Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Cornell Medical College

Dr. Kandula reports no financial relationships relevant to this field of study.

SYNOPSIS: In this systematic review, the evidence supporting the use of intravenous phenytoin for convulsive status epilepticus was analyzed critically and did not demonstrate strong evidence to support its use as a preferred second-line agent.

SOURCE: Brigo F, Bragazzi NL, Lattanzi S, et al. A critical appraisal of randomized controlled trials on intravenous phenytoin in convulsive status epilepticus. Eur J Neurol 2018;25:451-463.

Convulsive status epilepticus (SE) is a neurologic and medical emergency with an incidence rate of up to 41/100,000 cases per year and estimated deaths of 22,000 to 42,000 annually. Yet, most treatment algorithms for benzodiazepine-resistant or second-line treatment in SE largely are based on clinical experience and anecdotal evidence rather than multicenter, randomized, controlled trials (RCT). In this systematic review of RCTs of intravenous (IV) phenytoin for convulsive status, the authors weighed the evidence regarding the use of phenytoin in convulsive status, with attention to second-line treatment.

The authors included eight studies (544 patients) with Cochrane-quality methodology after meeting criteria as an RCT. All studies from 1988-2015 included both adult and pediatric patients. All studies also included convulsive status, although additional SE subtypes, such as subtle generalized convulsive status, also were included in some studies. Six studies used IV phenytoin as first-line or second-line treatment, although not clearly benzodiazepine resistant (concurrent or immediate use of phenytoin along with benzodiazepine). In two of the eight studies with 72 combined patients, phenytoin was used in benzodiazepine-resistant cases as defined by ongoing clinical semiology and/or electrographic activity.^1,2 Of the remaining 472 patients, 185 received phenytoin as first drug;^1,2,3 269 patients received IV phenytoin immediately after IV diazepam^3,4 or lorazepam.⁵ In 18 patients, phenytoin was administered simultaneously with IV diazepam.⁶

Treatment success was defined variably in the studies, with the primary endpoint cessation of clinically overt convulsive activity ranging from 42-100%. In those defined as subtle convulsive SE, treatment success was significantly lower at 8.3% with combined diazepam and phenytoin treatment and 7.7% in those with phenytoin alone.

Interestingly, in the two studies with benzodiazepine-resistant cases, use of second-line phenytoin resulted in clinical seizure cessation of 68-96%.^1,2 With either simultaneous or near immediate administration of IV phenytoin after IV diazepam^3,4,6 or IV lorazepam,⁵ clinical seizure cessation was 55.8-100% (excluding patients with subtle SE). IV phenytoin used as a first-line drug controlled status in 42-88% of cases.^3,7,8 In a landmark study, Treiman et al found that IV lorazepam was more effective (64.9%) than either phenytoin (43.6%), phenobarbital (58.2%), or diazepam followed by phenytoin (55.8%) for aborting convulsive SE.³ Misra et al found that IV phenytoin was less effective than sodium valproate (42% vs. 66%) as first-line treatment for convulsive status.⁷

COMMENTARY

Historically, benzodiazepines have been the mainstay as initial treatment for convulsive status. The superiority of lorazepam was demonstrated nicely in the Veteran’s Affairs Cooperative Study initially published in 1998 by David Treiman. Two decades later, the mainstay of first-line treatment has not changed. However, 20 years later, there is still no evidence-based rationale regarding the use of second-line agents in SE. The waters are even murkier regarding refractory status epilepticus, defined as failure of second-line agents. The authors of this paper challenged the widespread use of an established agent (phenytoin) as second-line treatment in an era of evidence-based medicine. To date, the largest RCT using phenytoin as a second-line agent after demonstrated benzodiazepine failure suffers from a relatively small treatment population (n = 50).¹ Hence, the authors have concluded accurately that the overall evidence favoring the use of phenytoin as second-line treatment for status is relatively weak. Yet, the evidence for other IV options such as valproic acid, levetiracetam, and lacosamide are even more limited. Nonetheless, as SE continues, there is progressive reduction of available synaptic GABA receptors, leading to less GABA-mediated inhibition and need for a potential alternative mechanism of action. The exact role for the second-generation IV anticonvulsants remains to be seen. The promise of an answer may come shortly with the conclusion of the ESETT (Established Status Epilepticus Treatment Trial) study comparing valproic acid, levetiracetam, and fosphenytoin in benzodiazepine refractory status.

REFERENCES

1. Agarwal P, Kumar N, Chandra R, et al. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure 2007;16:527-532.
2. Chakravarthi S, Goyal MK, Modi M, et al. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci 2015;22:959-963.
3. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792-798.
4. Sreenath TG, Gupta P, Sharma KK, Krishnamurthy S. Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2010;14:162-168.
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7. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: A pilot study. Neurology 2006;67:340-342.
8. Gilad R, Izkovitz N, Dabby R, et al. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin. Acta Neurol Scand 2008;118:296-300.