Sleep, Fatigue and Neurodevelopmental Outcomes in Pediatric Sickle Cell Disease

Research Article

Austin Pediatr. 2017; 4(2): 1056.

Sleep, Fatigue and Neurodevelopmental Outcomes in Pediatric Sickle Cell Disease

Rogers VE¹* and Lance EI²

¹School of Nursing Department of Family & Community Health, University of Maryland Baltimore, USA

²Department of Neurology, Kennedy Krieger Institute, Baltimore, USA

*Corresponding author: Rogers VE, School of Nursing Department of Family & Community Health, Baltimore, USA

Received: May 12, 2017; Accepted: June 13, 2017; Published: June 20, 2017

Abstract

Background: Children with sickle cell disease (SCD) experience neurodevelopmental decline over time. They also tend to have short duration, poor quality sleep and elevated fatigue levels. This study aimed to describe sleep and fatigue in children and adolescents with SCD and their association with neurodevelopmental measures.

Methods: Participants included 19 children and adolescents with SCD, aged 7-18 years, recruited from a tertiary care SCD clinic. The majority were referred for neurodevelopmental testing due to academic or behavioral difficulties. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants completed the Wide Range Achievement Test (WRAT) and wore an actigraph for one week. Both completed the PedsQL Multidimensional Fatigue scale.

Results: Short duration or poor quality sleep were identified in every participant. Fatigue was common. Eighteen participants had at least one abnormal result of the six neurodevelopmental subscales administered. No sleep measure was associated with any neurodevelopmental measure. Greater parent-proxy reported cognitive fatigue was associated with lower WRAT reading (p=0.041), spelling (p=0.002) and math (p=0.010) scores, and with poorer scores on two BRIEF subscales. Greater reported parent-proxy general fatigue was associated with elevated scores on all three BRIEF subscales.

Conclusion: Fatigue more importantly than sleep appears to be related to deficits in academic skills and executive function in a clinical sample at risk for neurodevelopmental problems. Larger studies are needed to better define the effects of sleep and fatigue on specific aspects of cognition and behavior in children and adolescents with SCD across early development.

Keywords: Sickle Cell Disease; Children; Adolescents; Sleep; Fatigue; Cognition

Abbreviations

BRIEF: Behavioral Rating Inventory Of Executive Function; FI: Fragmentation Index; Hb: Hemoglobin; MRI: Magnetic Resonance Imaging; SCD: Sickle Cell Disease; SE: Sleep Efficiency (%); SOL: Sleep Onset Latency (Min); TCD: Transcranial Doppler Ultrasonography; TST: Total Sleep Time (Min); WASO: Wake After Sleep Time (Min); WRAT-4: Wide Range Achievement Test–Version 4

Introduction

Sickle cell disease (SCD) is a group of genetic disorders characterized by the presence of abnormal hemoglobin S, which has a propensity to polymerize, or sickle, under certain conditions. This process leads to anemia with accompanying decreased oxygen delivery, and tissue hypoxemia due to vaso-occlusion. Multiple genotypes of SCD have been identified, with homozygous hemoglobin (Hb) SS and HbSβ0 thalassemia generally demonstrating more severe phenotypes, while HbSC and HbS-β+ thalassemia generally have milder presentations. However, these pathobiological processes occur in all individuals with SCD regardless of disease severity [1]. In turn, they contribute to ongoing, progressive organ damage [2], a high risk for stroke and silent cerebral infarct [3,4] and progressive decrements in cognition and behavior. The term neurodevelopmental functioning is used in this in this article to refer to the way the brain and nervous system affect learning, cognition and behavior.

Neurodevelopmental impairment is common in children with SCD compared to their siblings and healthy peers [5,6]. It presents in a number of domains such as academic achievement, intelligence, executive function and behavior. Impairment begins in infancy [7] and can progress over time. While the aforementioned SCD-related sequelae are significant contributors to this decline, deficits cannot be attributed exclusively to these events. Family and environmental factors such as poverty, stress, maternal education, parenting skills and the home environment [8] have also been shown to impact the development of children with SCD. Fatigue, too, can impact cognitive development [9] and has additionally been associated with disrupted sleep in children with SCD [10].

