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IV LEV appears to be as effective as PHT, VPA, and LOR for the treatment of SE.
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IV LEV as add-on therapy of CNP had no superiority in seizure cessation than CNP plus placebo.
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IV LEV may have a better tolerability profile than other AEDs do.
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More rigorous RCTs are required to determine the place of IV LEV in SE.
Abstract
Purpose
We performed this analysis to evaluate the efficacy and safety of intravenous levetiracetam (IV LEV) in patients with status epilepticus.
Method
Studies were searched in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for available randomized controlled trials(RCTs) comparing the efficacy and/or safety of IV LEV with other antiepileptic drugs (AEDs). Meta-analysis was performed using the random-effects model to calculate risk ratio with the RevMan 5.3 software.
Results
Six RCTs with a total of 543 patients were included. There was no significant differences in clinical seizure cessation and hospital mortality, either between IV LEV and IV phenytoin (PHT) or between IV LEV and IV valproate (VPA). Compared with IV PHT, IV LEV had a lower risk of poor neurological outcome. For IV LEV compared with IV lorazepam (LOR), no significant difference in efficacy was found, but IV LEV patients had significantly lower need for ventilatory assistance. Adding IV LEV to clonazepam (CNP), compared with adding placebo showed no significant differences in seizure cessation at 15 min.
Conclusions
Our results suggested that IV LEV was comparable to IV PHT,VPA, or LOR in efficacy, and IV LEV as add-on therapy of CNP had no superiority in seizure cessation than CNP plus placebo. IV LEV may have a better tolerability than other AEDs do. More RCTs are needed to validate the role of IV LEV in status epilepticus.
Status epilepticus (SE) often resulting in serious complications and even death if can’t be controlled in time, and so be considered as the most extreme form of seizure [
]. Due to high fever, circulation failure, aspiration or neuronal toxicity, irreversible brain injury and pulmonary infection often occurred, leading to high mortality and high disability rates [
]. Early intervention of SE is crucial to prevent above mentioned complications and effectively reduce the mortality. The ideal antiepileptic drug should work rapidly, can be administered intravenously, and last for a long time without serious adverse effects [
].Currently, benzodiazepines such as diazepam, LOR and CNP are most commonly used in clinical practice and still recommended as first-line strategy in SE treatment [
]. By binding to the allosteric regulatory sites of the gamma-aminobutyric acid (GABAA) receptors, these drugs increasing the frequency of chloride channel openings, thereby leading to enhanced inhibitory neurotransmission and antiepileptic action [
]. LEV is characterized by linear pharmacokinetics, low serum protein binding rate(<10 %), low liver and kidney toxicity, minimal risk of other adverse reactions, and little interaction with other drugs but are costly [
].Unique mechanisms of action provide chance for the control of SE that cannot be controlled by the conventional first-line drugs. Italian Anti-Epilepsy Association(IAEA) has recommended new treatment option for children in 2013,that LEV should be try if without contraindications after failure to treat SE by using conventional first-line drugs [
]. Only limited RCTs compared IV LEV with other AEDs, and there is a lack of high-quality, evidence-based meta-analysis of prospective randomized controlled trials (RCTs).
The aim of our study is to evaluate the efficacy and safety of IV LEV in the treatment of SE, and find more evidences for the drug treatment of SE.
2. Methods
2.1 Search strategy
We searched online databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) for RCTs from the inception of each database to October 30, 2018. We used the following keywords: SE, Status Epilepticus, intravenous levetiracetam, LEV. No limitations on language and race were imposed. All final titles and abstracts were carefully evaluated, then through reading full texts to determine the included articles. Reading the references of the included studies to find other relevant trials.
2.2 Selection of studies
Inclusion criteria: randomized, blinded or not blinded, prospectively designed controlled trials. Trials comparing IV LEV to other AEDs were included. Convulsive or non-convulsive SE at any age was considered.
Exclusion criteria: design of trial was uncontrolled, non-randomized.
2.3 Data extraction and evaluation of evidence
Two reviewers independently assessed trials according to inclusion and exclusion criteria, extracted the needed information from included trials. We resolved disagreement through discussion. The following data were collected: first author, publication year, numbers of participants, sex ratio (M/F) for each treatment group, age, inclusion and exclusion criteria of each trial, definition of SE applied in each study, SE type, intervention details, primary outcome, secondary outcomes. Refered to the guideline for assessing risk of bias in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 [
J.P.T. Higgins, S. Green, (Eds.), Cochrane handbook for systematic reviews of interventions.Version 5.1.0 (updated March 2011). The Cochrane collaboration; 2011. In: www.cochrane-handbook.org.
