Neurology -- Correspondence for Misra et al., 67 (2) 340-342

Correspondence published:

Sodium valproate vs phenytoin in status epilepticus: A pilot study: Andrea O. Rossetti (19 September 2006)

Reply from the Authors: Usha Kant Misra, Kalita, DM, R Patel, DM, Department of Neurology, Sanjay Gandhi PGIMS, Lucknow (19 September 2006)

Sodium valproate vs phenytoin in status epilepticus: A pilot study 19 September 2006

Andrea O. Rossetti,
Service de Neurologie
CHUV BH-07, CH-1011-Lausanne, Switzerland
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Re: Sodium valproate vs phenytoin in status epilepticus: A pilot study

andrea.rossetti{at}chuv.ch Andrea O. Rossetti

Misra et al should be commended for performing a randomized study comparing the treatment of status epilepticus with phenytoin (PHT) and valproic acid (VPA). [1] Very few trials have addressed this issue and all of them investigated the first-line treatment, mainly with benzodiazepines.
However, there are some concerns. Firstly, although VPA or PHT are generally used as second-line treatment according to most recent guidelines [2], in the current study they were prescribed as first-line agents. This does not reflect clinical practice. Secondly, the sample size calculation appears peculiar: running the calculation with the same data, with a two-sided test and a relative difference in efficacy of 20%, one is given a result of 807 subjects. [3] The use of a two-sided test is mandatory in this setting, as the authors cannot predict a priori which treatment will be superior to the other. This is also true for the analysis of the primary outcome: a 2-sided Fisher exact test gives a p of 0.088. [4]
Under these conditions, it appears misleading to state that the study shows that VPA was more effective than PHT. [1] A more correct interpretation might be that, considering that the study was underpowered, a tendency towards better efficacy of VPA was found. Finally, as a tolerability measure, it may be interesting to add the incidence of VPA encephalopathy. [5]
These considerations illustrate the difficulty of recruiting a suitable sample size to study the pharmacological treatment of status epilepticus, and reinforce the need for a large, collaborative multicenter trial.
References
1. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 2006;67:340-342.
2. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol 2006;13:445-50.
3. http://stat.ubc.ca/~rollin/stats/ssize/b2.html, accessed July 25 2006.
4. http://www.matforsk.no/ola/fisher.htm, accessed July 25 2006.
5. Rossetti AO, Bromfield EB. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005;65:500-1; author reply 500-501.
Disclosure: The authors report no conflicts of interest.

Reply from the Authors 19 September 2006

Usha Kant Misra,
Professor & Head, Department of Neurology
Rae Bareily Road,Lucknow 226014, INDIA,
Kalita, DM, R Patel, DM, Department of Neurology, Sanjay Gandhi PGIMS, Lucknow
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Re: Reply from the Authors

drukmisra{at}rediffmail.com Usha Kant Misra, et al.

We appreciate Dr. Rossetti's comments. Our choice of reference and study drugs was based on the possibility of drugs not only in aborting status epilepticus (SE) but also to continue the same drug as maintenance therapy for preventing seizure recurrence.
Regarding the sample size and statistical power of the study, we agree that our sample size is rather small; therefore we have used one-sided P values. Our preliminary results are suggestive of better efficacy of valproate (VPA) than phenytoin (PHT). Because of this limitation, we designated this as a pilot study and have concluded that our results need confirmation in a larger study.
It is ironic that there is no sufficiently large randomized controlled trial (RCT) to evaluate the role of VPA in SE in spite of approval of intravenous VPA by FDA in 1996. This is probably due to lack of interest of pharmaceutical companies and sponsoring agencies. Under these circumstances, small, well-conducted studies should be published and results subjected to meta analysis to obtain valid conclusions.
The efficacy of all the drugs used in SE is limited by their side effects. Phenytoin results in hypotension in 27%, cardiac arrhythmias in 6.9% and hypoventilation in 9.9% in patients with convulsive SE. The frequency of these side effects is similar to those following lorazepam. [6] In contrast, VPA has better tolerability and safety. In 318 patients receiving about 2200 doses of VPA, there was no cardiovascular or respiratory complications. [7] We found one patient had hypoventilation and three had raised transaminase levels but none had VPA encephalopathy.
Valproate encephalopathy is a concern because of several case reports and short series of encephalopathy following VPA, especially in conjunction with topiramate. [8] Children with carnitine deficiency and those with urea cycle enzyme defects are more prone to VPA encephalopathy and need close monitoring. No case of VPA encephalopathy was reported in various prospective and retrospective studies on children [9] or adults [10] with SE receiving intravenous VPA. However, patient receiving VPA, if consciousness is not improved after cessation of SE should be carefully monitored clinically and biochemically for possible continued subtle SE and VPA encephalopathy.
References
6. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998; 339: 792-798.
7. Devinsky O, Leppik I, Willmore LJ, et al. Safety of intravenous valproate. Ann Neurol. 1995;38:670-674.
8. Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate induced hyperammonemic encephalopathy in the presence of topiramate. Neurology 2000; 54:230-233.
9. Uberall MA, Trollmann R, Wunsiedler U, Wenzel D. Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology 2000;54:2188-2189.
10. Limdi NA, Shimpi AV, Faught E, Gomez CR, Burneo JG. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005;64:353-355.
Disclosure: The authors report no conflicts of interest.