Is it time to ditch Phenytoin?


By Gabriel Jones, Consultant EM.

Epilepsy is common, with a prevalence of approximately 1% in adults (1,2). Annual costs are estimated to be 1.6 billion pounds (3,4). Status epilepticus (SE) is a neurological emergency which still has a significant mortality (4-32%) (5,6,7). The current definition is a seizure lasting longer than five minutes or two seizures without a return of consciousness between seizures (8).

Until recent years, the management of SE has changed little. The established consensus being initial treatment with repeated Benzodiazepines (BZD) followed by a second line agent. A third line drug or General Anaesthetic (GA) may follow. In the United Kingdom (UK) and abroad this has conventionally equated to Lorazepam (LOR) then Phenytoin (PHT)9 which is in keeping with National Institute for Health and Clinical Excellence (NICE) guidance (7). Whilst most emergency physicians will be familiar with using Phenytoin, the evidence for its use is largely based on low quality data some 20 years old (10).

PHT has a potentially dangerous side effect profile including respiratory depression, hypotension, toxicity in overdose, numerous interactions and contraindications including pregnancy (7,10). We all read the recent RCEM safety alert. In addition, PHT infusion is slow, requires a filtered giving set, electrocardiogram monitoring and subsequent drug level monitoring. The NICE 2014 Evidence Update Advisory Group suggested a safer alternative to Phenytoin is needed (11).

So what are the options?

With the advent of newer Anti-Epileptic Drugs (AEDs), clinicians are increasingly considering alternative agents to manage SE (9). Sodium Valproate (VPA) is considered to be effective but is not without risk (12,13). Levetiracetam (LEV) is currently licensed for monotherapy and adjunctive treatment of focal seizures and is widely regarded as safe (14). It has an acceptable side effect profile including haemodynamic stability and no known drug interactions due to its minimal protein binding (15,16). LEV can be administered rapidly and does not require subsequent serum level monitoring making it an attractive emergency drug for the management of SE. Already LEV is the first AED of choice for many intensive care units, particularly specialist neurosurgical units. So why are we still exposing our patients to a single dose of a dangerous drug in the emergency department when we know our intensive care colleagues are likely to take a very different approach?

So what is the evidence for the use of Keppra?

The 2004 NICE clinical guidance 137 and subsequent 2012 (7), 2014 (11) updates do not include any studies that evaluate Levetiracetam use in SE. The Cochrane review 2014, Anticonvulsant therapy for SE (20), concluded that, ‘beyond initial treatment with a benzodiazepine, there is uncertainty as to the effectiveness of other AEDs versus each other’.

The only study that included LEV found it to be as effective as LOR as a first-line agent. There are several more recent small prospective studies that compare LEV to PHT but most were conducted in the Indian subcontinent. They do not demonstrate a difference in efficacy and none were powered for equivalence or non inferiority. There are of course numerous case series that document the use of LEV in SE and suggest a similar efficacy to other AEDs.

Synthesis of what little data is available is inherently difficult because the outcome measure seizure cessation is inconsistently defined. Most prospective studies defined this as an assessment at 30 minutes; (18,23,28) however, there was a range from 331 minutes to 24 hours. Some studies gave no detail. Redecker et al.(39) recently published an analysis of efficacy of four AEDs based on four different efficacy criteria. Unsurprisingly, there was huge variation in reported efficacy highlighting the need for standardisation of outcome data. There is no strong evidence to identify LEV as either more or less effective than PHT or any other AED. We should, however, put this in the context of only weak evidence for current practice.

Given the apparently excellent safety profile that LEV offers, one could argue that the exact efficacy may not be important. If this safety profile is confirmed, it may be reasonable to accept the current limited published efficacy data. If LEV is approximately as effective, but much safer, quicker and easier to administer than the current available alternatives, this could justify its full endorsement within current practice.



