Intravenous lacosamide for treatment of status epilepticus
Christoph Kellinghaus, Department of Neurology, Klinikum Osnabrück, Am Finkenhügel 1, 49076 Osnabrück, Germany
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Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F, Rossetti AO, Tilz C, Trinka E. Intravenous lacosamide for treatment of status epilepticus.
Acta Neurol Scand: 2011: 123: 137–141.
© 2010 John Wiley & Sons A/S.
Objectives – Treatment of established status epilepticus (SE) requires immediate intravenous anticonvulsant therapy. Currently used first-line drugs may cause potentially hazardous side effects. We aimed to assess the efficacy and safety of intravenous lacosamide (LCM) in SE after failure of standard treatment.
Methods – We retrospectively analyzed 39 patients (21 women, 18 men, median age 62 years) from the hospital databases of five neurological departments in Germany, Austria and Switzerland between September 2008 and January 2010 who were admitted in SE and received at least one dose of intravenous LCM.
Results – Types of SE were generalized convulsive (n = 6), complex partial (n = 17) and simple partial (n = 16). LCM was administered after failure of benzodiazepins or other standard drugs in all but one case. Median bolus dose of LCM was 400 mg (range 200–400 mg), which was administered at 40–80 mg/min in those patients where infusion rate was documented. SE stopped after LCM in 17 patients, while 22 patients needed further anticonvulsant treatment. The success rate in patients receiving LCM as first or second drug was 3/5, as third drug 11/19, and as fourth or later drug 3/15. In five subjects, SE could not be terminated at all. No serious adverse events attributed to LCM were documented.
Conclusions – Intravenous LCM may be an alternative treatment for established SE after failure of standard therapy, or when standard agents are considered unsuitable.
Status epilepticus (SE) is defined as prolonged seizures or repeated seizures where the patient does not regain consciousness between the seizures. International treatment guidelines for treatment of early status recommend unanimously benzodiazepines (1), which may control 50–65% of all cases. Thus, 35–50% need an intravenous anticonvulsant to control the seizure activity. Traditionally, phenytoin and phenobarbital have been used since decades in the treatment of established status, although there have been no randomised controlled trial to support their use after failure of benzodiazepines. These agents are associated with significant sedation, hypotension, cardiac arrhythmias, or a complex pharmacokinetic. There is accumulating evidence that valproate may be effective for therapy of SE as a potentially safer alternative (2). However, adequate studies comparing established agents for SE treatment with some of the new anticonvulsants or sedatives are lacking.
Lacosamide (LCM) has been approved as add-on treatment for localization-related epilepsies in 2008 by the FDA and the EMEA. Although its mechanisms of action are not fully understood, it likely exerts the anticonvulsive effect by enhancing the slow inactivation of voltage-dependent sodium-channels. There is no significant protein binding and a low interaction potential. The intravenous solution of LCM (LCM IV) can be administered without dilution or other preparation. It is well tolerated and does not have any influence on heart rate, blood pressure or ventilation even with infusion rates of 10 min per 200 mg bolus (3). Previous single case reports on LCM in SE have been published by our group (4, 5). We now report our experience regarding efficacy and safety of LCM in the treatment of established SE, when usual agents have failed or were contraindicated.
We retrospectively identified patients from the Neurological Departments of two German (Klinikum Osnabrück, University Hospital Marburg), two Austrian (University Hospital Innsbruck, Krankenhaus Barmherzige Brüder Linz), and one Swiss hospital (Centre Hospitalier Universitaire Vaudois, Lausanne) who received at least one dose of LCM IV for treatment of SE between September 2008 and January 2010. Their complete charts, electrophysiological, and imaging data were reviewed regarding sociodemographic data, seizure type, etiology, onset and duration of SE, doses and modes of application of all anticonvulsant agents including the order in which they were administered, tolerability, and outcome. A standardized data sheet was used for documentation in all participating centers. SE was defined as seizures lasting 5 min or longer. Cessation of SE was defined as disappearance of EEG status-/seizure activity or disappearance of previous ictal symptoms without any suspicion of ongoing subclinical seizure activity, if confirmed by a subsequent EEG recording. The last antiepileptic drug (AED) administered before SE cessation was defined as termination drug, regardless of the latency between its first administration and SE cessation. Tolerability was determined using all available documentation including local injection reaction, cardio-respiratory and neurologic effects. We retrospectively defined subgroups according to the order of LCM during the course of SE treatment (LCM first/second, LCM third, LCM fourth or later).
