and Conner scores) variables, EEG abnormalities, and serum iron parameters of the children participating in the study are shown in Table 1. None of the subjects diagnosed with ADHD and controls showed intellectual deficit; there was no significant difference between the groups by means of IQ. An abnormal EEG was observed in 17.9% of children with ADHD. There was no difference in serum iron parameters between ADHD children and controls. Table 2 includes sleep disorders as reported by clinical interview, and Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale results. Subjective data on sleep habits and disturbances provided information mainly on chronic sleep onset insomnia (P < .001) and sleep talking (P ¼ .001), which were higher in the ADHD group compared to controls. Although more children in the ADHD group subjectively reported restless legs syndrome, the difference was not statistically significant. Similarly, slightly more children with ADHD had positive family history for restless legs syndrome, although the difference between the groups was not statistically significant (Table 2). Pittsburgh Sleep Quality Index total score was significantly higher in the ADHD group compared to controls. Sleep latency
was higher and sleep efficiency was lower in children diagnosed with ADHD. Epworth Sleepiness Scale scores were higher in the ADHD group. Table 3 shows the comparison of macrostructural sleep parameters between children with ADHD and normal controls. The sleep architecture did not differ significantly between the groups, with the exception of percentage of REM sleep, which was higher in the ADHD group. There was no statistical difference in terms of apnea–hypopnea index between both groups, although more children in the ADHD group had apnea–hypopnea index > 1 by polysomnography. On the other hand, children diagnosed with ADHD had lower SpO2 and NREM SpO2. Periodic limb movement index was higher in the ADHD group (P ¼ .024). However, it was not statistically different between the groups when periodic limb movement index > 5 per hour of sleep was applied as a cutoff, a value generally considered abnormal in children. Table 4 shows the comparisons of microstructural sleep parameters between children diagnosed with ADHD and normal controls. Children diagnosed with ADHD had lower cyclic alternating pattern rate % in total NREM and also N2, reduced A1 index in N2, shorter sequences mean duration, and lower cyclic alternating pattern rate A1. Compared to children without sleep onset insomnia, ADHD children with sleep onset insomnia had reduced mean duration of sequences (3.7 [3.25] vs 5.75 [3.55-7.33], P ¼ .043). Although sleep onset insomnia positive children also had lower cyclic alternating pattern rate % in total NREM and N2, the differences were not statistically significant (cyclic alternating pattern rate % in total NREM: 46.8 [18.5-58.2] vs 60.65 [30.6-65.73], P ¼ .052; cyclic alternating pattern rate % in N2: 46.2 [22.1-61.6] vs 59.65 [35.08-70.23], P ¼ .056).
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
4
Journal of Child Neurology
Table 2. Results of Subjective Studies for Sleep. Control (n ¼15) Confusional arousal Chronic sleep onset insomnia Night terror Sleep talking Bruxism Motor restlessness Snoring Restless leg syndrome Family history for RLS PSQI Total sleep quality score Sleep latency (min) Sleep efficiency (%) ESS score
Table 3. Comparison of Sleep Macrostructural Parameters in Children With ADHD and Controls.
