We aimed to develop a program director-derived model of essential components of child neurology residency training. All 79 child neurology residency programs in the United States were invited to submit a block diagram with 48 months of required rotations, the minimum clinical requirement across all approved pathways. These block diagrams were then analyzed for consensus. Program directors were anonymously surveyed regarding whether a child neurology resident could be adequately trained using the consensus curriculum if implemented in either a 4- or a 5-year training program, and whether 4 years of residency could provide adequate training. Fifty of 79 residency programs (63%) submitted a block diagram (54% in pediatrics departments, 46% in neurology departments). Greater than 75% of program directors recommended the following rotations with the average number of months recommended across all program directors in parentheses: pediatric inpatient/hospital medicine (3), pediatric non-consult intensive care (3), healthy newborn (0.5), pediatric acute/emergency care (1), genetics (1), child development (1), child neurology inpatient/consults (8), child neurology general outpatient (4), child psychiatry (1), adult neurology inpatient/consults (3), neurology specialties outpatient (4), electroencephalography (2), neuroradiology (1), and electives (7). Of the program directors (53 of 79, 67%) who completed the post-survey, 87% agreed that these requirements would be adequate, and 89% agreed that child neurologists could be adequately trained for independent practice within 4 years. The program director consensus supports modification of existing child neurology training requirements, with general agreement that 4 years of clinical training would be adequate.
Our aim was to investigate the advantages of exome sequencing versus panel testing for patients with unexplained seizures. We reviewed the diagnostic outcomes of exome sequencing by a commercial genetics laboratory for more than 16 000 individuals with a clinical history of seizures or suspected seizures. Exome sequencing identified diagnostic variants (pathogenic and/or likely pathogenic; L/PATH) in 778 seizure-related genes, resulting in diagnoses in 4035 individuals (24.6% of the cohort). Of the 778 genes, 454 (58.4%) were not present on a comparison sample of six commercially available epilepsy panel tests. The analysis predicted that the epilepsy panels would have missed 52%-63% of diagnostic cases reported by exome sequencing. Nineteen percent (753/4035) of the cohort had a previous epilepsy panel. Exome sequencing added new diagnostic information in this panel-tested sub-cohort, including L/PATH variants not reported on the epilepsy panel (74.2% of patients) and L/PATH variants that were originally classified as variants of uncertain significance by the panel (11.2% of patients). Exome sequencing identified L/PATH variants likely to have immediate implications for clinical intervention in 17.9% of diagnostic cases and in 10.0% of cases with a previous nondiagnostic epilepsy panel. The data demonstrated limitations of epilepsy panels and several advantages of exome sequencing over panels for patients with unexplained seizures. Exome sequencing offered a higher diagnostic rate than previously published for panels and the identification of variants with implications for clinical intervention among patients with prior nondiagnostic epilepsy panels. Another advantage of exome sequencing was the identification of clinically relevant findings unrelated to seizures. Together, these data further support the use of exome sequencing as a first-tier test for patients with unexplained seizures and demonstrate the potential clinical benefits of comprehensive genetic testing. Not applicable.
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. 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. 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. Recommendations highlight a flexible, patient-centered approach to trofinetide use to optimize efficacy while addressing tolerability challenges and supporting adherence.
