Original Article

Relationship Between Polysomnographic Sleep Architecture and Behavior in Medication-free Children with TS, ADHD, TS and ADHD, and Controls Robyn J. Stephens, PhD, C. Psych,*†‡§ Sharon A. Chung, PhD,*\ Dragana Jovanovic, BSc, RPSGT,‡ Randy Guerra, MD,* Brandon Stephens, BA,* Paul Sandor, MD,*†§\ Colin M. Shapiro, PhD, MD†‡\ ABSTRACT: Objective: To describe the relationship between sleep architecture and behavioral measures in unmedicated children and adolescents with Tourette syndrome (TS), attention-deficit hyperactivity disorder (ADHD), TS and comorbid ADHD (TS 1 ADHD), and healthy controls. The study also set out to examine differences in sleep architecture with each diagnosis. Method: A cross-sectional, 2-night consecutive polysomnographic sleep study was conducted in 90 children. All participants were matched for age, gender, and level of intelligence. Results: Scores on the Child Behavior Checklist delinquency measure were modestly but significantly correlated with the number of movements during REM sleep (r 5 .36, p 5 .003). Significant correlations were also noted among the number of total arousals and arousals from slow wave sleep (SWS), and scores on the measures of conduct disorder, hyperactivity/immaturity, and restless/disorganized behaviors. There were a few significant differences in sleep architecture among the diagnostic groups. The ADHD-only group exhibited a significantly higher number of total arousals (p < .01) and arousals from SWS (p < .01) compared with the other three study groups. Discussion: Our findings indicate that children with TS and/or ADHD and who have more arousals from sleep are significantly more likely to have issues with conduct disorder, hyperactivity/immaturity, and restless/disorganized behavior. It was also noted that having ADHD, alone or comorbid with TS, is associated with a significantly greater number of movements during both non-REM and REM sleep. This study underscores the compelling need for the diagnosis and treatment of any sleep disorders in children with TS and/or ADHD so as to facilitate better management of problem behaviors. (J Dev Behav Pediatr 34:688–696, 2013) Index terms: ADHD, Tourette syndrome, sleep, behavior, polysomnographic, unmedicated.

P

roblem behaviors in children can be a result of or exacerbated by disrupted sleep. This reasoning is based on several lines of evidence. Poor sleep has been strongly linked with deregulation of emotion and difficulty with impulse modulation, even in children with no history of behavioral problems.1 Sleep-disordered breathing, restless legs syndrome, or disturbed sleep in children can present with hyperactivity, inattention, and temper outbursts and mimic attention-deficit hyperactivity disorder (ADHD).2 Lastly, behavioral issues and attentional difficulties secondary to problems with sleep can resolve with treatment of the pediatric sleep disorder.2

From the *Youthdale Treatment Centres, Toronto, ON, Canada; †Department of Psychiatry, University of Toronto, Toronto, ON, Canada; ‡Youthdale Child and Adolescent Sleep Centre, Toronto, ON, Canada; §Tourette’s Syndrome Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; \Department of Psychiatry, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. Received March 2013; accepted August 2013. Disclosure: The authors declare no conflict of interest. Address for reprints: Sharon Chung, PhD, Youthdale Treatment Centers, 227 Victoria Street, Toronto, ON M5B 1T8, Canada; e-mail: [email protected]. Copyright Ó 2013 Lippincott Williams & Wilkins

688 | www.jdbp.org

Disorders of sleep in children remain a significantly undertreated public health problem worldwide. Although the exact function of sleep is not known, numerous associations have been observed between the amount and quality of sleep in children and disturbances in regulation of attention and arousal.1,3 Historically, research into pediatric sleep medicine has focused on nighttime behaviors, parasomnias, bedtime routines, and the interactions between the child and their parents. However, more recently, there has been growing movement toward recognizing that not only are sleep disorders common in children but that the presentation in children, compared with adults, can differ significantly. Improvements in sleep quality resulting from treatment of a sleep disorder have been shown to manifest in better functional daytime behavior and improved quality of life.4 The field of pediatric sleep medicine demands well-designed investigations of the relationship between sleep architecture and corresponding daytime maladaptive behavior in children with the goal toward a clearer understanding of clinical risk factors, to provide a more comprehensive and accurate diagnosis, to better understand the pathophysiology of the disorders, and to design and implement the most effective treatments. Journal of Developmental & Behavioral Pediatrics

