Treatment Of Neonatal Seizures Research Articles

Comparative Outcomes of Levetiracetam and Phenobarbital Usage in the Treatment of Neonatal Seizures: A Retrospective Analysis.

The primary aim of this study was to conduct a comparative analysis of the safety and efficacy of levetiracetam (LEV) and phenobarbital (PB) as first-line treatments for neonatal seizure management. This study was designed to measure and compare the incidence of adverse effects and to determine the discharge and mortality rates associated with the use of these antiseizure medications (ASMs). Through this comparison, this research sought to provide insights to optimise care for neonates experiencing seizures. This retrospective cohort study evaluated 104 neonates treated for seizures at Zeynep Kamil Hospital from 2015 to 2020 after excluding those on non-PB/LEV antiseizure medications. Seizures were characterised using electroencephalogram (EEG) and categorised according to aetiology and frequency. Treatment efficacy was gauged by seizure cessation, as confirmed using EEG. Adverse effects and demographic data were recorded. Statistical analyses were conducted using SPSS, employing the Shapiro-Wilk, independent t-test, Mann-Whitney U test, and chi-square test, with a significance threshold of p < 0.05. Overall, 104 neonates treated with first-line ASM were evaluated for efficacy; PB was administered in 68.26% of the cases, while LEV was utilised in 31.74%. The total complete response rate was 40.38%, with no significant difference between the PB and LEV groups (p = 0.309). The incidence rate ratios (IRRs) demonstrated that seizure frequency profoundly influenced treatment effectiveness, with IRRs of 2.09 for rare seizures, 3.25 for frequent seizures, and 4.01 for status epilepticus, indicating a higher treatment response rate with increasing seizure frequency. For second-line treatment, among a subset of 62 patients, PB had a slight, non-significant advantage over LEV, with an odds ratio of 1.09, suggesting a marginally better response to LEV. Adverse events were significantly more frequent in the PB group, affecting 19 of 67 neonates (28.36%), compared to only 2 of 71 neonates (2.82%) in the LEV group (p < 0.001). No significant difference was observed in the discharge rates between the two groups (PB, 67.61%; LEV, 75.76%; p = 0.674). Interestingly, the mortality rate was significantly higher in the LEV group (45.45%) than that in the PB group (22.54%; p = 0.045). This study underscores LEV's superior safety profile over PB in neonatal seizure management, evidenced by a significantly lower rate of adverse events. PB seems to be more effective in the second-line treatment of neonatal seizures. Despite the lack of significant differences in the discharge rates, the higher mortality rate associated with LEV warrants further investigation. These findings advocate the cautious selection of antiepileptic drugs in neonatal care, with a preference for LEV based on its safety profile.

Enhancing GABAergic Tonic Inhibition Reduces Seizure-Like Activity in the Neonatal Mouse Hippocampus and Neocortex.

Approximately one-third of neonatal seizures do not respond to first-line anticonvulsants, including phenobarbital, which enhances phasic inhibition. Whether enhancing tonic inhibition decreases seizure-like activity in the neonate when GABA is mainly depolarizing at this age is unknown. We evaluated if increasing tonic inhibition using THIP [4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, gaboxadol], a δ-subunit-selective GABAA receptor agonist, decreases seizure-like activity in neonatal C57BL/6J mice (postnatal day P5-8, both sexes) using acute brain slices. Whole-cell patch-clamp recordings showed that THIP enhanced GABAergic tonic inhibitory conductances in layer V neocortical and CA1 pyramidal neurons and increased their rheobase without altering sEPSC characteristics. Two-photon calcium imaging demonstrated that enhancing the activity of extrasynaptic GABAARs decreased neuronal firing in both brain regions. In the 4-aminopyridine and the low-Mg2+ model of pharmacoresistant seizures, THIP reduced epileptiform activity in the neocortex and CA1 hippocampal region of neonatal and adult brain slices in a dose-dependent manner. We conclude that neocortical layer V and CA1 pyramidal neurons have tonic inhibitory conductances, and when enhanced, they reduce neuronal firing and decrease seizure-like activity. Therefore, augmenting tonic inhibition could be a viable approach for treating neonatal seizures.

