Neuroinflammation is a key contributor to pathology in many central nervous system (CNS) diseases. While cerebrospinal fluid (CSF) proteomic studies in adult neurologic conditions have identified insightful inflammatory signatures, fewer studies have been conducted in pediatric diseases. Moreover, past studies primarily employed proteomic approaches that are less suited to detect novel, low-abundance inflammatory mediators that may be critical in pediatric CNS pathophysiology. To address this gap, we applied high-sensitivity, multi-targeted proteomic profiling to characterize the neuroinflammatory signatures across three distinct pediatric neurologic diseases: post-hemorrhagic hydrocephalus (PHH), N-methyl-D-aspartate receptor encephalitis (NMDARE), and brain tumor-associated hydrocephalus. CSF samples from controls (n = 5) and patients with PHH (n = 9), NMDARE (n = 5), and brain tumor-associated hydrocephalus (n = 10) were obtained from a pediatric CSF biorepository. After proteomic profiling using the Olink Explore platform, 641 inflammation-related proteins were retained for analysis. Differentially abundant proteins (DAPs) were identified using limma with false discovery rate (FDR) correction (FDR < 0.05, |log₂FC| >1). Pathway enrichment of DAPs was performed with Reactome via Enrichr, and protein–protein interaction networks were constructed using STRING to identify functional modules and key hub proteins. Principal component and hierarchical clustering analyses revealed separation of PHH and brain tumor samples from controls, while NMDARE partially overlapped. CSF in PHH contained 532 DAPs, with pathway enrichment analysis identifying alternative complement activation, coagulation, and platelet degranulation pathways as top hits. Conversely, CSF in NMDARE showed only 65 DAPs, with the top pathways involving IL-10 and IL-18 signaling, and the top 3 DAPs involving humoral immunity (IGLC2, MZB1, CD79B). DAPs did not meet statistical significance in brain tumor patients. Longitudinal analysis of serial collections from PHH patients suggested a persistence of coagulation- and complement-related neuroinflammation over time. NELL2 emerged as a consistently downregulated protein in PHH for weeks after the initial hemorrhage. PHH and NMDARE revealed distinct neuroinflammatory proteomic signatures compared to our control samples. PHH was marked by a broad increase in detection of the majority of inflammation-related proteins, with highest representation among the alternative complement and coagulation-related pathways. The persistent detection of these proteins for weeks after the initial hemorrhage may be indicative of chronic neuroinflammation, even at the time of permanent CSF diversion. Conversely, NMDARE induced a narrower lymphocyte-driven profile, more consistent with an antibody-mediated autoimmune disease. Furthermore, suppression of NELL2 and up-regulation of immunoglobulin-related markers (IGLC2, MZB1, CD79B) are potential candidates for biomarkers in PHH and NMDARE, respectively.

Background and ObjectivesHeadache evaluation and treatment are believed to be influenced by race and ethnicity. Specific headache diagnosis assigned in the pediatric emergency department (ED) may compound disparities. We sought to investigate racial and ethnic disparities in the diagnosis, testing, and treatment of pediatric patients with headache presenting to the ED. MethodsWe performed a cross-sectional analysis of ED visits from 49 children's hospitals between 2016 and 2022 from the Pediatric Health Information System, an administrative database of ED and hospitalized encounters within children's hospitals in the United States. Index encounters in the ED from patients (aged 5-21 years, median age 13 [10-15]) with a primary diagnosis of migraine, headache, new daily persistent headache, or tension-type headache were included. Encounters with trauma, infection, and malignancy where secondary headache was possible were excluded. The primary outcomes were the rates of migraine diagnosis, testing, and treatment. We used generalized estimating equations to estimate associations between race and ethnicity and outcomes after adjusting for demographic factors, medical complexity, visit timing, and final headache diagnosis. ResultsA total of 309,678 encounters were included while 61,677 repeat visits, 81,821 visits with diagnoses suggestive of secondary headache, and 5,714 visits from 3 hospitals with sparse data on patient race/ethnicity were excluded. Of 160,466 eligible visits (59.8% female), 41% were by non-Hispanic White (NHW) children, 24.8% non-Hispanic Black (NHB), and 26.0% Hispanic/Latino (HL). NHW children were more frequently diagnosed with migraine (45.5% vs NHB 28.2% and HL 28.3%, p < 0.001). NHB and HL children compared with NHW children received less testing including brain MRI scans (adjusted odds ratio [aOR]: NHB 0.56 [95% CI 0.46-0.69] and HL 0.54 [0.36-0.82]). There was no difference in the proportion of visits without administration of headache-related medications (NHW 23.3% vs NHB 24.6% and HL 23.4%, p = 0.64). NHB and HL children were more likely to receive only oral medications (aOR: NHB 1.37 [1.2-1.56] and HL 1.54 [1.34-1.76]) and less likely to be admitted inpatient (aOR: NHB 0.8 [0.66-0.97] and HL 0.65 [0.44-0.94]). DiscussionNHB and HL children in the pediatric ED with headache receive fewer migraine diagnoses, less testing, and less intensive treatment compared with NHW children. Beyond affecting headache management, this inequity in migraine diagnosis requires further consideration to include children from marginalized racial and ethnic groups in future migraine research.

