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.
In 1999, a randomized controlled trial comparing phenobarbital and phenytoin in neonates revealed that each drug had 45% efficacy. These treatments remain the standard of care for neonatal seizures. Levetiracetam has a better safety profile; however, its efficacy is unproven in neonates.
In this study conducted in the hypothermia era and with near real-time response to continuous video EEG monitoring, phenobarbital was more effective than levetiracetam in achieving seizure cessation. Dose-finding studies and phase III trials with long-term outcomes are needed.
Neonatal seizures affect 1 to 4 of 1000 newborns1 and are associated with poor outcomes: 7% to 33% of infants with neonatal seizures die, and 40% to 60% of survivors have permanent disabilities, including cerebral palsy, global developmental delay, and epilepsy.2 Mortality and morbidity of neonatal seizures are in large part attributed to the underlying condition; however, there is mounting evidence that seizures themselves are harmful, especially in the asphyxiated neonatal brain.3–9 Neonatal seizures frequently fail to respond to the most common treatments: phenobarbital and phenytoin.10–13 Acute side effects of phenobarbital include hypotension, respiratory suppression, and sedation; chronic exposure to phenobarbital may cause decreased cognitive ability.14–17 In animal studies, phenobarbital causes accelerated neuronal apoptosis in the immature brain.18–22
Levetiracetam has good efficacy and an excellent safety profile. Most animal studies have revealed that levetiracetam does not cause neuronal apoptosis or disruption of synaptic development; in fact, it may have neuroprotective effects.23–29 These qualities and the availability of an intravenous (IV) preparation have led to its widespread use in neonates, ahead of prospective evidence of its efficacy.30,31 Because the neonatal response to anticonvulsants is fundamentally different from that of the older brain, specific study of levetiracetam within the neonatal population is essential; drugs that are effective in terminating seizures in older patients may be less effective and more toxic in neonates. The pharmacokinetics of levetiracetam in neonates have been studied.32–34 The efficacy of levetiracetam used mostly as a second-line agent for neonatal seizures has been reported in case series to be between 30% and 84%.35,36 NEOLEV2 was conducted with the specific objectives of studying the efficacy of levetiracetam compared with phenobarbital in the first-line treatment of neonatal seizures, the additional efficacy of loading-dose escalation from 40 to 60 mg/kg of levetiracetam, and the safety of levetiracetam in neonates.
Methods
Study Design
NEOLEV2 was a multicenter, randomized, blinded, controlled, phase IIb efficacy, dose-escalation, and safety study of levetiracetam compared with phenobarbital in the first-line treatment of neonatal seizures. NEOLEV2 was an investigator-initiated, US Food and Drug Administration (FDA)-funded study. The participating hospitals were Rady Children’s Hospital–San Diego; Sharp Mary Birch Hospital for Women & Newborns (San Diego, CA); University of California, San Diego Medical Center; University of California, San Francisco Benioff Children’s Hospital (Oakland, CA); Auckland City Hospital (Auckland, New Zealand); and Loma Linda University Medical Center (Loma Linda, CA). The Loma Linda site closed early because of low recruitment. The study was approved by the institutional review boards of each center, and written consent was obtained from parents of all patients. A steering committee and separate data-safety monitoring board guided and monitored the study.
Inclusion and Exclusion Criteria
Infants at risk for developing seizures or suspected of having seizures were enrolled. Patients were term infants of a corrected gestational age between 36 and 44 weeks (<2 weeks of age) with a weight of at least 2.2 kg. Weight criteria were used to ensure that blood volumes drawn for monitoring were safe. Patients were excluded if they had received any previous anticonvulsants (with the exception of short-acting benzodiazepines administered for sedation >24 hours before enrollment), if the serum creatinine level was >1.6 mg/dL, or if seizures were due to correctable metabolic abnormalities (such as hypoglycemia or hypocalcemia). Patients in whom death was imminent were excluded. Patients in whom EEG monitoring could not be commenced before the need to treat definite clinical seizures were not recruited.
Eligible enrolled infants were started on continuous video EEG monitoring (cEEG). Seizures were defined as abrupt onset of rhythmic EEG activity lasting at least 10 seconds with a change in at least 2 of the following features: amplitude, frequency, or spatial distribution. Only neonates with electrographically confirmed seizures were treated. Video review was used to identify rhythmic artifact, such as patting or sucking.
Patients were randomly assigned to the levetiracetam or control phenobarbital treatment group in a 60:40 allocation ratio by using a block randomization strategy and stratified by site. Randomization lists, generated by the independent study statistical team, were communicated directly from the statistical center to the individual research pharmacies. Sterile dilution of phenobarbital injection (Westward or Martindale brand) was performed by research pharmacies, and prediluted Mylan-brand levetiracetam injection (15 mg/mL) was used according to a single standardized study protocol. Blinded study drugs were provided to the NICUs. All study investigators, medical staff, neurophysiologists, and patient families were blinded to treatment arm. Blinding was maintained by dilution of levetiracetam and phenobarbital such that the same volume (milliliters per kilogram) load was given to both treatment groups.
Our previous pharmacokinetic study of neonatal levetiracetam informed the loading and maintenance dosage of levetiracetam.32 In adults on levetiracetam, trough concentrations are typically in the range 6 to 20 µg/mL. Given the intractability of neonatal seizures, for the dosing regimen, we aimed to maintain trough levels at >20 µg/mL for the first 3 days of treatment, when seizures are most active.37,38
Treatment Protocol
Patients confirmed to have electrographic seizures received infusion over 15 minutes of either levetiracetam at 40 mg/kg or the control treatment with phenobarbital at 20 mg/kg, with an additional 15 minutes allowed for the medication to take effect (Fig 1). If electrographic seizures persisted or recurred 15 minutes after the first infusion was complete, an additional dose of the same treatment type was given. Patients who had received levetiracetam at 40 mg/kg received an additional 20 mg/kg infusion over 15 minutes; patients who had received phenobarbital at 20 mg/kg received an additional 20 mg/kg infusion over 15 minutes. If electrographic seizures persisted or recurred 15 minutes after the second infusion was complete, the patient was then treated with the alternate treatment. The protocol ensured that the initial 40 mg/kg load of levetiracetam was completed a minimum of 45 minutes before the escalation to phenobarbital and balanced the need to ensure that all patients received standard-of-care treatment with phenobarbital within 60 minutes if levetiracetam was ineffective. Patients given any levetiracetam loading doses received maintenance levetiracetam at 10 mg/kg per dose, given IV every 8 hours for 5 days. Patients given any phenobarbital loading doses received maintenance phenobarbital at 1.5 mg/kg per dose, given IV every 8 hours for 5 days. The phenobarbital dose was divided this way to maintain blinding. If seizures persisted after treatment with both study drugs, patients exited the study protocol and received additional treatment according to institutional protocols.