Neonatal Seizures in Low- and Middle-Income Countries: A Review of the Literature and Recommendations for the Management.

Neonatal seizures are a common cause of neonatal intensive care unit (NICU) admission and a significant source of morbidity and mortality worldwide. Over the recent decades, there have been significant improvements in perinatal and neonatal medicine and electroencephalograp hic monitoring that have enhanced the diagnosis and treatment of neonatal seizures in highincome countries. However, the management of neonatal seizures remains a major challenge in low- to middle-income countries, where the availabilityof resources is limited. The purpose of this article is to present a comprehensive review of the current evidence on the etiology, pathophysiology, diagnosis, and treatment of neonatal seizures and to offer practical management recommendations that could be implemented in resource-limited settings. Cite this article as: Spenard S, Ivan Salazar Cerda C, Cizmeci MN. Neonatal seizures in low and middleincome countries: Review of the literature and recommendations for the management. Turk Arch Pediatr. 2024;59(1):13-22.

Questions and Controversies in Neonatal Seizures.

Neonatal seizures are relatively common, but their diagnosis and management remain challenging. We reviewed the scientific literature on neonatal seizures from July 1973 to November 2023. Several parameters were considered, including pathophysiology, diagnostic criteria, electroencephalographic findings and treatment. Recent classification system of seizures and epilepsies in the newborn, as well as treatment recommendations of neonatal seizures, have been proposed. Nonetheless, the approach to neonatal seizures varies among clinicians and centres, including detection, investigation, treatment and follow-up of patients. There are still many issues on the diagnosis and treatment of neonatal seizures, including the meaning or relevance of some electroencephalographic findings, the precise estimation of the seizure burden, the limited efficacy and side effects risk of antiseizure medications, and the best measures to establish the outcome.

Efficacy of Levetiracetam as Add-On Therapy in the Treatment of Seizures in Neonates

Introduction: There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add-on therapy with LEV for achieving >80% seizure reduction after phenobarbital (PB) treatment. Methods: Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG-confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd-, 3rd- or 4th-line treatment. Antiseizure medication was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography. The total seizure burden in minutes, 2 h before and 4 h after administration of LEV, was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving >80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated. Results: A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36–44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (n = 11), hemorrhagic or ischemic stroke (n = 16), central nervous system infection (n = 8), genetic (n = 8), metabolic disorders (n = 3), and unknown (n = 1). Following LEV administration, >80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration. Discussion: Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration.

Lacosamide for the Treatment of Seizures in Neonates and Infants: A Retrospective Assessment of Efficacy and Tolerability

BackgroundA retrospective study was conducted to assess the safety and efficacy of lacosamide in children aged less than 24 months. MethodsPatients were included if they were ≤24 months when they first received lacosamide; patients were excluded if they were enrolled in research studies investigating lacosamide or if there were insufficient data in the chart. Treatment response was assessed by reviewing charts and electroencephalographic reports to determine reduction in seizure burden. ResultsIn this sample, 53 of 86 patients (61.63%) in status epilepticus had good response to lacosamide, defined by ≥50% reduction in seizure burden. In addition, patients’ charts were reviewed until age 24 months to assess for any adverse effects attributed to maintenance lacosamide therapy, with adverse effects noted in three patients (abnormal movements in two patients, worsened seizures in one patient). ConclusionsThis study is among the largest retrospective chart reviews investigating the use of lacosamide in children and the first investigating the efficacy of lacosamide in children aged ≤24 months. Lacosamide was efficacious in reducing seizure burden in status epilepticus, and it was very well-tolerated in this age group. This study should prompt further investigation into the use of lacosamide in this age group.

High Effectiveness of Midazolam and Lidocaine in the Treatment of Acute Neonatal Seizures.

