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Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.
To investigate whether left-handed children with right-sided neonatal brachial plexus palsy (NBPP) exhibited differences in handwriting speed compared to typically developing left-handed children. If differences were identified, potential contributing factors were explored. In this observational study with comparison groups, 74 left-handed children aged 6 to 21 years, all with right-handed parents, were included: 32 with right-sided NBPP (16 females) and 42 typically developing controls (22 females). Handwriting speed was measured using the 'Vlaamse schrijfsnelheidstest' (Flemish Writing Speed Test) and compared to age- and sex-normed centile scores. Functional assessments included grip strength (E-LINK), fine motor proficiency (Bruininks-Oseretsky Test of Motor Proficiency, Second Edition), and manual dexterity (Purdue Pegboard Test [PPT]). Cognitive ability was assessed via a derived IQ (DIQ). Group comparisons were conducted using general linear models adjusted for age. In the group with NBPP, linear and multiple regression analyses examined associations with handwriting speed. Children with NBPP showed significantly slower handwriting speed than typically developing controls (mean difference = 25.04 [6.20]; p < 0.001). The score on the PPT performed with the left hand (β = 4.787, 95% confidence interval [CI] = 0.332-9.242; p = 0.036) and the DIQ score (β = 0.730, 95% CI = 0.104-1.355; p = 0.024) were identified as determinants of handwriting speed in the group with NBPP. Despite writing with the unaffected hand, children with right-sided NBPP demonstrated significantly reduced handwriting speed, best predicted by the manual dexterity of the writing hand and cognitive capacity.
Migraine affects up to 11% of children and adolescents, leading to substantial disability through school absenteeism, cognitive impairment, and reduced quality of life. Traditionally, preventive treatment options for this population have been limited to the off-label use of nutraceuticals, antiseizure medications, calcium channel blockers, serotonin modulators, antidepressants, or beta-blockers, with limited efficacy and tolerability data. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have transformed adult migraine prevention, and fremanezumab is the first in this class to receive regulatory approval for pediatric use. In August 2025, the US Food and Drug Administration approved fremanezumab for the preventive treatment of episodic migraine in patients aged 6-17 years weighing at least 45 kg, based on the pivotal phase three SPACE trial. This randomized, placebo-controlled study demonstrated significant reductions in monthly migraine and headache days, with nearly half of treated participants achieving a ≥50% response rate, and a safety profile consistent with adult data. In this review, we provide an integrated, pediatric-focused synthesis of the pharmacokinetic, pharmacodynamic, and regulatory evidence supporting fremanezumab use in children and adolescents. In particular, we contextualize population pharmacokinetic modeling and pediatric phase 1 data to explain the rationale for weight-based dosing, exposure matching with adults, and the selection of the dosing regimens used in clinical trials and regulatory labeling. Pharmacokinetic analyses indicate that fremanezumab follows a two-compartment model with first-order absorption and a terminal half-life of approximately 30 days in pediatric patients, similar to adults, with body weight as the primary determinant of exposure. Finally, we discuss unresolved issues related to long-term CGRP blockade during growth, including theoretical effects on vascular regulation, bone metabolism, and neurodevelopment. Overall, fremanezumab represents a novel, mechanism-based preventive option for older children and adolescents with episodic migraine, while highlighting the need for continued longitudinal studies to define its long-term safety and optimal role in pediatric migraine management.
To examine concurrent validity between the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) gross motor subtest and the Alberta Infant Motor Scale (AIMS), and evaluate agreement among the Bayley-4 (full test and gross motor subtest), AIMS, and Hammersmith Infant Neurological Examination (HINE) in identifying atypical development at 12 months of age. This cross-sectional observational study included Bayley-4, AIMS, and HINE scores from 123 children (56 females, 67 males) with varied risk profiles at approximately 12 months of age. Concurrent validity was assessed using Spearman's rank correlation of raw scores. Agreement was evaluated using Cohen's kappa (k) and evidence-based thresholds of typicality for each assessment. Additional assessment comparisons, including AIMS and HINE, were conducted for benchmarking. The Bayley-4 gross motor subtest was strongly correlated (r = 0.90, p < 0.01) with the AIMS. Both the Bayley-4 full test and gross motor subtest demonstrated substantial agreement with the AIMS 5th centile (k = 0.72-0.73) and fair agreement (k = 0.28-0.32) with the HINE. By comparison, the AIMS and HINE were moderately correlated (r = 0.48), with fair agreement (k = 0.34). This study provides the first evidence of concurrent validity and agreement for the Bayley-4, supporting its use as a reliable developmental assessment in clinical and home settings. The Bayley-4 aligned more closely with the motor-focused AIMS than with the neurologically focused HINE.
