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Levetiracetam as alternative stage two antiepileptic drug in status epilepticus: A systematic review

Open ArchivePublished:February 10, 2012DOI:https://doi.org/10.1016/j.seizure.2012.01.008

      Abstract

      Background

      The role of new antiepileptic drugs (AED) in the treatment of status epilepticus (SE) is of interest, especially in benzodiazepine-resistant status epilepticus where phenytoin is deemed inappropriate due to allergy or comorbidity. Levetiracetam (LEV) is a new AED with few side effects. It is easy to administer. Reports exist of its use in SE in adults.

      Aims

      To clarify the evidence for use of LEV as an alternative stage two AED in treatment of SE by a systematic review of the literature.

      Method

      An online MEDLINE search identified 118 articles. The abstracts were screened for studies written in English, in which (1) at least two adults had been treated, and (2) LEV had been administered intravenously as the first AED, on its own or together with benzodiazepines. Ten studies were included.

      Results

      Out of the ten studies, seven were retrospective observational, two prospective observational, and one prospective randomized. The studies described a total of 334 patients. The most common reason for administrating LEV was that standard treatment was deemed inappropriate. The efficacy ranged from 44% to 94%, with higher efficacy reported in the retrospective studies.

      Conclusions

      The evidence for use of LEV as an alternative stage two AED in SE is limited. The higher efficacy reported in retrospective studies indicates possible publication bias, and caution is advised when the results of these retrospective studies are considered in clinical decision-making.

      Keywords

      1. Introduction

      The standard treatment for status epilepticus (SE) in Europe is benzodiazepines in treatment stage one, which is followed by phenytoin or its equivalents in treatment stage two, and in refractory cases sedation and intensive care in treatment stage three.
      • Shorvon S.
      • et al.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      • Meierkord H.
      • et al.
      EFNS guideline on the management of status epilepticus in adults.
      This treatment regime carries risks, especially for certain patient categories. For instance, phenytoin is associated with circulatory side effects, which makes the drug unsuitable for frail, elderly, or cardiologically compromised patients. Other antiepileptic drugs (AED) such as valproic acid, levetiracetam (LEV), and lacosamide have therefore attracted interest as alternative stage two AEDs in cases where phenytoin is not appropriate due to allergy or comorbidities.
      • Shorvon S.
      • et al.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      LEV is one of the newer AEDs. Introduced in 1999, the drug has achieved rapid spread in clinical practice, due in large part to its pharmacological properties (e.g. minimal protein-binding and drug–drug interactions).
      • Crepeau A.Z.
      • Treiman D.M.
      Levetiracetam: a comprehensive review.
      Compared to many other AEDs, LEV has fewer reported major side effects, although this may be a consequence of its relatively short period of clinical use. Some years ago, reports on the use of LEV as an add-on therapy in treatment of SE emerged.
      • Patel N.C.
      • et al.
      The use of levetiracetam in refractory status epilepticus.
      • Rossetti A.O.
      • Bromfield E.B.
      Levetiracetam in the treatment of status epilepticus in adults: a study of 13 episodes.
      Theoretically, the excellent safety profile of LEV and its broad spectrum efficacy make it a good candidate for use in frail patients with SE. Following the introduction of an intravenous preparation in 2006, some literature has accumulated on this topic.
      The initial case series on the use of LEV in SE reported the drug to be highly successful in terminating seizures.
      • Patel N.C.
      • et al.
      The use of levetiracetam in refractory status epilepticus.
      • Abend N.S.
      • et al.
      Intravenous levetiracetam terminates refractory focal status epilepticus.
      • Beyenburg S.
      • Reuber M.
      • Maraite N.
      Intravenous levetiracetam for epileptic seizure emergencies in older people.
      • Knake S.
      • et al.
      Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus.
      Subsequent studies and reviews have somewhat modulated this view, but despite this LEV is still considered one of the possible AEDs for use in the treatment of SE. However, many of the above studies describe the use of LEV as an add-on treatment in SE in addition to other AEDs, and have therefore failed to clarify the benefits of LEV as an alternative stage two AED in patients where standard treatment cannot be given.
      • Patel N.C.
      • et al.
      The use of levetiracetam in refractory status epilepticus.
      • Abend N.S.
      • et al.
      Intravenous levetiracetam terminates refractory focal status epilepticus.
      We are interested in the clinical problem of patients with benzodiazepine-resistant SE where phenytoin is deemed inappropriate. The clinician is then faced with the dilemma of either administrating an alternative AEDs or proceeding directly to intensive care, which also carries risks.
      Against this background, we wanted to clarify the evidence for the use of LEV as an alternative stage two AED in SE and undertook a systematic review of the literature. Because of the scarcity of randomized evidence regarding treatment of SE, we did not expect to find studies fit for a meta-analysis. Instead, the aim of the study was to qualitatively characterize the current literature with a focus on studied patient populations, efficacy and safety.

