Clin Drug Investig (2015) 35:463–469
DOI 10.1007/s40261-015-0295-5
SHORT COMMUNICATION
Observational Study of Intravenous Lacosamide in Patients
with Convulsive Versus Non-Convulsive Status Epilepticus
Eros Yamel Moreno Morales1 • Manuel Fernandez Peleteiro1 •
Ernesto Carlo Bondy Peña1 • Jose Maria Domı́nguez Lorenzo1
Elva Pardellas Santiago1 • Anxo Fernández2
Published online: 25 June 2015
 euratom: universidad de santiago de compostela;  European Union 2015
Abstract
Background and Objectives Status epilepticus (SE) is an
important emergency situation associated with high mor-
bidity and mortality. The goal of pharmacological ther-
apy—rapid seizure termination—is only achieved in just
over half of patients with first-line anti-epileptic drug
(AED) therapy and many patients require second and
higher lines of AEDs to achieve seizure termination;
therefore, there is a clear need for more effective treatment
options. Lacosamide is a relatively new AED and the in-
travenous formulation has shown promise for treatment of
SE. The aim of the current study was to compare elec-
troencephalographic (EEG) response and seizure termina-
tion with intravenous lacosamide (±other AEDs) in
patients with convulsive versus non-convulsive SE, in a
Spanish intensive care setting.
Methods In this prospective, observational study, patients
with convulsive or non-convulsive SE who received in-
travenous lacosamide 400 mg/day for 8 days were com-
pared in terms of EEG response and seizure termination.
Adverse events were not specifically assessed.
& Manuel Fernandez Peleteiro
manuel.peleteiro.fernandez@sergas.es;
manuel.peleteiro@usc.es
1
Clinical Neurophysiology, University Hospital of Santiago de
Compostela, Outpatient Building (Floor 1), Office 325,
Santiago de Compostela, Spain
2
Clinical Pharmacology Service, University Hospital of
Santiago de Compostela, Santiago de Compostela, Spain
•
Results Fifty-three patients (69.8 % male; mean age
55.2 years) were treated with lacosamide (mean dose
390.6 mg) as first- (20.8 %), second- (34 %), third
(22.6 %) or fourth-line (22.6 %) treatment for convulsive
(n = 23, 43.4 %) or non-convulsive (n = 30, 56.6 %) SE.
The majority of patients (73.6 %) had a comorbid condi-
tion, predominantly hypertension (35.8 %), and most
(79.2 %) received at least one concomitant AED, including
midazolam (54.7 %), valproic acid (52.8 %), and leve-
tiracetam (30.2 %). Patient characteristics and treatment
received did not differ significantly between the convulsive
and non-convulsive SE groups. EEG recordings following
lacosamide treatment demonstrated the elimination of
paroxysmal activity (disappearance and/or attenuation of
epileptiform activity in [60 % of recording time) in
56.6 % of patients; 69.6 % of convulsive and 46.7 % of
non-convulsive SE groups. Among all patients, 90.6 %
showed some EEG improvement (disappearance of
epileptiform activity in \30 % total recording time or
disappearance and/or attenuation of epileptiform activity in
30–60 % total recording time); and there was no significant
between-group difference for achievement of seizure ter-
mination (90.0 vs. 91.3 % for non-convulsive vs. convul-
sive SE).
Conclusions Intravenous lacosamide (±other AEDs) was
similarly effective in patients with convulsive or non-
convulsive SE. Further investigation into the use of la-
cosamide in the treatment of SE is warranted.
464
Key Points
This prospective, observational study compared
electroencephalographic response and seizure
termination in 53 patients with convulsive versus
non-convulsive status epilepticus (SE) treated with
intravenous lacosamide 400 mg/day with or without
other anti-epileptic drugs (AEDs).
Intravenous lacosamide therapy (±other AEDs)
resulted in elimination of paroxysmal activity in
56.6 % of SE patients (69.6 % convulsive SE and
46.7 % non-convulsive SE).
Seizure termination was seen in 91.3 % of patients
with convulsive and 90.0 % non-convulsive SE.
1 Introduction
Status epilepticus (SE) is an important emergency situation
associated with high morbidity and mortality, and requiring
immediate, effective treatment [1, 2]. The condition is