], we conducted bias analysis of the included studies.
2.4 Outcome measures
To evaluate the efficacy and safety of IV LEV in SE, the following outcomes were chosen. (1) The primary outcome was termination of SE after drug administration. (2) The secondary outcomes include hospital mortality, neurological outcome (mRS score) at discharge, recurrence of seizures within 24 h or 24 -h freedom from seizure, drug-related adverse events, and number of patients requiring assisted breathing.
2.5 Statistical analysis
Our objective was to perform separate analyses for different controlled drugs. Trials with the same controlled drug were combined to carry out meta-analysis, whereas those comparing different drugs were analyzed separately. Meta-analysis of all RCTs comparing IV LEV to IV PHT or IV VPA were performed using the random-effects model. The Mantel-Haenszel model and risk ratios (RRs) with 95 % confidence intervals (CIs) for interest outcomes were used to compare dichotomous variables. It indicates that LEV is superior to other drugs when the RR < 1. A P-value less than 0.05 was considered statistically significant. Statistical heterogeneity between the trials was evaluated using the I2 test (I2 >50 % was considered heterogeneous). The above statistical values were calculated using statistical method provided by Review Manager software (RevMan version 5.3).
The stability of meta-analysis results was evaluated by sensitivity analysis. The random-effects model was converted to the fixed-effects model, the RR values were transformed into odds ratio (ORs) values, and the 95 % CI was calculated again. The consistent results obtained after these conversions indicated that the meta-analysis results were stable; otherwise, the reverse was not.
3. Results
3.1 Study selection
The search strategy previously described produced 527 results (345 in MEDLINE, 137 in EMBASE, 45 in CENTRAL) (Fig. 1).By excluding duplicate referrences, retrospective studies, case reports and case series, reviews, and uncontrolled trials, finally 6 [
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
] compared adding IV LEV to CNP with adding IV placebo to CNP. Studies were integrated separately for meta-analysis according to the type of comparison.
]. Nonetheless, only those with SE were included in our meta-analysis. All studies included generalized convulsive SE (GCSE) participants, whereas three [
] of them included several patients presenting with focal or subtle convulsive SE. In addition, the definition of SE varies slightly from study to study (shown in Table 1). Even so, we assumed that the type and definition of SE were similar.
Table 1Definition of status epilepticus in included studies.
Convulsive SE defined as two or more convulsive seizures without full recovery of consciousness between the seizures or continuous convulsions lasting for more than 5 min.
SE defined as continuous, generalized, convulsive seizure lasting >5 min, or two or more seizures during which the patient does not regain normal sensorium.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
SE defined as a prolonged (>5 min) or recurrent generalized tonic-clonic seizure(s) with no regain of consciousness between attacks, or partial seizures persisting for more than 10 min.
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
], drugs were intravenously administered in prehospital patients. The dose, maintenance dose, and injection timing of LEV and control drugs varied between studies (Table 2). Mundlamuri et al. followed their participants for one month after discharge from hospital [
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
]), and in other studies patients were followed only during their hospital stay. All studies considered the clinical termination of SE as the primary outcome, yet the time between the start of the injection and end of SE varied among studies. Other outcomes were recurrence of seizures within 24 h or seizure freedom for 24 h (h), neurological outcome (mRS score) at discharge, drug-related adverse events, hospital mortality, and ventilatory assistance. Characteristics of the included trials are reported in Table 2.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting were involved in study bias according to the Cochrane Handbook of Systematic Review [
J.P.T. Higgins, S. Green, (Eds.), Cochrane handbook for systematic reviews of interventions.Version 5.1.0 (updated March 2011). The Cochrane collaboration; 2011. In: www.cochrane-handbook.org.
