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LEVETIRACETAM VS. PHENOBARBITAL FOR NEONATAL SEIZURES: A RETROSPECTIVE COHORT STUDY

Open AccessPublished:October 21, 2022DOI:https://doi.org/10.1016/j.pediatrneurol.2022.10.004

      Abstract

      Objectives

      Although phenobarbital (PB) is commonly used as a first-line anti-seizure medication (ASM) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASM. Here, we compared the safety and efficacy of LEV and PB as first-line ASM, considering the years before and after modifying our treatment protocol.

      Methods

      We conducted a retrospective cohort study of 108 neonates with EEG-confirmed seizures treated with first-line LEV or PB in 2012-2020.

      Results

      First-line ASM was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included acute symptomatic seizures in 69% of cases (30% hypoxic-ischemic encephalopathy, 32% structural vascular, 6% infectious, otherwise metabolic), and neonatal epilepsy in 22% (5% structural due to brain malformation,17% genetic). Forty-two of 108 (39%) neonates reached seizure freedom following first-line therapy. Treatment response did not vary by first-line ASM among all neonates, those with acute symptomatic seizures, or those with neonatal onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency, particularly for those with status epilepticus vs. rare seizures (p<0.001), irrespective of gestational age, etiology, or EEG findings. Adverse events were noted in 22 neonates treated with PB and in only one treated with LEV (p<0.001).

      Conclusion

      Our study suggests a potential non-inferiority and a more acceptable safety profile for LEV that may thus be a reasonable option as first-line ASM for neonatal seizures in place of PB. Treatment should be initiated as early as possible since higher seizure frequencies predispose to less favorable responses.

      Keywords

      1. INTRODUCTION

      Neonatal seizures occur in 1-4 of 1000 neonates [
      • Lanska M.J.
      • Lanska D.J.
      • Baumann R.J.
      • Kryscio R.J.
      A population-based study of neonatal seizures in Fayette County, Kentucky.
      ,
      • Ronen G.M.
      • Penney S.
      • Andrews W.
      The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study.
      ,
      • Saliba R.M.
      • Annegers J.F.
      • Waller D.K.
      • Tyson J.E.
      • Mizrahi E.M.
      Incidence of neonatal seizures in Harris County, Texas, 1992-1994.
      ,
      • Glass H.C.
      • Pham T.N.
      • Danielsen B.
      • Towner D.
      • Glidden D.
      • Wu Y.W.
      Antenatal and intrapartum risk factors for seizures in term newborns: a population-based study.
      ], with substantially higher rates reported in preterm neonates [
      • Kohelet D.
      • Shochat R.
      • Lusky A.
      • Reichman B.
      Israel Neonatal Network
      Risk factors for neonatal seizures in very low birthweight infants: population-based survey.
      ]. Neonatal seizures, particularly when recurrent or prolonged [
      • Pisani F.
      • Cerminara C.
      • Fusco C.
      • Sisti L.
      Neonatal status epilepticus vs recurrent neonatal seizures: Clinical findings and outcome.
      ,
      • Ronen G.M.
      • Buckley D.
      • Penney S.
      • Streiner D.L.
      Long-term prognosis in children with neonatal seizures: a population-based study.
      ], have been shown to increase the risk for neurological sequelae, including cognitive and motor impairment and post-neonatal epilepsy [
      • Ramantani G.
      • Schmitt B.
      • Plecko B.
      • Pressler R.M.
      • Wohlrab G.
      • Klebermass-Schrehof K.
      • et al.
      Neonatal Seizures-Are We there Yet?.
      ,
      • Pisani F.
      • Spagnoli C.
      • Falsaperla R.
      • Nagarajan L.
      • Ramantani G.
      Seizures in the neonate: A review of etiologies and outcomes.
      ,
      • Ramantani G.
      Neonatal epilepsy and underlying aetiology: to what extent do seizures and EEG abnormalities influence outcome?.
      ]. Despite the urgent need to control neonatal seizures, there is still an open debate concerning their optimal management [
      • Pressler R.M.
      • Mangum B.
      Newly emerging therapies for neonatal seizures.
      ]. Phenobarbital (PB), the oldest and most popular first-line anti-seizure medication (ASM)[
      • Glass H.C.
      • Kan J.
      • Bonifacio S.L.
      • Ferriero D.M.
      Neonatal seizures: treatment practices among term and preterm infants.
      ], displays efficacy in only half of cases [
      • Painter M.J.
      • Scher M.S.
      • Stein A.D.
      • Armatti S.
      • Wang Z.
      • Gardiner J.C.
      • et al.
      Phenobarbital compared with phenytoin for the treatment of neonatal seizures.
      ], and produces the phenomenon of electroclinical uncoupling in treated neonates [
      • Scher M.S.
      • Alvin J.
      • Gaus L.
      • Minnigh B.
      • Painter M.J.
      Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use.
      ]. Moreover, PB has been associated with widespread neuronal apoptosis [
      • Bittigau P.
      • Sifringer M.
      • Genz K.
      • Reith E.
      • Pospischil D.
      • Govindarajalu S.
      • et al.
      Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.
      ] and impaired synaptic maturation [
      • Forcelli P.A.
      • Janssen M.J.
      • Vicini S.
      • Gale K.
      Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development.
      ] in the immature rat brain. The main adverse effects of PB, including hypotension, respiratory suppression, and sedation, are particularly relevant in the neonatal intensive care unit. Third-generation ASM with a good efficacy and safety profile, particularly levetiracetam (LEV), have emerged as novel treatment options for neonatal seizures [
      • Ramantani G.
      • Ikonomidou C.
      • Walter B.
      • Rating D.
      • Dinger J.
      Levetiracetam: safety and efficacy in neonatal seizures.
      ,
      • Thibault C.
      • Naim M.Y.
      • Abend N.S.
      • Licht D.J.
      • Gaynor J.W.
      • Xiao R.
      • et al.
      A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
      ,
      • Rao L.M.
      • Hussain S.A.
      • Zaki T.
      • Cho A.
      • Chanlaw T.
      • Garg M.
      • et al.
      A comparison of levetiracetam and phenobarbital for the treatment of neonatal seizures associated with hypoxic-ischemic encephalopathy.
      ,

      Han JY, Moon CJ, Youn YA, Sung IK, Lee IG. Efficacy of levetiracetam for neonatal seizures in preterm infants 2018:1–6.

