Challenges in the Clinical Recognition of Acute Flaccid Myelitis and its Implications.

OBJECTIVES: To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition. STUDY DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Acute flaccid myelitis: cause, diagnosis, and management.

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.

Continuous Electroencephalogram and Antiseizure Medication Use in an International Pediatric Traumatic Brain Injury Population.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

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.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

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.

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

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.

GCS-Pupil Score Has a Stronger Association with Mortality and Poor Functional Outcome than GCS Alone in Pediatric Severe Traumatic Brain Injury.

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.

Functional deficiency in endogenous interleukin-1 receptor antagonist in patients with febrile infection-related epilepsy syndrome.

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 IL1ß 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 IL1ß 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 IL1ß 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.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives.

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.

Fueling the FIRES: Hemophagocytic lymphohistiocytosis in febrile infection-related epilepsy syndrome.

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-1ß (IL-1ß) 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.

Early ictal and interictal patterns in FIRES: The sparks before the blaze.

OBJECTIVE: 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.

A Practical Approach to Ketogenic Diet in the Pediatric Intensive Care Unit for Super-Refractory Status Epilepticus.

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). METHODS: Patients with SRSE who had KD initiation in the PICU were identified. Data from the hospital course were supplemented by review of the electronic medical record. RESULTS: Nine children with SRSE who had KD initiated in the PICU were identified. Descriptive analysis was performed. Mean age was 5.4 years (SD 2.24). Median number of days to start KD from detection of seizures was 13 [interquartile range (IQR) 10-16]. Mean time to achieve ketosis was 4.2 days (SD 3.4). The median number of antiepileptic drugs (AEDs) trialed before KD was started was 4 [IQR 3-4], and the median number of continuous infusions was 2 [IQR 2-3]. After initiation of KD, most patients were weaned off anesthetic infusions by 1 week. Outcomes were variable. CONCLUSIONS: We demonstrated the feasibility of a practical approach to initiation of KD for children with SRSE. These children were successfully weaned off continuous anesthetic infusions. Larger studies are needed to determine effectiveness, safety, and tolerability of KD in the management of SRSE as well as ease of implementation.

Paroxysmal Sympathetic Hyperactivity in Critically Ill Children with Encephalitis and Meningoencephalitis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Supporting parents while their child is receiving neurocritical care.

The post-intensive care syndrome (PICS) concept whereby the ICU experience of the patient as well as their family can have long-term deleterious health outcomes in both the patient and the family provides a rationale and impetus for modifying the ICU experience for the parents of patients receiving pediatric neurocritical care. This article uses the PICS framework to provide insight to that parental experience. Included are the words of parents who tell what they felt and what they most needed from their children's doctors while their children were receiving neurocritical care. Based on their and many other ICU parents' advice and the PICS research, we identify a short list of specific steps the medical team can take immediately to support these parents.

Accuracy of Early Neuroprognostication in Pediatric Severe Traumatic Brain Injury.

BACKGROUND: Children with severe traumatic brain injury (sTBI) are at risk for neurological sequelae impacting function. Clinicians are tasked with neuroprognostication to assist in decision-making. We describe a single-center study assessing clinicians' neuroprognostication accuracy. METHODS: Clinicians of various specialties caring for children with sTBI were asked to predict their patients' functioning three to six months postinjury. Clinicians were asked to participate in the study if their patient had survived but not returned to baseline between day 4 and 7 postinjury. The outcome tool utilized was the functional status scale (FSS), ranging from 6 to 30 (best-worst function). Predicted scores were compared with actual scores three to six months postinjury. Lin concordance correlation coefficients were used to estimate agreement between predicted and actual FSS. Outcome was dichotomized as good (FSS 6 to 8) or poor (FSS ≥9). Positive and negative predictive values for poor outcome were calculated. Pessimistic prognostic prediction was defined as predicted worse outcome by ≥3 FSS points. Demographic and clinical variables were collected. RESULTS: A total of 107 surveys were collected on 24 patients. Two children died. Fifteen children had complete (FSS = 6) or near-complete (FSS = 7) recovery. Mean predicted and actual FSS scores were 10.8 (S.D. 5.6) and 8.6 (S.D. 4.1), respectively. Predicted FSS scores were higher than actual scores (P < 0.001). Eight children had collective pessimistic prognostic prediction. CONCLUSIONS: Clinicians predicted worse functional outcomes, despite high percentage of patients with near-normal function at follow-up clinic. Certain patient and provider factors were noted to impact accuracy and need to be studied in larger cohorts.

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Neural representations of self-perception of voice: An intracortical evoked potential analysis based on an adolescent with right temporal lobe epilepsy.

INTRODUCTION: The neural bases for language perception have been studied elsewhere using Transcranial Magnetic Stimulation, functional Magnetic Resonance Imaging and Direct Cortical Stimulation. However, to our knowledge, there is no previous report about a patient identifying the change in his voice tone, speed, and prosody because of right temporal cortical stimulation. Nor has there been a cortico-cortical evoked potential (CCEP) assessment of the network underlying this process. CASE REPORT: We present CCEP from a patient with right focal refractory temporal lobe epilepsy of tumoral etiology who reported changes in the perception of his own speech prosody during stimulation. This report will serve as a complement to the understanding of the neural networks of language and prosody. CONCLUSION: The present report shows that right superior temporal gyrus, transverse temporal gyrus, right amygdala, hippocampus, and fusiform gyrus (FG) are part of the neural network subjacent to own human voice perception.

Intrathecal Dexamethasone in Febrile Infection-Related Epilepsy Syndrome: A Case Report.

Objectives: Febrile 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. Methods: We 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. Results: He 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. Discussion: FIRES 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.

Drug-resistant seizures associated with hyperinflammatory monocytes in FIRES.

OBJECTIVE: Therapeutic strategies for patients with febrile infection-related epilepsy syndrome (FIRES) are limited, ad hoc, and frequently ineffective. Based on evidence that inflammation drives pathogenesis in FIRES, we used ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) to characterize the monocytic response profile before and after therapy in a child successfully treated with dexamethasone delivered intrathecally six times between hospital Day 23 and 40 at 0.25 mg/kg/dose. METHODS: PBMCs were isolated from serial blood draws acquired during refractory status epilepticus (RSE) and following resolution associated with intrathecal dexamethasone therapy in a previously healthy 9-year-old male that presented with seizures following Streptococcal pharyngitis. Cells were stimulated with bacterial or viral ligands and cytokine release was measured and compared to responses in age-matched healthy control PBMCs. Levels of inflammatory factors in the blood and CSF were also measured and compared to pediatric healthy control ranges. RESULTS: During RSE, serum levels of IL6, CXCL8, HMGB1, S100A8/A9, and CRP were significantly elevated. IL6 was elevated in CSF. Ex vivo stimulation of PBMCs collected during RSE revealed hyperinflammatory release of IL6 and CXCL8 in response to bacterial stimulation. Following intrathecal dexamethasone, RSE resolved, inflammatory levels normalized in serum and CSF, and the PBMC hyperinflammatory response renormalized. SIGNIFICANCE: FIRES may be associated with a hyperinflammatory monocytic response to normally banal bacterial pathogens. This hyperinflammatory response may induce a profound neutrophil burden and the consequent release of factors that further exacerbate inflammation and drive neuroinflammation. Intrathecal dexamethasone may resolve RSE by resetting this inflammatory feedback loop.