A Comparison of Automatically Extracted Quantitative EEG Features for Seizure Risk Stratification in Neonatal Encephalopathy.

PURPOSE: Seizures occur in up to 40% of neonates with neonatal encephalopathy. Earlier identification of seizures leads to more successful seizure treatment, but is often delayed because of limited availability of continuous EEG monitoring. Clinical variables poorly stratify seizure risk, and EEG use to stratify seizure risk has previously been limited by need for manual review and artifact exclusion. The goal of this study is to compare the utility of automatically extracted quantitative EEG (qEEG) features for seizure risk stratification. METHODS: We conducted a retrospective analysis of neonates with moderate-to-severe neonatal encephalopathy who underwent therapeutic hypothermia at a single center. The first 24 hours of EEG underwent automated artifact removal and qEEG analysis, comparing qEEG features for seizure risk stratification. RESULTS: The study included 150 neonates and compared the 36 (23%) with seizures with those without. Absolute spectral power best stratified seizure risk with area under the curve ranging from 63% to 71%, followed by range EEG lower and upper margin, median and SD of the range EEG lower margin. No features were significantly more predictive in the hour before seizure onset. Clinical examination was not associated with seizure risk. CONCLUSIONS: Automatically extracted qEEG features were more predictive than clinical examination in stratifying neonatal seizure risk during therapeutic hypothermia. qEEG represents a potential practical bedside tool to individualize intensity and duration of EEG monitoring and decrease time to seizure recognition. Future work is needed to refine and combine qEEG features to improve risk stratification.

Macroperiodic Oscillations: A Potential Novel Biomarker of Outcome in Neonatal Encephalopathy.

PURPOSE: Neonatal encephalopathy (NE) is a common cause of neurodevelopmental morbidity. Tools to accurately predict outcomes after therapeutic hypothermia remain limited. We evaluated a novel EEG biomarker, macroperiodic oscillations (MOs), to predict neurodevelopmental outcomes. METHODS: We conducted a secondary analysis of a randomized controlled trial of neonates with moderate-to-severe NE who underwent standardized clinical examination, magnetic resonance (MR) scoring, video EEG, and neurodevelopmental assessment with Bayley III evaluation at 18 to 24 months. A non-NE cohort of neonates was also assessed for the presence of MOs. The relationship between clinical examination, MR score, MOs, and neurodevelopmental assessment was analyzed. RESULTS: The study included 37 neonates with 24 of whom survived and underwent neurodevelopmental assessment (70%). The strength of MOs correlated with severity of clinical encephalopathy. MO strength and spread significantly correlated with Bayley III cognitive percentile (P = 0.017 and 0.046). MO strength outperformed MR score in predicting a combined adverse outcome of death or disability (P = 0.019, sensitivity 100%, specificity 77% vs. P = 0.079, sensitivity 100%, specificity 59%). CONCLUSIONS: MOs are an EEG-derived, quantitative biomarker of neurodevelopmental outcome that outperformed a comprehensive validated MRI injury score and a detailed systematic discharge examination in this small cohort. Future work is needed to validate MOs in a larger cohort and elucidate the underlying pathophysiology of MOs.

Retrospective Evaluation of First-line Levetiracetam use for Neonatal Seizures after Congenital Heart Defect repair with or without Extracorporeal Membrane Oxygenation.

OBJECTIVE: Levetiracetam (LEV) efficacy for neonatal seizures is debated. We evaluated LEV as a first line anti-seizure medicine (ASM) in neonates following neonatal congenital heart defect (CHD) repair who did not require extracorporeal membrane oxygenation (ECMO) vs neonates who required ECMO. METHODS: A single center retrospective review of neonates with CHD from 2015 to 2020 was conducted. Neonates were included if seizures were present on continuous EEG after CHD repair either on or off ECMO, and they received LEV as a first line ASM. Primary outcomes were seizure resolution with LEV, adverse events and response to subsequent ASM. RESULTS: Eighteen total neonates were evaluated, 10 with seizures post-CHD repair who did not require ECMO and 8 who required ECMO. In the non-ECMO cohort, nine of ten were successfully treated with LEV monotherapy with no adverse events. In comparison, the eight neonates who required ECMO had a higher initial seizure burden (1.6% vs 17%, p=0.003), were more likely to have injury on neuroimaging (12.5 vs 75%, p= 0.04), and all neonates required multiple ASMs. Seizure burden did not decrease with LEV, but significantly decreased with phenobarbital and fosphenytoin (14.4% and 10.5%, p = 0.024). CONCLUSIONS: Neonates with CHD and seizures on and off ECMO demonstrated divergent seizure characteristics including seizure burden and response to LEV. LEV may reduce neonatal seizure burden after uncomplicated CHD repair. However, in neonates requiring ECMO, multiple ASMs were required. A prospective evaluation of ASM efficacy and safety in this high-risk population is urgently needed.

Treatment of Neonatal Seizures: Comparison of Treatment Pathways From 11 Neonatal Intensive Care Units.

OBJECTIVE: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability. METHODS: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose. RESULTS: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing. CONCLUSIONS: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation.

Optimized Benzodiazepine Treatment of Pediatric Status Epilepticus Through a Standardized Emergency Medical Services Resuscitation Tool.