EEG Monitoring and Assessment of Seizure Cessation
We developed an infrastructure for cEEG monitoring using remote review via the Internet, EEG technicians from a commercial EEG monitoring company (CortiCare) who continuously reviewed the EEG for the first 24 hours, and automated neonatal seizure detection software (Persyst, Solana Beach, CA) to optimize early seizure detection.39 Cadwell EEG machines displaying 16-channel EEG and amplitude-integrated EEG were used. Neonates underwent cEEG monitoring for periods of 2 to 6 days. Neurologists at each site directed all anticonvulsant treatments.
Assessments of medication efficacy in seizure cessation were verified by review of the EEG by 2 independent neurophysiologists (S.L.D., J.J.G., S.W., M.N., N.R., M.L., or R.K.). Timed seizure markings from neurophysiologists were imported into a database. A third independent neurophysiologist (A.M. or S.L.D.) acted as a tiebreaker if discrepancies between the first 2 EEG reviewers impacted assessment of outcomes. Adjudication was required in 22 cases.
Outcomes
Seizure-Cessation Efficacy End Points
The primary outcome measure, which was validated by neurophysiologist review of the EEG, was the rate of achieving and maintaining electrographic seizure freedom for 24 hours. The original primary end point was 48-hour seizure freedom. After recruitment was complete, because EEG data were curated for data extraction, it was evident that EEG monitoring had been discontinued before 48 hours in many patients for clinical reasons, for example, to allow MRI or transfer of patients. After FDA approval, the primary outcome measure was, therefore, changed to 24-hour seizure cessation, which was the same time period used by Painter et al.13 The statistical analysis plan was reviewed by the FDA and finalized before database lock and unblinding to ensure that no bias was introduced by this change. Seizure cessation for 48 hours was maintained as a secondary outcome. Other prespecified secondary outcomes included the rate of achieving and maintaining seizure freedom for 1 hour and subanalyses of the primary outcome measure for subjects with hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia.
Dose-Escalation Analysis
The percentage of subjects who achieved the primary outcome measure of seizure freedom for 24 hours after treatment with 60 mg/kg of levetiracetam (having not responded to 40 mg/kg of levetiracetam) was calculated.
Safety
Patient characteristics, drug dosing, safety laboratory tests, and adverse events were recorded by clinical trial coordinators at each site and entered into the study Research Electronic Data Capture40 database hosted at University of California, San Diego. Because the study was conducted in a sick neonatal population, high rates of morbidity, clinical adverse events, abnormal laboratory values, and mortality were expected. In addition to the notification of recognized adverse events, systematic daily monitoring was conducted for hypotension, heart rate abnormality, respiratory abnormality, sedation, irritability, poor feeding, infection, need for oxygen, ventilation, or vasopressor treatment. A complete blood cell count and a comprehensive metabolic panel were measured before treatment and after 48 hours of treatment.
Statistical Analysis
Power calculations were based on a 2-sided χ2 test for detecting a difference between 2 proportions, assuming a type 1 error of 0.05. With a sample size of 60 subjects receiving levetiracetam and 40 subjects receiving phenobarbital and assuming a seizure-cessation rate of 50% in the control arm,13 the study had 80% power to detect an absolute difference in seizure outcome rates of ≥28% in the levetiracetam group.
Demographic and baseline characteristics of the 2 treatment groups were compared by using Fisher’s exact test for categorical variables and the Wilcoxon rank test for continuous variables.
All efficacy outcomes were analyzed according to the randomized treatment assignment in a modified intention-to-treat population that included all randomly assigned subjects with neurophysiologist-confirmed seizures and a seizure-termination assessment at 24 hours. The primary outcome, which was a comparison of the 24-hour seizure-termination rate between the 2 treatment arms, was calculated by using Fisher’s exact test. Secondary outcomes of 1- and 48-hour seizure-termination rates were analyzed similarly. A multivariate logistic regression analysis, adjusting for hypothermia treatment and HIE etiology, was performed as a secondary analysis. Three post hoc analyses were performed: to assess the possible impact of missing outcome data on the study results, post hoc sensitivity analyses using the best-worst case and worst-best case scores to impute missing primary outcome data were performed; an assessment of the primary outcome as assessed by the neurologist at the bedside was performed; and an additional post hoc analysis using a covariate-adjusted model, adjusted for baseline seizure severity, hypothermia treatment, and HIE etiology, was conducted.
Safety analyses were conducted on all randomly assigned participants. Fisher’s exact tests were used to compare rates of adverse events, serious adverse events, study discontinuations, and deaths. All safety measures were analyzed by randomization arm (levetiracetam or phenobarbital) and by drugs received (levetiracetam, phenobarbital, or levetiracetam and phenobarbital). All analyses were repeated in the per-protocol population as well as in prespecified subgroups: hypothermia treatment and HIE etiology. There was no prespecified plan for adjustment for multiple comparisons of safety variables or secondary efficacy outcomes. However, all results are reported as point estimates and corresponding 95% confidence intervals (CIs) to provide an estimate of the variability of the estimate. Analyses were conducted by using the statistical software R (version 3.4.2; http://www.r-project.org).
Results
Patient Enrollment, Study Completion, and Analysis
Between March 21, 2013, and October 31, 2017, 280 subjects consented to the study and underwent cEEG monitoring (Fig 2). One hundred six subjects were treated with study drugs for seizures. Five patients left the study before achieving the study end point. Thirty-five patients exited the study after the study end point but before completing 5 days of maintenance treatment. Twelve patients were excluded from the modified intention-to-treat population because neurophysiologists reviewing the EEG did not confirm the presence of seizures. In 11 patients, the primary outcome measure could not be obtained; in 5 of the 11, EEG data were either completely lost or missing at critical times; in 6 of the 11, efficacy data became uninterpretable (for details, see Fig 2). Two patients were excluded from the per-protocol population analysis because of protocol deviations. Eighty-three patients are included in the efficacy analysis (modified intention-to-treat population). There are 81 patients in the per-protocol analysis. Safety data were analyzed for all 106 treated patients.
