Executive Functioning Predicts Adaptive Functioning and Self-Care Independence in Pediatric Sickle Cell Disease.

OBJECTIVE: This study examined the impact of executive functioning (EF) on adaptive functioning and self-care independence in pre-transition youth with sickle cell disease (SCD). METHODS: Thirty-four youth with SCD (ages 12-18 years) completed a brief neuropsychological battery and their caregivers completed questionnaires assessing adaptive functioning, EF behaviors, and independence in completing self-care tasks, including disease management. Hierarchical linear regression analyses were utilized to investigate if EF predicted significantly more variability in adaptive functioning and self-care independence than what is accounted for by socioeconomic status (SES), disease knowledge, and estimated intellectual functioning. RESULTS: Mean performance on standardized measures assessing working memory, processing speed, and EF skills fell in the low average range. Performance-based EF and caregiver-reported EF behaviors predicted variance in adaptive functioning and self-care independence above and beyond that accounted for by SES, disease knowledge, and intelligence, with moderate to large effect sizes. CONCLUSIONS: EF skills may support the ability of youth with SCD to adequately achieve independence in self-care, including medical self-care, and other adaptive skills, which may increase the likelihood of successful transition to young adulthood. These findings provide support for the role of neuropsychological screening and individualized intervention in interdisciplinary transition programs.

Hydroxyurea Use Associated with Nonverbal and Executive Skills in Sickle Cell Anemia.

OBJECTIVE: Hydroxyurea (HU) is used in children with sickle cell disease (SCD) to increase fetal hemoglobin (HF), contributing to a decrease in physical symptoms and potential protection against cerebral microvasculopathy. There has been minimal investigation into the association between HU use and cognition in this population. This study examined the relationship between HU status and cognition in children with SCD. METHODS: Thirty-seven children with SCD HbSS or HbS/ß0 thalassaemia (sickle cell anemia; SCA) ages 4:0-11 years with no history of overt stroke or chronic transfusion completed a neuropsychological test battery. Other medical, laboratory, and demographic data were obtained. Neuropsychological function across 3 domains (verbal, nonverbal, and attention/executive) was compared for children on HU (n = 9) to those not taking HU (n = 28). RESULTS: Children on HU performed significantly better than children not taking HU on standardized measures of attention/executive functioning and nonverbal skills. Performance on verbal measures was similar between groups. CONCLUSIONS: These results suggest that treatment with HU may not only reduce physical symptoms, but may also provide potential benefit to cognition in children with SCA, particularly in regard to attention/executive functioning and nonverbal skills. Replication with larger samples and longitudinal studies are warranted.

Family Functioning, Medical Self-Management, and Health Outcomes Among School-Aged Children With Sickle Cell Disease: A Mediation Model.

Background: Informed by the Pediatric Self-Management Model, the present study tested relationships between parent and family functioning, sickle cell disease (SCD) self-management, and health outcomes for children with SCD. Method: 83 children with SCD and a parent completed baseline data as part of a larger investigation of a family-based, problem-solving intervention for children with SCD (M age = 8.47). Youth and parents completed a measure of child health-related quality of life (HRQOL), and parents completed measures of family efficacy, parenting stress, and SCD self-management. SCD pain episodes and urgent health utilization information over the past year were obtained via medical chart review. Results: SCD self-management mediated the relationship between parent-reported family efficacy and parent proxy HRQOL, as well as the relationship between parenting stress and child and parent proxy HRQOL. Mediation models were nonsignificant for outcomes beyond HRQOL, including SCD pain episodes and urgent health utilization. Conclusion: Fostering family efficacy and reducing parenting stress may be meaningful intervention targets for improving SCD self-management and child HRQOL among school-aged children. Although findings were consistent with the Pediatric Self-Management Model in terms of HRQOL, the model was not supported for pain episodes or urgent health utilization, highlighting the need for multi-method, longitudinal research on the SCD self-management behaviors that are linked to preventable health outcomes.