      ,
      • Abend N.S.
      • Gutierrez-Colina A.M.
      • Monk H.M.
      • Dlugos D.J.
      • Clancy R.R.
      Levetiracetam for treatment of neonatal seizures.
      ,
      • Khan O.
      • Cipriani C.
      • Wright C.
      • Crisp E.
      • Kirmani B.
      Role of intravenous levetiracetam for acute seizure management in preterm neonates.
      ].
      Over the last decade, the use of PB has declined, whereas the use of LEV has increased ten-fold, as demonstrated in a US report [
      • Ahmad K.A.
      • Desai S.J.
      • Bennett M.M.
      • Ahmad S.F.
      • Ng Y.-T.
      • Clark R.H.
      • et al.
      Changing antiepileptic drug use for seizures in US neonatal intensive care units from 2005 to 2014.
      ]. One of the key arguments for LEV use in neonatal seizures is the more favorable pharmacokinetics, characterized by a linear clearance, few drug interactions, and a wide therapeutic index [
      • Lima-Rogel V.
      • López-López E.J.
      • Medellín-Garibay S.E.
      • Gómez-Ruiz L.M.
      • Romero-Méndez C.
      • Milán-Segovia R.C.
      • et al.
      Population pharmacokinetics of levetiracetam in neonates with seizures.
      ]. At the same time, PB is linked to auto-inducible clearance with use and numerous drug interactions [
      • Pacifici G.M.
      Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics.
      ]. However, unequivocal evidence for the efficacy of LEV in the treatment of neonatal seizures, particularly compared to PB, is yet lacking [
      • Hooper R.G.
      • Ramaswamy V.V.
      • Wahid R.M.
      • Satodia P.
      • Bhulani A.
      Levetiracetam as the first-line treatment for neonatal seizures: a systematic review and meta-analysis.
      ,
      • McHugh D.C.
      • Lancaster S.
      • Manganas L.N.
      A Systematic Review of the Efficacy of Levetiracetam in Neonatal Seizures.
      ]. In a recent randomized controlled study [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ], PB was considerably more effective than LEV for treating neonatal seizures but higher rates of adverse effects were seen with PB treatment [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ]. This finding of significantly poorer LEV efficacy than PB increases treatment uncertainty in neonatal seizures. Evaluating current practices is urgently needed to refine our treatment strategies and, ultimately, facilitate the best possible outcome for affected neonates.
      In 2015, motivated by several studies indicating that LEV is at least as effective as PB and has lower adverse effect rates [
      • Ramantani G.
      • Ikonomidou C.
      • Walter B.
      • Rating D.
      • Dinger J.
      Levetiracetam: safety and efficacy in neonatal seizures.
      ,
      • Abend N.S.
      • Gutierrez-Colina A.M.
      • Monk H.M.
      • Dlugos D.J.
      • Clancy R.R.
      Levetiracetam for treatment of neonatal seizures.
      ,
      • Khan O.
      • Cipriani C.
      • Wright C.
      • Crisp E.
      • Kirmani B.
      Role of intravenous levetiracetam for acute seizure management in preterm neonates.
      ,
      • Khan O.
      • Chang E.
      • Cipriani C.
      • Wright C.
      • Crisp E.
      • Kirmani B.
      Use of intravenous levetiracetam for management of acute seizures in neonates.
      ,
      • Rakshasbhuvankar A.
      • Rao S.
      • Kohan R.
      • Simmer K.
      • Nagarajan L.
      Intravenous levetiracetam for treatment of neonatal seizures.
      ], we modified the neonatal seizure treatment protocol in our institution and introduced LEV as first-line ASM in place of PB. In the present study, we aimed to evaluate this paradigm shift by comparing the safety and efficacy of LEV to PB as first-line ASM in EEG-confirmed neonatal seizures, considering the years before and after the modification of our treatment protocol. Our findings may shed some light on treatment options in this particularly vulnerable age group.

      2. PATIENTS AND METHODS

      2.1 Study population

      We retrospectively identified from our institutional database at the University Children’s Hospital Zurich preterm and term neonates (≤30 days of age, corrected gestational age ≤44 weeks) with seizures diagnosed and treated from December 2011 to July 2020. Only neonates 1) with EEG-confirmed seizures, 2) with either LEV or PB as first-line ASM, and 3) with available informed general consent were considered for this study. We excluded neonates 1) who received first-line treatment with an ASM other than LEV or PB, and 2) whose parents had not given informed general consent. The sequence of ASM administration was determined by the currently pertinent institutional treatment protocol and the discretion of the attending physician of the neonatal intensive care unit. Abnormal neurologic examination at the time of seizure manifestation was determined by abnormalities in consciousness, tone, and reflexes, as documented by the treating clinicians.
      The collection of patient data and the scientific analysis were approved by and performed according to the guidelines and regulations of the local ethics committee (KEK-ZH PB-2019-01878). All parents gave informed general consent to re-use clinical data for research.

      2.2 EEG acquisition and review

      Neonates underwent scalp video-EEG with 12 or 21 electrodes placed according to the international 10-20 system, depending on the infant’s head circumference. Extracerebral leads were applied for respiratory and electrocardiogram recording and surface electromyography. EEG recordings in neonates included a complete cycle of awake, quiet, and active sleep states. Whenever state changes were not distinguishable, EEGs lasted ≥ 1 h, according to our institutional protocol. Neonates underwent their first EEG recording within minutes to a few hours from seizure suspicion, depending on the day and time of the first event. Subsequently, neonates underwent sequential EEGs to the end of their hospitalization and continuous seizure monitoring by EEG/aEEG at the discretion of the attending physician.
      The EEGs were scored [
      • Pisani F.
      • Cerminara C.
      • Fusco C.
      • Sisti L.
      Neonatal status epilepticus vs recurrent neonatal seizures: Clinical findings and outcome.
      ,
      • Holmes G.L.
      • Lombroso C.T.
      Prognostic value of background patterns in the neonatal EEG.
      ] as follows: 1) normal, 2) mildly/moderately abnormal = excess sharp activity, absence or decreased frequency of normal patterns, excessively long low-voltage periods or overall slightly decreased voltage, asymmetries in voltage or frequencies, asynchrony for age, and 3) severely abnormal = isoelectric or low voltage invariant activity, burst-suppression pattern, permanent discontinuous activity.

      2.3 Characterization of seizures

      Electrographic seizures in neonates were defined as sudden, abnormal EEG events with a repetitive and evolving pattern with a peak-to-peak voltage of >2μV and a duration of >10sec [
      • Tsuchida T.N.
      • Wusthoff C.J.
      • Shellhaas R.A.
      • Abend N.S.
      • Hahn C.D.
      • Sullivan J.E.
      • et al.
      American clinical neurophysiology society standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates: report of the American Clinical Neurophysiology Society critical care monitoring committee.
      ], while “evolving” refers to an unequivocal evolution in frequency, voltage, morphology, or location. Seizures were classified as electrographic only if no clinical signs were observed by the bedside provider or on video review, or electroclinical if a clinical sign was associated with an ictal discharge [
      • Pressler R.M.
      • Cilio M.R.
      • Mizrahi E.M.
      • Moshé S.L.
      • Nunes M.L.
      • Plouin P.
      • et al.
      The ILAE classification of seizures and the epilepsies: Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures.
      ]. Seizure etiology was classified based on the current framework for neonatal seizures and epilepsy syndromes [
      • Pressler R.M.
      • Cilio M.R.
      • Mizrahi E.M.
      • Moshé S.L.
      • Nunes M.L.
      • Plouin P.
      • et al.
      The ILAE classification of seizures and the epilepsies: Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures.
      ] as hypoxic-ischemic, structural vascular (Including acute ischemic stroke, hemorrhage and other vascular induced ischemia), structural due to brain malformation, genetic, infectious, metabolic, and unknown. We further divided seizure etiology to acute symptomatic seizures, including hypoxic-ischemic, structural vascular, infectious, and metabolic, and neonatal epilepsies, including structural due to brain malformation and genetic.
      Seizure frequency within the first 24 hours was determined by clinical reports, and findings of continuous monitoring by EEG/aEEG if available, as 1) rare (<5 seizures), 2) occasional (5-10 seizures), 3) frequent (>10 seizures), or 4) status epilepticus, when the summed duration of seizures comprised ≥50% of an 1-hour epoch [
      • Tsuchida T.N.
      • Wusthoff C.J.
      • Shellhaas R.A.
      • Abend N.S.
      • Hahn C.D.
      • Sullivan J.E.
      • et al.
      American clinical neurophysiology society standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates: report of the American Clinical Neurophysiology Society critical care monitoring committee.
      ].