Overall, 57 of 106 patients had HIE as the underlying cause of their seizures (54%); 42 patients underwent therapeutic hypothermia. Other seizure etiologies included stroke (18), hemorrhage (17), infection (6), brain malformation (5), pyridoxine-responsive epilepsy (2), drug withdrawal (2), glucose transporter defect (1), KCNQ2 (2), and unknown cause (12). The groups were well balanced at baseline on demographics, clinical variables, and pretreatment seizure severity (Table 1). Ethnicity, race, pregnancy abnormality, delivery situation, mode of delivery, and anesthesia (not shown) were all distributed evenly between randomization arms.
. | Levetiracetam . | Phenobarbital . | Overall . | Pa . |
---|---|---|---|---|
HIE as seizure etiology, n (%) | 35 (55) | 22 (52) | 57 (54) | Not tested |
Received hypothermia treatment, n (%) | 24 (38) | 18 (43) | 42 (40) | .7 |
Male sex, n (%) | 31 (48) | 24 (57) | 55 (52) | .4 |
Cord pH | .2 | |||
n | 31 | 20 | 51 | — |
Mean (SD) | 7.07 (0.2) | 7.15 (0.17) | 7.1 (0.19) | — |
Minimum, Q1, median | 6.65, 6.94, 7.09 | 6.76, 6.99, 7.22 | 6.65, 6.99, 7.15 | — |
Q3, maximum | 7.23, 7.35 | 7.28, 7.37 | 7.28, 7.37 | — |
5-min Apgar score | — | |||
n | 64 | 40 | 104 | — |
Mean (SD) | 6.52 (3.01) | 6.47 (2.4) | 6.5 (2.78) | .6 |
Minimum, Q1, median, Q3, maximum | 0, 4, 7.5, 9, 10 | 2, 4, 7, 9, 10 | 0, 4, 7, 9, 10 | — |
Gestational age | — | |||
n | 64 | 42 | 106 | — |
Mean (SD), wk | 39.3 (1.3) | 39.1 (1.3) | 39.3 (1.3) | .3 |
Minimum, Q1, median, wk | 36.4, 38.3, 39.5 | 36, 38.3, 39.3 | 36, 38.3, 39.4 | — |
Q3, maximum, wk | 40.3, 41.6 | 40, 42 | 40, 42 | — |
Birth wt | ||||
n | 64 | 42 | 106 | — |
Mean (SD), g | 3342 (577) | 3317 (501) | 3332 (546) | .9 |
Minimum, Q1, median, g | 2070, 3051, 3303 | 2200, 2993, 3298 | 2070, 3033, 3298 | — |
Q3, maximum, g | 3640, 4880 | 3745, 4300 | 3685, 4880 | — |
Pretreatment seizure severity | — | |||
n | 52 | 29 | 81 | — |
Mean (SD), min/h | 12.3 (12.0) | 9.1 (9.3) | 11.1 (11.2) | .5 |
Minimum, Q1, median, Q3, maximum, min/h | 0.5, 2.2, 7.1, 16.3, 41.2 | 0.2, 2.4, 6.8, 12, 38 | 0.2, 2.4, 7.0, 15.3, 41.2 | — |
. | Levetiracetam . | Phenobarbital . | Overall . | Pa . |
---|---|---|---|---|
HIE as seizure etiology, n (%) | 35 (55) | 22 (52) | 57 (54) | Not tested |
Received hypothermia treatment, n (%) | 24 (38) | 18 (43) | 42 (40) | .7 |
Male sex, n (%) | 31 (48) | 24 (57) | 55 (52) | .4 |
Cord pH | .2 | |||
n | 31 | 20 | 51 | — |
Mean (SD) | 7.07 (0.2) | 7.15 (0.17) | 7.1 (0.19) | — |
Minimum, Q1, median | 6.65, 6.94, 7.09 | 6.76, 6.99, 7.22 | 6.65, 6.99, 7.15 | — |
Q3, maximum | 7.23, 7.35 | 7.28, 7.37 | 7.28, 7.37 | — |
5-min Apgar score | — | |||
n | 64 | 40 | 104 | — |
Mean (SD) | 6.52 (3.01) | 6.47 (2.4) | 6.5 (2.78) | .6 |
Minimum, Q1, median, Q3, maximum | 0, 4, 7.5, 9, 10 | 2, 4, 7, 9, 10 | 0, 4, 7, 9, 10 | — |
Gestational age | — | |||
n | 64 | 42 | 106 | — |
Mean (SD), wk | 39.3 (1.3) | 39.1 (1.3) | 39.3 (1.3) | .3 |
Minimum, Q1, median, wk | 36.4, 38.3, 39.5 | 36, 38.3, 39.3 | 36, 38.3, 39.4 | — |
Q3, maximum, wk | 40.3, 41.6 | 40, 42 | 40, 42 | — |
Birth wt | ||||
n | 64 | 42 | 106 | — |
Mean (SD), g | 3342 (577) | 3317 (501) | 3332 (546) | .9 |
Minimum, Q1, median, g | 2070, 3051, 3303 | 2200, 2993, 3298 | 2070, 3033, 3298 | — |
Q3, maximum, g | 3640, 4880 | 3745, 4300 | 3685, 4880 | — |
Pretreatment seizure severity | — | |||
n | 52 | 29 | 81 | — |
Mean (SD), min/h | 12.3 (12.0) | 9.1 (9.3) | 11.1 (11.2) | .5 |
Minimum, Q1, median, Q3, maximum, min/h | 0.5, 2.2, 7.1, 16.3, 41.2 | 0.2, 2.4, 6.8, 12, 38 | 0.2, 2.4, 7.0, 15.3, 41.2 | — |
Q1, lower quartile; Q3, upper quartile; —, not applicable.
Fisher’s exact test for categorical variables; Wilcoxon rank test for continuous variables.
