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Jcn500849 1.6Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1
Amy K. Licis, Alicia Vallorani, Feng Gao, Cynthia Chen, Jason Lenox, Kelvin A. Yamada, Stephen P. Duntley and The online version of this article can be found at: can be found at:
Journal of Child Neurology
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ª The Author(s) 2013Reprints and permission: Amy K. Licis, MD1, Alicia Vallorani, BA1, Feng Gao, MD, PhD2,Cynthia Chen, BA1, Jason Lenox, MS1, Kelvin A. Yamada, MD1,Stephen P. Duntley, MD1, and David H. Gutmann, MD, PhD1 AbstractChildren with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function,and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorderneurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2 to 17years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantlymore likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but notproblems with abnormal sleep breathing, or excessive somnolence. Although the overall sleep scores were higher in children withneurofibromatosis type 1, this was not related to a coexisting attention deficit disorder, cognitive impairment, or stimulant med-ication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep dis-turbances, and support the use of appropriate interventions for this at-risk population.
KeywordsNF1, sleep disturbances, neurocutaneous disorders, brain tumor Received April 28, 2013. Received revised May 14, 2013. Accepted for publication July 16, 2013.
Neurofibromatosis type 1 is one of the most common autosomal in math, reading, gross motor, fine motor, and self-help dominant tumor predisposition syndromes in which affected children develop nervous system abnormalities.1 In addition to An important contributing factor to cognitive and behavior an increased risk for developing benign and malignant tumors deficits in children is the presence of sleep disturbances.10,11 of the central and peripheral nervous system, individuals with In this regard, children with sleep disturbances frequently score neurofibromatosis type 1, especially young children, are prone significantly lower on tests of overall intelligence and some to a wide range of cognitive and behavioral issues.2,3 Whereas aspects of executive function.12,13 Moreover, some children approximately 8.4% of children in the general population meet with disordered sleep exhibit hyperactivity and depression as criteria for attention deficit-hyperactivity disorder (ADHD),4 well as reduced social competency (internalizing and externa- approximately 40%-50% of children with neurofibromatosis type 1 are diagnosed with attention deficit-hyperactivity disor- Only 1 prior study has assessed sleep issues in children with der. Of these children, 60% show impairments in sustained atten- neurofibromatosis type 1. In this study, children with neurofi- tion, divided attention, and response inhibition.5-7 bromatosis type 1 had higher rates of parasomnias (sleepwalk- Moreover, learning disabilities, as defined by discrepancies ing and night terrors), which correlated with conduct problems, in Intelligence Quotient and achievement, are present in about20% of children with neurofibromatosis type 1,5 compared to8% in the general population.8 A left-shift in Intelligence Quo- 1 Department of Neurology, Washington University School of Medicine, St tients has been reported for children with neurofibromatosis type 1, with 20% of children with neurofibromatosis type 1 2 Division of Biostatistics, Washington University School of Medicine, St Louis, having an Intelligence Quotient score that falls 1 to 2 standard deviations below those of their unaffected siblings.5 School- age children with neurofibromatosis type 1 have been noted David H. Gutmann, MD, PhD, Department of Neurology, Washington University to have more extensive academic and cognitive delays relative School of Medicine, Box 8111, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
to younger children with neurofibromatosis type 1, specifically Table 1. Sleep Disturbances in Children With Neurofibromatosis Type 1 and Unaffected Siblings.
a Unadjusted P values.
b P values after adjusting age and gender.
hyperactivity, and emotional problems.15 However, the preva- Washington University institutional review board and appropriate lence of sleep disturbances, spectrum of sleep abnormalities, and associated features has not been fully examined in this The Sleep Disturbance Scale for Children questionnaire scores population. The purpose of this study was to address these (overall and subscores) and the sleep characteristics (average hours issues in children with neurofibromatosis type 1.