Thirty-nine patients (21 women) were analyzed. Mean age was 63 ± 20 years (range 18–90 years). Almost half of them presented with simple partial semiology without significant impairment of awareness (Table 1). Most of the patients (67%) had a remote symptomatic etiology.
Table 1. Epidemiology, semiology, EEG characteristics, etiology, and anticonvulsive medication
| Mean ± standard deviation||62.64 ± 19.7||45.8 ± 25.5||63.5 ± 19.7||64.5 ± 16.2|
| Median (range)||62 (18–90)||40 (28–90)||62 (18–90)||71 (25–83)|
|Semiology of SE|
| Convulsive generalized||6/15%||1||3||2|
| Complex partial||16/41%||1||10||5|
| Simple focal||17/44%||3||6||8|
| No ictal EEG||3/8%||1||0||2|
| Acute symptomatic||10/26%||2||2||6|
| Remote symptomatic (new onset of epilepsy)||9/23%|| ||6||3|
| Remote symptomatic (pre-existing epilepsy)||19/49%||3||11||5|
| Others/unknown||1/3%|| ||0||1|
|AED medication before SE|
| LCM||2/5%|| ||1||1|
| VPA||2/5%||1|| ||1|
| PHT||2/5%||1|| ||1|
| LTG||3/8%||1||2|| |
| Benzodiazepines||5/13%|| ||3||2|
| others||6/15%||3||3|| |
| none||15/38%|| ||8||7|
The median interval from SE onset to the start of SE therapy was 0.75 h (range 0.1–336). All but two patients received benzodiazepines as first-line treatment (Table 2). LCM was started after a median latency of 30 h (range 0.5–1440). The first LCM bolus was 400 mg in 24 patients, 300 mg in 2 patients, and 200 mg in 13 patients. Infusion rate was documented in 23 patients. In all of them, the first bolus was administered over 5 min or less. In 17 patients (44%), LCM terminated the SE, and in seven of them, SE ceased within 6 h after first administration of LCM. In 22 subjects, further AED therapy was required. In five patients (13%), SE could not be terminated.
Table 2. Treatment parameters and outcome
|Latency (h) onset SE – SE therapy|
| Mean (SD)||17.5 (57.1)||8.26 (11.6)||8.3 (27.7)||37.8 (89.1)|
| Median (range)||0.75 (0.1–336)||2 (0.1–27)||0.5 (0.3–122)||2 (0.5–336)|
|Treatment before LCM with|
| PHT||14|| ||2||12|
| Other AED||5|| ||0||5|
| Anesthesia||4|| ||0||4|
|Latency (h) onset SE – LCM i.v.|
| Mean (SD)||116.5 (304.4)||18.9 (26.1)||30.1 (32.1)||258.4 (462.5)|
| Median (range)||30 (0.5–1440)||2 (1.75–60)||11 (1–171)||52 (0.5–1440)|
|LCM Dosing (mg)|
| Bolus: mean (range)||328 (200–400)||280 (200–400)||342 (200–400)||326 (200–400)|
| 1st day: mean (range)||424 (200–600)||320 (200–400)||431 (200–600)||446 (400–600)|
|Termination of SE by LCM i.v.|
| <6 h after LCM i.v., No other AED after LCM||7/18%||2||4||1|
| >6 h after LCM i.v. No other AED after LCM||10/26%||1||7||2|
| Further AED therapy needed||22/56%||2||8||12|
| PHT successful||5/13%||1||3||1|
| OXC/CBZ successful||4/10%|| ||2||2|
| VPA/TPM successful||2/5%|| ||1||1|
| Anesthesia successful||6/15%||1||1||4|
| Termination of SE||34/87%||5||18||11|
| Termination, no change in mRS||21/54%||3||13||5|
| No termination||5/9%|| ||1||4|
Lacosamide was the first agent used for treatment of SE in one patient (3%), the second agent in four patients (10%), the third in 19 patients (49%), and the fourth or subsequent agent in 15 patients (38%). The patient who received LCM as first therapy, a 29-year-old women, who suffered from right hemispheric partial epilepsy as a consequence of previous aluminum intoxication, was on a high-dose combination AED therapy consisting of clonazepam 8 mg/day, phenytoin 500 mg/day, levetiracetam 3000 mg/day and pregabalin 600 mg/day, all with appropriate serum levels when SE occurred (left clonic SE). Therefore, for subgroup analysis, we included this patient in the LCM first/second group. Patients who received LCM as first or second agent were younger (median age 40 years) compared to the patients of the other groups, but this was not significant. SE etiology was acute symptomatic in 40% of the patients of the LCM first/second as well as the LCM fourth or later group, but only in 11% of the LCM third group. Treatment of the patients of the LCM fourth or later group tended to start later compared to the other subgroups. LCM terminated the SE in 60% of the LCM first/second group and in 57% of the LCM third group, but only in 20% of the LCM fourth or later group.
