Comorbid ADHD and Pediatric Sickle Cell Disease: Prevalence and Risk Factors.

Sickle cell disease (SCD) is a genetic blood condition that places youth at increased risk for deficits in complex attention suggestive of increased risk for Attention-Deficit/Hyperactivity Disorder (ADHD). We used systematic screening to assess the prevalence of ADHD in a clinic-based sample of youth with SCD and explored factors related to ADHD. Caregivers of 107 children with SCD (ages 7-11 years) completed routine psychosocial screening which included inattentive symptoms of ADHD. Follow-up diagnostic procedures were completed for patients with elevated inattentive symptoms to assess for ADHD diagnoses. Biomedical and social-environmental variables were examined from the screening and medical records. Twenty-six percent of patients showed elevated inattentive symptoms with 13% meeting diagnostic criteria for ADHD diagnoses. Most children (75%) who met criteria for ADHD had not been previously diagnosed. Disease severity did not predict inattentive symptoms or ADHD diagnoses, though a measure of chronic inflammation was associated with ADHD. Family functioning was related to elevated inattentive symptoms but not ADHD diagnoses. Children with SCD show relatively high rates of ADHD with many cases not detected through routine care. Screening for ADHD as part of hematology care may be a feasible strategy to improve identification and access to intervention.

Fatigue, Stress Appraisal, and Emotional Functioning Among Youth With Sickle Cell Disease: A Daily Diary Study.

OBJECTIVE: The aim of this study was to assess how fatigue is related to mood among youth with sickle cell disease (SCD) by evaluating if the cognitive appraisal of stress moderates the impact of fatigue on emotional functioning consistent with the Risk-and-Resistance Model of Chronic Illness. METHODS: Daily diaries assessing fatigue (Numerical Rating Scale), pain intensity (Numerical Rating Scale), mood (Positive and Negative Affect Schedule for Children), and cognitive appraisal of stress (Stress Appraisal Measure for Adolescents) were collected from 25 youth with SCD (ages 11-18 years) for 8 consecutive weeks resulting in 644 daily diaries for analyses. RESULTS: When measured concurrently, higher fatigue was associated with higher negative mood controlling for pain and prior-night sleep quality. Fatigue predicted next-day negative mood through its interaction with primary and secondary appraisal of stress, consistent with stress appraisal as a protective factor. A similar pattern was observed for pain, which, like fatigue, is a common SCD-related stressor. CONCLUSION: Fatigue and negative mood are inter-related when concurrently assessed, but their temporal association in SCD suggests that mood changes are not an inevitable sequalae of increased fatigue; fatigue influenced subsequent levels of negative mood, but only in the presence of less adaptive cognitions about stress; specifically, a higher perceived threat from stress and a lower belief in the ability to manage stress. The results suggest specific cognitive targets for reducing the negative impact of fatigue on mood in SCD.

Preschool Pain Management Program for Young Children with Sickle Cell Disease: A Pre-Post Feasibility Study.

OBJECTIVE: Vaso-occlusive pain crises in sickle cell disease (SCD) often begin in early childhood. We developed an online pain management intervention to teach caregivers of preschool-aged children with SCD behavioral pain management strategies. The feasibility study goals were to examine response to recruitment, barriers to participation, engagement, acceptability and perceived usefulness of the intervention, and suitability of outcome measures. METHODS: Caregivers of children aged 2.0-5.9 years with access to text messaging and a device to access online videos were recruited from a Southeastern outpatient hematology clinic for a 12-week intervention consisting of pain management videos. Videos taught caregivers behavioral pain management strategies and adaptive responses to pain. Workbook activities helped tailor strategies to their child. Caregivers completed process measures as well as baseline and follow-up measures of pain catastrophizing (Pain Catastrophizing Scale-Parent Report) and responses to their child's pain (Adult Response to Children's Symptoms). RESULTS: Fifty percent (10 of 20) of eligible parents enrolled. Caregivers partially completed (N = 6), completed (N = 3), or did not engage (N = 1) in the intervention. Caregivers who engaged in the program reported implementing the pain management strategies. The intervention was rated as high quality, relevant, and useful. Measures of pain catastrophizing and responses to their child's pain appeared sensitive to change. CONCLUSIONS: The intervention to promote adaptive coping to pain was acceptable and feasible for caregivers though we found barriers to delivering the intervention to parents. Evaluation of a modified version of the program is indicated to assess implementation issues and effectiveness.

Sleep and fatigue among youth with sickle cell disease: A daily diary study.