      2.4 Treatment administration and response

      According to our institutional treatment protocol, neonates with seizures received infusion over 15 min of either LEV at 30 mg/kg or PB at 15-20 mg/kg, with an additional 15 min allowed for the ASM to take effect. If seizures persisted or recurred 30 min after the first infusion was complete, neonates received an extra dose of LEV at 30 mg/kg (up to a maximum dosage of 60 mg/kg) or PB at 5 mg/kg every 15 min (up to a maximum dosage of 40 mg/kg). If seizures persisted or recurred 30 min after reaching the maximum dosage of one ASM, the patient was then treated with the other ASM. First-line ASM was PB until we modified our institutional algorithm of neonatal seizure treatment in September 2015, introducing LEV as first-line ASM. If seizures persisted after treatment with both the first-line and second-line ASM, neonates received a third-line ASM such as midazolam, phenytoin, and lidocaine IV, and topiramate orally. Patients given any LEV loading doses received maintenance LEV at 15 mg/kg per dose, given IV twice daily. Patients receiving PB loading doses received maintenance PB at 2.5 mg/kg per dose, given IV once daily.
      Treatment response was defined as 1) complete cessation of EEG seizures following ASM administration, and 2) no administration of further ASM for seizure control. If ≥2 ASM were administered before seizure cessation, the last administered ASM was defined as effective.
      Adverse events were noted at the presence of hypotension, heart rate or respiratory abnormalities with need for oxygen, ventilation, or vasopressor treatment, irritability or sedation with poor feeding, and changes in laboratory parameters (complete blood cell count, electrolytes, liver enzymes, ammonia, and blood gas analysis) that were attributed to an ASM by the clinical team and documented in the medical record.

      2.5 Statistical analysis

      Comparative statistics 1) for the subgroups of neonates who received LEV vs. PB as first-line ASM, 2) for treatment response according to etiology, and 3) for treatment response according to dosage were performed with Fisher’s exact test for categorical variables (two-sided, no correction for multiple testing) and Wilcoxon rank-sum test for continuous variables. We fitted a quasi-Poisson generalized linear model with log link to assess the incidence risk ratio of incomplete treatment response to the first-line and second-line ASM, respectively. We included gestational age, etiology, seizure frequency, EEG findings, and ASM as explanatory variables. We excluded 9 neonates with seizures of unknown etiology from this analysis. Statistical analysis was performed with R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). We did not account for missing data in our analysis. Significance was established at p<0.05.

      3. RESULTS

      3.1 Patient characteristics

      Between December 2011 and July 2020, 180 neonates were diagnosed with EEG-confirmed seizures in our institutional setting. Seventy-two (40%) neonates were excluded from our study: 34 (19%) due to first-line treatment with ASM other than LEV or PB (mainly benzodiazepines, such as midazolam, diazepam, clonazepam) and 38 (21%) due to lack of general consent from parents (Supplementary Figure 1). The remaining 108 neonates (60 female) who received as first-line ASM LEV in 33 (31%) or PB in 75 (69%) cases were enrolled in our study (Table 1).
      Table 1Comparison of clinical features and treatment response in the subgroups of neonates that received levetiracetam (LEV) or phenobarbital (PB) as first-line anti-seizure medication (ASM).
      First-line ASMSecond-line ASM
      NIRR
      IRR = Incidence Rate Ratio, CI = Confidence Interval
      95% CI
      IRR = Incidence Rate Ratio, CI = Confidence Interval
      p-valueNIRR
      IRR = Incidence Rate Ratio, CI = Confidence Interval
      95% CI
      IRR = Incidence Rate Ratio, CI = Confidence Interval
      p-value
      Gestational Age
       Term8141
       Preterm180.950.61, 1.440.81100.960.48, 1.830.91
      Etiology
       Hypoxic-ischemic3212
       Structural: vascular341.060.70, 1.620.78170.800.44, 1.480.48
       Structural: brain malformation51.100.46, 2.290.8220.540.10, 1.870.40
       Genetic191.200.75, 1.900.45141.030.55, 1.950.92
       Infectious61.260.62, 2.430.5140.570.17, 1.560.31
       Metabolic31.390.47, 3.300.5020.860.16, 2.920.84
      Seizure frequency
       Rare seizures306
       Occasional seizures222.221.23, 4.080.01083.250.80, 19.30.14
       Frequent seizures233.261.93, 5.71<0.001184.951.44, 27.10.032
      statistical significance, p<0.05
       Status epilepticus243.532.14, 6.07<0.001196.221.89, 33.50.013
      statistical significance, p<0.05
      EEG findings
       Normal82
       Mildly/moderately abnormal
       Severely abnormal
      First-line ASM
       LEV27
       PB720.990.69, 1.450.95
      Second-line ASM
       LEV36
       PB151.230.73, 2.050.43
      The two subgroups did not differ significantly as to any of their clinical features or as to treatment response. Summary statistics of our cohort, including counts and percentages for categorical variables, mean and range for continuous variables. Percentages are given column-wise. N: number of patients, PB: phenobarbital, LEV: levetiracetam.
      statistical significance, p<0.05
      1 IRR = Incidence Rate Ratio, CI = Confidence Interval
      89 (82%) of neonates were full-term, and 19 (18%) were preterm (<37 weeks of gestational age). 69% of neonates had acute symptomatic seizures, including 30% hypoxic-ischemic (treated with therapeutic hypothermia in 18 of 32 cases), 32% structural vascular (12% acute ischemic stroke, 15% hemorrhage, 3% vascular induced ischemia related to cardiac surgery and 2% to head trauma), 6% infectious, and 3% metabolic. 22% of neonates had neonatal-onset epilepsy, including 17% genetic, and 5% structural due to brain malformation. In 9% of cases, seizure etiology remained unknown. The two subgroups who received as first-line ASM LEV or PB did not differ significantly as to any of their clinical features (Table 1).