      2. Methods

      We first searched the literature for studies describing the use of LEV as a first-line AED. The inclusion criteria were any study written in the English language describing more than two adult patients with: (1) SE, and; (2) LEV administered intravenously as the first AED, either on its own or together with or after benzodiazepines. The sought outcome measures were efficacy in terminating SE and reported adverse effects. For adverse events, we used a conservative approach and included all events reported for patients initially treated with LEV, regardless of subsequent administration of other AEDs. We also compiled information about the study populations.
      An online MEDLINE search in January 2011 for “Levetiracetam status epilepticus” resulted in 118 articles. The abstracts were assessed and 17 studies selected for additional analysis. Nine studies met the inclusion criteria. One study was excluded because the outcome of the relevant patients could not be extracted from the reported data, leaving eight studies.
      • Rossetti A.O.
      • Bromfield E.B.
      Levetiracetam in the treatment of status epilepticus in adults: a study of 13 episodes.
      • Beyenburg S.
      • Reuber M.
      • Maraite N.
      Intravenous levetiracetam for epileptic seizure emergencies in older people.
      • Knake S.
      • et al.
      Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus.
      • Aiguabella M.
      • et al.
      Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: a multicentric observational study.
      • Berning S.
      • et al.
      Intravenous levetiracetam as treatment for status epilepticus.
      • Eue S.
      • et al.
      Two years of experience in the treatment of status epilepticus with intravenous levetiracetam.
      • Gamez-Leyva G.
      • et al.
      Experience with intravenous levetiracetam in status epilepticus: a retrospective case series.
      • Uges J.W.
      • et al.
      Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus.
      To make sure that our search had adequately covered the literature, articles cited in the selected studies were also examined. This reference screening did not reveal any studies that had not been identified in the initial search. During the review process, two more relevant studies were published and added to the manuscript.
      • Alvarez V.
      • et al.
      Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam.
      • Misra U.K.
      • Kalita J.
      • Maurya P.K.
      Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
      Some methodological differences between the reviewed studies had to be reconciled for a digestible presentation. For instance, some of the larger studies describe the use of LEV in episodes of SE and the same patients may have been included multiple times.