Youth with sickle cell disease (SCD) experience disease effects including vaso-occlusive pain crises, poor sleep quality, and fatigue. The present study examines how sleep quality and pain medications impact fatigue in youth with SCD. Daily diaries assessing pain, fatigue, sleep quality, mood, and use of pain medications from 25 youth with SCD ages 11 to 18 years were collected for eight consecutive weeks. Poor sleep quality predicted increases in next-day fatigue levels while controlling for pain and mood. Sleep quality did not moderate the existing temporal relationship between pain and next-day fatigue established by Reinman et al. (2019) as predicted. Non-opioid medications affected ratings of next-day fatigue but opioid medications did not. Sleep quality appears to play an important role in predicting next-day fatigue levels and may be an important target for intervention. Pain medication use did not substantially contribute to prospective fatigue levels among youth, but requires further study.

Neurodevelopmental Outcomes in Preterm Children with Sickle Cell Disease.

OBJECTIVES: To explore the combined effect of pediatric sickle cell disease (SCD) and preterm birth on cognitive functioning. METHODS: Cognitive functioning was examined in children ages 6-8 with high risk SCD genotypes born preterm (n = 20) and full-term (n = 59) and lower risk SCD genotypes/no SCD born preterm (n = 11) and full-term (n = 99) using tests previously shown to be sensitive to SCD-related neurocognitive deficits. Factorial ANOVAs and log linear analyses were conducted to examine the relationship between SCD risk, preterm birth status, and cognitive outcomes. Continuous scores were examined for specific tests. Children were categorized as having an abnormal screening outcome if at least one cognitive score was ≥1.5 standard deviations below the population mean. RESULTS: Children with elevated risk due to high risk SCD and preterm birth performed worse than other groups on a test of expressive language but not on tests that emphasize processing speed and working memory. There was a three-way interaction between preterm status, SCD risk, and abnormal screening outcome, which was largely driven by the increased likelihood of abnormal cognitive scores for children with high risk SCD born preterm. CONCLUSIONS: The combination of SCD and preterm birth may confer increased risk for language deficits and elevated rates of abnormal cognitive screenings. This suggests that neurodevelopmental risk imparted by comorbid SCD and preterm birth may manifest as heterogenous, rather than specific, patterns of cognitive deficits. Future studies are needed to clarify the domains of cognitive functioning most susceptible to disease-related effects of comorbid SCD and preterm birth.

Changes in the developmental status of preschoolers with sickle cell disease.

Developmental monitoring and screening are recommended strategies for identifying children with sickle cell disease at high risk for cerebrovascular complications. Studies examining developmental screenings have provided little data on change over time. We examined screenings longitudinally in 43 children screened as two-year-olds and four-year-olds using the Ages and Stages Questionnaire, 2nd edition. Only two-thirds of children had stable screening outcomes. A new onset of cerebrovascular complications predicted the emergence of developmental delay (P = 0.017). Multivariate analysis suggested a benefit from formal developmental interventions. Regular developmental screening during the preschool period is important to identify systematic changes in developmental status.

A Randomized Controlled Trial of Working Memory Training in Pediatric Sickle Cell Disease.

OBJECTIVE: Youth with sickle cell disease (SCD) are at risk for neurocognitive deficits including problems with working memory (WM), but few interventions to improve functioning exist. This study sought to determine the feasibility and efficacy of home-based, digital WM training on short-term memory and WM, behavioral outcomes, and academic fluency using a parallel group randomized controlled trial design. METHODS: 47 children (7-16 years) with SCD and short-term memory or WM difficulties were randomized to Cogmed Working Memory Training at home on a tablet device (N = 24) or to a standard care Waitlist group (N = 23) that used Cogmed after the waiting period. Primary outcomes assessed in clinic included performance on verbal and nonverbal short-term memory and WM tasks. Secondary outcomes included parent-rated executive functioning and tests of math and reading fluency. RESULTS: In the evaluable sample, the Cogmed group (N = 21) showed greater improvement in visual WM compared with the Waitlist group (N = 22; p = .03, d = 0.70 [CI95 = 0.08, 1.31]). When examining a combined sample of participants, those who completed ≥10 training sessions exhibited significant improvements in verbal short-term memory, visual WM, and math fluency. Adherence to Cogmed was lower than expected (M = 9.07 sessions, SD = 7.77), with 19 participants (41%) completing at least 10 sessions. Conclusions: Visual WM, an ability commonly affected by SCD, is modifiable with cognitive training. Benefits extended to verbal short-term memory and math fluency when patients completed a sufficient training dose. Additional research is needed to identify ideal candidates for training and determine whether training gains are sustainable and generalize to real-world outcomes.

Does Obstructive Sleep Apnea Increase Cognitive Deficits in Pediatric Sickle Cell Disease?

