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Under-dosing of antiseizure medications was common in pediatric status epilepticus. Low doses were not associated with progression to refractory status epilepticus. Some factors related to refractoriness may be independent of the therapeutic scheme. Evaluate the relationship between first and second-line medication dosing and progression to refractory status epilepticus (RSE) in children. This is a retrospective analysis of prospectively collected data from September 2014 to February 2020 of children with status epilepticus (SE) who received at least two antiseizure medications (ASMs). We evaluated the risk of developing RSE after receiving a low total benzodiazepine dose (lower than 100 % of the minimum recommended dose for each benzodiazepine dose administered within 10 min) and a low first non-benzodiazepine ASM dose (lower than 100 % of the minimum recommended dose of non-benzodiazepine ASM given as the first single-dose) using a logistic regression model, adjusting for confounders such as time to ASMs. The proportion of patients receiving low first non-benzodiazepine ASM doses was calculated and a logistic regression model was used to evaluate risk factors for low dosing of the first non-benzodiazepine ASM. Among 320 children, 170 (53.1 %) developed RSE, and 150 (46.9 %) responded to the first non-benzodiazepine ASM dose (non-RSE). One hundred thirty-seven (42.8 %) received a low total benzodiazepine dose, and 128 (40 %) received a low first non-benzodiazepine ASM dose. The odds of developing RSE were not higher after a low total benzodiazepine dose (OR=0.76, 95 %CI 0.47–1.23, p = 0.27) or low first non-benzodiazepine ASM dose (OR=0.85, 95 %CI 0.42–1.71, p = 0.65). Receiving a low first non-benzodiazepine ASM dose was independently associated with having received a low total benzodiazepine dose (OR=1.65, 95 %CI 1.01–2.70, p = 0.04). For most patients, dosing variability in first and second-line medications for SE was not the sole clinical feature predicting progression to RSE in this cohort of benzodiazepine-resistant patients. Identification of additional modifiable clinical biomarkers that predict progression to RSE is needed. Though lower ASM doses did not predict RSE in this model, the administration of ASMs at doses likely to prevent RSE remains crucial in SE treatment. [ABSTRACT FROM AUTHOR]

Objective: Pediatric epilepsy is often associated with diminished health‐related quality of life (HRQOL). Our aim was to establish the validity of the Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS‐QOL‐2) questions, a novel two‐item HRQOL prompt for children with epilepsy, primarily for use in clinical care. Methods: We performed a multicenter cross‐sectional study to validate the PELHS‐QOL‐2. Construct validity was established through bivariate comparisons with four comparator measures and known drivers of quality of life in children with epilepsy, as well as by creating an a priori multivariable model to predict the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE‐55). Validity generalization was established through bivariate comparisons with demographic and clinical information. Content validity and clinical utility were established by assessing how well the PELHS‐QOL‐2 met eight design criteria for an HRQOL prompt established by a multistakeholder group of experts. Results: The final participant sample included 154 English‐speaking caregivers of children with epilepsy (mean age = 9.7 years, range =.5–18, 49% female, 70% White). The PELHS‐QOL‐2 correlated with the four comparator instruments (ρ =.44–.56), was significantly associated with several known drivers of quality of life in children with epilepsy (p <.05), and predicted QOLCE‐55 scores in the multivariate model (adjusted R2 =.54). The PELHS‐QOL‐2 item was not associated with the age, sex, and ethnicity of the children nor with the setting and location of data collection, although PELHS‐QOL‐Medications was significantly associated with race (worse for White race). Following both quantitative and qualitative analysis, the PELHS‐QOL‐2 met seven of eight design criteria. Significance: The PELHS‐QOL‐2 is a valid HRQOL prompt and is well suited for use in clinical care as a mechanism to routinely initiate conversations with caregivers about quality of life in children with epilepsy. The association of PELHS‐QOL‐Medications with race merits further study. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non‐BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). Methods: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non‐BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non‐BZD ASM. Results: We included 293 patients with a median (interquartile range) age of 3.8 (1.3–9.3) years. Thirty‐six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] =.998, 95% confidence interval [CI] =.997–.999 per minute, p =.01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out‐of‐hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73–3.46, p <.0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40–6.03, p <.0001) compared to patients with in‐hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01–2.06, p =.04). Forty‐seven percent of patients (n = 94) with out‐of‐hospital onset did not receive treatment before hospital arrival. Among patients with out‐of‐hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. Significance: Failure to escalate from BZDs to non‐BZD ASMs occurs mainly in out‐of‐hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non‐BZD ASMs after two BZD doses during handoffs between prehospital and in‐hospital settings. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to describe long‐term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE. Methods: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients. Results: Follow‐up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow‐up duration was 1.6 (.9–2.7) years. The in‐hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty‐six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1–134.5] h vs. 4 [1.6–16] h, p =.011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008–1.0069, p =.027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale‐Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion. Significance: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow‐up, with longer electroclinical RSE duration as a predictor. [ABSTRACT FROM AUTHOR]

