Lacosamide as Adjunctive Therapy in Nonconvulsive Status Epilepticus

Abstract & Commentary

By Padmaja Kandula, MD, Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College of Cornell University. Dr. Kandula reports no financial relationships relevant to this field of study.

Synopsis: The authors report a small, retrospective case series using low-dose intravenous lacosamide in the successful, adjunctive treatment of nonconvulsive status epilepticus.

Sources: Koubeissi MZ, et al. Efficacy and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus. Acta Neurol Scand DOI: 10.1111/j.1600-0404.2010.01430.x _ 2010.

Although overt convulsive status epilepticus has deservedly received wide spread attention due to systemic complications, nonconvulsive status epilepticus (NCSE) has become increasingly recognized in both comatose and noncomatose patients. As such, the ideal medication for nonconvulsive status should be intravenous, relatively free of drug interactions, and non-sedating. Lacosamide, already approved for adjunctive partial seizures in adults, meets the above three criteria, suggesting a potential role in the treatment of nonconvulsive status.

The authors of this paper report on their experience with intravenous lacosamide in the treatment of NCSE. The records of all patients with refractory nonconvulsive status epilepticus were reviewed at University Hospitals Case Medical Center (Cleveland). Four patients were identified who were treated with lacosamide and underwent continuous video EEG monitoring. EEG traces were blindly reviewed to confirm onset and offset of nonconvulsive status. Both general and neurologic examinations were performed before and after administration of intravenous lacosamide. All four patients were found to have medically resistant focal NCSE despite treatment with varying doses and combinations of lorazepam, levetiracetam, fosphenytoin, and enteral pregabalin. Intravenous lacosamide was administered between 3 and 50 hours after known diagnosis of NCSE. Side effects were recorded by patient-reported diary. Pre- and post-PR intervals were calculated after infusion of lacosamide.

Patient #1 presented with new onset prolonged convulsion and subsequent depressed mental status despite 2 mg of lorazepam and 1,000 mg fosphenytoin. Continuous electroencephalographic recording (cEEG) revealed nearly continuous left hemispheric ictal activity. An additional 2 g of levetiracetam and enteric 300 mg pregabalin were administered. Ictal activity persisted nearly 24 hours later, prompting intravenous infusion with low-dose (50 mg) lacosamide. There was electrographic cessation of ictal activity nearly 30 minutes after intravenous infusion. The patient returned to baseline neurologic status with eventual 100 mg twice daily maintenance dosing of lacosamide. No seizure recurrence occurred during subsequent 48 hour cEEG recoring.

Patient #2 presented with new onset symptomatic right hemispheric seizures in the setting of an acute right subdural hemorrhage. Two milligrams of lorazepam and three grams of intravenous levetiracetam were administered without seizure cessation. Subsequently, 100 mg of iv lacosamide was infused with reduction of electrographic seizures from 5 per hour to 1 every 2 hours. Intravenous maintenance lacosamide was escalated to 200 mg twice daily with improvement in seizure frequency to 3 per day.

Patient #3 presented initially with new onset seizures and electroclinical correlate in the setting of atypical recurrent right fronto-parietal meningioma. Seizures were characterized initially by focal facial clonic movements, vocalizations, and excessive salivation. Low-dose levetiracetam was initiated at 500 mg twice daily. Electroclinical seizures were replaced with electrographic seizures (recorded on cEEG) without clinical correlate from the right frontocentral region. Ictal activity persisted despite 4 mg of intravenous lorazepam and further escalation of levetiracetam to 4 grams per day. After a 15-minute infusion of 100 mg of intravenous lacosamide, complete cessation of ictal activity was noted.

Patient #4 presented with left hemibody clonic movements in the setting of a remote right sided hemorrhagic stroke. The patient was given rapid sequence lorazepam (6 mg), followed by fosphenytoin load, and increase in maintenance levetiracetam. Intravenous lacosamide was added after failure to control seizures, with cessation of ictal events within 2 hours of intravenous lacosamide infusion. The patient remained seizure-free on adjunctive maintenance lacosamide of 100 mg bid.

Commentary

Similar to levetiracetam, lacosamide is relatively free of drug interactions and has a good safety profile, both useful qualities in treating critically ill patients in a timely fashion. Although the preliminary experience of these authors is optimistic, only patient #4 truly met criteria for refractory partial non-convulsive status. Patients #1 and #2 received suboptimal benzodiazepine therapy. Patients #2 and #3 received subsequent levetiracetam, instead of the usual hydantoin load after benzodiazepine treatment.

Despite the obvious small numbers in this retrospective clinical case series, it is interesting that sustained cessation of ictal activity occurred in all 4 patients with a modest dose of lacosamide, suggesting that agents with different mechanisms of action may be useful in combating partial status. There is accumulating evidence at the receptor level that as time marches on, GABAergic mechanisms fail and seizures become drug-resistant, further emphasizing the waning utility of benzodiazepine effectiveness at the GABAA receptor over time.

Further large-scale studies are needed to define lacosamide's role in nonconvulsive status epilepticus. Lacosamide, with a novel mechanism of action and favorable pharmacokinetics, potentially may be useful in nonconvulsive status, particularly where it is desirable to avoid mechanical intubation.