The development of fatigue after treatment for pediatric brain tumors does not differ between tumor locations.

BACKGROUND: Children and adolescents treated for a brain tumor suffer from more fatigue than survivors of other types of childhood cancer. As tumor location might be predictive of fatigue, our aim was to investigate the longitudinal development of fatigue in children with brain tumors and risk factors for fatigue separately for different tumor locations. METHODS: Fatigue was assessed 1235 times for 425 participants. Self-report versions of PedsQL Multidimensional Fatigue Scale were used to repeatedly assess fatigue from the end of treatment up to 8 years later. Mixed models were used to analyze fatigue over time and determinants separately for infratentorial (N = 205), supratentorial hemispheric (N = 91), and supratentorial midline tumors (N = 129). RESULTS: Cognitive fatigue worsened with time, while sleep-rest and general fatigue first decreased and then increased. There was no difference in fatigue between the tumor locations, but the risk factors differed when stratified by location. Radiotherapy was associated with more fatigue for infratentorial tumors, and centralization of care was associated with less fatigue for the supratentorial midline tumors. For supratentorial hemispheric tumors, female sex was associated with more fatigue. Higher parental education was associated with less fatigue regardless of tumor location. CONCLUSIONS: The development of fatigue seems to be more related to sociodemographic and treatment variables than to tumor location. Healthcare providers need to be aware that fatigue may develop in the years following end of treatment, and that patients with a low/middle educational family background might be more vulnerable and in need of targeted support.

Perioperative risk factors for long-term intelligence in children with postoperative cerebellar mutism syndrome after medulloblastoma surgery.

OBJECTIVE: Approximately 7%-50% of children with medulloblastoma (MB) develop postoperative cerebellar mutism syndrome (pCMS). pCMS has a short-term negative impact on intelligence, but effects on long-term outcomes are contradictory. The aim of this study was to assess long-term effects of pCMS in MB patients on aspects of intelligence quotient (IQ) and its perioperative risk factors. METHODS: In this single-center retrospective cohort study, 31 children were included (14 pCMS). Perioperative risk factors included brainstem invasion, vermis incision, hydrocephalus, tumor size, severity of pCMS, neurological symptoms, mean body temperature (BT) on days 1-4 post surgery, and age at resection. Age-appropriate Wechsler Intelligence tests were assessed at least 2 years after tumor resection. RESULTS: Mean interval between tumor resection and neuropsychological evaluation was 3.9 years in pCMS and 4 years and 11 months in the no-pCMS group. No significant differences in IQ scores were found between groups. The pCMS group had a clinically relevant difference of 10 points when compared to age norms on verbal IQ (VIQ). Bilateral pyramidal and swallowing problems were risk factors for lower performance. In the overall group, tumor size, younger age at surgery, and raised mean BT were negatively correlated with aspects of IQ. CONCLUSIONS: We found a clinically significant reduction of VIQ in the pCMS patient group. pCMS patients with a larger tumor size, younger age at surgery, a higher mean BT in the first days after surgery, bilateral pyramidal symptoms, and swallowing problems 10 days post surgery are more at risk for VIQ deficits at long-term.

Cognitive performance as a predictor of healthcare transition in sickle cell disease.

Neurocognitive deficits in sickle cell disease (SCD) may impair adult care engagement. We investigated the relationship between neurocognitive functioning and socio-environmental factors with healthcare transition outcomes. Adolescents aged 15-18 years who had neurocognitive testing and completed a visit with an adult provider were included. Transition outcomes included transfer interval from paediatric to adult care and retention in adult care at 12 and 24 months. Eighty adolescents (59% male, 64% HbSS/HbSß0 -thalassaemia) were included. Mean age at adult care transfer was 18·0 (±0·3) years and transfer interval was 2·0 (±2·3) months. Higher IQ (P = 0·02; PFDR  = 0·05) and higher verbal comprehension (P = 0·008; PFDR  = 0·024) were associated with <2 and <6 month transfer intervals respectively. Better performance on measures of attention was associated with higher adult care retention at 12 and 24 months (P = 0·009; PFDR  = 0·05 and P = 0·04; PFDR  = 0·12 respectively). Transfer intervals <6 months were associated with smaller households (P = 0·02; PFDR  = 0·06) and households with fewer children (P = 0·02; PFDR  = 0·06). Having a working parent was associated with less retention in adult care at 12 and 24 months (P = 0·01; P = 0·02 respectively). Lower IQ, verbal comprehension, attention difficulties and environmental factors may negatively impact transition outcomes. Neurocognitive function should be considered in transition planning for youth with SCD.