thought to result from the failure of the mechanisms that
usually terminate an isolated seizure [2]. SE has tradi-
tionally been defined as a single seizure lasting more than
30 min, or repeated seizures over a period of more than
30 min without intervening recovery of consciousness.
However, for practical and ethical reasons, treatment is
generally initiated after seizure activity has persisted for
longer than 5 min [3, 4].
There are a number of different types of SE, although
one simple way in which to broadly classify the form of SE
is by the presence or absence of convulsions, that is, con-
vulsive (generalised tonic-clonic SE) or non-convulsive
(absence) SE (as reviewed previously) [5]. Correct identi-
fication of the type of SE is crucial for effective manage-
ment and, therefore, treatment outcome [6]. Non-
convulsive SE is a condition marked by non-convulsive
seizures and is often underdiagnosed because of the lack of
awareness of the condition [6]. Electroencephalography
(EEG) is used for objective identification of non-convul-
sive SE [7, 8].
The annual incidence of SE in Europe is approximately
10.3–17.1 per 100,000 population and that of non-convul-
sive SE is 2–8 per 100,000 [6, 9–12]. Due to under-
recognition of both forms of SE (but particularly non-
convulsive SE) in studies assessing the incidence of the
condition, it is likely that these estimates are on the low
side [5]. The incidence of SE is bimodally distributed, with
more patients affected during the first year of life and after
60 years of age [13, 14]. There is also evidence to suggest
E. Y. Moreno Morales et al.
that males are affected by SE more frequently than females
[13, 14]; however, this has not conclusively been
demonstrated.
Unsurprisingly, the aims of treatment are termination of
SE, prevention of seizure recurrence, management of pre-
cipitating causes and management of complications [1, 2].
The cause of SE is particularly important, as appropriate
treatment of the root cause affects clinical outcome. The
goal of pharmacological therapy for SE is the rapid ter-
mination of seizures [1, 2]. Traditional first-line treatments
for convulsive SE, effective in approximately 60 % of
episodes, include benzodiazepines and phenytoin/fos-
phenytoin. Valproic acid has more recently been approved
for the treatment of convulsive SE in some European
countries [1]. In patients who do not respond to first-line
therapies, general anaesthesia or narcotics may be used as
second-line agents [1, 2]. Given the fact that only just over
half of patients experience termination of seizures after
first-line treatment, there is a clear need for more effective
treatment options.
Lacosamide is a relatively new antiepileptic drug
(AED), which was approved in the EU and USA in 2008 as
an add-on (adjunctive) treatment for partial-onset seizures
with or without secondary generalisation in adults and
adolescents (aged 16–18 years) [15–17]. The agent has
been demonstrated to exert its anticonvulsant effects
through the enhancement of slow inactivation of voltage-
gated sodium channels [18]; however, the precise
mechanism of action of the drug has yet to be fully con-
firmed. Lacosamide is available in both oral and intra-
venous formulations, and in its intravenous form has shown
promise as a treatment for SE [16, 19, 20]; nevertheless,
prospective data of the use of this agent in such patients are
limited.
The aim of the current study was to compare EEG re-
sponse and seizure termination with intravenous la-
cosamide in patients with convulsive versus non-
convulsive SE in a hospital intensive care setting in Spain.
2 Patients and Methods
2.1 Study Design
This prospective, observational trial was conducted be-
tween January 2011 and December 2011 at the University
Clinical Hospital of Santiago de Compostela in Spain. Prior
to inclusion in this study, all patients received protocol
information and either they or their legal representatives
provided written informed consent. The study protocol was
reviewed and approved by the Teaching and Ethics Com-
mittee of the University Hospital of Santiago de
Compostela.
Lacosamide in Status Epilepticus 465