To assess the clinical effectiveness of treating acute seizures with midazolam and lidocaine infusion. This single-center historical cohort study included 39 term neonates with electrographic seizures who underwent treatment with midazolam (1st line) and lidocaine (2nd line). Therapeutic response was measured using continuous video-EEG monitoring. The EEG measurements included total seizure burden (minutes), maximum ictal fraction (minutes/hour), and EEG-background (normal/slightly abnormal vs. abnormal). Treatment response was considered good (seizure control with midazolam infusion), intermediate (need to add lidocaine to the control), or no response. Using clinical assessments supplemented by BSID-III and/or ASQ-3 at 2 to 9 years old age, neurodevelopment was classified as normal, borderline, or abnormal. A good therapeutic response was obtained in 24 neonates, an intermediate response in 15, and no response in any of the neonates. Babies with good response showed lower values in maximum ictal fraction compared with those with intermediate response (95% CI: 5.85-8.64 vs. 9.14-19.14, P = 0.002). Neurodevelopment was considered normal in 24 children, borderline in five, and abnormal in other 10 children. Abnormal neurodevelopment was significantly associated with an abnormal EEG background, maximum ictal fraction >11 minutes, and total seizure burden >25 minutes (odds ratio 95% CI: 4.74-1708.52, P = 0.003; 1.72-200, P = 0.016; 1.72-142.86, P = 0.026, respectively) but not with the therapeutic response. Serious adverse effects were not recorded. This retrospective study suggests that the midazolam/lidocaine association could potentially be efficacious in decreasing seizure burden in term neonates with acute seizures. These results would justify testing the midazolam/lidocaine combination as a first-line treatment for neonatal seizures in future clinical trials.

A Standardized, 3-Tiered, Seizure Burden-Based Protocol for the Treatment of Neonatal Seizures.

To evaluate use of a standardized, 3-tiered, seizure burden-based protocol for treatment of all electroencephalography (EEG)-confirmed seizures in a level IV neonatal intensive care unit (NICU). All infants admitted to the NICU with EEG-confirmed seizures over a 25-month period were enrolled in the study. We compared short-term outcomes before and after implementation of a standardized, 3-tiered protocol. A total of 107 infants were enrolled in the study. Use of midazolam infusions was reduced by 53.7% (p = 0.02). Midazolam infusion duration increased from 4 to 7.5 days (p = 0.003); however, when excluding 3 outliers, there was no significant difference between groups (-p = 0.67). Duration of EEG monitoring decreased from 5 to 3 days (p = 0.005). Hospital length of stay was unchanged. Implementation of a standardized, 3-tiered protocol for treatment of neonatal seizures improved short-term outcomes. Although not measured directly, reductions in EEG duration and midazolam use are promising indicators of overall seizure burden. More research is needed to evaluate impact on long-term neurodevelopmental outcomes.

The loop diuretic torasemide but not azosemide potentiates the anti-seizure and disease-modifying effects of midazolam in a rat model of birth asphyxia

Loop diuretics such as furosemide and bumetanide, which act by inhibiting the Na-K-2Cl cotransporter NKCC2 at the thick ascending limb of the loop of Henle, have been shown to exert anti-seizure effects. However, the exact mechanism of this effect is not known. For bumetanide, it has been suggested that inhibition of the NKCC isoform NKCC1 in the membrane of brain neurons may be involved; however, NKCC1 is expressed by virtually all cell types in the brain, which makes any specific targeting of neuronal NKCC1 by bumetanide impossible. In addition, bumetanide only poorly penetrates the brain. We have previously shown that loop diuretics azosemide and torasemide also potently inhibit NKCC1. In contrast to bumetanide and furosemide, azosemide and torasemide lack a carboxylic group, which should allow them to better penetrate through biomembranes by passive diffusion. Because of the urgent medical need to develop new treatments for neonatal seizures and their adverse outcome, we evaluated the effects of azosemide and torasemide, administered alone or in combination with phenobarbital or midazolam, in a rat model of birth asphyxia and neonatal seizures. Neither diuretic suppressed the seizures when administered alone but torasemide potentiated the anti-seizure effect of midazolam. Brain levels of torasemide were below those needed to inhibit NKCC1. In addition to suppressing seizures, the combination of torasemide and midazolam, but not midazolam alone, prevented the cognitive impairment of the post-asphyxial rats at 3 months after asphyxia. Furthermore, aberrant mossy fiber sprouting in the hippocampus was more effectively prevented by the combination. We assume that either an effect on NKCC1 at the blood–brain barrier and/or cells in the periphery or the NKCC2-mediated diuretic effect of torasemide are involved in the present findings. Our data suggest that torasemide may be a useful option for improving the treatment of neonatal seizures and their adverse outcome.

