First-line Treatment For Neonatal Seizures Research Articles

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 s eizure 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 s eizure 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.

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.

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.

A Comparative Study of Levetiracetam and Phenobarbital for Neonatal Seizures as a First Line Treatment.

We aimed to evaluate the use of intravenous levetiracetam as the first-line treatment of neonatal seizures compared with phenobarbital. The study was conducted on 104 neonates (0-28 days) with clinical seizures after inclusion criteria. They were assigned in equal ratio into 2 groups; 1 included neonates who received phenobarbitone, and the other included neonates who received levetiracetam. Neonates were loaded with 20 mg/kg of intravenous drug-A (phenobarbitone) or drug-B (levetiracetam). In persistent seizures, a second loading dose of the same drug was given. Crossover to other drugs occurred if seizures persisted after the second dose of the same drug. The proportion of neonates who achieved cessation of seizures following the first or second loading dose of either drug-A or drug-B (PB or LEV) was the main outcome measure provided that they remained free of seizure for the following 24 hours. After 1 or 2 doses of Levetiracatam or Phenobarbitone, clinical seizures stopped (and remained seizure-free for 24 hours) in 41 (78.84%) and 34 (65.38%) patients, respectively (P = .01). Neonates in the LEV group showed better seizure control than neonates in the PB group (RR = 0.57; 95% CI (0.17, 0.80). We did not report any adverse drug reactions in the LEV group. However, 12 (23.07%) neonates developed adverse drug reactions in the PB Group. Levetiracetam is considered an effective and safe drug as a first-line AED in neonatal seizures.

Levetiracetam as the first-line treatment for neonatal seizures: a systematic review and meta-analysis.

To assess the effectiveness and safety of levetiracetam when used as first-line treatment of neonatal seizures. Four electronic databases, Medline, Embase, Web of Science, and ClinicalTrials.gov were systematically searched from inception until 20th November 2020. Randomized controlled trials (RCTs) and observational studies that included neonates born preterm and term were eligible for inclusion. The primary outcome measure was levetiracetam effectiveness, defined as seizure cessation within 24hours of starting treatment. Secondary outcomes included short-term adverse events, mortality before discharge, and long-term neurodevelopmental outcomes. Fourteen studies assessing 1188 neonates were included: four RCTs, three observational trials with phenobarbital as the control arm, and seven observational studies of levetiracetam with no control arm. Pooled efficacy of levetiracetam from observational studies was 45% (95% confidence interval [CI] 34-57%) (GRADE - very low). Meta-analysis of RCTs evaluating levetiracetam versus phenobarbital showed that both were equally effective (risk ratio [95% CI] 0.6 [0.30-1.20]) (GRADE - very low). Levetiracetam resulted in a lower risk of short-term adverse events compared to phenobarbital (risk ratio [95% CI] 0.24 [0.06-0.92]) (GRADE - moderate). Very low certainty of evidence suggests levetiracetam might not be more effective than phenobarbital. Moderate certainty of evidence indicates levetiracetam is associated with a lower risk of adverse events. Future trials on neonatal antiseizure medication therapy should include continuous electroencephalogram (EEG) monitoring as standard of care and enrol a homogenous population with similar seizure aetiology. What this paper adds Levetiracetam is effective in 45% of neonatal seizures. Levetiracetam might not be more effective than phenobarbital. Levetiracetam is likely to be safer than phenobarbital. Evidence available is limited and of very low certainty.

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial

There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures. The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists. Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

A Randomized Controlled Trial of Levetiracetam Compared with Phenobarbital in the Treatment of Neonatal Seizures

