Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Biospecimens and Biomarkers.

BACKGROUND: In patients with disorders of consciousness (DoC), laboratory and molecular biomarkers may help define endotypes, identify therapeutic targets, prognosticate outcomes, and guide patient selection in clinical trials. We performed a systematic review to identify common data elements (CDEs) and key design elements (KDEs) for future coma and DoC research. METHODS: The Curing Coma Campaign Biospecimens and Biomarkers work group, composed of seven invited members, reviewed existing biomarker and biospecimens CDEs and conducted a systematic literature review for laboratory and molecular biomarkers using predetermined search words and standardized methodology. Identified CDEs and KDEs were adjudicated into core, basic, supplemental, or experimental CDEs per National Institutes of Health classification based on level of evidence, reproducibility, and generalizability across different diseases through a consensus process. RESULTS: Among existing National Institutes of Health CDEs, those developed for ischemic stroke, traumatic brain injury, and subarachnoid hemorrhage were most relevant to DoC and included. KDEs were common to all disease states and included biospecimen collection time points, baseline indicator, biological source, anatomical location of collection, collection method, and processing and storage methodology. Additionally, two disease core, nine basic, 24 supplemental, and 59 exploratory biomarker CDEs were identified. Results were summarized and generated into a Laboratory Data and Biospecimens Case Report Form (CRF) and underwent public review. A final CRF version 1.0 is reported here. CONCLUSIONS: Exponential growth in biomarkers development has generated a growing number of potential experimental biomarkers associated with DoC, but few meet the quality, reproducibility, and generalizability criteria to be classified as core and basic biomarker and biospecimen CDEs. Identification and adaptation of KDEs, however, contribute to standardizing methodology to promote harmonization of future biomarker and biospecimens studies in DoC. Development of this CRF serves as a basic building block for future DoC studies.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group in the Pediatric Population.

BACKGROUND: The fundamental gap obstructing forward progress of evidenced-based care in pediatric and neonatal disorders of consciousness (DoC) is the lack of defining consensus-based terminology to perform comparative research. This lack of shared nomenclature in pediatric DoC stems from the inherently recursive dilemma of the inability to reliably measure consciousness in the very young. However, recent advancements in validated clinical examinations and technologically sophisticated biomarkers of brain activity linked to future abilities are unlocking this previously formidable challenge to understanding the DoC in the developing brain. METHODS: To address this need, the first of its kind international convergence of an interdisciplinary team of pediatric DoC experts was organized by the Neurocritical Care Society's Curing Coma Campaign. The multidisciplinary panel of pediatric DoC experts proposed pediatric-tailored common data elements (CDEs) covering each of the CDE working groups including behavioral phenotyping, biospecimens, electrophysiology, family and goals of care, neuroimaging, outcome and endpoints, physiology and big Data, therapies, and pediatrics. RESULTS: We report the working groups' pediatric-focused DoC CDE recommendations and disseminate CDEs to be used in studies of pediatric patients with DoC. CONCLUSIONS: The CDEs recommended support the vision of progressing collaborative and successful internationally collaborative pediatric coma research.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

Trends in cyclicity and amplitudes on amplitude-integrated electroencephalography during transition in extremely low gestational age infants.

AIM: The aim of the study was to describe amplitude integrated electroencephalography (aEEG) cyclicity, background pattern, voltage margins and maturation scores in extremely low gestational age neonates (ELGANs) in the first 72 h. METHODS: Fifty infants with gestational age (GA) 23+0-27+6 weeks were prospectively studied. Infants with intraventricular haemorrhage ≦ Grade I and no disorders of transition (persistent pulmonary hypertension, hypotension, pulmonary haemorrhage) belonged to the 'Uncomplicated' group and those with intraventricular haemorrhage > Grade I and/or disorders of transition, to the 'Complicated' group. RESULTS: Thirty-six infants without opioid exposure were included: 23 with GA 25.9 (23.1-27.7) weeks in the 'Uncomplicated' group and 13 with GA 24.6 (23.3-27.4) weeks in the 'Complicated' group. Cyclicity was more common in the 'Uncomplicated' group [20/23 (87%) vs. 7/13 (54%), p = 0.045] with more cycles/hour [0.2 (0-0.78) vs. 0.03 (0-67), p = 0.036]. Age at appearance of cyclicity was similar [20 (7.7-40.7) hours in 'Uncomplicated' vs. 23.7 (5.4-60) hours in 'Complicated' group, p = 0.8]. In the 'Uncomplicated' group, maturation scores (p = 0.02), high (p < 0.0001) and low (p = 0.03) base voltage increased over time. CONCLUSION: During the first 72 h, clinically stable ELGANs without neurological injury demonstrate increased cyclicity compared to those with a complicated course. Maturation score, high and low base voltage increase over time.

