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.

Multimodal neuromonitoring in the pediatric intensive care unit.

Neuromonitoring is used to assess the central nervous system in the intensive care unit. The purpose of neuromonitoring is to detect neurologic deterioration and intervene to prevent irreversible nervous system dysfunction. Neuromonitoring starts with the standard neurologic examination, which may lag behind the pathophysiologic changes. Additional modalities including continuous electroencephalography (CEEG), multiple physiologic parameters, and structural neuroimaging may detect changes earlier. Multimodal neuromonitoring now refers to an integrated combination and display of non-invasive and invasive modalities, permitting tailored treatment for the individual patient. This chapter reviews the non-invasive and invasive modalities used in pediatric neurocritical care.

Changes in autonomic function and cerebral and somatic oxygenation with arterial flow pulsatility for children requiring veno-arterial extracorporeal membrane oxygenation.

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) carries variability in arterial flow pulsatility (AFP). Research question: What changes in cerebral and somatic oxygenation, hemodynamics, and autonomic function are associated with AFP during VA-ECMO? Methods: This is a prospective study of children on VA-ECMO undergoing neuromonitoring. AFP was quantified by arterial blood pressure pulse amplitude and subcategorized: no pulsatility (<1 mmHg), minimal pulsatility (1 to <5 mmHg), moderate pulsatility (5 to <15 mmHg) and high pulsatility (≥15 mmHg). CVPR was assessed using the cerebral oximetry index (COx). Cerebral and somatic oxygenation was assessed using cerebral regional oximetry (rSO2) or peripheral oxygen saturation (SpO2). Autonomic function was assessed using baroreflex sensitivity (BRs), low-frequency high-frequency (LF/HF) ratio and standard deviation of heart rate R-R intervals (HRsd). Differences were assessed across AFP categories using linear mixed effects models with Tukey pairwise comparisons. Univariate logistic regression was used to explore risk of AFP with brain injuries. Results: Among fifty-three children, comparisons of moderate to high pulsatility were associated with reductions in rSO2 (p < 0.001), SpO 2 (p = 0.005), LF/HF ratio (p = 0.028) and an increase in HRsd (p < 0.001). Reductions in BRs were observed across comparisons of none to minimal (P < 0.001) and minimal to moderate pulsatility (p = 0.004). Comparisons of no to low pulsatility were associated with reductions in BRs (p < 0.001) and ABP (p < 0.001) with increases in SpO2 (p < 0.001) and HR (p < 0.001). Arterial ischemic stroke was associated with higher pulsatility (p = 0.0384). Conclusion: During VA-ECMO support, changes toward high AFP are associated with autonomic dysregulation and compromised cerebral and somatic tissue oxygenation.

Reversal of Cerebral Arteriopathy Post-Hematopoietic Stem Cell Transplant for Sickle Cell Disease.

Sickle cell disease (SCD) is a chronic hematologic disorder which causes progressive cerebral arteriopathy beginning in childhood. As a result, arterial ischemic stroke is a major cause of morbidity and mortality in SCD, and SCD is a leading cause of childhood stroke worldwide. Allogenic hematopoietic stem cell transplant (HSCT) may be curative for individuals with SCD. Long-term outcomes and effects are currently being studied. In this report, we describe a child with SCD who presented with arterial ischemic stroke at 6 years of age and was found to have a severe form of cerebral large vessel arteriopathy by catheter-directed angiography. The patient initially underwent revascularization surgery by indirect superficial temporal artery to middle cerebral artery bypass, and 1 year later, he underwent curative HSCT. Approximately 3 years after HSCT, repeat catheter-directed angiography revealed a striking reversal of cerebral large vessel arteriopathy. This article reveals a previously unrecognized and potentially beneficial effect of HSCT that may ameliorate cerebral large vessel arteriopathy and improve cerebrovascular health for children with SCD.