Lessons Learned From a Randomized Controlled Trial of a Family-Based Intervention to Promote School Functioning for School-Age Children With Sickle Cell Disease.

OBJECTIVE: Tested a family-based group problem-solving intervention, "Families Taking Control," (FTC) to improve school functioning and health-related quality of life (HRQL) for children with sickle cell disease. METHOD: Children and caregivers completed questionnaires assessing HRQL and school functioning and children completed performance-based measures of IQ and achievement at baseline and 6 months later. Families were randomized to the intervention (FTC, n = 42) or delayed intervention control (DIC, n = 41) group. FTC involved a full-day workshop followed by 3 booster calls. RESULTS: There were no differences between FTC completers (n = 24) and noncompleters (n = 18). FTC group (n = 24) and DIC group (n = 38) did not differ significantly on primary outcomes at follow-up: number of formal academic and disease-related accommodations, individualized education plan/504 service plan, school absences, school HRQL, or academic skills. CONCLUSIONS: Although families found FTC to be acceptable, there were no intervention effects. Challenges of the trial and implications for future research are discussed.

Hypoxia and inflammation in children with sickle cell disease: implications for hippocampal functioning and episodic memory.

Children with sickle cell disease (SCD) suffer from systemic processes (e.g., chronic anemia, recurrent hypoxic-ischemic events, chronic inflammation) that have been associated with neurocognitive impairment in a range of clinical populations, but which have been largely understudied in relation to specific domains of cognitive functioning in children with SCD. This review focuses on episodic memory, as the hippocampus may be especially vulnerable to the systemic processes associated with SCD. The first part of the paper outlines the pathophysiology of SCD and briefly reviews the extant literature on academic and cognitive functioning in children with SCD, emphasizing the dearth of research on episodic memory. Next, the complex systemic processes of hypoxia and inflammation associated with SCD are reviewed, along with research that has associated these processes with hippocampal damage and memory impairment. The paper concludes with suggestions for future research that are informed, in part, by the literature on developmental amnesia.

Laboratory Biomarkers, Cerebral Blood Flow Velocity, and Intellectual Function in Children with Sickle Cell Disease.

OBJECTIVE: The aim of this preliminary study was to describe putative markers of cerebral vasculopathy and investigate relationships among these markers, demographic factors, and cognitive function in a young sample of neurologically normal children with SCD. Study Design. Thirty-eight children with homozygous HbS, aged 4-11 years, were included. Estimated IQ and markers of coagulation and endothelial activation, hemolysis, and inflammation, as well as transcranial Doppler velocities, hydroxyurea use, and demographic information were obtained. RESULTS: Using multiple regression analyses, there were few significant independent associations between biomarkers or blood flow velocity and estimated IQ. Lactic dehydrogenase (LDH) independently predicted cognitive function, but blood flow velocity did not mediate this relationship. Maternal education, patient age, and hydroxyurea status were independent predictors of cognition. Given the small sample size, a LASSO statistical model was employed to further identify potential predictors of IQ, which identified LDH, absolute neutrophil count (ANC), platelet count, thrombin-antithrombin (TAT), tissue factor (TF), maternal education, age, and hydroxyurea as potential predictors of cognition. CONCLUSIONS: In addition to effects of age and maternal education, some vasculopathic markers are associated with cognitive function in young children with SCD, and these relationships do not appear to be mediated through blood flow velocity. Although the lack of association among certain variables was not as predicted, results provide support for further research regarding the influence of vasculopathic markers on cognitive function in children with SCD without stroke, especially intravascular hemolysis and coagulation/endothelial activation, and a possible role for HU treatment in preventing or reversing cognitive decline.