      3.2 Treatment response according to etiology

      Among all neonates with seizures (n=108), only 39% reached seizure freedom following first-line therapy: treatment response did not vary by ASM (p = 0.40, Figure 1).
      Figure thumbnail gr1
      Figure 1Overall treatment response. Among all neonates with seizures, only 42 of 108 (39%) reached seizure freedom following first-line therapy: treatment response did not vary by ASM (LEV, 15/33 = 45%; PB, 27/75 = 36%; p = 0.40). Of the 18 neonates who did not respond to LEV as first-line therapy, 17 received PB as second-line ASM with seizure cessation in 4 (24%), with a total response to both ASM in 19/33 (58%). Of the 48 neonates who did not respond to PB as first-line therapy, 37 received LEV as second-line ASM with seizure cessation in 13 (35%), with a total response to both ASM in 40/75 (53%). Overall, seizure control had been obtained in 59 (55%) of neonates following first- and second-line therapy with LEV and PB. ASM: anti-seizure medication, LEV: levetiracetam, PB: phenobarbital.
      Among neonates with acute symptomatic seizures (n=75), only 39% reached seizure freedom following first-line therapy: treatment response did not vary by ASM (p = 0.59, Figure 2A). Specifically, in hypoxic-ischemic encephalopathy (N=32), 44% neonates reached seizure freedom after the first-line ASM: treatment response did not vary by ASM (p = 0.71, Figure 2B). Treatment response in hypoxic-ischemic encephalopathy did not vary depending on the use of therapeutic hypothermia in the overall group (p = 0.73) or in the subgroups of neonates who received LEV or PB as first-line ASM (p > 0.99 and p= 0.67 respectively).
      Figure thumbnail gr2
      Figure 2Treatment response according to etiology. A. Among neonates with acute symptomatic seizures (n=75), only 29/75 = 39% reached seizure freedom following first-line therapy: treatment response did not vary by ASM (LEV, 9/20 = 45%; PB, 20/55 = 37%; p = 0.59). B. Among neonates with seizures due to hypoxic-ischemic encephalopathy (N=32), only 44% neonates reached seizure freedom after the first-line ASM: treatment response did not vary by ASM (LEV, 5/10 = 50%; PB, 9/22 = 41%; p = 0.71). ASM: anti-seizure medication, LEV: levetiracetam, PB: phenobarbital.

      3.3 Treatment response according to dosage

      The highest administered dosage of both LEV and PB as first-line ASM did not differ significantly between neonates with an incomplete and complete response (Wilcoxon rank-sum test, LEV: p =0.29, PB: p=0.06, Figure 3).
      Figure thumbnail gr3
      Figure 3Highest administered dosage of the first-line anti-seizure medication (ASM) to the 108 neonates with seizures treated with levetiracetam (LEV) or phenobarbital (PB), stratified by first-line ASM response. The red rhombus depicts the mean and the bold black lines depicts the median in each boxplot. The highest administered dose of LEV did not differ significantly between neonates with complete response (mean ± SD: 42.8 ± 22.1 mg/kg, Wilcoxon rank-sum test, p = 0.29) and incomplete response (50.8 ± 22.0 mg/kg). Similarly, the highest administered dose of PB did not differ significantly between neonates with complete response (14.2 ± 9.7 mg/kg, Wilcoxon rank-sum test, p = 0.06) and incomplete response (20.1 ± 14.0 mg/kg).

      3.4 Treatment response according to seizure frequency

      The risk for incomplete response to the first-line ASM was 2.22, 3.26, 3.53 times higher for occasional seizures (p=0.01), frequent seizures (p<0.001), and status epilepticus (p<0.001) compared to rare seizures, based on the generalized linear model (Figure 4, Table 2). Treatment outcome risks did not differ significantly by gestational age, etiology, EEG findings, or ASM.
      Figure thumbnail gr4
      Figure 4Incidence rate ratios of the variables that determined the response to the first-line ASM based on the generalized linear model. In a fitted regression model including gestational age, etiology, seizure frequency, EEG findings, and first-line ASM, only higher seizure frequency (occasional seizures, frequent seizures, status epilepticus) was associated with a less favorable response to the first-line ASM (p<0.05). ASM: anti-seizure medication, PB: phenobarbital, LEV: levetiracetam. *: statistical significance, p<0.05
      Table 2Response to the first-line and second-line anti-seizure medication (ASM) according to the clinical features of the patients and to the respective ASM: multivariate analysis.
      STRUCTURAL EPILEPSIESCortical malformations (n=3)
      Aicardi syndrome (n=2)
      GENETIC EPILEPSIESKCNQ2 gene mutation (n=5)
      Zellweger syndrome (n=3)
      STXBP1 gene mutation (n=2)
      KCNT1 gene mutation (n=1)
      SCN2A gene mutation (n=1)
      SLC25A15 gene mutation (n=1)
      GTPBP2 gene mutation (n=1)
      BRPF1 gene mutation (n=1)
      CCDC141 gene mutation (n=1)
      TUBA1A gene mutation (n=1)
      MMACHC gene mutation (n=1)
      Trisomy 13 (n=1)
      In a fitted regression model including gestational age, etiology, seizure frequency, EEG findings, and ASM, only seizure frequency remained significantly associated with the response to first-line and second-line ASM (p<0.05). To be noted: in the first-line ASM column, 9 patients with unknown seizure etiology were excluded, in the second-line ASM column, only patients receiving PB or LEV as second-line ASM were included. N: number of patients, PB: phenobarbital, LEV: levetiracetam.
      *: statistical significance, p<0.05.

      3.5 Adverse events

      Adverse events were noted in 22 (24%) of neonates treated with PB and in only 1 (1%) of those treated with LEV (p<0.001).

      4. DISCUSSION

      Treatment response to the first-line ASM in neonates with EEG-confirmed seizures was overall low in our study and did not differ between LEV and PB among all neonates, or among those with acute symptomatic seizures and neonatal onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency but did not differ by gestational age, etiology, or EEG findings. The adverse-effect profile of LEV was more favorable compared to PB. Our study thus suggests that LEV may be a safe and effective alternative to PB as a first-line ASM in treating neonatal seizures.