Neurophysiologic Features Reflecting Brain Injury During Pediatric ECMO Support.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides lifesaving support to critically ill patients who experience refractory cardiopulmonary failure but carries a high risk for acute brain injury. We aimed to identify characteristics reflecting acute brain injury in children requiring ECMO support. METHODS: This is a prospective observational study from 2019 to 2022 of pediatric ECMO patients undergoing neuromonitoring, including continuous electroencephalography, cerebral oximetry, and transcranial Doppler ultrasound (TCD). The primary outcome was acute brain injury. Clinical and neuromonitoring characteristics were collected. Multivariate logistic regression was implemented to model odds ratios (ORs) and identify the combined characteristics that best discriminate risk of acute brain injury using the area under the receiver operating characteristic curve. RESULTS: Seventy-five pediatric patients requiring ECMO support were enrolled in this study, and 62 underwent neuroimaging or autopsy evaluations. Of these 62 patients, 19 experienced acute brain injury (30.6%), including seven (36.8%) with arterial ischemic stroke, four (21.1%) with hemorrhagic stroke, seven with hypoxic-ischemic brain injury (36.8%), and one (5.3%) with both arterial ischemic stroke and hypoxic-ischemic brain injury. A univariate analysis demonstrated acute brain injury to be associated with maximum hourly seizure burden (p = 0.021), electroencephalographic suppression percentage (p = 0.022), increased interhemispheric differences in electroencephalographic total power (p = 0.023) and amplitude (p = 0.017), and increased differences in TCD Thrombolysis in Brain Ischemia (TIBI) scores between bilateral middle cerebral arteries (p = 0.023). Best subset model selection identified increased seizure burden (OR = 2.07, partial R2 = 0.48, p = 0.013), increased quantitative electroencephalographic interhemispheric amplitude differences (OR = 2.41, partial R2 = 0.48, p = 0.013), and increased interhemispheric TCD TIBI score differences (OR = 4.66, partial R2 = 0.49, p = 0.006) to be independently associated with acute brain injury (area under the receiver operating characteristic curve = 0.92). CONCLUSIONS: Increased seizure burden and increased interhemispheric differences in both quantitative electroencephalographic amplitude and TCD MCA TIBI scores are independently associated with acute brain injury in children undergoing ECMO support.

Quantitative Electroencephalographic Changes Associated With Brain Tissue Hypoxia After Pediatric Traumatic Brain Injury: A Retrospective Exploratory Analysis.

PURPOSE: Brain tissue hypoxia is associated with poor outcomes after pediatric traumatic brain injury. Although invasive brain oxygenation (PbtO 2 ) monitoring is available, noninvasive methods assessing correlates to brain tissue hypoxia are needed. We investigated EEG characteristics associated with brain tissue hypoxia. METHODS: We performed a retrospective analysis of 19 pediatric traumatic brain injury patients undergoing multimodality neuromonitoring that included PbtO 2 and quantitative electroencephalography(QEEG). Quantitative electroencephalography characteristics were analyzed over electrodes adjacent to PbtO 2 monitoring and over the entire scalp, and included power in alpha and beta frequencies and the alpha-delta power ratio. To investigate relationships of PbtO 2 to quantitative electroencephalography features using time series data, we fit linear mixed effects models with a random intercept for each subject and one fixed effect, and an auto-regressive order of 1 to model between-subject variation and correlation for within-subject observations. Least squares (LS) means were used to investigate for fixed effects of quantitative electroencephalography features to changes in PbtO 2 across thresholds of 10, 15, 20, and 25 mm Hg. RESULTS: Within the region of PbtO 2 monitoring, changes in PbtO 2 < 10 mm Hg were associated with reductions of alpha-delta power ratio (LS mean difference -0.01, 95% confidence interval (CI) [-0.02, -0.00], p = 0.0362). Changes in PbtO 2 < 25 mm Hg were associated with increases in alpha power (LS mean difference 0.04, 95% CI [0.01, 0.07], p = 0.0222). CONCLUSIONS: Alpha-delta power ratio changes are observed across a PbtO 2 threshold of 10 mm Hg within regions of PbtO 2 monitoring, which may reflect an EEG signature of brain tissue hypoxia after pediatric traumatic brain injury.

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.

Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

Common Data Elements for Disorders of Consciousness: Recommendations from the Electrophysiology Working Group.

BACKGROUND: Electroencephalography (EEG) has long been recognized as an important tool in the investigation of disorders of consciousness (DoC). From inspection of the raw EEG to the implementation of quantitative EEG, and more recently in the use of perturbed EEG, it is paramount to providing accurate diagnostic and prognostic information in the care of patients with DoC. However, a nomenclature for variables that establishes a convention for naming, defining, and structuring data for clinical research variables currently is lacking. As such, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups composed of experts in the field to construct common data elements (CDEs) to provide recommendations for DoC, with the main goal of facilitating data collection and standardization of reporting. This article summarizes the recommendations of the electrophysiology DoC working group. METHODS: After assessing previously published pertinent CDEs, we developed new CDEs and categorized them into "disease core," "basic," "supplemental," and "exploratory." Key EEG design elements, defined as concepts that pertained to a methodological parameter relevant to the acquisition, processing, or analysis of data, were also included but were not classified as CDEs. RESULTS: After identifying existing pertinent CDEs and developing novel CDEs for electrophysiology in DoC, variables were organized into a framework based on the two primary categories of resting state EEG and perturbed EEG. Using this categorical framework, two case report forms were generated by the working group. CONCLUSIONS: Adherence to the recommendations outlined by the electrophysiology working group in the resting state EEG and perturbed EEG case report forms will facilitate data collection and sharing in DoC research on an international level. In turn, this will allow for more informed and reliable comparison of results across studies, facilitating further advancement in the realm of DoC research.