OBJECTIVES: Although pediatric obstructive sleep apnea (OSA) is estimated to affect 2-3% of the general population, its prevalence in sickle cell disease (SCD) is much higher, with research suggesting a prevalence rate of upwards of 40%. Despite the similar underlying pathophysiological mechanisms of neurocognitive effects in pediatric OSA and SCD, there is a scarcity of information on how these two conditions interact. The aim of this study was to better understand the contribution of sleep apnea to neurocognitive deficits in children diagnosed with SCD. METHOD: This study assessed cognitive function in 26 children with comorbid SCD and OSA, 39 matched comparisons with SCD only, and 59 matched comparisons in children without a chronic health condition. RESULTS: There were significant differences on measures of processing speed and reading decoding, with children without a chronic health condition scoring better than both chronic health condition groups. Additionally, the no chronic health condition group performed better on a test of quantitative knowledge and reasoning and a test of visual-spatial construction than the SCD-only group. Contrary to our hypotheses, there were no between-group differences suggesting an additive impact of OSA on cognition. Exploratory analyses revealed associations within the group that had OSA showing that more severe OSA correlated with lower performance on measures of processing speed and quantitative knowledge/reasoning. CONCLUSIONS: Children with comorbid OSA and SCD do not present with greater deficits in cognitive functioning than children with SCD alone. However, severe OSA may confer additional risk for neurocognitive impairments.

Predictive validity of developmental screening in young children with sickle cell disease: a longitudinal follow-up study.

AIM: To assess the predictive validity of developmental screenings in children with sickle cell disease (SCD) for academic outcomes and stroke risk. METHOD: Parent questionnaires and medical record data were collected for a cohort receiving developmental screenings between September 2004 and May 2008 as toddlers or early school age. Screening outcomes were dichotomized (positive, negative) by a priori criteria. Questionnaires assessed school and social functioning, services received, and quality of life. Medical record data assessed general SCD morbidity and stroke risk. RESULTS: Forty-one toddlers (mean age 2y 5mo; 25 males, 16 females) and 49 early school-age children (mean age 6y 5mo; 26 males, 23 females) completed follow-up. The mean follow-up period was 8 years 6 months (range 6.1-10.8y). For toddlers, positive screenings for language delays predicted lower academic performance (p=0.023). For older children, positive screenings for cognitive delays predicted more frequent academic/attentional problems at school (p<0.001), grade retention (p=0.007), and lower academic performance (p=0.001). Positive screenings were associated with an earlier onset of school problems and lower quality of life. Positive screenings for language/cognitive delays predicted increased stroke risk (both p<0.05). INTERPRETATION: Screening for language or cognitive development in young children with SCD predicts academic outcomes and stroke risk. WHAT THIS PAPER ADDS: Developmental screening predicts academic outcomes in sickle cell disease. Children with concerning language/cognitive screenings have early-onset school difficulties. Developmental screenings may help predict cerebrovascular complications.

Comorbid obstructive sleep apnea and increased risk for sickle cell disease morbidity.

PURPOSE: Sickle cell disease (SCD) imparts an increased risk for obstructive sleep apnea (OSA) in childhood. Studies of pediatric SCD have identified an increased risk for pain and neurologic complications with comorbid OSA. We determined the rate of a broad range of SCD-related medical complications to better characterize the spectrum of SCD complications related to OSA. METHODS: Retrospective chart review at a single hematology clinic identified 641 youth with SCD who received consistent screenings for OSA as part of routine hematological health maintenance visits over an 11-year period. Medical complication rates in the 136 children with OSA determined by polysomnography exams were compared to 136 matched controls at lower risk for OSA due to negative OSA screenings or exams. RESULTS: Children with SCD and OSA had higher overall rates of SCD complications than low OSA-risk controls; lung morbidity showed the largest effect size. Infection, cardiovascular, and neurologic complications occurred at higher rates in children with OSA. Children with comorbid OSA had higher rates of SCD complications both before and after OSA diagnosis. CONCLUSIONS: OSA in children with SCD is associated with higher rates of a broad range of SCD complications, including pneumonia and acute chest syndrome. Routine screenings, diagnosis, and increased therapeutic intervention for children with comorbid OSA could decrease SCD morbidity.

Feasibility of Home-Based Computerized Working Memory Training With Children and Adolescents With Sickle Cell Disease.

