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Keywords:

  • Intravenous lacosamide;
  • Seizure clusters;
  • Status epilepticus

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Status epilepticus (SE) and seizure clusters (SC) represent neurologic emergencies with a case fatality rate up to 34%, depending on cause and comorbidity. As SE becomes more refractory to treatment over time, appropriate medication is important. This study aimed to investigate efficacy and tolerability of intravenous (IV) lacosamide (LCM) in treatment of SC and SE. Data of patients with SE or SC who were treated with IV LCM between December 2009 and February 2011 in two Austrian centers were analyzed retrospectively. Clinical information was extracted from patients’ charts. Forty-eight patients (26f/22m) aged median 62 years (range 17–95 years) were identified. Thirty-five percent of patients (17 of 48) had SC and 65% (31 of 48) had SE. SE was nonconvulsive in 10 (32%), convulsive in 11 (36%), and focal in 10 (32%) patients. SE was acute symptomatic in six (20%) and remote symptomatic in 11 (35%) patients. Fourteen (45%) had preexisting epilepsy. Median initial bolus dose was 200 mg (range 200–400 mg) in patients with SE and 200 mg in patients with SC. Maximum infusion rate was 60 mg/min. Cessation was observed in 42 patients (88%). Success rate in patients with SE receiving LCM as first or second drug was 100% (8 of 8), as third drug 81% (11 of 15), and as fourth or later drug 75% (6 of 8). There were no side effects observed except for pruritus and skin rash in two patients. These data support use of IV LCM as a potential alternative to standard antiepileptic drugs for acute treatment of seizure emergency situations, although randomized controlled studies are needed.

Neurologic emergencies such as status epilepticus (SE) and seizure cluster (SC) require urgent and consequent treatment with antiepileptic drugs (AEDs). Current first-line treatment with intravenous (IV) lorazepam will control about 60% of generalized convulsive SE, irrespective of its cause (Treiman et al., 1998; Alldredge et al., 2001). Those who do not respond will need further treatment with other IV AEDs. Although there are no randomized controlled trials in the established stage of SE, IV phenytoin is the most commonly used AED despite its well-known side effects (Litt et al., 1998; Shorvon et al., 2008; Trinka & Shorvon, 2009; Meierkord et al., 2010). The risk of cardiac arrhythmias and hypotension is still one of the major concerns with standard AEDs. Various alternatives such as IV valproate or levetiracetam have been used in clinical practice (Misra et al., 2006; Agarwal et al., 2007; Knake et al., 2007; Mehta et al., 2007; Goraya et al., 2008; Rüegg et al., 2008; Trinka & Dobesberger, 2009; Trinka & Shorvon, 2009). None of the currently available IV AEDs has been assessed in a randomized controlled trial in stage II treatment, and expert recommendations are based on clinical judgement and retrospective case series only.

Lacosamide (LCM) became recently available as an IV solution based on bioequivalence to the oral formulation (Biton et al., 2008; Krauss et al., 2010). LCM is a functionalized amino acid with anticonvulsant properties. It acts by enhancing the slow inactivation of sodium channels. LCM was effective in different rodent seizure models for generalized and complex partial seizures as well as for SE (Beyreuther et al., 2007; Stöhr et al., 2007). Experimental evidence (Stöhr et al., 2007), safety studies in healthy individuals and in patients (Ben-Menachem et al., 2007; Biton et al., 2008; Krauss et al., 2010) as well as first case series with SE in humans (Kellinghaus et al., 2009; Tilz et al., 2010; Albers et al., 2011; Chen et al., 2011; Goodwin et al., 2011; Kellinghaus et al., 2011; Koubeissi et al., 2011; Parkerson et al., 2011) suggest that IV LCM is a potential alternative to common standard treatments in this field. Here we report our first experience of short-term efficacy and safety of IV LCM in the treatment of SC and SE.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

We retrospectively analyzed data of all patients who received at least one dose of IV LCM for treatment of SE or SC between December 2009 and February 2011 in two large Austrian centers [Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University of Salzburg (25 patients) and Department of Neurology, Innsbruck Medical University (23 patients)].

Demographic data, seizure history, indications for treatment, loading and maintenance dose of IV LCM, as well as responsiveness and adverse events during the first 24 h were extracted from patient’s charts.

Patients were grouped into SC and SE. SC was defined if two distinct generalized tonic–clonic seizures or three focal seizures without secondary generalization occurred within 1 h. Generalized convulsive SE (CSE) was defined as ongoing seizure activity for at least 5 min or two generalized tonic–clonic seizures without regaining consciousness. Nonconvulsive SE (NCSE) was defined as 30 min of continuous seizure activity without major motor phenomena. Cessation of SE or SC was defined as disappearance of ictal symptoms without any subtle signs of ongoing subclinical seizure activity, or electroencephalographic seizure activity. The last AED administered before SE cessation was defined as termination drug, regardless of the latency between its first administration and SE cessation.