EBNEO Commentary: Need to further study levetiracetam as first-line drug for neonatal convulsions.

This prospective multicentre randomised controlled trial compared the efficacy and safety of levetiracetam (40 mg/Kg) with phenobarbital as the first-line treatment for neonatal epilepsy, which showed that phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures.1 This study differs from others in that it is one of the first prospective studies using cEEG in neonates, and the use of cEEG to confirm the presence of electrographic epilepsy is a strength of this study. Because not all electrographic seizures can be accurately identified by clinicians only by visual assessment. However, Methodological biases may render a clinical study underpowered. While it is true that 280 patients were enrolled, only 30 patients were analysed in the Phenobarbital arm and 53 patients were analysed in the LEV arm, which is a small phase IIb study rather than a large phase III randomised control trial. When power calculations are calculated on a predicted response and the measured response is considerably different, it is difficult to interpret the study's validity. This has probably been one of the more controversial aspects of this publication, being that the efficacy of the phenobarbital was so high in this small population. Compared with older children and adults, the pharmacokinetics of levetiracetam in neonates has a wider volume of distribution and faster clearance, and tends to be administered in higher doses,2 but the appropriate dose has not been determined. In addition, the study found that only 26% of premature infants less than 28 weeks could be controlled by LEV (80 mg/kg/day), suggesting that small gestational age is a risk factor for LEV treatment failure.3 A retrospective study showed that LEV at an initial dose of 50–100 mg/Kg was as effective as PB in controlling neonatal epilepsy (gestational age ≥ 35 weeks).4 Liu BK et al. found that there was no significant difference in the short-term efficacy (3 days) between the phenobarbital and levetiracetam group (8–54 mg/kg/d) in the treatment of neonatal epilepsy (gestational age: 38 [38,40] weeks).5 The gestational age of newborns in the study by Sharpe et al. was 36 to 44 weeks, and LEV (40 mg/Kg) was less effective than PB.1 Neonatal gestational age and dosing range of levetiracetam were inconsistent across the three studies, so definite conclusions were ultimately unable to make. Based on the above studies, it is highly controversial whether LEV or PB should be used as a first-line drug to treat neonatal seizures. However, because levetiracetam has a neuroprotective effect with fewer adverse reactions,6, 7 it is of great significance to further study whether LEV is stronger than phenobarbital and whether it can be used as a first-line drug for the treatment of neonatal seizures. I am eagerly looking forward to determining the optimal dose and dosing schedule of levetiracetam with uniform observational metrics and criteria, which need to include the effect of gestational age on the drug. URL LINK: https://ebneo.org/ebneo-review-study-of-levetiracetam-for-neonatal-convulsions The authors have no conflicts of interest to declare.

Ganaxolone versus Phenobarbital for Neonatal Seizure Management.

Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia. Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology. Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus. Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.

Levetiracetam or Phenobarbitone as a First-Line Anticonvulsant in Asphyxiated Term Newborns? An Open-Label, Single-Center, Randomized, Controlled, Pragmatic Trial.