Executive function "drives" differences in simulated driving performance between young adults with and without autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) may experience greater difficulty learning to drive than peers who do not have ASD, but reasons for those differences are unclear. This study examined how diagnostic symptoms of ASD and commonly co-morbid executive dysfunction relate to differences in simulated driving performance between young, inexperienced drivers with and without ASD. Participants included 98 young adults, ages 16-26 years, half of which were diagnosed with ASD. Participants with ASD completed the Autism Diagnostic Observation Schedule (ADOS-2) and self- and parent-report versions of the Social Responsiveness Scale (SRS-2) to confirm diagnosis and assess the severity of ASD symptoms. All participants completed neuropsychological tests measuring executive functioning. Driving behaviors, including speed and lane positioning, were assessed on a virtual reality driving simulator. Analyses were conducted to first examine relationships between autism severity and driving behaviors, and then to examine whether neurocognitive performance mediated differences in driving behaviors between young adults with and without ASD. Controlling for age, gender, and licensure status, ASD symptom severity was not significantly related to driving. Neurocognitive variables were grouped into three factors: Speed of Information Processing, Auditory Attention and Working Memory, and Selective and Divided Attention. Speed of Information Processing significantly mediated group driving differences. Results suggest that assessment of executive functions such as processing speed may be more useful than the diagnostic assessment of ASD symptoms for evaluation of driving readiness.

Neuropsychological outcome following thalamic stroke in adolescence: an identical twin comparison.

Objective: Medial thalamic stroke in adults commonly results in severe learning and memory impairments and executive dysfunction, particularly during the acute phase. However, there is limited research on the cognitive recovery from thalamic stroke in physically healthy adolescents. This study aimed to fill this gap in the literature by utilizing a monozygotic twin control to investigate the neuropsychological outcomes of bilateral thalamic stroke in adolescence. Method: We evaluated an otherwise healthy 17-year-old male with a history of premature birth, developmental delay, and learning disability 2 and 7 months after he sustained a bilateral medial/anterior thalamic stroke of unknown etiology. His identical twin brother served as a case control. Results: The patient presented with improvements in many cognitive skills between assessments, most notably processing speed. Despite some mild improvement, however, he presented with significant deficits in fine motor speed/coordination, spatial perception, and rapid naming. Additionally, he exhibited persistent, severe deficits in verbal learning and memory. Relative sparing of executive functions (i.e., planning and set-shifting) and attention on standardized measures in this case may be explained by good underlying health, limited extra-thalamic damage, and/or recovery of function. The effects of thalamic injury resulted in minimal adaptive dysfunction or deterrence from academic or athletic success for the presented case. Conclusions: These results suggest risk for deficits in encoding of new verbal information following bilateral thalamic stroke in adolescence, as well as risk for persistent cognitive deficits despite initial improvements. This is consistent with descriptions of anterograde memory impairments in adults with similar lesions.

Driving Comparisons Between Young Adults with Autism Spectrum Disorder and Typical Development.

OBJECTIVE: Many individuals with autism spectrum disorder (ASD) are reluctant to pursue driving because of concerns about their ability to drive safely. This study aimed to assess differences in simulated driving performance in young adults with ASD and typical development, examining relationships between driving performance and the level of experience (none, driver's permit, licensed) across increasingly difficult driving environments. METHOD: Participants included 50 English-speaking young adults (16-26 years old) with ASD matched for sex, age, and licensure with 50 typically-developing (TD) peers. Participants completed a structured driving assessment using a virtual-reality simulator that included increasingly complex environmental demands. Differences in mean speed and speed and lane variability by diagnostic group and driving experience were analyzed using multilevel linear modeling. RESULTS: Young adults with ASD demonstrated increased variability in speed and lane positioning compared with controls, even during low demand tasks. When driving demands became more complex, group differences were moderated by driving experience such that licensed drivers with ASD drove similarly to TD licensed drivers for most tasks, whereas unlicensed drivers with ASD had more difficulty with speed and lane management than TD drivers. CONCLUSION: Findings suggest that young adults with ASD may have more difficulty with basic driving skills than peers, particularly in the early stages of driver training. Increased difficulty compared with peers increases as driving demands become more complex, suggesting that individuals with ASD may benefit from a slow and gradual approach to driver training. Future studies should evaluate predictors of driving performance, on-road driving, and ASD-specific driving interventions.