ADHD (n ¼28)
0 0
7 (25%) 15 (53.6%)
0 1 2 4 2 1 1
2 17 12 15 9 9 7
(6.7%) (13.3%) (26.7%) (13.3%) (6.7%) (6.7%)
2 (1-3)
Control (n ¼15)
P .077 1)
ADHD (n ¼28)
P
473.3 (455.3-494.3) 460.85 (429.28-487.9)
.296
424.2 (358.1-457.5) 432.25 (376.25-457.45)
.558
12.95 (7.08-26.7)
.565
10.95 (5.25-31.28)
14.2 (7.2-29.4) 8.15 (3.58-27.43) 25.1 (8.2-30.8) 12.45 (4.88-32.73) 39.4 (20.2-67.9) 25.55 (13.5-41.75) 163 (96-237) 253 (165.38-307.75) 3.5 (2.5-7.5) 4.75 (2.63-7.25) 0.9 (0.6-2) 1.05 (0.58-1.88) 218.5 (164-254) 208.75 (147.13-266.38) 53.6 (44-60.3) 51.6 (37.53-65.88) 120 (104.5-168.5) 154.45 (104-203.85) 33.5 (24.9-39.4) 35.15 (26.6-47.25) 44 (33-69) 31.25 (21.33-56.5) 12.8 (9.6-14.5) 8.35 (4.53-12.73) 87 (71.2-92) 88.8 (82.6-96.55)
.126 .226 .114 .05 .838 .929 .899 .999 .194 .221 .053 .015 .181
0.1 (0-0.3) 97.9 (97.4-98) 98 (97.85-98.1) 97.9 (97.4-98)
0.25 (0-0.6) 97.1 (96.35-97.88) 98.05 (97-98.15) 97.05 (96.53-98.88)
.499 .006 .927 .007
98.2 (98-98.6) 1.6 (0-4.6) 4 (26.7%) 1 (6.7%)
97.75 (96.90-97.18) 3.95 (1.73-8.23) 10 (35.7%) 5 (17.9%)
.038 .024 .735 .403
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AHI, apnea– hypopnea index; PLMI, periodic limb movement index; REM, rapid eye movement; TST, total sleep time. Data are presented as median (25-75 percentiles), unless otherwise noted.
with ADHD. Gruber et al22 have suggested that the major differences between children with or without ADHD might be related to a difficulty the regulating and organizing the sleep-wake rhythms, which in turn would determine the irregularity of their arousal levels. The results revealed a higher modified Epworth Sleepiness Scale scores in children diagnosed with ADHD, suggesting that they were sleepier during the day than control children. Partly inconsistent results between the subjective and objective tests observed in this study by means of sleep efficiency, sleep latency and the sleep disorders might be possibly attributable to night-to night variability. In fact, it has been repeatedly observed that subjective data on sleep disturbance and objectively established facts and figures in children diagnosed with ADHD can vary.4,23,24 Two studies reported different results on the analysis of sleep microstructure in children with ADHD. Miano et al9 reported a lower cyclic alternating pattern rate and a lower
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
Akinci et al
5
Table 4. Comparison of Sleep Microstructural Parameters in Children With ADHD and Controls
CAP rate, % In total NREM In N1 In N2 In N3 CAP rate A1 CAP rate A2 CAP rate A3 A1 index, n/h In N1 In N2 In N3 A2 index, n/h In N1 In N2 In N3 A3 index, n/h In N1 In N2 In N3 A mean duration, s B mean duration, s Sequences (n) Sequences mean duration, s
Control (n ¼15)
ADHD (n ¼28)
P
61.1 (37.8-66.35) 6.1 (1.15-22.4) 67.3 (44.4-70.8) 49.2 (33.5-67.55) 48 (29.35-55.15) 6.2 (2.6-10.35) 2.7 (1.35-4.6) 66.2 (40.45-81.85) 0 (0-12.85) 65.9 (39.8-83.6) 70.7 (45.3-86.75) 7.6 (3.8-13.2) 0 (0-0) 12.4 (7.1-16.5) 1.7 (0.2-3.85) 2.8 (1.75-6.2) 8.6 (0-21) 4.8 (2.1-9) 0 (0-1) 6.4 (5.85-8.55) 19 (17.85-20.95) 30 (24-41.5) 6 (4.05-7.7)
48.95 (19.25-59.65) 0 (0-22.6) 48.8 (22.38-62.05) 47.3 (18.43-56.63) 39.55 (17.83-47.08) 4.85 (1.38-6.93) 1.45 (0.5-3.45) 53 (21.48-69.5) 0 (0-2.4) 46.75 (23.83-60.18) 60.1 (25.08-78.05) 6.25 (1.73-10.3) 0 (0-2.1) 8.9 (2.35-16.18) 1.25 (0.33-4.58) 2 (0.8-5.08) 0 (0-0) 3.6 (1.13-9) 0 (0-0.95) 6.75 (5.93-8.03) 19.85 (17.95-23.95) 32 (15.75-39.75) 3.95 (3.2-6.75)
.031 .217 .019 .353 .025 .186 .090 .058 .407 .033 .249 .249 .648 .226 .989 .249 .187 .338 .772 .688 .260 .750 .044
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CAP, cyclic alternating pattern; NREM, non–rapid eye movement. Data were presented as median (25-75 percentiles), unless otherwise noted.
