PREVALENCE OF PERIODIC LIMB MOVEMENTS DURING SLEEP IN NORMAL CHILDREN http://dx.doi.org/10.5665/sleep.3928

Prevalence of Periodic Limb Movements during Sleep in Normal Children

Carole L. Marcus, MBBCh1; Joel Traylor, RPsgT1; Paul R. Gallagher, MA2; Lee J. Brooks, MD1; Jingtao Huang, PhD1; Dorit Koren, MD3; Lorraine Katz, MD3; Thornton B.A. Mason, MD, PhD, MSCE1; Ignacio E. Tapia, MD1 Sleep Center, 2Clinical and Translational Research Center, and 3Division of Endocrinology, Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, PA

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Study Objectives: Although the American Academy of Sleep Medicine (AASM) mandates that periodic limb movements during sleep (PLMS) be scored on every polysomnogram, and considers a periodic limb movement index (PLMI) > 5/h abnormal in children, there is a lack of communityderived data regarding the prevalence of PLMS in children, and no data to support this cutoff value. Therefore, the aim of this study was to determine the prevalence of PLMS in a sample of normal children. Design: Retrospective study. Participants: 195 healthy, non-snoring children aged 5-17 years, recruited from the community, who underwent polysomnography for research purposes. Methods: PLMS were scored using the AASM 2007 criteria. Measurements and Results: The group age (median [IQR]) was 12.9 [10-15] years, and 58% were male. Sleep architecture was normal, and the obstructive apnea hypopnea index was 0.1 [0-0.3]/h. The median PLMI was 0/h, ranging from 0 to 35.5/h. Fifteen (7.7%) subjects had a PLMI > 5/h, and only 3 (1.5%) met the adult pathologic criterion of more than 15/h. Use of the 95th percentile PLMI cutoff of 7.2/h produced little difference in categorization between groups. Children with a PLMI > 5/h had a higher arousal index than those with a lower PLMI (11.6 [8.8-14.6] vs 8.1 [6.19.9]/h, respectively, P = 0.003). Conclusions: This study provides normative data to the field and supports the clinical periodic limb movement index cutoff of > 5/h based on both prevalence and the correlate of increased sleep fragmentation. Periodic limb movements during sleep are infrequent in normal children recruited from the community. Keywords: pediatrics, periodic limb movements, normative data Citation: Marcus CL, Traylor J, Gallagher PR, Brooks LJ, Huang J, Koren D, Katz L, Mason TB, Tapia IE. Prevalence of periodic limb movements during sleep in normal children. SLEEP 2014;37(8):1349-1352.

INTRODUCTION Periodic limb movements during sleep (PLMS) occur in children, as in adults. The standard polysomnography scoring manual mandates that PLMS be scored on every polysomnogram,1 and this is reasonable in view of the fact that many parents are unaware that their child has PLMS.2 However, the normal cutoff for elevated PLMS is not known. The International Classification of Sleep Disorders defines periodic limb movement disorder in children as a periodic limb movement index (PLMI) > 5/h, in association with clinical sleep disturbance or daytime fatigue.3 However, knowledge of normative data on PLMS in children is derived from high-risk or symptomatic populations, and there are no community-based PLMI data to support this definition. Thus, the utility of scoring PLMS in the absence of knowledge of what is normal is unclear. Therefore, the objective of this study was to determine the prevalence of PLMS in a community-based sample of healthy normal children and adolescents. METHODS Study Design This was a retrospective review of all healthy children aged 5-17.9 years who underwent polysomnography as research

controls at our institution between 2005 (when our database was established) and 2013. Children were recruited from the community by means of generic advertisements. The advertisements specified that normal, healthy children without sleep problems were being recruited. Respondents underwent a telephone interview to ensure that they had no chronic sleep symptoms including snoring (although questions about restless legs syndrome were not specifically asked), and medical records were reviewed for those subjects receiving care at the Children’s Hospital of Philadelphia. Children with chronic medical conditions other than mild asthma (not using daily controller medications), obesity, or those on chronic medications, were ineligible. Any subject found to have obstructive sleep apnea on polysomnography (obstructive apnea hypopnea index ≥ 1.5/h) was excluded. Children participated in a number of different research studies (NIH R01 HL58585, UL1 TR000003, KL2 RR024132-05, AHA 10CRP376001, AHA 0825666D). The Institutional Review Board at the Children’s Hospital of Philadelphia approved each study, and informed consent was obtained from parents/guardians. Assent was obtained from children ≥ 7 years of age.