Neuropsychological functioning in preschool-age children with sickle cell disease: the role of illness-related and psychosocial factors.

Cognitive and academic deficits have been identified in school-aged children with sickle cell disease (SCD). However, there have been very few identified studies that examine neuropsychological functioning in preschool-age children with SCD. It is important to understand effects of SCD from a developmental perspective and to consider the contribution of environmental factors in this at-risk population. Neuropsychological functioning of preschool-age children with SCD and no history of overt stroke (n = 26) was examined across several domains (language, immediate memory/brief attention, visuospatial/visuoconstructional, motor/visuomotor). The mean Full Scale IQ for the sample was 89.0. Performance on the Immediate Memory/ Brief Attention domain was significantly higher than the other domains, although the pattern of performance was relatively consistent, with mean standard scores ranging from 88.0 to 95.0. Disease severity was not significantly related to cognitive functioning in this group of young children with SCD. Socioeconomic status (SES) was significantly correlated with most domain scores and, based on regression analyses, accounted for 18% to 47% of the variance in functioning. Psychosocial factors, such as number of children living in the home and parental stress levels, were negatively associated with Motor/Visuomotor skills, and weekly hours in school/day care was positively associated with language-related skills. Results suggest that, at this young age, psychosocial risk factors appear to be appropriate targets for intervention, with the goal of improving long-term outcome in children with SCD. Further investigations should include comparison to a matched control group.

The Kennedy Krieger Independence Scales-Sickle Cell Disease: Executive components of transition readiness.

PURPOSE/OBJECTIVE: Youth with sickle cell disease (SCD) are at an increased risk for executive dysfunction and simultaneously have increased self-management needs compared to typical adolescents. This unique combination may contribute, in part, to difficulties during transition to young adulthood. Current measures assessing adaptive skills do not assess the executive components (e.g., initiation, prospective memory) of SCD-related self-care tasks. Modeled on the KKIS-Spina Bifida (Jacobson et al., 2013), the Kennedy Krieger Independence Scales-Sickle Cell Disease (KKIS-SCD) is a new caregiver-report measure that assesses independence with self-management of SCD-specific demands as well as routine daily activities in adolescents with SCD. Research Method/Design: Thirty-three youth with SCD and their caregivers participated in this preliminary validation study examining the construct validity of the KKIS-SCD total and composite scores (Initiation of Routines, Prospective Memory) and exploring relationships of this measure with intellectual functioning, demographic factors, illness severity, and age. RESULTS: The KKIS-SCD exhibited generally good internal consistency (Cronbach's alpha = .733 to .803), and demonstrated evidence for construct and discriminant validity when compared to an existing measure of adaptive function. The KKIS-SCD was significantly associated with caregiver-report of executive behaviors but not with intellectual functioning, demographic factors, illness severity, or age. CONCLUSIONS/IMPLICATIONS: Results provide preliminary support for the KKIS-SCD as a reliable and valid tool for the assessment of executive components of self-care management skills for youth with SCD. Identifying specific weaknesses in executive function related to self-care management skills might assist in guiding intervention and individualizing transition planning in these at-risk youth. (PsycINFO Database Record

A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder.

