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Abstract

The purpose of this study was to compare safety and efficacy of intravenous (IV) levetiracetam (LEV) with IV phenytoin (PHT) in management of status epilepticus (SE). The second-line treatment of SE is limited to a few drugs available in an IV formulation such as PHT, fosphenytoin and valproate. The relative lack of serious side effects and favourable pharmacokinetics of LEV made it a promising option in management of SE. Randomized trials comparing relative efficacy of second-line agents are remarkably lacking. In this study, consecutive patients of SE (n=44) were randomized to receive either IV PHT (20mg/kg) or IV LEV (20mg/kg). The primary end point was successful clinical termination of seizure activity within 30min after the beginning of the drug infusion. Secondary end points included recurrence of seizures within 24hours, drug related adverse effects, neurological outcome at discharge, need for ventilatory assistance, and mortality during hospitalization. Both LEV and PHT were equally effective with regard to primary and secondary outcome measures. PHT achieved control of SE in 15 (68.2%) patients compared to LEV in 13 (59.1%; p=0.53). Both the groups showed comparable results with respect to recurrence of seizures within 24hours (p=0.34), outcome at discharge as assessed by functional independence measure (p=0.68), need of ventilatory assistance (p=0.47) and death (p=1). From this study it can be concluded that LEV may be an attractive and effective alternative to PHT in management of SE. Copyright © 2015 Elsevier Ltd. All rights reserved.

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... After removing 299 duplicate results and excluding 888 records by title and abstract (751 records were not RCTs, 95 not levetiracetam vs phenytoin, and 42 not status epilepticus), 14 full-text reports were reviewed for possible eligibility. After exclusion of incomplete reports [14,[26][27][28][29][30][31], seven trials [13,[15][16][17][18]32,33] were deemed eligible and included in the meta-analysis. The reasons for excluded trials in the full-text selection are presented in Supplemental eTable 3. ...
... The number of participants ranged from 44 to 286. The trials were published between 2015 and 2019.Three trials [13,17,18] were multicenter, and four [15,16,32,33] were single-center. ...
... Fig. 11 and Fig. 22. Three trials [15,17,18] were deemed at high risk of bias because of unblinded design; one trial [32] was high risk for selection bias. Two trials [16,33] were ranked as unclear risk, and one low risk [13]. ...
Article
Objectives To compare the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus. Methods In this systematic review, we searched Medline, Embase, and Cochrane databases from their inception with no language restrictions until May 8, 2019 and updated on February 5, 2020, for randomized controlled trials comparing the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus. A Meta-analysis was conducted to calculate the risk ratio (RR) using random-effects models. Results We identified 7 trials with a total of 1028 participants. Levetiracetam was not associated with an increased rate of clinical seizure cessation within 60 min compared with phenytoin (RR, 1.02; 95%CI, 0.92-1.13; I² = 3%; 60.0 % [309/515] vs 59.3 % [275/463];12 more events [95% CI, -48 to 77] per 1000 participants; moderate-quality evidence). Results were similar in the subgroup analysis of adults and children. The sample size met the optimum size in trial sequential analysis. There were also no statistically significant effects on good functional outcome (RR, 1.05; 95% CI, 0.90-1.23), admission to critical care (RR, 1.09; 95% CI, 0.95-1.24), or all-cause mortality (RR, 1.09; 95% CI, 0.55-2.16). Conclusions Moderate-quality evidence suggested that levetiracetam was not significantly superior to phenytoin in seizure cessation in patients with established status epilepticus.
... Of these, 288 studies were excluded after title/abstract screening, and 104 studies were selected for full-text review. And 43 reports met the inclusion criteria after full-text review: 5 SRs/metaanalyses (Liu et al., 2012;Zelano and Kumlien, 2012;Prasad et al., 2014;Yasiry and Shorvon, 2014;Brigo et al., 2016), 9 RCTs (Misra et al., 2012Chakravarthi et al., 2015;Mundlamuri et al., 2015;Navarro et al., 2016;Gujjar et al., 2017;Singh et al., 2018;Dalziel et al., 2019;Lyttle et al., 2019;Nene et al., 2019), 1 non randomized trial (Tripathi et al., 2010), 27 case series/reports (Falip et al., 2006;Baulac et al., 2007;Michaelides et al., 2008;Ruegg et al., 2008;Abend et al., 2009;Berning et al., 2009;Beyenburg et al., 2009;Kirmani et al., 2009;Moddel et al., 2009;Wheless et al., 2009;Depositario-Cabacar et al., 2010;Ng et al., 2010;Reiter et al., 2010;Usery et al., 2010;Khan et al., 2011;Standish et al., 2011;Bahr et al., 2012;McTague et al., 2012;Rakshasbhuvankar et al., 2013;Isguder et al., 2014;Koklu et al., 2014;Atmaca et al., 2015;Lang et al., 2015;Bernatowicz and Li, 2017;Kim and Shin, 2017;May et al., 2017;Shahbaz et al., 2017), and 1 economic study (Sańchez Fernańdez et al., 2019) ( Figure 1). ...
... Among the included RCTs, 6 compared LEV with PHT for second-line treatment (Chakravarthi et al., 2015;Mundlamuri et al., 2015;Gujjar et al., 2017;Singh et al., 2018;Dalziel et al., 2019;Lyttle et al., 2019), 2 compared LEV with VPA (Mundlamuri et al., 2015;Nene et al., 2019), 1 compared LEV with LOR (Misra et al., 2012), and 1 compared LEV plus clonazepam with placebo plus clonazepam (Navarro et al., 2016), One non randomized trial compared LEV with VPA was included (Tripathi et al., 2010). Study characteristics of included RCTs and the non randomized trial were showed in Table 2. ...
... Four RCTs (Misra et al., 2012;Chakravarthi et al., 2015;Dalziel et al., 2019;Lyttle et al., 2019) evaluated the rates of seizure freedom within 24 h and indicated no statistically significant difference in rates of seizure freedom within 24 h when LEV was compared with LOR (Misra et al., 2012) [first-line treatment, OR = 1.83, 95% confidence interval (CI) 0.57 to 5.90], PHT (Chakravarthi et al., 2015;Dalziel et al., 2019;Lyttle et al., 2019) (second-line treatment, OR = 1.08, 95% CI 0.63 to 1.87) (Figure 3). ...
Article
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Objective To evaluate efficacy, safety, and economics profiles of intravenous levetiracetam (LEV) for status epilepticus (SE).Methods We searched PubMed, Embase, the Cochrane Library, Clinicaltrials.gov, and OpenGrey.eu for eligible studies published from inception to June 12th 2019. Meta-analyses were conducted using random-effect model to calculate odds ratio (OR) of included randomized controlled trials (RCTs) with RevMan 5.3 software.ResultsA total of 478 studies were obtained. Five systematic reviews (SRs)/meta-analyses, 9 RCTs, 1 non-randomized trial, and 27 case series/reports and 1 economic study met the inclusion criteria. Five SRs indicated no statistically significant difference in rates of seizure cessation when LEV was compared with lorazepam (LOR), phenytoin (PHT), or valproate (VPA). Pooled results of included RCTs indicated no statistically significant difference in seizure cessation when LEV was compared with LOR [OR = 1.04, 95% confidence interval (CI) 0.37 to 2.92], PHT (OR = 0.90, 95% CI 0.64 to 1.27), and VPA (OR = 1.47, 95% CI 0.81 to 2.67); and no statistically significant difference in seizure freedom within 24 h compared with LOR [OR = 1.83, 95% CI 0.57 to 5.90] and PHT (OR = 1.08, 95% CI 0.63 to 1.87). Meanwhile, LEV did not increase the risk of mortality during hospitalization compared with LOR (OR = 1.03, 95% CI 0.31 to 3.39), PHT (OR = 0.89, 95% CI 0.37 to 2.10), VPA (OR = 1.28, 95% CI 0.32 to 5.07), and placebo (plus clonazepam, OR = 0.73, 95% CI 0.16 to 3.38). LEV had lower need for artificial ventilation (OR = 0.23, 95% CI 0.06 to 0.92) and a lower risk of hypotension (OR = 0.15, 95% CI 0.03 to 0.84) compared to LOR. A trend of lower risk of hypotension and higher risk of agitation was found when LEV was compared with PHT. Case series and case report studies indicated psychiatric and behavioral adverse events of LEV. Cost-effectiveness evaluations indicated LEV as the most cost-effective non-benzodiazepines anti-epileptic drug (AED).ConclusionsLEV has a similar efficacy as LOR, PHT, and VPA for SE, but a lower need for ventilator assistance and risk of hypotension, thus can be used as a second-line treatment for SE. However, more well-conducted studies to confirm the role of intravenous LEV for SE are still needed.
... In the hopes of finding a safer alternative to phenytoin, recent studies have compared the efficacy of this AED in treating SE to that of levetiracetam, a relatively newer AED [18][19][20][21][22][23][24][25][26][27][28]. This article provides an overview of the different stages of SE, discusses the use of phenytoin and levetiracetam in treating SE patients, and highlights the key benefits of levetiracetam over phenytoin in treating SE patients. ...
... A systematic review of various clinical studies evaluating phenytoin and levetiracetam effectiveness in treating SE patients reveals that levetiracetam is comparable to phenytoin in suppressing seizure activity in SE patients and has fewer adverse effects. Table 1 highlights the findings of clinical studies making efficacy comparisons between phenytoin and levetiracetam in the acute setting to treat SE [18][19][20][21][22][23][24][25][26]. ...
... The primary outcome measure was successful termination of seizure activity 30 minutes after drug administration. Secondary outcome measures included recurrence of seizures after 24 hours, mortality during hospitalization, need for ventilatory assistance, and neurological state at discharge [24]. However, the sample size was small as the trial enrolled only 44 patients. ...
Article
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For decades, phenytoin has been the drug of choice for the treatment of epilepsy but also the second-line treatment for status epilepticus (SE). However, newer antiepileptic drugs (AEDs) have emerged as safer alternatives for the suppression of seizures. Consequently, phenytoin has recently fallen under scrutiny in the research world, prompting many studies to compare its efficacy to these other drugs, most notably levetiracetam. Levetiracetam is a second-generation AED, which is gaining wide clinical use as the second-line agent in treating SE patients. This review focuses on several clinical studies that have directly compared the effectiveness of phenytoin and levetiracetam in suppressing SE seizure activity. Additionally, this review highlights several advantages of using levetiracetam over phenytoin in this clinical context.
... Earlier observational studies show that levetiracetam is similarly effective and that it is associated with less adverse effects than those of phenytoin (7)(8)(9)(10)(11). Similar findings have been reported from small randomized control studies (12)(13)(14). Neurocritical Care Society guidelines recommended levetiracetam use in addition to phenytoin/fosphenytoin (5), but other guidelines do not recommend levetiracetam use (15,16). ...
... Outcomes including in-hospital mortality, death within 24 h, neurological outcome at discharge, mechanical ventilation and the use of third-line treatments on the day of admission were not significantly different between the levetiracetam and fosphenytoin groups examined in this study. These findings were consistent with those of earlier RCTs comparing levetiracetam and phenytoin (12)(13)(14) and earlier observational studies comparing levetiracetam and phenytoin or fosphenytoin (8)(9)(10)(11)30). ...
... In terms of the adverse events, our results suggest that levetiracetam is superior to fosphenytoin in vasopressor use on the day of admission. Earlier studies showed that severe adverse events such as cardiac arrest or hypotension occurred in the phenytoin group, but not in the levetiracetam group (12)(13)(14). However, because the sample size was insufficient to detect such a small difference in the adverse events, no significant difference was found in adverse effects in earlier studies. ...
Article
Full-text available
Objective: Status epilepticus is a major emergency condition. The choice of antiepileptic drugs for second-line treatment after benzodiazepine remains controversial, including levetiracetam vs. fosphenytoin. We compare the safety of intravenous levetiracetam and fosphenytoin as a second-line treatment in patients with status epilepticus using a nationwide database. Methods: An observational study conducted with the Japanese Diagnosis Procedure Combination inpatient database identified adult patients who had been admitted for status epilepticus and who had received intravenous diazepam on the day of admission from March 1, 2011 to March 31, 2018. Patients who received intravenous levetiracetam on the day of admission were defined as the levetiracetam group and those who received intravenous fosphenytoin on the day of admission were defined as the fosphenytoin group. Propensity score matching was performed to compare outcomes obtained for the levetiracetam and fosphenytoin groups. Results: The analysis examined data of 5,667 patients. Overall, 1,403 (25%) patients received levetiracetam; 4,264 (75%) received fosphenytoin. One-to-one propensity score matching created 1,363 matched pairs. No significant difference was found in in-hospital mortality (5.2 vs. 5.1%; odds ratio, 1.03; 95% confidence interval, 0.73–1.46). The proportion of vasopressor use on the day of admission was significantly lower for the levetiracetam group than for the fosphenytoin group (3.2 vs. 4.9%; odds ratio, 0.63; 95% confidence interval, 0.43–0.92). No significant difference was found in other secondary outcomes including total hospitalization cost. Conclusion: Levetiracetam was related to significantly reduced vasopressor use on the day of admission than that found for fosphenytoin, in adult status epilepticus.