Submitted for publication February, 2014 Submitted in final revised form February, 2014 Accepted for publication February, 2014 Address correspondence to: Carole L. Marcus, MBBCh, Children’s Hospital of Philadelphia, Sleep Center, Suite 9NW50, Main Hospital, 34th Street & Civic Center Boulevard, Philadelphia, PA 19104; Tel: (267) 426-5842; Fax: (267) 426-9234; E-mail:[email protected] SLEEP, Vol. 37, No. 8, 2014 1349 Downloaded from https://academic.oup.com/sleep/article-abstract/37/8/1349/2416898 by guest on 05 January 2018

Polysomnography Polysomnography was performed overnight. A Rembrandt polysomnography system (Embla, Broomfield, CO) recorded the following parameters: electroencephalogram (C3/A2, C4/A1, F3A2, F4A1, O1/A2, O2/A1), left and right electrooculograms, submental electromyogram (EMG), chest and abdominal wall motion using respiratory inductance plethysmography, heart rate by electrocardiogram, arterial oxygen saturation (SpO2) by pulse oximetry (Masimo, Irvine, CA); end-tidal PCO2 (PETCO2), measured at the nose by infrared PLMS in Children—Marcus et al.

Table 1—Study group demographics and polysomnography results

School-aged

195 12.9 (10-15) 112 (57%) 0.7 (0.1-1.6) 431 (394-456) 85 (79-91) 5 (3-8) 50 (43-55) 25 (20-30) 20 (16-24) 8.2 (6.2-10.2) 0.1 (0-0.3) 94 (92-95) 53 (50-55)

Statistical Analysis Statistical analyses were conducted using SPSS version 20.0 software (IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY). The Kolmogorov-Smirnov test was used to test for normality. As most data were skewed, data are presented as median (interquartile range [IQR]). Categorical data were compared using the χ2 test. Continuous data were compared using the Mann Whitney rank sum test. Associations between variables were determined using Pearson correlation. A P value < 0.05 was considered statistically significant.

30

20

10

0

4

6

8

10

Age

12

14

16

18

Figure 1—The periodic limb movement index for each subject plotted as a function of age. School-aged children are represented by open circles, and adolescents by solid circles.

Data shown as median (interquartile range) or N (%). TST, total sleep time

capnometry (Novametrix Medical System, Inc., Wallingford, CT), airflow using a 3-pronged thermistor (Pro-Tech Services, Inc., Mukilteo, WA), nasal pressure by a pressure transducer (Pro-Tech Services, Inc., Walnut Cove, NC), and bilateral tibialis anterior EMG. Subjects were continuously observed by a polysomnography technician, and were recorded on video with the use of an infrared video camera. Studies were scored using standard pediatric sleep scoring criteria.1 Periodic limb movements were scored manually by 4 sleep technologists, using the 2007 American Academy of Sleep Medicine criteria.1 In brief, limb movements were scored if they were 0.5-10 sec and had an EMG amplitude ≥ 8 microvolts above the resting EMG; periodic limb movements were scored if limb movements occurred as part of a series ≥ 4, with 5-90 sec between each movement in a series. Interscorer reliability for the laboratory shows 99% ± 1% (range 97%-100%) agreement for PLMS. As per the International Classification of Sleep Disorders, a PLMI > 5.0/h was considered abnormal.3

Adolescent

40

Periodic limb movement index

N Age (year) Males Body mass index z-score TST (min) Sleep efficiency (%) N1 (% TST) N2 (% TST) N3 (% TST) REM sleep (% TST) Arousal index (N/h) Obstructive apnea hypopnea index (N/h) SpO2 nadir (%) Peak end-tidal CO2 (mm Hg)