A large international database notes that 55% of children clinically referred for Tourette syndrome (TS) also meet criteria for comorbid ADHD.5 Problems with sleep are considered to be an integral part of the ADHD psychopathology3,6 with a 25% to 43% prevalence of sleep disorders. Although there is substantial evidence that sleep architecture disturbances exist in children with ADHD, no specific sleep disorder has been clearly or consistently identified.7 It is possible that the differing reports of sleep in children with ADHD may be in part accounted for by methodological differences in the studies, including the use of medication, inclusion of wide age ranges, inconsistencies in the definition and diagnoses of ADHD, the presence of comorbidities, the number of nights of polysomnographic (PSG) sleep studies and gender distribution. Each of the above variables may potentially compromise the findings of previous studies. Despite the variability in the reported results, the prevalence of increased periodic leg movements (PLMs) in ADHD compared with controls has emerged as the singular significant global effect.8 This suggests a possible association between PLM and hyperactivity,9 although no direct relationship has been documented. Interestingly, despite the relatively higher frequency of obstructive sleep apnea and PLM in children with ADHD,10 parental reports of poor or disturbed sleep remain largely unsubstantiated with overnight sleep polysomography.11 In the TS population, clinical complaints of sleep problems are reported in about 1 in 4 children12 with rates increased to 65% when TS is comorbidly diagnosed with ADHD.12,13 A report describing the sleep characteristics of children with TS 1 comorbid ADHD (TS 1 ADHD),7 reported shorter REM latency and increased percentage of REM sleep in the TS 1 ADHD group compared with matched controls. Additionally, increased movements during sleep Stages 1 and 2 were noted in the clinical group.7 The interpretation of these results are problematic because of the potential REM rebound effects of the medications listed for 12 of the 19 children in the clinical group (ADHD and TS 1 ADHD).7 This study was designed to overcome the methodological and clinical issues identified in previous PSG studies, including applying comprehensive and rigorous diagnostic criteria, recruiting children who were medication naive or medication free for a minimum of 6 weeks, and maintaining a consistent group age distribution and a gender representation within each group reflective of the general and clinical populations. This study set out to examine the sleep in children with TS. This study included children with TS with and without ADHD because of the high degree of comorbidity between TS and ADHD and the presence of sleep problems and aggression in both of these populations. In addition to healthy controls, we also included a group of children with only ADHD (without tics) to tease out the possible separate contributions of ADHD versus TS 1 ADHD to abnormal sleep. In essence, we set out to explore Vol. 34, No. 9, November/December 2013

whether there are sleep and behavioral issues in the TS versus TS 1 ADHD groups, whether findings differ based on diagnosis, and if there was any association between PSG sleep findings and the frequency of tics. Our main hypotheses were (1) There would be sleep architectural abnormalities among the study groups, and (2) abnormal/non-restorative sleep may contribute to daytime irritability and aggressive behavior.

METHODS Recruitment A research assistant approached the parents/guardians of the children who were referred to the Toronto Western Hospital Tourette Syndrome Clinic with a primary diagnosis of Tourette Syndrome (TS) (with/without attention-deficit hyperactivity disorder [ADHD]) and provided them with information about this study. Subjects with a single diagnosis of ADHD were referred by community pediatricians and by the physicians at the Child Health Unit at the Toronto Western Hospital. Healthy controls were recruited from the Child Health Unit at the Toronto Western Hospital, by local family physicians and pediatricians, and through self-referral in response to posters placed in the community and within referring physician offices. All participants were matched for age, gender, and level of intelligence.

Subjects All subjects and their parents were proficient in English language (sufficient to understand and to respond to questions from the investigators). Inclusion criteria for the TS group, ADHD, and TS 1 ADHD groups were based on the diagnostic criteria according to DSM-3-R.14 Subjects with evidence of pervasive developmental disorder, established seizure disorder, history of severe head trauma, post-traumatic stress disorder, depression, or an estimated Full Scale Intellectual Quotient below 80 were excluded from the study. Subjects with complaints of poor or disturbed sleep but who had not been diagnosed with or received treatment for a sleep disorder (e.g., obstructive sleep apnea, insomnia, etc.) were included in the study. Joint research ethics approval was received from the University Health Network Research Ethics Board and the University Of Toronto Office Ethics Review Committee before the recruitment of subjects. After undergoing the consent process, consenting parents/guardians signed the informed consent and consenting children/adolescents signed the informed assent and were enrolled in the study.