BACKGROUND: Optimized benzodiazepine (BZD) dosing decreases morbidity and mortality in children with status epilepticus (SE), but previous studies have documented widespread underdosing. Prior interventions have focused on in-hospital SE treatment, although more than 75% of pediatric patients with SE are initially treated by emergency medical services (EMS). Our goal was to assess whether an EMS-focused, collaboratively developed dosing resuscitation aid (Medic One Pediatric [MOPed] cards) and training could improve BZD dosing and pediatric SE outcomes. METHODS: We conducted a retrospective review of patients aged 12 years and younger treated by EMS for SE and transferred to Seattle Children's Hospital during the 1 year before and immediately after MOPed card training. The primary outcome was the percentage of patients receiving underdosed BZD treatment. Secondary outcomes included time to second-line antiseizure medication (ASM), intubation, and intensive care unit (ICU) admission. RESULTS: The 44 children before and 33 after MOPed implementation were similar with respect to age, gender, and pre-existing epilepsy diagnosis. The percentage of children receiving underdosed BZDs fell from 52% to 6% after MOPed implementation (P < 0.001). There was no significant decrease in requirement for intubation and ICU admission. The interval to treatment with a second-line ASM remained prolonged. CONCLUSIONS: EMS-focused training significantly increased the percentage of outpatient pediatric patients with SE who received recommended initial BZD treatment. This improvement in management of SE did not significantly alter the rate of intubation or ICU admission, suggesting the need for further optimization of out-of-hospital SE care, particularly access to and timely use of second-line ASMs.

A testbed for optimizing electrodes embedded in the skull or in artificial skull replacement pieces used after injury.

BACKGROUND: Custom-fitted skull replacement pieces are often used after a head injury or surgery to replace damaged bone. Chronic brain recordings are beneficial after injury/surgery for monitoring brain health and seizure development. Embedding electrodes directly in these artificial skull replacement pieces would be a novel, low-risk way to perform chronic brain monitoring in these patients. Similarly, embedding electrodes directly in healthy skull would be a viable minimally-invasive option for many other neuroscience and neurotechnology applications requiring chronic brain recordings. NEW METHOD: We demonstrate a preclinical testbed that can be used for refining electrode designs embedded in artificial skull replacement pieces or for embedding directly into the skull itself. Options are explored to increase the surface area of the contacts without increasing recording contact diameter to maximize recording resolution. RESULTS: Embedding electrodes in real or artificial skull allows one to lower electrode impedance without increasing the recording contact diameter by making use of conductive channels that extend into the skull. The higher density of small contacts embedded in the artificial skull in this testbed enables one to optimize electrode spacing for use in real bone. COMPARISON WITH EXISTING METHODS: For brain monitoring applications, skull-embedded electrodes fill a gap between electroencephalograms recorded on the scalp surface and the more invasive epidural or subdural electrode sheets. CONCLUSIONS: Embedding electrodes into the skull or in skull replacement pieces may provide a safe, convenient, minimally-invasive alternative for chronic brain monitoring. The manufacturing methods described here will facilitate further testing of skull-embedded electrodes in animal models.

Licking microstructure reveals rapid attenuation of neophobia.

Many animals hesitate when initially consuming a novel food and increase their consumption of that food between the first and second sessions of access-a process termed attenuation of neophobia (AN). AN has received attention as a model of learning and memory; it has been suggested that plasticity resulting from an association of the novel tastant with "safe outcome" results in a change in the neural response to the tastant during the second session, such that consumption increases. Most studies have reported that AN emerges only an hour or more after the end of the first exposure to the tastant, consistent with what is known of learning-related plasticity. But these studies have typically measured consumption, rather than real-time behavior, and thus the possibility exists that a more rapidly developing AN remains to be discovered. Here, we tested this possibility, examining both consumption and individual lick times in a novel variant of a brief-access task (BAT). When quantified in terms of consumption, data from the BAT accorded well with the results of a classic one-bottle task-both revealed neophobia/AN specific to higher concentrations (for instance, 28mM) of saccharin. An analysis of licking microstructure, however, additionally revealed a real-time correlate of neophobia-an explicit tendency, similarly specific for 28-mM saccharin, to cut short the initial bout of licks in a single trial (compared with water). This relative hesitancy (i.e., the shortness of the first lick bout to 28-mM saccharin compared with water) that constitutes neophobia not only disappeared between sessions but also gradually declined in magnitude across session 1. These data demonstrate that the BAT accurately measures AN, and that aspects of AN-and the processes underlying familiarization-begin within minutes of the very first taste.

Dopamine modulates Ih in a motor axon.

We studied the axons of the pyloric dilator neurons in the stomatogastric nervous system of the lobster. The several-centimeters-long portions of these axons in the motor nerves depolarize in response to low concentrations of dopamine (DA) and exhibit peripheral spike initiation in the absence of centrally generated activity. This effect is inhibited by blockers of hyperpolarization-activated inward current (I(h)). We show here that peripheral spike initiation was also elicited by D(1)-type receptor agonists and drugs that increase cAMP. This suggests that DA acts via a D(1)-type receptor mechanism to modulate hyperpolarization-activated cyclic nucleotide-gated channels. We used two-electrode voltage clamp of the axon to directly study the effect of DA on I(h). Surprisingly, DA decreased the maximal conductance. However, because of a shift of the activation curve to more depolarized potentials, and a change in the slope, conductance was increased at biologically relevant membrane potentials. These changes were solely caused by modulation of I(h), as DA had no discernible effect when I(h) was blocked. In addition, they were not induced by repeated activation and could be mimicked by application of drugs that increase cAMP concentration. DA modulation of I(h) persisted in the presence of a protein kinase A inhibitor and is therefore potentially mediated by a phosphorylation-independent direct effect of cAMP on the ion channel. A computer model of the axon showed that the changes in maximal conductance and voltage dependence were not qualitatively affected by space-clamp problems.