Practice Standards for the Use of Multimodality Neuromonitoring: A Delphi Consensus Process.

OBJECTIVES: To address areas in which there is no consensus for the technologies, effort, and training necessary to integrate and interpret information from multimodality neuromonitoring (MNM). DESIGN: A three-round Delphi consensus process. SETTING: Electronic surveys and virtual meeting. SUBJECTS: Participants with broad MNM expertise from adult and pediatric intensive care backgrounds. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two rounds of surveys were completed followed by a virtual meeting to resolve areas without consensus and a final survey to conclude the Delphi process. With 35 participants consensus was achieved on 49% statements concerning MNM. Neurologic impairment and the potential for MNM to guide management were important clinical considerations. Experts reached consensus for the use of MNM-both invasive and noninvasive-for patients in coma with traumatic brain injury, aneurysmal subarachnoid hemorrhage, and intracranial hemorrhage. There was consensus that effort to integrate and interpret MNM requires time independent of daily clinical duties, along with specific skills and expertise. Consensus was reached that training and educational platforms are necessary to develop this expertise and to provide clinical correlation. CONCLUSIONS: We provide expert consensus in the clinical considerations, minimum necessary technologies, implementation, and training/education to provide practice standards for the use of MNM to individualize clinical care.

Approaches to neuroprotection in pediatric neurocritical care.

Acute neurologic injuries represent a common cause of morbidity and mortality in children presenting to the pediatric intensive care unit. After primary neurologic insults, there may be cerebral brain tissue that remains at risk of secondary insults, which can lead to worsening neurologic injury and unfavorable outcomes. A fundamental goal of pediatric neurocritical care is to mitigate the impact of secondary neurologic injury and improve neurologic outcomes for critically ill children. This review describes the physiologic framework by which strategies in pediatric neurocritical care are designed to reduce the impact of secondary brain injury and improve functional outcomes. Here, we present current and emerging strategies for optimizing neuroprotective strategies in critically ill children.

Early Clinical Variables Associated With Refractory Convulsive Status Epilepticus in Children.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory convulsive status epilepticus (RSE) in children. METHODS: An observational case-control study was conducted comparing pediatric patients (1 month-21 years) with convulsive SE whose seizures stopped after benzodiazepine (BZD) and a single second-line antiseizure medication (ASM) (responsive established status epilepticus [rESE]) with patients requiring more than a BZD and a single second-line ASM to stop their seizures (RSE). These subpopulations were obtained from the pediatric Status Epilepticus Research Group study cohort. We explored clinical variables that could be acquired early after presentation to emergency medical services with univariate analysis of the raw data. Variables with p < 0.1 were retained for univariable and multivariable regression analyses. Multivariable logistic regression models were fit to age-matched and sex-matched data to obtain variables associated with RSE. RESULTS: We compared data from a total of 595 episodes of pediatric SE. Univariate analysis demonstrated no differences in time to the first BZD (RSE 16 minutes [IQR 5-45]; rESE 18 minutes [IQR 6-44], p = 0.068). Time to second-line ASM was shorter in patients with RSE (RSE 65 minutes; rESE 70 minutes; p = 0.021). Both univariable and multivariable regression analyses revealed a family history of seizures (OR 0.37; 95% CI 0.20-0.70, p = 0.0022) or a prescription for rectal diazepam (OR 0.21; 95% CI 0.078-0.53, p = 0.0012) was associated with decreased odds of RSE. DISCUSSION: Time to initial BZD or second-line ASM was not associated with progression to RSE in our cohort of patients with rESE. A family history of seizures and a prescription for rectal diazepam were associated with a decreased likelihood of progression to RSE. Early attainment of these variables may help care for pediatric rESE in a more patient-tailored manner. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patient and clinical factors may predict RSE in children with convulsive seizures.

