Elysa Widjaja

Aim: To assess the relationship between neonatal dysglycemia and early school‐age neurodevelopmental outcomes after neonatal encephalopathy. Method: A prospective cohort born at 36 weeks or more of gestation with neonatal encephalopathy underwent continuous glucose monitoring, neonatal magnetic resonance imaging, and neurodevelopmental assessments at 5 years 6 months (5 months). Linear regression analyses assessed the relationship between glucose (minimum, maximum thresholds of 8–13 mmol/l, and SD) and neurodevelopmental outcomes (Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition and Child Behavior Checklist composite scores), adjusting for sex, neonatal brain injury severity, and parental education. Results: Of 61 newborn infants (40 males), three had mild, 55 had moderate, and three had severe encephalopathy. Maximum glucose greater than 13 mmol/L was associated with a 17.4‐point lower full‐scale IQ ( p = 0.043), 17.4 lower Fluid Reasoning Index ( p = 0.037), and 13.5 lower Processing Speed Index ( p = 0.032). Higher SD of glucose was associated with a 5.0‐point lower Fluid Reasoning Index ( p = 0.038). Significance was lost after adjusting for neonatal brain injury and/or paternal education. No associations were found between minimum glucose and 5‐ to 6‐year outcomes ( p > 0.456). Interpretation: In the era of therapeutic hypothermia, hyperglycemia and increased glucose variability during the first few days of life are associated with worse neurodevelopmental outcomes at early school‐age in survivors of neonatal encephalopathy. These associations could be explained by neonatal brain injury and/or paternal education.

BACKGROUND AND OBJECTIVES: Of 50 million people with epilepsy globally, up to 10 million with lesional drug resistance epilepsy may be able to achieve seizure control with surgical options. Although multidisciplinary surgical care for epilepsy is available in high-income countries, few programs exist in low- and middle-income countries (LMICs). In 2019, a global collaboration between CURE Uganda and Ann & Robert H. Lurie Children's Hospital in the United States established a surgical epilepsy program in Uganda for the pediatric population. This study identifies key pillars for sustainable neurosurgical program development in LMICs. METHODS: Interdisciplinary health care providers from CURE and Lurie Children's who participated in the development of the surgical epilepsy program from 2019 to 2024 underwent semistructured qualitative interviews. A thematic analysis framework was used to identify themes from interviews related to program development, sustainability, and targets for future work. RESULTS: Nine participants were interviewed, with representation from roles of pediatric neurologist, pediatric neuroradiologist, electroencephalogram technologists, medical officer, and pediatric neurosurgeon. Thematic analysis revealed 4 themes (with subthemes) related to sustainable global surgical program development: (1) Intentional planning (integrating global policies into program development, rigorous case selection for great outcomes to build confidence for public/administrative support, defining barriers and optimizing solutions); (2) interdisciplinary collaboration (communication and trust are vital, new initiatives may require sacrifice, true partnerships allow for bidirectional learning, creative problem solving is crucial); (3) skill transfer and education (on-the-ground skill transfer needed, technology integration facilitates continuous learning, enable development opportunities for teammates); and (4) targets for future work (public education, expanding clinical capacity in LMICs, sustainable education centers, research dissemination). CONCLUSION: Global collaborations create opportunities to increase access to neurosurgical care. Creating interdisciplinary programs across borders requires trust and open communication by all members. Sustainable programs can be further enabled with intentional planning, humility, and bidirectional skill transfer.

Objective: The aims of this study were to examine whether there are distinct biopsychosocial phenotypes among children with drug‐resistant epilepsy (DRE) and to determine whether these phenotypes are related to the longitudinal trajectories of child, parent, and family outcomes after epilepsy surgery compared to medical treatment. Methods: This prospective cohort study recruited children with DRE aged 4–18 years who were evaluated for epilepsy surgery and their parents. Baseline clinical variables, child characteristics, parent depressive and anxiety symptoms, and family factors (household income, family demands, family resources, and satisfaction with family relationships) were used to identify distinct phenotypes using hierarchical k‐means clustering. The trajectories of child health‐related quality of life (HRQOL), parent depressive and anxiety symptoms, family resources, and satisfaction with family relationships over 2 years in the surgical and medical treatment groups were compared across the phenotypes using linear mixed models. Results: There were 105 surgical and 197 medical patients. Three distinct biopsychosocial phenotypes were identified among children with DRE: the psychosocial vulnerability phenotype had the poorest psychological and social (family) functioning, the well functioning phenotype had substantially better clinical and psychosocial functioning, and the neurological burden phenotype demonstrated the highest seizure burden and intermediate psychosocial functioning. The most pronounced improvements in child HRQOL, parent emotional functioning, and family functioning over time were observed among those with psychosocial vulnerability , especially after epilepsy surgery. The well functioning and neurological burden phenotypes showed more limited change across most outcomes in both treatment groups. Significance: Identifying biopsychosocial phenotypes may enhance prediction of child, parent, and family outcomes and identify children and families who could benefit from targeted interventions. Despite experiencing more psychosocial disadvantages, the psychosocial vulnerability phenotype demonstrated the largest improvement in outcomes following surgery, suggesting that surgical treatment has the potential to promote more equitable psychosocial outcomes, alongside clinical and HRQOL outcomes.