A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome (ELEKTRA).

OBJECTIVE: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452). METHODS: ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs). RESULTS: ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported. SIGNIFICANCE: Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.

A practical approach toward interpretation of amplitude integrated electroencephalography in preterm infants.

The developing preterm brain is vulnerable to injury, especially during periods of clinical instability; therefore, monitoring the brain may provide important information on brain health. Over the last 2 decades, a growing body of literature has been reported on preterm amplitude integrated electroencephalography (aEEG) with regards to normative data and associations with adverse outcomes. Despite this, the use of aEEG for preterm infants remains mostly a research tool with limited clinical applicability. In this article, we review the literature on normal and abnormal aEEG patterns in preterm infants and propose a stepwise clinical algorithm for aEEG assessment at the bedside that takes into account assessment of maturation and identification of pathological patterns. CONCLUSION: This algorithm may be used by clinicians at the bedside for interpretation to integrate it in clinical practice for neurological surveillance of preterm infants. WHAT IS KNOWN: • Studies have reported normative data on aEEG in preterm infants for different gestational ages. • Burst suppression pattern and absent sleep-wake cycling have been described to be associated with brain pathology and adverse outcomes in preterm infants. WHAT IS NEW: • We have synthesized aEEG characteristics in preterm infants across the spectrum of prematurity reported in the literature. • We present a stepwise approach for clinically applicable interpretation of aEEG in preterm infants.

Educational initiatives for electroencephalography in the critical care setting: a systematic review and meta-analysis.

PURPOSE: We systematically reviewed existing critical care electroencephalography (EEG) educational programs for non-neurologists, with the primary goal of reporting the content covered, methods of instruction, overall duration, and participant experience. Our secondary goals were to assess the impact of EEG programs on participants' core knowledge, and the agreement between non-experts and experts for seizure identification. SOURCE: Major databases were searched from inception to 30 August 2020. Randomized controlled trials, cohort studies, and descriptive studies were all considered if they reported an EEG curriculum for non-neurologists in a critical care setting. Data were presented thematically for the qualitative primary outcome and a meta-analysis using a random effects model was performed for the quantitative secondary outcomes. PRINCIPAL FINDINGS: Twenty-nine studies were included after reviewing 7,486 citations. Twenty-two studies were single centre, 17 were from North America, and 16 were published after 2016. Most EEG studies were targeted to critical care nurses (17 studies), focused on processed forms of EEG with amplitude-integrated EEG being the most common (15 studies), and were shorter than one day in duration (24 studies). In pre-post studies, EEG programs significantly improved participants' knowledge of tested material (standardized mean change, 1.79; 95% confidence interval [CI], 0.86 to 2.73). Agreement for seizure identification between non-experts and experts was moderate (Cohen's kappa = 0.44; 95% CI, 0.27 to 0.60). CONCLUSIONS: It is feasible to teach basic EEG to participants in critical care settings from different clinical backgrounds, including physicians and nurses. Brief training programs can enable bedside providers to recognize high-yield abnormalities such as non-convulsive seizures.

