Assistant Professor of Clinical Neurology, New York Presbyterian/Weill Cornell Medical College

Dr. Chuang reports he receives research funding from UCB and Eisai.

SYNOPSIS: Intravenous lacosamide was found to be noninferior to fosphenytoin in the treatment of nonconvulsive seizures in a prospective, multicenter, randomized clinical trial.

SOURCE: Husain AM, Lee JW, Kolls BJ, et al; for the Critical Care EEG Monitoring Research Consortium. Randomized trial of lacosamide vs fosphenytoin for nonconvulsive seizures. Ann Neurol 2018;83:1174-1185. doi: 10.1002/ana.25249.

Nonconvulsive seizures (NCS) are seizures that can be identified only with electroencephalography (EEG) because of an absence of obvious clinical correlation. Up to 21% of patients monitored with continuous EEG in the intensive care unit have been found to have NCS.¹ The presence of NCS is associated with worse overall outcome, and experts recommend treating NCS with multiple trials of nonsedating anti-seizure drugs (ASD) before moving on to anesthetic agents. Fosphenytoin (fPHT), the prodrug of phenytoin, is an ASD that long has been used in treatment of NCS, whereas lacosamide (LCM) is a newer ASD with recent data suggesting its role in treating NCS. Husain et al compared an intravenous (IV) formulation of LCM and fPHT to determine if IV LCM is noninferior to IV fPHT.

The authors performed a prospective, multicenter (12 centers), randomized clinical trial in which they recruited patients monitored with continuous EEG (cEEG) who had a nongeneralized convulsive seizure. Patients were randomized to receive either IV LCM or IV fPHT. The study also included a crossover phase in which the other study ASD was added if seizures persisted on the first study ASD. Patients were excluded if they already were taking the study ASD or phenytoin, had anoxic encephalopathy, were undergoing hypothermia protocol, or did not have at least 16 hours of cEEG following ASD administration. The cEEGs were read on site by one blinded reader, and NCS was determined using previously established criteria.² The direct caregivers were not blinded to which ASD the patients received. The cEEG later was transferred to a central site where it was reviewed by two blinded readers for seizure burden.

Sixty-two patients completed the study, of which there were 30 in the LCM arm and 32 in the fPHT arm. The demographics of both arms were similar, and there was no statistical difference in baseline seizure burden prior to treatment. The authors found that 63.3% of the LCM arm and 50% of the fPHT arm became seizure-free after the study ASD was administered, which was statistically significant for noninferiority of LCM compared to fPHT (P = 0.02) but not superiority of LCM over fPHT (P = 0.29). Baseline seizure burden also was found to be reduced by 98% in the LCM arm vs. 76% in the fPHT arm, but it did not reach statistical significance (P = 0.129). No significant differences were seen during the crossover phase and incidence of adverse events between LCM and fPHT.

The authors found that IV LCM was noninferior to IV fPHT in the treatment of NCS and that there was no significant difference in adverse events. A limitation to the study included the potential bias to recruit subjects during working hours when study coordinators are more likely to be available. In addition, this was not a true blinded study since only the EEG reader was blinded. Finally, there was no placebo arm; it is possible some of the NCS would have self-resolved, but given that treatment of NCS is standard of care, it is not possible to have a placebo arm. Authors also noted the study specifically excluded NCS lasting more than 30 minutes; thus, the question of IV LCM vs. IV fPHT was not assessed in that group.

COMMENTARY

Currently, both IV LCM and IV fPHT are used for treatment of NCS, but no one has performed a head-to-head comparison until now. The authors showed that LCM is just as good an option as fPHT. In fact, LCM had a higher seizure cessation rate, and perhaps a larger sample size would have shown statistical superiority. Of interest, adverse events were similar between the two groups despite prior studies suggesting LCM may have a superior adverse event profile. In light of these results, the decision about which ASD to use needs to be determined based on the clinical situation. The advantage of LCM is that it has a favorable drug interaction profile compared to fPHT. The benefit of fPHT is that patients can be discharged on oral phenytoin, which is more affordable and thus patients are more likely to be compliant.

In addition to the limitations raised by the author, this study likely overestimated the efficacy of LCM and fPHT because patients were monitored on cEEG for only 24 hours after the study ASD was administered. A previous study showed that 12% of NCS occurs after the first 24 hours.³

Further prospective studies comparing the efficacy of ASD in NCS are needed in this field, as administering the most effective ASD theoretically would give the highest chance of NCS cessation in the shortest time possible, which hopefully will translate to better outcomes.

REFERENCES

1. Swisher CB, Shah D, Sinha SR, Husain AM. Baseline EEG pattern on continuous ICU EEG monitoring and incidence of seizures. J Clin Neurophysiol 2015;32:147-151.
2. Chong DJ, Hirsch L. Which EEG patterns warrant treatment in the critical ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol 2005;22:79-91.
3. Claassen J, Mayer SA, Kowalski RG, et al. Detection of electrographic seizure with continuous EEG monitoring in critically ill patients. Neurology 2004;62:1743-1748.