Background: There are no FDA approved therapies for neonatal seizures. Previous studies demonstrated that phenobarbital (PHB) and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam (LEV) has proven efficacy in children and adults and has an excellent safety profile; therefore, there is great interest in its use in neonates, but randomized studies have not been performed. Methods: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of LEV compared with PHB in the first-line treatment of neonatal seizures, and including a dose escalation component. The primary outcome measure was complete seizure freedom for 24 hours after medication administration. Efficacy in seizure control was determined by independent review of the video EEGs by two neurophysiologists. Results: Eighty percent of subjects (24 of 30) randomized to PHB remained seizure free for 24 hours as compared with 28% of subjects (15 of 53) randomized to LEV (p <0.001). There were trends towards more adverse effects in subjects randomized to PHB including hypotension, respiratory suppression and sedation. A 7.5% improvement in efficacy was achieved with dose escalation of LEV from 40mg/kg to 60mg/kg. Conclusions: In this phase IIb study PHB was more effective than LEV for the treatment of neonatal seizures. Higher rates of adverse effects were seen with PHB treatment. Trial Registration Number: (NCT01720667). Funding Statement: The NEOLEV2 study was funded by the FDA 1 RO1FD004147 The Persyst EEG software company worked closely with the authors on the NEOLEV2 study and provided their software to the researchers free of charge but have had no input into this manuscript. The Corticare commercial EEG monitoring company worked closely with the authors on the NEOLEV2 study on a commercial basis. They have had no input into the writing of this manuscript. This manuscript discusses use of the automated neonatal seizure detection algorithm created by the Persyst EEG software company, which is not yet FDA approved for commercial use. The REDCap database is supported by NIH Cooperative Agreement UL1TR001442. Declaration of Interests: The authors state: None. Ethics Approval Statement: The study was approved by the institutional review boards of each institution and written consent was obtained from parents of all subjects. A steering committee and data safety monitoring board guided and monitored the study.

Short-Term Neurodevelopmental Outcome in Term Neonates Treated with Phenobarbital versus Levetiracetam: A Single-Center Experience

Background Phenobarbital (PB) has been traditionally used as the first-line treatment for neonatal seizures. More recently, levetiracetam (LEV) has been increasingly used as a promising newer antiepileptic medication for treatment of seizures in neonates. Objectives The aim of our study was to compare the effect of PB vs. LEV on short-term neurodevelopmental outcome in infants treated for neonatal seizures. Method This randomized, one-blind prospective study was conducted on term neonates admitted to the Neonatal Intensive Care Unit of S. Bambino Hospital, University Hospital “Policlinico-Vittorio Emanuele,” Catania, Italy, from February 2016 to February 2018. Thirty term neonates with seizures were randomized to receive PB or LEV; the Hammersmith Neonatal Neurological Examination (HNNE) was used at baseline (T0) and again one month after the initial treatment (T1). Results We found a significantly positive HNNE score for the developmental outcomes, specifically tone and posture, in neonates treated with LEV. There was no significant improvement in the HNNE score at T1 in the neonates treated with PB. Conclusion This study suggests a positive effect of levetiracetam on tone and posture in term newborns treated for neonatal seizures. If future randomized-controlled studies also show better efficacy of LEV in the treatment of neonatal seizures, LEV might potentially be considered as the first-line anticonvulsant in this age group.

Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial

IntroductionTherapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED)....

Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring

Continuous video electroencephalography (cEEG) monitoring is the recommended gold standard of care for at-risk neonates but is not available in many Neonatal Intensive Care Units (NICUs). To conduct a randomized treatment trial of levetiracetam for the first-line treatment of neonatal seizures (the NEOLEV2 trial), we developed a monitoring infrastructure at five NICUs, implementing recent technological advancements to provide continuous video EEG monitoring and real-time response to seizure detection. Here, we report on the feasibility of providing this level of care. Twenty-five key informant interviews were conducted with study neurologists, neonatologists, coordinators, and EEG technicians from the commercial EEG monitoring company Corticare. A general inductive approach was used to analyze these qualitative data. A robust infrastructure for continuous video EEG monitoring, remote review, and real-time seizure detection was established at all sites. At the time of this survey, 260 babies had been recruited and monitored for 2 to 6 days. The EEG technician review by the commercial EEG monitoring company was reassuring to families and neonatologists and led to earlier detection of seizures but did not reduce work load for neurologists. Neurologists found the automated neonatal seizure detector algorithm provided by the EEG software company Persyst useful, but the accuracy of the algorithm was not such that it could be used without review by human expert. Placement of EEG electrodes to initiate monitoring, especially after hours, remains problematic. Technological advancements have made it possible to provide at-risk neonates with continuous video EEG monitoring, real-time detection of and response to seizures. However, this standard of care remains unfeasible in usual clinical practice. Chief obstacles remain starting a recording and resourcing the real-time specialist review of suspect seizures.

Midazolam as a first-line treatment for neonatal seizures: Retrospective study.

