Efficacy and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus

Authors


Mohamad Z. Koubeissi, Department of Neurology, University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5040, USA
Tel.: (216) 844 1764
Fax: (216) 983 3153
e-mail: mohamad.koubeissi@uhhospitals.org

Abstract

Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus.
Acta Neurol Scand: 2011: 123: 142–146.
© 2010 John Wiley & Sons A/S.

Background –  Lacosamide (LCM) is a novel antiepileptic drug (AED) recently approved as an adjunctive therapy in the treatment of partial seizures in adults. LCM is available in oral and intravenous formulations, has linear pharmacokinetics and a unique mechanism of action.

The aim of this study –  To evaluate the safety and efficacy of intravenous LCM in the treatment of nonconvulsive status epilepticus (NCSE) after failure of conventional therapy.

Methods –  We retrospectively reviewed all patients with NCSE treated with LCM. We reviewed the clinical and electrographic changes before and after LCM administration. We also noted any reported side effects including electrocardiographic changes.

Results –  We report four cases of NCSE that were refractory to conventional treatment, but readily responsive to LCM. No side effects attributable to LCM were identified.

Conclusions –  Intravenous LCM may be safe and efficacious as an add-on AED for the treatment of NCSE when standard therapy fails.

Introduction

Status epilepticus (SE) is a common neurologic condition characterized by prolonged or repetitive seizures without intervening recovery of consciousness. SE is divided into convulsive (CSE) and nonconvulsive status epilepticus (NCSE). CSE is a life-threatening condition requiring emergent treatment with intravenous antiepileptic drugs (AEDs) and mechanical ventilation (1). In contrast, NCSE usually carries a lower risk of morbidity and mortality favoring a less invasive approach (2, 3).

Established AEDs for the initial treatment of SE consist of benzodiazepines, phenytoin, and phenobarbital (4). Intravenous (IV) anesthetics such as propofol or pentobarbital have also been widely used for refractory CSE. Unlike GSE, the treatment of NCSE does not usually warrant as much an aggressive and emergent approach. Thus, AEDs with relatively low potential for adverse events constitute a more favorable strategy in treating patients with NCSE.

Lacosamide (LCM) is a new AED, recently approved in the United States and Europe as an adjunctive therapy in adults with partial-onset seizures (5). It has a favorable side effect profile and is available in IV formulation. It also has linear pharmacokinetics and low potential for drug–drug interaction, making it a potentially appealing treatment choice for patients with NCSE.

We report four cases of NCSE successfully treated with intravenous LCM, suggesting a possible role of LCM in the treatment of this condition.

Methods and results

We retrospectively reviewed all adult patients treated with LCM for refractory NCSE at University Hospitals Case Medical Center. We found four female patients who received LCM and were admitted to the neuroscience intensive care unit (ICU). Continuous video-electroencephalogram (EEG) monitoring (cEEG) was performed and reviewed on all four patients to confirm the diagnosis of NCSE and monitor response to treatment. This was performed by blinded reviewer (NA) who determined the time of cessation of NCSE based on the EEG, with no knowledge about the administration of medications. General and neurologic examinations were also reviewed before and after the administration of IV LCM.

All patients were found to have resistant focal NCSE pattern despite treatment with IV lorazepam, IV fosphenytoin, IV levetiracetam, and enteral pregabalin. IV LCM was administered between 3 and 50 h after the onset of NCSE. Safety of IV LCM was concluded from reported absence of side effects noted in patients’ record. In addition, we sampled five P–R intervals on electrocardiograms before and five intervals after administration of LCM and calculated their means for comparison, as an objective measure of electrocardiographic side effects (Table 1).

Table 1.   Baseline patient demographics, seizure history, and NCSE management data
 Patient 1Patient 2Patient 3Patient 4
  1. AED, antiepileptic drug; NCSE, non-convulsive status epilepticus; LRZ, lorazepam; LEV, levetiracetam; PGB, pregabalin; LCM, lacosamide; FOS, fosphenytoin; VPA, valproic acid.