One allergic skin reaction following LCM administration was observed although the simultaneous administration of domperidon in this patient may be a possible alternative etiology [for details see (4)]. Sedation was observed in 25 patients during the treatment of SE, always after administration of benzodiazepines, barbiturates or propofol. Hypotension was seen in four patients but was clearly associated with administration of phenytoin or propofol. No further adverse events were observed with LCM administration, and no ECG-changes were documented.
Lacosamide was the last drug before termination of SE in 44% of the observed cases. When administered early during the course of the treatment, it was successful in 60% of the cases, whereas there was only a 20% success rate in more refractory patients. Apart from one case with allergic rash after LCM administration, there were no other adverse events clearly attributable to LCM.
In our series, LCM was used mainly after failure of benzodiazepines, levetiracetam and phenytoin. Therefore, most of the patients would have to be classified as ‘refractory’ according to the commonly used definition (1, 6). This may explain that the overall success rate was lower than in the Veteran’s affairs (VA) study (7), which included mainly untreated patients. In several recent retrospective case series on IV levetiracetam response rates of about 70% were found, but many patients received IV levetiracetam as first-line therapy before or immediately after administration of benzodiazepines (8–11). Our subgroup analysis demonstrates that the earlier LCM was administered, the higher were the chances of success. The subgroup treated with LCM directly after benzodiazepines or benzodiazepines plus levetiracetam showed a success rate similar to those reported for levetiracetam (8–11) or valproate (11, 12).
Even in clearly refractory SE, when used after adequate doses of benzodiazepines, levetiracetam and phenytoin, and even after failure of coma induction, LCM was able to terminate SE in 20% of these patients. Thus, one can assume that more aggressive therapy (coma induction) may have been prevented by using LCM even after failure of standard first- and second-line agents.
There were no relevant changes of heart rate, respiration/oxygenation or blood pressure associated with infusion of LCM in spite of the advanced age of the patients and the fast infusion rate documented in more than half of the patients. Almost all patients had received therapeutic doses of benzodiazepines, barbiturates, or propofol. Therefore, it was not possible to discern whether LCM significantly contributed to any decrease of consciousness seen during the course of the treatment. In addition, there was no local injection site reaction.
There are several limitations to our study. First, the retrospective design limits the side-effect ascertainment. In addition, a selection bias may exist, i.e. LCM may have been administered to a selected group of patients, and more patients with successful outcome than patients in whom LCM has failed may have been included. However, these limitations are inherent to all retrospective series.
Lacosamide is currently not approved for treatment of SE. However, our data show that it may be an alternative treatment of SE when standard drugs fail or should be avoided. Prospective studies are urgently needed to assess its efficacy compared to standard drugs.
We thank Dr. Ch. Eggers, Department of Neurology with Stroke Unit, Hospital Barmherzige Brüder Linz, for his helpful comments on the manuscript.
Dr. Kellinghaus received honoraria and travel support from UCB, Eisai, Pfizer, Desitin, Novartis and Sanofi-Aventis. Dr. Berning received honoraria and travel support from UCB. Dr. Rosenow received honoraria, research grants and travel support from UCB. He received honoraria from Eisai, Pfizer, Desitin, Novartis and Sanofi-Aventis. Dr Rossetti received research support from Pfizer, AstraZeneca and UCB, and honoraria from UCB, Eisai, and Janssen-Cilag. Dr. Tilz received honoraria Eisai and travel support from Biogen-Idec, Eisai, Lundbeck, Merck-Serono, Sanofi-Aventis and UCB. Dr. Trinka has received speaker honoraria from UCB Pharma and Eisai; he served on scientific advisory boards for UCB, Eisai, J&J and Medtronics; Dr. Trinka received funding for a conference trip by UCB Austria as well as travel expenses and honoraria for lectures or educational activities not funded by industry. Dr. Trinka is a member of UCB Speakers Bureau. Dr. Immisch and Dr. Larch report no disclosures.