BACKGROUND: Cerebral folate transporter deficiency ( FOLR1 -related CFTD, MIM #613068) is a rare, autosomal recessive neurological disease characterized by markedly deficient CSF folate levels arising from impaired transport of folate across the blood-brain barrier. Current research highlights the role of folinic acid in treatment for patients with CFTD. To date, there has been minimal published evidence on seizure management for CFTD patients whose conditions are refractory to folinic acid treatment, and there are no standardized approaches for guiding care in this subset. OBSERVATIONS: The authors report a successful clinical outcome after corpus callosotomy in a patient with drug-resistant epilepsy (DRE) secondary to folinic acid–refractory CFTD. LESSONS: This case represents the first documented surgical treatment for DRE in this patient population. Intracranial epilepsy surgery might play an important role for managing DRE in this patient population in the future. https://thejns.org/doi/10.3171/CASE25793

Cerebral folate transporter deficiency (FOLR1-related CFTD, MIM #613068) is a rare, autosomal recessive neurological disease characterized by markedly deficient CSF folate levels arising from impaired transport of folate across the blood-brain barrier. Current research highlights the role of folinic acid in treatment for patients with CFTD. To date, there has been minimal published evidence on seizure management for CFTD patients whose conditions are refractory to folinic acid treatment, and there are no standardized approaches for guiding care in this subset. The authors report a successful clinical outcome after corpus callosotomy in a patient with drug-resistant epilepsy (DRE) secondary to folinic acid-refractory CFTD. This case represents the first documented surgical treatment for DRE in this patient population. Intracranial epilepsy surgery might play an important role for managing DRE in this patient population in the future. https://thejns.org/doi/10.3171/CASE25793.

Objective: This cohort study examined the agreement between youth‐ and parent‐reported health‐related quality of life (HRQOL) of children treated with epilepsy surgery compared to medical therapy. A second aim was to evaluate whether changes in HRQOL over 2 years differed between the two groups, and to determine whether these trajectories differed by informant (youth or parent). Methods: A total of 255 youth–parent dyads participated, of whom 95 youth underwent epilepsy surgery and 160 continued medical management. Participants completed the KIDSCREEN‐27 at baseline, 6‐month, 1‐year, and 2‐year follow‐up. Youth–parent agreement was evaluated at the individual level as well as at the group level. Linear mixed models were used to evaluate changes in HRQOL over time. Results: Among 255 youth, 46% were female, and ages ranged from 8 to 18 years (mean 13 years) at baseline. Most parents were female (85%) and 40–49 years of age (58%). The surgical and medical group were largely similar across baseline characteristics. Agreement across HRQOL domains ranged from fair to good intraclass correlation coefficient (ICC .32–.66). Although average youth–parent differences were small (−1 to +3 points), Bland–Altman plots showed large discrepancies, and substantial differences between dyads were frequent. Youth reported increasing Physical Well‐being and School Environment scores in the first year after surgery and remaining stable or slightly decreasing thereafter. In contrast, parent‐reported trajectories for Physical Well‐being and School Environment did not show a significant difference. For other domains—Psychological Well‐being, Autonomy and Parent Relation, and Social Support and Peers—no differences were identified across treatment groups, and findings were consistent among youth and parent reports. Significance: The results emphasize the need for considering the perspective of youth as well as their parents when evaluating the outcomes of surgery or other treatments for epilepsy.

BACKGROUND AND PURPOSE: Neonatal encephalopathy (NE) is a risk factor for long-term neurodevelopmental impairments, and early measures of brain function may help understand which survivors are most at risk. This study investigates the relationship between resting-state network (RSN) functional connectivity (FC) in the first week of life and long-term neurodevelopmental outcomes after NE. MATERIALS AND METHODS: A prospective cohort of therapeutic hypothermia-treated neonates ≥36 weeks gestational age with NE had resting-state functional MRI (rs-fMRI) in the first week of life, and follow-up at 18 and 36 months. Subject-wise Pearson correlations between each pair of 27 seeds (seed-to-seed correlation matrix) that represent 6 RSNs of interest (Language, Somatomotor, Default Mode, Frontoparietal, Dorsal attention, Ventral Attention), and subject-wise seed-based mean z scores for each seed were generated. Spearman correlations assessed the associations between 6 intra-RSN FC strength values (averaged subject-wise z-transformed seed-to-seed correlations within each RSN) and 18- and 36-month neurodevelopmental outcomes. Based on primary analyses findings, Spearman correlations also assessed the associations between seed-based mean z scores for specific RSNs and neurodevelopmental outcomes at 36 months. RESULTS: Of 72 neonates, 52 (72%) had adequate quality rs-fMRI data. Based on Barkovich scoring, 3 (6%) neonates had basal ganglia, 2 (4%) had watershed, and 10 (19%) had both brain injury patterns. Of 52, 47 (90%) neonates had follow-up at 19 ± 1.7 months, and 45 (87%) at 36.8 ± 1.5 months. Correcting for multiple comparisons, intra-RSN FC strength was not correlated with 18- or 36-month outcomes. Correcting for multiple comparisons, mean z scores for the right motor, and the right and left supplementary motor area within the Somatomotor RSN were positively correlated with Bayley-III language composite score, and mean z scores for the right temporoparietal junction within the Ventral Attention RSN were positively correlated with Child Behavior Checklist Externalizing Problems composite T-score at 36 months. CONCLUSIONS: RSN FC in the first week of life is correlated with 36-month neurodevelopmental outcomes after NE. Early rs-fMRI could provide meaningful clinical insight for predicting long-term neurodevelopmental outcomes after NE. Graphical Abstract