number of cyclic alternating pattern sequences in the ADHD group, suggesting that the microstructure of sleep was altered in children with ADHD. Their findings supported the hypothesis of the existence of a hypoarousal state in these patients. After all, they speculated that intrinsic sleep problems specific to ADHD might play a role in the etiology of ADHD. On the other hand, in the following study, Prihodova et al10 reported no significant alteration in sleep microstructure in children with ADHD. As for the microstructure of sleep, they were not able to confirm the hypothesis of a disorder of arousal mechanisms, conflicting with the former study. In this study, the authors showed that total cyclic alternating pattern rate and cyclic alternating pattern sequences mean duration were reduced in children diagnosed with ADHD, mostly because of the low cyclic alternating pattern rate during sleep stage 2. This reduction was associated with a selective decrease of A1 index during stage 2 NREM, in consistent with the study of Miano et al.9 Considering that A1 subtype, which is involved in the build-up and maintenance of deep NREM sleep, has a protective role for sleep continuity, the significant decrease in A1 cyclic alternating pattern subtypes might present a characteristic feature for ADHD. The cyclic alternating pattern changes observed in the ADHD group in this study seem to be similar to changes, which Ferri et al25 reported recently in narcoleptic patients, who displayed reduced cyclic alternating pattern rate and a low percentage/number of A1 subtypes. These similarities also can
support the hypothesis of that insufficient vigilance is the underlying pathology in ADHD and excessive motor activity is seen as a strategy to stay awake and alert. Lower cyclic alternating pattern rate during stage 2 NREM was also reported in Fragile X patients previously.26 Cyclic alternating pattern alterations observed in children with ADHD might link to a deficit of executive functions as it is the case for patients with Fragile X syndrome. Although the incidence of sleep disordered breathing, which was defined as apnea–hypopnea index > 1, showed no significant difference between the groups, SpO2 in total sleep was decreased mostly because of NREM SpO2 in children with ADHD. Pittsburgh Sleep Quality Index total score was significantly correlated with SpO2 and NREM SpO2, and modified Epworth Sleepiness Scale scores was correlated with apnea– hypopnea index. Several studies have reported that children with ADHD can have a mild form of sleep disordered breathing.5,27-29 Evidence suggests that intermittent hypoxia during sleep is the main causes of the diurnal neurocognitive consequences which are observed in subjects with obstructive sleep apnea syndrome (OSAS).30,31 However, since the authors chose apnea–hypopnea index > 1 as the cut-off value for abnormality and yet found no difference between children diagnosed with ADHD and controls, the authors cannot support this hypothesis. Furthermore, we should note that, although statistically significant, the difference in NREM SpO2 was very slight between the 2 groups making it doubtful if the difference in NREM SpO2 observed in this study had a clinical translation.
Conclusion By using both subjective and objective tests, the authors were able to show that children diagnosed with ADHD had impaired sleep quality even in the absence of any medication. Cyclic alternating pattern scoring would provide a further insight to obtain a better understanding of the sleep structure in children diagnosed with ADHD. Author Contributions The manuscript was prepared by GA. Objective sleep studies were conducted and interpreted by GA, IO, and OA. Subjective studies and neurological assessments were done by GA and SH. Psychiatric evaluation was done by DK, HO, and AA. Mentors were SH, IO, and AA.
Acknowledgments The authors would like to acknowledge the children and parents who participated in this study.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Dokuz Eylul University Scientific Research Projects (2010KBSAG047).
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
6
Journal of Child Neurology
Ethical Approval The protocol was approved by the local Ethics Committee of the Medical Faculty of Dokuz Eylul University (2010-12/18).
16.