Continuous variables were summarized using mean, standard deviation (SD), median, minimum, and maximum; categorical variables were summarized using counts and percentages.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Patients

Forty-eight patients (26f/22m) with SE or SC aged 17–95 years (median 62 years) were included in the study. Thirty-five percent of patients (17 of 48) had SC and 65% (31 of 48) SE. In patients with SE, 36% (11 of 31) patients had CSE, 32% (10 of 31) NCSE, and 32% (10 of 31) had focal SE (FSE) without major convulsions. The etiology of SE was acute symptomatic in 20% (6 of 31) of patients and remote symptomatic in 35% (11 of 31). Forty-five percent (14 of 31) had a previous diagnosis of epilepsy and received a median of 2 (range 1–4) AEDs. Demographic data are listed in Table 1.

Table 1.   Demographic data of 48 patients who received intravenous lacosamide for treatment of seizure clusters or status epilepticus
 Total (n = 48)Status epilepticus (n = 31)Seizure cluster (n = 17)
  1. SE, status epilepticus; SC, seizure clusters; CSE, convulsive status epilepticus; NCSE, nonconvulsive status epilepticus; FSE, focal status epilepticus; LCM, lacosamide; LEV, levetiracetam; VPA, valproic acid; CBZ, carbamazepine; OXC, oxcarbamazepine; LTG, lamotrigine; PHE, phenytoin; PGB, pregabalin; AEDs, antiepileptic drugs.

Median age (years)62 (17–95)67 (22–95)54 (17–80)
Men/women22/26 (46%/54%)17/14 (55%/45%)5/12 (29%/71%)
Type of SE   
 CSE 11 (36%) 
 NCSE 10 (32%) 
 FSE 10 (32%) 
Etiology   
 Acute symptomatic6 (12%)6 (20%)
 Remote symptomatic11 (23%)11 (35%)
 Preexisting epilepsy31 (65%)14 (45%)17 (100%)
 Cryptogenic716
 Specific etiology413011
 Traumatic lesions55
 Cortical dysplasia413
 Vascular lesions1495
 Tumor633
 Encephalitis11
 Others1111
AED before SE/SC (patients, multiple AEDs possible)   
 LCM312
 LEV241311
 VPA624
 CBZ312
 OXC321
 LTG532
 PHE211
 PGB523
 Benzodiazepines514
 Others22

Dose of IV LCM

The median initial bolus dose in patients with SC was 200 mg. In patients with SE initial bolus dose ranged between 200 and 400 mg, with a median of 200 mg. The maximum infusion rate was 60 mg/min. The initial bolus dose was followed by median 0 mg (range 0–200) in patients with SC and median 200 mg (range 0–400) in patients with SE.

Efficacy and order of application of IV LCM

In 21% (10 of 48) of patients IV LCM was the first AED; two of them had SE and both were controlled after IV LCM. In 19% (9 of 48) LCM was introduced as a second agent; six of them had SE and all were fully controlled after LCM. In 43% (21 of 48) of patients LCM was used as the third drug; 15 of them had SE, which was stopped in 11 by IV LCM. In one patient, SE was already terminated before treatment with IV LCM. In 17% (8 of 48) IV LCM was the fourth AED, all of them had SE, and 75% (6 of 8) were responders; one patient was already controlled before he received IV LCM. Cessation of SE was achieved in 81% (25 of 31). SCs were controlled in all patients. In two patients SE was already terminated before administration of LCM; both patients had complex focal SE. Cessation rate of NCSE was 70% (7 of 10), in CSE 91% (10 of 11), and in FSE 80% (8 of 10) of patients. There was no significant difference between the distinct types of status and between the group of nonresponders and responders (Table 2).

Table 2.   Dose and responsiveness of intravenous lacosamide in 48 patients with status epilepticus and seizure clusters
 Total (n = 48)Status epilepticus (n = 31)Seizure cluster (n = 17)
  1. SE, status epilepticus; SC, seizure clusters; LCM, lacosamide; LEV, levetiracetam; VPA, valproic acid; PHE, phenytoin.

Treatment before LCM   
 Benzodiazepines37298
 LEV22211
 PHE33
 VPA55
 Anesthesia11
LCM dose (median, range)   
 Median initial bolus (mg, range)200 (r 200–400)200 (r 200–400)200 (r 200–200)
 Median loading dose/24 h (mg, range)0 (r 0–400)200 (r 0–400)0 (r 0–200)
Order of LCM i.v.   
 LCM first10 (21%)2 (7%)8 (47%)
 LCM second9 (19%)6 (19%)3 (18%)
 LCM third21 (43%)15 (48%)6 (35%)
 LCM fourth or later8 (17%)8 (26%)
Termination of SE/SC by LCM   
 LCM first100%2/28/8
 LCM second100%6/63/3
 LCM third81% (17/21)11/156/6
 LCM fourth or later75% (6/8)6/8

Adverse events

All adverse events were mild in intensity. In 2 of 48 patients, pruritus and skin rash occurred after administration of IV LCM, which led to discontinuation in one patient. In our study population, no cardiac adverse events were observed.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

In our series, 86% of patients with SE and all patients with SC were controlled with IV LCM. There was a clear order effect of the drug, with 100% response rate in all 10 patients in which LCM was used as the first drug and 87% response (in 26 of 30 patients) in which LCM was used as the second or the third drug.