2.2 Patients and Treatment • elimination of paroxysmal activity (disappearance and/

or attenuation of epileptiform activity in [60 % of total
Male and female patients, aged C15 years, who were ad- recording time).
mitted to the intensive care unit (ICU) at the University
The secondary endpoint, effectiveness of intravenous
Clinical Hospital of Santiago de Compostela for any reason
lacosamide treatment (±other AEDs), was also assessed
and then experienced a seizure after admission and met the
and was defined as achievement of seizure termination.
criteria of convulsive or non-convulsive SE were enrolled
prospectively in this trial. The attending physician sus-
2.4 Safety Assessments
pected SE (convulsive or non-convulsive) if patients pre-
sented with an altered level of consciousness, abnormal
Safety was not specifically assessed in this study. However,
movements, not awakening after sedation withdrawal or
patients in this study were monitored as per the usual ICU
presented with any other situation that made the physician
protocols which included: continuous monitoring of ECG,
suspect SE. Convulsive and non-convulsive SE status was
respiratory flow, pulse oximetry and vital signs; medical
confirmed by a neurologist using a 30-min EEG and de-
assessment by ICU specialists every 12 h; and laboratory
fined according to Kaplan diagnostic criteria [21].
tests every 24 h. The latter comprised of: blood cell count,
On enrolment into the study, a detailed history was ac-
QT interval, activated partial thromboplastin time, fib-
quired from each patient, with an emphasis on any history
rinogen, total protein, glucose urea, creatinine, cholines-
(whether in the family or themselves personally) of
terase, erythrocyte sedimentation rate, albumin, uric acid,
epilepsy. The number and name of anti-epileptic drugs the
bilirubin, cholesterol, triglycerides, aspartate aminotrans-
patient had received over the course of their illness (if
ferase, alanine aminotransferase, gamma-glutamyl trans-
diagnosed with epilepsy prior to admission) was noted, as
ferase, alkaline phosphatase, sodium, potassium and
well as dose and time intervals. The duration of epilepsy (if
calcium levels.
applicable) was also recorded.
All enrolled patients received intravenous lacosamide
2.5 Statistical Analyses
400 mg infused over 30 min for 8 days following SE onset,
either as first-line therapy for SE or after other AED
Qualitative and quantitative descriptive analyses were
therapy.
performed for the variables collected. For each qualitative
variable assessed, the frequency and percentage were cal-
2.3 Efficacy Assessments
culated; whereas the mean, standard deviation, median,
minimum and maximum values, 25th–75th percentiles, and
The primary measure of efficacy was based on bioelectric
the number of valid cases were calculated for each appli-
response to treatment, as measured by changes in EEG
cable quantitative variable.
response and seizure termination. The first EEG was per-
Patient groups (convulsive vs. non-convulsive SE) were
formed before lacosamide administration for diagnosis, and
compared using the Chi-square test (or Fisher’s exact test)
subsequent EEGs were performed every 24 h during la-
for qualitative variables and the U test of Mann–Whitney
cosamide administration until the disappearance/atten-
for quantitative variables. The significance level for all
uation of paroxysmal activity or eight days after the start of
analyses was set at 5 %. All analyses were performed with
treatment. Electrodes were placed on a sulphureted silver
SPSS v17.
surface and attached to the scalp with Collodion, in ac-
cordance with the International System 10–20 method for
the application of scalp electrodes. All electrodes were
3 Results
referenced to C3–C4. All EEGs were performed by neu-
rophysiology residents and the resulting 20-min EEG
3.1 Patient Characteristics
tracings were analysed by two specialist registrar neuro-
physiologists with experience in epilepsy. EEG response
The trial enrolled 53 patients who presented with SE in the
(as evidenced by the EEG recording) was defined accord-
ICU and began treatment with intravenous lacosamide.
ing to degree of improvement in the EEG as follows:
Most patients were male (69.8 %); the mean patient age
• no change; was 55.2 ± 16.78 years. Most patients had a comorbid
• reduced paroxysmal activity (either a disappearance of condition (73.6 %), predominantly hypertension (35.8 %).
epileptiform activity in \30 % of total recording time Of the 53 patients enrolled, 13.2 % had prior epilepsy. A
or a disappearance and/or attenuation of epileptiform total of 43.4 % of patients had convulsive SE and 56.6 %
activity in 30–60 % of total recording time; had non-convulsive SE. Patient characteristics did not
466 E. Y. Moreno Morales et al.

