Levetiracetam as a second line agent for terminating seizures in adults in status epilepticus.
Date First Published:
August 21, 2016
Last Updated:
October 26, 2016
Report by:
Dr Martin Dore, ST5 Emergency Medicine (Musgrave park hospital. Royal Devon and Exeter Hospital NHS trust)
Search checked by:
Dr James Gagg, , Musgrave park hospital. Royal Devon and Exeter Hospital NHS trust
Three-Part Question:
In [adult patients in status epilepticus who have received benzodiazepines] is [levetiracetam as effective as phenytoin] at [safely terminating seizure activity]
Clinical Scenario:
A 75 year old patient has been brought into the emergency department having been seizing for 20 minutes. The prehospital crew have administered buccal midazolam followed by IV Lorazepam but the seizure is ongoing. You have heard that phenytoin has side effects and drug interactions and you don't know the patients background history. You wonder whether levetiracetam is a safe and effective alternative to phenytoin in terminating this seizure.
Search Strategy:
Both Medline and Embase were searched using NHS evidence HDAS portal (Health Database Advanced Search)
Search Details:
MEDLINE (["status epilepticus".ti,ab OR exp STATUS EPILEPTICUS/] AND [levetiracetam.ti,ab OR phenytoin.ti,ab OR exp PHENYTOIN/] AND [seizure*.ti,ab OR exp SEIZURES/] LIMIT to [2006-2016])
EMBASE (["status epilepticus".ti,ab OR exp EPILEPTIC STATE/ OR exp EPILEPSY/] AND [levatiracetam.ti,ab OR keppra.ti,ab OR levetiracetam.ti,ab OR exp ETIRACETAM/] AND [phenytoin.ti,ab OR dilantin.ti,ab OR exp PHENYTOIN/] AND [seizure*.ti,ab OR exp SEIZURE, EPILEPSY AND CONVULSION/] LIMIT to [2006-2016])
Terms in CAPITALS are MeSH headings (medical subject headings) appropriate to each database.
EMBASE (["status epilepticus".ti,ab OR exp EPILEPTIC STATE/ OR exp EPILEPSY/] AND [levatiracetam.ti,ab OR keppra.ti,ab OR levetiracetam.ti,ab OR exp ETIRACETAM/] AND [phenytoin.ti,ab OR dilantin.ti,ab OR exp PHENYTOIN/] AND [seizure*.ti,ab OR exp SEIZURE, EPILEPSY AND CONVULSION/] LIMIT to [2006-2016])
Terms in CAPITALS are MeSH headings (medical subject headings) appropriate to each database.
Outcome:
318 papers found of which 1 was a meta-analysis of 8 papers. 305 papers were not included as they were either irrelevant or of insufficient quality.
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies. Yasiry Z, Shorvon SD 2013 Dec 25 India | A total of 27 papers of which 8 were relevant to the efficacy of levetiracetam in SE. | Systematic review of the efficacy of five antiepileptic drugs - lacosamide, levetiracetam, valproate, phenytoin and phenobarbital - in convulsive benzodiazepine-resistant status epilepticus. | clinically detectable cessation of seizure activity | Efficacy of levetiracetam was 68.5% (95% CI: 56.2-78.7%), phenytoin 50.2% (95% CI: 34.2-66.1%) | Studies mainly retrospective and small in population number. Absence of double blinded trials. Most prospective trials were open label. Significant clinical and statistical heterogeneity. |
| Comparison of Antiepileptic Approaches in Treatment of Benzodiazepine Nonresponsive Status Epilepticus Bachhuber A et al 2015 Germany | 66 patients treated for status epilepticus (SE) or cluster seizures (CE) who initially failed to respond to benzodiazepine therapy with the equivalent dosage of at least 20 mg of diazepam. | Retrospective cohort study | termiantion of seizure within 24 hr | compared drugs equally effective | Retrospective.single centre.Not ED population. time to cessation or need for intubation not reported. included seizure clusters. |
| Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or leve Mundlamuri RC et al 2015 South India | 15-65 years old presenting to the neurological emergency services with generalised convulsive status epileptics. | Prospective randomised control trial - Pilot study | control of seziure with AED within 30 minutes of infusion. | Seizure termination with 1st AED 68% in phenytoin group, 68% in valproate group,78% in levetiracetam group. no statistically significant difference (p 0.044) | Pilot study. no power calculation. single centre. Not blinded |
| Levetiracetam versus phenytoin in management of status epilepticus Chakravarthi S et al 2014 North India | 44 consecutive patients with SE, following benzodiazepine administration | Prospective randomised control trial | Cessation of seizure within 30 mins of drug administration | Phenytoin - 68.2%, Levetiracetam 59.1% (P = 0.53) | Small population group. Double blinding could not be achieved. No power calculation. |
| Seizure recurrence in 24 hrs | phenytoin - 40.9% Levetiracetam 27.9% (P = 0.34) | ||||
| Levetiracetam Vs phenytoin for status epilepticus/cluster seizures: A prospective randomised study. Gujjar AR et al 2015 Oman | 71 patients (> 18 years old) with SE or CS following an initial dose of benzodiazepine | Prospective randomised control trial (interim analysis). | prevention of seizure over 24Hrs | no recurrence in 65% of Levetiracetam, 73% in phenytoin (p = 0.06) | Interim study. conference abstract. Included more CS patient than SE.primary outcome not relevant to ED management. |
Author Commentary:
Status epilepticus is a neurological emergency with significant morbidity and mortality. First line therapy with benzodiazepines is widely accepted best practice. In the UK it has become common practice to use phenytoin if the seizure continues, despite its significant side effect and drug interaction profile. Levetiracetam has been introduced more recently and is believed to have fewer adverse effects or drug interactions and is well tolerated in children, adults and the elderly.
There remains a lack of level 1 evidence with the use of levetiracetam in status epilepticus. Most studies to date are of small number and are retrospective. The studies do however report similar findings in terms of efficacy ( 67.5% levetiracetam Vs 64.9% phenytoin) and adverse effects, levetiracetam showing fewer. Levetiracetam has been demonstrated to be an effective alternative to phenytoin in the management of status epilepticus.
The EcLiPSE Study: Emergency treatment with levetiracetam or Phenytoin in Status Epilepticus, is underway in the UK currently and should add to evidence with regard to the use of levetiracetam in children. These findings may be extrapolated to the adult population.
There remains a lack of level 1 evidence with the use of levetiracetam in status epilepticus. Most studies to date are of small number and are retrospective. The studies do however report similar findings in terms of efficacy ( 67.5% levetiracetam Vs 64.9% phenytoin) and adverse effects, levetiracetam showing fewer. Levetiracetam has been demonstrated to be an effective alternative to phenytoin in the management of status epilepticus.
The EcLiPSE Study: Emergency treatment with levetiracetam or Phenytoin in Status Epilepticus, is underway in the UK currently and should add to evidence with regard to the use of levetiracetam in children. These findings may be extrapolated to the adult population.
Bottom Line:
Levetiracetam is effective and safe in the management of status epilepticus. Its Use should be considered in those in which phenytoin is contraindicated. Further analysis in larger RCTs would be beneficial before using levetiracetam first line following benzodiazepines.
References:
- Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies.
- Bachhuber A et al. Comparison of Antiepileptic Approaches in Treatment of Benzodiazepine Nonresponsive Status Epilepticus
- Mundlamuri RC et al. Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or leve
- Chakravarthi S et al. Levetiracetam versus phenytoin in management of status epilepticus
- Gujjar AR et al. Levetiracetam Vs phenytoin for status epilepticus/cluster seizures: A prospective randomised study.