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Electrographic seizures are frequent and associated with worse outcomes following traumatic brain injury (TBI). Despite this, the use of continuous electroencephalogram (cEEG) remains low. Our study describes cEEG usage and treatment dosing antiseizure medications (ASMs) in an international pediatric TBI population, hypothesizing that children monitored with cEEG have an increased rate of treatment ASMs because of electrographic seizure detection, compared with children who are not monitored with cEEG. This subanalysis of the TBI cohort of the international PANGEA study included children, 7 days to 17 years of age, with acute neurological insults admitted to pediatric intensive care units. We analyzed demographics, injury severity, and therapies including prophylactic or treatment ASMs. We evaluated the relationships between cEEG use, seizure frequency, and receipt of treatment ASMs. $$\chi^{2}$$ or Fisher’s exact test was used to analyze categorical variables, and the Kruskal–Wallis or Mann–Whitney U-test was used for continuous variables. Multivariable analysis for treatment ASM use was performed using logistic regression. One hundred-twenty-three of 174 patients with TBI were included. Twenty-seven patients (21.9%) underwent cEEG at any point during pediatric intensive care unit admission. Preexisting seizure disorder (18.2% vs. 2.3%, p = 0.014) and neuromuscular blockade use (52.4% vs. 24.1%, p = 0.011) were more frequently observed in the group monitored on cEEG when compared with those that were not. Presenting median Glasgow Coma Scale score was worse in the cEEG group (7 vs. 9, p = 0.044). There was no significant difference in age, use of intracranial pressure monitoring, or hyperosmolar therapy between the cEEG monitored and nonmonitored groups. Patients who were monitored on cEEG were more likely to receive a treatment dose ASM than those without cEEG monitoring (66.7% vs. 28.1%, p = 0.0002). When compared with those without treatment ASM, the treatment ASM group had more electrographic seizures on their first electroencephalogram following injury (51.6% vs. 4%, p = 0.0001) and more clinical seizures (55.8% vs. 0%, p

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.

ObjectivesFebrile infection–related epilepsy syndrome (FIRES) is characterized by explosive onset refractory status epilepticus (RSE) in healthy individuals that is refractory to antiseizure medication (ASM), continuous anesthetic infusions (CIs), and immunomodulators. Recently, a case series of patients receiving intrathecal dexamethasone (IT-DEX) was reported with improved RSE control.MethodsWe present a child with FIRES with favorable outcome after receiving concomitant anakinra and IT-DaEX. A 9-year-old male patient presented with encephalopathy following a febrile illness. He developed seizures evolving to RSE refractory to multiple ASM, 3 CIs, steroids, IVIG, plasmapheresis, ketogenic diet (KD), and anakinra. After continued seizures and inability to wean off CI, IT-DEX was initiated.ResultsHe received 6 doses of IT-DEX with resolution of RSE, rapid wean off CI, and improved inflammatory markers. At discharge, he was ambulating with assistance, speaking 2 languages, and ingesting food orally.DiscussionFIRES is a neurologically devastating syndrome with high mortality and morbidity. Proposed guidelines and various treatment strategies are becoming available in the literature. Although treatment with KD, anakinra, and tocilizumab has been successful in previous FIRES cases, our results suggest that the addition of IT-DEX may allow for faster weaning off CI and better cognitive outcomes when initiated early in the course.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

ObjectiveTo identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation.MethodsThis was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation.ResultsWe included 289 patients (55.7% male) with a median age of 4.3 (1.3–9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18–3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05–1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23–3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24–3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57–0.95).ConclusionBZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation.Classification of evidenceThis study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.

Introduction:In young children, excessive cow’s milk intake causes iron-deficiency anemia, which is associated with hypercoagulable states. We present a case series of 4 toddlers with excessive milk intake iron-deficiency anemia and cerebral sinovenous thrombosis.Methods:Retrospective chart review of 4 patients was performed for patients with cerebral sinovenous thrombosis and iron-deficiency anemia secondary to excessive milk intake. Iron-deficiency anemia was defined as hemoglobin 24 oz daily. Clinical, laboratory, and radiographic features were reviewed.Results:Age ranged from 12 to 24 months. Average hemoglobin, hematocrit, mean corpuscular volume, and ferritin levels were 6.1 g/dL, 22.7 g/dL, 52.7 fL, and 3.2 ng/mL, respectively. Daily milk consumption ranged from 40 to 60 oz. All patients presented with focal neurologic deficits, including seizures in 3. The location of cerebral sinovenous thrombosis varied, and 3 patients had venous infarcts, one of them hemorrhagic. All patients had a limited diet and were described as “picky eaters” by their parents, and only 1 had transitioned of a bottle. All patients were treated with anticoagulation, iron supplementation, and extensive dietary counseling to reduce cow’s milk intake.Conclusion:Iron-deficiency anemia due to excessive milk intake is an important and preventable etiology of pediatric cerebral sinovenous thrombosis. Focused anticipatory guidance is necessary for at-risk groups to prevent this neurologic emergency.