Longitudinal Trajectories of Neurocognitive Functioning in Childhood Acute Lymphoblastic Leukemia.

OBJECTIVE: Children with acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits, and examining individual variability is essential to understand these risks. This study evaluated latent longitudinal trajectories and risk factors of neurocognitive outcomes in childhood ALL. METHODS: There were 233 participants with ALL who were enrolled on a phase 3, risk-stratified chemotherapy-only clinical trial (NCT00137111) and who completed protocol-directed neurocognitive assessments [47.6% female, mean (SD) = 6.6 (3.7) years]. Measures of sustained attention, learning/memory, and parent ratings of attention were completed during and after treatment. Longitudinal latent class analyses were used to classify participants into distinct trajectories. Logistic regression was used to identify predictors of class membership. RESULTS: Within the overall group, attention performance was below age expectations across time (Conners Continuous Performance Test detectability/variability, p < 0.01); memory performance and parent ratings were below expectations at later phases (California Verbal Learning Test learning slope, p < 0.05; Conners Parent Rating Scale, Revised attention/learning, p < 0.05). Most participants (80-89%) had stable neurocognitive profiles; smaller groups showed declining (3-6%) or improving (3-11%) trajectories. Older age (p = 0.020), female sex (p = 0.018), and experiencing sepsis (p = 0.047) were associated with greater attention problems over time. Lower baseline IQ was associated with improved memory (p = 0.035) and fewer ratings of attention problems (p = 0.013) over time. CONCLUSIONS: Most patients with ALL have stable neurocognitive profiles. Smaller groups have significant impairments shortly after diagnosis or have worsening performance over time. A tiered assessment approach, which includes consideration of individual and clinical risk factors, may be useful for monitoring neurocognitive functioning during treatment and survivorship.

White matter but not grey matter predicts change in reading skills after intervention.

This study examined changes in white matter microstructure and grey matter volume, cortical thickness, and cortical surface area before and after reading intervention. Participants included 22 average readers and 13 dyslexic readers (8-9 years old in third grade); the dyslexic readers were enrolled in reading intervention programs at their elementary school. Participants completed scans of diffusion tensor imaging and T1-weighted MRI before and after 3 months of instruction. An a priori region of interest (ROI) analysis was used. Dyslexic readers, compared to average readers, showed higher mean diffusivity in white matter ROIs including bilateral inferior frontal, bilateral insula, left superior temporal, and right supramarginal gyri across time points. Dyslexic readers also had thicker cortex in left fusiform and bilateral supramarginal gyri; whereas, average readers had greater surface area in right fusiform across time. There were no significant changes in white or grey matter following intervention; however, mean diffusivity in the right hemisphere was associated with reading gains over time. White matter organization in the right hemisphere predicts reading changes, and dyslexic readers may have persistent differences in white and grey matter due to ongoing reading deficits.

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease.

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16-17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSß+ thalassaemia; n = 52 HbSS/HbSß0 thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSß+ thalassaemia; n = 8 HbSS/HbSß0 thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSß thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSß0 thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSß0 thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSß+ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSß+ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSß0 thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.

Longitudinal outcomes of an individualized and intensive reading intervention for third grade students.

Early intervention is known to reduce reading disabilities; however, treatment response is variable, and some students have persistent deficits that require intensive supports. This study examined the immediate and 1-year outcomes of an individualized and intensive reading program for third grade students, which was delivered throughout the school day for an average of 189 hr of instruction over 3 months. These students' performances were compared with two comparison groups, including poor readers who received small group supports and good readers who did not have additional reading instruction. The intensive group showed an improvement in word recognition and decoding fluency immediately after the program and 1 year later, and there was a decrease in significant reading impairments from 62% before intervention to 35% at follow-up. Furthermore, baseline reading, spelling, phonological awareness, and rapid naming skills were predictive of persistent reading deficits at a later time point. Although improvements in reading skills were shown, a significant gap between poor and good readers persisted in the third and fourth grades. This study illustrates the importance of a tertiary intensive reading program, but also the need for continuing supports.

Neural Correlates of Speed-Tuned Motion Perception in Healthy Adults.