1.MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and prevalence of neurological dis orders in a prospective community based study in the United Kingdom. Brain 2000; 123:665-676
2.Purcell B, Gaitatzis A, Sander JW, Majeed A. Epilepsy prevalence and prescribing patterns in England and Wales. Health Statistics 2002; 15:23-31.
3.Cockerell OC, Hart YM, Sander JW et al. The cost of epilepsy in the United Kingdom:an estimation based on the results of two population-based studies. Epilepsy Res. 1994; 18(3):249-260.
4.Fineberg NA et al. The size, burden and cost of disorders of the brain in the UK. J Psychopharmacol 2013; 27(9): 761-770
5.Claassen J, Lokin JK, Fitzsimmons B-FM, Mendelsohn FA, Mayer SA. Predictors of functional disability and mortality after status epilepticus. Neurology 2002; 58(1):139–42.
6.Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. Neurol NeurosurgPsychiatry2006; 77(5):611–5.
7.Langan Y et al. Certification of deaths attributable to epilepsy. J Neurol Neurosurg Psychiatry 2002; 73:751-752
8. last accessed 26th November 2015
9.Riviello JJ Treatment of status epilepticus: an international survey of experts. Neurocritical care society status epilepticus guideline writing committee. Neurocrit care 2013; 18(2):193-200.
10.David M. Treiman, M.D. et al. A comparison of four treatments for generalized convulsive status epilepticus. For the Veterans Affairs Status Epilepticus Cooperative Study Group N Engl J Med 1998; 339:792-798
11. last accessed 26th November 2015
12.Segura-Bruna et al. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand 2006; 114(1):1-7.
13.Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol 2000; 22(January–February(1)):62–5
14.Uges JW et al. Safety and pharmacokinetics of intravenous levetiracetam Infusion as add-on in status epilepticus. Epilepsia 2009; 50(3):415–21
15.Ramael S et al. Levetiracetam intravenous infusion: a randomized, placebo controlled safety and pharmacokinetic study. Epilepsia 2006; 47(7):1128–35
16.De Smedt T et al. Levetiracetam: part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev 2007; 13(1):57–78
17.Cook AM, Castle A, Green A, Lesch C, Morrison C, Rhoney D, et al. Practice variations in the management of status epilepticus. Neurocrit Care 2012; 17(1):24-30.
18.Misra et al. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labelled pilot study J Neurol 2012; 259:645–648
19.Luchi T et al. Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. J Neurol Neurosurg Psychiatry. 2015; 86(10): 1158-62
20.Prasad M et al. Anticonvulsant therapy for status epilepticus (Review).
21.Yasiry Z et al. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: A meta-analysis of published studies. Seizure 2014; 23:167–17
22.Eue S, Grumbt M, Latsch A, Irimie A, Macieik-Zuj G, Muller M, et al. Five years in the treatment of status epilepticus with intravenous levetiracetam. The 29th International Congress of Epilepsy. Roma: Epilepsia- Blackwell Publishing Ltd.; 2011. p. 23–263.
23.Mundlamuri 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 levetiracetam – Pilot study. Epilepsy Research 2015; 144:52–58
24.Rossetti AO et al. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol. 2008; 255(10):1561-6
25.Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134:663-94
26.Jadad AR et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12
27.Chakravarthi S et al. Journal of Clinical Neuroscience 2015; 22:959–963
28.Tripathi M et al. Management of refractory status epilepticus at a tertiary care centre in a developing country Seizure 2010; 19:109–111
29.Atmaca et al. Intravenous levetiracetam treatment in status epilepticus: A prospective study Epilepsy Research 2015; 114:13-22
30.Eue et al. Two years of experience in the treatment of status epilepticus with intravenous Levetiracetam. Epilepsy & Behaviour 2009; 15:467-469
31.Eue et al. 100 cases in the treatment of status epilepticus with intravenous levetiracetam. Epilepsia 2014; 55:168
32.Liu J et al. A two one-sided tests procedure for assessment of individual bioequivalence. J Biopharm Stat. 1997 Mar;7(1):49-61
33.Philips B et al.
34.Langer et al. A retrospective observational study of current treatment for generalized convulsive status epilepticus. Epilepsy & Behavior 2014; 37:95-99
35.Alvarez et al. Second-line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam. Epilepsia, 2011; 52(7):1292–1296
36.Solinas C et al. Intravenous valproate and levetiracetam as innovative therapy of the epileptic emergencies. Bollettino – Lega Italiana control’Epilessia, 2011; 142:83-86
37.Aiguabella et al. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study. Seizure 2011; 20:60–64
38.S Berning et al. Intravenous levetiracetam as treatment for status epilepticus. J Neurol 2009; 256:1634- 1642
39.Redecker et al. Comparison of the effectiveness of four antiepileptic drugs in the treatment of status epilepticus according to four different efficacy criteria. Epilepsy & Behavior 2015; 49:351-353
40.Bleck T et al. The Established Status Epilepticus Trial 2013. Epilepsia 2013; 54(6): 89-92