Table 1 Patient demographics Characteristic Non-convulsive SE (n = 30) Convulsive SE (n = 23)

and clinical characteristics
Age, years
Median 56.5 53.7
Range 19–73 21–71
Sex, n (%)
Male 19 (63.3) 18 (78.3)
Female 11 (36.7) 5 (21.7)
Prior epilepsy, n (%) 2 (6.7) 5 (21.7)
Comorbiditiesa, n (%)
Hypertension 10 (33.3) 9 (39.1)
Head injury 2 (6.7) 4 (17.4)
Dyslipidaemia 2 (6.7) 3 (13.0)
Diabetes mellitus 2 (6.7) 2 (8.7)
Myocardial infarction 2 (6.7) 2 (8.7)
Sepsis 2 (6.7) 1 (4.3)
No. of prior/concomitant AEDs, n (%)
None 8 (26.7) 3 (13.0)
1 11 (36.7) 7 (30.4)
2 6 (20.0) 6 (26.1)
3 5 (16.7) 7 (30.4)
Concomitant AEDs, n (%)
Midazolam 9 (30.0) 20 (87.0)
Valproic acid 15 (50.0) 13 (56.5)
Levetiracetam 9 (30.0) 7 (30.4)
Pentobarbital 4 (13.3) 0
Phenytoin 1 (3.3) 0
Location of intravenous lacosamide treatment, n (%)
Intensive care unit 18 (60.0) 17 (73.9)
Revival unit 8 (26.7) 2 (8.7)
Recovery room 3 (10.0) 2 (8.7)
Coronary unit 0 2 (8.7)
Abdominal transplant unit 1 (3.3) 0
AEDs antiepileptic drugs, SE status epilepticus
a
Present in C5 % of patients

differ significantly between the convulsive and non-con-
vulsive SE groups (Table 1).
3.2 Treatment
The mean dose of lacosamide was 390.6 mg, given as the
first AED in 20.8 % of patients, and in combination with
one (34 %), two (22.6 %) or three concomitant AEDs
(22.6 %) as treatment for SE. There were no significant
differences between non-convulsive and convulsive SE
groups in the mean dose of lacosamide received (383.3 vs.
400.0 mg; p = 0.122, Mann–Whitney test) or lines of
treatment received (26.7 vs. 43.5 % and 73.3 vs. 56.5 %,
for first- and second-line treatment, respectively;
p = 0.200, Chi-square test). The majority of patients
(66 %) received intravenous lacosamide in the ICU
(Table 1), but no test for statistical significance could be
made due to limited data.
Similarly, the majority (79.2 %) of patients received at
least one concomitant AED—either one (34 %), two
(22.6 %) or three (22.6 %) agents, with no statistically
significant differences between groups (Table 1;
p = 0.455, Chi-square test).
Before treating with lacosamide, many intensivists tried
sedation with propofol or midazolam in combination with
other AEDs. Prior/concomitant AEDs included midazolam
(54.7 %), valproic acid (52.8 %) and levetiracetam
(30.2 %); however, there were distinct numerical differ-
ences between the groups with respect to the other AEDs
received. Whereas 87 % of patients with convulsive SE
Lacosamide in Status Epilepticus 467