Clinical Assessment An experienced neuropsychiatrist (P.S.) confirmed each subject’s diagnosis of TS according to the DSM-3-R criteria.14 The diagnosis of ADHD for all subjects recruited the study was based on the DSM-3-R criteria14,15 to maintain consistency between subjects recruited at an earlier and later date and also because the © 2013 Lippincott Williams & Wilkins

689

Conner’s Rating Scale (CPRS-93), used as the primary parental reporting measure to support the distinction between subgroups for the purpose of identifying the presence/absence of hyperactivity behavioral characteristics and the “level/severity” of the same, was developed based on the DSM-3 criteria, semi-structured interviews were conducted as part of the diagnostic process and included assessment for tics, obsessive compulsiveness, attentional difficulties, impulsivity, and motor hyperactivity. Subjects also underwent psychiatric evaluation, and the presence of broader psychiatric comorbidity was assessed using a widely used semi-structured clinical interview (K-SADS-E: The Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version).16 Detailed medical histories were taken before enrollment to screen for existing medical conditions and to rule out a diagnosis of ADHD or TS in controls. Subjects were also screened for existing emotional and behavioral disorders using the Child and Adolescent Symptom Inventory.17 Tic severity was assessed using the Yale Global Tic Severity Scale18 and the Global Tic Severity Scale (GTSS).19 The GTSS rating is based on a history of lifetime severity of tics up to and including the past year and was combined with current clinical observation. Estimates of pubertal level were obtained using the Self-Administered Rating Scale for Pubertal Development,20 which is a selfreport version of the Pubertal Development Scale.21 This latter scale correlates well (r 5 .82) with physician Tanner ratings while being much less invasive. An estimated General Intelligence Quotient was obtained by a neuropsychologist (R.S.) using the Vocabulary, Information, Block Design and Picture Completion subtests (correlation .93 to .95 with full administration) of the Wechsler Intelligence Scale for Children, Third Edition.22 Five behavioral measures were also used to capture the extent of aggressive behavior: Brief Anger-Aggression Questionnaire23; Child Behavior Checklist (CBCL): Aggression (Parent-T), Delinquency, and Conduct (Parent-T) subscales24 ; and the Connors Parent Rating Scale (CPRS-93): Hyperactive/Immature and Restless/Disorganized subscales.25

Design and Procedure Sleep Study Participants were booked (along with an accompanying parent/guardian) to attend either the Sleep and Alertness Clinic of the Toronto Western Hospital or the Child and Adolescent Sleep Centre at the Youthdale Treatment Centres for two consecutive nights of sleep studies. To maintain consistency, one experienced female sleep technician (D.J.), who was blinded to the subjects’ diagnosis, conducted and scored all the overnight polysomnographic (PSG) studies in both sleep clinics. Small surface electrodes were secured to the participants’ scalp and face to record electroencephalogram (EEG), electrooculogram, and electromyogram 690 Sleep and Behavior in ADHD

(EMG) activity as per standard criteria26 to enable PSG monitoring throughout the night and to allow for the staging of sleep. Respiration belts were connected across the children’s upper rib cage and around the abdomen. Arterial blood oxygen saturation (SaO2) was measured during sleep by applying an infrared light sensor to the child’s finger. Leg EMG activity was measured using 2 electrodes on the tibialis anterior for both the left and right legs. Each of these 4 electrodes was connected to separate channels. The children were monitored on video from an adjacent technician’s room. Children were permitted to sleep ad lib. They requested lights out when they wished to and were not awakened until they arose spontaneously. Should the child awaken during the night or very early morning, the parent/guardian and the technician were asked to attempt to soothe the child and have them return to bed. Standard sleep measures including sleep onset latency, wakefulness after sleep onset, total sleep time in minutes, sleep efficiency, REM percentage and REM sleep latency (taken from sleep onset to the first appearance of REM), and percentage of sleep Stages 1 and 2, and slow wave sleep during non-REM sleep were assessed. The results from both PSG nights were recorded, scored, and reviewed. The first PSG night was deemed necessary for adaptation to a novel environment and to avoid first night effect27; therefore, only the results of the second PSG night were used for analyses. The data on first night effect of being in the laboratory setting on sleep in children will be presented elsewhere. Scoring Parameters An arousal was defined as an abrupt shift in the EEG frequency, which may include theta, alpha, and other frequencies .16 Hz but not sleep spindles. An arousal was scored when there was an EEG frequency shift of $3 seconds in duration.28 Leg movements not periodic leg movements (PLMs) were scored when there was a 0.5- to 5-second burst of anterior tibialis activity with an amplitude .25% of calibration movements.29 PLMs were scored when there were $4 leg movements (see definition above) separated by .5 seconds and ,90 seconds. For the PLMs, all leg movements were scored during all stages of sleep and wakefulness.29 Arousals associated with PLMs were scored when the arousal onset followed the leg movement onset by not more than 3 seconds.29 Movement time were scored as such when at least half of the EEG activity in an epoch (30 seconds duration) was obscured by muscle tension and/ or amplifier blocking artifacts associated with movement of the subject. For each epoch, the movement time ranged from 16 to 30 seconds. The total movement time is the summation of each of those individual movementtime durations. If the epoch was obscured by muscle tension and/or amplifier blocking artifacts associated with movement of the subject but was immediately preceded and followed by time awake, the epoch was scored the Awake Stage and not movement time. Journal of Developmental & Behavioral Pediatrics

Statistical Analyses Descriptive statistics provided an overview of the data. Multivariate analysis of variance was used to test for group effects among the 4 study groups. If the overall group effect was significant, then least square difference post hoc tests were used to determine which groups were significantly different. Chi-square analyses were used to determine differences in frequency rates and Pearson correlation analyses were used to determine the degree of association between variables. Level of significance was set at p , .05.