Objective To describe the characteristics of pediatric intensive care neurologists and their practice in the United States and Canada. Methods We performed a survey-based study of child neurologists who self-identify as ‘intensive care neurologists’. The survey included questions about demographics, training, pediatric neurocritical care service and job structure, teaching, academics, challenges, and views on the future of pediatric neurocritical care. Results We analyzed 55 surveys. Most respondents were 31-50 years of age with ≤10 years of practice experience. Fifty-four percent identified as female. Most completed subspecialty training after child neurology residency. The majority practice at highly resourced centers with >45 intensive care unit beds. Respondents cover a variety of inpatient (critical and noncritical care) services, at times simultaneously, for a median of 19.5 weeks/y and work >70 hours/wk when on service for pediatric neurocritical care. The top 3 challenges reported were competing demands for time, excess volume, and communication with critical care medicine. Top priorities for the “ideal pediatric neurocritical care service” were attendings with training in pediatric neurocritical care or a related field and joint rounding with critical care medicine. Conclusion We report a survey-based analysis of the demographics and scope of practice of pediatric critical care neurologists. We highlight challenges faced and provide a framework for the further development of this rapidly growing field.

To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition.This was a retrospective multicenter study of pediatric patients (≤18 years) who were diagnosed with AFM from 2014 to 2018 using the Centers for Disease Control and Prevention's case definition.In 72% of the cases (126 of 175), AFM was not considered in the initial differential diagnosis (n = 108; 61.7%) and/or the patient was not referred for acute care (n = 90; 51.4%) at the initial clinical encounter, and this did not improve over time. Although many features of the presentation were similar in those initially diagnosed with AFM and those who were not; preceding illness, constipation, and reflexes differed significantly between the 2 groups. Patients with a non-AFM initial diagnosis more often required ventilatory support (26.2% vs 12.2%; OR, 0.4; 95% CI, 0.2-1.0; P = .05). These patients received immunomodulatory treatment later (3 days vs 2 days after neurologic symptom onset; 95% CI, -2 to 0; P = .05), particularly intravenous immunoglobulin (5 days vs 2 days; 95% CI, -4 to -2; P .001).Delayed recognition of AFM is concerning because of the risk for respiratory decompensation and need for intensive care monitoring. A non-AFM initial diagnosis was associated with delayed treatment that could have a clinical impact, particularly as new treatment options emerge.

Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C).Multicenter, cross-sectional study of neurological manifestations in children aged18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed.Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P 0.05.In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

New-onset refractory status epilepticus (NORSE) is a rare clinical presentation of refractory status epilepticus (RSE) that occurs in people without active epilepsy or preexisting neurologic disorder. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE. New-onset refractory status epilepticus/FIRES are becoming increasingly recognized; however, information pertaining to disease course, clinical outcomes, and survivorship remains limited, and mortality and morbidity are variable, but often high. The objective of the NORSE/FIRES Family Registry is to (1) provide an easily accessible and internationally available multilingual registry into which survivors or NORSE/FIRES surrogates or family members of people affected by NORSE/FIRES or their physicians can enter data in a systematic and rigorous research study from anywhere in the world where internet is available; and (2) to examine past medical history, outcomes, and quality of life for people affected by NORSE/FIRES., SCOPUS: ar.j, info:eu-repo/semantics/published

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

OBJECTIVES To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients. DESIGN Retrospective cohort study with prospectively collected data between June 2011 and January 2019. SETTING Seventeen academic hospitals in the United States. PATIENTS We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments. CONCLUSIONS Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.

Objective We recently reported successful treatment of a child with febrile infection-related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin-1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. Methods Levels of IL1β and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell-based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real-time polymerase chain reaction. Results Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1β in a cell-based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. Interpretation Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision-making. Ann Neurol 2019;85:526-537.