RéSUMé: OBJECTIF: Nous avons réalisé une revue systématique des programmes éducatifs d'électroencéphalographie (EEG) en soins intensifs s'adressant aux non-neurologues, avec pour but principal de rapporter le contenu couvert, les méthodes d'enseignement, la durée globale et l'expérience des participants. Nos objectifs secondaires étaient d'évaluer l'impact des programmes d'EEG sur les connaissances de base des participants, et l'accord entre non-experts et experts pour l'identification des convulsions. MéTHODE: Les principales bases de données ont été consultées depuis leur création jusqu'au 30 août 2020. Les études randomisées contrôlées, les études de cohorte et les études descriptives ont toutes été prises en compte si elles décrivaient un programme de formation en EEG pour les non-neurologues en milieu de soins intensifs. Les données ont été présentées thématiquement en ce qui touchait notre critère d'évaluation principal qualitatif, et une méta-analyse utilisant un modèle à effets aléatoires a été exécutée pour les critères secondaires quantitatifs. CONSTATATIONS PRINCIPALES: Vingt-neuf études ont été incluses après avoir examiné 7486 citations. Vingt-deux études étaient monocentriques, 17 provenaient d'Amérique du Nord et 16 avaient été publiées après 2016. La plupart des études sur l'EEG visaient le personnel infirmier en soins intensifs (17 études); elles se concentraient sur les formes analysées d'EEG; l'EEG à amplitude intégrée était le thème le plus fréquemment abordé (15 études), et la plupart duraient moins d'un jour (24 études). Dans les études avant-après, les programmes d'EEG ont considérablement amélioré les connaissances des participants du matériel testé (changement moyen normalisé, 1,79; intervalle de confiance [IC] à 95 %, 0,86 à 2,73). L'accord en matière d''identification des convulsions entre non-experts et experts était modéré (kappa de Cohen = 0,44; IC 95 %, 0,27 à 0,60). CONCLUSION: Il est possible d'enseigner l'EEG de base dans des milieux de soins intensifs à des participants provenant de différents milieux cliniques, y compris les médecins et le personnel infirmier. De brefs programmes de formation peuvent permettre aux fournisseurs de soins au chevet de reconnaître les anomalies à haut impact comme par exemple des crises épileptiques non convulsives.

Emergency management of the paediatric patient with convulsive status epilepticus.

This guideline addresses the emergency management of convulsive status epilepticus (CSE) in children and infants older than 1 month of age. It replaces a previous position statement from 2011, and includes a new treatment algorithm and table of recommended medications based on new evidence and reflecting the evolution of clinical practice over the past several years. This statement emphasizes the importance of timely pharmacological management of CSE, and includes some guidance for diagnostic approach and supportive care.

Seizure Detection Algorithms in Critically Ill Children: A Comparative Evaluation.

OBJECTIVES: To evaluate the performance of commercially available seizure detection algorithms in critically ill children. DESIGN: Diagnostic accuracy comparison between commercially available seizure detection algorithms referenced to electroencephalography experts using quantitative electroencephalography trends. SETTING: Multispecialty quaternary children's hospital in Canada. SUBJECTS: Critically ill children undergoing electroencephalography monitoring. INTERVENTIONS: Continuous raw electroencephalography recordings (n = 19) were analyzed by a neurophysiologist to identify seizures. Those recordings were then converted to quantitative electroencephalography displays (amplitude-integrated electroencephalography and color density spectral array) and evaluated by six independent electroencephalography experts to determine the sensitivity and specificity of the amplitude-integrated electroencephalography and color density spectral array displays for seizure identification in comparison to expert interpretation of raw electroencephalography data. Those evaluations were then compared with four commercial seizure detection algorithms: ICTA-S (Stellate Harmonie Version 7; Natus Medical, San Carlos, CA), NB (Stellate Harmonie Version 7; Natus Medical), Persyst 11 (Persyst Development, Prescott, AZ), and Persyst 13 (Persyst Development) to determine sensitivity and specificity in comparison to amplitude-integrated electroencephalography and color density spectral array. MEASUREMENTS AND MAIN RESULTS: Of the 379 seizures identified on raw electroencephalography, ICTA-S detected 36.9%, NB detected 92.3%, Persyst 11 detected 75.9%, and Persyst 13 detected 74.4%, whereas electroencephalography experts identified 76.5% of seizures using color density spectral array and 73.7% using amplitude-integrated electroencephalography. Daily false-positive rates averaged across all recordings were 4.7 with ICTA-S, 126.3 with NB, 5.1 with Persyst 11, 15.5 with Persyst 13, 1.7 with color density spectral array, and 1.5 with amplitude-integrated electroencephalography. Both Persyst 11 and Persyst 13 had sensitivity comparable to that of electroencephalography experts using amplitude-integrated electroencephalography and color density spectral array. Although Persyst 13 displayed the highest sensitivity for seizure count and seizure burden detected, Persyst 11 exhibited the best trade-off between sensitivity and false-positive rate among all seizure detection algorithms. CONCLUSIONS: Some commercially available seizure detection algorithms demonstrate performance for seizure detection that is comparable to that of electroencephalography experts using quantitative electroencephalography displays. These algorithms may have utility as early warning systems that prompt review of quantitative electroencephalography or raw electroencephalography tracings, potentially leading to more timely seizure identification in critically ill patients.