3.4 Effects of interventions and meta-analysis outcomes
Four comparisons were available (IV LEV vs. IV PHT, IV LEV vs. IV VPA, IV LEV vs. IV LOR, IV LEV plus CNP vs. IV placebo plus CNP); however, only the former two included more than one study with enough information that could be used for meta-analysis.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
], with 196 participants, comparing IV LEV and IV PHT could be combined to conduct a meta-analysis. Clinical cessation of SE after infusion of the first study drug and hospital mortality was available in three studies. Secondary outcome of neurological outcome (mRS score) at hospital discharge was available in two studies [
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
]. No statistically significant differences in clinical cessation of SE after drug infusion was found between the two groups (70/94 vs. 71/102 patients; RR 1.09, 95 % CI [0.92,1.29]) (Fig. 4a). The test for heterogeneity between the studies was not significant (I2 = 0 %). There were no statistically significant differences in risk of hospital mortality between the two groups (9/94 vs. 11/102 patients; RR 0.88, 95 % CI [0.38, 2.04]) (Fig. 4b), and the test result for heterogeneity between the studies was not significant (I2 = 0 %). Compared with PHT, LEV had a statistically lower risk of resulting in poor neurological outcome (mRS score: 4–6) (17/72 vs. 31/72 participants; RR 0.55, 95 % CI [0.36, 0.84]) (Fig. 4c), and no statistically significant heterogeneity among trials was detected (I2 = 0 %).
Fig. 4Studies comparing IV LEV and IV PHT. (a)Clinical seizure cessation after drug administration. (b) Hospital mortality. (c) Poor neurological outcome (mRS 4-6). mRS: modified Rankin Scale.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
] with 182 participants could be combined to conduct a meta-analysis. No statistically significant heterogeneity among the trials was detected (I2 = 0 %). There were no statistically significant differences in clinical cessation of SE after drug administration between the IV LEV and the IV VPA groups (67/91 vs. 60/91 participants; RR 1.12, 95 % CI [0.93, 1.36]) (Fig. 5a); no statistically significant differences in hospital mortality among the trials (7/91 vs. 6/91 participants; RR 1.17, 95 % CI [0.41, 3.34]) (Fig. 5b); and the test result for heterogeneity between the studies was not significant (I2 = 0 %).
Fig. 5Studies comparing IV LEV versus and IV VPA. (a) Clinical seizure cessation after drug administration. (b) Hospital mortality.
], with 79 patients (73 patients presented with convulsive SE and 6 patients with subtle convulsive SE), was included. In this study, 83 participants were initially included; however, 4 patients were excluded because of lack of consent, liver failure, or already on the study drug. Definition of SE in this study is shown in Table 1. Patients were randomized in LOR (0.1 mg/kg in 10 ml saline IV in 2–4 min) and LEV (20 mg/kg infused in 15 min); 41 patients received LOR and 38 LEV. Patients who had ongoing SE 10 min after the first infusion drug were treated with another drug. As first infusion AEDs, there were no statistically significant differences in termination of SE within 10 min between the two groups (29/38 vs. 31/41 participants; 76.3 % vs. 75.6 %, P = 1.00). No statistically significant differences in 24 -h freedom from seizure was found (23/29 vs. 21/31 participants; 79.3 % vs. 67.7 %, P = 0.38) among patients whose SE was controlled by the first infusion drug. The patients treated with LEV were significantly less likely to use assisted breathing (4/38 vs. 10/41, P = 0.03).
3.4.4 Adding IV LEV to CNP vs. Adding IV placebo to CNP
For this comparison, only one RCT included 203 participants presenting with GCSE [
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
]. This study did a prehospital trial, aiming to determine the efficacy of adding intravenous LEV to CNP for treatment of GCSE. Patients were given 1 mg CNP by intravenous perfusion for 1 min, and were randomly assigned to receive intravenously 2.5 g LEV or placebo for 5 min. As last, 68 patients in each group were included in the modified intention-to-treat (ITT) analysis. There were no statistically significant differences in termination of SE at 15 min after the injection among the groups (LEV vs. placebo: 57/68 vs. 50/68 participants; RR = 0.88, 95 % CI: 0.71–1.05, P = 0.14). The incidence of serious and non-serious adverse reactions was comparable in two groups (serious adverse events: LEV vs. placebo, 19/47 vs. 28/47; non-serious adverse events: LEV vs. placebo, 90/197 vs. 107/197).
3.5 Sensitivity test
In the evaluation of efficacy and tolerability of IV LEV in the treatment of SE, the random-effects model was converted to the fixed-effects model, and the RR value was transformed into the OR. The research conclusions were consistent, indicating that the results of the meta-analysis were stable (Table 3).
Table 3Sensitive analysis of interconversion between random-effects model and fixed-effects model, and exchange of statistical values.
This study was performed to evaluate the role of IV LEV in SE. Meta-analyses showed there was no significant difference in clinical seizure cessation when IV LEV compared with IV PHT,IV VPA or IV LOR. IV LEV had a lower risk of poor neurological outcome compared with IV PHT and significantly lower need of ventilatory assistance compared with IV LOR. However, adding IV LEV to CNP had no superiority in seizure cessation than CNP plus placebo.