... Nine studies, comprising 77 study sites and 1732 patients, were selected for final analysis (Table 1) [16][17][18][19][20][26][27][28][29]. Studies were conducted throughout the world, and most were performed in an ED or neurologic service unit. ...
... One study had some risk of bias because the randomization sequence was not described; however, there were no baseline differences between groups [29]. Two studies had high risk of bias: one because the randomization process allocated patients based on order of enrollment and the other because of the selection of reported results where multiple eligible outcome measures were based on time points [20,27]. The funnel plot analysis depicted no evidence of publication bias (Fig. 7). ...
... Fosphenytoin lacks propylene glycol; however, both PHT and FOS may have similar cardiac and blood pressure-lowering effects [4,12,32,33]. In our SRMA, two studies used FOS [17,29], and seven studies used PHT [16,[18][19][20][26][27][28], which may confound conclusions related to cardiac or blood pressure adverse effects. However, 4 of the 16 cardiac instability events in our review occurred in the ESETT trial, which only used FOS (25% of total; all life threatening hypotension) [17]. ...
Article
Objective The objective of the study was to perform a systematic review and meta-analysis to evaluate the efficacy and safety of levetiracetam (LEV) or phenytoin (PHT) as second-line treatment for status epilepticus (SE). Methods PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American and Caribbean Health Sciences Literature (LILACS), Scopus, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Google Scholar were assessed for prospective randomized trials comparing LEV with PHT as second-line treatment of SE published from inception until December 18th, 2019. The primary outcome was seizure cessation. Data were analyzed using a random-effects model. Quality analysis was performed using version 2 of the Cochrane risk-of-bias tool (RoB 2). The study protocol was registered on PROSPERO (CRD42020136417). Results Nine studies with a total of 1732 patients were included. Overall, seizure cessation occurred in 657 of 887 (74%) of patients in the LEV group and 600 of 845 (71%) in the PHT group. Treatment success did not differ significantly between groups, and the relative risk (RR) was 1.05 (95% confidence interval (CI): 0.98–1.12; I² = 53%). Six of the studies were at low risk of bias, one study had some risk, and two studies had high risk. Conclusions The use of LEV or PHT as second-line agents after benzodiazepine (BZD) for the treatment of SE was not associated with a difference in seizure cessation. Because there are minimal differences in efficacy at this time, clinicians should consider alternative factors when deciding on an antiepileptic drug (AED).
... Previous studies have shown brand-name IV LEV to be an effective treatment for SE, with a seizure control rate ranging from 59.1 to 76.6% [8][9][10][11]. This study found that patients taking brand-name IV LEV had a seizure control rate of 75% at 24 h after administration. ...
... Although generic IV LEV led to a slightly lower seizure control rate at 24 h after treatment, it was equal to brand-name IV LEV in this respect (75%) at 48 h after treatment, and was within the range of the rates found in previous reports (65% vs 59.1-76.6%) [8][9][10][11]. The generic IV LEV also had comparable outcomes in terms of recurrent seizures at 24 h, EEG outcomes, discharge outcomes, mortality rate, major side effects, and length of hospital stay ( Table 2). This suggests that generic IV LEV was equally effective as the brand-name version of the drug. ...
... Regarding safety, the results showed that neither brand-name nor generic IV LEV exhibited any serious side effects. These results were supported by those of previous published studies [8][9][10]. For example, one study found that there were no serious adverse reactions from IV LEV in 18 children and 37 adults with SE. ...
Article
Full-text available
Introduction Intravenous levetiracetam (IV LEV) is approved for treatment status epilepticus (SE). However, the drug’s high cost must be considered when deciding on a treatment strategy. This study aimed to compare the efficacy of brand-name and generic IV LEV for acute repetitive convulsive seizure (ARCS) or SE. Methods Forty patients aged 18 years or older who had been diagnosed with SE or ARCS were included in this double-blind study. Patients were randomly assigned at a 1:1 ratio (via computer-generated code) to receive either brand-name or generic IV LEV. The primary outcomes were seizure control and the number of seizure exacerbations during the 24 h after drug administration, while the secondary outcomes were electroencephalographic (EEG) findings, serious adverse events, and clinical outcome at hospital discharge. Results Forty patients were randomly assigned administration with either brand-name IV LEV (10 SE and 10 ARCS patients) or generic IV LEV; 7 SE and 13 ARCS patients). There was no significant difference in patients’ baseline characteristics. The seizure control rate was 75% in the brand-name IV LEV group and 65% in the generic IV LEV group (p value: 0.490). Five (25%) patients in the brand-name IV LEV group, and six (30%) patients in the generic IV LEV group developed seizure exacerbations within 24 h after drug administration (p value 0.723). There were no reports of drug-related adverse events. Two of the patients taking brand-name IV LEV and one taking the generic IV LEV died (p value > 0.999). Conclusion Treatment with the generic IV LEV had comparable outcomes with brand-name IV LEV. The generic IV LEV may be an alternative medication for the treatment of SE and ARCS to reduce treatment costs. Trial Registration TCTR20190513001. Funding Great Eastern Drug Company.
... 70,71 Prior to the publication of the ConSEPT trial, reported CSE cessation rates for levetiracetam and phenytoin were broadly similar to a number of previously reported observational retrospective, and predominantly adult, studies. 14,30,31 However, CSE cessation rates as high as 85-95% have been reported, although these studies display significant heterogeneity in design and outcomes. [72][73][74] A recent prospective RCT 74 of only 50 children recruited over a 6-month period reported that levetiracetam (at a dose of 30 mg/kg) terminated CSE in 92% of children and fosphenytoin (at a dose of 20 mg/kg) terminated CSE in 84% of children (p = 0.66). ...
... 10-15 minutes). 27,30,31 Agitation was the most commonly reported AE in the levetiracetam-treated group, as reported previously. 26 There were no new or unexpected SARs with levetiracetam. ...
... levetiracetam doses range from 20 to 60 mg/kg. Chakravarthi et al.30 and Mundlamuri et al.31 used doses of 20 mg/kg and 25 mg/kg, respectively. Adverse reactions (ARs) with levetiracetam seem to be infrequent and mild, even at high doses. ...
Article
Background Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. Objective To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. Design A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. Setting Participants were recruited from 30 paediatric emergency departments in the UK. Participants Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. Interventions Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). Main outcome measures Primary outcome – time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes – further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. Results Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20–not assessable) minutes in the levetiracetam group and 45 (interquartile range 24–not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. Limitations First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of ‘cessation of all signs of continuous, rhythmic clonic activity’ as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. Conclusions Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. Future work Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. Trial registration Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.
... Misra et al. 2012 [18] 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. Chakravarthi et al. 2015 [20] S Ed e fined as continuous, generalized, convulsive seizure lasting > 5 min, or two or more seizures during which the patient does not regain normal sensorium. Mundlamuri et al. 2015 [21] GCSE defined as continuous, generalized seizures of ≥10 min or ≥2 discrete seizures without complete recovery of consciousness in between. ...
... 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 [18][19][20][21][22][23] studies were included in the qualitative synthesis, and 4 [19][20][21][22] of them were included in the quantitative synthesis. Two studies [19,20]compared IV LEV with IV PHT, one study compared [22] it with IV VPA, and another one [21] investigated the difference among IV LEV,IV PHT and IV VPA. ...
... 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 [18][19][20][21][22][23] studies were included in the qualitative synthesis, and 4 [19][20][21][22] of them were included in the quantitative synthesis. Two studies [19,20]compared IV LEV with IV PHT, one study compared [22] it with IV VPA, and another one [21] investigated the difference among IV LEV,IV PHT and IV VPA. ...
Article
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.
... 8 In adult patients, a small, underpowered trial com paring both drugs as second-line treatments for convulsive status epilepticus (n=22 per treatment group) found similar efficacy rates to those in our study, with no difference in primary and secondary outcomes between treatment groups. 27 Two further small trials (n=22-50 per treatment group) in adult patients have compared benzodiazepines plus the addition of either phenytoin or levetiracetam, with no difference in primary or secondary outcomes between groups. 12,28 Paediatric convulsive status epilepticus has a different aetiology and outcome to adult convulsive status epilepticus. ...
... [4][5][6] Although the definition of seizure cessation used was precise, and required considerable clinical judgment, this endpoint is highly meaningful to clinicians treating a child in active convulsive status epilepticus-ie, it determines whether or not a child requires further treatment. By contrast, trials in adult patients have reported seizure activity 30 min after, 27 and 24 h after, the commencement of study infusion. 12,28 Following failure of a second-line agent (phenytoin or fosphenytoin), international management guidelines for convulsive status epilepticus in children universally recommend control of convulsive status epilepticus with RSI, intubation, and thiopentone or benzodiazepine infusion (or both), with the aim of promptly terminating convulsive status epilepticus. ...
Article
Background: Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus. Methods: ConSEPT was an open-label, multicentre, randomised controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus that failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes 2 and 4) randomisation sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 min). The primary outcome was clinical cessation of seizure activity 5 min after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. Findings: Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed, and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 min after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference −9·2% [95% CI −21·9 to 3·5]; p=0·16). One participant in the phenytoin group died at 27 days because of haemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events. Interpretation: Levetiracetam is not superior to phenytoin for second-line management of paediatric convulsive status epilepticus. Funding: Health Research Council of New Zealand, A+ Trust, Emergency Medicine Foundation, Townsville Hospital Private Practice Fund, Eric Ormond Baker Charitable Fund, and Princess Margaret Hospital Foundation.
... It is progressively more given for rapid control of convulsions and SE. However, as LEV is used for controlling SE, there is a scarcity of documents approving its role in SE and contrasts of its efficiency by the secondline medications [11]. It was stated that LEV poses an advantage over fosphenytoin in its safety outline because of deficiency of opposing actions as cardiopulmonary depression and the nonexistence of any end-organ damage. ...
... Neurological results of the phenobarbital group were better than those of the valproate group. S. Chakravarthi et al.[11] reported that both LEV and PHT were similar in effect. PHT gained SE control in (68.2%) patients in comparison with LEV in (59.1%). ) were not meaningfully dissimilar in LCM and SVA individuals. ...
Article
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Background: Time-dependent pharmacoresistance is a major therapeutic problem in SE and CSE. As seizures continue, pharmacoresistance develops progressively. The anti-seizure effectiveness of benzodiazepines could reduce 20-fold in 30 min of seizures. The objective of this study is to précis the existing proof that compares ‎the effect of valproate, phenytoin, diazepam, ‎‎phenobarbital, lacosamide, and levetiracetam on benzodiazepine-resistant convulsive status ‎‎epilepticus.‎ Method: This systematic review was conducted, including PubMed, Google Scholar, and EBSCO that examining randomized trials of non-benzodiazepine antiepileptic drugs in benzodiazepine-resistant ‎convulsive status epilepticus. Authors extracted the data, and then the author's names, year and region of publication, the study type, period of study, and the result were reported. Results: The review included 9 randomized studies that compared non-benzodiazepine antiepileptic drugs in terms of efficacy and adverse effects for SE management. Conclusion: Valproate, phenytoin, diazepam, ‎‎phenobarbital, lacosamide, and levetiracetam are all conventional agents that could be given as second-line management of status epilepticus and in cases of benzodiazepine-resistant convulsive status ‎‎epilepticus. Though, the use of these medications is restricted due to their toxicity.
... Unalp et al. [5] noted that 104 (78%) out of 133 children who were given levetiracetam showed total seizure control and did not recur during the follow-up period. Singh et al. [7] conducted a study on 44 patients and concluded that phenytoin achieved seizure control in 68.2% and levetiracetam in 59.1%. Both the groups showed comparable result (P = 0.34). ...
... In a study by Satishchandra et al., [8] IV loading dose of levetiracetam was 25 mg/kg which was found to be effective in controlling seizures in 78% of patients. In a study by Singh et al., [7] IV levetiracetam was given at a loading dose of 20 mg/kg and there was successful termination of seizure within 30 min in 59.1% of patients. Unalp et al. [5] used a mean loading dose of 18.2 mg/kg/dose and a mean maintenance dose of 35.3 mg/kg/day and seizures were controlled in 78% of patients. ...
Article
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Background: To compare the efficacy and safety of intravenous levetiracetam and phenytoin in status epilepticus. Methodology: A prospective, randomized controlled, nonblinded study was conducted in children 1 month to 12 years of age with active seizure and with status epilepticus. A total of 104 children were randomly allocated to either group 1 (levetiracetam) or group 2 (phenytoin) on the basis of computer-generated random number table. Children already on antiepileptic drugs, very sick children with shock, impending respiratory failure, or head injury, and children hypersensitive to phenytoin or levetiracetam were excluded. Data analysis was done by IBM SPSS statistics. Results: The mean age was 4.09 years with a male preponderance with the most common type of seizure being generalized type (74%). The seizures were controlled in all 104 patients initially within 40 min. Seizure control for 24 h was significantly better in group 1 (96%) when compared with group 2 (59.6%) (P = 0.0001). Minibolus of drug was given in 28.8% in group 1 and 46.2% in group 2 (P = 0.068). The seizure recurrence in groups 1 and 2 in the first hour was 1.9% and 5.8%, respectively (P = 0.61), whereas the recurrence between 1 and 24 h was significantly more in group 1 (34.6%) when compared with group 2 (3.8%) (P = 0.0001). The mean time to control seizure was comparable between both the groups (P = 0.71). There was no significant adverse effect in both the groups. Conclusion: Levetiracetam is more effective than phenytoin for seizure control for 24 h in children with status epilepticus, and it is safe and effective as a second-line therapy.