BACKGROUND: Currently, there is no consensus on the best therapeutic approach to chronic tic disorders and comorbid attention-deficit/hyperactivity disorder (ADHD). To address this issue, we evaluated the tolerability and efficacy of the noradrenergic tricyclic antidepressant desipramine hydrochloride in the treatment of children and adolescents with chronic tic disorders and comorbid ADHD. METHODS: Forty-one children and adolescents with chronic tic disorders, including Tourette disorder and comorbid ADHD, were studied in a 6-week, double-blind, placebo-controlled, parallel trial. Desipramine was titrated weekly up to 3.5 mg/kg per day. We rated ADHD and tic symptoms weekly and monitored adverse effects, laboratory findings, and cardiovascular parameters. RESULTS: Treatment with desipramine (mean total daily dose, 3.4 mg/kg per day) was well tolerated without meaningful adverse effects. Desipramine significantly reduced core symptoms of ADHD (ADHD Rating Scale; 42% decrease from baseline relative to placebo, P<.001), with equal response in inattentive symptoms and hyperactive/impulsive symptoms (P<.001 for both). The ADHD response rate was robust (71% vs 0%; desipramine vs placebo, P<.001). Likewise, desipramine significantly reduced tic symptoms (Yale Global Tic Severity Scale; 30% decrease from baseline relative to placebo, P<.001), with equal response in motor and phonic tic symptoms (P<.01 for both). The tic response rate was substantial (58% vs 5%; desipramine vs placebo, P<.001). There were small but statistically significant differences between desipramine and placebo in heart rate and blood pressure. CONCLUSIONS: Treatment with desipramine was well tolerated and was associated with robust clinically significant reductions in tic and ADHD symptoms in children and adolescents with chronic tic disorders and ADHD diagnoses.

Psychosocial and pharmacological management of pain in pediatric sickle cell disease.

For children with sickle cell disease (SCD), pain is associated with significant current and future morbidity and mortality. Unfortunately, few evidence-based guidelines exist for the management of pain episodes in children with SCD. To inform empirically based treatment strategies for pain management in pediatric SCD, this review integrates and evaluates the extant literature on psychosocial and pharmacological approaches to the management of pain. Findings reveal a paucity of rigorous investigations of psychosocial and pharmacological pain management interventions in children with SCD. Psychosocial interventions included were primarily cognitive-behavioral in nature, whereas pharmacological approaches targeted non-opioid analgesics (ie, nonsteroidal anti-inflammatory drugs and corticosteroids) and opioid medications (ie, morphine and oxycodone). However, to date there is not a "gold standard" for pain management among children with SCD. Because psychosocial and physiological processes each play a role in the etiology and experience of pain, effective pain management requires multidimensional, comprehensive treatment approaches. Considering the significant impact of pain on functional outcomes and quality of life among children with SCD, additional clinical trials are warranted to ensure that interventions are safe and efficacious.

Predictors of Academic Achievement for School Age Children with Sickle Cell Disease.

BACKGROUND: Children with sickle cell disease (SCD) are at risk for neurocognitive impairment and poor academic achievement, although there is limited research on factors predicting academic achievement in this population. This study explores the relative contribution to academic achievement of a comprehensive set of factors, such as environmental (socioeconomic status), disease-related (stroke, transfusion therapy, adherence), and psychosocial variables (child behavior, child quality of life (QoL)), controlling for intellectual functioning (IQ). METHODS: Eighty-two children with SCD completed measures assessing IQ and academic achievement, while parents completed questionnaires assessing adherence, child behavior, and child quality of life. Medical chart reviews were conducted to determine disease-related factors. RESULTS: Hierarchical regression analyses indicated that 55% of the variance in academic skills was accounted for by IQ, parent education, chronic transfusion status, and QoL [R2 = .55, F(5, 77) = 18.34, p < .01]. Follow-up analyses for broad reading [R2 = .52, F(5, 77) = 16.37, p < .01], and math calculation [R2 = .44, F(5, 77) = 12.14, p < .01] were also significant. CONCLUSION: The findings suggest a significant contribution of factors beyond IQ to academic achievement. Findings allow for identification of children with SCD at risk for academic difficulties for whom psychoeducational interventions may enhance academic achievement.

The Kennedy Krieger Independence Scales-Spina Bifida Version: a measure of executive components of self-management.