To systematically review the current knowledge gap in, and impact of, long-term respiratory support in children and young people (CYP) with cerebral palsy (CP). We searched six databases from inception until 30th January 2025. Grey literature was also searched. Screening and data extraction using Covidence software, quality of evidence (Risk Of Bias In Non-randomized Studies - of Interventions), and certainty of evidence (Grading of Recommendation, Assessment, Development and Evaluation) grading were independently conducted by two reviewers, with a third reviewer resolving any lack of consensus. Title and abstract screening (n = 1994) and full-text reviews (n = 45) identified four studies (with moderate to severe risk of bias) for data extraction. Findings presented as a narrative synthesis from vote counting suggest improvement in sleep study parameters for CYP with CP on long-term respiratory support and quality of life for their parents (low certainty of evidence). This review identified a significant knowledge gap in the use of long-term respiratory support in CYP with CP and its impact on health-related outcomes for such young people. This limits the information that can be offered when counselling parents/carers before initiating respiratory support in CYP with CP. Further research is needed to allow better service-planning at national and local levels.
To determine the testing rate and pathogenic or probably pathogenic positivity rate of genetic testing in children with cerebral palsy (CP) in Korea using data from a nationwide multicentre registry, and to identify clinical features associated with positive genetic findings. Baseline data from 539 children enrolled in the Korean Cerebral Palsy Registry were analysed. Genetic testing modalities included chromosomal microarray, whole-exome sequencing, whole-genome sequencing, clinical exome sequencing, and karyotyping. Pathogenic and probably pathogenic variants were categorized into primary genetic contributors to CP, genetic motor disorders outside the CP construct, diagnostic interface cases between CP and other genetic motor disorders, and co-occurring genetic conditions. Among 539 children (304 males), 92 (17.1%) underwent genetic testing, yielding a pathogenic or probably pathogenic positivity rate of 37.0%. Primary genetic contributors to CP accounted for 35.3% of positive results and genetic motor disorders outside the CP construct for 8.8%. Positive findings were more frequent in children born at 32 or more weeks without perinatal risk factors, or presenting dyskinetic features or atypical magnetic resonance imaging patterns. Clinicians most frequently requested testing because of absent perinatal risk factors or atypical magnetic resonance imaging findings. Genetically relevant variants were identified in over one-third of tested children, especially those with atypical phenotypes or absent perinatal risk factors. These findings support incorporating genomic testing into routine CP evaluation, particularly for cryptogenic or atypical presentations.
To review barriers to ethical and equitable access to disease-modifying therapies (DMTs) and newborn screening (NBS) for spinal muscular atrophy (SMA). We searched PubMed, Scopus, Web of Science, EBSCOhost, the Cochrane Library, Google Scholar, and Primo for content on the ethics or equity of access to SMA DMTs or NBS from January 2014 to May 2025. Only evidence sources that had a primary focus on equity or ethics regarding access to either DMTs or NBS for children aged less than 18 years were eligible. Forty publications were included: all but one were published in English; three-quarters were published after 2020 and were either narrative reviews (45%) or cross-sectional studies (35%). The largest proportion were from North America (40%) and only three (7%) offered commentary on low- and middle-income countries. Inequity in access to SMA DMTs and NBS were consistently reported to persist even within countries due to multiple factors, which include variation in health system resources and funding mechanisms. Lack of robust clinical data on the long-term safety, efficacy, and cost-effectiveness of DMTs hampers advocacy efforts, particularly in resource-constrained settings. Questions remain around autonomy and distributive justice in diagnosis and care for this ultra-rare disease. A decade after the approval of clinically transformative therapies, children with SMA continue to fall on the wrong side of an avoidable divide. Urgent and coordinated action is needed to establish regulated minimum clinical standards, generate robust real-world data, and redesign funding models to ensure that NBS and treatment innovation serves all populations, not only those with politico-economic advantage.