Midazolam is commonly used to treat refractory seizures in newborns and as a first-line anti-epileptic drug in children. Its use as first-line treatment of neonatal seizures has not been investigated so far. We retrospectively studied the tolerability of midazolam in 72 newborn infants who received i.v. or i.n. midazolam as first-line treatment for seizures. No major side-effect exclusively due to midazolam was reported. The i.n. route was used for 20 patients (27.8%). Effectiveness could not be formally evaluated due to the absence of systematic electroencephalogram recording while midazolam was administered. In conclusion, midazolam was well-tolerated as a first-line abortive emergency treatment of neonatal seizure. The i.n. route offers a useful alternative to i.v. phenobarbital or phenytoin in emergency settings.

Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.

Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. Level 3 neonatal ICU. Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. None. A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain

The induction of neuronal apoptosis throughout many regions of the developing rat brain by phenobarbital and phenytoin, two drugs commonly used for the treatment of neonatal seizures, has been well documented. However, several limbic regions have not been included in previous analyses. Because drug-induced damage to limbic brain regions in infancy could contribute to emotional and psychiatric sequelae, it is critical to determine the extent to which these regions are vulnerable to developmental neurotoxicity. To evaluate the impact of antiepileptic drug (AED) exposure on limbic nuclei, we treated postnatal day 7 rat pups with phenobarbital, phenytoin, carbamazepine, or vehicle, and examined nucleus accumbens, septum, amygdala, piriform cortex, and frontal cortex for cell death. Histologic sections were processed using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay to label apoptotic cells. Nucleus accumbens displayed the highest level of baseline cell death (vehicle group), as well as the greatest net increase in cell death following phenobarbital or phenytoin. Phenobarbital exposure resulted in a significant increase in cell death in all brain regions, whereas phenytoin exposure increased cell death only in the nucleus accumbens. Carbamazepine was without effect on cell death in any brain region analyzed, suggesting that the neurotoxicity observed is not an inherent feature of AED action. Our findings demonstrate pronounced cell death in several important regions of the rat limbic system following neonatal administration of phenobarbital, the first-line treatment for neonatal seizures in humans. These findings raise the possibility that AED exposure in infancy may contribute to adverse neuropsychiatric outcomes later in life.

The newborn drug development initiative workshop: Summary proceedings from the neurology group on neonatal seizures

Background: The neonatal period eclipses all other epochs of the human life span for the highest incidence of seizures. Neonatal seizures are most commonly incited by serious acute illnesses such as hypoxic-ischemic cephalopathy, birth trauma, or infection. Objective: The goal of this article was to summarize some of the Neurology Group's discussion on neonatal seizures and their treatment with phenobarbital (PB). Methods: Information for this article was gathered from a workshop held March 29 and 30, 2004, in Baltimore, Maryland, as part of the Newborn Drug Development Initiative. A group of national experts was invited to form the Neurology Group to review certain aspects of neonatal seizures. Literature reviews were conducted using MEDLINE searches for original research studies, commentaries, and review articles between 1980 and 2004 using the key words neonatal seizures, treatment, and phenobarbital. Results: It has been empirically established that infants who experience seizures face substantially higher mortality and morbidity rates than those who do not. Basic research indicates that neonatal seizures themselves are not innocuous and actively contribute to adverse neurodevelopmental outcomes. Current worldwide clinical practice most often includes empiric treatment with PB for definite or suspected seizures in the newborn. Unfortunately, this common practice has never been proven by even a single, rigorous, randomized controlled trial. The Neurology Group identified the treatment of neonatal seizures with PB as an important topic in the practice of neonatal neurology for further investigation. Three possible frameworks for ethically acceptable, clinical treatment trials were explored. From these, a suitable scenario was selected—an electroencephalographir-blinded study of PB versus placebo in a homogeneous group of newborns who are at high risk of developing early subclinical electroencephalographic neonatal seizures (ENSs). Prospective video-electroencephalogram monitoring performed immediately after an insult (such as major cardiac surgery for a serious congenital heart defect) would establish the presence and number of subclinical ENSs. For a brief period of time, neonates with subclinical ENSs would be randomized to PB (dosed to match the PB-binding characteristics of the individual) or placebo. Clear criteria for escape from the study to active treatment are defined. Conclusion: The investigation proposed here could refute or confirm the contemporary practice of PB administration as the first-line treatment of neonatal seizures.