of sleep, time to fall asleep, number of awakenings per night, andnumber of daily naps) were summarized by means and standarddeviations in children with neurofibromatosis type 1 and unaffected siblings. The differences between subjects with neurofibromatosis type1 and unaffected siblings were compared using a generalized estimating Parents of children with neurofibromatosis type 1, age 2 to 17 years, equation to account for potential correlations among children from the cared for in the Neurofibromatosis Clinical Program at Saint Louis same family. Age and gender were further included in the model to Children’s Hospital and Washington University Neurofibromatosis adjust for their potential confounding effects. Regression analysis was Center completed the Sleep Disturbance Scale for Children question- performed to assess which factors had significant associations with the naire. The Sleep Disturbance Scale for Children is a validated question- sleep score in children with neurofibromatosis type 1. All the above naire for which a total sleep disturbances score as well as subscores for tests were 2-sided and a P-value of .05 or less was taken to indicate disorders of initiating and maintaining sleep, sleep breathing disorders, statistical significance. The statistical analysis was performed using disorders of arousal, sleep-wake transition disorders, disorders of exces- Statistical Analysis Software® (SAS Institutes, Cary, NC).
sive somnolence, and sleep hyperhidrosis can be calculated.16 On theSleep Disturbance Scale for Children questionnaire, disorders of arousalinclude sleepwalking, night terrors, and nightmares, whereas sleep-wake transition disorders include hypnic jerks, rhythmic movements, vivid dreams, leg jerking while asleep, sleep-talking, and bruxism.16 A total of 218 children were enrolled, including 129 children Parents also completed the Sleep Disturbance Scale for Children with neurofibromatosis type 1 (64 males, 65 females) and 89 questionnaire for unaffected siblings of children with neurofibromatosis siblings of children with neurofibromatosis type 1 (50 males, type 1, age 2 to 17 years. Parents were asked questions addressing the 39 females) from April 2010 to August 2012. The mean age for pediatric criteria for restless legs syndrome diagnosis.17 Inclusion criteria for the subjects with neurofibromatosis type 1 children with neurofibromatosis type 1 was 8.58 years (stan- required that children were between the ages of 2 and 17 years with dard deviation 4.18, minimum age 2 years, maximum age 17 a diagnosis of neurofibromatosis type 1 established using National years), whereas the mean age for siblings of children with Institutes of Health Consensus Development Conference diagnostic neurofibromatosis type 1 was 9.24 years (standard deviation criteria.18 Exclusion criteria included a diagnosis of neurofibromatosis 4.40, minimum age 2 years, maximum age 17 years).
type 2, age less than 2 years or greater than 17 years, and children who Compared to their unaffected siblings, children with neuro- fibromatosis type 1 were significantly more likely to exhibit A control group was also recruited, consisting of unaffected sib- sleep disturbances (Table 1). Of note, the overall sleep score lings of children with neurofibromatosis type 1 who were between the was higher in children with neurofibromatosis type 1 compared ages of 2 and 17 years and slept in a different bedroom separate from to their unaffected siblings (neurofibromatosis type 1 subject their siblings with neurofibromatosis type 1. Control group exclusion mean score ¼ 43.49, sibling mean score ¼ 38.71; P < .001) criteria included known or suspected neurofibromatosis type 1 or neu-rofibromatosis type 2, sleeping in the same bedroom as their siblings (Table 1). More than half (53.5%, 68/127) of children with neu- with neurofibromatosis type 1, ages less than 2 years or greater than 17 rofibromatosis type 1 had abnormal sleep scores (39 or years, and children who were wards of the state. This study was per- higher),14 whereas 40.5% (36/89) of unaffected siblings had formed under an active human studies protocol approved by the Table 2. Somnolence Disorders Score.
Table 3. Mean Total Sleep Score by Gender and Age.
Abbreviation: SD, standard deviation.
a P values after adjusting age and gender.
