Aim: Accuracy of neuroprognostication after pediatric cardiac arrest (CA) is critical for directing clinical care. Current limitations include imprecise neuroprognostication models, inability to discriminate between degrees of disability, and lack of modifiable post-CA biomarkers. Models including quantitative EEG (qEEG) characteristics may improve post-CA prognostic accuracy. Methods: Retrospective multicenter cohort of children (3mo-18 yr) without return to neurologic baseline post-CA at two pediatric tertiary care hospitals (2010-2016) with >= 6-hours of EEG within 24-hours post-CA and baseline Pediatric Cerebral Performance Category (PCPC) 1-3. Primary outcome measure was 6-month PCPC dichotomized into favorable (1-3) and unfavorable (4-6 and D > 1). Training and validation sets were derived from clinical variables, qualitative EEG (qualEEG) features, and qEEG analysis using Persyst software. Results: Among 221 subjects, 84 (38%) had favorable 6-month outcomes. All models including clinical features (AUC 0.73 [0.59-0.87]), qualEEG (0.90 [0.81-0.97]) and qEEG features (0.85 [0.74-0.94]) predict outcomes well. A parsimonious model incorporating clinical, qualEEG and qEEG variables had an AUC of 0.92 (0.85-0.97) for predicting outcome. Increased SR was associated with degree of disability and unfavorable outcomes. Machine learning models were not superior to the more transparent parsimonious model. Conclusions: qEEG features measured with 24-h post-CA add to predictive outcome models and can be trended at the bedside. SR is an objective measure that may improve the precision of outcome prediction. qEEG features maybe targetable dynamic brain injury biomarkers which could aid in future studies of neuroprotective interventions.

AIM:Accuracy of neuroprognostication after pediatric cardiac arrest (CA) is critical for directing clinical care. Current limitations include imprecise neuroprognostication models, inability to discriminate between degrees of disability, and lack of modifiable post-CA biomarkers. Models including quantitative EEG (qEEG) characteristics may improve post-CA prognostic accuracy. METHODS:Retrospective multicenter cohort of children (3mo-18 yr) without return to neurologic baseline post-CA at two pediatric tertiary care hospitals (2010-2016) with ≥ 6-hours of EEG within 24-hours post-CA and baseline Pediatric Cerebral Performance Category (PCPC) 1-3. Primary outcome measure was 6-month PCPC dichotomized into favorable (1-3) and unfavorable (4-6 and Δ > 1). Training and validation sets were derived from clinical variables, qualitative EEG (qualEEG) features, and qEEG analysis using Persyst software. RESULTS:Among 221 subjects, 84 (38%) had favorable 6-month outcomes. All models including clinical features (AUC 0.73 [0.59-0.87]), qualEEG (0.90 [0.81-0.97]) and qEEG features (0.85 [0.74-0.94]) predict outcomes well. A parsimonious model incorporating clinical, qualEEG and qEEG variables had an AUC of 0.92 (0.85-0.97) for predicting outcome. Increased SR was associated with degree of disability and unfavorable outcomes. Machine learning models were not superior to the more transparent parsimonious model. CONCLUSIONS:qEEG features measured with 24-h post-CA add to predictive outcome models and can be trended at the bedside. SR is an objective measure that may improve the precision of outcome prediction. qEEG features may be targetable dynamic brain injury biomarkers which could aid in future studies of neuroprotective interventions.

After traumatic brain injury (TBI), monocyte/macrophage infiltration is a key early step in the development of an inflammatory cascade that leads to substantial secondary damage. Intravenous (IV) immunomodulatory nanoparticle (IMP) administration after TBI limits inflammatory cell infiltration and reduces both behavioral decline and lesion size without any noticeable toxicity. Here we show that there is a dose-response relationship between the amount of IMP administered and tissue damage which plateaus at a well-tolerated dose. There is a therapeutic window of efficacy for IMP administration of at least 6 h after injury with some benefit observed when treatment was delayed for 12 h after injury. Single cell RNA sequencing demonstrated substantial changes in gene expression after TBI in both neural and non-neural cells in the brain, and IMP administration ameliorated many of the changes. Particularly notable were significant unexpected changes in CCR1, CXCR2, and BDNF expression in vascular smooth muscle cells that may participate in injury responses after TBI. Thus, IMP treatment within 6 h after TBI limits inflammatory responses and gliosis, improves anatomical and behavioral outcomes and prevents detrimental changes in gene expression in both neural and non-neural cellular elements of the brain. IMPs are non-toxic and are made of an FDA-approved material that is stable at room temperature. They could easily be given IV immediately after TBI in the field by emergency medical technicians or in the emergency room to prevent secondary damage, thereby improving outcomes.