Sleep problems are common in children with SYNGAP1-Related Disorder (SYNGAP1-RD). The use of devices that objectively estimate sleep are complicated by co-occurring sensory disorders in this population. We examined the feasibility and validity of wrist actigraphy to examine sleep and rest-activity rhythms (RAR). Data from five children with SYNGAP1-RD and 42 typically developing children were analyzed. All children were asked to wear the Actiwatch-2 for 14 continuous days and caregivers were asked to complete a sleep diary and the Children Sleep Health Questionnaire (CSHQ). Parametric (alpha, beta, acrophase, amplitude, up/down mesor, mesor), nonparametric (intradaily variability, interdaily stability, M10/L5 and relative amplitude), and sleep metrics-total sleep time (TST), wake after sleep onset (WASO), fragmentation index (restlessness throughout the rest period), the time of sleep bout onset, the number, and duration of sleep bouts, and the number and duration of wake bouts-were analyzed. In children with SYNGAP1-RD, sleep bouts were distributed across the day and night and were consistent with a higher alpha. Fewer sleep bouts occurred in the early morning aligning with parent report of early morning arousal. Although there was no difference in average TST, children with SYNGAP1-RD, had fewer sleep and wake bouts that were longer in duration. Additionally, they had greater WASO and higher fragmentation index, the latter was a strong predictor of subjects with SYNGAP1-RD. Actigraphy provides an objective measure of sleep that aligns with RAR, is consistent with parent report, and provides an ethological approach to monitoring sleep in children with SYNGAP1-RD.
This study sought to define the therapeutic drug monitoring (TDM) reference range and assess the efficacy-safety profile along with its determinants for levetiracetam (LEV) in Chinese children with epilepsy. We conducted a retrospective study (2021-2023) at Children's Hospital of Nanjing Medical University in children with epilepsy taking LEV therapy with routine TDM. The observational LEV reference range was defined by the generalized additive models for location, scale, and shape (GAMLSS) analysis. A linear mixed-effects model identified concentration determinants. Efficacy was assessed via propensity score matching (PSM)-adjusted logistic regression, time-to-failure via Kaplan-Meier/Cox regression (monotherapy), and adverse events (AEs) temporal patterns via Weibull distribution analysis. This study (n = 1,174) proposed an observational LEV reference range of 2.82-24.37 µg/mL based on the 2.5th-97.5th percentile distribution. Predictors of LEV levels included age, body weight, oxcarbazepine (OXC)/topiramate use, and developmental delay. OXC lowered concentration-to-dose (C 0/D) (β = -0.1824, P = 0.0012). The 12-month response rate was 81.01% (90.89% monotherapy vs 70.78% polytherapy). Concentration-response correlation was significant only in focal epilepsy. Protective factors for response were female sex, generalized epilepsy, and longer treatment; risk factors were polytherapy and infectious etiology. Comorbid attention deficit and hyperactive disorder improved, but developmental delay did not affect, response. Neuropsychiatric AEs were most frequent (median onset: 196.5 days); gastrointestinal and systemic reactions showed early failure patterns. This real-world study confirmed the efficacy and safety of LEV in Chinese children with epilepsy and revealed relevant drug interactions. By proposing an observational LEV reference range (2.82-24.37 µg/mL), it provides a critical evidence base for TDM and guides the personalized treatment. To better understand how to personalize LEV dosing for children with epilepsy, we studied over 1,000 cases and proposed an observational reference range of 2.82 to 24.37 µg/mL. We revealed that the link between drug levels and seizure control was only significant in those with focal epilepsy, not in all cases. Impressively, children with comorbid ADHD responded better to the treatment than those without. Regarding safety, while 17.25% of adverse events occurred early, 33.1% occurred post 360 days, highlighting the requirement for long-term monitoring. These findings offered new insights into TDM guide personalized LEV dosing for clinical practice.