... 90 Chakravarthi et al reported a class III study in which 44 adults first treated with LZP were then given either LEV or PHT, both at 20 mg/kg. 91 There was no difference: 28 of 44 had initial CSE controlled, but 16 required further treatment. Phenytoin was associated with hypotension in 2 patients. ...
... With regard to LEV dosing, the 2016 AES guideline for treatment of established CSE is to give a BDZ, followed by an IV loading dose of LEV of 60 mg/kg (maximum 4500 mg). 3 Older studies reported an adult loading dose of LEV 20 to 30 mg/kg infused at 5 mg/kg/min followed by a maintenance dose. 91 Rossetti et al reported that LEV may be useful in SE, but escalating the dose above 3000 mg/d was unlikely to provide further benefit. 95 Gallentine et al investigated LEV in children aged 0 to 8 years with RSE and reported a mean loading dose of 30 mg/kg IV with daily titration for persistent seizures. ...
Article
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Purpose: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE. Methods: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process. Results: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study). Conclusions: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.
... and 50 ClinicalTrials.gov). After excluding duplicates and reading title and abstracts, 6 RCTs were initially included [13][14][15][16][17][18]. One study comparing VPA with PHT [13] was eventually excluded, as it provided data on SE control within 7 days of administration, and this time cutoff was considered to be too long to be clinically meaningful. ...
... Hence, five RCTs were included in our review, involving 349 patients ( Fig.1). Following comparisons were included: IV VPA versus PHT [14], IV LEV versus PHT [15], IV LCM versus VPA [16], diazepam (DZP) versus VPA [17], and PHB versus VPA 30 [18]. Details of included interventions (dosages and rate of drug administration) and characteristics of the included trials are reported in Table 1. ...
Article
Aim: The aim of this study was to estimate the comparative efficacy and safety of antiepileptic drugs (AEDs) in adults with benzodiazepine-resistant convulsive status epilepticus (SE). Methods: MEDLINE, CENTRAL, ClinicalTrials.gov, and Opengrey.eu were searched (from inception to 3rd April, 2018) for randomized controlled trials (RCTs) of AEDs used intravenously to treat benzodiazepine-resistant SE in adults. Efficacy outcomes were SE cessation within 1 h from drug administration and seizure freedom at 24 h. Safety outcomes were respiratory depression and hypotension. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA) and mean ranks. Results: Five RCTs were considered, involving 349 patients. Included interventions were valproate (VPA; 20-30 mg/kg), phenytoin (PHT; 20 mg/kg), diazepam (DZP; 0.2 mg/kg, then 4 mg/h), phenobarbital (PHB; 20 mg/kg, then 100 mg every 6 h), lacosamide (LCM; 400 mg), and levetiracetam (LEV; 20 mg/kg); PHB was superior to PHT, VPA, DZP, LEV, and LCM with respect to SE cessation and performed better than VPA, DZP, and LCM in the achievement of seizure freedom at 24 h. No differences were noted between drugs in the occurrence of respiratory depression and hypotension. According to SUCRA, PHB had the greatest probabilities of being best in the achievement of SE control and seizure freedom, whereas VPA and LCM ranked best for the safety outcomes. Conclusions: Our study suggests that high-dose PHB is effective in controlling SE and preventing seizure recurrence, and LCM and VPA could be better tolerated options. Further head-to-head comparative studies are strongly required to provide more definitive evidence. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
... We identi fied 1,103 studies from the electronic databases, and 1,090 studies were excluded because they were not RCTs. Finally, the full texts of 13 studies were reviewed, and 10 studies [20][21][22][23][24][25][26][27][28][29] were included in the final analysis ( Fig. 1). ...
... antiepileptic medications (VPA, LEV, and PB) given to adult patients receiving second-line treatment for benzodiazepinerefractory convulsive SE. The 10 RCTs retrieved in this study were published from 1988 to 2018 [20][21][22][23][24][25][26][27][28][29] and carried out in hospital settings. Phenytoin was significantly inferior to other medications in terms of the cessation of seizures. ...
Article
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Aim Status epilepticus (SE) is a life-threatening neurological emergency. There is insufficient evidence regarding which antiepileptic therapy is most effective in patients with benzodiazepine-refractory convulsive SE. Therefore, this study aimed to evaluate intravenous phenytoin (PHT) and other intravenous antiepileptic medications for SE. Methods We searched PubMed, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for published randomized controlled trials (RCTs) in humans up to August 2019. We compared outcomes between intravenous PHT and other intravenous medications. The important primary composite outcomes were the successful clinical cessation of seizures, mortality, and neurological outcomes at discharge. The reliability of the level of evidence for each outcome was compared using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results A total of 1,103 studies were identified from the databases, and 10 RCTs were included in the analysis. The ratio of successful clinical seizure cessation was significantly lower (risk ratio [RR] 0.89; 95% confidence interval [CI], 0.82–0.97) for patients treated with intravenous PHT than with other medications. When we compared mortality and neurological outcomes at discharge, we observed no significant differences between patients treated with PHT and those treated with other medications. The RRs were 1.07 (95% CI, 0.55–2.08) and 0.91 (95% CI, 0.72–1.15) for mortality and neurological outcomes at discharge, respectively. Conclusions Our findings showed that intravenous PHT was significantly inferior to other medications in terms of the cessation of seizures. No significant differences were observed in mortality or neurological outcomes between PHT and other medications.
... The mean age and sex distribution of our study was similar to previous studies [2,8,25]. Mean duration of the seizure episode at the time of presentation (Table 1) was higher than reported previously [26]. This could be due to lack of awareness among general public, inadequacy of the peripheral health care system and ignorance among the treating physicians. ...
... The difference could be due to higher loading dose (50mg/kg) used for LEV in these studies and use of these drugs as first line. We observed a seizure recurrence rate of 50% in LEV and 57.5% in VPA group within 24 hours of admission, this was higher than that observed previously [26,27]. This difference could be due to longer duration of seizure episode at presentation in our study. ...
... 24 [14,15] Stunden. Eine weitere Studie [13] hatte ansonsten ein vergleichbares Erfolgskriterium (siehe ▶Tab. 1), aber keinen definierten Einfluss eines Anfallsrezidivs auf die Klassifikation des Behandlungsergebnisses. Nun hatten in dieser Studie 40,9 % der behandelten Patienten ein Anfallsrezidiv innerhalb von 24 Stunden, ohne dass referiert wird, dass diese Patienten alle bereits initial nicht erfolgreich behandelt wurden. ...
... Wäre ein zeitlicher Mindestabstand für ein Anfallsrezidiv in die Auswertekriterien mit aufgenommen worden, hätte die angegebene Erfolgsrate möglicherweise nach unten korrigiert werden müssen. Tatsächlich berichteten drei der vier Studien mit anfallsfreiem Mindestintervall als Teil des Erfolgskriteriums [15][16][17] eine mehr als 10 % niedrigere Erfolgsrate als die Studie mit ansonsten vergleichbarem Erfolgskriterium [13]. Wie bereits erwähnt messen Studien mit einem Erfolgskriterium einer SE-Unterbrechung innerhalb von deutlich weniger als 30 Minuten nach LEV-Gabe vermutlich Spontanverläufe. ...
Article
Zusammenfassung Seit 2004 liegen Publikationen zum Einsatz von Levetiracetam beim Status epilepticus vor. In der vorliegenden Arbeit werden basierend auf einer PubMed-Literatur-Recherche vom 06.07.2018 die nach dem 12.12.2011 erschienenen Arbeiten zusammenfassend dargestellt und in der Diskussion mit den älteren Arbeiten verglichen. Es wurden 28 Behandlungsepisoden in Berichten über 1-2 Fälle und 412 Behandlungsepisoden in Fallserien und prospektiven Studien beschrieben. Dabei ließ sich aus den Fallserien und Studien ein hochwahrscheinlicher Mittelwert der Erfolgsrate für die Status-Durchbrechung von 55,0 %-59,4 % ableiten. Auf-grund des zu vermutenden verzögerten Wirkungseitritts des Levetiracetams ist sein Einsatz beim Status generalisierter tonisch-klonischer Anfälle dennoch zu hinterfragen. Als Loading-Dosis erscheinen 30 mg / kg KG angemessen
... This result is consistent with what has been previously reported in literature (59-68%). 12,13 Furthermore, a meta-analysis of 22 studies looking at the effectiveness of multiple AEDs in SE has reported the efficacy of PHT at 50.2%. 14 We identified three variables that are possibly associated with PHT's effectiveness. ...
Article
Background: Status epilepticus (SE) is a neurological emergency associated with significant morbidity and mortality. The objective of this study was to review the critical care management of patients with SE focusing on antiepileptic drugs (AEDs) as well as to determine the optimal dosing strategies of phenytoin (PHT) and predictors of its effectiveness. Methods: A retrospective chart review of adult patients with SE admitted to the University of Alberta Hospital, Canada, was conducted. Results: Fifty-six admissions were included. Benzodiazepines (BDZs) were initially given in 89% of our patients. Following BDZs, PHT and levetiracetam were the most commonly initiated AEDs as first- and second-line agents and were deemed effective in 30/44 and 5/11 patients, respectively. Patients who received a PHT loading dose (LD) of 1000 mg were less likely to reach target levels compared with a weight-based LD ≥15 mg/kg (29% vs. 60%). Likewise, patients who received a maintenance dose (MD) of 300 mg/day were less likely to reach target compared with 400 mg/day or >5 mg/kg per day; however, this did not reach statistical significance. Three variables were found to be associated with PHT effectiveness: tonic-clonic SE (OR 5.01, 95% CI 1.02-24.7, p = 0.048), history of seizures and BMI <30 kg/m2 (OR 0.16, 95% CI 0.03-1.07, p = 0.059). Conclusions: Further studies of the predictors of PHT effectiveness, specifically obesity, are necessary to help individualize care. Finally, we suggest that PHT should be loaded according to the guidelines as 20 mg/kg followed by an MD of at least 400 mg/day or >5 mg/kg per day.
... levetiracetam. [10][11][12] Side effects of levetiracetam were psychiatric disorders of agitation or somnolence and were not severe even if high-dose levetiracetam was administered. 24) Because of safety, p.o. levetiracetam has been used most frequently as a routine epilepsy treatment in the United States. ...
Article
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Intravenous (i.v.) phenytoin/fosphenytoin is recommended as the second-line therapy of antiepileptic drugs in patients with status epilepticus (SE). i.v. Levetiracetam is regarded as an effective and safe equivalent with i.v. phenytoin/fosphenytoin. However, i.v. levetiracetam is not covered by public health insurance for SE in most countries. For this study, we performed the real-world practice pattern survey of antiepileptic drugs for status epilepticus using the nationwide inpatient database. We used the Japanese Diagnosis Procedure Combination inpatient database in Japan and identified all cases of emergency admission attributable to status epilepticus from March 2011 through March 2018. We described the patient characteristics and practice pattern of antiepileptic drugs. The analysis conducted for this study examined 31,472 cases. As the second-line therapy, the use of i.v. levetiracetam increased rapidly from 2016; 35% of cases received i.v. levetiracetam in 2017. By contrast, the use of i.v. phenytoin/fosphenytoin decreased from 2016. In-hospital mortality decreased year-by-year. No year-by-year change was observed for deaths within 24 h, length of hospital stay, drug-induced hepatitis, or drug-induced eruption. Although the use of levetiracetam for treatment of SE is not compensated by public health insurance in Japan, i.v. levetiracetam use is increasing dramatically as the second-line SE therapy. We propose that health insurance coverage be extended to include i.v. levetiracetam treatment for SE.
... An observational study on adults by Nakamura et al. [30], concluded that levetiracetam and fosphenytoin were equally efficacious in preventing seizure recurrence while the power of present study was not adequate to determine seizure recurrence in both groups. A randomized control study with levetiracetam and phenytoin on adults [31], showed levetiracetam is superior with respect to seizure terminating effect, similar to present study results. ...