Seizure Cessation Efficacy
Phenobarbital was more effective than levetiracetam in eradicating all seizures for 24 hours (primary outcome measure) (Tables 2 and 3, Fig 3). Of the patients randomly assigned to phenobarbital, 80% (24 of 30) remained seizure free for 24 hours, compared with 28% (15 of 53) of patients randomly assigned to levetiracetam (P < .001). Most patients randomly assigned to phenobarbital (70%; 21 of 30) remained seizure free with just a 20 mg/kg loading dose and maintenance. Covariate-adjusted analyses revealed results consistent with the results from the primary analysis (all P <.001).
. | Phenobarbital (20–40 mg/kg), n (Cessation %) . | Levetiracetam (40–60 mg/kg), n (Cessation %) . | Fisher’s Exact P . | Relative Risk (95% CI) . |
---|---|---|---|---|
Primary outcome measure | ||||
24-h seizure cessation rate (N = 83) | 24 of 30 (80) | 15 of 53 (28) | <0.001 | 0.35 (0.22–0.56) |
Secondary outcome measures | ||||
48-h Seizure cessation rate (N = 75) | 18 of 28 (64) | 8 of 47 (17) | <0.001 | 0.26 (0.13–0.53) |
1-h Seizure cessation rate (N = 83) | 28 of 30 (93) | 26 of 53 (49) | <0.001 | 0.53 (0.39–0.7) |
Subanalysis of patients with HIE treated with hypothermia | ||||
24-h seizure cessation rate (N = 27) | 9 of 10 (90) | 6 of 17 (35) | 0.014 | 0.39 (0.2–0.77) |
. | Phenobarbital (20–40 mg/kg), n (Cessation %) . | Levetiracetam (40–60 mg/kg), n (Cessation %) . | Fisher’s Exact P . | Relative Risk (95% CI) . |
---|---|---|---|---|
Primary outcome measure | ||||
24-h seizure cessation rate (N = 83) | 24 of 30 (80) | 15 of 53 (28) | <0.001 | 0.35 (0.22–0.56) |
Secondary outcome measures | ||||
48-h Seizure cessation rate (N = 75) | 18 of 28 (64) | 8 of 47 (17) | <0.001 | 0.26 (0.13–0.53) |
1-h Seizure cessation rate (N = 83) | 28 of 30 (93) | 26 of 53 (49) | <0.001 | 0.53 (0.39–0.7) |
Subanalysis of patients with HIE treated with hypothermia | ||||
24-h seizure cessation rate (N = 27) | 9 of 10 (90) | 6 of 17 (35) | 0.014 | 0.39 (0.2–0.77) |
. | Phenobarbital (20–40 mg/kg), n (Cessation %) . | Levetiracetam (40–60 mg/kg), n (Cessation %) . | Fisher’s Exact P . | Relative Risk (95% CI) . |
---|---|---|---|---|
Post hoc analysis: efficacy as assessed by a neurologist at the bedside | ||||
24-h seizure cessation rate (N = 106) | 35 of 42 (83) | 23 of 64 (36) | <0.001 | 0.43 (0.3–0.61) |
24-h seizure cessation rate (N = 94), excludes subjects without confirmed seizures | 27 of 33 (82) | 20 of 61 (33) | <0.001 | 0.4 (0.27–0.59) |
Post hoc imputation analyses for missing primary outcome data | ||||
Best-worsta case 24-h seizure cessation rate (N = 106) | 36 of 42 (86) | 18 of 64 (28) | <0.001 | 0.33 (0.22–0.49) |
Worst-bestb case 24-h seizure cessation rate (N = 106) | 33 of 42 (79) | 26 of 64 (41) | <0.001 | 0.52 (0.37–0.72) |
. | Phenobarbital (20–40 mg/kg), n (Cessation %) . | Levetiracetam (40–60 mg/kg), n (Cessation %) . | Fisher’s Exact P . | Relative Risk (95% CI) . |
---|---|---|---|---|
Post hoc analysis: efficacy as assessed by a neurologist at the bedside | ||||
24-h seizure cessation rate (N = 106) | 35 of 42 (83) | 23 of 64 (36) | <0.001 | 0.43 (0.3–0.61) |
24-h seizure cessation rate (N = 94), excludes subjects without confirmed seizures | 27 of 33 (82) | 20 of 61 (33) | <0.001 | 0.4 (0.27–0.59) |
Post hoc imputation analyses for missing primary outcome data | ||||
Best-worsta case 24-h seizure cessation rate (N = 106) | 36 of 42 (86) | 18 of 64 (28) | <0.001 | 0.33 (0.22–0.49) |
Worst-bestb case 24-h seizure cessation rate (N = 106) | 33 of 42 (79) | 26 of 64 (41) | <0.001 | 0.52 (0.37–0.72) |
In the analysis, no patients randomly assigned to levetiracetam with a missing primary outcome measure were imputed as seizure free to 24 h, and all patients randomly assigned to phenobarbital with a missing primary outcome measure were imputed as seizure free to 24 h. Patients in whom seizures were not confirmed were imputed as seizure free to 24 h.
In the analysis all patients randomly assigned to levetiracetam with a missing primary outcome measure were imputed as seizure free to 24 h, and no patients randomly assigned to phenobarbital with a missing primary outcome measure were imputed as seizure free to 24 h. Patients in whom seizures were not confirmed were imputed as seizure free at 24 h.
Similar efficacy results were seen in the per-protocol population. Sensitivity analyses in which the missing outcome data were imputed were also consistent with the results from the primary analysis (Table 3). Patients with and without the primary outcome measure had similar baseline demographic characteristics.
Ninety-three percent of patients randomly assigned to phenobarbital were seizure free for at least 1 hour, compared with 49% of patients randomly assigned to levetiracetam. Sixty-four percent of patients randomly assigned to phenobarbital remained seizure free for 48 hours, compared with 17% of patients randomly assigned to levetiracetam. Similar efficacy results were seen in the subset of patients treated with hypothermia for HIE.
Dose-Escalation Data
Of the 42 patients who had ongoing seizures after 40 mg/kg of levetiracetam, the 20 mg/kg levetiracetam dose increment to 60 mg/kg resulted in seizure control for 24 hours in an additional 4 patients (7.5% increased efficacy of levetiracetam at 24 hours).