      3. Results

      Of the ten studies included, all but one
      • Misra U.K.
      • Kalita J.
      • Maurya P.K.
      Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
      were performed in Europe. In these studies, which described a total of 334 patients treated with LEV, 55 patients had received LEV alone and 279 had received LEV in conjunction with benzodiazepines. Because of the large variability in the size of the studies, their different treatment protocols, and their observational nature, a quantitative meta-analysis of the data was considered inappropriate. Instead, we focused on qualitatively describing the literature.
      All reviewed studies but one were observational and uncontrolled. Seven studies were retrospective and three studies were prospective, out of which one was randomized.
      • Misra U.K.
      • Kalita J.
      • Maurya P.K.
      Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
      In most studies, where that information was presented, there was a majority of focal SE among the patients receiving LEV as an alternative AED. The definition of SE varied somewhat between the studies. Some authors used a time limit of 30 min with seizure or clusters of seizures without intervening restoration of consciousness. Other authors used the more aggressive time limit of five minutes. Importantly, in a majority of the studies it was clearly stated that patients received iv LEV because standard treatment was deemed inappropriate. Doses given in the reviewed studies varied from 250 to 2500 mg. For efficacy, we relied on the definitions used by the authors. This was generally a cessation of clinical seizure activity or seizure activity on EEG within a certain time frame without the need for any additional antiepileptic drugs. The efficacy measurement for each study is shown in Table 1. The reported efficacy (Table 2) was 44% in two prospective studies, and 75% in one prospective study. Efficacy ranged from 60% to 94% in the retrospective studies.
      Table 1Studies included in this review and description of study populations.
      StudyCountrySample (described patients receiving iv LEV ± BZ)Definition of treatment effect
      Retrospective
      Aiguabella 2011Spain13 out of 40 patients treated during 2008 in 8 hospitals, where standard treatment with phenytoin or valproate was contraindicated. All patients suffered focal SE.Clinical or EEG cessation of seizures within 24 h after start of iv LEV without need for other AED
      Alvarez 2011Switzerland58 patients retrospectively identified in a prospectively kept registry of SE patients 2006–2011.Need to introduce a further compound to control SE.
      Fatouch 2010Italy9 patients over 65 years of age where standard treatment was considered unsafe. 8 patients suffered partial and 1 generalized SE.Disappearance or significant reduction of EEG abnormalities and subsequent clinical improvement.
      Berning 2009Germany27 out of 32 patients treated at 2 hospitals between May 2007 and February 2008 where standard treatment was deemed unsafe.Cessation of SE as shown by neurologic examination, electroencephalography (EEG), or both
      Gámez-Leyva 2009Spain16 out of 34 patients treated with iv LEV July 2007–July2008. 8 patients suffered focal and 8 suffered generalized SE.(i) The absence of seizures within, at most 24 h after iv levetiracetam was infused; (ii) no other antiepileptic drugs administered during this time; and (iii) no recurrence of status epilepticus during the hospital stay
      Beyenburg 2008Luxembourg5 out of 14 patients treated with iv LEV for SE or series of complex partial seizures during 2007.Complete seizure cessation in the 24 h after starting LEV IV
      Knake 2008Germany13 out of 16 patients treated with iv LEV for SE between May 2006 and February 2007. All suffered focal SE.Not stated
      Prospective
      Uges 2009Netherlands9 out of 11 patients in a safety trial received iv LEV as the first non-BZ AED for SE. Four suffered focal and five suffered generalized SE.Not stated
      Eue 2009Germany43 hospitalized patients where SE was not controlled by bensodiazepines and who did not tolerate phenytoin or phenobarbital. 35 suffered focal and 8 suffered generalized SE.Cessation of the clinical manifestation of convulsive SE and lectroencephalographically in non-convulsive and subtle SE within approximately 3 min.
      Misra 2011India48 out of 79 patients received iv LEV on its own or after failure of lorazepam.Primary endpoint was clinical seizure cessation within 30 min and secondary endpoints were 24-h seizure freedom, mortality, and adverse events.
      Table 2Efficacy, dose, and side effects in the reviewed studies.
      StudyPatients receiving BZ + LEV/only LEVEfficacyDose LEVSide effects
      Retrospective
      Aiguabella 20118/577%1000–1500 mg15% somnolence 1 trombocytopenia
      Alvarez 201158/052%20 mg/kgNot stated
      Fatouch 20100/989%1500 mgNot stated
      Berning 200925/274%1000–3000 mgSedation (6/32), nausea (1/32), liver enzymes (1/32)
      Gámez-Leyva 200916/094%500–1500 mgNone
      Beyenburg 20084/180%250–1000 mgSedation 4/10
      Knake 200813/085%250–1500 mgSedation 2/16
      Prospective
      Uges 20099/044%2500 mgRespiratory 2/9, red face 1/9
      Eue 200943/044%1000 or 2000 mgSomnolnce “common”
      Misra 201110/3875%20 mg/kgAgitation 4, rash 1, thrombocytopenia 4, pneumonia 8, urinary infection 1
      With regards to safety, none of the studies reported any serious side effects related to treatment with LEV. Sedation was the most common side effect, occurring in quantities ranging from 12.5% to 40%. All side effects are listed in Table 2.