      4.1 ASM efficacy

      Seizures ceased after administration of LEV or PB as first-line ASM in less than one-half of neonates and as first- and second-line ASM combined in just over one-half of neonates, reflecting the results of the clinical trial of PB vs. PHT [
      • Painter M.J.
      • Scher M.S.
      • Stein A.D.
      • Armatti S.
      • Wang Z.
      • Gardiner J.C.
      • et al.
      Phenobarbital compared with phenytoin for the treatment of neonatal seizures.
      ] performed over 20 years ago. These findings underline the still unmet need for effective therapies in neonatal seizures, despite the introduction of newer ASM in the last two decades [
      • Thibault C.
      • Naim M.Y.
      • Abend N.S.
      • Licht D.J.
      • Gaynor J.W.
      • Xiao R.
      • et al.
      A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
      ,
      • Glass H.C.
      • Soul J.S.
      • Chu C.J.
      • Massey S.L.
      • Wusthoff C.J.
      • Chang T.
      • et al.
      Response to antiseizure medications in neonates with acute symptomatic seizures.
      ,
      • Boylan G.B.
      • Rennie J.M.
      • Chorley G.
      • Pressler R.M.
      • Fox G.F.
      • Farrer K.
      • et al.
      Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study.
      ]. The low first-line ASM efficacy of both LEV (45%) and PB (36%) in our study is in line with contemporary real world data [
      • Glass H.C.
      • Shellhaas R.A.
      • Wusthoff C.J.
      • Chang T.
      • Abend N.S.
      • Chu C.J.
      • et al.
      Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study.
      ] but stands in contrast with the much higher efficacy of PB (80%) in a recent multicenter randomized trial [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ]. Higher seizure control rates in that clinical trial [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ] may be attributed to the implementation of continuous video-EEG for early seizure identification in neonates at risk, thus enabling timely treatment initiation that can considerably improve ASM efficacy [
      • Williams R.P.
      • Banwell B.
      • Berg R.A.
      • Dlugos D.J.
      • Donnelly M.
      • Ichord R.
      • et al.
      Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
      ,
      • Harris M.L.
      • Malloy K.M.
      • Lawson S.N.
      • Rose R.S.
      • Buss W.F.
      • Mietzsch U.
      Standardized Treatment of Neonatal Status Epilepticus Improves Outcome.
      ]. However, continuous video-EEG monitoring is unattainable in the daily clinical practice, despite the recent technological advances, including the remote review of video-EEG and the development of automated neonatal seizure detection algorithms [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ,
      • Sharpe C.
      • Davis S.L.
      • Reiner G.E.
      • Lee L.I.
      • Gold J.J.
      • Nespeca M.
      • et al.
      Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring.
      ]. Chief obstacles remain the EEG electrode placement to start monitoring and the availability of real-time expert review of suspect events captured by video-EEG [
      • Sharpe C.
      • Davis S.L.
      • Reiner G.E.
      • Lee L.I.
      • Gold J.J.
      • Nespeca M.
      • et al.
      Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring.
      ].
      Treatment response to the first-line ASM in neonates with seizures of various etiologies and, specifically, with acute symptomatic seizures did not differ between LEV and PB in our study, in line with previous observations [
      • Glass H.C.
      • Soul J.S.
      • Chu C.J.
      • Massey S.L.
      • Wusthoff C.J.
      • Chang T.
      • et al.
      Response to antiseizure medications in neonates with acute symptomatic seizures.
      ,
      • Shellhaas R.A.
      • Chang T.
      • Wusthoff C.J.
      • Soul J.S.
      • Massey S.L.
      • Chu C.J.
      • et al.
      Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study.
      ]. It should be noted that seizures were acute symptomatic in over two-thirds of our cohort, consistent with large population studies [
      • Shellhaas R.A.
      • Wusthoff C.J.
      • Tsuchida T.N.
      • Glass H.C.
      • Chu C.J.
      • Massey S.L.
      • et al.
      Profile of neonatal epilepsies: Characteristics of a prospective US cohort.
      ], and that the findings in neonates with hypoxic-ischemic encephalopathy support the generalizability of our results to that crucial patient group. Our findings of equal though incomplete efficacy of LEV and PB are in line with a recent systematic review [
      • McHugh D.C.
      • Lancaster S.
      • Manganas L.N.
      A Systematic Review of the Efficacy of Levetiracetam in Neonatal Seizures.
      ] and a later meta-analysis [
      • Qiao M.-Y.
      • Cui H.-T.
      • Zhao L.-Z.
      • Miao J.-K.
      • Chen Q.-X.
      Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis.
      ] that showed no difference in efficacy between LEV and PB in treating neonatal seizures. However, it should be noted that these analyses considered studies that differed as to the criteria for neonatal seizure diagnosis and treatment response [
      • McHugh D.C.
      • Lancaster S.
      • Manganas L.N.
      A Systematic Review of the Efficacy of Levetiracetam in Neonatal Seizures.
      ,
      • Qiao M.-Y.
      • Cui H.-T.
      • Zhao L.-Z.
      • Miao J.-K.
      • Chen Q.-X.
      Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis.
      ], while only few studies have employed continuous video-EEG for treatment initiation and monitoring or followed the requirements of a randomized controlled trial. The disparity in study design may at least partly account for the divergent results between our study (and other past studies) and the recent trial that reported a considerably higher efficacy for PB than for LEV [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ].
      Neonates with a higher seizure frequency in our study were less likely to respond to the first-line ASM. In contrast, treatment response did not differ by gestational age, etiology, or EEG findings, in line with previous reports [
      • Painter M.J.
      • Scher M.S.
      • Stein A.D.
      • Armatti S.
      • Wang Z.
      • Gardiner J.C.
      • et al.
      Phenobarbital compared with phenytoin for the treatment of neonatal seizures.
      ,
      • Thibault C.
      • Naim M.Y.
      • Abend N.S.
      • Licht D.J.
      • Gaynor J.W.
      • Xiao R.
      • et al.
      A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
      ,
      • Glass H.C.
      • Soul J.S.
      • Chu C.J.
      • Massey S.L.
      • Wusthoff C.J.
      • Chang T.
      • et al.
      Response to antiseizure medications in neonates with acute symptomatic seizures.
      ]. Ever since the clinical trial of PB vs. PHT [
      • Painter M.J.
      • Scher M.S.
      • Stein A.D.
      • Armatti S.
      • Wang Z.
      • Gardiner J.C.
      • et al.
      Phenobarbital compared with phenytoin for the treatment of neonatal seizures.
      ], it has been noted that the likelihood of treatment success in neonatal seizures decreases with increasing seizure frequency. This observation should be considered when comparing ASM efficacy in our study with the recent trial that identified seizures by continuous video-EEG [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ], thus including patients at seizure onset, and with a yet low seizure frequency. High seizure frequency, with status epilepticus and frequent seizures in one-fourth each of our cohort, may at least partly account for the relatively low rates of seizure cessation after first-line ASM administration in our study, compared to previous work [
      • Thibault C.
      • Naim M.Y.
      • Abend N.S.
      • Licht D.J.
      • Gaynor J.W.
      • Xiao R.
      • et al.
      A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
      ,
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ]. Interestingly, higher ASM doses were not linked to improved efficacy in our cohort, although some neonates received LEV dosages higher than the licensed 60mg/kg per day that have recently been shown to improve seizure control [
      • Hnaini M.
      • Darwich M.
      • Koleilat N.
      • Jaafar F.
      • Hanneyan S.
      • Rahal S.
      • et al.
      High-Dose Levetiracetam for Neonatal Seizures: A Retrospective Review.
      ]. Although it is tempting to try higher doses, particularly of LEV, due to its favorable safety profile, to overcome incomplete seizure response, this should not lead to unnecessary delays in treatment with other, potentially effective ASM.