The natural history of the most common ATP1A3-related disease, alternating hemiplegia of childhood (AHC), has not been determined. We investigated three hypotheses: (1) AHC worsens over time; (2) several novel factors correlate with long-term outcomes; and (3) AHC manifests high mortality. In a large cross-sectional study with a nested period of prospective 1-3-year follow-up, 115 patients (0.3-46.0 years old, 9 centers/5 countries) were evaluated using across-center-standardized protocol and validated scales. Univariable and multivariable linear-mixed-effects models with random intercepts and random slopes for age, adjusted for confounding variables, allowed for the determination of the effect of age throughout the total age range of patients studied. Course: We identified a distinction between two periods, namely the period of early childhood (age 1-5 years) and the period of later childhood to mid-adulthood. Intellectual and non-paroxysmal disability indexes (IDS, NPDI) scores as well as the Vineland Adaptive Behavior Composite and its subscales worsened during early childhood, but not in the period after that. The extent of motor skills impairment did not differ with age in either period. Within the PDI (paroxysmal disability index) scores, dystonia severity scores did not differ with age in either period; however, plegia severity scores did improve with age after 5 years of age. Prognostic variables included the following: (1) Epilepsy was associated with worse NPDI, intellectual, and fine and gross motor skills. (2) Worse early life PDI and NPDI scores were significantly associated with worse respective scores at the latest follow-up. (3) Worse early life NPDI scores were also associated with worse IDS and fine and gross motor scores at the latest follow-up. (4) D801N mutation was associated with worse PDI. (4) E815K mutation was associated with worse IDS. Mortality was 1.12 deaths/100 patient-years and 6.5 sudden unexpected death in epilepsy (SUDEP) deaths/1000 patient-years. AHC is a progressive disease, and early childhood is the vulnerable period. We identified several novel prognostic indicators and a mortality rate, which provide critical information not only regarding prognostication, counseling, and underlying pathophysiology but also for planning therapeutic studies.
The objective of this study was to examine the correctness of the statement that the diagnosis of shaken baby syndrome (SBS) is a "medical conclusion." If the outcome of an event is considered bad, people tend to attribute intent or responsibility. Against this backdrop, a randomized, blinded trial was applied using two case-based questionnaires of possible violent shaking of an infant, identical except for the outcome: fatal or nonfatal. We used a report of a 2-month-old baby who had suddenly stopped breathing and was subsequently shaken by the father with the intention to resuscitate him. After admission, encephalopathy, subdural hemorrhages, and retinal hemorrhages were detected. A total of 1269 randomly selected physicians received the questionnaire, whose distribution was randomized and blinded. The participants were not informed about the existence of two versions of the questionnaire. The participants who responded to the fatal version considered in a significantly higher proportion (79% [95% CI: 73-85]) that shaking caused the triad findings than those who responded to the nonfatal version (68% [95% CI: 61-75]) (p = 0.01). When pediatricians and ophthalmologists are merged, the corresponding proportions were (91% [95% CI: 86-96]) versus (74% [95% CI: 66-82]) (p = 0.001). Radiologists and forensic pathologists did not distinguish significantly between fatal and nonfatal outcomes. The study indicates that among pediatricians and ophthalmologists, the diagnostic process in suspected SBS is more value-based than evidence-based. As these two specialties dominate the SBS diagnostic procedure, the SBS diagnosis is, in this sense, not strictly a "medical conclusion."
Epilepsy with myoclonic and atonic seizures (EMAtS), also known as Doose syndrome, accounts for 1%-2% of childhood epilepsies, and various genes have been implicated in causing this epilepsy syndrome. NUS1 encodes for Nogo-B receptor (NgBR), which stabilizes the dehydrodolichyl-diphosphate synthase complex in the endoplasmic reticulum, promoting its enzymatic activity (cis-IPTase) and thereby regulating cholesterol biosynthesis. Pathogenic variants in NUS1 have been associated with movement disorder and epilepsy; however, the spectrum of epilepsy and electroencephalogram (EEG) phenotype has not been well characterized. We describe a single-center case series of five patients with NUS1-related disorder. In our cohort, three patients met the diagnostic criteria of EMAtS, and the remainder had a milder form of generalized epilepsy. Four patients had a pathogenic variant in NUS1 on one allele, and one patient had a missense change of unclear significance but fit the phenotype of NUS1-related disorder. All patients bearing the pathogenic variants in NUS1 had normal to mild developmental delay at the onset of epilepsy, with normal brain magnetic resonance imaging. Age of seizure onset in these patients was 1-7 years, and patients responded to levetiracetam and/or valproic acid. The EEG findings for these patients included the presence of spike and slow wave discharges, as well as the presence of generalized, invariant monomorphic theta range activity in the awake state, which was seen in four out of the five patients. Taken together, NUS1 variants are associated with generalized epilepsy phenotype and an invariant EEG pattern of monomorphic theta activity.
