Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers.

OBJECTIVE: This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. METHODS: The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. RESULTS: Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). CONCLUSION: These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

Determining an infectious or autoimmune etiology in encephalitis.

OBJECTIVES: Early presentation and workup for acute infectious (IE) and autoimmune encephalitis (AE) are similar. This study aims to identify routine laboratory markers at presentation that are associated with IE or AE. METHODS: This was a multi-center retrospective study at three tertiary care hospitals in New York City analyzing demographic and clinical data from patients diagnosed with definitive encephalitis based on a confirmed pathogen and/or autoantibody and established criteria for clinical syndromes. RESULTS: Three hundred and thirty-three individuals with confirmed acute meningoencephalitis were included. An infectious-nonbacterial (NB) pathogen was identified in 151/333 (45.40%), bacterial pathogen in 95/333 (28.50%), and autoantibody in 87/333 (26.10%). NB encephalitis was differentiated from AE by the presence of fever (NB 62.25%, AE 24.10%; p < 0.001), higher CSF white blood cell (WBC) (median 78 cells/µL, 8.00 cells/µL; p < 0.001), higher CSF protein (76.50 mg/dL, 40.90 mg/dL; p < 0.001), lower CSF glucose (58.00 mg/dL, 69.00 mg/dL; p < 0.001), lower serum WBC (7.80 cells/µL, 9.72 cells/µL; p < 0.050), higher erythrocyte sedimentation rate (19.50 mm/HR, 13.00 mm/HR; p < 0.05), higher C-reactive protein (6.40 mg/L, 1.25 mg/L; p = 0.005), and lack of antinuclear antibody titers (>1:40; NB 11.54%, AE 32.73%; p < 0.001). CSF-to-serum WBC ratio was significantly higher in NB compared to AE (NB 11.3, AE 0.99; p < 0.001). From these findings, the association of presenting with fever, CSF WBC ≥50 cells/µL, and CSF protein ≥75 mg/dL was explored in ruling-out AE. When all three criteria are present, an AE was found to be highly unlikely (sensitivity 92%, specificity 75%, negative predictive value 95%, and positive predictive value 64%). INTERPRETATIONS: Specific paraclinical data at initial presentation may risk stratify which patients have an IE versus AE.

Delays in Diagnosis and Treatment of Bacterial Meningitis in NYC: Retrospective Cohort Analysis.

Community-acquired bacterial meningitis (CABM) morbidity and mortality remains high in those infected. Rapid diagnosis and treatment is paramount to reducing mortality and improving outcome. This retrospective cohort study aims to assess the time from presentation to diagnosis and treatment of vaccine preventable CABM as well as identify possible factors associated with delays in diagnosis and antibiotic administration. A retrospective chart review was conducted of individuals who presented to Columbia University Irving Medical Center (CUIMC), Children's Hospital of New York (CHONY), Mount Sinai Medical Center, and Weill Cornell Medical Center with BM due to Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis between January 1, 2012 and December 31, 2017. Diagnosis was delayed by more than 8 hours in 13 patients (36.1%) and 5 individuals (13.9%) had a delay of 4 hours or more from presentation to the administration of antibiotics with appropriate CNS coverage. All of these patients were also initially misdiagnosed at an outpatient clinic, outside hospital, or emergency department. This retrospective study identified febrile and/or viral infections not otherwise specified and otitis media as the most common misdiagnoses underlying delays from presentation to diagnosis and to antibiotic treatment in those with BM.

The clinical, economic, and humanistic burden of Dravet syndrome - A systematic literature review.

Dravet syndrome (DS) is a developmental and epileptic encephalopathy with evolving disease course as individuals age. In recent years, the treatment landscape of DS has changed considerably, and a comprehensive systematic review of the contemporary literature is lacking. Here we synthesized published evidence on the occurrence of clinical impacts by age, the economic and humanistic (health-related quality-of-life [HRQoL]) burden, and health state utility. We provide an evidence-based, contemporary visualization of the clinical manifestations, highlighting that DS is not limited to seizures; non-seizure manifestations appear early in life and increase over time, contributing significantly to the economic and humanistic burden of disease. The primary drivers of HRQoL in DS include seizure severity, cognition, and motor and behavioral problems; in turn, these directly affect caregivers through the extent of assistance required and consequent impact on activities of daily living. Unsurprisingly, costs are driven by seizure-related events, hospitalizations, and in-home medical care visits. This systematic review highlights a paucity of longitudinal data; most studies meeting inclusion criteria were cross-sectional or had short follow-up. Nonetheless, available data illustrate the substantial impact on individuals, their families, and healthcare systems and establish the need for novel therapies to address the complex spectrum of DS manifestations.