Background and Purpose: Children with developmental disabilities have increased risk of epilepsy and need for overnight video electroencephalographic (EEG) monitoring. However, video EEGs have historically been considered difficult to complete for this population. An autism support service at a pediatric tertiary care hospital implemented a coordinated team approach to help children with developmental disability tolerate overnight video EEGs. The project included completion of a caregiver-report preprocedure questionnaire that then was shared with the multidisciplinary team and used to create individualized care plans. The current study aims to describe rates of video EEG completion and need for lead placement under general anesthesia among children with autism and related disabilities who received these supports. Methods: Rates of video EEG completion and general anesthesia use were analyzed for children referred to the support service between April 2019 and November 2021. Results: A total of 182 children with developmental disability (mean age = 10.3 years, 54.9% diagnosed with autism) met inclusion criteria. 92.9% (n = 169) of children successfully completed EEG (leads on ≥12 hours). Only 19.2% (n = 35) required general anesthesia for video EEG lead placement. The majority (80.2%) of parents (n = 146) completed the preprocedure questionnaire. Video EEG outcomes did not differ based on completion of the questionnaire. Parent-reported challenges with communication and cooperation were associated with shorter video EEG duration and greater use of general anesthesia. Conclusions: These findings suggest that most children with developmental disability can complete video EEG with sufficient support. Preprocedure planning can identify children who would benefit from additional accommodations. Further research is necessary to clarify which supports are most helpful.

Abstract BACKGROUND Electrographic seizures (ES) are common in critically ill children with the incidence of ES ranging from 10-50%. Continuous EEG (cEEG) is frequently obtained in children with brain tumors due to encephalopathy or concern for seizures. Despite this, little is known about the incidence of ES, EEG background features, or the impact of EEG on clinical management in this population. METHODS This is a prospective single center study of critically ill children with brain tumors admitted to the pediatric intensive care unit (PICU) from July 2021 to July 2023. Patients with new or known primary brain tumors and cEEG completed during their admission were included. We excluded patients with planned admissions for EEG. Clinical variables included age, sex, oncologic diagnosis, tumor grade and location, indication for EEG, EEG features, and changes in management. RESULTS Thirty-six patients were identified who met the inclusion criteria. 21 patients were female. The median age was 11.0 years (IQR 6.6– 15.4 years). The most common indication for EEG was encephalopathy in 42% followed by clinical seizure in 31%. ES were captured in 19% (7/36) with the majority being subclinical; in patients with acute encephalopathy, ES were captured in 20% (3/15). The EEG background was abnormal in 97% of cases. The most common EEG background was slow disorganized with background asymmetry seen in in 74%. EEG background features met criteria for the ictal-interictal continuum in 14%. A higher rate of ES was seen in patients with disseminated tumors (p=0.03) and severe encephalopathy on EEG (p=0.006). EEG led to a change in management in 31% of patients. CONCLUSIONS ES are common in critically ill children with brain tumors and would go undetected without cEEG. EEG findings often led to a change in clinical management and is a vital tool for the evaluation of this population.

Here we describe a pediatric patient with febrile infection–related epilepsy syndrome with a good functional and neurologic outcome after treatment with early and aggressive cytokine-directed immunomodulatory therapy and a seizure management strategy that intentionally avoided a barbiturate coma. A 5-year-old previously healthy male presented with staring, behavioral arrest, and encephalopathy evolving to super-refractory status epilepticus. He had had onset of fever 5 days prior. He was treated with early and aggressive immunomodulatory therapy targeted to his evolving cytokine profile. He was also treated with the ketogenic diet, antiseizure medications, and continuous anesthetic infusions. Pentobarbital was purposely avoided. Now, 2½ years later, he attends mainstream school, has attention-deficit hyperactivity disorder (ADHD), mild neurocognitive impairment, and well-controlled epilepsy. By using cytokine-directed immunotherapy and avoiding a barbiturate coma, we were able to successfully treat a pediatric patient with febrile infection-related epilepsy syndrome and achieve a good outcome.

