ABSTRACT Background and Objectives Leukodystrophies are neurogenetic diseases affecting the white matter of the central nervous system. The contributing factors for leukodystrophy mortality are incompletely understood. Our objectives were to characterize inpatient deaths of pediatric leukodystrophies, including demographics and risk factors. Methods This retrospective cohort analysis utilized the national Pediatric Health Information System (PHIS) database. Patients under age 19 years with an (ICD‐10) diagnosis of leukodystrophy and an inpatient encounter at a PHIS hospital between 2016 and 2024 were included. Analysis included descriptive and multivariate statistics. Results In all, 613 patients with 15 different leukodystrophies were identified; 32 patients died (5.2%). The most common diagnoses of patients who died were Krabbe disease (KD) (31%), adrenoleukodystrophy (ALD) (28%), metachromatic leukodystrophy (MLD) (28%), and vanishing white matter disease (VWM) (6%). Volume of leukodystrophy admissions at individual hospitals was inversely correlated with mortality. Small numbers limited statistical significance, but mortality rates were higher in females than males (8.3% vs . 3.8%); and Black, Asian, and multiracial patients were more likely to die than White patients, 8.4%, 7.7%, and 8.7%, versus 4.1%. Conclusions In this large national administrative database study, we characterized and helped define risks for inpatient mortality of pediatric leukodystrophies. Inpatient mortality was correlated with clinical risk factors, and further, although small numbers precluded statistical significance, mortality disparities by sex and race were identified. The reasons for these differences are not known and warrant further study. Our findings identify directions for new research and underscore the potential impact of specialized institutional experience.
ABSTRACT Objective The current clinical nomenclature for individuals with ABCD1 gene dysfunction is often uninformative. The disorder was initially described as a combination of adrenal insufficiency and leukodystrophy, leading to the widespread use of “X‐linked adrenoleukodystrophy” (ALD). However, this term is inaccurate for individuals who never develop these features. ABCD1 dysfunction can cause various symptom complexes: adrenal insufficiency, myelopathy, neuropathy, and leukodystrophy, which may occur consecutively, simultaneously, or not at all. Methods We developed an intuitive annotation system to precisely convey phenotype status for individuals with ABCD1 dysfunction. The “AMNL score” assesses the presence and severity of [A]drenal insufficiency, [M]yelopathy, [N]europathy, and [L]eukodystrophy, with scores ranging from 0 (no symptoms) to 3 (severe) per domain. Results Applied to initial clinical encounters with 101 Dutch patients and 30 patients from the California newborn screening (NBS) program, the system identified 33 unique presentations. The most common was isolated mild myelopathy (A0M1N0L0). Including predominantly asymptomatic NBS newborns (mostly A0M0NUL0) broadened the spectrum and highlighted the need for precise classification across ages. Longitudinal use over 2 years in 99 Dutch patients showed progression in one or more domains in 41.4%, most often worsening myelopathy. In the NBS cohort (median follow‐up: 3.5 years; range: 0.3–12.2), most patients showed no myelopathy or leukodystrophy, though adrenal involvement was detected in half. Initial inter‐rater reliability was high ( α = 0.996). Interpretation The AMNL score's ability to quantify domain‐specific changes over time makes it valuable for monitoring disease evolution in clinical practice and research.
ABSTRACT Objective Pediatric neuroprognostication is often complicated by uncertainty and embedded in high‐stakes medical decisions. For child neurology residents, participation in neuroprognostication can represent key learning experiences but also comes with emotional and ethical challenges, which poses a risk of moral distress. This study sought to describe contextual influences and impacts on residents participating in neuroprognostication. Methods One‐on‐one, semi‐structured virtual interviews were conducted with senior (postgraduate year 5–6) child neurology residents. Deidentified transcripts were iteratively analyzed to develop themes and generate a narrative of resident experiences. Initial themes were shared with participants for additional feedback. Final themes were synthesized to characterize contextual influences and the emotional and professional impacts of participating in neuroprognostication. Results Fifteen residents from 12 institutions across 10 states participated, representing a range of program sizes and geographic locations across the United States. Qualitative analysis identified five themes: (1) Serious neurologic pathology and decisions with high stakes , highlighting neurology teams' roles in major medical decisions; (2) Navigating uncertainty and hope , describing the difficulty of limited data; (3) Systemic barriers and challenges to prognostic communication , underscoring team‐ and institution‐level factors; (4) Negative emotional impacts , with concerns of developing emotional exhaustion; and (5) The importance of neuroprognostication , emphasizing the gravity of this responsibility and distress when residents felt ineffective in this role. Conclusions Residents describe neuroprognostication as an emotionally salient experience carrying a strong sense of responsibility. This narrative highlights opportunities to support residents in training, improve prognostic communication, and address potential threats to resident well‐being.