Specifically, children with neurofibromatosis type 1 exhibited Abbreviation: SD, standard deviation.
a higher frequency of symptoms indicating abnormalities in initi-ating and maintaining sleep (neurofibromatosis type 1 subjectmean score ¼ 14.16, sibling mean score ¼ 12.37; P ¼ .006), 13 to 17 years. Although the mean total sleep scores were con- sleep-wake transition (neurofibromatosis type 1 subject mean sistently higher in children with neurofibromatosis type 1 than score ¼ 10.14, sibling mean score ¼ 8.78; P ¼ .002), and hyper- unaffected siblings in all age groups, none of the differences hidrosis (neurofibromatosis type 1 subject score ¼ 3.20, sibling were statistically significant, possibly because of relatively score ¼ 2.35; P < .001) but were not more likely to have small sample sizes. Interestingly, there was a trend toward symptoms indicating problems with sleep breathing (neurofibro- significance in the 5- to 9-year-old age group (P ¼ .055). How- matosis type 1 subject mean score ¼ 4.49, sibling mean score ¼ ever, when only mean total sleep scores of children with 4.10; P ¼ .119) or excessive somnolence (neurofibromatosis type neurofibromatosis type 1 among age groups were compared, 1 subject mean score ¼ 8.03, sibling mean score ¼ 7.42; P ¼ there were no significant differences (P ¼ .777).
.134). However, children with NF1 exhibited a lower frequency Children with neurofibromatosis type 1 had a more disrupted of disturbances in arousal compared to their unaffected siblings sleep schedule than their unaffected siblings, with several signif- (NF1 mean score 3.52, sibling mean score 3.82, P = 0.041). In icant differences. Children with neurofibromatosis type 1 had addition, subjects with breathing disturbances were not more reduced mean nightly sleep durations (neurofibromatosis type likely to exhibit hyperhidrosis. When stratified for nightly hours 1 subject mean time ¼8.74 hours, sibling mean time ¼ 9.07 of sleep obtained, scores indicating excessive somnolence were hours; P ¼ .044), longer mean sleep onset latency (neurofibro- higher in children with neurofibromatosis type 1 compared to matosis type 1 subject mean time ¼ 31.48 minutes, sibling mean their unaffected siblings if the most typical hours of sleep were time ¼ 21.84 minutes; P ¼ .009), and a greater mean number of obtained (7-8 hours and 9-10 hours; Table 2). The differences awakenings per night (neurofibromatosis type 1 subject mean in somnolence subscores were significant for 7 to 8 hours of sleep awakenings ¼ 0.85, sibling mean awakenings ¼ 0.55; P ¼ .024).
(neurofibromatosis type 1 subject mean score ¼ 8.92, sibling Diagnoses of attention deficit disorder, cognitive impair- mean score ¼ 7.07; P ¼ .006) and marginally significant for 9 ment, or stimulant medication use did not significantly affect to 10 hours of sleep (neurofibromatosis type 1 subject mean score the overall sleep scores in children with neurofibromatosis ¼ 7.35, sibling mean score ¼ 6.69; P ¼ .079) but not significant if type 1 (Table 4). However, other medications and coexisting other amounts of sleep were obtained nightly. The conclusions medical conditions can also affect sleep. In this regard, 7 of regarding the subscores and total scores in subjects with neurofi- the 67 children with neurofibromatosis type 1 and sleep dis- bromatosis type 1 and their unaffected siblings remained the same turbances had allergies and were prescribed medications for this condition (cetirizine, fexofenadine, mometasone furoate, The mean total sleep scores by gender and age are shown in loratadine). Additionally, 4 children with neurofibromatosis Table 3. The differences in mean total sleep scores between type 1 and sleep problems had asthma and were taking med- children with neurofibromatosis type 1 and unaffected siblings ications (albuterol, fluticasone/salmeterol, montelukast). It were significant in both girls (P ¼ .024) and boys (P ¼ .021).
should be noted that the nature and severity of the asthma Boys with neurofibromatosis type 1 had a higher mean total or allergies (eg, exercise-induced, seasonal) as well as the sleep score than girls with neurofibromatosis type 1, but the dif- frequency and specific formulations (eg, ‘‘non-drowsy’’ pre- ference was not significant (boys: mean ¼ 45.54, standard parations) of the prescribed medications could not be accu- deviation ¼ 15.42; girls: mean ¼ 41.53, standard deviation ¼ rately assessed in these children. Finally, birth order can 10.85; P ¼ .332), and differences in subscores between boys contribute to the frequency of sleep problems. However, the and girls with neurofibromatosis type 1 were not significant.