AbstractObjectiveOverlap syndromes have been described between N‐methyl‐ d‐aspartate receptor encephalitis (NMDARE) and other neuroinflammatory conditions, although rarely involving neurosarcoidosis. Molecularly targeted immunotherapy may be helpful in the empiric treatment of these conditions.MethodsWe describe a 9‐year‐old boy with new‐onset seizures and worsening encephalopathy.ResultsInitial evaluation was concerning for neurosarcoidosis, including elevated cerebrospinal fluid (CSF) and serum angiotensin‐converting enzyme and leptomeningeal with multiple cranial nerve enhancement on magnetic resonance imaging. CSF and serum cytokine profiles were used to choose targeted empiric immunotherapy, and the boy's seizure burden and encephalopathy improved after treatment with tocilizumab. The NMDA receptor antibody titer was later found to be elevated, raising suspicion for a novel overlap syndrome.InterpretationOur patient met the criteria for definite NMDARE and possible neurosarcoidosis. Given the mixed radiographic and serologic markers in this child, cytokine levels were used to direct the choice of empiric treatment, resulting in excellent clinical response. This case suggests that targeted immunotherapy informed by cytokine testing may be helpful in cases of high‐acuity pediatric neuroinflammatory disease with limited diagnostic clarity.

Background and objective Evidence for the treatment of multisystem inflammatory syndrome in children (MIS-C) is lacking. Anakinra, which targets IL-1-mediated inflammation, is reserved for refractory cases of MIS-C; however, its use in the treatment of MIS-C is not clearly established. Patients and methods To examine a role for anakinra in MIS-C, we performed a single center observational cohort study of all MIS-C patients diagnosed at our children’s hospital from May 15 to November 15, 2020. Demographics, clinical features, diagnostic testing, and cardiac function parameters were compared between MIS-C patients treated with intravenous immunoglobulin (IVIG) monotherapy and IVIG with anakinra (IVIG + anakinra). Results Among 46 patients with confirmed MIS-C, 32 (70%) were in the IVIG + anakinra group, of which 9 (28%) were also given corticosteroids (CS). No patients were treated with anakinra alone. MIS-C patients in the IVIG + anakinra group were enriched in a CV shock phenotype (p = 0.02), and those with CV shock were treated with higher doses of anakinra for a longer duration. Furthermore, MIS-C patients in the IVIG + anakinra group exhibited improvements in fever and cardiac function with or without CS. No significant adverse events were observed, and no differences in IL-1β levels were found among MIS-C patients in the IVIG + anakinra group. Conclusions Anakinra treatment, which was co-administered with IVIG primarily in patients with severe MIS-C, was associated with improvements in fever and cardiac function, and demonstrated a favorable side-effect profile. These findings suggest a role for adjunctive anakinra in the treatment of severe MIS-C.

AbstractObjectivesAcute inflammatory demyelinating polyneuropathy (AIDP) is the leading cause of acute flaccid paralysis in children and hypothesized to be triggered by antecedent infection. We sought to determine the association between AIDP and commonly acquired community infections in children. We utilized the reduction in these infections due to measures during coronavirus disease 2019 (COVID‐19) to serve as a natural experiment and determine their contribution to AIDP.MethodsThis cross‐sectional study used administrative and billing data from children's hospitals contributing to the Pediatric Health Information System. We included hospitalizations of children with a diagnosis of AIDP from (January 2017 through February 2021). Encounters for infection‐ (including respiratory, gastrointestinal, and COVID‐19) related diagnoses were measured as a marker of community incidence.ResultsA total of 1111 index encounters for AIDP were included. Pre‐COVID‐19, AIDP was not associated with respiratory or gastrointestinal infections, specifically, influenza or campylobacter. During the COVID‐19 period from March 2020 to February 2021, respiratory, gastrointestinal, and influenza infections decreased compared to expected (for the same time of year pre‐COVID‐19) by 59.6%–90.1%, 51.5%–68.9%, and 54.5%–97.9%, respectively. In contrast, AIDP hospitalizations and all hospitalizations only decreased by 11.5%–39.3% and 14.2%–25%, respectively. COVID‐19 was not positively associated with AIDP overall or at individual hospitals.InterpretationCommon community‐acquired infections including COVID‐19 were not strongly associated with hospitalizations for AIDP in children. AIDP persisted despite the dramatic reduction in infection‐related encounters during the pandemic. These results suggest that recent antecedent community‐acquired infections were not the primary driver of AIDP and that alternative triggers should be explored.