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks–24 h), and without fever. Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection‐related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes. [ABSTRACT FROM AUTHOR]

Objective: Retrospective chart review to assess the effectiveness of an institutional intravenous (IV) dihydroergotamine (DHE) therapy protocol for refractory migraine in the pediatric population. Background: Limited high‐quality evidence exists to guide the approach to treatment of refractory migraine with IV DHE, particularly in the pediatric population. This study reviews our institutional experience in implementing an IV DHE protocol in children to identify areas for improvement. We specifically sought to determine whether the outcome differed at follow‐up between children who completed the full course of DHE (8 or 9 doses) as specified in our institutional protocol and those who did not. In addition, given the limited Food and Drug Administration‐approved treatments for chronic migraine (CM) in the pediatric population, re‐evaluating the response rate in this group of patients was of particular interest. Methods: A retrospective cohort based on a chart review of 159 consecutive pediatric patients who received IV DHE while inpatient at University of Virginia Children's Hospital over a 9‐year period (January 2011‐January 2019) was identified. Patients were classified according to the International Classification of Headache Disorders, 3rd edition criteria as having CM, status migrainosus, or, in a small number of patients, Other headache with migrainous features. To investigate any benefit of completing the full course of DHE, patients were categorized as having completed the DHE protocol ("Protocol Complete" 8 or 9 doses) or not completing the protocol ("Protocol Incomplete" <8 doses). Patient‐reported pain scores upon admission and discharge were recorded, and follow‐up outcomes were categorized as headache freedom, >50% relief, <50% relief, or no relief. Pain outcomes were analyzed with respect to DHE protocol complete status and headache classification. Results: A total of 159 patients were included in the analysis. The headache diagnosis was CM in 49% (78/159), status migrainosus in 44% (70/159), and Other headache with migrainous features in 7% (11/159). At discharge, 60% (96/159) of patients achieved headache freedom, and no statistically significant difference was found in relative change in headache among the CM, status migrainosus, and Other headache groups. Patients who completed the full 8 or 9 dose IV DHE protocol were more likely to have persistent headache at discharge, with a median pain score of 1.0 (IQR 0.0‐4.0) compared to a score of 0.0 (IQR 0.0‐1.0) in the DHE incomplete group (P <.001). No difference was found in pain relief outcomes at follow‐up in the DHE protocol complete and DHE protocol incomplete groups. Conclusions: Although limited by the absence of a control group, our data support repetitive IV DHE as an abortive therapy for pediatric patients with status migrainosus or CM, with no evidence of differential efficacy in these groups. A higher rate of headache at discharge in the DHE protocol complete group reflects in large part the common decision to discontinue treatment once headache freedom was achieved, resulting in nonresponders being more likely to complete the full course of DHE. In our cohort, there was no difference in pain relief at follow‐up between patients who completed the full 8 or 9 doses of DHE and those that did not. Discontinuing DHE once the patient has achieved headache freedom would therefore achieve the therapeutic goal while shortening the hospital stay. To potentially impact longer term pain relief, incorporation of a comprehensive treatment approach into the IV DHE admission is of interest for future study and quality improvement initiatives. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether the onset of pediatric refractory status epilepticus (rSE) is related to time of day.Method: We analyzed the time of day for the onset of rSE in this prospective observational study performed from June 2011 to May 2019 in pediatric patients (1 month to 21 years of age). We evaluated the temporal distribution of pediatric rSE utilizing a cosinor analysis. We calculated the midline estimating statistic of rhythm (MESOR) and amplitude. MESOR is the estimated mean number of rSE episodes per hour if they were evenly distributed. Amplitude is the difference between MESOR and maximum rSE episodes/hour, or between MESOR and minimum rSE episodes/hour. We also evaluated the temporal distribution of time to treatment.Results: We analyzed 368 patients (58% males) with a median (p25 - p75) age of 4.2 (1.3-9.7) years. The MESOR was 15.3 (95% CI: 13.9-16.8) and the amplitude was 3.2 (95% CI: 1.1-5.3), p = 0.0024, demonstrating that the distribution is not uniform, but better described as varying throughout the day with a peak in the morning (11am-12 pm) and trough at night (11 pm-12 am). The duration from rSE onset to application of the first non-benzodiazepine antiseizure medication peaked during the early morning (2am-3 am) with a minimum during the afternoon (2 pm-3 pm) (p = 0.0179).Conclusions: The distribution of rSE onset is not uniform during the day. rSE onset shows a 24-h distribution with a peak in the mid-morning (11am-12 pm) and a trough at night (11 pm-12am). [ABSTRACT FROM AUTHOR]