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Ventricular assist devices (VADs) are increasingly used for end-stage heart failure in children. VAD-associated neurologic dysfunction, including stroke and intracranial hemorrhage, occurs in more than 20% of patients. Starting in 2019, we implemented a protocol to diagnose stroke in relation to VAD to facilitate treatment. A multidisciplinary approach was implemented including targeted education for providers. VAD goals, structured neurologic exam, and frequency of neuromonitoring were incorporated into daily rounds, tailored to patient's phase of recovery. A protocolized neurocritical team assessment was implemented. A VAD-specific stroke algorithm and order set were implemented to facilitate rapid neuroimaging. We performed a pre- and postimplementation analysis from 2015 to 2020. Forty-six patients had VADs placed, 25 preintervention, and 21 postintervention. We compared the number of patients evaluated for stroke, time to imaging, and documentation of last known normal exam. Preintervention, time to imaging was 7 hours, and documentation was inconsistent. Postintervention, time to imaging decreased to 2.8 hours (p = 0.038) with universal documentation of last known normal (p = 0.009). The use of head computerized tomographies decreased from 11 preintervention to three postintervention. Development of a VAD protocol decreased time to imaging for suspected stroke and reduced unnecessary imaging. Further studies are required to validate these data.

OBJECTIVES:Survivors of the PICU face long-term morbidities across health domains. In this study, we detail active PICU follow-up programs (PFUPs) and identify perceptions and barriers about development and maintenance of PFUPs.METHODS:A web link to an adaptive survey was distributed through organizational listservs. Descriptive statistics characterized the sample and details of existing PFUPs. Likert responses regarding benefits and barriers were summarized.RESULTS:One hundred eleven respondents represented 60 institutions located in the United States (n = 55), Canada (n = 3), Australia (n = 1), and the United Kingdom (n = 1). Details for 17 active programs were provided. Five programs included broad PICU populations, while the majority were neurocritical care (53%) focused. Despite strong agreement on the need to assess and treat morbidity across multiple health domains, 29% were physician only programs, and considerable variation existed in services provided by programs across settings. More than 80% of all respondents agreed PFUPs provide direct benefits and are essential to advancing knowledge on long-term PICU outcomes. Respondents identified "lack of support" as the most important barrier, particularly funding for providers and staff, and lack of clinical space, though successful programs overcome this challenge using a variety of funding resources.CONCLUSIONS:Few systematic multidisciplinary PFUPs exist despite strong agreement about importance of this care and direct benefit to patients and families. We recommend stakeholders use our description of successful programs as a framework to develop multidisciplinary models to elevate continuity across inpatient and outpatient settings, improve patient care, and foster collaboration to advance knowledge.

Background Nonconvulsive seizures occur frequently in pediatric intensive care unit patients and can be impossible to detect clinically without electroencephalogram monitoring. Quantitative electroencephalography uses mathematical signal analysis to compress data, monitoring trends over time. Nonneurologists can identify seizures with quantitative electroencephalography, but data on its use in the clinical setting are limited. Local Problem Bedside quantitative electroencephalography was implemented and nurses received education on its use for seizure detection. This quality improvement project aimed to describe the time between nurses’ recognition of electrographic seizures and seizure treatment. Methods Education was provided in phases over several months. Retrospective medical record review evaluated quantitative electroencephalograms and medication interventions from September 2019 through March 2020. A bedside form was used to measure nurses’ use of quantitative electroencephalograms, change recognition, clinician notification, and seizure treatment. A nurse survey evaluated the education after implementation. Results Data included 44 electroencephalograms from 30 pediatric intensive care unit patients aged 18 years or less with electroencephalogram monitoring durations of 4 hours or longer. Nurses monitored quantitative electroencephalograms in 73% of cases, documented at least 1 change in the quantitative electroencephalogram display in 28% of these cases, and contacted the neurocritical care team in 78% of cases in which they documented a change. Seizure treatment was initiated in response to the nursing call in 1 patient. Time to treatment was approximately 20 minutes. Conclusions An education program for quantitative electroencephalogram interpretation by nurse providers is feasible yet complex, requiring multiple reeducation cycles.