      4. Discussion

      Here we have reviewed the published experience of LEV as an alternative stage two AED in the treatment of SE. SE is a clinical scenario well known for its lack of randomized controlled evidence,
      • Shorvon S.
      • et al.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      so it is no surprise that our review revealed only studies traditionally categorized as low-grade evidence – with one notable exception, Misra et al., which is discussed in detail below.
      Regarding study design, all studies except Misra et al. were observational and uncontrolled. The majority were retrospective and small. The main method used to find patients was retrospective analysis of the medical records for all patients treated with iv LEV during a defined period. In the reviewed studies, the reported efficacy for patients treated with LEV as a first line AED ranged from 44% to 94%. We believe that the most interesting finding in our review is that higher efficacy was reported in the retrospective studies compared to the prospective ones (Fig. 1). This indicates a possible publication or selection bias in some of the retrospective data. For example, centers with a less favorable experience with LEV in SE might have refrained from further use of the drug and thereby publication. Another possible explanation for the large variability in efficacy is variation in the study populations and the small number of patients in some of the studies.
      Figure thumbnail gr1
      Fig. 1Box plot comparing the reported efficacy in the retrospective versus the prospective studies. Box indicates median and first and third interquartile range, error bars represent max and min.
      The differences between the prospective studies underline the need for further investigation into the use of LEV in SE. The differences between the two large prospective studies in this review, which report efficacies of 44% and 75% respectively, are most likely due to differences in patient population and treatment protocol.
      • Eue S.
      • et al.
      Two years of experience in the treatment of status epilepticus with intravenous levetiracetam.
      • Misra U.K.
      • Kalita J.
      • Maurya P.K.
      Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
      In Eue et al., an observational study where the efficacy was 44%, many patients were elderly, their SE was not controlled by bensodiazepines, and they were judged not to tolerate phenytoin or phenobarbital. In Misra et al., a randomized study where efficacy was 75%, LEV was administered as first treatment without prior bensodiazepines. The patient population in Misra et al. was younger and it is likely that many of those responding to LEV as first-line treatment would have also responded to benzodiazepines. However, the absence of benzodiazepine treatment is most likely not the explanation for the large difference in efficacy compared to Eue et al., since even among patients refractory to Lorazepam, Misra et al. report efficacy of LEV in seven out of ten patients. While this patient group is very small in Misra et al., it still indicates that differences in study populations, for example etiology and demographics, underpin some of the dissimilarities between Eue et al. and Misra et al.
      It is important to note that the patient populations described in the reviewed articles are most likely not representative of patients with SE in general. In at least six of the studies it is clearly stated that the reason for giving iv LEV was because standard treatment was considered inappropriate, for instance due to circulatory instability or known drug allergy. This is well in line with the clinical scenario we set out to investigate, but more importantly means that the patient population might be frailer or have more co-morbidities than patients with SE who are able to receive the standard treatment. One should therefore avoid drawing conclusions from these studies regarding the efficacy of LEV for SE in patients where standard treatment is not contraindicated, and the efficacy of LEV reported therein should not be compared with that of, for instance, phenytoin in regular patients with SE. Another important point regarding the current literature is that many of the studies were not designed to prove efficacy, but merely to publish the clinical experience with LEV. This might explain the very small number of patients in some of the case series. Finally, in many of the reviewed studies the majority of patients suffered focal seizures, which makes it even harder to draw conclusions regarding the efficacy of LEV in all patients with SE. In fact, some authors report failure of LEV in generalized SE, but good effects in non-convulsive SE.
      • Eue S.
      • et al.
      Two years of experience in the treatment of status epilepticus with intravenous levetiracetam.
      Whether LEV might be of more value in treatment of focal rather than in generalized SE is a very important issue to address in future studies.
      With regard to safety, the data in the reported studies confirms the previous picture of LEV as a relatively safe drug, although thrombocytopenia was noted in some patients. This side effect has attracted increasing attention in recent years and should be closely monitored in future trials.
      • Sahaya K.
      • et al.
      Levetiracetam-induced thrombocytopenia among inpatients: a retrospective study.
      The most commonly reported side effect was sedation/somnolence, which is common in all treatment regimes of SE. It is important to bear in mind that in our compilation we decided to include all side effects stated for patients initially treated with LEV with or without benzodiazepines, even if those patients later received other AEDs. This conservative approach, chosen so as not to underestimate the risks associated with LEV, makes it likely that some of the reported cases of sedation were not attributed to LEV, but to benzodiazepines or other AEDs. Nonetheless, the reviewed studies support the notion that LEV is a relatively safe AED, although long-term side effects may have not emerged yet. The relatively good safety profile of the drug is underlined by the fact that the majority of the studies were performed on patients where co-morbidity prevented the use of standard treatment.
      We conclude that the evidence for LEV as an alternative stage two AED in SE is scarce. The number of patients described in the literature is still low and the data is largely uncontrolled and observational. The patient populations in the reviewed studies are very heterogeneous, not only regarding personal characteristics such as age, but also the etiology of the SE and the reason for selecting iv LEV as the treatment.
      Pending randomized controlled data comparing the efficacy of LEV to that of phenytoin, valproic acid, and other potential first-line AEDs, the main use of LEV will most likely remain cases of SE where standard treatment is contraindicated. Given the mild side effects associated with LEV described in the reviewed studies, we think that this use might be motivated in selected cases, as suggested by the most current consensus document.
      • Shorvon S.
      • et al.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      However, clinicians should be aware of the current paucity of evidence and be cautious in order that administration of LEV does not unduly delay progression to the next treatment stage. As indicated in one of the most recent studies, LEV might not be the first alternative AED to consider if phenytoin is contraindicated, since LEV might be less effective than both phenytoin and valproate in terminating SE.
      • Alvarez V.
      • et al.
      Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam.
      It should also be noted that LEV is not licensed for use in status epilepticus, so the medico-legal situation of each specific country determines whether it is an available treatment option.
      In current high-quality reviews, LEV is listed as an alternative stage two AED in the treatment of SE.
      • Shorvon S.
      • et al.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      • Shorvon S.
      The treatment of status epilepticus.
      Our short review supports this notion, but also demonstrates that different centers have varying experiences with LEV, underlining the need for more randomized data before the place of LEV in treatment of SE can be properly determined.

