Is it a Tie at This Point in the Game? Efficacy of Levetiracetam and Phenytoin for the Second-Line Treatment of Convulsive Status Epilepticus.

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Commentary

Convulsive status epilepticus (CSE) is a medical emergency which is now formally defined as a tonic–clonic convulsion lasting >5 minutes.[1] Older consensus-based guidelines on the initial treatment of SE[2] have been replaced with modern evidence-based guidelines.[3-5] The medications recommended in the American Epilepsy Society (AES) guideline[3] for the initial treatment of CSE are to first give a bolus of intravenous (IV) lorazepam or diazepam, or IV or intramuscular midazolam, and second to administer a bolus of IV phenytoin/fosphenytoin (PHT) 20 mg PE/kg (maximum, 1500 mg), valproic acid (VPA) 40 mg/kg (maximum, 3000 mg), or levetiracetam (LEV) 60 mg/kg (maximum, 4500 mg).

The AES guideline on the treatment of CSE[3] reviewed the published literature through April 2015. It indicated that in adults, “there is no difference in efficacy between IV lorazepam followed by IV PHT, IV diazepam plus PHT followed by IV lorazepam, and IV phenobarbital followed by IV PHT (level A).” It further indicated that, “insufficient data exist in adults about the efficacy of LEV as either initial or second therapy (level U)”, and that, “insufficient data exist in children regarding the efficacy of PHT or LEV as second therapy after failure of a benzodiazepine (level U).”[3] The randomized controlled trial (RCT) supporting the use of LEV for the treatment of CSE was a single open-label class III study in adults and children.[6] With respect to children, this study found that as the first therapy, the success rate of lorazepam (76.3%) was similar to that of LEV 20 mg/kg (75.6%).[6] Given the low level of the evidence behind the recommendations for second-line therapy, the AES guideline recommended that a class I RCT be conducted.[3]

Since April 2015, additional studies have been published on the use of LEV and PHT in the treatment of CSE after an initial benzodiazepine. Mundlamuri et al[7] published a class II RCT comparing LEV 25 mg/kg, PHT 20 mg/kg, and VPA 30 mg/kg in adults with CSE who also received lorazepam. There was no efficacy difference in the subgroups (P = .44). Chakravarthi et al[8] published a class II RCT of patients aged 14 to 75 years who first received lorazepam, and secondly received PHT or LEV, both at 20 mg/kg. Phenytoin controlled SE in 68.2% and LEV controlled SE in 59.1% of patients (N.S.). A limitation in the above 3 studies is that the LEV doses selected were probably too low.

Navarro et al[9] conducted a class I superiority RCT comparing 68 adults who received 2.5 gm of LEV to 68 who received placebo after an initial dose of 1 to 2 mg of clonazepam for either CSE or acute repetitive seizures. There was no difference in seizure control 15 minutes after receiving LEV (74%) or placebo (84%). This study[9] indicates that as second-line therapy for CSE, LEV is no more effective than placebo. Finally, Gujjar et al[10] found in a group of 52 patients with mixed focal and CSE, treated initially with lorazepam or diazepam, that the efficacy of LEV 30 mg/kg or PHT 20 mg/kg was similar (82% vs 70%, respectively; P = .33).

Anti-seizure drugs (ASDs) can fail to be effective when inadequate doses are used. In pharmacokinetics, a loading dose for an IV drug is defined by the formula: DL = Vd × Css (DL = loading dose in mg/kg, Vd = volume of distribution, Css = steady state serum concentration). The Vd of PHT is 0.64 L/kg, LEV is 0.5 to 0.7 L/kg and VPA is 0.22 L/kg. When one is researching the comparative efficacy of different ASDs, appropriate comparable loading doses must be utilized. Therefore, it follows that larger doses of LEV and VPA than used in these past trials should be investigated.

The 2 new RCTs reviewed herein, published in the May 29, 2019 issue of The Lancet, were quite similar in design, and indeed used larger loading doses of LEV than older studies. They included children ranging from infancy to adolescence, compared the same 2 ASDs delivered with the same doses over the same duration, and were the first ASD used after failure of an initial benzodiazepine to control CSE. Both studies were conducted in regions where patients were mostly of Caucasian descent.

The EcLiPSE open-label RCT in the United Kingdom was a class II study comparing second-line treatment with loading doses of IV LEV at 40 mg/kg and IV PHT at 20 mg/kg in 286 children. Convulsive status epilepticus was terminated slightly more often and faster with LEV than with PHT (P = .20), and serious adverse effects (AEs) occurred with PHT (life-threatening hypotension, worsened focal seizures, and decreased level of consciousness).

The ConSEPT open-label RCT in Australia and New Zealand was also a class II study, and compared second-line treatment with loading doses of IV LEV at 40 mg/kg and IV PHT at 20 mg/kg in 352 children. Clinical cessation of CSE 5 minutes after the completion of the loading dose occurred in 60% of children in the PHT group and 50% in the LEV group (P = .16), and there were no serious AEs.

Using the classification of evidence scheme of the American Academy of Neurology,[11] these 2 newest RCTs meet the criteria for class II studies; they are not class I because of their open-label designs. The fact that these 2 studies were consistent in showing that the efficacy of LEV and of PHT is not significantly different allows this conclusion: following administration of a benzodiazepine, IV loading doses of LEV 40 mg/kg and PHT 20 mg PE/kg are probably equally effective in the treatment of children with CSE (Level B).

The Established Status Epilepticus Treatment Trial is a randomized, triple-masked class I trial funded by the United States National Institutes of Health to compare IV fosphenytoin 20 mg PE/kg, VPA 40 mg/kg, and LEV 60 mg/kg in children greater than age 2 years and adults with CSE which does not respond to initial treatment with an adequate dose of a benzodiazepine (NCT01960075). Assignment to a treatment arm is adaptive in order to optimize identification of the most and least effective drug. The doses studied are the same as recommended in the ASD guideline for the treatment of CSE.[3] The Established Status Epilepticus Treatment Trial began in October 2015, is closed to new patients, and has enrolled 478 participants. It is expected to reach completion in October 2019. As a class I study, the results will perhaps provide final evidence of the efficacy and tolerability of these 3 agents at full loading doses in the second-line treatment of both adults and children with CSE.