Use of Intravenous Levetiracetam for Management of Acute Seizures in Neonates

doi:10.1016/j.pediatrneurol.2010.11.005

Pediatric Neurology

Volume 44, Issue 4, April 2011, Pages 265-269

https://doi.org/10.1016/j.pediatrneurol.2010.11.005 Get rights and content

Antiepileptic drugs used for the treatment of neonatal seizures have limited efficacy and undesirable side effects, leading to increased off-label use in neonates. Intravenous levetiracetam became available in August 2006 for use in patients above 16 years of age. Insufficient data are available about the efficacy and safety of intravenous levetiracetam in neonates. Data captured from our institution's electronic medical records were retrospectively analyzed for neonates treated with intravenous levetiracetam between January 2007 and December 2009. Data were acquired by reviewing our electronic medical records. Twenty-two patients received a levetiracetam load of 10-50 mg/kg for neonatal seizures. Nineteen of 22 patients (86%) demonstrated immediate seizure cessation at 1 hour. Seven of 22 patients (32%) achieved complete seizure cessation after administration of the loading dose, 14 (64%) achieved seizure cessation by 24 hours, 19 (86%) by 48 hours, and all 22 (100%) by 72 hours. No serious side effects were evident. Nineteen patients (86%) were discharged on oral levetiracetam, and only two patients (9%) were discharged with an additional oral antiepileptic drug. Intravenous levetiracetam can be used as monotherapy and adjunctively in acute seizure management during the neonatal period.

Introduction

Few medications have been studied and approved for the treatment of neonatal seizures, and none have exhibited superior efficacy over the others. With a high incidence of seizures refractory to currently approved antiepileptic drugs, a pressing need exists for alternative treatments in neonates. Seizures affect approximately 1-4 out of 1000 live births in North America, and constitute a major predictor of future adverse outcomes [1], [2]. The most common causes of neonatal seizures include hypoxic ischemic encephalopathy, intracranial hemorrhages, infections of the central nervous system, cerebral infarctions, and metabolic disturbances [1], [2]. The treatment of neonatal seizures is often of limited efficacy and leads to deleterious adverse effects. Two antiepileptic drugs presently approved by the United States Food and Drug Administration in the neonatal period, phenobarbital and phenytoin, demonstrate efficacy in less than 50% of cases and undesirable side-effect profiles in major studies [3], [4], [5], [6], [7], [8]. The off-label use of antiepileptic drugs in children and neonates is increasing, and an imperative need exists to investigate the use of newer antiepileptic drugs in neonates [9].

Levetiracetam is a pyrrolidine-derivative antiepileptic drug chemically different from all previous antiepileptic drugs, with a novel mechanism of action that remains incompletely understood. Intravenous levetiracetam was approved by the Food and Drug Administration in August 2006 for patients above 16 years of age. Both intravenous and oral levetiracetam have been increasingly used off-label in pediatric patients because of documentation in the literature of efficacy and safety in adults, along with favorable reports in younger patients [4], [5], [9], [10], [11], [12], [13], [14], [15]. We report on our experience with intravenous levetiracetam in the management of neonatal seizures.

Section snippets

Patients and Methods

Infants were eligible for inclusion if they were born at term gestational age (≥37 weeks) and received their first dose of intravenous levetiracetam during the neonatal period (0-28 days of age). A retrospective electronic medical record review was performed on all patients who met the inclusion criteria between January 2007 and December 2009 at our institution. This study was approved by our institutional review board.

Results

We retrospectively analyzed 22 neonates treated with intravenous levetiracetam at our institution. Several variables were taken into consideration (Table 1).

Discussion

Our data suggest that intravenous levetiracetam can be used for the management of acute seizures in neonates. The use of intravenous levetiracetam demonstrated immediate cessation of seizures in 86% (19/22) of our study patients. Painter et al. [6] and Boylan et al. [7] demonstrated efficacy in cessation of seizures among less than 50% of their patients treated with phenobarbital and phenytoin. In those studies, phenobarbital and phenytoin were used to treat a variety of neonatal seizure

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Cited by (113)

Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India
2024, The Lancet Regional Health - Southeast Asia
Although levetiracetam and phenytoin are widely used antiseizure medications (ASM) in neonates, their efficacy on seizure freedom is unclear. We evaluated electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin in neonatal seizures unresponsive to phenobarbital.
We recruited neonates born ≥35 weeks and aged <72 h who had continued electrographic seizures despite phenobarbital, from three Indian hospitals, between 20 June 2020 and 31 July 2022. The neonates were treated with intravenous levetiracetam (20 mg/kg x 2 doses, second line) followed by phenytoin (20 mg/kg x 2 doses, third line) if seizures persisted. The primary outcome was complete seizure freedom, defined as an absence of seizures on EEG for at least 60 min within 40 min from the start of infusion.
Of the 206 neonates with continued seizures despite phenobarbital, 152 received levetiracetam with EEG. Of these one EEG was missing, 47 (31.1%) were in status epilepticus, and primary outcome data were available in 145. Seizure freedom occurred in 20 (13.8%; 95% CI 8.6%–20.5%) after levetiracetam; 16 (80.0%) responded to the first dose and 4 (20.0%) to the second dose. Of the 125 neonates with persisting seizures after levetiracetam, 114 received phenytoin under EEG monitoring. Of these, the primary outcome data were available in 104. Seizure freedom occurred in 59 (56.7%; 95% CI 46.7%–66.4%) neonates; 54 (91.5%) responded to the first dose and 5 (8.5%) to the second dose.
With the conventional doses, levetiracetam was associated with immediate EEG seizure cessation in only 14% of phenobarbital unresponsive neonatal seizures. Additional treatment with phenytoin along with levetiracetam attained seizure freedom in further 57%. Safety and efficacy of higher doses of levetiracetam should be evaluated in well-designed randomised controlled trials.
National Institute for Health and Care Research (NIHR) Research and Innovation for Global Health Transformation (NIHR200144).
Current evidence for adjunct pyridoxine (vitamin B6) for the treatment of behavioral adverse effects associated with levetiracetam: A systematic review
2023, Epilepsy and Behavior
Levetiracetam (LVT), while an effective treatment for multiple seizure types, is associated with a high incidence of neuropsychiatric adverse events (NPAEs). In predominantly retrospective studies, supplementation with pyridoxine/vitamin B₆ (PN) was associated with improvement in NPAEs in some people. A previous review highlighted a lack of double-blind, controlled trials of PN for the treatment of NPAEs in individuals treated with LVT. The current paper updates the findings from the previous review to include evidence from studies published since June 2019.
An updated systematic review of the published literature was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies published between June 2019 and 2nd November 2022 in which supplementary PN was initiated for the treatment of LVT-associated NPAEs. All study types were eligible. The risk of bias in randomized trials was assessed using the Cochrane risk-of-bias tool.
Seven additional studies were identified: two double-blind, randomized controlled trials (RCTs), four retrospective studies, and one retrospective case series. One RCT reported significant improvements from baseline in behavioral adverse events (BAEs) in both the intervention (PN) group and the low-dose control group (both p < 0.05), with a significantly greater improvement in the intervention group (p < 0.001). In the second RCT, differences in BAE severity between PN and placebo groups at the endpoint were not statistically significant. In one retrospective study, subjective irritability was reported to have improved from baseline in 9/20 individuals (45%) treated with supplementary PN. Data for systematic assessments (PHQ-9 and GAD-7) were available for 10 individuals. Assessment by PHQ-9 showed that six individuals improved, two worsened and two had no change. Based on the GAD-7, three people improved, two worsened and five had no change. In the second retrospective study, 18/41 individuals (44%) who commenced PN following the emergence of BAEs showed “significant” improvement. In a separate group of individuals with pre-existing behavioral problems in whom PN treatment was initiated at the same time as commencing LVT, 3/18 (16.7%) developed BAEs. This compared with 79/458 people (17.2%) who were initially treated only with LVT. The third retrospective study compared treatment-related irritability in individuals who had been treated with both LVT and perampanel, either sequentially or concomitantly. Two people who developed irritability while receiving LVT monotherapy were able to continue treatment with the addition of PN. The fourth study reported a significantly lower LVT discontinuation rate in individuals taking PN and a higher rate of improved behavior in those who were able to continue LVT. The case series reported improvements in behavioral symptoms in six people within two to three weeks of commencing supplementary PN.
Data published within the last three years add to earlier evidence suggesting that PN might be effective in the treatment of NPAEs associated with LVT. However, the quality of evidence remains poor and only a few prospective trials have been published. Data from placebo-controlled trials are still largely lacking. Currently, there is insufficient evidence to justify any firm recommendation for PN supplementation to treat NPAEs associated with LVT. Further well-designed, prospective trials are warranted.