RESULTS Descriptive Statistics Ninety subjects (aged 6 to 16 years, mean 10.8 years; 75 males [83.3%] and 15 females [16.7%]) of the 96 asked to participate were recruited for the study (94% recruitment rate). No subjects had to be excluded for obstructive sleep apnea diagnosed at the time of the initial PSG study. Twenty subjects were recruited into the Tourette syndrome (TS) group; 21 in the TS 1 attention-deficit hyperactivity disorder (ADHD) group, 16 healthy controls, and 33 patients in the ADHD group. An initial ADHD group of 20 subjects was statistically younger in age than the 3 comparison groups and an additional 13 older ADHD subjects were enrolled to eliminate the age variance across the 4 study groups. The 6 families who declined participation stated conflicts in schedule times. All subjects were medication-free for a minimum of 6 weeks at the time of the study, and 72.4% were medication naive. There were no statistically significant differences in age, gender, body mass index, pubertal development, or intelligence level (as measured using the Wechsler Intelligence Scale for Children, Third Edition) among subjects in the 4 study groups. A greater proportion of males in the TS, TS 1 ADHD, and ADHD groups are consistent with the observed gender ratio of both TS and ADHD in the general population.15 Chi-square analysis revealed group differences in tic severity with significantly more subjects in the TS 1 ADHD group presenting with moderate-to-severe tic severity (52.6%) compared with those with TS alone (25%) (p 5 .002). No statistically significant differences in PSG sleep architectural variables were noted between subjects with mild versus those with moderate/severe tic severity.

Group Differences: Sleep Parameters The sleep architectural parameters for the second PSG night are listed in Table 1. The data from the first PSG night were not included in the analysis because there were significant differences (p values ranging from ,.001 to .032) between the first (acclimatization) and second PSG nights for all sleep architectural parameters except for Stages 1 and 3 (slow wave sleep [SWS]), total leg movements, and arousals from SWS. Multivariate analysis of variance (MANOVA) revealed a significant group effect of diagnostic group on the Vol. 34, No. 9, November/December 2013

number of periodic limb movement during sleep (F3,82 5 2.7, p , .005), the number of total leg movements (F3,82 5 2.2, p , .01), the number of arousals from sleep (F3,82 5 6.2, p , .01), the number of arousals during SWS (F3,82 5 4.6, p , .01), and the number of movements recorded during REM sleep (F3,82 5 2.7, p , .05). Diagnostic groups were similar to each other and to controls for the remaining sleep architectural variables. Least square difference (LSD) post hoc testing of differences among the diagnostic groups (Table 1) demonstrated that the number of periodic limb movements was significantly higher in the TS 1 ADHD group as compared with the other groups and that the total number of leg movements during sleep were significantly greater in both the TS 1 ADHD and the ADHD-only groups when compared with the TS-only and control groups. The ADHD-only group had significantly more movements during REM sleep, a greater number of total arousals from sleep, and more arousals from SWS, compared with the TS-only and control groups. The relationship between hyperactivity and sleep was examined by dividing the groups with ADHD into low and high hyperactivity levels, creating 6 subgroups: TSonly, TS 1 ADHD low, TS 1 ADHD high, ADHD low, ADHD high, and controls (Table 2). Subjects with moderately to markedly atypical hyperactivity were grouped into the “high” hyperactivity group. Eleven sleep parameters from Night 2 were examined using MANOVA: periodic leg movement index, percent of REM sleep, REM latency, sleep onset latency, total sleep minutes, sleep efficiency, duration of SWS, total awakenings, duration of REM sleep, total number of arousals, and number of arousals during SWS. Significant subgroup differences emerged for the last 2 sleep parameters (total arousals: F5,81 5 4.61, p 5 .001; SWS arousals: F5,82 5 3.82, p 5 .004). LSD post hoc tests indicated that the ADHD-only groups (low and high) had significantly more total arousals than the TS-only, TS 1 ADHD low, and control groups. The number of arousals in the TS 1 ADHD high hyperactivity group fell within the middle range; it did not differ from the ADHD-only groups nor was it significantly higher than the other diagnostic subgroups.