PURPOSE/OBJECTIVE: Successful implementation of functional self-care skills depends upon adequate executive functioning; however, many scales assessing adaptive skills do not address the inherent executive burden of these tasks. This omission is especially relevant for individuals with spina bifida, for whom medical self-care tasks impose a significant burden requiring initiation and prospective memory. The Kennedy Krieger Independence Scales-Spina Bifida Version (KKIS-SB) is a caregiver-reported measure designed to address this gap; it assesses skills for managing both typical and spina bifida-related daily self-care demands, with a focus on the timely and independent initiation of adaptive skills. RESEARCH METHOD/DESIGN: Parents of 100 youth and young adults with spina bifida completed the KKIS-SB. Exploratory factor analysis and Pearson's correlations were used to assess the factor structure, reliability, and construct validity of the KKIS-SB. RESULTS: The scale demonstrates excellent internal consistency (Cronbach's alpha = .891). Exploratory factor analysis yielded four factors, explaining 65.1% of the total variance. Two primary subscales were created, initiation of routines and prospective memory, which provide meaningful clinical information regarding management of a variety of typical (e.g., get up on time, complete daily hygiene routines on time) and spina bifida-specific self-care tasks (e.g., begin self-catheterization on time, perform self-examination for pressure sores). CONCLUSIONS/IMPLICATIONS: Based upon internal consistency estimates and correlations with measures of similar constructs, initial data suggest good preliminary reliability and validity of the KKIS-SB.

The role of neuropsychological evaluation in pediatric sickle cell disease.

Neuropsychological impairment occurs in children and adolescents with sickle cell disease. While the neuropsychological sequelae associated with cerebrovascular disease in these children have been identified, a well-informed clinical approach to neuropsychological evaluation for these vulnerable children has not been delineated. Moreover, issues related to standard of care for children and adolescents with sickle cell disease and transition to adulthood remain understudied despite the relevance to long-term medical, psychosocial, and neuropsychological outcomes. We provide recommendations for an informed approach to neuropsychological evaluation of youth with sickle cell disease that is determined by pertinent illness-related factors, consideration of general developmental level and timing of evaluation (i.e., baseline vs follow-up evaluation), relationship to medical treatment, and transition to adulthood. Although the neuropsychological methods presented in this manuscript are specific to sickle cell disease, this empirically informed approach may serve as a model for other pediatric populations.

Age-related differences in executive function among children with spina bifida/hydrocephalus based on parent behavior ratings.

Previous research has suggested that adolescents with myelomeningocele and shunted hydrocephalus (MMH) have difficulties with aspects of executive functioning and, in turn, with functional independence. There is little research, however, examining patterns of executive functioning across adolescence in this population. The goal of this cross-sectional study was to examine parent ratings of executive function in children with MMH and in typically developing peers across late childhood and adolescence. Parents of 36 individuals with MMH and 35 typically developing peers, ages 10 to 18 years, completed the Behavior Rating Inventory of Executive Function (BRIEF). The BRIEF is organized into eight scales and two primary indices-Metacognition (MCI) and Behavioral Regulation (BRI). As a whole, the children with MMH had significantly higher BRIEF T-scores, as well as a higher prevalence of clinically significant T-scores across subscales, particularly those representing cognitive control. Effects of group, age, and age-by-group interactions on the mean raw scores of the MCI and BRI were examined using regression analyses. There were significant group effects (p <. 05) for both the BRI and MCI, with the controls having significantly lower mean ratings than the MMH group. There was also a significant contribution of age-by-group interaction on the BRI (p <. 05). Although mean raw scores on the BRI for the MMH group remained stable across ages, mean raw scores in the control group decreased as age increased. Thus, healthy children have age-related improvements in executive control behaviors across adolescence, particularly behavioral control, while children with MMH demonstrate no age-related improvements in parent reported executive behaviors across adolescence. Therefore, children with MMH may continue to require targeted interventions and modifications to address executive dysfunction into young adulthood in order to promote functional independence.