Developmental and epileptic encephalopathies (DEEs), epilepsy-associated neurodevelopmental disorders (NDD), and epileptic syndromes with or without encephalopathy (ES±E) share overlapping genetic architectures where both etiology and seizures impair development. Despite genomic advances, many patients remain pharmacoresistant, and molecular diagnoses seldom translate into targeted treatments. This review connects mechanistic categories to precision therapies, providing a clinical decision-making framework. We outline pharmacological and investigational strategies-including antiseizure medications, dietary therapies, and disease-modifying approaches-across major mechanistic categories, including ion channel/receptor dysfunctions, synaptic/signaling defects, metabolic disorders, and neurodegenerative storage diseases. For each condition, potential therapeutic options are interpreted within a hierarchical precision-based framework, ranging from empiric seizure-type-driven treatments to gene-specific molecular interventions. A narrative literature search was conducted across major databases for English-language articles on DEEs, NDD, ES±E, and precision therapeutic approaches published up to early 2026. We categorized potential therapeutic interventions into five hierarchical tiers based on etiological specificity and evidence. Classification, achieved by expert consensus, distinguishes established (Tiers 1-3) from emerging strategies (Tiers 4-5). Progress depends on early etiological diagnosis and timely, mechanism-informed therapy. Future advances require expanded genomic testing, natural history studies, mechanism-based biomarkers, and innovative trial designs tailored to complex pediatric populations.
To synthesize evidence on cognitive functioning in adults with cerebral palsy (CP), evaluate the feasibility and validity of cognitive screens, determine whether cognitive functioning declines with age, identify factors associated with cognitive outcomes, and summarize interventions reporting cognitive outcomes. Five databases were searched through 2025. Eligible studies enrolled adults with CP and reported cognitive outcomes. Two reviewers screened and extracted data; quality was appraised with JBI tools and certainty graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Findings were synthesized narratively according to cognitive domain. Thirty studies (estimated 1150 adults, 3900 assessments) were included. Executive function, and visuospatial and perceptual-motor skills, were most frequently impaired. Attention and processing speed and episodic memory were also commonly reduced. Certainty was moderate for executive function and very low for other domains because of small samples, bias, inconsistency, and imprecision. Longitudinal and registry data suggested stability from late adolescence through mid-adulthood. Greater motor severity and reduced manual ability were associated with lower cognitive performance. No motor-minimized, CP-validated screening battery was identified across 48 instruments. Adults with CP commonly show domain-specific cognitive difficulties that are established early and remain stable through mid-adulthood. Measurement limitations and selection biases constrain prevalence estimates. Priorities include motor-minimized tools with CP-specific norms, adequately powered trials with standardized cognitive endpoints, and longitudinal cohorts examining modifiable factors.
To determine the extent to which specific patho-aetiological subgroups contributed to declines in prevalence of cerebral palsy (CP) observed in many high-income countries over this millennium. This epidemiological study used data from the Victorian CP Register on 2303 children born in Victoria between 2000 and 2019. Joinpoint regression analysis was used to assess trends in birth cohort prevalence of CP per 100 000 live births for well-defined subgroups based on likely causal pathway, birth condition, and neonatal course. Linear rate decreases were seen for two subgroups: (1) children born before 35 weeks' gestation with perinatal insults (annual percent change -3.12 [95% confidence interval - 4.63, -1.58]) and (2) children born from 35 weeks with perinatal, non-focal hypoxic-ischaemic insults and encephalopathy (annual percent change -5.98 [95% confidence interval - 8.46, -3.44]). Evidence was lacking for sustained decreases in CP rates for subgroups of children with early developmental causes, perinatal arterial ischaemic strokes, predominant white matter injury patterns in association with birth from 35 weeks, and postneonatal causes. The steepest declines in rates of CP in Victoria were for causal subgroups involving perinatal cerebral insults and significant neonatal complications, suggesting that advances in perinatal care may be driving the decreasing CP rates.