A Survey of Pediatric Neurocritical Care Fellowship Training in North America.

BACKGROUND: Pediatric neurocritical care (PNCC) has emerged as a field to care for children at the intersection of critical illness and neurological dysfunction. PNCC fellowship programs evolved over the past decade to train physicians to fill this clinical need. We aimed to characterize PNCC fellowship training infrastructure and curriculum in the United States and Canada. METHODS: Web-based survey of PNCC fellowship program leaders during November 2019 to January 2020. RESULTS: There were 14 self-identified PNCC fellowship programs. The programs were supported by Child Neurology and/or Pediatric Critical Care Medicine divisions at tertiary/quaternary care institutions. Most programs accepted trainees who were board-eligible or board-certified in child neurology or pediatric critical care medicine. Clinical training consisted mostly of rotations providing PNCC consultation (n = 13) or as a provider on the pediatric intensive care unit-based neurointensive care team (n = 2). PNCC-specific didactics were delivered at most institutions (n = 13). All institutions provided training in electroencephalography use in the intensive care unit and declaration of death by neurological criteria (n = 14). Scholarly activity was supported by most programs, including protected time for research (n = 10). CONCLUSIONS: We characterized PNCC fellowship training in the United States and Canada, which in this continuously evolving field, lays the foundation for exploring standardization of training going forward.

Development of Expert-Level Classification of Seizures and Rhythmic and Periodic Patterns During EEG Interpretation.

BACKGROUND AND OBJECTIVES: Seizures (SZs) and other SZ-like patterns of brain activity can harm the brain and contribute to in-hospital death, particularly when prolonged. However, experts qualified to interpret EEG data are scarce. Prior attempts to automate this task have been limited by small or inadequately labeled samples and have not convincingly demonstrated generalizable expert-level performance. There exists a critical unmet need for an automated method to classify SZs and other SZ-like events with expert-level reliability. This study was conducted to develop and validate a computer algorithm that matches the reliability and accuracy of experts in identifying SZs and SZ-like events, known as "ictal-interictal-injury continuum" (IIIC) patterns on EEG, including SZs, lateralized and generalized periodic discharges (LPD, GPD), and lateralized and generalized rhythmic delta activity (LRDA, GRDA), and in differentiating these patterns from non-IIIC patterns. METHODS: We used 6,095 scalp EEGs from 2,711 patients with and without IIIC events to train a deep neural network, SPaRCNet, to perform IIIC event classification. Independent training and test data sets were generated from 50,697 EEG segments, independently annotated by 20 fellowship-trained neurophysiologists. We assessed whether SPaRCNet performs at or above the sensitivity, specificity, precision, and calibration of fellowship-trained neurophysiologists for identifying IIIC events. Statistical performance was assessed by the calibration index and by the percentage of experts whose operating points were below the model's receiver operating characteristic curves (ROCs) and precision recall curves (PRCs) for the 6 pattern classes. RESULTS: SPaRCNet matches or exceeds most experts in classifying IIIC events based on both calibration and discrimination metrics. For SZ, LPD, GPD, LRDA, GRDA, and "other" classes, SPaRCNet exceeds the following percentages of 20 experts-ROC: 45%, 20%, 50%, 75%, 55%, and 40%; PRC: 50%, 35%, 50%, 90%, 70%, and 45%; and calibration: 95%, 100%, 95%, 100%, 100%, and 80%, respectively. DISCUSSION: SPaRCNet is the first algorithm to match expert performance in detecting SZs and other SZ-like events in a representative sample of EEGs. With further development, SPaRCNet may thus be a valuable tool for an expedited review of EEGs. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with epilepsy or critical illness undergoing EEG monitoring, SPaRCNet can differentiate (IIIC) patterns from non-IIIC events and expert neurophysiologists.

Cerebrovascular dynamics after pediatric traumatic brain injury.