Sleep and Behavioral Indices Results of the behavioral measures across the diagnostic groups are shown in Table 3. MANOVA testing noted significant group differences across all behavioral measures; the ADHD-only and the TS 1 ADHD groups had scores that were significantly higher than that of control subjects. The association between the PSG variables and behavioral indices is found in Table 4. For this analysis, only PSG variables that were found to be significantly different across the diagnostic study groups were included. A modest but significant correlation was found between scores on the Child Behavior Checklist (CBCL) delinquency measure and the number of movements during REM sleep (r 5 .36, p 5 .003). An increased number of total arousals and arousals from SWS © 2013 Lippincott Williams & Wilkins

691

Table 1. Polysomnographic Sleep Architectural Variables Grouped by Diagnostic Categories (N 5 90) TS 1 ADHD (n 5 21)

TS Only (n 5 20) Mean SD

p

Mean

ADHD Only (n 5 33)

p

SD

Mean

p

SD

Controls (n 5 16) Mean SD

Overall Mean (n 5 90) p

Mean

SD

p

Total leg movement index*

18.7 14.5 .04

39.7 57.5a —

22.2 19.0

ns

16.9 18.1 .04

24.5

32.2

—

Periodic leg movement index*

18.5 14.7 .05

39.6 57.3a —

16.0 27.9

.02

11.2 11.6 .02

21.5

35.0

—

b

REM sleep movement index * REM sleep, % REM latency, min No. of REM sessions per night

7.0

3.7 .01

8.1

3.6

ns

10.3

4.3

—

6.2

4.4 .01

8.2

4.2

—

19.2

2.8 —

20.9

3.9

—

20.2

4.6

—

21.9

4.4 —

20.4

4.1

—

108.0 47.1

—

127.7 51.1

—

97.2 36.0 —

116.7

46.4

—

4.8

1.0 —

4.7

1.1

—

0

120.6 40.1 — 4.6

0.8 —

4.8

1.2

—

a

4.7

1.3

—

0.3

0.5

—

0

—

0.2

0.4

—

12.3 12.1

—

10.6

5.3 —

11.5

8.7

—

0.2

0.4 —

0.2

0.4

—

11.2

5.8 —

11.0

6.6

—

Stage 1, %

4.7

2.0 —

4.7

1.9

—

5.7

3.0

—

4.6

2.2 —

5.1

2.5

—

Stage 2, %

43.9

6.0 —

43.3

5.1

—

43.9

4.0

—

45.2

3.6 —

44.0

4.7

—

Stage 3 (SWS), %

28.5

3.3 —

28.3

3.7

—

26.0

3.1

—

25.7

2.8 —

27.1

3.3

—

Sleep onset latency, min

15.1 11.0 —

14.1

8.1

—

15.4 19.2

—

12.8

5.6 —

14.6

13.6

—

—

507.9 58.0

—

488.0 31.9 —

500.5

47.9

—

95.4

1.8 —

94.7

3.4

—

10.8

Wakefulness, % No. of episodes of intervening wakefulness and movements per night

Total sleep time, min Sleep efficiency, %

488.3 44.6 — 94.0

3.4 —

10.8

6.2 —

508.0 40.1 95.1

2.2

—

11.6

94.4

4.3

—

10.6

6.7

—

6.4

—

5.5 —

10.9

6.2

—

140.8 28.6 —

147.9 33.3

—

130.9 32.2

—

127.2 22.5 —

136.8

30.9

—

REM duration, min

94.9 18.3 —

102.4 20.7

—

105.1 22.3

—

108.6 21.9 —

102.6

21.2

—

Arousal index (all stages of sleep)**

48.3 17.7 .03

53.0 15.1

.04

69.3 23.4a —

49.6 22.4 .03

57.4

22.0

—

6.9

2.6

—

No. of awakenings per night SWS duration, min

Arousal index: SWS only**

6.1

2.4 .01

6.3

1.7

.01

8.2

2.7a —

6.2

2.7 .02

The above figures represent the average values for each diagnostic group. Index refers to the hourly rate of occurrence. Total leg movement index refers to all types of leg movements (periodic or nonperiodic) for all stages of sleep. MANOVA was conducted for results for the TS-only, TS 1 ADHD, ADHD-only and control groups. ADHD, attention-deficit hyperactivity disorder; LSD, least square difference; MANOVA, multivariate analyses of variance; REM, rapid eye movement; SWS, slow wave sleep; TS, Tourette syndrome. *p , .05; **p , .01; ***p # .001. aPost hoc testing was conducted on the above diagnostic categories for which MANOVA indicated a significant difference. The p values in the table represent a significant difference based on LSD post hoc testing, indicating the diagnostic category for which the difference was found. bThis variable has 21 cases with missing information (11 from ADHD-only group).

were also moderately but significantly correlated with scores on the conduct disorder subscale (total arousals: r 5 .33, p 5 .002; SWS arousals: r 5 .26, p 5 .016) and the CPRS-93 subscales measuring hyperactivity/immaturity (total arousals: r 5 .3, p 5 .009; SWS arousals: r 5 .3, p 5 .006) and restless/disorganized behaviors (total arousals: r 5 .32, p 5 .005; SWS arousals: r 5 .34, p 5 .002).