Age/Gender53/F79/F64/F66/F
Prior history of seizuresNoNoNoYes
AEDs at baseline (doses per day)LEV 2000 mg
VPA 1000 mg
Seizure localization during NCSELeft hemisphericRight hemisphericRight fronto-central regionRight hemispheric
NCSE etiologyLeft frontal hemorrhageRight subdural hemorrhageRight fronto-parietal meningiomaRight temporal encephalomalacia
AEDs and total doses used to treat NCSELRZ 2 mg
FOS 1500 mg
LEV 4000 mg
PGB: 600 mg
LRZ 2 mg
LEV 2000 mg
LRZ 4 mg
LEV 5000 mg
LRZ 6 mg
FOS 1000 mg
LEV 3000 mg
VPA 1000 mg
LCM initial dose50 mg100 mg100 mg100 mg
Time of LCM dose since NCSE onset50 h32 h36 h3 h
Time from LCM dose to seizure control30 min2 h15 min2 h
Mean PR interval before LCM (ms)137 ± 0130 ± 5126 ± 3130 ± 4
Mean PR interval after LCM (ms)131 ± 3128 ± 3126 ± 3137 ± 9
LCM maintenance dose100 mg twice daily200 mg twice daily100 mg twice daily200 mg twice daily
Confirmed duration of NCSE resolution after LCM initiation48 h2 h48 h24 h

Patient 1. A 53- year-old woman, with history of deep venous thrombosis and liver cirrhosis related to hepatitis C infection, had no prior history of seizures. She was brought to the emergency department (ED) because of a witnessed generalized tonic-clonic seizure lasting 10 min followed by another similar seizure. In the ED, she was lethargic, typical of a post-ictal state. Her blood work revealed liver failure and thrombocytopenia. She was given IV lorazepam (2 mg) and fosphenytoin (1000 mg) and transferred to the ICU. Her CT scan showed an intraparenchymal hemorrhage in the left frontal region measuring 2.4 × 1.9 cm.

In the ICU, her mental status remained depressed and cEEG revealed continuous left hemispheric focal seizures (Fig. 1A). IV levetiracetam (2000 mg) and enteric pregabalin (300 mg) were given and continued twice daily. NCSE persisted and the patient remained obtunded for the next day despite therapy with fosphenytoin (with target range levels), levetiracetam, and pregabalin. IV LCM was initiated at 50 mg with total resolution of seizure activity within 30 min. The patient’s mental status returned to baseline shortly after seizure cessation (Fig. 1A). There was no seizure recurrence for the next 48 h of cEEG while on IV LCM (200 mg/day).

Figure 1.

 A–D are EEG samples of patients 1–4, respectively, before (left) and after (right) the administration of IV lacosamide, showing electrographic resolution of NCSE. All the recordings are displayed using the longitudinal bipolar montage according to the international 10–20 system.

Patient 2. A 79-year-old woman with Parkinson’s disease and no history of epilepsy was admitted after a fall and left hemiparesis. Her brain MRI showed a right subdural hemorrhage. Clinically, the patient was confused. Her cEEG recorded about five right hemispheric seizures per hour. She received IV lorazepam (2 mg) and was started on IV levetiracetam (1500 mg twice daily). Her cEEG showed persistent right hemispheric seizures, averaging 2–3 seizures per hour, and her mental status remained depressed. Then, IV LCM (100 mg) was administered with significant reduction in seizures to one every two hours, with progressive recovery of baseline mental status. The following day, her IV LCM dose was increased to 200 mg twice a day with further reduction in seizure frequency to three per day and remarkable normalization of her mental status.

Patient 3. A 64- year-old woman with history of recurrent atypical right frontoparietal meningioma had multiple resections and several cycles of radiation for tumor recurrence. She had mild left-sided hemiparesis, but no history of seizures. During hospitalization for the management of deep venous thrombosis, she suddenly became unresponsive with left face twitching, repetitive vocalizations, and increased salivation. Oral levetiracetam (500 mg twice daily) was started. The patient remained obtunded. Her cEEG revealed recurrent electrographic seizures and periodic lateralized epileptiform discharges (PLEDs) from the right fronto-central region. IV lorazepam (4 mg) was given, and IV levetiracetam was increased to 1500 mg then 2000 mg twice daily. Seizures continued to be frequent and the patient remained obtunded. Then, IV LCM (100 mg) was started with the complete resolution of seizures within 15 min (Fig. 1C). She progressively regained her baseline mental status and LCM was continued at 100 mg twice daily with no seizure recurrence.