Article
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Objectives To determine whether levetiracetam is an alternative to fosphenytoin to control Benzodiazepine Refractory Status Epilepticus (BRSE) in pediatric population and also to compare the acute drug related side-effects and ventilation requirement among the both arms of anti-epileptic drug therapy.Methods All consecutive children admitted with BRSE were randomized to group A, who received fosphenytoin at 20 mg/kg phenytoin equivalents (PE) dose and group B who received levetiracetam at 40 mg/kg over 10 min. Time to terminate seizure (response latency) was measured. If seizure remained refractory after 20 min of test drug administration, appropriate drug escalation was made according to pediatrician’s discretion. All primary and secondary outcome measures were compared between the two therapeutic groups.ResultsOf 61 children enrolled over 18 mo period, 29 (47.5%) were randomized to group A and 32 (52.5%) were randomized to Group B. Baseline characteristics were comparable between the two groups. Among 61 children, 58(98%) required Pediatric Intensive Care Unit (PICU) admission and among those 5(8.2%) children required mechanical ventilation. Duration of PICU stay, hospital stay, the response latency and seizure recurrence were compared between both groups. Significant number of children received additional anti-epileptic drugs (AEDs) in fosphenytoin group [9/29(31%)] compared to levetiracetam group [2/32(7%)] to control seizure.Conclusions Levetiracetam may be an effective alternative to fosphenytoin in management of BRSE in children but multicentric trials with large sample size are needed to substantiate this observation.
... Sin embargo, un estudio prospectivo posterior que compara estos mismos FAE en EEC no encuentra diferencias estadísticamente significativas entre ellos (tasa de éxito del 68, 68 y 78%, respectivamente) 15 . Otro estudio prospectivo compara PHT y LEV en EE de tipo no especificado sin encontrar diferencias estadísticamente significativas ni en cuanto al control de crisis ni en cuanto a su recurrencia, efectos adversos o pronóstico funcional 16 . ...
Article
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Resumen Introducción El estatus epiléptico (EE) es una urgencia neurológica asociada a una elevada mortalidad y morbilidad. Uno de los factores pronósticos es el tipo de EE. El objetivo de este trabajo es analizar las últimas recomendaciones de las distintas sociedades científicas y grupos de expertos sobre el tratamiento del EE, así como los estudios más recientes, para evaluar las referencias sobre el manejo del EE de tipo focal. Métodos Se realizó una búsqueda en PubMed entre el 01/08/2008 y el 01/08/2018 sobre el tratamiento farmacológico del EE focal y sus distintos tipos en adultos. Resultados Se encontraron 29 publicaciones entre revisiones, guías terapéuticas, metaanálisis, ensayos clínicos y estudios de casos sobre el tratamiento del EE. De estas, solamente 3 tienen en cuenta si el EE es focal o generalizado, 4 se centran exclusivamente en EE focales y 7 diferencian entre EE convulsivo o no convulsivo especificando si incluyen crisis focales. Las recomendaciones terapéuticas para un EE focal no difieren de las de un EE generalizado en las fases I y II: inicialmente lorazepam o diazepam intravenoso si hay acceso venoso o midazolam intramuscular en caso contrario, seguido de fenitoína, valproato, levetiracetam o lacosamida intravenosos si persisten las crisis. En EE focales refractarios se recomienda retrasar en lo posible el inicio de fármacos anestésicos. Conclusiones Actualmente no disponemos de suficiente evidencia científica para afirmar que el tratamiento farmacológico del EE focal debe ser distinto al del EE generalizado. Son necesarios más registros con un amplio número de pacientes.
... Chakravarthi et al. 18 conducted a randomized comparison trial of LEV versus PHT in the management of CSE in 44 children. That study found that LEV and PHT were equally effective with regard to both primary and secondary outcome measures, from which it can be concluded that LEV may be an attractive and effective alternative to PHT for managing CSE. ...
Article
Full-text available
Background and purpose: There is sparsity of quality evidence for the use of drugs after first-line benzodiazepines in convulsive status epilepticus in children. The aim of the study was to compare the clinical efficacy and safety of intravenous levetiracetam versus intravenous phenytoin as second-line drugs in the management of generalized convulsive status epilepticus in children. Methods: This open-label randomized controlled trial was conducted in the Emergency Department of The Children's Hospital and The Institute of Child Health, Multan, Pakistan over a period of 4 years and 6 months from January 2014 to June 2018. This study included 600 children with generalized convulsive status epilepticus: 300 in the 40 mg/kg levetiracetam group, and 300 in the 20 mg/kg phenytoin group. Cessation of a clinical seizure (seizure cessation rate) within 30 minutes after the end of drug administration was the primary outcome in this study, and the presence or absence of adverse effects was noted as the secondary outcome. Data were analyzed using SPSS (version 20.0). Results: The children in the levetiracetam and phenytoin were aged 3.5±0.2 and 3.4±0.2 years (mean±SD), respectively, their seizure durations before the start of treatment were 25.1±0.6 and 23.8±0.4 minutes, and their treatment efficacies were 278/300 (92.7%) and 259/300 (83.3%). Levetiracetam was significantly more effective than phenytoin (p=0.012), with no significant difference in safety. Adverse events were observed in eight children in the phenytoin group. Conclusions: Levetiracetam is significantly more effective than phenytoin for the treatment of convulsive status epilepticus in children who have failed to respond to benzodiazepines.
... Three randomized trials investigating efficacy of LEV versus PHT or VPA reported comparable efficacy (Chakravarthi et al. 2015;Gujjar et al. 2017;Misra and Kalita 2016;Mundlamuri et al. 2015). However, sample sizes were based on feasibility. ...
... It has a high solubility and permeability and is used to treat specific types of seizures in adults and children with epilepsy and recent formulations are reported. [1][2][3][4][5][6][7] The purpose of this study is to analyze levitiracetam extended-release tablets using HPMC K100, HPMC K15, and Xanthan gum/ Ethyl cellulose. The hydration of HPMC, which forms the gel barrier through which the drug diffuses, is known to limit drug release from the hydrophilic matrix tablet. ...
... Chakravarthi et al. 18 conducted a randomized comparison trial of LEV versus PHT in the management of CSE in 44 children. That study found that LEV and PHT were equally effective with regard to both primary and secondary outcome measures, from which it can be concluded that LEV may be an attractive and effective alternative to PHT for managing CSE. ...
Article
Full-text available
1 Background and Purpose There is sparsity of quality evidence for the use of drugs after first-line benzodiazepines in convulsive status epilepticus in children. The aim of the study was to compare the clinical efficacy and safety of intravenous levetiracetam versus intravenous phe-nytoin as second-line drugs in the management of generalized convulsive status epilepticus in children. Methods This open-label randomized controlled trial was conducted in the Emergency Department of The Children's Hospital and The Institute of Child Health, Multan, Pakistan over a period of 4 years and 6 months from January 2014 to June 2018. This study included 600 children with generalized convulsive status epilepticus: 300 in the 40 mg/kg levetiracetam group, and 300 in the 20 mg/kg phenytoin group. Cessation of a clinical seizure (seizure cessation rate) within 30 minutes after the end of drug administration was the primary outcome in this study, and the presence or absence of adverse effects was noted as the secondary outcome. Data were analyzed using SPSS (version 20.0). Results The children in the levetiracetam and phenytoin were aged 3.5±0.2 and 3.4±0.2 years (mean±SD), respectively, their seizure durations before the start of treatment were 25.1±0.6 and 23.8±0.4 minutes, and their treatment efficacies were 278/300 (92.7%) and 259/300 (83.3%). Levetiracetam was significantly more effective than phenytoin (p=0.012), with no significant difference in safety. Adverse events were observed in eight children in the phenytoin group. Conclusions Levetiracetam is significantly more effective than phenytoin for the treatment of convulsive status epilepticus in children who have failed to respond to benzodiazepines.
... Although the data of ivLEV as first line treatment is limited, however, the results in this study shown that Compare to other antiepileptic drugs in the previous studies, ivLEV is as effective as phenytoin and valproic acid for treatment status epilepticus after administered benzodiazepines (12,13) . Moreover, Misra (14) showed that ivLEV and lorazepam were not different in seizure control rate (76.3% and 75.6%, respectively). ...
Article
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Background: Epilepsy is a current important health problem. Status epilepticus is a medical emergency condition which may be lifethreatening, increased mortality rate and hospitalization. However, some patients with epilepsy could not control their symptoms and anticonvulsant medications have some adverse effects. Intravenous levetiracetam (ivLEV) is a new antiepileptic drug which its use tends to be increased. Objective: To study the prescription pattern of ivLEV and its adverse drug reactions (ADRs) in hospitalized patients and to define the efficacy of iv LEV as first line treatment for status epilepticus. Materials and Methods: This was a descriptive retrospective study to review medical records of all inpatients receiving ivLEV at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University during January 1st 2010 to December 31st 2014. Results: During the study period, there were 406 hospital visits that met the study criteria. The average age of the patients was 54.32+20.36 years with nearly equal sex distribution. The indications of ivLEV were status epilepticus (22.4%), previous treatment with oral levetiracetam (9.6%), perioperative craniectomy/craniotomy (8.6%), and acute seizure with non-status epilepticus (59%). Most of the patients (63.3%) received ivLEV as first line treatment antiepileptic drug and the most loading dose range of ivLEV that the patients received was 500 to 1,000 mg/day (78.3%). All of the patients had been followed vital signs and plasma electrolytes. 98.5% and 45.8% of hospital visits had been monitored liver/kidney function and electroencephalogram (EEG), respectively. Adverse effects during the treatment of ivLEV occurred 0.98%, which were hypotension, drowsiness, and maculopapular rash. No major ADRs were detected in any patients after the ivLEV treatment. Regarding process indicators, overall seizure control rate was 76.4%, of which 35.2% and 85.9% were for the patients with status epilepticus and acute seizure with non-status epilepticus, respectively. ivLEV could be used as first line treatment effectively in patients with status epilepticus (80.2%). In the patients with renal impairment receiving adjusted dosage regimen ivLEV could be control seizure 73.1%. Conclusion: The treatment of ivLEV was effective and safe for control seizure, including status epilepticus and acute seizure with non-status epilepticus. Thus, ivLEV could be the first line antiepileptic drug for the treatment of status epilepticus and brain surgery prevention. However, due to the high cost of the drug and the treatment course, there would be further study of cost-effectiveness. Keywords: Levetiracetam, Epilepsy, Acute seizure, Status epilepticus, Drug use review, Inpatient
... Keep IV line, normal saline IV infusion, blood sugar test, blood sampling (ABGA, CBC, Electrolyte, Ca, Mg, BUN, Cr, Lactate, ammonia, cardiac marker, LFT, CK, CRP, AED level) Thiamine 100 mg IV bolus infusion, followed by 50% glucose 50 mg IV bolus infusion Lorazepam (0.1 m/kg) IV bolus (<2 mg/min), 1 additional injection is possible [10][11][12][13][14][15][16][17][18][19][20] If the seizures persist, secondary medications should be administrated (one or combination of the following medications can be administrated) Phenytoin (20 mg/kg) IV bolus infusion (<50 mg/min, vital sign and EKG monitoring) Fosphenytoin (30 mg/kg) IV bolus infusion (<150 mg/min, vital sign and EKG monitoring) Valproic acid (30 mg/kg over 10 min) IV bolus infusion Levetiracetam (50 mg/kg) IV bolus infusion (<500 mg/min) Lacosamide (400 mg over 5 min) IV bolus infusion Check the EEG rapidly If possible, perform the Brain CT or diffusion MRI 30-40 ...
... The mean age of study participants was similar to reported in a study by Depositario-Cabacar et al. [6] Both the study groups predominantly had males. In seizure type, most of the children had generalized type of seizures and was comparable to another study by Chakravarthi et al., [7] generalized 20 (90%) and focal 2 (10%). The duration of status in our study groups was lesser as compared to Chakravarthi et al. ...
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Objectives: The aim of this study was to compare the efficacy and safety of intravenous levetiracetam and fosphenytoin in the management of pediatric status epilepticus. Materials and methods: This is an open-labeled randomized controlled trial, conducted at tertiary care pediatric intensive care unit. Subjects between 1 month and 18 years who presented with status epilepticus were enrolled. If seizures persisted even after two doses of lorazepam, participants were randomized to receive either fosphenytoin 30 mg/kg or levetiracetam 30 mg/kg intravenously and followed up till 48h, for seizure recurrence and adverse drug effects. Outcome measures were cessation of seizures within 10-20 min following the end of the infusion of drugs fosphenytoin and levetiracetam, respectively, and no recurrence of seizures was noted over next 48h. Results: Subjects in both study groups were comparable in baseline characteristics. Seizures stopped in 54 (93.1%) and 53 (91.4%) in fosphenytoin and levetiracetam groups, respectively (P = 1.000). Seizure recurrence was noted in 13 (22.4%) and 10 (17.2%) patients in fosphenytoin and levetiracetam groups, respectively (n = 0.485). In fosphenytoin group, one (1.7%) child had bradycardia, two (3.4%) children required inotropes, and three (5.2%) children required intubation. In levetiracetam group, none had bradyarrhythmia, required inotropes, and intubation was required in one (1.7%) child each. No statistically significant difference was observed in outcome parameters in two groups. Conclusion: Levetiracetam is as efficacious as fosphenytoin in control of pediatric status epilepticus and is associated with lesser side effects.