      4.2 ASM adverse events

      Adverse events, including hypotension, respiratory suppression, and sedation, were noted in one-fourth of neonates treated with PB and only in a single case of those treated with LEV. Our study thus supports a more favorable adverse-effect profile of LEV than PB, in line with previous work [
      • Thibault C.
      • Naim M.Y.
      • Abend N.S.
      • Licht D.J.
      • Gaynor J.W.
      • Xiao R.
      • et al.
      A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
      ,
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ]. In particular, hypotension attributed to PB administration has been reported in one-half of treated neonates with hypoxic-ischemic encephalopathy [
      • Filippi L.
      • la Marca G.
      • Cavallaro G.
      • Fiorini P.
      • Favelli F.
      • Malvagia S.
      • et al.
      Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia.
      ] and one-sixth of treated neonates with seizures related to cardiac surgery [
      • Thibault C.
      • Naim M.Y.
      • Abend N.S.
      • Licht D.J.
      • Gaynor J.W.
      • Xiao R.
      • et al.
      A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
      ]. Hypotension and respiratory depression following PB administration are alarming side-effects in neonates with hemodynamic instability, requiring necessary adaptations of treatment management. In contrast, LEV has an excellent safety profile. It has not been associated with any serious adverse effects in numerous clinical studies, including those employing high doses for neonatal seizure control [
      • Ramantani G.
      • Ikonomidou C.
      • Walter B.
      • Rating D.
      • Dinger J.
      Levetiracetam: safety and efficacy in neonatal seizures.
      ,
      • Abend N.S.
      • Gutierrez-Colina A.M.
      • Monk H.M.
      • Dlugos D.J.
      • Clancy R.R.
      Levetiracetam for treatment of neonatal seizures.
      ,
      • Hnaini M.
      • Darwich M.
      • Koleilat N.
      • Jaafar F.
      • Hanneyan S.
      • Rahal S.
      • et al.
      High-Dose Levetiracetam for Neonatal Seizures: A Retrospective Review.
      ,
      • Fürwentsches A.
      • Bussmann C.
      • Ramantani G.
      • Ebinger F.
      • Philippi H.
      • Pöschl J.
      • et al.
      Levetiracetam in the treatment of neonatal seizures: a pilot study.
      ,
      • Falsaperla R.
      • Vitaliti G.
      • Mauceri L.
      • Romano C.
      • Pavone P.
      • Motamed-Gorji N.
      • et al.
      Levetiracetam in Neonatal Seizures as First-line Treatment: A Prospective Study.
      ,
      • Han J.Y.
      • Moon C.J.
      • Youn Y.A.
      • Sung I.K.
      • Lee I.G.
      Efficacy of levetiracetam for neonatal seizures in preterm infants.
      ]. Our study thus verifies a crucial difference in the safety profile of LEV compared with PB that has been previously noted in the recent randomized controlled trial of neonatal seizure treatment [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ] but failed to reach statistical significance in that cohort. It should be noted that the administration of PB had not been associated with any changes in heart rate, heart rhythm, mean arterial pressure, or respiratory status in the clinical trial of PB vs. PHT [
      • Painter M.J.
      • Scher M.S.
      • Stein A.D.
      • Armatti S.
      • Wang Z.
      • Gardiner J.C.
      • et al.
      Phenobarbital compared with phenytoin for the treatment of neonatal seizures.
      ]. This observation leads to think that therapeutic hypothermia and concurrent morphine treatment as the current standard of care, may at least partly exacerbate the side effects of PB [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ].

      4.3 Limitations

      Although our findings derive from a large, well-studied cohort, with EEG-confirmation of neonatal seizures, first-line treatment with either LEV or PB, and inclusion of many important clinical characteristics for analysis, our study still has several limitations. First, the size of our cohort and the retrospective design of our study may have prevented the identification of specific subgroups which may have shown an optimal response to a particular ASM. However, our results are overall consistent with other contemporary multicentric studies and with recent meta-analyses, supporting the generalizability of our findings. Second, by considering only neonates with EEG-confirmed seizures, we may have introduced a bias towards a higher seizure frequency, considering the sampling limitations of routine EEG recordings. Studies deriving from continuous video-EEG monitoring are bound to include neonates with less abundant seizure activity that may show a more favorable response to ASM [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ]. Third, the precise latency from seizure manifestation to treatment initiation and treatment response in our study remained unknown due to the lack of continuous video-EEG monitoring. However, this latency may prove crucial for ASM efficacy in neonatal seizures [
      • Sharpe C.
      • Reiner G.E.
      • Davis S.L.
      • Nespeca M.
      • Gold J.J.
      • Rasmussen M.
      • et al.
      Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      ]. Fourth, ASM use was not randomized in our study that originated from a change in our institutional protocol. Since the choice of first-line ASM depended on the treating physician’s decision, it cannot be ruled out that a higher proportion of more severely affected neonates received PB as first-line ASM for presumably difficult to treat seizures and that this bias may have negatively impacted PB efficacy in our study. Finally, more than one-third of neonates with EEG-confirmed seizures who received ASM treatment in our institution could not be included in our study due to first-line treatment with ASM other than LEV or PB or due to lack of general consent from parents. It cannot be ruled out that the personal preference of physicians for benzodiazepines and the personal decision of parents to refuse informed general consent may account for a selection bias in our study.
      Despite these limitations, the findings of our retrospective cohort study have significant implications for neonatal seizure management since they offer crucial and complementary knowledge deriving from a real-world clinical setting. In contrast to previous studies, our findings stem from a neonatal cohort with EEG-confirmed seizures [
      • Wagner C.B.
      • Kreimer A.M.
      • Carrillo N.P.
      • Autry E.
      • Schadler A.
      • Cook A.M.
      • et al.
      Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response.
      ,
      • Gowda V.K.
      • Romana A.
      • Shivanna N.H.
      • Benakappa N.
      • Benakappa A.
      Levetiracetam versus Phenobarbitone in Neonatal Seizures - A Randomized Controlled Trial.
      ], treated with first-line LEV or PB in a standardized dosage [
      • Abend N.S.
      • Gutierrez-Colina A.M.
      • Monk H.M.
      • Dlugos D.J.
      • Clancy R.R.
      Levetiracetam for treatment of neonatal seizures.
      ,
      • Khan O.
      • Cipriani C.
      • Wright C.
      • Crisp E.
      • Kirmani B.
      Role of intravenous levetiracetam for acute seizure management in preterm neonates.
      ,
      • Khan O.
      • Chang E.
      • Cipriani C.
      • Wright C.
      • Crisp E.
      • Kirmani B.
      Use of intravenous levetiracetam for management of acute seizures in neonates.
      ,
      • Rakshasbhuvankar A.
      • Rao S.
      • Kohan R.
      • Simmer K.
      • Nagarajan L.
      Intravenous levetiracetam for treatment of neonatal seizures.
      ], and enabling the comparison of LEV vs. PB in sizeable subgroups that do not differ significantly as to their key clinical features. Furthermore, our study addresses the impact of these clinical features such as gestational age, seizure etiology, EEG findings, and seizure frequency, on treatment response, in addition to the first-line ASM.

      CONCLUSION

      PB was associated with more adverse events than LEV, and the two ASMs were equally but incompletely effective in treating neonatal seizures. Our findings suggest that LEV may be a safe and effective alternative to PB as a first-line therapy in these neonates. Treatment of EEG-confirmed neonatal seizures should be initiated as early as possible considering that a higher seizure frequency predisposes to a less favorable response. In future studies, further subgroup analyses of treatment response may shed some light on the efficacy of LEV vs. PB in specific settings. Long-term follow-up analyses in infants previously treated with LEV vs. PB for neonatal seizures are crucial to address the impact of these ASMs on long-term seizure and cognitive outcomes.

      DATA SHARING

      Source code and data necessary for the replication of our results and figures will be available at publication.

      Acknowledgments

      We thank the neurophysiology technicians, H. Critelli, I. Knaus, C. Huber, L. Dube, and S. Gräub, for their assistance with EEG recordings and data analysis. We thank the Vontobel Foundation (to G.R.) for funding. The funder had no role in the design or analysis of the study.