Holtkamap et al. proposed that IV LEV could be used for the treatment of focal onset SE after the failure of traditional AEDs [
]. Some research data also indicate that LEV is fairly safe to administering intravenously or pumping continuously at a relatively rapid rate, and the pharmacokinetics of intravenous administration are consistent with oral administration [
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
], recommending LEV as either initial or second therapy (level U) although, there are insufficient evidence on whether LEV is noninferior to other AEDs in controlling SE or not.
In our study, meta-analyses showed no differences in clinical seizure cessation and hospital mortality, either between IV LEV and IV PHT or between IV LEV and IV VPA. These results were consistent with the study comparing LEV with PHT or VPA by direct and indirect comparison [
]. Meta-analysis showed that IV LEV had a statistically lower risk of poor neurological outcome than IV PHT did, the results should be read with extreme caution because only a limited number of studies were included. Also IV LEV was comparable to IV LOR in seizure cessation, but IV LEV patients had significantly lower need for ventilatory assistance. The reason for the reduction of breathing side effect of LEV compared to LOR may be that LOR acts on GABAA receptors and inhibits the central nervous system, even inhibits the nervous that controls the respiratory muscle movement, while LEV has a completely different mechanism, almost has no impact on the movement of respiratory muscles. LEV acts unique mechanism by interfering the neuronal binding to synaptic vesicle protein 2A, inhibiting the release of stored calcium in neurons and thus excessive synchronized neuronal activity [
]. Studies are needed to confirm the exact mechanisms. However, only one study with 79 patients presenting convulsive SE was included. We needed more high-quality RCTs to compare IV LEV to IV LOR. The SAMUKeppra study is a very well conducted study and showed that additional LEV did not show even a trend towards higher cessation rates as CNP alone. This result is inconsistent with the conclusions of other included studies, which may be related to the different trial design, and the result should be interpreted with caution.
No statistically significant heterogeneity was found for all pooled analysis. Sensitivity test results indicated that the results of the meta-analyses were stable.
From our study, we can draw a conclusion that LEV might be as efficacious as PHT and VPA while it is better tolerable. To date, no high-quality evidence is available for choosing IV LEV over another AED. We suggest LEV may be an option when first-line medication for SE treatment remain ineffective. Recently, several ongoing clinical RCTs have been established to compare the efficacy of LEV with other AEDs [
Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial.
A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.
]; these trials may provide a new strategy for the treatment of SE.
This study was potentially limited in some aspects. First, only studies published in journals or in certain trial registers were included. Second, the included trials were varied in terms of trial design, type of comparator drugs, and outcomes. We combined all the studies with the same controlled drug to conduct meta-analysis, using a random-effects model, and tested heterogeneity among trials. Third, SE requires rapid intervention with antiepileptic treatment to avoid serious complications even life-ending. Almost all SE patients had a conscious disturbance during the episode, sometimes a part of patients were delivered to hospital without family members or guardians accompany. Hence, in such situations, it is very difficult for us to obtain the informed consent for the trial. So far, the research on LEV compared with other AEDs for SE was almost observational and retrospective studies. Fourth, the number of included studies and participants was limited and might be underpowered to detect potential differences among drugs, thus leading to the inability to stratify analysis according to different etiologies. Fifth, the follow-up period of the included studies was relatively short; thus, the long-term efficacy and neurological outcomes cannot be concluded from this work, making it difficult to obtain implications for clinical practice. Futher more, we did not compare the specific adverse events (AEs), because they might be different among different comparators, and reported LEV-related AEs were less and mild.
5. Conclusion
In this study, we found that IV LEV appears to be as effective as PHT, VPA, and LOR for the treatment of SE. Besides, IV LEV could reduce the necessity for assisted breathing in the hospital and, in the long run, it may reduce the incidence of poor neurological outcome. But more high-quality RCTs are urgently required to determine the value of IV LEV for SE.
Study funding
This study was funded by the Science and Technology Department of Sichuan Province [grant number 2018SZ0166].
Declaration of Competing Interest
All authors report no conflict of interest.
Acknowledgments
We would like to thank all of the participants for their cooperation.
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J.P.T. Higgins, S. Green, (Eds.), Cochrane handbook for systematic reviews of interventions.Version 5.1.0 (updated March 2011). The Cochrane collaboration; 2011. In: www.cochrane-handbook.org.
Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam – pilot study.
Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial.
A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.
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