Implementation of amplitude-integrated electroencephalography in tertiary Canadian Neonatal Intensive Care Units-a longitudinal study.

AIM: To investigate the implementation of amplitude-integrated electroencephalography (aEEG) as bedside monitoring tool of cerebral function in tertiary Canadian Neonatal Intensive Care Units (NICU) over the past decade. METHODS: Longitudinal study consisting of online surveys of neonatologists on the use of aEEG in 2009 and 2018. RESULTS: The response rate to the survey was 72 of 149 (49%) in 2009 and 18 of 30 (60%) in 2018, respectively. aEEG has been implemented in almost all (2009: 62.5%; 2018: 94%) tertiary Canadian NICUs. Two-thirds (2009: 67%; 2018: 71%) of the respondents considered information from aEEG tracing helpful in clinical practice. The main indications for aEEG were term neonates with hypoxic ischemic encephalopathy (2009 and 2018: 76%) and seizure detection/surveillance (2009: 88%; 2018: 94%). Teaching on aEEG has been implemented for neonatologists (2018: 100%) and health care providers (2018: 50%) in tertiary Canadian NICUs but there is a lack of standardization of training. Use of aEEG in preterm neonates (2009: 37%, 2018: 33%) and application of aEEG in research (18% reported occasional use) is less common. CONCLUSION: aEEG is well established in tertiary Canadian NICUs to monitor cerebral function and detect seizure activity. There is a need to develop formalized aEEG training programs and methods to assess competence. Further implementation of aEEG in preterm neonates and research is desirable.

Hyperglycemia and Glucose Variability Are Associated with Worse Brain Function and Seizures in Neonatal Encephalopathy: A Prospective Cohort Study.

OBJECTIVES: To investigate how glucose abnormalities correlate with brain function on amplitude-integrated electroencephalography (aEEG) in infants with neonatal encephalopathy. STUDY DESIGN: Neonates born at full term with encephalopathy were enrolled within 6 hours of birth in a prospective cohort study at a pediatric academic referral hospital. Continuous interstitial glucose monitors and aEEG were placed soon after birth and continued for 3 days. Episodes of hypoglycemia (≤50 mg/dL; ≤2.8 mmol/L) and hyperglycemia (>144 mg/dL; >8.0 mmol/L) were identified. aEEG was classified in 6-hour epochs for 3 domains (background, sleep-wake cycling, electrographic seizures). Generalized estimating equations assessed the relationship of hypo- or hyperglycemia with aEEG findings, adjusting for clinical markers of hypoxia-ischemia (Apgar scores, umbilical artery pH, and base deficit). RESULTS: Forty-five infants (gestational age 39.5 ± 1.4 weeks) were included (24 males). During aEEG monitoring, 16 episodes of hypoglycemia were detected (9 infants, median duration 77.5, maximum 220 minutes) and 18 episodes of hyperglycemia (13 infants, median duration 237.5, maximum 3125 minutes). Epochs of hypoglycemia were not associated with aEEG changes. Compared with epochs of normoglycemia, epochs of hyperglycemia were associated with worse aEEG background scores (B 1.120, 95% CI 0.501-1.738, P < .001), less sleep-wake cycling (B 0.587, 95% CI 0.417-0.757, P < .001) and more electrographic seizures (B 0.433, 95% CI 0.185-0.681, P = .001), after adjusting for hypoxia-ischemia severity. CONCLUSIONS: In neonates with encephalopathy, epochs of hyperglycemia were temporally associated with worse global brain function and seizures, even after we adjusted for hypoxia-ischemia severity. Whether hyperglycemia causes neuronal injury or is simply a marker of severe brain injury requires further study.

Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures.

OBJECTIVE: The optimal treatment of nonconvulsive seizures in critically ill patients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. METHODS: The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. RESULTS: Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). INTERPRETATION: LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.

Recommendations for the design of therapeutic trials for neonatal seizures.

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

Electrographic seizure burden and outcomes following pediatric status epilepticus.