Neonatal seizures are one of the most challenging problems for experts across the globe. Although there is no consensus on the "ideal" treatment of neonatal seizures, phenobarbitone has been the drug of choice for decades. Unfortunately, although extensively studied in adults and children, levetiracetam lacks rigorous evaluation in the neonatal population, despite its frequent use as an off-label drug. The objective of this open-label, randomized, active-control, single-center, pragmatic trial was to compare the effectiveness of levetiracetam with phenobarbitone for term asphyxiated infants as a first-line drug. The participants included in this study were inborn term asphyxiated infants with seizures in the first 48 hours of life. Infants satisfying the inclusion criteria were randomized to receive levetiracetam (20 mg/kg) or phenobarbitone (20 mg/kg). Clinical seizure control was noted. Infants who failed to respond to the primary drug were given the other group drug. Of 103 eligible infants, 82 were randomly assigned (44 levetiracetam group, 38 phenobarbitone group). Clinical seizure control with the primary drug and maintenance of the same for 24 hours was observed in 29 infants (65.9%) in the levetiracetam group and 13 infants (34.2%) in the phenobarbitone group (P < .05, relative risk 0.52, 95% confidence interval 0.32-0.84). Of the infants in the phenobarbitone group who did not respond to the primary drug, 57.8% were controlled after adding levetiracetam. Levetiracetam can be used with effectiveness as a first- and second-line drug in asphyxiated term infants. A more extensive study on pharmacokinetics and optimal regimen is required.

P.090 Symptomatic neonatal seizure treatment duration and seizure recurrence: a retrospective single center study

Background: While seizures have adverse neurological effects, the prescribed antiseizure medications (ASMs) may also have a negative impact on neonatal brains and contribute to detrimental neurodevelopmental outcomes. The objectives were to evaluate: 1) the impact of implementing a neonatal seizure treatment protocol in 2016; 2) the influence of ASM duration and other clinical factors on seizure recurrence and epilepsy onset. Methods: Retrospective chart review of 139 term newborns born between 2013 and March 2021 admitted at Sainte-Justine University Center Hospital with acute symptomatic seizures. Associations were assessed using Student T-test and Fisher exact test. Results: We did not observe significant change in the number of ASMs prescribed for acute seizure control (33% required 33 ASMs before vs 22% after 2016) nor significant change in frequency of prescription of ASM at discharge over time. ASM continuation at discharge was not associated with seizure recurrence (p=0.14, OR 2.14, 95%CI 0.78-5.86) or epilepsy (p=0.78, OR 1.32, 95% CI 0.45-3.90). Epilepsy occurred in 15 (12%) of children between 15 days to 72 months of age. Conclusions: No association was found between ASM maintenance at discharge following acute symptomatic neonatal seizures and the occurrence of epilepsy. Discontinuation of ASMs should be considered prior to discharge.

The debate on the treatment of neonatal seizures: Introductory remarks.

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Finally, a controversy about neonatal seizure treatment.

EpilepsiaEarly View COMMENTARY Finally, a controversy about neonatal seizure treatment Stéphane Auvin, Corresponding Author Stéphane Auvin stephane.auvin@aphp.fr orcid.org/0000-0003-3874-9749 APHP, Service de Neurologie Pédiatrique, Hôpital Universitaire Robert Debré, Université Paris-Cité, Paris, France Institut Universitaire de France (IUF), Paris, France Correspondence Stéphane Auvin, APHP, Service de Neurologie Pédiatrique, Hôpital Universitaire Robert Debré, Université Paris-Cité, Paris, France. Email: stephane.auvin@aphp.frSearch for more papers by this author Stéphane Auvin, Corresponding Author Stéphane Auvin stephane.auvin@aphp.fr orcid.org/0000-0003-3874-9749 APHP, Service de Neurologie Pédiatrique, Hôpital Universitaire Robert Debré, Université Paris-Cité, Paris, France Institut Universitaire de France (IUF), Paris, France Correspondence Stéphane Auvin, APHP, Service de Neurologie Pédiatrique, Hôpital Universitaire Robert Debré, Université Paris-Cité, Paris, France. Email: stephane.auvin@aphp.frSearch for more papers by this author First published: 06 May 2022 https://doi.org/10.1111/epi.17277Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

Clarifications regarding bumetanide for neonatal seizures.