BACKGROUND: Children with sickle cell disease (SCD) are at increased risk for neurocognitive deficits, yet the literature describing interventions to ameliorate these problems and promote academic achievement is limited. We evaluated the feasibility and preliminary efficacy of a home-based computerized working memory (WM) training intervention (Cogmed) in children with SCD. PROCEDURE: Youth with SCD between the age of 7 and 16 years completed an initial neuropsychological assessment; those with WM deficits were loaned an iPad on which they accessed Cogmed at home. Participants were instructed to work on Cogmed 5 days each week for 5 weeks (25 training sessions). We examined Cogmed usage characteristics and change on WM assessment scores following the intervention. RESULTS: Of the 21 participants (M age = 11.38, SD = 2.78; Mdn age = 10.00, interquartile range [IQR] = 5.00; 52% female) screened, 60% exhibited WM deficits (n = 12) and received the intervention and 50% (n = 6) completed Cogmed. The mean number of sessions completed was 15.83 (SD = 7.73; Mdn = 17.00, IQR = 16.00); females were more likely to complete Cogmed, χ(2) (1) = 6.00, P = 0.01. Participants who reported lower SCD-related pain impact completed more sessions (r = 0.71, P = 0.01). Children who completed Cogmed exhibited improvements in verbal WM, visuospatial short-term memory, and visuospatial WM. CONCLUSIONS: Initial findings suggest Cogmed is associated with WM improvement in youth with SCD; however, adherence was lower than expected. Home-based WM interventions may ameliorate SCD-related WM deficits but strategies are needed to address barriers to program completion.

Examining Biopsychosocial Factors in Relation to Multiple Pain Features in Pediatric Sickle Cell Disease.

OBJECTIVE: To examine biopsychosocial variables in relation to multiple pain features in pediatric sickle cell disease (SCD). METHODS: 76 children with SCD (M = 14.05, SD = 3.26), ages 8-19 years, and 70 caregivers completed measures of coping, mood, and family functioning and reported on multiple pain features via retrospective interviews during routine hematological visits. Sickle cell genotype and health care utilization were collected via medical record review. Using hierarchical regression, biological (genotype), child psychological (coping and mood), and social factors (caregiver coping and family functioning) were evaluated in relation to multiple pain features. RESULTS: Genotype was associated with pain intensity, and child psychological factors were associated with pain frequency. Multiple biopsychosocial factors were related to health care utilization. CONCLUSIONS: Biopsychosocial factors may have distinct relationships with pain features in pediatric SCD. Understanding these relationships may refine the biopsychosocial model and inform integrated medical and psychosocial approaches in SCD.

Modulation of pain in pediatric sickle cell disease: understanding the balance between endothelin mediated vasoconstriction and apelin mediated vasodilation.

Children with sickle cell disease (SCD) have painful vaso-occlusive episodes (VOEs), which often reoccur across the individual's lifespan. Vaso-constrictive and vaso-dilatory molecules have been hypothesized to play a role in VOEs. Endothelin-1 (ET-1) is a potent vasoconstrictor that is released during VOEs and is correlated with pain history. Apelin is a vaso-dilatory peptide that also has a modulatory role in pain processing. We hypothesize that the ratio between vaso-dilatory and vaso-constrictive tone in children with SCD may be a marker of pain sensitization and vaso-occlusion. Plasma endothelin and apelin levels were measured in 47 children with SCD. Procedural pain and baseline pain were assessed via child- and caregiver-reports and observational distress. Pain history was assessed using retrospective chart review. Plasma apelin was related to age, with decreased levels in older children. The ratio between apelin and ET-1 was negatively correlated to observational baseline pain. The ratio between apelin and Big ET was negatively correlated to caregiver ratings of baseline pain and positively correlated to history of VOEs, which is possibly due to hydroxyurea treatment. These results suggest that an imbalance in the apelin and endothelin systems may contribute to an increasing number of VOEs and baseline pain in children with SCD.

EXAMINER executive function battery and neurologic morbidity in pediatric sickle cell disease.

Sickle cell disease (SCD) is blood disorder with a high risk for cerebral vascular morbidities that impact neurocognitive functioning. Specific cognitive abilities are known to be more sensitive to neurologic effects of SCD than IQ scores, yet there is little consensus about which measures to use to assess neurocognitive functioning. We evaluated the ability of the Executive Abilities: Methods and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Battery to detect neurologic effects in SCD. Thirty-two youth with SCD and sixty demographically-matched comparison youth completed the EXAMINER Battery and selected tests from the Woodcock-Johnson Tests of Cognitive Ability, 3rd edition (WJ-III). Neurologic severity was examined via clinical history for morbidities and midsagittal corpus callosum (CC) area. Results indicated cognitive performance decreased with increasing neurologic morbidity across all cognitive measures; two of four EXAMINER factors were related to CC area. The association with clinical history and midsagittal CC area appeared at least as large for the Examiner Battery scores as for the WJ-III measures. The Examiner Battery showed sensitivity to neurologic history and white matter effects in SCD; this new measure compares favorably to established measures of disease-related neurocognitive effects, but would benefit from further development.