References 1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942-948. 2. International Classification of Sleep Disorders. Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association; 2000. 4. O’Brien LM, Ivanenko A, Crabtree VM, et al. Sleep disturbances in children with attention deficit hyperactivity disorder. Pediatr Res. 2003;54(2):237-243. 5. O’Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity disorder. Pediatrics. 2003;111(3):554-563. 6. Cortese S, Faraone SV, Konofal E, Lecendreux M. Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies. J Am Acad Child Adolesc Psychiatry. 2009;48(9):894-908. 7. Terzano MG, Gatti PL, Manzoni GC, Formentini E, Mancia D. Is the EEG cyclic alternating pattern a true autonomous entity? Analytic study in a case of post-traumatic coma with good prognosis. Eur Neurol. 1982;21(5):324-334. 8. Terzano MG, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med. 2001;2(6):537-553. 9. Miano S, Donfrancesco R, Bruni O, et al. NREM sleep instability is reduced in children with attention-deficit/hyperactivity disorder. Sleep. 2006;29(6):797-803. 10. Prihodova I, Paclt I, Kemlink D, Nevsimalova S. Sleep microstructure is not altered in children with attention-deficit/hyperactivity disorder (ADHD). Physiol Res. 2012;61(1):125-133. 11. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. J Child Neurol. 1998;13(12):588-594. 12. Picchietti DL, Underwood DJ, Farris WA, et al. Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord. 1999;14(6):1000-1007. 13. Agargun MY, Kara H, Anlar O. The validity and reliability of the Pittsburgh Sleep Quality Index. Turk Psikiyatri Derg. 1996;7: 107-115. 14. Erdem E, Ersu R, Karadag B, et al. Effect of night symptoms and disease severity on subjective sleep quality in children with noncystic-fibrosis bronchiectasis. Pediatr Pulmonol. 2011;46(9):919-926. 15. Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in
17.
18.
19.
20.
21.
22.
23.
24.
25.
26. 27.
28.
29.
30. 31.
children: a randomized placebo-controlled trial. J Child Neurol. 2001;16(2):86-92. Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003;42(11):1286-1293. AASM Manual for the Scoring of Sleep and Associated Events. Rules, Terminology and Technical Specifications. Darien, IL: American Academy of Sleep Medicine; 2007. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med. 1996;153(2):866-878. Marcus CL, Omlin KJ, Basinki DJ, et al. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis. 1992;146(5 pt 1):1235-1239. Zucconi M, Ferri R, Allen R, et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2006;7(2):175-183. Bruni O, Novelli L, Miano S, Parrino L, Terzano MG, Ferri R. Cyclic alternating pattern: a window into pediatric sleep. Sleep Med. 2010;11(7):628-636. Gruber R, Sadeh A, Raviv A. Instability of sleep patterns in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(4):495-501. Corkum P, Tannock R, Moldofsky H. Sleep disturbances in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1998;37(6):637-646. Owens JA, Maxim R, Nobile C, McGuinn M, Msall M. Parental and self-report of sleep in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2000;154(6):549-555. Ferri R, Miano S, Bruni O, et al. NREM sleep alterations in narcolepsy/cataplexy. Clin Neurophysiol. 2005;116(11): 2675-2684. Mazzocco MM. Advances in research on the fragile X syndrome. Ment Retard Dev Disabil Res Rev. 2000;6(2):96-106. Walters AS, Silvestri R, Zucconi M, Chandrashekariah R, Konofal E. Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. J Clin Sleep Med. 2008;4(6):591-600. Chervin RD, Dillon JE, Bassetti C, Ganoczy DA, Pituch KJ. Symptoms of sleep disorders, inattention, and hyperactivity in children. Sleep. 1997;20(12):1185-1192. Chervin RD. How many children with ADHD have sleep apnea or periodic leg movements on polysomnography? Sleep. 2005;28(9): 1041-1042. Kheirandish L, Gozal D. Neurocognitive dysfunction in children with sleep disorders. Dev Sci. 2006;9(4):388-399. Chervin RD, Ruzicka DL, Archbold KH, Dillon JE. Snoring predicts hyperactivity four years later. Sleep. 2005;28(7):885-890.
Downloaded from jcn.sagepub.com at RUTGERS UNIV on April 9, 2015