It has been suggested that slow and medium-to-fast speeds of motion may be processed by at least partially separate mechanisms. The purpose of this study was to establish the cortical areas activated during motion-defined form and global motion tasks as a function of speed, using functional magnetic resonance imaging. Participants performed discrimination tasks with random dot stimuli at high coherence, at coherence near their own thresholds, and for random motion. Stimuli were moving at 0.1 or 5 deg/s. In the motion-defined form task, lateral occipital complex, V5/MT+ and intraparietal sulcus showed greater activation by high or near-threshold coherence than by random motion stimuli; V5/MT+ and intraparietal sulcus demonstrated greater activation for 5 than 0.1 deg/s dot motion. In the global motion task, only high coherence stimuli elicited significant activation over random motion; this activation was primarily in nonclassical motion areas. V5/MT+ was active for all motion conditions and showed similar activation for coherent and random motion. No regions demonstrated speed-tuning effects for global motion. These results suggest that similar cortical systems are activated by slow- and medium-speed stimuli during these tasks in healthy adults.

Unraveling the relations between post-traumatic stress symptoms, neurocognitive functioning, and limbic white matter in pediatric brain tumor patients.

Background: Pediatric brain tumor patients are at risk of developing neurocognitive impairments and associated white matter alterations. In other populations, post-traumatic stress symptoms (PTSS) impact cognition and white matter. This study aims to investigate the effect of PTSS on neurocognitive functioning and limbic white matter in pediatric brain tumor patients. Methods: Sixty-six patients (6-16 years) completed neuropsychological assessment and brain MRI (1-year post-diagnosis) and parents completed PTSS proxy questionnaires (CRIES-13; 1-3 months and 1-year post-diagnosis). Mean Z-scores and percentage impaired (>1SD) for attention, processing speed, executive functioning, and memory were compared to normscores (t-tests, chi-square tests). Multi-shell diffusion MRI data were analyzed for white matter tractography (fractional anisotropy/axial diffusivity). Effects of PTSS on neurocognition and white matter were explored with linear regression models (FDR correction for multiple testing), including age at diagnosis, treatment intensity, and tumor location as covariates. Neurocognition and limbic white matter associations were explored with correlations. Results: Attention (M = -0.49, 33% impaired; P < .05) and processing speed (M = -0.57, 34% impaired; P < .05) were significantly lower than healthy peers. PTSS was associated with poorer processing speed (ß = -0.64, P < .01). Treatment intensity, age at diagnosis, and tumor location, but not PTSS, were associated with limbic white matter metrics. Neurocognition and white matter metrics were not associated. Conclusions: Higher PTSS was associated with poorer processing speed, highlighting the need for monitoring, and timely referrals to optimize psychological well-being and neurocognitive functioning. Future research should focus on longitudinal follow-up and explore the impact of PTSS interventions on neurocognitive performance.

Consensus framework for conducting phase I/II clinical trials for children, adolescents, and young adults with pediatric low-grade glioma: Guidelines established by the International Pediatric Low-Grade Glioma Coalition Clinical Trial Working Group.

Within the last few decades, we have witnessed tremendous advancements in the study of pediatric low-grade gliomas (pLGG), leading to a much-improved understanding of their molecular underpinnings. Consequently, we have achieved successful milestones in developing and implementing targeted therapeutic agents for treating these tumors. However, the community continues to face many unknowns when it comes to the most effective clinical implementation of these novel targeted inhibitors or combinations thereof. Questions encompassing optimal dosing strategies, treatment duration, methods for assessing clinical efficacy, and the identification of predictive biomarkers remain unresolved. Here, we offer the consensus of the international pLGG coalition (iPLGGc) clinical trial working group on these important topics and comment on clinical trial design and endpoint rationale. Throughout, we seek to standardize the global approach to early clinical trials (phase I and II) for pLGG, leading to more consistently interpretable results as well as enhancing the pace of novel therapy development and encouraging an increased focus on functional endpoints as well and quality of life for children faced with this disease.

Sleep problems during and after paediatric brain tumours.

Brain tumours are among the most common cancer diagnoses in paediatrics. Children with brain tumours are at risk of developing sleep problems because of direct and indirect effects of the tumour and its treatment, in addition to psychosocial and environmental factors. Sleep has an important role in physical and psychological wellbeing, and sleep problems are associated with many adverse outcomes. In this Review, we describe the state of the evidence regarding sleep in people with paediatric brain tumours, prevalence and types of sleep problems, risk factors, and effectiveness of interventions. Evidence shows that sleep problems, particularly excessive daytime sleepiness, are common in people with paediatric brain tumours, with high BMI emerging as a consistent predictor of sleep disruption. Further intervention studies are needed, and clinical evaluation of sleep is warranted for people with paediatric brain tumours.

A joint international consensus statement for measuring quality of survival for patients with childhood cancer.