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. Descriptive statistics were used to characterize the population seen in this clinic and to analyze outcomes. 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. 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.
Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays. We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0-18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug-resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra- and inter-institution variability and to delineate institutions with the shortest added duration for each variable. Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3-22); 453 (27%) were short-duration evaluations and 414 (25%) were long-duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups. Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commonly employed in epilepsy surgery evaluations. This predictive model can not only estimate evaluation duration but also identify opportunities to improve systemic efficiency. Institution-level modeling identifies specific program strengths, providing an opportunity to learn from successful processes. Subsequent research will focus on institutional process mapping to better understand systemic practices that lead to improved efficiencies, then sharing these processes across the consortium to shorten evaluation durations.
Pathogenic CYFIP2 variants cause developmental and epileptic encephalopathy (DEE), characterized by early-onset intractable epilepsy and developmental delay. The disease course has not been delineated. Codon Arg87 is a de novo mutational hotspot associated with a severe DEE phenotype via gain-of-function mechanisms. Currently, there are no targeted therapies for CYFIP2-related DEE. Genetic therapies initiated at early symptomatic stages have demonstrated benefit in other disorders and may be an important consideration for this patient population. We describe a child with a de novo CYFIP2 Arg87Cys variant and a unique clinical course, along with a comprehensive literature review of reported cases. We identified 41 additional patients with pathogenic or likely pathogenic CYFIP2 variants. The Arg87Cys variant was present in 12/42 (29%) patients. An additional 27 variants are described across 30 patients. All individuals had global developmental delay, 32/42 (76%) developed epilepsy, and 25/42 (60%) experienced seizure onset in the first year of life. Of those with seizures, 16/32 (50%) had epileptic spasms, and 5/32 (16%), including our patient, developed other seizure types before epileptic spasm onset. Interestingly, our patient is the only report of developmental and electroencephalographic (EEG) normalization after initial seizure onset and before spasms. Our patient expands the phenotype of CYFIP2-related DEE by demonstrating developmental and EEG normalization after seizure onset and before onset of epileptic spasms and global developmental delay. Given the growing field of genetic therapies and other precision medicines, this period of normalization may represent a window of opportunity for future early intervention.
Transition refers to the planned, coordinated movement of adolescents from the child- and family-centered environment of pediatric care to the adult healthcare system. A well-structured transition process is essential for ensuring adolescents with chronic health conditions continue to thrive in young adulthood. Poor transitions can lead to negative health outcomes, worsening of comorbidities such as anxiety and depression, and poorer psychosocial well-being. This topical review combines literature from general pediatrics, adolescent medicine, general child neurology, and child neurology subspecialities to provide holistic recommendations for the transition of pediatric patients to adulthood. Core principles of transition include starting transition planning early, creating individualized transition plans, providing support before transition, and ensuring ongoing support after transition to adult care. For adolescents with neurological conditions, additional considerations include recognizing that many childhood neurological disorders are now lifelong conditions, addressing the impact of varying levels of intellectual disability, reevaluating the diagnosis at the time of transfer, and establishing emergency care planning.
