Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): A prospective randomized controlled pilot study

Nene, Devavrat; Mundlamuri, Ravindranadh Chowdary; Satishchandra, Parthasarathy; Prathyusha, Parthipulli Vasuki; Nagappa, Madhu; Bindu, Parayil Sankaran; Kenchaiah, Raghavendra; Saini, Jitender; Bharath, Rose Dawn; Thennarasu, Kandavel; Taly, Arun B.; Sinha, Sanjib

doi:10.1016/j.seizure.2019.01.015

Cited by 19 publications

(21 citation statements)

References 27 publications

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“…Nene et al conducted a class II study of 118 patients older than age 60 years with CSE not controlled with first-line LZP. 89 Patients received 20 to 25 mg/kg of either LEV or VPA. Control of CSE was not different between the groups, but higher STESS was associated with poorer therapeutic response ( P < .05).…”

Section: Resultsmentioning

confidence: 99%

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

et al. 2020

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“…Meta-analyses of newly included RCTs showed no statistically significant difference in SE cessation when LEV was compared with LOR (Misra et al, 2012) (first-line treatment, OR = 1.04, 95% CI 0.37 to 2.92), PHT (Chakravarthi et al, 2015;Mundlamuri et al, 2015;Gujjar et al, 2017;Singh et al, 2018;Dalziel et al, 2019;Lyttle et al, 2019) (second-line treatment, OR = 0.90, 95% CI 0.64 to 1.27), and VPA (Mundlamuri et al, 2015;Nene et al, 2019) (second-line treatment, OR = 1.47, 95% CI 0.81 to 2.67). And there was no statistically significant difference when LEV plus clonazepam was compared with placebo plus clonazepam (Misra et al, 2012) (OR = 1.00, 95% CI 0.43 to 2.35) ( Figure 2).…”

Section: Se Cessationmentioning

confidence: 94%

“…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.…”

Section: Study Characteristics and Quality Assessmentmentioning

confidence: 99%

“…The included nine RCTs were generally of unclear or high risk of bias mainly due to unclear risk of bias in allocation concealment and blinding domains, only two RCTs were of low risk of bias (Dalziel et al, 2019;Lyttle et al, 2019). The included RCTs were generally open-label randomized clinical trials, only one RCT used the double-blind design (Navarro et al, 2016) and one RCT used the single-blind design (Nene et al, 2019). All included nine RCTs analyzed data with the intention-to-treat principle ( Table 4).…”

Section: Study Characteristics and Quality Assessmentmentioning

confidence: 99%

“…Nine RCTs (Misra et al, 2012;Chakravarthi 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) reported total AEs. Meta-analysis of eight included RCTs (Misra et al, 2012;Chakravarthi et al, 2015;Mundlamuri et al, 2015;Gujjar et al, 2017;Singh et al, 2018;Dalziel et al, 2019;Lyttle et al, 2019;Nene et al, 2019) showed no statistically significant difference when LEV was compared with LOR (OR = 1.22, 95% CI 0.37 to 4.02) (Misra et al, 2012), PHT (OR = 0.89, 95% CI 0.46 to 1.75) (Chakravarthi et al, 2015;Mundlamuri et al, 2015;Gujjar et al, 2017;Singh et al, 2018;Dalziel et al, 2019;Lyttle et al, 2019), and VPA (OR = 1.48, 95% CI 0.44 to 4.91) (Mundlamuri et al, 2015;Nene et al, 2019) in rates of total AEs ( Figure 6). Another RCT reported lower but no statistically significant difference total non-serious AEs of LEV plus clonazepam compared with placebo plus clonazepam (90/197 versus 107/197) (Navarro et al, 2016).…”

Section: Total Adverse Eventsmentioning

confidence: 99%

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Efficacy, Safety, and Economics of Intravenous Levetiracetam for Status Epilepticus: A Systematic Review and Meta-Analysis

et al. 2020

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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 12 th 2019. Metaanalyses were conducted using random-effect model to calculate odds ratio (OR) of included randomized controlled trials (RCTs) with RevMan 5.3 software. Results: A total of 478 studies were obtained. Five systematic reviews (SRs)/metaanalyses, 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).

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A Simulation‐Based Assessment of Levetiracetam Concentrations Following Fixed and Weight‐Based Loading Doses: A Meta‐Regression and Pharmacokinetic Modeling Analysis

Lau,

Haag,

Maharaj

2024

The Journal of Clinical Pharma

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Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight‐based loading doses of LEV with respect to established therapeutic target concentrations. Meta‐regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight‐based dosing) to achieve maximum (Cpeak) and 12‐h (C12h) plasma concentrations that exceed 12 mg/L. The meta‐regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight‐based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight‐based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

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Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): A prospective randomized controlled pilot study

Cited by 19 publications

References 27 publications

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee

Efficacy, Safety, and Economics of Intravenous Levetiracetam for Status Epilepticus: A Systematic Review and Meta-Analysis

A Simulation‐Based Assessment of Levetiracetam Concentrations Following Fixed and Weight‐Based Loading Doses: A Meta‐Regression and Pharmacokinetic Modeling Analysis

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