Impact of Pubertal Status Given the age range (6–16 years) of the study group, and since adolescence brings major changes, separate subanalyses according to pubertal status were conducted. Subjects were grouped into 2 subgroups based on pubertal status: (1) Pre- and Early pubertal, and (2) Mid to Post-pubertal because subdividing each diagnostic group into 5 separate pubertal status groupings would have reduced the group numbers to the extent that would have hindered proper statistical techniques. The distribution of pubertal ratings among the study participants, as grouped by diagnosis, did not differ among the study groups (TS, TS 1 ADHD, ADHD, and controls; p 5 .24). Among the PSG sleep architectural 692 Sleep and Behavior in ADHD

variables, only 2 variables evinced significant differences based on pubertal status: Total Sleep Time (p 5 0.001) and % Slow Wave Sleep (p , 0.001). However, no pubertal status differences were noted for the number of total arousals (p 5 .8) and the number of arousals from SWS (p 5 .3) across the study groups. The latter 2 sleep architectural variables had been found to be significantly higher in the ADHD-only study group. Similarly, no pubertal differences for the study groups were noted for the scores on the behavioral measures (Brief Anger Questionnaire [p 5 .19], CBCL Aggression [Parent-T] [p 5 .86], CBCL Delinquency [Parent-T] [p 5 .17], CBCL Conduct Disorder [Parent-T] [p 5 .23], CPRS-93 Hyperactive/ Immature T-Score [p 5 .63], or CPRS-93 Restless/ Disorganized T-Score [p 5 .85]).

DISCUSSION This is the first published study investigating behavior and sleep data obtained by polysomnography in 3 groups of unmedicated children (Tourette syndrome [TS], TS 1 attention-deficit hyperactivity disorder [ADHD], and ADHD) and normal healthy controls. We found that our subjects with ADHD alone or comorbid TS and ADHD Journal of Developmental & Behavioral Pediatrics

Vol. 34, No. 9, November/December 2013

Table 2. Sleep Variables for Diagnostic Subgroups Arranged by Level of Hyperactivity

PLMi

SOL, min TST, min

% SE

No. of subjects % Mean SD Mean SD Mean SD Mean SD

Total No. of Awakenings per night REM Latency, min %REM Sleep Mean

SD

Mean

SD

Mean

SWS, min

REM, min

Arousals

Arousals: SWS

SD Mean SD Mean SD Mean SD Mean SD

TS only

20

22.2

2.6

3.0 15.1 11.0 488.3 44.5 94.0 3.4

120.6

40.1

19.2

2.9

10.8

6.2

140.8 28.6

94.9 18.3 43.8

17.7 3.4

2.2

TS 1 ADHD low

15

16.7

2.7

2.9 13.7

112.3

49.2

20.9

3.0

10.5

6.5

148.8 32.6 104.0 14.5 43.2

16.3 3.3

2.6

13.6 3.5

6.2 509.7 39.8 95.3 1.9

TS 1 ADHD hi

6

6.7

2.7

2.3 17.3 15.0 499.5 51.5 94.5 3.7

100.5

44.6

20.7

7.4

12.5

5.2

154.0 39.4 103.9 38.1 55.5

ADHD only low

17

18.9

0.8

1.6 13.5 13.1 519.5 52.2 95.5 2.6

135.7

54.1

20.4

4.6

9.5

6.2

138.3 29.8 111.3 22.3 79.4* 23.3 4.4**

2.3

ADHD only high

11

12.2

1.7

3.0 20.8 28.3 487.5 70.0 91.9 5.9

120.2

49.3

19.3

4.5

13.1

7.0

125.5 32.7

2.6

Controls

16

17.8

2.7

2.1 12.6

96.8

34.8

22.0

4.3

11.2

5.9

142.2 25.6 105.4 23.2 40.8

5.7 493.4 31.8 95.7 1.7

94.9 19.2 65.9* 17.3 5.8** 19.9 3.6

3.9

1.8

Data for the above table were missing for 5 subjects. Values above are mean and standard deviation. Level of hyperactivity was determined by the CPRS-93 (25); low indicates mildly atypical level of hyperactivity and high indicates severely atypical level of hyperactivity. ADHD, attention-deficit hyperactivity disorder; Arousals, total arousals for all stages of sleep; Arousals: SWS, arousals during SWS; PLMi, periodic limb movement index; REM, REM sleep duration; SE, sleep efficiency; SOL, sleep onset latency; SWS, slow wave sleep duration; TS, Tourette syndrome; TST, total sleep time. Significance: *p 5 .001; **p 5 .004.