all subjects had normal breathing during sleep, with an obstructive apnea hypopnea index < 1.5/h. The periodic limb movement index varied between 0 to 35.5/h (Figure 1), with a median (IQR) of 0 (0-1.2)/h. Almost two-thirds of the subjects (122; 62.6%) had a PLMI of 0/h. Only 15 (7.7%) subjects had a PLMI in the abnormal range of > 5/h, and only 3 (1.5%) met the adult abnormal criterion > 15/h (Figure 2). Children with a PLMI > 5/h had a higher arousal index than those with a lower PLMI (P = 0.003), although other aspects of sleep architecture were preserved (Table 2). The 95th percentile value for PLMI was 7.2/h. A grouping based on the 95th percentile produced groups of N = 186 (PLMI ≤ 7.2/h) vs N = 9 (PLMI > 7.2/h), as opposed to N = 180 vs N = 15, based on the standard cutpoint of 5/h, i.e., very little difference in classification. There was no significant difference in the periodic limb movement index (PLMI) between age groups (median for school-aged children 0 [0-1.3]/h, and for adolescents 0 [0-0.7]/h, P = 0.566) (Figure 1). Similarly, there was no significant correlation between age and PLMI (r = 0.09, P = 0.21). Although a higher percentage of adolescents had a PLMI in the abnormal range of > 5/h, this was not statistically significant (5.0% of preschool children vs 10.5% of adolescents, P = 0.239). Males and females had a similar median PLMI (0 [0-1.3] and 0 [0-0.6]/h, respectively, P = 0.245). Although the percentage of males with a PLMI > 5/h was greater than females, this was not statistically significant (10.5% vs 3.7%, respectively, P = 0.078).

RESULTS Study Group A total of 195 subjects were studied, of whom 100 were school-aged (5-12 years) and 95 were adolescents (13-17.9 years). Details of the study population are shown in Table 1. There were no significant differences in gender or body mass index z-scores between the 2 age groups. As per study design, SLEEP, Vol. 37, No. 8, 2014 1350 Downloaded from https://academic.oup.com/sleep/article-abstract/37/8/1349/2416898 by guest on 05 January 2018

DISCUSSION This study has shown that PLMS are uncommon in normal children. In fact, the median PLMI was 0/h. Only 7.7% of subjects had a PLMI > 5/h, suggesting that the currently recommended cutoff of > 5/h as one of the criteria for the diagnosis of pediatric periodic limb movement disorder is epidemiologically appropriate. Furthermore, children with a PLMI > 5/h had increased sleep fragmentation as demonstrated by a higher arousal index, indicating that this cutoff is also clinically PLMS in Children—Marcus et al.

140

Table 2—Comparison of sleep architecture in children with and without a periodic limb movement index > 5/h PLMI ≤ 5/h 180 428 (393-456) 85 (79-91) 5 (3-8) 50 (44-55) 25 (20-30) 20 (16-23) 8.1 (6.1-9.9)

120

PLMI > 5/h 15 438 (425-454) 82 (79-88) 5 (4-9) 49 (39-56) 22 (19-25) 24 (16-26) 11.6 (8.8-14.6)

100

Subjects

Parameter N TST (min) Sleep efficiency (%) N1 (% TST) N2 (% TST) N3 (% TST) REM sleep (% TST) Arousal index (N/h) *

60 40 20

* P = 0.003. Data shown as median (interquartile range). TST, total sleep time

appropriate. Using a 95th percentile cutoff value of 7.2/h resulted in reclassification of only a few individuals. There was no effect of age or gender on the frequency of PLMS. There are very few studies of normative pediatric PLMS data in the literature. Montgomery-Downs and colleagues published normative polysomnography data on a large sample of 542 normal children recruited form the school system. They reported a mean PLMI of 1.5 ± 1.4/h. However, children found to have a PLMI ≥ 5/h were specifically excluded from analysis, and the number of such exclusions was not reported.4 Kirk and Bohn performed a retrospective study of 591 children referred for clinical polysomnography because of symptoms of sleep disorders.5 They found that 5.6% of children aged 0-18 years had a PLMI > 5/h. However, 60% of these children had coexistent obstructive sleep apnea, and many of the children had medical comorbidities. Our center previously reported on PLMS in a younger and smaller cohort of 52 children aged 2-9 years who were undergoing brain magnetic resonance imaging but had no major neurological issues.6 In this group of preschool and schoolaged children, the mean PLMI was 1.3 ± 2.2 (SD)/h, with a range of 0-9.5/h, and 8% had a PLMI > 5/h. Thus, the current study is the first to evaluate PLMS in a relatively large, community-based sample spanning the school-age and adolescent age range. PLMS can be a useful clinical finding as a marker of restless legs syndrome, especially in children unable to fully articulate their symptoms. One study found a PLMI > 5/h in three-quarters of children with restless legs syndrome.7 However, even in the absence of restless legs syndrome, the finding of elevated PLMS may be important. Increased PLMS in children, even in the absence of restless legs syndrome, may be associated with insomnia and sleep disturbances,8 as well as daytime behavioral problems.9 These sleep-related findings are supported by the finding of a higher arousal index in children with an elevated PLMI in the current study. PLMS have been associated with abnormal autonomic control10 and hypertension in children.11 PLMS are also elevated in children with disorders such as attention deficit hyperactivity disorder,12 iron deficiency,13 and sickle cell disease.14 For these reasons, it is important to understand the prevalence of PLMS in normal children, so that pathologic levels can be identified. One limitation of this study is that children and their parents were not specifically questioned about symptoms of restless