... Although several therapeutic targets have been ascribed for levetiracetam, it is clear that it modulates the synaptic vesicle glycoprotein 2A, with consequent reduction of the release of synaptic excitatory neurotransmitters, restoring the balance between inhibitory and excitatory synaptic activities [3][4][5][6][7]. This unique mechanism of action may be linked with the usefulness of levetiracetam for the management of status epilepticus in pediatric and adult patients [8][9][10][11][12], prophylaxis of seizures from post-traumatic brain injury [13][14][15][16][17], neuropathic pain [18], and some psychiatric pathologies [19]. Moreover, its safety profile and linear pharmacokinetics, together with its low ability to cross the placental barrier, make levetiracetam a first-line option in pregnant women with epilepsy [20]. ...
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Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy.
... 127 Equal efficacy of LEV and phenytoin was also reported in another trial in 44 patients. 128 In a randomized controlled trial in 118 elderly patients with ongoing convulsive status epilepticus after initial intravenous lorazepam, LEV and valproate were likewise similarly effective. Seizure control was achieved in 68.3% of patients with valproate and in 74.1% under LEV. ...
Article
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Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.
... Radic et al. concluded that levetiracetam is associated with a lower risk of adverse drug effects. Chakravarthi et al. aimed to compare the safety and efficacy of intravenous levetiracetam with intravenous phenytoin in the management of status epilepticus [13]. In this study, 44 patients were randomized to receive either phenytoin or levetiracetam. ...
Article
Phenytoin and levetiracetam are both antiepileptic drugs (AEDs) used for seizure prophylaxis. However, to date, there is a paucity of literature comparing their relative efficacies. In this narrative review, we seek to determine if there is greater advantage between the two AEDs, levetiracetam and phenytoin. Phenytoin is the more traditional AED of the two as it has been medically used for a much longer time than levetiracetam. However, levetiracetam, the newer AED of the two, has fewer side effects than phenytoin and fewer drug-drug interactions. Although past studies have aimed to compare the efficacy of phenytoin versus levetiracetam, there is no clear consensus as to if there is a clinical advantage to one over the other. Here, we have analyzed several studies published between 2013 and 2020 in the hopes of having a better understanding of which AED is more efficient in preventing seizures. Many factors can contribute to determining which AED is the better fit for patients, including pricing, risk for adverse drug effects, and level of patient monitoring. After analysis of past research, the more advantageous AED still remains unclear. Future research must be conducted that involve large patient populations, stratifying age populations, and studies analyzing cost-effectiveness to clearly determine if there is indeed a more advantageous AED between levetiracetam and phenytoin.
... Three small randomized controlled trials (RCTs) compared IV levetiracetam and IV phenytoin in adult SE. The findings obtained revealed similar efficacies and fewer severe adverse events in the levetiracetam group [13][14][15]. Two large RCTs compared these treatments for pediatric SE, with similar findings [16,17]. ...
Article
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Background Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE. Methods This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is “continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance.” In both groups, diazepam is initially administered at 1–20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000–3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes. Discussion The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application. Trial registration Japan Registry of Clinical Trials jRCTs031190160. Registered on December 13, 2019
... LTC is the most common of the newer AEDs used in SSA has been reported to have excellent pharmacokinetic neuroprotective, antiepileptogenic, and cognitive enhancing properties. (Chakravarthi et al., 2015;Fukuyama et al., 2012). LTC inhibits IL-1b inflammatory responses and reduced reactive gliosis in the hippocampus and piriform cortex in a rat model of epilepsy suggesting it could be an important agent in the prevention of epileptogenesis (Kim et al., 2016). ...
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Background This study aims to identify the determinants of cognitive dysfunction and compare the effect of CPZ and LTC on cognition in WWE. Methods An observational study involving 87 consenting adult WWE aged between 16 and 40 years on LTC or CZP monotherapy. At enrollment, an interviewer‐based questionnaire was used to obtain demographic and clinical information from participants. The diagnosis of epilepsy was mainly clinical and supported by electroencephalographic (EEG) features and classified based on recommendation by the 2017 International League Against Epilepsy (ILAE). Zung Self‐Reporting Depression Scale (ZSRDS) was used to assess the mood of participants. The Community Screening Interview for Dementia (CSID) was used to assess various cognition domains. The National Hospital Seizure Severity Scale (NHS‐3) was used to assess disease severity. Results There were statistical differences between the CZP and LTC groups in all domains of cognition assessed except for orientation. The total CSID scores of the LTC group were 59.2 (4.9) as opposed to CZP group, 57.2 (5.0); p: .005. Those with focal onset seizures had lower median total CSID score (58; IQR: 54–62) when compared to those with generalized onset seizures (62; IQR: 58–62), p: .012. There was a significant correlation between ZSRD score and NHS‐3 score; rho: 0.30, p: .007. Bivariate analysis shows statistically significant correlation between total CSID score and ZSRDS (rho: −0.65), BMI (rho: 0.22), and NHSS‐3 score (rho: −0.36), respectively. However, the effect of AED on CSID scores was lost after multivariate quantile regression with only ZSRDS retaining significance. Conclusion Depression, seizure severity, type and structural etiology were associated with cognitive impairment among WWE. However, on regression model, only depression was statistically significant. The presence of more risks for cognitive impairment in the CZP group limits possible conclusion of LTC superiority.
... A randomized study found that levetiracetam was equally effective at terminating seizures and preventing recurrence at 24 hours when compared with PHT. 7 Another study in patients with benzodiazepine-refractory GCSE showed no differences in efficacy with IV PHT (88%) and IV valproate (84%). 8 A subgroup analysis of pediatric patients found that seizures stopped in 91% and 75% of those given valproate and PHT, respectively. ...
Article
Since its introduction in 1950, phenytoin (PHT) has been the premier parenteral anticonvulsant used in the management of generalized convulsive status epileptics (GCSE) that is refractory to benzodiazepines. Without question, its arrival was vital to the care of patients with acute seizures and was a welcomed alternative to paraldehyde and phenobarbital. However, after more than half a century of use, there continues to be insufficient evidence-based data to support its efficacy over other anticonvulsants as a first-line agent in pediatric or adult patients with GCSE. This coupled with its narrow mechanism of action, complex pharmacokinetics and pharmacogenomics, drug-drug interactions, unique adverse effects, and formulation issues that make administration difficult mandates that PHT be replaced by safer and superiorly effective anticonvulsants for the treatment of GCSE when benzodiazepines are ineffective. We believe that levetiracetam should become the preferred agent for seizures unresponsive to or recurring after treatment with a benzodiazepine as it is at least equally effective to PHT and has several important advantages. PHT has overstayed its welcome and it is simply time for it to exit the realm of acute seizure management as a first-line agent for benzodiazepine-refractory GCSE.
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Objective: Compare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE). Methods: Decision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters. Results: We included 24 studies with 1,185 SE episodes. The most effective non-BZD AED was phenobarbital (PB) with a probability of SS of 0.8 (95% confidence interval [CI]: 0.69-0.88), followed by valproate (VPA) (0.71 [95% CI: 0.61-0.79]), lacosamide (0.66 [95% CI: 0.51-0.79]), levetiracetam (LEV) (0.62 [95% CI: 0.5-0.73]), and phenytoin/fosphenytoin (PHT) (0.53 [95% CI: 0.39-0.67]). In pairwise comparisons, PB was more effective than PHT (p = 0.002), VPA was more effective than PHT (p = 0.043), and PB was more effective than LEV (p = 0.018). The most cost-effective non-BZD AED was LEV (incremental cost-effectiveness ratio [ICER]: $18.55/SS), followed by VPA (ICER: $94.44/SS), and lastly PB (ICER: $847.22/SS). PHT and lacosamide were not cost-effective compared to the other options. Sensitivity analyses showed marked overlap in cost-effectiveness, but PHT was consistently less cost-effective than LEV, VPA, and PB. Conclusion: VPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness.
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Levetiracetam Versus Phenytoin for Second-Line Treatment of Pediatric Convulsive Status Epilepticus (EcLiPSE): A Multicentre, Open-Label, Randomized Trial Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Woolfall K, Roper L, Nablet J, Lee ED, Potter S, Tate P, Iyer A, Evans V, Appleton RE. Lancet. 2019;393:2125-34. doi:10.1016/S0140-6736(19)30724-X. Background: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the United Kingdom; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of pediatric convulsive status epilepticus. Methods: This open-label, randomized clinical trial was undertaken at 30 United Kingdom emergency departments at secondary and tertiary care centers. Participants aged 6 months to less than 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomization schedule to receive levetiracetam (40 mg/kg over 5 minutes) or phenytoin (20 mg/kg over at least 20 minutes), stratified by centre. The primary outcome was time from randomization to cessation of convulsive status epilepticus, analyzed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomization and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. Findings: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomized participants were treated and had available data: 152 allocated to levetiracetam and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomization to cessation of convulsive status epilepticus was 35 minutes (interquartile range: 20 to not assessable) in the levetiracetam group and 45 minutes (24 to not assessable) in the phenytoin group (hazard ratio: 1.20, 95% confidence interval: 0·91-1.60; P = .20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral edema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of pediatric convulsive status epilepticus. Levetiracetam Versus Phenytoin for Second-Line Treatment of Convulsive Status Epilepticus in Children (ConSEPT): An Open-Label, Multicentre, Randomized Controlled Trial Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, Francis KL, Sharpe C, Harvey AS, Davidson A, Craig S, Phillips N, George S, Rao A, Cheng N, Zhang M, Kochar A, Brabyn C, Oakley E, Babl FE. Lancet. 2019;393:2135-45. doi:10.1016/S0140-6736(19)30722-6. Background: Phenytoin is the current standard of care for second-line treatment of pediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for pediatric convulsive status epilepticus. Methods: ConSEPT was an open-label, multicenter, randomized controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus who failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes: 2 and 4) randomization sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 minutes) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 minutes). The primary outcome was clinical cessation of seizure activity 5 minutes after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. Findings: Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 minutes after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference: -9.2% [95% confidence interval: -21.9 to 3.5]; P = .16). One participant in the phenytoin group died at 27 days because of hemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events. Interpretation: Levetiracetam is not superior to phenytoin for second-line management of pediatric convulsive status epilepticus.
Article
Purpose : Multiple interventions have been studied for benzodiazepine-resistant status epilepticus (SE) in children and adults. This review aimed to summarize the available evidence and provide estimates of comparative effectiveness and ranking of treatment effects. Methods : All randomized controlled trials studying patients (>1 month of age) with benzodiazepine-resistant SE were included. Outcomes including seizure cessation within 60 minutes, seizure freedom for 24 hours, death, respiratory depression warranting intubation and cardiovascular instability were studied. Conventional and network meta-analyses (NMA) were done. Results : Seventeen studies were included (16 in NMA). Phenobarbital and high-dose levetiracetam were significantly superior to phenytoin with respect to seizure cessation within 60 min. Network ranking demonstrated that phenobarbital had the highest probability of being the best among the studied interventions followed by high-dose levetiracetam and high-dose valproate. Network meta-analysis was limited by predominant indirect evidence and high heterogeneity.On pairwise comparisons, phenobarbital was found to be associated with a higher risk of need for intubation and cardiovascular instability. Levetiracetam had a better safety profile than fosphenytoin. Conclusions : Based on low quality evidence, phenobarbital appears to be the most effective agent for seizure cessation within 60 minutes of administration in patients with benzodiazepine resistant status epilepticus. High-dose levetiracetam, high-dose valproate and fosphenytoin are probably equally effective. Choice of medication may be guided by effectiveness, safety concerns, availability, cost and systemic co-morbidities.
Chapter
Elevations in intracranial pressure (ICP) constitute neurological emergencies, and a significant amount of time in the neurological critical care unit (NCCU) is spent diagnosing and treating increased ICP. It is pivotal to understand the signs of increased ICP, and treatment should be implemented without delay. Most institutes utilize an algorithmic-based approach for ICP management. This chapter will review the etiologies and diagnosis of increased ICP and will summarize our treatment algorithm. The available evidence for each intervention will be discussed.
Chapter
Status epilepticus is a neurologic emergency that requires prompt recognition and intervention, with the primary goal of controlling electrographic and clinical seizures, to avoid neuronal injury. This chapter aims to guide the clinician in defining status epilepticus, ordering appropriate diagnostic tests, and administering proper therapeutic interventions. It also provides insight into management of special patient populations and novel therapies on the horizon.
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Status epilepticus (SE) is a collective term that is used to describe a variety of subtypes. Forgetting this point can be perilous, even resulting in exposing patients to unnecessary harms. This review revisits the foundations of many of our current treatment guidelines, providing context to the ever-growing options in the treatment of SE. It aims to highlight the uncertainties that clinicians and EEGers face when treating SE. Several promising future approaches are raised. These bring hope of transitioning to therapies that are based on correcting maladaptive neuronal responses that are personally tailored using real time measures. All types of SE should be diagnosed as soon as possible, and treatment should be started expeditiously. For convulsive SE, treatment should be aggressive with full doses and cessation of seizures should be confirmed with EEG if patients are not returning to normal rapidly. For most other types of SE, the perennial debate about the tortoise or the hare continues: When should we be more measured and conservative and when should we rapidly escalate therapies to a combination of highly sedating agents?