Electrographic seizures are frequent and associated with worse outcomes following traumatic brain injury (TBI). Despite this, the use of continuous electroencephalogram (cEEG) remains low. Our study describes cEEG usage and treatment dosing antiseizure medications (ASMs) in an international pediatric TBI population, hypothesizing that children monitored with cEEG have an increased rate of treatment ASMs because of electrographic seizure detection, compared with children who are not monitored with cEEG.This subanalysis of the TBI cohort of the international PANGEA study included children, 7 days to 17 years of age, with acute neurological insults admitted to pediatric intensive care units. We analyzed demographics, injury severity, and therapies including prophylactic or treatment ASMs. We evaluated the relationships between cEEG use, seizure frequency, and receipt of treatment ASMs. [Formula: see text] or Fisher's exact test was used to analyze categorical variables, and the Kruskal-Wallis or Mann-Whitney U-test was used for continuous variables. Multivariable analysis for treatment ASM use was performed using logistic regression.One hundred-twenty-three of 174 patients with TBI were included. Twenty-seven patients (21.9%) underwent cEEG at any point during pediatric intensive care unit admission. Preexisting seizure disorder (18.2% vs. 2.3%, p = 0.014) and neuromuscular blockade use (52.4% vs. 24.1%, p = 0.011) were more frequently observed in the group monitored on cEEG when compared with those that were not. Presenting median Glasgow Coma Scale score was worse in the cEEG group (7 vs. 9, p = 0.044). There was no significant difference in age, use of intracranial pressure monitoring, or hyperosmolar therapy between the cEEG monitored and nonmonitored groups. Patients who were monitored on cEEG were more likely to receive a treatment dose ASM than those without cEEG monitoring (66.7% vs. 28.1%, p = 0.0002). When compared with those without treatment ASM, the treatment ASM group had more electrographic seizures on their first electroencephalogram following injury (51.6% vs. 4%, p = 0.0001) and more clinical seizures (55.8% vs. 0%, p 0.0001).Children monitored with cEEG after TBI have an increased prescription of treatment ASMs and clinical and electrographic seizures. The increased rate of treatment ASMs in the cEEG group may indicate increased recognition of electrographic seizures.

Summary Objective To investigate parental perception of FIRES outcomes, assess emotional states and related social media usage. Methods A survey‐based study of parents of children with FIRES participating in a FIRES‐specific Facebook group was performed. The survey collected information on medical aspects of their child's course in the acute, subacute, and chronic periods, emotional states, and social media usage. Child outcome was assessed utilizing the pediatric extended Glasgow outcome scale (GOS‐E). Parental emotional states were assessed utilizing the Depression, Anxiety and Stress Scale (DASS). Descriptive statistics were performed. Associations were described using the Spearman rank correlation. Open‐ended questions were included. Thematic analysis was performed. Results Twenty‐nine surveys were analyzed. All children were in the chronic phase at time of survey response, except for two who died. Mothers answered 22 surveys, and fathers answered seven. Median age at FIRES presentation was 5.6 years [IQR 4.2‐8.95], with a median number of 3 seizures per week [IQR 0‐10, range 0‐50], 4 daily anti‐seizure medicines [IQR 3‐5], and chronic GOS‐E of 6 [IQR 2‐8 range 2‐8]. Most parents reported none to mild levels of depression, anxiety, and stress. Higher seizure burden positively correlated with parental depression symptoms (r = .41 (95% CI 0.01, 0.70), P = .045). Most parents found social media helpful with coping and 96% desired FIRES research advertised. Twenty‐five parents shared their recommendations to fellow parents and the medical team in an open‐ended format. Themes included support, expertise, and medical advice. Significance Despite their children's significantly impaired functional outcome after FIRES and high rates of medically refractory epilepsy, the cohort demonstrated remarkable emotional resilience. They perceive social media as beneficial, are interested in social media‐advertised research, and share valuable advice. Social media may serve as an introductory platform to enhance the physician‐scientist‐parent/patient relationship.

