Monday, January 7, 2013

Post traumatic seizure prophylaxis - Phenytoin

Our current therapeutic interventions that are directed at mitigating the damage of secondary injuries after TBI (ischemia, brain edema, vasospasm and seizures) lack robust data supporting their use. For clinicians in the ED, it’s difficult to make sound therapeutic decisions to help the patient and the team.  Although these are difficult areas to study, we never the less still need to make the best decisions we can.

Posttraumatic seizures (PTS) are seizures that occur after TBI are one of those gray areas of therapeutics. It seems logical to attempt to prevent PTS; it can cloud the neurologic evaluation, aggravate intracranial pathology, and, in some patients, be the precipitating event that leads to herniation—in part because seizures are accompanied by changes in oxygen delivery and CBF, altered blood pressure, and increases in ICP. But since PTS only occurs in approximately 15% of patients with blunt severe, and that antiepileptic drugs (AED) therapy is certainly not benign - risk factors have been identified to provide PTS prophylaxis in appropriate patients.  The BTF guidelines suggest that AEDs are indicated to decrease the incidence of EARLY PTS in patients with one or more PTS risk factors. The BTF guidelines go on to only suggest phenytoin as the preferred first line agent.  A stronger recommendation isn’t possible because, again, there is little robust data to go on.

I wont say phenytoin has been extensively studied in this field, but it is the most studied AED for PTS prophylaxis and its data is the most favorable.

From a meta-analysis conducted by Temkin, phenytoin demonstrated a favorable and significant risk reduction for early seizures, but not for late seizures. And as you can see it and CBZ were the only agents (alone or in combination) that demonstrated a benefit in early seizures.  The use of carbamazepine is limited because it does not have an IV formulation and valproic acid, though a proposed alternative, is not recommended to be used since, when compared to phenytoin has been shown to increase the incidence of late seizures and trend towards worse mortality.

One of, if not the best piece of evidence we’ve got with phenytoin for prevention of phenytoin was conducted back in 1990. The investigators randomized patients to phenytoin or placebo for PTS for one year after serious TBI.  Compared to placebo, patients given phenytoin suffered fewer early seizures compared to placebo.

This risk reduction reached significance for early seizures [RR 0.27 (0.12-0.62)] but no difference for late seizure, or mortality.  ADRs, predomninantly rash cause more patients in the phenytoin arm to discontinue treatment early compared to placebo, but overall, what this study provided was that it added to the data regarding the benefit of phenytoin compared to placebo in preventing early phenytoin and that no benefit exists after 7 days,

Now, yes, this trial was conducted 22 years ago, very little robust data has been published to add or challenge the results of this trial. Small single center studies, case reports are what we’ve got to go on, and the meta-analyses of all these studies again, do little to add or challenge the results of this trial.

In the September issue of Neuro critical care, there was a great series of articles discussing Emergency Neurological Life Support by a number of ED and Neuro physicians (one of those being S Weingart) covered PTS for TBI. This modern, up-to-the-minute review they recommended phenytoin for first line treatment of PTS in appropriate sTBI patients, citing the 1990 Temkin NEJM article reflecting the lack of good, recent data.

Having newer AEDs on the market now compared to 1990, begs the question whether there is a better alternative AED for PTS

In the article, Weingart and his colleagues gave just a one-liner regarding a potential alternative to phenytoin for PTS. That AED is levetiracetam.
Again, since it’s not 1990 anymore, we now know more about the intracranial pathophysiology that occurs after TBI. Looking closer, on a cellular and molecular level, current therapeutic targets under evaluation aim to minimize activation of toxic pathways and to enhance activity of endogenous neuroprotective mechanisms and establishing a balance between these pathways.

It’s been proposed that the reason why the previously studied AEDs have failed to show benefit is that 1) they do not address these mechanisms, being devoid of antiepilepogentic properties (actually preventing seizures rather than just preventing the propagation of localized seizure activity) and 2) are not given at an optimal dose as soon after the primary injury as possible.

Since we know that valproic is probably not the best agent to investigate, levetiracetam is one AED that has been identified to have these properties.

More to come next week.

1.     Bratton SL, et al. Guidelines for the Management of Severe Traumatic Brain Injury, 3rd edition: Antiseizure prophylaxis. Journal of Neurotrauma 2007;24(S1):S82-S86
2.     Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 2001;42(4): 515-524
3.     Temkin NR, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. NEJM 1990;323(8):497-502
4.     Jensen FE. Posttraumatic epilepsy: Treatable epileptogenesis. Epilepsia, 50(Suppl. 2):1-3, 2009
5.     Benardo LS. Prevention of epilepsy after head trauma: Do we need new drugs or a new approach. Epilepsia 2003;44(Suppl. 10):27-33

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