Objective: To identify racial/ethnic disparities in testing, treatment, and diagnosis of headache and migraine in the pediatric ED. Background: Diagnostic workup and treatment for headache or migraine in the pediatric emergency department (ED) may vary by race and ethnicity. Prior social disparities research has not explored differences in pediatric headache diagnosis in this setting which could impact care. Design/Methods: We identified ED visits with a primary diagnosis of headache or migraine from the Pediatric Health Information Systems database between 2016–2021, excluding diagnoses suggesting secondary headache. We compared rates of diagnosis, testing, and treatment between non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic/Latino (HL) children and adolescents. Results: Across 142,250 visits (60% female), NHW children comprised 41.1% of visits, NHB 24.2%, and HL 27.4%. Migraine was diagnosed more often in NHW (45.5%) compared to NHB (28.4%) and HL (28.5%) children; NHB (67.3%) and HL (67.5%) were disproportionately diagnosed with non-specific headache (NHW: 52.3%; p<.001). Adjusting for diagnosis, insurance, and other demographic traits, NHW children received more MRI scans (6.7% [95% CI: 4.7–9.4%] vs. NHB 4.0% [2.8–5.6%] and HL 3.7% [2.8–4.9%]; p=0.005), blood tests (25.0% [20.5–30.2%] vs. NHB 21.2% [18.4–24.3%] and HL 21.9% [19.6–24.4%]; p=.013), and intravenous medications (54.2% [50.2–58.1%] vs. NHB 44.2% [40.9–47.6%] and HL 43.7% [39.0–48.5%]; p<.001). Conclusions: NHW children were more likely to receive testing and intravenous medications compared to children of color during ED headache visits. Race and ethnicity appear strongly associated with diagnosis of migraine vs. unspecified headache which could point to healthcare access or diagnostic biases among other factors. This likely impacts interpretation of research centered on visits with a migraine diagnosis. Such disparities in disease management may contribute to overall undertreatment and underdiagnosis of pediatric headache, particularly for children of color. Future research should investigate the validity of using diagnostic codes to select children with migraine compared to alternative methods. Disclosure: The institution of Ms. Kellier has received research support from National Institute of Neurological Disorders and Stroke. Dr. Anto has nothing to disclose. Dr. Hall has received personal compensation for serving as an employee of Children's Hospital Association. The institution of Dr. Szperka has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Allergan. Dr. Szperka has received research support from Pfizer. Dr. Szperka has received research support from FDA. Dr. Nash has nothing to disclose. Dr. Hutchinson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Katz, Korin, Cunningham Attorneys At Law. The institution of Dr. Wells has received research support from National Institute of Allergy and Infectious Diseases. Dr. Moharir has nothing to disclose. Dr. Abend has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Epilepsy Foundation. The institution of Dr. Abend has received research support from NIH. The institution of Dr. Abend has received research support from PCORI. Dr. Abend has received publishing royalties from a publication relating to health care. Dr. Messer has nothing to disclose. Dr. Palaganas has nothing to disclose. Dr. Piantino has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Applied Cognition. Dr. Press has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Marinus Pharmaceuticals. Dr. Press has received research support from Marinus Pharmaceuticals.

Introduction: We describe 5 children with GFAP astrocytopathy with the goal of further characterizing this rare form of meningoencephalomyelitis. Methods: Retrospective chart review of patients diagnosed with GFAP astrocytopathy between 2019 and 2021. Results: Patients were 8-17 years old, and all were male. Fever, headache, and vomiting were common presenting symptoms, and weakness, tremor, and ataxia were common initial examination findings. Initial magnetic resonance imaging (MRI) showed spinal cord abnormalities in 2 patients and leptomeningeal enhancement in 1. Most patients had cerebral spinal fluid pleocytosis, and all screened negative for malignancy. Three patients progressed to coma, and all were treated with immunosuppressant therapy. By discharge, all patients had improved over their clinical nadir, although none had returned to baseline. Discussion: GFAP astrocytopathy is a recently recognized cause of meningoencephalomyelitis in children. Here, we expand our understanding of this entity with the goal of aiding those treating children with GFAP astrocytopathy.