Pediatric status epilepticus carries a substantial risk for morbidity and mortality, but the relationship between seizure burden, treatment, and outcome remains incompletely understood. This review summarizes the evidence linking seizure burden and outcomes among critically ill children in the intensive care unit (ICU), a population in whom accurate quantification of seizure burden is possible using continuous electroencephalographic monitoring. Several high-quality observational studies among critically ill children have reported an association between higher seizure burden and worse outcome, even after adjusting for potential confounders such as age, etiology, and illness severity. Although these studies support the hypothesis that seizures contribute to brain injury and worsen outcome, a causal link between seizures and outcome remains to be proven. The relationship between seizures and outcome is likely complex, and dependent on factors such as etiology, preexisting neurological disability, medication exposure, and possibly individual genetic factors. Studies attempting to define this complex relationship will need to measure and account for these factors in their analyses. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Continuous Electroencephalography Monitoring for Critically Ill Neonates: A Canadian Perspective.

BACKGROUND: Continuous EEG monitoring, in the form of amplitude-integrated (aEEG) or conventional EEG (cEEG), is used in the neonatal intensive care unit (NICU) to detect subclinical central nervous system pathologies, inform management, and prognosticate neurodevelopmental outcomes. To learn more about provider attitudes and current practices in Canada, we evaluated neurologist and neonatologist opinions regarding NICU EEG monitoring. METHODS: A 15-item electronic questionnaire was distributed to 114 pediatric neurologists and 176 neonatologists working across 25 sites. RESULTS: The survey was completed by 87 of 290 physicians. Continuous EEG monitoring is utilized by 97% of pediatric neurologists and 92% of neonatologists. Neurologists and neonatologists differ in their EEG monitoring preferences. For seizure detection and diagnosis of encephalopathy, significantly more neonatologists favor aEEG alone or in combination with cEEG, whereas most neurologists prefer cEEG (p = 0.047, 0.001). There is a significant difference in the perceived gaps in monitoring patients with cEEG between neonatologists (13% would monitor more) and neurologists (41% would monitor more) (p = 0.007). Half of all respondents (53%) reported that they would be interested in attending an education session on neonatal EEG monitoring. CONCLUSIONS: Canadian neurologists and neonatologists do not agree on the best monitoring approach for critically ill neonates. Furthermore, neonatologists perceive a smaller cEEG monitoring gap as compared with neurologists. However, many participants from both specialties would like to increase long-term EEG monitoring in the NICU setting. Facilitating access to EEG monitoring and enhancing education may help to address these needs.

La surveillance continue par électroencéphalographie dans le cas de nouveau-nés gravement malades : une perspective canadienne. Contexte: La surveillance continue par électroencéphalographie (EEG), que ce soit à amplitude intégrée (EEGai) ou conventionnelle (EEGc), est utilisée dans les unités de soins intensifs néonatals (USIN) afin de détecter des pathologies sous-cliniques du système nerveux central, de fournir des indications en matière de prise en charge et d'établir des pronostics quant à l'évolution neuro-développementale de ces nouveau-nés. Afin d'en savoir plus au sujet des attitudes des prestataires de soins et des pratiques actuelles dans ce domaine au Canada, nous avons cherché à évaluer les points de vue de neurologues et de néonatologistes en ce qui regarde la surveillance continue par EEG dans les USIN. Méthodes: Un questionnaire en ligne abordant 15 aspects a été envoyé à 114 neuro-pédiatres et à 176 néonatologistes travaillant dans 25 établissements différents. Résultats: Ce sondage a été complété par 87 médecins sur 290. Il en ressort que la surveillance continue par EEG est utilisée par 97 % des neuro-pédiatres et par 92 % des néonatologistes. Cela dit, les neuro-pédiatres et les néonatologistes n'ont pas les mêmes préférences quant à l'utilisation de cet examen. Quand il s'agit de détecter des crises convulsives et de diagnostiquer des cas d'encéphalopathie, on remarque qu'un nombre nettement plus élevé de néonatologistes favorisent la seule EEGai ou la combinent avec la EEGc tandis que davantage de neurologues ont dit préférer la seule EEGc (p = 0,047 ; p = 0,001). Qui plus est, on peut dénoter une différence notable entre les néonatologistes et les neurologues en ce qui a trait aux écarts perçus de surveillance des patients au moyen de la EEGc, 13 % des premiers assurant une surveillance supérieure alors qu'ils sont 41 % parmi les deuxièmes à assurer une surveillance supérieure (p = 0,007). Enfin, plus de la moitié des répondants (53 %) ont affirmé être intéressés à assister à des séances de formation portant sur la surveillance continue par EEG destinée aux nouveau-nés. Conclusions: Les neurologues et les néonatologistes canadiens divergent quant à la meilleure approche de surveillance dans le cas de nouveau-nés gravement malades. En outre, les néonatologistes ont tendance à percevoir un écart de surveillance moins important si on les compare aux neurologues. Néanmoins, nombreux sont les répondants formés dans ces deux spécialités qui souhaiteraient augmenter à long terme la surveillance par EEG dans les USIN. Le fait de faciliter l'accès à ces examens et d'améliorer l'enseignement pourrait ainsi permettre de répondre aux besoins.