Objective: Although vagus nerve stimulation (VNS) is a well‐established neuromodulation therapy for drug‐resistant epilepsy, treatment outcomes remain heterogeneous. One possible source of variability lies in differing interpretations of seizure frequency ratings (SFRs). This study examined interrater reliability (IRR) in SFRs between (1) retrospective clinician–clinician chart reviews and (2) prospective caregiver–clinician reports, and explored sources of disagreement. Methods: Data were collected from the CONNECTiVOS database. In the retrospective cohort ( n = 254), two clinicians independently reviewed medical records and rated seizure frequency across multiple timepoints. In the prospective cohort ( n = 214), caregivers and clinicians independently reported SFR in children treated with VNS. IRR was assessed across different measurement thresholds, and potential causes of disagreement were analyzed. Results: Clinician–clinician agreement in retrospective chart reviews was excellent (intraclass correlation coefficient [ICC] > .90, Cohen κ > .80), with 18.8% divergent ratings and 4.8% exceeding the reliable change index. Disagreement was significantly associated with higher mean seizure frequency at baseline ( p = .004) and at postoperative timepoints ( p < .001). In the prospective caregiver–clinician comparison, agreement for absolute seizure frequency was poor (ICC < .50), with discrepancies in 86.5% of cases, although only 1.8% were statistically significant. When rating pairs diverged, clinicians more often reported lower absolute seizure frequencies ( p = .002) and greater relative seizure reductions ( p = .023) and were more likely to classify patients as achieving a 90% reduction ( p = .043). Significance: This study highlights interrater variability in both retrospective and prospective SFR assessments, a finding systematically related to baseline seizure frequency. Coarser classifications (e.g., 50% or 90% seizure reduction) may improve agreement but reduce clinical nuance. Future efforts should focus on structured, patient‐centered documentation and the development of objective outcome measures in VNS evaluation, particularly for children with high seizure burden.

Objectives: Responsiveness to vagus nerve stimulation (VNS) in children with drug‐resistant epilepsy (DRE) is often defined based on reduction in seizure frequency, typically at the 50% threshold, with limited consideration to the effects of therapy on seizure severity and health‐related quality of life (HRQoL). In the current report, we sought to better characterize the effects of VNS beyond seizure frequency in children with DRE. Methods: Sixty‐seven children from the Connectomic profiling and Vagus nerve stimulation Outcomes Study (CONNECTiVOS) database, a multicenter study including children aged 0–18 who underwent VNS at eight North American centers, were included. Data were collected prospectively at baseline and 6, 12, and 24 months after VNS. Seizure outcomes were assessed using the 50% threshold, percentage change in seizure count and change on a frequency timescale, a categorical measure of seizure occurrence (e.g., daily to weekly seizures). The Seizure Severity Questionnaire and the Quality of Life in Childhood Epilepsy were also collected. Linear mixed models were constructed to study longitudinal changes in seizure severity and HRQoL. Results: Among 67 children, 55.2% experienced >50% reduction in seizures, whereas only 37.3% demonstrated reductions in seizure timescales. Notably, 17.9% experienced no reduction in timescales despite meeting the 50% threshold. Furthermore, 31.9% of children experienced a meaningful improvement in seizure severity without any reduction in seizure timescales. HRQoL improvements were driven by the reduction in timescales (mean yearly increase of 3.65; 95% confidence interval [CI]: 0.71–6.52, p = 0.023), rather than responsiveness based on the 50% threshold or percentage change in seizure counts ( p > 0.05). Reduced overall seizure severity was also independently associated with higher HRQoL after VNS ( p = 0.035). Significance: The conventional 50% responder threshold failed to capture meaningful gains in HRQoL, which aligned more closely with seizure timescales. Furthermore, nearly one‐third of children realized improvements in seizure severity without any reduction in timescales. Improvements in both seizure frequency timescales and seizure severity drive postoperative HRQoL gains.