2064 Background: Tumor-associated epilepsy (TAE) is a frequent complication of diffusely infiltrative gliomas. TAE not only impairs quality-of-life, but it can even be life-threatening. Furthermore, glioma cells have been shown to proliferate and migrate faster when exposed to firing neurons. We previously showed that isocitrate dehydrogenase 1 mutant (IDHmut) gliomas were more likely to cause preoperative seizures than IDH wildtype (IDHwt) gliomas, and that the chemical product of IDHmut, D2HG, increased synchronized network bursts in cultured neurons (PMID: 28404805). But the mechanism whereby this occurs, whether IDHmut inhibitors can block this, and whether seizure risk also varies by IDHmut status postoperatively, are unknown. Methods: Methods are embedded in Results. Results: We discovered that exogenous 3 mM D2HG had a 150% greater effect on the firing rate of cultured mouse cortical neurons when nonneoplastic glia cells were present versus when they were absent ( P=0.002). Although a recently published study suggested that D2HG causes seizures through mTOR activation (PMID: 34994387), we found that D2HG reduced neuronal mTOR activity in neuronal-glial cocultures by 54% ( P=0.0004). Patch clamp analyses showed that, while D2HG does not directly activate glutamate receptors, it does act as a glutamate transport substrate, thus potentially interfering with the ability of glial cells to take up glutamate released into the synaptic cleft. Coculture with patient-derived IDHmut glioma cells increased the firing rate of human cortical neuron/astrocyte spheroids by up to 272%, and an IDHmut inhibitor currently being tested in clinical trials, AG881, reduced the excitatory effect of IDHmut glioma cells on spheroids by 79% ( P=0.0008). Using a novel in vivo model of TAE, wherein EEG recordings were taken of immunocompetent mice engrafted with an isogenic pair of Sleeping Beauty transposase-engineered mouse glioma lines (NRAS/ATRX/TP53mut ± IDHmut), we found that IDHmut gliomas produced 7.6-fold more epileptiform spikes than IDHwt gliomas ( P=0.004). RNA-Seq analysis of the peritumoral mouse brain tissue showed that this increase in spikes was associated with significantly increased expression of key genes known to be upregulated in epilepsy, including SLC12A5, THSB1, VEGFA, FOSL2, and SYNPO. Treatment with 5 mg/kg AG881 by daily oral gavage reduced those spikes in IDHmut-engrafted mice by 51% within three days ( P=0.027), whereas vehicle control had no effect ( P=0.33). Among 247 patients with grade 2–4 adult-type diffuse gliomas, multivariable time-to-event analysis showed that postoperative seizure risk increased with preoperative seizures, subtotal resection, and IDHmut astrocytoma. Conclusions: Together, these data show that (i) the D2HG product of IDHmut gliomas increases neuronal excitation in a glial-dependent manner; (ii) IDHmut also affects postoperative seizure risk; (iii) IDHmut inhibitors may improve TAE control.

Tumor-associated epilepsy (TAE) is a frequent complication of diffusely infiltrative gliomas, and impairs quality-of-life. We previously showed that isocitrate dehydrogenase 1 mutant (IDHmut) gliomas were associated with preoperative seizures, and that D2HG increased synchronized bursts in cultured neurons (PMID: 28404805). But the mechanism whereby this occurs, whether IDHmut inhibitors can block this, and whether seizure risk varies by IDHmut status post-operatively, are unknown. We discovered that exogenous 3 mM D2HG had a 150% greater effect on the firing rate of cultured mouse cortical neurons when nonneoplastic glia cells were present versus when they were absent (P=0.002). Coculture with patient-derived IDHmut glioma cells increased the firing rate of human cortical neuron/astrocyte spheroids by up to 272%, and the IDHmut inhibitor AG881 reduced the excitatory effect of IDHmut glioma cells on spheroids by 79% (P=0.0008). Using a novel in vivo model of TAE, wherein EEG recordings were taken of immunocompetent mice engrafted with isogenic mouse glioma lines (NRAS/ATRX/TP53mut ± IDHmut), we found that IDHmut gliomas produced 7.6-fold more epileptiform spikes than IDHwt gliomas (P=0.004). RNA-Seq analysis of the peritumoral mouse brain tissue showed that this increase in spikes was associated with significantly increased expression of key genes known to be upregulated in epilepsy, including SLC12A5, THSB1, VEGFA, FOSL2, and SYNPO. Treatment with 5 mg/kg AG881 by daily oral gavage reduced those spikes in IDHmut-engrafted mice by 51% within three days (P=0.027), whereas vehicle control had no effect (P=0.33). Among 247 patients with grade 2–4 adult-type diffuse gliomas, multivariable time-to-event analysis showed that post-operative seizure risk was positively associated with pre-operative seizures, subtotal resection, and IDHmut astrocytoma. Together, these data show that (i) the D2HG product of IDHmut gliomas increases neuronal excitation in a glial-dependent manner; (ii) IDHmut also affects post-operative seizure risk; (iii) IDHmut inhibitors may improve TAE control.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels regulate neuronal excitability and represent a possible therapeutic target for major depressive disorder (MDD). These channels are regulated by intracellular cyclic adenosine monophosphate (cAMP). However, the relationship between cAMP signaling and the influence of HCN channels on behavior remains opaque. In this study, we investigated the role of hippocampal cAMP signaling on behavior using chemogenetic technology in mice. Acutely increasing cAMP limited spatial memory and motivated behavior by increasing HCN function. However, chronically elevated cAMP limited surface trafficking of HCN channels by disrupting the interaction between HCN and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit. Chronically increased cAMP in the dorsal hippocampus was also sufficient to rescue cognitive deficits induced by chronic stress in mice. These results reveal a behaviorally relevant form of regulation of HCN channel surface expression that has potential as a therapeutic target for cognitive deficits related to chronic stress.