Article
Background: Recent studies have shown conflicting results regarding the effectiveness of levetiracetam for treating benzodiazepine-refractory status epilepticus (SE) compared with phenytoin. Therefore, a meta-analysis was carried out to assess the value of levetiracetam versus phenytoin in the pharmacotherapy of benzodiazepine-refractory SE. Objective: The aim of this systematic review and meta-analysis was to compare the efficacy and safety of levetiracetam and phenytoin in the treatment of benzodiazepine-refractory SE. Methods: The MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) that had been conducted to evaluate levetiracetam versus phenytoin for benzodiazepine-refractory SE, to April 2020. The data were assessed using Review Manager 5.3 software. The risk ratio (RR) was analyzed using dichotomous outcomes, and calculated using a random-effect model. Results: We pooled 1850 patients from 12 RCTs. Patients in the levetiracetam group had a significantly higher rate of clinical seizure cessation than in the phenytoin group (75.2% vs. 67.8%; RR 1.14, 95% confidence interval [CI] 1.05-1.25, p = 0.003). Moreover, less adverse events were observed in the levetiracetam group than in the phenytoin group (17.8% vs. 21.4%; RR 0.82, 95% CI 0.70-0.97, p = 0.02). In subgroup analysis, clinical seizure cessation was achieved more frequently with a higher dose of levetiracetam (> 30 mg/kg) [RR 1.15, 95% CI 1.00-1.32, p = 0.05]. Furthermore, in the subgroup of children, levetiracetam showed a higher rate of clinical seizure cessation than phenytoin (RR 1.13, 95% CI 1.02-1.25, p = 0.02). Conclusion: Pharmacotherapy for BZD-refractory SE by LEV is superior to PHT in efficacy and safety outcomes.
Article
Status epilepticus (SE) is one of the most common neurological emergencies in children and has a mortality of 2 to 4%. Admissions for SE are very resource-consuming, especially in refractory and super-refractory SE. An increasing understanding of the pathophysiology of SE leaves room for improving SE treatment protocols, including medication choice and timing. Selecting the most efficacious medications and giving them in a timely manner may improve outcomes. Benzodiazepines are commonly used as first line and they can be used in the prehospital setting, where most SE episodes begin. The diagnostic work-up should start simultaneously to initial treatment, or as soon as possible, to detect potentially treatable causes of SE. Although most etiologies are recognized after the first evaluation, the detection of more unusual causes may become challenging in selected cases. SE is a life-threatening medical emergency in which prompt and efficacious treatment may improve outcomes. We provide a summary of existing evidence to guide clinical decisions regarding the work-up and treatment of SE in pediatric patients.
Article
Objective: To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. Data sources: We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Study selection: Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. Data extraction and synthesis: Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. Results: We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). Conclusions: The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.
Article
Introduction Status epilepticus (SE) is a neurological emergency associated with high morbidity and mortality. One prognostic factor is the type of SE. The purpose of this review is to analyse the most recent recommendations of different scientific societies and expert groups on the treatment of SE, and the latest studies, to assess the literature on the management of focal SE. Methods We searched PubMed for studies published between 1 August 2008 and 1 August 2018 on the pharmacological treatment of focal SE and its different types in adults. Results We identified 29 publications among reviews, treatment guidelines, meta-analyses, clinical trials, and case series on the treatment of SE. Only 3 of them accounted for whether SE was focal or generalised; 4 focused exclusively on focal SE, and 7 differentiated between convulsive and non-convulsive SE and also record the presence of focal seizures. Treatment recommendations for focal SE do not differ from those of generalised SE in stages I and II: initially intravenous lorazepam or diazepam, if the intravenous route is available, and otherwise intramuscular midazolam, followed by intravenous phenytoin, valproate, levetiracetam, or lacosamide if seizures persist. Use of anaesthetic drugs should be delayed for as long as possible in patients with refractory focal SE. Conclusions The available scientific evidence is insufficient to claim that pharmacological treatment of focal SE should be different from treatment for generalised SE. More studies with a greater number of patients are needed.
Article
Awake craniotomy is an established procedure for resecting brain tumors in eloquent lesions, and intraoperative seizure is one of the most important complications. Phenytoin is normally used to control intraoperative seizures. Recently, phenytoin was replaced with levetiracetam at our institution because the latter has fewer side effects. While the phenytoin dose is calibrated in accordance with the serum concentration, there is currently no consensus on a method of monitoring the serum concentration of levetiracetam or the effective concentration range needed to control intraoperative seizures during awake craniotomy. The present study therefore aimed to determine whether monitoring the serum levetiracetam concentration is useful for controlling intraoperative seizures during awake craniotomy. The intraoperative serum concentration of levetiracetam during awake craniotomy was measured in 34 patients and compared with that of phenytoin in 33 patients undergoing the same procedure. The levetiracetam concentration inversely correlated with body surface area (BSA) and estimated glomerular filtration rate (eGFR). Levetiracetam was superior to phenytoin in terms of the correlation between the serum concentration and the dose adjusted for BSA and eGFR (correlation coefficient, 0.49 vs 0.21). Furthermore, the serum levetiracetam concentration in patients with intraoperative seizures was below the 95% confidence interval (CI) of the regression line whereas the serum phenytoin concentration of two patients with seizures was within the 95% CI, indicating that evaluating the serum levetiracetam concentration against the BSA and eGFR-adjusted dosage may be useful in preventing intraoperative seizures during awake craniotomy by allowing prediction of the seizure risk and enabling more accurate dosage calibration.
Article
Status epilepticus (SE) is the second most critical neurological illness after cerebrovascular disease. Phenytoin has traditionally been considered the second-line drug of first choice after failure of first-line treatment using benzodiazepines. In recent years, levetiracetam has been proposed as a potential substitute for phenytoin. To comprehensively evaluate the efficacy and safety of levetiracetam and phenytoin in the treatment of patients with established SE, we integrated the data from 11 eligible studies and conducted a systematic review and meta-analysis. The PubMed, Web of Science, Cochrane Library, and Embase databases were searched to identify eligible articles reporting outcomes including clinical seizure cessation within 60 min, clinical recurrence rate within 24 h, good final outcome at discharge, and adverse events (AEs) of treatment with levetiracetam and phenytoin. Our study included a total of 11 trials including a total of 1933 patients. The outcomes showed that the pooled Risk Raito (RR) of clinical seizure cessation within 60 min was 1.08 (95% CI = 1.02–1.14, P = 0.01). The pooled RR of clinical recurrence rate within 24 h was 1.03 (95% CI = 0.66–1.59, P = 0.91). The pooled RR of AEs was 0.83 (95% CI = 0.57–1.21, P = 0.34). The pooled RRs of life-threatening hypotension and acute respiratory depression were 0.29 (95% CI = 0.10–0.81, P = 0.02) and 0.63 (95% CI = 0.40–0.98, P = 0.04), respectively. Levetiracetam might be more effective than phenytoin for the treatment of established SE and is associated with a lower incidence of more serious AEs. Levetiracetam can be used as an alternative to phenytoin for the treatment of benzodiazepine-refractory SE.
Article
Objectives: To assess the efficiency and safety profiles of levetiracetam and (fos)phenytoin (phenytoin or fosphenytoin) for second-line treatment of seizures by performing a meta-analysis of RCTs. Methods: We systematically searched PubMed, Embase, Cochrane, FDA.gov, and ClinicalTrials.gov for RCTs (published before July 31, 2020; no language restrictions). Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO: CRD42020202736. Eleven studies fulfilled the established criteria. We assessed pooled data by using a random-effects model. Quality analysis was performed by using version 2 of the Cochrane risk-of-bias tool (RoB 2). RevMan v.5.3 was used to perform statistical analyses, and publication bias (egger's test) was assessed with Stata MP v.14.0. Results: Levetiracetam was similar to (fos)phenytoin in seizure termination rate (risk ratio [RR] 0.94; 95% CI 0.87 to 1.01), time of seizure termination (mean difference [MD] 0.44; -0.60 to 1.49), and drug resistance ([RR] 1.12, 0.86 to 1.45). The safety outcome showed a significant statistical difference between fosphenytoin group and levetiracetam group ([RR] 1.44, 1.14 to 1.81), while there was no significant difference observed between phenytoin treatment and levetiracetam treatment ([RR] 1.26, 0.99 to 1.60). Conclusion: Levetiracetam was similar to (fos)phenytoin in cessation rate convulsive status epilepticus, and drug resistance, while it was superior (fos)phenytoin in pooled safety outcome. Further exploration is still needed as to whether it is the first choice for second-line drugs.
Article
Background: Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line treatment but fails to control SE in about one-third of patients. Levetiracetam may be used for SE that is refractory to benzodiazepine therapy. Objective: To examine, by means of a systematic review, the role of IV levetiracetam for the treatment of SE in adults. Data sources: MEDLINE, Embase, CENTRAL, and CINAHL databases were searched, from inception to August 18, 2020. Study selection and data extraction: Included in this review were prospective randomized controlled trials comparing levetiracetam with another antiepileptic drug, given with or after a benzodiazepine, in adult patients with SE. The primary outcome was cessation of SE. Quality of evidence was assessed with the Cochrane risk-of-bias tool. Characteristics of the included studies were reported using descriptive statistics. Data synthesis: Five studies compared IV levetiracetam with valproic acid, phenytoin (or its prodrug fosphenytoin), or both. All 5 studies found no statistically significant differences in efficacy or safety end points. There were numerically more cases of hypotension and respiratory failure with phenytoin, and more cases of psychiatric adverse effects (e.g., post-ictal psychosis) with levetiracetam. Conclusions: Available evidence suggests that levetiracetam is as effective as valproic acid or phenytoin for the cessation of SE in adults. Other factors should therefore dictate the choice of antiepileptic drug for patients with SE, such as adverse effect profile, logistics of administration, drug cost, inclusion on hospital formularies, and drug availability.
Article
Background Intravenous (IV) levetiracetam (LEV) is an antiseizure medication traditionally given as an intermittent infusion to mitigate potential adverse effects given its acidic formulation. The process of compounding may lead to delays in treating status epilepticus, which is why administration of undiluted doses is of interest. Prior studies have shown safety of IV doses from 1000 mg to 4500 mg; however, assessments of adverse side effects outside IV site reactions have not been studied. Methods A retrospective analysis was completed with patients who received 1500 mg doses of undiluted IV LEV. We included patients ≥ 18 years old that received at least 1 dose of IV LEV 1500 mg from January 2018 to February 2021. Study end points included assessment of hemodynamic disturbance (bradycardia [HR less than 50 beats per minute] or hypotension [SBP less than 90 mmHg] within 1 hour or documented infusion reaction within 12 hours of LEV. Descriptive statistics were utilized. Results A total 213 doses of 1500 mg of IV LEV were administered to 107 patients. Peripheral lines were used for 85.9% of doses. Approximately half of doses (57) were administered to patients on the general wards, with the remainder in the intensive care unit or emergency department. Two patients (1.9%) experienced bradycardia; however, 1 patient had pre-existing bradycardia. Three patients (3.8%) experienced hypotension; however, those patients were receiving vasopressors prior to the dose. There were no cases of infusion reaction. Conclusion Undiluted, rapid administration of IV LEV 1500 mg was well tolerated and safe.
Article
Purpose Although phenytoin is one of the most commonly used antiepileptic drugs (AEDs), it has potential serious side effects and drug interactions. Levetiracetam is a relatively newer AED with favorable pharmacokinetics and could be an effective and safer option for the treatment of convulsive status epilepticus (CSE). We aimed to compare the efficacy and safety profile of intravenous levetiracetam and phenytoin as second-line treatment agents in children with CSE and acute repetitive seizures (ARS). Method Two hundred seventy-seven patients aged between 1 month and 18 years who received intravenous levetiracetam or phenytoin as a second-line AED with the diagnosis of CSE or ARS were retrospectively evaluated. Drug efficacy was defined as control of seizures without the need for any additional medication after completion of the infusion and no recurrence in the following 12 h. The primary outcome was drug efficacy. The secondary outcomes included application of an additional second-line AED, induction of anesthesia, and admission to the intensive care unit (ICU), and drug-related adverse reactions. Results No differences were found between the two treatment groups with regard to patient characteristics and seizure type. The efficacy of levetiracetam was higher than that of phenytoin (77.6% vs 57.7%, P = 0.011) in children with CSE. There was no significant difference between the efficacy rates of levetiracetam and phenytoin for ARS (55.8% vs 58.8%, P = 0.791). Overall, drug efficacy was 70.9% for levetiracetam and 58.1% for phenytoin (P = 0.048). For CSE, the need for additional second-line treatment, anesthesia induction, and ICU admission was higher in the phenytoin group (P = 0.001, P = 0.038, P = 0.02, respectively). Drug-related adverse reactions were more frequent in the phenytoin group than the levetiracetam group (23.3% vs 1.4%; P < 0.001). The most common adverse reaction in the phenytoin group was hypotension. Phenytoin-related anaphylaxis was detected in one patient. No serious adverse effects related to levetiracetam were observed. Conclusions Intravenous levetiracetam seems as effective as intravenous phenytoin in emergency treatment of children with ARS and more effective for CSE in stopping the seizure with less risk of recurrence. Levetiracetam has fewer cardiovascular side effects and has a safer profile than phenytoin. Intravenous levetiracetam is a favorable option as a first second-line AED for pediatric seizures.