Background: The Glasgow Coma Scale (GCS), used to classify the severity of traumatic brain injury (TBI), is associated with mortality and functional outcomes. However, GCS can be affected by sedation and neuromuscular blockade. GCS-Pupil (GCS-P) score, calculated as GCS minus Pupil Reactivity Score (PRS), was shown to better predict outcomes in a retrospective cohort of adult TBI patients. We evaluated the applicability of GCS-P to a large retrospective pediatric severe TBI (sTBI) cohort. Methods: Admissions to pediatric intensive care units in the Virtual Pediatric Systems (VPS, LLC) database from 2010 to 2015 with sTBI were included. We collected GCS, PRS (number of nonreactive pupils), cardiac arrest, abusive head trauma status, illness severity scores, pediatric cerebral performance category (PCPC) score, and mortality. GCS-P was calculated as GCS minus PRS. χ2 or Fisher’s exact test and Mann-Whitney U test compared categorical and continuous variables, respectively. Classification and regression tree analysis identified thresholds of GCS-P and GCS along with other independent factors which were further examined using multivariable regression analysis to identify factors independently associated with mortality and unfavorable PCPC at PICU discharge. Results: Among the 2,682 patients included in the study, mortality was 23%, increasing from 4.7% for PRS = 0 to 80% for PRS = 2. GCS-P identified more severely injured patients with GCS-P scores 1 and 2 who had worse outcomes. GCS-P ≤ 2 had higher odds for mortality, OR = 68.4 (95% CI = 50.6–92.4) and unfavorable PCPC, OR = 17.3 (8.1, 37.0) compared to GCS ≤ 5. GCS-P ≤ 2 also had higher specificity and positive predictive value for both mortality and unfavorable PCPC compared to GCS ≤ 5. Conclusions: GCS-P, by incorporating pupil reactivity to GCS scoring, is more strongly associated with mortality and poor functional outcome at PICU discharge in children with sTBI.

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.

Objective To determine whether publication of evidence on delays in time to treatment shortens time to treatment in pediatric refractory convulsive status epilepticus (rSE), we compared time to treatment before (2011-2014) and after (2015-2019) publication of evidence of delays in treatment of rSE in the Pediatric Status Epilepticus Research Group (pSERG) as assessed by patient interviews and record review. Methods We performed a retrospective analysis of a prospectively collected dataset from June 2011 to September 2019 on pediatric patients (1 month-21 years of age) with rSE. Results We studied 328 patients (56% male) with median (25th-75th percentile [p(25)-p(75)]) age of 3.8 (1.3-9.4) years. There were no differences in the median (p(25)-p(75)) time to first benzodiazepine (BZD) (20 [5-52.5] vs 15 [5-38] minutes,p= 0.3919), time to first non-BZD antiseizure medication (68 [34.5-163.5] vs 65 [33-142] minutes,p= 0.7328), and time to first continuous infusion (186 [124.2-571] vs 160 [89.5-495] minutes,p= 0.2236). Among 157 patients with out-of-hospital onset whose time to hospital arrival was available, the proportion who received at least 1 BZD before hospital arrival increased after publication of evidence of delays (41 of 81 [50.6%] vs 57 of 76 [75%],p= 0.0018), and the odds ratio (OR) was also increased in multivariable logistic regression (OR 4.35 [95% confidence interval 1.96-10.3],p= 0.0005). Conclusion Publication of evidence on delays in time to treatment was not associated with improvements in time to treatment of rSE, although it was associated with an increase in the proportion of patients who received at least 1 BZD before hospital arrival., This study and consortium were funded by the Epilepsy Research Fund, the Epilepsy Foundation of America (EF-213583, Targeted Initiative for Health Outcomes), by the American Epilepsy Society/Epilepsy Foundation of America Infrastructure Award, and by the Pediatric Epilepsy Research Foundation.

We report the proceedings of the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. To promote awareness of this condition and foster research efforts, we conveyed the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood- and adult-onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine-mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES.

Background Super-refractory status epilepticus (SRSE) ensues when there is no improvement of seizure control in response to anesthetic therapy or seizure recurrence after reduction of anesthetic agents. There is no consensus on standard of care for SRSE. Ketogenic diet (KD) has reported success, but technical challenges exist including inability to feed patients, concomitant steroid use, acidotic states, and lack of dieticians with experience. The optimal protocol for KD is yet to be determined. We describe our approach to initiation of KD in the pediatric intensive care unit (PICU).

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).