Levetiracetam versus Phenobarbital for Neonatal Seizures: A Retrospective Cohort Study
2023, Pediatric Neurology
Although phenobarbital (PB) is commonly used as a first-line antiseizure 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.
We conducted a retrospective cohort study of 108 neonates with electroencephalography (EEG)-confirmed seizures treated with first-line LEV or PB in 2012 to 2020.
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 versus 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).
Our study suggests a potential noninferiority and a more acceptable safety profile for LEV, which 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.
Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multicenter Study
2022, Journal of Pediatrics
To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease.
The Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease.
We evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P < .001) and experience their first seizure later than those without cardiopulmonary disease (174 vs 21 hours of age, P < .001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs 43%, P = .27). Phenobarbital was the primary initial antiseizure medication for both groups (90%), and both groups had similarly high rates of incomplete response to initial antiseizure medication administration (66% vs 68%, P = .75). Neonates with cardiopulmonary disease were discharged from the hospital later (hazard ratio 0.34, 95% CI 0.25-0.45, P < .001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95% CI 0.66-1.94, P = .64).
Neonates with and without cardiopulmonary disease had a similarly high seizure exposure, but neonates with cardiopulmonary disease were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial antiseizure medication. These data support guidelines recommending continuous EEG in neonates with cardiopulmonary disease and indicate a need for optimized therapeutic strategies.
Use of levetiracetam in neonates: Features and applications (a narrative review)
2021, Diagnosis, Management and Modeling of Neurodevelopmental Disorders: The Neuroscience of Development
Seizures are common in the neonatal period and are often a result of hypoxia, brain bleed, or structural abnormalities. Rapid and effective treatment is critical without significant concern for detrimental long-term effects on neurodevelopment. Phenobarbital (PHB) remains the standard of care for newborns; however, given the side effect profile of PHB, other alternative antiepileptic drugs (AEDs) have been utilized as a result. Several case reports and systematic reviews suggest that Levetiracetam (LEV) may be as efficacious as PHB without significant concern for neurotoxicity or long-term developmental side effects. Unfortunately, high-quality efficacy and safety data is limited warranting clinical trials to clearly establish the role of LEV in treatment of neonatal seizures. Here we review evidence for LEV use in neonatal seizures.
Comparison of the neurocognitive outcomes in term infants treated with levetiracetam and phenobarbital monotherapy for neonatal clinical seizures
2020, Seizure
Citation Excerpt :
Currently, there is no consensus regarding the second-line antiepileptic drugs, such as levetiracetam (LEV), benzodiazepine, fosphenytoin, or lidocaine [6–8]. In the last decade, case series and clinical studies have suggested LEV as a first-line antiepileptic drug in neonatal seizures because of its good pharmacokinetics and having an acceptable side effect profile [9–20]. The potential neurotoxic effects of antiepileptic drugs have been known for decades [21,22].
This study aims to compare the neurocognitive outcome in term infants who were treated using phenobarbital (PB) and levetiracetam (LEV) monotherapy for neonatal clinical seizures.
Term infants who were treated using PB or LEV monotherapy as the first-line anti-epileptic treatment for neonatal clinical seizures and followed-up in a pediatric neurology outpatient clinic were enrolled in this study. Neurodevelopmental outcome assessments were carried out using the Bayley Scales of Infant Development, third edition (BSID-III), including cognitive, receptive language, expressive language, fine motor and gross motor subscales.
The study group consisted of 62 infants who received monotherapy with PB monotherapy (n = 22) and LEV (n = 40). The mean duration of monotherapy treatment was 8 ± 6 months. There was no statistically significant difference between PB and LEV monotherapy groups concerning each outcome parameter on the BSID-III. There was also no statistically significant difference between PB and LEV monotherapy subgroups excluding the infants with neurodevelopmental impairment with a BSID-III scale score<7 or a composite score<85.
Our findings suggest that both LEV and PB therapy can be equally safe as monotherapy for neonatal clinical seizures for the neurodevelopmental outcome assessment with BSID-III.

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Original ArticleUse of Intravenous Levetiracetam for Management of Acute Seizures in Neonates

Introduction

Section snippets

Patients and Methods

Results

Discussion

Pediatr Neurol

Pediatr Neurol

Brain Dev

Pediatr Neurol

Pediatr Neurol

Epilepsy Res

Epilepsy Res

Epilepsy Behav

Neonatal seizures

Pediatr Rev

Original Article
Use of Intravenous Levetiracetam for Management of Acute Seizures in Neonates