Safety Analyses
Three patients died during the study period, and 3 patients died after the study period but within the neonatal period (Table 4). One patient died of subgaleal hemorrhage and HIE, and 5 were withdrawn from life support because of severe HIE. By using standardized definitions for the grading of adverse events,41 additional grade 4 serious adverse events affected an additional 6 patients: 5 patients experienced hypotension, and 1 patient experienced respiratory depression that was probably or possibly due to the study medication. Milder adverse events were recorded on at least 1 study day in 25 patients. Adverse events, including hypotension, respiratory suppression, sedation, and requirement for pressor support, were more common in patients randomly assigned to phenobarbital. Patients who received only 20 mg/kg of phenobarbital still experienced higher rates of adverse events (column 7 in Table 4). As would be expected in a phase IIb study, powered for the primary outcome analysis, these differences were not statistically significant.
. | Randomized Treatment Arm . | Drugs Received . | |||||||
---|---|---|---|---|---|---|---|---|---|
Phenobarbital (N = 42), n (%) . | Levetiracetam (N = 64), n (%) . | All (N = 106), n (%) . | Fisher’s Exact Test, P . | Relative Risk (95% CI) . | Phenobarbital Only (N = 32), n (%) . | Phenobarbital, 20 mg/kg Only (N = 22), n (%) . | Levetiracetam Only (N = 19), n (%) . | Levetiracetam and Phenobarbital (N = 55), n (%) . | |
Death during study | 1 (2) | 2 (3) | 3 (3) | — | — | 0 (0) | 0 (0) | 0 (0) | 3 (5) |
Neonatal death after study | 0 (0) | 3 (5) | 3 (3) | — | — | 0 (0) | 0 (0) | 0 (0) | 3 (5) |
Grade 4 or 5 AE or SAE | 5 (12) | 4 (6) | 9 (8) | .48 | 0.52 (0.15–1.84) | 3 (9) | 2 (9) | 1 (5) | 5 (9) |
AE on at least 1 d | 13 (31) | 12 (19) | 25 (24) | .17 | 0.61 (0.31–1.2) | 9 (28) | 7 (32) | 3 (16) | 13 (24) |
Hypotension AEa | 7 (17) | 3 (5) | 10 (9) | .05 | 0.28 (0.08–1.03 | 5 (16) | 4 (18) | 0 (0) | 5 (9) |
Respiratory abnormality AEa | 11 (26) | 8 (13) | 19 (18) | .12 | 0.48 (0.21–1.09) | 8 (25) | 6 (27) | 1 (5) | 10 (18) |
Sedation AEa | 8 (19) | 7 (11) | 15 (14) | .27 | 0.57 (0.23–1.47) | 5 (16) | 4 (18) | 1 (5) | 9 (16) |
Heart rate abnormality AEa | 1 (2) | 3 (5) | 4 (4) | >.99 | 1.97 (0.21–18.3) | 1 (3) | 1 (5) | 1 (5) | 2 (4) |
Poor feeding AEa | 7 (17) | 6 (9) | 13 (12) | .36 | 0.56 (0.2–1.56) | 5 (16) | 4 (18) | 1 (5) | 7 (13) |
Infection AEa | 3 (7) | 2 (3) | 5 (5) | .38 | 0.44 (0.08–2.51) | 3 (9.4) | 2 (9) | 1 (5) | 1 (2) |
Vasopressor supportb | 13 (31) | 10 (16) | 23 (22) | .09 | 0.5 (0.24–1.04) | 12 (22) | 7 (32) | 1 (5) | 10 (31) |
Ventilatedb | 19 (45) | 24 (38) | 43 (41) | .54 | 0.83 (0.52–1.31) | 10 (31) | 8 (36) | 4 (21) | 27 (49) |
Oxygen requiredb | 24 (57) | 38 (59) | 62 (59) | .84 | 1.04 (0.75–1.45) | 17 (53) | 12 (55) | 9 (47) | 36 (66) |
. | Randomized Treatment Arm . | Drugs Received . | |||||||
---|---|---|---|---|---|---|---|---|---|
Phenobarbital (N = 42), n (%) . | Levetiracetam (N = 64), n (%) . | All (N = 106), n (%) . | Fisher’s Exact Test, P . | Relative Risk (95% CI) . | Phenobarbital Only (N = 32), n (%) . | Phenobarbital, 20 mg/kg Only (N = 22), n (%) . | Levetiracetam Only (N = 19), n (%) . | Levetiracetam and Phenobarbital (N = 55), n (%) . | |
Death during study | 1 (2) | 2 (3) | 3 (3) | — | — | 0 (0) | 0 (0) | 0 (0) | 3 (5) |
Neonatal death after study | 0 (0) | 3 (5) | 3 (3) | — | — | 0 (0) | 0 (0) | 0 (0) | 3 (5) |
Grade 4 or 5 AE or SAE | 5 (12) | 4 (6) | 9 (8) | .48 | 0.52 (0.15–1.84) | 3 (9) | 2 (9) | 1 (5) | 5 (9) |
AE on at least 1 d | 13 (31) | 12 (19) | 25 (24) | .17 | 0.61 (0.31–1.2) | 9 (28) | 7 (32) | 3 (16) | 13 (24) |
Hypotension AEa | 7 (17) | 3 (5) | 10 (9) | .05 | 0.28 (0.08–1.03 | 5 (16) | 4 (18) | 0 (0) | 5 (9) |
Respiratory abnormality AEa | 11 (26) | 8 (13) | 19 (18) | .12 | 0.48 (0.21–1.09) | 8 (25) | 6 (27) | 1 (5) | 10 (18) |
Sedation AEa | 8 (19) | 7 (11) | 15 (14) | .27 | 0.57 (0.23–1.47) | 5 (16) | 4 (18) | 1 (5) | 9 (16) |
Heart rate abnormality AEa | 1 (2) | 3 (5) | 4 (4) | >.99 | 1.97 (0.21–18.3) | 1 (3) | 1 (5) | 1 (5) | 2 (4) |
Poor feeding AEa | 7 (17) | 6 (9) | 13 (12) | .36 | 0.56 (0.2–1.56) | 5 (16) | 4 (18) | 1 (5) | 7 (13) |
Infection AEa | 3 (7) | 2 (3) | 5 (5) | .38 | 0.44 (0.08–2.51) | 3 (9.4) | 2 (9) | 1 (5) | 1 (2) |
Vasopressor supportb | 13 (31) | 10 (16) | 23 (22) | .09 | 0.5 (0.24–1.04) | 12 (22) | 7 (32) | 1 (5) | 10 (31) |
Ventilatedb | 19 (45) | 24 (38) | 43 (41) | .54 | 0.83 (0.52–1.31) | 10 (31) | 8 (36) | 4 (21) | 27 (49) |
Oxygen requiredb | 24 (57) | 38 (59) | 62 (59) | .84 | 1.04 (0.75–1.45) | 17 (53) | 12 (55) | 9 (47) | 36 (66) |
AE, adverse event; SAE, serious adverse event; —, not applicable.