Objective: We aimed to investigate model-based indices of cerebrovascular dynamics after pediatric traumatic brain injury (TBI) using transcranial Doppler ultrasound (TCD) integrated into multimodality neurologic monitoring (MMM). Methods: We performed a retrospective analysis of pediatric TBI patients undergoing TCD integrated into MMM. Classic TCD characteristics included pulsatility indices and systolic, diastolic and mean flow velocities of the bilateral middle cerebral arteries. Model-based indices of cerebrovascular dynamics included the mean velocity index (Mx), compliance of the cerebrovascular bed (Ca), compliance of the cerebrospinal space (Ci), arterial time constant (TAU), critical closing pressure (CrCP) and diastolic closing margin (DCM). Classic TCD characteristics and model-based indices of cerebrovascular dynamics were investigated in relation to functional outcomes and intracranial pressure (ICP) using generalized estimating equations with repeated measures. Functional outcomes were assessed using the Glasgow Outcome Scale-Extended Pediatrics score (GOSE-Peds) at 12 months, post-injury. Results: Seventy-two separate TCD studies were performed on twenty-five pediatric TBI patients. We identified that reduced Ci (estimate -5.986, p = 0.0309), increased CrCP (estimate 0.081, p < 0.0001) and reduced DCM (estimate -0.057, p = 0.0179) were associated with higher GOSE-Peds scores, suggestive of unfavorable outcome. We identified that increased CrCP (estimate 0.900, p < 0.001) and reduced DCM (estimate -0.549, p < 0.0001) were associated with increased ICP. Conclusion: In an exploratory analysis of pediatric TBI patients, increased CrCP and reduced DCM and Ci are associated with unfavorable outcomes, and increased CrCP and reduced DCM are associated with increased ICP. Prospective work with larger cohorts is needed to further validate the clinical utility of these features.

Interrater Reliability of Expert Electroencephalographers Identifying Seizures and Rhythmic and Periodic Patterns in EEGs.

BACKGROUND AND OBJECTIVES: The validity of brain monitoring using electroencephalography (EEG), particularly to guide care in patients with acute or critical illness, requires that experts can reliably identify seizures and other potentially harmful rhythmic and periodic brain activity, collectively referred to as "ictal-interictal-injury continuum" (IIIC). Previous interrater reliability (IRR) studies are limited by small samples and selection bias. This study was conducted to assess the reliability of experts in identifying IIIC. METHODS: This prospective analysis included 30 experts with subspecialty clinical neurophysiology training from 18 institutions. Experts independently scored varying numbers of ten-second EEG segments as "seizure (SZ)," "lateralized periodic discharges (LPDs)," "generalized periodic discharges (GPDs)," "lateralized rhythmic delta activity (LRDA)," "generalized rhythmic delta activity (GRDA)," or "other." EEGs were performed for clinical indications at Massachusetts General Hospital between 2006 and 2020. Primary outcome measures were pairwise IRR (average percent agreement [PA] between pairs of experts) and majority IRR (average PA with group consensus) for each class and beyond chance agreement (κ). Secondary outcomes were calibration of expert scoring to group consensus, and latent trait analysis to investigate contributions of bias and noise to scoring variability. RESULTS: Among 2,711 EEGs, 49% were from women, and the median (IQR) age was 55 (41) years. In total, experts scored 50,697 EEG segments; the median [range] number scored by each expert was 6,287.5 [1,002, 45,267]. Overall pairwise IRR was moderate (PA 52%, κ 42%), and majority IRR was substantial (PA 65%, κ 61%). Noise-bias analysis demonstrated that a single underlying receiver operating curve can account for most variation in experts' false-positive vs true-positive characteristics (median [range] of variance explained ([Formula: see text]): 95 [93, 98]%) and for most variation in experts' precision vs sensitivity characteristics ([Formula: see text]: 75 [59, 89]%). Thus, variation between experts is mostly attributable not to differences in expertise but rather to variation in decision thresholds. DISCUSSION: Our results provide precise estimates of expert reliability from a large and diverse sample and a parsimonious theory to explain the origin of disagreements between experts. The results also establish a standard for how well an automated IIIC classifier must perform to match experts. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an independent expert review reliably identifies ictal-interictal injury continuum patterns on EEG compared with expert consensus.

Early Electroencephalographic Features Predicting Cerebral Physiology and Functional Outcomes After Pediatric Traumatic Brain Injury.