Objectives Although secondary hemophagocytic lymphohistiocytosis (HLH) has been reported in children with critical illness of various etiologies, it has not been reported in patients with febrile infection-related epilepsy syndrome (FIRES). We describe a series of patients with concurrent HLH and FIRES in an effort to establish common pathophysiologic abnormalities. Methods Five patients with FIRES who were assessed for HLH were identified from a neurocritical care database. All were previously healthy and had extensive diagnostic testing. All had clinical deterioration with multiorgan dysfunction prompting HLH screening 20-29 days after hospitalization. Markers for inflammatory dysregulation were assessed in cerebrospinal fluid (CSF) and serum at various time points. Outcomes were assessed 6 months after presentation. Results Three patients met clinical criteria for secondary HLH. Elevation of specific cytokines/chemokines was variable. CSF neopterin, high mobility group box 1 (HMGB1), and C-X-C motif chemokine ligand 8 (CXCL8) were significantly elevated in all. Interleukin-1β (IL-1β) and IL-18 were not elevated in any of the samples. Treatment and outcomes were variable. Significance We describe 3 patients with HLH and FIRES. The co-occurrence of these 2 rare disorders suggests the possibility of a common immune dysregulation phenotype prolonging epileptogenesis. HLH screening in critically ill patients with FIRES may yield a broader understanding of shared inflammatory processes.

Purpose To summarize the available evidence related to pediatric refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE), with emphasis on epidemiology, etiologies, therapeutic approaches, and clinical outcomes. Methods Narrative review of the medical literature using MEDLINE database. Results RSE is defined as status epilepticus (SE) that fails to respond to adequately used first- and second-line antiepileptic drugs. SRSE occurs when SE persist for 24 h or more after administration of anesthesia, or recurs after its withdrawal. RSE and SRSE represent complex neurological emergencies associated with long-term neurological dysfunction and high mortality. Challenges in management arise as the underlying etiology is not always promptly recognized and therapeutic options become limited with prolonged seizures. Treatment decisions mainly rely on case series or experts’ opinions. The comparative effectiveness of different treatment strategies has not been evaluated in large prospective series or randomized clinical trials. Continuous infusion of anesthetic agents is the most common treatment for RSE and SRSE, although many questions on optimal dosing and rate of administration remain unanswered. The use of non-pharmacological therapies is documented in case series or reports with low level of evidence. In addition to neurological complications resulting from prolonged seizures, children with RSE/SRSE often develop systemic complications associated with polypharmacy and prolonged hospital stay. Conclusion RSE and SRSE are neurological emergencies with limited therapeutic options. Multi-national collaborative efforts are desirable to evaluate the safety and efficacy of current RSE/SRSE therapies, and potentially impact patients’ outcomes.

SummaryObjective Febrile infection–related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy described as explosive onset of super refractory status epilepticus (SRSE) in previously healthy children. We describe electroencephalography (EEG) abnormalities in the hyperacute phase of FIRES, with the aim of contributing to the diagnostic characterization of a syndrome otherwise lacking specific biomarkers. Methods This is a retrospective single-center, case series of seven children with FIRES. Cases were identified from a Neurocritical Care database. Patient characteristics and clinical course were obtained from electronic medical records. Electroencephalography recordings were reviewed in two segments: the initial 12 h of recording and the 12 h prior to initiation of a medically induced burst suppression (BS). Results Fourteen 12-h segments of video–electroencephalography (EEG) recordings were analyzed for commonalities. A beta–delta complex resembling extreme delta brush (EDB) occurred in at least one 12-h segment for all patients. In six patients, seizures were brief and relatively infrequent during the first recording, with a gradual evolution to status epilepticus by the second. We observed a characteristic electrographic seizure pattern in six of seven patients with prolonged focal fast activity at onset. Shifting seizures were seen in four of seven patients. Significance The diagnosis of FIRES is typically assigned late in a patient's clinical course, which has broad implications for clinical care and research. We retrospectively analyzed acute EEG features in seven patients with FIRES and discovered three common features: gradual increase in seizure burden, presence of a recurrent EDB, and a typical seizure pattern. Recognition of this pattern may facilitate early diagnosis and treatment.