ABSTRACT Objective Little is known about shifting from pediatric to adult‐focused multiple sclerosis (MS) care. This study aims to explore transition of care and follow‐up in the US pediatric‐onset MS (POMS) population. Methods Surveys were distributed to 10 sites in the US Network of Pediatric MS Centers (US NPMSC) about transition‐of‐care practices. A cohort of POMS/clinically isolated syndrome (CIS) at 12 US NPMSC sites was analyzed. The primary comparison was between < 18 and ≥ 18‐years of age. The primary outcome was 1‐ and 2‐year lapse in last follow‐up visit, measured from last recorded database visit to data lock date or, if ≥ 18 years of age, up to 1 year after a patient reached their site's typical transition age, if earlier. Secondary outcomes were baseline factors associated with follow‐up lapse. The model was adjusted for preidentified confounders. Results Compared with < 18 years, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse. In POMS/CIS, the estimated hazard was 1.61 for 1‐year lapse (95% confidence interval [CI] 1.32–1.97, p < 0.001) and 1.40 for 2‐year lapse (95% CI 1.11–1.76, p = 0.004). In POMS‐only, the estimated hazard was 1.70 for 1‐year lapse (95% CI 1.33–2.18, p < 0.001) and 1.49 for 2‐year lapse (95% CI 1.11–1.99, p = 0.007). Platform injectable disease‐modifying therapy was associated with greater and intravenous with lesser hazard of lapse in follow‐up, while MS was associated with lower hazard than CIS. Conclusion Variable transition‐of‐care practices and barriers were reported by major US POMS centers. Before typical transition age, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse than < 18. Developing standardized, targeted transition‐of‐care practices in POMS may be important.
ABSTRACT Purpose X‐linked adrenoleukodystrophy (ALD) encompasses a wide range of neurological manifestations, classically described as distinct phenotypes including childhood cerebral adrenoleukodystrophy and adult‐onset adrenomyeloneuropathy (AMN). Corticospinal tract (CST) and cerebellar involvement on brain magnetic resonance imaging (MRI) are typically attributed to long‐tract axonopathy in AMN, yet the extent to which these features span the ALD spectrum is unclear. To explore whether CST and infratentorial lesions reflect discrete phenotypes or a continuous disease spectrum, we examined their onset and prevalence across the lifespan. Methods We retrospectively analyzed 1189 brain MRIs from 218 male patients diagnosed with ALD evaluated at Massachusetts General Hospital from 2005 to 2024. Imaging reports were screened for CST and infratentorial lesion presence, and serial scans were reviewed to determine chronological patterns of involvement. In pediatric patients with isolated CST lesions, treatment data and post‐treatment imaging were assessed. Results Isolated CST lesions were identified in 8.7% of pediatric and 11.4% of adult patients. All but one adult with cerebellar lesions also demonstrated CST lesions, which preceded or occurred concurrently with the cerebellar abnormalities. Among pediatric patients with isolated CST lesions, 38.5% underwent lentiviral gene therapy, and 23.1% received hematopoietic stem cell transplantation. Imaging post‐treatment revealed lesion size reduction in 87.5%. Conclusion CST involvement, including isolated lesions and those preceding cerebellar involvement, occurs across age groups and may represent a continuous ALD disease spectrum rather than a strictly phenotype‐specific feature. These findings support the importance of dedicated CST assessment in routine MRI review and highlight its potential role in earlier diagnosis and therapeutic decision‐making.