distribution of birth order in children with neurofibromatosis The mean total sleep scores by age groups in subjects with neu- type 1 and sleep disturbances relative to those children with rofibromatosis type 1 and unaffected siblings are shown in neurofibromatosis type 1 and no sleep problems was similar Table 3 for ages 2 to 4 years, 5 to 9 years, 10 to 12 years, and Table 4. Correlation Between Clinical Features and Mean Total Sleep Score in Children With Neurofibromatosis Type 1.
Children without the neurofibromatosis type Neurofibromatosis type1–associated feature Abbreviations: ADHD, attention-deficit hyperactivity disorder; IEP, individualized educational plan.
Interestingly, there was a trend toward significance in the higher total sleep score. Insomnia and sleep-wake transition association between the presence of a coexisting optic pathway disorders can be associated with sleep disruption and sleepi- glioma and the total sleep score (P ¼ .055). The mean total sleep ness,30-31 potentially affecting daytime functioning. The pres- score did not significantly change with the location of the tumor ence of hyperhidrosis is also suggestive of poor-quality sleep.
along the optic pathway when gliomas along the optic nerve, In a study of 6381 children, 11.7% had weekly night sweats, optic chiasm, and optic tract were compared. Only 1 child with and these children were significantly more likely than children an optic pathway glioma had hypothalamic involvement, and 7 without night sweats to have allergic rhinitis, tonsillitis, and subjects had optic chiasm involvement. No child had surgery for symptoms suggestive of obstructive sleep apnea, insomnia, and an optic pathway glioma. The association between the presence parasomnias.32 In an adult study of 363 patients, night sweats of cognitive impairment and the total sleep score was also mar- were associated with sleepiness, legs jerking during sleep, and ginally significant, and subjects with cognitive impairment had a awakening with pain in the night.33 Night sweats could also be higher mean total sleep score (46.1 vs 41.6; P ¼ .075). Restless found in panic attacks,34 arousal responses during nightmares, legs syndrome was diagnosed in 1 child with neurofibromatosis or autonomic dysfunction from sympathetic overstimulation of type 1 and in 1 unrelated unaffected sibling.15 Although sleep disorders can affect cognitive functioning, our study did not show statistical differences in the mean total sleep scores in patients with neurofibromatosis type 1 relative Children with neurodevelopmental disorders have a high to those without cognitive impairments or those requiring an prevalence of sleep disturbances, with estimates of prevalence individualized educational plan. However, subjects with neuro- ranging from 13% to 86%,19 compared to 11% to 37% reported fibromatosis type 1 and cognitive impairment or requiring an for children with typical development.20,21 Addressing sleep individualized educational plan had higher mean total sleep issues is particularly important in children with neurodevelop- scores than subjects with neurofibromatosis type 1 without mental disorders because of the influence of sleep issues on known cognitive impairment or an individualized educational other spheres of functioning, including learning, behavior, and plan. Future larger studies focused on this association will be mental health. Sleep disturbances in the pediatric population required to confirm these suggestive differences.
dramatically impair school performance, memory, and cogni- In all age groups, children with neurofibromatosis type 1 had tion.22-26 In this regard, children with sleep-disordered higher mean total sleep scores, with the difference approaching breathing are significantly more likely to exhibit hyperactivity, significance in the 5-to 9-year-old age group. Middle-childhood- inattention, and aggressiveness relative to their unaffected age subjects with neurofibromatosis type 1 could be in a transi- counterparts.27 In addition to affecting childhood functioning, tion phase, perhaps exhibiting vulnerability to both sleep disor- childhood insomnia can predispose individuals to develop ders more prevalent in early childhood (bedtime resistance, depression and anxiety later in life.28 Fortunately, treatment parasomnias, and night wakings) and sleep disorders more pre- of the underlying sleep abnormalities has been shown to valent in adolescence, as reported in a study of children with aut- improve the quality of life and behavior in children with ism (delayed sleep onset, shorter sleep duration, and daytime sleepiness).35 Children with neurofibromatosis type 1 also had Given the high incidence of cognitive and behavioral more disrupted sleep relative to their unaffected siblings, with problems in children with neurofibromatosis type 1, we reduced mean nightly sleep durations, longer mean sleep-onset hypothesized that 1 etiologic factor is disturbed sleep. In this latencies, and greater mean numbers of awakenings per night.