Patients in whom this clinical problem and an AE was documented on the same day.
Patients in whom this support was required on at least 1 d.
Laboratory Data
In 80 of 106 patients, the full set of monitoring laboratory data, collected after 48 hours on treatment with the study drug, was available. No significant treatment-emergent trends were seen for either treatment arm in these data (Supplemental Information).
Discussion
NEOLEV2 provides randomized controlled prospective efficacy data for levetiracetam and phenobarbital in neonates in the hypothermia era. Previous data come from uncontrolled case series, often retrospective, using levetiracetam for second-line treatment, and without cEEG assessment or neurophysiologist review.35,36,42,43 Given the high rates of subclinical seizures and abnormal movements without electrographic seizures seen in neonates, cEEG monitoring is vital to validate any neonatal seizure research. The waxing-then-waning time course of acute symptomatic seizures particularly makes data from uncontrolled studies and second-line treatment studies unreliable.37,38,44 It is recognized that timeliness in the treatment of seizures can double the efficacy of anticonvulsants.45 Systematic cEEG monitoring, remote review, and seizure detection technologies optimized early identification of seizures in NEOLEV2 and may have improved drug efficacy.39 To our knowledge, in no other pediatric treatment trial have investigators attempted real-time response to cEEG-detected seizures. An additional strength of the study is the validation of seizure diagnosis and drug-efficacy assessments by 2 independent neurophysiologists. Because we recruited all comers with seizures, our results are generalizable to all term neonates with seizures. The subanalysis of patients with acute symptomatic seizures due to HIE suggests our results are generalizable to that important group.
We observed greater efficacy of phenobarbital than that reported by Painter et al,13 in which patients received on average 35 mg/kg of phenobarbital titrated to serum levels. In that study, the authors recruited patients with more severe seizures, and the study was conducted before hypothermia, which reduces neonatal seizures and increases treatment response,37,46 becoming the standard of care for HIE. Our data reveal clinically important, albeit not statistically significant, differences in the side-effect profile of levetiracetam compared with phenobarbital. Increased rates of sedation, respiratory suppression, and hypotension were demonstrated with phenobarbital, including in patients who received 20 mg/kg. It is unclear why Painter et al13 found no adverse side effects. Hypothermia and morphine cotreatment may exacerbate the side effects of phenobarbital.
Sixty milligrams per kilogram is the maximal dose for which levetiracetam is licensed in any age group, and therefore it is as high as was ethical in this first controlled study in vulnerable neonates. Case series in children have revealed that high doses of levetiracetam (up to 275 mg/kg per day) can achieve seizure freedom when standard dosing has failed.47,48 If higher-dose levetiracetam has increased efficacy in neonatal seizures, the excellent safety profile of levetiracetam should be exploited to realize this potential. The increased efficacy seen with modest dose escalation in NEOLEV2 is encouraging in this regard.
The exclusion of 23 patients from the modified intention-to-treat population is a limitation of our study. This resulted from our stipulation that seizure diagnosis and cessation must be validated by neurophysiologist review, which is a necessary rigor given interrater variability in neonatal cEEG interpretation.49–51 Using assessments by the neurologist at the bedside for the primary outcome would have been less accurate. Because of the consistency of results observed from best-worst case sensitivity analyses and analysis by using the assessment by the neurologist at the bedside, we are confident that the missing outcome data did not significantly bias our results (Table 3).
We began treatment whenever a seizure was confirmed, and some patients with low pretreatment seizure burden may have had resolution of their seizures without any drug treatment. A higher seizure burden pretreatment of at least 30 seconds/hour is recommended in new guidelines and would have avoided drug treatment in some patients and improved interreader agreement for electrographic seizure diagnosis.44
The chief limitation of this study is its short-term end point. For our aim of obtaining preliminary prospective efficacy data for levetiracetam in neonates, it was appropriate to use seizure cessation as the primary outcome measure. However, the end point of greatest concern in neonatal seizure trials is long-term neurodevelopmental outcome. A drug that is less effective in achieving seizure cessation but leads to a better neurodevelopmental outcome through a neuroprotective effect or lack of neurotoxicity may be the preferred first-line treatment option. Once optimal dosing is defined for levetiracetam and other candidate treatments for neonatal seizures, much larger neonatal seizure trials will be needed to study these long-term outcomes and guide treatment decisions definitively.
Conclusions
This phase IIb study has revealed greater efficacy of 20 to 40 mg/kg of phenobarbital than 40 to 60 mg/kg of levetiracetam. More adverse events occurred with phenobarbital. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.
Acknowledgments
Grateful thanks to the NEOLEV2 Data-Safety Monitoring Committee: Maria Cilio (Chair), Sonia Jain, Donna Ferriero, Terrie Inder, and James Cloyd. Thanks also to the NEOLEV2 Steering Committee for their helpful advice and guidance: Kevin Staley, Taeun Chang, Faye Silverstein, Ronnie Guillet, and Renee Shelhaas.
We thank the patients and parents who participated in this study. We acknowledge the invaluable support of Melly Massie and John Widjaja in providing information technology support for the study. We acknowledge the work of the many NICU nurses, respiratory technicians, and EEG technicians who contributed to this study. We thank the research pharmacies and information technology departments at each hospital and Jose Entrican for her expert database assistance. We thank Cadwell for EEG systems support, Persyst for their seizure detection and trending software, and CortiCare for providing real-time monitoring of subjects by EEG technicians. We thank also the Thrasher Foundation, whose funding of our pharmacokinetic study made NEOLEV2 possible.