ABSTRACT Background Perinatal arterial ischemic stroke (AIS) affects 1 in 4000 live births. Dystonia, affecting ~20% of children following AIS, is characterized by involuntary muscle contractions and abnormal movements. Why some develop dystonia post AIS, while others do not, remains unclear. We hypothesized that dystonia after AIS is associated with two key features: lesions involving frontal–basal ganglia network regions and corresponding disruptions in motor oscillatory activity. Methods Monozygotic twin brothers aged 11 years were recruited to a study investigating neural correlates of motor control in post‐stroke dystonia. Brain magnetic resonance imaging (MRI) assessed lesion localization, volume, and white matter structure. Magnetoencephalography measured timing and localization of neural oscillations during movement execution and inhibition on the “go”/”no‐go” task. Clinical history was obtained from charts. Neurological outcome was evaluated with the Pediatric Stroke Outcome Measure (PSOM). Results MRI showed mirrored hemispheric lesions in the twins, with additional basal ganglia involvement in Twin A. Diffusion tensor imaging revealed lower corticospinal tract integrity in Twin A. MEG in Twin A revealed increased frontal theta (4–8 Hz) during correct inhibition. Sensorimotor gamma was reduced for Twin A but upregulated for Twin B during contralesional hand movement. Clinically, Twin A had a PSOM score of 2 (moderate motor and cognitive deficits); Twin B scored 0 (no deficits). Conclusions Our findings suggest that dystonia following perinatal AIS is associated with altered frontal–basal ganglia network function, with increased frontal recruitment reflecting compensatory disinhibition during motor control.
ABSTRACT Background Epilepsy affects up to 90% of patients with tuberous sclerosis complex (TSC); earlier seizure onset is associated with worse neurocognitive outcomes. The incidence of neonatal seizures in TSC is unknown, although in a recent multicenter trial 23% of infants with TSC were excluded prior to randomization because of pre‐existing seizures prior to age 4 months, suggesting that neonatal or early infantile seizures may be a common occurrence. Aims We aimed to determine the rate of neonatal seizures in our cohort of TSC patients. Methods We performed a single‐center medical records review of patients with TSC who were seen between 2020 and 2025 to identify patients with neonatal seizure onset. Summary and Conclusions Of six patients with data from the neonatal period, four (67%) had neonatal seizures. Two had confirmed electrographic seizures in the first week of life, and another two had clinical seizure onset during the neonatal period. All patients with neonatal seizures had TSC2 and developed drug‐resistant epilepsy, and two of four developed infantile spasms despite intensive early medical management, including vigabatrin. The two patients without neonatal seizures had TSC1 and mosaic TSC2, respectively. They have not developed epilepsy and have had milder neurodevelopmental impairment. In conclusion, data from our center suggest that neonatal seizures may be common in TSC, especially in high‐risk infants with TSC2 with highly epileptogenic lesions. With recent preliminary data about safety and efficacy of mTOR inhibitor treatment in infants with TSC, early EEG monitoring should be considered.
ABSTRACT Objective Children with Down syndrome follow distinct developmental trajectories that require specialized monitoring and counseling. We aimed to provide updated estimates of developmental milestone attainment using a nonparametric approach and to compare these results with previously reported generalized linear mixed‐effects model (GLMM) estimates. Methods We reanalyzed developmental data from 842 children with Down syndrome (ages 2 months to 24 years). For each milestone, achievement rates were calculated within overlapping 0.5‐year time windows, and shape‐constrained additive models were used to derive monotonic regression curves. Results Compared with GLMM‐based estimates, the nonparametric approach predicted milestone attainment at least 1 year earlier for 17 of 25 milestones at the highest comparable percentile. Early gross motor milestones showed consistent achievement patterns across methods, whereas more complex adaptive, language, and academic skills demonstrated greater variability and were more sensitive to modeling assumptions. Females achieved 17 of 25 milestones at least 1 year earlier than males. Conclusions These findings highlight substantial developmental heterogeneity and support the potential for continued skill acquisition throughout childhood and adolescence in individuals with Down syndrome. The updated estimates provide clinically relevant reference points to guide individualized monitoring, anticipatory guidance, and family counseling.