A recent Phase II randomized, controlled trial of bumetanide as an adjunctive treatment for neonatal seizures showed a robust efficacy signal and no evidence of toxicity. Concerns regarding bumetanide as an adjunctive anticonvulsant are addressed here. An adequately powered multi-institutional trial is needed to accurately determine efficacy.

Modern aspects of anticonvulsant pharmacotherapy in newborns

Proper treatment of neonatal seizures is crucial for reducing long-term neurological disorders. None of the currently used drugs to treat neonatal seizures has sufficient evidentiary base to make an unambiguous conclusion about its effectiveness. There are no results of large-scale studies that allow choosing an anticonvulsant drug for starting therapy and an alternative to it, in case the drug of choice is ineffective. The review summarizes the data on the effectiveness of anticonvulsants of different pharmacologic classes and considers their benefits, drawbacks, and possible mechanisms of variability in effectiveness when used in newborns. The review also analyzes approaches to the duration of the anticonvulsant therapy and discusses the problems and prospects of clinical trials for increasing the effectiveness and safety of anticonvulsant therapy in newborns.

Efficacy of Levetiracetam and Phenobarbital as First-Line Treatment for Neonatal Seizures.

High neonatal seizure burden is associated with worsened neurodevelopmental outcomes. We compared the efficacy of initial treatment with levetiracetam vs phenobarbital for maintaining low seizure burden in a retrospective cohort of 25 neonates monitored with video electroencephalography (EEG). Video EEG tracing were reviewed and paired with medication bolus times to determine seizure burden after treatment. Initial cumulative dose of phenobarbital was 20 mg/kg in all but 1 case; initial cumulative dose of levetiracetam ranged from 50 to 100 mg/kg. Eleven of 17 (65%) patients sustained seizure burden <10% following initial treatment with levetiracetam, compared with 5 of 8 (63%) with phenobarbital. Thirteen (76%) patients treated with levetiracetam had sustained seizure burden <20% compared with 6 (75%) treated with phenobarbital. The phenobarbital group showed a larger absolute reduction in average seizure burden in the hour before and after treatment (-24.3 vs -14.2 minutes/h). Six of 17 (35%) patients treated with levetiracetam remained seizure free after initial treatment, compared with 2 of 8 (25%) patients treated with phenobarbital. Initial treatment with levetiracetam was associated with shorter average time to seizure freedom (15 vs 21 hours). None of these results were statistically significant. Cumulative doses of levetiracetam 100 mg/kg were well tolerated and associated with substantial decrease in seizure burden in several cases. Levetiracetam remains a promising first-line treatment for neonatal seizures; additional randomized controlled trials evaluating the effects of high-dose levetiracetam on seizure burden and long-term outcomes are warranted.

Principles of GABAergic signaling in developing cortical network dynamics.

GABAergic signaling provides inhibitory stabilization and spatiotemporally coordinates the firing of recurrently connected excitatory neurons in mature cortical circuits. Inhibition thus enables self-generated neuronal activity patterns that underlie various aspects of sensation and cognition. In this review, we aim to provide a conceptual framework describing how and when GABA-releasing interneurons acquire their network functions during development. Focusing on the developing visual neocortex and hippocampus in mice and rats invivo, we hypothesize that at the onset of patterned activity, glutamatergic neurons are stable by themselves and inhibitory stabilization is not yet functional. We review important milestones in the development of GABAergic signaling and illustrate how the cell-type-specific strengthening of synaptic inhibition toward eye opening shapes cortical network dynamics and allows the developing cortex to progressively disengage from extra-cortical synaptic drive. We translate this framework to human cortical development and discuss clinical implications for the treatment of neonatal seizures.

Practical Approaches to the Treatment of Neonatal Seizures

Practical Approaches to the Treatment of Neonatal Seizures