Article
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Intravenous (IV) levetiracetam (LEV) is currently approved as an alternative or replacement therapy for patients unable to take the oral form of this antiepileptic drug (AED). The oral form has Food and Drug Administration (FDA) indications for adjunctive therapy in the treatment of partial onset epilepsy ages 1 month or more, myoclonic seizures associated with juvenile myoclonic epilepsy starting with the age of 12 and primary generalized tonic-clonic seizures in people 6 years and older. Since the initial introduction, oral and IV LEV has been evaluated in various studies conducted in the critical care setting for the treatment of status epilepticus, stroke-related seizures, seizures following subarachnoid or intracerebral hemorrhage, post-traumatic seizures, tumor-related seizures, and seizures in critically ill patients. Additionally, studies evaluating rapid infusion of IV LEV and therapeutic monitoring of serum LEV levels in different patient populations have been performed. In this review we present the current state of knowledge on LEV use in the critical care setting focusing on the IV uses and discuss future research needs.
Article
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For the management of status epilepticus (SE), lorazepam (LOR) is recommended as the first and phenytoin or fosphenytoin as the second choice. Both these drugs have significant toxicity. Intravenous levetiracetam (LEV) has become available, but its efficacy and safety has not been reported in comparison to LOR. We report a randomized, open labeled pilot study comparing the efficacy and safety of LEV and LOR in SE. Consecutive patients with convulsive or subtle convulsive SE were randomized to LEV 20 mg/kg IV over 15 min or LOR 0.1 mg/kg over 2-4 min. Failure to control SE within 10 min of administration of one study drug was treated by the other study drug. The primary endpoint was clinical seizure cessation and secondary endpoints were 24 h freedom from seizure, hospital mortality, and adverse events. Our results are based on 79 patients. Both LEV and LOR were equally effective. In the first instance, the SE was controlled by LEV in 76.3% (29/38) and by LOR in 75.6% (31/41) of patients. In those resistant to the above regimen, LEV controlled SE in 70.0% (7/10) and LOR in 88.9% (8/9) patients. The 24-h freedom from seizure was also comparable: by LEV in 79.3% (23/29) and LOR in 67.7% (21/31). LOR was associated with significantly higher need of artificial ventilation and insignificantly higher frequency of hypotension. For the treatment of SE, LEV is an alternative to LOR and may be preferred in patients with respiratory compromise and hypotension.
Article
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Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.
Article
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Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding. LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies.
Article
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To assess risk factors and prognosis in patients with refractory status epilepticus (RSE). We retrospectively analysed all episodes of status epilepticus (SE) treated between 1993 and 2002 on the neurological intensive care unit (NICU) of the Charite-Universitatsmedizin Berlin. The predictive and prognostic features of RSE were compared with non-RSE (NRSE). All patients with "de novo" SE were followed up to identify the possible development of post-SE symptomatic epilepsy. A total of 83 episodes fulfilled our criteria of SE. Of these 43% were refractory to first line anticonvulsants. The mean age of patients with SE was 53.3 (SD 19) years, with only two patients younger than 18 years. Encephalitis was significantly more often the primary cause in RSE (p<0.05), whereas low levels of antiepileptic drugs were significantly more often associated with NRSE (p<0.001). Hyponatraemia within the first 24 hours after onset of status activity was significantly more often associated with RSE (p<0.05). In RSE, compared with NRSE, significantly longer duration of seizure activity (p<0.001), more frequent recurrence of epileptic activity within the first 24 hours after the end of seizure activity (p<0.001), longer stay in the NICU and in hospital (p<0.001 and p<0.01, respectively), and more frequent development of symptomatic epilepsy (p<0.05) were seen. SE treated in the NICU is frequently refractory to first line anticonvulsant drugs. Encephalitis is a predictor for RSE, which is associated with markedly poor outcome, in particular, the development of post-SE symptomatic epilepsy. Thus prevention of this most severe form of SE should be the primary target of treatment of SE.
Article
Full-text available
Sixty-eight patients with convulsive status epilepticus (SE) were randomly assigned to two groups to study the efficacy of sodium valproate (VPA) and phenytoin (PHT). Seizures were aborted in 66% in the VPA group and 42% in the PHT group. As a second choice in refractory patients, VPA was effective in 79% and PHT was effective in 25%. The side effects in the two groups did not differ. Sodium valproate may be preferred in convulsive SE because of its higher efficacy.
Article
The etiology, clinical features and outcome of generalized major motor status epilepticus in 98 patients over the age of 14 years have been reviewed. Approximately half of the patients had not had previous seizures. The most common single cause of the status was noncompliance with anticonvulsant drug regimens and this accounted for the status in 53 percent of the patients with previous seizures and in 28 percent of all the patients in our series. The other causes in our series were alcohol-withdrawal, cerebrovascular disease, cerebral tumors or trauma (involving especially the frontal lobe), intracranial infection, metabolic disorders, drug overdose and cardiac arrest. In 15 percent of the patients, however, no specific cause could be found. Status was never the initial manifestation of primary (constitutional) generalized epilepsy in our experience. The etiology of the status was sometimes multifactorial, so patients must be screened as fully as possible even when a likely cause is readily apparent. The motor manifestations of the convulsions were frequently restricted in distribution (62 percent of the cases). Focal or lateralized convulsive activity, especially during the course of continued seizure activity, did not necessarily indicate that localized structural pathology was responsible for the status. The seizures were of the tonic variety in a few of our patients and in such circumstances were usually associated with cerebral anoxia. We found that a poor outcome of the status was more likely as its duration increased, and the morbidity rate from the status itself was 12.5 percent among our patients, with a mortality rate of 2.5 percent. The episode of status was usually accompanied by hyperthermia, and often by a brisk peripheral leukocytosis, and in some of our patients a status-induced cerebrospinal fluid pleocytosis also developed. These features may lead to diagnostic confusion if their basis is not recognized. In most of our patients a systemic acidosis developed during the course of the status, but this did not appear to greatly influence the outcome.
Article
Status epilepticus (SE) is a condition requiring emergency care, which is often poorly managed in developing countries due to the lack of personnel, drugs, and insufficient technical and medical means. This study aims at determining the epidemiologic and etiologic characteristics and the difficulty in treating SE under the existing medical practice conditions in a developing country such as Senegal. A retrospective study was therefore carried out based on SE medical files at the University Hospital of Dakar over the period January 1988 to December 1998, and included several hospital departments, i.e., paediatrics, infectious diseases and neurology. Over an 11-year period 697 cases were recorded; of these, 48.2% of patients were under 5 years of age. The seizures were generalized in 58.2% of cases, partial in 21.2%, partial secondarily generalized, or with an association of both clinical presentations in 20.6% of cases. The etiology was as follows: mainly infectious (67%), followed by resistant and/or unbalanced epilepsy (9.9%), epilepsy of vascular origin (8%), and various other causes. The overall mortality rate was 24.8%. A long period between the onset of clinical symptoms and hospital treatment was noted, with an average time lapse of 16.6 h before treatment. The drugs utilized were diazepam and phenobarbitol, administered by injection. The overall outcome could be improved by better management, i.e., better prevention and an efficient treatment of infectious diseases, a reduction in the time before treatment, and improved means of intensive care.
Article
Levetiracetam was approved by the US FDA in 1999 after failing the traditional screening tests for antiepileptic drugs. In the 10 years since its introduction, it has become one of the first-line antiepileptic agents and has been evaluated in small uncontrolled studies and case series as an off-label treatment for status epilepticus, for nonepileptic neurological conditions, such as movement disorders, neuropathic pain and headaches, and for some psychiatric conditions. It has not been approved for any indication other than chronic epilepsy. A significant factor in using levetiracetam for seizures and other disorders has been its ease of dosing and tolerability. In this article, we outline how levetiracetam was discovered, the animal and human data showing its antiepileptic activity, its potential use in other neurological conditions and the significant adverse events. We also discuss the direction antiepileptic drug development will take in the future.
Article
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. 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. 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. 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. 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.
Article
Phenytoin (PHT), valproic acid (VPA), or levetiracetam (LEV) are commonly used as second-line treatment of status epilepticus (SE), but comparative studies are not available. Among 279 adult SE episodes identified prospectively in our tertiary care hospital over 4 years, we retrospectively identified 187 episodes in which PHT, VPA, or LEV were given after benzodiazepines. Patients with postanoxic SE were not included. Demographics, clinical SE features, failure of second-line treatment to control SE, new handicap, and mortality at hospital discharge were assessed. Uni- and multivariable statistical analyses were applied to compare the three agents. Each compound was used in about one third of SE episodes. VPA failed to control SE in 25.4%, PHT in 41.4%, and LEV in 48.3% of episodes in which these were prescribed. A deadly etiology was more frequent in the VPA group, whereas SE episodes tended to be more severe in the PHT group. After adjustment for these known SE outcome predictors, LEV failed more often than VPA [odds ratio (OR) 2.69; 95% confidence interval (CI) 1.19-6.08]; 16.8% (95% CI: 6.0-31.4%) of second-line treatment failures could be attributed to LEV. PHT was not statistically different from the other two compounds. Second-line treatment did not seem to influence new handicap and mortality, whereas etiology and the SE Severity Score (STESS) were robust independent predictors. Even without significant differences on outcome at discharge, LEV seems less efficient than VPA to control SE after benzodiazepines. A prospective comparative trial is needed to address this potentially concerning finding.
Article
Status epilepticus is a condition of prolonged/repetitive seizures that often occurs in the elderly. Treatment in the elderly can be complicated by serious side effects associated with traditional drugs. The aim of this pilot study was to evaluate the short-term efficacy/safety of intravenously administered LEV (IVLEV) as the treatment of choice for SE in the elderly. We enrolled nine elderly patients (five female/four male; median age 78 years) with SE. Two patients had a previous diagnosis of epilepsy; in the remaining seven, SE was symptomatic. SE was convulsive in five and non-convulsive in four. All the patients presented concomitant medical conditions (arrhythmias/respiratory distress/hepatic diseases). As the traditional therapy for SE was considered unsafe, IVLEV was used as first-line therapy (loading dose of 1500 mg/100 ml/15 min, mean maintenance daily dose of 2500 mg/24 h) administered during video-EEG monitoring. In all the patients but one, IVLEV was effective in the treatment of SE and determined either the disappearance of (7/8), or significant reduction in (1/8), epileptic activity; no patient relapsed in the subsequent 24 h. No adverse events or changes in the ECG/laboratory parameters were observed. These data suggest that IVLEV may be an effective/safe treatment for SE in the elderly.
Article
Since its introduction in 2006, 43 patients with various forms of status epilepticus (SE) have been treated with the intravenous formulation of levetiracetam (LEV) in our clinic. After ineffective treatment with benzodiazepines, intravenous LEV was administered as a short infusion (nonconvulsive and subtle SE) at a dose of 1000 or 2000 mg. In cases of convulsive SE, a fractionated injection of 1000 or 2000 mg was used. When the results for both are combined, SE could be terminated in 19 of 43 patients. Intravenous LEV was more effective in simple focal SE (3/5), complex focal SE (11/18) and myoclonic status (2/2) than in nonconvulsive (2/8) and subtle (1/2) SE. In no case was (secondarily) generalized convulsive status epilepticus (0/8) terminated. Intravenous LEV was also well-tolerated when injected in fractionated form. No severe adverse reactions were observed. As a result of this investigation, intravenous LEV in moderate doses may represent an efficacious and well-tolerated alternative for the treatment of focal (simple and complex focal) and myoclonic SE. Further investigations are needed to confirm this assumption as the patient numbers are quite low.
Article
Status epilepticus (SE) will occur in 50,000 to 60,000 individuals in the United States annually: one third as the presenting symptom in patients with a 1st unprovoked seizure or with epilepsy, one third in patients with established epilepsy, and one third in individuals with no history of epilepsy. The greatest number of cases will occur in children, although the risk is equally high in the over-60 population. In patients with epilepsy, SE is more likely to occur in those with partial seizures and in those with remote symptomatic epilepsy. The presence of a preexisting neurologic abnormality is associated with an increased risk of SE in those with acute systemic insults. There is a high mortality reported, but this is related predominantly to the underlying condition. The 1 to 2% mortality attributed to SE probably reflects an overestimation of the risk. There is an increased risk of seizures and of intellectual dysfunction following the occurrence of an episode of SE, although the causal association is not clear. Individuals with epilepsy who experience an episode of SE probably have a lower likelihood of remission of epilepsy.