report, we show that children with neurofibromatosis type 1 Short sleep duration has been associated with worse school per- were significantly more likely to have symptoms indicating formance, sleepiness, and depression.36 In contrast, coexisting abnormalities in initiating and maintaining sleep, sleep-wake attention deficit disorder, cognitive impairment, or stimulant transition, and hyperhidrosis and were more likely to have a medication use did not significantly affect the overall sleep score among children with neurofibromatosis type 1, although there created the tables. FG and AKL edited the tables. AV and CC col- was a trend toward significance in association with optic path- lected the data. JL collected and compiled the data. KAY and SPD provided expert input. DHG performed the final editing of the To our knowledge, this is the first and largest report to characterize sleep disturbances in children with neurofibromato-sis type 1, and the first to assess for associations between specific clinical characteristics in children with neurofibromatosis type 1 The authors declared no potential conflicts of interest with respect to and sleep disturbance scores. The use of unaffected siblings as the research, authorship, and/or publication of this article: Dr. Duntley control group is a major advantage of the current study, because has a consulting relationship with UCB, Inc, and is participating in amulticenter trial involving Rotigotine for restless leg syndrome. Dr.
it accounts for unobserved family-based confounding factors.
Duntley has a consulting relationship with Jazz Pharmaceuticals. The The mean total sleep score of our control group (38.71) was other authors have no financial conflicts of interest to report.
relatively similar to the mean sleep score of the validation studyfor the Sleep Disturbance Scale for Children questionnaire. In the validation study, the mean total sleep score for control sub- The authors disclosed receipt of the following financial support for the jects was 35.05 (standard deviation ¼ 7.70) and the mean total research, authorship, and/or publication of this article: AKL was sup- score in children with sleep disorders was 54.87 (standard devia- ported by the Neurological Sciences Academic Development Award tion ¼ 12.49) with a cut-off score for abnormality of 39 with (K12 NS001690) and the Washington University Institute of Clinical sensitivity of 0.89 and specificity of 0.74.16 and Translational Sciences grant (UL1 TR000448; National Center for There are limitations to this study, including the limitations Advancing Translational Sciences). The authors also wish to acknowl- associated with the use of parental questionnaires for assessing edge the support of the Biostatistics Core, Siteman Comprehensive sleep characteristics. For example, in a study of adolescents Cancer Center and a National Cancer Institute Cancer Center Support using sleep diary estimates, actigraphic estimates of wake after Grant (P30 CA091842). There was no funding for this study.
sleep onset were substantially greater and total sleep timeswere substantially shorter than reported.37 In addition, future prospective studies will be required to define the potential con- This study was conducted under an approved Human Studies Protocol tributions of other medications, coexisting medical conditions, at the Washington University School of Medicine (#201103204).
and parental occupation (eg, night shift workers) on sleep inchildren with neurofibromatosis type 1.
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Élisabeth Garanger, PhD November 10th 1977 (age 32 ) Laboratoire de Chimie des Polymères Organiques LCPO (UMR5629) - ENSCBP 16 Avenue Pey-Berland, 33607 Pessac Cedex, FRANCE Tel: +33 5 40 00 64 14 E-mail: [email protected] EDUCATION 2001 – 2005: PhD. in chemistry & biology (Joseph Fourier University, Grenoble, 2000 – 2001: MSc. degree in biological organic chemi