Seizure Identification by Critical Care Providers Using Quantitative Electroencephalography.

OBJECTIVES: To compare the performance of critical care providers with that of electroencephalography experts in identifying seizures using quantitative electroencephalography display tools. DESIGN: Diagnostic accuracy comparison among healthcare provider groups. SETTING: Multispecialty quaternary children's hospital in Canada. SUBJECTS: ICU fellows, ICU nurses, neurophysiologists, and electroencephalography technologists. INTERVENTION: Two-hour standardized one-on-one training, followed by a supervised individual review of 27 continuous electroencephalography recordings with the task of identifying individual seizures on eight-channel amplitude-integrated electroencephalography and color density spectral array displays. MEASUREMENTS AND MAIN RESULTS: Each participant reviewed 27 continuous electroencephalograms comprising 487 hours of recording containing a total of 553 seizures. Performance for seizure identification was compared among groups using a nested model analysis with adjustment for interparticipant variability within groups and collinearity among recordings. Using amplitude-integrated electroencephalography, sensitivity for seizure identification was comparable among ICU fellows (83.8%), ICU nurses (73.1%), and neurophysiologists (81.5%) but lower among electroencephalographic technologists (66.7%) (p = 0.003). Using color density spectral array, sensitivity was comparable among ICU fellows (82.4%), ICU nurses (88.2%), neurophysiologists (83.3%), and electroencephalographic technologists (73.3%) (p = 0.09). Daily false-positive rates were also comparable among ICU fellows (2.8 for amplitude-integrated electroencephalography, 7.7 for color density spectral array), ICU nurses (4.2, 7.1), neurophysiologists (1.2, 1.5), and electroencephalographic technologists (0, 0) (p = 0.41 for amplitude-integrated electroencephalography; p = 0.13 for color density spectral array). However, performance varied greatly across individual electroencephalogram recordings. Professional background generally played a greater role in determining performance than individual skill or electroencephalogram recording characteristics. CONCLUSIONS: Following standardized training, critical care providers and electroencephalography experts displayed similar performance for identifying individual seizures using both amplitude-integrated electroencephalography and color density spectral array displays. Although these quantitative electroencephalographic trends show promise as a tool for bedside seizure screening by critical care providers, these findings require confirmation in a real-world ICU environment and in daily clinical use.

Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.

We convened an international group of experts to standardize definitions of New-Onset Refractory Status Epilepticus (NORSE), Febrile Infection-Related Epilepsy Syndrome (FIRES), and related conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in-person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion-Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super-refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.

Outcomes following electrographic seizures and electrographic status epilepticus in the pediatric and neonatal ICUs.

PURPOSE OF REVIEW: Increasing recognition of electrographic seizures and electrographic status epilepticus in critically ill neonates and children has highlighted the importance of identifying their potential contributions to neurological outcomes to guide optimal management. RECENT FINDINGS: Recent studies in children and neonates have found an independent association between increasing seizure burden and worse short-term and long-term outcomes, even after adjusting for other important contributors to outcome such as seizure cause and illness severity. The risk of worse neurological outcome has been shown to increase above a seizure burden threshold of 12-13 min/h, which is considerably lower than the conventional definition of status epilepticus of 30 min/h. Randomized controlled trials in neonates have demonstrated that electroencephalography-targeted therapy can successfully reduce seizure burden, but due to their small size these trials have not been able to demonstrate that more aggressive electroencephalography-targeted treatment of both subclinical and clinical seizures results in improved outcome. SUMMARY: Despite mounting evidence for an independent association between increasing seizure burden and worse outcome, further study is needed to determine whether early seizure identification and aggressive antiseizure treatment can improve neurodevelopmental outcomes.