Children with autism spectrum disorder (ASD) often experience challenges integrating visual information to guide motor behavior, particularly in dynamic (speeded) contexts. We investigated the effects of varying stimulus tracking speed on visual-motor integration (VMI), addressing our hypothesis that ASD diagnosis and symptom severity would be associated with impaired performance on dynamic, speeded (vs. slow/static) VMI. Fifty-four children aged 8-12 years (ASD: n = 16; typically developing [TD] controls: n = 38) successfully completed a continuous grip-force tracking task involving three conditions: static, slow, and fast visual trajectories. A linear mixed-effects model was used to examine the effects of ASD (vs. TD) diagnosis on speeded VMI. We further examined the correlation between speeded VMI and both clinician-rated (Autism Diagnostic Observation Schedule, Second Edition [ADOS-2]) and parent-reported Social Responsiveness Scales, Second Edition (SRS-2) autism symptoms. A significant interaction between diagnosis and condition was observed (p = 0.03), indicating that group differences in tracking accuracy varied by stimulus speed. Children with ASD showed significantly greater tracking error than TD peers in the fast condition (ASD: 13.5 ± 1.0 [95% CI: 11.3-15.7]; TD: 10.5 ± 0.7 [95% CI: 9.1-12.0]; p = 0.02), but not in the static (p = 0.80) or slow (p = 0.55) conditions. Both groups showed increased error as speed increased, but the ASD group showed greater impairment under speeded conditions. Higher ADOS-2 Total scores predicted greater error in the fast versus slow (p = 0.009) and fast versus static (p = 0.06) contrasts and in the fast condition alone (p = 0.02). Elevated SRS-2 Total scores were similarly associated with greater error in the fast versus slow (p = 0.02) and fast versus static (p = 0.02) comparisons, though not in the fast condition alone (p = 0.23). The findings support difficulty with speeded dynamic VMI as a scalable autism biomarker. Further development of these biomarkers could be helpful to guiding behavioral interventions, for instance, identifying children who would best respond to slowing visual cues during therapy. Future studies should refine assessment tools to extend assessments of dynamic VMI to younger and more affected children and explore developmentally appropriate interventions tailored for children showing difficulties with speeded VMI.
Pain perception is a conscious experience, but neither pain nor consciousness is defined in the developing human fetus. Emergent consciousness may be regarded as a phenomenon that ultimately arises from an essential minimum of functional neuronal connectivity. Proposed U.S. federal legislation asserts that a functioning cerebral cortex is not necessary to experience pain. We assess the scientific premise of the 13 assertions in the "Pain-Capable Unborn Child Protection Act" with analysis and interpretation from a developmental neuroscience perspective. We review the biological requisites of fetal sentience, the emergence of involuntary spinal cord and brainstem reflexes, the early appearance of autonomic homeostatic stress reactions, and measures of synaptogenesis and neuronal connectivity through immunocytochemistry and fetal functional neuroimaging. The formation of functional synapses can be demonstrated by synaptophysin immunoreactivity in the receptive sensory layers of fetal cerebral cortex at around 25 weeks' gestation, but immunoreactivity is not uniformly intense until after 35 weeks. In vivo, fetal functional magnetic resonance imaging confirms immunocytochemical results by showing complex, interconnected brain networks developing at similar gestational ages. Fetal magnetoencephalography detects magnetic fields from fetal brain activity and demonstrates second-order rule learning in fetuses over 35 weeks' gestation. The neural pathways required for the emotional and evaluative aspects of pain processing in the brain are still incomplete in term newborns. Given the limitations of reductionism to explain the subjective nature of consciousness, evidence from developmental neuroanatomy, neurophysiology, and functional neuroimaging infers that fetal pain perception requires the emergence of conscious cortical processing beginning with weak functional thalamocortical connectivity well after the age of fetal viability.
The Developmental and Epileptic Encephalopathies (DEE) are associated with serious and life-long neurological conditions and risk of early mortality. Here we describe the chronic treatment of a boy with PLCB1-related DEE with enteral myo-inositol supplementation as an add-on therapy to standard antiseizure medications that had been ineffective, and present novel findings in our lethal Slc5a3 knockout mouse model to substantiate our hypothesis for a novel role of myo-inositol in prenatal life. Myo-inositol levels were measured in plasma, urine, and cerebrospinal fluid (CSF) using stable isotope dilution and selected ion monitoring gas chromatography/mass spectrometry. Brain function and structure was monitored with magnetic resonance spectroscopy, magnetic resonance imaging and electroencephalograms. Safety studies were performed according to FDA requirements. Treatment was well tolerated without any reported adverse events. There was an improvement in seizure burden and stabilization of brain atrophy that was most evident in the first and second years of life. Myo-inositol administration to the pregnant Slc5a3 carrier mice increased the myo-inositol content in CSF of the Slc5a3 knockout pups, which prevented their death. High-dose enteral myo-inositol supplementation was safely used in a patient with epileptic encephalopathy due to PLCB1 deletion, increasing CSF levels and improving seizures and brain atrophy. The hypothesized mechanism involves restoring a fetal-like state with increased membrane potential, thereby reducing neuronal firing. Based on our experience, we encourage the exploration of high-dose myo-inositol in clinical trials involving infants with severe epileptic encephalopathy.