Sleep is a less commonly considered variable that may impact pediatric neurodevelopment. Research in the general pediatric population suggests that short duration and poor quality sleep contribute to neurodevelopmental impairment [11]. Disturbances in sleep duration and quality are common in children with SCD due to sleep-interfering disease symptoms such as pain and enuresis [12,13]. Little is known about neurodevelopmental risks posed by sleep problems in children with SCD, yet it is conceivable that the impairment they cause might be even greater than seen in typically developing children due to their additional underlying neurological vulnerability [14,15]. Given the high prevalence of sleep disturbances in children with SCD, if short duration or poor quality sleep are found to be risk factors for neurodevelopmental impairment, a majority of these children could be affected. Minimizing adverse neurodevelopmental outcomes is imperative to helping children with SCD achieve optimal health, quality of life, and academic and personal potential.

There were two aims to this study. The first aim was to describe the sleep of children with SCD who underwent neurodevelopmental testing and compare it to the sleep of typically developing children without SCD reported in the literature and research-based sleep recommendations [16-19]. Given the association between fatigue and sleep, and the potential for both to affect cognitive development, the second aim was to explore associations between sleep, fatigue and neurodevelopmental outcomes. It was hypothesized that shorter duration and poorer quality sleep, and greater levels of fatigue, would be associated with greater neurodevelopmental deficits.

Materials and Methods

Procedures

Participants were recruited from a tertiary care SCD clinic between September 2013 and April 2015. Recruitment occurred only during the school year to standardize the sleep schedule. Data were not collected during periods of transition that affect sleep, such as the first and last two weeks of the school year, major holidays, and the week following the daylight savings time change. Baseline evaluation included questionnaires, neurodevelopmental testing if not completed previously for clinical reasons, and training on use of the actigraph and sleep diary. This was followed by seven consecutive days of wearing the actigraph at home, and concurrently completing a sleep diary. Families received compensation for participation.

Participants

Children and adolescents aged 7-18 years with any type of SCD were recruited. Participants were specifically recruited, where possible, if they had been referred for neurodevelopmental testing due to academic or behavioral difficulties. All children had either undergone recent clinically indicated formal neurodevelopmental assessment or were willing to undergo assessment as part of study participation. Exclusion criteria were major psychiatric illness, neurological, or neuromuscular disorder severe enough to disrupt regular school attendance, and pregnancy.

This study was approved by the Institutional Review Boards of Johns Hopkins Hospital and the University of Maryland, Baltimore Human Research Protections Office. Prior to participation, parents provided written informed consent for children less than 18 years of age, and children 7-17 years provided written assent. Participants 18 years old self-consented.

Measures

Information was collected by parent report and from the medical record, and included age, sex, race, SCD genotype, results of neuroimaging studies including brain magnetic resonance imaging (MRI) and transcranial Doppler (TCD) velocities, and current use of hydroxyl urea or chronic blood transfusion.

Sleep was measured with an actigraph (Actiwatch2, Philips Respironics, and Bend, OR), a wrist-worn battery operated device that measures movement and translates it into measures of sleep and wake. It also contains a light meter that continuously measures light exposure. Actigraphy has demonstrated validity as an objective measure of sleep [20,21]. The actigraph was worn on the nondominant wrist continuously for seven days and nights, a period of time that produces the most reliable measures of sleep minutes in children [22]. Data were collected in 60 second epochs, and sleep and wake were calculated using the medium sensitivity (default) threshold. Actigraphs were not removed for bathing.

Sleep parameters collected for this study were defined as follows. Total sleep time (TST) was minutes of sleep between nocturnal sleep onset and morning awakening. Total nap time included the number of minutes of any daytime sleep. Sleep onset latency (SOL) was the number of minutes from bedtime to sleep onset. Sleep efficiency (SE) was the total minutes of sleep divided by total minutes from sleep onset to sleep offset, as a percent. Wake after sleep onset (WASO) was the number of minutes of wake between sleep onset and sleep offset. Finally, the sleep fragmentation index (FI) was defined as the sum of percent mobile and percent immobile (no movement) bouts of less than one-minute duration to the number of immobile bouts for the given interval. The FI is an index of restlessness during sleep, where a higher score indicates greater sleep disruption. An event marker on the actigraph was pressed at bedtime and wake time each day to mark the sleep period.