Dr Haas conceived and designed the study, provided overall supervision, recruited and studied subjects, interpreted the data, and critically revised the manuscript; Dr Sharpe conceived and designed the study, recruited and studied subjects, obtained data, provided supervision, interpreted data, and wrote the initial draft of the manuscript; Dr Reiner contributed to the study design, recruited and studied subjects, constructed and supervised the database, obtained data, and critically revised the manuscript; Ms Lee assisted with the construction and supervision of the database and contributed to and critically revised the manuscript; Ms Ernstrom and Dr Raman contributed to the design of the study, performed the statistical analyses, interpreted the data, and critically revised the manuscript; Ms Davis, Drs Nespeca, Gold, Wang, Rismanchi, Kuperman, Le, Mower, Rasmussen, Harbert, Michelson, Joe, and Kim, Mr Battin, Drs Lane and Honold, Ms Knodel, Ms Arnell, and Ms Bridge each made substantial contributions to the acquisition and analysis of data and critically revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
This trial has been registered at www.clinicaltrials.gov (identifier NCT01720667).
FUNDING: The NEOLEV2 study was funded by the US Food and Drug Administration Orphan Products Division (1 RO1FD004147). The Research Electronic Data Capture database is supported by National Institutes of Health Cooperative Agreement UL1TR001442. 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 article. 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 article. The authors of this article discuss the use of the automated neonatal seizure detection algorithm created by the Persyst EEG software company, which is not yet US Food and Drug Administration–approved for commercial use. Funded by the National Institutes of Health (NIH).
References
Competing Interests
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: Mark Nespeca, David Michelson, Neggy Rismanchi, Andrew Mower, and Richard Haas each declare only lunch or dinner educational interactions with UCB Pharmaceutical representatives. Richard Haas declares that he consulted for Sun Pharma Advanced Research Company Ltd. following presentation of study results at the Society for Pediatric Research. Sonya Wang declares clinical trial participation and service on data safety monitoring boards for Ovid Therapeutics. The remaining authors have indicated they have no financial relationships relevant to this article to disclose.
Comments
Reply to comment "Does temporal relationship of seizure burden and its timing in HIE cases affect anti seizure drug efficacy"
Dear Dr’s Jain and Konanki,
Thank you for your comments on our study.
We agree that a crescendo-decrescendo pattern of HIE induced neonatal seizures is an important consideration, more-so in trials of second-line treatment where more variability in the time of administration of study drug within that crescendo-decrescendo pattern is possible. Our study was designed to randomize and initiate treatment with detection of the first seizure.
We believe randomization within NEOLEV2 should indeed have distributed equal numbers of neonates in each phase of their seizures to each treatment arm, however we acknowledge it is possible that despite randomization the LEV group in our trial may have been slightly disadvantaged, although not to a degree which would substantially change the overall result.
Certainly, the efficacy of Levetiracetam seen in our phase IIB trial was at the lower end of what might have been hoped for and requires confirmation in larger phase III randomized controlled trials.
Yours sincerely,
Dr Sharpe and Dr Haas
RE: Does temporal relationship of seizure burden and its timing in HIE cases affect anti seizure drug efficacy ??
Dear Editor,
We have read the article entitled “Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial” by Sharpe C, et al. published in May edition of Pediatrics 2020.1 We want to commend the whole team of NEOLEV2 investigators for presenting a robust randomised control study on efficacy of Levetiracetam compared to Phenobarbital.
Since last published randomised control trial by Painter et al2 more than 21 years ago comparing phenobarbital and phenytoin, there has been dearth of well-structured efficacy trials for anti-seizure drugs in neonates. Also, significant increase in off-label use of Levetiracetam as first line therapy in last decade necessitated this study. This study also stands out because of the use of real time continuous EEG monitoring as a standard for identification and treatment of neonatal seizures, as less than 10% electrographic seizures have been found to be accompanied by clinical manifestations identifiable by neonatal staff.3
At the same time, evidence suggests that distribution of seizure burden in neonates with hypoxic ischemic encephalopathy (HIE) is not uniform, with crescendo-decrescendo pattern of seizure evolution in majority of neonates.4 The time from first recorded seizure to maximum seizure burden is significantly shorter than the time from maximum seizure burden to last recorded seizure.4 As 54% of the cases had HIE as aetiology in NEOLEV2 trial, this temporal evolution of seizure burden should be taken into consideration in estimating the efficacy of anti-seizure drugs. While randomization of the groups should be expected to distribute cases equally in both interventional arms as shown by non-significant difference in pre-treatment seizure severity between the groups, providing data regarding mean time of seizure onset, peak time of seizure burden and timing of intervention in each arm especially in HIE subset would make for a more credible comparison. Although, HIE and its severity (based on APGAR and cord pH) as aetiology is equally distributed in both arms, the severity and distribution of other aetiologies in both groups can be potential bias explaining failure of both drugs in higher proportion of subjects i.e. 28.3% (15/53) in Levetiracetam group as compared to 16.6% (5/30) subjects in Phenobarbital group.
References:
1. Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics. 2020;145(6): e20193182
2. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital compared to phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485–489.
3. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008;93:F187‐F191.
4. Lynch NE, Stevenson NJ, Livingstone V, Murphy BP, Rennie JM, Boylan GB. The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy. Epilepsia 2012;53:549-557.
RE: Levetiracetam versus Phenobarbital for neonatal seizures: “The pendulum swings”
Dear Editor,
We thank Shaw et al. for their interest in our paper and value the opportunity to clarify some aspects of the trial.
The trial was designed to study efficacy of intravenous levetiracetam given as first line therapy. Additionally, it aimed to obtain dose escalation data, including pharmacokinetics at higher doses, and further document safety profile. The allocation 60:40 LEV to PHB, was selected to optimize data collection on the newer drug LEV in the neonatal period. Using this design, the trial was powered to have an 80% chance of detecting a difference in efficacy between the two treatments of 28% or more. Indeed, a significant difference was subsequently reported.
Although only 30 subjects received PHB as first line treatment, due to lower LEV efficacy, a further 37 subjects received PHB as 2nd line treatment. Secondary efficacy of PHB in this group was 54%, and combined efficacy of PHB was 66%; 44 of 67 subjects, (figure 3). The minor differences in pH and seizure activity were not statistically significant.
Our pharmacokinetic results are being prepared for separate publication. We agree that the optimal dose of LEV in neonatal seizures has not been determined and higher dose studies are warranted.