Measurable outcomes for pediatric epileptic encephalopathy: a single-center experience with corticosteroid therapy.

Corticosteroids are commonly used to treat refractory epilepsy in children, but the heterogeneity of the population and lack of standardized outcome measures have limited understanding of their effectiveness. We conducted a single-center study of corticosteroids for epileptic encephalopathy to (a) identify domains for measurement and estimate potential effect sizes, (b) characterize heterogeneity, and (c) identify outcomes that may need better tools for measurement. In this retrospective single-center cohort study, children with epileptic encephalopathy (excluding infantile spasms) were treated with a standardized course of oral dexamethasone or IV methylprednisolone. Long-term video electroencephalography (EEG) was assessed via novel ordinal scales for five features: seizure semiology/burden, epileptiform activity, slowing, organization, and sleep architecture. We abstracted parental assessment of functional domains (i.e., cognition) from the medical records. Pre-treatment and post-treatment EEG features, functional domains, and treatment regimens were compared. Thirty-five children with refractory epilepsy were included. Overall, 16/35 (46%) of individuals had a >50% reduction in seizure frequency from the pre-treatment EEG to the initial post-treatment EEG. In particular, tonic seizures (in a subset of 23 children) were reduced (24-hour tonic seizure count pre-treatment was 8 [4-13] and 3 [1-5] post-treatment EEG#1, p=0.04). For follow-up post-treatment EEGs, there was: (1) better formation of sleep spindles (37% normal pre-treatment to 63% normal post-treatment; p=0.04); and (2) improvement in parental reported cognition (in 43%). Improved cognition was the only outcome that differed between the dexamethasone and methylprednisolone treated groups (58% for dexamethasone [n=11/19] vs. 25% for methylprednisolone [n=4/16]; p=0.03). Large studies should be powered to detect reductions in seizures (particularly tonic as we identified a 2.6-fold reduction), improved EEG organization, and improved sleep architecture (21 percentage points). Cognitive improvements following steroid treatment, reported by parents, should be quantified and fully characterized in future work.

Clinical and electrographic features of persistent seizures and status epilepticus associated with anti-NMDA receptor encephalitis (anti-NMDARE).

Based on a multicenter cohort of people with anti-NMDA receptor encephalitis (anti-NMDARE), we describe seizure phenotypes, electroencephalographic (EEG) findings, and anti-seizure treatment strategies. We also investigated whether specific electrographic features are associated with persistent seizures or status epilepticus after acute presentation. In this retrospective cohort study, we reviewed records of children and adults with anti-NMDARE between 2010 and 2014 who were included in the Rare Epilepsy of New York City database, which included the text of physician notes from five academic medical centers. Clinical history (e.g., seizure semiology) and EEG features (e.g., background organization, slowing, epileptiform activity, seizures, sleep architecture, extreme delta brush) were abstracted. We compared clinical features associated with persistent seizures (ongoing seizures after one month from presentation) and status epilepticus, using bivariate and multivariable analyses. Among the 38 individuals with definite anti-NMDARE, 32 (84%) had seizures and 29 (76%) had seizures captured on EEG. Electrographic-only seizures were identified in five (13%) individuals. Seizures started at a median of four days after initial symptoms (IQR: 3-6 days). Frontal lobe-onset focal seizures were most common (n=12; 32%). Most individuals (31/38; 82%) were refractory to anti-seizure medications. Status epilepticus was associated with younger age (15 years [9-20] vs. 23 years [18-27]; p=0.04) and Hispanic ethnicity (30 [80%] vs. 8 [36%]; p=0.04). Persistent seizures (ongoing seizures after one month from presentation) were associated with younger age (nine years [3-14] vs. 22 years [15-28]; p<0.01). Measured electrographic features were not associated with persistent seizures. Seizures associated with anti-NMDARE are primarily focal seizures originating in the frontal lobes. Younger patients may be at increased risk of epileptogenesis and status epilepticus. Continuous EEG monitoring helps identify subclinical seizures, but specific EEG findings may not predict the severity or persistence of seizures during hospitalization.