Variations in cerebral venous development can influence the ability to regulate drainage. In cerebral sinovenous thrombosis, these variations can be associated with elevated intracranial pressure. We present a series of pediatric patients with unilateral cerebral sinovenous thrombosis and investigate whether the contralateral venous sinus size increases the risk of developing elevated intracranial pressure. Patients diagnosed with a unilateral cerebral sinovenous thrombosis were identified by querying our institutional radiology data base. The difference in the occurrence of elevated intracranial pressure in patients with cerebral sinovenous thrombosis with and without hypoplastic venous sinuses was studied. Twelve cases of unilateral cerebral sinovenous thrombosis met the inclusion criteria and had sufficient images. Six patients had hypoplastic contralateral venous sinuses. The presence of hypoplastic contralateral venous sinus in the setting of thrombosis of a dominant sinus was associated with elevation of intracranial pressure (83% versus 0%, P = .015). Patients with cerebral sinovenous thrombosis and contralateral hypoplastic venous sinuses are at higher risk of developing elevated ICP and may benefit from screening with an ophthalmologic examination.

Introduction There is limited literature on pediatric super refractory status epilepticus (SRSE). We aimed to identify clinical variables associated with the occurrence of SRSE and to describe variability in SRSE treatment in a cohort of children admitted to pediatric intensive care units (ICU) with refractory status epilepticus (RSE). Methods This prospective, observational study was performed at 14 US hospitals. Inclusion criteria: (1) hospital admission between June 2011 and September 2017, (2) convulsive RSE defined as focal or generalized convulsive seizures at onset that continued after administration of at least 2 anti-seizure drugs (ASDs), including one non-benzodiazepine ASD or use of continuous infusion (CI) and (3) age 1 month to 21 years. We divided the cohort into SRSE and non-SRSE groups. SRSE was defined as continuous or intermittent seizures lasting ⩾ 24 h following initiation of CI. We used Fisher’s exact test and Wilcoxon rank sum test in the univariate analysis. Results The initial cohort included 264 patients with a median (p25–p75) age of 4 (1.23–9.50) years. Thirty-five patients (19 males) were identified as SRSE cases, with a median age of 4.5 (1.91–8.45) years. Univariate analysis did not show significant differences between the groups for: sex, age, etiology, prior SE, diagnosis of epilepsy, in-hospital seizure onset, generalized tonic-clonic seizures or continuous SE. SRSE patients had delayed first line treatment initiation (71(15–135.5) vs. 16(5–40.5) min; p = 0.017), longer ICU stay (17(9–42) vs. 3(1.86–8.66) days; p Conclusion SRSE patients had delayed first-line treatment administration in comparison to non-SRSE patients. Once SRSE was established, children had significantly higher morbidity and mortality. Treatment approaches were heterogeneous, probably reflecting limited evidence to guide clinical decision-making in SRSE. (Funded by the Pediatric Epilepsy Research Foundation and Epilepsy Research Fund ).

Autonomic dysfunction in pediatric patients with acquired brain injury is often encountered and greatly understudied. We sought to identify the incidence of Paroxysmal Sympathetic Hyperactivity (PSH) in critically ill pediatric patients with meningoencephalitis and encephalitis, associated risk factors and influence on outcome. Children admitted to the pediatric intensive care unit (PICU) with a diagnosis of meningoencephalitis and/or encephalitis were identified from a single institution Neurocritical Care database. The patients were stratified as having a bacterial or non-bacterial cause of their meningoencephalitis/encephalitis. Data from their hospitalization was supplemented with a retrospective review of the electronic medical record. PSH was defined as episodic lability in heart rate and/or blood pressure, hyperthermia, diaphoresis, dystonic posturing, tachypnea and/or agitation without any other cause. Statistical analysis was performed using t-test and chi-squared to compare outcomes and risk factors between patients with PSH and without. PSH was found in 41 % of children studied. Subgroup analysis revealed patients with non-bacterial encephalitis were more likely to experience PSH (51 %) as compared to those with bacterial causes (27 %). Fever and/or seizures on presentation and female gender were associated with higher occurrence of PSH but only in the non-bacterial etiology group. There were trends toward increased length of PICU and overall hospital stay for patients with PSH. PSH was found in a high percentage of our patients with significant variation in risk factors and outcome noted between patients with bacterial and nonbacterial causes of their meningoencephalitis/encephalitis.

This study aims to determine if stroke volume as measured on diffusion-weighted imaging is associated with neurologic outcome in children with acute arterial ischemic stroke. A cohort of patients presenting to a tertiary care children's hospital with acute ischemic stroke were studied. The relationship between stroke volume, clinical characteristics, and neurologic outcome utilizing the Glasgow Outcome Scale were analyzed. In children with poor outcome, the median volume of infarction on diffusion-weighted imaging was larger when compared with children who had a good outcome. Children with stroke volume >10% of total brain volume were more likely than patients with stroke volume