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. 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. 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%. 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.
Manganese is the 12th most common element in the Earth's crust and is an essential industrial component. Biologically, this metal plays an important role as a constituent of numerous enzymes. While manganese is required for normal biochemical and physiological processes, manganese excess can lead to significant toxicity, particularly to the central nervous system. Over the past 25 years, three inherited disorders of manganese transport have been described, leading to a model of how this essential metal is absorbed, distributed to tissues, and eliminated. The first part of this review describes the clinical features and cellular mechanisms of manganese toxicity due to occupational and environmental exposure. The remainder of the review discusses the familial disorder associated with hypomagnesemia, SLC39A8 deficiency, and the two genetic diseases resulting in hypermanganesemia, SLC30A10 deficiency and SLC39A14 deficiency. These latter two disorders are treatable, and the early recognition and institution of chelation therapy and iron supplementation can improve neurological disability. Ongoing research regarding the tissue-specific role of each transporter and their regulatory interplay, the varied mechanisms of manganese toxicity, and its treatment are also described.
Walking capacity declines prematurely in individuals with ataxia telangiectasia. However, granular data on walking capacity loss in ataxia telangiectasia are scarce. In this large cross-sectional cohort, we describe age-related walking capacity loss reported by participants and compare categories of a subjective walking capacity scale with the International Cooperative Ataxia Rating Scale (ICARS) walking categories. Children with ataxia telangiectasia who presented with neurological symptoms at 5 years of age or younger and were 18 years of age or younger at the time of walking capacity reporting were included. Descriptive statistics, Spearman's rank correlations, and simple linear regression of score versus age were used to analyze the data. Mean walking capacity scores from 372 participants remained stable until age 5, followed by progressive worsening between ages 5 and 14, with persistently high scores thereafter. Categories from the subjective walking capacity scale were mapped to ICARS and its abbreviated, more functional version, Rescored modified ICARS (RmICARS) walking categories. Correlation with age was similar across all three scales (Spearman's rho: 0.711, 0.713, and 0.714). Linear regression in participants aged 5-14 years (N = 220) showed consistent R² values (~0.45) across all scales and confirmed a statistically significant relationship between age and diminished walking capacity (p < 0.001). Although age-related loss of ambulation was statistically significant, it accounted for just under half of the variability in walking capacity progression. Controlling for disease severity, i.e., classical or the mild variant of ataxia telangiectasia, and capturing more granular data on walking with assistance may improve the prediction of age-associated walking capacity loss.
Tumefactive demyelinating lesions (TDLs) are large lesions (> 2 cm) seen in demyelinating syndromes such as multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated disorder, and neuromyelitis optica spectrum disorder. They rarely occur in children and most often have a monophasic course. TDLs can cause severe presentations given their size, edema, and associated mass effect, making prompt diagnosis and effective treatment crucial. We present four adolescents with TDLs who tested negative for aquaporin-4-IgG and myelin oligodendrocyte glycoprotein (MOG)-IgG and did not meet diagnostic criteria for any known demyelinating disorder. All four patients underwent extensive and inconclusive workup for the etiology of their radiographic and clinical findings and received multiple immunomodulators with some clinical improvement, although three of the four had multiple relapses. TDLs that do not meet criteria for the known demyelinating syndromes can cause significant neurological sequelae. We describe four adolescents with neurological symptoms associated with TDLs. Given the rare but serious occurrence of these non-syndromic TDLs, more well-powered studies are critical to guide diagnosis, management, and response to therapies and eventually develop evidence-based protocols to manage other patients with similar presentations.