We agree that the results differ from previously published non-randomized LEV experience. However, the 2018 systematic review by Mc Hugh(1) that was cited “found no studies of LEV with comparison or control groups", which demonstrates very clearly the paucity of good trial data. Furthermore, the study cited by Gowda et al. (2) used a clinical definition and did not use EEG to diagnose seizures. This is problematic as most neonatal seizures are electrographic only and many “clinical seizures” ie abnormal movements in neonates raising concern for seizure, have no electrographic correlate, and do not require anti-seizure medication.
Overall, we consider there is an urgent requirement for further work to develop proven evidence-based therapies for neonatal seizures.
1. McHugh DC, Lancaster S, Manganas LN. A Systematic Review of the Efficacy of Levetiracetam in Neonatal Seizures. Neuropediatrics. 2018;49(1):12-7.
2. Gowda VK, Romana A, Shivanna NH, Benakappa N, Benakappa A. Levetiracetam versus Phenobarbitone in Neonatal Seizures - A Randomized Controlled Trial. Indian Pediatr. 2019;56(8):643-6.
RE: Levetiracetam versus Phenobarbital for neonatal seizures: “The pendulum swings”
Dear Editor,
We thank Shaw et al. for their interest in our paper and value the opportunity to clarify some aspects of the trial.
The trial was designed to study efficacy of intravenous levetiracetam given as first line therapy. Additionally, it aimed to obtain dose escalation data, including pharmacokinetics at higher doses, and further document safety profile. The allocation 60:40 LEV to PHB, was selected to optimize data collection on the newer drug LEV in the neonatal period. Using this design, the trial was powered to have an 80% chance of detecting a difference in efficacy between the two treatments of 28% or more. Indeed, a significant difference was subsequently reported.
Although only 30 subjects received PHB as first line treatment, due to lower LEV efficacy, a further 37 subjects received PHB as 2nd line treatment. Secondary efficacy of PHB in this group was 54%, and combined efficacy of PHB was 66%; 44 of 67 subjects, (figure 3). The minor differences in pH and seizure activity were not statistically significant.
Our pharmacokinetic results are being prepared for separate publication. We agree that the optimal dose of LEV in neonatal seizures has not been determined and higher dose studies are warranted.
We agree that the results differ from previously published non-randomized LEV experience. However, the 2018 systematic review by Mc Hugh(1) (ref) that was cited “found no studies of LEV with comparison or control groups", which demonstrates very clearly the paucity of good trial data. Furthermore, the study by Gowda et al. (2) used a clinical definition and did not use EEG to diagnose seizures. This is problematic as most neonatal seizures are electrographic only and many “clinical seizures” ie abnormal movements in neonates raising concern for seizure, have no electrographic correlate, and do not require anti-seizure medication.
Overall, we consider there is an urgent requirement for further work to develop proven evidence-based therapies for neonatal seizures.
1. McHugh DC, Lancaster S, Manganas LN. A Systematic Review of the Efficacy of Levetiracetam in Neonatal Se
Levetiracetam versus Phenobarbital for neonatal seizures: “The pendulum swings”
Dear Editor,
We read with great interest the paper by Sharpe C et al which reported that phenobarbital was far more superior to levetiracetam in the treatment of neonatal seizures.1 The study suggests the exact opposite of all that has emerged from studies on the subject so far.2 We complement the authors for their work and in particular the excellent study design. However, we would like to seek certain clarifications and offer few comments.
We have not understood why a 60:40 treatment allocation ratio was chosen with the higher percentage in levetiracetam group. In the end, the study has based its conclusions on just around 30 neonates in phenobarbital group and 53 neonates in levetiracetam group, the population in levetiracetam group increasing by a factor of 16 % from the pre-decided 60:40 allocation. Another point bothering us is that the population of neonates in the levetiracetam group seem to have been slightly more sick (cord pH and pre-treatment seizure activity).
Though the authors have mentioned in the article that they aimed to maintain trough levels at > 20 µg/mL for the first 3 days of treatment in levetiracetam arm, the drug level data is itself missing . It will be worthwhile, to know the drug trough levels in each treatment group if available; in the levetiracetam group to see whether optimal levels were achieved and in phenobarbital group to see if the therapeutic levels were exceeded given the adverse effects seen in the study population.
While the optimal loading dose of phenobarbital and phenytoin is established, the same cannot be said for levetiracetam, where the equipotent dose of levetiracetam compared to the other first line agents is not yet clear. The authors themselves have suggested that higher dose of levetiracetam may be needed for its optimal effects.3
There could be several reasons for variable efficacy of an anticonvulsant drug such as its loading dose, individual differences in pharmacokinetics and pharmacogenomics and the underlying aetiologies. There is a possibility that levetiracetam may be more suitable in non HIE causes of neonatal seizure or even in milder HIE as is evident from a recent paper from India. In this randomised trial, where non HIE aetiologies as a whole were more in number than those with HIE, the authors reported overall clinical suppression of seizures in 43 (86%) and 31 (62%) neonates in Levetiracetam and Phenobarbitone group respectively with RR of 0.37 (95%CI 0.17 to 0.80).4
Given the excellent safety profile and large therapeutic window of levetiracetam and a possibility of better long term outcomes in comparison to phenobarbital in at least a certain subset of neonates.5 It might be worthwhile to pursue this area of research with a larger sample size and with different doses. It may be premature yet to write off this drug as a first line agent in neonatal seizures. It won’t be surprising to see the phenobarbital versus levetiracetam pendulum continue to swing in future.
References:
1. Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics. 2020;145(6): e20193182
2. McHugh DC, Lancaster S, Manganas LN. A systematic review of the efficacy of levetiracetam in neonatal seizures. Neuropediatrics 2018; 49 (01): 012-017
DOI: 10.1055/s-0037-1608653
3. Obeid M, Pong AW. Efficacy and tolerability of high oral doses of levetiracetam in children with epilepsy. Epilepsy Res. 2010;91(1):101–105
4. Gowda, V.K., Romana, A., Shivanna, N.H. et al. Levetiracetam versus Phenobarbitone in Neonatal Seizures — A Randomized Controlled Trial. Indian Pediatr 56, 643–646 (2019). https://doi.org/10.1007/s13312-019-1586-3
5. Swami, M., Kaushik, J.S. Levetiracetam in Neonatal seizures. Indian Pediatr 56, 639–640 (2019). https://doi.org/10.1007/s13312-019-1585-4