To determine the interrater reliability and stability of the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS)/Mini-MACS, and Communication Function Classification System (CFCS) in individuals with STXBP1- and SYNGAP1-related disorders. Data were collected from 83 individuals with STXBP1-related disorders (34 females, 49 males; mean age = 9 years 10 months) and 101 individuals with SYNGAP1-related disorders (51 females, 50 males; mean age = 10 years 11 months) who participated in a prospective natural history study with both cross-sectional and longitudinal phases. Two raters completed the GMFCS, MACS/Mini-MACS, and CFCS assessments on the same day; test-retest stability was evaluated for participants with two longitudinal assessments. Interrater agreement varied from 73.8% to 77.3% for the STXBP1-related disorder cohort and from 60.5% to 83.3% for the SYNGAP1-related disorder cohort. Interrater reliability weighted kappa scores for the STXBP1-related disorder cohort varied from 0.83 to 0.93, while scores for the SYNGAP1-related disorder cohort ranged from 0.66 to 0.81. Test-retest stability scores for the STXBP1-related disorder group varied from 0.62 to 0.94, while scores for the SYNGAP1-related disorder group ranged from 0.38 to 0.78. Significant correlations were found between all assessment scales for both STXBP1-related disorders (Kendall's tau range from 0.25 to 0.42) and SYNGAP1-related disorders (Kendall's tau range from 0.19 to 0.45). The GMFCS, MACS/Mini-MACS, and CFCS demonstrate appropriate levels of interrater reliability and stability for individuals with STXBP1- and SYNGAP1-related disorders.
To establish an overall description of people with cerebral palsy (CP) in Brazil, including the epidemiology, clinical features, functioning, and access to rehabilitation and equipment, through the lens of the International Classification of Functioning, Disability and Health (ICF) framework, using preliminary data from the Brazilian Cerebral Palsy Register (BrCPR). Data were extracted from the ongoing BrCPR for individuals with CP aged 0 to 100 years. The information collected included aetiological risk factors and, from the ICF, personal and health-related factors, environmental factors, body functions and structures, activity, and participation. A total of 1098 participants were included (median age 9 years [interquartile range 5-15 years]; 57.6% male). Most brain injuries occurred pre- or perinatally (68.1%), with preterm birth (44.8%) and perinatal asphyxia (51.1%) being common risk factors. Postneonatal CP (>28 days) was often infection-related (23.0%). One-third of all children were diagnosed before 6 months of age. Bilateral spastic CP predominated (59.4%), and 54.9% were classified in Gross Motor Function Classification System levels IV or V. Co-occurring conditions included epilepsy (57.5%), hip dislocation (31.0%), and cognitive impairment (55.3%). Severe activity limitations were reported, for example dressing (58.9%). Considering participation, 10.0% never attended school. Among environmental barriers, 67.7% lacked home adaptations, 14.0% received no rehabilitation, and 44.7% lacked necessary assistive devices. The BrCPR highlights substantial unmet needs among individuals with CP in Brazil.
To map and summarize available clinical and instrumented assessment tools for evaluating trunk control in individuals with spastic or dyskinetic cerebral palsy (CP) across Gross Motor Function Classification System (GMFCS) levels, describing their current application, assessed features, and psychometric properties, to provide first practical guidance for tool use. For this scoping review, eight databases were systematically searched. Studies were included if they evaluated reliability, validity, or responsiveness of tools assessing trunk control in spastic/dyskinetic CP. The review followed the methodology of the JBI and the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). The search yielded 27 332 publications, of which 110 met the inclusion criteria. Twenty-two distinct assessment tools were identified, including 12 clinical and 10 instrumented. Instrumented assessment tools were most frequently investigated (65%). Validity was reported in 62% of studies; reliability and responsiveness in 30% and 0% respectively. Notably, 85% of studies focused exclusively on individuals with spastic CP, only 28% addressed individuals with CP classified in GMFCS levels IV or V. This review highlights critical gaps in research on trunk control assessment in CP, particularly for patients with severe disabilities, tool responsiveness, and coverage of key facets of trunk control. Future research should prioritize thorough psychometric evaluation of tools, across facets, accounting for the diverse applications and heterogenous clinical presentations in CP.
Absorption, distribution, metabolism and excretion of antiseizure medications may undergo significant modifications throughout pregnancy. These necessitate careful and proactive monitoring to avoid breakthrough seizures during pregnancy with potentially lethal consequences for both mother and child. Based on the available literature, pharmacokinetics of both older and newer antiseizure medications are examined by the authors, emphasizing the important available data and the missing ones for which it is necessary to expand knowledge. Therapeutic drug monitoring is a valuable tool for tailoring antiseizure treatment in women with epilepsy. When monitoring is not feasible, clinicians may need to adjust doses based on seizure severity and the well-documented pharmacokinetic changes of specific medications such as lamotrigine, levetiracetam, oxcarbazepine. The goal is to maintain effective seizure control while minimizing teratogenic risks and ensuring safe fetal development.