Purpose: To summarize the pathophysiology of convulsive status epilepticus (SE) with a focus on practical implications for treatment.Method: Narrative review of the medical literature on the pathophysiology of convulsive SE. We considered both animal models of SE and clinical studies.Results: Convulsive SE is an emergency in which prolonged convulsive seizures are associated with cardiorespiratory instability, hypoxia, hypoglycemia, and hyperthermia. Supportive treatment helps correct these physiological imbalances. When treatment is delayed, the ability of first line seizure suppressing medications to terminate the seizure can be reduced. Animal studies have suggested that GABAA receptor trafficking may contribute to the failure of the first line therapies and that NMDA receptor antagonists such as ketamine may become more effective as seizures last longer. Potential strategies to take advantage of these changes in pathophysiology include a rapid escalation from benzodiazepines to non-benzodiazepine antiepileptic drugs (AEDs), early polytherapy and use of NMDA antagonists such as ketamine for refractory convulsive SE. Despite the importance of a timely treatment of convulsive SE, major treatment delays are frequent in clinical practice. Policies to improve time to treatment, especially in convulsive SE that starts outside the hospital, may improve response to treatment and convulsive SE outcomes.Conclusions: Convulsive SE is a time-sensitive emergency in which the underlying pathophysiology may provide targets for improving treatment strategies. A timely transition from benzodiazepines to other AEDs may help reduce treatment resistance in convulsive SE. [ABSTRACT FROM AUTHOR]

Background: The differential diagnosis of encephalitis in childhood is vast, and evaluation for an etiology is often unrevealing. Encephalitis by way of autoimmunity has long been suspected, as in cases of acute disseminated encephalomyelitis; however, researchers have only recently reported evidence of antibody-mediated immune dysregulation resulting in clinical encephalitis.Main Findings: These pathologic autoantibodies, aimed at specific neuronal targets, can result in a broad spectrum of symptoms including psychosis, catatonia, behavioral changes, memory loss, autonomic dysregulation, seizures, and abnormal movements. Autoimmune encephalitis in childhood is often quite different from adult-onset autoimmune encephalitis in clinical presentation, frequency of tumor association, and ultimate prognosis. As many of the autoimmune encephalitides are sensitive to immunotherapy, prompt diagnosis and initiation of appropriate treatment are paramount.Conclusions: Here we review the currently recognized antibody-mediated encephalitides of childhood and will provide a framework for diagnosis and treatment considerations. [ABSTRACT FROM AUTHOR]

Early posttraumatic seizure is a paramount clinical issue in pediatric traumatic brain injury patients as it is a common occurrence, yet an understudied entity at present. Recent literature recognizes several posttraumatic seizure subtypes based on time of presentation and the underlying pathophysiology: impact, immediate, delayed early, and late/posttraumatic epilepsy. Appropriate classification of pediatric posttraumatic seizure subtypes can be helpful for appropriate management and prognosis. This review will focus on early posttraumatic seizures, and the subtypes of early posttraumatic seizure. Incidence, risk factors, diagnosis, seizure semiology, status epilepticus, management, risk of recurrence, and prognosis were reviewed. The integration of continuous electroencephalographic (EEG) monitoring into pediatric traumatic brain injury management may hold the key to better characterizing and understanding pediatric early posttraumatic seizures. Topics for future research pertaining to pediatric early posttraumatic seizure are identified. [ABSTRACT FROM AUTHOR]

Background: Time to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency.Methods: We performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus.Results: We included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01).Conclusions: The time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing. [ABSTRACT FROM AUTHOR]