Table 3. Differences on Behavioral Measures Across Diagnostic Groups Behavioral Measures (t-score Comparisons) by Diagnostic Group (One-way ANOVAs) Behavioral Measure

TS

TS 1 ADHD

ADHD

Controls

Post hoc Tests (LSD)*

8.5 (6.9)

9.8 (6.4)

11.8 (6.4)

5.6 (3.6)

CTL vs ADHD CTL vs TS 1 ADHD

CBCL Aggression (Parent-T)**

58.8 (12.8)

64.7 (11.3)

63.4 (11.6)

51.9 (3.8)

CTL vs ADHD CTL vs TS 1 ADHD

CBCL Delinquency (Parent-T)***

55.2 (8.2)

60.9 (10.4)

64.1 (11.2)

53.2 (6.0)

CTL vs ADHD CTL vs TS 1 ADHD TS vs ADHD Only

Conduct Disorder (Parent-T)**

48.4 (12.0)

56.0 (11.0)

57.8 (11.1)

44.6 (5.2)

CTL vs ADHD CTL vs TS 1 ADHD TS vs ADHD

CPRS-93 Hyperactive/Immature T score***

46.4 (10.6)

56.5 (13.3)

60.8 (15.9)

43.1 (7.0)

CTL vs ADHD CTL vs TS 1 ADHD TS vs ADHD TS vs TS 1 ADHD

CPRS-93 Restless/Disorganized T score***

51.4 (15.6)

60.4 (14.2)

68.7 (20.4)

46.9 (7.5)

CTL vs ADHD CTL vs TS 1 ADHD TS vs ADHD TS vs TS 1 ADHD

Brief Anger Questionnaire** © 2013 Lippincott Williams & Wilkins

*p # .05; **p , .01; ***p # .001. ADHD, attention-deficit hyperactivity disorder; ANOVA, analysis of variance; CBCL, child behavior checklist; CPRS, Connors Parent Rating Scale; CTL, control; LSD, least square difference; TS, Tourette syndrome.

693

Table 4. Correlations Between Behavioral Measures and Indices of Sleep Disturbance

Behavioral Measure

Total Arousals

Arousals From SWS

Periodic Leg Movements

Total Leg Movements

Movements During REM Sleep

0.2

0.14

0.07

0.11

0.21

Brief Anger Questionnaire

Pearson r N

87

88

87

90

69

CBCL Aggression (Parent-T)

Pearson r

0.16

0.08

0.05

0.08

0.20

N

87

88

87

90

69

CBCL Delinquency (Parent-T)

Pearson r

0.15

0.15

0.01

0.03

0.36**

N

87

88

87

90

69

Conduct Disorder (Parent-T)

Pearson r

0.33**

0.26*

0.14

0.09

0.14

87

88

87

90

69

CPRS-93 Hyperactive/Immature Pearson r T score N

N

0.29**

0.30**

0.12

0.04

0.11

79

80

79

82

62

Pearson r

0.32**

0.34**

0.12

0.06

0.12

N

79

80

79

82

62

CPRS-93 Restless/Disorganized T score

*p , .05; **p , .01. CBCL, child behavior checklist; CPRS, Connors parent rating scale; REM, rapid eye movement; SWS, slow wave sleep duration.

had a significantly greater number of movements during both non-REM and REM sleep and had a significantly higher level of arousals from sleep as compared with controls. As the children in our study were unmedicated, most being medication naive, the greater number of arousals and movements during sleep in the study children with ADHD and TS 1 ADHD were not a result of medication effects. Apart from the aforementioned differences, there were no further sleep architectural differences between children with ADHD or combined TS 1 ADHD and controls. There were no differences in PSG sleep architectural measures between children with TS alone and the control group. This study is the first to specifically identify the link between greater arousals from sleep and conduct disorder, hyperactivity/immaturity, and restlessness/disorganized behavior in children with primary or comorbid ADHD. It is also important to underscore the greater degree of arousals from sleep in children with ADHD when comparing those with TS or healthy controls. Gruber et al1 have reported a significant deterioration in behavior among children with ADHD with sleep restriction. Our results indicate that sleep fragmentation is also associated with problem behaviors in children with ADHD. The findings of this study strongly support the need for careful screening of sleep in children with ADHD as part of routine medical management. The literature suggests that between one-quarter to half of the children and adolescents with ADHD have sleep problems, including increased sleep onset latency, reduced sleep duration, more parasomnias, and an overall increased level of problems with their sleep.30 The fact that parents’ reports of sleep problems in children with ADHD are not supported by overnight PSG recording11 highlights the need for a thorough clinical sleep history and both subjective (questionnaire) and objective (PSG sleep studies) sleep evaluation in this patient population. 694 Sleep and Behavior in ADHD