Patient 4. A 66- year-old woman has a known history of epilepsy attributed to a prior right-sided hemorrhagic stroke. Her seizures always consisted of focal SE manifesting as left face and arm clonic movements with alteration of awareness, averaging once per year and lasting 2–8 h. Her baseline AEDs included levetiracetam (1000 mg twice daily) and valproic acid (500 mg twice daily). She presented with NCSE, which was initially treated successfully with IV lorazepam (total of 6 mg), IV fosphenytoin load (1000 mg), increased dose of IV levetiracetam (1000 mg), and continued valproic acid. However, she had respiratory depression requiring sedation with propofol and mechanical ventilation. Two days after extubation, she was found confused with left hemineglect and left homonymous hemianopsia. Her cEEG showed recurring right hemispheric seizures consistent with her typical NCSE. As she had already been maintained on phenytoin, valproic acid (both within target range levels), and levetiracetam, the decision was to add IV LCM (100 mg) in an attempt to control the seizures. Her NCSE was electrographically aborted after 2 h of LCM initiation and was replaced with intermittent right hemispheric PLEDs (Fig. 1D). Her mental status progressively returned to baseline with no recurrence of seizures on maintenance dose of LCM (100 mg twice daily).

Discussion and conclusions

In this series, we report four cases of refractory NCSE successfully treated with IV LCM. Cessation of NCSE was confirmed both electrographically and clinically. There were no adverse events attributed to IV LCM, including allergic reactions, cardiac, or respiratory problems. There were no ECG abnormalities. P-R intervals did not differ before (130 ± 5 ms) and after (129 ± 3 ms) LCM infusions (P = 0.8571, Wilcoxon two sample test). We conclude that LCM may be safe and efficacious alternative in the treatment of refractory NCSE. This corroborates the conclusions of an earlier report of successful treatment of NCSE with IV LCM (6) and another report of successful treatment of CSE with non-parenteral LCM (7).

NCSE was aborted in all four patients within 15–120 min of administration of IV LCM. The time between onset of NCSE and initial dose of LCM was variable ranging 3–50 h. This may suggest that LCM efficacy is probably independent of ongoing SE time or refractoriness. In addition, the effective initial and maintenance LCM dose was either 50 or 100 mg, but since 100 mg did not cause any adverse reactions, the use of this higher dose may be preferred in NCSE. Of note, all four patients had symptomatic SE caused by a known structural lesion. This is probably a coincidence and does not necessarily signify selective efficacy of LCM in lesional NCSE.

All four patients received other AEDs prior to LCM with no resolution of NCSE. The choice or order of use of these AEDs did not necessarily follow recommended treatment guidelines of SE (8). For example, patient 1 and 2 received suboptimal doses of lorazepam, patient 2 and 3 received levetiracetam, rather than hydantoins, after benzodiazepine failure, and patient 1 received pregabalin, due, in part, to liver failure. None of the patients received barbiturates. The treatment approach did not follow ‘standard’ AED sequencing but rather consisted of repeated small doses of benzodiazepines and chronic IV AED therapy. The aim was to avoid potential respiratory and cardiovascular compromise of certain AEDs in patients with significant comorbidities (patients 1–3) or to avoid re-intubation (patient 4). This unorthodox strategy was however informative in proving that LCM may be more effective in treating SE when AEDs with different mechanism of actions have failed. One explanation for this phenomenon is the novel and unique mechanism of action of LCM. Unlike conventional sodium blocking AEDs such as phenytoin or carbamazepine which slow the recovery rate of the fast inactivation of sodium channels, LCM selectively enhances slow inactivation of voltage-gated sodium channel (9, 10).

In conclusion, our promising observations may prompt future studies evaluating the safety and efficacy of LCM in SE on a larger scale, as well as the effective LCM dose and priority of use. LCM, like levetiracetam, carries the advantage of having linear pharmacokinetics, relatively safe side effect profile and availability in IV form. Levetiracetam has been used in SE (11), but its role in SE still needs universal acceptance. LCM, with a new mechanism of action, may gain wider use in treating SE as second-line therapy.

Acknowledgements

The data were presented in part at the 62nd Annual Meeting of the American Academy of Neurology in Toronto, Canada April 2010.

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