The aim of treating childhood cancer remains to cure all. As survival rates improve, long-term health outcomes increasingly define quality of care. The International Childhood Cancer Outcome Project developed a set of core outcomes for most types of childhood cancers involving relevant international stakeholders (survivors; pediatric oncologists; other medical, nursing or paramedical care providers; and psychosocial or neurocognitive care providers) to allow outcome-based evaluation of childhood cancer care. A survey among healthcare providers (n = 87) and online focus groups of survivors (n = 22) resulted in unique candidate outcome lists for 17 types of childhood cancer (five hematological malignancies, four central nervous system tumors and eight solid tumors). In a two-round Delphi survey, 435 healthcare providers from 68 institutions internationally (response rates for round 1, 70-97%; round 2, 65-92%) contributed to the selection of four to eight physical core outcomes (for example, heart failure, subfertility and subsequent neoplasms) and three aspects of quality of life (physical, psychosocial and neurocognitive) per pediatric cancer subtype. Measurement instruments for the core outcomes consist of medical record abstraction, questionnaires and linkage with existing registries. This International Childhood Cancer Core Outcome Set represents outcomes of value to patients, survivors and healthcare providers and can be used to measure institutional progress and benchmark against peers.

Neuropathic pain and neurocognitive functioning in children treated for acute lymphoblastic leukemia.

ABSTRACT: Children with acute lymphoblastic leukemia (ALL) often experience treatment-related neurocognitive deficits and significant pain. Pain may exacerbate these cognitive impairments. This study examined neuropathic pain and neurocognitive outcomes in survivors of childhood ALL treated with contemporary therapy on a clinical trial (NCT00137111). There were 345 survivors (45% female, M = 6.9 years at diagnosis) who completed neurocognitive assessments including measures of sustained attention, learning and memory, and parent ratings of attention during at least one of 4 time points: on-therapy (Induction and Reinduction), end of therapy, and 2 years post-therapy. At-risk performance was defined as a score at least 1SD below the age-adjusted mean. Data on neuropathic pain (events, duration, and severity according NCI Common Toxicity Criteria) and pharmacologic pain management (opioids and gabapentin) were ascertained. Results showed that 135 survivors (39%) experienced neuropathic pain during treatment. Compared with those without pain, survivors with pain had greater memory impairments at end of therapy (California Verbal Learning Test [CVLT]-Total, 24% vs 12%, P = 0.046). Within the pain group, survivors who experienced a greater number of pain events (CVLT-Total = -0.88, P = 0.023) and those who were treated with opioids (versus gabapentin) had poorer learning and memory performance (CVLT-Total = -0.73, P = 0.011; Short Delay = -0.57, P = 0.024; Long Delay = -0.62, P = 0.012; and Learning Slope = -0.45, P = 0.042) across time points. These are considered medium-to-large effects (SD = 0.45-0.88). Neuropathic pain may be a risk factor for learning problems after therapy completion, and treatment for pain with opioids may also adversely affect neurocognitive performance. Therefore, patients who experience pain may require closer monitoring and additional intervention for neurocognitive impairment.

Effect of reading intervention and task difficulty on orthographic and phonological reading systems in the brain.

Children with poor reading skills have differences in brain function when compared to typically-developing readers, and there may also be changes in the brain following reading intervention. However, most functional imaging studies focus on phonological reading tasks with one level of task difficulty. The purpose of this study was to compare good and poor readers on functional magnetic resonance imaging (fMRI) tasks of orthography (spelling) and phonology (rhyming) before and after 3 months of school-based intervention. These tasks were also modulated by task difficulty based on printed word frequency. The results showed that primarily left hemisphere regions were activated for the spelling and rhyming tasks, and poor readers showed a pattern of increased activation in bilateral inferior frontal, bilateral insula, right parietal, and left cerebellum following intervention. Activity in left pars triangularis and right parietal regions were associated with gains in decoding skills. Intervention effects appeared across blocks of easy and difficult words, except for the right parietal cortex. In this region, poor readers had greater activity on the easy word blocks after intervention, which indicates that there was increased recruitment of the right parietal cortex for relatively easy words. These results indicate that effects of intervention may be more evident on phonological tasks in comparison to orthographic tasks, and some of these effects may be modulated by relative task difficulty.

Reading ability of children treated for amblyopia.

