Late effects of pediatric brain tumors.

PURPOSE OF REVIEW: Adverse late effects of pediatric brain tumors can be numerous and complex and potentially alter the life trajectories of survivors in a multitude of ways. We review these inter-related late effects that compromise neurocognitive function, general health, social and psychological adjustment, and overall adaptive and vocational outcomes, and threaten to undermine the ability of survivors to transition independently into adulthood and effectively manage their care. Intervention/prevention strategies and advances in treatment that may reduce such late effects are discussed. RECENT FINDINGS: Studies of neuropsychological late effects have revealed specific deficits in core cognitive functions of attention, working memory and processing speed, with many survivors demonstrating decline in working memory and processing speed over time, irrespective of tumor type or treatment. This in turn affects the ongoing development of higher order neurocognitive skills. Research also highlights the increasing burden of health-related, neuropsychological and psychosocial late effects into adulthood and impact across life outcomes. SUMMARY: Pediatric brain tumor survivors require coordinated interdisciplinary care, ongoing evaluation and management of late effects, and timely interventions focused on mitigating the impact of late effects. The transition to adulthood can be especially vulnerable and addressing barriers to care is of paramount importance.

Implementing guidelines: Proposed definitions of neuropsychology services in pediatric oncology.

Several organizations have published guidelines for the neuropsychological care of survivors of childhood cancer. However, there is limited consensus in how these guidelines are applied. The model of neuropsychology service delivery is further complicated by the variable terminology used to describe recommended services. In an important first step to translate published guidelines into clinical practice, this paper proposes definitions for specific neuropsychological processes and services, with the goal of facilitating consistency across sites to foster future clinical program development and to clarify clinical practice guidelines.

Executive function in children with attention deficit/hyperactivity disorder: the NIH EXAMINER battery.

Theories of attention deficit/hyperactivity disorder (ADHD) increasingly highlight the role of neuropsychological impairment in ADHD; however, a consistent and identifiable pattern of performance on tests is not well established. The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) battery provides measures of common variance across multiple executive function tests within specific domains and was used to characterize which executive functions are most affected in children with ADHD. Thirty-two children (24 male), ages 8-15 years (M = 12.02; SD = 2.29), diagnosed with ADHD and no comorbid disorder completed the NIH EXAMINER battery. Sixty age and gender matched healthy controls were chosen from a database of participants enrolled in the NIH EXAMINER multi-site study. Children with ADHD performed worse on the working memory score compared with the controls. No differences were found on the cognitive control or fluency scores. For children with ADHD, poorer working memory performance predicted parent report of child learning problems. Cognitive control and fluency scores did not predict learning problems. In summary, working memory emerges as a primary impairment in children with ADHD who have no comorbid disorders. Furthermore, working memory weaknesses may underlie the academic problems often seen in children with ADHD.

Extremely preterm birth outcome: a review of four decades of cognitive research.

Premature birth incidence and survival rates are increasing steadily due to advances in obstetric and neonatal intensive care. Those born at the limits of viability are highly at-risk of adverse neurocognitive function over their lifespan, leading to current controversy regarding aggressive resuscitation efforts for these extremely preterm children. However, data from earlier generation cohorts who were born in substantially different eras of neonatal intensive care cannot be relied on to predict outcome of today's newborn. Our review by the crucial variable of birth cohort year shows a changing developmental trajectory in which today's extremely preterm survivor is likely to have fewer severe medical complications, better neurological outcomes, and fewer adverse cognitive late effects. Such data further underscore the importance of concurrently considering medical, familial, socioenvironmental, and neurobiological factors in combination with individual neonatal intensive care center protocols when studying outcomes of the preterm child. This complex, interrelated range of factors directly affects the immature, rapidly developing premature brain. However, ongoing surveillance to detect subsequent delay or impairment and to apply interventional strategies early in the developmental course holds promise for further enhancement of functional outcome.

Visual spatial learning outcomes for clinical trials in neurofibromatosis type 1.