80

0

0

0.1-5

5.1-10

> 10

Periodic limb movement index Figure 2—The number of subjects at each level of periodic limb movement index.

legs syndrome, although they were asked whether they had any sleep problems (and responded negatively). Thus, these data are useful in establishing the prevalence of PLMS in normal children but cannot be used for the diagnosis of periodic limb movement disorder. In summary, this study has provided much-needed normative data about the prevalence of PLMS in children, and supports the International Classification of Sleep Disorders cutoff parameter of 5/h. ACKNOWLEDGMENTS The authors thank all of the Children’s Hospital of Philadelphia research coordinators and sleep laboratory technologists who helped conduct this study. We are grateful to the children and their families for their enthusiastic participation in this study.

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ABBREVIATIONS AASM, American Academy of Sleep Medicine EMG, electromyogram IQR, interquartile range PLMI, periodic limb movement index PLMS, periodic limb movements during sleep TST, total sleep time DISCLOSURE STATEMENT This was not an industry supported study. The study was supported in part by NIH R01 HL58585, UL1 TR000003, KL2 RR024132, AHA 10CRP376001, AHA 0825666D and Research Electronic Data Capture (REDCap). Dr. Marcus has received research support from Ventus and Philips Respironics in the form of loaned equipment only for investigator-initiated studies, not relevant to the current manuscript. The other authors have indicated no financial conflicts of interest. REFERENCES

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PLMS in Children—Marcus et al.

2. Picchietti DL, Walters AS. Moderate to severe periodic limb movement disorder in childhood and adolescence. Sleep 1999;22:297-300. 3. American Academy of Sleep Medicine. The international classification of sleep disorders: diagnostic and coding disorder. 2nd ed. Westchester, IL: American Academy of Sleep Medicine, 2005. 4. Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic characteristics in normal preschool and early schoolaged children. Pediatrics 2006;117:741-53. 5. Kirk VG, Bohn S. Periodic limb movements in children: prevalence in a referred population. Sleep 2004;27:313-5. 6. Traeger N, Schultz B, Pollock AN, Mason T, Marcus CL, Arens R. Polysomnographic values in children 2-9 years old: additional data and review of the literature. Pediatr Pulmonol 2005;40:22-30. 7. Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA. Pediatric restless legs syndrome and periodic limb movement disorder: parentchild pairs. Sleep Med 2009;10:925-31. 8. Gingras JL, Gaultney JF, Picchietti DL. Pediatric periodic limb movement disorder: sleep symptom and polysomnographic correlates compared to obstructive sleep apnea. J Clin Sleep Med 2011;7:603-9A.

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9. Gaultney JF, Merchant K, Gingras JL. Parents of children with periodic limb movement disorder versus sleep-disordered breathing report greater daytime mood and behavior difficulties in their child: the importance of using ICSD-2nd Edition criteria to define a PLMD study group. Behav Sleep Med 2009;7:119-35. 10. Walter LM, Foster AM, Patterson RR et al. Cardiovascular variability during periodic leg movements in sleep in children. Sleep 2009;32:1093-9. 11. Wing YK, Zhang J, Ho CK, Au CT, Li AM. Periodic limb movement during sleep is associated with nocturnal hypertension in children. Sleep 2010;33:759-65. 12. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movement disorder and restless legs syndrome in children with attentiondeficit hyperactivity disorder. J Child Neurol 1998;13:588-94. 13. Simakajornboon N, Gozal D, Vlasic V, Mack C, Sharon D, McGinley BM. Periodic limb movements in sleep and iron status in children. Sleep 2003;26:735-8. 14. Rogers VE, Marcus CL, Jawad AF, et al. Periodic limb movements and disrupted sleep in children with sickle cell disease. Sleep 2011;34:899908.

PLMS in Children—Marcus et al.

Prevalence of periodic limb movements during sleep in normal children.

Although the American Academy of Sleep Medicine (AASM) mandates that periodic limb movements during sleep (PLMS) be scored on every polysomnogram, and...
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