Seizures are among the most prevalent co-morbidities associated with glioma, and pose a serious threat to patients. Our prior work showed that IDH mutation (IDHmut) was associated with much greater seizure frequency at the time of initial glioma diagnosis. However, less is known about the variables that contribute to seizure risk throughout the course of disease. We therefore collected data from 247 patients with grade 2–4 glioma, and determined seizure risk using Kaplan-Meier survival probabilities and multivariable cox regression analyses. Median follow-up of IDH wildtype (IDHwt) and IDHmut glioma patients was 15 months and 36 months, respectively. Incidence of pre-operative seizures for IDHwt and IDHmut patients was 75/168 (45%) and 60/79 (76%), and incidence of post-operative seizures was 70/168 (42%) and 43/79 (54%), respectively. Patients who had a pre-operative seizure had a shorter time to their first post-operative seizure than patients who never had a pre-operative seizure in both IDHwt (P< 0.0001) and IDHmut (P= 0.039) cohorts. Among IDHmut glioma patients, those with subtotal resections developed post-operative seizures faster (median time to first seizure= 9.9 months) than those with gross-total resections (median not reached) (P= 0.0005), but a similar pattern was not observed in IDHwt glioma patients (P= 0.20). Those with IDHmut astrocytomas more quickly developed post-operative seizures (median= 11.1 months), compared to those with IDHwt astrocytomas (24.9 months) or IDHmut oligodendrogliomas (median not reached) (P= 0.033). Tumor progression closely followed post-operative seizures in patients with IDHwt gliomas when either their first post-operative seizure occurred longer than 6 months following resection, or when their post-operative seizures worsened in quality. These data suggest the best predictors of post-operative seizures are as follows: the presence of pre-operative seizures; extent of surgical resection; IDHmut status. These data will help clinicians better manage glioma patients by identifying those at greatest risk of seizures.

ObjectiveThere are currently no definitive disease‐modifying therapies for traumatic brain injury (TBI). In this study, we present a strong therapeutic candidate for TBI, immunomodulatory nanoparticles (IMPs), which ablate a specific subset of hematogenous monocytes (hMos). We hypothesized that prevention of infiltration of these cells into brain acutely after TBI would attenuate secondary damage and preserve anatomic and neurologic function.MethodsIMPs, composed of US Food and Drug Administration–approved 500nm carboxylated‐poly(lactic‐co‐glycolic) acid, were infused intravenously into wild‐type C57BL/6 mice following 2 different models of experimental TBI, controlled cortical impact (CCI), and closed head injury (CHI).ResultsIMP administration resulted in remarkable preservation of both tissue and neurological function in both CCI and CHI TBI models in mice. After acute treatment, there was a reduction in the number of immune cells infiltrating into the brain, mitigation of the inflammatory status of the infiltrating cells, improved electrophysiologic visual function, improved long‐term motor behavior, reduced edema formation as assessed by magnetic resonance imaging, and reduced lesion volumes on anatomic examination.InterpretationOur findings suggest that IMPs are a clinically translatable acute intervention for TBI with a well‐defined mechanism of action and beneficial anatomic and physiologic preservation and recovery. Ann Neurol 2020;87:442–455

Investigators from the University of Pittsburgh (Department of Emergency Medicine and Division of Pediatric Radiology) and Feinberg School of Medicine (Division of Emergency Medicine) studied the rates of neuroimaging (rapid brain MRI [rMRI], head CT [HCT], and full MRI) before and after implementation of four rapid MRI protocols in their ED.

Investigators from 10 French academic centers studied a retrospective cohort of 60 patients aged 10-18 years (mean age 15.2 years) presenting with first-time stroke, as identified from discharge ICD-10 codes.