Cognitive problems are common in children with neurofibromatosis type 1, representing a significant source of lifelong morbidity. Assessment of cognitive function has been challenging in the setting of clinical trials. Spatial learning deficits may be an important target for cognitive interventions. We leveraged a large, international cognitive study in affected children with NF1 treated with lovastatin to assess spatial learning using the "Arena Maze", a portable, computerized task that allows for retesting in the same environment. As with the parent study, spatial learning assessed with this task did not improve with lovastatin treatment.

Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only.

BACKGROUND: Surgical resection is often the only treatment necessary for pediatric low-grade gliomas (LGGs) and is thought to define a population with an excellent long-term prognosis. The goal of this study was to describe the multidimensional late-effects of pediatric LGG survivors treated exclusively with surgery. METHODS: A retrospective chart review of "surgery-only" LGG survivors followed at Dana-Farber/Children's Hospital Cancer Care was undertaken. Patients had to be diagnosed with an LGG before the age of 22 years, treated with "surgery-only" and be at least 2 years from diagnosis. RESULTS: Sixty survivors were eligible with a median age at the time of review of 16.3 years and the median time since diagnosis of 8.4 years. Tumor locations were predominantly posterior fossa (47%) or cortical (33%). Eighty-five percent of patients had at least one ongoing late-effect, and 28% had three or more. The most common late-effects consisted of motor dysfunction (43%), visual problems (32%), anxiety (19%), social difficulties (19%), seizure disorders (17%), depression (15%), poor coordination/ataxia (14%), behavioral problems (13%), and endocrinopathies (10%). Nine patients had a history of suicidal ideation; two with suicide attempts. The mean full-scale IQ was normal, however, the number of survivors scoring one standard deviation below the mean was twice the expected number. Special education services were utilized by more than half of the survivors. CONCLUSIONS: "Surgery-only" LGG survivors may be more affected by their tumor and its resection than previously appreciated. A prospective study is needed to address this survivor population.

School-aged Children Who Are Not Progressing Academically: Considerations for Pediatricians.

Pediatricians and other pediatric primary care providers may be consulted when families have concerns that their child is not making expected progress in school. Pediatricians care not only for an increasingly diverse population of children who may have behavioral, psychological, and learning difficulties but also for increasing numbers of children with complex and chronic medical problems that can affect the development of the central nervous system and can present with learning and academic concerns. In many instances, pediatric providers require additional information about the nature of cognitive, psychosocial, and educational difficulties that affect their school-aged patients. Our purpose for this report is to describe the current state of the science regarding educational achievement to inform pediatricians' decisions regarding further evaluation of a child's challenges. In this report, we review commonly available options for psychological evaluation and/or treatment, medical referrals, and/or recommendations for referral for eligibility determinations at school and review strategies for collaborating with families, schools, and specialists to best serve children and families.

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

OBJECTIVE: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). METHODS: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. RESULTS: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. CONCLUSIONS: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. CLINICALTRIALSGOV IDENTIFIER: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Supervision in neuropsychological assessment: a survey of training, practices, and perspectives of supervisors.

Within the psychology supervision literature, most theoretical models and practices pertain to general clinical or counseling psychology. Supervision specific to clinical neuropsychology has garnered little attention. This survey study explores supervision training, practices, and perspectives of neuropsychology supervisors. Practicing neuropsychologists were invited to participate in an online survey via listservs and email lists. Of 451 respondents, 382 provided supervision to students, interns, and/or fellows in settings such as VA medical centers (37%), university medical centers (35%), and private practice (15%). Most supervisors (84%) reported supervision was discussed in graduate school "minimally" or "not at all." Although 67% completed informal didactics or received continuing education in supervision, only 27% reported receiving training specific to neuropsychology supervision. Notably, only 39% were satisfied with their training in providing supervision and 77% indicated they would likely participate in training in providing supervision, if available at professional conferences. Results indicate that clinical neuropsychology as a specialty has paid scant attention to developing supervision models and explicit training in supervision skills. We recommend that the specialty develop models of supervision for neuropsychological practice, supervision standards and competencies, training methods in provision of supervision, and benchmark measures for supervision competencies.

Pediatric neuropsychology: toward subspecialty designation.