BACKGROUND: We investigated whether early electroencephalographic features predicted intracranial pressure (ICP), cerebrovascular pressure reactivity, brain tissue oxygenation, and functional outcomes in patients with pediatric traumatic brain injury (TBI). METHODS: This was a retrospective analysis of a prospective data set of 63 patients with pediatric TBI. Electroencephalographic features were collected in the first 24 h of recording to predict values of ICP, pressure reactivity index (PRx), and brain tissue oxygenation (PbtO2) through the initial 7 days of critical care monitoring, in addition to Glasgow Outcome Scale Extended-Pediatric Revision (GOSE-Peds) scores at 12 months. Electroencephalographic features were averaged over all surface electrodes and included seizures, interictal epileptiform discharges, suppression percentage, complexity, the alpha/delta power ratio, and both absolute asymmetry indices and power in beta (13-20 Hz), alpha (8-13 Hz), theta (4-7 Hz) and delta (0-4 Hz) bands. Demographic data and injury severity scores, such as the Glasgow Coma Scale (GCS) and Pediatric Risk of Mortality III (PRISM III) scores, at presentation were also assessed. Univariate and multiple linear regression with guided stepwise variable selection was used to find combinations of risk factors that best explain variability in ICP, PRx, PbtO2, and GOSE-Peds values, and best fit models were applied to pediatric age strata. We hypothesized that suppression percentage and the alpha/delta power ratio in the first 24 h of recording predict ICP, PRx, PbtO2, and GOSE-Peds values. RESULTS: Best subset model selection identified that increased suppression percentage and PRISM III scores predicted increased ICP (R2 = 79%, Akaike information criterion [AIC] = 332.30, root mean square error [RMSE] = 6.62), with suppression percentages < 5% (slope = - 5687.0, p = 0.0001) and ≥ 45% (slope = 9825.9, p = 0.0000) being predictive of dose of intracranial hypertension. When accounting for age and GCS score, increased suppression percentage predicted increased PRx values, suggestive of inefficient cerebrovascular pressure reactivity (R2 = 53%, AIC = 3.93, RMSE = 0.23), with suppression percentages ≥ 5% (p = 0.0033) and ≥ 45% (p = 0.0027) being predictive of median PRx values ≥ 0.3. Lower GCS scores, the presence of seizures, and increased suppression percentages each were independently associated with higher GOSE-Peds scores (R2 = 52%, AIC = 194.04, RMSE = 1.58), suggestive of unfavorable outcomes, with suppression percentages ≥ 5% (p = 0.0005) and ≥ 45% (p = 0.0000) being predictive of GOSE-Peds scores ≥ 5. At the univariate level, no electroencephalographic or clinical feature was associated with differences in PbtO2 values. CONCLUSIONS: Increased electroencephalographic suppression percentage on the initial day of monitoring may identify patients with pediatric TBI at risk of increased ICP, inefficient cerebrovascular pressure reactivity, and unfavorable outcomes.

Neonatal Aneurysm Rupture in a Child with a De Novo Variant to ANKRD17.

Ankyrin repeat domain 17 (ANKRD17) is postulated to play a role in the integrity of blood vessels and has been reported to be associated with developmental delays, epilepsy, and growth restriction. Whereas ANKRD17-deficient mice have been demonstrated to experience catastrophic hemorrhages, vascular malformations have not been reported in human patients with pathogenic variants to ANKRD17. We report a term male neonate with a heterozygous de novo variant to ANKRD17 (ANKRD17; c6988 C > G, P.[P2330a]) who experienced subarachnoid hemorrhage from a ruptured aneurysm involving the left middle cerebral artery. He experienced acute symptomatic seizures and required clipping of his aneurysm at 35 days of life, later progressing to developing multifocal drug-resistant epilepsy. To our knowledge, this case represents the first report of a cerebrovascular malformation from a patient with ANKRD17. Further work is needed to investigate whether pathogenic variants to ANKRD17 can lead to cerebral aneurysms or other cerebrovascular malformations in children.

Electroencephalogram in the intensive care unit: a focused look at acute brain injury.

Over the past decades, electroencephalography (EEG) has become a widely applied and highly sophisticated brain monitoring tool in a variety of intensive care unit (ICU) settings. The most common indication for EEG monitoring currently is the management of refractory status epilepticus. In addition, a number of studies have associated frequent seizures, including nonconvulsive status epilepticus (NCSE), with worsening secondary brain injury and with worse outcomes. With the widespread utilization of EEG (spot and continuous EEG), rhythmic and periodic patterns that do not fulfill strict seizure criteria have been identified, epidemiologically quantified, and linked to pathophysiological events across a wide spectrum of critical and acute illnesses, including acute brain injury. Increasingly, EEG is not just qualitatively described, but also quantitatively analyzed together with other modalities to generate innovative measurements with possible clinical relevance. In this review, we discuss the current knowledge and emerging applications of EEG in the ICU, including seizure detection, ischemia monitoring, detection of cortical spreading depolarizations, assessment of consciousness and prognostication. We also review some technical aspects and challenges of using EEG in the ICU including the logistics of setting up ICU EEG monitoring in resource-limited settings.