Information-seeking coping behaviors during painful procedures in African-American children with sickle cell disease.

This study examined the frequency of information-seeking coping behaviors in 37 African-American children (ages 5-17 years) with sickle cell disease during venipuncture. The relationships between coping behaviors and child- and parent-reported pain and observational distress were also assessed. The majority of children attended to the procedure, but did not seek information via questions. This pattern of coping was only partially effective at reducing distress and had no relation to pain. This pattern of coping is discussed within the context of cultural factors that may be important in understanding responses to procedural pain in pediatric sickle cell disease.

Implementation of Two Developmental Screening Programs in Sickle Cell Disease Specialty Care.

Objective: Developmental screening is a critical component of care for children with sickle cell disease (SCD), who are at elevated risk for neurodevelopmental disorders. This report describes the implementation of two related developmental screening programs implemented in different SCD specialty care settings with the purpose of describing screening protocols, outcomes, and lessons learned. Methods: Program One reviewed medical records for 201 children with SCD screened at ages 2 and 4 years. Program Two reviewed program tracking and visit notes for 155 screenings across 67 children screened between 9 and 66 months of age. Key outcomes included characteristics of children screened, screening results, concordance between parent concerns and screening outcomes, and access to evaluation and intervention services. Results: Each program identified a substantial number of children with developmental concerns, including 42% of screenings in Program One and 36% of unique children screened in Program Two. Program One resulted in 56% of identified children receiving follow-up developmental services and 62% receiving developmental monitoring. Program Two resulted in 58% of identified children receiving further evaluation following developmental screening, with 67-75% of children with neurodevelopmental diagnoses receiving intervention services following evaluation. While parent concerns were related to screening outcomes, screening instruments detected many children whose parents did not express developmental concerns. Conclusions: Routine developmental screening is a feasible, acceptable, and effective method for identifying concerns in children with SCD in specialty care. Flexible and collaborative care and sustainability are key considerations for effective programming, with pediatric psychologists uniquely positioned to provide optimal integrated care.

Responsiveness of the PedsQL to pain-related changes in health-related quality of life in pediatric sickle cell disease.

OBJECTIVE: To determine if caregiver report of the pediatric quality of life inventory (PedsQL) is responsive to changes in health-related quality of life (HRQL) associated with pain episodes in pediatric sickle cell disease (SCD). METHODS: 81 caregivers of children ages 2-19 years with SCD completed the PedsQL as part of routine psychosocial screenings at 2 time points, ranging from 6 to 18 months apart. Frequency of SCD-related pain episodes between time points was assessed using medical chart review. RESULTS: The frequency of pain episodes between time points was a significant predictor of decreases in physical, psychosocial, and total HRQL, even after controlling for time interval, demographic, and medical variables. CONCLUSIONS: The caregiver report of the PedsQL appears to be a useful tool for capturing changes in HRQL over time associated with pain episodes in SCD.

Sociodemographic and Biomedical Correlates of Developmental Delay in 2- and 4-Year-Olds with Sickle Cell Disease.

BACKGROUND: Developmental delay occurs frequently in sickle cell disease (SCD). Psychosocial and biomedical factors contribute to delays, but most studies have not examined the timing of risk factors and developmental delay. We examined sociodemographic and biomedical factors to evaluate whether risks of developmental delay differed across 2 developmental periods. METHODS: We examined Ages and Stages Questionnaire, second edition (ASQ-2), outcomes in 2-year-olds (n = 100) and 4-year-olds (n = 101) with SCD. ASQ-2 data were obtained from routine developmental screenings administered as part of health care between 2009 and 2016 at a single hematology clinic. Medical record reviews were used to identify sociodemographic and biomedical factors associated with positive screenings for developmental delay. RESULTS: Two-year-olds with positive ASQ-2 screenings (n = 32; 32%) were less likely to have private health insurance or to have been in formal daycare and more likely to have a severe SCD genotype. Four-year-olds with positive screenings (n = 40; 40%) were more likely to have a severe SCD genotype or an abnormal transcranial Doppler ultrasound (TCD) examination indicating high stroke risk. The strength of the association between positive screenings and insurance status, severe genotypes, and TCD examinations differed across the 2 age groups. Domain-level outcomes on the ASQ-2 also differed across the 2 age groups. CONCLUSION: The cross-sectional data indicate biomedical and psychosocial risks are related to developmental delay, but the association with specific risk factors differs across age.