A worldwide shortage of pediatric neurologists, combined with increased demand, increased wait times, and clinician burnout, have led to substantial access limitations. Given these challenges, we need to ensure advanced practice providers (APPs) in pediatric neurology are utilized effectively. Our results provide a framework for optimizing modern pediatric neurology practice through a thoughtful consideration of APP integration. A survey was sent through two large neurology academic organizations. Emails were also sent to known professional contacts across 59 practice sites. An electronic survey in REDCap with 31 open-ended or multiple-choice questions about demographics, supervision, inpatient and outpatient clinical processes, procedures, and scholarly activities was sent. Surveys were completed from 29 sites. Sixteen of these sites (55%) reported APPs do not have demographic restrictions in their outpatient practice. At many practice sites APPs perform inpatient consultations, with variable models for independence and partnership with attending neurologists. APPs subspecialize frequently and perform a variety of procedures including lumbar punctures and headache treatment injections. Most US-based APPs in outpatient pediatric neurology practice autonomously and also frequently perform procedures. APP independence in the inpatient setting should be expanded. As pediatric neurology practices evolve, information regarding the landscape of APP clinical responsibilities will aid in increasing access to care.
Leukodystrophies are a diverse group of rare disorders that disrupt central myelination. These disorders present with a broad spectrum of neurologic severity and are associated with a range of potential secondary complications, such as scoliosis and failure of independent feeding. we explore real-world data of leukodystrophy complications to inform future evidence-based care guidelines across these rare diseases. In a cross-sectional observational study, we use a leukodystrophy-specific research consortium and the availability of electronic health records (EHR) to capture a cross-section of real-world data. Subjects were identified using EHR data from five hospital systems with established expertise in leukodystrophies. Principal investigators or genetic counselors confirmed leukodystrophy diagnoses in all subjects. Time-to-event measures were collected, including orthopedic complications (scoliosis, hip subluxation/dislocation), loss of ambulation, artificial ventilation, gastrostomy tube placement, and urinary tract infections (UTIs). Maximum motor milestones, including gain of ambulation by 2 years old, were captured to stratify cohorts by neurologic severity. A primary outcome was not prespecified as this was an observational study. In total, 1203 subjects were identified across 42 leukodystrophies (age range of nine days to 89 years at last encounter). The most common event was feeding tube placement, and the median time to any first complication varied between disorders (Fleming-Harrington weighted log-rank test). The specific diagnosis correlated with maximum gross motor milestone attainment (Chi-square test of independence). When all disorders were stratified by maximum motor milestone attainment (not specific diagnosis), the median time to adverse events was significantly associated with function (Fleming-Harrington weighted log-rank test). This cross-sectional, retrospective observational study demonstrated that key medical events could be identified across institutions using EHR capture. Rates of health events and attainment of maximum motor milestones varied by specific leukodystrophy type. However, when the overall cohort was stratified by severity of motor impairment rather than individual diagnoses, the frequency of health events was associated with motor function. Our findings suggest utility for development of comprehensive care models for leukodystrophies as stratified by motor function, and demonstrate the utility of integrated EHR review for real-world data analyses.
Sturge-Weber syndrome (SWS) symptoms frequently overlap in neurological acute crises (ACs) presenting with seizures, stroke-like episodes (SLE), and headaches. Recent efforts to develop a prospective drug trial highlighted the need for a new outcome measure capable of quantifying these symptoms during an SWS AC. We aimed to develop such a measure and evaluate its practical application. The Sturge Weber Acute Crisis (SWAC) index was developed based on clinical care guidelines and experience. We retrospectively applied the SWAC to an open-label prospective drug trial published in 2020; SWAC scores were assigned for every AC during 6-month baseline and treatment phase periods. Six of 10 subjects experienced 670 ACs; only 78/670 ACs were included in the primary quantitative analyses (one subject was an extreme outlier) and 71/78 events were single-symptom while 7/78 included multiple symptoms. Three of six subjects experienced improved median seizure total score; all three improved their median SLE total score. Three of five subjects with headache improved their median headache total score. Poisson-log GLMM models demonstrated significant improvements in composite severity and total, SLE duration and total, and headache severity and total index scores. The newly developed SWAC index, applied retrospectively, reflected site-PI clinical experience, quantified the severity and duration of SWS ACs ranging from mild to severe, and better enabled comparison of treatment versus baseline responses. These results support additional studies with the SWAC index to further assess clinical utility and use in future treatment trials in SWS.