New-onset headache after stroke is common among adult stroke survivors. However, pediatric data are limited. The primary aim of this study was to investigate the prevalence of new-headache after pediatric ischemic stroke. Secondary outcomes were to describe the characteristics of patients experiencing poststroke headache and the association between poststroke headache and stroke recurrence.We conducted a single-center retrospective study on children aged 30 days to 18 years with a confirmed radiographic diagnosis of arterial ischemic stroke (AIS) from January 1, 2008, to December 31, 2016. Patients were identified from an internal database, with additional data abstracted from the electronic medical record. Poststroke headache (occurring >30 days after stroke) was identified through electronic searches of the medical record and confirmed by chart review.Of 115 patients with confirmed AIS, 41 (36%) experienced poststroke headache, with headache developing a median of 6 months after stroke. Fifty-one percent of patients with poststroke headache presented to the emergency department for headache evaluation; 81% of the patients had an inpatient admission for headache. Older age at stroke (odds ratio [OR] 21.5; p = 0.0001) and arteriopathy (OR 8.65; p = 0.0029) were associated with development of poststroke headache in a multivariable analysis. Seventeen patients (15%) had a recurrent stroke during the study period. Poststroke headache was associated with greater risk for stroke recurrence (p = 0.049).Remote poststroke headache is a common morbidity among pediatric stroke survivors, particularly in older children. Headaches may increase health care utilization, including neuroimaging and hospital admissions. We identified a possible association between poststroke headache and stroke recurrence.

Background New-onset headache after stroke is common among adult stroke survivors. However, pediatric data are limited. The primary aim of this study was to investigate the prevalence of new-headache after pediatric ischemic stroke. Secondary outcomes were to describe the characteristics of patients experiencing poststroke headache and the association between poststroke headache and stroke recurrence. Methods We conducted a single-center retrospective study on children aged 30 days to 18 years with a confirmed radiographic diagnosis of arterial ischemic stroke (AIS) from January 1, 2008, to December 31, 2016. Patients were identified from an internal database, with additional data abstracted from the electronic medical record. Poststroke headache (occurring >30 days after stroke) was identified through electronic searches of the medical record and confirmed by chart review. Results Of 115 patients with confirmed AIS, 41 (36%) experienced poststroke headache, with headache developing a median of 6 months after stroke. Fifty-one percent of patients with poststroke headache presented to the emergency department for headache evaluation; 81% of the patients had an inpatient admission for headache. Older age at stroke (odds ratio [OR] 21.5; p = 0.0001) and arteriopathy (OR 8.65; p = 0.0029) were associated with development of poststroke headache in a multivariable analysis. Seventeen patients (15%) had a recurrent stroke during the study period. Poststroke headache was associated with greater risk for stroke recurrence (p = 0.049). Conclusions Remote poststroke headache is a common morbidity among pediatric stroke survivors, particularly in older children. Headaches may increase health care utilization, including neuroimaging and hospital admissions. We identified a possible association between poststroke headache and stroke recurrence.

Introduction: Diagnostic delay is a common difficulty in pediatric stroke care, driven by poor recognition, non-specific symptoms, and difficulty obtaining magnetic resonance imaging (MRI). In prior studies, pediatric stroke algorithms improved recognition and decreased diagnostic delay. Our hospital recently developed a pediatric stroke care guideline incorporating a fast MRI protocol. This study presents the process of algorithm development, barriers to implementation, and effects of the guideline on stroke care. Methods: Representatives were identified from neurology, critical care, cardiology, emergency medicine, hematology, nursing, pharmacy, radiology and quality improvement. The group was surveyed to identify algorithm goals and barriers to implementation. An algorithm and order sets were developed to provide children with an acute focal neurologic deficit immediate neuroprotective care and urgent MRI. New MRI workflows, metal screening protocols, and a rapid MRI sequence (including diffusion and gradient echo) that did not require sedation were implemented. Results: Between October 2017 and June 2018, 55 patients were treated via the new pathway. Median time from presentation to our hospital to diagnostic imaging decreased from 223 minutes to 86 minutes post-algorithm. 20% of children were diagnosed with acute arterial ischemic stroke (AIS). Other diagnoses included migraine (30.9%) and seizure (16.4%). All children with AIS were admitted to the intensive care unit, while no children with migraine or a functional disorder were. Conclusions: This study provides a unique description of the steps involved in development and implementation of a pediatric stroke pathway. Implementation of the algorithm decreased time to diagnosis and standardized early treatment. Stroke mimics were common; however, use of the pathway prevented unnecessary admission of children ultimately found to have benign diagnoses.