Clinical neuropsychology is a rapidly expanding field of study in the psychological sciences whose practitioners are expert in the assessment, treatment, and research of individuals with known or suspected central nervous system disease or disorder. Pediatric neuropsychology has emerged as a distinct subspecialty area with related education, training, and clinical expertise for a growing number of neuropsychologists. This paper details the numerous steps taken by two affiliated organizations, the American Board of Clinical Neuropsychology and its membership organization, the American Academy of Clinical Neuropsychology, in the interest of the larger pediatric neuropsychology community and in pediatric neuropsychology subspecialty development.

Know thyself: real-world behavioral correlates of self-appraisal accuracy.

Accurate appraisal of one's own abilities is one metacognitive skill considered to be an important factor affecting learning and behavior in childhood. The present study measured self-appraisal accuracy in children using tasks of executive function, and investigated relations between self-appraisal and informant ratings of real-world behaviors measured by the BRIEF. We examined self-appraisal accuracy on fluency tasks in 91 children ages 10-17. More accurate self-appraisal was correlated with fewer informant ratings of real-world behavior problems in inhibition and shifting, independent of actual performance. Findings suggest that self-appraisal represents cognitive processes that are at least partially independent of other functions putatively dependent on the frontal lobes, and these self-appraisal-specific processes have unique implications for optimal daily function.

Pilot study of a novel computerized task to assess spatial learning in children and adolescents with neurofibromatosis type 1.

Difficulties with visual-spatial learning are frequently observed and often considered to be the hallmark of neurocognitive impairment in neurofibromatosis type 1. The computerized Arena Maze is a virtual environment task that has been developed as a human paradigm to the Morris Water Maze, which is used to evaluate spatial learning in animal models. The authors evaluated this task as a measure of spatial learning in children with neurofibromatosis type 1 compared with their unaffected siblings. Affected children were able to learn the task and navigate the virtual environment; however, they performed more poorly on standard measures of spatial learning and spatial working memory than their siblings. The group with neurofibromatosis type 1 demonstrated decreased proficiency in earlier target trials and had more difficulty in remembering target location. This study demonstrates the potential utility of a novel virtual task to assess spatial learning deficits in children with neurofibromatosis type 1.

Late effects of therapy for pediatric brain tumor survivors.

Approximately 2 of every 3 of all pediatric patients with brain tumors will be long-term survivors. However, there is a steep cost for pediatric brain tumor survivors, and the group as a whole faces significantly more late effects than many other survivors of pediatric cancers. Most of these effects can be attributed to direct neurologic damage to the developing brain caused by the tumor and its removal, the long-term toxicity of chemotherapy, or the effects of irradiation on the central nervous system. The late effects experienced by childhood brain tumor survivors involve multiple domains. This article will review the significant late effects that occur within the medical, neurocognitive, psychosocial, and economic domains of the survivorship experience. We conclude by discussing how the late effects in different domains often coexist and can create a complex set of obstacles that pose significant challenges for a survivor of a pediatric brain tumor on a daily basis.

Developmental perspectives on optimizing educational and vocational outcomes in child and adult survivors of cancer.

Over the last few decades, long-term survival rates of children diagnosed with the two most common forms of childhood cancer, acute lymphoblastic leukemia (ALL) and brain tumors have improved substantially. Neurodevelopmental and psychosocial sequelae resulting from these diseases and their treatment have a direct impact on the developing brain and on the quality of life of these children and their families. The focus of this article is on optimizing neuropsychological and adaptive outcomes for children who have been successfully treated for these cancers and whose prospects for long-term survival are increasingly encouraging. We present a model for understanding systemic interactions among the multiple factors that influence the child's development over time and take into account contextual variables. Strategies for optimizing cognitive and psychosocial outcomes or ameliorating late effects need to consider treatment histories, specific stages of development, the contextual demands/developmental challenges associated with each, and the resources (internal and external to the child) available to meet these challenges. The challenges faced by survivors at the early childhood, middle childhood, adolescent, and emerging adulthood stages are discussed. We review different types of interventions and discuss how these can contribute to optimal functioning in survivors of childhood ALL and brain tumors.