were also treated with midazolam, only 30 % of those with
non-convulsive SE received that agent; instead, half of
patients with non-convulsive SE received valproate, 30 %
levetiracetam, 13.3 % pentobarbital and 3.3 % phenytoin.
Furthermore, pentobarbital and phenytoin were not used in
any of the patients with convulsive SE; rather, these pa-
tients received midazolam (50 %), valproate (56.5 %) or
levetiracetam (30.4 %) in addition to lacosamide. The most
common AED combinations overall were la-
cosamide ? levetiracetam ? midazolam ? valproic acid
(n = 12), lacosamide ? midazolam (n = 9) and la-
cosamide ? midazolam ? valproic acid (n = 8).
Treatments used after lacosamide treatment were not
recorded; patients in the study remained in the ICU after
lacosamide therapy for other reasons and were then treated
in internal medicine or other wards. Patients were not
followed beyond ICU as this was not an aim of the study.
group achieved elimination of paroxysmal activity (46.7
and 69.6 % of those with non-convulsive and convulsive
SE, respectively) (Table 2). Although differences were
noted between groups, no statistical analyses could be
made because over half of the variables had an expected
frequency of less than five patients.
In terms of effectiveness, no significant between-group
difference was observed, with 90.0 and 91.3 % of those in
the non-convulsive and convulsive SE groups, respectively,
achieving seizure termination (Table 2).
3.4 Adverse Events
Safety was not specifically assessed in this study, but as a
result of usual patient monitoring as per ICU protocols, no
adverse events were reported during the eight days of la-
cosamide administration.

3.3 Response
Intravenous lacosamide treatment (±other AEDs), resulted
in the elimination of paroxysmal activity in EEG readings
in 56.6 % of patients, with the majority of patients
(90.6 %) showing some improvement in EEG readings
(disappearance and/or attenuation of epileptiform activity
in [30 % of total recording time). The majority of patients
in both treatment groups (non-convulsive SE and convul-
sive SE) responded to intravenous lacosamide (±other
AEDs), to some degree, with 9.4 % (n = 5) overall failing
to show any EEG improvement. Slight differences in re-
sponse were noted between the two groups; however, due
to the small number of patients involved, no statistical
analysis could be conducted. Despite these small numerical
differences, the pattern of response was the same regardless
of the form of SE. That is, the majority of patients in each
4 Discussion
In this prospective, observational study, 53 patients with
non-convulsive or convulsive SE received eight days of
treatment with intravenous lacosamide 200–400 mg.
Maximal treatment response denoted by the elimination of
paroxysmal activity in EEG readings was observed in
56.6 % of patients overall (46.7 and 69.6 % of those with
non-convulsive and convulsive forms of SE, respectively).
Furthermore, the vast majority of patients in both treatment
groups responded to treatment to some degree, with only
9.4 % (n = 5) failing to show any improvement in EEG
readings. There were no unexpected findings in this study.
These findings are in keeping with previous reports of
intravenous lacosamide in patients with SE [16, 17, 19].
Seizure termination was achieved in 88 % of patients with

Table 2 Response to Parameter Non-convulsive SE Convulsive SE

intravenous lacosamide (n = 30) (n = 23)

EEG improvement, n (%)