Article
Two hundred and thirty-nine cases of status epilepticus in children 0–15 years old have been studied. Generalized tonic-clonic and unilateral clonic convulsions constituted the bulk of cases. Status is mostly observed in young infants since 37% of all cases occurred in the first year, 73% in the first 3 years and 85% before 5 years of age. In only 23% of the patients did brief convulsions precede the episode of status epilepticus. Conversely seizures were noticed after status in almost three quarters of patients followed for one year or more. One half of our cases were apparently due to organic brain damage, either acute or chronic, the remaining half had no recognized etiological factors. More than half of these cryptogenic cases were related to non-specific febrile episodes. The prognosis of children's status epilepticus is grave, mental or neurological residua or both being present in at least 57% of our patients. Approximately one half of these children had had normal development prior to their bout of convulsions.
Article
A retrospective study of 42 patients admitted to The London Hospital between 1948–1968 with 50 episodes of major status epilepticus is reported with particular reference to cause and outcome. It was found that the commonest precipitating factors were drug irregularity and/or systemic infections. The duration of the status was greater in the younger age group (below 10 years) and in the older age group (over 60 years), and it was further noted that this factor was closely linked with neurological outcome. Overall mortality was 21 per cent, and a further 26 per cent of the patients suffered neurological sequelae. This was particularly likely in patients with asymmetrical motor seizure activity. Frontal lobe involvement was suggested in 42 per cent of patients. The duration of status particularly before treatment was commenced was closely related to mortality and morbidity. The findings are discussed.
Article
Lorazepam was compared with diazepam for the treatment of status epilepticus in a double-blind, randomized trial. Seventy-eight patients with 81 episodes were enrolled. Patients received one or two doses of either 4 mg of lorazepam or 10 mg of diazepam intravenously. Seizures were controlled in 89% of the episodes treated with lorazepam and in 76% treated with diazepam. The times for onset of action of the medications did not differ significantly. Adverse effects occurred in 13% of the lorazepam-treated patients and in 12% of the diazepam-treated patients. Respiratory depression and arrest, the most frequent adverse effects, were treated symptomatically; no adverse sequelae were noted.
Article
The etiology, clinical features and outcome of generalized major motor status epilepticus in 98 patients over the age of 14 years have been reviewed. Approximately half of the patients had not had previous seizures. The most common single cause of the status was noncompliance with anticonvulsant drug regimens and this accounted for the status in 53 percent of the patients with previous seizures and in 28 percent of all the patients in our series. The other causes in our series were alcohol-withdrawal, cerebrovascular disease, cerebral tumors or trauma (involving especially the frontal lobe), intracranial infection, metabolic disorders, drug overdose and cardiac arrest. In 15 percent of the patients, however, no specific cause could be found. Status was never the initial manifestation of primary (constitutional) generalized epilepsy in our experience. The etiology of the status was sometime multifactorial, so patients must be screened as fully as possible even when a likely cause is readily apparent. The motor manifestations of the convulsions were frequently restricted in distribution (62 percent of the cases). Focal or lateralized convulsive activity, especially during the course of continued seizure activity, did not necessarily indicate that localized structural pathology was responsible for the status. The seizures were of the tonic variety in a few of our patients and in such circumstances were usually associated with cerebral anoxia. We found that a poor outcome of the status was more likely as its duration increased, and the morbidity rate from the status itself was 12.5 percent among our patients, with a mortality rate of 2.5 percent. The episode of status was usually accompanied by hyperthermia, and often by a brisk peripheral leukocytosis, and in some of our patients a status-induced cerebrospinal fluid pleocytosis also developed. These features may lead to diagnostic confusion if their basis is not recognized. In most of our patients a systemic acidosis developed during the course of the status, but this did not appear to greatly influence the outcome.
Article
Using univariate and multivariate regression analysis, we studied seizure duration, seizure type, age, etiologies, other clinical features, and mortality among 253 adults with status epilepticus (SE) admitted to the Medical College of Virginia. Cerebral vascular disease and discontinuation of antiepileptic drugs (AEDs) were the most prominent causes of SE, each accounting for approximately 22% of all patients in the series. The other principle etiologies were alcohol withdrawal, idiopathic, anoxia, metabolic disorders, hemorrhage, infection, tumor, drug overdose, and trauma. When the patients were divided into two groups, the group with SE lasting < 1 h had a lower mortality as compared with seizure duration > or = 1 h. Low mortality rates were noted in alcohol and AED discontinuation etiologies. Anoxia and increasing age were significantly correlated with higher mortality. The mortality rates of partial and generalized SE were not significantly different. Race and sex did not affect mortality significantly. Our findings represent the first multivariate analysis of predictive indicators of mortality in SE and demonstrate that specific factors influence mortality rate in SE.
Article
Status epilepticus (SE) is defined as recurrent epileptic seizures without full recovery of consciousness before the next seizure begins, or more-or-less continuous clinical and/or electrical seizure activity lasting for more than 30 min whether or not consciousness is impaired. Three presentations of SE are now recognized: recurrent generalized tonic and/or clonic seizures without full recovery of consciousness between attacks, nonconvulsive status where the patient appears to be in a prolonged "epileptic twilight state," and continuous/repetitive focal seizure activity without alteration of consciousness. Generalized convulsive status epilepticus (GCSE) encompasses a broad spectrum of clinical presentations from repeated overt generalized tonic-clonic seizures to subtle convulsive movements in a profoundly comatose patient. Thus, GCSE is a dynamic state that is characterized by paroxysmal or continuous tonic and/or clonic motor activity, which may be symmetrical or asymmetrical and overt or subtle but which is associated with a marked impairment of consciousness and with bilateral (although frequently asymmetrical) ictal discharges on the EEG. Just as there is a progression from overt to increasingly subtle clinical manifestations of GCSE, there is also a predictable sequence of progressive EEG changes during untreated GCSE. A sequence of five patterns of ictal discharges has been observed: discrete electrographic seizures, waxing and waning, continuous, continuous with flat periods, and periodic epileptiform discharges on a relatively flat background. A patient actively having seizures or comatose who exhibits any of these patterns on EEG should be considered to be in GCSE and should be treated aggressively to stop all clinical and electrical seizure activity to prevent further neurological morbidity and mortality.
Article
To determine the incidence, risk factors, and long-term sequelae of the purple glove syndrome (PGS) in hospital patients receiving IV phenytoin. PGS is a poorly understood, potentially serious local complication of IV phenytoin administration characterized by progressive distal limb edema, discoloration, and pain. The pharmacologic records of the Mayo Foundation hospitals were reviewed to identify 179 consecutive patients who had IV phenytoin ordered during a 3-month period. Their hospital records were then reviewed to confirm IV phenytoin treatment, the frequency of PGS (defined as the progressive development of edema, discoloration, and pain in the limb after administration of IV phenytoin), and the outcome of PGS. A total of 152 patients received IV phenytoin, and nine (5.9%) developed PGS. PGS patients received a greater median initial dose of phenytoin, total 24-hour dose, and total number of doses (all p < 0.05). In addition, the median age of the PGS patients was older, their infusion was more often given for acute seizures, it was less likely to be administered in the operating room, and the length of their hospital stay was longer (all p < 0.05). One patient required surgical therapy, and all other patients resolved within 3 weeks with conservative management. PGS is not rare and elderly patients and individuals receiving large, multiple doses are particularly at risk. This iatrogenic complication may be preventable by substituting fosphenytoin for IV phenytoin.
Article
The authors derived a clinical score to predict mortality in status epilepticus (SE) from analysis of a retrospective SE cohort, using four variables available at presentation: history of seizures, age, seizure type, and consciousness impairment. Validation on a small prospective SE series (34 patients) resulted in sensitivity, 1.000; specificity, 0.643; negative predictive value, 1.000; and unweighted accuracy, 0.822. This simple clinical score may reliably identify patients surviving after SE.
Article
Convulsive status epilepticus is the most common childhood medical neurological emergency, and is associated with significant morbidity and mortality. Most data for this disorder are from mainly adult populations and might not be relevant to childhood. Thus we undertook the North London Status Epilepticus in Childhood Surveillance Study (NLSTEPSS): a prospective, population-based study of convulsive status epilepticus in childhood, to obtain a uniquely paediatric perspective. Clinical and demographic data for episodes of childhood convulsive status epilepticus that took place in north London were obtained through a clinical network that covered the target population. We obtained these data from anonymised copies of a standardised admission proforma; accident and emergency, nursing, ambulance, and intensive-care unit notes; and interviews with parents, medical, nursing, and paramedic staff. We investigated ascertainment using capture-recapture modelling. Of 226 children enrolled, 176 had a first ever episode of convulsive status epilepticus. We estimated that ascertainment was between 62% and 84%. The ascertainment-adjusted incidence was between 17 and 23 episodes per 100,000 per year. 98 (56%, 95% CI 48-63) children were neurologically healthy before their first ever episode and 56 (57%, 47-66) of those children had a prolonged febrile seizure. 11 (12%, 6-18) of children with first ever febrile convulsive status epilepticus had acute bacterial meningitis. Conservative estimation of 1-year recurrence of convulsive status epilepticus was 16% (10-24%). Case fatality was 3% (2-7%). Convulsive status epilepticus in childhood is more common, has a different range of causes, and a lower risk of death than that in adults. These paediatric data will help inform management of convulsive status epilepticus and appropriate allocation of resources to reduce the effects of this disorder in childhood.
Article
Levetiracetam (LEV) is used in the setting of acute brain injury for seizure treatment or prophylaxis but its safety and efficacy in this setting is unknown. We retrospectively analyzed the patterns of use and safety/efficacy of LEV in 379 patients treated in the neuroscience intensive care unit (NSICU). We extracted from the charts clinical data including diagnosis, AED therapy before and during stay in the NSICU, complications of treatment, length of stay, and clinical outcomes (improvement, Glasgow Coma Scale, and death). We analyzed the data using binary and ordered (multi-category) logistic regression. Overall, our findings are that phenytoin used prior to the NSICU admission was frequently replaced with LEV monotherapy (P < 0.001). Patients treated with LEV monotherapy when compared to other AEDs had lower complication rates and shorter NSICU stays. Older patients and patients with brain tumors or strokes were preferentially treated with LEV for prevention and/or management of seizures (all P < or = 0.014). The results of this study suggest that LEV is a frequently used AED in the setting of acute brain injury and that it may be a desirable alternative to phenytoin. Prospective studies evaluating the long-term safety, efficacy and outcomes of LEV in this setting are indicated.
Article
The evidence based data to guide management in patients of benzodiazepine refractory status epilepticus (SE) is still lacking. We conducted a randomized study to evaluate the comparative effect of intravenous (IV) phenytoin and intravenous valproate (IV VA) in patients of benzodiazepine refractory SE. Hundred, age and sex matched, patients of benzodiazepine refractory SE were randomly divided into Group A (50 patients), treated with IV VA and Group B (50 patients) treated with IV phenytoin. Twelve patients, in whom SE was not controlled with a single drug, were switched over to the other group. Treatment was considered successful when all motor or EEG seizure activity ceased within 20 min after the beginning of the drug infusion and no return of seizure activity during the next 12h. Secondary study end points were adverse events to treatment, in-hospital complications and the neurological outcome at discharge. In this study, IV VA was successful in 88% and IV phenytoin in 84% (p>0.05) of patients of SE with a significantly better response in patients of SE <2h (p<0.05). The total number of adverse events did not differ significantly between the two groups (p>0.05). There were no differences among the treatments with respect to recurrence after 12-h study period or the outcome at 7 days. IV VA is as effective as IV phenytoin. It is easy to use, better tolerated and can be used as an alternative to IV phenytoin in patients of benzodiazepine refractory SE, especially in patients of cardio-respiratory disease. The better outcome in patients having shorter duration of SE (<2h) suggests need of immediate treatment.
Article
Status epilepticus (SE) is a medical emergency requiring prompt treatment to try to limit mortality and improve outcome. So far, newer antiepileptic drugs (AED) have not assumed a noticeable role in the treatment of SE. This may be in part due to the lack of IV forms for the newer AEDs. The IV form of Levetiracetam (IV-LEV) has recently become available and has a potential role in the treatment of SE. We report two cases of non-convulsive SE that responded favorably to IV-LEV. The first patient is an 83-year-old male with a history of complex partial seizure disorder who presented with impaired consciousness. The second patient is an 82-year-old male with history of old left middle cerebral artery ischemic infarction, who presented with confusion. Both patients were found to have a non-convulsive status epilepticus on electroencephalography (EEG) and treated with IV-LEV. In both cases, electrographic SE stopped with marked clinical improvement. Both patients tolerated the medication well and no significant side effects occurred. IV-LEV may have a potential role in the treatment of non-convulsive status epileptics.
Article
In 2006, levetiracetam was approved as the first of the newer anticonvulsive drugs as an intravenous formulation (ivLEV) for patients with epileptic seizures who are unable to take oral medication. We report our experience with the use of ivLEV for the treatment of 18 episodes of benzodiazepine refractory focal status epilepticus (SE) in 16 patients, including four patients with secondary generalised SE. SE was controlled in all patients by the given combination of drugs; application of further antiepileptic medications after ivLEV was necessary in two episodes. No severe side effects occurred. Our data suggest that ivLEV may be an alternative for the treatment of SE in the future, even in patients that did not respond to benzodiazepines. A large prospective, randomised, controlled study is warranted to investigate the efficacy and safety of ivLEV for the treatment of SE.