A sleep diary was kept concurrently with actigraphy. Parents or participants recorded bedtimes, wake times, actigraph off-wrist times, and presence of pain and pain medication use during the previous night. Sleep diary data, event markers, and light measurements recorded by the actigraph were used to manually edit sleep periods in order to optimize the scoring and interpretation of sleep [23].

Quality of life related to fatigue was measured using the PedsQL™ Multidimensional Fatigue Scale developed by Dr. James W. Varni [24]. This is an 18-item child/adolescent report and parent-proxy report of child fatigue that yields three 6-item subscale scores: general fatigue, sleep/rest fatigue, and cognitive fatigue. Responses are rated on a 5-point Likert scale from 0 (never) to 4 (almost always). Items are then scored or reverse-scored such that lower scores indicated greater fatigue, and linearly transformed to a 0-100 scale. This scale has been validated in children with SCD [25,26], and yielded Cronbach’s alphas for the child self-report and parent-proxy report fatigue subscales of, respectively, 0.84 and 0.93 for general fatigue, 0.77 and 0.90 for sleep/ rest fatigue and 0.84 and 0.97 for cognitive fatigue. Scales with alphas of =0.70 are recommended for group comparisons [27].

The Wide Range Achievement Test-Version 4 (WRAT-4) is a measure of academic performance validated in a sample of over 15,000 people aged 5-94 years in the U.S. Reported scores are standardized to a mean (SD) of 100 (15), with scores <90 classified as below average [28]. Three subscales of the WRAT-4 were completed by participants: word reading, spelling, and math computation.

The Behavioral Rating Inventory of Executive Function (BRIEF) [29] is an 86-item parent-report assessment of executive function behaviors of children and adolescents ages 5–18 years. The scale was normed on data from 1419 parents from a representative distribution of socioeconomic statuses [29]. Scores are reported as t-scores normed at a mean (SD) of 50 (10), with higher scores indicating higher dysfunction. T-scores of =65 were classified as ‘elevated’ [30]. Three subscales of the BRIEF were measured: behavioral regulation index (ability to shift cognitive set and modulate behavior and emotions), metacognition index (ability to plan, organize, initiate, self-monitor and sustain working memory) and global executive composite (overall executive function).

Statistical analysis

Descriptive statistics were used to describe the sample and their sleep, fatigue and neurodevelopmental test scores. Actigraphic sleep parameters were compared descriptively to published sleep parameters of healthy children and research-based sleep recommendations [16-19]. Paired t-tests were used to test for differences between parent-proxy and self-reported fatigue subscales. Spearman correlation was used to test associations between sleep, fatigue and neurodevelopmental scores. WRAT-4 scores were dichotomized into ‘average or above average’ and ‘below average’ (standardized score <90). BRIEF scores were dichotomized into ‘normal’ or ‘elevated’ (t-score =65) for descriptive purposes. Analyses were carried out using IBM SPSS Statistics, Version 21. Statistical significance was a p-value <0.05.

Results

Nineteen children and adolescents with SCD and their parent participated in the study. Sample descriptors are detailed in Table 1. Details regarding enrollment rates and reasons for nonparticipation were not recorded; however, failing to keep scheduled study appointments was common, with eight children who qualified and were scheduled for participation failing to keep their appointment. Mean lag time between neurodevelopmental testing and the start of the study for 12 patients who had previously undergone clinically indicated testing was 30.7±39.0 days (range 0-131 days). The remaining 7 participants were evaluated on the first day of the study. All testing was performed in a private room in an outpatient clinic by one of the authors (EIL), a neurodevelopmental physician who works with children with SCD. Three of ten participants who had brain MRIs had evidence of overt stroke and one had a silent cerebral infarct.