The usefulness of the IV LCM formulation in CSE, as well as in NCSE, was first documented in two independent case reports (Kellinghaus et al., 2009; Tilz et al., 2010). The largest retrospective series of 39 patients showed a cessation of SE with IV LCM in 44% of patients, including 33 patients who were refractory to LEV (Kellinghaus et al., 2011). A second study reported a response of 88% in 17 patients with SE or SC (Parkerson et al., 2011). A case series of four patients with resistant NCSE described a successful treatment with IV LCM in all patients (Koubeissi et al., 2011). In a recent report on seven patients with focal SE, all cases were terminated within 24 h after application of IV LCM (Albers et al., 2011). In contrast to this, a retrospective study on nine patients with refractory SE reported no success in any patients. In addition, angioedema was observed in two of them (Goodwin et al., 2011). The relationship of angioedema and LCM treatment is unclear. The median dose in this study was only 200 mg (range 100–200 mg), which was <50% of the dose we used in patients with SE. Furthermore, the rate of infusion was not mentioned in the study, which might have been too slow. This may indicate that the patients were underdosed, leading to poorer efficacy in these series, compared to all other published reports.

In our series, we observed a tendency to use IV LCM earlier in the treatment algorithm. This was most likely due to an increase in experience with the drug over time. Despite the recommended treatment protocols for SE, which were in use in both centers (Shorvon et al., 2008; Trinka & Shorvon, 2009), the treating physician had the option to avoid the standard IV AEDs depending on clinical background and comorbidity of the patients, especially cardiovascular morbidity, renal and hepatic failure led to the avoidance of standard AEDs. We also found a clear order effect of IV LCM with decreasing success rates as SE progresses. A decreasing efficacy with increasing duration of SE has been recently demonstrated experimentally (Wasterlain et al., 2011). These data may suggest using LCM in the early or established stages of status and not in the refractory later stages.

Until now data on 63 patients with various forms of SE treated with IV LCM are published (Kellinghaus et al., 2009; Tilz et al., 2010; Albers et al., 2011; Chen et al., 2011; Goodwin et al., 2011; Kellinghaus et al., 2011; Koubeissi et al., 2011; Parkerson et al., 2011). The overall success rate was 32% (20 of 63). In our series, effective treatment was achieved with a loading dose between 200 and 600 mg IV LCM, which is well in line with the most of the previously published literature. In one safety study, four patients received 800–1,000 mg/day IV LCM, which was well tolerated with transient headache in one patient (Krauss et al., 2010); therefore, the upper dose range is not well explored. In our study, IV LCM was well tolerated in doses up to 400 mg at 60 mg/min. Only two patients had pruritus and mild skin rash, which disappeared after discontinuation of LCM.

In a bioequivalence study one patient had vasovagal response and one patient had a mild prolongation of QT-interval, which was not symptomatic (Krauss et al., 2010). A case report after suicide attempt with 12 g LCM in combination with other AEDs (56 g of gabapentin, 2 g of topiramate, and 2.8 g of zonisamide) observed a large PR interval increase and hypotension (Bauer et al., 2010). Notably, in our series there was no cardiovascular adverse event or hypertension observed. None of our patients had changes in baseline ECG; however, this was not analyzed systematically due to the retrospective nature of the study.

Although our observations are limited by the lack of a control group, the retrospective design, and the short-term follow-up as well as the small cohort, we consider IV LCM in seizure emergency situations as a potentially effective alternative to standard treatments. However, a randomized control trial is needed to establish the therapeutic effect of IV LCM in the acute treatment of SE and SC.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

None of these patients were included in our previous report authored by Kellinghaus et al. 2010. Results of this study have been presented as a poster at the 3rd London-Innsbruck-Colloquium on Status Epilepticus 7–9 April 2011.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

J. Höfler has received speaker’s honoraria from UCB and travel grants from UCB, Eisai, and Gerot. I. Unterberger has received speaker’s honoraria from UCB and travel grants from UCB, Eisai, and Gerot. J. Dobesberger has received speaker’s honoraria from UCB and travel grants from UCB, Eisai, and Gerot. G. Kuchukhidze has received travel grants from UCB, Gerot, and Eisai. G. Walser has travel grants from UCB and Eisai. E. Trinka has acted as a paid consultant to Eisai, Medtronics, Bial, and UCB. He has received research funding from UCB, biogen-idec, sanofi-aventis, and speakers’ honoraria from Bial, Cyberonics, Desitin Pharma, Eisai, Gerot, Böhringer, Sanofi, Medis, and UCB. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References