ABSTRACT Introduction Sturge–Weber syndrome (SWS) brain involvement has been associated with impairments in the blood–brain barrier (BBB) and microglial activation within involved cortical regions. Acute neurological crises, including seizures, stroke‐like episodes, and/or significant headaches, are common in these patients. This report describes in detail an adolescent with SWS and acute drug‐resistant status epilepticus, headache, and stroke‐like episode who improved clinically when treated with high‐dose steroids. Review of medical records identified two other patients previously treated with steroids for acute neurological symptoms. Case Presentation A 13‐year‐old boy with SWS brain involvement presented with fever, headache, seizures, and right‐sided weakness. Brain magnetic resonance imaging (MRI) revealed characteristic findings of SWS. The patient was placed on continuous electroencephalogram that showed findings consistent with electrographic status epilepticus. Seizures were refractory to multiple anti‐seizure medications as well as to an intravenous midazolam drip. A repeat MRI of the brain documented a significant increase in leptomeningeal enhancement with associated gyral edema and sulcal effacement. Steroid therapy with methylprednisolone and prednisone improved his status epilepticus and stroke‐like symptoms, including resolution of seizures and marked improvement in his hemiparesis. Conclusion This patient suggests a potential role for inflammation‐targeted therapies in individuals with SWS brain involvement who present with prolonged neurological crises. Two other patients with SWS brain involvement who were treated with high‐dose steroids in the context of acute neurological episodes also support the need for future clinical and preclinical research to validate this approach.
ABSTRACT Objective Pediatric neuropalliative medicine (PNPM) is a recently developed area of subspecialty neurology practice focused on supporting the complex emotional, psychological, and physical aspects of caring for a child with serious neurological disease. This study aims to characterize the establishment and inaugural 5 years of an academic, consultative pediatric neuropalliative medicine (PNPM) clinic at a large, quaternary care children's hospital in the US. Methods Descriptive statistics were used to characterize the population seen in this clinic and to analyze outcomes. Results Over 5 years, 250 patients were seen, totaling 682 clinic visits. Primary diagnoses of patients included epileptic encephalopathy (30%), acquired brain injury (24%), and neuromuscular diseases (16%); 64% of patients had a confirmed genetic condition. The most common referral sources included child neurology (33%) and rehabilitation medicine (20%). Referral to this clinic was the first contact with palliative medicine for 82% of patients. In PNPM clinic, all families participated in facilitated narrative debriefing of their prior experiences related to serious illness. Future decision‐making considerations were highlighted, including initiation of life‐sustaining medical technology and emergency management including code status. Of the 51 patients (20%) who died within the study period, 90% had code status discussions in the clinic and 89% died in a supportive setting, including home hospice or inpatient care. Summary PNPM clinic promotes tailored and proactive decision‐making support for families affected by serious neurological illnesses. All patients had health fragility and some of them died in childhood, though the majority of the cohort remained alive beyond the study period.
ABSTRACT Objective Trofinetide is the first approved treatment for Rett syndrome (RTT) in the United States and Canada. Trofinetide improved the core symptoms of RTT in clinical trials, and real‐world evidence supports the findings of clinical trials. As RTT experts in the United States have now gained nearly 3 years of real‐world experience with trofinetide, a modified Delphi process was conducted in the United States to establish consensus recommendations for the practical use of trofinetide in the treatment of RTT. Methods A multidisciplinary steering group of five trofinetide‐experienced RTT experts practicing at an International Rett Syndrome Foundation (IRSF)‐designated center of excellence convened and developed 72 consensus statements across six domains: first‐line use, pre‐treatment assessment, initiation, benefit evaluation, tolerability management, and discontinuation strategies. The statements were then assigned a 4‐point Likert scale for testing via email by the Delphi panel identified by the steering group. Consensus was reached for individual statements if they met the pre‐specified consensus threshold of ≥ 75% agreement. Results Two rounds of assessments were completed by 25 respondents in each round, resulting in agreement ≥ 75% being reached across the final statement set. The consensus supports trofinetide as the standard of care for eligible patients with early initiation and an individualized approach to titration to maximize efficacy and tolerability. The panel reflected the steering group's view that trofinetide is efficacious. While side effects can emerge with trofinetide, they are manageable in most cases. Conclusions Recommendations highlight a flexible, patient‐centered approach to trofinetide use to optimize efficacy while addressing tolerability challenges and supporting adherence.