      REFERENCES

        • Lanska M.J.
        • Lanska D.J.
        • Baumann R.J.
        • Kryscio R.J.
        A population-based study of neonatal seizures in Fayette County, Kentucky.
        Neurology. 1995; 45: 724-732
        • Ronen G.M.
        • Penney S.
        • Andrews W.
        The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study.
        J Pediatr. 1999; 134: 71-75https://doi.org/10.1016/s0022-3476(99)70374-4
        • Saliba R.M.
        • Annegers J.F.
        • Waller D.K.
        • Tyson J.E.
        • Mizrahi E.M.
        Incidence of neonatal seizures in Harris County, Texas, 1992-1994.
        Am J Epidemiol. 1999; 150: 763-769https://doi.org/10.1093/oxfordjournals.aje.a010079
        • Glass H.C.
        • Pham T.N.
        • Danielsen B.
        • Towner D.
        • Glidden D.
        • Wu Y.W.
        Antenatal and intrapartum risk factors for seizures in term newborns: a population-based study.
        California. 1998-2002; 154 (J Pediatr 2009): 24-28.e1https://doi.org/10.1016/j.jpeds.2008.07.008
        • Kohelet D.
        • Shochat R.
        • Lusky A.
        • Reichman B.
        • Israel Neonatal Network
        Risk factors for neonatal seizures in very low birthweight infants: population-based survey.
        J Child Neurol. 2004; 19: 123-128https://doi.org/10.1177/08830738040190020701
        • Pisani F.
        • Cerminara C.
        • Fusco C.
        • Sisti L.
        Neonatal status epilepticus vs recurrent neonatal seizures: Clinical findings and outcome.
        Neurology. 2007; 69https://doi.org/10.1212/01.wnl.0000295674.34193.9e
        • Ronen G.M.
        • Buckley D.
        • Penney S.
        • Streiner D.L.
        Long-term prognosis in children with neonatal seizures: a population-based study.
        Neurology. 2007; 69: 1816-1822https://doi.org/10.1212/01.wnl.0000279335.85797.2c
        • Ramantani G.
        • Schmitt B.
        • Plecko B.
        • Pressler R.M.
        • Wohlrab G.
        • Klebermass-Schrehof K.
        • et al.
        Neonatal Seizures-Are We there Yet?.
        Neuropediatrics. 2019; 50: 280-293https://doi.org/10.1055/s-0039-1693149
        • Pisani F.
        • Spagnoli C.
        • Falsaperla R.
        • Nagarajan L.
        • Ramantani G.
        Seizures in the neonate: A review of etiologies and outcomes.
        Seizure. 2021; 85: 48-56https://doi.org/10.1016/j.seizure.2020.12.023
        • Ramantani G.
        Neonatal epilepsy and underlying aetiology: to what extent do seizures and EEG abnormalities influence outcome?.
        Epileptic Disord Int Epilepsy J Videotape. 2013; 15: 365-375https://doi.org/10.1684/epd.2013.0619
        • Pressler R.M.
        • Mangum B.
        Newly emerging therapies for neonatal seizures.
        Semin Fetal Neonatal Med. 2013; 18: 216-223https://doi.org/10.1016/j.siny.2013.04.005
        • Glass H.C.
        • Kan J.
        • Bonifacio S.L.
        • Ferriero D.M.
        Neonatal seizures: treatment practices among term and preterm infants.
        Pediatr Neurol. 2012; 46: 111-115https://doi.org/10.1016/j.pediatrneurol.2011.11.006
        • Painter M.J.
        • Scher M.S.
        • Stein A.D.
        • Armatti S.
        • Wang Z.
        • Gardiner J.C.
        • et al.
        Phenobarbital compared with phenytoin for the treatment of neonatal seizures.
        N Engl J Med. 1999; 341: 485-489https://doi.org/10.1056/NEJM199908123410704
        • Scher M.S.
        • Alvin J.
        • Gaus L.
        • Minnigh B.
        • Painter M.J.
        Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use.
        Pediatr Neurol. 2003; 28: 277-280
        • Bittigau P.
        • Sifringer M.
        • Genz K.
        • Reith E.
        • Pospischil D.
        • Govindarajalu S.
        • et al.
        Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.
        Proc Natl Acad Sci U S A. 2002; 99: 15089-15094https://doi.org/10.1073/pnas.222550499
        • Forcelli P.A.
        • Janssen M.J.
        • Vicini S.
        • Gale K.
        Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development.
        Ann Neurol. 2012; 72: 363-372https://doi.org/10.1002/ana.23600
        • Ramantani G.
        • Ikonomidou C.
        • Walter B.
        • Rating D.
        • Dinger J.
        Levetiracetam: safety and efficacy in neonatal seizures.
        Eur J Paediatr Neurol EJPN Off J Eur Paediatr Neurol Soc. 2011; 15: 1-7https://doi.org/10.1016/j.ejpn.2010.10.003
        • Thibault C.
        • Naim M.Y.
        • Abend N.S.
        • Licht D.J.
        • Gaynor J.W.
        • Xiao R.
        • et al.
        A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.
        Epilepsia. 2020; 61: 627-635https://doi.org/10.1111/epi.16469
        • Rao L.M.
        • Hussain S.A.
        • Zaki T.
        • Cho A.
        • Chanlaw T.
        • Garg M.
        • et al.
        A comparison of levetiracetam and phenobarbital for the treatment of neonatal seizures associated with hypoxic-ischemic encephalopathy.
        Epilepsy Behav EB. 2018; 88: 212-217https://doi.org/10.1016/j.yebeh.2018.09.015
      1. Han JY, Moon CJ, Youn YA, Sung IK, Lee IG. Efficacy of levetiracetam for neonatal seizures in preterm infants 2018:1–6.