      Conflict of interest and sources of funding statement

      This work was supported by Uppsala University Hospital. Eva Kumlien is a member of an advisory board, GSK.

      Acknowledgement

      None.

      References

        • Shorvon S.
        • et al.
        The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
        Epilepsia. 2008; 49: 1277-1285
        • Meierkord H.
        • et al.
        EFNS guideline on the management of status epilepticus in adults.
        Eur J Neurol. 2010; 17: 348-355
        • Crepeau A.Z.
        • Treiman D.M.
        Levetiracetam: a comprehensive review.
        Expert Rev Neurother. 2010; 10: 159-171
        • Patel N.C.
        • et al.
        The use of levetiracetam in refractory status epilepticus.
        Seizure. 2006; 15: 137-141
        • Rossetti A.O.
        • Bromfield E.B.
        Levetiracetam in the treatment of status epilepticus in adults: a study of 13 episodes.
        Eur Neurol. 2005; 54: 34-38
        • Abend N.S.
        • et al.
        Intravenous levetiracetam terminates refractory focal status epilepticus.
        Neurocrit Care. 2009; 10: 83-86
        • Beyenburg S.
        • Reuber M.
        • Maraite N.
        Intravenous levetiracetam for epileptic seizure emergencies in older people.
        Gerontology. 2009; 55: 27-31
        • Knake S.
        • et al.
        Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus.
        J Neurol Neurosurg Psychiatry. 2008; 79: 588-589
        • Aiguabella M.
        • et al.
        Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: a multicentric observational study.
        Seizure. 2011; 20: 60-64
        • Berning S.
        • et al.
        Intravenous levetiracetam as treatment for status epilepticus.
        J Neurol. 2009; 256: 1634-1642
        • Eue S.
        • et al.
        Two years of experience in the treatment of status epilepticus with intravenous levetiracetam.
        Epilepsy Behav. 2009; 15: 467-469
        • Gamez-Leyva G.
        • et al.
        Experience with intravenous levetiracetam in status epilepticus: a retrospective case series.
        CNS Drugs. 2009; 23: 983-987
        • Uges J.W.
        • et al.
        Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus.
        Epilepsia. 2009; 50: 415-421
        • Alvarez V.
        • et al.
        Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam.
        Epilepsia. 2011;
        • Misra U.K.
        • Kalita J.
        • Maurya P.K.
        Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
        J Neurol, 2011
        • Sahaya K.
        • et al.
        Levetiracetam-induced thrombocytopenia among inpatients: a retrospective study.
        Epilepsia. 2010; 51: 2492-2495
        • Shorvon S.
        The treatment of status epilepticus.
        Curr Opin Neurol. 2011; 24: 165-170