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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)
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.

Search 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)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
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.
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.
Mundlamuri RC, Sinha S, Subbakrishna DK, Prathyusha PV, Nagappa M, Bindu PS, Taly AB,... 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
Chakravarthi S, Goyal MK, Modi M, Bhalla A, Singh P. 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)
Gujjar AR, Al-Asmi AR, Nandhagopal R, Jacob PC, Obaidi A, Ganguly SS, Al-Hashim A, Al-Amrani K 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.

Comment(s)

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.

Clinical 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

1. 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. Seizure. 2014 Mar;23(3):167-74
2. Bachhuber A et al Comparison of Antiepileptic Approaches in Treatment of Benzodiazepine Nonresponsive Status Epilepticus CNS Neurosci Ther 2016 Mar;22(3):178-83
3. 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 Epilepsy Res 2015 Aug;114:52-8
4. Chakravarthi S et al Levetiracetam versus phenytoin in management of status epilepticus J Clin Neurosci 2015; 22: 959–963
5. Gujjar AR et al Levetiracetam Vs phenytoin for status epilepticus/cluster seizures: A prospective randomised study. J Neurol Sci 2015; 357: e324-e327