Central nervous system (CNS) enterovirus infections: A single center retrospective study on clinical features, diagnostic studies, and outcome.

Enteroviruses (EV) are responsible for a large number of meningoencephalitis cases, especially in children. The objective of this study was to identify modes of diagnosis including the significance of respiratory and cerebrospinal fluid samples, associated clinical characteristics, inpatient management, and outcome of individuals with EV infections of the central nervous system (CNS). Electronic medical records of individuals with enterovirus infections of the CNS who presented to the Columbia University Irving Medical Center and Children's Hospital of New York between January 1, 2012 and December 31, 2017 were reviewed retrospectively for demographic, epidemiological, and clinical data. The median age overall was 1.7 months (interquartile range 14 years) and most (62.4%) were male. The majority of CNS infections presented as meningitis (95.7%) and occurred in the summer (45.2%) and fall seasons (37.6%). Eighty-five cases (91.4%) demonstrated EV positivity in cerebrospinal fluid, thirty cases (32.3%) exhibited both cerebrospinal fluid and respiratory positivity, and eight cases (8.6%) exhibited respiratory positivity with coinciding neurological findings. Eighty-nine individuals overall (95.7%) received antibiotics and 37 (39.8%) received antiviral treatment. All surviving individuals had favorable Modified Rankin Scores (MRS) within the zero to two ranges upon discharge. Testing respiratory samples in addition to cerebrospinal fluid was found to be an important diagnostic tool in EV-associated cases. While clinical outcomes were favorable for an overwhelming majority of cases, etiological understanding of CNS infections is essential for identifying ongoing and changing epidemiological patterns and aid in improving the diagnosis and treatment.

Neurotoxicity after CTL019 in a pediatric and young adult cohort.

OBJECTIVE: To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion. METHODS: We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor-modified T-cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity. RESULTS: Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31-60%) and was positively associated with higher CRS grade (p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)-2, IL-15, soluble IL-4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL-12 and soluble tumor necrosis factor receptor-1 within the first 3 days were seen in subjects with neurotoxicity. INTERPRETATION: Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537-546.

Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.

Treatment of Chronic Enterovirus Encephalitis With Fluoxetine in a Patient With X-Linked Agammaglobulinemia.

INTRODUCTION: Enterovirus may result in a devastating chronic encephalitis in immunocompromised patients, particularly in patients with X-linked agammaglobulinemia. Prognosis for patients with chronic enterovirus encephalitis is poor, almost invariably resulting in mortality without specific treatment. There are currently no approved antiviral agents for enterovirus, but the antidepressant drug fluoxetine has been identified through library-based compound screening as a potential anti-enteroviral agent in vitro. However, use of fluoxetine has not previously been studied in humans with enteroviral disease. PATIENT DESCRIPTION: A five year old boy with X-linked agammaglobulinemia presented with progressive neurological deterioration and was found to have chronic enterovirus encephalitis by brain biopsy. He failed to respond to standard treatment with high dose intravenous immunoglobulin, but showed stabilization and improvement following treatment with fluoxetine. CONCLUSIONS: This is the first report to describe the use of fluoxetine as a potential therapy for chronic enterovirus infection. Further investigation of fluoxetine as a treatment option for chronic enterovirus encephalitis is necessary.

Diagnosis and Management of Childhood Headache.

Headache is one of the most common chief complaints seen in the pediatrician's office. Oftentimes, identifying the etiology of headache and differentiating primary and secondary causes can present a diagnostic conundrum. Understanding the most common causes of primary and secondary headache is vital to making a correct diagnosis. Here we review the typical presentations of the most common primary headache disorders and the approach to evaluation of the pediatric patient presenting with headache. Diagnostic workup, including the key features to elicit on physical examination, when to order head imaging, and the use of other ancillary tests, is discussed. Current treatment modalities and their indications are reviewed. We will also describe some of the new, emerging therapies that may alter the way we manage headache in the pediatric population. Headache can, at times, be a frustrating symptom seen in the pediatrician's office, but here we hope to better elucidate the approach to evaluation, management, and treatment as well as provide some hope in regards to more effective upcoming therapies.