Previous studies have reported compromised reading ability in children with amblyopia. Standardized psychoeducational test norms have not been used; therefore, the practical consequences of poor reading ability, such as eligibility for reading supports at school, have not been assessed. Furthermore, several studies have used atypical reading conditions such as monocular or distant viewing. It is also not clear how amblyopia treatment impacts reading ability. Thus, the goal of this study was to use standardized tests to compare binocular reading performance in children treated for amblyopia to that of a large normative sample, as well as to the types of control groups used in previous studies. Children treated for strabismic or anisometropic amblyopia (N = 14) were compared to children treated for strabismus without amblyopia (N = 12) and to children with healthy vision (N = 39). Visual acuity, stereoacuity, interocular suppression, intellectual functioning, oral single-word reading (TOWRE-2), and oral paragraph reading (GORT-5) were assessed. The control group showed significantly higher single-word reading accuracy than the amblyopia and strabismus groups. However, mean performance for all groups was within the average range of the normative sample. While mean scores were in the average range, six children (four amblyopia, two strabismus) performed below average on the single-word reading task; four of these children also showed below average paragraph reading. Reading scores were not correlated with visual acuity in the patient groups. The results raise the possibility that both strabismus and amblyopia can disrupt reading ability, even following successful treatment, to an extent that might benefit from reading supports at school.

Early changes in white matter predict intellectual outcome in children treated for posterior fossa tumors.

PURPOSE: Prospective and longitudinal neuroimaging studies of posterior fossa tumors are scarce. Here we evaluate the early changes in white matter and intellectual outcome up to 3 years after diagnosis. PATIENTS AND METHODS: Twenty-two children with posterior fossa tumors and 24 similarly-aged healthy children participated. Patients included: (a) 12 individuals who received surgery, cranial-spinal radiation (CSR), and focal radiation to the tumor bed (CSR group) and (b) 10 individuals who received local therapy, either surgery only or surgery and focal radiation to the tumor bed (Local group). Diffusion tensor imaging (DTI) and intelligence measures were obtained an average of 3 months after diagnosis and then at 12, 24, and 36 months later. DTI tractography and voxel-wise approaches were employed. The Neurological Predictor Scale was used to summarize the type and amount of treatment for PF tumor patients. Linear mixed modelling was used to evaluate group differences at baseline and changes over time in DTI metrics for both the specific white matter tracts and voxel-wise, as well as for intelligence measures. RESULTS: Based on tractography, patients treated with CSR had significantly higher Axial and Mean diffusivity in the cortical-spinal tracts (CST) 3 month after diagnosis - particularly on the right side, p < .003, compared to healthy children. Mean diffusivity in right CST decreased over time in this group of patients, p = .001. No differences compared to controls were evident in specific tracts for the Local group, p > .10. Voxel-wise analyses revealed multiple areas of white matter compromise in both patients groups. Notably, both patient groups had lower scores on intelligence measures compared to the Control group: The CSR group displayed lower performance 3 months following diagnosis, ps < 0.001, and their performance remained stable over time ps > 0.10, whereas the Local group displayed no differences at 3 months, ps> 0.10, but their performance declined over time, ps < 0.01. At baseline, higher MD in right CST predicted lower Perceptual Reasoning scores across all participants, p = .001. Furthermore, lower FA in left IFOF at baseline predicted decline in Processing Speed over time, p = .001. In patients, more aggressive treatment protocols and presence of mutism were related to lower performance on intelligence measures at baseline, ps < 0.04. CONCLUSIONS: Children treated with CSR displayed diffuse white matter compromise and poor intellectual outcome shortly after radiation treatment. There was evidence of subsequent growth of white matter structure, but stable intellectual insult. Conversely, in children treated with either surgery only or surgery and focal radiation to the tumor bed we observed less compromise of white matter early following treatment and no intellectual insult compared to healthy children. However, declines in intellectual function were evident for these children, though their performance remained within the average normative range. Overall, results suggest that early intervention is necessary to circumvent these deficits.

A Longitudinal Examination of the Persistence of Late Emerging Reading Disabilities.

There are some children who encounter unexpected reading difficulties in the fourth grade. This phenomenon has been described as late emerging reading disabilities (LERD). Using Grade 4 as a starting point, this study examined the reading development of 964 children between kindergarten and Grade 7. The results showed that 72.0% of children had typical reading performance in Grade 4, whereas there was 0.7% with poor word reading, 12.6% with poor reading comprehension, 2.5% with poor word reading and comprehension, and 12.2% with borderline performance. We also showed that there were similar proportions of children who had early versus late emerging reading difficulties; however, most of the late emerging poor readers recovered by Grade 7. Furthermore, our study showed that poor comprehenders showed poorer performance than typical readers on word reading, pseudoword decoding, and spelling between Grade 1 and Grade 7 and poorer performance on a working memory task in kindergarten. Overall, this study showed that most children recover from late emerging reading problems and that working memory may be an early indicator for reading comprehension difficulties.