        • Abend N.S.
        • Gutierrez-Colina A.M.
        • Monk H.M.
        • Dlugos D.J.
        • Clancy R.R.
        Levetiracetam for treatment of neonatal seizures.
        J Child Neurol. 2011; 26: 465-470https://doi.org/10.1177/0883073810384263
        • Khan O.
        • Cipriani C.
        • Wright C.
        • Crisp E.
        • Kirmani B.
        Role of intravenous levetiracetam for acute seizure management in preterm neonates.
        Pediatr Neurol. 2013; 49: 340-343https://doi.org/10.1016/j.pediatrneurol.2013.05.008
        • Ahmad K.A.
        • Desai S.J.
        • Bennett M.M.
        • Ahmad S.F.
        • Ng Y.-T.
        • Clark R.H.
        • et al.
        Changing antiepileptic drug use for seizures in US neonatal intensive care units from 2005 to 2014.
        J Perinatol Off J Calif Perinat Assoc. 2017; 37: 296-300https://doi.org/10.1038/jp.2016.206
        • Lima-Rogel V.
        • López-López E.J.
        • Medellín-Garibay S.E.
        • Gómez-Ruiz L.M.
        • Romero-Méndez C.
        • Milán-Segovia R.C.
        • et al.
        Population pharmacokinetics of levetiracetam in neonates with seizures.
        J Clin Pharm Ther. 2018; 43: 422-429https://doi.org/10.1111/jcpt.12658
        • Pacifici G.M.
        Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics.
        Curr Pediatr Rev. 2016; 12: 48-54https://doi.org/10.2174/1573397111666151026223914
        • Hooper R.G.
        • Ramaswamy V.V.
        • Wahid R.M.
        • Satodia P.
        • Bhulani A.
        Levetiracetam as the first-line treatment for neonatal seizures: a systematic review and meta-analysis.
        Dev Med Child Neurol. 2021; 63: 1283-1293https://doi.org/10.1111/dmcn.14943
        • McHugh D.C.
        • Lancaster S.
        • Manganas L.N.
        A Systematic Review of the Efficacy of Levetiracetam in Neonatal Seizures.
        Neuropediatrics. 2018; 49: 12-17https://doi.org/10.1055/s-0037-1608653
        • Sharpe C.
        • Reiner G.E.
        • Davis S.L.
        • Nespeca M.
        • Gold J.J.
        • Rasmussen M.
        • et al.
        Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
        Pediatrics. 2020; 145e20193182https://doi.org/10.1542/peds.2019-3182
        • Khan O.
        • Chang E.
        • Cipriani C.
        • Wright C.
        • Crisp E.
        • Kirmani B.
        Use of intravenous levetiracetam for management of acute seizures in neonates.
        Pediatr Neurol. 2011; 44: 265-269https://doi.org/10.1016/j.pediatrneurol.2010.11.005
        • Rakshasbhuvankar A.
        • Rao S.
        • Kohan R.
        • Simmer K.
        • Nagarajan L.
        Intravenous levetiracetam for treatment of neonatal seizures.
        J Clin Neurosci Off J Neurosurg Soc Australas. 2013; 20: 1165-1167https://doi.org/10.1016/j.jocn.2012.08.014
        • Holmes G.L.
        • Lombroso C.T.
        Prognostic value of background patterns in the neonatal EEG.
        J Clin Neurophysiol Off Publ Am Electroencephalogr Soc. 1993; 10: 323-352https://doi.org/10.1097/00004691-199307000-00008
        • Tsuchida T.N.
        • Wusthoff C.J.
        • Shellhaas R.A.
        • Abend N.S.
        • Hahn C.D.
        • Sullivan J.E.
        • et al.
        American clinical neurophysiology society standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates: report of the American Clinical Neurophysiology Society critical care monitoring committee.
        J Clin Neurophysiol Off Publ Am Electroencephalogr Soc. 2013; 30: 161-173https://doi.org/10.1097/WNP.0b013e3182872b24
        • Pressler R.M.
        • Cilio M.R.
        • Mizrahi E.M.
        • Moshé S.L.
        • Nunes M.L.
        • Plouin P.
        • et al.
        The ILAE classification of seizures and the epilepsies: Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures.
        Epilepsia. 2021; 62: 615-628https://doi.org/10.1111/epi.16815
        • Glass H.C.
        • Soul J.S.
        • Chu C.J.
        • Massey S.L.
        • Wusthoff C.J.
        • Chang T.
        • et al.
        Response to antiseizure medications in neonates with acute symptomatic seizures.
        Epilepsia. 2019; 60 (4): e20https://doi.org/10.1111/epi.14671
        • Boylan G.B.
        • Rennie J.M.
        • Chorley G.
        • Pressler R.M.
        • Fox G.F.
        • Farrer K.
        • et al.
        Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study.
        Neurology. 2004; 62: 486-488
        • Glass H.C.
        • Shellhaas R.A.
        • Wusthoff C.J.
        • Chang T.
        • Abend N.S.
        • Chu C.J.
        • et al.
        Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study.
        J Pediatr. 2016; 174 (e1): 98-103https://doi.org/10.1016/j.jpeds.2016.03.035
        • Williams R.P.
        • Banwell B.
        • Berg R.A.
        • Dlugos D.J.
        • Donnelly M.
        • Ichord R.
        • et al.
        Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
        Epilepsia. 2016; 57: 786-795https://doi.org/10.1111/epi.13354
        • Harris M.L.
        • Malloy K.M.
        • Lawson S.N.
        • Rose R.S.
        • Buss W.F.
        • Mietzsch U.
        Standardized Treatment of Neonatal Status Epilepticus Improves Outcome.
        J Child Neurol. 2016; 31: 1546-1554https://doi.org/10.1177/0883073816664670
        • Sharpe C.
        • Davis S.L.
        • Reiner G.E.
        • Lee L.I.
        • Gold J.J.
        • Nespeca M.
        • et al.
        Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring.
        J Clin Neurophysiol Off Publ Am Electroencephalogr Soc. 2019; 36: 9-13https://doi.org/10.1097/WNP.0000000000000525
        • Shellhaas R.A.
        • Chang T.
        • Wusthoff C.J.
        • Soul J.S.
        • Massey S.L.
        • Chu C.J.
        • et al.
        Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study.
        J Pediatr. 2017; 181 (e1): 298-301https://doi.org/10.1016/j.jpeds.2016.10.039
        • Shellhaas R.A.
        • Wusthoff C.J.
        • Tsuchida T.N.
        • Glass H.C.
        • Chu C.J.
        • Massey S.L.
        • et al.
        Profile of neonatal epilepsies: Characteristics of a prospective US cohort.
        Neurology. 2017; 89: 893-899https://doi.org/10.1212/WNL.0000000000004284
        • Qiao M.-Y.
        • Cui H.-T.
        • Zhao L.-Z.
        • Miao J.-K.
        • Chen Q.-X.
        Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis.
        Front Neurol. 2021; 12747745https://doi.org/10.3389/fneur.2021.747745
        • Hnaini M.
        • Darwich M.
        • Koleilat N.
        • Jaafar F.
        • Hanneyan S.
        • Rahal S.
        • et al.
        High-Dose Levetiracetam for Neonatal Seizures: A Retrospective Review.
        Seizure. 2020; 82: 7-11https://doi.org/10.1016/j.seizure.2020.08.030
        • Filippi L.
        • la Marca G.
        • Cavallaro G.
        • Fiorini P.
        • Favelli F.
        • Malvagia S.
        • et al.
        Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia.
        Epilepsia. 2011; 52: 794-801https://doi.org/10.1111/j.1528-1167.2011.02978.x
        • Fürwentsches A.
        • Bussmann C.
        • Ramantani G.
        • Ebinger F.
        • Philippi H.
        • Pöschl J.
        • et al.
        Levetiracetam in the treatment of neonatal seizures: a pilot study.
        Seizure. 2010; 19: 185-189https://doi.org/10.1016/j.seizure.2010.01.003
        • Falsaperla R.
        • Vitaliti G.
        • Mauceri L.
        • Romano C.
        • Pavone P.
        • Motamed-Gorji N.
        • et al.
        Levetiracetam in Neonatal Seizures as First-line Treatment: A Prospective Study.
        J Pediatr Neurosci. 2017; 12: 24-28https://doi.org/10.4103/jpn.JPN_172_16
        • Han J.Y.
        • Moon C.J.
        • Youn Y.A.
        • Sung I.K.
        • Lee I.G.
        Efficacy of levetiracetam for neonatal seizures in preterm infants.
        BMC Pediatr. 2018; 18: 131https://doi.org/10.1186/s12887-018-1103-1
        • Wagner C.B.
        • Kreimer A.M.
        • Carrillo N.P.
        • Autry E.
        • Schadler A.
        • Cook A.M.
        • et al.
        Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response.
        J Pediatr Pharmacol Ther JPPT Off J PPAG. 2021; 26: 144-150https://doi.org/10.5863/1551-6776-26.2.144
        • Gowda V.K.
        • Romana A.
        • Shivanna N.H.
        • Benakappa N.
        • Benakappa A.
        Levetiracetam versus Phenobarbitone in Neonatal Seizures - A Randomized Controlled Trial.
        Indian Pediatr. 2019; 56: 643-646