No changea 3 (10) 2 (8.7)
Reduced paroxysmal activityb 13 (43.3) 5 (21.7)
Elimination of paroxysmal activityc 14 (46.7) 16 (69.6)
Effectivenessd, n (%)
Yes 27 (90.0) 21 (91.3)
No 3 (10.0) 2 (8.7)
SE status epilepticus
a
Insignificant or no changes measured by EEG
b
Either a disappearance of epileptiform activity in \30 % of total recording time or a disappearance and/
or attenuation of epileptiform activity in 30–60 % of total recording time
c
Disappearance and/or attenuation of epileptiform activity in [60 % of total recording time
d
Achievement of seizure termination
468
SE or seizure clusters treated with lacosamide in one ret-
rospective Austrian study (n = 48) [19]; furthermore, the
success rate in patients receiving lacosamide as a first- or
second-line drug was 100 % (8/8) and 80.9 % (17/21) in
those receiving it as a third-line agent. A slightly larger
multicentre retrospective study (n = 39) [16], found that
treatment with intravenous lacosamide achieved a lower
response rate, with seizures terminated in 17 patients
(43.6 %), while 22 required additional treatment. The
success rate in patients receiving the agent as a first- or
second-line drug was 3/5 [16]. In a systematic review of
case reports and case series (total n = 136), the overall rate
of seizure termination with intravenous lacosamide was
56 % [17]. Conversely, in a retrospective study in nine
patients with refractory SE none of the patients achieved
seizure termination with intravenous lacosamide [22]. The
reasons underlying this lack of response to lacosamide in
the Goodwin et al study is unclear, but are likely due to
small patient numbers and the use of the agent as at least a
third-line therapy in known refractory patients. In the
Goodwin trial, the most frequently used regimen of intra-
venous lacosamide was a 200 mg initial dose, followed by
200 mg every 12 h [22]. This is similar to the dose used in
the current trial (400 mg/day for 8 days), perhaps negating
the suggestion that patients were under dosed. However, it
should also be noted that the nine patients all received
lacosamide after failing to respond to at least two other
AEDs. This is in contrast to the other studies/case reports
discussed here, where patients could have received la-
cosamide as a first-line AED, and in fact, 20.8 % of the
patients in our study did so. Minor adverse events were
noted in this trial [22], although only one allergic skin
reaction was clearly associated with intravenous la-
cosamide and three of the nine patients reported an-
gioedema with lacosamide leading to discontinuation in
one patient [22]. In the systematic review of case reports
and case series in 136 patients with SE, the overall rate of
adverse events was low and the most common was mild
sedation in 25 cases. Other adverse events reported were
angioedema, allergic skin reactions, hypotension, and
pruritus [17]. A number of case reports and retrospective
studies have also demonstrated similar positive safety re-
sults with intravenous and non-parenteral lacosamide [16,
19, 20, 23]. All other investigations of the agent in SE to
date have been positive, and no other cases of angioedema
have been observed.
There are a number of limitations of the current study.
These include its observational design, which may impact
upon the ascertainment of adverse events, as well as the
validity of results due to the lack of control group. How-
ever, these limitations are possibilities with any such trial.
The sample size of the trial was also small, again, limiting
the applicability of the results and our ability to analyse the
E. Y. Moreno Morales et al.
results for significance. The majority of patients in this
study were also receiving at least one other AED in addi-
tion to lacosamide, which may have affected the patients’
response to treatment. Furthermore, the vast majority of
patients (66 %) were treated in an ICU where they were
likely receiving other medications for either SE or any
number of other medical conditions; again, we cannot rule
out the possibility that these medications may have affected
the response to treatment with lacosamide, whether through
synergistic drug interactions or their own effects. However,
given the seriousness of SE and the fact that most patients
would be treated for the condition in either an emergency
room or ICU situation, these limitations are common in
trials in this indication.
5 Conclusions
This prospective observational study of intravenous la-
cosamide (±other AEDs) in patients with convulsive ver-
sus non-convulsive SE, in a Spanish intensive care setting
showed that intravenous lacosamide was similarly effective
in terms of EEG response and seizure termination in pa-
tients with convulsive or non-convulsive SE. Further large
clinical trials investigating the use of intravenous la-
cosamide in the treatment of SE are warranted.
Acknowledgments The authors would like to thank the Clinical
Pharmacology Service, Hospital Universitario de Santiago de Com-
postela for providing the necessary data for the study.
Medical writing assistance with the preparation of this manuscript
was provided by Claire Pouwels, Tracy Harrison and Mary Hines of
inScience Communications, Springer Healthcare with funding pro-
vided by Hospital Universitario de Santiago de Compostela.
Author contributions All authors participated in the conception,
design, and implementation of the study. All authors were involved in
the analysis and interpretation of data and the decision to submit for
publication.
Conflict of interest Eros Yamel Moreno Morales, Manuel Fer-
nandez Peleteiro, Ernesto Carlo Bondy Peña, Jose Maria Domı́nguez
Lorenzo, Elva Pardellas Santiago and Anxo Fernández have no
conflicts of interest to disclose.
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