Accordingly, previous investigations of sleep in children with ADHD have produced conflicting reports including increased and decreased duration of REM sleep, greater REM latency, reduced sleep duration, and decreased sleep efficiency.7,10 A meta-analysis of PSG studies in children with ADHD noted that the only significant finding to emerge is the greater frequency of PLMs in children with ADHD,8 a finding that is in line with those of this study. Our data point to a greater level of arousals from sleep and movements during sleep, whereas the majority of sleep architectural variables do not differ between the control and ADHD group. One implication is that arousals during the night negatively impact existing deficits in daytime attention. This has face validity and our clinical experience leads us to believe that in some cases of ADHD, the treatment and resolution of the repeated disruption of sleep leads to an improvement in daytime behavioral symptoms. In general, there is evidence that better sleep in children is associated with improved behavior1,2 but given the lack of wellconducted studies specifically exploring the impact of improved sleep on behavior in children with ADHD, further research would be required to additionally test this hypothesis. In contrast to the paper by Cohrs et al,31 this study noted no relationship between sleep variables and the overall frequency of tics. However, the study by Cohrs et al did not control for ADHD, had a very small sample size, and their subjects were using a variety of medications. It is possible that $1 of the above confounding variables may have contributed to the findings of tics by Cohrs et al during REM sleep that did not emerge in our study. Several limitations must be highlighted when considering this study. First, there may have been a sampling bias because the children with TS and TS 1 ADHD were Journal of Developmental & Behavioral Pediatrics

recruited from a specialty TS clinic. These children may have a more severe presentation of TS, since milder cases may go undiagnosed and/or be managed by family physicians and pediatricians. However, there was a wide range of tic severity within the 2 TS groups, and many of the children were not seeking pharmacological interventions, suggesting that there was ample variation in TS severity within the sample. The same technician conducted and scored the studies so as to ensure that all studies were conducted and scored in the same manner. Furthermore, this technician was the most experienced in scoring pediatric records and had the most training in keeping children with developmental issues calm during the study. To avoid possible bias in scoring, the PSGs were rendered anonymous by another member of the team, and the studies were not scored immediately. The scoring was done in batches of at least 6 to 8 studies so that the scoring occurred, on average, 2 to 3 months later. Although scoring by an independent blinded technician would have been preferable, we believe that this compromise made the best use of our technician’s experience and expertise so as to ensure the best quality of the data. The study group was between 6 and 16 years of age, and results should not be generalized to older patients with ADHD and TS because sleep architecture is known to naturally evolve with age. Symptoms of hyperactivity decreases with age in ADHD32 and most of the TS cases experience an overall and sustained reduction in tics because they emerge from their teens.19 It is not known if age-related changes in sleep and/or the underlying neuropathology of patients with ADHD or TS have an impact on the association between disturbed sleep and behavioral indices. Longitudinal studies are needed to assess the above relationship. A further limitation is that Tanner staging was conducted using a questionnaire—the Pubertal Development Scale. This enabled us to minimize stress and avoid the more invasive Tanner staging procedure given the vulnerability of the study population. Carskadon and Acebo20 have demonstrated that this scale has reasonable reliability and consistency for the determination of pubertal status. Lastly, children with comorbid obsessive-compulsive disorder (OCD) (TS 1 OCD and TS 1 ADHD 1 OCD) were intentionally excluded from this study so as to obtain a manageable number of parameters examined in this study. However, given that OCD is present in about 30% of the clinical population of children with TS, these patients should be investigated in future studies. The findings of this study suggest that the presence of ADHD, whether alone or comorbid with TS, is associated with more arousals and movements during sleep and that this sleep fragmentation has a significant negative impact on daytime behavior. The degree of hyperactivity does not appear to influence the number of arousals during sleep with ADHD as children with both low and high levels of hyperactivity had a similar level of arousals. Thus, our data paves the path toward a clearer Vol. 34, No. 9, November/December 2013

understanding of the degree of disruption of sleep parameters resulting from the occurrence of ADHD comorbid with TS, in comparison with the diagnosis of either of these conditions. Our results go a step further and add a significant body of data to the small literature on the impact of sleep disruption, as determined objectively with polysomnography, on behavior measures in the pediatric TS, ADHD, and TS 1 ADHD populations. ACKNOWLEDGMENTS The authors wish to generously thank the children, adolescents, and their families who so cheerfully and willingly participated. The authors also would like to recognize the financial support received by the James T. Cummings Foundation and a Fellowship grant from the Department of Psychiatry, University Health Network, Toronto, ON, Canada.

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